Vedavathi 2

DESIGN, DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASE
BY
Vedhavathi S .V
DISSERTATION SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF PHARMACY
IN
PHARMACEUTICS
UNDER THE GUIDANCE OF
Dr. C.S.R LAKSHMI
DEPARTMENT OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY BANGALORE-85.
FEBRUARY 2011
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.
DECLARATION BY THE CANDIDATE
I hereby declare that the matter embodied in the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide and genuine research work carried out by me under the guidance of Dr. C.S.R Lakshmi, Head of Department of Pharmaceutics, Nargund college of pharmacy, Bangalore.
Date:
Place: Bangalore
Ms. Vedhavathi S.V Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.
NARGUND COLLEGE OF PHARMACY BANGALORE-85
CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.
Date
Place: Bangalore
Dr. C.S.R Lakshmi HOD of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.
CERTIFICATE BY THE CO-GUIDE
This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.
Date
Place: Hosur
Mr. Durai Venkadesh .R Deputy manager, FR&D, Micro Labs Ltd, Hosur
ENDORSEMENT BY THE HEAD OF DEPARTMENT
This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets Containing Acarbose as Immediate Release and Metformin as Sustained release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. This work was carried out by her in the library and laboratories of Micro Labs Ltd. Hosur under the guidance Dr. C.S.R Lakshmi, Head of Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore.
Date
Place: Bangalore
Dr. C. S. R. Lakshmi HOD Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.
ENDORSEMENT BY THE PRINCIPAL
This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. This work was carried out by her in the library and laboratories of Micro Labs Ltd. Hosur under the guidance of Dr. C.S.R Lakshmi, Head Of Department of pharmaceutics, Nargund College of Pharmacy.
Date Place: Bangalore
Dr. L. V. G. Nargund Principal, Nargund College of Pharmacy, Bangalore 85.
COPYRIGHT
I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall have the rights to preserve, use and disseminate this dissertation / thesis in print or electronic format for academic / research purpose.
Date
Place: Bangalore
Ms. Vedhavathi S.V Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.
Rajiv Gandhi University of Health Sciences, Karnataka.
Though words are seldom sufficient to express gratitude and feelings, it somehow gives me an opportunity to acknowledge those who helped me during the tenure of my study. The work of dissertation preparation was a challenging task and fascinating experience.
I consider myself very much lucky with profound privilege and great pleasure in expressing my deep sense of gratitude to work under the guidance of Dr.C.S.R Lakshmi, Head Of Department of Pharmaceutics , Nargund college of pharmacy, for her continuous guidance, supportive suggestion, innovative ideas, with constant inspiration, help and encouragement have always propelled me to perform better.
It is my privilege and honor to extend my profound gratitude and express my indebtedness to Dr L.V.G Nargund, Director of Nargund institute,Bangalore, for his enduring support. He has been generous with providing facilities to carry out this work.
I would also like to thank Prof. C. R. Mahendra Shetty, Prof. Y. R. Shivaraj, Dr. Gopal Muralidharan, Asst. prof. Mrs. Preeti Karwa, Asst. prof. Mrs. Rama Rajesha, Pof. Mrs. Ritu Kimbahune, Lect. Mrs. Prachi kabra, Asst. prof. Mrs.C. D. Saraswathi, Lect. Mrs. Jayanthi A. and Lect. Mr. Atul Kakade for their helpful suggestion and advice.
I express my sincere thanks and respectful regards to the Executive Vice President Mr. K. Rajeshkshirsagar, Formulation R&D, Micro Labs Ltd., Hosur in acknowledging all the facilities provided to us to carry out this work with great ease and precision.
I owe my gratitude to Mr. Sanjay C Pawar, Assistant general manager, Formulation R&D, Micro Labs Ltd., Hosur for his teaching and moral support.
I extend my gratitude and express my sincere thanks to my guide in industry, Mr. R. Durai venkadesh, Deputy Manager, Formulation R&D, Micro Labs Ltd., Hosur for his valuable guidance and support throughout this work.
I express my deepest and very special thanks to all the staff members of entire Formulation R&D, Documentation team, Analytical R&D and management of M/s. Micro Labs Ltd., Hosur, for allowing me to carry out this project successfully. The words are insufficient to thank Jitesh, Anup, Sagar and Ravindharan, who stood beside me each and every hour during my project and given me constant support.
Most of all I would like to thank my beloved Parents, Brother, and all other dearest friends for their priceless support, love and encouragement throughout the entire tenure of this course.
Vedhavathi S.V
LIST OF ABBREVIATIONS USED
API APS BP BHA BHT BD CPR CCS Conc. cm CMC CI cp DCP DM DCL et al FDA
: Active Pharmaceutical Ingredient : Amino Propyl Silane : Alpha : British Pharmacopoeia : Butylated Hydroxyanisole : Butylated Hydroxytoluene : beta : Bulk Density : Cumulative percent release : Croscarmellose sodium : Concentration : Centimeter : Carboxy Methyl Cellulose : Carrs index : Centi Poise : Di Calcium Phosphate : Diabetes mellitus : Directly compressible lactose : and others : Food and Drug administration
Fig. FTIR gm GI GIT GMP Hrs HR HCl HPMC HPLC IB IP IR ICH IDDM IVIVC KBr L - HPC M mg
: Figure : Fourier transformed infrared spectroscopy : gram : Gastrointestinal : Gastrointestinal tract : Good Manufacturing Practice : hours : Hausners ratio : Hydrochloric Acid : Hydroxy Propyl Methyl Cellulose : High performamce liquid chromatography : Ibuprofen : Indian pharmacopoeia : immediate release : International Conference on Harmonization : Insulin dependent diabetes mellitus : invitro- invivo corelation : Potasium bromide : low substituted Hydroxy propyl cellulose : Molar : milligram
mm ml min MTH g NIDDM NC pH Ph.Eur PVP PDA rpm R2 RT RSD RH SD Sec. SSG SR
: millimeter : milliliter : minute : Metoclotramide Hydrochloride : microgram : Non insulin dependent diabetes mellitus : No change : Negative logarithm of hydrogen ion concentration : European Pharmacopoeia : poly vinyl pyrolidone : Photodiode Array : revolutions per minute : Correlation factor : Real time : Relative Standard Deviation : Relative Humidity : Standard dviation : Second : Sodium starch glycolate : Sustained release
: Time required to reduce the amount to half of its original concentration
TDD TD temp. USP UV v w WS
: Traditional drug delivery : Tapped Density : Temperature : United States Pharmacopoeia : Ultraviolet : Volume : Weight : Working Standard
ABSTRACT
BACKGROUND AND OBJECTIVE Hyperglycemia is the technical term for high blood glucose (sugar). Hyperglycemia happens when the body has too little or not enough insulin or when the body cant use insulin properly. The main objective of the present research work was to develop a bilayer tablet of immediate release Acarbose and sustained release Metformin Hydrochloride, which is used as an Anti-hyperglycemic agent which improves glucose tolerance in patients with the type 2 diabetes by lowering both basal and postprandial plasma glucose and by inhibiting the - glucosidase inhibitor.
METHOD Metformin Hydrochloride has biological half-life nearly about 6 hours, so, an attempt was made in the direction of preparation and optimization of a combination of sustained release and immediate release in a single tablet. In sustained release layer sodium carboxy methyl cellulose and hydroxy propyl methyl cellulose K4M were used as retarding materials and in immediate release layer croscarmellose sodium was used as a superdisintegrent to give the faster release of Acarbose. The tablets were prepared by wet granulation method and by direct compression. Granules were evaluated for precompression parameters and the tablets were evaluated for post compression parameters.
RESULTS The formulation gave an initial bursting effect and followed by sustained release for 8 hours. Final formulation showed release of drug up to 96.75% in 8 hours. The formulation F- 9b and F- 9c were prepared based on optimized formulation F- 9a for stability studies. The stability batches F-9b and F-9c showed no significant changes during stability studies when stored at 40oC/75%RH for three months according to ICH guidelines. FTIR studies revealed that there was no interaction between the drugs and polymers used in the study. INTERPRETATION AND CONCLUSION The drug release from optimized formulation (F-9a) was found to be diffusion process which follows non fickian type of diffusion. It also showed almost linear regression in Higuchis plot which confirms that diffusion is one of the mechanisms for drug release. In this study optimized fomulation F-9a released the drug till 8 hours. KEY WORDS Bilayer tablets, Metformin Hydrochloride, Acarbose, hydroxy propyl methyl cellulose K4M, sodium carboxy methyl cellulose, and croscarmellose sodium.
TABLE OF CONTENTS
1. Introduction
...
2. Aims & Objectives
...
27
3. Review of Literature
29
4. Methodology
42
5. Results
....
102
6. Discussion
....
130
7. Conclusion
....
137
8. Summary
....
138
9. Bibliography
140
10. Annexure
146
LIST OF TABLES
Table No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Tables Materials used with their company name Excipient profile Hydroxy Propyl Methyl Cellulose Excipient profile Croscarmellose sodium Excipient profile Magnesium stearate Excipient profile Povidone Excipient profile Calcium phosphate dibasic anhydrous Excipient profile Carboxymethylcellulose sodium Excipient profile Colloidal silicon dioxide Excipient profile Talc Excipient profile Sunset yellow lake Excipient profile Butylated Hydroxyanisole Excipient profile Butylated hydroxytoluene Excipient profile Hydroxypropyl Cellulose, Low-Substituted Excipient profile Sodium starch glycolate Equipments used with their company name Solubility studies Dissolution limits Composition of Metformin HCl Sustained Release layer Composition of Acarbose Immediate Release layer Angle of repose as an indication of granule flow properties Carrs index as an indication of granule flow properties Page No. 43 53 54 55 56 57 58 59 60 61 62 63 64 65 66 69 72 73 74 80 81
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Hausners ratio as an indication of granule flow properties Weight variation parameters Storage Conditions Evaluation of drug (Metformin HCl) characterization Evaluation of drug (Acarbose) characterization Results of loss on drying of Metformin HCl bulk drug Results of evaluation of Metformin HCl bulk powder Results of loss on drying of Acarbose bulk drug Results of evaluation of Acarbose bulk powder Characteristic peak of pure Metformin HCl Characteristic peak of Metformin HCl SR layer Characteristic peak of pure Acarbose Characteristic peak of Acarbose IR layer Exipient compatibility for Metformin HCl Exipient compatibility for Acarbose Evaluation of granules of Metformin HCl sustained release Layer Evaluation of granules of Acarbose immediate release Layer Evaluation of bilayer tablets Metformin HCl SR and Acarbose IR: F-1 to F- 9a Evaluation of In vitro dissolution and Assay of bilayer tablets Metformin HCl SR and Acarbose IR: F-1 to F-9a. In vitro release study of Bilayer tablets of different formulation.
81 83 99 102 103 104 104 104 105 106 107 108 109 111 112 114 114 117
40 41
118 120
42
Data of various parameters of model fitting for Metformin HCl for optimized formulation F 9a. Data of various parameters of model fitting for Metformin HCl for different formulation. Evaluation of Bilayer tablets of Stability Batch: F-9b Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9b Evaluation of Bilayer tablets of Stability Batch: F-9c Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9c
123
43 44 45 46 47
126 127 127 128 129
LIST OF FIGURES
Fig. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure No. Cross section of bilayer tablet Multilayer Compression Bilayer tablet compression machine Sustained release drug delivery system Matrix tablet Diffusion release pattern. Osmotic release pattern Chemical structure of Metformin Hydrochloride Chemical structure of Acarbose Drug-Excipient Compatibility Studies by FTIR Manufacturing process flow chart FTIR spectrum of pure Metformin HCl FTIR spectrum of Metformin HCl Layer FTIR spectrum of pure Acarbose FTIR spectrum of Acarbose Layer Chromatogram of sample B (metformin HCl) Chromatogram of sample A (Acarbose) and standard chromatogram CPR of different formulation of Acarbose IR layer CPR of different formulation of Metformin HCl SR layer CPR of F-9a of Metformin HCl SR layer and Acarbose IR layer Plot showing zero order kinetics of formulation F-9a. Plot showing First order kinetics of formulation F 9a. Plot showing Higuchi model of formulation F- 9a. Plot showing Peppas model of formulation F- 9a. Photograph of Bilayer tablets Page No. 6 10 10 11 19 20 21 44 48 70 77 106 107 108 109 115 116 121 121 122 124 124 125 125 129
DESIGN DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASE
INTRODUCTION Oral route is one of the most popular routes of drug delivery due to its ease of administration, patient compliance, least sterility constraints and flexible design of dosage form. 1.1 Tablets: 1, 2 Over 90% of the formulations manufactured today are ingested orally. This shows that this class of formulation is the most popular worldwide and the major attention of the researcher is towards this direction. With advancement in technology and increase in awareness, towards modification in standard tablet is done to achieve better acceptability as well as bioavailability because of which newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patients perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablets here are classified by their route of administration and by the type of drug delivery system they represent within that route. Overview on types and class of tablets: A) Oral tablets for ingestion: These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exceptions are chewable tablet and oral dispersible tablets. Standard compressed tablets this class includes tablets like, Multiple compressed tablets, compression coated tablet, layered tablet, modified release tablet etc.
DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY
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B) Tablets used in the oral cavity: The tablets under this group are aimed to release active pharmaceutical ingredient in the oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity. This class includes tablets like lozenges and troches, sublingual tablet, buccal tablet, dental cones, oral dispersible tablet etc. C) Tablets administered by other routes: These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application. This class includes tablets like vaginal tablet, implants etc. D) Tablets used to prepare solution: The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used. This class includes tablets like effervescent tablet, hypodermic tablet. 1.2 Bilayer tablets: 1 Definition: Dual release tablet is a unit compressed tablet dosage form intended for oral application. It contains two layers in which one layer having conventional or immediate release part of single or multiple actives; another layer is sustained or controlled release
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part of single or multiple actives. They are also called as Bilayer tablet, multi-layer matrix tablet. A bilayer tablet is a type of multiple compressed tablets. Tablets are composed of two layers of granulation compressed together. Monograms and other distinctive marking may be compressed in the surface of the bilayer tablets. Coloring the separate layer provide many possibilities for unique tablets identity. Applications: Bilayer tablets are mainly used in the combination therapy. Bilayer tablets are used to deliver the loading dose and sustained dose of the same or different drugs. Bilayer tablets are used for bilayer floating tablets in which one layer is floating layer another one is immediate release layer of the drug. Bilayer tablets are used to deliver the two different drugs having different release profiles. Advantages: They are used as an extension of a conventional technology. Potential use of single entity feed granules. Separation of incompatible components. Patient compliance is enhanced leading to improved drug regimen efficacy. Patient convenience is improved because fewer daily doses are required compared to traditional delivery system. Maintain physical and chemical stability. Retain potency and ensure dose accuracy.
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Disadvantages: Adds complexity and bilayer rotary presses are expensive. Insufficient hardness, layer separation, reduced yield. Inaccurate individual layer weight control. Cross contamination between the layers.
ADVANTAGES OF BILAYER TABLET OVER CONVENTIONAL TABLETS: Blood level of a drug can be held at consistent therapeutic levels for improved drug delivery, accuracy, safety and reduced side effects. Reduction of adverse effects can be accomplished by targeting the drug release to the absorption site as well as controlling the rate of release, enabling the total drug content to be reduced. Patient convenience is improved because fewer daily doses are required compared to traditional delivery systems. Patient compliance is enhanced leading to improved drug regimen efficacy. Bilayer tablets readily lend themselves to repeat action products, where in one layer on layered tablet provides the initial dose, rapidly disintegrate in the stomach. The other layers are insoluble in gastric media but are released in the intestinal environment. In bilayer tablets, where in one layer on layered tablet provides as immediate release and other layer acts as sustained release. In sustained release drug delivery system, several approaches are available to add the loading dose to the maintenance dose such as simple addition of a sustained dose of a drug to the sustained portion and placement of initial dose in a tablet coat with the sustaining portion in the core as in compression coated tablets.
DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 4
An alternative approach for having the loading dose and maintenance dose in a tablet is the formulation of drug in a multi layered tablet or bilayer tablet system3. This bilayer approach is a convenient method. Hence it makes possible to formulate sustained release preparations with the immediate release quantity in one layer and the slow release portion will disintegrate rapidly after ingestion thus providing the initial dose of medication for immediate onset of action, where as the another layer in the matrix layer remain intact during most of the time of its passage through the intestine, while dissolving slowly (sustained manner) from its exposed faces in this passage, which helps to maintain the blood level initially reached 4. LAYER THICKNESS: Layer thickness can be varied within a reasonable proportion within the limitations of the tablets press. Thickness is dependent on the fineness of the granulation1. SIZE AND SHAPES: Size is limited by the capacity of the machine with the total thickness being the same as for a single layer tablet. Many shapes other than round are possible and are limited only by the ingenuity of the die maker. However, deep concavities cause
distortion of the layers. Therefore, standard concave and flat-face beveled edge tooling make for the best appearance, especially when layers are of different colors.
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1.2.1 THE SHAPE OF THE PUNCHES: Punches with beveled edges or concave faces will make the top and bottom layers of a three layer tablets and appear thinner than the middle one. Flat-faced tooling will produce equal thickness of the layers, but unfortunately, the edges of the tablets tend to clip readily. Cross section of the layer tablets:
Fig no. 1 Cross section of bilayer tablet 1. Upper layer 2. Lower layer The above Figure - 1 illustrates how the shape of the upper punch determines the shape of the layers. If the upper punch faces have the monogram or other markings, the bonding between the layers will be strengthened because the device will act as key between the layers. 1.2.2 Ideal properties for bilayer tablets press: Preventing capping and separation of the two individual layers that constitute the bilayer tablet. Preventing cross-contamination between the two layers. Producing a clear visual separation between the two layers. High yield and accurate and individual weight control of the two layers.
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1.2.3 Types of bilayer tablet press: 1. Single sided tablet press. 2. Double sided tablet press. 3. Bilayer tablet press with displacement monitoring.
1.
Single sides press: The simplest design is a single sided press with both chambers of the doublet feeder separated from each other.
Each chamber is gravity or forced fed with different powers, thus producing the two individual layers of the tablets.
When the die passes under the feeder, it is at first loaded with the first layer powder followed by the second layer powder.
Then the entire tablet is compressed in one or two steps.
Limitations of single sided press: No weight monitoring / control of the individual layers. No distinct visual separation between the two layers. Very short first layer dwell time due to the small compression roller, possibly resulting in poor de-aeration, capping, and hardness problems. This may be corrected by reducing the turret-rotation speed (to extend the dwell time) but with the consequence of lower tablet output.
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Dwell time: Dwell time is defined as the time during which compression force is above 90% of its peak value. Longer dwell times are a major factor in producing a quality tablet, especially when compressing a difficult formulation. Compression force: Many bilayer formulations requires a first layer compression force of less than 100 daN in order to retain the ability to bond with the second layer. Above 100daN, this ability may be lost and bonding between both layers may not be sufficient, resulting in low hardness of the bilayer tablet and separation of the two layers. 2. Double sided tablet presses Most double sided tablet presses with automated production control use compression force to monitor and control tablet weight. The effective peak compression force exerted on each individual tablet or layer is measured by the control system at the main compression of the layer. This measured peak compression force is the signal used by the control system to reject out of tolerance tablets and correct the die fill depth when required. 3. Bilayer tablet press with displacement: The displacement tablet weight control principle is fundamentally different from the principle based upon compression force. When measuring displacement, the control system sensitivity does not depend on the tablet weight but depends on the applied precompression force.
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Advantages: Weight monitoring / control for accurate and independent weight control of the individual layers. Low compression force exerted on the first layer to avoid capping and separation of the two individual layers. Independence from the machine stiffness Increased dwell time at pre-compression of both first and second layer to provide sufficient hardness at maximum turret speed. Maximum prevention of cross-contamination between the two layers Clear visual separation between the two layers and maximized yield.
1.2.4 Multi-layer compression basics: Presses can be designed specifically for multi-layer compression or a standard double-sided press can be converted for multi-layers: The multilayer tablets concept has been long utilized to develop sustained release formulation. Such a tablet has a fast releasing layer and may contain bilayer or triple layers to sustain the drug release. The pharmacokinetic advantage relies on the fact that drug release from fast releasing granules leads to a sudden rise in blood concentration however, the blood level is maintained at steady state as the drug is released from the sustained granules.
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Fig no. 2 Multilayer Compression
Fig no. 3 Bilayer tablet compression machine
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1.3 Controlled / Sustained release drug delivery system: For many disease states the ideal dosage regimen is that by which an acceptable therapeutic concentration of drug at the site (s) of action is attainted immediately and is then maintained constant for the desired duration of the treatment. Over the past 30 years as the expense and complication involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantage of modified release per oral dosage forms, greater attention has been focused on development of sustained, controlled release and delayed release system. There are several reasons for the attractiveness of this dosage form. It is generally recognized that for many disease states, a substantial number of therapeutically effective compounds already exist. The effectiveness of these drugs however is often limited by side effects or the necessity to administer the compound in a clinical setting.
1.3.1
Sustained release drug delivery system:
Fig no. 4 Sustained release drug delivery system

