Determination of water content in pharmaceutical hydrates by differential scanning calorimetry

Abstract

Thermogravimetric analysis (TGA) and Karl Fischer titrimetry (KFT) are the most commonly used techniques for determination of the water content of pharmaceutical solids. We here report a novel method of determining water content of drug hydrates by differential scanning calorimetry (DSC). The method is based on the hypothesis that the enthalpy of binding of n moles of water molecules in the hydrate (enthalpy of dehydration, ΔH d) is the same as that of n moles of water molecules in liquid water ( nΔH v), where ΔH v is the enthalpy of vaporization of water. From the literature value of ΔH v and the ΔH d value for each dehydration endotherm the number of moles of water associated with each endotherm was calculated. This approach was applied to several non-ionic drug hydrates, such as hydrates of ampicillin, Carbamazepine, caffeine and theophylline, and to several metal salts of nedocromil. The results obtained by DSC agree well with the KFT and TGA data. Since enthalpy is a state function, the applicability of the above hypothesis does not necessarily support any particular mechanism of dehydration. The above hypothesis was also tested using the dehydration endotherms in the literature for a variety of organic and inorganic hydrates. For those hydrates which give more than one dehydration endotherm by DSC, it is hypothesized that each dehydration endotherm corresponds to a specific binding state or location of water molecules in the crystal lattice. Using this method, it is possible to apportion the water content in each location. The DSC method described cannot be applied when the dehydration endotherm overlaps another peak, such as a polymorphic change, melting, sublimation or decomposition, but can, in principle, be extended to other solvents of crystallization in organic and inorganic solvents. The method may complement the TGA and KFT methods and provide additional information about water binding in pharmaceutical solids.