Development of the next generation instrumented dissolution apparatus

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.