Development of the next generation instrumented dissolution apparatus

大多数制药产品的设计都是为了立即释放活性成分，其中微结构和崩解过程对产品性能起着关键作用。在造粒和压片过程中，颗粒间结合和气孔的形成决定了片剂的微观结构和冲击性能。片剂中的毛孔直接影响生理液体进入片剂的速度，导致颗粒膨胀，并最终将压片分解成凝聚体和初级颗粒。1这会导致比表面积增加，从而增加药物的溶出度。这些解体机制，即液体渗吸、膨胀和颗粒间键的断裂，是紧密相连的，因为颗粒的膨胀动态地改变了内部孔结构，从而影响液体渗吸过程，并影响颗粒-颗粒键的中断。开发一种药物产品需要深入了解片剂崩解过程中每个步骤的相互联系，以及它们与片剂微观结构、处方和原料属性的联系。由于缺乏合适的现场测量技术来解决崩解和溶出的基本过程，目前存在着很大的知识缺口。本项目旨在开发一种创新的仪器化溶出度USP装置2，以解决驱动片剂溶出的基本机理。它将带来变革性的结果，以达到对片剂溶出度的下一层次理解。具体目标是：1.片剂崩解和溶出的现场监测：该项目将生产第一台溶出度测试仪，可以同时测量片剂中液体的吸胀和膨胀、崩解颗粒的大小、溶解药物随时间的变化的动态过程。此外，原位拉曼光谱将使我们能够分析在溶解测试期间是否以及何时发生固态转变。对处方和片剂微结构如何影响片剂溶出度有更深一步的了解：将使用仪器溶出仪对处方、微结构和片剂溶出度之间的关系有基本的了解。将使用高端离线技术(X射线计算机断层扫描和太赫兹时域光谱)来量化片剂的微观结构。只有深入了解动态溶胀、液体吸收、颗粒间键断裂和溶出过程的复杂相互作用，才能优化片剂的崩解和溶出过程。这只能通过单独和同时监测每个过程才能实现，其中主要的技术差距在于在时间和空间上解决快速(几秒到几分钟)的片剂膨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。这种新颖的实验装置将能够同时测量三维(两个空间和一个时间维度)的溶胀和液体渗透，空间分辨率为5-10微米，时间分辨率为毫秒到秒。这一独特的设置将与现有的技术相结合，如聚焦光束反射率测量(FBRM)、紫外线(UV)和拉曼光谱的自动采样，以量化联合崩解-溶解过程中涉及的每一步。

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.