Abstract
Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C.
Highlights
In a pharmaceutical co-crystal (CC), the active pharmaceutical ingredient (API) and the coformer (CF) are arranged in a common crystal lattice [1]
The stability of a CC against relative humidity (RH) depends on three influencing factors: First, if the CC might form CC hydrates, the critical CC-hydrate RH needs to be con
Stability measurements of CC/fructose mixtures were performed at 58% RH and 76% RH
Summary
In a pharmaceutical co-crystal (CC), the active pharmaceutical ingredient (API) and the coformer (CF) are arranged in a common crystal lattice [1]. Developed an experimental evaluation of the CC stability at high RH conditions based on the addition of liquid water to a stoichiometric mixture of the CC components. With this method they investigated, if the phase behavior of the CC in water is congruent or incongruent [12]. This work proposes a thermodynamic in-silico approach to predict the stability of CCs against conversions as a function of moisture uptake This allows determining the critical RH up to which the CC is stable and predicting the influence of trace level impurities of API, CF, or additional excipients on this critical RH
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