A multivariate formulation and process development platform for direct compression

Jens Dhondt

doi:10.1016/j.ijpharm.2022.121962

2022-07-01

PRE

Jens Dhondt

Johny Bertels

Ashish Kumar

Daan Van Hauwermeiren

DOI：10.1016/j.ijpharm.2022.121962

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摘要

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The efficient development of robust tableting processes is challenging due to the lack of mechanistic under-standing on the impact of raw material properties and process parameters on tablet quality. The experimental determination of the effect of process and formulation parameters on tablet properties and subsequent optimi-zation is labor-intensive, expensive and time-consuming. The combined use of an extensive raw material property database, process simulation tools and multivariate modeling allows more efficient and more optimized development of the direct compression (DC) process. In this study, key material attributes and in-process me-chanical properties with a potential effect on tablet processability and tablet properties were identified. In a first step, an extensive characterization of 55 raw materials (over 100 material descriptors) (Van Snick et al., 2018) and 26 formulation blends (31 material descriptors) (Dhondt et al., 2022) was performed. These blends were subsequently compacted on a compaction simulator under multiple process conditions through a design of ex-periments (DoE) approach. A T-shaped partial least squares (T-PLS) model was established which correlates tablet quality attributes with process settings, raw material properties and blend ratios. During future devel-opment of the DC formulation and process for a new active pharmaceutical ingredient (API), this model can then be used to provide a preliminary formulation and compaction process settings as starting point to be further optimized during development trials based on well-defined raw material characteristics and compaction tests. This study hence contributes to a better understanding on the impact of raw material properties and process settings on a DC process and final properties of the produced tablets; and provides a platform allowing a more efficient and more optimized development of a robust tableting process.

Keyword:

Pharmaceutical drug product development

Multivariate data analysis

Material characterization

Tableting

Direct compression