Diffusion and Dissolution

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Diffusion Dissolution

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Diffusion and Dissolution:

Diffusion and Dissolution Gadade Dipak , Asst. Professor, Shri Bhagwan College of Pharmacy

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Dissolution- determined by studying rate at which dosage forms allow their formulated drug to dissolve Dissolution test- important when dissolution is rate limiting step For characterization of drug & Q.C. of dosage form

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Mechanisms of dissolution- Diffusion Theory/Film Theory Dankewert’s Model/ Surface renewal theory Interfacial Theory

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Late 1960’s- disso data determined Subsequently 6 products introduced in USP18 Importance of disso increased- of 674 monographs for tablets & capsules 582 included disso testing in USP28 USP28 includes disso & drug release test for various formulations like granules, suppositories, suspension, transdermal formulation, etc

Non-official methods of dissolution-:

Non-official methods of dissolution-

Non-official methods of dissolution-:

Non-official methods of dissolution- Chewing gum Apparatus Flow thr’ Cell for Semisolids Release thr’ dialysis membrane

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Dissolution of particles Noyes-Whitney equation dC = DS (C s -C) dt h Where, dC/dt- rate of dissolution D- diffusion coefficient S- Surface area h- Thickness of stagnant layer C s - Conc. in stagnant layer C- Conc. in bulk

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USP apparatus list:- Basket Apparatus (USP Apparatus 1) Paddle Apparatus (USP Apparatus 2) Reciprocating Cylinder Apparatus (USP Apparatus 3) Flow-Through Cell Apparatus (USP Apparatus 4) Paddle-over-Disk Apparatus (USP Apparatus 5) Cylinder Apparatus (USP Apparatus 6) Reciprocating Holder Apparatus (USP Apparatus 7)

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Apparatus Drug formulation tested 1. Basket Conventional, chewable tablets; control release formulations 2. Paddle Tablets, capsules, controlled release formulation, suspensions 3. Reciprocating Cylinder controlled release formulation, chewable tablets 4. Flow thr ’ Cell Formulations containing poorly soluble drugs, powders & granules, microparticles, implants 5. Paddle on disc Transdermal formulations 6. Cylinder Transdermal formulations 7. Reciprocating holder Controlled release formulation, non-disintegrating oral formulation, transdermal formulations

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Basket Apparatus (USP Apparatus 1) Dimensions taken from USP28 Apparatus consist of- motor, metallic drive shaft, cylindrical basket, covered vessel made of glass or other inert transparent material Temperature- 37±0.5 0 C

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Basket Apparatus (USP Apparatus 1) Vessel- 1) Shape:- Cylindrical vessel with hemispherical bottom 2) Height:- 160-210mm 3) Inner diameter:- 98-106mm 4) Capacity:- 1000ml Basket is attached to shaft & distance between inside bottom of vessel & basket is 25±2mm Covered with disc to retard evaporation

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Shaft (SS316) Basket (SS316/ Gold coating)

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Paddle Apparatus (USP Apparatus 2) Paddle replaces basket Distance between inside bottom of vessel & paddle is 25±2mm Metallic blade+ shaft= single entity Dosage form allowed to sink at bottom

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Reciprocating Cylinder Apparatus (USP Apparatus 3) For extended release dosage form Reciprocating cylinder has mesh at bottom Cylinder contains dosage form & it moves up & down in vessel containing dissolution medium It can be dipped sequentially into 6 different media vessels with varying speed & duration of immersion

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Flow-Through Cell Apparatus (USP Apparatus 4) Consist of- Dissolution cell of low volume(<30ml) Reservoir to provide fresh solvent Flow rate 240-960ml/hour (4/8/16 ml min -1 ) For extended release dosage forms

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Paddle-over-Disk Apparatus(USP Apparatus 5) For transdermal delivery system Uses the paddle apparatus (USP 2) Usually a transdermal delivery system, being attached to a stainless steel disk, which is then placed on the bottom of the vessel, directly under the paddle.

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Cylinder Apparatus (USP Apparatus 6) Modification of basket Basket placed by stainless steel cylinder Sample is again usually a transdermal delivery system attached to the outside of the cylinder.

APPARTUS 1,2,5,6:

APPARTUS 1,2,5,6

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Reciprocating Holder Apparatus (USP 7) Sample holder that oscillates up and down in the medium vessel Sample holder may take the form of a disk, cylinder, or a spring on the end of a stainless steel or acrylic rod, or it may simply be the rod alone. Sample is attached to the outside of holder. The sample either by virtue of being self-adhesive or is glued in place using a suitable adhesive.

DISSOLUTION MEDIUM:

DISSOLUTION MEDIUM The chosen medium must be able to distinguish between- Batch-to-batch variability Scale-up & post-approval change (SUPAC) Stability issues Physiological media is preferred over water-organic solvent mixtures or solutions + surfactants During dissolution method development, dissolution profiles in at least three media should be generated i.e. pH 1.2, 4.5, and 6.8 buffers For poorly soluble drugs- surfactants recommended

DISSOLUTION MEDIUM:

DISSOLUTION MEDIUM pH of dissolution medium-close to the pH anticipated in in-vivo fluids e.g. 0.1NHCl are used to mimic gastric pH Complex biorelevant media- mimic the physicochemical characteristics of the gastrointestinal tract in the fasting and fed states- to achieve IVIVC E.g. of biorelevant media- bile salt–phospholipids mixed micelle systems

ACCEPTANCE CRITERIA- IR :

ACCEPTANCE CRITERIA- IR

ACCEPTANCE CRITERIA- IR :

ACCEPTANCE CRITERIA- IR

ACCEPTANCE CRITERIA- ER:

ACCEPTANCE CRITERIA- ER

ACCEPTANCE CRITERIA- DR:

ACCEPTANCE CRITERIA- DR

ACCEPTANCE CRITERIA- TDDS:

ACCEPTANCE CRITERIA- TDDS

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Dissolution- primary constraint for comparison of 2 products Difference Factor (f1) 1, 2 : focuses on the difference in percent dissolved between reference and test at various time intervals f1= {[Σ  t=1 n  |R t -T t |] / [Σ  t=1 n  R t ]} ×100 n- no. of samplings performed R t - percent dissolved in time ‘t’ for reference T t - - percent dissolved in time ‘t’ for test Difference factor of 0-15 ensures minor difference between two products

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Similarity Factor (f2) 1, 2, 3 :  It stresses on the comparison of closeness of two comparative formulations similarity factor in the range of 50-100 is acceptable according to US FDA f2= 50×log {[1+ (1/n) Σ t=1 n (R t -T t ) 2 ] -0.5  ×100} Similarity factor- between 0 and 100 100- two comparative groups of reference and test are identical   0- the dissimilarity increases

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Different criteria's for dissolution profile comparison- The dissolution profiles can be compared only when number of dissolution units used are equal to or greater than 12 For accurate calculation of similarity factor, statistical approach may be used The dissolution conditions should be identical for both reference and test products

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Sampling once after 85% dissolution of product, since f2 values are sensitive to number of dissolution time points. For rapid dissolving products, that may dissolve 85% in 15 minutes, comparison of dissolution profiles is not mandatory. Similarity factor of 50-100 ensures sameness of two products Difference factor of 0-15 ensures minor difference between two products

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