Sustained release drug delivery system has been constantly used to retard the release of therapeutic agents such that its appearances in the circulation is delayed or prolonged and its plasma profile is sustained in duration. The onset of its pharmacological action is often delayed and duration of therapeutic action is sustained.
SUSTAINED RELEASE CONCEPT: 5 The goal of any drug delivery system is to provide a therapeutic amount of the drug to the proper site in the body to achieve promptly and then maintain, the desired drug concentration that is the drug delivery system should deliver drug at a rate dictated by the needs of the body over the period of treatment. This idealized objective points to the two aspects most important to the drug delivery, namely, spatial placement and temporal delivery of a drug. Spatial placement relates to targeting a drug to a specific organ or tissue, While temporal delivery refers to the controlling the rate of drug delivery to the tissue. An appropriately designed sustained release drug delivery system can be a major advance toward solving these two problems. It is for this reason that the science and technology responsible for development of sustained release pharmaceuticals have been and continued to be the focus of great deal of attention in both industrial and academic laboratories.
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The bulk of research has been directed at oral dosage forms that satisfy the temporal aspect of drug delivery but many of the newer approaches under investigation may allow for spatial placement as well. Goal in designing delayed release sustained or controlled drug delivery system The goal in designing delayed release sustained or controlled drug delivery system is to: Reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery. It would be a single dose for the duration of treatment whether it is for days or weeks, as with infection, or for the life time of the patient, as in hypertension or diabetes. It should deliver the active entity directly to the site of action, minimizing or eliminating side effects. This may necessitate delivery to specific receptors or to localization to cells or to specific areas of the body. The safety margin of high potency drug can be increased and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient. 1.4 Mechanism of drug release for sustained release drug delivery system: On exposure to aqueous fluid, hydrophilic matrices take up water, and polymer starts hydrating to form a gel layer. Drug release is controlled by diffusions barriers / or by surface erosion. An initial burst of soluble drug may occur due to surface leaching when a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state which is associated
with swelling process with time, water infiltrates deep into the case increasing the thickness by the gel layer. Concomitantly the second layer becomes fully hydrated and starts dissolving or eroding. When water reaches the center of the system and the concentration of drug falls below the solubility value, the release rate of drug begins to reduce. At the same time, an increase in thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug release kinetic associated with these gel layer dynamic, range initially from Fickian to anomalous (Non Fickian) and subsequently from quasi Constant ( near Zero order ) to constant. In general, two major factors control the drug release from swelling controlled matrix system. They include 1. The rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelation or swelling). 2. The rate of matrix erosion. Swelling of HPMC matrix tablet was higher for higher molecular weight. They attributed this to the large hydrodynamic volume occupied by higher molecular weight chain when hydrated. As the polymer chain becomes more hydrated and the gel becomes more dilute, the disentanglement concentration may be reached, i.e., the critical polymer concentration below which the polymer chain disentangles and get detached from gelled matrix.
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1.5 Sustained release dosage form:

