English

• 1. INTRODUCTION

  Drugs need to undergo absorption and distribution to achieve the goal of treating diseases. Nevertheless, most of the drugs produced in the pharmaceutical industry today, such as ibuprofen, belong to class II of the biopharmaceutical classification system (BCS) which show high permeability but low solubility^{[1, 2]}. Low solubility is the main limiting step affecting absorption and bioavailability^[3]. Up to now, there are many ways to improve solubility^{[4, 5]} and bioavailability^[6] of the oral drugs, such as amorphous form, polymorphs, salts, hydrates, solvates, etc^{[7, 8]}. However, if a molecule has no ionizable group, it cannot form salt^[8]. In addition, solvates increase the instability of drugs during production and transportation^{[9, 10]}. Recently, a relatively new solid modification method, as called pharmaceutical cocrystal, has attracted more and more attention in the pharmaceutical field^{[11, 12]}. Compared with other methods, it has more advantages^[13]. For instance, pharmaceutical cocrystal is an important means which can alter the physicochemical properties of non-ionizable drug without changing its structure and can also extend the patent protection.

  There has never been a standard definition of pharmaceutical cocrystals. By comparing various literatures, it is generally accepted that the cocrystal is a single-phase crystal material, which is composed of two or more molecular or ionic components^[14] and depends on non-covalent bonds (mainly through hydrogen bonds)^[15] to bind together in a certain molar ratio. Several types of hydrogen bonds such as carboxyl-carboxyl and carboxyl-amide groups have been reported in present papers^{[16, 17]}. In addition to improving the solubility and bioavailability, the melting points of drugs also change after cocrystallization^[18-20]. It has been reported that melting point is directly related to solubility and stability^[15]. The melting points of most cocrystals which have been successfully synthesized are between active pharmaceutical ingredients (APIs) and coformers.

  Ibuprofen (IBU), as a derivative of propionic acid (Fig. 1a), is a non-steroidal antipyretic, analgesic and anti-inflammatory drug, which is often used in the treatment of arthritis, fever and so on^[3]. Although ibuprofen is very stable at ambient temperature, it is almost insoluble in water, which makes people have been looking for several ways to alter its solubility^[21-23]. The main purpose of this paper is to manipulate the solubility and dissolution rate of ibuprofen by synthesizing cocrystals with appropriate coformers. Various coformers which have been approved by Food and Drug Administration (FDA) have been applied^[24] and the cocrystal with isonicotinamide (INA) (Fig. 1b) was successfully obtained by solvent evaporation method combined with ultrasound technology.

  Figure 1

  

  Figure 1.  Molecular structures of (a) Ibuprofen and (b) Isonicotinamide

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  In this work, ibuprofen-isonicotinamide (IBU-INA) cocrystal was obtained, which meet the requirements of single crystal diffraction. The physical characteristics of ibuprofen cocrystal were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD)^[25] and Fourier transform infrared spectroscopy (FT-IR). Using the melting point and bond length theory, it was judged that IBU-INA was cocrystal rather than salt. In vitro dissolution experiments and simulated gastric fluid experiments showed that the formation of cocrystal increased the aqueous solubility of ibuprofen and had no effect on stability.

  2. EXPERIMENTAL

  2.1 Materials

  IBU was provided by Xinhua Pharmaceutical Co., Ltd. The ligands used in the experiments were purchased from J & K Scientific. Organic reagents such as methanol, ethanol and acetonitrile were all manufactured by Fisher Chemical (HPLC grade). The water used in the study was distilled water.

  2.2 Synthesis of IBU-INA cocrystal

  2.5 mmol API was added to acetonitrile (about 10 mL) in a colorimetric tube. After IBU was completely dissolved, ligands were added according to the molar ratio of 1:1. The mixture was sonicated for 1 h to dissolve and react adequately. After reaction, the solution was cooled to room temperature, filtered and placed under ambient conditions for slow solvent evaporation. IBU-INA was grown about two days later. The preparation of cocrystals was scaled up proportion^[25] for characterization and property experiments.

