Toward engineering granules to facilitate the compaction phase of tablet manufacture: Investigations of granular mechanical properties and establishment of spectroscopic monitoring techniques
Abstract
High-shear wet granulation (HSWG) is a common unit operation used to improve flow and compaction characteristics of pharmaceutical formulations. Deficiencies in the fundamental understanding of the HSWG process have precluded the identification of a standardized method for the determination of process end-point. In order to build quality into the manufacturing process by means of monitoring and arriving at an end-point, it is necessary to develop techniques to determine physical attributes of granules before and during their manufacture. A surrogate method to characterize the extent of granule densification during processing was sought. The mechanical behavior of mock liquid-bound granules has been investigated to predict the extent of granule consolidation during HSWG. It was found that the maximum strain accommodation during mechanical testing of the liquid-bound formulation could be used to characterize the relative granule densification during granulation. This methodology using small scale experiments will become increasingly important as there is increasing demand for enhanced product understanding with fewer full scale granulation experiments. Embracing the Quality by Design (QbD) approach, it is necessary to ensure that the characteristic that is being measured will translate into the desired result. The structural dependence of granule strength on the compaction phase was investigated to establish the validity of controlling granule density to ensure acceptable and reproducible compaction characteristics. Granulations were prepared under varying binder (water) levels, shear rates and wet massing times to investigate the role of granule densification on the overall compaction quality. Functional relationships between granule density, granule strength and compact strength have been determined. The path independence of granule performance suggests that no matter the method of attainment, once a certain granule density has been reached, the compaction properties can be determined. This establishes the validity of controlling granule density during HSWG to obtain the desired compaction characteristics. With the hypothesis of controlling granule density during HSWG to assess the end-point supported, methods have been employed to monitor granule densification during granulation. In order to evaluate the in-line density of granules, near-infrared (NIR) spectroscopy has been used because of its non-invasive nature and sensitivity to changes in sample density. Spectroscopic modeling of highly characterized granules was carried out to aid in gaining knowledge from in-line monitoring of the granulation process. Implementation of NIR will allow for assessment of product quality before stopping the granulation process and proceeding to the drying phase. Ultimately, a reduced order model was derived to describe the entire granulation process from setting the formulation through tablet compression. This systematic approach to process understanding and monitoring is necessary to advance the transition from traditional, time-based granulation to the ideal platform of ensuring product quality through process analytical technology (PAT).
Degree
Ph.D.
Advisors
Carvajal, Purdue University.
Subject Area
Chemical engineering|Pharmacy sciences
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