DISSOLUTION TECHNOLOGY IN PHARMACEUTICS

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DISSOLUTION TECHNOLOGY:

DISSOLUTION TECHNOLOGY MOHD. KAMRAN M.Pharm (1 st sem ) Department of pharmaceutics(Q.A) Faculty of pharmacy Jamia hamdard New Delhi 1

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DISSOLUTION TESTING IS THE HEART OF PHARMACEUTICAL SCIENCES 2

CONTENTS:

CONTENTS General introduction Importance and application Theories of drug dissolution Variables affecting dissolution of drugs from tablet and capsules Environmental factors affecting dissolution of drug In vitro dissolution testing models 3

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GENERAL INTRODUCTION 4

WHY WE NEED TO STUDY DISSOLUTION IN PHARMACEUTICAL SCIENCES?:

WHY WE NEED TO STUDY DISSOLUTION IN PHARMACEUTICAL SCIENCES? 5 Drug in systemic circulation Drug at target site Drug showing therapeutic effect

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6 SOLID SOLUTE enters into SOLUTION DEFINITION DISSOLUTION RATE OF DISSOLUTION AMOUNT OF DRUG SUBSTANCE goes in solution per unit time UNDER STANDARDIZED CONDITON OF SOLID/LIQUID INTERFACE, TEMP.,SOLVENT COMPOSITION

HISTORICAL PROGRESS:

HISTORICAL PROGRESS YEAR SCIENTIST NAME WORK DONE 1987 Noyes and Whitney rate of dissolution of solid substances is determined by rate of diffusion of a very thin layer of saturated solution that forms instantaneous around the solid particles. 1907 Nernst and Brunner introduce fick’s law of diffusion to the Noyes and Whitney equation. during 1950s investigations shifted from the influence of physicochemical characteristics of drugs on dissolution to an examination of the effects of dissolution behavior of drugs on the biological activity of dosage forms. 7

HISTORICAL PROGRESS:

HISTORICAL PROGRESS YEAR SCIENTIST NAME WORK DONE 1951 Edwards analgesic activity of aspirin tablet can be controlled and/or modified by its rate of dissolution within the GIT. 1960 Levy and Hayes incidence of local irritation and the absorption rate of acetyl salicylic acid are a function of its dissolution rate in its particular dosage form. late 1960s dissolution testing became a mandatory U.S. pharmacopoial requirement for several dosage forms. 8

MECHANISM OF DISSOLUTION:

MECHANISM OF DISSOLUTION liberation of the solute or drug from the formulation matrix (disintegration) dissolution of the drug (solubilisation of the drug particles) in the liquid medium. If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled. 9

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Intrinsic dissolution rate Rate of mass transfer per area of dissolving surface and its unit is mg cm -2 min -1 . IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH, ionic strength, counters ions etc. 10

IMPORTANCE AND APPLICATIONS :

IMPORTANCE AND APPLICATIONS IMPORTANCE (Need of dissolution): Explain the observed differences in in-vivo availability. Evaluate adequate bioavailability and provides information to formulator in development of more efficacious and therapeutically optimal dosage forms. Most sensitive and reliable predictors of in-vivo availability. Ensure quality of product. Ensure bioavailability of product between batches that meet dissolution criteria. Ensure batch-to-batch quality equivalence both in-vitro and in-vivo Screen potential drug and their associated formulations for dissolution and absorption characteristics. APPLICATIONS: Product development Quality assurance Product stability Comparability assessment Waivers of in-vivo bioequivalence requirements 11

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THEORIES OF DRUG DISSOLUTION 12

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Diffusion layer model/Film Theory Danckwert’s model/Penetration or surface renewal Theory Interfacial barrier model/Double barrier or Limited solvation theory. 13

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It involves two steps :- Formation of stagnant film or layer at solid/liquid interface which is saturated with the drug. Diffusion of soluble solute from the stagnant layer to the bulk of the solution; slower and R.D. step in drug dissolution. Diffusion layer model/Film Theory 14

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The rate of dissolution is given by Noyes and Whitney: Where, dc/ dt = dissolution rate of the drug K= dissolution rate constant C s = concentration of drug in stagnant layer C b = concentration of drug in the bulk of the solution at time t 16 = k (C s - C b ) dc dt

