Handbook of Dissolution Testing Third Edition, Revised Royal Hanson and Vivian Gray Dissolution Technologies, Incorporated Hockessin, DelawareDisclaimer “The abruory rosednes desi hercin myo ras tel Te ators, speaking for themselves expressly disclsim any Habiity to users ofthese ab procedares and apparatus fr consequential damages of any kind arsing out of or connected with Thee seems of apparatus and test methodology describe in this handbook are in- tended to Mstate proper tchnigues to obtain quality analysis and are not to be ‘considered offi! andor required. Offa compendia and regulatory reguiremen are to be considered th enly authoritative source for such mater, [Copysamt © 2004 by Royal A. Hanson Al ight exerved. No prt of this book may be reprodved or used in any form or by ‘ny means whoever without the peamisson ofthe polisher except in the case of bref ‘quttons embod in rial ariles or reviews. Prine inthe Ute States of America 2VD9876S43 Library of Congress Control Number 2005118666 Hanson, Royal md Gray, Vivian Handbook of Dissolution Teting/Roysl Hanson and Vivian Gray Includes bibliographical retereness and index ISBN 0.9761519-0-1 hardcover) Poblished by Dissolution Technolgies, Incomporsted 9 Yorkridge Tal Hockessin, DE 19707 sworarsoltiontch.com Dedication "Tis te tie tition tthe Hotbot o Disetion Tsing. dss oe mermny of Willan A Hagen Ps onde Manson Resch Ceram, De His mas egies tet tnd longs eaten e ei of slong Thor desh ae ed of 1984 Dx Han asa coment cout evsun ef st appa ond peste: Hs nica experimen the ete he concen a Det Pipeenng ih sertionon eva emeatrenpan tc dan tng Dr Hon sone bis wa work by wing the Hon boot of Dison Teng in 8, elon by» Seco Bi a apo to loi Hanon’ a fost in psig Tid Eo otis impor bckForeword To the Third Edition protester oy tty si el Sree Pom ik! beep manufac or contol witha hs Un esng a fo The daar opt on lon Stay inclng mylene ote nad fr and 8 Swe for vo denote eltusp ete dso ter danke nt ht lown «scan eas tees fre pear Te gal os coupon ages 0s hy ose asad sc he mpd ape ise ton rene fra azn Tle women 195s popes spre rnin of ae coms Th work med sine pte service Homage cierto oa iia Ac Hanson. Ings the serena bone cmon, CSP and NE casbe ki Parton ieee hat isd vrk Ooh T9 yas cated) Ralph Be ane of Sth Kis Fenn Labor Oa marked he weno Sposa dogs fom, Tasted wig the SkEastoped NE Resa Bo Ayu for SKPy Bi Hon So Bye ad al pune oe Pel lence Foreword vii On the compendial side, my mentor in pharmaceutical analysis, Wil liam J. Mader, was Director of the Drug Standards Laboratory, jointly sponsored by the American Medical Association, the American Phar= maceutical Association, and the United States Pharmacopcia, A close ‘working relationship developed between him and Bill Hanson, Bill Mader told me this was because Bill Hanson was “so dared easy to work with.” Subsequently, I also found him to be darned easy to work with. Starting with an apparatus published by Prof. Pernarowski of Canada, the Joint Panel recommended the Rotating Basket Apparatus, USP and NF adopted it in 1975 in the form elaborated by Mader and Hanson as something workable in a quality control environment and that could be manufactured reliably at reasonable cost ‘Throughout the early years of dissolution testing, Bill Hanson was a constant contributor to the evolution of test apparatus and procedures. His experiments were so significant as to eam him a Doctorate in en- incering. He supplemented the technical work with the very valuable Handbook of Dissolution Testing, to be followed by the Second tion. His personal value to the process was thrown into stark recogni tion in the early 1970's when he was in a serious auto accident in Los Angeles airport. The entire program of the compendia to adopt disso Jution standards was at actual risk but he soon was re-engaged. There ‘were strong forees then opposing the adoption oF public standards for issolution because they went to the heart of the brand versus generie cconllict. Fortunately for corporate continuity in this important area, his son Royal Hanson has made the tradition his own and he now presents us with this timely and comprehensive Third Edition. Vivian A. Gray as co-author is the best possible choice since she was at the heart of the USP effort for twenty years, first performing the experiments in the Drug Research and Testing Laboratory, and later as the scientific staff Tisison with USP Dissolution Subcommittees, FDA and USP's Drug Research and Testing Laboratory. In that latter role she succeeded Bar- bara B, Hubert and then was followed by William E. Brown. These ane the USP staff scientists who kept the USP policy initiatives alive and on track. We should recognize the rightful place of this Third Edition in lab- oratories of pharmaceutical analysis, All complex analytical methods depend on a tradition of testing that arises out of the accumulated ex- perience during method development and history of use in a variety of the siwations—technique, controls, sequence, manipulations, problem solving and data reduction, This Handbook is essenHANDBOOK OF DI lation of the engineering efforts and the findings that workers have made inthe field of dissolution, It constitutes the tradition of testing of drug solid dosage forms for dissolution of the ative ingredients. There- fore this Handbook. is an essential reference for any dissolution labo- ratory. Key sources of experience were DRTL and the FDA National Center for Drug Analysis at St. Lou “The obvious roles of this new edition ae in training new analysts and in university instruction. But itis also recommended that estab- lished workers in the field make a careful extmination. This is because ‘we of long-term experience recognize two trends—those are “drift and drop." Over time analysts tend to change slightly the way they carry ‘outa procedure. This is an evolutionary process. Also some procedural detail oF comtrol gets dropped as a matter of repetition unnoticed in the data at the time. The result is that an experienced analyst after a few years may in fact be doing a somewhat different procedure or may itave lost contol ever some parameter of « test apparatus. Dissolution calibrators one would hope would signal that some change has oc- ‘erred, and the guidance offered by this Handbook could afford reso- lution of the situation, A separate challenge arises in the training of new analyst, where the experienced laboratory scientist does not pass along the entice tradition of testing so this Handbook is « necessary backstop. Tcomimend the authors for their very considerable effort in bringing ‘out this valuable publication. Lee Timoruy Graby, PHD. Vice President and Director, Emeritus United States Pharmacopeia MeLean, VA March 2004 Introduction Royal Hanson “Our biggest problem in China is counterfeit and sub-standard drugs.” Professor Jin Shaohong of the NICPBP (National Institute for Control of Pharmaceutical and Biological Products) told me recently in his Temple of Heaven office in Beijing. Professor Jin's team is leading 8 nationwide effort to promote dissolution testing as a valuable and cost-effective tool for drug quality control in China, Dissolution testing, once the prerogative of a small group of committed scientists ane re- searchers in the USA and Europe, is now a worldwide standard for pharmaceutical quality assurance, One of the early pioneers in dissolution testing was my father, Dr William (Bill) Hanson, with whom T served a twenty-year apprentice- ship. Bill Hanson worked closely with Dr. Tim Grady and other entists at USP and FDA, engineering innovative apparatus and solving ‘ough, practical problems related to the discipline. My co-author, Vivian Gray, worked in Dr. Grady’s lab atthe time. I think we were both “ab grunts” back then. Vivian and T are pleased to update Bill Hanson’s “Handbook of ‘lution Testing” as a bench manual for the 2ist century practi- tioner, and are honored with Dr. Grady’s Foreword to this 3rd Edition, Vivian Gray When Roy asked me to assist him in updating his father’s book, Handbook of Dissolution Testing, I was very appreciative of the op- portunity. Knowing that the earlier editions of the Handbook have been the primary reference in dissolution labs all over the country, and even ‘worldwide, I believe this third edition will be a very valuable tool for analysts, While some aspects remain the same, the field has grown andx HANDBOOK OF DISSOLUTION TESTING changed. My conttibution to the third edition is to educate the analyst regarding these changes and to expand the subject matter to include new aspects of the field. | have expanded on method development and validation, Though not beyond the scope of the Handbook, some subjects just could not be thoroughly discussed and the book still be of manageable size. There- fore, many references have been provided (o ease further research andl information gather “There are thre voices in this edition, Bill and Roy Hanson and mine Bill's words and anecdotes are sil ete. Most are left in because the information is sill corect. In addition, the historical aspects of isso- lution are interesting and may help the analysts understand the devel- opment ofthe field, The sources of error that Bill deseribes are still pertinent while Taded more that have come to my tention over the years. “The equipment aspects have been mainly revised and updated by Roy who has the mest dieet involvement with instrumentation day to day, Roy has his pulse on the engineering aspect, equipment variables and improvements. His addition of the Appendix of installation, oper ational and performance qualifications (IQ, OQ, and PQ) is a very Caluable addition tht readers will ind helpful in Lab qualifications. Tadded and updated the Handbook with regulatory and compendia references as the dissolution testis critical test in the GMP environ- meat of pharmaceutical development and commercial production ‘vr hope is thatthe bench chemist wil find this Handbook a useful tool for everyday work, helping to improve the dissolution methods and produce accurate and precise results, Table of Contents DEDICATION FOREWORD TO THE THIRD EDITION INTRODUCTION CHAPTER 1 OVERALL CONSIDERATIONS, Why Dissolution Testing? Disintegration Tests Early Dissolution Test Development Development of Dissolution Testing Standards Calibrators Methods of Dissolution ‘Testing Basket Method Paddle Method Flow-Through Methods Reciprocating Cylinder Apparatus ‘Transdermal Dissolution Testing Classification of Dissolution Techniques Agitation Methods Defining an Apparatus Use of Dissolution Test Data Role of USP in Dissolution Testing Role of FDA in Dissolution Test Chapter | References CHAPTER 2 THEORETICAL CONSIDERATIONS Definition of the Dissolution Rate Surface Atea Surface Area and Flow Dynamics Input and Output Variables Bioequivalence and Dissolut FDA Guidances USP General Chapters Summary of Useful Theoretical Concepts Beyond Dissolution 9xii HANDBOOK OF DISSOLUTION TES1 Chapter 2 References CHAPTER 3 DISSOLUTION TESTING OF SOLID DOSAGE FORMS Introduction (o Current Methods Manufacturers of Dissolution ‘Test Equipment Apparatus 1-4 Overview ‘The Basket (USP Apparatus 1) Basket Specifications Basket Variations ‘The Paddle (USP Apparatus 2) Paddle Specifications Paddle Variations ‘Compendial Constraints Common to Apparatus and 2 Geometry and Alignment Eccentricity (Wobble) Vertical Position of the Basket or Paddle Stirring Rate (rpm) Vessel Media Sampling Point Time Apparatus Suitability Test Reciprocating Cylinder (USP Apparatus 3) Reciprocating Cylinder Speci Flow-Through Cell (USP Apparatus 4) Flow-Through Cell Specifications ‘Summary Chapter 3 References ations | CHAPTER 4 DISSOLUTION TESTING OF SPECIAL DOSAGE FORMS Rate Limiting Processes Problems Unique to Transeermal Testing Variables in Percutaneous Absorption Testing Dissolution of Oral vs. Special Dosage Forms ‘Apparatus 4 Flow-Through Cell “Apparatus 5 Paddle Over Disk Apparatus 6 Rotating Cylinder Apparatus 7 Reciprocating Holder tical Diffusion Cell, 54 55 56 57 37 59 59 60 60 61 Table of Contents Ointment Cell Suppository Basket Special Dosage Form Recommendations ‘Oral Suspensions (for systemic use) Orally Disintegrating Tablets Chewable Tablets ‘Transdermal Patches Semi-Solid Topical Dosage Forms Suppositories Liquid-Fitled Capsules Chewing Gums Powders, Granules, Solid Solutions and Solid Dispersions Parentetals: Implants and Microparticulate Formulations Dissolution Test Considerations Special Dosage Apparatus Summary Chapter 4 References CHAPTER 5 CONTROLLING VARIABLES Apparatus 1 and 2—Eccentrcity of Stirring Drive Shaft Straighiness Guiding the Shaft Other Stirring Device Variables Vibration Sources of Vibration ‘Torsional Vibration Alignment of Stirring Device Centering the Stirring Shaft in Flask Agitation Rate Apparatus 1 (Basket) Variables Dissolution Media Variables—Dissolved Gas Deaerating Medi Influence of Released Gases Media Variables—pH Media Variables—Volume ‘Media Variables—Temperature Media Vatiables—Sink Condition Flow Pattern and Vessel Hydrodynamies Sorption Checklist for Variables and Follow Chapter 5 Refer 1g GMP 6 65 65 66 61 a 7 a a 68 68 70 R B 5 © 1 B 7” 80 80 22 83 87 89 0. 1 92 2 95 ”xiv HANDBOOK OF DISSOLUTION TESTING CHAPTER 6 SETTING UP FOR DISSOLUTION TESTING Checklist for Dissolution Protocol Inspecting Paddles and Shatts Checking the Eccentricity of Paddles or Baskets Checking the Speed Control Checking Vibration Centering Flasks to the Stirring Drive Analytical Methods and Filtration Distance of the Paddle or Basket from the Bottom, of the Vessel Calibration of Equipment Calibrator Tablets Compendia} Calibration Requirements ‘Meeting Calibration Limits Calibration of Non-Compendial Equipment Chapter 6 References CHAPTER 7 SOLVING PRACTICAL PROBLEMS, METHOD DEVELOPMENT, AND METHOD VALIDATION Calibration of Apparatus Intinsic Dissolution Variations of Methods Checklist for Method Development Selecting Methods for New Drug Entities Poorly Soluble Drugs—Inadequate Sink Low Concentrations Difficult Analysis Problem Dosage Forms Dosage Composition Dosage Size/Type Floating Dosage Forms and Sinkers Change in pH during Testing Making a Good Profile ‘Two Tier Testing or Adding Enzyme to the Medium Challenging the Method In Viteo and In Vivo Correlations (VIVO) Method Validation Basie Concepts Robustness Ruggedness 103 los Los i 1 m2 13 3 us 7 us 18 19 120 124 128 125 127 128 129 130 11 BL IL 132 132 133 134 13s 135 136 136 136 137 138 Table of Contents Manual Testing Versus Automation Computer Software Comparison of Various Dissolution Methods Emerging Technologies Harmonization Chapter 7 References 8 AUTOMATION OF DISSOLUTION ING Advantages of Automation Unit Operations in Dissolution Automation of Setup Automation of the Dissolution Process ing Sampling Classification of Automated Sampling Systems Hidden Problems of Automated Samplers Automating Analytical Procedures ction in Automated Dissolution ing Alternative Dissolution Methods —Systems Analysis of Automation Chapter 8 References APPENDIX. DISSOLUTION TEST 1Q/OQIPQ ion ls Functional Validation Guideline ion 2: Insallation Qualification (1Q) ion 3: Operational Qualification (OQ) ce Qualification (PQ) STATION ACKNOWLEDGMENTS ABOUT THE AUTHORS 138 19 139 142 1B M44 149 150 152 153 Iss 158 159 lot 165 166 168 168 m 173 13 178 180 181 190 194 1961 Overall Considerations Ocean, dsclton hs gon fn along poco ein eo pmol Js ire een pe anette yeas sey Tat foro le hart, or besa ny Ot condoning sums ane rie me The sol eno is Hank of Dsolin Tsing (99) war ite ahr te met, ecnmes ai cos oF sh ton tng atone sn Apa 1 Che) at A fants? Waid he tcf Soe Theo ars Fomine dominio acre sla of mete (ss doi fT USP fs aed App 9 ep ting Cn) pea ny Tah Cl Aaa 3a ss Over Ds). Aats Cie nd Aaa? Rese ie ote ane Ph lee ow hen ep ene ear an de ove sh weal aps OA of thay Ss eal Chaps 3 a ss Ti Ein goss ts colibrion fe haeeniz he US? Gon Capen Distt and Dap Reese wih Eup Pharma ace Pap eg Splice Thi ly einai Cfo tar wnat et, wl ne ont a many see2 HANDBOOK OF DISSOLUTION TESTIN tions, equipment modifications, and use of validated sinkers ancl auto- ‘mated equipment are included (see Chapter 7 for more details). Why Dissolution Testing? Besides accommodating the obvious need for mecting the legal re- quirements for compendial drugs, dissolution testing is increasingly used (© test special oral dosage forms now listed in the compendia. ‘Those dosage forms include vitamins, herbals, veterinary drugs, ck able tablets, suppositories, suspensions, soft gelatin capsules, creams, ‘ointments, gels, ansdermal systems, andthe vist everinereasing num- ber of extended-release preparations, In addition, there are new product types and dosage forms under development, such as chewing gums, powders, granules, dispersions, microparticles, stents, liposomes, nano- spheres and implants, which may require dissolution testing, The phe tmaceutcal industry will continue to use dissolution testing as a Taud- able quality control measure for their produetion operations, They’ also ‘are acutely aware thatthe worldwide sociological wend is toward ex- tension of regulation, In the pharmaceutical business, as in any other, ic pays to aulerpate future developments Dissolution testing, of course, is regular quality control procedure in 200d manufacturing practives (GMP). Whether of not is numbers have boen correlated with blog sth standard dissolution est, isa simple and inexpensive indicator of a products physical consistency IF one batch differs widely from others in its dissolution characteristics, or ifthe dissolution times of production batches show a consistent ened upwards or downward it sounds a sure warming that some Factor ithe raw material, Formulation, oF process is out of contro Dissolution data are also useful in the ea ‘opment and formulation, In the eaey stages of development, researchers may take steps to optimize drug and dosage-form characteristics that will influence subsequent bioavailability data, al effective y stages of drug devel- Disintegration Tests More than fifty years ago, it was recognized that unless an oral dos- ‘ge form disintegrated into small ageregates, the body could not absorb it efficiently. A unique apparatus was devised to establish a standard for disintegration. ls description is still published in USP, but now the twend is to omit disintegration specifications and to include dissolution Overall Considerations 3 testing. Disintegration testing was originally proposed in an attempt to establish minimum standards, In the early stages of pharmaceutical developme “elegant” tablet: a tablet of beauty that did not chip, deteriorate or change color. OF course, the harder the tablet, the less likely it was to chip or fracture during packaging or shipment Hardness can be increased by inereasing the binding agent and com- pression forces. Unfortunately, hardness can be increased to the point ‘where the tablet will not disintegrate in the alimentary tract and where the only release of drug will arise from the relatively small surface area Of the outside of the dosage form. In 1997, an important discovery by Ralph Shangraw, et al. (3) showed that many vitamin products con- taining folic acid were not meeting the standard of dissolving within an hour. This has important implications for the absorption of drugs in vivo. Even today, physicians have observed non-disintegrated tablets in patients’ stools, ‘The disintegration test was introduced 10 avoid such problems. ‘The apparatus consists of six vertical tubes, each about one inch (25 mm) in diameter, arranged in a rack with a 10-mesh sereen atiaehed to the under ‘surfiee. The tubes are moved 5.5 em up and dawn 30 imes/minate while submerged in water or simulated intestinal fluid at body temperature (37 °C). To help the process along, complicated plastic disc “hammers” the tablet during the up-and-down movement (Figure 1-1). ‘Tho disintegration test has been official since 1950 (USP XV), and it bad enjoyed international acceptance. Various modifications have been introduced, one incorporating a 10-mesh sereen on the top of the tubes 10 keep capsules from floating out, Also available is a sophisti ccated apparatus that rogisters the time for total tablet disintegration and plots results on a digital printer. The tablet is sid to pass the test when ‘ho palpable mass remains on the 10-mesh sereen after the designated time, typically 30 minutes for ordinary tablets and 60 minutes for en teric-conted tablets, ‘The test had been mandatory for oral dosage forms for more than 40 years, but its elimination and replacement with a universal disso- Totion standard was encouraged in Pharmacopeial Forum in 1981 (4) probably because the disintegration fest in general had litle statistical correlation with bioavailability (5). In the early 1960s, the industry recognized that the ultimate solution of a drug depends upon two fac~ tors: the disintegration of the tablet and the deaggregation of the par- ticles im the tablet, That process is outlined in Figure 1-2 (and will receive greater attention in Chapter 2).4 HANDBOOK OF DISSOLUTION TESTING 9 | CL) 95m stk 20nirte ‘Sj |— neain 37°C J+ 1000- mt Beaker | _6Gass Tubes, ch nme Plastic Disks (ion spoetied) “Taba |— 10-Mesh Sreen Figure 1-1 USP disinregration testing apparatus, (See USP <701> Disintegration.) From the pattern shown in the diagram it is apparent that the dis- solution rate includes the time factor resulting from the disintegration process. It also becomes obvious that dissolution testing includes dis- integration time and, therefore, that if dissolution data become man- datory, then disintegration information becomes super‘luous During the period 1990-1995, many USP disintegration tests were replaced with dissolution tests, and the disks were removed from <701> Disintegration USP General chapter. Disks may stil be called for in individual USP monographs. Early Dissolution Test Development In the early 1960s, problems regarding the bioavailability of drugs \were receiving more and more attention from industry, regulatory agen- Overall Considerations 5 Solid dosage form | o Disintegration from gross Inblet size to particles of various sizes (depending — | fn formulation): <2 mm diameter ‘Rate measured by the disintegration test Deaggregation: breakdown into discrete particles that ereatly increase surface area, providing bolidtiguid interface und beginning) dissolution: <0.25 mm diameter | ? Dissolution —, Rate measured by the dissolution test Figure 1-2 The three stages in the dissolution process. cies, and compendial standards groups, A prominent pharmaceutical ‘manufacturer forcibly brought the matter into focus by a routine in- vestigation of identical competitive products. Bioavailability tests in- dicated a substantial difference in the performance of the Iwo items, which were otherwise pharmaceutically identical according 10 all then= existing tests for physical properties ‘The matter was brought to the attention of eompendial committees, tnd a study of various dissolution test methods was inaugurated. At that time, the major concern involved life-saving drugs, particularlyHANDBOOK OF DISSOLUTION TESTING those with a narrow range between ineffective and toxic blood levels Digoxin is an example, because the physician must establish in a ti= trated dosage the effective but nontoxic dosage levels for each patient If the patient switches brand sources of this medication, it naturally follows that the second brand must closely approximate the frst in its ability to sustain therapeutic blood levels. Studies suggested that this ability could be correlated (0 some degree with dissolution rate chat= acteristics. Coordination of the studies was assigned to William Mader, director of the Drug Standards Laboratories (later evolved into the USP labo- ratory) in Washington, D.C., USA, which operated alongside the com pendial groups. Mader took on a formidable job; evaluation and selec- tion of a new and official test procedure affecting the pharmaceutical and medical professions, regulatory agencies, and drug manufacturers constitutes an awesome and agonizing task. Everyone in industry. gov- cerament, and academia who suggested methodology seemed to have a private ax to grind. Through that petied, Bill Hanson's experimental ‘machine shop worked closely with