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Slide 1 - DRUG DISSOLUTION Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in 19 November 2010 1 KLECOP, Nipani
Slide 2 - CONTENTS Definition Theories of Drug Dissolution Noyes-Whitney’s Dissolution rate law Factors affecting Drug Dissolution Study of various approaches to improve dissolution of poorly soluble drug In-vitro dissolution testing models In-vitro-In-vivo correlation References 19 November 2010 2 KLECOP, Nipani
Slide 3 - 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. 19 November 2010 3 KLECOP, Nipani
Slide 4 - 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. 19 November 2010 4 KLECOP, Nipani
Slide 5 - 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. 19 November 2010 5 KLECOP, Nipani
Slide 6 - 19 November 2010 6 KLECOP, Nipani
Slide 7 - The rate of dissolution is given by Noyes and Whitney: Where, dc/dt= dissolution rate of the drug K= dissolution rate constant Cs= concentration of drug in stagnant layer Cb= concentration of drug in the bulk of the solution at time t = k (Cs- Cb) dc dt 19 November 2010 7 KLECOP, Nipani
Slide 8 - Modified Noyes-Whitney’s Equation - 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. (Cs – Cb )= conc. gradient for diffusion of drug. DAKw/o (Cs – Cb ) Vh = 19 November 2010 8 KLECOP, Nipani
Slide 9 - 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. Cb=0 and rate of dissolution is maximum. 19 November 2010 9 KLECOP, Nipani
Slide 10 - 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. = K 19 November 2010 10 KLECOP, Nipani
Slide 11 - 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. 19 November 2010 11 KLECOP, Nipani
Slide 12 - Hixon-Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W01/3 – W1/3 = Kt Where, W0=original mass of the drug W=mass of drug remaining to dissolve at time t Kt=dissolution rate constant. 19 November 2010 12 KLECOP, Nipani
Slide 13 - 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. 19 November 2010 13 KLECOP, Nipani
Slide 14 - 19 November 2010 14 KLECOP, Nipani
Slide 15 - The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma (γ) = rate of surface renewal dC dt = dm dt = A (Cs-Cb). D γ V 19 November 2010 15 KLECOP, Nipani
Slide 16 - Interfacial barrier model/Double barrier or Limited solvation theory :- The concept of this theory is explained by following equation- G = Ki (Cs - Cb) Where, G = dissolution rate per unit area, Ki = effective interfacial transport constant. 19 November 2010 16 KLECOP, Nipani
Slide 17 - Factors affecting Drug Dissolution :- Factors relating to the physicochemical properties of drug. Factors relating to the dosage forms. 19 November 2010 17 KLECOP, Nipani
Slide 18 - Factors relating to the physicochemical properties of drug- Solubility- Solubility plays important role in controlling dissolution from dosage form. From Noyes-Whitney equation it shows that aqueous solubility of drug which determines its dissolution rate. 19 November 2010 18 KLECOP, Nipani
Slide 19 - Particle size and effective surface area of the drug – Particle size and surface area are inversely related to each other. Two types of surface area – Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the dissolution medium. 19 November 2010 19 KLECOP, Nipani
Slide 20 - Effective surface area is directly related to the dissolution rate. Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution. 19 November 2010 20 KLECOP, Nipani
Slide 21 - Polymorphism and amorphism – When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism. Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility. 19 November 2010 21 KLECOP, Nipani
Slide 22 - Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms. E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form. Thus, the order for dissolution of different solid forms of drug is – amorphous > metastable > stable 19 November 2010 22 KLECOP, Nipani
Slide 23 - Salt form of the drug- Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form. With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides. With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs. 19 November 2010 23 KLECOP, Nipani