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Nernst and B runner incorporated fick’s law of diffusion and modified Noyes-Whitney’s Equation - Where, D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw/o = water/oil partition coefficient of drug. V= volume of dissolution medium. h= thickness of stagnant layer. (C s – C b )= conc. gradient for diffusion of drug. 17 DAKw/o (C s – C b ) Vh = dc dt

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First order dissolution rate process, for which the driving force is concentration gradient. This is true for in-vitro dissolution which is characterized by non-sink conditions in a limited dissolution medium. In-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. C b =0 and rate of dissolution is maximum. 18

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Under sink conditions, if the volume and surface area of the solid are kept constant, then This represents that the dissolution rate is constant and follows zero order kinetics. 19 = K dc dt

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Conc. of dissolved drug Time first order dissolution under non-sink condition zero order dissolution under sink condition Dissolution rate under non-sink and sink conditions. 20

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Hixon -Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W 0 1/3 – W 1/3 = K t Where, W 0 =original mass of the drug W=mass of drug remaining to dissolve at time t K t =dissolution rate constant. 21

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22 what is Sink condition? Sink conditions describe a dissolution system that is sufficiently dilute so that the dissolution process is not impeded by approach to saturation of the compound of interest. Sink conditions affect the production of the sample but not the condition of the solution upon sampling. In vivo condition, there is no conc. build up in the bulk of the solution and hence no retarding effect on the dissolution rate of the drug i.e. Cs>>Cb and sink condition maintain.

In vitro sink conditions can be achieved by::

In vitro sink conditions can be achieved by: Bathing the dissolving solid in fresh solvent from time to time. Increasing the vol. of dissolving fluid. Removing the dissolving drug by partitioning it from the aqueous phase of the dissolving fluid into an organic phase either below or above the dissolution fluid. Adding a water miscible solvent such as alcohol to the dissolution fluid. Adding selective adsorbent to the dissolved drug. NOTE : the in vitro sink condition are so maintained that C b is always less than 10% of C s . 23

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Danckwert’s model/Penetration or surface renewal Theory Eddies or packets are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. Packets get continuously replaced by new ones due to which drug conc. at the solid-liquid interface never reaches ‘Cs’ and solvent packets are exposed to new solid surface each time, thus the theory is called as surface renewal theory. 24

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The Danckwert’s model is expressed by equation: Where, m = mass of solid dissolved Gamma ( γ ) = rate of surface renewal(interfacial tension) dC dt = dm dt = A (Cs-Cb). D γ V 26

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The concept of this theory is explained by following equation- G = K i (C s - C b ) Where, G = dissolution rate per unit area, K i = effective interfacial transport constant. An intermediate concentration can exist at the interface as a result of solvation mechanism and is a function of solubility rather than diffusion. Interfacial barrier model/Double barrier or Limited solvation theory 27

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Variables affecting dissolution of drugs from tablet and capsule 28

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Environmental factors Factors relating to the Physiochemical properties of drug Factors related to the dosage forms Processing factors Factors relating dissolution apparatus intensity of agitation, rate and type of flow of fluids and geometrical factors. Concentration gradient Composition of the dissolution medium ; pH , ionic strength,viscosity,surface tension, etc Temperature of the dissolution medium Affecting solubility Polymorphism Amorphous state and solvation Free acid, free base, or salt form Complexation , solid solution and eutectics Particle size Surfactants. Affecting surface area Particle size Manufacturing variables Co-precipitation Granule size and size distribution. Amount and type of diluent or filler Amount and type of disintegrant and method of Incorporating it. Amount and type of surfactant (if any) and method of Incorporating it. Amount and type of binders and granulating agent and method of Incorporating it. Amount and type of lubricants and method of Incorporating it. Composition and properties of the capsule shell. Water soluble dyes Coating polymers Method of granulation Wet granulation Direct compression Agglomerative phase of communication (APOC) Compression force Drug excipient interaction Intensity of packing of capsule contents Stirring element alignment Eccentricity of agitating element Sampling probe position and filters Vibration Flow Pattern Disturbances Dosage form position Environmental factors involved with dosage forms Humidity during manufacture Storage condition for dosage forms Age of dosage forms 29

