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

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.