Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder

This paper describes the kinetics of the solution-mediated phase transformation of the anhydrous monoclinic polymorph of carbamazepine (CBZ(A)) to the dihydrate crystal form (CBZ(D)). Monitoring both solution concentration and solid phase composition identified the steps and mechanisms that control the kinetic processes, and regulate the concentration of drug achieved during dissolution of the metastable solid phase, CBZ(A). The results show that the kinetics and the rate-controlling step for the transformation depend on grinding and storage conditions of CBZ(A). Grinding CBZ(A) shortened the transformation times and changed the rate-controlling step from crystallization of CBZ(D) to dissolution of CBZ(A). Grinding may cause various degrees of disorder in the form of lattice defects and/or amorphous regions. These disordered regions promote the anhydrous to dihydrate transformation by facilitating the surface nucleation of CBZ(D) on freshly ground CBZ(A) and on amorphous CBZ. The concentration-time profiles revealed aging effects on the solution-mediated transformation of ground CBZ(A) that were undetectable by diffraction and thermal analysis. These results have significant consequences on the concentration-time profiles of active pharmaceutical ingredients during dissolution of metastable solid phases, crystalline or amorphous. [Copyright &y& Elsevier]