Advantages: 1. It improves patient compliance 2. It may improve the pathophysiology of the disease. a. It minimizes or eliminates local side effects. b. It minimizes or eliminates systemic side effects. c. It obtains less potentiation or reduction in drug activity with chronic use. d. It minimizes drug accumulation with chronic dosing 3. It improves the efficiency in treatment a. It cures or controls the condition more promptly b. It improves bioavailability of some drugs c. Reduction in fluctuation in steady-state levels and therefore better control of disease condition. d. Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtimes. 4. Improved therapy a. Sustained blood level- the dosage form provided uniform drug availability or blood levels unlike peak and valley pattern obtained by intermittent administration. b. Attenuation of adverse effects- the incidence and intensity of undesirable side effects caused by excessively high peak drug concentration resulting from the administration of conventional dosage forms is reduced.
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Disadvantages: 1. Cost is very high. 2. Unpredictable and often poor IVIVC. 3. Dose dumping. 4. Reduce potential for dosage adjustment of drugs normally administered in varying strengths 5. For oral SR dosage forms there is an additional disadvantage that the effective drug release period is influenced and limited by GI residence time. 6. Retrieval of the drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. 1.6 Criteria to be met by drug proposed to be formulated in sustained release dosage forms: a) Desirable half-life: The half life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hrs), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours.
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b) High therapeutic index: Drugs with low therapeutic index are unsuitable for incorporation in controlled release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin. c) Small dose: If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for controlled release is seriously undetermined. This is chiefly because the size of a unit dose controlled release formulation would become too big, to administer without difficulty. d) Desirable absorption and solubility characteristics: Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is therefore unrealistic and may reduce overall absorption efficiency. e) Desirable absorption window: Certain drugs when administered orally are absorbed only from a specific part of GIT. This part is referred to as the absorption window. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable.
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f) First pass clearance: Delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms. 1.7 Benefits of modified drug delivery system: Decrease in dosing frequency. Reduced peak to trough ratio of drug in systemic circulation. Reduced rate of rise of drug concentration in blood. Sustained & Consistent blood level with in the therapeutic window. Enhanced bioavailability. Customized delivery profiles. Reduced side effects, improved patient compliance.
1.8 Sustained release matrix system of highly water soluble drugs: Matrix systems are favored because of their simplicity, patient compliance etc, than Traditional drug delivery (TDS) which have many drawbacks like repeated administration, fluctuation in blood concentration level etc. Developing oral sustained release matrix tablets for highly water-soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. Most of highly water-soluble drugs, if not formulated properly, may readily release the drug at a faster rate, and are likely to produce toxic concentration of the drug on oral administration.
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Hydrophilic polymers have become a product of choice as an important ingredient for formulating sustained release formulations of highly water-soluble drugs.
Drug release through matrix system is determined by water penetration, polymer swelling, drug dissolution, drug diffusion and matrix erosion.
Highly water-soluble drugs like Metformin, metoprolol tartrate, diltiazem, tramadol, ranitidine have been formulated as sustained release matrix tablets.
1.8.1
Matrix Technology Classically matrix products exhibit first order (or perhaps square-root-of-time)
drug release characteristics. In order to achieve zero order release characteristics, its necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry for which combination of conventional HPMC matrix technology with upper and lower layer is necessary. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.
Fig no. 5 Matrix tablet
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DRUG RELEASE MECHANISM Release of medicament can follow various mechanisms; A) Diffusion: Diffusion is a rate limiting step for the release of drug. Diffusion is the driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.
Fig no. 6 Diffusion release pattern.
In practice, we can follow either of the two methods, 1. The drug is formulated in an insoluble matrix. The gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion. 2. The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood. B) Dissolution: Dissolution is a rate limiting step for the release of drug. The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for
water soluble drugs, its possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release.
C) Osmotic pressure: Osmotic pressure is a rate limiting step for the release of drug. Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But it declines to zero once the concentration drops below saturation.
Fig no. 7 Osmotic release pattern
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D) Release controlled by ion exchange: Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.
1.9 HYPERGLYCAEMIA:6 Hyperglycemia is the technical term for high blood glucose (sugar). High blood glucose happens when the body has too little or not enough insulin or when the body cant use insulin properly. Three peptide hormones secreted by the pancreas occupy a central role in the regulation of metabolism of carbohydrates, lipids and amino acids. They are insulin,
glucagons and somatostatin. Insulin is the primary hormone which is responsible for controlling the storage and utilization of cellular nutrients. It activates the transport system and the enzymes involved in the intracellular utilization and storage of glucose, amino acids and fatty acids. Insulin inhibits catabolic process such as the breakdown of glycogen, fat and protein. Whereas the overall effect of insulin is hypoglycemic, the other pancreatic hormone glucagons mobilizes glucose from its store and causes hyperglycemia, the third pancreatic hormone somatostatin, originally discovered as hypothalamic hormone, inhibits the secretion of both insulin and glucagons.
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1.9.1 Diabetes mellitus:7 Definition: The term mellituria means sweet urine. It is a part of metabolic syndrome of multi-factorial etiology characterized by chronic hyperglycemia with disturbance of carbohydrate, fat and protein metabolism and water and electrolyte imbalance resulting from defects in insulin secretion and insulin action or both. Deficiency of effective insulin in the body cause a disease called diabetes mellitus in which there is altered metabolism of lipid, carbohydrates and protein. This results in hyperglycaemia and glycosuria. A) Early signs of hyperglycaemia in diabetes include: Polydipsia (increased thirst) Headaches Difficulty concentrating Polyurea (increased urinary output) Ketonaemia and ketourea (presence of ketone bodies in the blood and urine, respectively) Blur sight, Fatigue (weak, tired feeling) Itches on skin and mucus membranes Permanent hunger Outstanding tiresomeness/lack of energy. Sudden weight loss, Blood glucose more than 180mg/dl.
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B) Prolonged hyperglycaemia in diabetes may result in: Vaginal and skin infections. Slow-healing cuts and sores. Nerve damage causing painful cold or insensitive feet, loss of hair on the lower extremities, and/or erectile dysfunction. Stomach and intestinal problems such as chronic constipation or diarrhea. Decreased vision.
C) Two major types of Diabetes mellitus: 1. Type I / Insulin Dependent Diabetes Mellitus (IDDM), juvenile onset diabetes mellitus. 2. Type II / Non Insulin Dependent Diabetes Mellitus (NIDDM), maturity onset diabetes mellitus. Type I: There is cell destruction in pancreatic islets, Type IA: Majority of cases is autoimmune antibodies that destroy cells are detectable in blood. Type IB: There are idiopathic no cell antibody is found. In all type I cases circulating insulin levels are low or very low, and patients are more prone to ketosis. This type is less common and has a low degree of genetic predisposition. Type II: There is no loss or moderate reduction is cell mass, insulin in circulation is low, normal or even high, no anti cell antibody is demonstrate, has a high degree of genetic predisposition, generally has a late onset (past middle age) over 90% cases are type 2 diabetes mellitus.
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D) Causes: Abnormality in gluco-receptor of cells so that they respond at higher glucose concentration. Reduced sensitivity of peripheral tissues to insulin, reduction in number of insulin receptors, down regulation of insulin receptors. Many hypertensive are hyperinsulinemic but normoglycemic, exhibit insulin resistance, hyperinsulinemia has been implicated in causing angiopathy. Excess of hyperglycemic hormones (glucagons etc)/obesity, causes relative insulin deficiency the cells lag behind. Diagnostic criteria Diagnosis is by history of symptoms of polydipsia, polyuria recurrent infections, fatigue, unexplained weight loss and blurring of vision with blood sampling. The cut off values of venous plasma samples are: Fasting blood sugar 126 mg/ dl (After minimum 8 hrs of fasting) Random blood sugar 200 mg/dl (Sample taken at any time of the day) Postprandial blood sugar 200 mg/dl (2 hrs postprandial state) Oral glucose tolerance test is the gold standard for diagnosis of DM.
Problems in diagnosis Stress hyperglycemia should not be confused with DM Asymptomatic patient require several sugar samples to confirm the diagnosis
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The hypoglycaemic drugs can be discussed under two categories insulin preparation which are used parentrally only and oral hypoglycaemic agents 1.9.2 Insulin and insulin preparation: 1.9.3 Oral hypoglycaemic drugs:9 1) Sulfonyl Ureas First generation: Tolbutamide, Chlorpropamide Second generation: Glibenclamide (glyburide), Glipizide, Gliclazide,
Glimepiride. 2) Biguanides:Phenformin, Metformin 3) Meglitinide Analogues: Repaglinide, Nateglinide 4) Thiazolidine Diones: Rosiglitozone, Pioglitazone 5) Glucosidase Inhibitors: Acarbose, Miglitol.
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2. AIM & OBJECTIVE OF THE STUDY Aim of the study: The aim of the study is to formulate and evaluate the bilayer tablets containing sustained release layer of Metformin Hydrochloride 500 mg and Immediate release layer containing Acarbose 50 mg for treatment of type 2 diabetes mellitus. Rational behind the suitability of Metformin Hydrochloride 500 mg SR and Acarbose 50 mg IR for drug delivery system. The half-life of Metformin Hydrochloride is 5-6 hrs, hence it is a suitable candidate for the design of sustained release drug delivery system. The Bilayer effect of Metformin Hydrochloride and Acarbose was always greater than the sum of their individual effect. Patient compliance is improved when two drugs are used in a single dosage form rather than taking individual. By using sustained release dosage form the therapeutically effective concentration can be maintained for longer time than the conventional dosage form. By the use of sustained release dosage form, saw tooth kinetics of blood levels associated with conventional multi dosage can be eliminated. By using the sustained release dosage form incident of the local and systemic adverse effects can be reduced.
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Reason for the formulating as Bilayer tablets: Bilayer tablets are preferred when the release profile of the drugs are different from one another (i.e.) in the present case 50 mg Acarbose has to be released Immediately and the remaining 500 mg of Metformin Hydrochloride has to be released maintained. Moreover Metformin Hydrochloride release should be less in stomach and further release should be increased in the intestine and completed within eight hours. Hence an attempt was made to develop a bilayer tablet comprising of Metformin Hydrochloride sustained Release and Acarbose immediate release layers with the following objectives. To improve the patient compliance when the drug has been used in an extended release dosage form rather than conventional tablets. To enhance bioavailability For better clinical effects To reduce the incidence of adverse effects. in a sustained manner, so that therapeutic concentration can be
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3. REVIEW OF LITERATURE RELATED TO METFORMIN HYDROCHLORIDE Rachmani R. et al. have evaluated the safety of continued use of Metformin in patients with contraindications to this agent. Some 393 patients with type 2 diabetes mellitus (serum creatinine 130-220 mol/l) were studied. Among them were 266 patients with coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease (COPD), all of whom had been treated with Metformin. The patients were randomized to either continue or to stop Metformin and were then followed for 4 years. The results of analysis were the patients who stopped taking Metformin showed a rise in body mass index and in hemoglobin significantly greater than those who continued the drug. There were no cases of lactic acidosis.10 Mubeen G. and Noor K., have developed and validated a simple and sensitive spectrophotometric method for the estimation of Metformin Hydrochloride in bulk and in tablet formulations. Here the primary amino group of Metformin Hydrochloride reacts with Ninhydrin in alkaline medium to form a violet colour chromogen, which is determined spectrophotometrically at 570 nm. It obeyed Beers law in the range of 8-18 g/ml. Percentage recovery of the drug for the proposed method was found to be accurate and precise for routine estimation of Metformin Hydrochloride in bulk and from tablet dosage forms.11 Hoffman A. et al. have studied the pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the
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gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. 12 Mubeen G. et al. have developed and validated a simple and sensitive spectrophotometric method for the estimation of Metformin Hydrochloride in bulk and in tablet formulation. Here the primary amino group of Metformin Hydrochloride was oxidized using hydrogen peroxide to form a yellow chromogen, which is determined spectrophotometrically at 400 nm. It obeyed Beers law in the range of 4-26mcg/ml. The percentage recovery of the drug for the proposed method ranged from 99-101.3% indicating no interference of the tablet excipients. The proposed method was found to be accurate and precise for routine estimation of Metformin hydrochloride in bulk and in tablet dosage forms.13 Hamdan et al. a simple and a stability indicating capillary electrophoresis method was developed and validated for the analysis of metformin hydrochloride in tablet formulations. The method was validated in accordance with the ICH requirements, which involved accuracy, precision, linearity, selectivity and both limit of detection and limit of quantitation. The limit of detection and limit of quantitation were 2.0g/ml and 8.0g/ml, respectively. The stability indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using photodiode array detection.14
Armagan O. have developed three spectrophotometric methods and one HPLC method for analysis of anti-diabetic drugs in tablets. The two spectrophotometric methods were based on the reaction of rosiglitazone (RSG) with 2, 3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) and bromocresol green (BCG). The third spectrophotometric method consists of a zero-crossing first-derivative spectrophotometric method for simultaneous analysis of RSG and Metformin (MTF) in tablets. The fourth method is a rapid stability-indicating HPLC method developed for the determination of RSG. The proposed methods have been successfully applied to the tablet analysis.15
Mathew F. et al. have formulated Metformin Hydrochloride matrix tablets by sintering technique and they evaluated them. Since metformin hydrochloride is widely chosen as the first line drug in the treatment of type 2 DM, because of its minimal risk and maximum efficacy this formulation was taken into consideration. Matrix tablets reduce the frequency of dose administration, and are found to have increased patient complaince. A relatively recent technique called sintering technique was involved in the formulation which aims to extend the release of Metformin hydrochloride from the matrix tablets. After formulation the tablets where subjected to preformulation studies, micromeritic studies, stability studies and other tablet evaluation methods. 16
Kumar R. have formulated sustained release floating matrix tablets of Metformin Hydrochloride. Floating matrix tablets of Metformin hydrochloride were developed and evaluated for increase in bioavailability by increasing gastric residence time and sustained release of drug on the upper part of gastrointestinal tract thereby diminishing side effects and enhanced patient compliance. Metformin hydrochloride, an oral
antidiabetic having narrow absorption window in the upper part of gastrointestinal tract, was formulated as floating matrix tablet using gas generating agent (potassium bicarbonate) and hydrophilic gelling polymer hydroxyl propyl methyl cellulose (hypromellose) by wet granulation technique. The prepared formulations were evaluated for floating time and in vitro drug release characteristics using modified dissolution method. All formulations possessed good floating properties with total floating time more than 12 hours.17
Ching-Ling C. et al. in their article demonstrated the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride, that where rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of Metformin was also explored. A randomized, open-label, twoperiod crossover study was conducted in 12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of Metformin were followed for 24 h. No significant formulation effect was found for the bioequivalence metrics: areas under concentrationtime curve (AUC0t, AUC0) and maximal concentration (Cmax). Based on their results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters of Metformin in Chinese for both products were similar and were in good agreement with those reported for Metformin IR tablets in other ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.18
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Hu L. et al. have prepared Metformin Hydrochloride sustained release pellets by centrifugal granulation method. The influence of surface modification by Talc, the effects of Eudragit types and ratios, as well as the correlation between invitro release and invivo absorption were investigated in detail. Experimental results indicated that Talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Following coating with a blend of Eudragit L30D-55 and Eudragit
NE30D (1:20), at 7% or 10% coating level, respectively. The pellets acquired perfect sustained- release properties and good relative bioavailability. The use of two Eudragit polymers with different features as coating materials produced the desired results.19 Mandal U. et al. designed an oral sustained release matrix tablet of Metformin HCl to optimize the drug release profile using response surface methodology. Tablets where prepared by non-aqueous wet granulation method using HPMC K15M as matrix forming polymer. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile. The formulated tablets followed Higuchi drug release kinetics and diffusion was the dominant mechanism of drug release, resulting in release within 8 hours. 20 Basak SC. et al. have formulated Metformin Hydrochloride as a hydrophobic matrix sustained release tablet employing wax materials and the sustained release behavior of the fabricated tablet was investigated. Sustained release matrix tablets containing 500mg Metformin HCl were developed using different bees wax
combinations. The tablets were prepared by wet granulation technique. The formulation was optimized on the basis of acceptable tablet properties and in vitro drug release. The resulting formulation produced monolithic tablets with optimum hardness, uniform
thickness, consistent weight uniformity and low friability. Statistically significant differences were found among the drug release profile from different bees wax combination matrices.21 Corti G. et al. have developed a Metformin Hydrochloride sustained release formulation. The method proposed is based on direct-compressed matrix tablets consisting of a combination of Metformin Hydrochloride with the hydrophobic Triacetyl-cyclodextrin (TACD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. Hydroxypropyl methylcellulose, Xanthan gum, Chitosan, Ethylcellose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (Hydroxypropylmethylcellulose or Chitosan) with a pH-dependent one (Eudragit L10055) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TACD system preparation method (i.e. grinding or spraying) in determining the behavior of the final formulation was evidenced. In fact, for a given matrix- tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH- TACD as ground or spray-dried product.22 Naim et al. have studied the effect of model cationic drug Metformin Hydrchloride on swelling and erosion and in turn, the release of potassium chloride and drug itself, from -carrageenam matrices. Water uptake by the matrix up to 2 hours was found to increase with KCl concentration from the plain matrix. Erosion was not affected by concentration of KCl. Incorporation of drug favours water uptake, but in presence of
KCl it was found to be reduced. Drug-containing matrices have shown higher release of KCl as compared with plain batches. Drug release was retarded as KCl concentration increased up to 5%, above which the reduced cohesivity of the matrix caused increase in drug release.23 Palmer F. et al. Extended release (ER) formulation of Metformin hydrochloride (HCl) presents the formulator with significant challenges due to its poorinherent compressibility, high dose and high water solubility. This study investigates the possibility for development of a direct compression ER matrix tablet using hypromellose.24
RELATED TO ACARBOSE: Kumar G. et al. have developed Spectrophotometric Method for Acarbose from bulk and in its tablet dosage form. A simple rapid spectrophotometeric method has been developed for estimation of Acarbose from bulk drug and tablet dosage form by using potassium permanganate and sodium hydroxide as oxidizing agent. The method is based on the formation of green colored complex of drug with 0.1 N alkaline potassium permanganate having absorbance maxima at 625 nm. The method is applied to the marketed tablet formulation. The developed method was found to be simple, sensitive and reproducible and can be used for routine analysis of Acarbose from bulk and tablet dosage form.25 Kumar G. et al. formulated Monolithic matrix tablets of Acarbose as controlled release tablets employing Hydroxypropyl methylcellulose and Eudragit in different
concentrations and combinations, and investigated sustained release behavior of the fabricated tablets. Controlled released matrix tablets containing 350mg Acarbose were developed using different drug: polymers combination. Tablet prepared by direct compression method were subjected to physical characterization. Formulation was optimized on the basis of acceptable properties and in-vitro drug release. In-vitro drug release was carried out using USP Type II at 50 rpm in 900 ml of acidic dissolution medium (pH 1.2) for 1hr, followed by 900 ml alkaline dissolution medium (pH 7.4) upto 12 hr. Their result suggested that the drug release rate was strongly influenced by the type of polymer and concentration of polymer. To analyze the release mechanism zero order, Higuchi model and Kosmeyer -Peppas model were used. The use of simplified methodology is demonstrated to evolve unified mathematical model.26 Kumar G. et al. formulated Hydrogel matrix tablets of Acarbose using hydroxypropyl methyl cellulose and guar gum with the aim to study of release kinetics and to attain a near zero order release. In-vitro dissolution studies were carried out using USP type 2 dissolution test apparatus. The release of drug followed a typical Higuchian pattern. Matrix tablets formulated employing hydroxypropyl methyl cellulose and guar gum slow release of Acarbose over a period of 12 h and were found suitable for maintenance portion of oral controlled release tablets. Acarbose release from these tablets was diffusion controlled and followed zero order kinetics after a lag time of 1h. 27
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RELATED TO BILAYER TABLETS:
Shiyani B. et al. formulated bi-layer tablets of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB). MTH was formulated as immediate release layer by using various disintegrants like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum. IB was formulated as sustained release layer using hydrophilic matrix [hydroxy propyl methyl cellulose (HPMC K4M)].28 Atram SC. et al. developed an optimized bilayer tablet for antihypertension patients using Metoprolol succinate and Amlodipine besylate as model drug candidates by optimization technique. A 32 factorial design was employed in formulating bilayer tablet with individual release layers i.e. sustained release layer and immediate release layer. The independent variables selected both cases HPMC(X1), Starch 1500 (X2) and SSG (X1), MCC (X2), respectively. Two dependent variables were considered: t50 (Y1), Q1 (Y2) and t50 (Y1), Q2 (Y2), respectively. The main effect and interaction terms were quantitatively evaluated using mathematical model. Bilayer tablets were evaluated for thickness, hardness, friability, drug content and in vitro dissolution studies. The drug release of Amlodipine besylate and Metoprolol succinate depicted non-fickian diffusion and Super Case II transport mechanism, respectively.29 Amrutkar JR. et. formulated bilayer tablet of Metformin Hydrochloride and Gliclazide. Sustained release layer of Metformin Hydrochloride as an immediate layer of Gliclazide was optimized separately and then constituted in bilayer tablets. Hydrogenated castor oil and HPMC K100m polymers were used in combination as matrix forming agent for sustaining Metformin release. Effect of these polymers concentration and
different diluents were studied. Effect was evaluated by swelling studies and dissolution studies of prepared matrix formulations. f2 value was taken as basis to optimize the sustained release formula. Drug to polymer ratio (125:1:4) with lactose monohydrate as a diluent to showed better performance among all and shows Higuchi model as the best suited. Sodium starch glycolate at the concentration range of 16 % gives fastest disintegration i.e. in 17 sec.30 Kulkarni A. et al. formulated bilayer floating tablets comprising two layers, i.e. Lovastatin as immediate release and Atenolol as controlled release layers. The immediate release layer comprised sodium starch glycollate as a super disintegrant and the sustained release layer comprised HPMC K100M and xanthan gum as the release retarding polymers. Sodium bicarbonate was used as a gas generating agent. Direct compression method was used for formulation of the bilayer tablets. All formulations floated for more than 12 h. More than 90% of lovastatin was released within 30 min. HPMC K100M and xanthan gum sustained the release of atenolol from the controlled release layer for 12h.31 Patra CN. et al. developed a bilayer tablet of propranolol hydrochloride using superdisintegrant sodium starch glycolate for the fast release layer and water immiscible polymers such as ethylcellose, Eudragit RLPO and Eudragit RSPO for the suataining layer. In vitro dissolution studies were carried out in a USP 24 apparatus . The formulations gave a initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h from the sustaining layer of matrix embedded tablets. In vitro dissolution kinetics followed the Higuchi model via a non-Fickian diffusion controlled release mechanism after the initial burst release. FT-IR studies revealed that there was no interaction between the drug and polymers used in the study. Statistical
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analysis (ANOVA) showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05) in the amount of drug released after 12 h from optimized formulations was observed.32 Ramesh et al. developed bilayered sustained release matrix tablets of Metformin HCl (SR) 1000mg and Pioglitazone HCl 15mg. The tablets were prepared using sodium carboxymethylcellulose (SCMC) and Hydroxypropyl Methyl Cellulose [HPMC K4M & HPMC (15cps)] as bio-adhesive polymers and cross carmellose sodium to act as an impermeable backing layer. The physico-chemical property of the finished product complies with the in-house specifications of Micro Labs Limited. The formulations gave an immediate release effect followed by sustained release for 8 h which indicates bimodel release of Metformin HCl from the matrix tablets. The data obtained were fitted into Higuchis models. Analysis of n values of Korsmeyer equation indicated that the drug release involved both diffusional and dissolutional mechanisms.33 Arunachalam A. et al. formulated and evaluated bilayer sustained release tablets of Metoprolol Succinate and Telmisartan. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong cardiovascular system. Various polymers, such as hydroxypropyl methylcellulose K4M (HPMC- K4M), hydroxy propyl methylcellulose K100M (HPMC- K100M), MCC pH102, Lactose DCL 11, Bronopol, were studied. The HPMC K4M was found to be best in controlling the release. The tablets were prepared by Direct Compression method and the prepared blend and tablets were evaluated for their physicochemical properties and in-vitro dissolution studies were carried out for all the bi-layered tablets developed using USP dissolution apparatus type 2 (paddle). It was found that the tablet F1-F6 showed 50% release of
Metoprolol succinate in first hour and the remaining was released for eight hours. However, Telmisartan was found to be released as per the USP specifications.34 Gohel MC. et al. formulated the bilayer tablets containing paracetamol as immediate release and diclofenac sodium as modified release. A 2 3 full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac sodium tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for the manufacturing of bilayer tablets. 35 Mehul P. et al. studied the challenges in the formulation of bilayered tablets. Several pharmaceutical companies are currently developing bilayer tablets, for a variety of reasons: patent extension, therapeutic, marketing to name a few. To reduce capital investment, quite often existing but modified tablet presses are used to develop and produce such tablets. This article explains why the development and production of quality bilayer tablets needs to be carried out on purpose-built tablet presses to overcome common bilayer problems, such as layer-separation, insufficient hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced yield, etc. Using a modified tablet press may therefore not be the best approach in producing a quality bilayer tablet under GMP-conditions, especially when high production output is required. 36
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Remya PN. et al. developed a formulation of bilayer tablets of ibuprofen and methocarbamol using povidone K-30 as the binder. The basic aim of any bilayer tablet formulation is to separate physically or chemically incompatible ingredients and to produce repeat action or prolonged action tablet. A total number of nine formulations have been taken to optimize and develop a robust and stable formulation. Wet granulation process was used for the formulation of both layers and the final film coated tablets were evaluated for the thickness, weight variation, hardness, friability, disintegration time, dissolution study. Among the formulations tablets of formulation -8 was taken as optimized formula due to its higher rate of dissolution and compiled all the other parameters with the official specifications.37
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4. METHODOLOGY 4.1 Plan of Work: 1. Design of bilayer tablets formulations: sustained release (layer ) by wet granulation method and immediate release (layer ) by direct compression. 2. Drug-excipient compatibility studies by IR. 3. Evaluation for the precompression parameters of the formulations prepared by both direct and wet granulation method: Bulk density Tapped density Angle of repose Carrs index Hausners ratio 4. Evaluation of bilayer tablets formulations: Physical appearance Hardness and friability Drug content uniformity In vitro dispersion time In vitro dissolution rate 5. Short-term stability studies for the selected formulations.
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4.2 Materials and equipments: Table no.1 Materials used with their company name. Sr.No Materials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Metformin Hydrochloride Acarbose Sodium CMC Dibasic Calcium Phosphate Hydroxy Propyl Methylcellulose (HPMC K4M) Hydroxy Propyl Methylcellulose (HPMC 15 cps) Povidone (PVP K-30) Colloidal Silicon Dioxide (Aerosil-200) Croscarmellose Sodium (Primellose) Talc Magnesium Stearate Sunset yellow Low substituted Hydroxy Propyl Cellulose(L-HPC) Butyl Hydroxy Anisole (BHA) Butyl Hydroxy Toluene (BHT) Anhydrous Lactose DCL 15 Manufacturer/Supplier Wanbury Ltd, India. Huadong Medicine co.Ltd. Pioma Chemicals, India. Sudeep pharma Ltd, India. Shin Etsu Chemicals Co, Ltd. Feicheng Ruitai Fine Chem, Ltd. BASF Ltd, Germany. Cabot Sanmar Ltd, India. DMV Fonterra excipients, Ltd. Prakash & Co, Ltd. Amishi Drugs & Chemicals, India. Roha Chemicals, India. Shin-Etsu chemicals Co, Ltd. Lobha Chemicals. Merck Limited. DMV Fonterra excipients, Ltd.
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4.3 Drug Profile: 1) METFORMIN HYDROCHLORIDE: 2, 38 Therapeutic category: Hypoglycaemic Structure:
Fig no. 8 Chemical structure of Metformin Hydrochloride
Metformin hydrochloride (N, N dimethyl imidodicarbo nimidic diamide hydrochloride) Molecular formula: C4H11N5.HCl Molecular weight: 165.62. Description: White to off-white crystalline compound. Appearance: White crystals. Solubility: Freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. Melting point: 222oc to 226oc Water: Not more than 0.5%.
Dose: 500mg to 3000mg (3g) daily, in divided doses. Usual strengths: 500 mg; 850 mg. Mechanism of Action: Metformin is an anti-hyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycaemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves sensitivity by increasing peripheral glucose uptake and utilization. Pharmacodynamics: Absorption: Metformin is rapidly absorbed from the gastrointestinal tract and give adequate plasma levels. Indications: Monotherapy for adults with Type 2 Diabetes Mellitus, where non pharmacological treatment like controlled diet, weight reduction and exercise have failed to control blood sugar levels. Metformin is especially useful if the patient is obese, as it helps to reduce weight however, there is no contraindication to the use of the drug in patients who are not overweight, as it helps to normalize weight and blood sugar levels rather than reduce it below normal. It may be added as a co-prescription with Sulphonylureas, Glitazones and or Insulin, where the latter when given alone failed to control hyperglycemia.
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Dosage and administration: For treatment of Type 2 Diabetes mellitus uncontrolled by diet alone. For Monotherapy Oral dosage for adults: Initially, Metformin 250 mg to 500 mg is given twice daily with the meal. Metformin 1000mg formulation should be given for higher dosage requirement. In order to monit0r the response to treatment, an estimation of blood glucose levels should be carried out at regular intervals, if adequate glycemic control is not achieved with the maximum dose of Metformin 4000 mg. Similarly, in those who do not have adequate glycemic control with maximum dosages of insulin secretagogues like Sulphonyureas or glitazones, it can be added and the dosage of all oral hypoglycemic agents treated as per individual requirement with proper blood glucose monitoring. Adults and Elderly If there is no adequate response after 4 weeks of the maximum dose of Metformin as described in monotherapy without adequate response consider the gradual addition of an oral Sulphonylurea. If after 1-3 months of concominants therapy, responses are unsatisfactory, consider insulin therapy and discontinuation of insulin secretagogues if required. Contraindications: Renal disease/dysfunction; Serum Creatinine Level 1.5 mg/dl as a result of, cardiovascular shock, acute myocardial infraction, septicemia, congestive heart failure requiring pharmacological treatment.
Do not administer Metformin in patients who have known Metformin hypersensitivity. Use Metformin with caution in the elderly. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in patients with reduced renal function. Because aging is associated with decline in renal function, care should be taken with dose selection and titrations. Metformin is classified in FDA as pregnancy risk category B. Drug interactions Vitamin B12 absorption is retarted by Metformin. Metformin absorption is increased by Nifedipine. Metformin activity is increased by ACE inhibitors, salicylates, NSAIDs. Metformin action is decreased by Thiazide diuretics, Progestins, Estrogens, Oral contraceptives, phenytoin, Quinolones. Adverse reactions Metformin is usually well tolerated. The most common side-effect is minor gastrointestinal disturbance, which is often self-liminting or minimized by lowering the dose. Lactic acidosis has occurred but is very rare, and is usually due to a specific contraindicated state rather than the drug. In patients with metabolic acidosis, even if there is an evidence of ketoacidosis it must be stopped and the condition treated as a medical emergency. It does not lower blood sugar levels in non-diabetics when used as a monotherapy. Weight loss often occurs during therapy and levels of serum cholesterol, triglycerides and pre--lipoproteins may be lowered.
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2) ACARBOSE: 2, 38 Therapeutic category: Oral Hypoglycaemic, - glucosidase inhibitor. Structure:
