Pharmaceutical Dissolution TestingTeaching Module

Bo Hu

Chemical Engineering @ UPRM

Outline

• Introduction

• Dissolution procedure

• IVIVC

• Dissolution Analysis

• Applications

Activity of GI-tract

Dosage Forms• Storage

• Separation – depending on technological type

• Transport

• Processing

–disintegration

–dissolution

–decomposition

• Absorption of drugs

–many xenobiotics are absorbed by passive diffusion (lipophilicity, molecular weight)

• Resecretion of drugs to GI-Tract

• Drug disintegration --- first order process

• Drug dissolution ---proportional to the concentration difference of the drug between the particle surface and the bulk solution

Definition

• Dissolution testing is a critical formulation tool in the process of drug discovery that entails measuring the stability of the investigational product, achieving uniformity in production lots and determining its in vivo availability. Thus this method is useful in the pharmaceutical and biotechnology industry to formulate drug dosage forms and to develop quality control specifications for its manufacturing process.

Dissolution Method Development

• Physical and chemical properties of the drug

• Determination of the dissolution apparatus

• Selection of the dissolution medium

• Determination key operating parameters

• Method optimization

• Validation of the methodology

Physical and Chemical Properties

• Ionization constants (pKa)

• Solubility as a function of pH

• Solution stability as a function of pH

• Particle size

• Crystal form

• Common ion, ion strength, and buffer effects

Apparatus USP

• Apparatus 1 (Rotating basket)

• Apparatus 2 (Paddle assembly)

• Apparatus 3 (Reciprocating cylinder)

• Apparatus 4 (Flow-through cell)

• Apparatus 5 (Paddle over disk)

• Apparatus 6 (Cylinder)

• Apparatus 7 (Reciprocating holder)

Key Operating Parameters

• Media– Volume– Temperature: 37 0.5ºC– Deareation

• Sinker evaluation• Analytical detection• Sampling time points and

specifications

Deaeration

• Heating of the medium, followed by filtration and drawing of a vacuum for a short of time

• Temperature filtration

• Sonication

• Helium sparging

Analytical detection

• UV detection --- easy for automation and faster analysis

• HPLC --- recommended method

Sampling time points

Time Points

IR products

• Test time : 30 to 60 minutes

Specifications

• Single point : NLT 85% in 15 minutes

• Dissolution profile : sampling at 5-, 10-or 15-minute intervals

Extended-Release Products

Test time : at least 3 test times

• Early time point : 1-2 hours : potential dose dumping

• Intermediate time point : define the release profile

• Final time point : show complete release of the drug

Optimization

• Re-evaluation and optimization should be done when human BA data are available.

Validation

• Linearity

• Accuracy

• Precision

• Specificity

• Robustness / ruggedness

Robustness

Parameters for medium used are• pH• Medium volume or flow rate• Rotation speed• Apparatus sample position• Sinkers• Media deaeration• Temperature• Filters• Column and mobile conditions (if analyzed with HPLC)

Dissolution procedure:• Discriminating method• Sufficient ruggedness• Reproducible operation• Transferable• Assessment of the batch-to-batch quality of a

drug product • Assessment of the physical stability of the

formulation• Low variability in dissolution results

Qualitative tool

• Biological availability (BA)

• Biological equivalency (BE) (and / or)– Biowaivers (waivers from additional in vivo

studies for immediate release solid oral dosage forms)

• Batch to batch consistency– Product characterization– Quality control (QC)

Bioequivalent drug products

• Pharmaceutical equivalency: the rate and extent of adsorption do not show a significant difference when administered at the same molar dose of therapeutic moiety under similar experimental moiety under similar experimental conditions, either single dose or multiple.

In vitro/in vivo correlation (IVIVC)

• The main objective of the IVIVC is to establish the dissolution test as a surrogate for BE studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and post approval changes.

Definition of IVIVC

• Predicative mathematical model describing the relationship between an in vitro property of the dosage form and an in vivo response.

• A general term that refers to a relationship between a biological property produced by a dosage form and a physicochemical characteristic of the same dosage form.

• Facilitate drug development by reducing the in vivo studies

In Vivo Drug Release May Depend on

• TECHNOLOGY OFDOSAGE FORM• dissolution rate

– robustness of rate controlling mechanism

• .....• ANATOMY & PHYSIOLOGY of THE

GASTROINTESTINAL TRACT• Geometry (pylorus)• Mechanics (peristalsis)• Chemistry (pH)• Biochemistry (enzymes)• .....

Approaches to obtain IVIVC

• Look for appropriate mathematical model to describe the relationship between in vitro-in vivo dissolution.

• Choose different dissolution conditions to match in vivo dissolution profile

• Non-quantitative

• Quantitative IVIVC• Single-point correlation• Point-to-point IVIVC

Interpretation of IVIVC time profiles

• Extent --- profile vertically in terms of its final plateau

• Rate --- process as fast or slow in terms of its mean time

• Shape --- additional information about the profile in terms of the variance or another equivalent metric

Quality control

100

11log50

5.0

1

22

n

ttt TR

nf

Extended application

• Ordinary tablets and capsules

• Extended –release

• Delayed-release

• Transdermal

• Multivitamin

• Mineral

• Class Monographs for non-prescription drug combinations

References

• Textbook: Pharmaceutical Dissolution Testing (Hardcover) by Jennifer J. Dressman (Editor), Johannes Kramer (Editor) Publisher: Informa Healthcare; 1 edition (July 8, 2005)

• Other References: Seubpong Kumpusiri, Patima Maneesatid, The dissolution procedure: development and validation, Pharmacopeial forum Vol.31(5), 26May 2006