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Guided by: Mrs. Ahirrao mam MET Institute of pharmacy, Nasik . 1CONTENTS:: CONTENTS: Definition Theories of Drug Dissolution Factors affecting Drug Dissolution In-vitro dissolution testing models Calibration In-vitro-In-vivo correlation References 2Definition: Definition 3Definition- : Definition- Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. 4Theories of Drug Dissolution: Theories of Drug Dissolution 5Theories of Drug Dissolution: Theories of Drug Dissolution Diffusion layer model/Film Theory Danckwert’s model/Penetration or surface renewal Theory Interfacial barrier model/Double barrier or Limited solvation theory. 6PowerPoint Presentation: Diffusion layer model/Film Theory :- It involves two steps :- Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug dissolution. 7PowerPoint Presentation: 8PowerPoint Presentation: 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 9 = k (C s - C b ) dc dtPowerPoint Presentation: Modified Noyes-Whitney’s Equation - 10 dC dt 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. DAKw/o (C s – C b ) Vh =PowerPoint Presentation: This is 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. The 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. 11PowerPoint Presentation: Under sink conditions, if the volume and surface area of the solid are kept constant, then dC dt This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. 12 = KPowerPoint Presentation: 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. 13PowerPoint Presentation: 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. 14PowerPoint Presentation: Danckwert’s model/Penetration or surface renewal Theory :- Dankwert takes into account the eddies or packets that 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. These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory. 15PowerPoint Presentation: 16PowerPoint Presentation: The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma ( γ ) = rate of surface renewal 17 dC dt = dm dt = A (Cs-Cb) . D γ VPowerPoint Presentation: Interfacial barrier model/Double barrier or Limited solvation theory :- 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. 18PowerPoint Presentation: Factors affecting Drug Dissolution :- Factors relating to the physicochemical properties of drug. Solubility Particle size and effective surface area of the drug Polymorphism and amorphism Salt form of the drug Hydrates/solvates 19PowerPoint Presentation: Factors relating to the dosage forms – Pharmaceutical excipient Manufacturing processes 20IN-VITRO DISSOLUTION TESTING MODELS: IN-VITRO DISSOLUTION TESTING MODELS 21INTRODUCTION: INTRODUCTION Alternative to in vivo bioavailability determination Dissolution testing – Official in pharmacopeias Quantify the extent of release of drug Routinely used by Q.C. and R&D Q.C. Evaluate – batch consistency R&D Prediction of drug release 22Official dissolution apparatus: Official dissolution apparatus USP 30 classification Rotating Basket Paddle Reciprocating Cylinder Flow Through Cell Paddle Over Disk Rotating Cylinder Reciprocating Holder 23Which type of dissolution apparatus ?: Which type of dissolution apparatus ? Depends on intention Quality control examining batch homogeneity examining batch to batch conformity examining stability Research & Development examining drug release behavior of preformulations in vitro simulation of the gastrointestinal passage IVIVC 24PowerPoint Presentation: 25 DISSOLUTION MEDIUM EXAMPLE Water Ampicillin caps., butabarbital sodium tabs. Buffers Azithromycin caps., paracetamol tabs. HCL solution Cemetidine tabs. Simulated gastric fluid Astemizole tabs., piroxicam caps. Simulated intestinal fluid Valproic caps., Glipizide tabs. Surfactant solution Clofibrate caps, danazol capsa. Oficial methods: : a. Oficial methods: There are basically three general categories of dissolution apparatus : Beaker methods Open flow-through compartment system Dialysis concept 261. Beaker method: Rotating Basket Apparatus (Apparatus 1): 1. Beaker method: Rotating Basket Apparatus (Apparatus 1) It is basically a closed-compartment, beaker type apparatus. It comprising of a cylindrical glass vessel with hemispherical bottom of one litre capacity partially immersed in a water bath. A cylindrical basket made of #22 mesh is located centrally in the vessel at a distance of 2 cm from the bottom and rotated by a variable speed motor through a shaft. 27PowerPoint Presentation: All metal parts like basket and shaft are made of stainless steel 316. 28PowerPoint Presentation: Useful for capsules beads delayed release / enteric coated dosage forms floating dosage forms surfactants in media Standard volume 900/1000 ml 1, 2, 4 liter vessels 29PowerPoint Presentation: Advantages breadth of experience(more than 200 monographs) full pH change during the test can be easily automated which is important for routine investigations Disadvantages disintegration-dissolution interaction hydrodynamic „dead zone“ under the basket degassing is particularly important limited volume sink conditions for poorly soluble drugs ? 