  2.3 PXRD

  PXRD was performed by Bruker D8 Focus with a target of CuKα at a wavelength of 1.54060 Å. The divergent and scattering slits were set to 1° and the receiving slit was set to 0.15 mm. Optical tube voltage and current were 40 kV and 40 mA, respectively. The scanning angle was in the range of 10°~40° at a scanning rate of 1° per minute.

  2.4 Single-crystal X-ray diffraction

  A suitable amount of IBU and INA was mixed in a molar ratio of 1:1. The reaction lasted for 1 h under heating and stirring conditions of 60 ℃ and 400 rpm. After reaction, the solution was filtered, and the filtrate was placed in a refrigerator at 4 ℃ for solvent evaporation. Four days later, transparent lamellar crystal of IBU-INA was selected. Then, it was scanned by Bruker D8 Quest X-ray single-crystal diffractometer with a target of MoKα at a wavelength of 0.71073 Å and 273 K.

  2.5 Thermal analysis

  DSC was completed by Perkin-Elmer DSC 6000. A suitable amount of samples was placed in non-hermetic aluminium crucible and the temperature rose from 30 to 200 ℃ at a rate of 10 ℃ per minute under a dry nitrogen atmosphere (flow rate 20 mL·min^-1).

  TGA was completed by Perkin-Elmer TGA 4000. A suitable amount of samples (about 7~8 mg) was placed in a container made of alumina which can withstand high temperature. The temperature rose from 30 to 400 ℃ at a rate of 30 ℃ per minute and the flow rate of nitrogen was 20 mL·min^-1.

  2.6 FT-IR

  IR spectra were measured by Perkin Elmer Spectrum 65 FT-IR Spectrometer in KBr diffuse reflectance mode. About 200 mg KBr (as the diluent) and 2 mg samples (1% of the diluent) were mixed and ground. The mixture was manually pressed and scanned from 4000 to 400 cm^-1.

  2.7 Aqueous solubility

  First, the samples were sifted (100 meshes) to avoid the influence of particle size on the test results. And then IBU and its cocrystals were dissolved on Agilent 708-DS dissolution device by propeller method. The dissolution medium was water. The temperature and rotation speed were 25 ℃ and 200 rpm, respectively. An appropriate amount of IBU and cocrystals (all samples were subjected to two parallel experiments) was added to the dissolution cup (100 mL). 1.5 mL solvent was automatically sampled at specific time (2, 4, 6, 8, 10, 12, 14, 16 and 18 h). After filtration, the sample solutions were detected by HPLC.

  2.8 Stability in simulated gastric fluid

  We also tested the stability in simulated gastric fluid. First, simulated gastric fluid needed to be prepared. Dilute hydrochloric acid was obtained by mixing 23.4 mL hydrochloric acid with 76.6 mL water. 1.64 mL dilute hydrochloric acid and 1 g pepsin were dissolved in 98.36 mL water. 20.6 mg (0.1 mol) IBU and 32.8 mg (equivalent to 0.1 mol IBU) cocrystals were severally added to the simulated gastric fluid and reacted in a water bath at 37 ℃ for 2 h. After reaction, the solutions were sampled at a specific time (0, 30, 60, 90, 120 min), filtered and detected by HPLC.

  3. RESULTS AND DISCUSSION

  3.1 PXRD

  The PXRD patterns for parent compounds and cocrystal are shown in Fig. 2. As can be seen, the pattern for IBU-INA showed new peaks at 2θ = 12.77° and 17.46°, which was different from both IBU and INA. The characteristic diffraction peaks of IBU or INA disappeared and new peaks occurred in cocrystal, which indicated that a new phase was formed.

