Process Design and Scale-Up Elements for Solvent Mediated Polymorphic Controlled Tecastemizole Crystallization

Tecastemizole, an active metabolite of the histamine H1-receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of process interest. A process design switch from a seed controlled growth approach to a solvent mediated interconversion based approach was adopted for reasons of simplicity and robustness during early Phase II development. The effects of dissolution, mass transfer, and surface-controlled growth on the observed interconversion rate were studied under well-defined seeding conditions. The experimental results show a significant effect of operating temperature on the interconversion rate and also show that the rate-limiting step is the growth of form A. Growth controlled kinetic parameters were estimated and are reported here. A nonlinear cooling profile was developed to take advantage of the temperature rate effect on form interconversion. Scale-up of the modified procedure was performed at both pilot and full-scale manufacturing, and the results confirmed the laboratory findings.