Formulation and Evaluation of Darifenacin Extended Release Matrix Tablets

FORMULATION AND EVALUATION OF DARIFENACIN EXTENDED RELEASE MATRIX TABLETS
1. INTRODUCTION1
Oral route is the most oldest and convenient route for the administration of therapeutic agents because of low cost of therapy and ease of administration leads to higher level of patient compliance. Approximately 50% of the drug delivery systems available in the market are oral drug delivery systems and historically too, oral drug administration has been the predominant route for drug delivery. It does not pose the sterility problem and minimal risk of damage at the site of administration.
During the past three decades, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate. The oral controlled release formulation have been developed for those drug that are easily absorbed from the gastrointestinal tract (GIT) and have a short half-life are eliminated quickly from the blood circulation. As these will release the drug slowly into the GIT and maintain a constant drug concentration in the plasma for a longer period of time. In oral controlled drug delivery the amount of drug release is constantly predetermined and these constant releases of drug provide a constant blood plasma level of the drug for optimal therapeutic response. The oral controlled drug delivery has many advantages to conventional drug delivery.
The ideal and most important objectives of drug delivery are spatial placement and temporal delivery of the drug. Spatial placement relates to targeting a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue. An appropriately designed sustained release drug delivery system can be a major advance towards solving issues related to spatial placement and temporal delivery. 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 special placement as well.
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The potential problems associated with conventional (multiple dosages) delivery are:
If the dosing is not appropriate according to the biological half-life of the drug, the concentration of drug level in blood may result in large "Peaks" and "Valleys". For example, drugs with short half-lives require frequent dosing to maintain constant therapeutic levels. The drug blood level may not be within the therapeutic range at sufficiently early times, an important consideration for certain disease states. Patient noncompliance with the multiple-dosing regimen can result in failure of the conventional approach.
Frequently these problems are significant enough to make drug therapy with conventional dosage forms less desirable than sustained release drug therapy. This fact, coupled with the intrinsic inability of conventional dosage forms to achieve spatial placement, is a compelling motive for investigation of sustained-release drug delivery systems.
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2.EXTENDED RELEASE SYSTEM:2
Extended release drug delivery system achieves a slow release of the drug over an extended period of time or the drug is absorbed over a longer period of time. Extended release dosage form initially releases an adequate amount of drug to bring about the necessary blood concentration (loading dose, DL) for the desired therapeutic response and therefore, further amount of drug is released at a controlled rate (maintenance dose, DM) to maintain the said blood levels for some desirable period of time.
The sustained release, sustained action, prolonged action, controlled release, extended action, timed release, depot and respiratory dosage forms are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.
Extended release formulation is an important program for new drug research and development to meet several unmet clinical needs. There are several reasons for attractiveness of these dosage forms viz. provides increase bioavailability of drug product, reduction in the frequency of administration to prolong duration of effective blood levels, Reduces the fluctuation of peak trough concentration and side effects and possibly improves the specific distribution of the drug.
2.1. Objectives of Extended Release Drug Delivery System:
Every noval drug delivery system had a rationale for developing the dosage form likewise, ERDDS also having some objectives that are discussed below:
2.2. Suitable Drug Candidate for Extended Release Drug Delivery System The drugs that have to be formulated as a ERDDS should meet following parameters. It should be orally effective and stable in GIT medium. Drugs that have short half-life, ideally a drug with half life in the range of 2 4 hrs makes a good candidate for formulation into ER dosage forms eg. Captopril, Salbutamol sulphate.
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The dose of the drug should be less than 0.5g as the oral route is suitable for drugs given in dose as high as 1.0g eg. Metronidazole. Therapeutic range of the drug must be high. A drug for ERDDS should have therapeutic range wide enough such that variations in the release do not result in concentration beyond the minimum toxic levels.
2.3. Merits of Extended Release Drug Delivery System: The extended release formulations may maintain therapeutic concentrations over prolonged periods. avoids the high blood concentration. Reduce the toxicity by slowing drug absorption. Minimize the local and systemic side effects. Improvement in treatment efficacy. Minimize drug accumulation with chronic dosing. Improvement of the ability to provide special effects. Enhancement of activity duration for short half life drugs.