  Figure 2

  

  Figure 2.  PXRD patterns of IBU, INA and IBU-INA

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  3.2 Single-crystal X-ray diffraction

  The structure of IBU-INA cocrystal was characterized by X-ray single-crystal diffraction. The results showed that the crystal belongs to the triclinic system with P$ \overline 1 $ space group. Selected bond lengths, bond angles and torsion angles for IBU-INA are listed in Table 1. The asymmetric unit of the IBU-INA cocrystal contains an IBU and an INA molecules (Fig. 3a). There are three intermolecular hydrogen bonds in the crystal structure, as listed in Table 2. A hydroxyl group of an IBU molecule and a pyridyl nitrogen atom of INA form a hydrogen bond O(3)–H(3A)···N(1) (1.821 Å, 162.8°), while the carbonyl group of this IBU molecule and the pyridine ring carbon atom and imino group of another INA form hydrogen bonds C(3)–H(3)···O(2) (2.495 Å, 163.4°) and N(2)– H(2B)···O(2) (2.287 Å, 160.5°), respectively. As can be clearly seen in Fig. 3b, the IBU and INA form IBU-INA cocrystal by hydrogen bonding. One IBU and one INA molecules are connected by hydrogen bonding to form a supramolecular assembly unit. IBU provides a hydrogen bond acceptor and donor, which are combined with the donor and acceptor in the INA molecule, respectively, to form an infinitely extended zigzag chain structure (Fig. 3c).

  Table 1

  

  Table 1.  Selected Bond Lengths (Å) and Bond Angles (°)

  DownLoad: CSV

  Bond	Dist.		Bond	Dist.		Bond	Dist.
  C(1)–O(1) C(1)–C(2) C(3)–C(4) C(7)–O(2) C(8)–C(12) C(9)–C(11) C(12)–C(15) C(16)–C(17)	1.234(5) 1.491(6) 1.376(6) 1.190(5) 1.326(8) 1.363(9) 1.358(10) 1.240(2)		C(1)–N(2) C(2)–C(3) C(5)–N(1) C(7)–O(3) C(8)–C(90 C(10)–C(14) C(13)–C(15) C(17)–(19)	1.327(5) 1.370(5) 1.300(6) 1.289(5) 1.383(8) 1.376(9) 1.387(12) 1.220(2)		C(2)–C(6) C(4)–N(1) C(5)–C(6) C(7)–C(10) C(8)–C(10) C(11)–C(13) C(13)–C(16) C(17)–C(18)	1.387(6) 1.317(6) 1.372(6) 1.522(7) 1.524(8) 1.354(10) 1.842(17) 1.495(17)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–C(1)–N(2) C(3)–C(2)–C(6) C(2)–C(3)–C(4) C(5)–C(6)–C(2) O(3)–C(7)–C(10) C(9)–C(8)–C(10) C(14)–C(10)–C(8) C(8)–C(12)–C(15) C(15)–C(13)–C(16) C(19)–C(17)–C(16) C(5)–N(1)–C(4)	121.6(4) 115.7(4) 119.4(4) 120.9(4) 111.6(5) 121.0(6) 119.1(6) 122.5(7) 119.0(9) 125.0(2) 117.7(4)		O(1)–C(1)–C(2) C(3)–C(2)–C(1) N(1)–C(4)–C(3) O(2)–C(7)–O(3) C(12)–C(8)–C(9) C(11)–C(9)–C(8) C(7)–C(10)–C(8) C(11)–C(13)–C(15) C(12)–C(15)–C(13) C(19)–C(17)–C(18)	120.6(4) 124.9(4) 123.8(4) 123.3(4) 117.2(6) 121.1(6) 108.9(5) 116.7(8) 120.9(7) 110.0(2)		N(2)–C(1)–C(2) C(6)–C(2)–C(1) N(1)–C(5)–C(6) O(2)–C(7)–C(10) C(12)–C(8)–C(10) C(14)–C(10)–C(7) C(13)–C(11)–C(9) C(11)–C(13)–C(16) C(17)–C(16)–C(13) C(16)–C(17)–C(18)	117.8(4) 119.3(4) 122.5(4) 125.1(5) 121.8(7) 117.9(6) 121.3(8) 121.4(10) 99.1(14) 119.7(19)

