Investigation of the Storage and Stability as Well as the Dissolution Rate of Novel Ilaprazole/Xylitol Cocrystal

Abstract

Reflux esophagitis, a treatment for gastric ulcers known as Ilaprazole (Ila), is not stable during storage and handling at room temperature, requiring storage at 5 degrees Celsius. In this study, to address these issues with Ila, coformers rich in oxygen (O) and hydroxyl (OH) groups capable of forming hydrogen bonds with were selected. These coformers included Xylitol (Xyl), Meglumine (Meg), Nicotinic acid (Nic), L-Aspartic acid (Asp), and L-Glutamic acid (Glu). A 1:1 physical mixture of Ila and each coformer was prepared, and the potential for cocrystal formation was predicted using differential scanning calorimetry (DSC) screening. The results indicated the potential for cocrystal formation in the Ila/Xyl physical mixture. Subsequently, Ila and Xyl were mixed in ethyl acetate (EA) in a 1:1 ratio, and after 28 h of slurry, the formation of Ila/Xyl cocrystal was confirmed through solid-state CP/MAS 13C NMR spectrum analysis, showing intermolecular hydrogen bonding and conformational changes. Furthermore, the 1:1 ratio of Ila/Xyl cocrystal was confirmed through solution-state NMR (1H, 13C, and 2D) molecular structure analysis. To assess the stability of Ila/Xyl cocrystal at room temperature, it was stored and compared with Ila at 25 ± 2 °C and relative humidity (RH) of 65 ± 5% over three months. The results showed that the purity of Ila/Xyl cocrystal remained at 99.8% from the initial purity of 99.75% over the three months, while Ila was predicted to decrease from an initial 99.8% purity to 90% after three months. Additionally, at 25 ± 2 °C and RH 65 ± 5%, a specific impurity B in Ila/Xyl cocrystal was observed to be 0.03% over three months, whereas Ila was predicted to increase from an initial 0.032% to 2.28% after three months. To evaluate the dissolution rate of Ila/Xyl cocrystal, a formulation was prepared and compared with Ila at pH 10, with a dosage equivalent to 10 mg of Ila. The results showed that Ila/Xyl cocrystal reached 55% within 15 min and 100% within 45 min, while Ila was predicted to reach 32% at 15 min and 100% only after 60 min. However, overall, the Ila/Xyl cocrystal showed results equivalent to or exceeding the dissolution rate of Ila. Therefore, it is predicted that the Ila/Xyl cocrystal will maximize its effectiveness as a more convenient crystal structure for formulation development, allowing storage and preservation at room temperature without the need for the problematic 5 °C refrigeration during ambient conditions and storage, addressing the issues associated with Ila.