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Environmental Factors affecting dissolution testing 30

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Agitation conditions markedly affect diffusion controlled dissolution, as thickness of diffusion layer is inversely proportional to agitation speed. Agitation intensity can be varied by dimensions and geometry of dissolution apparatus, vol. of dissolution medium and degree of agitation or shaking. Agitation should be maintained at a relatively low rate, in order to prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results. BASKET METHOD- 100 rpm PADDLE METHOD- 50-75 rpm AGITATION INTENSITY: 31

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Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important. Generally, a temp of 37º ± 0.5 is maintained during dissolution determinations. The effect of temp. variations depends mainly on the temp./solubility curves of the drug and excipients in the formulation. TEMPERATURE: 32

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It is very imp factor affecting dissolution and is itself affected by number of factors such as: Effect of pH: In present of acidic buffers(with a pH close to gastric juice), instead of distilled water the dissolution rate increases as effective surface area increases. DISSOLUTION MEDIUM: 33

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composition of dissolution medium and sink conditions Volume: 500, 900 or 1,000 ml. Simulated gastric fluid(SGF) - pH 1.2. Simulated intestinal fluid (SIF)- pH 6.8 (not exceed pH 8.0). enzymes should be evaluated case-by-case like…. (Pepsin with SGF and pancreatin with SIF) for poorly soluble, a relatively large amount of fluid is used if complete dissolution is to be expected. To minimize the effect of conc. gradient and maintain sink conditions, the conc. of drug should not exceed 10-15% of its max. Solubility in dissoln . medium selected. For most of the drugs about 1 L is more than sufficient to maintain sink conditions. 34

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Size reduction technology (micronization, nanonisation, supercritical fluid recrystallization ) Spray freezing into liquid (SLF) Evaporative precipitation into aqueous solution(EPAS) Use of non-ionic surfactant in conc. above CMC. Use of salt forms Use of precipitation inhibitors Alteration of the pH of the drug microenvironment 35 Approaches to improve dissolution rate of poorly soluble drugs Solvent deposition Precipitation Selective adsorption on insoluble carriers Solid solution Eutectic mixtures Solid dispersions Inclusion complexes (Molecular encapsulation with cyclodextrins)

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Dissolved gases-air Dissolved air in distilled water lower its pH and affect the dissolution rate of drugs that are sensitive to pH changes. When temp. changes dissolved gases release in the form of bubbles and collect at the screen of the basket, changing the effective mesh porosity thus interferes with the dissolution rate. Air bubbles also collect at the surface of the dosage forms and act as a hydrophobic barrier between solvent and solid surface. This inhibits wetting and reduction of S.A. and lower dissolution rate. 36

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Viscosity: Dissolution rate decreases with increased viscosity of the dissolution medium; especially in the case of diffusion controlled dissolution process. viscosity has very little effect on interfacial controlled dissolution process. Surface tension: surfactant and wetting agents improve the penetrability of the dissolution medium into the matrix by lowering the contact angle, thereby enhancing the dissolution process. 37

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IN-VITRO DISSOLUTION TESTING MODELS 38

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I.P. USP B.P. E.P. Type 1 Paddle apparatus Basket apparatus Basket apparatus Paddle apparatus Type 2 Basket apparatus Paddle apparatus Paddle apparatus Basket apparatus Type 3 Reciprocating cylinder Flow through cell apparatus Flow through cell apparatus Type 4 Flow through cell apparatus Type 5 Paddle over disk Type 6 cylinder Type 7 Reciprocating holder 42

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USP APP. DESCRIPTOIN ROT. SPEED DOSAGE FORM Type 1 Basket apparatus 50-120rpm Conventional tablets, chewable tablets, CR Type 2 Paddle apparatus 25-50rpm orally Disintegrating tablets, chewable tablets, CR, suspensions Type 3 Reciprocating cylinder 6-35rpm CR, chewable tablets Type 4 Flow through cell apparatus N/A ER , poorly soluble API, powder, granules, microparticles, implants Type 5 Paddle over disk 25-50rpm Transdermal Type 6 cylinder N/A Transdermal Type 7 Reciprocating holder 30rpm CR(non disintegrating oral and Transdermal ) 43

