Water clusters in amorphous pharmaceuticals

Amorphous materials, although lacking the long-range translational and rotational order of crystalline and liquid crystalline materials, possess certain local (short-range) structure. This paper reviews the distribution of one particular component present in all amorphous pharmaceuticals, that is, water. Based on the current understanding of the structure of water, water molecules can exist in either unclustered form or as aggregates (clusters) of different sizes and geometries. Water clusters are reported in a range of amorphous systems including carbohydrates and their aqueous solutions, synthetic polymers, and proteins. Evidence of water clustering is obtained by various methods that include neutron and X-ray scattering, molecular dynamics simulation, water sorption isotherm, concentration dependence of the calorimetric Tg , dielectric relaxation, and nuclear magnetic resonance. A review of the published data suggests that clustering depends on water concentration, with unclustered water molecules existing at low water contents, whereas clusters form at intermediate water contents. The transition from water clusters to unclustered water molecules can be expected to change water dependence of pharmaceutical properties, such as rates of degradation. We conclude that a mechanistic understanding of the impact of water on the stability of amorphous pharmaceuticals would require systematic studies of water distribution and clustering, while such investigations are lacking.