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PREFORMULATION – SOLUBILITY

PREFORMULATION – SOLUBILITY. Dr. Dinesh M. Biyani , M. Pharm. Ph.D. DBM, DIRPM, Dip TD Associate Professor, SKB College of Pharmacy, Kamptee dineshbiyani10@gmail.com. SOLUBILITY. PREFORMULATION SOLUBILITY INTRINSIC SOLUBILITY pKa SALTS SOLVENTS K o/w PREFORMULATION AND DRUG DESIGN

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PREFORMULATION – SOLUBILITY

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

  2. SOLUBILITY PREFORMULATION SOLUBILITY INTRINSIC SOLUBILITY pKa SALTS SOLVENTS Ko/w PREFORMULATION AND DRUG DESIGN DISSOLUTION

  3. Preformulation

  4. Solubility • Availability of the bulk drug during Preformulation? • Compound new – quality? • Solubility and pka must. • Aqueous solubility – excess of 1% (10 mg/ml) over pH range 1-7 at 370 C • Solubility < 1% - salt formation • If solubility manipulation not possible – liquid filling in softgels or as a paste/ semisolid in hard gelatin capsule

  5. Intrinsic Solubility • Chemical Structure • Solubility in 0.1 N HCl, 0.1 N NaOH, and water - Implications – Acid, Alkali, both, not in any • If purity is assured, then the value obtained in acid for a WA or alkali for a WB is assumed as to be INTRINSIC SOLUBILITY i.e. the unionized form. • If not purity, then find from phase – solubility diagram • Solubility ideally determined at two temperatures – 40C and 370C • Method- 3 ml solvent – vials containing different amount of sample agitated continuously for 16 hours and conc. determined

  6. pKa • 75% drugs – weak base • 20% drugs - weak acids • 5% drugs – non ionics, amphoterics etc. • Henderson – Hasselbalch equation - to determine the pKa by observing changes in solubility, - to allow the prediction of solubility at any pH (Co is known), - to facilitate the selection of suitable salt-forming compounds, - to predict the solubility and pH properties of salts

  7. Salts Decision tree for Salt selection Determine need for salt form Measure solubility as a function of pH ACIDS BASES Prepare sodium salt Prepare HCl salt Study physical properties as a function of temperature and humidity Prepare metallic salts Prepare mineral acid salts Characterize chemical stability Prepare organic salts Test for absorption Select salt form to commercialize

  8. Solvents Water miscible solvents – • Cosolvents in formulations to improve solubility or stability • In analysis to facilitate extraction and separation • Oils

  9. Ko/w Applications of measurement • Solubility: aqueous and mixed solvents • Drug absorption in- vivo: used in a homologous series for SAR • Extraction: particularly for biological fluid samples • Partition chromatography: choice of column (HPLC) or plate (TLC) and mobile phase • Emulsions: to establish effective levels in the aqueous phase (particularly w.r.t. preservatives) • Release from semisolids: dissolution from topicals and suppository bases • Solubilization: an increase in solubility by entrapment in micelles still requires effective levels in the external aq. Phase • Complexation: Certain complexes partition differently to the substrate (drug ligand) and complexing agent. This change in lipophilocity will affect the activity of the drug and can also be used to measure the extent of complexation

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