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The assembly consists of the following : covered vessel, motor, metallic drive shaft, cylindrical basket, The water bath permits the holding of temp inside vessel at 37±0.5 ̊C The vessel is a cylindrical with hemispherical bottom with dimension and capacity of. Liter Height Inside diameter 1 160-210 mm 98-106 mm 2 280 – 300 mm 98-106 mm 4 280 – 300 mm 145-155 mm 44

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The shaft is positioned so that its axis is not more than 2mm at any point from the vertical axis of the vessel and rotates smoothly and with out significant wobble. Use 40mm mesh cloth. A basket having a gold coating 0.0001 inch thick may be used. The dosage unit is place in a dry basket at the beginning of each test. The distance between the inside bottom of the vessel and the basket is maintained at 25± 2m. Drug product: Solids (mostly floating) Monodisperse (tablets) Polydisperse (encapsulated beads) Disadvantage: Formulation may clog to 40 mesh screen 45

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The assembly from apparatus 1 . Except paddle formed from a blade. a shaft is used as the stirring element The vertical center line of the blade is flush with the bottom of the shaft. The distance of 25±2 mm between the blade and the inside bottom of the vessel. 46

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The paddle, blade and shaft may be coated with a suitably inert coating. The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade. A small, loose piece of non reactive material such as wire helix may be attached to dosage units in order to prevent floating. Drug product : Solids (mostly non floating) Monodisperse (tablets) Polydisperse (encapsulated beads) Standard volume: 900/1000 ml Advantages: 1. Easy to use and robust 2. pH change possible 3. Can be easily adapted to apparatus Disadvantages Floating dosage forms require sinker Positioning of tablet 47

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PROCEDURES Place the stated volume of the dissolution medium in the vessel. Equilibrate the dissolution medium to 37±o.5 ̊c Place 1 tablet or 1 capsule in the apparatus. Operate the apparatus Within the time interval, withdraw a specimen from zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, not less than 1cm from vessel wall. Replace the aliquots withdrawn for analysis with equal volume of dissolution medium at 37 ̊c. 48 INTERPRETATION:

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Limitations of USP Apparatus 1and 2: USP 2 (and USP1) Apparatus has plenty of HYDRODYNAMICS. Complicated 3-dimensional flow generated by the paddle. Significant impact of convective transport –Conditions used (50 – 100 rpm) highly exaggerates flow in the GI. Use of solvents and surfactants non-native to GI. 49

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The assembly consists of: set of cylindrical, flat-bottomed glass vessels; set of glass reciprocating cylindrical; stainless steel fitting; screen; motor and drive. The vessel is immersed in water bath holding temp at 37± 0.5 ̊ 50

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PROCEDURE: Place the stated volume of the dissolution medium in each vessel . Equilibrate the dissolution medium to 37 + 0.5° Place 1 dosage-form unit in each of the six reciprocating cylinders. Operate the apparatus During the upward and downward stroke, the reciprocating cylinder moves through a total distance of 9.9 to 10.1 cm Within the time interval specified withdraw a portion of the solution under test from a zone midway between the surface of the dissolution medium and the bottom of each vessel. Perform The analysis as directed in the individual monograph. 51

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Useful for : Tablets , Beads , controlled release formulations Standard volume : 200-250 ml/station Advantages: Easy to change the pH-profiles Hydrodynamics can be directly influenced by varying the dip rate. Disadvantages: small volume (max. 250 ml) Limited data 52

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The assembly consists of: reservior and pump for the dissolution medium; flow-through cell; water bath. The pump forces the dissolution medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 mL per hour, with standard flow rates of 4, 8, and 16 mL per minutes. The cell is immersed in a water bath and the temperature is maintained at 37 + 0.5° The apparatus uses a clamp mechanism and two O-rings for the fixation of the cell assembly. Apparatus 4- Flow through cell 53

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PROCEDURE: Place the glass beads into the cell specified in the monograph. Place 1 dosage form unit on top of the beads. Assemble the filter head and fix the parts together by means of a suitable clamping device. Introduce by the pump the dissolution medium warmed to 37 + 0.5° through the bottom of the cell. Collect the eluate by fractions at each of the times stated. Perform the analysis as directed in the individual monograph. 54

