Dissolution

detail about dissolution

1. DISSOLUTION BY: Shreeshail Tumbagi 1 st year M.Pharm ABMRCP-107 1

2. CONTENTS:- Definition BCS Classification Noyes-Whitney’s dissolutions rate law Study of various approaches to improve dissolution of poorly soluble drug In-vitro dissolution testing models In-vitro release kinetic models similarity and dissimilarity factors In-vitro- In –vivo correlation. 2

3. DEFINITION:- Dissolution is defined as the 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. 3

4. BCS Classification:- I t   is a system to differentiate the drugs on the basis of their solubility and permeability. The drug substances are classified as: Class I - High  permeability, High   solubility. E x:- Metoprolol. Class II - High permeability, Low solubility. Ex:- Ezetimibe. Class III - Low permeability, High solubility. Ex:- Cimetidine. Class IV - Low permeability, Low solubility. Ex:- Hydrochlorothiazide 4

5. THEORIES OF DISSOLUTION:- I) Diffusion Layer Model (Film Theory ) :- It is a simplest model where dissolution of crystal, immersed in liquid takes place without involving reactive or electrical forces It consist of two stages:- Solution of the solid to form a thin film or layer at the solid / liquid interface called as stagnant film or diffusion layer which is saturated with the drug this step is usually rapid (instantaneous). Diffusion of the soluble solute from the stagnant layer to the bulk of the solution this step is slower and is therefore the rate determining step in the drug dissolution . 5

6. Diffusion Layer Model Diagrammatic:- 6

7. NOYES AND WHITNEY EQUATION The rate of change in concentration of dissolved material with time it directly proportional to the concentration difference between the two sides of diffusion layer i.e. = k (C s - C b ) Where, dc/ dt - Dissolution rate of drug. k - Rate constant Cs - Concentration of solution at solid surface C ь - Bulk of the solution dc dt 7

8. Modified Noyes-Whitney’s Equation :- Brunner incorporated surface area ‘A’ in Noyes & Whitney equation . dc/ dt = kA ( Cs – Cb ) Afterwards Brunner, incorporated Fick’s law of diffusion & expanded his given eq to include diffusion coefficient ‘D’, thickness of stagnant diffusion layer ‘h’ & volume of dissolution medium ‘v’. 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 = 8

9. Non sink conditions :- Modified noyes-whitney’s equation represents the first order dissolution process, the driving force which the concentration gradient (C s - C b ) , and this condition is said as non sink condition , done only for in-vitro Sink conditions :- The in-vivo dissolution is always rapid than in-vitro dissolution because the moment the drugs dissolves , it is absorbed in the systemic circulation , as a result C b = 0 and the dissolution is at maximum. 9

10. 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. 10

11. HIXON-CROWELL CUBE ROOT RELATIONSHIP Major assumptions in Noyes-Whitney relationship is that the S.A.(A) term remains constant throughout dissolution process. This is true for some formulations, such as transdermal patches. However , size of drug particles from tablets, capsules and suspensions will decrease as drug dissolves. This decrease in size of particles changes the effective S.A. Thus, Hixon & Crowell modified the equation to represent rate of appearance of solute by weight in solution by multiplying both sides of volume term. W o 1/3 - W 1/3 = kt Where , W = Original mass of drug W = Mass of drug remaining to dissolve at time t K = Dissolution rate constant. 11

12. II) 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 . The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma ( γ ) = rate of surface renewal D = diffusion coefficient of drug. A = surface area of dissolving solid. dC dt = dm dt = A (Cs-Cb) . D γ V 12

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14. 14 STUDY OF VARIOUS APPROACHES TO IMPROVE DISSOLUTION OF POORLY SOLUBLE DRUG 14

15. IN-VITRO DISSOLUTION TESTING MODELS ACCORDING TO B P OFFICIAL METHODS :- Apparatus are used according to standards specified. The B P includes seven apparatus design for drug release and dissolution testing of immediate release and for oral dosage form, for extended release, enteric coated, transdermal drug delivery system. Methods are listed below :-  Rotating basket method  Paddle method  Flow-through method 15

16. ROTATINGBASKETMETHOD :(APPARATUS-1) It is basically a closed compartment, beaker type apparatus comprising of a cylindrical glass vessel with hemispherical bottom of one liter. capacity immersed in a water bath to maintain constant temperature at 37 + 2c. Basket of 40 mesh rotated at constant speed between 25 and 150 rpm. Basket is to hold the dosage form and it is located centrally in vessel. Basket should be placed at 20mm above from the bottom. Sample should withdraw periodically at regular interval of time, each time replace same volume of dissolution medium after withdrawal. Sample should be withdraw from the top end of the basket and basket should remain in motion during drawing samples. All the metal part should be of 316 grade stainless steel . Basket of mesh size 10,20,30 and 40 mesh screen can be used depending on dosage form and to avoid clogging . 16

17. PADDLE METHOD : (APPARATUS-2) It was originally developed by Poole 1969 and was refined by scientists at USFDA. The specification of Apparatus-2 are identical with those of apparatus -1 except that paddle is substituted for the rotating basket . The paddle which acts as a stirrer and the dosage form allow to sink to the bottom of the vessel . The area of paddle blade creates considerable flow, and wobble has the effect of increasing the angular velocity at the paddle tips in the manner that couples with the fluid much more significantly than would comparable wobble in basket . The counter of the paddle blade must not included any sharp edges at the tips, for instance that could produce turbulent instead of laminar flow. 17

18. FLOW-THROUGH CELL :(APPARAYUS-3) It consists of following parts, A dissolution chamber: which acts as a reservoir of dissolution media. A pump: to pump the medium. Dissolution chamber: to hold the dosage form and also it consists of glass beads to trap the large particles, filter to trap the un dissolved drug from dosage form. A reservoir: to collect the sample . 18

19. In this method, a tablet or capsule is placed in dissolution chamber and dissolution medium is pumped through the dissolution chamber. The flow rate is usually maintained between 10 and 100 ml/min. this dissolution fluid is collected and assayed for drug content . It has been extensively used by the Europe before introducing in USP method. The flow rate should be held constant, and it is difficult to get laminar flow wit out turbulence. This can be minimize by using pulse free pumps. And also difficult to obtain desire filter pore size, and dosage composition . The main dis advantage of this is filter get clogged, flow rate decreases pump pressure increases to the point that it damages equipment . 19

20. ADVANTAGES :- Infinite sink condition can be achieved hence low soluble drugs studies can be done. It is easy to change pH of media during test, avoiding hot spots as seen in basket method. Minimum dwell time, avoiding problems of degradation of drug during process . Ease of sampling and automation of data reduction. Adaptability to current USP calibrators . 20

21. DIS-ADVANTAGES : Large volume of media is required. Control of constant flow rate is difficulty. Clogging results in damage to equipment. Pump should produce pulse free flow. Pressure may build up due to clogging hence pressure transducer should used to regulate pressure and to maintain constant flow rate . 21

22. In Vitro–In Vivo Correlation Level A IVIVC , the model should predict the entire in vivo time course from the in vitro data. In this context, the model refers to the relationship between in vitro dissolution of an extended release (ER) dosage form and an in vivo response such as plasma drug concentration or amount of drug absorbed .’’ Level B IVIVC uses the principles of statistical moment analysis. The mean in vitro dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. Level B correlation, like a Level A, uses all of the in vitro and in vivo data, but is not considered to be a point-to-point correlation . Level C IVIVC establishes a single-point relationship between a dissolution parameter, for example, T 50% dissolved in four hours and a pharmacokinetic parameter [e.g., 50% area under the curve (AUC), Cmax , Tmax ]. 22

23. REFERENCE : Fonner . D. E, Banker. G. S., Granulation & Tablet Characteristics , In Pharmaceutical Dosage Forms: Tablets . Vol. 2. Edited by H. Lieberman & L. Lachman , Dekker, New York, 1982, p. 202 Leon Lachman , Herbert. A. Lieberman, The Theory and Practice of Industrial Pharmacy , 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 301-303 Brahmankar . D. M. , Sunil Jaiswal . B, Biopharmaceutics and Pharmacokinetics—A Treatise , 1 st edition, Vallabh Prakashan , New Delhi, 2006, pp. 19-25 Alfred Martin , James Swarbrick, Physical Pharmacy , 3 rd edition, Varghese Publishing House, Bombay, 1991, pp. 408-12 23

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