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Pharmaceutical Dissolution Testing

Teaching 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 (p
K
a
)


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 0.5
ºC


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
1
1
log
50
5
.
0
1
2
2
n
t
t
t
T
R
n
f
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