Physicochemically Relevant Modeling of Nucleation-And-Growth Kinetics: Investigation of Additive Effects on the Solvent-Mediated Phase Transformation of Carbamazepine

Abstract

The effect of various additives on the nucleation-and-growth rate-limited phase transformation of anhydrous carbamazepine (CBZA) to its hydrate form (CBZH) was investigated using a recently developed dispersive kinetic model. The curve-fitting of the “acceleratory”, sigmoidal transients obtained experimentally for this conversion (at both 10 and 15 °C), taken from the recent literature (Qu, H.; Louhi-Kultanen, M.; Kallas, J. Cryst. Growth Des. 2007, 7, 724.), yielded values for the two semiempirical kinetic parameters, α and β, that could be compared directly to each other to ascertain the physicochemical effects of the additives on the nucleation kinetics of CBZH. In the present model, the positive β term relates an increase in the activation entropy as a function of conversion time, for nucleation rate-limited conversions, while the α parameter describes the “classical Arrhenius”/time-independent portion of the overall rate coefficient for the conversion. While the effect of temperature and most of the additives investigated predominantly affected the β term, the α term was found to play an important role in differentiating the underlying nucleation mechanisms for at least two of the systems. Four of the additives examined, polyethylene glycol 6000 (PEG), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and d-mannitol, were found to have generally inhibitory effects on the nucleation of CBZH; of these additives, only HPMC was able to completely suppress the product formation such that sigmoidal conversion transients were not observed. Using the 15 °C data, a scenario was proposed whereby the additive sodium lauryl sulfate (SLS) could have a promoting effect on the nucleation of CBZH.