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INTRODUCTION Dissolution is the process by which a solid solute enters a solution, and is characterized by rate (amount dissolved by time). In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Dissolution is the quality control measure and potential to provide in sight into the in vivo performance of the drug product. In vitro release test that predicts the drug in vivo would be optimal and highly desirable.

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A variety of designs of apparatus for dissolution testing have been proposed and tested, varying from simple beaker with stirrer to complex systems . Different apparatus, procedures and techniques are required for different dosage forms because of significant differences in formulation design and the physicochemical properties of the drugs. Dissolution tests have been developed for various drug delivery systems including immediate release solid dosage forms, several controlled release solid dosage forms and many novel and special dosage forms . Most of the tests with recommended apparatus and other specifications are now available as compendial standards in Pharmacopoeias and are used in pharmaceutical analysis and drug development for the various drug delivery systems.


THE IDEAL FEATURES OF A DISSOLUTION APPARATUS Must be simply designed. Must be enough sensitive. Uniform hydrodynamic flow is essential. An easy means of introducing dosage form. Provide minimum mechanical abrasion to the dosage form. The medium must be maintained at a fixed temperature. Samples should be easily withdrawn.


USP DISSOLUTION APPARATUS Apparatus 1 - Basket (37º) Apparatus 2 - Paddle (37º) Apparatus 3 - Reciprocating Cylinder (37º) Apparatus 4 - Flow-Through Cell (37º) Apparatus 5 - Paddle over Disk (32º ) Apparatus 6 - Rotating Cylinder (32º) Apparatus 7 - Reciprocating Holder

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Apparatus 1 – Basket

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Apparatus 2 – Paddle

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Apparatus 3 – Reciprocating cylinder

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Apparatus 4 – Flow-Through Cell

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Apparatus 5 – Paddle over disk

Apparatus 6 - Rotating Cylinder :

Apparatus 6 - Rotating Cylinder

Apparatus 7 – Reciprocating holder:

Apparatus 7 – Reciprocating holder


NOVEL DRUG DELIVERY SYSTEMS A drug delivery system ideally should deliver a specified amount of medication to the site of action at an appropriate time and rate as dictated by the needs of the body. Novel drug delivery system is a system for delivery of drug other than conventional drug delivery system. To optimize drug’s therapeutic effect, convenience and dose. To enhance a product’s life-cycle. To improve `patient compliance. To target drug delivery. To control overall health care costs. To facilitate biological drug delivery.

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General principles of dissolution tests for conventional oral dosage forms also apply to the in vitro release tests for novel dosage forms. For orally administered immediate release solid drug products, the test is referred to as a “dissolution” test, since the drug is intended to dissolve rapidly in the test medium. For non-oral dosage forms the test is referred as “drug release test” or “in vitro release test”. Dissolution testing was initially developed for immediate release solid dosage forms and then extended to controlled/modified release solid oral dosage forms and has recently widened to a variety of “novel” or “special” dosage forms .

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PARENTERALS IMPLANTS AND MICROPARTICULATE FORMULATIONS The compendial and the modified flow-through cell have been used successfully for implants and microparticulate formulations. The compendial flow-through method is modified with regard to the inner diameter to suit the special properties for testing parenterals i.e a low volume of the fluid is used in the acceptor compartment and the flow rate is set very slow. Use of High Pressure Liquid Chromatography (HPLC) pumps may be considered to provide the necessary accuracy and precision at very low flow rates. Static or rotating bottles have also been used for in vitro testing.

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TRANSDERMAL PATCHES Compendial apparatus include the paddle over disk/disk assembly (USP apparatus 5), the rotating cylinder (USP apparatus 6), the reciprocating disk (USP apparatus 7), and a paddle over extraction cell method. The paddle over disk procedure with a watch glass-patch-screen sandwich assembly is considered to be the method of choice, as it has been shown experimentally that this procedure results in almost the same release profile as others. Ex: Franz diffusion cell The pH of the medium ideally should be adjusted to pH 5 to 6 and the test temperature typically set at 32 0 C,reflecting physiological skin conditions. The European Pharmacopoeia considers 100rpm a typical agitation rate and also allows for testing an aliquot patch section.

