Dissolution testing

Contents:- Definition of dissolution Purpose and concept of dissolution testing History Dissolution testing apparatus:-

- Types- Dimensions

Experimental Testing conditions Factors affecting the dissolution test Dissolution Specifications

In Vivo-In Vitro Correlations Validation Calibration Of Dissolution Test Apparatus Acceptance criteria General care and precaution

Definition of Dissolution :-

Dissolution is defined as the process by which a solid substance enters in the solvent to yield a solution .

It is the process by which a solid substances dissolves .

Purpose & Concept of Dissolution Testing

Drug absorption from a solid dosage form after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the GIT. Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance.

Based on this, in vitro dissolution tests are used to (1) Assess the lot-to lot quality of drug product (2) Guide development of new formulations (3 ) Ensure continuing quality & performance during the

changes, such as, change in formulation, manufacturing process, site of manufacturing etc.

So, the dissolution testing is an important tool-1) For characterizing the biopharmaceutical quality of

product2) For evaluation of active ingredients 3) For evaluation of possible risk such as - Dose dumping, Food effects, Interaction with other drugs

History:- It all started in 1897 with the first reference to

dissolution: Noyes and Whitney publish a paper on "The Rate of Solution of Solid Substances in Their Own Solution." They suggested that the dissolution rate was controlled by a layer of saturated solution that forms instantly around a solid particle.

1904-Nernst and Brunner modified he Noyes-Whitney equation by applying Fick's law of diffusion. A relationship between the dissolution rate and the diffusion coefficient was established.

1930-Experiments begin with in vivo-In vitro correlations

1934-Switzerland's Pharmacopoeia Helvetica was the first regulatory body to introduce a disintegration test for tablets.

1950's-Emphasis moved from studying the effects of physiochemical properties of drugs on dissolution to correlation of dissolution to bioavailability of dosage forms.

1950-Disintegration became an official USP Method, USP 14.

1960's-Although it was recognized that disintegration was a critical process, deaggregation was essential for bioavailability. USP recognized a need for a standardized dissolution test. The USP began experimenting with a variety of basket and stirring devices.

1960-Levy and Hayes, utilizing a beaker and a three blade stirrer at 30-60 RPM, found significant differences in the in vitro dissolution rates of different brands of aspirin tablets and linked them to the incidence of gastrointestinal irritation caused by various brands due to their slow dissolution rates.

1970- USP 18 incorporated the first official dissolution test for solid dosage forms. Twelve Monographs published in USP-NF with the official dissolution test- a rotating basket.

1990-Paddle over disk, Rotating Cylinder Reciprocating Disk 1995-Reciprocating Cylinder, Flow through cell 1997 FDA: SUPAC-MR 1997 FDA: Guidance ER IVIVC

Apparatus:- Apparatus 1 (basket):- For capsules, for dosage forms

that tend to float or that disintegrate slowly. Apparatus 2 (paddle):- For tablets Apparatus 3 (reciprocating cylinder):-For bead –type

modified-release dosage forms Apparatus 4 (flow cell):- For modified-release dosage

forms Apparatus 5 (paddle over disc) & Apparatus 6

(cylinder) :- For evaluating & testing transdermal dosage forms Apparatus 7 (reciprocating disc):- For non-

disintegrating oral modified-release & transdermal dosage forms

Paddle Apparatus – 6 stations

Paddle Apparatus – 4 stations

Paddle apparatus Basket apparatus

Calibration of Dissolution Apparatus

Dimensions of Paddle Apparatus:-Parameter Size (mm)Vessel height 160-175Vessel internal diameter 98-106Paddle shaft diameter 9.4-10.1Blade upper chord 74-75Lower chord 42Blade height 19±0.5Radius of risk of which the blade is cut out

41.5

Thickness 4.0Positioning the stirring device 25±2

Dimensions of Basket Apparatus:-

Parameter Size (mm)Basket shaft diameter 9.4-10.1Screen wire diameter 0.254Height of screen 27.0Internal diameter of basket 20.2±1.0External diameter of basket 22.2±1.0Total height of basket 36.8±3.0Openings 0.381

Experimental Testing conditions:- Dissolution medium – deaerated water, buffered

solution (pH- 4 to 8),dilute acid (0.001N to 0.1N HCl) Volume of dissolution medium - 500-1,000 ml

The quantity should be not less than 3 times that required to form a saturated solution of the drug substance.

The pH of the test medium - within pH 1.0 - 6.8. Speed

100 rpm (for apparatus 1-basket) 50 rpm (for apparatus 2-paddle)

Temperature - 37 ± 0.5 0

Factors affecting the dissolution test:-

Related to dosage form Related to apparatus -Polymorphism -Type of apparatus-Particle size distribution -Dissolution media-Solubility -pH-Dissolution rate -Temperature-Type of dosage form -Speed of rotation

ABSORBTION OF A DRUG AN INTACT TABLET

Dissolution Specifications:-

Single-point specifications As a routine quality control test. (For highly soluble

and rapidly dissolving drug products.)

Two-point specifications For characterizing the quality of the drug product.

As a routine quality control test for certain types of drug products (e.g., slow dissolving or poorly water soluble drug product like carbamazepine).