Slide 24 - Hydrates/solvates – The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates. When the solvent in association with the drug is water, the solvate is known as hydrate. The organic solvates have greater aqueous solubility than the nonsolvates. E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms 19 November 2010 24 KLECOP, Nipani
Slide 25 - Factors relating to the dosage forms – Pharmaceutical excipients – Vehicle Diluents Lubricants Binders Surfactants colorants 19 November 2010 25 KLECOP, Nipani
Slide 26 - Manufacturing processes - Method of granulation – Wet granulation Direct compression Agglomerative phase of communication (APOC) 19 November 2010 26 KLECOP, Nipani
Slide 27 - Compression Force :- Rate of drug dissolution A B C D Compression force Influence of compression force on dissolution rate of tablet 19 November 2010 27 KLECOP, Nipani
Slide 28 - Intensity of packing of capsule contents – Diffusion of GI fluids into the tightly filled capsules creates a high pressure within the capsule resulting in rapid bursting and dissolution of contents. On other hand, it shows that capsule with finer particles and intense packing have poor drug release and dissolution rate due to decrease in pore size of the compact and poor penetrability by the GI fluids. 19 November 2010 28 KLECOP, Nipani
Slide 29 - Approaches to improve dissolution of poorly soluble drug – Lipid based formulations – These include lipid solutions, micro-emulsions. Lipid solutions consist of drug dissolved in vegetable oil or in triglycerides. The high lipophilicity facilitates absorption into the intestinal lymphatics and then to the systemic circulation. The presence of surfactant in this formulation causes the enhanced absorption due to membrane induced permeation changes. 19 November 2010 29 KLECOP, Nipani
Slide 30 - Size reduction technology – Surface area increases by decreasing particle size which results in higher dissolution rate. Reduction in particle size can be accomplished by micronization, cryogenic and supercritical fluid technology. 19 November 2010 30 KLECOP, Nipani
Slide 31 - Functional polymer technology – This technique enhance the dissolution rate of poorly soluble drug by avoiding the lattice energy of the drug crystal. These polymers (amberlite, duolite) are ion exchange materials that interact with the ionizable molecules of the surrounding medium and exchange their mobile ions of equal charge with surrounding medium reversibly. The resultant complex, known as resinate can be formulated as suspension, dry powder or tablet. 19 November 2010 31 KLECOP, Nipani
Slide 32 - Porous microparticle technology – The poorly water soluble drug is embedded in a microparticle having a porous, water soluble, sponge like matrix. when mixed with water, the matrix dissolves, wetting the drug and leaving a suspension of rapidly dissolving drug particles. This is the core technology applied as HDDS (Hydrophobic Drug Delivery System). These drug particles provide large surface area for increased dissolution rate. 19 November 2010 32 KLECOP, Nipani
Slide 33 - The hydrophilic solubilization technology (HST) for poorly soluble drugs uses a lecithin and gelatin based water soluble coating to improve dissolution and hydration of lecithin-gelatin coat forms micelles which improve oral bioavailability of the insoluble drugs. 19 November 2010 33 KLECOP, Nipani
Slide 34 - Controlled precipitation technology – In this process, the drug is dissolved in a water miscible organic solvent and then dispersed into aqueous medium containing stabilizers (HPMC, cellulose ethers, gelatin) The solvent dissolves in water and causes precipitation of the drug in the form of micro-crystal The stabilizers control particle growth and enhances the dissolution rate of poorly soluble drug due to large surface area hydrophilized by the adsorbed stabilizer. 19 November 2010 34 KLECOP, Nipani
Slide 35 - Inclusion complexes – These complexes can be prepared with β-cyclodextrin and HP-β-CD. The required quantity of β-CD is weighed and water added to get consistancy. To the mass weighed quantity of the drug is added. The mixture is kneaded in a glass mortar for 1 hr. and then completely dried in hot air oven at 60oC for 2 hrs. The dried mass is sieved through mesh no. 120 19 November 2010 35 KLECOP, Nipani
