Development of the next generation instrumented dissolution apparatus

下一代仪器化溶出度仪的开发

• 批准号: 2441956
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2441956
• 关键词: Development; next; generation; instrumented; dissolution

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.

大多数药品的设计目的是立即释放活性成分，其中微观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，颗粒间键和孔隙的形成决定了片剂的微观结构和冲击性能。片剂中的孔隙直接影响生理液体进入片剂的速度，导致颗粒膨胀，最终将致密物分解成团块和初级颗粒这导致比表面积的增加，从而导致药物溶出率的增加。由于颗粒的膨胀动态地改变了内部孔隙结构，从而影响了液体的吸胀过程，影响了颗粒间键的中断，因此这些崩解机制（即液体吸胀、颗粒间键的膨胀和断裂）之间存在着紧密的联系。药品的开发需要深入了解片剂崩解过程中每个步骤的相互关系，以及它们与微观结构、配方和原料属性的联系。由于缺乏适当的原位测量技术，目前存在很大的知识差距，无法解决导致解体和溶解的基本过程。本项目旨在开发一种创新的仪器溶出度USP仪器2，以解决驱动片剂溶出的基本机制。它将带来变革性的结果，以达到对片剂溶出度的下一个理解水平。具体目标是：1。片剂崩解与溶出的现场监测：本项目将生产第一台同时测量片剂液体吸胀动态过程、崩解颗粒大小、溶解药物随时间变化的溶出度测试仪。此外，原位拉曼光谱将允许我们分析在溶解测试过程中是否以及何时发生固态转变。2。进一步了解制剂和片剂微观结构如何影响片剂溶出度：仪器溶出度仪将用于获得制剂、微观结构和片剂溶出度之间关系的基本见解。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、液体吸胀、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过程。这只能通过同时单独监测这些过程来实现，其中主要的技术差距是在时间和空间上解决快速（秒到分钟）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）的膨胀和液体渗透，空间分辨率为5-10微米，时间分辨率为毫秒到秒。这种独特的装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，以量化分解-溶解联合过程中涉及的每一步。