In Vivo-In Vitro Correlations:-

This concept firstly arised as result of awareness of bioavailability and in vitro dissolution rate determinations. This term refers the establishment of a rational relationship between a biological property & a physicochemical property.

The in vitro test serves as a tool to distinguish between acceptable and unacceptable drug products.

Acceptable products are bioequivalent, in terms of in vivo performance, whereas unacceptable products are not.

To achieve an in vitro-in vivo correlation, at least three batches that differ in the in vivo as well as the in vitro performance should be available. If the batches show differences in in vivo performance, then in vitro test conditions can be modified to correspond with the in vivo data to achieve an in vitro-in vivo correlation. Possible reasons for poor in vivo-in vitro correlations:- Study design:- Inappropriate In vivo- In vitro

test conditions. Dosage form:- Drug release not controlled by

the dosage form. Drug release strongly affected by intestinal transport kinetics.

Drug substance :- Chemical degradation in the gastrointestinal tract. Absorption of

undissolved particles.

Validation :-- The system suitability test using calibrators

- Deaeration, if necessary

- Validation between manual and automated procedures

- Validation of a determinative step (i.e., analytical methods employed in quantitative analysis of dissolution samples).

- Validation of analytical procedure applied in dissolution testing includes , accuracy, precision, linearity & range.

Calibration Of Dissolution Test Apparatus:-

- The shaft is positioned so that, its axis is NMT 2mm at any point from the vertical axis of the vessel & rotates smoothly & without significant wobble that could affect the results.

- A speed regulating device is used that allows the shaft rotation speed to be selected & maintained at the specified rate, within ±4%.

- The distance between the inside bottom of the vessel &

the bottom of the basket (& blade also) is maintained at 25 ± 2mm during the test.

- Temperature of water bath should maintain at 37±0.5°C during the test.

- During sampling, withdraw a specimen from a zone midway between the surface of the dissolution medium & the top of the rotating basket or blade, NLT 1cm from the vessel wall. Specimens are to be withdrawn only at the stated times within a tolerance of ±2%.

Acceptance criteria:-

Stages Number tested

Acceptance criteria

S1 6 Each unit is NLT Q+5%S2 6 Avg. of 12 units (S1+S2) is equal to or

greater than Q,& no unit is less than Q-25%

S3 12 Avg. of 24 units (S1+S2 +S3) is equal to or greater than Q, NMT 2 units are less than Q- 15%, no unit is less than Q-25%

Q= amount of dissolved active ingredient

For immediate-release dosage forms :-

Stage Number tested

Acceptance criteria

S1 6 Avg amount dissolved is NLT Q+10%

S2 6 Avg amount dissolved (S1 + S2) is equal to or greater than Q+5%

S3 12 Avg amount dissolved (S1 + S2 +S3) is equal to or greater than Q.

For pooled sample:-

For Extended-Release Dosage Forms:- Level No.

testedCriteria

L1 6 No individual value lies outside each of the stated ranges & no individual value is less than the stated amount at the final test time

L2 6 The avg. value of 12 units ( L1+L2) lies within each of the stated ranges, & is NLT the stated amount at the final test time; none is more than 10% of labeled content outside each of the stated ranges; & none is more than 10% of labeled content below the stated amount at the final test time.

For Extended-Release Dosage Forms:-

Level

No.tested

Criteria

L3 12 The avg. value of 24 units ( L1+L2 +L3) lies within each of the stated ranges, & is NLT the stated amount at the final test time; NMT 2 of the 24 units are >10% of labeled content outside each of the stated ranges; & NMT 2 of the 24 units are >10% of labeled content below the stated amount at the final test time: & none of the unit is >20% of labeled content outside each of the stated ranges or >20% of labeled content below the stated amount at the final test time.

Acid stageLevel Number

testedCriteria

A1 6 No individual value exceeds 10% dissolved

A2 6 Avg. of 12 units (A1+A2) is NMT 10% dissolved , & no individual unit is greater than 25% dissolved.

A3 12 Avg. of 24 units (A1+A2+A3) is NMT 10% dissolved , & no individual unit is greater than 25% dissolved.

Level Number tested

Criteria

B1 6 Each unit is NLT Q+5%

B2 6 Avg. of 12 units (B1+B2) is equal to or greater than Q,& no unit is less than Q -15%

B3 12 Avg. of 24 units (B1+B2 +B3) is equal to or greater than Q, NMT 2 units are less than Q - 15%, no unit is less than Q - 25%

Buffer stage:-

General care and precautions:-

Proper handling of the instrument.

Do not start the heater if there is no water in the tank upto the mark level.

While filling the tank with water make sure that water should not fall on the stirrer unit and on the heater cover.

Do not pull or force the paddle or basket.

Do not over tighten the paddle

Do not disturb the sensor tube while cleaning the tank.

Handle the external probe with care.

Do not use any pointed objects for setting the parameters.

While paddles are rotating so first stop the paddle and then press lift UP switch.

MAINTENANCE / REPAIRS :- If the instrument does not produce required calibration

results or its response is poor then it should be labeled ˝FAULTY” and should be repaired or serviced.

Tablet Dissolution Test in Different Stages (S1, S2 and S3)