# Cocrystallization of Febuxostat with Pyridine Coformers: Crystal Structural and Physicochemical Properties Analysis

Authors: Lei Gao; Xianrui Zhang
Journal: Journal of Chemistry
 (2021)

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## Abstract

Drug cocrystals and salts have promising applications for modulating the physicochemical properties and solubility of pharmaceuticals. In this study, a cocrystal and two salts of febuxostat (FEB) with pyridine nitrogen coformers, including 4, 4′-bipyridine (BIP), 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP), were designed to improve the solubility of FEB. The single-crystal structures were elucidated, and their physical and chemical properties were investigated by IR, PXRD, and DSC. In addition, drug-related properties, including the solubility and powder dissolution rate were assessed. The solubility and powder dissolution studies showed that the FEB-BIP cocrystal and FEB-3AP salt have superior dissolution compared to FEB.


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## Body

## 1. Introduction

Over the past decades, drug cocrystals and salts screening has been an important tool for optimizing the drug-forming properties [1–8]. Due to the diversity of cocrystal formers (CCFs), researchers can design drug cocrystal and salt forms in a targeted manner to optimize their solubility, mechanical properties, hygroscopicity, stability, and bioavailability [9–14]. However, due to the low success rate of the screening process, it remains a challenge to rationally assemble the structure of API molecules through hydrogen bonding to obtain the desired properties in drug crystal engineering. Thus, cocrystal and salt screening has become an essential part of the preliminary drug development process [15].Febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, FEB) is a famous nonpurine selective inhibitor of xanthine oxidase for the treatment of gout [16–18]. FEB is classified as a biopharmaceutical classification system (BCS) II compound with a low water solubility and high penetrability. Its poor aqueous solubility affects its absorption in the body and limits its bioavailability. Many previous reports have shown that cocrystals and salts can improve the solubility of febuxostat [12, 19–24]. Herein, we designed new cocrystal or salt forms of febuxostat to modulate its solubility and dissolution rate. Based on the structural analysis of previous-reported cocrystals and salts of febuxostat, we identified those cocrystal coformers containing pyridine nitrogen with the potential to form hydrogen bonds with FEB. Thus, a series of cocrystal coformers containing pyridine nitrogen was employed to screen the cocrystals and salts of FEB (Supplementary Materials, Figure S1). The ΔpKa values between FEB and coformers are given in Table S1. For acid-base complex whose ΔpKa >3, the probability of salt formation will be high, and when 0 <ΔpKa <3, it is difficult to predict whether proton transfer will occur [14, 25, 26]. Whether the final product is a cocrystal or a salt will be disclosed by crystallographic data. The main research is focused on the crystallographic investigations of these novel crystalline samples. Finally, a novel cocrystal of FEB and 4, 4′-bipyridine (BIP) and two salts of 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP) were successfully designed, synthesized, and characterized (Figure 1).Figure 1
Chemical structures of FEB and coformers.


