A Novel Drug-Drug Salt of Naproxen and Vortioxetine: Synthesis, Characterization, and Solubility Study

Zhang, Xianrui; Gao, Yuting

doi:https://doi.org/10.1155/2023/6678252

Journal of Chemistry

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Abstract Introduction Results and Discussion Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 6678252 | https://doi.org/10.1155/2023/6678252

A Novel Drug-Drug Salt of Naproxen and Vortioxetine: Synthesis, Characterization, and Solubility Study

Xianrui Zhang¹and Yuting Gao¹

Academic Editor: Josefina Pons

Received20 Apr 2023

Revised04 Jul 2023

Accepted07 Jul 2023

Published25 Jul 2023

Abstract

Naproxen (NAP) is an aromatic propionic acid nonsteroidal anti-inflammatory drug, and vortioxetine (VOT) is a novel antidepressant drug. In this study, a new 1 : 1 drug-drug salt of NAP and VOT (namely, NAP-VOT) was designed and synthesized by liquid-assisted grinding and slow evaporation. The obtained salt was characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Single-crystal structure showed that NAP-VOT is a molecular salt. The NAP and VOT molecules in the salt were connected by N-H⁺⋯O hydrogen bonds between the carbonyl oxygen of NAP and the piperazine group of VOT. In addition, solubility and dissolution rate experiments were performed in water and pH 6.86 phosphate buffers, and the result suggested that salt formation could increase the solubility and dissolution rate of NAP and VOT in water. Furthermore, this study provides a new research idea to solve the problem of drug-drug combination by achieving drug-drug association at the molecular level.

1. Introduction

Drug-drug cocrystals and salts are an emerging pharmaceutical technology that allows multiple drugs to combine together to improve the efficacy and safety of drugs [1–10]. In recent years, research into drug-drug cocrystal and salts has made great strides and has become a hot topic in the pharmaceutical industry. The advantages of drug cocrystals and salts are that the cocrystal structure can be used to improve drug efficacy and safety, increase drug stability, extend drug shelf life, reduce drug side effects, increase drug bioavailability, reduce drug toxicity, and alter drug efficacy properties and drug intestinal absorption [11–20].

Research has shown that there is an interaction between pain and depression. Chronic pain often triggers depression, and mental depression can exacerbate physical pain, so drug combinations between depression and painkillers have become routine [21, 22]. However, drug combinations are a physical mix and there is no guarantee of physical and chemical compatibility between the two APIs. This paper is the first attempt to achieve a combination between antidepressants and anti-inflammatory and analgesic drugs at the molecular level. Compared to fixed-dose combinations, drug-drug cocrystallization has greater advantages. It avoids the stability and chemical incompatibility problems between drug molecules and is more conducive to drug absorption.

Naproxen is a commonly used aromatic propionic acid nonsteroidal anti-inflammatory drug that exerts anti-inflammatory and analgesic effects by inhibiting the synthesis of prostaglandins [23–26]. Vortioxetine (VOT) is a novel antidepressant that is not only effective in improving the symptoms of depressed patients, but also in improving the mood of depressed patients, reducing anxiety, and improving sleep quality [27–29]. In the present work, a novel drug-drug salt comprised of NAP and VOT (namely NAP-VOT) with a 1 : 1 stoichiometric ratio was synthesized and characterized by single-crystal X-ray diffraction data (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimeter (DSC) measurements. In addition, the solubility and powder dissolution rate of the NAP-VOT were compared with that of the parent drug NAP and VOT. The molecular structures of NAP and VOT are displayed in Scheme 1.

2. Experimental Section

2.1. Instrumentations and Materials

All chemicals and reagents were obtained from a variety of business sources and utilized without further purification. The powder X-ray diffraction (PXRD) of NAP, VOT, and NAP-VOT salt were performed using a Bruker corporation D8 ADVANCE diffractometer with a Cu-Kα radiation tube (λ = 1.5418 Å) at 40 mA and 40 kV. Differential scanning calorimetry (DSC) measurements were performed on a Mettler–Toledo analyzer at a heating rate of 10°C/min in a nitrogen environment. On a Bruker Apex II CCD diffractometer operating at 50 kV and 30 mA, single-crystal X-ray diffraction measurements of the NAP-VOT was recorded using Mo Kα radiation (λ = 0.71073 Å). The SHELXS program was used to solve the crystal structure, which was then refined with the SHELXL program [30]. The NAP-VOT salt was analyzed and produced on the basis of its single-crystal data using CrystalExplorer 3.1 software. Tables 1 and 2 show the crystal structure parameters as well as hydrogen bond distances and angles.

