Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

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.

Importance of Nuclear Quantum Effects for Molecular Cocrystals with Short Hydrogen Bonds

“…Multicomponent pharmaceutical solids, such as cocrystals and salts, affect the bioavailability and pharmaceutical compatibility of an active pharmaceutical ingredient (API). , Determining whether a proton transfer between the API and the coformer has taken place, resulting in a salt or a cocrystal, is a key challenge in the pharmaceutical industry because different solid forms have different physicochemical and pharmacokinetic properties. − Furthermore, the characterization of the solid form is crucial from the regulatory and intellectual property perspective as well. − …”

Drug–Drug Cocrystallization Simultaneously Improves Pharmaceutical Properties of Genistein and Ligustrazine

“…Pharmaceutical cocrystals are composed of an API and one or more pharmaceutically acceptable cocrystal formers (CCFs) with a well-defined stoichiometry, interacting through hydrogen bond, π–π conjugation, and other noncovalent bonds . Pharmaceutical applications of cocrystals lie in their ability to modify physicochemical properties, such as solubility, dissolution rate, physical stability, tabletability, , and bioavailability, , without altering the pharmacological activity of the API. − Cocrystals formed between APIs, i.e. , drug–drug cocrystals, can overcome problems in physicochemical properties of individual APIs and, sometimes, even exhibit synergistic pharmacological effects .…”

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“…Over the last two decades, pharmaceutical cocrystals have attracted significant attention from academia and pharmaceutical industries due to the potential to improve the physicochemical properties of APIs by modifying the crystal structure without altering the pharmacological nature 11 , 12 . With the development of the cocrystal field, several pharmaceutical cocrystals have been approved, such as Steglatro®, Entresto®, and more are in clinical trials 13 , 14 , 15 , 16 .

Figure 1 Different solid forms of active pharmaceutical ingredients.

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