Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. Theophylline

The hydration state of a hydrate depends on the water activity, a w in the crystallization medium. Selection of an appropriate ratio of water to cosolvent in the crystallization medium of a hydrate is critical and is often semi-empirical. This study attempts to elucidate this selection process by studying the conditions of physical stability of the solid phases of theophylline, which comprise an anhydrate and a monohydrate. A mixture of the anhydrate and the monohydrate may sometimes be obtained, if the system is not in equilibrium. The excess solid phase was characterized by powder X-ray diffractometry and the water content was measured by Karl-Fischer titrimetry. In contact with methanol + water or 2-propanol (isopropyl alcohol, IPA)+ water mixtures, at a w < 0.25, the anhydrate was the only solid phase at equilibrium, no matter which solid form was initially added. At a w > 0.25 in either solvent mixture, the monohydrate was obtained as the most stable form at equilibrium. These results suggest (a) that water activity is the major factor determining the nature of the solid phase of theophylline which crystallizes from methanol + water or IPA + water mixtures and (b) that the system, theophylline anhydrate ⇌ theophylline monohydrate, is in equilibrium at a w = 0.25 and at 25°C. The solubilities of the two solid forms in each of the mixed solvent systems were also measured and are discussed. The concepts presented, tested and discussed may, in principle, be applied to any pharmaceutical system consisting of an anhydrate and a hydrate, or a lower hydrate and a higher hydrate.