Development of the next generation instrumented dissolution apparatus

大多数药品的设计是立即释放活性成分，其中微观结构和崩解过程在产品性能中起着关键作用。在制粒和压片过程中，形成了颗粒间结合和孔隙，这些结合和孔隙限定了片剂的微观结构和影响性能。片剂中的孔直接影响生理液体进入片剂的速率，导致颗粒溶胀，并最终将压块破碎成团聚体和初级颗粒。1这导致比表面积增加，从而导致药物溶出速率增加。这些崩解机制，即液体吸胀、溶胀和颗粒间键的断裂，强烈地相互关联，因为颗粒的溶胀动态地改变内部孔结构，这影响液体吸胀过程并影响颗粒-颗粒键的中断。制剂的开发需要深入了解片剂崩解所涉及的每个步骤的相互联系以及它们与微观结构、处方和原材料属性的联系。由于缺乏合适的原位测量技术来解决崩解和溶出的基本过程，目前存在很大的知识差距。本项目旨在开发一种创新的仪器化溶出USP Apparatus 2，以解决驱动片剂溶出的基本机制。它将提供变革性的成果，以达到对片剂溶出度的下一个理解水平。具体目标是：一。片剂崩解和溶出度的现场监测：该项目将生产第一台溶出度测试仪，可同时测量片剂的液体吸收和溶胀、崩解颗粒的大小、溶出药物随时间的变化等动态过程。此外，原位拉曼光谱将允许我们分析在溶解测试期间是否以及何时发生固态转化。二.深入了解处方和片剂微观结构如何影响片剂溶出度：仪器化溶出仪将用于深入了解处方、微观结构和片剂溶出度之间的关系。高端离线技术（X射线计算机断层扫描和太赫兹时域光谱）将用于量化片剂的微观结构，只有深入了解动态溶胀、液体吸收、颗粒间键断裂和溶解过程的复杂相互作用，才能优化片剂的崩解和溶解。这只能通过单独和同时监测这些过程中的每一个来实现，其中主要的技术差距在于在时间和空间上解析快速（秒至分钟）片剂溶胀和液体渗透动力学。这一差距将通过开发世界上第一个基于OCT的溶出度测试平台来解决。这种新的实验装置将能够同时测量3D（两个空间维度和一个时间维度）中的溶胀和液体渗透，空间分辨率为5-10微米，时间分辨率为毫秒至秒。这种独特的设置将与现有的技术相结合，如聚焦光束反射测量（FBRM），紫外线（UV）和拉曼光谱的自动采样，以量化组合崩解-溶解过程中涉及的每个步骤。

The majority of pharmaceutical products are designed to immediately release the active ingredient, where the microstructure and the disintegration process play a pivotal role in product performance. During granulation and tableting, interparticle bonds and pores are formed that define the tablet microstructure and impact performance. The pores in a tablet directly affect the rate at which a physiological fluid enters the tablet, leading to swelling of particles and the eventual break-up of the compact into agglomerates and primary particles.1 This leads to an increase in the specific surface area causing an increase in dissolution rate of the drug. These disintegration mechanisms, i.e. liquid imbibition, swelling and breakage of interparticle bonds, are strongly interconnected as the swelling of particles dynamically changes the internal pore structure which influences the liquid imbibition process and affects the interruption of particle-particle bonds. The development of a drug product requires a deep understanding of the interconnection of every step involved in tablet disintegration as well as their link to the microstructure, formulation and raw material attributes. There is currently a substantial knowledge gap due to the lack of appropriate in-situ measurement techniques that can resolve the fundamental processes underpinning disintegration and dissolution.This project aims to develop an innovative instrumented dissolution USP Apparatus 2 to resolve the fundamental mechanisms driving tablet dissolution. It will deliver transformative outcomes to reach the next level of understanding in tablet dissolution. The specific aims are:I. In-situ monitoring of tablet disintegration and dissolution: This project will produce the first dissolution tester that simultaneously measures the dynamic processes of liquid imbibition in and swelling of a tablet, size of disintegrated particles, the dissolved drug as a function of time. In addition, in-situ Raman spectroscopy will allow us to analyse if and when a solid-state transformation takes place during the dissolution testing. II. Gain next level of understanding of how formulation and tablet microstructure impacts tablet dissolution: The instrumented dissolution apparatus will be used to gain fundamental insights into the relationship between the formulation, microstructure and tablet dissolution. High-end off-line techniques (X-ray computed tomography and terahertz time-domain spectroscopy) will be used to quantify the tablet microstructure.The tablet disintegration and dissolution can only be optimised by having a deep understanding of the complex interactions of the dynamic swelling, liquid imbibition, break-up of interparticle bonds and dissolution processes. This can only be achieved by monitoring each of these processes separately and at the same time, where the major technological gap is in temporally and spatially resolving the fast (seconds to minutes) tablet swelling and liquid penetration kinetics. This gap will be addressed by developing the world's-first OCT-based dissolution testing platform. This novel experimental setup will be capable of simultaneously measuring the swelling and liquid penetration in 3D (two spatial and one temporal dimension) with a spatial resolution of 5-10 microns and a temporal resolution of milliseconds to seconds. This unique setup will be combined with established techniques, such as focused beam reflectance measurement (FBRM), an automated sampling for ultra-violet (UV) and Raman spectroscopy, to quantify every step involved in the combined disintegration-dissolution process.