反流性食管炎,一种治疗胃溃疡被称为伊拉拉唑(Ila),在室温下储存和处理期间不稳定,需要在5摄氏度下储存。在这项研究中,为了解决伊拉的这些问题,选择了富含氧(O)和能够与之形成氢键的羟基(OH)的共形成剂。这些共形成物包括木糖醇(Xyl),葡甲胺(Meg),烟酸(Nic),L-天冬氨酸(Asp),和L-谷氨酸(Glu)。制备Ila和每种共形成物的1:1物理混合物,使用差示扫描量热法(DSC)筛选预测共晶形成的潜力。结果表明在IIa/Xyl物理混合物中形成共晶的可能性。随后,将IIa和Xyl以1:1的比例在乙酸乙酯(EA)中混合,在28小时的泥浆后,通过固态CP/MAS13CNMR光谱分析证实了Ila/Xyl共晶的形成,显示分子间氢键和构象变化。此外,通过溶液状态NMR(1H,13C,和2D)分子结构分析。为了评估Ila/Xyl共晶在室温下的稳定性,将其在25±2°C和65±5%的相对湿度(RH)下储存并与Ila比较三个月。结果表明,Ila/Xyl共晶的纯度在三个月内从初始纯度99.75%保持在99.8%,而Ila预计在三个月后从最初的99.8%纯度降低至90%。此外,在25±2°C和相对湿度65±5%时,在三个月内观察到Ila/Xyl共晶中的特定杂质B为0.03%,而Ila预计在三个月后从最初的0.032%增加到2.28%。为了评估Ila/Xyl共晶体的溶解速率,制备制剂并在pH10下与Ila比较,剂量相当于IOmgIla。结果表明,Ila/Xyl共晶体在15min内达到55%,在45min内达到100%,而预计Ila在15分钟达到32%,仅在60分钟后达到100%。然而,总的来说,Ila/Xyl共晶显示的结果等于或超过Ila的溶解速率。因此,据预测,Ila/Xyl共晶将最大限度地发挥其效力,作为一种更方便的晶体结构,用于配方开发,允许在室温下储存和保存,而无需在环境条件和储存期间进行有问题的5°C冷藏,解决与伊拉有关的问题。
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.