L14 - Pre-formulation of solid dosage forms 1

• Principles of Dosage Form Design(what are the aims?)

  To convert a NCE (New Chemical Entity - the drug) into a deliverable medicineAims to facilitate delivery of therapeutic drugs:- safely- efficiently- reproducibly- conveniently
• Preformulation(what is it? what does it involve? what does it produce? what's the aim?)


  - First step in dosage form design- characterises physical/chemical properties (eg pH/pKa of API)- produces maths model for in vitro and in vitro behaviour of drug dosage form. Model evaluates parameters for stable and bioavailable dosage form that can be mass produced- aim - to decrease development time and cost.
• Aqueous solubility(what's the optimum? what can we do if much less than optimal solubility?

  - 10mg/ml or higher optimal- if solubility < 1mg/ml, use a salt form - strong electrolytes readily ionise in solution
• Solubility vs dissolution rate(What are they? What equation is dissolution rate described by?)

  solubility = constantdissolution rate = variable. how many molecules dissolve per unit time. Described by Noyes-Whitney.

  
• Factors affecting dissolution rate


  - particle size- diffusion contant- [drug] around particles- membrane thickness- solid SA- solubility of solid- [solute] in solution at given time

  
• Noyes-Whitney equation(what does it describe? what is it?)

  describes dissolution rate∆mass / ∆time = DA (Cs - Cb) / hOR = kA (Cs - Cb)where k = rate constantA = particle sizeCs = [solution] at solid surfaceCb = [bulk solution]

  
• Biopharmaceutical Classification System (BCS)(what is it? what can we change?)

  Classification system for oral dosage forms- can only change solubility - can't control permeability
• Class I (BCS)

  high solubility, high permeability

  
• class II (BCS)

  low solubility, high permeability

  
• class III (BCS)

  high solubility, low permeability

  
• class IV (BCS)

  low solubility, low permeability

  
• How can we increase solubility?

  - cosolvents- salt forms- surfactants-cyclodextrins- decrease particle size (increase SA)
• What physicochemical tests are used to choose dosage form?

  - NMR- IR- UV spec- mass spec- pKa- logP (lipophilicity)- hygroscopicity
• Hygroscopicity


  ability to attract water in air.Eg, some meds can degrade in air so need special containers
• How is solubility affected if a drug has an ionisable group?(What's Henderson-Hasselbalch eqn? What does it describe?)

  - solubility will change as a funntion of pH- HH describes the relationship between pH and pKapH = pka + log [base]/[acid]OR [base]/[acid] = 10^pH-pKa
• Pharmaceutical Salts(why are they useful? how do they work in this way? when are they useful? what's the criteria for salt formation?

  - Increase solubility by decreasing surface tension between polar/non-polar environments- useful if drug is a weak acid/base with poor aqueous solubility- salt formation requires a pKa difference of at least 3
• Advantages of pharmaceutical salts

  - increase solubility- increase dissolution rate- increase bioavailabilty- better taste- easier synthesis/purification- increased photostability- increased melting point
• Disadvantages of pharmaceutical salts

  - decrease % of drug- increased hygroscopicity (attraction to moisture)- increased toxicity- decreased chemical stability- no solubility change at different pH in GI tract- increased number of polymorphs
• What needs to be considered when choosing target salts?

  - drug structure- pKa difference between acid and base (~3)- chemical/physical stability- ease of large scale production- which counterion to choose