Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907.
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285.
J Pharm Sci. 2020 Mar;109(3):1312-1323. doi: 10.1016/j.xphs.2019.11.016. Epub 2019 Nov 22.
Amorphous solid dispersions typically improve the oral bioavailability of poorly soluble drugs. However, residual crystallinity is always a concern, in terms of potential impact on the product stability and performance. Consequently, in vitro tools that allow biorelevant assessment of residual crystallinity are of interest. The goal of the present study was to use absorptive dissolution testing to evaluate the impact of different levels of crystallinity in an amorphous formulation on membrane mass transport kinetics and supersaturation-time profiles. Partial crystallinity was induced in commercially available tacrolimus formulations by exposure to moderate temperature and high relative humidity. A hollow fiber membrane was coupled to a dissolution vessel to create an absorptive dissolution testing apparatus, and concentration-time profiles were simultaneously monitored during dissolution (donor compartment) and after absorption across the membrane (receiver compartment). The coupled dissolution-absorption measurements indicated that residual crystallinity impacted the absorption profiles in a manner that depended on the volume of fluid used for the dissolution measurement. A high percentage of residual crystallinity hampered the drug release from the formulation. Higher supersaturation in nonsink dissolution conditions improved mass transfer rates; however, the presence of seed crystals led to rapid desupersaturation. Further systematic studies to delineate the interplay between the rate of absorption and desupersaturation revealed that for a given dissolution rate, the crystallization rate would supersede the absorption rate only at high supersaturations. Thus, seeds have a lower impact on absorption when the overall supersaturation generated is lower. This study underscores the importance of considering competing physical processes when evaluating amorphous formulations. A further consideration highlighted is that different fluid volumes may impact the absorption profile for supersaturating dosage forms. Absorptive dissolution testing appears to be a potentially valuable tool to mechanistically investigate amorphous solid dispersion formulation release and phase behavior under more biorelevant conditions.
无定形固体分散体通常可提高难溶性药物的口服生物利用度。然而，就产品稳定性和性能的潜在影响而言，残留结晶度始终是一个关注点。因此，人们对能够进行相关生物评估的残留结晶度的体外工具很感兴趣。本研究的目的是使用吸收溶解试验来评估不同程度的无定形制剂中的结晶度对膜传质动力学和过饱和度-时间曲线的影响。通过在中等温度和高相对湿度下暴露，使市售他克莫司制剂产生部分结晶。将中空纤维膜与溶解容器耦合，形成吸收溶解试验装置，并在溶解过程中（供体隔室）和吸收穿过膜后（受体隔室）同时监测浓度-时间曲线。耦合的溶解-吸收测量表明，残留结晶度以依赖于用于溶解测量的流体体积的方式影响吸收曲线。高比例的残留结晶度阻碍了药物从制剂中的释放。在非溶胀条件下更高的过饱和度提高了传质速率；然而，晶种的存在导致快速过饱和度下降。进一步的系统研究表明，在吸收和过饱和度下降之间的相互作用，对于给定的溶解速率，只有在高过饱和度下，结晶速率才会超过吸收速率。因此，当产生的总过饱和度较低时，晶种对吸收的影响较小。本研究强调了在评估无定形制剂时考虑竞争物理过程的重要性。另一个需要考虑的问题是，不同的流体体积可能会影响过饱和剂型的吸收曲线。吸收溶解试验似乎是一种很有前途的工具，可以在更相关的生物条件下对无定形固体分散体制剂的释放和相行为进行机制研究。