Mader, supplying him with a variety of baskets and stirring devices that would easily have challenged the imagination of Rubs Goldberg. (Aa example of one early prototype design is shown in Figure 1-3.) Each device hid 10 be tested and evaluated on its ability to diserin inate between subtle variations in dissolution characteristies, on the repeatability of results from test to fest and on its adaptab pletely as possible to existing, standard laboratory apparatus. The latter Criterion was most difficult to assess, because itis always possible to design sophisticated tests and equipment that are more functional than existing hardware. Nevertheless, the cost of dissolution testing ulti- imately is borne by the (already) overburdened consumer, and the test costoffectiveness in terms of overall health care costs must remain consideration, Helping Mader with his project at the Drug Standards Laboratory was Dr. Tim Grady, who later took over as director when Mader retired, ‘This pioneering dissolution research continued, and the variables af- fecting consistent and repeatable results were studied for more than ten years ‘The task had fallen to Mader to forge the first widely accepted dis- solution test procedure, and it was published in NF XIII in 1970. Dis: solution test methods were made a part of the specification for five «drugs: indomethacin capsules, and acelohexamide, methandrostenolone, ‘methyprednisolone, and sulfamethoxazole tablets. Overall Considerations 1 Simple Lab Apparatus Drive Motor ‘Stand 1-L Resin Vessel Prottype asket-miner Hot Pate Figure 1-3 An early primitive dissolution tester. (Note basket-propel- ler assembly.) Method 3 (not to be confused with today's Apy duced for indomethacin capsules because oF a pre-established datas ‘That method used a modification of the existing disint ment (described above) and has not been extended to any other drug ‘This method has since been eliminated from the USP. As initially specified, the primary dissolution method included the rotating basket in essentially the same dimensions as now. It Featured 2.0.25-inch (6,35 mm) shalt, 2 37°C water bath, and a standard 1000- mL. resin flask similar to the one now specified but with a flat or con- cave indention atthe apex of the bottom. Any speed-controlled string device able (0 operate at 100 rpm + 4% could be used, aldhough other speeds were allowed.8 HANDBOOK OF DISSOLUTION TESTING Development of Dissolution Testing Standards Once the dissolution test became offical, iiformation from induste- al, academic, and regulatory laboratories expanded the literature. A series of collaborative tests were conducted for various drugs and the relative standard deviation (coelficient of variance) in the results from ifforent laboratories turned out (o be wider than expected. Repeatability of analytical results from laboratory to laboratory and within narrow limits is essential where the specified dissolution rate for 42 drug is set al a minimum percent dissolved in a stated time and where the product in question dissolves just a few percentage points above that minimum, For example, prednisolone tablets have @ minimum dis- solution rate of 80% dissolved in 30 minutes, If the manufacturer and ‘outside laboratories or both report numbers in the 84-88% range but the regulatory agency reports numbers in the 77-79% range, a serious legal problem develops (that is, when 84-88% pass but 77-79% does no. Clearly, when two laboratories are within + 5 absolute percentage points but are above and below the limits, precise definitions and eon- trol of all equipment and analytical variables are necessary. Problems Of this sort have actually occurred with both U.S. and Canadian segue latory agencies. During the 1970s and later, a vast amount of research ‘was performed to determine the effect of outside variables, Summaries ‘were published and serve as a valuable reference for analysts conduct- ing dissolution tests (6-11), A significant step toward standardizing dissolution methods occurred with the introduction of calibrator tablets. Salieylie acid tablets d onstrated remarkably consistent and stable dissolution characteristics, QD, but they are non-disintegrating dosage forms. A large batch of a prednisone/lactose formulation was prepared to serve as a disintegrating counterpart to the salicylic acid tablets. Several laboratories then par- ticipated in a collaborative study to determine dissolution rates of both Of these tablets in tests using identical protocols. The results of these studies provided a foundation to define and con- ‘rol variable inputs to the current dissolution protocol (13). A tvo- sigma range was established as the first crude eriterion for calibrating equipment and methods. The ranges allowed may now seem inordi- nately wide, but they were a place to star, Publication of those results stimulated more extensive research into dissolution technique and instrumentation. The compendia added Steietions on vibration and dissolved gas and expanded the statistical Overall Considerations 9 evaluation of test results. Compendial requirements for the use of the calibrators ensured that the alignment and geometric specifications of the stiring apparatus would be mote rigidly followed: ultimately, even the wide ranges allowed with the calibrators cannot be met unless the equipment is properly aligned USP continues its research and evaluation of dissolution tes technique and methodology 10 this day. The most recent collaborative study is published in the Pharmacopeial Forum (14), The USP Dissolution Cal- ibrator Tablet Collaborative Study—An overview of the 1996 process. Calibrators USP now specifies the calibration of dissolution equipment using disintegrating and non-disintegrating calibrator tablets (prednisone and salicylic acid) available through their headquarters at 12601 Twinbrook Parkway, Rockville, MD 20852, USA. The performance-valie ranges for calibrating equipment ace not outlined in the compendium, but they appear in certificates that come with the calibrator tablets. The allowed ranges are wide, and itis a point of discussion for those involved in establishing the ranges; the debate about calibrator tablets continues, ‘The PhRMA (Pharmaceutical Research and Manufacturers of America) Dissolution committee undertook a study t0 examine mechanical calie brations as a possible replacement for calibrator tablets (9). USP, along with other experts and equipment manufacturers, continues to examine the use of calibrator tablets and ways to ensure the equipment is work ing properly. There will be much work in the area in the future. European scientists are less than enthusiastic about the use of eali= brators. One report points out the difficulties of non-uniformity and instability of calibrator tablets and argues that strict geometry, close tolerances, and a regular check of the dynamic parameters of dissolu- tion equipment are the only reliable means of ensuring standardized performance (15) A regular check of equipment with USP calibrators in order to de- termine drift or gradual failure in performance is usually @ necessary routine in GMP laboratories. This includes situations where equipment is moved and reinstalled in another lab, Calibrator tests also carry the ‘added benefit of “system suitability”; that is, calibrators provide a mon- itor of not only the experimental conditions but the analytical echnique as well It has been suggested that in-house calibrators should be used as standards and should be run simultaneously with each dissolution test10 HANDBOOK OF DISSOLUTION TE TING (16), Such a method! provides the maximum assurance against ina tent equipment malfunction, but practical difficulties arise because USP specifies increments of six tests and most commercial dissolution equipment provides only six vessels. Manufacturers using, this te nique have run stations of 12 vessels, placing their in-house ealibrator in atleast two. Dissolution test stations with seven or eight stirrers have become commercially available, Methods of Dissolution ‘Testing Many schemes have been reported for the determination of disso- lution rate. A detailed review of these is inappropriate for this publ cation. In sum, though, all methods involve providing a renewable sol- id-liquid interface between the dosage Form and the dissolution Muid, censuring that this can be defined and controlled and is thus repeatable— Which is more easily said than done! The controlled flow of fluid over 4 solid introduces requirements of maintaining the surface of the solid in-a position exposed to non-acvelerating flow—aquite a requirement for & tablet that moves about because of the similarity of its density to that of the liquid or for a tablet that disint particles that float in the stream, Most of the variations in dissolution methods have been devised 10 bring such variables under control. Unfortunately, some of the methods are applicable only to unique dosage forms and become unsatisfactory ‘with others. The only methods that will be discussed in detail in this ‘manual are those that are already established in the compendia or are likely to receive serious consideration as official methods in the next few years. Some excellent methods must be omitted, but that is no reflection on their probable value or unique characteristics. For various reasons. itis unlikely they will be seriously considered as official meth- cox in the near future. The spin-filter method of Shah and co-workers (17), for example, solves a number of the problems of dissolution test- ing, largely by avoiding the clogging of the filters used in automated sampling. It seems unlikely, however, hat their spin filter method will ever be universally accepted in the compendia because of cost, com Plexity, and the unrealistic manufacturing tolerances required to avoid vibration and other disturbances; considerations that are added to ob- vious problems of maintenance and operation ‘The methods to be discussed are briefly described below. Basket Method. Originally proposed by Pernarowski (18) and moa ified to become the first official method adopted in USP in 1970, the rates into various buvyit Overall Considerations u rotating basket method has enjoyed more than 30 years of extensive testing for numerous dosage forms. It has been modified, and the of- 1 method! (Apparatus 1) is described in Chapter 3. ‘The basket method represents an attempt to constrain the position of the dosage form in order (0 provide the maximum probability of a consistent solid-liquid interface. This method has several disadvantages: icy for gummy substances 10 clog the basket sereen, extreme sensitivity to dissolved gases in the dissolution fluid, inadequate flow rates when particles leave the basket and float in the medium, and construction difficulties when automated methods are attempted, Paddle Method. Originally developed by Poole (19), the paddle ‘method was modified through the work of scientists at US Food and Drug Administration (FDA)'s National Center for Drug Analysis (NCDA) in St. Louis, Missouri, USA. It consists essentially of lating paddle with a blade of specific dimensions conforming to the inside radius of a round-bottomed flask, This method (Apparatus 2) overcomes many of the disadvantages of the rotating basket, but it requires careful precision in the geometry of the paddle and flask and suffers from unacceptable variations in dissolution data following even ‘minor changes in paddle orientation, Its convenience for automated systems, lnowever is its strong. point, Flow-Through Methods. Proposed by many but most extensively studied by Langenbucher (20), flow-through methods involve constrain- ing the dosage form in a cell and pumping dissolution fluid through that cell Langenbucher studied the geometry of the cell and the variables introduced by variable and/or pulsating flow rates. Although the system hhas not been used extensively in the United States, its obvious advan- tages in maintaining sink conditions for drugs with low solubility, but high dosage amounts, which saturate in volumes more than 25% of specified media volume, suggest benefits. ‘The method also ha the add- ed advantage of inherent adaptability 10 automated sampling tech- niques. The flow-through method is now official in the United States (Apparatus 4) and the European Pharmacopeia, and may be considered for drugs that impose saturation problems with the basket or paddle methods, Reciprocating Cylinder Apparatus, The veciprocating eylinder is now listed in USP as Apparatus 3 for extended-release dosage forms. This is lunigue system that “floats” deageregated particles in a reciprocating stream. It has advantages of lower volumne of solvent, exse of pH change: reduced dwell time to avoid degradation; ease of automated sampling:2 HANDBOOK OF DISSOLUTION TESTING correlation with the database from the now-dliscanded rotating bottle ap- paratus; and impressive correlations with bioavailability data (21), Transdermal Dissolution Testing. Apparatus for this testing is dis- ‘cussed in Chapter 4, Several methods are now in the USP for these dosage forms, and the vertical diffusion cell is under current consid eration for semisolid formulations and topieals, Chapter 4 also discusses the testing of other novel and special dosage forms, Classification of Dissolution Techniques At present, USP accepts the following methods of dissolution testing: (See Chapters 3 and 4 for a detailed discussion on each apparatus.) USP Appa Number Suse tortion ah (Basket Sot, Bais Rote Sir 2a) Salis, Suspmsions Rowing Sir 2 Resipcaing Clin) Sli, ands Reirocaon oe tgn cay Sai Beals Fhid Movant SiPadeQve Disk) Trades Paces ‘Rtg Sine (Cyne) TrrsdemalPacbes Rotting Siar Transdermal Pac, TiRecinocaing Holds Tans Recipocation ‘To those nay be ade the flowing noncompendin eth Percutaneous Absorption Topical, Tansdenmals, Fluid Movennent, (Ditasion Can) Inplans Agitation Methods Each dissolution technique offers a unique means to provide a eon- trolled flow of solvent over the surface of the solute, ice. the solid- liquid interface. Four agitation methods ean be used: * Rotating Stirrer. This is based on the original dissolution test drive, 1 rotates the dosage form or stirs the medium in which the dosage form is held, Many variations are commercially available as illustated in Figures 3-2, 3.3, 4-4 and 4-5. This is used as the drive in current USP Apparatus 1, 2, 5 and 6. Overall Considerations 3 + Reciprocating. A sophisticated development from the old disinte- aration test, reciprocating agitation moves the dosage form up and down in a succession of media. These apparatus are illustrated in Fig- 4 and 4-6, This is used as the drive in USP Apparatus 3 and 7, + Fluid Movement. Known as a flow-through system, this agitation holds the dosage form relatively stationary while a controlled stream of media is pumped past it. A schematic is illustrated in Figure 3-5 ‘This is used as the drive in USP Apparatus 4. * Percutaneous Absorption. This agitation is used 10 study the r= lease or transfer of a dosage form from or through membranes. Typical applications are topical and transdermal formulations. This apparatus is illustrated in Figures 4-7 and 4-8, Defining an Apparatus ‘The apparatus used in a specific dissolution (est or method includes fan agitation method as described above, and details of dosage form ‘mounting within the system, Other parameters of the system are also defined, including temperature, flow rates, dissolution medium, and constraints on environmental input variables, such as external vibration, In this handbook, cach apparatus is described in as much detail as current compendia have established. Solid dosage form methods are described in Chapter 3 and special dosage forms in Chapter 4. Use of Dissolution Test Data Dissolution testing is a useful method for: ensuring the bioeguiva- lence of different batches of solid dosage forms when a rank-order correlation between dissolution characteristics and bioavailability has been most likely in situations where dissolution is rate limiting in the dissolution/absorption system for the drug—see Chapter 2 for further discussion); monitoring formulation and manu- facturing processes by quality control personnel; and establishing the ntrinsic dissolution rate (see Chapter 2), which is somewhat useful in screening compounds being considered for new drug applications (NDAY). Finally and most basically, the FDA requires dissolution tests in re tlatory filings for all oral dosage forms and many other dosage forms as well. This is true of the regulatory agencies in most other industrial ‘countries. I is likely that dissolution testing will inerease and will be: ‘come more complicated and more global in the futute4 HANDBOOK OF DISSOLUTION TESTING Role of USP in Dissolution Testing General Chapters: Disintegration Dissolution Drug Release <1087> Intrinsic Dissolution <1088> In Vitro and In Vivo Evaluation of Dosage Forms, <1090> In Vivo Bioequivalence Guidances <1092> Dissolution Procedure: Development & Validation (pro- posed) 25> Validation of Compendial Methods Olficial Monographs for Drug Dosage Forms USP Calibrator Tablets and Reference Standards Co-sponsors Workshops with American Association of Pharma tical Scientists (APS) and FDA ‘Training Courses, Annual Meetings, Open Committee Meetings and Forums Role of FDA in Dissolution Testing Performs Off Shelf Testing Performs Validation of NDA Methods Performs Inspections Orders Recalls Issues Product Approvals Enjorees USP Publishes Guidances Co-sponsors Workshops with APS, FIP and USP Forms Task Fore Researches and Evaluates New Methods and Technology a ey 6 © 0 6 © ao ay Overall Considerations 15 References ‘SP Dissolution General Chapter <711> and USP Drug Re lease General Chapter <724>", 2004, United States Pharmaco- pela and Nevional Formulary, United States Pharmacopeial Con. vention, Ine., 27" E “2.9.3, Dissolution Test for Solid Dosage Forms”, 2002, pean Pharmacopoeia, European Directorate for the Quality of Medicines of the Council of Europe, 4° Ealtion, Supplement 4.4, 3247-3250, Hoag, SW, Ramachandruni, H and Shangeav, RE, “Failure of Pre= scription Prenatal Vitamin Products to Meet USP Standards for Folie Acid Dissolution", 1997, Journat of the American Phar- ‘maceutical Association, 37(4), 397-400. “USP Policy on Dissolution Standards”, 1981, Pharmacopeial Forum, 7, 1225-1226. Wagner, J and Pernarowski, M, “Biopharmaceuties and Relevant Pharmacokinetics”, 1971, Drug duelligence Publications. Cox, D and Wells, C, “In Vitro Dissolution of Digitoxin Tablets”, 1978, Internal Document, National Center of Drug Analysis, Hanson, W, “Solving the Puzzle of Random Variables in Disso- lution Testing”, 1977, Pharmaceutical Technology, 1(5). 30-41, Thakker, D, Naik, N, Gray, V and Sun $, “Fine Tuning of Dis- solution Apparatus", 185. PhRMA Subcommittee on Dissolution Calibration: Brune, S, Bucko, J, Emr, S, Gray, V, Hippeli, K, Kentrup, A, Whiteman, D, Loranger, M and Oates, M, “Dissolution Calibrator: Recommen- dations for Reduced Chemical Testing and Enhanced Mechanical Calibration", 2000, Pharmacopeial Forum, 26(4), 1149-1166. 1980, Pharmacopeial Forum, 6 7 Cox D and Furman, W, “Systematic Error Associated with Ap- paratus 2 of the USP Dissolution Test: Effects of Physical Align- ‘ment of the Dissolution Apparatus”, 1982, Journal of Pharma ceutical Sciences, 71(4), 451-452. Hamilton, JE. Moore, TW and Kemer, CM, “Reproducibility of Dissolution Test Results”, 1995, Pharmacopeial Forum, 21(3), 1383-1386,16 HANDBOOK OF DISSOLUTION TESTING (12) Hanson, W, “Studies on the Effects of Some Variables Commonly Encountered in the Measurement Of Dissolution Rate of Solids" 1979, Ph.D. Dissertation, California Westera University. (13) Sarapu, A, Lewis A and Grostic M, “Analysis of PMA Collab- ‘orative Studies of Dissolution Test Calibrators”, 1980, Pharma: copeial Forum, 6(2), 172-173. (14) PhRMA, “The USP Dissolution Calibrator Tablet Collaborative ‘Study—An Overview of the 1996 Process”, 1997, Pharmacopeial (3), 4198-424: (15) FIP, 1997—Joint Report of the Section for Official Laboratories ‘and Medicines Control Services and the Section of Industrial Pharmacists of the FIP, “FIP Guidelines for Dissolution Testing of Solid Oral Products", 1997, Dissolution Technologies, 44), 5~ 4, Forum, (16) Konieczny, J, Cohen, E, Thomas, A and Van Dame, H, “Vali dation Technique of Dissolution Test for Control of Drug Quality ‘and Bioequivalence”, 1980, Presented at the Intexphex USA Tech- nical Conference, (17) Shah, A, Poet, C and Ochs, J, “Design and Evaluation of a Ro- tating Filter-Stationary Basket In Vitro Dissolution Test Appara- tus, [: Fixed Fluid Volume System”, 1973, Journal of Pharma ceutical Sciences, 62, 671-677. (18) Pernarowski, M, Woo, W and Searl, R, “Continuous Flow Ap- pparatus for the Determination of Dissolution Characteristics of Tablets and Capsules”, 1968, Journal of Pharmaceutical Sciences, 57, 1419-1421 (19) Poole, J, “Some Experiences in the Evaluation of Formulation Variables in Drug Availability’, 1969, Drug nformation Bulletin, 3, 816. 20) Langenbucher, F, “In Vitro Assessment of Dissolution Kinetics: Description and Evaluation of a Column-Type Method”, 1969, Journal of Pharmaceutical Sciences, 58, 1265-1272, (21) Borst, I, Ugwu, S and Beckett, AH, “New and Extended Appli- cations for USP Drug Release Apparatus 3", 1997, Dissolution Technologies, 4(1), 11-15. 