2.2. Preparation of NAP-VOT

NAP-VOT salt was synthesized using a slow evaporation method. NAP (10 mg, 43.4 mmol) and VOT (13 mg, 43.4 mmol) solutions were prepared in a 1 : 1 equimolar ratio using a mixture of solvents (5 mL, acetonitrile: water, / 80 : 20%). The solutions were stirred at 50°C for 1 hour and left to evaporate slowly at room temperature. After 7–10 days, colorless needle crystals were obtained. Yield: 7.2 mg (31%). NAP-VOT salt was also prepared by the acetonitrile-assisted grinding method.

2.3. High-Performance Liquid Chromatography (HPLC) Assay

The concentration of NAP and VOT was determined by an Agilent 1260 Infinity II HPLC system. NAP and VOT were separated by an EC-C18 column (150 mm × 3.0 mm and 2.7 μm particle size). Mobile phase consisting of 60 : 40 (v/v) acetonitrile and potassium phosphate (pH 2.50, 0.01 M) was run at 0.6 mL/min. The column temperature was kept at 35°C and both NAP and VOT were detected at 226 nm.

2.4. Solubility and Powder Dissolution Studies

Solubility and powder dissolution tests were carried out in a round-bottomed flask containing water and pH 6.86 phosphate buffer medium at 37 ± 0.5°C. Excess sample was added to 25 mL mother liquor in a round bottom flask and stirred magnetically for 24 h. Then, the suspension was taken and filtered through a 0.22 μm membrane and the concentration of the filtrate was determined and analyzed by HPLC (n = 3). Residual samples were also collected for PXRD and DSC testing, the aim of which was to determine the stability of the residual samples. Powder dissolution experiments were similar to the solubility test, the difference being that the samples were taken at a fixed point in time while an equal amount of fresh mother liquor is added to keep the volume of the solution constant.

3. Results and Discussion

3.1. Crystal Structure Analyses

The crystal structure of NAP drug (CCDC reference: 1130671 [31]) showed that adjacent NAP molecules were associated through strong O-H⋯O (O2-H14⋯O3, 1.63 Å, 162°) hydrogen bonds in a one-dimensional wavy linear structure (Figure 1). The crystal structure of VOT drug (CCDC reference: 1408949 [32]) revealed that VOT molecules formed a parallel displaced manner through π⋯π interactions (Figure 2). In NAP-VOT salt, these abovementioned hydrogen bonds and π⋯π interactions belonging to NAP and VOT single crystals were substituted by stronger ionic variant carboxylate⋯piperazine salt heterosynthons. NAP-VOT salt crystallized in the monoclinic crystal system with the P121/c1 space group and comprised one NAP anion and one VOT cation in the asymmetric unit. Two NAP anions and two VOT cations formed a (12) tetramer through N1-H1C⁺⋯O2 (1.88 Å, 154°) and N1-H1D⁺⋯O1 (1.68 Å, 171°) hydrogen bonds, and these (12) tetramer were further bridged through C-H⋯π interactions (Figure 3).

3.2. Hirshfeld Surface Analyses

Hirshfeld surface analysis provides a visual insight into the weak force interactions between molecules [33, 34]. In order to compare the change in molecular weak forces after salt formation, the Hirshfeld surface analyses of NAP, VOT, and NAP-VOT were generated, and the Hirshfeld surfaces are shown in Figure 4. As can be seen from Figure 4, the H⋯H weak interaction contribution values in NAP, VOT, and NAP-VOT account for 44.8%, 74.2%, and 58.5%, respectively. It is clear that the H⋯H weakly interacting contribution values are dominant in the corresponding groups, where the contribution of H⋯H weakly interacting NAP is smaller than that of VOT. Currently, the H⋯H weak interaction contribution values of NAP-VOT are between NAP and VOT, indicating the NAP-VOT are structurally denser than NAP and looser VOT, which provide an opportunity to regulate the NAP and VOT solubility by creating favourable conditions. In addition, the intermolecular O---H hydrogen bonding interactions in NAP-VOT have a combined polar contact of 14.1%, which is better than that of pure VOT molecules (0%). The enhanced polar weak interaction provides more polar bonding sites for the solvation effect, which might enhance the solubility of NAP-VOT.

