Abstract

Cocrystallisation can enhance the solubility and bioavailability of active pharmaceutical ingredients (APIs); this method may be applied to improve the availability of materials that were previously considered unsuitable. Terahertz (THz) spectroscopy provides clear, substance-specific fingerprint spectra; the transparency of the THz wave allows us to probe inside a sample to identify medicinal materials. In this study, THz and infrared (IR) spectroscopy were used to characterise cocrystallisation in solid-phase reactions between ibuprofen and nicotinamide. Multivariate curve resolution with alternating least squares (MCR-ALS) was applied to both time-dependent THz and IR spectra to identify the intermolecular interactions between these cocrystallising species. The analytical results revealed cocrystal formation through a two-step reaction, in which the steps were dominated by thermal energy and water vapour, respectively. We infer that the presence of water molecules significantly lowered the activation energy of cocrystal formation.

Highlights

  • Cocrystallisation can be used to enhance the solubility and bioavailability of active pharmaceutical ingredients (APIs), classified according to the Biopharmaceutical Classification System (BCS) as ClassII materials

  • We confirmed new characteristic peaks associated with cocrystal formation in these regions using the pre-processed

  • The cocrystal formation process was analysed by Fourier-Transform Infrared Spectroscopy (FT-IR) and THz spectroscopy, and data were fed into an Multivariate curve resolution with alternating least squares (MCR-ALS) algorithm

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Summary

Introduction

Cocrystallisation can be used to enhance the solubility and bioavailability of active pharmaceutical ingredients (APIs), classified according to the Biopharmaceutical Classification System (BCS) as ClassII materials. Cocrystals are a molecular complex of APIs with a highly water-soluble cocrystal former (coformer). Medicines Agency (EMA) and Food and Drug Administration (FDA) have released guidelines that consider cocrystals identical to APIs as long as they do not exhibit different pharmacokinetics [3,4]. This led to the introduction of cocrystal-based medicines in 2014. Four candidate cocrystalline materials are currently in clinical trials [5]. For at least 30% of currently marketed drugs, the replacement of APIs with cocrystals is expected to significantly improve patients’ quality of life. Candidate compounds previously deemed unsuitable may be acceptable when incorporated into a cocrystal

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