2 Theoretical Considerations iin tsing i epopinte fr bnch econ eas he 1.0 mefmin/em® suggest negligible problems with dis- solution rate limiting, but rates < 0.1 mg/minfew indicate the likeli hood of such problems (8). Although the intrinsic dissolution rate is Useful in studying the solubility characteristics of a substance, it has limited practical value in describing the characteristics ofa solid dosage form because, in practice, the surface area of an actual dose changes with time as it disintegrates and dissolves. The apparent dissolution value, the total mass of the solid dissolved in unit time, is therefore more significant, (See Figure 2-1.) In practice, & also includes the dynamics of the shear rate between solid and solvent, that is, the rate at which lresh solvent contacts the surface of the solid; highly complex processes, including diffusion rate through boundary layers, depend upon this rate ‘The shear rate depends upon & multitude of variables that must be Controlied in order for the test to be repeatable, Those variables include the flow pattern of solvent in the apparatus, turbulence, viscosity, sur face tension, and dissolved gases, all of which are subject to uncon- trolled input variables to the system, such as vibration and system Theoretical Considerations 9 Large volume of solvent Nonaisinwegrating pellet of material being studied | Magnetic sirer Figure 2-1 Apparatus for stadving dissolution rare while maineain. ing a constant surface area. A pellet of the substance is held in the ‘cup, whick may rotate. Only one surface is exposed to the solvent. (See USP <1087> Intrinsic Dissolution.) geometry. The theoretical busis for those inputs rests in the realm of chemical engineering theories regarding Muid flow and surface bound- aries, which are discussed in detail in chemical engineering texts and are reviewed in another publication (9). ‘The practical aspect of controlling such variables rests at the heart of this manual and involves the recognition of suitable parameters in the initial experimental design and of unsuspected outside influences that must be controlled, Surface Area It is obvious that the surface area of a solid-dosage form will change during the dissolution process. The change in surface area will alter the20 HANDBOOK OF DISSOLUTION TESTING p+ saree ToS . ‘ aap Taos ‘ecninepatng) dunce gee 7 acs of dg fuser ’ y eae | | v Pres ofan df] Fin psn v Difision of solved seve ingredient ino slssolution solvent Figure 2-2 Paths of the general dissolution process. Note the sev- eral steps of particle-size reduction for a disintegrating aggregate by comparison with a nondisintegrating homogeneous tablet. Figure 2-3 Giotlowing) represems how surface areas, S, may vary during dis- solution of homogeneous nondisintegrating dosage forms as com ared 10 nonhomogeneous disintegrating dosage forms, Aluid-ow dynamics involved in the dissolution constant, k, defined in the previous equations. uch an effect is more pronounced in disintegrating dosage forms than in non-disintegrating forms. Non-disintegrating dosage forms, sub- iscted to an unvarying shear of passing Muid, gradually reduce their surface area during the process. Disintegrating forms, however, are sub- Ject to complicated disintegration and deaggregation as they release Particles of various sizes and density into the solvent stream, ‘The several paths of the total dissolution process ate shown in Figure 2-2, The illustration shows that a non-disintegrating solid exhibits a Theoretical Considerations a Nondisntgrating homogencous¢ype tablet \ sues |S Dpto, ae) \ oo _ a Son erates Tine ——— Figure 2-3 Surface area vs. time in the process of dissolution. reduction in surface area, S, from the moment the test begins. A dis- integrating ageregate, however, goes through steps in which the surface area increases much more significantly—and in diserete steps—during the total time necessary for dissolution. (See Figure 2-3.) ‘The dissolution curve of a disintegrating solid does not, oF course, change as abruptly as is shown in the graph in Figure 2-3; however, as the processes of disintegration into granules and deaggregation into fine particles take place, significant changes in the slope of the dissolution curve actually do occur, The typical dissolution-curve prof in Figure 2-4 may be explained in light of these changes. Any one of the three processes—disintegration into granules, deagsregation into fine particles, and the process of dissolution—may vary with time. In some cases, one or the other may be rate limiting, that is, may take a ‘much greater proportion of the total dissolution time than do the others. Variation in fuid-flow parameters from the use of different equipment may result in one design of equipment or procedure exhibiting better correlation to bioavailability than do other types of equipment oF pro- codures. (See 2a.) When the disintegration time is rate limiting, the standard USP dis integration test may correlate well with biological data (10). The tur Dulent agitation in this test, however, makes it unsatisfactory for dosage forms in which the process of dissolution is rate limiting. The standard disintegration test, therefore, is seldom specified for any official test. In fact, because disintegration time is included in the total dissolution time, it is generally recognized that the disintegration test itself has been superseded by the dissolution test (11) Surface Area and Flow Dynamics. The S in the dissolution equation offered above interacts with the dissolution constant, & The shear rate les shown2 HANDBOOK OF DISSOLUTION TESTING Nondisinegrating tablet S/o Surface area gradually reduced fring test. Dissolution rate f etc by provers of| dissolution nd difson, Concentration Dissolved Time a Disintegrasing tablet: fo Rapid disimegration and / ssagregation ies slow process 4 ‘of dssolaton and difuson. solution sate limiting. Time Pa Disintegrating table Slows disintegration and Aeagereption te; rapid process ‘of dissolution and difason. Disintegration ert initing. Concentration Dissolved Tine Figure 2-4 Typical dissoluion profile curves observed with various solids of nondisintegrating and disintegrating aggregate types. of fresh solvent in contact with the surfee area of the solid varies with Particle size, shape, and density—and indireetly, therefore, with the surface area. Common experience indicates that the dissolution rate increases as the panicle size decreases (Figure 2-4), an observation consistent with experiments on many pharmaceutical preparations. ‘That correlation cannot, however, be freely extended. As particle size reduced—and although surface area is accordingly inereased—there ‘be mutual interference in the motion of particles, changes in elec: trical potential among pasticles, molecular layers of solvent tightly bound around particles, and other retarding influences, including Wer infiuenee of hydrophobic properties imparted to the liquid-solid Theoretical Considerations 2B interface by various means, Smaller particles may actually exhibit slow- cr dissolution rates than do larger ones in such cases (12, 13). ‘The solid-liquid interface may also be influenced by tablet lubricants, such ‘as magnesium stearate, and by adsorption of gases onto the surface of the particle. [tis thus evident that the flow dynamies of a multiparticutate mixture will be highly complex. As the mass of the individual particle decreas- cs, the solid-liquid shear or the rate of passage of the fresh solvent ‘across the solid surface will change as the particle drifts in the Muid stream, Repeatability of dissolution test data, therefore, will not be aecept- able if the size of the particles released from aggregates varies sub- stantially from sample f© sample, It will be seen in later chapters that this phenomenon is extremely significant when one must choose among ‘compendial methods, Entirely different dissolution data might be pro- vided by the basket, for a disintegrating solid—the particles of which could become small enough (© pass through the standard 40-mesh seteen, drop to the bottom of the dissolution flask, and remain in. ra dom, stationary positions undisturbed by the relatively mild agitation inherent in the basket method—and a solid with particles that obedi ently remain inside the basket, Similarly, shape and specific gravity may cause particles released from a tablet aggregate 10 float in different patterns when the paddle method is used. The relative shear between Tiguid and solid is also unduly influenced by interference and turbulence caused by probes (temperature or sample) placed in the vesse] during the test. The par licles may even accumulate on the bottom of the flask in @ random manner if the agitating paddle is not exactly centered with its vertical and horizontal planes aligned in elose tolerance to the dimensions of the flask. Such aberrations also arise iff the contours of the rounded bottom of the flask are not geometrically perfect (14) Early on, Cox and co-workers at FDA had emphasized the necessity of laminar, nonturbulent fluid flow in the dissolution flask, Turbulent flow must be avoided because it leads to eddy viscosity, which is a fluid property difficult to control and which introduces accelerations superimposed on the mean uid motion, Turbulent low is associated with high velocities and low viscosity (15). It may also be generated by sharp edges (such as the tips of a stirring paddle) or by sudden cchanges in flow path caused by probes inserted into the vessel. Because most dissolution tests use aqueous fluids of low viscosity, it followsBy HANDBOOK OF DISSOLUTION TESTING that fluid velocity (that is, the stirring rates) shoukd be kept low and that probes should not be left in the flask: The authors note that over the last thirty years, the modem manu- facture of dissolution test equipment, including flasks, baskets and pad- les, has provided relatively rugged and robust design that minimizes the potential impact of adverse variables in the test setup. A specialized “peak” vessel (16) has been suggested as an alternative to the standard paddle method and I-L vessel, but any variances in compendial stan- dards must be independently validated. Flow dynamics are related to the surface area generated by the par ticle size ofthe solid, and that relationship must be carefully considered both in selecting a dissolution test procedure and in outlining its pro- tocol. Generalizations are unwise, and any positive statement of pref- erence for a method or procedure should be accompanied by a delini- tion of the predictable constraints invalved Krowezynski provides a detailed and formal mathematical analysis Of the dissolution process by starting with the Noyes-Whitney equation and assuming steady-state conditions (2). This leads 10 an extensive analysis of the diffusion layer that forms the basis of all chemical et sincering analysis of the kinetics of transfer from a solid-liquid inter- face. Theoretical information such as that provided by Kréwezynski is heeded by those engaged in developing formulations to meet dissolu- ‘ion requirements. The reader is encouraged to consult the original ref- erence (2) for a detailed analysis. Input and Output Variables Input variables involved in the & and S of the dissolution equation fare included in the list of input and state variables listed in Figure 2-6, The list is not necessarily complete, and, as more is learned about the complex subject of dissolution, it will no doubt need to be expanded, The authors have derived the following chart (Figure 2-S) from the inl fra zener dynam pte presented by Kamopp aed Ron berg (17): a Figure 2-5 A general dynamic system, Theoretical Considerations 28 In the dissolution test system, the state variables, X, are those defined for the test protocol. Some, but not all, of those are constraints listed in the official methods, but all are significant in the dynamic system known as the dissolution test protocol or method. ‘The input variables to be tested are limited to the few mentioned in cluding the rate of tablet disintegration and deaggregation, ize of deagereguted components, the effects oF manuf Figure 2-6, i the particle luring variations, and the ultimate solubility rate of the active ingredi- cent. The other input variables are those that interfere with a consistent repeatable state of the dynamic system, such as the introduction of energy of random vibration, changes in medium characteristics, vavia- tion in the flow dynamics of agitation, and others. Those will be dis- ‘cussed in Chapter 5, and each must be carefully considered and con- trolled to produce repeatable data with a dissolution test. (See Figure 2-6.) ‘The sole output variable, oF course, is information about the sol bility rate ofthe active ingredient in the solid when the solid is exposed controlled parameters of the system, cteristies Bioequivalence and Dissolution Cha ‘The biological availabilty of the ative ingredients of a solid dosage form is clearly central to the formulation’s purpose. Bioequivalence, or production of the same biological avaiability from diserete batches of ‘rugs, is also clearly desirable. This is particularly true in the ease of ‘drugs with titrated dosages, such as digoxin, Cabana and! O'Neil (18) reported that poor dissolution characteristics were responsible for 80% of the documented cases of bioineguivalence found in FDA files at that time, ‘An active ingredien’s dissolution characteristics do not bear any strictly rigorous relationship to that drug's bioavailability. A rapidly Lissolving drug, for example, may not exhibit bioavailability correlation (in terms of blood oF urine values) with dissolution test data—anless, that is, the drug formulation or the manufacturing procedures have been designed specifically to impede dissolution. Only when the dissolution rate is comparable to or slower than the absorption rate does the di solution rate become the limiting step, and only inthis case will clear- cut, rank-onder correlations appear (19) ‘The use of dissolution characteristics to predict the bioavailability of a solid dosage form is not, therefore, universal, Nevertheless, dissolu- acteristics will vary with factors of formutation and with the tion cl26 HANDBOOK OF DISSOLUTION TESTING + Rctmtexces sme = Spee gem of partes [7 digerson ar ] Reohewsceofcp — ‘arian of tie tage [a oniggeer oars esta Revie te: Sek senins aot serum ot |____wienpcts mse | entail ld ogo cst sd ee The comune an esy hop vars ner way eae Figure 2-6 Input and system variables in a dissolution test system, nufucturing process, Dissolution testing is thus, aside from its uses in bioavailability prediction, an important and highly valuable toot in drug development and batch-to-batch quality control. It can be used to identify bioavailability problems and can function as a signal of bio- inequivalence as well (20), FDA Guidances. Because of the importance of dissolution, FDA has recently developed dissolution-related guidances that provide informa, tion and recommendations on developing methodology, setting speci fications, and regulatory applications (20), The recent Biopharmaceu- ‘Theoretical Considerations ” tics Classification System (BCS) guidance takes into account three ma- jor factors—dissolution, solubility and intestinal permeability—which jgovern the rate and extent of drug absorption from immediate release IR) solid dosage forms. This guidance provides a scientific framework for classifying drug substances, and in combination with dissolution data, provides a rationale for biowaver of IR products. Additionally, a General Bioavailability and Bioequivalence guidance allows bio\ for lower strength immediate release and modified release drug prod- ucts based on formulation/dissolution profile comparisons. These and other relevant guidances are as follows: 1. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms, August 1997, 2. Guidance for Industry: Extended Release Solid Oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations, September 1997, 3. Guidance for Industry: Waiver of In Vivo Bioavailability and Bio- equivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Aus gust 2000, 4. Guidance for Industry: Bioavailability and Bioequivalence Stud ies for Orally Administered Drug Products—General Consider- ations, October 2000, USP General Chapter, Current USP General Chapter <1088> (6) provides an informative guidance on in vitro and in vivo evaluation of dosage forms. Note that the goal of the pharmaceutical scientist is to find a relationship between an in vitro characteristic of a dosage form and its in vivo performance. Drug release testing is required for all solid oral and modified-release dosage forms in which absorption of the drug is necessary for the product to exert the desired therapeutic effect. The term in vitro-in vivo correlation (IVIVC) refers 10 the es: tablishment of a rational relationship between a biological property, or ‘a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form. In summary, in vitro dissolution in quality control should be opti~ mized to detect manufacturing variations within the range of variations \ypically encountered in normal manufacturing procedures. These vat- itions should be validated by in vivo studies. The suggested approach is to subject a specific range of in vitro data to in vivo testing to28 HANDBOOK OF DISSOLUTION TESTING establish the in vito limits defining the bioequivaleney of dosage forms Proxluced under a variety of manufacturing conditions USP <1088> (6) has defined and categorized three levels of cor relation in descending order of usefulness. Level A is a correlation of I points on a preduet’s in vitro dissolution curve with all points on its in vivo input curve (1e., the curve produced by deconvolution of plasma level data). Level B, a second level correlation, compares the ‘mean dissolution time with the mean residence time in vivo. Level C is a single-point correlation and is not considered adequate for relative bioequivalence determinations Summary of Useful Theoretical Concepts shurinsic dissolution is measured when the surface atca of the solid is held at a constant evel in a rotating cup, and the resulting rates are expressed as mg/ime/em". This technique is most often used to deter mine the actual dissolution rates of new compounds under study in new ding delivery systems. Apparent dissolution is determined by measur. ing the total amount of solid dissolved per unit time, according to the method in common use and epeeitied in the cumpendia. The speci. cations derived through ils use establish standard conditions of liquid. solid interface, temperature, and media composition, ‘The rate-fimiting factor in dissolution is complex, because the transfer of a solid active ingredient from its delivery system involves the sequential processes of disintegration, deaggregation imto small particles, and dissolution of those particles. Each of the processes may take a different percentage oof the total time required for the active ingredient to be dissolved. und any of those processes may be rate limiting depending upon the per- centage of the total time taken, Sink conditions are acceptable if the solvent does not significantly ‘approach saturation in the course of testing, Practically, this means that the volume of solvent present in the system is at least three times sreater than the amount required for a saturated solution, The status of the solid-tiguid interface is the key parameter for disintegration, deas- fregation, and dissolution: it is the point at which fresh solvent comes {nto contact with the surface of the solid being dissolved Theory involves extensive studies of film barriers atthe interface, as Well as diffusion constants and other factors. From a practical stand, Point, however, in order for an experiment to be repeatable, the rate at Which fresh solvent contacts a surface area should be kept as constant Possible. This means the flow should be laminar and devoid of tur. Theoretical Considerations 29 butence caused hy extemal inereence—probes inthe vessel, shap protuberances in th Taw path. eeemiies, or anything thal might Cause sete of he fox ptem The suc area ofthe sold will vary unde all cteumsanes Ae the ts prose, sic ae decreases with anowdsnegrang sold and inresses wh a dsine trating slid The ae of pstge ofthe es solvent ovr te sls Stfoe ae shoul be hep coson—or at east comtetale andr peste: Whon the patiles besome sal, however, coteling the Satie aca becomes pata : Input variables should be considered separately from state variables, Sete varibles ave hoe dete forthe est sich 3 sing spesd amount ad compost ofthe medium, geometry ofthe ppartas tempera, an so forth, Those vale ae reltvely easy enol amare defined inthe experimental prot. pu rable include the desi ad measurable varables ofthe dstge frm composition feat, physi characteristics ofthe sol ands on) ut he to inch multe of nvantedvaabes such 25 vibration ot nmcreplable aration of Sa varabls(emperanie, geometry. te), ce factors mus be ly onl ion, oa sa sry So, cones wi with dsolton ate only when dsolotton time longer tha cin ition time that when dsolton sate ining forthe sthton System, The teria for bieaalliyconelation have become Ta Imoe complex and rie asthe emphasis on dome forms his pro bes nea om nd ves So Se anae bes introduced many theoretical concepts that are desired in vive level a“ notaries bln The importance of ei ‘io dsslton io profit onli even when csohion dala de wed asa quay conl tool camo be undo Beyond Dissolution Dissolution has ben defined sth ate at which a slid is dsoled ", 2004, United States Pharmacopeia and National For- rmulary, United Stares Pharmacopeial Convention, lne., 27 Eali- tion, 2513-2518, (2) “USP Intrinsic Dissolution General Chapter <1087>", 2006, United States Pharmacopeia and National Formulary, United States Pharmacopeial Convention, Inc., 27 Euition, 2512-2513. ® Kaplan, $, “Biological Implications of In Vitro Dissolution Test- ing”, 1974, Dissolution Technology, Leeson, Land Carstensen, J, Editors, APS, Washington, DC. (9) Hanson, W, “Studies on the Effects of Some Variables Common! Encountered in the Measurement of Dissolution Rate of Solids”, Janvary 1979, Ph.D. dissertation, California Westem University, Santa Ana, CA, M, “Biopharmaceuties and Relevant vokineties”, 1971, Drug Intelligence Publications, Ham- Pharma ikon, TL. (11) USP Policy on Dissolution Standards”, 1981, Pharmacopeal Forum, 7, 1040, 1225-1226. . T, “Formulation”, Remington’s Pharmaceutical Seiences,32 HANDBOOK OF DISSOLUTION TESTING 15 edition, Osol, A, Editor, M lack Publishing Co., Easton, (13) Brossard, D, “Contrdle de la Vitesse de Dissolution”, May 1981, dissertation, Université René Dese: tes le Paris, No. 52, (14) Cox. D, Douglas, C, Furman, W, Kirchhoefer, R, Myrick, J and Walls, C, “Guidelines for Dissolution Testing”, 1978, Pharma: ceutical Technologies, 2(4), 40 (15) Olson, R, Essentials of Fluid Mechanics, 1961, International Texte book Co., Scranton, PA, (16) Becket, AH, Quach, TT, and Kurs, GS, “Improved Hydrodynam- ies for USP Apparatus 2", 1996, Dissofation Techuologies, 3(2) Ts, (17) Karmopp. DC and Rosenberg, RC, System Dynamics: A Unified Approach, 1974, John Wiley, New York (18) Cabana, B and O'Neil, R, “FDA Report on Drug Dissolution”, 1980, Pharmacopeial Forum, 6, T1=15, (19) FIP Working Group No. 5, “Guidelines for Dissolution Testin of Oral Products,” [981, Joint Committee Report, Pharmaceutical Industry, 43, 334-343. (20) Shah, VP, alence Test” Dissolution: A Quality Control Test vs. A Bioequ 2001, Dissolution Technologies, 8(4), 6-7. (21) Kost, J, Editor, Pulsed and Self-Regulated Drug Delivery, 1990, ERC Press, Boca Raton, FL. 3 Dissolution Testing of Solid Dosage Forms Ac tne phamacicl indy sows int ay ae etn rane nea psc nine menes Ont te or ments to rely spetfe defects inthe ld systems. ‘The fick of dis: ston eg eecogy bt aceon Te wer vet indusolaion equine sa td posed sae) rome insmaion! atte ting Appar Apart 2nd he a breached snr enanngyan he ern nebisag ths dat as bes eee Ait aig in rnin eins me ox encourgs, encouraging Tully new metvots may impose fae pores st ae we covet hog oor Rea Whe compel aera esse ef rine mc retinas foray ew dslaton mae to bese fc te tro lr ed tt aot be ees sea ease Ted, by cnet ts This piso may tthe iene hc sci nl sper wating for tna beac ae pis dees Gee on os a at Sarat Sr cd «sa Hsia Hay cAOEET EN 0s OnE pra aeons f fing ledge aan seep et Woe alba option ws 33M HANDBOOK OF DISSOLUTION TESTING have presented new dissolution techniques that offer superior eharac- teristies by comparison with the compendial methods, A review of those presentations is vital to the scientist working in this field, but is ‘ot germane to the day-to-day performance of dissolution testing. Be ceause this manual is intended for the person wrestling with the im- mediate requirements of dissolution testing, only established methods will be discussed, ‘When selecting a method and setting up a protocol for dissolution testing, whether for new drug development, quality control, or meeting regulatory requirements, the analyst should consult the latest eompen- ia, ineluding any proposed revisions Introduction to Current Methods Current official methods listed in USP represent compendial efforts of the last decade to promote international harmonization in dissolution testing, methodology and apparatus employed (1-4). The current stam and <724>. EP Section 2.9.3, and JP Chapter 15 all specify the basket, Paddle and flow-through cell methods. Appropriate pharmacopeial up. «lates andl monographs should always be checked for specfie requires ments, OF the more than 600 official drug monographs in USP. a majority Specifies Apparatus | (Basket) or Apparatus 2 (Paddle) testing. The testing platform employed is the standard 6-spindle dissolution drive, although a 7 and 8 position may be added for reference and blank (Figure 3-1), This equipment was first commercialized in 1969, and is now available from a host of international manufacturers, Current instrument manufacturers of Apparatus 1 & 2 dissolution fest equipment include but are not necessarily limited to these compa nies: * Caleva (UK) + Distek (USA) + Erweka (Germany) + Hanson Research (USA) * Logan (USA) Dissolution Pesting of Solid Dosage Forms Divetted —x | sume \ ‘Spindle Dig Pale Kemal (orbuted cot Vent ue Pte Heated Hath (also "Bathe Figure 3-1 Example of modern dissolution test equipment. + Pharma Test (Germany) + Sotax (Switzerland) + Toyama (lapan) + Varian (USA) + Others in China, India, ete ‘The Figures below illustrate and summarize the current official USP methods for dissolution testing of tablets, capsules and extended-release dosage forms. A more detailed discussion of each apparatus follows. ‘The Basket (USP Apparatus 1) Adopted in 1970, the basket method of dissolution testing was th first official USP method. Essentially, it consists of an approximately [Linch (25-mm) diameter by 1.5-inch (37-mm) high, 40-mesh stainless steel wire basket, rotated at a constant speed (typically 50 or 100 rpm). ‘This method is now called Apparatus | and is Mustrated in Figures 3-2, 3-6 and 3-7. Basket Specifications Apparatus | consists of a covered vessel (glass or other inert trans- parent material), motor, a metallic drive shaft and a cylindrical basket.36 HANDBOOK OF DISSOLUTION TESTING Standard Basket "40Mesh Staines 900 mt at 37°C #100 pm CFypicaty Medications #10 0 100-Mesh 5100 0 4000-mL Volume ‘Basket Dimcnsions Seppstoy si) EN Chet Us er { * Modified Release \ \— posse Figure 3-2 USP Apparatus I: Basket Standard Pate Inert Material 58900 mL-at 39°C #30 mm (Typed) "Wire Sinker for oaers Modifications 100 9 4000s Volume = Media pl Change ‘Apparatus S (Pate ove Disk) Useful or "Tablet and Solids Maid Release "Transdermal Patch | A | rz | Se ten Figure 3-3 USP Apparanus 2: Paddle Dissolution Testing of Solid Dosage Forms 3” Subsequ Recipeocting Cylinder i "With Mosh Screen t 3 Top and Bot on Sequemsl Media Tubes ‘Typical Vote 200 ml. Volume * Number oF Rows Useful for "=H Profiles sods ‘Sustained Rolese Figure 3-4 USP Apparatus 3: Reciprocating eylinder. Flow-Through Cell Collet Samples |= Waste or Reryle Open/Closed System Ope Ji Usefl fr ker Flow ‘Love Solubility Drugs i ‘Rapid Degraaion # Metin pl Change Goss Beads (Optional Media Souets) Figure 3-5 USP Apparamus 4: F thirough cell.38 HANDBOOK OF DISSOLUTION TESTING [i] LP —— set com spain omen Sampling Pact Figure 3-6 Basket, ‘The vessel Partially immersed in a suitable waterbath of any con ‘enient size or placed in a heating jacket, maintaining temperate in side the vessel at 37 = 015 °C. No par ofthe assembly, including the environment in which itis placed, contributes significant motions ‘ation oF vibration beyond that of the smowthly rotating string element, Apparatus that permits observation ofthe specimen ad stning clement Sect os sii moog Y cea ray | | i | | Spetiepsah —r — Figure 3-8 Paddle sd Made and sed during the es The metic osu inet, sii late Ga compe sgl ny. A uate top dete design ny be eed proved th asym fy ngoped ding he ta The pode adc and shat may be cad i sable et ‘The dosage unit is allowed to sink to the bottom of the vessel ine ctton he Hae ar A al ae fn of nomen Patel nt meta fe ws of Wen my ested temp unis th wel eerie oa. Oe vated snes de ese may also be ed2 HANDBOOK OF DISSOLUTION TESTING Shon ames i ——-_ beastie Figure 3-9 USP paddte stirring element Padile Variations. Paddle geometry, slong with smooth rotation (without significant wobble), must be maintained to provide consistent hydrodynamics, and hence repeatable test conditions with Apparatus 2. Paddles may be coated with a suitable inert coating, typically polyfluo- ‘ocarbon or equivalent, preventing both corrosion and the introduction ‘oF unwanted ions into the media. Although more expensive than coated. Paddles, solid inert paddle assemblies that prevent peeling or faking ane also commercially available for USP testing. Type 316 stainless wire has typically been used to form sinkers, and other small inert assemblies or clips are also commercially available. When evaluating sinkers, note that gummy excipients may randomly , and its development grew from prior work with the rotating bottle apparatus (NF XII 1965-XIV 1975). In the 1970s, many re searchers used the rotating bottle method for the evaluation of con trolled release products, especially for pellets. Despite its proven pH profiling capability and highly reproductble dissolution profiles, the ap- Paratus suffered serious shortcomings because it was labor intensive and not easily adaptable to automated sampling and media change, The reciprocating eylinder apparatus addressed these earlier constraints, Apparatus 3 consists of a heated bath containing rows of outer tubes (usually 6) that contain the media, while in each row there are 6 inner tubes containing the product to be analyzed (and an optional 7th tube for standard solution). The apparatus may be programmed for recip- rocating agitation rate (dips per minute), time in each media tube, and time in each subsequent media tube. Commonly referred to a the “BioDis™ (a trade name), the apparatus is commercially available from Varian, Erweka and others. Reciprocating Cylinder Specifications The assembly consists of a set of cylindrical, Nat-bottomed glass vessels, a set of glass reciprocating cylinders, stainless ste! fitings (type 316 or equivalent), and screens made of suitable nonsorbing and nonreactive material that are designed 1o fit the tops and bottoms of the reciprocating cylinders. A motor and drive assembly is used to reciprocate the cylinders vertically inside the vessels, and to index the inders horizontally to subsequent rows of vessels. Dissolution Testing of Solid Dosage Forms a7 sete, Atlas Shinde Figure 3-11 USP Apparatus 3: Reciprocating eylinder, ‘The vessels are partially immersed in a suitable water bath that main- tains the temperature at 37 + 0.5 °C during the test. No part of the assembly, including the environment in which itis placed, contributes ignificant motion, agitation or vibration beyond that due to the smooth, vertically reciprocating cylinder. ‘A control device is used to select and maintain within = 5 the reciprocating dip rate specified in the individual monograph. An ap- Paratus that permits observation of the specimens and reciprocatin cylinders is preferred. The components must conform to the dimensions shown in Figure 3-11 unless otherwise specified in the individual monograph48 HANDBOOK OF DISSOLUTION TESTING A USP reference standard, Chlorpheniramine Extended-Release Tab- lets, is available for the apparatus suitability test, A second calibrator, ‘Theophylline Extended-Release Beads, was used previously but is no longer available, Individually test 1 tablet of the USP Drug Release Calibrator Tablets (Single Unit) according to the operation conditions specified. The apparatus is suitable if the results obtained are within the acceptable range stated in the certificate for that calibrator in the apparatus tested The Flow-Through Cell (USP Apparatus 4) ‘The flow-through cell technique was developed at Ciba-Geigy in Switzerland under the direction of Dr. FE Langenbucher (19). It has been extensively evaluated in Europe and was recommended by the Feder- ation Internationale Pharmaceutique (20). I was officaly listed in USP 23. (1995), ‘The Apparatus 4 system is illustrated in Figure 3-5, When tested in the flow-through cell, a specimen is placed in a small testing chamber with a volume of about 20 mL (which is maintained at 37 °C), and release is studied under continuous flow conditions. From a reservoin the medium is pumped up through the bottom of the cel, and solvent flows upward through the cell and a filter system that removes undis- solved parices. The cone ofthe cells typically filled with small glass beads to ensure laminar low (oF turbulent flow without) Flow mte is a critical parameter and must be held constant. This often requires a careful match involving pump setting, filter pore size and dosage composition. A precision pump (typically a piston pump) can be regulated at flow rate ranges of 4-32 mL fminute, Pharmaceutical laboratories frequently use 16 mL/minute as a standard flow rate. Typ- ical systems provide 6 cells for samples and a 7 cell for a standard, ‘The apparatus can be adapted to automation Apparatus 4 is well suited to the determination of the dissolution rate of tablets and coated tablets, suppositories, soft gelatin capsules, im plants/microcapsules, powders and granules (21), Iti particularly use- ful for sustained release products and analyses where pH changes are desired, as well as providing infinite sink for low-solubility drugs. Ap- Paratus 4 is commercially avaiable from Sota . LEAP and others. Flow-Through Cell Specifications ‘The assembly consists of a reservoir and a pump for the dissolution ‘medium, « flow-through cell, and a water bath that maintains required Dissolution Testing of Solid Dosage Forms 49 7 Fike FV Lian tse LW, re. Figure 3-12 USP Apparatus 4 (flow-through cell): Large cell with holder. temperature, The cell size is specified in the individual monograph (Fi- ures 3-12 and 3-13), The pump forces the medium upwards through the cell, and has a delivery range between 4 and 16 mL/minute, with 4, 8 and 16 mL/minute standard flow rates, It must be volumetric to deliver constant flow independent of flow resistance in the filter device, the flow profile is sinusoidal with a pulsation of 120 = 10 pulses! ‘minute, ‘The flow-through cell, made of transparent and inert material, is ‘mounted vertically with a filter system (see individual monograph that prevents escape of undissolved particles from the top of the cell, Stan dard cell diameters are 12 and 22.6 mm (“'small” and “large”). The bottom cone is usually filled with small glass beads of about 1 mm diameter, with one bead of about 5 mm positioned at the apex to protect the fluid entry tube. A tablet holder is available for positioning of spe-30 HANDBOOK OF DISSOLUTION TESTING an ‘Sieve 40-mesh hE" Secor eh, Figure 3-13 USP Apparatus 4 (flow-through cell): Small celt with holder. cial dosage forms, such as inlay tablets. The cell is immersed in a water bath and the temperature maintained at 37 * 0.5 °C. ‘The apparatus uses a clamp mechanism and two O-rings for the fixation of the cell assembly. The pump is separated from the disso- Tution unit to shield the latter against any vibrations originating from the pump. The position af the pump should not he on a level higher than the reservoir flasks. Tube connections should be kept as short as possible, and “polytef™ tubing with a 1.6-mm id, and chemically inert flanged-end connections are used. An appropriate Apparatus Suitability ‘Test is under development at USP. Summary Apparatus 1 (Basket) and 2 (Paddle). These methods remain in USP and other compendia as preferred for solid dosage formulations. Chang- Dissolution Testing of Solid Dosage Forms st 6 in the specifications have been minor during the past 20 years, Dis- solution test equipment is easily automated for sample collection ancl detection, and is commercially available from a host of international manufacturers, The Reciprocating Cylinder (Apparatus 3). This method has been suggested for delayed and extended-release applications. I provides an improved pH change system; it replaces the rotating bottle method; and it offers advantages in testing bead-type products. It is commercially available from several manufacturers and is available with automated sampling The Flow-Through Cell (Apparatus 4). There is a substantial da- ibase in Eutope for this method, and along with the reciprocating cylinder, it was officially listed in USP 23 (1995). lts primary appli- cation is for fow-solubility drugs, but itis also useful for media and pH change, suppositories, implants, microcapsules, powders and gran ules. It is available from several manufacturers with automated sam- pling52 HANDBOOK OF DISSOLUTION TESTING References (1) “FIP Guidelines for Dissolution Testing of Solid Oral Products” 1997, Dissolution Technologies, (4), 5-14, (2) Shah, V, Williams, R, Siewert, M and Dressman, J, “Roles of Dissolution Testing: Regulatory. Industry and Academic Perspee- tives”, 1999, Dissolution Technologies, 6(3), 7-9. Gray, V, “Update on Dissolution Testing—Recent Activities and Trends", 2002, Dissolution Technologies, M1), 13-17 8 (4) ‘Harmonization <711> Dissolution and <724> Drug Release”, 2002. Pharmacopeial Forum, 28(6) 1972-1987, Patel, DM et al., “Effect of Rotating Basket Mesh Openings on Dissolution Rates of Aspirin with Magnesium-Aluminum Hy- droxide Tablets", 1980, Pharmacopeial Forum, 5(4), 376-377. (6) Gray, V, Begey, M, Brockson, R, Cozzigan, N and Mullen, J, “A Comparison of Dissolution Results Using O-ring vs. Clipped Bas- ket Shafts", 2001, Dissolution Technologies, 8(4), 8-11 6 a Palmicri, A, “Suppository Dissolution Testing: Apparatus Design and Release of Aspirin”, 1981, Drug Development in Industrial Pharmacy, (7), 246-258. Brinker, G and Gold: ‘System Performance", 14. (9) Poole, J. “Some Experiences in the Evaluation of Formulation Variables in Drug Availability”, 1969, Drug fnformarion Bulletin 3, 8-16. (10) Beckett, AH, Quach, TT and Kurs, GS, “Improved Hydrodynam- ies for USP Apparatus 2”, 1996, Dissolution Technologies, 3(2), 7-18. (11D Hanson, R, Swartz, M and Jarnutowski, R, “Pooled Dissolution ‘Testing: A Primer”, 1998, Dissolution Technologies, S(1), IS-U7. ®) in, B, “Bathless Dissolution: Validation of 1998, Dissolution Technologies, 5(2), T= (42) Hanson, W, “Studies onthe Efets of Some Variables Commonly the Measurement of Dissolution Rate of Sol 1979, Ph.D. dissertation, California Western University, Santa Ana, CA. (13) Cox, D, Douglas, C, Fuems W, Kirchhoefer, R, Myrick, J and Dissolution Testing of Solid Dosage Forms 53 Wells, C, “Guidelines for Dissolution Testing”, 1978, Pharma: ceuical Technology. (4), 40-53. (14) “USP In Vivo and In Vitro Evaluation of Dosage Forms General Chapter <1088>", 2004, United States Pharmacopeia and Na: sional Formulary, United States Pharmacopetal Convention, Ine, 27" Edition, 2513-2518, (15) “USP <1092> The Dissolution Procedure: Development and Validation”, 2004, Pharmacopeial Forum, 30(1), 351-363. (16) Robrs, B and Stelzer, D, “Deaeration Techniques for Dissolution Media”, 1995, Dissolution Technologies, 22), 1-8. (17) Drug Research and Tes ables 11”, and DRTL * (18) Borst, I, Ugwu, $ and Beckett, AH, “New and Extended Appli- cations for USP Drug Release Apparatus 3°, 1997, Dissolution Technologies, 4(1), 11-15. (29) Langenbucher, E Benz, D, Korth, W, Moller Hand Ot, M, “Standardized Flow-Cell Method as an Altemative to Existing Pharmacopoeial Dissolution Testing”, 1989, Pharmaceutical dn usury, 511), 1276-1281, (20) FIP Working Group No. 5, “Guidelines for Dissolution Testing ing Laboratory, USP, “Dissolution Vari- issolution Variables III”, Jan, 1978 (21) Looney, T, “USP Apparatus 4 (Flow-Through Method) Primer”, 1996, Dissolution Technologies, 3(4), 10~12.4 Dissolution Testing of Special Dosage Forms Besse nary nore pec age fs note peso of Snployel rhe ng of pcan ile ee Ts Ship alcove ne gins (1 foresees fr The salsa elton ety we comet it Sr bale pa surance has om csi el o Oth i avo modo ysage og si orb Sct ulina i aur cand wander pation Tandems age sens ile nore ares ina dag ton eyes an do te ob el Spe frm ge a4 Dissolution Testing of Special Dosage Forms 58 =e Cone Viable piers Dermis Bypodermis Figure 4-1 Representation of four compartments of the skin. transfer kinetics, can be studied with in vitro techniques (2, 3), Any one of these factors may be rate limiting, and at the very least each factor contributes to the multiple order equations that are necessary in order to model the absorption process. In vitro dissolution testing procedures and apparatus used with (op- reals and transdermal systems include a wide variety of technologies, and several standards have now been established. Current technigues apply to all or a portion of the transfer barriers. To classify these tech- niques properly, it is appropriate t segment the transfer kinetics, A useful place to begin to approach the analysis of transdermal drug de- livery systems is to consider rate-limiting processes involved Rate Limiting Processes Bio-absorbance from transdermal dosage devices is characterized by several pharmacokinetic barriers, cach of which displays individual transfer characteristics (4). Some of these barriers may be better un- derstood through in vitwo permeability studies 2) ‘These barriers may be classified as follows: + Drug release kinetics (all dosage forms) + Vehicle membrane (transdermal forms and implants) + Stratum comeum (transdermal Forms) + Viable epidermis (transdermal forms) + Dermis (all dosage Forms) + Blood transport metabolistw/excretion (all dosage forms). ‘The first five items in this list (drug release kinetics, vehicle membrane,56 HANDBOOK OF DISSOLUTION TESTING stratum comeum, viable epidermis, and dermis) can be defined by vitro tests. The last item (blood transport/netabolism/exeretion) at pre= sent can be defined only by in vivo procedures, ‘Transdermal patches, implants, medicated ointments, cosmeties, and foreign environmental contaminants are all studied in relation to one (or more of these transfer barriers. In vitro systems for these studies are complex, especially when one considers the multiple events and vati- ables in the tortuous diffusion through these portals (5). In vito dissolution test methods, therefore, have expanded from the simple measurement of rate of dissolution across a solid-iquid interface and now include also the kinetics of membrane transfer. These studies are also suggested in the design of moxifed-release oral dosage Forms (6). Problems Unique to Transdermal Testing Analytical methods must be sensitive to remarkably low concentra- tions. Patch or transplant delivery systems always involve controlled- release kinetics. This requires much lower concentrations than are ust- ally measured in standard oral dosage testing In studies of standard percutaneous absorption membranes, these low concentrations often require much smaller receptor volumes, for ex- ample, 5-25 mL, compared to the 500-1000 mL suggested for USP bbasket and paddle methods. As a result, the sample aliquot volume may be limited. Formulation additives often include complex polymers that are used 88 convenient rate controlling mechanisms in delivery systems (7), ‘These often exhibit the disagreeable characteristic of forming degra- dation produets that complicate the analyst Controlled-telease forms are designed to dissolve over long periols of time, but patch or implant systems may require an order or two of ‘magnitude longer. In cumulative in vitro procedures, degradation of active or excipient constituents may occur. One advantage of the flow- through cell in vitro dissolution test apparatus is the elimination of dogradation-produet interference, because analysis can be performed on an aliquot immediately after contact with the solute, However, the re- sulting lower concentrations are a disadvantage, These longer in vitro times may require sampling at periodic inter that can extend over days, weeks, or months! This becomes an exacting and burdensome laboratory chore, For these reasons, in vitro techniques for measuring transdermal and Pereutancous absorption almost invariably require the use of high per- Dissolution Testing of Special Dosage Forms 37 formance liquid chromatography (HPLC) because it requires much smaller aliquot volumes and has the ability to clearly define the pres- ence of degradation products. Indeed, the trend in dissolution testing, especially for more complex dosage forms, is 1o move away from tra- ditional UV absorbance and toward HPLC analysis (8). Automated sampling is almost a must in order (o avoid laboratory errors and ex- sive workloads, Variables in Percutaneous Absorption Testing Regardless of the choice of diffusion cell or test system, investigators must carefully list the input variables they wish 10 measure and the state variables inherent in the system they select. Input and state vari= ables are discussed in depth in Chapter 2. In addition, Smith and Haigh hhave presented a thorough review of these vatiables (5), Any serious investigator in this field should carefully review this reference. In surn- ‘mary, these variables include: + Rate limiting characteristics of the membrane, + Homogeneous mixing of denor and receptor fluids or both. + Diffusion layer on receptor side of membrane, + Membrane (skin) modification from hydration, + Effects of solubilizers on partition coefficients, + Chemical nature of system components. + Location of sample aliquot acquisition + Membrane area/volume ratio, + Temperature differences in the system, The need for extensive studies to define and classify these system var- iables cannot be too highly stressed. Dissolution of Oral vs. Special Dosage Forms Recent Fédération Internationalé Pharmaceutigue/Ametican Associ ation of Pharmaceutical Scientists (FIP/AAPS) Guidelines (1) provide a valuable review for dissolutionfin vitro release testing of novel and special dosage forms. Specific recommendations are discussed later in this chapter. It is noted in these guidelines that dissolution testing is @ very im- Portant too! in drug development and quality control. Dissolution was initially developed for immediate release (IR) solid oral dosage forms, and then extended to controlled/modified release solid oral dosage58 HANDBOOK OF DISSOLUTION TESTING (aE | [cee Pagel Seay | fo Topiatoas |__[— ew] wenearan |_, [Parmaagia ‘tows [-~[_ nee nae Tenant Figure 4-2 Comparison of oral and topicat drugs, forms. In recent years the application of dissolution testing has widened to include a variety of novel or special dosage forms. For oral immediate release solid drug producis it is customary 10 refer to the test as a dissolution test found in USP Dissolution General Chapter <711> (9), as the drug typically dissolves rapidly in the test ‘medium. For extended release and non-oral dosage forms, such as top- ical and transdermal delivery systems, suppositories and others, the test is referred to as a drug release or in vitro release test procedure in USP Drug Release General Chapter <724> (10). ‘There are significant differences in formulation design among the ‘many novel and special dosage forms, which in turn lead to very dif- ferent physicochemical and release characteristics (Figure 4-2). Due to these differences. itis not possible to devise one single test system to study the drug release properties of each form, Rather, different appa- ratus, procedures and technique are employed on a case-by-case basis. FIP/AAPS Guidelines (1) state that the general principles of disso- lution tests for solid oral dosage forms (Chapter 3) are also applicable to in vitro dissolutionfdrug release tests for novelspecial dosage Forms, The ultimate goal of these tests is analogous to that for solid oral dosage forms, that is, (0 use the test for the biopharmaceutical characterization of the drug product, and as a tool t0 assure consistent product (batch) quality within a defined set of specific eriter Appropriate drug release test apparatus and recommendations for dif- ferent special dosage forms are discussed below. It is recognized that for several novelspecial dosage forms, the methodology is well evolved, but for others more method development will be required. In general, compendial apparatus and methods should be used as a first ‘approach in drug development. The method used in the early phase of product formulation development could be different from the final test Dissolution Testing of Special Dosage Forms 59 Flow-Thzough Cel Collet Samples, Waste or Recycle Flow Rate iter pen/Closed System Use for Fiber“ = Low Solubility Drugs Flow 1 Rapid Deron hea pl Chance Dosage Form Gus Beas —|/ ‘Ono CP Media Sources) Figure 4.3 USP Apparatus 4: Flow-isrough cell procedure utilized for control of product quality. The final method may not mimic the in vivo environment, but should still test the Key pes formance indicators of the formulation Apparatus 4 Flow-Through Cell Apparatus 4 is ilustrated in Figure 4-3, and its specifications are discussed in Chapter 3. In addition to dissolution testing of solid oral dosage Formulations, the flow-through cell is also useful for dissolution studies of suppositories, powders and granules, micropaniculates and implants, Apparatus 5 Paddle Over Disk ‘The paddle over disk method was fist listed by the USP in 1990. Current USP Apparatus 5 uses the same paddle and vessel assembly from Apparatus 2 (Chapter 3), with the addition of a disk assembly designed 10 hold the transdermal system at the bottom of the vessel Figure 4-1), A stainless stel disk assembly, a watchglass-patch-polytet| sandwich (shown), or other appropriate device may be used provided it does not sorb, react with, or interfere withthe specimen being tested The vessel temperature is maintained at 32 = 0.5 °C. Paddle height is audjusted to 25 = 2 mm from the surface ofthe disk. The disk assembly that holds the transdermal system is designed to minimize any dead60 HANDBOOK OF DISSOLUTION TESTING Standard Pade Used dk "eTypieal Volume 900 ma q aay? Use for "Transdermal Patches Oinnents eaters <= Emulsions Bolus | — 7 Mesieations Disk Design| Volume dh r “Sandwich” stem Assembly Shown Dosage Foor Covered by Screen (Relea side up) Figure 4-4 USP Apparauus 3: Paddle over