Preformulation considerations in biopharmaceutics

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Preformulation considerations in biopharmaceutics

• Gregory Poon
• PHM224Y
• October 11, 2002
• Study version

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Topics

• Dissolution
• pH
• Polymorphism
• Particle
• Ionic form
• Pharmceutical examples
• Griseofulvin, nitrofurantoin, erythromycin

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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

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Acid-base theory

• Based on solubility in aqueous solution
• Not very vigorous, often problematic
• Acid is charged when deprotonated
• Base is charged when protonated

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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?

lidocaine (base)
hydrocyanic acid
2,3-dimethyl-4-nitrophenol
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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

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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

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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)

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Example nitrofurantoin

• pKa 7.2
• Antibacterial
• Uncomplicated UTI
• Where does absorption occur after oral
  administration?
• Stomach
• Small intestine

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Nitrofurantoin crystals

• Anhydrous nitrofurantoin
• Microcrystal (lt10 µm)
• Macrocrystal (74-177 µm)
• Which dissolves more quickly?
• Microcrystals nausea, vomiting
• Nitrofurantoin monohydrate
• Pseudopolymorph

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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

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MacroBID

• Tablets within a capsule
• Hard capsule containstwo pellets
• 75 mg as macrocrystal
• 25 mg as monohydrate
• Macrocrystal is contained in delayed-release gel
  matrix
• Prevents dose dumping

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Example erythromycin

• Erythromycin base (pKa 8)
• Hydroylzable at acidic pH
• Supposed to take on emptystomach to hurry
  emptying
• (Also makes you puke on empty stomach)
• Strategies
• Encapsulate in enteric coating (Eryc, PCE)

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Erythromycin salts

• Organic salts are much less soluble
• Base 2 mg/mL
• Estolate 0.024 mg/mL
• Stearate lt0.01 mg/mL
• Solution chemistry cannot occur if reactants are
  not dissolved