DISSOLUTION AND DIFFUSION

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A SEMINAR ON Diffusion and dissolution :

A SEMINAR ON Diffusion and dissolution PRESENTED BY Mr.SARDA R.R. (M.Pharm 1 st semester) Padm. Dr. D.Y. Patil College of Pharmacy, Pune. 1

CONTENTS:

CONTENTS INTRODUCTION TO DISSOLUSION PROCESS OF DISSOLUTION THEORIES OF DISSOLUTION DISSOLUTION APPARATUS DISSOLUTION MEDIUM BIOEQUIVALENCE DISSOLUTION KINETICS 2

IMPORTANT TERMS:

IMPORTANT TERMS Dissolution is the process by which a solid substance solubilizes in a given solvent. Dissolution rate is defined as the amount of solid substance that reaches into solution per unit time. Diffusion describes the spread of particles through random motion from regions of higher concentration to regions of lower concentration 3

PROCESS OF DISSOLUTION:

PROCESS OF DISSOLUTION The process of dissolution involves breaking of intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, and the interaction between the solvent and solute molecule or ion. 4

THEORIES OF DISSOLUTION :

THEORIES OF DISSOLUTION Dissolution layer model or film theory Danckwert’s Model or Surface Renewal Theory Interfacial Barrier Model or Limited Solvation Theory 5

FICK'S FIRST LAW:

FICK'S FIRST LAW It states that the flux goes from regions of high concentration to regions of low concentration, with a magnitude that is proportional to the concentration gradient. J = -D. dØ/dæ where, J=flux D=coefficient of diffusivity dØ=change in concentration dæ=change in position 6

FICK'S SECOND LAW:

FICK'S SECOND LAW Fick's second law predicts how diffusion causes the concentration field to change with time. dc/ dt = D.d 2 c/d 2 x Where, dc= the concentration dt = is time D= is the diffusion coefficient 7

NOYES-WHITNEY EQUATION:

NOYES-WHITNEY EQUATION Noyes Whitney equation based on Fick’s second law of diffusion. i.e. 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. dc/ dt = KS (Cs- Cb ) where, dc/ dt -Rate of dissolution K- is the rate constant, S -is the surface area (Cs- Cb ) - is the difference in concentration. 8

MODIFIED NOYES- WHITNEY EQUATION:

MODIFIED NOYES- WHITNEY EQUATION It is based on the Ficks first law of diffusion dm/ dt = K DS (Cs- Cb ) vh Where, dm/ dt =Rate of mass transfer D=diffusion coefficient(m2/s) S=surface area (Cs- Cb )=concentration gradient V=volume of dissolution media h=Thickness of boundary layer 9

DISSOLUTION TESTING:

DISSOLUTION TESTING 10

GOALS OF DISSOLUTION TESTING:

GOALS OF DISSOLUTION TESTING Prediction of bioavailability. It provides necessary information to the formulator in the development of more efficacious dosage form. Optimization of therapeutic effectiveness. Routine assessment of production quality to ensure uniformity between productions lots. Assessment of ‘bioequivalence’. 11

DISSOLUTION APPARATUS:

DISSOLUTION APPARATUS 12

THE IDEAL FEATURES OF A DISSOLUTION APPARATUS:

THE IDEAL FEATURES OF A DISSOLUTION APPARATUS Must be simply designed. Must be enough sensitive. Uniform hydrodynamic flow is essential. An easy means of introducing dosage form. Provide minimum mechanical abrasion to the dosage form. The medium must be maintained at a fixed temperature. Samples should be easily withdrawn. 13

USP DISSOLUTION APPARATUS:

USP DISSOLUTION APPARATUS Apparatus 1 - Basket (37º) Apparatus 2 - Paddle (37º) Apparatus 3 - Reciprocating Cylinder (37º) Apparatus 4 - Flow-Through Cell (37º) Apparatus 5 - Paddle over Disk (32º ) Apparatus 6 - Rotating Cylinder (32º) Apparatus 7 - Reciprocating Holder 14