disk. volume between the disk assembly and the botiom of the vessel. The disk holds the system flat and parallel to the bottom of the paddle, with the release side up. The paddle over disk method has been extensively studied and ree- ‘ommended by the FDA for transdermal patch drug release testing (11), Apparatus 6 Rotating Cylinder USP Apparatus 6, frst listed in 1999, provides an alternative method for testing transdermal patches, The vessel assembly from Apparatus 1 is used (see Chapter 3), except thatthe standard basket and shaft are replaced with a cylindrical stainless steel stirring element (Figure 4-5). Detailed cylinder specifications are listed in USP Drug Release General Chapter <724> (10). As with Apparatus 5 (Paddle over Dish) vessel temperature is maintained at 32 = 0.5 °C, The dosage unit is placed on the eylinder with release Side out, and the rotating eylinder is po- sitioned at 25 + 2 mm from the botiom of the vessel. Apparatus 7 Reciprocating Holder The reciprocating holder method was first listed by USP in 1990. lly developed by ALZA Corp. (Palo Alto, California USA), it Dissolution Testing of Special Dosage Forms 6 Special Cynder Used Typieal Volume 900 mi. 1 Adapss to Standard { Dissolton Tet Station Temperature 32°C Useful for ‘Transdermal Paths | nore (Release side out) Figure 4-5 USP Apparatus 6: Cylinder: hnas been used for drug release testing of transdermal drug delivery systems (12), and may be specified for other dosage Forms. The rec rocating cylinder (Apparatus 3, Chapter 3) evolved in part from this method and desiga, Apparatus 7 consists of volumetrically calibrated solution containers :made of glass or other suitable inert material, a motor and drive assembly to reciprocate the system vertically and to index the system horizontally to subsequent rows of vessels, and a set of suitable sample holders (Fig- ure 4-6). Specifications for a variety of suitable dosage holders are de- tailed in USP Drug Release General Chapter <724> (10), ‘The solution containers are immersed in a suitable water bath, with temperature inside the containers maintained at 32 * 0.5 °C, No past of the assembly, including its environment, contributes significant mo- tion, agitation or vibration beyond that due to the smooth reciprocating holder. Apparatus that permits observation of the system and holder is preferred, Container and sample holder sizes are specified in the indi- Vidual monograph, Vertical Diffusion Cell ‘The vertical diffusion cell, or “Franz cell” for the release testing of topical and transcermal dosage forms, was pioneered by Dr, TJ. Franze HANDBOOK OF DISSOLUTION TESTING Reciprocating Holder ssSample Holder Subseguen Rows ‘= Tomparate 32°C I r Sequential Media Tubes | ‘Typical Volumes 30 w 200m Useful for i: TT "Transdermal Patches | ‘Solid Dosage Forme |_| sol Profile | Soll Volumes Typical Modifications Dosaae ‘Dosage Farm Holder tats Dosage {4 | Fon [| seme j | Scou | Figure 4-6 USP Apparatus 7: Reciprocating holder in the 1970s. The method has also been applied to ophthalmic, cos- ‘matics and pesticide studies. The diffusion cell is composed of a donor side for drug dosage, a membrane (cadaver skin or synthetic), and a receptor side with appropriate media solution (Figure 4-7), Early cell ‘configurations were vertical and side-by-side, but the vertical configu- rations were preferred (13). Of the many methods available to the analyst, the vertical diffusion cell may best replicate the physiological conditions at the site of drug administration for topical applications (j.e., skin). The cell was devel- ‘oped to best simulate in vivo absorption, as the donor dose is compar rable to the concentration per square centimeter in clinieal use, and the Opener celudes Top —T] I Menke x. SESE —— Do Pe Drug Permeation fe 3 | § ‘hough Membrane Fa Sample ot Receptor Mea | Ditfsin all aes pice 32°C) — Miner igure 4-7 Generalized digiusion cell: “Franz cel." Dissolution Testing of Special Dosage Forms 6 Useful for "Skin Person "Patch Stuties Dosa Glass Disk ‘Topicalsand Skin Care Donor Ares Prodets Membrane Dosage Water (l — — Solution Benton Fs f May Be Avtomsied Maintains 32°C! go tate Figure 4-8. Vertical diffusion cell: 7 ml. standard. donor side of the membrane need not be hydrated (14). Dr: Vinod Shah of the FDA used the vertical diffusion cell in pioneering efforts to standardize the method for release testing of semisolids (15-17). ‘The vertical diffusion cell has been refined over the years to provide a precise in vitro test instrument (Figure 4-8). Staulaed receptor voli is 7 mL, although small (4 mL) and large (12 mL) sizes have also been used. The cell inclides a receptor port where replacement media is volumetrically added, and a sampling port where equivalent sample volumes are withdrawn, typically in smal aliquots for HPLC analysis, Samples are withdrawn over time for release rate determination, Cells are generally used in banks of six, and temperature is maintained at 32 °C. For automated sampling purposes the top may be ovcluded (closed), A smooth mixing element is recommended 10 maintain homogenous receptor solution. The cell is available from Hanson Research and oth- ers, and may be modified for use with implants and other special dosage forms. Ointment Cell Alternatives to the diffusion cell are the ointment cell (Hanson Re- search and others) and the enhancer cell (popularized by VanKel/Var- jan), which have been shown in some studies to provide comparable results (13, 18). The ointment cell typically consists of a small volume vessel (150200 mL) adaptable to « standard 1-L dissolution tester, and a special mini-paddle modeled after the standard USP Apparatus 2 pucl- dle (Figure 4-9), Temperature is maintained at 32 + 0,5 °C. The cell“4 HANDBOOK OF DISSOLUTION TESTING Adapter for Standard Distoluton Equipment Media 325C Cinzment Cel Fst} (1800 200 mL Typical) -sieccugs |/— sete Membrane intmeat Cett— / Dosage Area Figure 4-9 Ointment cell and enkancer cell. may be used with or without a membrane (with ointments), and dead volume between the cell and vessel bottom should be minimized. Suppository Basket Although suppositories are commonly used in Europe, they are not popular in the United States. Palmieri (19) has designed a suppository basket that adapts to the drive of the standard Apparatus 1 (Basket) (Figure 4-10). The suppository basket is made of inert plastic with the same dimensions as the standard basket, substituting 12 linear slots ich wide (3.2.mu), to provide porosity of approximately 50%, roughly equivalent o that of a [0-mesh basket. Using Apparatus 1 (Basket) as deseribed, his studies report repreducible data for aspirin release from suppository bases Special Dosage Form Recommendations ‘The special dosage form commentary and recommendations that fol- ow draw on and benefit from an extensive FIP/AAPS, academic, in- Dissolution Testing of Special Dosage Forms 6 Standard [+L Dissolution ese and Rotating Basket Shaft | | ] semper —\ i } 4 \ KL a Figure 410° Suppository basket dustry and regulatory review (1), It is recognized that although tradi- tional oral dosage formulations are well documented and standardized, some special dosage forms may still require further research and eval- uation. Oral Suspensions (for systemic use) Apparatus 2 (Paddle), using an aqueous dissolution medium, is pen- craly recommended for dissolution testing of suspensions. Product preparation should follow a standardized procedure (shaking or mix- j sample weight and volume should reflect a typical dose of the product. Method parameters such as sample introciction and agitation fate should be based on the viscosity and composition ofthe suspension matrix. Agitation rate is typically 25 rpm for less viscous suspensions and 50 oF 75 spin for high viscosity suspensions, Orally Disintegrating Tablets Orally disimegrating tablets (ODT) ereate an in situ suspension by ating rapidly, typically in one minute or less, Administration alsin66 HANDBOOK OF DISSOLUTION TESTING of ODT may not result in a faster therapeutic onset, but ean circumvent patient problems such as swallowing difficulties. In vitro dissolution testing should therefore follow the principles for testing of solid oral dosage formulations or suspensions (20). Appacatus 2 (Paddle) is gen- erally recommended, at 50 rpm, and a single point specification is con- cred appropriate for ODT. Chewable Tablets ‘The exemption for dissolution testing for chewable tablets was re- moved from <711> in the early 1990's. This is based on the possibility that a patient may swallow the dosage form without proper chewing, in which case the drug will still need to be released to ensure the desired pharmacological action. As a general rule, test conditions should be the same as those used 10 test conventional tablets of the Sime active phat= ‘maceutical ingredient. More vigorous agitation may be needed to over- come the harder composition oF some chewables, ‘Transdermal Patches Current compendial apparatus include USP Apparatus 5 (Paddle over Disk), USP Apparatus 6 (Cylinder), USP Apparatus 7 (Reciprocating Holder), and a paddle over extraction cell (EP Section 2.9.4.2). The Apparatus 5 (Paddle over Disk) procedure using the watchglass-patch- screen sandwich assembly is considered the method of choice due to its successful application in testing & wide range of transdermal patches a. Semi-Solid Topical Dosage Forms Semi-solid topical dosage forms include creams, gels and ointments, In vitro drug release from semi-solid dosage forms has been extensively investigated using the Franz diffusion cell with a symthetie membrane, and to some extent using the ointment cell and enhancer cell. Although no official compendial methods are specified to date, FDa\s Seale-Up and Post Approval Changes Guidances (SUPAC) for semisolids (SS), Q1) describes release rate studies using the vertical diffusion cell, Mde- ally, sample weight/volume should reflect a typical product dose. Mast (opical forms are tested at 32.°C, although vaginal creams may be tested a 37°C. Dissolution Testing of Special Dosage Forms a Suppositories In principle, the basket, paddle or flow-through cell can all be used {o test hydrophilic suppositories that release the drug by dissolving in the rectal fluids, For lipophilic suppositories that release the drug after melting in the rectal cavity, a modified basket, « paddle with 3 wired screen and sinker, ands modified flow-through cell with dual ehamber have all been recommended. EP Section 2.9.3.6 gives additional guid- ance on test er flow-through cell. ‘The USP recommends Apparatus 2 (Paddle) method, with a mini- ‘mum amount of surfactant (if needed for lipophilic formulations), for liquid-filled capsules. The modified dual chamber flow-through cell (EP Section 2.9.3.6) is also considered an appropriate test apparatus. Ap. paratus 1 (Basket) and Apparatus 3 (Reciprocating Cylinder) have also been used, Chewing Gums In the ease of chewing gums, the intensity and frequency of shearing forces/activities can have a significant influence on drug release rate. Although an international standard is yet co be established, EP lists one apparatus that may be employed (see EP Section 2.9.25 “Medicated Chewing Gums”) Powders, Granules, Solid Solutions and Solid Dispersions ‘The flow-through apparatus offers specific sample cells for studying drug release from powder and granular dosage forms. For solid solu= tions and dispersions presented in oral dosage forms (e-g., capsules and. tablets), their in vitro release characteristics can be determined using the same methods as for solid oral dosage forms. Parenterals: Implants and Microparticulate Formulations New novelispecial dosage forms such as implants present challenges in establishing appropriate test methods for determining drug release Compendial and modified flow-through cells have been used success-68 HANDBOOK OF DISSOLUTION TESTING fully for implants and microparticulate formulations, For special dosage forms with subcutaneous site drug administration, « modified diffusion cell may also be evaluated for suitability. Dissolution Test Considerations As stated in the FIP/AAPS Guidelines (1), in order to adequately characterize the release from the dosage form, a drug release profile should be generated in which release (dissolution) values are deter- mined as a tunetion of time. This multi-point characterization has been place for some time for modified release oral dosage forms, as well 8 for slower dissolving IR products. Many of the special dosage forms -ussed in this chapter are complex in terms of composition and ri lease mechanism, so a multi-point drug release testis required to char- acterize release of the drug product, in general, as well as to test bated- to-batch and shelf life consistencies. Experimental test conditions should be discriminating enough to de- tect manufacturing variables that may affect biopharmaceutical product performance (1). As with solid oral dosage forms, development of in vibe dissulutuuftelease tests aid specifications for novelspecial Uus- age forms should take into account relevant bioavailability and clinical data. Ideally, physiological conditions atthe site of drug administration should be taken into account when selecting the in vitro dissolution! release test conditions, FDAYs SUPAC-SS (21) stipulates the specific value of in vitro di solution/drug release testing in its application as a batch-to-bateh « ity control (est and its value in evaluation and approval of scale-up and post approval changes. The SUPAC document for semisolid dose, forms (SUPAC-SS) defines the levels of changes with respect to for: ‘mulation composition, manufacturing site, scale of manufacturing, and process and equipment changes. In vitro drug release is used to assure product sameness, and these principles can be extended to other dosage forms. Special Dosage Apparatus Summary [An appropriate drug release testis required to characterize the drug product and assure batch-o-batch reproducibility for consistent phat- macologicaVbiological activity. The apparatus summary and recom ‘mendations listed below represent current status of scientific develop- Dissolution Testing of Special Dosage Forms o ‘ment of special dosage formulations, recent FIP/AAPS Guidelines (1), and the authors’ experience in the field. * Solid Oral Dosage Forms (conventional): Basket, Paddle, Reciprocating Cylinder or Flow-Throwgh Cell + Oral Suspensions: Paddle Orally Disintegrating Tablets: Paddle Chowable Tablets: Basket, Paddle or Reciprocating Cytinder with glass beads ‘Transdermals—Patehes: Paddle over Disk Topicals—Semisolids: Vertical Diffusion Celt Suppositories: Paddle, Suppository Basket or Flow-Through Celt (dual chamber) Liquid Fitled Capsules: Basket, Paddle, Reciprocating Cylinder or Plow-Through Celt Chewing Gum: Special Apparaius (European Pharmacopeia) Powders and Granules: Flow-Through Cell (powder/granule sample cell) Mieroparticulate Formulations: Modified Flow-Through Cell, Modified Diffusion Cell Implants: Modified Flo Through Cell, Modified Diffusion Cell0 HANDBOOK OF DISSOLUTION TESTING References (1) Siewert, M, Dressman, J, Brown, C find Shah, ¥, “FIP/AAPS Guidelines for Dissolution/In Vitro Release Testing of Novel/Spe- | Dosage Forms”, 2003, Dissolution Technologies, 11), 6 15. Q Bronaugh, RL and Maibach, Hl, Percutaneous Absorption, 2nd edition, 1989, Marcel Dekker, NY. 3 Krowezynshi, L, Ewended-Release Dosage Forms, 1987, CRC Press, Boca Raton, FL, a Guy, RH and Hadgraft, J, “Mathematical Madels of Percutaneous Absorption”, 1989, Percutaneous Absorption, 2nd edition, Chap. ter 2, Marcel Decker, NY. 6 ‘Smith, EW and Haigh, JM, “In Vitro Assessment of Drug Release from Topical Formulations”, 1989, Percutaneous Absorption, 2nd edition, Chapter 29, Marcel Decker, NY. (©) Amidon, GL, AAPS-FDA-FIP-USP Workshop, Dec. 1988, Wash- ington, DC. a (Ouellette, RP and Cheremisinolf, PN, Essentials of Biotechnology, 1985, Technomie Publications, Lancaster, PA, Swartz, M and Ni Sensitivity Analysis ® g, 1, “Dissolution Testing Requiring High 1990, American Laboratory, o “USP General Chapter on Dissolution <711>", 2004, United States Pharmacopeia and National Formulary, United States Pharmacopeial Convention, tne., 27 Edition, 2303-2304, (10) “USP General Chapter on Drug Release <724>", 2004, United States Pharmacopeia and National Formulary, United States Pharmacopeial Convention, fne., 27 Edition, 2305-2312, (11) Shab, VB Tymes, NW, Mem, W and Skelly JP, “Collaborative Study Results of a Test Procedure Developed by FDA for Nitro- glycerine Transdermal Delivery Systems”, 1988, Pharmacopeiat Forum, 14(1), 3458. (12) Chaisson, D, “Dissolution Performance ‘Testing of Transdermal Systems”, 1995, Dissolution Technologies, 241), 7-11 (13) Markovich, R, “Dissolution Testing of Semisolid Dosage Forms”, 2001, American Pharmaceutical Review, 4(2), 71-79. (ay a3) 6) an «as) ay 20) en Dissolution Testing of Special Dosage Forms 1 Franz, TH, Crrent Problems in Dermatology, 1978, Karger, Basel, 58-68 Shah, VP, Bikins, J, Lam, SY and Skelly, JP, “Determination of In Vitro Drug Release from Hydrocortisone Creams”, 1989, In= ternational Journal of Pharmaceutics, (53), 53-59. Shah, VP, Elkins, J, Hanus, J, Noorizadeh, C and Skelly, JP. “In Vitro Release of Hydrocortisone from Topical Preparations and Automated Procedure,” 1991, Pharmaceutics Research, (8), 55~ 59, Shah, V, Elkins, J, and Williams, R, “I ment for Topical Glucocorticoid C Forum, 19(2), 5048-5060. Vitro Release Measure- 15", 1993, Pharmacopeial Zatz, JL and Segers, MS, “Techniques for Measuring In Vitro Release from Semisolids”, 1998, Dissolution Technologies, 5(1), 33 Palmieri, A, “Suppository Dissolution Testing: Apparatus Design and Release of Aspisin", 1981, Drug Development in Industrial Pharmacy, (7), 246-259. Klancke, J, “Dissolution Testing of Orally Disintegration Tab- lets", 2003, Dissolutton Technologies, 10(2), 6-8, “Guidance for Industry, Nonsterile Semisolid Dosage Forms, Seale-up and Postapproval Changes: Chemistry, Manufacturing sand Controls; In Vitro Release testing and In Vivo Biocquivalence Documentation,” US. Deparment of Health and Human Serv- es, Food and Drug Administration, Center for Drug Evaluation tand Research (CDER), May, 1997.5 Controlling Variables Tay acnin tt pce pinion Te wan snap ne ct fy of Usa eng ees Ionarts: Brg te 1S ode apt ena eel si sd in op se en ewe Pe Chopery hs cingenin gly sed te spite strane rb ic pu ade costs soy tc inane be pec Tic orton eve ingen abu a the sont 1-4). Tele ay tain acy DT Dincion Connie Seo on Deolee cae tae stconmis ome or sem elo ert sith tutes The tn "Doi Caen Resonate fr Reel Chonl Testa el on potaon pened by te RSI tease ee <3. ao ote cana a gerne nage tea saab at eine aes fre ae Son to US Tes guste ha OSE Seige aoa cipal Faom US repens pte eeopane ne Usb edehy cele cater eee ranertce eee n Controlling Variables B Another series of joint publications from FDA and the University of ‘Maryland (8) shows extensive work on bath performance vatiables us- ing a new calibrator tablet bused on the FDA internal calibrator tablet, NCDA #2, This tablet was shown to be very sensitive to deaeration and centering and somewhat sensitive to vibration. In 2001, the USP Prednisone calibrator tablet S0-mg formulation was replaced by this 10-mg tablet formulation, Problems with Apparatus I and 2 seem to be confined to meeting calibration specifications. Some of the practical equipment variables that may cause difficulty in meeting calibration requitements are dis- cussed in this chapter. These will be listed with an outline of (1) the ‘minimum practical limits for each random variable; (2) an estimate of the extent of change of dissolution rate that can be expected from ine terference by those random variables; and (3) a means of correcting them, Sources of error can also apply to calibration and sampling and these topics have been covered in the literature (9, 10), ‘As discussed in Chapters 3 and 4 of this handbook, during the 1990s, several additional dissolution apparatus became official. With USP General Chapter <724> Drug Release, in 1990 the reciprocating cyl- inder (Apparatus 3), the paddle over disk (Apparatus 5), and rotating cylinder (Apparatus 6) became official. The flow-through cell (Appa- ratus 4) for extended-release items, and reciprocating holder (Apparatus 7), that has several design modifications for transdermal items and ex- tended release products, became official in 1995. Apparatus I and 2—Eccentricity of Stirring Drive ‘Theoretically, as the basket rotates it imparts a gentle moyement of ‘luid through the basket, The paddle, of course, is designed to create {uid movement in the vessel. It follows that eceentrcity in either device will alter the pattern of fluid movement, The fluid movement due (0 this string defines the rate of shear of fluid past any solid and thus affects the dissolution rate. Eccentricity, therefore, will change the dis solution rate. At issue then, is defining how much eccentricity is ac ceplable and what effect i¢ will have on dissolution, ‘The USP General Chapter on Dissolution <7]1> and other phar- ‘macopoeias use the description “without significant wobble" for the stirring drive, The word “signi pus the burden on the operator to ensure that whatever wobble may exist does not significantly affect the dissolution rate. USP further states that the axis of rotation of the slirting shat shall not deviate more than 2.0 mm from the axis of the1" HANDBOOK OF DISSOLUTION TESTING vessel. Although it appears that this statement is not meant to define eccentricity, it can be interpreted to constrain it within * 2 mm (total ‘of Yj inch). This is generous specification, and should probably be ¥y ean significantly affect the dissolution Eccentricity can be measured with several commercially available tools, Eccentricity is measured in terms of total indicator reading (TTR), hich determines the sum of the distance on both sides (180) of the axis of rotation. ‘The effects of eccentricity, like those of any random input variable, should not be generalized, They can vary significantly from test method to test method and from dosage form to dosage form. A few rules of thumb, however, may serve as guidelines to the analyst, A study was performed (11, 12) where both the rotating basket and paddle shaft were purposely bent to introduce eccentricity. The effect of these i regularities on USP Salicylic Acid and Prednisone calibrator tablets \were studied. The results of those tests indicated that, using the rotating basket, eccentricity in the 2.0- to 5.0-mm TIR range increased the dis- solution rate for both calibrators by approximately $¢ over the values ‘obtained when eccentricity was held below 2.0 mm TIR. Similar results \were obtained with both calibrators using the paddle, for which eccen- Iricity in the 1.0- to 2.0-mm TIR range (ie., within USP specifications) inereased the dissolution rate by approximately 8% for Salicylic Acid and 4% for Prednisone calibrator tablets compared with eccentricity held below 0.5 mm. This study suggests that the degree of eccentricity may be more sigaificant with the paddle than with the basket, and certainly that eccentricity should be kept below 1,0 mm TIR with the paddle in order to avoid significant modification of the dissolution rate. ‘These TIR values are measured at the junction of the shaft with the paddle blade or basket. It is quite difficult to maintain close concen \vivity of a rotating shat in this equipment, largely because these mea- surements are made about 6 inches (15.2 em) from the chuck, This indicates that the TIR at this point should certainly be held less than LO mm and even under 0.5 mm on commercial equipment, ‘Two factors in equipment design are eritical in meeting this speci fication: First, the rotating shaft must be held to very close tolerances of straightness; and second, the shaft must be guided in wo places, preferably as far apart as the distance between the chuck and the basket or paddle blade. This means that the lower the drive chuck is positioned with respect to the Mask, the lower the amount of eccentricity. With the introduction of roboties and automated samplers, this distance has tend= Controlling Variables 18 ed to increase in onder o provide clearance. This is necessary in these ations, but the laws of mechanics tellus thatthe higher the chuck from the surfice of the dissolution vessel, the more likely ¥y will be a problem. In summary, an excess of eccentric within the compendial standards, may alter dissolution rate as much as 8-10%. Other random input variables such as tlt, centering, or vibra- tion may have a much greater disturbing influence (Figure 5-6). Shaft Straightness. This is a estical equipment requirement in the control of eccentricity. The manufacturer should re-straghten shafts be- fore shipment to ensure close straightness tolerances—at least a 0.005- inch TIR over the whole length. Many operations in the manufacturing process cause shatis to bend machining, assembly, polyfluorocarbon coating, and others, Manufacturers are remiss if they do not check each shaft atthe time of shipment to ensure the straightness tolerances spec- ified above, Laboratory Gowx! Manufacturing Practices (GMPs) should require that when shat are received, they are inspected for straightness: further this should be a part of the periodic calibration required by GMBS. Shafts can be checked on a simple V-block with an indicator This technique is reviewed in Chapter 6, 1s almost impossible to Keep a Jinch (6.35-mm) diameter shaft straight within these. specifications. Recognizing this, the compendia suggested %inch (9.53-mm) diameter shafts. Because the original spec- ifications stipulated Y-inch diameter shat in-use, the specific ilies 9.4-10.1 mm shaft diameter, and the compendial tolerance is broad enough to include English stainless stock (standard 0,375-inch oF the ‘equivalent 9.53-mm) and metric stainless stock (10-mm standard). The Yoinch diameter shafts are virtually obsolete today. Guiding the Shaft. This is the responsibility of the designer of the stiring apparatus. A single chuck mounting is simply not an adequate engineering solution to provide a precision drive. Even precision dill press chucks and collet can seldom repeat inside a total af 0.005 inch TIR at a distance of 1 inch (25.4 mm) from the chuck. The design of the dissolution flask demands that the paddle blade or the basket be at least 6 inch (15.2 em) from the chuck or eollet in the lowest postion, ALG inches, a chuck eccentricity of 0.005 inches will result in an eccentricity of 0.030 inch at the blade or basket; this is an acceptable maximum (<1 mm), From a design standpoint, driving the stitring shaft between wo points that are as far apart as possible can minimize this multiplication of eccentricity with length, This is shown in Figure 5-1, Most com and many such drives were ions were set to include both The USP now spec-6 HANDBOOK OF DISSOLUTION TESTING | _

