Concept of dissolution testing methodology

brief introduction of drug dissolution

1. Concept of dissolution testing methodology By: N. Siva Naga Tejaswini Y14PH0505 Chalapathi Institute Of Pharmaceutical Sciences

2. Contents… Definitions Drug dissolution process Theories of dissolution Factors affecting drug dissolution and dissolution rate Official methods of dissolution Conclusion References

3. Definition: Dissolution is a process in which solid substance solubilises in a given solvent i.e., mass transfer from the solid surface to the liquid phase. Dissolution rate is defined as the amount of solid substance that undergoes into solution per unit time under standard conditions of temperature, pH and solvent composition and constant surface area.

4. The effectiveness of a tablet in releasing the drug for absorption depends upon four steps step:1 Breaking of tablets into granules (disintegration) Step:2 Some times, times the granules further break into small fine particles (deaggregation) Step:3 The release of drug into solution (dissolution) Step:4 Absorption Drug dissolution process:

5. Why dissolution studies?? To show release of drug from the tablet is close to 100% To show that rate of drug release is uniform batch to batch. To show that release is equivalent to those batches proven to be bioavailable and clinically effective.

6. THEORIES OF DRUG DISSOLUTION: Diffusion layer model/Film theory Danckwert’s model/Surface renewal theory Interfacial barrier theory/ Limited solvation theory

7. 1. Diffusion layer model / film theory: The process of dissolution of solid particles in a liquid involves two steps: S olution of the solid to form a thin layer or film at the solid / liquid interface called the Stagnant film or diffusion layer which is saturated with the drug. D iffusion of the soluble solute from the stagnant layer to the bulk of the solution.

8. 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. This above equation is based on the Fick’s second law of diffusion. Nernst and Brunner incorporated Fick’s first law of diffusion and modified the Noyes-Whitney equation: dC/dt = DAK w/o (C s -C b ) Vh where, D = diffusion coefficient of drug A = surface area of dissolving solid K w/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

10. This is first order dissolution rate process, for which the driving force is the 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. Under sink conditions, if volume and surface of the solid are kept constant then, dc/dt=k This represents that dissolution rate is constant under sink conditions and follows zero order kinetics.

11. Dissolution rate under sink and non-sink conditions:

12. limitation: The Noyes-Whitney’s equation assumes that the surface area of the dissolving solid remains constant during dissolution, which is practically not possible for dissolving particles. Hence, dissolution methods that involve constant use of surface area discs are employed to determine the rate of dissolution. To account for the particle size decrease and change in surface area accompanying dissolution, Hixson and Crowell’s cubic root law of dissolution is used: W o 1/3 – W 1/3 = K.t where, W = mass of drug remaining to be dissolved at time t K = dissolution rate constant W o = original mass of the drug

13. 2. danckwert’s model: Also called as Penetration or surface renewal theory. Danckwert’s takes into account that eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it out into the bulk of the solution The solute containing packets are continuously replaced by new ones and exposes to new solid surface each time, thus the theory is called as Surface renewal theory.

14. The Danckwet’s model is expressed by the equation m = mass of solid dissolved, and γ = rate of surface renewal (or the interfacial tension)

15. 3. Interfacial barrier model: Also called as Double barrier Or Limited solvation theory According to this theory , an intermediate concentration can exist at the interface as a result of solvation mechanism and is a function of solubility rather than diffusion. Such a concept is given by the equation:

16. Factors affecting drug dissolution and dissolution rate: Physicochemical properties of the drug Dosage form Factors Patient related factors

17. 1. Physicochemical factors: Particle size and effective surface area: Particle size and surface area of a solid are inversely related to each other. Smaller the drug particle greater the surface area. Two types of surface area : Absolute surface area which is total area of solid surface of any particle. Effective surface area which is the area of solid surface to the dissolution medium.

18. According to Noyes-whitney’s equation larger the surface area higher the dissolution rate. Since, the surface area increases with decreasing the particle size, which can be accomplished by micronisation, will result in higher dissolution rates. Greater the surface area more intimate the contact b/w the solid surface and the aqueous solvent and faster the dissolution. EXAMPLES: Griseofulvin- 250mg Spiranolactoine- 20mg

19. 2. Polymorphism and amorphism When a substance exist in more than one crystalline form, the different forms are designated as Polymorphs and the phenomenon as Polymorphism Polymorphs are two types: Enantiotropic polymer is the one which can be reversibly changed into another form by altering the temperature or pressure. Ex: Sulphur. Monotropic polymer is the one which is unstable at all temperatures and pressures. Ex: Glyceryl stearates. Depending on the relative stability polymeric forms will be more stable than the others.

20. S table polymorphs represents the low energy state, has high melting point and least aqueous solubility. Metastable forms represent high energy state , has lower melting point and high aqueous solubility thereby, better Bioavailability. Due to higher energy state, has thermodynamic tendency to convert to stable form. Examples: Chloramphenicol palmitate A, B and C, the B form is best available and the A form is inactive biologically. Riboflavin form III is 20 times more water soluble than form I

21. Some drugs exists in Amorphous form i.e , having no internal structure. Such drugs represent higher energy state and can be considered as supercooled liquids. These have greater aqueous solubility than the crystalline forms. Examples: Amorphous form of novobiocin is 10 times more stable than crystalline form. Chloramphenicol palmitate Cortisone acetate Therefore; Amorphous> Metastable> Stable

22. 3. Salt form of the drug Most drugs are either weak acids or weak bases To enhance the solubility and dissolution rate of such drugs is to convert them into their salt forms. Generally weak acidic drugs, a strong base salt is prepared such as sodium and potassium salts of barbiturates and sulphonamides. In case of weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulphate salts of several alkaloid drugs.

23. 2. Dosage form factors: A drug is rarely administered in its original form. Excipients are added to ensure acceptability, physicochemical stability during the shelf-life, uniformity of composition and dosage and optimum bioavailability. Vehicle: is the major component of liquid orals and parentrals. Aqueous : water, syrup etc; Non-aqueous: sorbitol, glycerol etc; Bioavailability of the drug from vehicles depends to a large extent on its miscibility with the biological fiuids .

24. 2. Diluents(fillers): commonly added to tablets where the drug is very potent and less dose so to produce necessary bulk. Organic diluents: Starch, lactose, micro crystalline cellulose. Inorganic diluent: Dicalcium phosphate. 3. Binders and granulating agents: Materials to hold powders to form granules or promote cohesive compacts for directly compressable materials. Examples: Starch, cellulose derivatives like gelatin, ethyl cellulose, methyl cellulose, HPC; PVP, acacia.

25. Official methods of dissolution

26. According to Indian Pharmacopeia : Two types of apparatus are present: Type I - Paddle apparatus TypeII - Basket apparatus.

27. According to USP:

28. Conclusion: By studying various factors influencing rate of dissolution, we can optimize the different properties of the formulations. By conducting dissolution studies we can know the batch to batch reproduciblity We can estimate the solubility profile of the drugs. The best available tool today which can atleast quantitatively assure about the biological availability of the drug from its formulation is its in-vitro dissolution.

29. References: Brahmankar, D. M; Sunil B. jaiswal, Biopharmaceutics and Pharmacokinetics – A Treatise , 3 rd edition, vallabh Prakashan, New Delhi. Page No. 29-56 C.V.S. Subhramanyam (2000), “ Text book of physical pharmaceutics” Vallabh Prakashan, 2 nd Edition, Page No. 85-105 United States Pharmacopoeia, Page No. 24 1942-1951.