USP_Disso_Bazil_2013_Method_Final2

Jian-Hwa Han
USP Dissolution Workshop
Rio de Janeiro - Brazil
May 20-21, 2013
Dissolution Method –
The Intended Use and
Discriminating Power
SUB-TITLE, DATE

• The Functions of Dissolution
• Starting Point – The API Properties
• Know Your Product
• Critical Elements of Dissolution Testing
• Sources of Variability
• How to Achieve Discriminating Power
• Examples
• Conclusion
Presentation Outline
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013
2

• Dissolution is In–Vitro Drug Release Testing
• Very important to show product quality
• The expectation is to be able to predict in vivo performance
(with the assumption that the product is dissolution rate
limited)
Basics of Dissolution
3

The Functions of Dissolution
4
Support Product Development –
Formulations & Process
Bio-Predictive /
Bio-relevant
Quality Control

Starting Point – API Properties
5
Property Value Source
melting point 234 dec °C PhysProp
water solubility 312 mg/L Not Available
logP 1.46
HANSCH,C
ET AL. (1995)
Property Value Source
water solubility 1.11e-01 g/l ALOGPS
logP 2.07 ALOGPS
logP 1.66 ChemAxon
logS -3.5 ALOGPS
pKa (strongest acidic) 12.58 ChemAxon
pKa (strongest basic) -3.3 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 91.67 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 97.57 ChemAxon
polarizability 38.17 ChemAxon
Experimental
Properties
Predicted
Properties
Data Source: Drug Bank (http://www.drugbank.ca/drugs/DB00635)

• Particle size
• Intrinsic Dissolution Rate (IDR)
• Solid State Properties
• Acid, Base, Salt
• Amorphous, Crystalline (Crystal Forms)
• Excipient Compatibility
• Stability
API Properties – Early Development
6

Biopharmaceutical Classification (BCS)
7

BCS High Solubility Criteria
8
A drug substance is considered
“highly soluble” when the highest
dose strength is soluble in 250 ml
or less of aqueous media over a
pH range of 1-7.5 at 37°C.

BCS High Permeability Criteria
9
A drug substance is considered to be
“highly permeable” when the extent
of absorption in humans is
determined to be ≥ 90% of an
administered dose based on a mass
balance determination or in
comparison to an i.v. reference dose

Pharmaceutical Dosage Form Taxonomy
Know Your Product
10
Reference: “The Role of Dissolution Testing: A USP Perspective” by Dr. Roger Williams, AAPS
Dissolution Workshop – South Africa, 2009

 Wrong size
 Incomplete milling
Mill
 Inconsistent raw materials
 Segregation in feed
 Variable API particle size
 Impurities in API
API ExcipientsBinder
Fluid bed
 Excessive attrition
 Segregation
Granulator
 Incorrect endpoint distribution (fine, coarse,
or bimodal)
 API agglomeration
 Wet massing or moisture addition leading to
inconsistent density
 Poor flow properties
 Segregation
 Variable tablet properties
Tablet press
Blender
 Over Lubrication
 Over Blended
Know Your Product –
Dissolution Supports Product Development

• Predictive/
Bio-relevant
• Discriminating
• Reproducible
• Transferable
• Rugged/Robust
Critical Elements of Dissolution Testing
12
}
The Deliverables:
Understand the product for it’s
design, formulation, and process.
Define what parameters influence
product quality, and develop the
method to meet the requirements
for it’s intended use.
}
The Quality Assurance:
Consistent performance (i.e.
maintaining discriminating and
predictive power) of the method is
critical for quality assurance and
quality controls

Sources of Variability in Dissolution testing
13

14
Method Control Strategies
• Adequate Training for Analysts
• Equipment Calibration and Qualification
• High Quality Materials and Chemicals/Reagent
• Knowledge of Method Parameters and their impact on Drug
Release Profiles
• Dissolution is a Huge Sample Preparation Process.
Tightening down the control and minimize the impacts
from those critical parameters can assure a more
reproducible method

15
How to Achieve Discriminating Power –
The Method Basics
• Apparatus – Different Hydrodynamic Designs
• RPM/DPM/Flow Rate – Different Agitation Rate
• pH
• Buffer Type and Concentration
• Surfactant Type and Concentration
• Other Method-related Parameters