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APPARATUS 1 – BASKET 15

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APPARATUS 2 – PADDLE 16

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APPARATUS 3 – RECIPROCATING CYLINDER 17

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APPARATUS 4 – FLOW-THROUGH CELL 18

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APPARATUS 5–PADDLE OVER DISK 19

APPARATUS 6 - ROTATING CYLINDER :

APPARATUS 6 - ROTATING CYLINDER 20

APPARATUS 7–RECIPROCATING HOLDER:

APPARATUS 7–RECIPROCATING HOLDER 21

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DISSOLUTION MEDIA :

DISSOLUTION MEDIA 23

DISSOLUTION MEDIA :

DISSOLUTION MEDIA 1) Compendial dissolution media The dissolution media which are official in pharmacopeias is known as Compendial dissolution media. 2) Biorelevant dissolution media The medium prepared by addition of synthetic surfactant and enzymes to this Compendial media known as biorelevant media. In this media we are trying to simulating the condition as is in GIT. 24

DISSOLUTION MEDIUM OFFICIAL IN I.P:

DISSOLUTION MEDIUM OFFICIAL IN I.P Hydrochloric acid. Phosphate buffer. Acid phthalate buffer. Neutralized phthalate buffer. Alkaline borate buffer. Acetate buffer. Imidazole buffer. Glycine buffer Palladium chloride solution buffer. Citro-phosphate buffer. Ammonia buffer. Boric buffer Carbonate buffer. 25

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SIMULATED FLUIDS I). Simulated gastric fluid Dissolve 2 gm of NaCl, 3.2 gms of pepsin in 7 ml of HCL and add sufficient water to make 1000ml. This test solution has pH about 1.2. II). Simulated intestinal fluid Dissolve 6.8 gms of monobasic potassium phosphate in 250ml of water, mix and add 190ml of 0.2 N NaOH and 400 ml of water. Add 10 gm of pancreatin mix and adjust the resulting solution with 0.2 N NaOH to a pH of 7.5 +/- 0.1. Dilute with water 2000 ml. 26

MEDIA WITH SURFACTANTS:

MEDIA WITH SURFACTANTS Commonly acceptable ionic or nonionic surfactants include- sodium lauryl sulfate (SLS), Polyoxyethylene sorbitan monolaurate (Tween) cetyltrimethylammoniumbromide (CTAB) nonylphenol, ethoxylate (Tergitol), cyclodextrins, lecithin. non ionic detergents (e.g., SPANS). 27

UN-OFFICIAL MEDIA USED :

UN-OFFICIAL MEDIA USED BIORELEVANT MEDIA Fasted State Simulated Intestinal Fluid (FaSSIF) Sodium taurocholate 3mM Lecithin 0.75 mM NaOH (pellets) 0.174 g NaH2PO4.H2O 1.977 g NaCl 3.093 g Purified water qs. 500 mL Media has a pH of 6.50 osmolality of about 270 m.osmol /kg . 28

Fed State Simulated Intestinal Fluid (FeSSIF):

Fed State Simulated Intestinal Fluid (FeSSIF) Sodium taurocholate 15 mM Lecithin 3.75 mM NaOH (pellets) 4.04 g Glacial Acetic Acid 8.65 g NaCl 11.874 g Purified water qs. 1000 mL Media has a pH of 5.00. osmolality of about 670 m.osmol /kg 29

Simplified Biorelevant Media:

Simplified Biorelevant Media Due to complex composition (FaSSIF) and (FeSSIF) are expensive and, to date, need to be prepared on the day of the experiment. so sodium taurocholate and lecithin were replaced with surfactants viz Brij 35, Span 80, Tween 20,40,60,80, triethanalomine to obtain simplified, inexpensive, biorelevant media. 30

BIOEQUIVALENCE:

BIOEQUIVALENCE 31

BIOEQUIVALENCE:

BIOEQUIVALENCE "Bioequivalence" is a comparison of the bioavailability of two or more drug products. Thus, two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same 32

WHY TO CARRY OUT BIOEQUIVALENCY STUDIES?:

WHY TO CARRY OUT BIOEQUIVALENCY STUDIES? Generic product & innovator product must be: they are pharmaceutical equivalents. they are bioequivalent. they are in compliance with compendial standards for strength, quality, purity and identity. they are adequately labelled. they have been manufactured in compliance with Good Manufacturing Practices. 33

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HIGH RISK POTENTIAL MODERATE RISK POTENTIAL LOW RISK POTENTIAL Aminophylline Amphetamine acetaminophen Aspirin{in high doses} Chloramphenicol ephedrine Digoxin Chlorpromazine codeine Prednisolone Erythromycin isoniazid Warferin Griseofulvin sulfasoxazole Phenytoin Oxytetracycline meprobamate Quinidine Phenacetin hydrochlorthiazid 34

MARKET BRANDS LOSING PATENTS IN NEAR FUTURE:

MARKET BRANDS LOSING PATENTS IN NEAR FUTURE 1. Cozaar / Hyzaar - Merck 2. Lipitor - Pfizer 3. Flomax - Boehringer Ingelheim 4. Arimidex - AstraZeneca 5. Climara - Bayer HealthCare 6. Aricept - Aricept 7. Invirase - Roche 8. Hycamtin - GlaxoSmithKline 9. Protonix - Pfizer 10. Levaquin - Levaquin 35

CONCERNS:

CONCERNS Appropriate choice of pharmacokinetic parameters to assess bioequivalence. Problems involved in extrapolating from single-dose studies to steady-state. Bioequivalence does not always ensure therapeutic equivalence. Lack of clear guidelines for evaluation of bioequivalence. 36

DISSOLUTION KINETICS:

DISSOLUTION KINETICS 37

ZERO ORDER DRUG RELEASE :

ZERO ORDER DRUG RELEASE Q = Q 0 + K 0 t Where, Q = amount of drug released Q 0 = amount of drug in the solution K 0 = Zero order release constant 38

FIRST ORDER DRUG RELEASE:

FIRST ORDER DRUG RELEASE Q t = Q 0 e -kt Where , Q t = amount of drug remaining to release Q 0 = amount of initial drug k = First order drug release constant 39

HIXSON-CROWELL CUBE ROOT EQUATION :

HIXSON-CROWELL CUBE ROOT EQUATION For spherical particle, W t 1/3 = W 0 – k 1/3 t where, W t = particle weight at time t W 0 = initial particle weight k 1/3 = dissolution rate constant 40

Higuchi equation-diffusion controlled release:

Higuchi equation-diffusion controlled release DM/ dx = C 0 dx – C s /2 DM = change in amount of drug released per unit area dx = change in the thickness of the zone of matrix C 0 = total amount of drug in unit volume in matrix C s = saturated concentration of drug in the matrix 41

Korsmeyer peppas equation:

Korsmeyer peppas equation M t /M ∞ = Kt n M t /M ∞ = fraction of drug released after time t in respect to amount of drug released at infinite time K = rate constant n = diffusional exponent 42

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n value Diffusion mechanism < 0.5 fickian 0.5<n<1 Anomalous >1 Non fickian 43

REFERENCES:

REFERENCES Welling P.G, Tse F.L, Dighe S.V , Pharmaceutical Bioequivalence, New York; Marcel Dekker, Inc; 1991, 1-37. Dressman J, Kramer J, Pharmaceutical Dissolution Testing, NewYork ; Taylor and Fancis Group; 2005, 69-80. Krishna R, Yu L, Biopharmaceutics Application in Drug Development, USA; Springer ,2008, 47-74. Costa P, Manuel J, Lobo S, Modeling and Comparision of Dissolution Profiles, European Journal of Pharmaceutical Sciences; Elsevier; 2001, 123-133. 44

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Questions?:

Questions? 46

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