Slide 36 - Solid dispersions – It is defined as the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the fusion or melting solvent method. Carriers for solid dispersion- Sugars- dextrose, sorbitol, mannitol. Acids- Citric acid, tartaric acid, succinic acid. Polymeric materials- PEG 4000, PEG 6000, HPMC, polyvinyl pyrrolidone. 19 November 2010 36 KLECOP, Nipani
Slide 37 - Methods of preparation – Melting method/Fusion method – In this method, the physical mixture of a drug and water soluble carrier was heated directly until it is melted, which was then cooled and solidified rapidly in an ice bath. To facilitate faster dissolution, the melt was poured in the form of thin layer onto a stainless steel plate and cooled by flowing air or water on opposite side of plate. The final solid mass is then crushed, pulverized and sieved. 19 November 2010 37 KLECOP, Nipani
Slide 38 - Solvent method – Solid solutions or mixed crystals can be prepared by dissolving a physical mixture of two solid components in a common solvent, followed by evaporation of the solvent. Thermal decomposition of drugs or carriers can be prevented because of low temperature. E.g. – solvent dispersions of β-carotenes-PVP, griseofulvin –PVP, tolbutamide-PVP, etc. 19 November 2010 38 KLECOP, Nipani
Slide 39 - Melting-Solvent method – The drug is first dissolved in a solvent and then the solution is incorporated directly into the melt of the carrier. A liquid drug such as methyl salicylate, Vitamin-E, clofibrate can be formulated as a solid dosage form and mixing it with melted liquid of PEG-6000 and cooling the mixture. 19 November 2010 39 KLECOP, Nipani
Slide 40 - Simple Eutectic mixtures – Rapid solidification of fused liquid of two components which shows complete liquid miscibility and negligible solid-solid solubility yields a simple eutectic mixture. When a eutectic is exposed to GI fluids, both poorly soluble drug and carrier may crystallize out in very small particulate size. 19 November 2010 40 KLECOP, Nipani
Slide 41 - Factors contributing to the faster dissolution rate of a drug dispersed in eutectic are :- Reduction of particle size. An increase in drug solubility Absence of aggregation and agglomeration between the fine crystallites of pure drug. Excellent wettability and dispersibility of a drug as the encircling soluble carrier readily dissolves and causes the water to contact and wet the particles. Crystallization of the drug in metastable form after solidification from the fused solution which has high solubility 19 November 2010 41 KLECOP, Nipani
Slide 42 - Solid solution :- It is made up of a solid solute molecularly dispersed in a solid solvent. The two components crystallize together in a homogenous one-phase system and thus they are referred to as mixed crystals or molecular dispersions. They are generally prepared by fusion method where a physical mixture of solute and solvent are melted together followed by rapid solidification. 19 November 2010 42 KLECOP, Nipani
Slide 43 - The two mechanisms suggested for rapid dissolution of molecular dispersions – When the binary mixture is exposed to water, the soluble carrier dissolves rapidly leaving the insoluble drug in a state of microcrystalline dispersion of very fine particles. Solute and solvent molecules randomly arranged themselves to form crystal lattice, when dissolution fluid is exposed to such crystal, soluble solvent molecules get dissolved in dissolution fluid and leaves behind insoluble drug molecules. 19 November 2010 43 KLECOP, Nipani
Slide 44 - Glass solutions and glass suspensions – It is a homogenous glassy system in which a solute dissolves in a glassy solvent. Glass solution is metastable and it amorphous to x-ray diffraction. Polyhydroxy molecules like sugars form glasses which may be due to strong hydrogen bonding prevent crystallization. 19 November 2010 44 KLECOP, Nipani
Slide 45 - Amorphous precipitations in a crystalline carrier – The drug precipitate out in an amorphous form in the crystalline carrier from a melting or solvent method of preparation. Amorphous form produces faster dissolution rate than crystalline form. 19 November 2010 45 KLECOP, Nipani
Slide 46 - IN-VITRO DISSOLUTION TESTING MODELS 19 November 2010 46 KLECOP, Nipani
Slide 47 - 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 19 November 2010 47 KLECOP, Nipani
Slide 49 - Factors relating to the dissolution apparatus Design of the container Size of the container Shape of the container Nature of agitation Speed of agitation Performance precision of the apparatus 19 November 2010 49 KLECOP, Nipani
Slide 50 - Factors relating to the dissolution fluid Composition Viscosity Volume Temperature Sink condition 19 November 2010 50 KLECOP, Nipani
Slide 51 - 19 November 2010 51 KLECOP, Nipani
Slide 52 - Process parameters Method of introduction of dosage form Sampling techniques Changing the dissolution fluid 19 November 2010 52 KLECOP, Nipani
Slide 53 - OFFICIAL METHODS 19 November 2010 53 KLECOP, Nipani
Slide 54 - There are basically three general categories of dissolution apparatus : Beaker methods Open flow-through compartment system Dialysis concept Classification 19 November 2010 54 KLECOP, Nipani
Slide 55 - BEAKER METHODS 19 November 2010 55 KLECOP, Nipani
Slide 56 - 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. 19 November 2010 56 KLECOP, Nipani
Slide 57 - Contd….. All metal parts like basket and shaft are made of stainless steel 316. 19 November 2010 57 KLECOP, Nipani
Slide 58 - 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. 19 November 2010 58 KLECOP, Nipani
Slide 59 - 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 19 November 2010 59 KLECOP, Nipani
Slide 60 - 19 November 2010 60 KLECOP, Nipani
Slide 61 - 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. 19 November 2010 61 KLECOP, Nipani
Slide 62 - 19 November 2010 62 KLECOP, Nipani
Slide 63 - 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. 19 November 2010 63 KLECOP, Nipani
Slide 64 - 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. 19 November 2010 64 KLECOP, Nipani
Slide 65 - 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. 19 November 2010 65 KLECOP, Nipani
Slide 66 - 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. 19 November 2010 66 KLECOP, Nipani
Slide 67 - 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 19 November 2010 67 KLECOP, Nipani
Slide 68 - 19 November 2010 68 KLECOP, Nipani
Slide 69 - 19 November 2010 69 KLECOP, Nipani
Slide 70 - 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. 19 November 2010 70 KLECOP, Nipani
Slide 71 - 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. 19 November 2010 71 KLECOP, Nipani
Slide 72 - 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. 19 November 2010 72 KLECOP, Nipani
Slide 73 - 19 November 2010 73 KLECOP, Nipani
Slide 74 - NON OFFICIAL METHODS 19 November 2010 74 KLECOP, Nipani
Slide 75 - THE 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. 19 November 2010 75 KLECOP, Nipani
Slide 76 - 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. 19 November 2010 76 KLECOP, Nipani
Slide 77 - 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 19 November 2010 77 KLECOP, Nipani
Slide 78 - IN VITRO IN VIVO CORRELATION 19 November 2010 78 KLECOP, Nipani
Slide 79 - 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 19 November 2010 79 KLECOP, Nipani
Slide 80 - 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 19 November 2010 80 KLECOP, Nipani
Slide 81 - 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” 19 November 2010 81 KLECOP, Nipani
Slide 82 - 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 19 November 2010 82 KLECOP, Nipani
Slide 83 - LEVELS OF CORRELATION Level A correlation Level B correlation Level C correlation Multiple level C correlation Level D correlation 19 November 2010 83 KLECOP, Nipani
Slide 84 - Level A correlation Highest category correlation Represents point to point relationship Developed by two stage procedure Deconvulation Comparison Purpose – define direct relationship 19 November 2010 84 KLECOP, Nipani
Slide 85 - Level B correlation Utilizes the principle of statistical moment analysis MDTvitro is compared with MRTvivo No point to point correlation Does not reflect the actual in vivo plasma level curves Thus we can not rely to justify the formulation modification, mfg site change and excipient source change. 19 November 2010 85 KLECOP, Nipani