## 2. Materials and Methods

### 2.1. Materials and Equipment

All chemicals were obtained from commercial sources and were used as received. Fourier infrared (IR) spectra were performed on a Nicolet iS5 FTIR spectrometer in the scan range of 4000–400 cm−1 range. The thermal properties were measured on a Mettler-Toledo differential scanning calorimeter (DSC) equipped with a heating rate of 10°C/min using N2 as the dry air. Powder X-ray diffraction (PXRD) measurements were collected using a German Bruker corporation D8 ADVANCE X-ray diffractometer. All single-crystal X-ray diffraction data were recorded on a Bruker Apex-II CCD diffractometer with enhanced Mo-Kα radiation (λ = 0.71073 Å). All crystal structures were determined by direct methods using the SHELXS program and refined by the SHELXL program package [27]. Crystallographic data of the FEB cocrystal and salts are given in Table 1, and the hydrogen bond parameters are given in Table 2.Table 1
Crystallographic parameters of FEB cocrystal and salts.
CompoundsFEB-BIP (2 : 1)FEB-3AP (2 : 1)FEB-4HP-H2O (1 : 1 : 1)Empirical formulaC21H20N3O3SC37H38N6O6S2C21H23N3O5SFormula weight394.46726.85429.48Wavelength(A)0.710730.710730.71073Crystal systemTriclinicTriclinicTriclinicSpace groupP−1P−1P−1a (Å)9.1689 (5)10.6113 (6)8.9314 (7)b (Å)10.9904 (10)12.1040(6)8.9382 (8)c (Å)11.8036 (10)15.3760 (7)14.0069 (11)α (°)63.220 (9)76.703 (4)103.517 (7)β (°)79.983 (6)81.454 (4)98.686 (6)γ (°)89.499 (6)70.809 (5)99.661 (7)V (Å3)1042.40 (14)1809.40 (16)1050.46 (16)Z222T/K293 (2)293 (2)293 (2)Density (calculated) (g/cm3)1.2571.3341.358Absorption coefficient (mm−1)0.1810.2020.192Parameters260482278F(000)414764452Goodness-of-fit onF21.0131.0211.014FinalR indices (I > 2σ(I))R1 = 0.0554R1 = 0.0467R1 = 0.0769ωR2 = 0.1289ωR2 = 0.1084ωR2 = 0.1333Δρmax/Δρmin (e Å−3)0.327/−0.2330.254/−0.2320.673/−0.578CCDC200250020994392099438Table 2
Hydrogen bond parameters of FEB cocrystal and salts.
CompoundD-H⋯Ad (D-H)d (H···A)d (D···A)<(DHA)Symmetry codeFEB-BIPO2–H1⋯N31.001.592.586 (3)168x −1, y +1, zFEB-3APN5–H5B⋯O50.902.303.130 (3)153−x +1, − y + 1, − zN6+-H6···O2−1.001.682.660 (3)164−x + 2, − y +1, − z +1O4–H1⋯O10.861.622.471 (3)175x, y, z −1FEB-4HP-H2ON3+-H3···O1−0.911.842.753 (4)176x +1, y +1, z +1O5–H5A···N10.852.212.983 (5)150x +1, y +1, zO5–H5B⋯O40.852.032.872 (5)169x,y, z


### 2.2. Preparation of Cocrystal and Salts of FEB

Preparation of FEB-BIP (2 : 1) cocrystal: febuxostat (20.00 mg, 0.0632 mmol) and 4, 4′-bipyridine (9.87 mg, 0.0632 mmol) were dissolved in methanol (4 mL) or acetone (4 mL) at room temperature. Then, the solutions were allowed to evaporate slowly at room temperature for 4–6 days to obtain block crystals of FEB-BIP. A large amount of FEB-BIP samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and BIP (49.35 mg) were placed into an agate mortar and the obtained was ground three times with methanol (1 mL) to produce FEB-BIP.Preparation of FEB-3AP (2 : 1) salt: febuxostat (20.00 mg, 0.0632 mmol) and 3AP (5.95 mg, 0.0632 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and then, the solutions were allowed to evaporate slowly at room temperature for 5–8 days to obtain block crystals of FEB-3AP. A large amount of FEB-3AP samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and 3AP (29.75 mg) were placed into an agate mortar and the obtained was ground three times with acetonitrile (1 mL) to produce FEB-3AP.Preparation of FEB-4HP-H2O (1 : 1 : 1) salt: febuxostat (20.00 mg, 0.0632 mmol) and 4HP (6.01 mg, 0.0632 mmol) were dissolved in 5 mL of acetonitrile, and then, 100 μL of water was added into this solution. The solutions were allowed to evaporate slowly at room temperature for 5–8 days to get block crystals of FEB-4HP-H2O. A large amount of FEB-4HP-H2O samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and 4HP (60.1 mg) were placed into an agate mortar and the obtained was ground three times with the acetonitrile-water solvent mixture (49 : 1 v/v, 1 mL) to produce FEB-4HP-H2O.


### 2.3. Solubility and Powder Dissolution Study

The equilibrium solubility tests were performed with a Shimadzu UV-2600 using the Beer–Lambert law at 315 nm. The concentrations of solubility and dissolution rate of the four samples (including FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O) were determined by a UV spectrophotometer, and the corresponding standard curve equations are given in Table S2. The solubility and powder dissolution were investigated by dissolving excess solid samples in water under a rotation speed of 500 rpm at 37°C. Approximately 100 mg FEB samples (or its cocrystal/salts) were deposited in a round-bottomed flask with a stopper containing 20 mL aqueous medium, followed by heating and stirring at a constant temperature of 37°C in a waterbath for 24 h. The solution was allowed to stand for 10 minutes, and then, the supernatant was removed and filtered through a 0.22 μm filter membrane. Then, the concentration was analyzed by UV after suitable dilution. The powder dissolution experiments were performed at 5, 10, 15, 20, 25, 30, 45, 60, 90, and 120 min and analyzed by UV.