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OCULAR DRUG DELIVERY SYSTEMS A number of methods are used to conduct in-vitro evaluation of controlled ocular drug delivery systems. (a) Bottle method In this method, dosage forms are placed in the culture bottles containing phosphate buffer at pH 7.4. The culture bottles are shaken in a thermostatic water bath at 37°C. A sample of medium is taken out at appropriate intervals and analyzed for drug contents.

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b) Modified rotating basket method In this method, dosage form is placed in a basket assembly connected to a stirrer. The assembly is lowered into a jacketed beaker containing buffer medium. The temperature of system is maintained at 37°C. A sample of medium is taken out at appropriate time intervals and analyzed for drug content. c) Modified rotating paddle apparatus In this method, diffusion cells (those that are used for analysis of semi-solid formulations) are placed in the flask of rotating paddle apparatus. The buffer medium is placed in the flask and paddle is rotated at 50 rpm. The entire unit is maintained at 37 + 0.5° C. Samples are removed at appropriate time intervals and analyzed for drug content.

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MUCOSAL DRUG DELIVERY SYSTEMS In vitro release studies were performed in phosphate buffer solution (pH 6.6, 150 mL) at 37°C using a modified dissolution apparatus. The modified dissolution apparatus consisted of a 250-mL beaker as a receptor compartment and a glass rod attached with a grounded glass disk (2-cm diameter) as a donor tube. The back surface of NBAS or sustained release buccal tablet was attached to the glass disk with instant adhesive (cynoacrylate adhesive). The donor tube was then dipped into the receptor compartment containing dissolution medium, which was maintained at 37°C ± 0. 2°C, and stirred at a constant speed using a magnetic bead. Aliquots (5 mL each) were withdrawn at preset times (0.08, 0.16, 1, 2, 3, 4, 5, and 6 hours), filtered through a 0.2-µ filter, and then the amount of drug released was estimated by measuring the absorbance at 290 nm using a UV spectrophotometer (n = 3).

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MICROSPHERES Beaker method The dosage form in this method is made to adhere at the bottom of the beaker containing the medium and stirred uniformly using over head stirrer. Volume of the medium used for the studies varies from 50-500 ml and the stirrer speed form 60-300 rpm. Modified Keshary Chien Cell A specialized apparatus was designed in the laboratory. It comprised of a Keshary Chien cell containing distilled water (50ml) at 37 0 c as dissolution medium. TMDDS (Trans Membrane Drug Delivery System) was placed in a glass tube fitted with a 10# sieve at the bottom which reciprocated in the medium at 30 strokes per min. Samples are removed at appropriate time intervals and analyzed for drug content.

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COLON SPECIFIC DRUG DELIVERY SYSTEMS The ability of the tablets to remain intact in the physiological conditions of the stomach and small intestine is generally assessed by conducting drug release studies in 0.1M HCl for 2 hours (mean gastric emptying time) and in phosphate buffer (pH 7.4) for 3 hours (mean small intestinal transit time) using USP dissolution rates test apparatus or flow-through dissolution apparatus. The ability of the delivery system to release the drug in the colon is tested in vitro by incubating it in a buffer medium in the presence of enzymes (e.g pectinase, dextranase) or rat, guinea pig or rabbit ceacal content. The amount of drug release at different time intervals during the incubation is estimated to find out the degradation of the carrier under study.

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Another in vitro method involves incubation of the drug delivery system in a fermenter with commonly found colonic bacteria, such as Streptococcus feacium and Bacillus ovatus in a suitable medium under anaerobic conditions in which the amount of drug released at different intervals is determined.

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SEMISOLID TOPICAL DOSAGE FORMS Semisolid topical dosage forms include creams, ointments and gels. In vitro release from semisolid topical dosage forms has been extensively investigated using the Franz cell diffusion system with a synthetic membrane and to some extent using the enhancer cell. Depending on the solubility of the drug substance, the receptor medium may contain alcohol and/or surfactant. Deaeration is critical to avoid bubble formation at the interface with the membrane. Depending on the characteristics of the drug product, it may be possible to conduct the in vitro test without a synthetic membrane, the test temperature is typically 32 o C to reflect skin temperature except for products for specific sites of action.

