Chemical kinetics and stability of dosage forms

Hydrolysis oxidation isomerization Photochemical degradation Polymerization

The most common pathway for drug breakdown Susceptible drugs include aspirin, procaine (ester), penicillins (amide, lactam) and benzodiazepines (lactam) Can be H+ or OH- catalyzed (optimize formulation to minimize) May be be possible to modify drug structure to prevent hydrolysis

Commonly via a peroxy radical (ROO*) but there are other mechanisms Susceptible drugs include steroids & sterols and polyene antibiotics (C=C), ethers and sulphur groups also prone Can be catalyzed by action of UV, heat or trace metals Use antioxidants

Racemization, where an enantiomerically pure compound becomes a racemic mixture

Amber glass to block UV, coat tablets with UV-absorbing polymer

Can occur at high concentration

direct dynamic equilibrium competitive sequential

Order of reaction is the sum of the powers

ln[A]t= ln[A]0 -kt c= ln[A]0 slope= -k y= [A] x=time half-life t1/2 =0.693/k shelf life ln(1/percentage as decimal)/ k t95%= 0.0513/k is independent of initial conc Ratio of t½ to t95% t1/2 / t95% find values u have to take the ln

The shelf life of a medicine is the time that a specific drug characteristic remains within a particular specification (“acceptance criteria”) after manufacture when stored according to the label. Can be based on the amount of drug remaining or the accumulation of a degradation product. Definitions vary and can depend on a number of factors. Can be estimated mathematically, by extrapolation, but requires analytical confirmation. For these lectures we will define shelf life as the time that the drug remains at or above 95% of the label dose (t95%).

ln[A]t= ln[A]0 -kt Rate is independent of concentration of reacting species [A]solution is constant Thus, the rate is constant slope = -k t1/2 = [A]0/2k t95% = [A]0/20k shelf - life is dependent on initial concentration Once the solid particles in suspension are fully solubilized by the solution, the degradation will no longer follow zero order!

The rates of bimolecular reactions, which occur when two molecules come together to form the product, are commonly described by the 2nd order equation. Two possibilities exist: • Rate is proportional to the product of two equal concentrations, either involving a single reactant or two different reactants: • Rate is proportional to two different concentrations:

1/[A]t =1/[A]0+kt slope= k t1/2= 1/[A]0 k t95= 1/19 [A]0 k Shelf life is dependent on initial concentration

different

substitution method shelf life method Based on the relationship between [A]0, t95% and reaction order: For zero order, increasing [A]0 increases t95% For first order, [A]0 and t95% are independent For second order, increasing [A]0 decreases t95% graphical method in ln [A] zero- first second

A number of other factors other than concentration may affect reaction rates, including: Temperature pH Pressure Catalysts Solvent Ionic strength Relative humidity (RH) Excipients Light

slope = -Ea/r

Need to define: Temperature and humidity of storage Storage time before sampling Number of batches to be sampled Number of replicates within each batch A suitable light challenge Details of assay

By determining the rate constant at various temperatures, the rate of decomposition can be determined at 25°C (or lower) using the Arrhenius equation.

equation lnk = ln A - Ea/RT