2.4. Demerits of Extended Release Drug Delivery System: In case of acute toxicity, prompt termination of therapy is not possible. Less flexibility in adjusting doses and dosage regimens. Risk of dose dumping upon fast release of drug. High cost of preparation. The release rates are affected by various factors such as, food and the rate transit through the gut. The larger size of extended release products may cause difficulties in ingestion or transit through gut.
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3. Matrix System 3
A polymer and active ingredient are mixed to form a homogenous mixture called as matrix system. The matrix system is often used for a controlled drug release from a pharmaceutical dosage form; it is used for delay and control release of the drug that is dissolved or dispersed in a resistant support. To define matrix, it is necessary to know the characteristics that differentiate it from other controlled release dosage forms:
The chemical nature of support (generally formed by polymeric net) The physical state of drug (dispersed under molecular or particulate form or both) The matrix shape and alteration in volume as a function of time. The route of administration (oral administration remains the most widely used but other route are adaptable) The release kinetic model.
Advantages of Matrix System :
The interest awakened by matrix system in last few years is completely justified in view of its major advantages. Among these, the following stand out:
With proper control of manufacturing process, reproducible release profiles are possible. There is no risk of "dumping" a large part of dose, as the structure makes the immediate release of a small amount of active principle unavoidable. Their capacity to incorporate active principle is large, which suits them to deliver large dosag
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4. Principle of Modified Drug Release4
Either of the following two principles can modify drug release:
Barrier principle In this method the retardant material is imposed between the drug and elution medium. Drug release is by diffusion of the drug through the barrier and or erosion of the barrier or permeation of the barrier by moisture.
Embedded matrix In this drug is dispersed or embedded in a matrix of retardant material that may be encapsulated in particulate form or compressed into tablet. Drug release occurs by permeation of water leaching extraction or diffusion of drug from the matrix and erosion of matrix material.
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5.Mechanisms of Drug Release from Matrix5
6. Advantages of Hydrophilic Matrix Tablets6
1. With proper control of the manufacturing process, reproducible release profiles are possible. The variability associated with them is slightly less than that characterizing coated release form.
2. Structure allows an immediate release of small amount of active principle and furthermore there is no risk of dose dumping. 3. Their capacity to incorporate active principle is large, which suits them to deliver large doses. 4. The manufacturing processes are notably simple. Tablet formulation can be done via direct compression or by wet granulation techniques. 5. Large varieties of non expensive gelling agents are approved for oral use by the competent official organization. 6. The safety margin of high-potency drugs can be increased.
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7. The drug release from hydrophilic matrices show a typical time dependent profile i.e decreased drug release with time because of increased diffusion path length.
7. OVER ACTIVE BLADDER7
Overactive bladder (OAB) is a syndrome characterised by urinary urgency, with or without urgency urinary incontinence(UUI) usually with frequency and nocturia, in the absence of causative infection or pathologic conditions and suggestive of underlying detrusor overactivity (phasic increases in detrusor pressure). Urgency, is defined as the sudden compelling desire to urinate, a sensation that is difficult to defer. UUI is urinary leakage associated with urgency. Some women may have both stress urinary incontinence and UUI, and this is called mixed urinary incontinence. Urinary frequency is defined as voiding 8 or more times in a 24-hour period. Nocturia is defined as the need to wake 1 or more times per night to void. Treatment of OAB is aimed at reducing the debilitating symptoms in order to improve the overall the quality of life in affected patients and Anticholinergic agents that target the muscarinic receptors in the bladder (antimuscarinic agents) are the medical treatment of choice because they reduce the contractility of the detrusor muscle. 7.1 CAUSES: Overactive bladder is typically caused by spasms of the muscles of the bladder, resulting in an urge to urinate (hence, urge incontinence). Overactive bladder is primarily a problem of the nerves and muscles of the bladder. Detrusor is one of the major muscles of the bladder. Its contraction in response to filling of the bladder by urine is one the steps in the normal process of urination. The contraction and relaxation of the detrusor muscle is regulated by the nervous system. Approximately 300 cc of urine in the bladder can signal the nervous to trigger muscles of the bladder to coordinate urination. Voluntary control of the sphincter muscles at the opening of the bladder can hold the urine in the bladder for longer. Up to 600 cc of urine can be contained in a normal adult bladder. Overactive bladder typically results from inappropriate contraction of the detrusor muscle regardless of the amount of urine.
