Thermal Decomposition of Amorphous β-Lactam Antibacterials

The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems

“…As one might expect, the presence of sorbed water has been reported to increase the degradation of a range of drugs including insulin (Strickley and Anderson, 1996) and the aforementioned i-lactam antibiotics (Pikal et al, 1977). In the latter study, the authors discussed the kinetics of the degradation process, finding that in general the antibiotics showed what appeared to be first order kinetics as opposed to the sigmoidal curve expected for solid state reactions (although this was not the case for all the drugs under study).…”

“…For example, the temperature dependent degradation of cefoxitin sodium was found to be markedly enhanced when the drug was prepared in an amorphous form (Fig. 16, Oberholtzer and Brenner, 1979), while Pikal et al (1977) showed that the degradation rate of a range of i-lactam antibiotics was enhanced by approximately an order of magnitude for amorphous as opposed to crystalline drugs, even when sorbed water levels were very low. Interestingly, these authors also reported a discoloration of amorphous cephalothin sodium prior to the development of a measurable potency loss.…”

“…However, the authors also reported that the temperature dependence of the decomposition rate indicated that the activation energy for the process was decreasing as the temperature was raised. Pikal et al (1977) suggested that this may be a function of the rate limiting step of the decomposition being associated with molecular reorientation processes, whereby certain steric conditions need to be satisfied in order for the reaction to occur. In other words, the degradation may be a function of molecular mobility and relaxation behaviour.…”

“…Similarly, Strickley and Anderson (1996) demonstrated that the formation of the [desamido A21 -Gly A1 ] dimer was enhanced in glassy insulin compared to the aqueous solution. Pikal et al (1977) suggested that as non-Arrhenius behaviour (involving the activation energy decreasing with temperature) is characteristic of glassy behaviour in the vicinity of T g then the kinetics of degradation may be associated with relaxation behaviour of the amorphous solid. This is also consistent with the observation that the presence of water enhanced the decomposition rate, as over and above the presence of a chemical reactant, the water may be plasticizing the amorphous material and decreasing the relaxation time at the temperature of storage, several other studies have demonstrated a correlation between the chemical reactivity of an amorphous material and the glassy behaviour (Roy et al, 1992;Levine and Slade, 1993).…”

Hydrates and Solid-State Reactivity: A Survey of β-Lactam Antibiotics

“…Instability in the hydrate can be attributed to the physical loss of crystalline water, which may result in an increase of amorphous material, making the material significantly more susceptible to degradation in the solid state even under ostensibly dry conditions. 16 …”