Module 1 The concept of in vitro dissolution – Definition and application.pdf

Course Overview

1. The concept of in vitro dissolution – Definition and

1. The concept of in vitro dissolution Definition and application

2. Compendial dissolution/ drug release testing

3. Method development – selection of test conditionsp

4. Dissolution method assessment – IVIVC(R)

5. Setting specifications

6. Product/ profile comparison – product similarity/

6. Product/ profile comparison product similarity/ interchangeability

7. Analytical instrument qualification

Disclaimer

Because USP text and publications may have legal implications in the U.S. and

elsewhere, their language must stand on its own. The USP shall not provide an official ex post facto interpretation to one party, thereby placing other parties without that

p p p y, y p g p

interpretation at a possible disadvantage. The requirements shall be uniformly and equally available to all parties.

In addition USP shall not provide an official opinion as to whether a particular article In addition, USP shall not provide an official opinion as to whether a particular article does or does not comply with compendial requirements, except as part of an established USP verification or other conformity assessment program that is conducted separately from and independent of USP's standard-setting activities.

Certain commercial equipment, instruments or materials may be identified in this

presentation to specify adequately the experimental procedure. Such identification does not imply approval, endorsement, or certification by USP of a particular brand or product, nor does it imply that the equipment, instrument or material is necessarily the best

Dissolution Rate

The dissolution rate of a drug from the solid state is The dissolution rate of a drug from the solid state is defined as the amount of drug substance that goes into solution per unit time under standardized

diti f li id/ lid i t f t t d

Goals of a Dissolution Test

ƒ Predict the bioavailability–surrogate parameter of the

th ti ffi

therapeutic efficacy

ƒ Indicate the robustness of the dosage form–drug product related safety

related safety

ƒ Sensitive to variations in the manufacturing process which have critical influence on the dosage form

performance

ƒ Quality control tool to ensure the uniformity of a product

– within 1 batch

– within 1 batch

The Dissolution Test

ƒ The dissolution procedure is a performance test applicable to majority of dosage forms

ƒ It is one test in a series of tests that constitutes the

ƒ It is one test in a series of tests that constitutes the

dosage form’s public specification (tests, procedures for tests, acceptance criteria)

ƒ The procedure should be appropriately discriminating, capable of disting ishing significant changes in a

Noyes-Whitney Equation

dM

)

(

C

C

k

dt

dM

s

−

×

=

dt

M amount of drug dissolved

t time

k dissolution coefficient

Cs concentration of drug in stagnant layer

Cs concentration of drug in stagnant layer

C concentration of drug in bulk solvent

Nernst-Brunner Equation

Modified Noyes-Whitney Equation

h

C

C

k

A

D

d

dM

×

×

×

(

_s

−

)

=

M amount of drug dissolved

h

dt

g

t time

D diffusion coefficient of drug

A surface area of drug particle

k dissolution rate constant

k dissolution rate constant

h thickness of stagnant layer

Cs concentration of drug in stagnant layer

C concentration of drug in bulk solvent

Sink Conditions

ƒ Sink conditions exist when the volume of the dissolution medium is at least 3 times greater than the volume

medium is at least 3 times greater than the volume required to make a saturated drug solution

k

A

D

dM

×

×

ƒ Overall dissolution rate increases with increased surface

s

C

h

k

A

D

dt

dM

×

×

×

=

ƒ Overall dissolution rate increases with increased surface area A

ƒ By maintaining y g A constant, the dissolution rate can be conveniently determined

(Note that C_S and k are constant at a given temperature for each solvent unstirred)

Intrinsic Dissolution Rate Constant

ƒ Intrinsic dissolution rate constant k (cm/s) varies from drug to drug and is a function of the diffusion coefficient

D (cm2_{/s) of the drug and the thickness of liquid film, l}

(cm)

D

( )

l

D

k

=

ƒ As the agitation intensity is increased, the thickness of the film decreases progressively

k is therefore a f nction of the test

Dissolution in the Context of Bioavailability

TABLET

DISINTEGRATION

GRANULES DISAGGREGATION

DRUG PARTICLES IN SUSPENSION SUSPENSION

DRUG IN SOLUTION IN GI FLUIDS

IN GI FLUIDS

Dissolution Pathway

Initial Exposure of the Tablet

dissolved drug

• • • •

dissolution

• •

• • • • • _• • _•

• •

tablet

Dissolution Pathways

# Drug molecules

release

• • • • • ••

• • •

•

• •

• •

S-Shaped Dissolution Curve—Solid Dosage Forms

e.g. occlusion

100%

v

ed

M h i l L

Dissolution Profiles

ƒ

e.g. Apparatus 1 and 2 (cumulative

results)

Dissolution Profiles

Factors Influencing Dissolution

ƒ Physico-chemical properties of the drug substance

l bili

– solubility

– particle size

ƒ Formulation characteristics of the dosage formFormulation characteristics of the dosage form

– Wettability

– Diffusion

R l h i

– Release mechanism

• Swelling

• Erosion

• Diffusion

Factors Influencing Dissolution

ƒ Apparatus choice

ƒ Media composition

ƒ Agitation V l

Bioavailability of Solid Oral Dosage Forms

ƒ Bioavailability is the rate and extent to which the drug

b t A ti Ph ti l I di t (API) i

substance or Active Pharmaceutical Ingredient (API) is absorbed from the drug product and becomes available at the site of action

ƒ exemplified for disintegrating immediate release solid dosage forms:

  _{Solid oral  Disintegration Dissolution Absorption}

dosage form 

Solid 

particles

Drug in 

solution

Drug in the 

Dissolution/ Drug Release Test

Dosage forms requiring dissolution/drug release test

ƒ Tablets C

ƒ Suppositories

ƒ Capsules

ƒ Suspensions

ƒ Transdermals

ƒ Implants

ƒ Ointments

ƒ Creams

ƒ Medicated gums

Goals of a Dissolution Test

ƒ Predict the bioavailability – surrogate parameter of the y g p therapeutic efficacy

ƒ Indicate the robustness of the dosage form – drug d t l t d f t

product related safety

ƒ Sensitive to variations in the manufacturing process which have critical influence on the dosage form

Goals of a Dissolution Test

ƒ Quality control tool to ensure the uniformity of a product

– Within one batch

Dissolution Testing

ƒ Dissolution assesses the performance of drug products

.

ƒ To be effective, the test should be:

– Predictive - relationship to in vivo response

Comparative - prediction only possible with comparative tests

– Comparative - prediction only possible with comparative tests

– Discriminatory - comparison only possible with discriminatory tests

Reproducible discrimination only possible with reproducible

Significance of Dissolution Testing

ƒ Important in the early stages of formulation development

ƒ It can be an indicator of in vivo performance

ƒ Extensively used for testing product stability

ƒ Serves as a quality control test by providing evidence of

ƒ Serves as a quality control test by providing evidence of the product’s physical consistency and manufacturing process

ƒ Serves as a quality assurance tool for

ƒ Serves as a quality assurance tool for

– batch to batch consistency and

Significance of Dissolution Testing

ƒ It is a critical regulatory and compendial requirement in the testing of solid dosage forms

ƒ Provides data facilitating initial approval, scale-up and post-approval changes

post-approval changes

ƒ Assists regulatory agencies in making approval

decisions pertaining to minor process and formulation changes

ƒ In combination with the BCS characterization allows Biowaivers

Dissolution Testing

ƒ Dissolution testing is comparative

– Formulation to formulation

– Fresh product to aged product Batch to batch

– Batch to batch

– Old process to new process