There are also some causes of overactive bladder and urge incontinence with a normal nervous system. For example, urinary tract infection, bladder stones, or bladder tumors can cause also cause overactivity of the detrusor muscle, leading to overactive bladder.
8.TREATMENT OF OAB
Anticholinergics inhibit the binding of acetylcholine to the muscarinic receptor in the detrusor, thereby suppressing involuntary bladder contractions. They are associated with an increase in bladder volume voided, as well as a decrease in micturition frequency and sensation of urgency.
Muscarinic antagonists are the drugs that bind with muscarinic cholinergic receptors but do not activate them, thus preventing access to acetylcholine; examples include atropine, scopolamine, propantheline, and pirenzepine. Muscarinic Receptor antagonists are often referred to as parasympatholytic because they selectively block the effects of parasympathetic nerve activity.
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9. LITERTURE REVIEW9
1.Darifenacin hydrobromide sustained-release tablet and preparation method Chuangxin pharmaceuticals RES AND DEV CO LTD:This invention belongs to medicine technology field specifically relates to a darifenacin hydrobromide slow release tablet and preparation method thereof the invention claims a darifenacin hydrobromide slow release tablet adopts the new retardant carbomer relative to the existing technology high expression processing method of a half of the retarding agent dosage of carbomer of occupying the preparation by weight 1%- 5% ~ it can achieve the same as the exterior of the releasing speed and biological utilization degree; New method of a retarding agent dosage of is greatly reduced it can greatly reduce the material the using amount of the technique is simple controllability is good the efficiency is improved the production cost is reduced greatly.
2.K.P.Sampath Kumar et al., (2012), reviewed recent trends in scope and opportunities of control release oral drug delivery systems. Many of new therapeutics under development are large molecules such as peptides, proteins, oligonucleotides, and vaccines. Their physical, chemical, and biopharmaceutical attributes distinct from small molecule drugs demand novel controlled release technologies to diminish barriers for oral delivery, such as instability in GI tract and poor absorption. Those unmet technology needs create great opportunities for research, development, and innovation. It is optimistic that breakthroughs in controlled oral delivery for water-insoluble drugs and biopharmaceuticals will have a significant impact on pharmaceutical and biotechnology industry. This article examines several aspects in oral drug delivery requiring implementation of novel ideas to improve oral drug delivery systems. Drug Delivery is a burgeoning field that represents one of the major research and development focus areas of pharmaceutical industry today, with new drug delivery system sales exceeding 10 billion dollars per year.
3.Madhusudhan Pogula et al., (2010), reviewed on Extended Release Formulation. Oral Extended release drug delivery medication will continue to account for the largest share of drug delivery systems. Hence, in this work to formulate tablets in order to avoid the first pass metabolism and increase the bioavailability. Hence in this work an attempt was made to formulate extended release system in order to achieve plasma concentration profile up to 24 hrs. The extended release formulations are the type of formulations which will improves the therapeutic index of drug concentration. These formulations make the drug available over
extended time period after oral administration. The extended release product will optimize therapeutic effect and safety of a drug at the same time improving the patient convenience and compliance.
4.Harnish Patel et al., (2011), reviewed on Matrix Type Drug Delivery System. Matrix system are favoured 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 tablet with constant release rate has always been a challenge to the pharmaceutical technologist. Most of 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. Hydrophilic polymers have become product of choice as an important ingredient for formulating sustained release formulations.