. A bubble at the bottom of the busket may dislodge itself after the basket starts to rotate (Figure 5-4B). Formation and disappearance of this bubble, if it occurs, should he observed by the analyst and docu- ‘mented in the testing, as it may change the dissolution rate. Dissolution Media Variables—Dissolved Gas Liguids are in equilibrium with surrounding gas at the gas-liquid interface. Ata given temperature and pressure, a portion of the gas 1s dissolved in the liquid. The amount of dissolved gas in equilibrium decreases substantially as temperature inereases, The equilibrium value of oxygen in water (measured in mg/L), for example, drops from 8.74 room temperature (22 *C) to 7.31 at 32 °C and 6.73 at 37 °C; 100% saturation at room temperature inereases to 120% at 32°C and 130% at 37 °C, the specified dissolution temperatures. ‘The excess from this supersaturation accumulates as minute bubbles in the med ‘This release of dissolved gas is one of the most annoying variables responsible for distorted dissolution data in all specified or proposed clissolution apparatus. Farly on, seientists at the FDA labs stated that a very appearance occasionally arising on the flask, rotating shaft, or basket or paddle is « warning of the release of dissolved gases that ‘may disturb the test (28). Since then there have been many publications dealing with dissolved gases, The silvery appearance is a result of m croscopic air or a gas bubble released as the medium adjusts to equ librium with the gas. ‘This phenomenon provides a warning 10 check deaeration methods and the influence of the released gas on the solution rate of the test under observation, ‘One may speculate about the many ways in which released affect dissolution, but most probably the small bubbles interfere with fluid dynamics or the area of the liguid-solid interface or both, The Conirolting Variables 87 bubbles may attach to the rotating busket or the sereen in the recipro cating cylinder, thereby altering the effective porosity. They may ac- ccumuilate on or in filers or the glass beads of the flow-theowsh appa- ratus, affecting the flow rate. They may accumulate in flow eells, where they could interfere with absorbance measurements, They may attach to aggregates from disintegrating dosage forms, changing thei eflective liquid-solid interface and flow patterns in Apparatus 1, 2, and 4, They may accumulate on the membranes in transdermal or percutaneous ab= sorption tests, The probable methods of interes ‘The effects of dissolved gases are significant. Studies with fiber optic probes (39) showed an inerease in variability (coefficient of variation) rates of 12% with Prednisone calibrators when the media Was not de- aerated, The presence of dissolved gases is suspected in many failures to meet calibration standards. The dissolution-rate data may be higher of lower, depending on the apparatus and dosage form, The analyst should recognize that no generalizations about the mag- nitude of the effect of dissolved gas in media are valid. The effects vary with the dosage form, and therefore, USP leaves decisions re- garding the presence of dissolved gases to the experimenter, stating only im Dissolution General Chapter <711>, that the presence oF bubbles ‘must not significantly affect the dissolution rate, Deaerating Media Release of dissolved gases can be prevented if the concentration of izases is kept befow the saturation value of the media during the test ‘To avoid problems, a value atleast $% below saturation atthe operating temperature should be obtained, A crude method in use at some labo ratories involves filing the flasks with media at 40 °C and operating the stirring device until the temperature reaches the prescribed 37 °C. This provides a 5% margin below saturation, In 1994, Qureshi and ¢o- workers described the various methods of deaeration (40), He studied the effect of deaeration by the following methods: heating alone, helium sparging, heating and and vacuum, sonication and clusion was that heating along with helium sparging was the best ap- proach. ‘This conclusion was confirmed by a more recent article (41), aand-many others have studied and compared dissolution deacration techniques (42, 43). EDA published in 1978 (28) a satisfactory method that involves sub- ily deaerating the media before its addition to the dissolution88 HANDBOOK OF DISSOLUTION TESTING Vacium Deseratod Media| Masi L } Source Figure 5-5 Deaevation system developed by NCDA. The medium is drawn through a fine spray nozcle By an 18 to 22 inch vacuum into a Jive-galton jug (protect personne! from implosion injury). Gas is re leased from the fine spray and the medium container can be sealed, ajier which it remains satisfactory for dissolution use for 2-3 days apparatus. A later version of this method was published by Moore (44), This method is shown in Figure 5-5, A commercial system, called the Media-Mate™, that uses a variation of the NCDA method, has been available for more than 20 years. Thi system is described in Chapter 8. It combines the spray with thin film to increase the surface area under vacuum. Langenbucher and co-work- cers (33) have reported a similar thin-film technique. Their system achieves a 30% reduction from saturated values (25% with house vac= tuum). The Media-Mate® regularly achieves greater than 10-15% re= duction when tested with a standard dissolved oxygen meter. By com- parison, checks in Bill Hanson's laboratory have achieved a practical 55% reduction through conventional boiling techniques. Subjecting 4 liguid to a vacuum wall result in vaporization as well as the release of dissolved gas. This cools the solution, Tests indicate 1 drop of approximately 1.5 °C when the thin-film method is used. When such a solution is used to directly fill dissolution-fluid systems, the source should be at Teast 1.5 °C higher in temperature than the system ‘There are other automated methods of deaeration, including an in situ deaeration method using the hollow shaft system (45). Diebold and Dressman published a study (46) deseribing in-depth Controtting Variables 89 the use of oxygen to measure de- and re-seration of aqueous media. ‘They describe an oxygen sensor bused on a Clark electrode, They con- cluded that the oxygen measurement method Was reproducible, that the efficiency of deaeration was highly dependent on the method used, and that re-introduction of air into the medium occurs not only during filling of the dissolution vessels but also during the dissolution test. Other studies have suggested that a level of dissolved oxygen with a range of 4-7 me/L produces an equilibrium effect (47). Influence of Released Gases ‘The major influence of gas or air in media seems to be physi js, the bubbles that appear in media may disturb the equi following ways: + Alter low patterns as they tise to the surface. * Associate with aggregate particles, resulting in random eoncentra- tions of the particles in the solvent stream, + Collect atthe sereen on the basket, changing the effective porosity of the mesh, + Collect on the sides of the vessel walls, providing a place for par- ticles to eling, rather than to mix properly + Attach to dosage forms before disintegration, thus altering the dis integration and de-ageregation process by reducing the surface area ‘exposed 0 the solvent siream and/or altering the specific gravity of the mass, resulting in a random, uncontrolled positioning of the ass in the solvent stream. + Contribute to the boundary layer at the solid-liquid interface in a random manner Media Variables—pH ‘Media composition is specified in the individual monographs. Un- butfered media may vary in pH. Typical values for pH in laboratories suggest ustal levels of pH 6.0 for distilled water, pH 6.6 for de-ionized Water (deaerated or not), and pH 7.2 for distilled water deserated by boiling. Some have recommended against water as a media (48), how- ever, others find using water can be practical and ean yield useful results (49). Variations in dissolution rate ut different pH levels is to be ex- pected if the drug has a steep pH/solubility curve, but the plUsolubility curve of various excipients should not be overlooked. tn the method development stage, the test solution pH should be checked at the end90 HANDBOOK OF DISSOLUTION TESTING of the run to see if there has been a pH change. Shorteni ening the disintegration and de-aggregation lag periods (C ures 2-2, 2-3, and 2-4) can exert significant effects on the dissolution rate, even for drugs with relatively flat pHisolubility characteristis, Absorbance may vary: with changes in pH. If the pH is changed uring the (st, for example, when studying delayed release dosage forms, the standard should be checked at each pH used, If pH. varies significantly, analysts should use multiple standards Media Variables—Volume Iris elementary, of course, that the volume of medium must b tained constant. Volume lost from sampling may be corrected in cal- culations, provided the correction factor is less than 25%, In dissolution testing of extended-release preparations, the volume of samples with= drawn may exceed this limitation, Sample volumes may therefore be replaced (at the same temperature); automated equipment is available to accomplish this task (Chapter 8). The amount of Tiguid lost by evaporation ean be considerable and should be checked. In some labs, the vessel and contents are weighed before and alter the run to determine just the evaporation Loss. In low- humidity environments, up to 15-mL losses from standard dissolution flasks have been measured, Environmental conditions should not be overlooked. There may be a vast difference in evaporation rate in a laboratory in Mexico City or Denver compared to one in Puerto Rico ‘or Thailand, Evaporation control should be included in all dissolution apparatus, Suitable curtain-type covers are supplied in the reciproe; and holder equipment, Tests i sampling equipment should not be considered in the absence of evap- ‘oration control on the sample receptacle unless automated samples are used within minutes of sample leposit. HPLC collectors commonly use septum closures that can be punctured for injection, Test tubes are avail- able with split-plastic throwaway evaporation covers that enable fl tnd emptying with sample probes, ‘The vessel covers specified for Apparatus | and 2 have been some- \what primitive, They do retard evaporation, but they also act as con- densers, accumulating considerable media, The covers could easily in- troduce errors in the 24% range. ‘A common practice is to fill dissolution vessels with accuracy and wait for them to. equilibrate at 37 °C. Considerable evaporation can inder icate they are 99% effective, Automated Controlling Variables a1 ‘occur unless covers are let on du ng this warm-up period, Automated automated equipment avoids this waiting period by loading the flask with prehented deaerated medium, Media Variables—Temperature Solubility is generally linear with temperature, and sometimes the curve is sleep. The effects of temperature variations will, of course, depend upon the temperature/solubility curves of the active ingredient, 1s well as those of the binders and excipients, Dosage forms may differ widely, ranging as high as 5% change in dissolution rate per degree Celsius (12). Because the compendia allow * 0.5 °C tolerance, a con- siderable variation within this range might be anticipated for some dos- age forms and this should be part of the robustness evaluation of the dissolution method ‘The temperature should be monitored at suitable intervals, at least before the test and if possible after the test. This can easily be done by automated systems, and recording deviees are also available, $0 this tay be a routine procedure, However, bath temperature does not ensure Mask content temperature in all situations, The differences might be subtle, but sometimes they are the cause of the puzzling inability (© meet calibration standards, For example, plastie flasks have a heat transfer coefficient that is ap- proximately 30% that of glass (50), In some environments it has been ‘ound impossible (© hold a plastie flask temperature at 37 °C without implementing substantially higher (38-39 °C) bath temperanures. The cooling from the surface of the medium in the flask ean exeeed the rate of heat transfer through the plastic (0 the extent that stability cannot be maintained. Tt is therefore of vital importance that covers always be used, especially with plastic flasks. When covers are used, there is little substantial differential between the temperature of the contents of glass flasks and the bath temperature, ‘The critical apparatus parameter is therefore a consistent temperature at all paris of the bath, This can be easily held within = 0.4 °C in properly designed and installed bath and should be a part of every manufacturer's warranty. Doing research on automatic sampling for percutaneous absorption systems, Bill Hanson was surprised ( find that there is a disturbing itference in flow rate vs. temperature, In small-diameter PTFE tubing, this can exceed 1%7°C. This suggests that care should be taken to useoy HANDBOOK OF DISSOLUTION TESTING only volumetric pumps in the flow-through apparatus and in sampling systems that depend on flow rate for volume measurement Media Variables—Sink Conditions When a low-solubitity drug is specified ut a dosage level that ca saturation in the dissolution medium, accurate dissolution profiles be- ‘come difficult or impossible (@ obtain, In dissolution testing, the rule of thumb has been that sink conditions fre approximated if the test volume is at least 3 times the saturation volume (Chapter 2), USP, in the General Chapter In Vitro and In Vivo Evaluation <1088>, gives the following description of solubility pa rameters when developing a method, “The quantity of mediam used should be not less than 3 times that required to form a saturated solution of the drug substance"(S1). The flow-through cell apparatus provides an infinite or variable sink and was and may still be the method of preference in Europe for low-solubility drugs (32). An alternative ap- paratus for low-solubility drug testing specifies an inerease in the me- «dium volume in Apparatus 1 or 2: a 4-1 flask has been used success- fully in Europe and North America (52). Spectal modifications of Ap- pparatus 1 and 2 for 2- and 4-L flasks are commercially avallable and ‘are allowed in the USP Dissolution General Chapter <711>, Finally, several suggestions have been put forth for media modifi cations in order to increase the solubility of specific dosage forms. The most common uses a surfactant, sodium Iauryl sulfate, in small amounts. Some have suggested that this is an acceptable alternative to media prepared with ionie bile salts that ane a part of the assimilation mechanism of the human (53-55). This proposal, therefore, is in har- ‘mony with the dissolution movement toward better in viteo in vivo correlations ‘The alternate situation, low concentrations of active ingredient but no sink condition issues, is 1 problem with some dosage forms, partie- lularly transdermal, high potency and extended-release dosage forms. ‘The test may require a greatly reduced media volume in order to obtain detectable concentrations; adaptations of a miniaturized basket have been successful (56). Modifications of Apparatus | and 2 have been made for 100- to 200-mL. beakers (57). Smaller volume media tubes may also be used, Flow Pattern and Vessel Hydrodynamics Uncontrolled variables inflow pattern have been extensively studied with Apparatus | and 2, but much investigation needs to be completed Controlling Variables 93 for Apparatus 3-7. Suggestions about unresolved problems were made in the first paragraphs of this chapter Asa result of Cox's studies at NCDA (28) the contours of dissolution flasks used in Apparatus 1 and 2 have been more rigorously defined, ‘The current commercial flasks are far more consistent than those avail- able 10 years ago—and the price has risen accordingly, however prob- lems still occur (58), Cox and co-workers also cautioned against the permanent intrusion Of sampling probes and thermometers into dissolution flasks because of the probes’ effects on dissolution patterns. Savage and Wells in [982 (59) found significant differences in dissolution rate when 7-ram di- ameter sample probes were used, but they found litle difference with 1.5-mm diameter probes. Automated systems are particularly vuln ble to this defect; some use two probes per vessel. Now, some manu- facturers have reconfigured equipment so that probes are removed ex- cept when sampling is actually taking place. NCDA scientists also commented on the return (replacement) of sub- stantial amounts of medium to the flask and the attendant effects that such returns have in disturbing flow patterns, particularly if the returned medium is at a different temperature, ‘The position of the stirring device from the bottom of the flask is well defined in the compendia, although available evidence suggests that this position is not a significant variable if itis held within rea- sonable Timits (12). This variable needs to be more precisely defined in the transdermal paddle over disk, Apparatus 5, Consistent flow pattems in Apparatus 1 and 2 make possible a reli- able sampling point. Gray and Foster in 1997 (60) published research performed at the Drug Research and Testing laboratories using USP Salicylic Acid calibrators anv! found consisteney at « point about one half-way trom the top of the basket or paddle to the top of the media aand not closer than | em to the side of the flask. This requirement has been in effect for many years, and no data refuting it have appeared, I causes some problems with automated equipment, however, when the media are changed during the test from 750 t© 1000 mL. as proposed for delayed release dosage forms. ‘There have been new studies performed on the hydrodynamics of the vessel flow by Mauger, Healy, and Muzzio (61-63), This is an area of great interest and more research is expected, Perhaps the least documented influence of flow-pattern vatiables ex- ists with respect to Apparatus 3 (reciprocating cylinder), and Apparatus94 HANDBOOK OF DISSOLUTION TESTING 4 (flow-through cell). Apparatus 7 (ceciprocating holler) and pereutae neous absorption cells are discussed in Chapter 4, ‘The low pattern of Apparatus 3 varies with reciprocating rate, the porosity of the top and bottom sereens and holes, and the plunger cou- pling (reflected by the respective diameters of the eylinder and vessel). ‘The elegant possibilities of this method for closely controlling the shear rate of particles (particularly beads) depend on rigorous definitions of these variables, Similar definitions are required for consistency with Apparatus 7. Published suggestions on the flow-through cell (Apparatus 4) vary from a smooth laminar flow to a sinusoidal pulse of defined frequency. It scems that this variable is critical; perhaps it should be closely de~ fined in the monograph for each item. More than any other technique, percutaneous absorption systems clearly depend on predictable diffusion-layer characteristies at the membrane. Without close control, consistent results in collaborative studies will not be possible. Current methods of maintaining a constant flow pattern in the receptor chamber of these cells have been improved lover the last decade by use of more precise speed control devices (such ‘ mixer for more homogeneous as Variomag), and use of a “helix” mixing. Sorption [Experience has shown that active ingredients may sorb excessively on certain materials, particularly some plastics, used in dissolution ap- paratus. This should be considered when one is attempting to validate amy new equipment or procedure, particulary automated systems Cox et al, 28) diseussed the bias from filters, A technique for s trating adsorptive sites on filters was studied by Hill and Snider in 1987 (64, Some filter bias ean be reduced by a preflush oF presatu- ration step—this is usually done by drawing enough sample through the filer to suurate the absorptive sites before collecting the sample ‘This way no drug is lost and the measurement of the sample should be accurate, Fillers should be selected with adsorptive characteristics in sind Potcatial sorption problems arise from tubing used in automated equipment. Cox and Wells (65) resolved tubing sorption problems with digoxin tablets by immediately introducing methyl aleahol inte the sample steam asthe aliquot was withdrawn, There have been aneedotal reports of excessive sorption bias with nitroglycerin and diazepam (up Conirolting Variables 95 to 10%%/foot forthe latter) when flexible laboratory tubing was used on ‘automated sampling devices such as perisaltic pumps. Halstead and ‘Theis (66) have reported similar studies on prostagkandin derivatives ‘The safest procedure isto limit materials of construction for automated systems to poly!luorocarbon, glass. and type 316 stainless steel Checklist for Variables and Following GMP. [No quantity of text on variables can substitute for good laboratory technique! Too many times the authors have helped solve dissolution problems for which the real causes were lack of GMP awareness and poor training. Situations such as failure to calibrate lab thermometers: dirty flow cells; use of theoretical values instead of tue standards; using Random Input Variables Checklist Figiere 5-6 Random input variables cheeklist.96 HANDBOOK OF DISSOLUTION TES’ TING six separate standards instead of six aliquots from one; failure to eali- brate instruments; careless sampling points; inadequate documentation, ‘and many other unacceptable practices have been observed. Dissolution isa precise wet-chemistry technique, and GMP must be observed. ‘A review of some of the random variables that atfeet dissolution rate hhas been presented in this chapter. Some of these are listed in the following checklist (Figure 5-6) with maximum allowable intensity that should be tolerated—along with expected changes in dissolution rates that have been reported in detailed studies. Some practical hin about controlling these variables have also been included for ready reference. GMP training is a Key t0 good laboratory results that are without random or human caused errors. There are many courses availabe from 1 number of organizations; this book is a good reference for any dis- solution training program. The key isto have a formal training program to track outside training courses and in-house training that has ocurred. This is a vital wecord for FDA inspections: as training records are & critical part of a quality system. Internal lab audits are a very good ‘way encourage analyst to keep GMP habits up to date. Sometime the analysts themselves will perform internal audits as a part of perfor- mance objectives (18). Controlling Variables 97 References (1) Skoug, JW, “Calibration of Dissolution Rate Apparatuses: User's Perspective”, 1994, Dissolution Technologies, \(2), 3-5 (2) Grady, LT, “Dissolution Calibrators Used by the United States Pharmacopeia’’, 1994, Pharmacopeial Forum, 20(6), 8567-8570. (3) McCormick, Tl, “Industry Perspective on Dissolution Apparatus Calibration”, 1995, Dissolution Technologies, 24), 12-15. Martin, GP, Reed, DG, Magiso, LE, Griffith, MF and Ip, D, “Tu- torial on Dissolution Calibration: An Industrial Perspective”, 1996, Dissolution Technologies, 3(1), 3-6. @ (5) PARMA, Subcommittee on Dissolution Calibration: Brune. S, Bucko, J, Emr, S, Gray, V, Hippeli, K, Kentrup, A, Whiteman, D, Loranger, M and Oates, M, “Dissolution Calibrator: Recommen- dations For Reduced Chemical Testing and Enhanced Mechanical Calibration”, 2000, Pharmacopeial Forum, 264), 1149-1166. (6) Mirza, T, Grady, LT and Foster, TS, “Merits of Dissolution Sys- lability Testing: Response to PARMA’s Propasal on Me. Calibration”, 2000, Pharmacopeial For, 26(4). 