Fig no. 9 Chemical Structure of Acarbose O-4, 6-Dideoxy-4-[[(1S, 4R, 5S, 6S)-4, 5, 6-trihydroxy-3-(hydroxymethyl) cyclohex-2enyl]amino]--D-glucopyranosyl-(14)-O- pyranose. Molecular formula: C25H43NO18 Molecular weight: 646.0 Description: White or yellowish amorphous powder hygroscopic compound. Appearance: White amorphous powder. Solubility: Very soluble in water, soluble in methanol, practically insoluble in methylene chloride. Melting point: 90oc to 105oc Water: Not more than 4%. Dose: 25mg 3 times daily, increasing to 100mg 3 times a daily. Usual strengths: 25 mg, 50mg and 100mg.
-D-glucopyranosyl
-(14)-D-gluco-
Mechanism of Action: Acarbose is a - glucosidase inhibitor, it reduces intestinal absorption of starch, dextrin and disaccharides by inhibiting the action of intestinal brush broder glucosidase. Acarbose inhibits alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides,
trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of the enzyme - glucosidase slows the absorption of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels and the long-term effect is a reduction in HbA1c level. This reduction averages an absolute decrease of 0.7%, which is a decrease of about 10% in typical HbA1c values in diabetes studies. - glucosidase inhibitors can have profound effects on hemoglobin A1c (HbA1c) levels in severely hyperglycemic type 2 DM patients. However, in patients with mild to moderate hyperglycemia, the glucose-lowering potential of - glucosidase inhibitors (assessed by hemoglobin A1c levels) is about 30% to 50% of that of other oral antidiabetic agents. - glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycemia. These agents may be considered as monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia.
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- glucosidase inhibitors typically are used in combination with other oral antidiabetic agents and/or insulin. The drugs should be administered at the start of a meal. They are poorly absorbed. Acarbose is an oral a-glycosidase inhibitor used in the management of noninsulin-dependent diabetes mellitus (NIDDM). It is obtained from fermentation processes of a microorganism, Actinoplanes utahensis. Acarbose is structurally similar to an oligosaccharide derived from starch digestion. Due to the presence of the intramolecular nitrogen, acarbose binds to the carbohydrate site of the a-glycosidase enzyme with an affinity exceeding that of the normal substrate. Hence, the enzymatic reaction stops because the CN linkage cannot be cleaved. Therefore, glucose absorption is delayed and consequently the postprandial rise in blood glucose is decreased.37
Side-effects:
Since acarbose prevents the degradation of complex carbohydrates into glucose, some carbohydrate will remain in the intestine and be delivered to the colon. In the colon, bacteria digest the complex carbohydrates, causing gastrointestinal side-effects such as flatulence (78% of patients) and diarrhea (14% of patients). Since these effects are doserelated, in general it is advised to start with a low dose and gradually increase the dose to the desired amount. One study found that G.I. side effects decreased significantly (from 50% to 15%) over 24 weeks, even on constant dosing.
If a patient using acarbose suffers from a bout of hypoglycemia, the patient must eat something containing monosaccharides, such as fruit juice or glucose tablets. Since
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acarbose will prevent the digestion of complex carbohydrates, starchy foods will not effectively reverse a hypoglycemic episode in a patient taking acarbose.
Hepatitis has been reported with acarbose use. It usually goes away when the medicine is stopped. Therefore, liver enzymes should be checked before and during use of this medicine.
Contraindications: Hypersensitivity to acarbose or any of the excipients. Acarbose is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, should not be used in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who suffer from states which may deteriorate as a result of increased gas formation in the intestine, e.g. larger hernias. Acarbose is contra-indicated in patients with hepatic impairment. As Acarbose has not been studied in patients with severe renal impairment, it should not be used in patients with a creatinine clearance < 25 ml/min/1.73m.
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EXCIPIENT PROFILE: Pharmaceutical excipients are substances, other than the pharmacologically active drug or prodrug, which are included in the manufacturing process or are contained in the finished pharmaceutical product dosage form. Excipients provide enhanced functionality to the pharmaceuticals, aid the innovations in the drug development and help improve patent life as well. Excipients make the products more functional at a lower cost, a benefit much desired by the pharmaceutical industry that is inundated with pressures to reduce costs. Excipients play a wide variety of functional roles in pharmaceutical dosage forms, including: Modulating the solubility and bioavailability of active pharmaceutical ingredients (APIs). Increasing the stability of active ingredients in dosage forms. Helping active ingredients maintain preferred polymorphic forms or
conformations. Maintaining the pH and/or osmolarity of liquid formulations. Acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and tablet disintegrates. Preventing aggregation or dissociation (e.g., of protein and polysaccharide actives). Modulating immunogenic responses of active ingredients (e.g., adjutants).
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4.4 Excipient Profile: 39 Table no: 2 Hydroxy Propyl Methyl Cellulose: Synonyms: Description: Methocel, Metolose, Benecal MHPC, pharmacoat It is odorless & tasteless, white or creamy white colored fibrous or granular powder. Structural Formula:
Solubility
It is soluble in cold water but insoluble in chloroform.
Functional categories: Tablet binder, coating agent, film former, stabilizing agent, suspending agent, viscosity increasing agent. Density (Bulk) : Density (Tapped): pH: Melting point: Loss on drying: Applications: 0.341 g / cm3 0.557 g / cm3 5.5 8.0 for a 1 % w/w aqueous solution. Browns at 190- 2000C; chars at 225-2300C. < 5.0 % It is widely used in oral and topical pharmaceutical formulations. Primarily used in film-coating, binder in tablets in concentrations of 2 5 %. Incompatibilities: Stability and storage conditions: Incompatible with some oxidizing agent. Stable material although it is hygroscopic after drying. It should be stored in a well- closed container, in a cool, dry place.
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Table no: 3 Croscarmellose sodium: Synonyms: Ac-Di-Sol; crosslinked carboxymethylcellulose sodium;
Explocel; modified cellulose gum; Nymcel ZSX; Pharmacel XL; Primellose; Solutab; Vivasol Nonpropietary Names: BP-Croscramellose sodium, PhEur- Carmellosum natricum conexum, USPNF- Croscarmellose sodium. Chemical Name and CAS Registry No.: Description: Structural Formula: Cellulose, carboxymethyl ether, sodium salt, crosslinked [74811-65-7]. CCS occurs as an odorless, white or grayish white powder.
Empirical Formula and The USPNF 23 describes carboxymethylcellulose calcium as Molecular Weight: Solubility and storage conditions: Functional categories: Use: Applications: the calcium salt of a polycarboxymethyl ether of cellulose. Insoluble in water, although. Practically insoluble in acetone, ethanol and toluene. Tablet and capsule disintegrant. Disintegrant in capsules 1025 & in tablets 0.55.0 It is used in oral pharmaceutical formulations as a disintegrant for capsules, tablets, and granules. In tablet formulations Stability and Storage Conditions: Incompatibilities: It is a stable though hygroscopic material. It should be stored in a well-closed container in a cool, dry place. The efficacy of disintegrants, such as CCS, may be slightly
reduced in tablet formulations prepared by either the wetgranulation or direct-compression process.
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Table no: 4 Magnesium stearate: Synonyms: Magnesium octadecanoate, Octadecanoic acid, magnesium salt, Stearic acid. Structure:
Molecular formula: Molecular weight: CB Number: Description
C36H70MgO4 591.24 CB5330900 It occurs as a fine, white, precipitated or milled impalpable powder with a faint odour of stearic acid and a characteristic taste.
Solubility:
Practically insoluble in ethanol, ether and water, slightly soluble in warm benzene and warm ethanol (95%).
Functional categories: Melting point:
Tablet and capsule lubricant. 1171500C(commercial magnesium stearate) 0.159 g/cm3 0.286 g/cm3 It is primarily used as a lubricant in tablet and capsules in concentrations between 0.25 % and 5 %. It is widely used in cosmetic and food industry. samples); 126-1300C(high purity
Density (Bulk): Density (Tapped): Applications:
Incompatibilities:
Incompatible with strong acids, alkalis and iron Salts.
Stability and storage It is stable and should be stored in well closed container in a conditions: cool and dry place.
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Table no: 5 Povidone: Synonyms: Acetic acid vinyl ester, polymer with 1-vinyl-2 pyrrolidinone; copolymer of 1-vinyl-2- pyrrolidone, and vinyl acetate in a ratio of 3:2 Description: White to yellowish-white, amorphous powder. It is typically spray-dried with a relatively fine particle size. It has a slight odour and a faint taste. Structure:
Functional Category:
Film-former; granulating agent; tablet binder
Solubility:
Greater than 10% solubility in 1, 4-butanediol, glycerol, butanol, chloroform, dichloromethane, ethanol (95%), glycerol, methanol, polyethylene glycol 400, propan-2-ol, propane, propylene glycol and water. Less than 1% solubility in cyclopean, diethyl ether.
Melting point: Applications:
140C Tablet binder, film former and as part of the matrix material used in controlled-release formulations. It provides good adhesion, elasticity, and hardness, and used as a moisture barrier.
Incompatibilities:
Copovidone is compatible with most organic and inorganic pharmaceutical ingredients.
Stability and Storage Copovidone is stable and should be stored in a well-closed Conditions : container in a cool, dry place.
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Table no: 6 Calcium phosphate dibasic anhydrous: Synonyms: Calcium monohydrogen phosphate; calcium orthophosphate; Dicalcium orthophosphate. Description: Anhydrous dibasic calcium phosphate is a white, odorless, tasteless powder or crystalline solid. It occurs as triclinic crystals. Emperical Formula: Molecular Fromula: Solubility: CaHPO4 136.06 Practically insoluble in ether, ethanol, and water soluble in dilute acids. Functional Category: Melting point: Tablet and capsule diluent. Does not melt; decomposes at 425C to form calcium pyrophosphate. Density (Bulk): Density (Tapped): Applications: 0.78 g/cm3 0.82 g/cm3 Excipient and as a source of calcium in nutritional supplements (particularly in the nutritional/health food sectors). Anhydrous dibasic calcium phosphate is used in toothpaste and dentifrice formulations for its abrasive properties. Stability and Storage Conditions: Anhydrous and is a nonhygroscopic, relatively stable material. Under conditions of high humidity it does not hydrate to form the dihydrate. The bulk material should be stored in a wellclosed container in a dry place.
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Table no: 7 Carboxymethylcellulose sodium: Synonyms: Cellulose gum; CMC sodium; SCMC; sodium carboxy methyl cellulose; sodium cellulose glycolate; sodium CMC. Description: Carboxymethylcellulose sodium occurs as a white to almost white, odorless, granular powder Structure:
Solubility:
Practically insoluble in acetone, ethanol (95%), ether and toluene. Easily dispersed in water at all temperatures, forming clear, colloidal solutions.
Functional Category:
Coating agent; stabilizing agent suspending agent; tablet and capsule disintegrant; tablet binder; viscosity increasing agent; water absorbing agent.
Melting point:
Browns at approximately 227C, and chars at approximately 252C. 0.52 g/cm3 0.78 g/cm3 Binder and disintegrant, and to stabilize emulsions. cosmetics, toiletries, surgical prosthetics, and incontinence, personal hygiene, and food products.
Density (Bulk): Density (Tapped): Applications:
Incompatibilities
Carboxymethylcellulose sodium is incompatible with strongly acidic and with soluble salts of iron and some other metals, such as aluminum, mercury and zinc.
Incompatibilities:
Carboxymethylcellulose sodium is incompatible with strongly acidic and with soluble salts of iron and some other metals, such as aluminum, mercury and zinc.
Stability and Storage The bulk material should be stored in a well- closed container in Conditions: a cool, dry place.
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Table no: 8 Colloidal silicon dioxide: Synonyms: Colloidal silica; fumed silica; light anhydrous silicic acid; silicic anhydride; silicon dioxide fumed Description: Colloidal silicon dioxide is submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-whitecolored, odorless, tasteless, nongritty amorphous powder. Empirical Formula: Molecular weight: Solubility: SiO2 60.08 Practically insoluble in organic solvents, water, and acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxides. Forms a colloidal dispersion with water. Functional Category: Adsorbent; anticaking agent; suspending agent; emulsion stabilizer; glidant; tablet disintegrant; thermal stabilizer; viscosity increasing agent. Density (Bulk): Density (Tapped): Applications: 0.0290.042 g/cm3 0.04 0.20 g/cm3 Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and food products. Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gels and semisolid preparations. Incompatibilities: Stability and Storage Conditions: Incompatible with diethylstilbestrol preparations. Colloidal silicon dioxide is hygroscopic but adsorbs large quantities of water without liquefying. When used in aqueous systems at a pH 0 -7.5. Colloidal silicon dioxide powder
should be stored in a well closed container.
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Table no: 9 Talc: Synonyms: Altalc; E553b; hydrous magnesium calcium silicate;
hydrousmagnesium silicate; Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus; Magsil Star; powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore. Nonpropietary Names: Chemical Name and CAS Registry No.: Description: Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness. Emperical Formula: Talc is a purified, hydrated, magnesium silicate, BP: Purified talc, JP: Talc, Ph.Eur: Talcum, USP: Talc Talc [14807-96-6]
approximating to the formula Mg6 (Si2O5)4(OH) 4. It may contain small, variable amounts of aluminum silicate and iron. Functional categories: Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant. Use: Talk is used as dusting powder in a Conc. of 90.099.0%, as a glidant and tablet lubricant 1.010.0, tablet and capsule diluent 5.030.0 Solubility: Practically insoluble in dilute acids and alkalis organic solvents, and water. Applications: It is widely used as a dissolution retardant in the development of controlled-release products. Talc is also used as a lubricant in tablet formulations; in a novel powder coating for extendedrelease pellets; and as an adsorbant. In topical preparations, talc is used as a dusting powder. Storage: Talc should be stored in a well-closed container in a cool, dry place
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Table no: 10 Sunset yellow lake: 2 Synonyms: Molecular Formula: Description: Orange yellows, FD&C Yellow 6; C.I.15985; E110. C16H1ONa2O7S2N2. It is a synthetic coal tar and azo yellow dye useful in fermented foods which must be heat treated. It may be found in orange squash, orange jelly, marzipan, swiss roll, apricot jam. Etc Structure:
Chemical Name:
Disodium 6-hydroxy-5-[(4-sulfophenyl) azo]-2naphthalenesulfononate.
Molar mass: Applications:
452.37 g/mol. Sunset Yellow is often used in conjunction with E123, Amaranth, in order to produce a brown coloring in both chocolates and caramel.
Stability
and At high concentrations, Sunset Yellow in solution with water undergoes a phase change from an isotropic liquid to a nematic liquid crystal. This occurs between 0.8 M and 0.9 M at room temperature of 250C and 100kpa.
Storage Condition:
Melting Point:
3000C , 573K, 5720F
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Table no: 11 Butylated Hydroxyanisole: Synonyms: BHA; tert-butyl-4-methoxyphenol; 1,1-dimethylethyl-4-
methoxyphenol. Molecular Formula: C 11 H 16 O 2 The Ph.Eur 2005 describes butylated hydroxyanisole as 2-(1,1dimethylethyl)-4-methoxyphenol containing not more than 10% of 3- (1, 1-dimethylethyl)-4-methoxyphenol. Structure:
Description:
Butylated hydroxyanisole occurs as a white or almost white crystalline powder or a yellowish-white waxy solid with a faint, characteristic aromatic odour.
Solubility:
practically insoluble in water; soluble in methanol; freely soluble in 550% aqueous ethanol, propylene glycol,
chloroform, ether, hexane, cottonseed oil, peanut oil, soybean oil, and in solutions of alkali hydroxides. Functional Category: Application: Antioxidant Butylated hydroxyanisole is an antioxidant with some antimicrobial properties. It is used in a wide range of cosmetics, foods, and pharmaceuticals. When used in foods, it is used to delay or prevent oxidative rancidity of fats and oils and to prevent loss of activity of oil soluble vitamins. Stability and Storage Exposure to light causes discoloration and loss of activity. Condition: Butylated hydroxyanisole should be stored in a well-closed container, protected from light, in a cool, dry place.
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Table no: 12 Butylated hydroxytoluene: Synonyms: Agidol; BHT; 2,6-bis(1,1-dimethylethyl)-4-methylphenol;
butylhydroxytoluene; Dalpac; Nipanox BHT. Molecular Formula Chemical Structure: C15 H24 O
Molecular weight: Description:
220.25 Butylated hydroxytoluene occurs as a white or pale yellow crystalline solid or powder with a faint characteristic odour
Functional category: Solubility:
Antioxidant.
Practically insoluble in water, glycerin, propylene glycol, solutions of alkali hydroxides, and dilute aqueous mineral acids. Freely soluble in acetone, benzene, ethanol (95%), ether, methanol, toluene, fixed oils, and mineral oil. 700 C Butylated hydroxyanisole is an antioxidant with some
Melting point: Applications:
antimicrobial properties. It is used in a wide range of cosmetics, foods, and pharmaceuticals. When used in foods, it is used to delay or prevent oxidative rancidity of fats and oils and to prevent loss of activity of oil soluble vitamins. Incompatibilities: Incompatible with strong oxidizing agents such as peroxides and permanganates. Contact with oxidizing agents may cause spontaneous combustion. Iron salts cause discoloration. Stability and Storage Conditions: Exposure to light, moisture, and heat causes discoloration and a loss of activity. Butylated hydroxytoluene should be stored in a well-closed container, protected from light, in a cool, dry place.
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Table no: 13 Hydroxypropyl Cellulose, Low-Substituted:39 Synonyms Nonpropietary Names Hyprolose, low-substituted; L-HPC JP: Low-substituted hydroxypropylcellulose, USPNF: Low substituted hydroxypropyl cellulose Chemical Name and CAS Registry No.: Description Cellulose, 2-hydroxypropyl ether (low substituted) [78214412]. Low-substituted hydroxypropyl cellulose occurs as a white to yellowish white powder or granules. It is odourless or has a slight, characteristic odour, and it is tasteless. Structural Formula:
Fig: Where is R is H or [CH2CH(CH3)O]mH Empirical Formula: Grade: Solubility and storage conditions: Melting point: Functional categories: Acidity/alkalinity: Applications: (OCH2CHOHCH3). LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30 L-HPC is a stable, though hygroscopic, material. The powder should be stored in a well- closed container. It decomposition is at 275C. Tablet and capsule disintegrant; tablet binder. pH = 5.07.5 for 1% w/v aqueous suspension. It is primarily used in tableting as a disintegrant, and as a binder in wet granulation. Stability and Storage Conditions: Incompatibilities: L-HPC is a stable, though hygroscopic, material. The powder should be stored in a well- closed container. It may react with as akaline substance.
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Table no: 14 Sodium Starch Glycolate:39 Synonyms: Carboxymethyl starch, sodium salt; Explosol; Explotab; Glycolys; Primojel; starch carboxymethyl ether, sodium salt; Tablo; Vivastar P. Nonpropietary Names: BP: Sodium starch glycollate, Ph.Eur:Carboxymethylamylum natricum, USPNF: SSG. Chemical Name and CAS Registry No.: Description: SSG is a white to off-white, odorless, tasteless, free-flowing powder. Structural Formula: Sodium carboxymethyl starch [9063-38-1]
Melting point: Functional categories: Bulk density: Tapped density: Specific surface area:
Does not melt, but chars at approximately 200C. Tablet and capsule disintegrant. 0.756 g/cm3 0.945 g/cm3 0.24m2/g; 0.202m2/g for Explotab; 0.185m2/g for Primojel; 0.335m2 /g for Tablo.
Applications:
It is commonly used in tablets prepared by either direct compression or wet-granulation processes. The usual Conc. employed in a formulation is between 2% and 8%, with the optimum Conc. about 4%, although in many cases 2% is sufficient.
Stability and storage properties: Incompatibilities:
SSG is stable and should be stored in a well-closed container.
SSG is incompatible with ascorbic acid.
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4.5 List of Equipments used: Table no: 15 Equipments used with their company name: Sr.No Equipments 1. 2. 3. Electronic Balance module-AUW 2200 pH Meter Manufacturer/Supplier Shimadzu Corporation, Japan. Metler Toledo, India.
UV-Visible Spectrophotometer (UV-1601), Shimadzu-Corporation, Japan. (UV-2550) FT-IR Spectrophotometer 8300 HPLC with PDA/Binary System Dissolution Apparatus Friability Test Apparatus Hardness Tester Tap Density Apparatus Filter (0.22m) Rapid Mixer Granulator Octagonal Blender Moisture Balance Vernier Caliper Vibratory Sifter Tray Drier Walk in Humidity Chamber Fluidized Bed Dryer Shimadzu-Corporation, Japan. Shimadzu-Corporation, Japan. TDT-08L, Electro lab, India. Electro Lab, ET-2, India. Pfizer Ltd. Electro Lab ETD 1020, India. Millipore, UK Sainath boilers, India Gansons, India. Sartorius, Germany Mitutoyo, Corps, Japan Gansons, India. Micro, S.B. Panchal and Co, India. Newtronic Pvt Ltd, India. Retsch,Germany
4. 5. 7. 8. 9. 10. 15. 16. 17. 18. 19. 20. 21. 22. 23.
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24. 25. 26. 27. 28. 29. 30. 31.
Hot plate Multi Mill Double Rotary Compression Machine (27 station) Dehumidifier Planetary Mixer (vertical main drive) Rapid dryer Blister packing machine Disintegration tester (USP)
Milton Plus Gansons, India. Cadmach, India. Tropical nortec, India Rimek, India Retsch, Germany Lab Module, India Electro Lab, India
4.6 Preformultaion Studies: Preformulation may be described as a phase of the research and development process where the formulation scientist characterizes the physical, chemical and mechanical properties of new drug substances, in order to develop stable, safe and effective dosage forms. Ideally the preformulation phase begins early in the discovery process such that the appropriate physical and chemical data is available to aid the selection of new chemical entities that enter the development process. During this evaluation, possible interaction with various inert ingredients intended for use in final dosage form is also considered in the present study. considered. The following data must be
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4.6.1 Organoleptic Properties: a) Colour: A small quantity of Metformin Hydrochloride and Acarbose powders were taken in butter paper and viewed in well-illuminated place. b) Taste and odour: Very less quantity of Metformin Hydrochloride and Acarbose was used to get taste with the help of tongue as well as smelled to get the odour. 4.6.2 Physical Characteristics: a) Solubility studies b) Loss on drying c) Micromeritic properties d) Compatibility studies e) pH studies
Solution properties: a) Solubility: The approximate solubilities of substances were indicated by the descriptive terms in the accompanying table. Solvents such as methanol, alcohol, water and isopropyl alcohol were used for the solubility studies. Solubility studies of Metformin Hydrochloride and Acarbose: An excess quantity of Metformin Hydrochloride and Acarbose were taken separately and added in 10ml of different solutions. These solutions were shaken well for few minutes. Then the solubility was observed.
Table no: 16 solubility studies. Descriptive Term Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically Insoluble insoluble or Parts of Solvent Required for 1 part of Solute Less than 1 From 1 to 10 From 10 to 30 From 30 to 100 From 100 to 1,000 From 1,000 to 10,000 Greater than or equal to 10,000
b) Loss on drying studies: 1 gm of granules where weighed and kept for checking the loss on drying on a moisture sensitive balance at 105C for 3 mins. Percentage loss of moisture content is determined. c) Micromeritic properties evaluation: Angle of repose of Metformin Hydrochloride and Acarbose were assessed by the fixed funnel method. A known amount of drug was allowed to flow through a funnel fixed at a constant height (h) and the height and diameter (2r) of the pile of powder were measured to calculate the angle of repose as = tan-1 (h/r). The loose Bulk density (LBD) and tapped bulk density (TBD) of Metformin Hydrochloride and Acarbose were determined using a Bulk density test apparatus. Carrs index and Hausners ratios were
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calculated using LBD and TBD values. Then again the micromeritic properties of these two drugs were checked with the addition of various fillers. d) Drug-Excipient Compatibility Studies by FTIR: Excipients are integral components of almost all pharmaceutical dosage forms. The successful formulation of a stable and effective solid dosage form depends on the careful selection of the excipients, which are added to facilitate administration, to promote the consistent release and bioavailability of the drug and protect it from degradation.
Fig no. 10 Drug-Excipient Compatibility Studies by FTIR Infra red spectroscopy is one of the most powerful analytical techniques to identify functional groups of a drug. Method Compatibility study was performed by preparing compatibility blends at different ratios of different excipients with the drug, based on tentative average weight. These blends were stored at accelerated condition of 400C/75% RH. Control samples were
stored at 400C. The ratio of drug to excipient varies from 1:1 to 1:10 depending on the purpose of use, and the samples were kept in double lined poly-bags. The samples were evaluated for any change in the physical characteristics with reference to its controlled sample stored at 400C for a period of 15 days. In the present study, the potassium bromide disc (pellet) method was employed. Chemical stability was confirmed by IR spectrometry. (e) pH of the solution The pH studies were done for both Metformin Hydrochloride and Acarbose by dissolving them in their suitable solvents and determining the pH with the help of pH potentiometer. 4.7 Formulation of bilayer tablets: To produce a quality bilayer tablet, in a validated and GMP-way, it is important that the selected press is capable of:
Preventing capping and separation of the two individual layers that constitute the bilayer tablet
Providing sufficient tablet hardness Preventing cross-contamination between the two layers Producing a clear visual separation between the two layers High yield The calculated amount of drug along with other excipients was dispensed
corresponding to a batch size of 1000 tablets. All the trials were carried out with direct
compression and wet granulation method. For all the trails 19.2 x 8.9mm oblong punches were used for compression. Then the batches formulated were evaluated for dissolution. The dissolution profile for Metformin Hydrochloride sustained release layer as per In-house specifications. The limits are mentioned in table no: 17. Table no: 17 Dissolution limits Time in hours Amount dissolved 1 4 8 Between 25% and 40% Between 60% and 80% Not more than 85%
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DESIGN DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE METFORMIN AS SUSTAINED
Table no: 18 Composition of Metformin Hydrochoride Sustained Release Layer (Layer 1) METFORMIN HYDROCHORIDE SUSTAINED RELEASE LAYER (LAYER 1) Sr. No 1 2 3 4 5 6 7 8 9 10 11 Ingredients (mg/tab) Metformin HCL DCP anhydrous. HPMC K4M HPMC 15cps Sodium CMC Povidone (K-30) Purified water Colloidal silicon dioxide Talc Magnesium stearate F-1 504.23 300.77 10 8 q.s 5 8 9 F- 2 504.23 216.27 10 84.5 8 q.s 5 8 9 845 F- 3 504.23 206.27 20 84.5 8 q.s 5 8 9 845 F- 4 504.23 121.77 20 169 8 q.s 5 8 9 845 F-5 504.23 111.77 30 169 8 q.s 5 8 9 845 F- 6 504.23 70.77 40 200 8 q.s 5 8 9 845 F- 7 504.23 60.77 50 200 8 q.s 5 8 9 845 F- 8 504.23 50.77 50 10 200 8 q.s 5 8 9 845 F-9a 504.23 45.77 50 15 200 8 q.s 5 8 9 845
Total weight of 845 Metformin HCl layer
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Table no: 19 Composition of Acarbose Immediate Release Layer (Layer 2) ACARBOSE IMMEDIATE RELEASE LAYER (LAYER 2) Sr. No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Ingredients (mg/tab) Acarbose BHA BHT SSG L HPC CCS Avicel pH 102 Lactose DCL 15 HPMC 15 cps Collidal silicon Dioxide Talc Magnesium stearate Sunset yellow lake Average weight of Acarbose layer Average weight of Bilayer tablet F-1 53.78 0.3 0.3 15 125.87 2 2 0.75 200 1045 F- 2 53.78 0.3 0.3 15 104.62 40 3 2 1 220 1065 F- 3 53.78 0.3 0.3 15 9 130.62 5 3 2 1 220 1065 F- 4 53.78 0.3 0.3 6 230.42 5 1.6 1.6 1 300 1145 F-5 53.78 0.3 0.3 9 6 221.42 5 1.6 1.6 1 300 1145 F- 6 53.78 0.3 0.3 15 9 212.42 5 1.6 1.6 1 300 1145 F- 7 53.78 0.3 0.3 15 9 212.42 5 1.6 1.6 1 300 1145 F- 8 53.78 0.3 0.3 15 9 212.42 5 1.6 1.6 1 300 1145 F-9a 53.78 0.3 0.3 15 9 212.4 2 5 1.6 1.6 1 300 1145
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Potency Calculation for Metformin hydrochloride: Actual quantity of Metformin hydrochloride required per tablet
Potency
= 504.23 mg/tablet. Potency calculation for Acarbose: The Actual quantity of Acarbose is required per tablet.
Potency =
= 53.78 mg/tablet. 4.8 Manufacturing process: Layer I Metformin hydrochloride SR granulation: 1) Sifting: Metformin Hydrochloride, Hydroxypropyl methyl cellulose K4M,
Hydroxypropyl methyl cellulose 15cps, Sodium carboxy methyl cellulose, dicalcium phosphate anhydrous were sifted through 40 mesh sieve (stage 1). 2) Binder preparation: Povidone (K- 30) was dissolved in purified water.
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3) Granulation a) Dry mixing: The materials of stage 1 were loaded into the rapid mixer granulator and mixed for 15 min at slow speed. b) Granulation: Granules were prepared by adding step 2 in step 3a. c) Drying: The produced Metformin Hydrochloride granules were dried in fluidized bed dryer at 500 C till the Loss on drying of 1.5- 2.0% is achieved. 4) Sizing: Dried granules were passed through 20 mesh sieve. 5) Lubrication: Sifted granules were transferred to double cone blender. Colloidal
Silicon dioxide was sifted through 40 mesh sieve and added to step 4. Magnesium stearate and Talc were sifted through 60 mesh sieve and added to step 4 and mixed for 2 minutes. Layer I Acarbose IR (direct compression) 1) Sifting: a. Acarbose was sifted through 30 mesh sieve. b. Lactose DCL 15, BHA, BHT, L-HPC, CCS, HPMC 15 cps were sifted through 40 mesh sieve, sunset yellow lake was sifted through 100 mesh. (Step1b). 2) Dry mixing: Mix Acarbose with Lactose DCL 15 in geometrical mixing method (step 2a). Then mix the materials of step 1b in to step 2a for 15mins in planetary mixer (step 2b). 3) Prelubrication: Talc was sifted through 40 # mesh and added to step 2b and mixed for 5 mins.
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4) Lubrication: Magnesium stearate was sifted through 60 mesh sieve and added to Step 3 and mixed for 2 minutes at fast speed. MANUFACTURING PROCESS FLOW CHART Metformin HCL(Layer 1) (SR Layer) Dispensing & sifting Binder preparation Dry mixing of drug, polymer and excipients Granulation Drying Lubrication Acarbose (Layer2) (IR Layer) Dispensing Sifting Dry mixing of drug, polymer and excipients Pre lubrication Lubrication For Compression
Granules compression Bilayer Tablet & Packaging Fig no: 11 Manufacturing Process Flow Chart
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Compression of bilayer tablets: Metformin Hydrochloride sustained release layer and Acarbose with immediate release layer granules were compressed in D- Tooling bilayer compression machine (27 station, Cadmach, India) using 19.2 8.9 mm oblong punches. 4.9 Evaluation of granules: Evaluation was performed to assess the physicochemical properties and release characteristics of the developed formulations. Preformulation studies: a) Bulk density(Db): 40, 42 It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve # 20) into a measuring cylinder and the initial volume was noted. This initial volume is called the bulk volume. From this, the bulk density is calculated according to the formula mentioned below. It is expressed in g/cc and is given by: Db = m/Vo Where, m = mass of the powder Vo = bulk Volume of powder.
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b) Tapped density: 42 It is the ratio of total mass of powder to the tapped volume of powder. The volume was measured by tapping the powder for 500 times. Then the tapping was done for 750 times and the tapped volume was noted (the difference between these two volumes should be less than 2%). If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. It is expressed in g/cc and is given by:
Dt = m/Vi
Where, m= mass of the powder Vi = tapped Volume of the powder. c) Flow properties (Angle of Repose ()): 42 This is the maximum angle possible between the surface of a pile of powder or granules and the horizontal plane. The angle of repose of granules was determined by funnel method. The funnel was fixed at a particular height (2.5 cm) on a burette stand. The powder sample was passed through the funnel until it forms a heap. Further adding of granules was stopped as soon as the heap touches the tip of the funnel. A circle was drawn across it without disturbing the pile. The radius and height of the heap was noted down. The same procedure was repeated for three times and the average value was taken. The angle of repose was calculated by using equation.
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Tan =h/r = tan 1(h/r) Where, = Angle of repose h = Height of the heap r = Radius of the heap. Table no: 20 Angle of repose as an indication of granule flow properties; Sr. No. 1 2 3 4 Angle of repose() <25 25-30 30-40 >40 Type of flow Excellent Good Passable Very poor
d) Measurement of Powder Compressibility: 42 1) Compressibility Index: The flowability of powder can be evaluated by comparing the loose Bulk density (LBD) and Tapped bulk density (TBD) of powder and the rate at which it packed down. Compressibility index of the granules was determined by the Carrs
compressibility index:
CI (%) =
x 100
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Table no: 21 Carrs index as an indication of granule flow properties Sr. No 1 2 3 4 5 6 % CI 5-12 12-16 18-21 23-35 33-38 >40 Properties Free flowing Good Fair Poor Very poor Extremely poor
2) Hausners Ratio: It is measurement of frictional resistance of the drug. The Ideal range should be 1.2 1.5, it was determined by the ratio of tapped density and bulk density.
HR=
Table no: 22 Hausner ratio as an indication of granule flow properties Sr. No 1 2 3 4 5 6 7 Hausner ratio 1.00 1.11 1.12 1.18 1.19 1.25 1.26 1.34 1.35 1.45 1.46 1.59 > 1.60 Properties Excellent Good Fair Passable Poor Very poor Extremely poor
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4.10 Post compression parameters: 42, 43 a) Shape of Tablet: Directly compressed tablets were examined under the magnifying lens for the shape of the tablet. b) Tablet Dimensions: Thickness and diameter were measured using a calibrated Vernier calipers. Five tablets of each formulation were picked randomly and thickness and diameter was measured individually. c) Hardness: Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm2. Five tablets were randomly picked and hardness of the tablets was determined. d) Friability test: The friability of tablets was determined by using Roche friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (W t) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (WF). The % friability was then calculated by%F = X100
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e) Weight Variation Test: Twenty tablets were selected randomly from each batch and weighed individually to check for weight variation. A little variation was allowed in the weight of a tablet according to U.S. Pharmacopoeia. The following percentage deviation in weight variation was allowed. Table 23 Weight variation parameters: Average weight of a tablet Percentage deviation 130 mg or less 10 >130 mg and <324 mg 324mg or more 7.5 5
In all the formulations, the tablet weight is 1045mg to 1145mg, hence 3% maximum difference allowed. 4.11 Evaluation of tablets: 4.11.1 Thickness: The thickness of the tablets was determined by Vernier calipers. Five tablets from each batch were used and the average values were calculated. 4.11.2 Hardness test: The Hardness of the tablet was measured using Tab-Machine hardness tester. 4.11.3 Uniformity of weight (weight variation test): This is an important in-process quality control test to be checked frequently (every half an hour). Corrections were made during the compression of tablets. Any
variation in the weight of tablet (for any reason) leads to either under medication or overdose. So, every tablet in each batch should have a uniform weight. 20 tablets were weighed individually. Average weight was calculated from the total weight of all tablets. The individual weights were compared with the average weight. The percentage difference in the weight variation should be within the permissible limits ( 3%). The percent deviation was calculated using the following formula.
% Deviation =
4.11.4 Disintegration test: The disintegration time for immediate release layer was determined using the disintegration apparatus. One tablet was placed in each of six tubes placed in a beaker containing 1000 ml of purified water maintained at 37 20 C and the apparatus was operated. The time taken for the tablets to disintegrate and pass through the mesh was noted.
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4.12 METHOD OF ANALYSIS:

4.12.1 In vitro dissolution study: FOR ACARBOSE: Apparatus Medium Speed Time : : : : Dissolution Apparatus IP Type I (Paddle) Water: 900ml 75 RPM 45 Minutes 37 0.5 0C.
Temperature :
Chromatographic Conditions: Apparatus Column Wavelength Detector Injection volume Flow rate : High Performance Liquid Chromatography system (HPLC) : 250x 4.6mm; 5 Aminopropyl silane (Hypersil APS-2 is suitable) : 210nm : UV/PDA : 20l. : 1.0ml/min
Sample cooler temp. : 250 C Run Time Elution : 40 minutes : Isocratic
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Buffer
: 0 .29 gm of Disodium hydrogen orthophosphate was dissolved in
1000 ml water and 0.87g of Di Potassium Hydrogen orthophosphate was separately dissolved in 1000 ml water and then both the above solutions were mixed together. Mobile Phase : Filtered and degassed mixture of Buffer and Acetonitrile in the
ratio of 27:73 v/v was used. Diluent (Blank) Sample Preparation: The dissolution test apparatus was kept as per the above conditions. One tablet was placed in each dissolution bowl and the apparatus was runned for 45 min. after 45 min the sample was collected and filtered through 0.45m membrane filter. The filtrate was collected after discarding the first few ml of the filtrate. Further 5 ml of the resulting solution was diluted to 20ml with diluent and mixed well. Standard Preparation: 25 mg of Acarbose was accurately weighed into a 50 ml volumetric flask, 30 ml of diluent was added and sonicated for 3 minutes with intermediate shaking to dissolve the contents and finally the volume adjusted with diluent. The resulting solution was filterd through membrane filter. The filtrate was collected after discarding the first few ml of the filtrate. Further 5 ml of the resulting solution was diluted to 100ml with diluent. Again 5ml of the resulting solution was diluted to 10ml with diluent and mixed well. It is used as working standard of Acarbose. The final concentrations of the standard solution were about Acarbose 12.5 ppm.
: Mobile phase was used as diluent.
System suitability parameters: 20 l volumes of standard solution were injected five times into the HPLC. The chromatogram was recorded and the response (Peak areas) for the Acarbose peak was measured. The system is valid for sample analysis if and only if, 1) The % RSD of peak areas of five replicate injections of Acarbose peak obtained from the standard chromatograms should be not more than 2.0%. 2) The USP Theoretical plates obtained with the first standard chromatogram should be Not less than 1500 for Acarbose peak. 3) The USP Asymmetry factor obtained with the first standard chromatogram should be Between 0.80 to 2.0 for Acarbose peak. Procedure 20 l of filtered portion of blank, sample preparation and standard preparation was injected separately into the chromatograph. The chromatogram was recorded and the response for the major peaks was measured. The release in percentage with respect to label claim was calculated by using the following expression. Calculation: Calculate the % drug release of Acarbose present in the tablet using the formula:
% Drug release of Acarbose=
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Where, Aa = Peak area of Acarbose obtained from the sample chromatogram Ba = Average Peak area of Acarbose obtained from the standard chromatogram Wa = Weight of Acarbose working standard taken in mg for standard preparation Pa = % Purity of Acarbose (WS) on as is basis. LC = Labeled amount of Acarbose in mg/tablet. FOR METFORMIN HYDROCHLORIDE DISSOLUTION SYSTEM Apparatus Medium Volume Speed : Paddle method : Phosphate Buffer pH 6.8 : 1000ml. : 50 RPM
Time intervals : 1st hour, 4th hour, & 8th hour. Temperature : 37 0.5C Dissolution medium Preparation (Phosphate Buffer, pH 6.8): About 6.8g of Potassium dihydrogen phosphate was dissolved in 1000ml of water; the pH was adjusted to 6.80.05 with 1M sodium hydroxide solution.
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Chromatographic conditions: Equipment Wave length : UV-Visible spectrophotometer : 233nm
Standard preparation: About 50mg of Metformin HCl working standard was accurately weighed and transferred into a 100ml volumetric flask. To that about 70ml of dissolution medium was added and sonicated for about 3 minutes with intermediate shaking to dissolve and finally diluted to the 100ml with dissolution medium and mixed well. Further 5ml of the resulting solution was diluted to 50ml with dissolution medium. Again 5ml of the resulting solution was diluted to 50ml with dissolution medium and mixed well. The final concentration of Metformin HCl in the standard preparation was about 5ppm. Sample preparation: The dissolution test apparatus was kept as per the above conditions. One tablet was placed in each dissolution bowl and the apparatus was runned. After Specified time interval 10 ml aliquot was withdrawn from zone midway between the top of rotating paddle and surface of dissolution medium and 1cm away from the wall of jar, the solution was filtered through 0.45 membrane filter, rejecting the first few ml of the filtrate, into a separate test tube. Further 5ml of the resulting solution was diluted to 50ml with dissolution medium. Again 5ml of the resulting solution was diluted to 50ml with dissolution medium and mixed well.
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Procedure: The instrument was switched on and stabilized. The instrument was made auto zero and then absorbance of blank, standard and sample was measured at 233nm using the dissolution medium as the blank. Calculation: Calculate the % drug release of Metformin HCl present in the tablet using the formula:
% Drug release of Metformin HCl=
Where, Am = Absorbance of Metformin HCl obtained from the sample preparation. Bm = Absorbance of Metformin HCl obtained from the sample preparation. Wm = Weight of Metformin HCl working standard taken in mg for standard preparation. Pm = % Purity of Metformin HCl (WS) on as is basis. LC = Labeled amount of Metformin HCl in mg/tablet.
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4.12.2 ASSAY
Chromatographic Conditions Apparatus Column Wavelength Detector Injection volume Flow rate Column temp. : High Performance Liquid Chromatography system (HPLC) : 250x 4.6mm; SCX (Whatman Partisil 10 SCX is suitable) : 205nm : UV/PDA : 20l. : 1.0ml/min : 400 C
Sample cooler temp. : 250 C Run Time Elution : 30 minutes : Gradient
Preparation of mobile phase A: 1ml of perchloric acid was pipetted out in to 1000ml of milli-Q water and the pH of the solution was adjusted to 3.00.1 with dilute sodium hydroxide (about 1%w/v). Finally filtered through 0.45m membrane filter and degased.
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Note: while adjusting the pH of the mobile Phase A, slowly add diluted solution of sodium hydroxide with constant stirring or otherwise it may lead to drastic change in the pH. Preparation of Buffer for Mobile Phase B: About 17.0g of Ammonium dihydrogen phosphate was weighed accuretly and dissolved in 1000ml of milli-Q water; the pH of the solution was adjusted to 3.00.1 with dilute phosphoric acid (10%w/v). Filtered through 0.45m membrane filter and degassed. Preparation of Mobile Phase B: Buffer and Acetonitrile were mixed in the ratio of 900:100 v/v respectively. Diluent (blank): Mobile phase A and Mobile Phase B was mixed in the ratio of 500:500v/v respectively. Standard preparation: Metformin Hydrochloride standard stock preparation: 50mg of Metformin HCl working standard was accurately weighed into a 50ml volumetric flask, about 30ml of diluent was added and sonicated for about 3 minutes with intermediate shaking to dissolve. Finally the volume was made up to 50ml with diluent and mixed well.
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Standard solution preparation: 25 mg of Acarbose was accurately weighed into a 50 ml volumetric flask; 30 ml of diluent was added and sonicated for about 3 min with intermediate shaking to dissolve. To the same volumetric flask, 5 ml of Metformin Hydrochloride working standard stock preparation was added and diluted to volume with diluents and mixed well. The final concentrations of the standard solution were about Acarbose 500ppm and Metformin HCl 100ppm. Sample preparation: (Stock Solution) Not less than 10 tablets were taken. The average weight of the tablet was calculated. The 10 tablets were transferred into a mortar, crushed them to fine powder and mixed well. The sample powder was accurately weighed equivalent to the average weight of the tablet and transferred into 100ml volumetric flask, about 70ml of diluent was added and sonicated for about 10 minutes with intermediate shaking. Finally diluted to 100ml with diluents and mixed well. Centrifuge a portion of the solution at 2500rpm for about 10 minutes and use this solution for sample preparations. Note: During sonication with intermediate shaking, slight foaming might be observed. After completion of sonication, slowly add the diluent and gently mix and finally dilute to the 100ml with diluent and mix well.
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Sample preparation A: (for Acarbose) The stock solution was used as sample solution A. Sample preparation B: (For Metformin HCl) 1ml of clear supernatant sample stock solution was pepetted out into a 500ml volumetric flask and diluted to volume with diluent and mixed well. Note: prepare sample solutions in duplicate. Procedure: The column equilibrated with mobile phase for sufficient time until stable baseline is obtained. Blank was injected in duplicate, standard preparation in five
replicates and each test preparation in duplicate into the chromatographic system; the chromatogram was recorded and the response (Peak areas) for Acarbose and Metformin HCl were measured. The standard preparation was injected as bracketing after every six injections of test preparations. System suitability parameters: 20 l volumes of standard solution were injected five times into the HPLC. The Chromatogram was recorded and the response (peak areas) for the Acarbose and Metformin HCl peaks were measured. The system is valid for sample analysis if and only if,
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1) The % RSD of peak areas of five replicate injections of Acarbose and Metformin HCl peaks obtained from the standard chromatograms should be not more than 2.0%. 2) The USP Theoretical plates obtained with the first standard chromatogram should be Not less than 1000 for Acarbose Peak. Not less than 10,000 for Metformin HCl peak.
3) The USP Asymmetry factor obtained with the first standard chromatogram should be Calculation: Calculate the % of Acarbose present in the tablet using the formula: Between 0.80 to 2.0 for Acarbose peak. Not more than 2.0 for Metformin HCl peak.
Where, AA = Peak area of Acarbose obtained from the sample chromatogram BA = Average Peak area of Acarbose obtained from the standard chromatogram WA = Weight of Acarbose working standard taken in mg for standard preparation. Aw = average weight of tablet (mg/tablet). PA = % Potency of Acarbose on as is basis. LC =Labeled amount of Acarbose in mg/tablet.
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Calculate the % of Metformin Hydrochloride present in the tablet using the formula:
Where, Am = Peak area of Metformin HCl obtained from the sample chromatogram Bm = Average Peak area of Metformin HCl obtained from the standard chromatogram Wm = Weight of Metformin HCl working standard taken in mg for standard preparation. Aw = Average weight of tablet (mg/tablet) Pm = % Potency of Metformin HCl on as is basis. LC =Labeled amount of Metformin HCl in mg/tablet. 4.13 Data analysis (Curve Fitting Analysis): 44. 45 To analyse the mechanism of the drug release rate kinetics of the dosage form, the data obtained were plotted as: 1) Cumulative percentage drug released Vs time (In-Vitro drug release plots) 2) Cumulative percentage drug released Vs Square root of time (Higuchis plots) 3) Log cumulative percentage drug remaining Vs time (First order plots) 4) Log percentage drug released Vs log time (Peppas plots)
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Higuchi release model: To study the Higuchi release Kinetics, the release rate data were fitted to the following equation, F = K .t1/2 Where, F is the amount of drug release, K is the release rate constant, and t is the release time. When the data is plotted as a cumulative drug released versus square root of time, yields a straight line, indicating that the drug was released by diffusion mechanism. The slope is equal to K.
Korsmeyer and Peppas release model: The release rate data were fitted to the following equation, Mt/M = K. tn Where, Mt/M is the fraction of drug release, K is the release rate constant, t is the release time. n is the diffusion exponent for the drug release that is dependent on the shape of the matix dosage form.
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When the data is plotted as log % of drug released versus log time, yields a straight line with a slope equal to n and the K can be obtained from Y- intercept. For non-Fickian release the n values falls between 0.5 and 1.0, while for Fickian (case ) diffusion n = 0.5 and zero order release (case transport) n=1.0 Zero order release rate kinetics: To study the Zero order release kinetics the release rate data are fitted to the following equation. F=K.t Where, F is the fraction of drug release, K is the release rate constant, and t is the release time. When the data is plotted as cumulative percent drug release versus time, if the plot is linear then the data obeys Zero-order release kinetics, with a slope equal to K0. 4.14 Stability Studies: 46, 47 In any rational drug design or evaluation of dosage forms for drugs, the stability of the active component must be a major criterion in determining their acceptance or rejection. Stability of a drug can be defined as the time from the date of manufacture and the packaging of the formulation, until its chemical or biological activity is not less than a predetermined level of labelled potency and its physical characteristics have not changed appreciably or deleteriously.
Objective of the study: The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, enabling recommended storage conditions, re-test periods and shelf-lives. The International Conference on Harmonization (ICH) guidelines titled Stability Testing of New Drug substance and Products (QIA) describes the stability test requirements for drug registration for drug registration applications in the European Union, Japan and The United States of America. ICH specifies the length of study and storage conditions. Table no: 24 Storage Conditions Study Long term Intermediate Accelerated Storage condition 25C 2 C/ 60% RH 5% RH 30C 2 C/ 65% RH 5% RH 40C 2 C/ 75% RH 5% RH Minimum time period covered by data at submission. 12 months 6 months 6 months
Stability studies were carried out at 400 c/75% RH for the selected formulation for the period of one month.
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Method: The selected formulations were blister packed. They were then stored at 40 0 C/75% RH for one month and evaluated for their physical appearance, drug content and in vitro dispersion time at specified intervals of time. When significant change occurs at any time during 6 months testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. In general significant change for a drug product is defined as: A 5% change in assay from its initial value; or failure to meet the acceptance criteria for when using biological or immunological procedures. Any degradation products exceeding its acceptance criterion. Failure to meet the acceptance criterion for appearance, physical attributes, and functionality test. E.g. Hardness, dose delivery per actuation; however some changes in physical attributes may be accepted under accelerated condition and as appropriate for the dosage form. Failure to meet the acceptance criterion for pH; or Failure to meet the acceptance criterion for dissolution for 12 dosage units. Storage conditions are maintained as stated in ICH guidelines. The globalization and increase in world wide trade in recent years has led to the need for international drug approvals and unification of regulatory requirements and evaluation products. ICH has already a number of harmonized guidelines providing guidance on generation of data that would be acceptable in European Union, Japan, and USA.
Evaluation: A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include as appropriate, results from the physical, chemical and microbiological tests, particular attributes of the dosage form. The purpose of the stability study is to establish based on testing a minimum of three batches of drug product, a shelf life and storage instruction applicable to all future batches of the drug product manufactured and packaged under similar circumstances. Any evaluation should consider not only the assay but also the degradation products and other attributes, where appropriate attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performances. Formulation of stability study batches: Two batches (F-9b & F-9c ) was taken using optimized formula of Layer- (F-9a) and optimized formula of Layer (F-9a) to check the reproducibility characters as shown in optimized formulation and to load the samples for stability testing of tablets according to ICH guidelines for different time periods. For the stability reproducible batch of selected formulation was used.
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5. RESULTS: The present study was aimed at the formulation of bilayer tablets of sustained release Metformin HCL and Immediate release Acarbose. The therapy with these drugs offers a good quality of life for patients who are suffering from type 2 diabetes mellitus. The key advantage of this drug is its specificity of action, high safety and excellent efficacy.
5.1 Pre-Formulation Studies:

Drug characterization: 5.1.1 Metformin Hydrochloride: Metformin HCl raw material obtained from M/S WANBURY LTD has been tested as per in-house specifications and the results are listed in table. 25. The drug source is identified and found complying with the specifications. Table no: 25 Evaluation of drug (Metformin HCl) characterization: Sr.No 1 2 3 4 5 6 7 8 Test Description Identification Loss on drying Heavy metals Related subatances Solubility Sulphated ash Specification A white powder Should pass the prescribed test Not more than 0.5% W/W Not more than 10 ppm Not more than 0.02% Results White crystals Passes prescribed test. 0.25% W/W Less than 10 ppm 0.006% the
Freely soluble in water, slightly Complies soluble in alcohol. Not more than 0.1% 0.05%
Assay (Calculated Not less than 98.5% and not more 95.88% as on dried basis) than 101.0%
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5.1.2 Acarbose : Acarbose raw material obtained from Huadong medicine co. Ltd has been tested as per in-house specifications and the results are listed in table. 10. The drug source is identified and found complying with the specifications. Table no: 26 Evaluation of drug (Acarbose) characterization: Sr.No 1 2 3 4 5 6 7 8 9 10 11 Test Description Identification Water Heavy metals Related subatances Solubility Sulphated ash Specification Results
white (or) yellowish amorphous Yellowish powder amorphous powder Should pass the prescribed test Not more than 4% Not more than 20 ppm Not more than 0.6% Passes prescribed test. 3.04% Less than 20 ppm 0.12% the
Very soluble in water, slightly soluble in methanol, practically Complies insoluble in methylene chloride. Not more than 0.2% 0.06%
Assay (Calculated Not less than 95% and not more 95.88% as on dried basis) than 102.0% pH Absorbance Specific rotation optical 5.5 7.5 0.04 +168 to +183 6.2 Maximum 0.15 at 425nm +174.26
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5.2 Physical characteristics:

