Pharmaceutics
Pharmaceutics tests dosage-form design and the physicochemical principles that determine whether a drug is released, dissolved and absorbed as intended: solubility, dissolution, polymorphism, excipient function, stability and isotonicity. Expect numerical items on tonicity adjustment and stability kinetics.
Biopharmaceutics classification
- Class I: high solubility, high permeability - rapid dissolution, usually complete absorption.
- Class II: low solubility, high permeability - dissolution-rate limited; particle-size reduction, amorphous solid dispersions, salts, co-solvents, surfactants or cyclodextrin complexation improve absorption.
- Class III: high solubility, low permeability - permeation limited; formulation changes rarely help.
- Class IV: low solubility, low permeability - the hardest to formulate.
- Biowaivers on the basis of the BCS are possible for immediate-release Class I products, and for Class III under defined conditions of rapid dissolution and excipient similarity.
Dissolution, solubility and solid state
- Noyes–Whitney describes dissolution rate as proportional to surface area and the concentration gradient, and inversely related to diffusion-layer thickness.
- Standard dissolution testing uses USP Apparatus I (basket) or II (paddle), 900 mL medium, 37 ± 0.5 °C; a typical immediate-release specification is not less than 80% (Q) dissolved in 30 minutes.
- Polymorphs differ in lattice energy, solubility and melting point. The amorphous form has the highest apparent solubility but is physically unstable and may crystallise on storage. Hydrates and solvates behave as distinct solid forms.
Stability
- First-order degradation gives t₉₀ = 0.105/k, the basis of shelf-life assignment.
- Arrhenius behaviour: k = A·e^(−Ea/RT); a Q10 of 2–3 means the rate roughly doubles to triples per 10 °C rise, which is why accelerated studies predict long-term behaviour.
- Common degradation routes are hydrolysis (esters, amides), oxidation (phenols, catecholamines, vitamin C), photolysis (nifedipine) and racemisation. Countermeasures include pH optimisation, antioxidants, chelating agents, amber glass, nitrogen overlay and refrigeration.
- ICH long-term storage for the EU, including Greece, is 25 °C/60% RH (Zone II), with accelerated conditions of 40 °C/75% RH for six months.
Worked example
The sodium chloride equivalent (E value) of a drug is 0.18, and a 1% w/v solution is to be made isotonic. A 1% solution of the drug contributes the osmotic effect of 0.18 g of NaCl per 100 mL. To reach the isotonic equivalent of 0.9 g/100 mL, add 0.9 − 0.18 = 0.72 g NaCl per 100 mL, that is 0.72% w/v added NaCl. Reasoning shown: the E value converts drug mass into an equivalent NaCl mass, so subtraction from 0.9 g gives the compensator. The same logic applies with freezing-point depression, where 0.52 °C corresponds to isotonicity.
Traps that cost marks
Confusing% w/w with% w/v when densities differ from 1; assuming faster dissolution always means better in vivo performance (a Class III drug gains nothing); ignoring excipient incompatibilities such as lactose with primary amines (Maillard reaction) or magnesium stearate over-lubrication reducing dissolution.