1167~ Brown, W, “United States Pharmacopeia Establishes Projeet Team fon Dissolution Calibration”, 2002, Dissolution Technologies, 92). 10. (8) Moore, TW, Shangrass, RF and Habib, Y, “Dissolution Calibrator Tablets: A Recommendation for New Calibrator Tablets to Re- place Both Current USP Calibrator Tablets”, 1996, Phurmaco- peial Forum, 223), 2423-2428, a (9) Gray, VA, Hubert, BB and Krasowski, JA, “Calibration of Dis- solution Apparatus 1 and 2—What To Do When Your Equipment Fails”, 1994, Pharmacopeial Forum, 20(6), 8571-8573. Identifying Sources of Error in Calibration and Sam- 2002, American Pharmaceutical Review, 5(2), 8-2. (10) Gray, VA ple Testing”, (11) Hanson, W, “Solving the Puzzle of Random Variables in Disso- 30-41. lution Testing”. 1977, Pharmaceutical Teclnology. 1 ¢ (12) Hanson, W, “Studies on the Effects of Some Variables Commonly98 a3) ay (1s) 16) an as) 09 (20) 23) HANDBOOK OF DISSOLUTION TESTING Encountered in the Measurement of Dissolution Rate of Solids”, 1979, Ph.D. Dissertation, California Western University. Gray. ¥, Beggy, M, Brockson, R, Corrigan N and Mullen J, “A Comparison of Dissolution Results using O-ring versus Clipped Basket Shatts", 2001, Dissolution Tecluologies, 84), 8-11 Beyer, W and Smith, D, “Unexpected Variable in the USP/NF Rolating Basket Dissolution Rate Test”, 1971, Journal of Phar- maceutical Sciences, 60, 2350-2351. Hanson, W, “Effect of Vibration on Dissolution Rates”, 1975, Presented at the Becknan Conference an Dissolution, Mountain- side, NI Cartwright, A, “Sources of Variation during Collaborative Eval- uation of In Vitro Dissolution ‘Tests for Two Solid Preparations” 1979, Journal of Pharmacewtical Pharmacology, 31, 434440, Collins, CC, “Vibration: What is it and How Might It Effect Dis solution Testing”, 1998, Dissolution Technologies, 5(4), 16-18. Gray. V and Miller. B. in the Dissolution Laboratory 313), 19-21 ‘Thakker, D, Naik, N, Gray, V and Sun S, “Fine Tuning of Di solution Apparatus”, 1980, Pharmacopetal Foren, 6(2), 177— 18s. Borst I, Ugwu, § and Beckett, AH, “New and Extended Appli cations for USP Drug Release Apparatus 3°, 1997, Dissolution Technologies, 41), 11-18. Rohrs, BR, Burch-Clark, DL, Witt, MJ and Stelzer DJ, “USP Dissolution Apparatus 3 (Reciprocating Cylinder): Instrument Pa- rameter Effects on Drug Release from Sustained Release For- 1995, Journal of Pharmaceutical Sciences, 84(8), Good Manufacturing Pr + 2002, Pharmaceutical Canada, mutations”, 922-926, Yang, LI, Ferguson, SM, Hudson, TJ, Watanabe, S, Katsume, M and Fix, JA, “In Vitro Evaluation of Dissolution Behavior for a Colon-Specifie Drug Delivery system (CODES™) in Multi-pH Media using United States Pharmacopeia Apparatus I and II", 2003, AAPS PharmSciTech, 3(4), Yu, LX, Wang, JT and Hussain, AS, “Evaluation of USP Appa- ey) 25) eo) en 28) ey Go) oD a2 (33) G4) Controlling Variables 99 ratus 3 for Dissolution Testi 2002, AAPS PharmSci, 4(1) of Immediate-Release Products”, Nicklasson, M- and Langenbucher, F, “Description of the Flow Cell Dissolution Apparatus as an Alternative Test Method for Drug Release", 1990, Pharmacopetal Forum, 18(3), 532-37. Looney, TJ, “USP Apparatus 4 (Flow Through Method) Primer” 1996, Dissolution Technologies, (4), 10-12. Nicolaides. E, Hempenstall, JM and Reppas, C, “Biorelev solution Tests with the Flow-Through Apparatus’, 2000, Disso- ution Technologies, 1). 8-U Biclen, N, “Performance of USP Calibrator Tablets. in. Flow- ‘Through Cell Apparatus”, 2002, fternational Journal of Phar Cox, D, Douglas, C, Furman, W, Kirchhoofer, R, Myrick, J and Wells, C. “Guidelines for Dissolution Testing”, 1978, Pharma: ceutical Technology, 2(8), 40-53. Carstensen, J, Lal, T and Prasad, ¥, “USP Dissolution IV, Com- parison of Methods", 1978, Journal uf Pharmaceutical Sciences, 67, 1303-1307. Noyes, A and Whitney, W, “The Rate of Solution of Solid Sub- stances in Their Own Solutions”, 1897, Jounal of the American Chemistry Society, 19, 930. Langenbucher, F. “In Vitro Assessment of Dissolution Kinetics: Description and Evaluation of a Column-Type Method”, 1969, Journal of Pharmacewicat Sciences, 58, 1265-1272. Langenbucher, “Use of Flow-Through Apparatus for Dissolu- 1980, Presented at Journe’s D’Actualites Biopharmaceutiques de Clermont-Ferrand, France Universite’, de Clermont-Ferrand, Langenbucher, F, Benz, D, Kirth, W, Moller, Hand Ov, M, “Standardized Flow-Cell Method as an Alternative to Existing Pharmacopeial Dissolution Testing”, 1989, Pharmaceutical In dusiry, 311), 1276-1281 Adamson, A., 1979, Physical Chemistry of Surfaces, Wiley science, New York,100 HANDBOOK OF DISSOLUTION TESTING (35) Hanson, W., 1968, U. S. Parent # 3.572.648. (36) “Cefaclor Extended-Release Tablets", 2004, United States Phar- macopeia and National Formulary, United States Pharmacopetal Convention, Inc., 27th Edition, 351 37) “Dirithromycin Delayed-Release Tablets", 2004, United States Pharmacopeia and National Formulary, United States Pharma copeial Convention, Inc., 27h Edition, 646-647. (38) Sarapa, A and Clark, L, “Elimination of Air Entrapment Using USP I Rotating Basket Dissolution Apparatus”, 1980, Jounal of Pharmaceutical Sciences, 69, 129. (39) Wunderlich, M, Way, T and Dressman, J, “Practical Consider- ations When Using Fiber Optics of Dissolution Testing”, 2003, Dissolution Technologies, 1064), 17-19. (40) Qureshi, SA and MeGilveray, 1J, “Impact of Different Deaeration ‘Methods on the USP Dissolution Apparatus Suitability Test Cri- 1994, Phurmacopeial Forwn, 26), 8565-8566. teria’ (41) Degenbarat, OS, Waters, B, Rebelo-Cameitao, A. Meyer, A, Brun- ner, H and Tolt, NP, “Comparison of the Effectiveness of Various Deaeration Techniques”, 2004, Dissolution Technologies, 11(1), IL (42) Griffith, ME. Curley, TE and Martin, GP, “Considerations in Choosing « Deaeration Technique for Dissolution Media, 1997, Dissolution Technologies, (1), 16-17. (45) Robrs, BR and Stelzer, DJ, “Deseration Techniques for Dissolu- tion Media, 1995, Dissolution Technologies, 202), 1 and 7, 8. (44) Moore, TW, “Dissolution Testing: A Fast, Efficient Procedure for Degassing Dissolution Medium”, 1996, Dissolution Technologies, 342), 345 Rolli, R, Fiechter, A and Hengst, R, “Jn-Situ Deaeration of Dis- solution Media through a Hollow Shaft® System”, 2000, Disso- ution Technotogies, 1(2), 20-2 (46) Diebold, SM and Dressman, JB, “Dissolved Oxygen as a Measure for De- and Reaeration of Aqueous Media for Dissolution Test- ing”, 1998, Dissolution Technologies, 5(3), 13-16. (47) Curley, T, Forsyth, R, Sun S, Fliszar K, Colletio, M and Martin, (as) (49) (30) Gb 62) 63) G4) (55) (56) (7) Comirolling Variables 101 GP, “Measurement of Dissolved Oxygen as a Determination of n During Dissolution Testing”, 2004, Dissol dion Technologies, 114), 6-11. Noory, C, Tran, N, Ouderkitk, L, Brown, , Perry, J, Lopez, Co- Jon, M, Faberile, M, Henry, K, Rorberg, J, li, SN and Shath, V, ‘Rethinking the Use of Water as a Dissolution Medium”, 1999, Dissolution Technologies, (4), 6-7. Leeson, LJ, “Some Observations on "Rethinking the Use of Water as Dissolution Medium”, 2000, Dissolution Technologies, 72), 16-17, Blanco, Personal Communication to Bill Hanson in 1980. “USP General Chapter on In Vitro and In Vivo Evaluation of Dosage Forms <1088>", 2004, United States Pharmacopeia and Nationat Formulary, United States Pharmacopeial Convention, Edition, 2513-2518, Ine Rothe, W and Schelthorn, Rate for the European Pharmacopei many, 22, 74-80. Shah, VP, Noory, A, Noory, C, McCullough, B, Clarke, S, Ev- crett, R, Navaisky, H, Srinivasan, BN, Fortman, D and Skelly, JP, “In Vitro Dissolution of Sparingly Water-soluble Drug Dosage Forms”, 1995, feternational Journal of Pharmaceutics, 125, 99 106. Noory, C, Tran, N, Ouderkirk, L and Shah, V, "Steps for Devel- ‘opment of a Dissolution Test for Sparingly Water-soluble Drug Products”, 2000, Dissolution Technologies, 7(1), 16-18, 21 “Determination of the Dissolution 1979, Drugs Made Ger. Robs, BR, “Dissolution Method Development for Poorly Soluble Compounds”, 2001, Dissolution Technologies, 8(3), 6-12. Abdou, HM, Ast, TM and Chioffi, Fl, “Chromatographic Deter mination of Dissolution Rate of Fluorocortisone Avetate Tablets”, 1978, Journal of Pharmaceutical Sciences, 67, 1397-1398, rail, DJ, Tunis, A and Danascreau, R, “Is the Use of a 200-mL. Vessel Suitable for Dissolution of Low Dose Drug Products?” 2004, dnternational Journal of Pharmaceutics, 269, 203-208. Scott, PR “Geometric Irregularities Common to the Dissolution Vessel”, 2005, Dissolution Technologies, 12().12 HANDBOOK OF DISSOLUTION TESTING (59) Savage, TS and Wells, CE, “Automated Sampling of In Vitro Dissolution Mediuny; Effect of Sampling Probes on Dissolution Rate of Prednisone Tablets”, 1982, Journal of Pharmaceutical Seiences, 71, 670-673. (60) Gray, VA and Foster, TS, “Utility of USP Salicylic Acid Cali- brator Tablets”, 1997, Pharmacopeial Forum, 23(6), 5360-5363, (61) Mauger, J, Ballard, J, Brockson, R, De, S, Gray, V and Robinson, D, “Intrinsic Dissolution Performance ‘Testing of the USP Dis- solution Apparatus 2 (Rotating Paddle) Using Modified Salicylic ‘Acid Calibrator Tablets: Proof of Principle”, 2003, Dissolution Technologies, 10(3), 6-15. (62) Healy, AM, McCarthy, G, Callagher, KM and Corrigan, O1, “Sen- sitivity of Dissolution Rate to Location in the Paddle Dissolution Apparatus”, 2002, Journal of Pharmacy and Pharmacology, 54 441444, (63) Kukura, J, Arratia, PC, Szalai “Understanding, Pharmaceu Technology, 26(10), 48-72. (64) Hill, RA and Snider, BG, “A Widely Applicable Automated Sam- pling Apparatus for Dissolution Testing”, 1987, tntermarional Jounal of Pharmaceutics, 36, 175-183, Bittorl, KJ and Muzzio, FI, sal Flows”, 2003, Pharmaceutical (65) Cox, D and Wells, C, “In Vitro Dissolution of Digitoxin Tablets 1978, Internal Documeat supplied to Bill Hanson in correspon- dence with Furman, WC, National Center for Drug. Analysi FDA, Si. Louis, MO. (66) Halstead, GW and Theis, GL, 1985, Jounal of Pharmaceutical Sciences, 74(10), 1086-1090. 6 Setting Up for Dissolution Testing Beto pein sitions says sta dlp imate cal cater tea asco espn Since the Sond aon ots handbook was pbs ta an fica USP Appr te on te ginal ts and pal {USE Appenes 1 a) lve on ve fer wig. Thc ce tha aos ss she sec eo. A cup inspect bs nd palit wil oe eaten Otc Ft! oe et de Saeictekbe ni wundzmal pepe el wih Oe te came wih yup th oy eg pas nd SF nein vse! mens ce an sony Treg te Cet rx Dolton Poss! pics a isco ain eau eae ir sonar pram fo ny Oe Ut Appr Ud forms such as 103104 HANDBOOK OF DISSOLUTION TESTING Checklist for the Dissolution Protocol First, record and check the last calibration date and whether the ap- pparatus has been calibrated for either basket or paddle. 1. General Designation of Method A. Apparatus 1, 2, or other B. RPM, flow rate, or stroke/dip rate C. Modifcations—basket-mesh size, paddle coating, sinker type. vessel size, sercen types, ete D. Sampling intervals) E, Dissolved Q specification: (%) or interimvin-house value. FE. Medium composition (w/w or w/¥) and amount in mL, G. Modifications of apparatus to be used (2-liter vessels, peak ves: sel, mini paddles and vessels, flow cell type, holders, sinkers, tc). H, Sampling method, including medium replacement automated. 1. Sample analysis protocol manual or Inspection of Equipment A. Check shalt straightness (2 0,005-inch total indicator reading (TIRD. B, Examine paddles for peeling or eracks in the coati . Check paddles for compendial dimensions, particularly blade tip dimension from axis. D. Mount paddles or baskets, anc! check eccentricity. Check speed control—muist be constant and without surges. E. Check vibration levels at vessels—if possible, with a vibration meter + Eliminate outside sources of vibration to keep readings under 1.05 mils displacement. If using baskets mount them on shalts and hand -adjust + Look for holes in sereens or tangs of wire extending into the basket at the seams, + Check that basket clips (USP refers to these as “tangs” are seated firmly in place + Verity chat basket is not malformed and screen is not frayed. + Keep eccentricity within 0.010-inch TR H. Inspect paddles or baskets and all portions of the apparatus in contact with solutions for cleanliness. s Setting Up for Dissolution Testing 103 + Look particularly for erevices or lines in the paddle and along the basket welds for adh + Look for residue build-up on se shaft joint 12 contaminants, 1. Ensure that the water bath is clean and transparent, so the dis- integration and deaggregation process can be visually monitored. The presence of air bubbles or air films can be detected only through a transparent bath, J, Determine when the system was last calibrated with USP cali Drators and if itis still within the calibration interval. 3. Dissolution Bath A. Adjust bath temperature to mainvain 37 °C in vessels—use the appropriate bath temperature for glass oF plastic vessels, as plas- tie vessels take longer to heat B. Insert shafis in the drive, and adjust each vessel with a entering ‘gauge if necessary, . Inspect vessels for abnormalities in dimensions and excessive bumps on the internal radius of the bottom of the vessel . Ensure that the bath fluid level is above the top level of the ‘medium in the vessel 4. Proparation of Medium A, Preheat medium to 37 °C or slightly higher—use NIST-raceable calibrated thermometers. B. Deuerate medium by a suitable method at 37 °C unl the testis performed, C. Check medium pH to two decimal places with a properly cali- brated pH meter: 1d equilibrate and keep 5. Select and Check Analytical Methods ‘A. Check for adsorption or interference because of filtering. B, Cheek for adsorption on tubing (or leaching by plastic tubing) used in automated equipment . Check for interference with sampling probes, . Include information on the standard, is preparation, and placebo interference in the calculations; check to see that it has the same pH as the test medium; and check the effect of water-miscible solvents. E, [absorption with spectrophotomettie methods is used, check to see if the data point at the tip of the curve has a minimum standard deviation (SD) from normal or if the SD is excessive ‘on the slope,106 HANDBOOK OF DISSOLUTION TESTING 6. Getting Ready for the Test A. Insert baskets or paddles —adjust to proper distance from bottom of yessel (2.5 em) when unit is in its operating position. B, Check to see if the water bath is level (OK if system has been brated! within a specified reiable time). C. Check the tilt and eccentricity ofall shafts (visual checks OK if system bs been calibrated within a specified reliable time). Recheck centering of vessels with a gauge if necessary. Set vertical frame limits so the unit ean be dropped atthe proper c, so that all baskets or paddles remain at the proper test hheight—or use markers or eollars on the top of the baskets so that each can be individually deopped to the proper depth at the start af the test F. Add the deaerated medium to the proper level and check the temperature of each vessel—check the average error of measur ing volume © within * 1%. G. Inser the dosage units into the baskets (be sure the baskets are dry) if baskets will be used, or have dosage units ready to drop into the vessels if paddles will be used. H. Chock to see thar the speed is stable to within * 4g without ‘automated sampling-automated detection is being used, adjust the specttophotometer or detector system 0 50% or 100% stan- dard and zero the base line, then calculate carry-over (if present) by running two solvents followed immediately by (wo standards, followed azain by two solvents; the frst pass in each ease will present information about the percentage of carry-over 7. Sampling Procedure A, Determine samp pler to match, + From the sampling procedure, decide whether staggered or simultaneous start of the six tests is needed. B. If manval sampling will be used, check to see that syringes and prepared with filters ready for 2 intervals, and program any automated sam- cannulas, if used, are clean a C. Determine whether the intervals between the sampling of vessels are adequate (if manual sampling will be performed) for the sampling time required by the sequential start of the test. (Is ne For filtration, replacement, simultaneous sam- there enous ple pulls?) 8. E Run Setting Up for Dissoluion Testing 107 Ensure that sampling location, whether manual or automated, is consistent and properly located, Determine whether the procedure is such that any effect of the filter on analytical results is either known or avoided Prepare test tubes or sample collection tubes if needed. ring the Test Place the dosage Forms in the baskets or, if the paddle is being used, have them ready for placement in vessels, Examine the system for air bubbles to check deacration of the ‘medium Start the test using a stopwatch if sequential sampling is to be uused—do not rotate the baskets until they are in their final po- sition nor start paddle rotation until dosage form is introduced, For simultaneous sampling: a For Apparatus 1, drop the baskets, using the frames then start rotation, For Apparatus 2, drop the dosage form into each vessel as rapidly as is possible, and then start paddle rotation. , As soon as baskets are in place, note any basket with a float- ing dosage (orn entrapped in an ait bubble (lates, disead 16> sults from that basket). For sequential sampling: a Drop the individual basket (using the elutches on the drive) against the collar or marks then engage the clutch € stat its rotation, repeating that procedure for baskets 2, 3, and the rest at stopwateh-timed intervals: proceed as in D (b), above the cluteh: drop the dosage form as close as is possible w the center of vessel 1; use the clutch to start rotation; then follow with 2, 3, and so on, b. Use the stopwatch as at E (a) with the paddles stopped by the clutch drop the dosage form as close as possible to the center Of the flask 1; use the elutch to start rotation; then follow with 2.3, and so on. Observe the dissolution test at certain intervals and record ob- servations for each vessel, especially in methoxl development or R&D settings. At a minimum, observations should be made when samples are withdrawn, ishing the Test ‘Check the temperatures of the flasks and record any aberrations from the * 0.5 °C tolerance.108 HANDBOOK OF DISSOLUTION TESTING B, Check and recon! speed. C. Be sure data are printed or recorded before discarding samples it is a good practice to save the samples (iF possible) until all data are processed, because there may be questions that ean be answered only by subsequent analysis, D. Examine the baskets to determine if air has trapped the dosage form—diseard (with proper documentation) results from that flask, E. Note whether any silvery sheen or air bubbles because they indicate the release of dissolved gas, F Note the condition of any remaining mass of the dosage form, its position, whether clogging of baskets has occurred, the nature of coning, and so on; such information may be valuable in at- to explain bizarre results from one flask that might ntly be disearded, G, Check the volume of one or two flasks to ensure that no evap- oration has been overlooked, because such evaporation could significantly affect the analytical data. This is especially true in extended release products that are tested over many hours. appeared ‘The dissolution protocol or test method should follow the standard ‘operating procedures that are unique to the quality assurance program developed by individual laboratories as a part of good laboratory and manufacturing practice (1, 2) Although there has been considerable concern over the adequacy of calibrator tablets, experience has shown them to be useful in standard- izing Apparatus 1 and 2. When the apparatus is regularly calibrated, normally at six-month intervals and when moved, many of the setup procedures (such as checking tilt) may be omitted from the checklist, Undoubtedly, similar standard calibration methods will be offered for all new proposed methods. Details of some of the methods of establishing the correct perfor mance of Apparatus 1 and 2 from the first and second edition ate repeated here. They may be helpful when setting up to run a test with calibration tables, Inspecting Paddles and Shafts Every laboratory should have an inspection and straightening fixture such as the one shown in Figure 6-L, This unit is commercially avail- able. but it may be easily fabricated by an in-house machine shop. Tt consists of two V-blocks firmly mounted on a base with two posts for Setting Up for Dissoluion Testing 109 Pas ” UZ LIE LEA LE LE A KE OOK. (Sor iY ao SY Figure 6-14 Use of machinist’s indicator for straightening shafts mounting a simple machinis’s dial indicator, The dial indicator should hhaye a small ball tip, read a toral travel of * 0.015 inches (* 0.4 mm), and be graduated in not more than 0,001-inch (0,02-mom) intervals, The figure shows three separate tests that should be made on paddles and baskers, View A of the fig ness for either baskets or paddles. The tip of the indicator just touches the shaft, which is slowly rotated by hand. The indicator will measure the degree of shaft crookedness. t should not read a total (TIR) greater than about 0.005 inch (0.1 mm). 