## 2.1. Materials and Equipment

All chemicals were obtained from commercial sources and were used as received. Fourier infrared (IR) spectra were performed on a Nicolet iS5 FTIR spectrometer in the scan range of 4000–400 cm−1 range. The thermal properties were measured on a Mettler-Toledo differential scanning calorimeter (DSC) equipped with a heating rate of 10°C/min using N2 as the dry air. Powder X-ray diffraction (PXRD) measurements were collected using a German Bruker corporation D8 ADVANCE X-ray diffractometer. All single-crystal X-ray diffraction data were recorded on a Bruker Apex-II CCD diffractometer with enhanced Mo-Kα radiation (λ = 0.71073 Å). All crystal structures were determined by direct methods using the SHELXS program and refined by the SHELXL program package [27]. Crystallographic data of the FEB cocrystal and salts are given in Table 1, and the hydrogen bond parameters are given in Table 2.Table 1
Crystallographic parameters of FEB cocrystal and salts.
CompoundsFEB-BIP (2 : 1)FEB-3AP (2 : 1)FEB-4HP-H2O (1 : 1 : 1)Empirical formulaC21H20N3O3SC37H38N6O6S2C21H23N3O5SFormula weight394.46726.85429.48Wavelength(A)0.710730.710730.71073Crystal systemTriclinicTriclinicTriclinicSpace groupP−1P−1P−1a (Å)9.1689 (5)10.6113 (6)8.9314 (7)b (Å)10.9904 (10)12.1040(6)8.9382 (8)c (Å)11.8036 (10)15.3760 (7)14.0069 (11)α (°)63.220 (9)76.703 (4)103.517 (7)β (°)79.983 (6)81.454 (4)98.686 (6)γ (°)89.499 (6)70.809 (5)99.661 (7)V (Å3)1042.40 (14)1809.40 (16)1050.46 (16)Z222T/K293 (2)293 (2)293 (2)Density (calculated) (g/cm3)1.2571.3341.358Absorption coefficient (mm−1)0.1810.2020.192Parameters260482278F(000)414764452Goodness-of-fit onF21.0131.0211.014FinalR indices (I > 2σ(I))R1 = 0.0554R1 = 0.0467R1 = 0.0769ωR2 = 0.1289ωR2 = 0.1084ωR2 = 0.1333Δρmax/Δρmin (e Å−3)0.327/−0.2330.254/−0.2320.673/−0.578CCDC200250020994392099438Table 2
Hydrogen bond parameters of FEB cocrystal and salts.
CompoundD-H⋯Ad (D-H)d (H···A)d (D···A)<(DHA)Symmetry codeFEB-BIPO2–H1⋯N31.001.592.586 (3)168x −1, y +1, zFEB-3APN5–H5B⋯O50.902.303.130 (3)153−x +1, − y + 1, − zN6+-H6···O2−1.001.682.660 (3)164−x + 2, − y +1, − z +1O4–H1⋯O10.861.622.471 (3)175x, y, z −1FEB-4HP-H2ON3+-H3···O1−0.911.842.753 (4)176x +1, y +1, z +1O5–H5A···N10.852.212.983 (5)150x +1, y +1, zO5–H5B⋯O40.852.032.872 (5)169x,y, z


