Vacuum drying of a multicomponent pharmaceutical product having different pseudo-polymorphic forms

The pharmaceutical drug under investigation in this paper has two hydration states with several polymorphic forms. The two hydration states are tetrahydrate and monohydrate. Two polymorphic forms of monohydrate are in competition: the therapeutic form and the non therapeutic form. The manufacturing process which includes removing of a multicomponent solvent must lead to the metastable therapeutic form although the non therapeutic form is the stable one. This quality problem has been underlined by a previous work about convective drying. During the drying stage of the manufacturing process, the non therapeutic form can be produced. The conclusions of the convective drying study have led to investigate vacuum drying. In vacuum drying, local thermodynamic paths are determined simply from the thermal behavior of the product. This behavior is caused by the presence of two miscible solvents and two hydration states. Under the commonly used assumption of local thermodynamic equilibrium, paths are reported on an equilibrium diagram. It is deduced that as opposed to convective drying, vacuum drying ensures to avoid the non therapeutic form appearance. (C) 1999 Elsevier Science S.A. All rights reserved.