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Pharmaceutical preformulation and formulation
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- 2. 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
- 3. Introduction To besuccessful 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.
- 5. To avoid backtrackingalong 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
- 6. Rational for work Forsuccessful product development which is often associated with Good team work Multidisciplinary process By in to the plansStrategies Descisions Project management system
- 7. Candidate drug selection Dependingon 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.
- 8. Selection of candidatedrug substance to form candidate drug product is crucial
- 10. Depending upon thetype of molecule the preformulation studies varies
- 11. Early development tocandidate drug selection Drug discovery Lead generation Lead optimization Hit to leadActive to hit
- 12. 100 mg approach Elementalanalysis -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
- 13. To check thesolid state characteristics of the drug
- 14. Pharmacological characteristics involve Acceptable absorption Potency Durationof action Selectivity for the receptor or enzyme Noncarcinogenicity Nonteratogenicity Nonmutagenicity
- 15. Most commonly used classesof 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
- 16. Biopharmaceutical support in candidatedrug selection Dissolution, solubility affects absorption of the drug Distribution Degradation and metabolism Models for study Computational 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 cannulated or fistulated animals and In vivo gavaged animals
- 17. Early Drug Developmentand 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
- 18. 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
- 19. Product optimization Formulate •Get specifications •Proposetablet properties •Choose fillers •Choose disintegrants •Choose binders •Choose surfectants •Choose glidants •Choose lubricants •Recommend formulation •Evaluate formulation •Compare against specifications •Change excipients •Optimize formulation
- 20. Post optimization Scale up Technology transfer Validation andlaunch Clinical trial process validation Validation of commercial process Preapproval inspection Postapproval changes
- 24. Conclusion These product optimizationis done for solid state only. For parenteral, ophthalmic, inhalational and oral different formulation excipients are taken into account.
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