usp_disso_bazil_2013_method_final2

Jian-Hwa HanUSP Dissolution Workshop

Rio de Janeiro - BrazilMay 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


The Functions of Dissolution


Support Product Development – Formulations & Process

Bio-Predictive /Bio-relevant

Quality Control

Starting Point – API Properties

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Property Value Sourcemelting point 234 dec °C PhysPropwater solubility 312 mg/L Not Available

logP 1.46HANSCH,C ET AL. (1995)

Property Value Sourcewater solubility 1.11e-01 g/l ALOGPSlogP 2.07 ALOGPSlogP 1.66 ChemAxonlogS -3.5 ALOGPSpKa (strongest acidic) 12.58 ChemAxonpKa (strongest basic) -3.3 ChemAxonphysiological charge 0 ChemAxon

hydrogen acceptor count 5 ChemAxonhydrogen donor count 2 ChemAxonpolar surface area 91.67 ChemAxonrotatable bond count 2 ChemAxonrefractivity 97.57 ChemAxonpolarizability 38.17 ChemAxon

Experimental Properties

Predicted Properties

Data Source: Drug Bank (http://www.drugbank.ca/drugs/DB00635)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

• Particle size

• Intrinsic Dissolution Rate (IDR)

• Solid State Properties

• Acid, Base, Salt

• Amorphous, Crystalline (Crystal Forms)

• Excipient Compatibility

• Stability

API Properties – Early Development

6USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

Biopharmaceutical Classification (BCS)


BCS High Solubility Criteria


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


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


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

Bio-Relevant ?

Over Lubrication

Over Blended

Know Your Product – Dissolution Supports Product Development

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• Predictive/Bio-relevant

• Discriminating

• Reproducible

• Transferable

• Rugged/Robust

Critical Elements of Dissolution Testing


}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



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


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


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 Incomplete milling Wrong size Incomplete milling

MillMill



API ExcipientsBinder API ExcipientsBinder

Fluid bedFluid bed

Excessive attrition Segregation Excessive attrition Segregation

GranulatorGranulator

Incorrect endpoint distribution (fine, coarse, or bimodal) API agglomeration Wet massing or moisture addition leading to inconsistent density

Incorrect endpoint distribution (fine, coarse, or bimodal) API agglomeration Wet massing or moisture addition leading to inconsistent density



Tablet pressTablet press

Blender

Bio-Relevant ?

Over Lubrication Over Blended Over Lubrication Over Blended


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


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


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


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


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

Dru

g R

elea

se, %

LC a

t 2.5

hou

rs


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 mgMean 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


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

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• 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


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