## 2.2. Preparation of Cocrystal and Salts of FEB

Preparation of FEB-BIP (2 : 1) cocrystal: febuxostat (20.00 mg, 0.0632 mmol) and 4, 4′-bipyridine (9.87 mg, 0.0632 mmol) were dissolved in methanol (4 mL) or acetone (4 mL) at room temperature. Then, the solutions were allowed to evaporate slowly at room temperature for 4–6 days to obtain block crystals of FEB-BIP. A large amount of FEB-BIP samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and BIP (49.35 mg) were placed into an agate mortar and the obtained was ground three times with methanol (1 mL) to produce FEB-BIP.Preparation of FEB-3AP (2 : 1) salt: febuxostat (20.00 mg, 0.0632 mmol) and 3AP (5.95 mg, 0.0632 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and then, the solutions were allowed to evaporate slowly at room temperature for 5–8 days to obtain block crystals of FEB-3AP. A large amount of FEB-3AP samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and 3AP (29.75 mg) were placed into an agate mortar and the obtained was ground three times with acetonitrile (1 mL) to produce FEB-3AP.Preparation of FEB-4HP-H2O (1 : 1 : 1) salt: febuxostat (20.00 mg, 0.0632 mmol) and 4HP (6.01 mg, 0.0632 mmol) were dissolved in 5 mL of acetonitrile, and then, 100 μL of water was added into this solution. The solutions were allowed to evaporate slowly at room temperature for 5–8 days to get block crystals of FEB-4HP-H2O. A large amount of FEB-4HP-H2O samples were prepared by the solvent-assisted grinding. In a typical experiment, FEB (200 mg) and 4HP (60.1 mg) were placed into an agate mortar and the obtained was ground three times with the acetonitrile-water solvent mixture (49 : 1 v/v, 1 mL) to produce FEB-4HP-H2O.


## 2.3. Solubility and Powder Dissolution Study

The equilibrium solubility tests were performed with a Shimadzu UV-2600 using the Beer–Lambert law at 315 nm. The concentrations of solubility and dissolution rate of the four samples (including FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O) were determined by a UV spectrophotometer, and the corresponding standard curve equations are given in Table S2. The solubility and powder dissolution were investigated by dissolving excess solid samples in water under a rotation speed of 500 rpm at 37°C. Approximately 100 mg FEB samples (or its cocrystal/salts) were deposited in a round-bottomed flask with a stopper containing 20 mL aqueous medium, followed by heating and stirring at a constant temperature of 37°C in a waterbath for 24 h. The solution was allowed to stand for 10 minutes, and then, the supernatant was removed and filtered through a 0.22 μm filter membrane. Then, the concentration was analyzed by UV after suitable dilution. The powder dissolution experiments were performed at 5, 10, 15, 20, 25, 30, 45, 60, 90, and 120 min and analyzed by UV.


## 3. Results and Discussion

### 3.1. Single-Crystal Structures

FEB-BIP cocrystal. The asymmetric unit of the FEB-BIP cocrystal contains one febuxostat molecule and one half of a 4, 4′-bipyridine molecule. In the cocrystal, two febuxostat molecules are connected by O2–H1⋯N3 (distance of 2.586 Å) hydrogen bonds to form a parallel chain (Figure2). The parallel chains are held together via C18–H18⋯N2 (distance of 3.515 Å) and C20–H20⋯N2 (distance of 3.633 Å) hydrogen bonds to produce a two-dimensional sheet framework (Figure 3).Figure 2
The parallel chain structures of FEB-BIP cocrystal.Figure 3
The two dimension sheet structures of FEB-BIP cocrystal.FEB-3AP salt: the asymmetric unit of the FEB-3AP salt contains one febuxostat molecule, one febuxostat anion, and one 3-aminopyridine cation caused by the proton transfer from the carboxylic acid of one febuxostat molecule to the pyridine ring of 3-aminopyridine. In the salt, one FEB anion and one 3AP cation are connected by N6+-H6···O2− (distance of 2.660 Å) hydrogen bonds, and the other FEB molecule through O4–H1⋯O1 (distance of 2.471 Å) form intramolecular hydrogen bonds with the FEB anion (Figure 4). The trimers interacted with each other through N5–H5B⋯O5 (distance of 3.130 Å) hydrogen bonds to form zigzag chain structures (Figure 5).Figure 4
The crystal structures of FEB-3AP salt.Figure 5
The zigzag chain structures of FEB-3AP salt.FEB-4HP-H2O salt: the crystal structure of FEB-4HP-H2O salt was determined to be the triclinic P-1 space group. The Fourier maps show that the proton transfer and the generation of symmetric hydrogen bonds led to the formation of two complex dimers, including the FEB dimer anion and 4HP dimer cation (Supplementary Materials, Figure S2). In the salt, one FEB dimer anion is connected to one 4HP dimer cation by N3+-H3···O1− (distance of 2.753 Å) hydrogen bonds to form a one-dimensional ribbon (Figure 6). The one-dimensional ribbons are extended by water molecules through O5–H5A···N1 and O5–H5B⋯O4 hydrogen bonding, forming a three-dimensional mesh structure. Moreover, the water molecules occupy the channels in the mesh structure (Figure 7).Figure 6
The crystal structures of FEB-4HP-H2O salt.Figure 7
The visualization of water molecules in the crystal structure channel of FEB-4HP-H2O salt.