3.3. PXRD Analyses

The PXRD patterns for NAP, VOT, and NAP-VOT are presented in Figure 5. NAP-VOT displayed major diffraction peaks at 4.04°, 8.04°, 9.66°, 12.52°, 12.96°, 15.48°, 15.9°, 17.3°, 18.18°, 19.62°, 21.22°, 22.36°, 23.44°, 24.96°, 25.62°, and 28.6°. Diffraction peaks at 2θ values of 6.44°, 12.48°, 13.16°, 16.64°, 17.82°, 18.82°, 20.16°, 22.4°, 23.54°, 27.2°, 27.64°, 28.38°, 29.7°, and 31.16° in NAP, and 11.06°, 12.36°, 14.32°, 16.86°, 17.4°, 18.64°, 19.04°, 22.48°, 24.38°, and 25.66° in VOT. The diffractogram of NAP-VOT was distinguishable from NAP and VOT, indicating the formation of a new crystalline phase. In addition, the experimental PXRD pattern of NAP-VOT was in good agreement with the calculated profile, suggesting the high purity of the powder sample.

3.4. Thermal Analyses

Thermal behaviours of NAP, VOT, and NAP-VOT are tested using differential scanning calorimetry (DSC), and thermograms are presented in Figure 6. Crystalline NAP, VOT, and NAP-VOT exhibited single-endothermic peak at 161°C, 117°C, and 144°C, respectively. The endothermic peak of NAP-VOT was between NAP and VOT, indicating the formation of a new solid form.

3.5. Solubility and Dissolution Studies

The solubility of NAP, VOT, and NAP-VOT in pure water and pH 6.86 buffer solution are shown in Table 3. The solubility order was NAP-VOT > NAP > VOT in water and NAP > NAP-VOT > VOT in pH 6.86 buffer solution. The NAP-VOT salt showed better solubility in water when compared to NAP and VOT, while the solubility of NAP-VOT at pH 6.86 phosphate buffers was in between that of NAP and VOT. The formation of the remaining materials after solubility studies was tested through PXRD and DSC, and the result of PXRD and DSC is shown in Figure 7. The remaining solids showed that NAP and NAP-VOT were stable in water and pH 6.86 buffer solutions, but VOT was unstable in pH 6.86.

(a)

(b)

The powder dissolution profiles of NAP-VOT were evaluated in water and pH 6.86 phosphate buffers, and the results are shown in Figure 8. The result showed that the dissolution profile of NAP-VOT in pH 6.86 was lower than NAP but better than VOT. On the other hand, the dissolution rate of NAP-VOT in water is superior to that of NAP and VOT.

(a)

(b)

4. Conclusions

In conclusion, a novel drug-drug salt comprised of NAP and VOT (NAP-VOT) with a 1 : 1 stoichiometric ratio was synthesized to solve the absorption problem when coadministering drugs and to truly achieve drug combination at the molecular level. The NAP and VOT molecules in the salt were connected by N-H⁺⋯O hydrogen bonds between the carbonyl oxygen of NAP and the piperazine group of VOT. In addition, the physicochemical properties, solubility, and dissolution rates of the salt were systematically investigated. As expected, the solubility and dissolution rate of the NAP-VOT salt significantly increased in comparison to NAP and VOT in water. Furthermore, this study is an important guide to address the problem of poor adherence to medication in drug combinations.

Data Availability

CCDC 2234586 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

The manuscript was written and analyzed through contributions of all authors. All authors conceptualized and designed the study. Material preparation and experimental study were performed by Xianrui Zhang and Yuting Gao. The data analysis and software calculation were performed by Xianrui Zhang. The funding support and first draft of the manuscript were written by Xianrui Zhang and all authors commented on the previous version of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

This work was supported by the Guangxi Science and Technology Base and Talent Project (grant no. GUIKE AD20159051); Wuzhou University Foundation (grant no. 2020B006), and Innovation and Entrepreneurship Training Program for College Students (grant no. 202211354012).

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Copyright © 2023 Xianrui Zhang and Yuting Gao. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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