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Useful for: Low solubility drugs , Micro particulates, Implants , Suppositories , Controlled release formulations Variations: Open system Closed system Advantages: Easy to change media pH PH-profile possible Sink conditions Disadvantages: Deaeration necessary High volumes of media Labor intensive Tablets 12 mm Tablets 22,6 mm Powders /Granules Implants Suppositories/soft gelatin capsule 55

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The paddle and vessel assembly from apparatus 2 with the addition of stainless steel disk assembly . The temperature is maintained at 32 + 0.5°C A distance of 25 + 2 mm between the paddle blade and the surface the disk assembly is maintained during the test. The disk assembly is designed to minimize any dead volume between the disk assembly and the bottom of the vessel. Apparatus 5- Paddle over disk 56

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PROCEDURE: Place the stated volume of dissolution medium in the vessel assemble the apparatus without the disk assembly and equilibrate the medium to 32 + 0.5°C Apply the transdermal system disk assembly. The system may be attached to the disk by a suitable adhesive. Place the disk assembly flat at the bottom of the vessel with the release surface facing up and parallel to of the paddle blade and surface of the dissolution medium. Operate the apparatus At each sampling time interval, withdraw a sample from a zone midway between the surface of the dissolution medium and the top of the blade, not less than 1 cm from the vessel wall. Perform the analysis on each sampled aliquot as directed in the monograph. Useful for: Transdermal patches Standard volume : 900 ml Disadvantages: Disk assembly restricts the patch size. 57

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The vessel assembly from apparatus 1 except to replace the basket and shaft with a stainless steel cylinder stirring element and to maintain the temperature at 32 + 0.05°C The dosage unit is placed on the cylinder at the beginning of each test. The distance between the inside bottom of the vessel and the cylinder is maintained at 25 + 2 mm during the test. PROCEDURES: Place the stated volume of the dissolution medium in the vessel. Equilibrate the dissolution medium to 32 + 0.5°C Prepare the test system prior to test as follows. Remove the protective liner from the system and place the adhesive side on a piece of cuprophan . Cuprophan covered side down, on a clean surface, and apply a suitable adhesive to the exposed cuprophan borders. Dry for 1 minutes. Press the cuprophan covering to remove trapped air bubbles. Place the cylinder in the apparatus and immediately rotate at the rate specified Within the time interval specified, withdraw a quantity of dissolution medium for analysis from a zone midway between the surface of the dissolution medium and the top of the rotating cylinder, not less than 1 cm from the vessel wall. Perform the analysis as directed in the individual monograph. Apparatus 6- Cylinder 58

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The assembly consists of: a set of volumetrically calibrated or tared solution containers, motor and drive assembly to reciprocate the system vertically, set of suitable sample holders. The solution containers are partially immersed in a suitable water bath, inside the temperature of the containers at 32 + 0.5°C 59

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Dosage form Apparatus Buccal and sublingual tablets. Model 1 Model 2 2. Lipid –filled soft gelatin capsules. Pillay & Fassihi model 3. Chewing gum European Pharmacopoeia chewing apparatus 4. I.R. Mini Paddle Apparatus 5. TDDS Franz diffusion apparatus Paddle over disk Cylinder method Flow through diffusion cell 6. Semisolid dosage form USP paddle over disk Franz diffusion apparatus Flow through apparatus Unconventional apparatus designed by chouhan 7. Parenteral Depot Rotating dialysis cell 61

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Dosage form Apparatus 8. Suspension Rotating Paddle 9. Inhaler A USP Apparatus 2, Hanson SR8-Plus dissolution test station 62

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Model I Model II Pillay & Fassihi model E.P. apparatus for Chewing gum Mini Paddle Apparatus Semisolid dosage form For ointment Rotating dialysis cell For suspension For inhaler 63

REFRENCES:

REFRENCES Banakar V. U. and et. al. , pharmaceutical dissolution testing, markcel deken , pg 4,16,57,136-137 Remington, the science and practice of pharmacy, mack pub. Co. , 19 th edition pg 594,601,602 Brahmankar D.M. , Jaiswal S. , biopharmaceutics and pharmacokinetics a treatise, vallab prakashan , 2 nd edition, pg 29-34 www.dissolutiontech.com U.S. Pharmacopia,2008 64

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