### 3.2. PXRD Analysis

The experimental PXRD patterns of FEB-BIP, FEB-3AP, and FEB-4HP-H2O were compared to FEB (Figure 8). This result showed that FEB-BIP, FEB-3AP, and FEB-4HP-H2O exhibited significantly different characteristic peaks than that of FEB, which further confirms the formation of new crystalline forms. Moreover, the experimental PXRD patterns of FEB-BIP, FEB-3AP, and FEB-4HP-H2O were in agreement with the corresponding single-crystal simulated data (Supplementary Materials, Figures S3–S5).Figure 8
PXRD pattern of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue).


### 3.3. IR Analysis

A comparative analysis of FTIR spectra for FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O is shown in Figure 9. FEB exhibits a characteristic peak at 1701 cm−1, which is assigned to the C=O stretching vibration. FEB-BIP, FEB-3AP, and FEB-4HP-H2O show the C=O stretching absorption peak at 1690, 1680, and 1699 cm−1, respectively, which indicate the change of hydrogen bonding interactions on the asymmetric vCOO vibration.Figure 9
IR spectra of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue).


### 3.4. DSC Analysis

The thermodynamic stability of FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O was examined by DSC (Figure 10), and they all exhibited single melting endothermic peaks at 201°C, 219°C, 186°C, and 151°C, respectively. Thus, the sequence of the thermodynamic stability is FEB-BIP > FEB > FEB-3AP > FEB-4HP-H2O.Figure 10
DSC curves of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue) recorded at 10°C /min heating rate.


### 3.5. Solubility and Powder Dissolution Rate Analysis

Solubility is a thermodynamic property that directly affects the in vivo absorption of orally administered drugs. The solubility and powder dissolution of FEB, FEB-BIP cocrystal, FEB-3AP salt, and FEB-4HP-H2O salt were determined in water at 37°C. The residual samples analysis showed that FEB, FEB-BIP, and FEB-3AP were stable in water (Supplementary Materials, Figures S6–S8), while FEB-4HP-H2O was unstable and underwent a phase change (Supplementary Materials, Figure S9). Both FEB-BIP and FEB-3AP were more soluble than FEB. The solubility of FEB-BIP and FEB-3AP was 5.15 and 15.19 times higher than that of pure FEB (17.7 mg L−1). As expected, cocrystals and salts offered a remarkably increased release rate compared with pure FEB (Figure 11). The solubility and powder dissolution results indicated that cocrystallization significantly improved the solubility and release rate of FEB.Figure 11
Powder dissolution profiles of FEB, FEB-BIP, and FEB-3AP at different time points in pure water at 37°C.


## 3.1. Single-Crystal Structures

FEB-BIP cocrystal. The asymmetric unit of the FEB-BIP cocrystal contains one febuxostat molecule and one half of a 4, 4′-bipyridine molecule. In the cocrystal, two febuxostat molecules are connected by O2–H1⋯N3 (distance of 2.586 Å) hydrogen bonds to form a parallel chain (Figure2). The parallel chains are held together via C18–H18⋯N2 (distance of 3.515 Å) and C20–H20⋯N2 (distance of 3.633 Å) hydrogen bonds to produce a two-dimensional sheet framework (Figure 3).Figure 2
The parallel chain structures of FEB-BIP cocrystal.Figure 3
The two dimension sheet structures of FEB-BIP cocrystal.FEB-3AP salt: the asymmetric unit of the FEB-3AP salt contains one febuxostat molecule, one febuxostat anion, and one 3-aminopyridine cation caused by the proton transfer from the carboxylic acid of one febuxostat molecule to the pyridine ring of 3-aminopyridine. In the salt, one FEB anion and one 3AP cation are connected by N6+-H6···O2− (distance of 2.660 Å) hydrogen bonds, and the other FEB molecule through O4–H1⋯O1 (distance of 2.471 Å) form intramolecular hydrogen bonds with the FEB anion (Figure 4). The trimers interacted with each other through N5–H5B⋯O5 (distance of 3.130 Å) hydrogen bonds to form zigzag chain structures (Figure 5).Figure 4
The crystal structures of FEB-3AP salt.Figure 5
The zigzag chain structures of FEB-3AP salt.FEB-4HP-H2O salt: the crystal structure of FEB-4HP-H2O salt was determined to be the triclinic P-1 space group. The Fourier maps show that the proton transfer and the generation of symmetric hydrogen bonds led to the formation of two complex dimers, including the FEB dimer anion and 4HP dimer cation (Supplementary Materials, Figure S2). In the salt, one FEB dimer anion is connected to one 4HP dimer cation by N3+-H3···O1− (distance of 2.753 Å) hydrogen bonds to form a one-dimensional ribbon (Figure 6). The one-dimensional ribbons are extended by water molecules through O5–H5A···N1 and O5–H5B⋯O4 hydrogen bonding, forming a three-dimensional mesh structure. Moreover, the water molecules occupy the channels in the mesh structure (Figure 7).Figure 6
The crystal structures of FEB-4HP-H2O salt.Figure 7
The visualization of water molecules in the crystal structure channel of FEB-4HP-H2O salt.


