Dissolution

Very limited dissolution

Limited dissolution

Dissolution

Drug in solution

Dissolution
3

In vitro Dissolution
Bioavailability and Bioequivalence
IR Products ER Products IR Products BCS Lower strength IVIVC Lower strength BE test

Quality Control
Product specification Batch release Shelf life

Official Dissolution Apparatus

4

Apparatus 1- Basket
5

Useful for

Capsules, beads, delayed release/

enteric coated dosage forms, floating

dosage forms, surfactants in media

Standard volume

900/1000 ml 1, 2, 4 liter vessels

Apparatus 1- Basket
6

Advantages

breadth of experience (more than

200 monographs)

full pH change during the test can be easily automated which is important for routine investigations

Apparatus 2 - Paddle
7

Useful for

tablets
capsules beads delayed release / enteric coated dosage forms

Standard volume 900/1000 ml

Apparatus 2- Paddle
8

Advantages

easy to use
robust can be easily adapted

to apparatus 5

long experience pH change possible

can be easily automated

which is important for routine investigations

Apparatus 2- Paddle
9

Disadvantages

pH/media change is often difficult

limited volume sink conditions for poorly soluble drugs hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution

Coning
sinkers for floating dosage forms

Apparatus 2- Paddle
10

Apparatus 3 Reciprocating cylinder(Bio-dis)

11

Useful for

tablets
beads controlled release formulations

Standard volume

200-250 ml per station

Apparatus 3 Reciprocating cylinder

12

Advantages

easy to change the pH pH-profiles hydrodynamics can be directly influenced by varying the dip rate

Disadvantages

small volume (max. 250 ml) little experience limited data

Apparatus 4 Flow-Through Cell

13

Useful for

low solubility drugs microparticulates

implants
suppositories

controlled release formulations

Apparatus 4 Flow-Through Cell

14

Laminar flow by pulse less pump Standard flow rate 4 -16 mL/min Must deliver a constant flow Open or close system

Apparatus 4 Flow-Through Cell

15

Advantages

easy to change media pH pH-profile possible sink conditions

Disadvantages

Deaeration necessary

high volumes of media

labor intensive

Apparatus 4 Flow-Through Cell

16

Apparatus 5 Paddle over disk

17

Useful for

transdermal patches

Standard volume

900 ml

Apparatus 5 Paddle over disk

18

Advantages

standard equipment (paddle) can be used, only add a stainless steel disk assembly

Disadvantages

disk assembly restricts

patch size

Discriminating method, sufficient ruggedness Reproducible and transferable operation Assessment of the batch-to-batch quality Assessment of the physical stability

Selection of Dissolution Medium

20

pH solublity profile, pKa of drug Drug permeability Solution state stability (buffers, pH, surfactants) Release mechanism (immediate, modified release

hardness friability excipients

Dissolution Medias
21

3 1 2 3 4 3 6

Water Dilute acid (0.001 N-0.1 N HCl) Buffered aqueous solution (pH 4-8)

Simulated gastric fluid (with or without enzymes)

Simulated intestinal fluid (with or without enzymes) Surfactants (with or without acids or buffers)

Apparatus used for various dosage form

Type of Dosage form Solid oral dosage form Transdermals-Patches Suppositories Suspensions Chewable Tablets Microparticles Implants Apparatus Type I/II Type V/VI Type I/II Type II Type I/II Type IV Type IV Name of apparatus Basket /Paddle Paddle over disk/rotating cylinder Basket /Paddle Paddle Basket /Paddle Flow through cell Flow through cell Reciprocating cylinder
22

Beaded type MR Products Type III

Agitation rate
23

IR Products

Apparatus 1-100 rpm Apparatus 2-50/75 rpm

Suspensions-25-50 rpm

MR Products

Apparatus 1- Higher rpm Apparatus 2- Higher rpm

Validation
24

Dissolution methods (HPLC, UV) should be fully validated:

Specificity Linearity

Accuracy
Repeatability Intermediate precision Robustness

Dissolution Profile Comparison

25

Model Independent approach using a difference factor (f1 ) and a

similarity factor (f2 ) to compare dissolution profiles .

The difference factor (f1) calculates the percent (%) difference

between the two curves at each time point and is a measurement of the relative error between the two curves

Cont..
26

The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves.
For curves to be considered similar,

f 1values should be close to 0

f2 values should be close to 100

Cont..
27

similarity factor in the range of 50-100 is acceptable

It can be computated using the formula

where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at time t, and Tt is the dissolution value of the test (postchange) batch at time t

Cont..
28

f1 values up to 15 (0-15)

f2 values greater than 50 (50-100)

ensure sameness or equivalence

The dissolution profiles can be compared only when number of

dissolution units used are equal to or greater than 12

Cont..
29

The mean data for comparison can be used only if the coefficient of

variation at the first time point is NMT 20%, and NLT 10% at the rest of time intervals.
Statistical approach of establishment of confidence intervals.

Cont..
30

The dissolution conditions should be identical for both reference

and test products.

The literature also states to consider only one time 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.

Conclusion
31

Human in vivo studies are usually conducted as confirmatory and in

most of cases seldom conducted. Therefore there is heavy reliance on dissolution testing for reflecting in vivo drug levels.
Dissolution testing surrogate in in-vitro bioequivalence test

32