Pharmaceutical preformulation and formulationSUCHANDRA BAGCHIM.S.(PHARMACEUTICS)NIPERA1517PE10

Flow of seminar

Introduction Candidate drug selection Pharmacological characterization Early of candidate drug selection Biopharmaceutical consideration Early drug development and product design Product optimization Post product optimization conclusion

Introduction

To be successful and competitive, research based pharmaceutical companies must ensure that new discoveries are frequently brought to the market to generate cash flow. This is required to find the next generation compounds, to meet the therapeutic needs of patients and of course, to benefit the shareholders. This cycle of events is sometimes referred to as Product Life Cycle.

Unsuccessful compounds should be removed at R&D level only to minimise expenses of clinical research.

In spite of high risk and high cost involved, there is still a huge incentive for pharmaceutical companies to seek financial rewards such as “blockbuster”(I billion US$ per year).

Hence the importance of accelerating and optimizing drug discovery and development, and getting to the market first with a new therapeutic class medicinal product, cannot be underestimated.

To avoid backtracking along the way with long life years investments a forward planning should provide opportunity for a well throughout and efficient approach to product development

• Product design• Process design• Product optimization• Process optimization• Scale up• Clinical trials• Scale up for commercial production• Process validation

The development process can be broken down into

several key defined

stages such as

Rational for workFor successful

product development which is often

associated with

Good team work

Multidisciplinary process

By in to the plansStrategies

Descisions

Project management

system

Candidate drug selection

Depending on potency, specificity, duration, safety and pharmaceutical aspects candidate drugs are nominated for development after being passed through “combinatorial chemistry” and automated “high throughput screenings”. To ease this burden some rational drug design and quantitative structure activity relationships (QSAR) are often introduced. Representative libraries of compounds are also present along with genomics.

During CD selection molecular lead is optimized by testing in vitro and in vivo studies with range of compounds.

Selection of candidate drug substance to form candidate drug product is crucial

Depending upon the type of molecule the preformulation studies varies

Early development to candidate drug selection

Drug discovery

Lead generation

Lead optimizatio

n

Hit to leadActive to

hit

100 mg approachElemental analysis -4mg

HPLC methodology-2mg

NMR spectroscopy-5mg

Mass spectroscopy-5mg

IR/UV-Visible spec -5mg

Karl Fisher -20mg

Pka -10mg

Log P/Log D -10mg

Initial solubility/stability-10mg

Crystallinity-20-30mg

Hygroscopicity-5-10mg

Initial solid stability-10mg

Salt selection-10-50mg of each salt

Initial polymorphism-100mg

DSC/TGA/HSM-2mg per technique

XRPD/RH-10mg

microscopy-/SEM/light-10mg

Stability -100 mg

To check the solid state characteristics of the drug

Pharmacological characteristics involve

Acceptable absorption

Potency

Duration of action

Selectivity for the receptor or enzymeNoncarcinogenicity

Nonteratogenicity

Nonmutagenicity

Most commonly used classes of enhancers to drug absorption from the GIT

NSAIDs

SURFECTANTS

BILE SALTS

MEDIUM CHAIN FATTY ACIDS

MEDIUM CHAIN GLYCERIDES

ENAMINES

MIXED MICELLES

EDTA

PHENOTHIAZINES

LIPOSOMES

AZONE

FATTY ACID DERIVATIVE OF CARNITINE AND

PEPTIDES

SAPONINS

CONCANAVALIN A

PHOSPHATE AND PHOSPHONATE

DERIVATIVE

POLY ACRYLIC ACID

To increase bioavailability we need to increase solubility of the drug if not the intrinsic solubility but the dependent ones and further increasing the permeability across the physiological membrane barrier by incorporating suitable enhancers in the formulation of by preparing certain delivery systems

Biopharmaceutical support in candidate drug selection

Dissolution,

solubility affects

absorption of the

drug

Distribution

Degradation and

metabolismModels

for studyComputational

method

Partitioning between

oil and water

Cell cultures

Membrane vesicles

Intestinal rings or

sacs

Excised segments

from animals using

suitable chamber

In vitro and in situ intestinal perfusions

In vivo cannulate

d or fistulated animals

and

In vivo gavaged animals

Early Drug Development and product design

To provide clear direction and objectives for the project team

To gain bye in and input from all key functions at the start of development

To asses the feasibility of the project in commercial and technical terms

To identify any risks early and hence manage them

To avoid wasting valuable resources on developing a product that is not needed or wanted

To provide a good reference source for the development plan

Product design considerations

Target product profile/minimum product profile Design specification and critical quality parameters Commercial and marketing considerations Technical issues and risk assessments Safety assessment considerations Environmental, health, and safety considerations Intellectual property considerations

Product optimization

Formulate• Get specifications• Propose tablet properties• Choose fillers• Choose disintegrants• Choose binders• Choose surfectants• Choose glidants• Choose lubricants• Recommend formulation• Evaluate formulation• Compare against specifications• Change excipients• Optimize formulation

Post optimizationScale up

Technology transfer

Validation and launch

Clinical trial process

validation

Validation of commercial

process

Preapproval inspection

Postapproval changes

Conclusion

These product optimization is done for solid state only. For parenteral, ophthalmic, inhalational and oral different formulation excipients are taken into account.

Thank you