dissolution testing in drug product development

Avivia

DISSOLUTION TESTING IN DRUG PRODUCT

DEVELOPMENT

Menno Wiltink 16/17-02-2016

CONTENT

Avivia company

Dissolution Platform

USP IV

USP III BioDis

Case studies

Excipient characterization

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AVIVIA

Bridge between idea and market

Project Management

Consultancy

IP Strategies

Contract Research and Development

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EXPERIENCE

20 years of experience in field of

Innovator drugs

Generics

Excipients

Veterinary

Small molecules

Solids, liquids

Oral and parenteral medications

MR/CR, DR, IR, ODT, sub-lingual, depot, etc.

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CRO SERVICES

Laboratory facilities

Pharmaceutical R&D

Analytical R&D

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DRUG PRODUCT DEVELOPMENT

Formulation and Process Development,

Improvement and Troubleshooting

Technical Feasibility and Concept Development

Patent evaluation

API assessment

Formulation selection and development

Process implementation and optimization

Scale-up and manufacturing

Clinical studies

Close cooperation with analytical department

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ANALTICAL RESEARCH

Non-GMP Highly flexible, fast and efficient

Cooperative direct support API and Formulation development

Stability indicating method development Troubleshooting, optimization and transfer

Excipient characterization platform Physico-chemical characterization, QbD support

Dissolution platform Bio-relevant, Preclinical Evaluation and Equivalence selection

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DISSOLUTION PLATFORM

Experience

Apparatus I, II, III, IV

Release vs R&D methods

GENERAL SCHEME IN VIVO

Drug

ProductFree API

Dissolved

API

Absorbed

Drug

Release Dissolution Absorption

In vivo dissolution

Can be simulated in vitro

J.M.Cardot 2010

BIO-RELEVANT DISSOLUTION METHODS

Translate knowledge into predictive dissolution methods

API

Process

Excipients

(Biorelevant) Dissolution Methods

PK information / Pilot Study / DesignGIT

Formulation

Clinical Study

OPTIMAL EXCHANGE OF INFORMATION

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Input for optimization API, excipients,

formulation, processes, manufacturing

OBSERVATIONS

APPARATUS 4 FLOW THROUGH CELL

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USP4 FLOW CELL TYPES

For tablets, powders and granulates, implants,

suppositories and soft gelatin capsules

APPARATUS 3 BIODIS

APPARATUS 3 BIODIS

DISSOLUTION METHOD VARIABLES

Apparatus 3 BioDis

• Volume: 100/300 mL up to 700/2100 mL

• Sample points per rows

• Dipping speed: 5 – 30 (60) dips per minute

• pH/dip/time step gradient

• mesh screens and material

DISSOLUTION APPARATUS PROPERTIES

Apparatus 3 BioDis

• MR, CR, ER

• pH gradient, up to six pH per run

• Various dipping rates per run

• “Turbulent” flow increase erosion rate

• Sink conditions

• Hydrogel matrix tablets

• Mechanical stability

• comparable profiles to apparatus 2 possible

• avoiding cone formation

APPARATUS 3 BIODIS

Cons

• Not for IR or fast eroding products

• Variable movement product (size, shape, stickiness)

• Variable flow (clogging screens, viscosity)

• Sediment on the bottom

• Limited simulation of the physiological conditions

• Sink conditions?

• Requires extensive method development

• Low throughput

• Labor intensive, half automated

• Not the preferred QC tool

Development 24 hours CR tablet

Approach: Fast, Target and Slow formulation

Initial method: Basket USP I

CASE 1 DEVELOPMENT GENERIC CONTROLLED RELEASE

Development of a multiple particulate dosage form

FDA/EMA recommended dissolution method for Delayed Release;

Gastric Challenge:

2 hours pH 1.0 0.1M HCl followed by 1 hour pH 6.8 phosphate buffer

CASE 2 DELAYED RELEASE AND BIODIS

TYPICAL RELEASE TEST

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

90,0

100,0

0 20 40 60 80 100 120 140 160 180 200

Dis

solv

ed a

mo

un

t (%

)

Sampling timepoints (hrs)

dissolution (n=6) 2hrs in 0.1M HCl pH1 and after full media-change 1hr in

phosphate buffer pH6.8

Gastric challenge pH 1.0 pH 6.8

CASE 3 MODIFIED RELEASE AND BIODIS :

• Generic CR polymer matrix tablet, 24 hours release

• Dissolution tests performed apparatus I Basket and II Paddle :

• FDA method

• pH

• Media compositions

• Rpm

• Combinations

• Disintegration tests

All tests: f2 > 58 Bioequivalency failed…………

EXCIPIENT CHARACTERIZATION PLATFORM

Stability issues

Incompatibility

Supplier variability

Batch tot batch variation

Physico chemical characterization

MW, PSD, surface area, water sorption, composition,

homogeneity, etc.

Reactive impurities

Compatibility studies

DEFORMULATION

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Avivia: Bridge between idea and market

Technical Feasibility and Concept Development

Formulation and Process Development, Improvement and Troubleshooting

Patent evaluation and strategy

Project management

Predictive Dissolution Testing, Preclinical Evaluation and Equivalence selection

Analytical Research and Support

QbD Excipient Characterization and Troubleshooting

Novio Tech Campus NijmegenTransistorweg 5 6534 AT Nijmegen

Netherlands

www.avivia.nl

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Thank you

For more information, please contact:

Menno Wiltink

Avivia

Transistorweg 5

6534 AT Nijmegen

The Netherlands

E-mail: mennowiltink@avivia.nl

www.avivia.nl