1F it does, the shaft should be rotated shows the proceduse for testing shaft stuaight- Figure 6-1B Use of machinists indicator for checking basket concen- icity.0 HANDBOOK OF DISSOLUTION TESTING Figure 6-1C Use of machinis’s indicator for checking paddle blades. the indicator reads high; a gentle push of the heel of the hand in this position will straighten it. The procedure should be continued until the maximum TIR is 0.005 ine! ‘The procedure may seem difficult, but itis really quite simple. Once the operator has learned the required amount of pressure, shafts can quickly be straightened, and the method works on shafts that are erook~ ed over their whole length. If a shaft has iwo high points, it cannot successfully be straightened, and should be discarded. Finally, the an- alyst should use care to see that the indicator tip does not rest on the polyfiuorocarbon surface of the paddle, if present, where it may indicate ‘surface roughness that has nothing to do with shaft straightness. View B illustrates the procedure for checking baskets. The basket should fit snugly and squarely against the drive-rod disk and should be held tightly in place by the clips. The indicator tip is held lightly against the bottom ring of the basket, and the whole assembly is slowly rotated by hand. The TIR can generally be kept to within approximately 0,010 inch (0.25 mm). The basket (not the shaft) may be bent by hand to bring it within that reading. Oller baskets that have seen much service in acid media tend to be very weak and flexible, and it may be im- Possible to straighten them; they should be discarded, Finally, take great care in attaching the properly aligned basket to the drive. Hold it by the top ring, not by the bottom, in order t avoid distortion, View C shows a procedure for ensuring that the tips of the paddle blades are equidistant from the axis of rotation, Care must be used in this test, because the blade tips have a radius, and one must be careful to measure each tip at the most extended point of that radius. ‘The blade Seating Up for Dissolution Testing mm Figure 6-2 Use of machinist’s indicator to check shaft runout tips should be equidistant from the axis of rotation within a maximum TIR of 0.080 inch (2 mm). This maximum is too generous: the blade lips should be kept to within a ‘TIR of 0.030 ineh (1mm). Checking the Kecentricity of Paddles or Baskets “The paddles or shafts should be inserted into the chucks of the drive spindles and mounted in approximately the vertical position that they will occupy during the test. The drive should be lifted to the extent that the paddles or baskets will rise above the Mask covers. A-ma- chinist’s dial indicator is then used fo determine runout ar eccentricity ‘The indicator must be mounted on a heavy base, of the sort available at a machine-shop supply house or from a dissolution equipment ven- dor. (Magnetic bases will not work because most dissolution drive bases fre not magnetic, A small block of seft iron or steel may be purchased and the standard magnetic base attached t0 it) This method of measuring eccentricity is illustrated in F set the contro! for minimum rpm (not move than 25 rpm), or manually42 HANDBOOK OF DISSOLUTION TESTING rotate the shalt with the clutches disengaged. Each shaft should be checked individually. The procedure requires only a few minutes, and it ensures that no errors are present because of improper or worn chuck grips. USP allows + 2 mm (0.160 inches TIR) if such an eccentricity does not alter the results of the test, Nonetheless, the authors feel that eccentricity should be held under a TIR of 1 mm (0.030 inches) or 0.5 mm for minimum disturbance, Methods of correcting excessive eccentricity are discussed in Chapter 5 Checking the Speed Control Digital tachometer readouts are available on al sate-of-the-art speed controls. The control may also offer a means of calibrating the digital readout against line frequency (50 Hz or 6D Hz), which in most coun- tries is Kept within tight limits. Checking the digital tachometer should bbe a part of the maintenance protocol for the speed control but itis not generally necessary for each dissolution test run. Do not use mechanical tachometers, They impose « load on the sys- tem and may change the speed, (The Toad is relatively constant in solution, and speed controls desisned for such purposes may be se sitive to load changes). If you wish to check the speed, put a piece of tape on the shaft, use a stopwatch, and, with your finger close to the shaft, count the revolutions as the tape tab snaps past your finger. To- day, optical tachometers (light or laser) are most conveniently used to cheek speed rotation, Surges in speed generally can be heard. They are sometimes present in older types of speed conteos, although in rare instances this ean be 4 malfunction in newer equipment. If the control produces surges, it should be replaced Checking Vibration Vibvation is one of the most common random input variables pro- ducing variation in dissolution data, The most satisfactory measurement requires the use of a vibration meter. Vibration exerts most of is infu ence at the vessel, and that is where it should be checked, Figure 5-2 iMustrates the use of a vibration meter that measures displacement in ins, Steps to correct random vibration in excess ofthe O.t-mil limit are diseussed in Chapter 5 TF no vibration meer is available, other techniques may serve in its place, With «litle experience, an analyst ean lean to place his or her Setting Up for Dissolution Testing 113 fingertips on a piece of apparatus and estimate the vibration rate. A visual inspection oF the surrounding area is paramount in a dissolution Jab, especially in lab that shares space with analysts performing other tests. Look for shakers, sonicators, centrifuges, and other equipment that may cause vibration, Install mechanical door closers on the labo- ratory doors, because slamming doors jolt the baths and affeet the dis- solution results, Centering Flasks to the Stirring Drive ‘This problem is discussed in Chapter 5. Various types of centeri gauges are commercially available: the simplest is n plastic disk with ‘taper that ean be located inside any vessel top and has « slotted hole, the center of which coincides with the stirring deviee. ‘When one uses such a gauge, the disk is centered on the shaft, and the vessel is moved until the disk drops into its inside diameter: if centering lugs are provided, they are then adjusted and tightened. Ves- sels are then marked and repliced in the same position from test to test. Modern dissolution test stands have various self-centering options, a discussed ins Chapter §. They may, however, be checked by this method. Analytical Methods and Filtration Special care must be taken to guard against errors resulting from sorption onto filters. Guidelines (3, 4) have outlined specific tests 10 determine the effects of filtration, When performing manual filtration the authors recommend discarding the fist portion of the filtrate (filter check validation establishes the amount to be discarded), They suggest that tests be run on both & 100% standard dissolved in the dissolution medium and on an aliquot from actual dissolution of the tablets in question at the end of the specified sampling time. Each should be subjected to filtration, and sequential S-inL aliquots should be collected. Each should be analyzed until final, reproducible values are obtained. Such a procedure establishes the portion of the sample that should be discarded before the actual analysis. The typical tolerance on the stan~ dard eould be around 99%-100% recovery. When filters are being reused (as in establishing a profile) or are used in automated equipment, more severe test is required and calls for the preparation of a 100% standard, as before, and a blank disso: lution medium, Analyses as in the previous paragraph are then per-14 HANDBOOK OF DISSOLUTION TESTING formed on aliquots from standard, then from blank, then from standard in succession, using the same filter Toleratices should be 99%-101% recovery for the first standard, no more than 54 in the blank, and 959%— 101% recovery in the second analysis of the standard, If those toler- ances are exceeded, there may be excessive dead volun carry-over, or cumulative sorption from some source that should be investigated and corrected Similar tests may be made on automated equipment by feeding 100% standard through the tubing and determi of suc cessive aliquots. That step is followed by feeding blank solution through the tubing and determining the carry-over content of the ali= quots. Repeating those steps in sequence should establish the suitability ‘and sorption characteristics of the tubing and flow materials in the apparatus Particular eare should be used in preparing the standard. ‘The inter- ference of media components or excipients from the dosage form should be considered. Some standards must be made via the addition Of organic solvent, Prednisone, for example, requires some alcohol for the preparation of a completely dissolved standard. Methods listed in the compendia for standard preparation should therefore be carefully followed, Check the ellect of the organic solvent by preparing several solutions of the same concentration per liter of the drug, but use dif- ferent concentrations of the solvent. Each of those should assay to with= in 99%-01% of the theoretical amount; failing that, a different organic should be selected. Finally, the stability of the standard should be considered. Prednisone standards used for calibrating dissolution equipment, for example, sometimes change in value because of (ap- parently) the precipitation of a minute, almost colloidal, form of the drug, Interference of sampling probes in the How dynamics can be easily checked, and generally will be bothersome only in automated equip- ‘ment from which successive aliqu taken. A dissolution test with the probes in place can be compared with a test conducted with the probes manually removed except during the sampling cycle (4). If the resulting mean deviations or RSDs of the tests are significantly differ- ent, the matter should be further explored; either the probe design will need to be ef J method of probe removal (except during sampling eyeles) should be installed. IF the probes return me= dium or are purged with air, they may have t be removed from the medium except when withdrawing samples (5 the recovery raged oF an aut Sesting Up for Dissolution Testing us Figure 6-3 Use of simple height gauge to establish distance from bot- tom of vessel (25 mm). Distance of the Paddle or Basket from the Bottom of the Vessel Because the overall depth of flasks may vary, should be individually adjusted to the compendia distance from the bottom, 2.5 em + 0.2 em. One simple way w accomplish this is 10 preset the drive in its vertical operating position, push the basket to the bottom, mark the top of the shaft where it protrudes from the hollow drive tube, carefully move it up 2.5 em, and mark or attach a collar 10 establish the proper position as located from the top of the drive tube, Several designs of licight gauges have been suggested. One com- ‘mercial type that can be easily fabricated from ¥-inch (about 3-mm) diameter stainless rod is shown in use in Figure 6-3. This gauge is convenient t0 use with either the basket or puddle. The proper proce- dure for setting shalt height requires that the drive first be set in its operating position, Stops or adjustable collars on the mounting posts ch paddle or basket116 HANDBOOK OF DISSOLUTION TESTING fare genetally used to establish this position so that it can be quickly accurately repeated. While they are in this position, the individual baskets or paddies are adjusted inside the hollow drive spindle using the height gauge. When one is using baskets, that operation should be performed without medium in the asks, if medium is present, the baskets must be thoroughly dried hefore the dosage form is ins (Figure 6-3) ‘Some commercial dissolution (est stations have snap locators or pre- positioned shafts so adjustment by the operator is not necessary. This is convenient but does not allow variation in the vertical position of the drive. This ean be a major defect in automation, particulaly with robotics, The whole drive head may then be lifted up out of the way, om if the basket shafis have been marked or collars attached, they may be individually raised, Retaining the collars and the stops for the vertical posts on the drive allows all six paddles or baskets to be lowered either individually or together at any time into their proper operating posi= tions. ‘When operating the paddle, the drive is dropped into its operating position with the paddles ready to start at the proper speed. The paddles should not rotate until the dosage forms are added and preferably not ‘until they setile into a position in the center of the round bottom of the flask. The addition of the dosage forms may then be staggered at the desired sampling intervals (using a stopwatch or an automated time signal) or dropped into all vessels at approximately the same time, Individual clutches are used for staggered operation, and the speed con trol is simply turned on for simultaneous operation, Clutches and speed ccontrol may be made responsive (o RS-232 input commands in robotic or other automated systems. When one is using the baskets, the baskets must be above the vessels when they ate loaded, Be sure the baskets are dry, They should be attached fo the drive by holding the top ring only, in order to avoid basket distortion. The FDA labs recommended that the basket—with its load—be dropped to the proper position without turning (3). This an be accomplished by turning on the drive (but disengaging the clutches) and pushing each basket down into the media agains its collar at the predetermined sampling interval and then immediately engaging the clutch for that drive, Or, with the baskets already in their proper ‘operating position (but above the medium) and the drive turned off, the ‘operator can lower the drive against its stops and engage the motor immediately Seutnyg Up for Dissolution Testing 417 ‘The analyst may comment that a considerable degree of dexterity is requited for these manual operations, particularly the dropping of dos- age forms for simultaneous operation with the paddle. USP allows a * 2% variation in sampling time, With automated samplers withdraw- ing simultaneously, this + 2% still allows a one seconel interval be- toveen each of six vessels, even with a minimum sampling interval of 5 minutes. Calibration of Equipment The dissoluion testi an analytical procedure designed to determine certain physical characteristies of a compound, One would expect any analytical procedure to produce repeatable results with the same com pound. Any variation in results may be classified as experimental ertor and, depending upon the nature of the procedure and on the state of the art, certain limits should be plaeed on the extent of such experi- imental error, Some philosophical questions have been raised with re- spect to dissolution, and, as yet, there is no consensus on their answers During te 1980s these questions involved wheter dissolution proc dures have any meuningful place as analytical quality control proce- ‘dures, but now there is no doubt, as the dissolution testis required by FDA for all solid oral dosage forms. However, problems arise regarding what degree of experimental error ‘or variation from test to test can be tolerated if the test is to be used as a quality contol and as u regulatory criteion, Dissolution is now ‘considered a mature test with coordinated research in its technology of cover 35 years. Sill the question is raised whether dissolution data have any value in QC if such data are not linked to in vivo performance. Indeed, now 4 current tend isto set in vitro QC dissolution its within thera of experimentally demonstrated acceptablefaon acceptable in vivo data, hhence an in vitro and in vivo relationship (6). European analysts have aptly stated that reproducibility and appa- ratus calibration ean best be achieved from “quality of design” (7, 8) As they further indicate, this requires that state Variables of simple gcometry be restricted by elose tolerances, qualified components, com prehensible and unambiguous description of protocols, and regular checks of dynamic parameters. No cngineer or scientist can dispute these points. The first step, therefore, is (© establish and rigorous! follow the checklist for dissolution protocol provided in this chapter,18. HANDBOOK OF DISSOLUTION TESTING including inspection of equipment, standards for the dissolution bath, ‘media standards, and details of analytical methods, ‘The first step in calibration of a dissolution test station to USP stan- dards must be checking the state variables. This cannot be overemph: sized. Many of these variables are discussed in detail in this chapter. ‘The extent of their influence over results from Apparatus 1 and 2, and suggestions for their correction are presented in Chapter 5, Calibrator Tablets. Calibrator tablets are available from USP Ref erence Standards, 12601 Twinbrook Parkway, Rockville, MD 20852, USA, They may be ordered in non-disintegrating and disintegrating Forms. The certificate of ranges and the applicable test method is sup- plied with the tablets As of this writing, the non-disintegrating tablets consist of salicylic acid, the disintegrating tablets of prednisone, Questions have arisen regarding standards, and some analytical chemists question whether those tablets are standards in the analytical sense. ‘This has been ex- plored in numerous dissolution workshop articles and seminars, Some say the calibrators are misnamed and should be proficiency or system suitability standards, ‘The answer Is that the standards are functional within the limits of today’s technology as physical standards for dissolution, Even such a basic unit as the speed of light has «a tolerance that we all accept. The tolerances of standards are historieally based upon state-of-the-art tech- nology, and it seems nonproductive to criticize the dissolmtion standards because the current state of the art in the physical test of dissolution does not meet the exactitude of more sophisticated analytical proce- dures, In other words, we have no better alternative at this time, but as ‘mentioned in Chapter 5 the quest continues, Questions about the stability of the currently available calibrators hhave been adequately answered. Studies on two separate batches of m-disintegrating Salicylic Acid calibrator tablets have established in- significant variation with different manufacturers and time—over seven yeurs (9, 5). Studies on the disintegrating calibrator indicate similar Stability and uniformity (10). Studies on laetose-based Prednisone eal- ibrator tablets, however, suggest that moisture exposure must be con- sidered to have significant effects on dissolution characteristics (1). ‘The USP laboratory continuously monitors the stability of the calibra- tos as part of the USP Reference Standards Program, Compendial Calibration Requirements. The instructions, methods, and acceptable ranges are supplied with each lot of calibrator tablets. Calibrator dosage forms and equipment suitability tests for Apparatus Setting Up for Dissolution Testing 119 3, Chlospheniramine Maleate Extended Release tablets are available No other calibrator tablets are availible as of the date of this publi tion, Calibrators for Apparatus 4 are under consideration at USP and are being evaluated in the USP laboratory. In 1979, the Hanson Research laboratory studied 400 different six- spindle dissolution drives using the USP disintegrating calibrator (pred= nisone), To test the hypothesis that the published acceptance ranges were too wide, the laboratory arbitrarily established its own, using the paddle at SO rpm, at * 5% of the acceptance mean of 64% dissolution in 30 min (that is, between 60.89% and 67.2%). ‘The laboratory estab- lished a further requirement that the RSD of the six vessels had to be <5%. OF the 400 units, 5% failed 10 meet the requirements (20 drives). ‘The reason for each failure was determined, corrected, and a subsequent test met the specifications. ‘The reasons for failure were: for nine units, problems with the belt, chain, or drive adjustment resulting in excessive vibrations for six units, misalignment or excessive till; for five units, problems with speed con ‘rol, resulting in roughness and variation; for three units, improper procedures, a dirty flow cell, a deteriorating standard, and so nd for one Unit, 2 Vessel temperature out of specification. These deleets add up t0 more than 20 failures because some tests included more than one faulty variable. Even though these tests were performed many years ago, these problems still plague the analysts (12, 13). ‘There was also reported some uiffieulty in meeting calibration ra with the non-disintegrating salicylic acid tablet. Because this isa heavy tablet that tends to settle to the bottom of the rounded vessel in random positions, the alignment of the drive becomes more critical. Failure to foblain laminar flow because of turbulence may cause the tablet to bounce around in a random manner, Such motion can be observed during the calibration test, and careful inspection oF paddle geometry (panicularly the equidistant position of the tips from the axis of rota- tion) and drive alignment may correct the problems. The salicylic acid test is also very sensitive to slight pH ch must be certain to use a pH meter properly calibrated to two decimal places ad, Meeting Calibration Limits + The analyst must always consider the complete dissolution test as aa system; no variable should be overlooked, ineluding the complete analytical protocol120 HANDBOOK OF DISSOLUTION TESTING + The analyst should refer to a checklist similar (© that provided at the beginning of this chapter and shoukl-begin with & rigorous inspection of the equipment, Following it through with each pro- cedure + The analyst must not assume—behind every scientific problem there is probably an invalid assumption, and this assumption must be found and corrected In summary, the concept of uppurstus suitability, using calibrator standard-dosage forms, has been generally accepted 3s a practical meth od of ensuring consistency in dissolution testing, Once the random input variables are defined and their acceptable limits are studied, there is no reason why equipment and methexls cannot qualify consistently under the restraints of calibration, The authors feel that the calibration procedure should be testing the rozal system. Problems arising during calibration can and should be comected by studying all the random variables, Apparatus suitability tests may be forthcoming for the newer pro- posed dissolution techniques suggested for extended-release and irans- dermal preparations. These suitability tests will help stabilize the field of dissolution testing. Equipment should be calibrated every time it is moved or w significant changes ane made in its immediate environment, Son even calibrate before moving so that if the equipment fails calibration after the move it ean be proven that the move did or didnot cause the equipment 10 go out of calibration, Automated systems should also be calibrated whenever changes are made in sampling, tubing, o¢ other adaptations. Although no compendial requirements exist, good labora tory practice would suggest a minimum 6-month calibration for the dissolution station (see Appendix for reference on IQIOQIPQ), Other ‘components of the system should be calibrated according to good lab- ‘orutory practice requirements for the instrument involved, Calibration of Non-Compendial Equipment Because of the rapid development of special dosage forms, other unique apparatus may become used routinely (15). The Franz diffusion cell and Enhancer eell have been used for ereams and ointments, A chewing gum apparatus has been specially designed for this unique dosage form: this apparatus is deseribed in the EP. Inirinsie dissolution is another test that has Several apparatus in use. With the addition of more intricate equipment and testing apparatus Setting Up Jor Dissolution Testing 2 available For dissolution testing, there isan absence of extensive studies fof the random variables that ate inherent 10 a forunately the burden is on the analyst to discover these sources of error and variability. The analyst does however have the equipment manufacturers” specifications as a starting pls (16). First, look for adjustments and moving parts. Set a baseline for ‘operational parameters, such as flow rate or dip rate, emperature, and volume controls. Choose an in-house calibrator tablet, if possible, with a well-characterized and stable product. The issues of alignment, hy drodynamies, and vibration should always be considered. and if pos sible, measured. A metrology document or protocol should be available for equipment operation, slong with logbooks to ack performance and ‘maintenance (17). new technique. Un- se for assessing variables