## 3.2. PXRD Analysis

The experimental PXRD patterns of FEB-BIP, FEB-3AP, and FEB-4HP-H2O were compared to FEB (Figure 8). This result showed that FEB-BIP, FEB-3AP, and FEB-4HP-H2O exhibited significantly different characteristic peaks than that of FEB, which further confirms the formation of new crystalline forms. Moreover, the experimental PXRD patterns of FEB-BIP, FEB-3AP, and FEB-4HP-H2O were in agreement with the corresponding single-crystal simulated data (Supplementary Materials, Figures S3–S5).Figure 8
PXRD pattern of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue).


## 3.3. IR Analysis

A comparative analysis of FTIR spectra for FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O is shown in Figure 9. FEB exhibits a characteristic peak at 1701 cm−1, which is assigned to the C=O stretching vibration. FEB-BIP, FEB-3AP, and FEB-4HP-H2O show the C=O stretching absorption peak at 1690, 1680, and 1699 cm−1, respectively, which indicate the change of hydrogen bonding interactions on the asymmetric vCOO vibration.Figure 9
IR spectra of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue).


## 3.4. DSC Analysis

The thermodynamic stability of FEB, FEB-BIP, FEB-3AP, and FEB-4HP-H2O was examined by DSC (Figure 10), and they all exhibited single melting endothermic peaks at 201°C, 219°C, 186°C, and 151°C, respectively. Thus, the sequence of the thermodynamic stability is FEB-BIP > FEB > FEB-3AP > FEB-4HP-H2O.Figure 10
DSC curves of FEB (black), FEB-BIP cocrystal (red), FEB-3AP salt (green), and FEB-4HP-H2O salt (blue) recorded at 10°C /min heating rate.


## 3.5. Solubility and Powder Dissolution Rate Analysis

Solubility is a thermodynamic property that directly affects the in vivo absorption of orally administered drugs. The solubility and powder dissolution of FEB, FEB-BIP cocrystal, FEB-3AP salt, and FEB-4HP-H2O salt were determined in water at 37°C. The residual samples analysis showed that FEB, FEB-BIP, and FEB-3AP were stable in water (Supplementary Materials, Figures S6–S8), while FEB-4HP-H2O was unstable and underwent a phase change (Supplementary Materials, Figure S9). Both FEB-BIP and FEB-3AP were more soluble than FEB. The solubility of FEB-BIP and FEB-3AP was 5.15 and 15.19 times higher than that of pure FEB (17.7 mg L−1). As expected, cocrystals and salts offered a remarkably increased release rate compared with pure FEB (Figure 11). The solubility and powder dissolution results indicated that cocrystallization significantly improved the solubility and release rate of FEB.Figure 11
Powder dissolution profiles of FEB, FEB-BIP, and FEB-3AP at different time points in pure water at 37°C.


## 4. Conclusions

In this study, one new cocrystal and two salts of febuxostat, an antigout drug, with pyridine derivatives were synthesized using a solvent evaporation method. They were characterized by single-crystal X-ray diffraction, PXRD, and DSC techniques. The solubilities of FEB-BIP and FEB-3AP were 5.15 and 15.19 times higher than that of pure FEB. Compared with FEB, FEB-BIP cocrystal and FEB-3AP salt exhibited better dissolution and release rates. Such results suggested both BIP and 3AP were potential coformers in regulating the dissolution properties of febuxostat.



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*Source: 3834368-2021-12-16.xml*