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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
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