Slide 86 - Level C correlation Dissolution time point (t 50%,t 90% ) is compared to one mean pharmacokinetic parameter ( Cmax ,tmax ,AUC) Single point correlation Weakest level of correlation as partial relationship b/w absorption and dissolution is established Useful in the early stages of formulation development 19 November 2010 86 KLECOP, Nipani
Slide 87 - Multiple level C correlation It reflects the relationship b/w one or several pharmacokinetic parameter of interest and amount of drug dissolved at several time point of dissolution profile Base on Early Middle Late stage 19 November 2010 87 KLECOP, Nipani
Slide 88 - 19 November 2010 88 KLECOP, Nipani
Slide 89 - EVALUTION OF PREDICTIBILITY CORRELATION Demonstrate – in vitro dissolution characteristic is maintained They focus the predictive performance or prediction error Depending of intended application of IVIVC and therapeutic index Internal evaluation External evaluation % PE = (Cmax observed – Cmax predicted) × 100 Cmax predicted 19 November 2010 89 KLECOP, Nipani
Slide 90 - 19 November 2010 90 KLECOP, Nipani
Slide 91 - 19 November 2010 91 KLECOP, Nipani
Slide 92 - Biopharmaceutics Classification System Absorption Number A function of GI Permeability to Drug Substance 19 November 2010 92 KLECOP, Nipani
Slide 93 - Biopharmaceutics Classification System Effective permeability Radius of GI Residence time in GI Time required for complete absorption 19 November 2010 93 KLECOP, Nipani
Slide 94 - Biopharmaceutics Classification System Dose Number A function of solubility of drug substance D / Vwater >> CS ~ High Do D / Vwater << CS ~ Low Do Solubility Issues Highest Dose Unit 250 mL Solubility 19 November 2010 94 KLECOP, Nipani
Slide 95 - Biopharmaceutics Classification System Dissolution Number A function of drug release from formulation 19 November 2010 95 KLECOP, Nipani
Slide 96 - Biopharmaceutics Classification System Solubility mg/mL Diffusivity 5x10-6 cm2/s Density 1.2 mg/cm3 Particle Radius 25 mm Residence time in GI 180 min Time required for complete dissolution 19 November 2010 96 KLECOP, Nipani
Slide 97 - Dissolution and IVIVC It has high discriminating power and able to detect minor changes in manufacturing process Purpose Batch consistency Quality performance Guide to new formulation Dissolution apparatus 19 November 2010 97 KLECOP, Nipani
Slide 98 - For IVIVC purpose dissolution profile of at least 12 dosage form each lot should be carried out Where Rt and Tt = cumulative % dissolved for reference and test Values range from 0 to 100 19 November 2010 98 KLECOP, Nipani
Slide 99 - Bioavailability studies in developing IVIVC Performed to characterize the plasma conc. versus time profile Performed with sufficient no. of subjects Appropriate deconvulation technique is to be applied for IVIVC Wegner Nelson method Loo – Riegelman method 19 November 2010 99 KLECOP, Nipani
Slide 100 - Factors to be considered while developing IVIVC Stereochemistry First pass effect Food effect 19 November 2010 100 KLECOP, Nipani
Slide 101 - APPLICATION OF IVIVC Early development of drug product and optimization Bio waiver for minor formulation and process changes Setting dissolution specification 19 November 2010 101 KLECOP, Nipani
Slide 102 - References D.M.Brahmankar, Biopharmaceutics and pharmacokinetics- A Treatise; Vallabh Prakashan, page no. 20–31. Hamed M. Abdou, Dissolution Bioavailability & Bioequivalence; MACK Publication, page no. 11-17, 53-84. Leon Shargel, Applied Biopharmaceutics & Pharmacokinetics; 4th edition, page no. 132-136. The Indian Pharmacist, February 2008, page no.10-12 19 November 2010 102 KLECOP, Nipani
Slide 103 - REFERENCES 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 19 November 2010 103 KLECOP, Nipani
Slide 104 - REFERENCES 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. Pharmaceutical Preformulation and Formulation, by Mark Gibson page no.: 241 – 244. 19 November 2010 104 KLECOP, Nipani
Slide 105 - Any Question ? 19 November 2010 105 KLECOP, Nipani
Slide 106 - THANK YOU 19 November 2010 106 KLECOP, Nipani Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in