Effect of type and extent of crystalline order on chemical and physical stability of carbamazepine

Abstract

Three crystalline phases of carbamazepine (C), namely (i) the needle-shaped form I (tempered) with high crystalline order, (ii) beam-shaped form I (anhydrate) with lower crystalline order, which was prepared by dehydration of the dihydrate, and (iii) the prismatic form III, which is stable at room temperature, were prepared and their physical properties were determined. Then they were separately mixed with 40% (w/w) colloidal silica and stored open under climatic stress at 4 temperatures (56–72°C) and 3 relative humidities (41–71%). The physial and chemical stability of C was followed for 200 days. Form I (anhydrate) transformed under all conditions to form III, with the highest rate at 51° C, while the other phases were physically stable. C degraded chemically by hydrolysis to iminostilbene (IS); about 10 mol% were formed at the highest stress after 200 days. Small amounts of secondary products were detected. An initial constant degradation rate up to 1 mol% IS was followed by a slower, again linear degradation. The initial rates of formation of IS per unit surface area of the crystals (°k, mol%/day) were highest for form I (anhydrate) and lowest to form I (tempered). The calculated Arrhenius activation energies up to 67° C were of the order form III > form I (anhydrate) > form I (tempered) with 135, 125 and 104 kJ/mol, respectively. The energies of activation for chemical degradation correlate well with the content in free enthalpy of the respective crystalline phases and their correspondent physical stability.