30Rotating Paddle Apparatus (Apparatus 2): Rotating Paddle Apparatus (Apparatus 2) Here, basket is replaced with a stirrer. A small, loose, wire helix may be attached to the dosage form that would otherwise float. The position and alignment of the paddle are specified in the official books. 31PowerPoint Presentation: Useful for tablets capsules beads delayed release / enteric coated dosage forms Standard volume 900/1000 ml Method of first choice !!! 32PowerPoint Presentation: 33 Advantages easy to use robust can be easily adapted to apparatus 5 long experience pH change possible can be easily automated which is important for routine investigationsPowerPoint Presentation: Disadvantages pH/media change is often difficult limited volume sink conditions for poorly soluble drugs ? coning hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution 34The Reciprocating Cylinder Method (Apparatus 3): The Reciprocating Cylinder Method (Apparatus 3) This method adopts the USP disintegration “basket and rack” assembly for the dissolution test. The disks are not used. This method is less suitable for precise dissolution testing due to the amount of agitation and vibration involved. E.g. Chlorpheniramine ER tablets, Carbamazepine chewable tablet 35PowerPoint Presentation: Useful for tablets beads controlled release formulations Standard volume 200-250 ml per station 36PowerPoint Presentation: Advantages easy to change the pH pH-profiles hydrodynamics can be directly influenced by varying the dip rate Disadvantages small volume (max. 250 ml) little experience limited data 37PowerPoint Presentation: 38Paddle over Disk method (Apparatus 5): Paddle over Disk method (Apparatus 5) Modification of Apparatus 2. Here, stainless steel disk designed for holding transdermal system at the bottom of the vessel. The disk/device should not sorb, react with, or interfere with the specimen being tested. The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. 39PowerPoint Presentation: Useful for transdermal patches Standard volume 900 ml 40PowerPoint Presentation: Advantages standard equipment (paddle) can be used, only add a stainless steel disk assembly Disadvantages disk assembly restricts patch size 41Cylinder method (Apparatus 6): Cylinder method (Apparatus 6) Same as apparatus 1,except to replace the basket and shaft with a S.S. cylinder stirring element. Temperature - 32 ± 0.5° The dosage unit is placed on the cylinder. Distance between the inside bottom of the vessel and cylinder is maintained at 25 ± 2 mm. 42Reciprocating Holder method (Apparatus 7): Reciprocating Holder method (Apparatus 7) The assembly consists of a set of calibrated solution containers, a motor and drive assembly to reciprocate the system vertically. Various type of sample holder are used. 43Advantages of the Beaker Methods: Advantages of the Beaker Methods The basket method is the most widely used procedure which confines the solid dosage form to a limited area which is essential for better reproducibility. It is advantageous for capsules as they tend to float at the surface thus minimizing the area exposed to the dissolution fluid. 44Limitation of the Beaker Methods : Limitation of the Beaker Methods Clogging of the basket screen by gummy particles. Tendency of the light particles to float. Sensitivity of the apparatus to variables such as vibration, eccentricity, etc. Rapid corrosion of the SS mesh in presence of HCl. Sensitivity of the apparatus to any slight changes in the paddle orientation. Non-reproducible position of the tablets at the bottom of the flask. 45 2. OPEN FLOW-THROUGH COMPARTMENT SYSTEM : 2. OPEN FLOW-THROUGH COMPARTMENT SYSTEM The dosage form is contained in a small vertical glass column with built in filter through which a continuous flow of the dissolution medium is circulated upward at a specific rate from an outside reservoir using a peristaltic or centrifugal pump. Dissolution fluid is collected in a separate reservoir. E.g. lipid filled soft Gelatin capsule 46PowerPoint Presentation: 47PowerPoint Presentation: Useful for low solubility drugs microparticulates implants suppositories controlled release formulations Variations open system closed system 48PowerPoint Presentation: Advantages easy to change media pH pH-profile possible sink conditions different modes a) open system b) closed system Disadvantages Deaeration necessary high volumes of media labor intensive 49Advantages : Advantages No stirring and drug particles are exposed to homogeneous, laminar flow that can be precisely controlled. All the problems of wobbling, shaft eccentricity, vibration, stirrer position don’t exist. There is no physical abrasion of solids. Perfect sink conditions can be maintained. 50Disadvantages : Disadvantages Tendency of the filter to clog because of the unidirectional flow. Different types of pumps, such as peristaltic and centrifugal, have been shown to give different dissolution results. Temperature control is also much more difficult to achieve in column type flow through system than in the conventional stirred vessel type. 51DIALYSIS SYSTEM: DIALYSIS SYSTEM Here, dialysis membrane used as a selective barrier between fresh solvent compartment and the cell compartment containing dosage form. It can be used in case of very poorly soluble rugs and dosage form such as ointments, creams and suspensions. 