Modeling of quantitative relationships between physicochemical properties of active pharmaceutical ingredients and tensile strength of tablets using a boosted tree

Abstract

Objectives: The aim of this study was to explore the potential of boosted tree (BT) to develop a correlation model between active pharmaceutical ingredient (API) characteristics and a tensile strength (TS) of tablets as critical quality attributes.

Methods: First, we evaluated 81 kinds of API characteristics, such as particle size distribution, bulk density, tapped density, Hausner ratio, moisture content, elastic recovery, molecular weight, and partition coefficient. Next, we prepared tablets containing 50% API, 49% microcrystalline cellulose, and 1% magnesium stearate using direct compression at 6, 8, and 10 kN, and measured TS. Then, we applied BT to our dataset to develop a correlation model. Finally, the constructed BT model was validated using k-fold cross-validation.

Results: Results showed that the BT model achieved high-performance statistics, whereas multiple regression analysis resulted in poor estimations. Sensitivity analysis of the BT model revealed that diameter of powder particles at the 10th percentile of the cumulative percentage size distribution was the most crucial factor for TS. In addition, the influences of moisture content, partition coefficients, and modal diameter were appreciably meaningful factors.

Conclusions: This study demonstrates that BT model could provide comprehensive understanding of the latent structure underlying APIs and TS of tablets.

Keywords:

• Tablet
• quality by design
• machine learning
• boosted tree
• tensile strength
• physicochemical property

Disclosure statement

The authors declare that they have no financial or noncompeting interests concerning this manuscript. The authors alone are responsible for the content and writing of the article.

Additional information

Funding

This study was supported by JSPS KAKENHI [Grant Number JP16K08192] and Tamura Science Foundation. The Department of Pharmaceutical Technology, Graduate School of Medicine, and Pharmaceutical Science for Research, University of Toyama is an endowed department, supported with an unrestricted grant from Nichi-Iko Pharmaceutical Co. Ltd. (Toyama, Japan).