16
How to Achieve Discriminating Power –
The Method Performance vs. Samples
• Sources of Variation:
Material,
Formulation, and
Process Parameters
• Perform process
DOE to identify
CQA’a and CPP’s
• Compare dissolution
data to Animal
and/or Clinical
results
• Need to have
RELEVANT SAMPLES
to develop the best
Discriminating
and Predictive
Dissolution Method
 Wrong size
 Wrong size
MillMill
API ExcipientsBinder API ExcipientsBinder
Fluid bedFluid bed
 Segregation
 Segregation
GranulatorGranulator
or bimodal)
or bimodal)
 Segregation
 Segregation
Tablet pressTablet press
Blender
Bio-Relevant ?
 Over Blended
 Over Blended

17
Example 1: DR + MR Product (Product A)
• Target Product Profiles:
• Bioequivalent to the reference (marketed product) with respect
to AUC under fed and fasted conditions
• Cmax_Product ≤ Cmax_Reference under fed and fasted conditions
• Hard Gelatin Capsule containing a discrete amount of coated
granules
• Each granule consists of an uncoated core and a film coat
• The rate of drug release in the intestine is controlled by the design
of MR formulation
• The granules are coated with an enteric polymer to prevent a food
effect on Cmax

18
Product A – Method Development
• Enteric Coating  Delayed Release:
Needs Dual Stage Dissolution Testing, i.e. [Acid Stage + Drug
Release Stage]
• Modified Release Controlled Release/Extended Release:
Need to provide multi-point specifications
• Hard Gelatin Capsule Product:
May Need Tier-2 Dissolution

19
Product A – Acid Stage Dissolution
• Acid drug has very low solubility at low pH  Low sensitivity &
discriminating. Action: Use pH 3.5 buffer as acid medium to
increase the method discriminating power

20
Product A – Coating Impact by pH
• There is no discrimination between coated vs. uncoated tablets using
pH 1 medium as the acid stage medium
• The discriminating power improved with pH 3.5 buffer as acid medium

21
Product A – Control by Drug Release Specification
• Typical Acid Stage Spec is NMT 10% LC
• The first drug release spec at 2.5 hours of NMT 30% provides much
tighter control for the quality of this product
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
0.0% 2.0% 4.0% 6.0% 8.0% 10.0%
Acid Stage, %LC at 2-hour
DrugRelease,%LCat2.5hours

22
Example 2: Prednisone Tablet Dissolution
• Prednisone Tablet –
USP monograph:
App 2 @50 rpm with
water
• Prednisone is BCS
Class I drug
• Criteria: NLT 80% at
30 minutes
• Sample: Commercial
20 mg Tablet
(Watson)
• Fast dissolving
formulation - No
significant impact
from deaeration
Commercial Prednisone Tablet, 20 mg
Mean Dissolution Plots with Error Bars
0
20
40
60
80
100
120
0 10 20 30 40 50 60
Time, minutes
%LC
Deaerated Non-deaerated
Q-spec: 80% at 30 min.

PVT - Prednisone Tablet (USP Std.)
Deaerated vs. non-Deaerated
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90
Time, Minutes
%LC
Deaerated non-Deaerated
23
USP Prednisone Tablet RS for PVT – Intended Use
• Prednisone Tablet –
App 2 @50 rpm with
500 mL water
• Super sensitive
dissolution method
designed as for
“Proficient Testing”
• Sensitive to
deaeration and
vibration
• Good to know the
impacts and to build
better controls for
our daily dissolution
experiments
App 2 @50 rpm; 1 hour
App 2 @200 rpm; 30 minutes

Conclusions – How to make your methods work
• Identify the sources of variability, and tighten the parameters which will
have significant impact to dissolution results
• Instrument/apparatus calibration and qualification – Ensure
minimization of instrument related variation ( i.e. a Must-to-have)
• High quality Materials/Reagent – Ensure consistent properties of
dissolution media used
• Minimize method variability to improve discriminating powder – Results
reflect more sample properties than method errors
• Need to have relevant samples to develop discriminating method
• Samples from animal and clinical studies
• Samples from process DOE
• Reproducible and Robust method
• Know your Product and develop the method for its intended use
• Successful dissolution method development requires good collaborations
among Analytical, Formulators, PK, and Regulatory functions
24

• Dr. Jian-Hwa Han is employed at Abbvie, and
currently is an active member of the USP Expert
Panel for “Use of Enzymes in Dissolution Testing for
Gelatin Capsules”
• Dr. Anagha Vaidya, and Dr. Paul Curry are employed
at Abbvie and all have contributed for scientific
discussions and reviewing the presentation materials
• USP provides the traveling fund for this presentation
Disclosures
25

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