Transcript Model stomach system

Pharmaceutical Dissolution Testing
Teaching Module
Bo Hu
Chemical Engineering @ UPRM
Outline
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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
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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
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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
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Linearity
Accuracy
Precision
Specificity
Robustness / ruggedness
Robustness
Parameters for medium used are
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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
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• ANATOMY & PHYSIOLOGY of THE
GASTROINTESTINAL TRACT
• Geometry (pylorus)
• Mechanics (peristalsis)
• Chemistry (pH)
• Biochemistry (enzymes)
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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
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Extended application
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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