*Article* **Measurement and Correlation of the Solubility of Florfenicol in Four Binary Solvent Mixtures from** *T* **= (278.15 to 318.15) K**

**Xinyuan Zhang 1, Pingping Cui 1, Qiuxiang Yin 1,2 and Ling Zhou 1,\***


**Abstract:** Florfenicol is an excellent antibiotic and is widely used in animal bacterial diseases. However, its poor water solubility leads to various problems, such as poor absorption and bioavailability. The development of nanocrystals is one of the most useful methods for solubilizing florfenicol, which often requires solubility data of florfenicol in different mixed solvents. In this work, the solubility of florfenicol was determined by the gravimetric method in methanol + water, ethanol + water, 1-propanol + water, and isopropanol + water binary solvents at temperatures from 278.15 to 318.15 K. In these four mixed solvents, the solubility of florfenicol increased with the increase in temperature. The solubility of florfenicol in methanol + water mixed solvent increases with the decrease in water ratio, while the solubility of florfenicol in ethanol + water, 1-propanol + water, or isopropanol + water mixed solvents increased first and then decreased with the decrease in water ratio, indicating a cosolvency phenomenon. The modified Apelblat model, CNIBS/R-K model, Jouyban–Acree model, and NRTL model were used to correlate the solubility data of florfenicol in four binary solvents. RMSD values indicated that the calculated values are in good agreement with the experimental solubility data for all four models, among which the CNIBS/R-K model provides the best correlation.

**Keywords:** florfenicol; solubility; binary solvent system; cosolvency; correlation model

**Citation:** Zhang, X.; Cui, P.; Yin, Q.; Zhou, L. Measurement and Correlation of the Solubility of Florfenicol in Four Binary Solvent Mixtures from *T* = (278.15 to 318.15) K. *Crystals* **2022**, *12*, 1176. https:// doi.org/10.3390/cryst12081176

Academic Editor: Jolanta Prywer

Received: 28 July 2022 Accepted: 18 August 2022 Published: 21 August 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Florfenicol (C12H14Cl2FNO4S, Figure 1) is broad-spectrum chloramphenicol antibiotic for bacterial diseases in animals [1]. Florfenicol has the advantages of good antibacterial effect, high safety, low toxicity and side effects, and low possibility for the development of drug resistance [2]. However, the solubility of florfenicol in water is only 0.9 mg/mL at 25 ◦C under atmospheric pressure. Its poor water solubility leads to problems such as poor absorption in animals and poor drug bioavailability [3], which limit the clinical application of florfenicol and the diversity of pharmaceutical preparations to a certain extent [4]. Therefore, it is of great importance to improve its bioavailability by solubilization.

**Figure 1.** Chemical structure of florfenicol.

Many studies have focused on the solubilization of drugs, and various solubilization methods have been developed such as chemical modification [5], cyclodextrin inclusion [6], and application of nanocrystals [7]. Among these methods, the development of nanocrystals is preferable for the solubilization of florfenicol due to the advantages of avoiding the involvement of unexpected chemicals or impurities, which can produce florfenicol products with higher drug purity, and less toxicity and side effects [8]. Antisolvent crystallization is an effective method to prepare nanocrystals. Meanwhile, florfenicol exhibited good solubility in alcohol solvents such as methanol, ethanol, 1-propanol, and isopropanol, which makes them potential solvents for the antisolvent crystallization of florfenicol. The determination of the solubility of florfenicol in the binary solvent mixtures is essential for the design of the antisolvent crystallization process and the production of nanocrystals. However, the fundamental data in these mixed solvents are rarely reported in the literature [9–13].

Many thermodynamic models have been commonly used to correlate solubility data and check the accuracy of the determined data. These models can describe the solid–liquid phase equilibrium relationship in the solution such as the dependence of solubility data on temperature and cosolvent composition, which allow the models to have practical application value in the field of engineering calculation and engineering design. In this work, the solubility of florfenicol in methanol + water, ethanol + water, 1-propanol + water, and isopropanol + water binary solvents was determined using the gravimetric method at temperatures ranging from 278.15 to 318.15 K under atmospheric pressure. To extend the applicability of the experimental solubility, the solubility data were then correlated by the modified Apelblat model, the CNIBS/R-K model, the Jouyban–Acree model, and the NRTL model, respectively.