5.Ranjani
et al.,
to develop model extended-release matrix tablet formulations for
metoprolol tartarate(100mg) sufficiently sensitive for regulatory policy development on scale-up and post approval changes for modified release dosage forms. Several grades and levels of Methocel K4M, K15M, K100M filler binders were studied. Three granulation process were evaluated direct compression, fluid-bed or high-shear granulation. At a fixed polymer level, drug release from the higher viscosity grades (K100LV). The study led to the choice of MethocelK100V as the hydrophilic matrix polymer and fluid-bed granulation as the process choice for further evaluation of critical and non-critical formulation and processing variables. Maria et al.,67 the potential value of hydroxyl propylmethyl cellulose mixture as gelling agents, and to investigate relationship between gelling agent viscosity and the kinetics of drug release from such tablets. Experiments were carried out with MethocelRK100M. trials were carried out with atenolol tablets made with 40% and 80% gelling agents. A negative relationship was observed between the Higuchi constant for each tablet type and the apparent viscosity of the corresponding gelling agent in aqueous dispersion. Tahara et al.,68 Application of model-independent and model analysis for the investigation of drug solubility on its release rate from hydroxyl propyl methyl cellulose sustained release
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tablets. Both in the model-independent and model analyses, the relationship obtained between drug solubility and release characteristic were similar. . Basak et al.,69 formulation and release behaviour of sustained release ambroxyl
hydrochloride HPMC matrix tablets and sustained release behaviour of the fabricated tablets was investigated. The most successful of the study exhibited drug release pattern very close to theoretical release profile. The mechanism of the drug release from diffusion coupled erosion. Hyun park et al.,71 prepared for on extended-release tablet using chitosan/carbopol interpolymer complex(Ipc), the chitosan/carbopol Ipc as characterized by FT-IR and turbidity measurements. The turbidity measurement revealed the complexation ratio of Ipc between chitosan/carbopol. The drug release profile from this tablet was similar to that from the HPMC tablet and showed at pH independent release profile. Rajin et al.721 preparation of extended release formulation of glipizide based on osmotic technology as developed and evaluated. Drug release as found to be affected by the level of solubility modifier in the core formulation. Glipizide release was inversely proportional to the membrane weight gain of the membrane. Drug release from the developed formulations was independent of pH and agitational intensity but dependent on the osmotic pressure of the release media. The number of pores in the membrane form where the drug release occurred. The number of pored were directly proportional to the initial level of pore former in the membrane. Srinivas et al.,73 to prepare glipizide matrix transdermal systems using the combination of ethyl cellulose polyvinylpyrrolidone and Eudragit RL-100/ Eudragit RS-100. The systems were evaluated for various in vitro and in vivo parameters. Drug content of the patches as found to be more than 98%. Variations in drug permeation profiles were observed among various formulations. The drug-polymer interaction results suggested no interaction between drug and polymers. The in vivo results revealed that the patches successfully prevented the serve hypoglycemia in the initial hours and they were also effective in chronic application.
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10.AIM OF THE STUDY The aim of the present study is to develop a robust formulation of anti muscarinic drug as an extended release matrix tablets. The polymers like HPMC K4M, HPMC K15M and HPMC K100M, Metalose 60 SH-50 and Xanthum gum were used as extended release polymer to retard the drug release. The invitro release pattern of final formulation was compared with the innovator.
OBJECTIVE The overall objective of the work is as follows To formulate and evaluate extended release Darifenacin hydrobromide by using various rate controlling polymers. To study the drug release profiles of the dosage form and to develop an optimized dosage form with better dissolution profile. To study the drug release profiles of formulations and To compare their drug-release profile with the innovator. To determine the best fit dissolution profile for dosage form. To study the stability of dosage form.
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11. PLAN OF WORK Literature review Procurement of API and Excipients Preformulation Studies: API Characterization Drug Excipient Compatibility Studies FTIR Studies Formulation of Darifenacin Hydrobromide extended release matrix tablets by using various drug: polymer ratios. Precompression Characterization Bulk Density Tapped Density Compressibility Index Hausners Ratio Angle of Repose Postcompression Characterisation Weight Variation Hardness Friability Uniformity of drug content
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In vitro dissolution studies
Comparision of drug release profile Study of Drug release kinetics Stability studies of the optimized formulation
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12. DRUG PROFILE Name of Drug Chemical Name
10-11
: :
Darifenacin hydrobromide (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3pyrrolidinyl}-2,2-diphenylacetamide hydrobromide
Formula Molecular Weight Structure:
: :
C28H30N2O2.HBr. 507.47 Daltons
Appearance Solubility
: White to almost white, crystalline powder : Soluble in dichloromethane, sparingly soluble in ethanol, practically insoluble in water
Storage Stability Melting point Pka (25oC) Loss On Drying
: : : :
Store in a cool, dry place. Store in a tightly closed conatiner Stable under normal temperature & pressure 229C 9.2 : Not more than 1.0%
Pharmacological Class: Genitourinary antispasmodic agent; an Antimuscarinic agent.
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Therapeutic Category:
Symptomatic treatment of urge incontinence and/or increased
urinary frequency and urgency as may occur in adult patients with overactive bladder syndrome. Mechanism of Action: Darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva
production, and iris sphincter function
Figure 5. Representing mechanism of antimuscarinic drug.