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SUPPOSITORIES In principle, for hydrophilic suppositories that release the drug by dissolving in the rectal fluids, the basket, paddle, or flow through cell, can all be used. For lipophilic suppositories, a modified basket method, a paddle method with a wired screen and a sinker, and modified flow-through cell with specific dual chamber suppository cell, has all been recommended. To achieve the specified temperature in the test cell, the temperature in the water bath may have to be set up to 5 o C higher.

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No single test method will be suitable for all suppository formulations. However, when starting the development of an in vitro dissolution/release test, it might be advantageous to begin with the basket or paddle in the case of hydrophilic, and with modified flow-through cell in the case of lipophilic suppositories.

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ORALLY DISENTEGRATING TABLETS In vitro dissolution testing should follow the principles of solid oral dosage forms (tablets) or suspension. The rotating paddle would be the method of first choice, with an agitation rate of 50 rpm. Higher agitation rates may be necessary in the case of sample mounding. If taste masking (using polymer coating) is a key aspect of the dosage form, a multipoint profile in a neutral medium with early points of analysis (e.g. ≤5minutes) may be recommended.

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DISSOLVE IN THE MOUTH DOSAGE FORMS It comprises a single, stirred, continuous flow-through filtration cell that includes a dip tube designed to remove finely divided solid particles. Filtered solution is removed continuously and used to analyze for dissolved drug. The volume of liquid in the cell is approximately 10ml and fluid is pumped through it at about 6ml per minute. This gives a residence time in the cell of approximately 100sec for 63% of the dosage form and gives almost complete removal in about 8minutes. Approximately two third of the flow exits via the dip-tube and the other third exits through the filter for analysis. In use, the cell is filled and flows as set up first and allowed to reach steady state before the dosage form (solid, liquid, suspension or powder) is introduced. The filtered sample is either analyzed in-line e.g. by UV flow-through cell, or samples are collected in a fraction collector for later analysis.

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CONCLUSION An appropriate drug release test is required to characterize the drug product and ensure batch-to-batch reproducibility and consistent pharmacological/biological activity. Dissolution test continues to increase in importance as a quality control test in pharmaceutical analysis and drug development. These methods are also designed to mimic the physiological environment of the GIT and have increased the likelihood of establishing in vitro – in vivo correlation, IVIVC for more pharmaceutical products . The in vitro drug release test for some novel/special dosage forms such as semisolid dosage forms and transdermal drug delivery systems has proven to be as valuable as the dissolution test for solid oral dosage forms.


REFERENCES Martin Siewert, Jennifer Dressman, Cynthia K. Brown, and Vinod P. Shah. FIP/AAPS Guidelines to Dissolution/in Vitro Release testing of Novel/Special dosage Forms. AAPS PharmSciTech 2003; 4 (1)Article7. Burgess DJ, Hussain AS, Ingallinera TS, Chen M. Assuring quality and performance of sustained and controlled release par-enterals: workshop report. AAPS PharmSci. 2002;4(2):article 7. Chein YW.Transdermal Controlled Systemic Medication. NewYork and Basel, Marcel Dekker Inc. 1987; 159 -176. Alagusundaram.M*, Madhu Sudana Chetty.C, Umashankari.K. Microspheres as a novel drug delivery system-A review article. International Journal of ChemTech Research. Vol.1, No.3 , pp 526-534.

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Kashappa Goud, H. Desai, and T.M. Pramod Kumar. Preparation and evaluation of a novel buccal adhesive system. AAPS PharmSciTech. 2004; 5(3):article 35. Shah VP, Elkins JS, Williams RL. Evaluation of the test system used for in vitro release of drugs from topical dermatological drug products. Pharm Develop Technol. 1999;4:377-385. Gjellan K, Graffner C. Comparative dissolution studies of rectal formulations using the basket, the paddle and the flow-through methods, II: ibuprofen in suppositories of both hydro-philic and lipophilic types. Int J Pharm. 1994;112:233-240. Reddy, S. M., Sinha, V. R. and Reddy, S. R. (1999) Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs. Drugs of Today. 35 (7): 537-580.

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