The dehydration of pharmaceutical hydrates under mechanical load

Nearly one-third of all pharmaceutical substances on the market are able to sorb water into their crystal lattices to form hydrates, which can often compromise stability during processing and/or storage[1]. The tendency of a hydrate to lose its water of crystallization during the manufacturing process of tablet compression is of particular concern to formulation scientists. The amount of water freed as a function of increasing compaction pressure can be explained by the mobility of water within the compact. The mobility of water is determined by the size and shape of the crystal lattice, the numbers and strengths of the hydrogen bonds, and the presence of high-energy sites of disorder[2]. Due to their differing crystal structures, theophylline monohydrate (THM), citric acid monohydrate (CAM), theophylline-water-citric acid cocrystal hydrate (CATHP hydrate), and dicalcium phosphate dihydrate (DCPD) make for interesting model systems to examine the dehydration under mechanical load.

The thermal dehydration of both powders and tablets was carried out via thermal gravimetric analysis (TGA). By comparing the temperatures required to start removal of water loss from the powder to that of the tablet, the average amount of water of crystallization that is freed by the compaction process may be quantified. The average amount of water freed by the compaction process results from a competition between the mechanically-induced disorder of the crystal structure that increases the molecular mobility of water within the tablets, and the trapping of water within the interparticulate void spaces at high compaction pressures.

The compressibilities, compactabilities, and tabletabilities of the materials were calculated as a function of increasing compaction pressure. The consolidation of the powder bed under pressure was modeled by out-of-die Heckel Analysis which demonstrated the ease of deformation of the model compounds. XRD was utilized to show the decrease in overall order of the crystal lattice as a result of compression as well as anisotropy within the tablets. Crystallographic approaches were utilized to demonstrate the compactness of the crystal structure, and how it affects water mobility.

Relaxation pulse experiments (T1, T2) utilizing solid-state NMR were used to directly probe the mobilities of the water molecules within the crystal lattice of THM. The results from T1 and T2 relaxation experiments directly measure the change in molecular mobility of water within the tablets as a function of compaction pressure. This provided independent verification of the trends in molecular mobility and average water freed as a function of compaction pressure observed during TGA dehydration. Raman spectroscopy was used to indirectly measure the polarizability and vibrational motions of THM, and these results corroborate those obtained from ssNMR and TGA dehydration experiments. Overall, this work highlights the potential impact that tablet compression can have on API hydrate stability.

1. Hilfiker R (editor). 2006. Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co, KGaA.

2. Byrn SR, Pfeiffer RR, Stowell JG. 1999. Solid-state chemistry of drugs. SSCI, Inc.