Pharmacokinetics Absorption: Bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets and steady-state plasma levels are achieved by the sixth day of administration. Distribution: 98% of darifenacin are bound to plasma proteins; steady-state volume of distribution (Vss) is estimated to be 163 litres
Metabolism: By CYP3A4 and CYP2D6; Three main metabolic routes: Monohydroxylation in the dihydrobenzofuran ring, Dihydrobenzofuran ring opening and N-dealkylation of the pyrrolidine nitrogen
Elimination: Approx. 60% urine; 40% faeces. Clearance: 40 L/h. Half life: 4-6 hours Pharmacodynamics Drug interactions: Metabolized principally by CYP2D6 and CYP3A4.May inhibit CYP2D6 and CYP3A4; not expected to inhibit CYP1A2 and CYP2C9.
Side effects: Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma or risk of these conditions. Recommended Dose: The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily, based on individual response.
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13.EXCIPIENT PROFILE12 Dibasic calcium phosphate Hypromellose (hydroxypropyl methylcellulose). Xanthan gum Magnesium stearate
13.1 DIBASIC CALCIUM PHOSPHATE
Table 1. Excipient profile of dibasic calcium phosphate
A TAB; calcium monohydrogen phosphate; calcium Synonyms orthophosphate, Di-Cafos AN, Dicalcium orthophosphate; E34 1; Emcompress Anhydrous; Fujicalin; phosphoric acid calcium salt (1 : 1); secondary calcium phosphate.Anhydrous dibasic calcium phosphate is a white, Description odorless,tasteless powder or crystalline solid. It occurs as triclinic crystals. Functional Category Solubility: Tablet and capsule diluent. Practically insoluble in ether, ethanol and water; soluble in dilute acids. Widely used in oral pharmaceutical products, food Safety: products, and toothpastes and is generally regarded as a relatively nontoxic and nonirritant material. Applications: used both as an excipient and as a source of calcium in nutritional supplements.
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13.2 HYPROMELLOSE Table2. Excipient profile of hypromellose Synonyms Benecel, HPMC, Methocel, Hydroxy propyl methyl cellulose Description White or creamy white fibrous or granular, odorless, tasteless powder. Functional categories Coating agent, film former, rate controlling polymer for sustained release, stabilizing agent, suspending agent, viscosity builder. Solubility Soluble in cold water, forming a viscous colloidal solution, practically insoluble in mixtures of ethanol and dichloromethane, mixtures of alcohol and water Applications High viscosity grades may be used to retard the release of drugs from a matrix at levels of 10-80%w/w in tablets and capsules .
13.3 XANTHUM GUM Table3. Excipient profile of xanthum gum Synonyms Corn sugar gum; E415; Grindsted; Keldent; Keltrol; polysaccharide B-1459; Rhodicare S; Rhodigel; Vanzan NF; xanthani gummi;Xantural. Description Xanthan gum occurs as a cream- or white-colored, odorless, freeflowing, fine powder. Functional categories Gelling agent; stabilizing agent; suspending agent; sustainedrelease agent; viscosity-increasing agent.
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Solubility
Practically insoluble in ethanol and ether; soluble incold or warm water.
Applications
Xanthan gum is widely used in oral and topical pharmaceutical formulations, cosmetics, and foods as a suspending and stabilizing agent. Although primarily used as a suspending agent, xanthan gum has also been used to prepare sustained-release matrix tablets.
13.4 MAGNESIUM STEARATE Magnesium Stearate is a fine, white, precipitated or milled, impalpable powder of low bulk density, having a faint, characteristic odor and taste. The powder is greasy to touch and easily adheres to the skin. The USPNF XVII describes magnesium stearate as a compound of magnesium with a mixture of solid organic acids obtained from fats and consists chiefly of variable proportions of magnesium stearate and magnesium palmitate. Table4.Excipient profile of magnesium stearate Synonyms Stearic acid magnesium salt, magnesium octadecanoate It is A fine, white, precipitated or milled, impalpable powder of Description low bulk density, having a faint odor of stearic acid & a characteristic taste. Functional Categories
Tablets & Capsule lubricant.
Solubility
It is insoluble in water, ethanol & ether. Slightly soluble in warm benzene & warm ethanol. It is widely used in cosmetics, food & pharmaceutical
Applications
formulations. It is primarily used as a lubricant in capsule & Tablets at concentration between 0.25-5.0 percent.
