Opinion paper
Simultaneously improving the physicochemical and pharmacokinetic properties of vemurafenib through cocrystallization strategy

https://doi.org/10.1016/j.jddst.2022.103230Get rights and content

Abstract

Vemurafenib (VEM) is a first-line drug for the treatment of metastatic melanoma with BRAFV600 mutation, which was developed in the form of amorphous solid dispersion to overcome the defects of poor aqueous solubility and oral absorption. However, the oral dose of VEM is still very high; besides, the poor stability of amorphous form may increase the risks in drug effectiveness and safety. Herein, we attempted to provide a solution to these issues based on cocrystallization strategy. Three cocrystalline forms involving VEM and D/L/dl-camphorsulfonic acid with stoichiometric ratio of 1:1 were synthesized and characterized by powder X-ray diffraction analysis, 1H nuclear magnetic resonance, thermal analyses and Fourier transform infrared spectroscopy. The in vitro evaluations show that all of the cocrystalline forms demonstrate improved hygroscopicity and stability compared to amorphous VEM; especially, the cocrystalline form with dl-camphorsulfonic acid exhibits much better tabletability and apparent solubility than all of other forms. Pharmacokinetic tests reveal that all the cocrystallized products show significantly enhanced Cmax and AUC0-t values compared to the amorphous form. Therefore, the newly discovered cocrystalline forms of VEM are expected to overcome the issues of poor solubility and oral absorption and provide great potential for the development of improved preparations of the drug.

Introduction

Vemurafenib (VEM, Scheme 1), N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide, is a selective BRAF kinase inhibitor developed by Plexxikon company with the trade name of Zelboraf [1,2]. VEM is used to treat the patients with metastatic or unresectable melanoma with BRAFV600 mutation, as well as a rare blood cancer Erdheim-Chester disease [3,4]. VEM is an insoluble drug with aqueous solubility less than 0.1 μg/mL, leading to low oral bioavailability [5]. In order to overcome the solubility challenge, VEM was developed and marketed in the form of amorphous solid dispersion [6]. However, the clinical recommended oral dose of VEM is still as high as 960 mg twice daily, which brings serious adverse reactions [7]. In addition, the amorphous solid dispersion suffers from complex preparation process, poor reproducibility and instability issues [8]. Therefore, it is necessary to develop new crystalline form of VEM with adequate stability and solubility as well as higher oral bioavailability, so as to develop improved preparations of VEM with better curative effects and less side effects.

Pharmaceutical cocrystallization refers to the strategy that an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable compounds which are solids under ambient conditions (commonly known as cocrystallization co-formers, CCFs) are crystallized in the same lattice to generate multicomponent crystals via noncovalent bonds, such as hydrogen bonds, ionic bonds, van der Waals force and π···π stacking interactions, etc. [[9], [10], [11]]. The cocrystallization products generally include salts and cocrystals. The intrinsical difference between them is that the former occurs proton transfer between API and CCF molecules, while each component of the latter is electrically neutral [12]. Cocrystallization strategy has been proved to be an effective means to directionally improve physicochemical properties, like dissolution, permeability and stability, as well as biological properties of drugs [[13], [14], [15], [16]]. In addition, as a new crystalline form of drugs, cocrystallized products possess significant patent value with great commercial potential, which can not only strengthen the intellectual property protection barrier of drugs, but also provide a breakthrough for overcoming the crystal form patent barrier of original drugs [17,18].

Up to now, a variety of VEM salts, such as methanesulfonate, toluenesulfonate, sulfate, hydrobromate and hydrochloride, have been disclosed [19,20]. However, systematic cocrystallization screening of VEM and relative property evaluations, especially pharmacokinetic property evaluation, have not been reported. In the present study, cocrystallization approach based on supramolecular synthon strategy was applied to VEM to discover alternative crystalline forms with gratifying physicochemical and pharmacokinetic properties. The possible hydrogen bonded supramolecular synthons of VEM are displayed in Scheme 2. It can be seen that VEM has the potential to construct hydrogen bonded supramolecular synthons with compounds containing carboxylic, amide and sulfonic acid groups. Therefore, a series of such compounds, including oxalic acid, succinic acid, fumaric acid, D/L/dl-camphorsulfonic acid, urea, nicotinamide, etc., were attempted to cocrystallize with VEM. Finally, three 1:1 cocrystalline forms of VEM with d-camphorsulfonic acid (VEM-D-CSA), l-camphorsulfonic acid (VEM-L-CSA) and dl-camphorsulfonic acid (VEM-DL-CSA) were synthesized by liquid assisted grinding or slurry methods. Camphorsulfonic acid is a commonly used salt forming reagent for solid drugs, and many drugs such as trimethofen and rucaparib are developed in the form of their camphor sulfonates [21,22].

The cocrystalline forms were fully characterized by powder X-ray diffraction (PXRD) analysis, 1H nuclear magnetic resonance (1H NMR), thermal analysis and Fourier transform infrared (FT-IR) spectroscopy. Further, physicochemical properties including hygroscopicity, stability, dissolution behavior and tabletability, as well as pharmacokinetic property of the three cocrystalline forms were evaluated and compared with those of amorphous VEM. The results demonstrate that all of the cocrystalline forms, especially VEM-DL-CSA, exhibit significantly improved in vitro and in vivo properties compared to amorphous VEM, which are promising as alternatives for the development of improved formulations of VEM.

Section snippets

Materials

VEM (form II) was purchased from Shanghai Shengde Chemical Co. Ltd. (Shanghai, China). D-CSA, L-CSA and DL-CSA were purchased from Aladdin Reagent Co., Ltd. All other chemicals and solvents were commercially available and used without further purification.

Preparation of amorphous VEM and cocrystalline forms

Amorphous form of VEM was prepared by grinding 500 mg form II of VEM for 5 h using a Retsch MM 400 mixer mill at frequency of 20 Hz.

Cocrystalline forms were prepared by two methods as follows: (I) A powdered mixture of VEM form II (30 mg,

PXRD analysis

PXRD technique is generally utilized to identify the crystalline phase of solid drugs [23]. The PXRD pattern of amorphous form of VEM exhibits typical dispersive without obvious diffraction peak (Fig. 1). The PXRD pattern of each cocrystalline form is obviously distinguished from that of its respective raw materials, indicating the generation of new crystalline phase. Furthermore, the characteristic peaks of the starting materials disappeared after cocrystallization, confirming the crystal

Conclusion

In the present work, three cocrystalline forms of VEM, namely VEM-D-CSA, VEM-L-CSA and VEM-DL-CSA, were prepared by liquid assisted grinding or slurry methods, and were then fully characterized by PXRD, 1H NMR, thermal analyses and FT-IR spectroscopy. The physicochemical property evaluations show that all of the cocrystalline forms exhibit improved hygroscopicity and stability as compared to the amorphous form; besides, VEM-DL-CSA demonstrates better tabletability and apparent solubility.

Author statement

Guan-Lan Huang: Investigation, Data curation. Ling Yang: Visualization, Investigation, Conceptualization, Methodology. Bo-Ying Ren: Methodology, Investigation. Xin-Yue Lv: Data curation, Investigation. Ling-Yi Song: Visualization, Methodology. Xia-Lin Dai: Conceptualization, Methodology, Writing – original draft. Jia-Mei Chen: Supervision, Conceptualization, Writing – review & editing, Funding acquisition.

Declaration of competing interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by College Students Entrepreneurship Innovation Training Program of China (No. 201910060062).

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  • 1

    Guan-Lan Huang and Ling Yang contributed equally to this work.

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