5.2.1 Metformin hydrochloride: Loss on drying Table no: 27 Results of loss on drying of Metformin HCl bulk drug. Sr.No 1 Test Loss on drying Specification / limits Not more than 0.5% w/w Observations 0.25%w/w
Table no: 28 Results of evaluation of Metformin HCl bulk powder: Sr. MATERIAL No 1 Metformin HCl BD (g/ml) TD* (g/ml) CI*(%) HR* ANGLE OF REPOSE* 32.820
0.444
0.625
28.96
1.40
Where, * All values are mean SD, n = 3. 5.2.3 Acarbose: Loss on drying Table no: 29 Results of loss on drying of Acarbose bulk drug. Sr.no 1 Test Specification / limits Observations 3.04%w/w
Loss on drying Not more than 4% w/w
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Table no: 30 Results of evaluation of Acarbose bulk powder. Sr.No MATERIAL BD*(g/ml) TD* (g/ml) CI *(%) HR* ANGLE OF REPOSE* 28.960
Acarbose
0.5872
0.6644
11.619
1.131
* All values are mean SD, n = 3.
5.3 Drug Excipient Compatibility Studies:

FTIR studies: The IR Spectra of both the drugs and the mixture of excipients and their tablets where prepared by wet granulation and direct compression method and is given in the fig no. 12 to 15 All the samples were scanned at the resolution of 4 cm-1 over the wave number region 4000-400 cm-1 using KBr disk method. This KBr disks where formed by taking Drug and KBr in a ratio of 1:100 respectively. Then this mixture was mixed well in mortar for three to five min. A very small amount of this mixture was uniformly spread and sandwich between the pellets and pressed using KBr pellet press at a pressure of 20,000 psi for 1 min. The pressure was then released and pellet was placed into the pellet holder and thus scanned in the IR region.
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Fig no. 12 FTIR spectrum of Pure Metformin HCl Table no: 31 Characteristic peak of pure Metformin HCl
Functional group C-N N-H C=N
Characteristic peak Stretching 1350-1000 cm-1 3500-3300 cm-1 1690 cm-1 and 1640 cm-1 Bending -1640-1500 cm-1 1450 & 1375 cm-1
Observed peak Stretching 1263.42 cm-1 and 1228.7 cm -1 3173.01 cm-1 1626.05 cm-1 Bending -1585.54 cm-1 1417.73 cm-1 & 1371.43 cm-1
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Fig no. 13 FTIR spectrum of Metformin SR layer
Table no: 32 Characteristic peak of Metformin HCl SR layer
Functional group C-N N-H C=N
Characteristic peak Stretching 1350-1000 cm-1 3500-3300 cm-1 1690 cm-1 and 1640 cm-1 Bending -1640- 1500 cm-1 1450 & 1375 cm-1
Observed peak Stretching 1263.42 cm-1 and 1228.7 cm -1 3187.42 cm-1 1626.05 cm-1 Bending -1583.36 cm-1 1417.73 cm-1 & 1371.43 cm-1
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Fig no. 14 FTIR spectrum of Pure Acarbose
Table no: 33 Characteristic peak of pure Acarbose
Functional group C-N N-H C-O O-H
Characteristic peak Stretching 1350-1000 cm-1 3500-3300 cm-1 1260-1100 cm-1 3650-3600 cm-1 Bending -1640-1500 cm-1 ---
Observed peak Stretching 1340.57 cm-1 2922.25 cm-1 1151.54 cm-1 3367.82 cm-1 Bending -1456.30 cm-1 ---
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Fig no. 15 FTIR spectrum of Acarbose IR layer
Table no: 34 Characteristic peak of Acarbose IR layer
Functional group C-N N-H C-O O-H
Characteristic peak Stretching 1350-1000 cm-1 3500-3300 cm-1 1260-1100 cm-1 3650-3600 cm-1 Bending -1640-1500 cm-1 ---
Observed peak Stretching 1340.57 cm-1 2945.40 cm-1 1143.83 cm-1 3410.36 cm-1 Bending -1471.74 cm-1 ---
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The compatibility studies are carried out to study the possible interactions between Metformin HCL and inactive ingredients as well as Acarbose and inactive ingredients, physical mixtures of both API and exipients were prepared separately as per the ratios mentioned in table 35 and 36 and kept for stability at 400 C and 75% RH and at 600 C and 90% RH for one month. Samples were taken out after 15 days and were subjected to physical and chemical testing. The pre-formulation study was carried out using drug and excipient compatibility studies. The results obtained from drug and excipient compatibility studies indicate that the, Metformin Hydrochloride is compatible with Acarbose and added excipients HPMCK4M, HPMC15cps, povidone, sodium CMC, Anhydrous DCP, Magnesium stearate and Colloidal silicon dioxide and thus further studies were carried out using these excipients. Acarbose is compatible with exipients BHA, BHT, L-HPC, CCS, Lactose DCL 15, HPMC 15cps, talc, magnesium stearate and sunset yellow lake. Thus further studies were carried out using these exipients.
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Table no: 35 Excipient compatibility study for Metformin Hydrochloride: CONDITIONS Sr.NO. DRUG EXCIPIENT INITIAL RT 400C/75%RH 2 week 1 2 3 4 5 6 7 8 Metformin HCl + Acarbose (1:1) Metformin HCl + Anhydrous dibasic calcium phosphate (1:1) Metformin HCl + HPMC K4M (1:1) Metformin HCl + HPMC 15cps (1:1) Metformin HCl + Sodium CMC (1:0.5) Metformin HCl + povidone (1:0.25) Metformin HCl + MagnesiumStearate (1:0.25) Metformin HCl + colloidal silicon dioxide (1:0.25) 0ff white colour White colour 0ff white colour White colour off white colour White colour White colour White colour NC NC NC NC NC NC NC NC 4 week NC NC NC NC NC NC NC NC 600C/90%RH 2 week NC NC NC NC NC NC NC NC 4 week NC NC NC NC NC NC NC NC compatible compatible Compatible Compatible Compatible Compatible Compatible Compatible COMMENTS
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Table no: 36 Exipient compatibility for Acarbose: Conditions Sr.no. Drug + Excipient Initial RT 400C/75%RH 2 week 1 2 3 4 5 6 Acarbose + BHA (1:0.25) Acarbose + BHT (1:0.25) Acarbose + L-HPC (1:1) Acarbose+ CCS(1:1) Acarbose + Lactose DCL 15 (1:1) Acarbose + HPMC15cps (1:0.5) Acarbose + magnesium stearate (1:0.25) Acarbose + sunset yellow lake (1:0.01) 0ff white colour White colour 0ff white colour Off white colour off white colour off white colour NC NC NC NC NC NC 4 week NC NC NC NC NC NC 600C/90%RH 2 week NC NC NC NC NC NC 4 week NC NC NC NC NC NC Compatible Compatible Compatible Compatible Compatible Compatible Comments
off white colour
NC
NC
NC
NC
Compatible
Orange colour
NC
NC
NC
NC
Compatible
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5.4 Formulation and Evaluation: Based on the inference from the excipient compatibility studies, the compatible exipients were used for formulation development of bilayer tablets which were further evaluated for various parameters. 5.4.1 Evaluation of blend The micromeritic properties such as angle of repose, Hausners ratio, bulk density, tapped density and Carrs index of Metformin HCL sustained released layer blend and Acarbose immediate release layer blend were studied. The overall results were tabulated in table no: 37 & 38 The value of Bulk density indicates good packing characters. The Compressibility index (CI) of the optimized formulation (F-9a) were found to be below 15, indicating excellent flow properties of granules which were further analysed by determining the angle of repose for all granules, it ranged between 25 0 to 270 which indicates good flow properties of granules.
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Table no: 37 Evaluation of granules of Metformin HCL sustained release Layer PARAMETERS Formulations F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 Where, *All values are mean SD, n = 3 Table no: 38 Evaluation of granules of Acarbose immediate release Layer PARAMETERS Formulations F-1 F-2 F-3 F-4 F-5 F-6 Where, Angle of Repose ( )* 30.96 0.23 26.56 0.21 28.2 0.13 25.24 0.19 24.1 0.21 25.8 0.23 BD (g/ml)* 0.64 0.02 0.52 0.02 0.57 0.00 0.55 0.01 0.55 0.01 0.53 0.01 TD (g/ml)* 0.76 0.02 0.62 0.04 0.66 0.01 0.66 0.01 0.64 0.00 0.60 0.01 CI (%)* 15.78 0.13 16.12 0.04 13.63 0.11 16.66 0.15 14.06 0.05 11.66 0.13 HR* 1.18 0.01 1.19 0.01 1.15 0.02 1.2 0.01 1.16 0.02 1.13 0.01 Angle of Repose ()* 29.1 0.13 24.5 0.28 27.8 0.19 29.2 0.16 25.9 0.21 26.8 0.23 26.2 0.17 27.9 0.08 27.9 0.22 BD (g/ml)* 0.47 0.02 0.51 0.02 0.48 0.00 0.50 0.01 0.50 0.01 0.46 0.01 0.53 0.02 0.47 0.01 0.58 0.00 TD (g/ml)* 0.58 0.02 0.64 0.04 0.57 0.01 0.55 0.01 0.57 0.00 0.54 0.01 0.64 0.02 0.57 0.01 0.66 0.00 CI (%)* 18.96 0.13 20.31 0.04 15.78 0.11 9.09 0.15 12.28 0.05 14.810.13 17.18 0.14 17.54 0.14 12.12 0.08 HR* 1.23 0.01 1.25 0.01 1.18 0.02 1.18 0.01 1.140.02 1.17 0.01 1.2 0.01 1.12 0.01 1.13 0.01
*All values are mean SD, n = 3
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5.5 Evaluation of the tablets: 5.5.1 Physical Parameters: The compressed tablets were evaluated for diameter, thickness, average weight, hardness, weight variation and friability. The results for formulations F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8 & F-9a are given in the table no: 39 Assay: The drug content of the tablets was assayed by using HPLC. The Assay result of formulations F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8 & F-9a are given in the table no: 40
Fig. no. 16 Chromatogram of Sample B (Metformin HCl)
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Fig. no. 17 Chromatogram of Sample A (Acarbose) and standard chromatogram
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Table no: 39 Evaluation of bilayer tablets of Metformin Hydrochloride SR and Acarbose IR: F-1 to F-9a Sr. No 1 TESTS SPECIFICATION White/orange coloured oblong shaped uncoated bilayer tablets. Should pass @@ 3% from average weight 18.2 18.5 8.8 9.1 3% from average 8 -10 kg/cm 2 NMT 0.8% w/w F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 a** Passes
Appearance Identification test Weight variation(mg)

#
Passes
passes
passes
passes
passes
Passes
Passes
Passes
2 3 4 5 6 7 8 Where,
*
Passes 1046 22.42 18.39 8.92 6 8.5 0.3
Passes 1068 21.98 18.35 8.9 6.4 8 0.3
passes 1067 19.52 18.4 8.91 6.34 8 0.3
passes 1149 24.3 18.37 8.92 6.54 8 0.21
passes 1154 23.32 18.39 8.9 6.42 8.5 0.15
Passes 1150 26.63 18.37 8.89 6.45 8.5 0.19
Passes 1148 23.98 18.35 8.9 6.47 8.5 0.14
Passes 1146 19.16 18.39 8.91 6.38 9.5 0.14
Passes 1146 20.56 18.38 8.9 6.34 9.7 0.11
Length (mm)# Width (mm) Thickness (mm)* Hardness (kg/cm2)* Friability (%w/w)#
#
All values are mean SD, n = 5. #All values are mean SD, n = 20.
**
All the parameters are within the limits and

@@
found to be satisfactory in F 9a and the sample complies with respect to dissolution as per In-house specification.
The retention time of the peaks due to Acarbose and metformin HCl as obtained in the sample chromatogram under test Assay should correspond to the standard chromatogram under similar condition.
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Table no: 40 Evaluation of In vitro dissolution and Assay of bilayer tablets of Metformin Hydrochloride SR and Acarbose IR: F-1 to F-9a Sr.No TESTS SPECIFICATION NLT 85% of the labeled amount dissolved in 45 min. F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 a**
Dissolution
1. Acarbose
75.5
78.5
82.4
87.2
90.1
98.2
97.9
98.96 98.73
2. Metformin HCl 1 1st Hr 4th Hr 8th Hr Between 25-40% Between 60-80% NLT 85% 95 110% of labeled amount 95 110% of labeled amount 66.98
Average 60.02 49.54 49.86 43.86 37.14 27.5 31.25 32.49
85.15 94.11
83.82 76.93 76.93 76.31 72.29
62.4
67.89 69.89
93.57 88.37 88.37 88.56 86.75 83.53 93.71 96.75
Assay 1. Acarbose 2 2. Metformin HCl 90.4 94.1 94.6 95.2 99.88 98.2 99.8 101.8 102.5
99.06
99.41 99.41 101.3
99.3
99.3
99.41
99.3
99.6
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5.6 In Vitro Dissolution Studies: 5.6.1 FOR ACARBOSE: For Acarbose layer, the dissolution studies were carried out in the water. Apparatus Medium Speed Time : : : : Dissolution Apparatus IP Type I (Paddle) Water: 900ml 75 RPM 45 Minutes 37 0.5 0C.
Temperature :
5.6.2 FOR METFORMIN HYDROCHLORIDE: For Metformin Hydrochloride layer, the dissolution studies were carried out as per In house method. Apparatus Medium Speed Time intervals Temperature : : : : : Dissolution Apparatus I of USP (Basket) Phosphate Buffer pH 6.8, 1000 ml 100 RPM 1st hour, 4th hour, & 8th hour. 37 0.5C
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Comparison of cumulative percentage release of different formulation of Bilayer tablets:

Table no: 41 In vitro release study of Bilayer tablets of different formulation. IMMEDIATE RELEASE LAYER ACARBOSE Sr. Time Limit Cumulative percentage drug release
no:
1 45 mins
(%)
NLT 85%
F-1(%)
75.5 1.64
F -2(%)
78.45 1.50
F -3(%)
82.4 1.44
F -4 (%)
87.2 1.65
F -5 (%)
90.1 1.82
F -6 (%)
98.2 1.55
F -7 (%)
97.9 1.29
F-8(%)
98.96 0.93
F-9a(%)
98.7 1.08
SUSTAINED RELEASE LAYER METFORMIN HCl 1 1 hr 20-40% 66.98 1.52 60.02 1.55 54.43 1.36 49.54 1.59 43.85 2.12 37.14 1.735 27.50 1.39 31.25 1.5 32.49 1.42
4 hr
60-80% NLT 85%
85.15
0.95 94.11 2.04
83.82
1.54 93.57 1.33
81.02
1.69 93.05 1.56
76.93
1.54 88.37 2.08
76.31
2.02 88.56 1.23
72.29
1.48 86.75 1.58
62.40
1.99 83.53 1.36
67.89
1.57 93.32 1.67
69.89
1.844 96.75 2.13
8 hr
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DESIGN DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASE 120 100 Cum % drug release 80 60 40 20 F-7 0 0 -20 10 20 Time (min) 30 40 50 F-8 F-9
Acarbose
F-1 F-2 F-3 F-4 F-5 F-6
Fig no. 18 CPR of different formulation of Acarbose IR layer (layer 2)
120 100 Cum % drug release 80 60 40 20 0 0 1 2 3
Metformin HCl
F1 F2 F3 F4 F5 F6 F7 F8 F9 4 5 Time (Hrs) 6 7 8 9
Fig no. 19 CPR of different formulation of Metformin HCl SR layer (layer 1)
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Based on the in vitro release profile of drug from the formulations F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, and F-9a. The formulation F-9a was optimized for further studies. The formulation F-9a showed better drug release, which was achieved by increasing the polymer concentration ratio of HPMC K4M to that of drug compared to formulation F-6, and by adding HPMC 15cps (channeling agent) compared to the formulation F-7. Hence the polymers in following ratios HPMC K4M (5.9%), Sodium CMC (23.66%) and HPMC 15 cps (1.77% w/w) release the drug in a controlled rate at regular time intervals in appropriate concentrations as per the limits. Hence the formulation F-9a was selected for stability and further studies.
120 100 80 60 40 20 0 0 -20 1 2 3
F -9a
Cum % drug release
metformin Acarbose
Time(Hrs)
Fig no. 20 CPR of F-9a of Metformin HCl SR layer and Acarbose IR layer
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5.7 Mathematical model fitting of obtained drug release data: The in-vitro release studies data was quantified to determine the release mechanism, to fit various mathematical models and to determine which was the best-fit model. The various parameters like the time exponent (n), the release rate constant (k) and the regression co-efficient (R2) were also calculated. In a set of data, the model showing the highest value to R2 was taken as the best-fit model. In the tables R2 = Regression coefficient. n = Time exponent. K = release rate constant. Table no: 42 Data of various parameters of model fitting for Metformin hydrochloride for optimized formulation F 9a. Formulation F-9a 0.922 0.974 0.999 0.998 0.529 Zero order R2 First order R2 Higuchi R2 Peppas R2 K
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zero order release (F- 9a)

