A multivariate formulation and process development platform for direct compression

Jens Dhondt; Johny Bertels; Ashish Kumar; Daan Van Hauwermeiren; Alexander Ryckaert; Bernd Van Snick; Didier Klingeleers; Chris Vervaet; Thomas De Beer

doi:10.1016/j.ijpharm.2022.121962

A multivariate formulation and process development platform for direct compression

Int J Pharm. 2022 Jul 25:623:121962. doi: 10.1016/j.ijpharm.2022.121962. Epub 2022 Jun 25.

Authors

Jens Dhondt¹, Johny Bertels², Ashish Kumar³, Daan Van Hauwermeiren⁴, Alexander Ryckaert⁵, Bernd Van Snick², Didier Klingeleers⁶, Chris Vervaet⁷, Thomas De Beer⁸

Affiliations

¹ Oral Solids Development, Drug Product Development, Pharmaceutical Product Development & Supply, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium; Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
² Oral Solids Development, Drug Product Development, Pharmaceutical Product Development & Supply, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
³ Laboratory of Pharmaceutical Engineering, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
⁴ Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium; BIOMATH, Department of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
⁵ Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
⁶ Pharmaceutical & Material Sciences, Pharmaceutical Product Development & Supply, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
⁷ Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
⁸ Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: thomas.debeer@ugent.be.

PMID: 35764260
DOI: 10.1016/j.ijpharm.2022.121962

Abstract

The efficient development of robust tableting processes is challenging due to the lack of mechanistic understanding 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 optimization 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 mechanical 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 experiments (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 development 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.

Keywords: Direct compression; Material characterization; Multivariate data analysis; Pharmaceutical drug product development; Tableting.

MeSH terms

Chemistry, Pharmaceutical*
Drug Compounding
Least-Squares Analysis
Powders
Pressure
Tablets
Technology, Pharmaceutical*

Substances

Powders
Tablets