Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

Kouya Kimoto,Masatoshi Karashima,Junpei Takeda,Yukihiro Ikeda,Miyuki Hohokabe,Katsuhiko Yamamoto,Mitsuo Yamamoto

doi:10.3390/cryst10030211

Abstract

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques—pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry.

Highlights

The oral route is the most common used for drug administration and is the first priority in pharmaceutical development
As a result of cocrystal screenings determined by Powder X-Ray Diffractometry (PXRD), seven types of probable TAK-020 cocrystal (TAK-020 with Citric acid (CA), malonic acid (MoA), maleic acid (MeA), malic acid (MaA), mandelic acid (MdA), gentisic acid (GA), and salicylic acid (SA)) were obtained in Cocrystal Grinding (CCG) and SCS
The observed endothermic peaks at lower temperatures among some forms might represent the eutectic melting of residual cocrystal former (CCF) and other things, and they were different from those of individual CCFs, suggesting that their unique endothermic peaks might show melting points of new crystal complex

Summary

Introduction

The oral route is the most common used for drug administration and is the first priority in pharmaceutical development. 40% of marketed drugs and 70% of drug candidates in current pharmaceutical development exhibit poor aqueous solubility. Aqueous solubility is one of the most important physicochemical properties for the success of oral dosage formulations, since poor aqueous solubility leads to low oral bioavailability and pharmacokinetic (PK) variability, resulting in insufficient therapeutic efficacy and limited exposure in toxicological studies [1,2,3]. Poor aqueous solubility of drugs often needs to be solved through pharmaceutical development. Numerous technologies, including crystal engineering, formulation, and both of these in combination were investigated for enhancing solubility and the dissolution rate. The rational selection of these technologies for Crystals 2020, 10, 211; doi:10.3390/cryst10030211 www.mdpi.com/journal/crystals

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