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14. MATERIALS AND EQUIPMENT
The following are the list of materials and equipments used in developing the formulation:
Table 5. List of Materials Used S. No. 1. 2. 3. 4. 5. 6. 6 7. Material Darifenacin Hydrobromide Dibasic Calcium phosphate HPMC K4M HPMC K15M HPMC K100 Metalose 60 sh 50 Xanthum Gum Magnesium stearate Name of supplier Shasun Chemicals and Drugs Ltd Signet chemicals Ltd. Colorcon Colorcon Colorcon Signet Chemicals Ltd. Signet Chemicals Ltd Signet chemicals Ltd.
Table6.List of Equipments s.no 1 2 3 4 5 6 7 8 9 10 11 Name of the Instrument

Electronic weighing balance pH meter Tablet hardness tester Digital Vernier callipers Friability Tester usp Bulk and Tapped Density Apparatus USP Coating machine Sieve Shaker dissolution apparatus USP I (basket) Uv_visible Spectrometer FTIR spectrophotometer
Manufacturer
Sartorious precision balance Thermo Lab Pharmatron tablet tester 8m Fischer scientific Electrolab Electrolab Neocota Retsch Electro lab Shimadzu Bruker
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12 13 14
HPLC Stability Chamber 25C/75%RH,40C/75%RH Octagonal Blender
Agilant Thermo Lab Rimet kalveka
15. List of ingredients used for the Extendeded release Darifenacin Hydrobromide matrix tablet :
INGREDIENTS
USES
Darifenacin Hydrobromide Di-BasicCalciumPhosphate(A-Tab) Methocel K 4 M Methocel K 15 M Methocel K 100 M HPMC Xanthan Gum Magnesium Stearate
Antispasmodic Diluent Matrix polymer and binder Matrix polymer and binder Matrix polymer and binder Matrix polymer and binder Binder Lubrient
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16. REFERENCES
Clive G Wilson and Patrick J Crowley. "Controlled Release in Oral Drug Delivery". Modi S A, Gaikwad P D, Bankar V H, Pawar S P, Sustained release drug delivery system: A review, International Journal of Pharma. Research and Development, 2011, 02(12), 147-59. Chien Y W, "Novel Drug Delivery System", Marcel Dekker, New York, 2nd edition, Revised and Expanded, Vol II, 1992, 139-140. Aulton M E. "Hand Book of Pharmaceutics", ELBS with Churchill Livingstone, Hong Kong, 2001, 291-295. Brahmankar D M and Sunil B Jaiswal. "Biopharmaceutics and Pharmacokinetics", Vallabh Prakashan, 1st edition, 1995, 347-371. Pogula M, Nazeer S, Extended release formulation, International Journal of Pharmacy and Technology, 2010, 02(04), 625-84.
Increased warning time with Darifenacin: a new concept in the management of urinary urgency Cardozo, Linda Dexon Andria, The journal of urology,173(4),p.1214-1218,Apr 2005.
Darifenacin-Pharmacology and clinical usage. Steers,William D-urologic clinics of NA 33(4),p.475-482,Nov 2006. Increased warning time with Darifenacin: a new concept in the management of urinary urgency Cardozo, Linda Dexon Andria, The journal of urology,173(4),p.1214-1218,Apr 2005.
The clinical Pharmacokinetics of Darifenacin Andry, clinical pharmacokinetics, 45(4),p.325-350,Jan 2006. International Union of Pharmacology. XVII. Classification of Muscarinic Acety choline Receptors. Malcolm p. Caulfield and Nigel J.M.Birdsall B. Dept of Pharmacology (M.P.C), University of Dundee, Scotland and division of Physical Bio chemistry (N.J.M.B)
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Koichiro Tahara, Ken Yamamoto, Toshiaki Nishihata. Application of Model-independent and model analysis for the investigation of effect of drug solubility on its Release rate from Hydroxypropyl Methylcellulose Sustained Release Tablets.I.J.Pharm. 1996;133:1727.
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FORMULATION AND EVALUATION OF DARIFENACIN EXTENDED RELEASE MATRIX TABLETS

NARASARAOPET INSTITUTE OF PHARMACEUTICAL SCIENCES