Nieuwmeyer Florentine, van der Voort Maarschalk Kees, Vromans Herman
Department of Pharmaceutics, Schering Plough Corporation, P.O. Box 20, 5340 BH, Oss, The Netherlands.
Pharm Res. 2008 Nov;25(11):2666-73. doi: 10.1007/s11095-008-9687-z. Epub 2008 Aug 1.
By pharmaceutical processes and in the presence of solid excipients physical-chemical changes are known to occur, leading to increased rate of chemical degradation. The purpose of this work was to determine the critical aspects in the stability of a steroid in the presence of a commonly used excipient, lactose.
A steroid was either mixed or wet granulated with lactose with different particle size.
Small lactose particles lead to a higher degree of degradation. Degradation was enhanced under warm humid conditions although the presence of water alone could not account for this effect. Lactose-phosphate, a known intrinsic contaminant in lactose is demonstrated to enhance the degradation of the steroid. Stability was improved in high purity lactose and deteriorated upon extra addition of phosphates. Since the exposure to the contaminant is a function of the surface area of the lactose, particle size differences of the excipient have a clear consequence. High shear granulated lactose granules exhibit a heterogeneous composition; large granules consist of small primary particles and vice versa. It is shown that the large granules, composed of the small primary lactose particles reveal the highest degree of degradation. Granule composition dictates the stability profile of the granules.
The lactose contaminant and granule composition dictates the stability profile of the granules and mixtures.
通过制药工艺可知，在固体辅料存在的情况下会发生物理化学变化，从而导致化学降解速率增加。本研究的目的是确定在常用辅料乳糖存在下甾体药物稳定性的关键因素。
将一种甾体药物与不同粒径的乳糖进行混合或湿法制粒。
小粒径乳糖颗粒会导致更高程度的降解。在温暖潮湿条件下降解加剧，尽管仅水的存在并不能解释这种现象。乳糖中的已知内在污染物乳糖 - 磷酸盐被证明会增强甾体药物的降解。高纯度乳糖可提高稳定性，而额外添加磷酸盐则会使其稳定性变差。由于与污染物的接触是乳糖表面积的函数，辅料的粒径差异会产生明显影响。高剪切制粒的乳糖颗粒表现出不均匀的组成；大颗粒由小的初级颗粒组成，反之亦然。结果表明，由小的初级乳糖颗粒组成的大颗粒显示出最高程度的降解。颗粒组成决定了颗粒的稳定性特征。
乳糖污染物和颗粒组成决定了颗粒及混合物的稳定性特征。