120 cum % drug release 100 80 60 40 20 0 0 2 4 Time (Hrs) 6
y = 11.322x + 12.98 R = 0.9225
10
Fig no. 21 Plot showing zero order kinetics of formulation F-9a.
2.5 Log % drug retained 2 1.5 1 0.5 0 0 2 2 1.83
First order (F- 9a)
y = -0.1817x + 2.0474 R = 0.9743
1.478
0.52
4 Time (Hrs)
10
Fig no. 22 Plot showing First order kinetics of formulation F 9a.
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Higuchi (F- 9a)

120 100 Cum % drug release 80 60 40 20 0 -20 0 0.5 1 1.5 square root T
y = 34.531x - 0.5544 R = 0.9991
2.5
Fig no. 23 Plot showing Higuchi model of formulation F- 9a.
2.5 Log Cum % drug release 2 1.5 1 0.5 0 0 0.2
Peppas (F- 9a)
y = 0.5299x + 1.5145 R = 0.9986
0.4 Log Time
0.6
0.8
Fig no. 24 Plot showing peppas model of formulation F 9a
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Table no: 43 Data of various parameters of model fitting for Metformin HCl for different formulation. Zero order Formulation R2 F-8 F-9a 0.921 0.922 R2 0.990 0.974 R2 0.998 0.999 R2 0.997 0.998 K 0.532 0.529 First order Higuchi Peppas
Stability Study of Optimized Formulation: Stability studies were conducted for the optimized batch (F9a). The stability study was performed at 40C 2C/75%RH5%RH for 3 months. The tablets were analyzed for hardness, drug content and in-vitro drug release, after a period of 90 days. The results obtained are shown in table no: 44, 45, 46, 47. The formulation showed no variation in the hardness, drug content (Assay) and in-vitro drug release (dissolution). The overall results showed that the formulation is stable for a period of 90 days at the above mentioned storage condition:
Stability studies of bilayer tablets of Metformin hydrochloride (SR) and Acarbose (IR) at 400C 2/75%RH. Batch number Batch Size Packing details : F 9b : 2000 tablets : Clear PVC Blister
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Table no: 44 Evaluation of Bilayer tablets of Stability Batch: F-9b Sr. no: Tests Limits White/orange coloured oblong shaped uncoated bilayer tablets. Should pass the test 1% from target weight 8 10 kg/cm2 Initial result 1st Month results passes 2nd Month results passes
Appearance Identification test Average weight Hardness
passes
2 3 4
passes 1149 9 kg/cm2
passes 1146 9.5 kg/cm2
passes 1149 9.6 kg/cm2
Table no: 45 Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9b Initial result 1st Month results 2nd Month results
Sr no:
Tests
Limits
1 2
1 2
Cumulative percent drug release NLT 85% of the labelled Acarbose 96.2% 95.9% 95.7% amount dissolved in 45 min. Metformin HCl st 1 hour Between 25-40% 32.6% 32.5% 32.4% 4th hour Between 60-80% 70.1% 69.9% 69.84% th 8 hour NLT 85% 96.8% 96.8% 96.6% Assay 95 110% of labeled Acarbose 101.7% 100.88% 99.8% amount Metformin 95 110% of labeled 99.6% 99.8% 99.4% HCl amount
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Stability studies of bilayer tablets of Metformin hydrochloride (SR) and Acarbose (IR) at 400 C/75%RH. Batch number Batch Size Packing details : F 9c : 2000 tablets : Clear PVC Blister
Table no: 46 Evaluation of Bilayer tablets of Stability Batch: F-9c Sl Tests no: Appearance Limits White/orange coloured oblong shaped uncoated bilayer tablets. Initial result 1st Month results Passes 2nd Month results Passes
Passes
2 3 4
Identification Should passes for Metformin test HCl & Acarbose Average weight Hardness Target weight 1145mg 1% 8 10 kg/cm2
Passes 1149.5 9
Passes 1147 9.5
Passes 1145 9.6
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Table no: 47 Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9c Sr no: Tests Limits Initial result 1st Month results 96.1% 2nd Month results 96.7%
1 2
1 2
Cumulative percent drug release NLT 85% of the labelled Acarbose 98.2% amount dissolved in 45 min. Metformin HCl st 1 hour Between 25-40% 32.8% th 4 hour Between 60-80% 70.4% 8th hour NLT 85% 96.6% Assay 95 110% of labeled Acarbose 102.7% amount Metformin 95 110% of labeled 99.8% HCl amount
32.5% 32.1% 69.94% 69.76% 96.3% 96.1% 102.6% 99.8% 101.8% 99.6%
Fig no: 25 Photograph of Bilayer tablets
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6. DISCUSSION In order to achieve the development of a combination of conventional and sustained release dosage forms, currently, the bilayer technology with multiple layers having a rapid and sustained phase has been investigated. This formulation can be used for the treatment for type-2 Diabetes Mellitus. For the study, Metformin hydrochloride and Acarbose were used as model drugs for the treatment of type-2 Diabetes Mellitus, which were formulated by using wet granulation method with Metformin Hydrochloride as sustained release layer where as the core consisted of an immediate release layer Acarbose made by direct compression. Compatibility studies: The IR Spectrum of pure Metformin Hydrochloride, Acarbose and other exipients was compared with the IR spectrum of formulated Metformin Hydrochloride sustained release and immediate release of Acarbose tablets. The IR spectrums of the formulation were matching with the IR spectrum of pure Metformin Hydrochloride and Acarbose. (Fig no. 12, 13, 14 &15) There is no appearance or disappearance of any characteristics peaks. This shows that there is no interaction between the drug, excipients and polymers used in the tablets. Evaluation of blend materials of Bilayer tablets: Angle of repose for layer 1 granules (Metformin HCl SR layer) was found to be between 24.5o 29.24o and layer 2 granules (Acarbose IR layer) was found to be between
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24.1o 30.96o, which is well within the specified limit of 20 - 30 and the type of flow is good. Bulk density for layer 1 granules was found to be between 0.46 0.58g/ml and layer 2 granules was found to be between 0.52-0.64g/ml. Tapped density for layer 1 was found to be between 0.54 0.66g/ml and layer 2 granules was found to be between 0.60 0.76g/ml. Carrs index for layer 1 was found to be in the range of 9.09 20.31 and for layer 2 was found to be in the range of 11.66 16.12. All the granules are well within the specification limit. Hausners ratio for layer 1 was found to be between 1.12 1.25 and for the layer 2 was found to be between 1.13 1.2. With this the granules were found to be free flowing material and showed suitability to be compressed as tablets of expected weight. Evaluation of Bilayer tablets: All the formulations of bilayer tablets fulfilled the official requirements of uniformity of dosage units. The average percentage of deviation of 20 tablets of each formula was less than 3% (Table no: 39). The thickness of all the formulations of bilayer tablet (F -1 to F-9) ranged from 6 6.6mm (Table no: 39). The hardness and percentage friability of all batches ranged from 8 10.0 Kg/cm2 and 0.11 0.3% respectively (Table -39).
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Formulation of Bilayer tablets: Based on the preformulation data, HPMC K 4 M and sodium CMC was taken as drug release retardants for sustained release layer of Metformin Hydrochloride. HPMC 15 CPs used as channeling agent. The formulation consists of two layers, Sustained release layer of Metformin Hydrochloride (845 mg), layer - 1. An immediate release layer of Acarbose (300 mg), layer 2
Layer 1 Metformin Hydrochloride: In formulation F 1, the sustained layer consists of 1.18% HPMC K4M. In F 2; sustained layer consists of HPMC K4M and sodium CMC in the ratio of 1.18%: 10%. In F- 3, the sustained layer consists of HPMC K4M and sodium CMC, in the ratio 2.3%: 10%. In all the three formulation the weight of the tablet was adjusted with DCP anhydrous to 845 mg. The release of the drug in F-1, F-2 and F-3 was not within the specification limits i.e. the release of the drug at 1st and 4th hour was more than the limits. In order to retard the release of the drug to be meet the specification limits, the HPMC K4 M conc. was increased from 1.18 % to 2.3% and sodium CMC conc. was increased from 10% to 20% in formulation F- 4. (Table no: 18)
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In F- 5, the HPMC K4 M conc. was increased from 2.3 % to 3.6% and sodium CMC conc. was maintained at 20%, while, the weight of the tablet was adjusted with DCP anhydrous to 845 mg. The release of the drug in F- 4 and F- 5 was not within the specification limits i.e. the release of the drug at 1st hour was more than the limits and in 4th hour the release was almost near to 80%. To match the release profile of the drug, the HPMC K4 M conc. was increased from 3.6 % to 4.9% and sodium CMC conc. Was increased from 20% to 23.66% in formulation F-6 (Table no.18),where as the weight of the tablet was adjusted with DCP anhydrous to 845 mg. It was found that the release profile of F-6 was within the specification limits i.e at 4th hour and 8th hour, where as the release of drug in the 1st hour was slightly on the higher side, i.e near to 40%. To match the release profile of the drug, only the HPMC K4 M conc. was increased from 4.9 % to 5.9% in formulation F- 7. F- 7, was found to be satisfactory, where the release of the drug in F- 7 at 1st and 4th hour was satisfactory but at 8th hour the release was less than the limits. To match the release profile of the drug, in formulation F- 8 and in F- 9, HPMC 15 cps was added in the ratio of 1.18% and 1.77% respectively, which acts as a channeling agent.
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F 8 and F- 9, was found to be satisfactory, where the release of the drug at 1st, 4th and 8th hour was within the limits. Among the two trials of F 8 and F-9, the trial F-9 was found to be satisfactory, which contained 1.77% of HPMC 15 cps, where the release of the drug at 1st, 4th and 8th hour was 32.49%, 69.89% and 96.75% and hence the reproducibility trials (F-9b and F9c) with the same formula of F9a was taken to confirm whether it meets the specification and it was found to be reproducible. Layer 2 (Acarbose) In the formulation F-1, immediate release layer of Acarbose was prepared by dry granulation method with BHA, BHT, SSG, microcrystalline cellulose PH 102, colloidal silicon dioxide, Magnesium stearate, sunset yellow lake. The immediate release layer consists of SSG in the conc. of 7.5%, where the weight of the tablet was adjusted with microcrystalline cellulose PH 102 to 200 mg. The release profile of Acarbose in F-1 was found to be lesser than the limits and assay was less than 95%. Hence further formulation was formulated by direct compression. In F-2 weight of the tablet was increased to 220mg. 18% of Lactose DCL 15 was added and the weight of the tablet was adjusted with microcrystalline cellulose PH 102 to 220 mg. The release profile of Acarbose in F-2 was found to be lesser than the limits.
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In order to increase the release rate, 3% L - HPC was added in formulation F-3 and the weight of the tablet was adjusted to 220mg with Lactose DCL 15. Again the release profile of Acarbose in F-3 was found to be lesser than the limits. The release profile of Acarbose for F-1 to F-3 was 75.5%, 78.5% and 82.4% respectively. In order to increase the release profile of Acarbose, in formulation F 4, 2% CCS was used as a super disintegrant, talc as a glident and weight of the tablet was increased to 300mg. The release profile of Acarbose in F - 4 was found to be near to the limits. To match the release profile of the drug with the limits, the concentration of CCS was increased from 2.0% & 3.0% w/w and the concentration L - HPC added was
3%and 5% in formulation F-5 & F-6 respectively, to meet the dissolution profile of Acarbose. The release profile of Acarbose for F-4 to F-6 was 87.2%, 90.1% and 98.2% respectively. From the above results it was found that release profile for Acarbose was better in formulation F- 6, where CCS and L- HPC used at concentration of 3% and 5%w/w respectively. Hence this trial was selected as an immediate release layer to formulate bilayered tablets with Metformin Hydrochloride as sustained release layer.
Mathematical model fitting of the data obtained from in vitro release study of formulation F-9a for sustained release layer: The data obtained from in vitro release study were fitted to various mathematical model like zero order, First order, Higuchi model and Peppas model. The results of mathematical model fitting of data obtained indicated that, the best fit model in
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all the cases the release was found to be by diffusion for optimized formulation (F- 9a). Thus the release of the drug from the dosage form was found to be diffusion and nonfickian release.
Stability studies The tablets from trials F 9b and F- 9c was charged for stability at 30oc/65%RH and 40oC/75% for three months and the 3months results was found to be satisfactory.
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7. CONCLUSION Success of the In vitro drug release studies recommends the product for further in vivo studies, which may improve patient compliance. From the literature Metformin HCl and Acarbose, individual dosage form was used in the management of diabetes mellitus. Combination of Acarbose as immediate release layer and Metformin HCl as sustained release layer improves the patient compliance. From the results formulation F-9a has been selected as best formulation among all the other formulations. Formulation F-9a provides better in vitro release from layer 1 as well as layer 2. The data obtained from in vitro release study were fitted to various mathematical model like zero order, First order, Higuchi model and Peppas model. The results of mathematical model fitting of data obtained indicated that, the best fit model in all the cases the release was found to be by diffusion for optimized formulation (F- 9a). Thus the release of the drug from the dosage form was found to be diffusion and nonfickian release. The formula optimized and it was selected for stability studies as per ICH guidelines. Based on the stability data the company (Micro Labs Ltd) may launch the product to trade.
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8. SUMMARY The present work involves the formulation development, optimization and in-vitro evaluation of bilayer tablet containing Acarbose in the immediate release layer and Metformin HCl in sustained release layer. Using croscarmellose sodium superdisintegrant for the immediate release layer and the hydrophilic matrix formers such as HPMC K4M, and sodium CMC for the sustained release layer. HPMC 15cps used as channeling agent in sustained release layer. Bilayer tablet showed as initial burst effect to provide dose of immediate release layer, Acarbose followed by sustained release of Metformin HCl for 8 hours indicating a promising potential for the bilayer tablet of Metformin HCl sustained release and immediate release of Acarbose as an alternative to the conventional dosage form for the treatment of type 2 diabetes mellitus. To minimize critical process parameters, direct compression method was selected for the formulation of Acarbose immediate release layer. Under the preformulation studies API (Active Pharmaceutical Ingredient) characterization, and drug-excipient compatibility studies were carried out. The API characterization showed compliance with the drug characteristics. The polymers and other excipients were selected based on the satisfying results produced during drug-excipient compatibility studies to develop the final formulation. The in vitro study showed that formulation 9a was ideally suited to be sustained release formulation.
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The final suitable formulation was achieved fruitfully by the wet granulation method for layer 1 and direct compression method for layer -2. HPMC K4M at a concentration of 5.9%, HPMC 15 cps at a concentration of 1.77% and Sodium CMC at a concentration of 23.66%, produced desired release profile for Metformin HCl sustained release layer as per in-house specifications.
The results reveal that trial F-9a has met the objective of sustained drug release, patient convenience and cost effectiveness as a once a day dose of the drug.
FUTURE PLAN Scale up studies of the optimized formulation. Bioequivalence studies with the marketed formulations. Stability study for developed dosage form as per current ICH guidelines. In-vivo and In-vitro correlation studies.
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9. BIBLIOGRAPHY 1. Gilbert S. Banker, Neil R. Anderson., tablets. In Leon Lachman, Herberta Liebermann, Joseph L Kanig. (Edition), the theory and practice of Industrial pharmacy, 3rd ed. Lea and Febiger, Philadelphia, 1987, page. no. (a) 293-294, (b) 330-331, (c) 430-431. 2. Available on online URL; www.wikipedia.com. 3. Abraham. M.A., Shirwaikar. A., Formulation of multilayered sustain release tablets using insoluble matrix systme., Indian Journal of Pharmaceutical Science. 1997; 59(6): page no. 312-315. 4. William C. Gunsel and Robert. G. Busel., compression coated and layer tablets, 1987, In: Herbert A Libermann, Leon Lachman, Joseph.B. Schwartz Pharmaceutical dosage form: Tablets 2 1,274. 5. Charles Slchioo, Joseph R. Robinson, Remingtons Pharmaceutical science 1985, 17
th nd
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edition page. no. 1644-1653.
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10. ANNEXURE
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ERRATA
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DESIGN, DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASE

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

UNDER THE GUIDANCE OF

Dr. C.S.R LAKSHMI

DEPARTMENT OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY BANGALORE-85.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.

DECLARATION BY THE CANDIDATE

NARGUND COLLEGE OF PHARMACY BANGALORE-85

CERTIFICATE BY THE GUIDE

NARGUND COLLEGE OF PHARMACY BANGALORE-85

CERTIFICATE BY THE CO-GUIDE

NARGUND COLLEGE OF PHARMACY BANGALORE-85

ENDORSEMENT BY THE HEAD OF DEPARTMENT

Dr. C. S. R. Lakshmi HOD Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.

NARGUND COLLEGE OF PHARMACY BANGALORE-85

ENDORSEMENT BY THE PRINCIPAL

Date Place: Bangalore

Dr. L. V. G. Nargund Principal, Nargund College of Pharmacy, Bangalore 85.

Rajiv Gandhi University of Health Sciences, Karnataka.

LIST OF ABBREVIATIONS USED

: Time required to reduce the amount to half of its original concentration

TDD TD temp. USP UV v w WS

2. Aims & Objectives

126 127 127 128 129

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

Then the entire tablet is compressed in one or two steps.

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

Fig no. 2 Multilayer Compression

Fig no. 3 Bilayer tablet compression machine

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

Sustained release drug delivery system:

Fig no. 4 Sustained release drug delivery system

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

1.5 Sustained release dosage form:

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

Fig no. 5 Matrix tablet

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

Fig no. 6 Diffusion release pattern.

Fig no. 7 Osmotic release pattern

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

RELATED TO BILAYER TABLETS:

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY