Dissolution

Dissolution.
Dissolution rate.
Noyes-Whitney Equation.
Factors affecting the dissolution rate.
References.

1. DISSOLUTION Subject Name: Advanced Biopharmaceutics & Pharmacokinetics. Subject Code: MPH202T. Prepared By: Patel Snehal. M Pharmacy Sem II Department of Pharmaceutics. 1

2. Contents: Dissolution. Dissolution rate. Noyes-Whitney Equation. Factors affecting the dissolution rate. References. 2

3. Dissolution:  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. DISSOLUTION RATE:  Dissolution rate is the transfer rate of individual drug molecules from the solid particles into solution as individual free drug molecules.  Rate of dissolution is the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature& solvent composition. 3

4. Theories of Dissolution: Diffusion Layer Model/ Film Theory. Danckwert’s Model (Penetration or Surface Renewal Theory). Interfacial Barrier Model (Double Barrier or Limited Solvation Theory). 1. Diffusion Layer Model/Film Theory. This is the simplest and the most common theory for dissolution. Here, the process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps: Solution of the solid to form a thin film or layer at the solid/ liquid interface called as the stagnant film or diffusion layer which is saturated with the drug. This step is usually rapid. 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 drug dissolution. 4

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6. Noyes-Whitney Equation The rate of change in concentration of dissolved material with time it is directly proportional to the concentration difference between the two sides of diffusion layer. dc = K(Cs- Cb ) dt Where, dc\dt= Dissolution rate of drug K=Rate constant Cs= Concentration of solution at solid surface Cb = Concentration of bulk of the solution 6

7. Modified Noyes-Whitney Equation Brunner incorporated surface area ‘A’ in Noyes & Whitney equation dc =KA(Cs- Cb ) dt Afterwards Brunner, incorporated fick’s law of diffusion & expanded his given equation to include diffusion coefficient ‘D’, thickness of stagnant diffusion layer ‘h’ & volume of dissolution medium ‘V’. dc = DAK w \o (Cs- Cb ) dt 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. Cs- Cb = conc. Gradient for diffusion of drug . 7

8. Factors Affecting Dissolution Rate 1.Factors related to physicochemical properties of drug. 2.Factors related to Drug Product Formulation. 3.Processing factors. 4.Factors relating Dissolution Apparatus. 5.Factors relating Dissolution Test Parameters. 8

9. 1. Physicochemical Properties of Drug A. Particle size and effective surface area of the drug Larger the surface area, higher the dissolution rate. Since the surface area increases with decreasing particle size, a decrease in particle size which can be accomplished by micronisation will result in higher dissolution rate. It is important to note that it is not the absolute surface area but the effective surface area that is proportional 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. E.g. Micronisation of poorly aqueous soluble drugs like griseofulvin, chloramphenicol & several salts of tetracycline leads to increase in dissolution rate. E.g. In case of hydrophobic drugs like aspirin, phenacetin & phenobarbital micronisation results in decrease in effective surface area and fall in dissolution rate. 9

10. b. Drug Solubility Minimum aqueous solubility of 1% required to avoid potential solubility limited absorption problems. Studies on several compound of different chemical classes and a wide range of solubility revealed that initial dissolution rate of these substances is directly proportional to their respective solubility. E.g. Poorly soluble drug: griseofulvin, spironolactone hydrophilic drug: neomycin. C. Solid State characteristics Anhydrous forms dissolve faster than hydrated form because they are thermodynamically more active than hydrates. eg Ampicillin anhydrate faster dissolution rate than trihydrate. 10

11. Amorphous forms of drug tend to dissolve faster than crystalline materials e.g. Novobiocin, Griseofulvin. Where in the dissolution rate of amorphous erythromycin estolate is markedly lower than the crystalline form of erythromycin estolate . Metastable polymorphic form have better dissolution than stable form eg Methyl prednisone. D. Salt formation. It is one of the common approaches used to increase drug solubility and dissolution rate. It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids.  Eg sodium & potassium salts of penicillin G, phenytoin, barbiturates, tolbutamide etc. While in case of phenobarbital dissolution of sodium salt was slower than that of weak acid. Due to decreased disintegration of sodium salt. Hydrochlorides and sulphates of weak bases are commonly used due to high solubility eg epinephrine, tetracycline. 11

12. 2. Factors related to Drug Product Formulation A. Binders The hydrophilic binders show better dissolution profile with poorly wettable drugs like phenacetin by imparting hydrophilic properties to the granule surface. Large amounts of binders increases hardness and decrease dissolution rate of tablets. Non aqueous binders such as ethyl cellulose retard the drug dissolution. Phenobarbital tablet granulated with gelatin solution provide a faster dissolution rate in human gastric juice than those prepared using Na-carboxymethyl cellulose or polyethylene glycol 6000 as binder. 12

13. b. Disintegrants Disintegrating agent added before and after the granulation affects the dissolution rate. Studies of various disintegrating agents on phenobarbital tablet showed that when copagel added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate. Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution. C. Effect of Lubricants Lubricants are hydrophobic in nature(metallic stearates) and prolong the tablet disintegration time by forming water repellent coat around individual granules. This retarding the rate of dissolution of solid dosage forms. 13

