Preformulation considerations in biopharmaceutics

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Topics. DissolutionpHPolymorphismParticleIonic formPharmceutical examplesGriseofulvin, nitrofurantoin, erythromycin. Dissolution rate. pH partition hypothesisDeveloped for drugs in solutionBut many drugs are given orally as solidsSolubilityDoes solubility always predict dissolution rate?T

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Preformulation considerations in biopharmaceutics

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1. Preformulation considerations in biopharmaceutics Gregory Poon PHM224Y October 11, 2002 Study version

2. Topics Dissolution pH Polymorphism Particle Ionic form Pharmceutical examples Griseofulvin, nitrofurantoin, erythromycin

3. Dissolution rate pH partition hypothesis Developed for drugs in solution But many drugs are given orally as solids Solubility Does solubility always predict dissolution rate? Thermodynamics vs. kinetics pH dependence of solubility Acid/base/neither

4. Acid-base theory Based on solubility in aqueous solution Not very vigorous, often problematic “Acid is charged when deprotonated” “Base is charged when protonated”

5. pKa: the classic trap pKa alone does not determine acid or base Indicates only how acidic or basic Must know chemistry! All of the following have pKa ~ 9, but which are acids and which are bases?

6. Solubility considerations Polymorphism Polymorphs have different physical properties Convert to most stable form at given T, p But at what rate? Possible limit on shelf life Particle size Surface area vs. volume Why do oil droplets coalesce? (To minimize total SA) Decreasing particles size improves dissolution Important for hydrophobic drugs

7. Salt form & solubility Not all salts are equally soluble Example: calcium supplements Ca salts not very soluble generally Soap scum (divalent salts of fatty acid) Solubility increases with falling pH Removing scale/stain (Ca(OH)2, etc.) with vinegar Ca2CO3 not very soluble Calcium citrate is more soluble at all pH Improved bioavailability Even in achlorhydric patients

8. Example: griseofulvin Antifungal Very hydrophobic Need to take with fatty meals Decreasing particle size reduces dose requirements “Regular” = 1 g/day Microsize = 500 mg/day (Fulvicin U/F®) Ultramicrosize = 250 mg/day (Fulvicin P/G®)

9. Example: nitrofurantoin pKa 7.2 Antibacterial Uncomplicated UTI Where does absorption occur after oral administration? Stomach Small intestine

10. Nitrofurantoin crystals Anhydrous nitrofurantoin Microcrystal (<10 µm) Macrocrystal (74-177 µm) Which dissolves more quickly? Microcrystals: nausea, vomiting Nitrofurantoin monohydrate Pseudopolymorph

11. Oral dosage forms Oral suspension (5 mg/mL) Capsule of macrocrystal (Macrodantin®, generics) Adult: 50-100 mg qid (treatment) Capsule of macrocrystal/monohydrate (MacroBID®) 100 mg bid

12. MacroBID “Tablets within a capsule” Hard capsule contains two pellets 75 mg as macrocrystal 25 mg as monohydrate Macrocrystal is contained in delayed-release gel matrix Prevents dose dumping

13. Example: erythromycin Erythromycin base (pKa ~ 8) Hydroylzable at acidic pH Supposed to take on empty stomach to hurry emptying (Also makes you puke on empty stomach) Strategies Encapsulate in enteric coating (Eryc®, PCE®)

14. Erythromycin salts Organic salts are much less soluble Base: 2 mg/mL Estolate: 0.024 mg/mL Stearate: <0.01 mg/mL Solution chemistry cannot occur if reactants are not dissolved

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