52PowerPoint Presentation: 53b. Non official meTHods: ROTATING FILTER METHOD: b. Non official meTHods : ROTATING FILTER METHOD It consists of a magnetically driven rotating filter assembly and a 12 mesh wire cloth basket. The sample is withdrawn through the spinning filter for analysis. 54ROTATING FLASK DISSOLUTION METHOD: ROTATING FLASK DISSOLUTION METHOD This consists of a spherical flask made of glass and supported by a horizontal glass shaft that is fused to its sides. The shaft is connected to a constant speed driving motor. The flask is placed in a constant temperature water bath and rotates about its horizontal axis. 55ROTATING AND STATIC DISK METHODS : ROTATING AND STATIC DISK METHODS The compound is compressed into non disintegrating disc Mounted – One surface is exposed to medium Assumption – Surface area remains constant Used to determine the intrinsic dissolution rate 56Calibration: 57 CalibrationCalibration: Calibration Why ? to confirm suitability of the equipment and proper operation of the apparatus How ? mechanical calibration (verification of physical parameters) chemical calibration (Apparatus Suitability Test – USP) When ? before using new test equipment after relocation or major maintenance at regular intervals (every 6 months) 58Mechanical calibration: Mechanical calibration Verification of physical parameters specified in the pharmacopoeia: USP apparatus 1 and 2 59Chemical calibration:: Chemical calibration: Apparatus suitability test (USP): Standard calibrators according to USP chapter <711> Apparatus I, II and V: disintegrating type USP Prednisone Tablets nondisintegrating type USP Salicylic acid Tablets Apparatus III: USP Chlorpheniramine Maleate Extended-Release Tablets 60PowerPoint Presentation: 1. USP Prednisone Tablets RS – current lot P0E203 (10 mg nominal prednisone content per tablet) disintegrating type paddle and basket, 50 rpm 500 ml deaerated water, 37°C quantity of prednisone released after 30 minutes is determined specified ranges Lot P0E203: Apparatus 1: 47-82 % Apparatus 2: 37-70 % 61PowerPoint Presentation: 2. USP Salicylic acid Tablets RS – current lot Q0D200 (300 mg nominal salicylic acid content per tablet) nondisintegrating type paddle and basket, 100 rpm 900 ml deaerated phosphate buffer, 37°C quantity of salicylic acid, released after 30 minutes is determined specified ranges Lot Q0D200: Apparatus 1: 23-30 % Apparatus 2: 17-25 % 62IN VITRO IN VIVO CORRELATION: IN VITRO IN VIVO CORRELATION 63INTRODUCTION: INTRODUCTION Key goal in development of dosage form is good understanding of in vitro and in vivo performance of dosage form Formulation optimization requires altering some parameters – bioavailability studies Delay in marketing, added in time and cost Regulatory guidance developed to minimize the additional bioavailability studies The guidance is referred as in vitro in vivo correlation 64IVIVC BASIC: IVIVC BASIC Simply a mathematical model describing the relationship b/w in vitro and in vivo properties of drug In vitro – in vivo correlation can be achieved using Pharmacological correlation Semi quantitative correlation Quantitative correlation 65DEFINITION: DEFINITION USP definition “The establishment of rational relationship b/w a biological property or a parameter derived from a biological property produced by a dosage form and physicochemical property of same dosage form” FDA definition “It is predictive mathematical model describing the relationship b/w in vitro property of dosage form and a relevant in vivo response” 66IMPORTANCE : IMPORTANCE Serves as a surrogate of in vivo and assist in supporting biowaivers Validates the use of dissolution methods and specification Assist in QC during mfg and selecting the appropriate formulation 67References: References 68References: References D.M.Brahmankar, Biopharmaceutics and pharmacokinetics- A Treatise; Vallabh Prakashan, page no. 20–31. Leon Shargel, Applied Biopharmaceutics & Pharmacokinetics; 4 th edition, page no. 132-136 Text book of Biopharmaceutics and pharmacokinetics, by Shobha Rani R. Hiremath. Principle and application of Biopharmaceutics and Pharmacokinetics, by Dr. H.P. Tipnis, Dr. Amrita Bajaj. “IVIVC : a ground discussion” by Kalaslar S.G., Yadav A.V. and Patil V.B., IJPER – vol. – 41, Dec. 2007. 69PowerPoint Presentation: United States Pharmacopoeia – 24, page no.: 1942 – 1951. “Current perspectives in dissolution testing of conventional and novel dosage forms”, by Shirazad Azarmi, Wilson Roa, Raimar Lobenberg, Int. jou. Of pharmaceutics 328(2007)12 – 21. Alton’s pharmaceutics “ The design and manufacturing of medicines”, by Michael E. Alton, page no.: 21 – 22. http://www.google.com 70PowerPoint Presentation: Any Question ? 71PowerPoint Presentation: THANK YOU 72 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.