14. Both amount and method of addition affect the property. It should be added in small amount and should be tumbled or mixed gently for only very short time. Prolonged mixing affect the dissolution time. The best alternative is use of soluble lubricants like SLS and carbowaxes which promote drug dissolution. D. Surfactants  They enhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area which in turn results in faster dissolution rate.  Eg Non ionic surfactant polysorbate 80 increase dissolution rate of phenacetin granules. The increase was more pronounced when the surfactant was sprayed on granules than when it was dissolved in granulating agent. 14

15. e. Coating Polymers Tablets with MC coating were found to exhibit lower dissolution profiles than those coated with HPMC at 37°c. The differences are attributed to thermal gelation of MC at temp near 37°, which create a barrier to dissolution process & essentially changes the dissolution medium. In general the deleterious effect of various coatings on drug dissolution from a tablet dosage forms is in the following order Enteric coat>Sugar coat>Non enteric film coat. The dissolution profile of certain coating materials change on aging eg shellac coated tablets, on prolonged storage dissolve more slowly in the intestine. 15

16. F. complexing agents A complexed drug may have altered stability, solubility, molecular size, partition coefficient and diffusion coefficient.  Eg enhanced dissolution through formation of a soluble complex of ergotamine tartarate -caffeine complex and hydroquinone-digoxin complex. 16

17. 3. Processing factors A. Method of granulation Wet granulation has been shown to improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of granules. A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method. 17

18. b. Compression force The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet. The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes. 18

19. On the one hand higher compression force increases the density and hardness of tablet, decreases porosity and hence penetrability of the solvent into the tablet, retards wettability by forming a firmer and more effective sealing layer by the lubricant and promotes tighter bonding between the particles all of which results in slowing of the dissolution rate of tablets. On the other hand higher compression forces cause deformation, crushing or fracture of drug particles into smaller ones or convert a spherical granule into a disc shaped particle with a large increase in the effective surface area. This results in increase in the dissolution rate of the tablet. C. Drug excipient interaction. These interactions occur during any unit operation such as mixing, milling, blending, drying and granulating result change in dissolution. Increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose result in enhance dissolution rate of prednisolone. 19

20. Polysorbate 80 used as excipient in capsules causes formation of formaldehyde by autoxidation which causes film formation by denaturing the inner surface of capsule. This causes decrease in dissolution rate of capsules. D. Storage conditions Dissolution rate of hydrochlorthiazide tablets granulated with acacia exhibited decrease in dissolution rate during 1yr of aging at R.T. A similar decrease was observed in tablets stored for 14days at 50-80°c or for 4 weeks at 37°c. Tablets with starch gave no change in dissolution rate either at R.T. or at elevated temperature. 20

21. 4.Factors related to Dissolution Apparatus A. Agitation  Speed of agitation generates a flow that continuously changes the liq /solid interface between solvent and drug. Inorder to prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results, agitation should be maintained at a relatively low rate. Thus in general relatively low agitation should be applied. 1.Basket method-100rpm 2.Paddle method-50-75rpm 21

22. b. Sampling Probe Position Sampling probe can affect the hydrodynamic of the system. USP states that sample should be removed at approximately half the distance from the upper surface of basket or paddle and surface of dissolution medium and not closer than 1cm to the side of the flask. C. Stirring element alignment The USP states that the axis of the stirring element must not deviate more than 0.2mm from the axis of the dissolution vessel. Studies indicate that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6mm from the centre axis of the flask. Tilt in excess of 1.5°c may increase dissolution rate from 2 to 25%. 22

23. 5.Factors relating Dissolution test Parameters A. Temperature Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important. Generally a temperature of 37°±0.5 is maintained during dissolution determination of oral dosage forms and suppositories. However for topical preparations temperature as low as 30° and 25° have been used. B. Vibration The excessive vibration of dissolution apparatus increases dissolution rates. 23

24. c. Vessel Design and construction Plastic vessels provide more perfect hemisphere than glass vessels. D. pH of dissolution medium Weak acids, dissolution rate increases with increase in pH where as for weak bases, increase with decrease in pH. 24

25. References: Biopharmaceutics and Pharmacokinetics A Treatise by D. M. Brahmankar, Sunil B. Jaiswal, 3 rd edition, Vallabh Prakashan. Biopharmaceutics and Clinical Pharmacokinetics by Milo Gibaldi, 4 th edition, Philadelphia, LeaandFebiger, 1991. Applied Biopharmaceutics and Pharmacokinetics by Shargel. LandYuABC, 2 nd edition, ConnecticutAppleton Century Crofts, 1985. Pharmacokinetics by Milo Gibaldi and D. Perrier, 2 nd edition, Marcel DekkerInc .,New York, 1982. Pharmaceutics The Science of Dosage Form Design edited by M.E. Aulton Second edition.   25

26. Questions: Discuss the diffusion layer theory using Noyes-Whitney’s equation and the variables that influence drug dissolution? Explain Noyes-Whitney equation and its importance in drug dissolution? 26

27. THANK YOU 27