剪切工艺对含黄原胶的口服混悬液溶出性能的影响

Effect of Shearing Process on Dissolution Properties of Oral Suspensions Containing Xanthan Gum

以黄原胶为增稠剂,采用不同的剪切工艺参数制备康唑类药物(BKZ)的口服混悬液,测定了所得混悬液的溶出度、粒径及黏度,并考察黄原胶及其与果葡糖浆和甘油的组合物的水分散液在溶出介质中的分散状态及溶解速度,以确定剪切工艺对含黄原胶口服混悬液的溶出速度的影响,并探讨其中的机制。结果表明,在BKZ口服混悬液中,黄原胶与果葡糖浆和甘油可形成稳定的凝胶结构,该凝胶结构的稳定性是影响混悬液溶出速度的关键因素。高剪切工艺对凝胶结构有不可逆的破坏作用,从而会加快主药的溶出速度和降低制剂的黏度;且随着剪切速率和剪切时间的增加,主药的溶出速度增加,混悬液的黏度下降并在停止剪切后不会恢复。根据QbD(quality by design)原则,在以黄原胶为增稠剂的口服混悬液的研发过程中,应充分重视黄原胶的流变学性质,以及剪切工艺对关键质量属性(溶出性能)的影响;并通过制剂溶出速度的变化,确定剪切工艺参数的操作范围,优化工艺设计,增强制备过程的工艺稳定性。

The aim of this study was to confirm the effect of shearing process on dissolution rate of oral suspensions containing xanthan gum and discuss its mechanism. Using xanthan gum as suspending agent, the oral suspensions of BKZ, a conazole drug, were prepared by different shearing processes. The dissolution, particle size and viscosity of the suspensions were measured. Furthermore, the disperse state and time of aqueous solutions with xanthan gum and the combinations of xanthan gum and other polysaccharides in dissolution medium were investigated. The results indicated that xanthan gum or xanthan gum combination could form gelatin when dispersed in water. What’s more, the stability of gelatin was critical for the dissolution rate of oral suspensions containing xanthan gum. With the increase of the shearing rate and shearing time, the dissolution rate increased, while the viscosity of the suspension decreased continuously. A high-shear process had an irreversible damage to the gelatin structure, so the viscosity of the oral suspensions would not recovered any more even though the shearing process was stopped. According to the principle of quality by design (QbD), it should be paid more attention to the rheological properties of xanthan gum and the effect of shearing process on the dissolution rate in the R&D process of the oral suspension containing xanthan gum. The dissolution rate of oral suspension could be controlled by varying the shearing process. More importantly, shearing parameters could be determined by monitoring the change of the critical quality attribute (COA), therefore, the process design would be optimized and the process stability should be enhanced .