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PREFORMULATION

PREFORMULATION. Dr. Dinesh M. Biyani, M. Pharm. Ph.D. DBM, DIRPM, Dip TD Associate Professor, SKB College of Pharmacy, Kamptee dineshbiyani10@gmail.com. AIDING CANDIDATE DRUG SELECTION. A medicinal product is developed from : Synthetic chemical compound

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PREFORMULATION

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  1. PREFORMULATION Dr. Dinesh M. Biyani, M. Pharm. Ph.D. DBM, DIRPM, Dip TD Associate Professor, SKB College of Pharmacy, Kamptee dineshbiyani10@gmail.com

  2. AIDING CANDIDATE DRUG SELECTION • A medicinal product is developed from : Synthetic chemical compound Chemical extracted from natural source Biotechnical process • It involves different disciplines to work together • Discovery & Development can be broken into 5 stages 1. Strategic research – feasibility study 2. Exploratory research – identification of “chemical lead” (can be had by using Combinatorial chemistry & high throughput screening.) even this may be tedious, so QSAR and molecular graphics are better 3. Candidate drug selection – chemical lead generates specific chemical compound with optimal, desired potency, specificity, duration and other pharmaceutical aspects. So, for rapid drug development, a compound with preferredpharmaceutical and chemicalsynthesisproperties should be selected.

  3. DRUG SYNTHESIS FACTORS Least complex structure( none or few chiral centers) Few synthesis steps as possible High yields as possible None explosive route or safety in use Commercial availability of building blocks and contract manufacturer Low cost of raw material No predicted problem in scale up FORMULATION FACTORS Exists as a stable polymorph form Non hygroscopic Crystalline Acceptable solid state stability of candidate drug Acceptable bioavailability Not highly colored or strong odour (ensure batch reproducibility) Compatible with key excipients Preferred drug synthesis & pharmaceutical properties for compounds intended for Oral Solid Dosage Form Development

  4. Exploratory Development – how candidate drug is absorbed and metabolized (phase I) • Full Development – (phase II and III) DISCOVERY DEVELOPMENT PREFORMULATION BRIDGE

  5. NEED OR IMPORTANCE In past, although low throughput due to animal testing, but proven results Now HTS, due to recombinant enzyme, but it is in vitro So drug may not absorbed in vivo DMSO, DMA etc. are versatile, but toxicity? THIS IS THE CHALLENGE TO PREFORMULATION SCIENTIST

  6. Integrating Discovery and Development require Preformulation scientist to be aware of molecular mechanisms of unfavourable physical properties such as aqueous solubility Best activity, least blood levels 1 aq. Solubility & due to less solubilityphase Bactivity bothoptimized simultaneously 2 recommended for development phase A 0 only activity as criterion Lead for further optimization Best activity, least blood levels 1 aq. Solubility & due to less solubilityphase Bactivity bothoptimized simultaneously 2 recommended for development phase A 0 only activity as criterion Lead for further optimization PREFORMULATION SCIENTIST TO DESIGN API ACTIVE AND TRANSPORTABLE THROUGH LIPOPHILIC MEMBRANE Best activity, least IN VITRO ACTIVITY AQUEOUS SOLUBILITY

  7. CRITICAL API DECISIONS Once a NCE is selected for development, the molecular form that will be the ACTIVE PHARMACEUTICAL INGREDIENT will be critical milestone because all subsequent development will be affected by this decision. For Preformulation, physical characterization decision should be like BALANCE PREFORMULATION Eg. Amorphous drug (greater solubility but conversion to crystalline in presence of heat, moisture and with time) HCl and Na salt (good solubility less toxicity but physical & chemical instability due to moisture and heat) Higher lipophilicity (good for absorption but may have dissolution problems) SOLID STATE: DISSOLUTION PROPERTIES MATERIAL CONSISTANCY: MFG. & STORAGE CONDITIONS

  8. Preformulation is the physicochemical characterization of the solid and solution properties of compounds for subsequent formulation of a stable and biopharmaceutically suitable dosage form. Preformulation typically begins in the earlier stages of Lead optimization (LO), however, there may be some involvement during Lead identification (LI) In LI, it supports to the medicinal chemist for solid state screening to ensure the consistency in polymorphism. During last 3- 6 months of LO (of total 2 years) total compounds are narrowed to around 3 for final nomination. This is known as prenomination.

  9. MINIMUM SUGGESTED PHYSICOCHEMICAL TESTS CARRIED OUT DURING PRENOMINATION (50 MG.)

  10. Preformulation Drug Characterization in a structured programme

  11. SALT SELECTION CHOOSE POLYMORPH, AMORPH OR HYDRATE

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