Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted

Area of Science:

• Pharmaceutical Science
• Physical Chemistry
• Materials Science

Background:

• Pharmaceutical formulation stability, particularly against relative humidity (RH), is critical for product development.
• Co-crystals (CCs) are increasingly utilized for active pharmaceutical ingredients (APIs), necessitating robust methods for predicting their stability under varying RH conditions.
• Elevated RH can induce deliquescence in CCs, leading to dissolution and potential phase transformations.

Purpose of the Study:

• To develop and validate a predictive in-silico model for co-crystal (CC) stability as a function of relative humidity (RH).
• To investigate the impact of phase purity and excipients on CC deliquescence relative humidity (DRH).
• To establish critical storage conditions for CCs to prevent instability.

Main Methods:

• Utilized Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) to predict deliquescence RH values for selected CCs.
• Generated predicted phase diagrams of CCs in water to identify critical instability points.
• Validated in-silico predictions through experimental stability measurements across a range of RH conditions (58%–98%) at 25 °C.

Main Results:

• Accurate prediction of deliquescence RHs for succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid CCs.
• Demonstrated that trace amounts of API or coformer phases significantly reduce CC stability (lower DRH).
• Predicted that excipients like fructose or xylitol further decrease the deliquescence RH, impacting CC stability.

Conclusions:

• PC-SAFT provides a reliable in-silico method for predicting CC stability concerning RH.
• Phase purity is a critical factor influencing CC stability under humid conditions.
• The findings are vital for designing stable pharmaceutical co-crystal formulations and defining appropriate storage conditions.