  Figure 3

  

  Figure 3.  (a) Molecular structure chart of IBU-INA, (b) The simplest hydrogen bond connection pattern and (c) The self-assembly expansion of hydrogen bond pattern generating one-dimensional zigzag chain structure. Hydrogen bonds are purple red

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  Table 2

  

  Table 2.  Selected Hydrogen Bond Lengths (Å) and Bond Angles (°) for IBU-INA

  DownLoad: CSV

  Hydrogen bonds	Distancea,	Distanceb,	Anglec,
  O(3)–H(3A)···N(1)#1 C(3)–H(3)···O(2)#2 N(2)–H(2B)···O(2)#2	1.821(4) 2.495(4) 2.287(3)	3.111(4) 3.397(6) 2.615(6)	160.5(2) 163.4(3) 162.8(2)
  a Distance between donor and acceptor. b Distance between hydrogen and acceptor. c Angle of acceptor-hydrogen-donor.

  It can be seen from the bond length table that the distance of C(7)–O(3) is 1.289(5) Å, while the length of C(7)–O(2) is 1.190(5) Å. The C=O is much shorter than C–O. According to the bond length theory^[26], it can be inferred that IBU-INA is a cocrystal rather than a salt.

  3.3 Thermal analysis

  The DSC curves are shown in Fig. 4. IBU-INA showed a single melting peak, which was between IBU and INA at about 122 ℃. Combining with the TGA curves in Fig. 5, it can be seen that the weight of cocrystal has not decreased before melting, indicating that there was no water or other solvents. And when a salt is formed, the intermolecular forces become stronger, which usually results in the melting points higher than that of the individual components. It can be inferred that the product were cocrystal rather than salt.

  Figure 4

  

  Figure 4.  DSC thermograms of IBU-INA, IBU and INA

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  Figure 5

  

  Figure 5.  DSC and TGA thermograms of IBU-INA

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  3.4 FT-IR

  Since the interaction between molecules can cause vibrational changes, FT-IR was used to analyze the formation of hydrogen bonds. -C=O of free IBU at 1722 cm^-1 shifts significantly to lower frequencies (1700 cm^-1) in the spectra of cocrystals. In the IR spectrum of INA, pyridine ring vibrations at 1595.26 and 1551.80 cm^-1 shift to 1562.27 and 1512.41 cm^-1. It can be inferred that there are some interactions between -N–H on the pyridine ring of INA and the -COOH group of IBU, which were consistent with the single-crystal diffraction results.

  3.5 Aqueous solubility

  The results of solubility study are shown in Fig. 7. The maximum dissolved concentration of IBU is about 0.052 mg·mL^-1. While the maximum dissolved concentration of IBU in IBU-INA was about 0.112 mg. Compared to parent IBU, cocrystal increased the solubility of IBU in water by approximately 2.2 times.

  Figure 6

  

  Figure 6.  IR spectra of IBU-INA, IBU and INA

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  Figure 7

  

  Figure 7.  Solubility curves of IBU and IBU-INA

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  3.6 Stability in simulated gastric fluid

  The stability of IBU and IBU-INA cocrystal in simulated gastric fluid is shown in Fig. 8. The columns 1 and 2 represent IBU and IBU-INA, respectively. The results showed that the formation of cocrystal did not affect the stability of IBU in simulated gastric fluid.

  Figure 8

  

  Figure 8.  Stability in simulated gastric fluid of IBU and IBU-INA

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  3.7 Discussion

  In this paper, aqueous solubility of ibuprofen has been improved by means of pharmaceutical cocrystals. Single-crystal diffraction data of IBU-INA were obtained and the results showed that the crystal belongs to the triclinic system with P$ \overline 1 $ space group. The asymmetric unit of IBU-INA cocrystal contains an IBU and an INA molecules. A hydroxyl group of an IBU molecule and a pyridyl nitrogen atom of INA form a hydrogen bond O(3)–H(3A)···N(1) (1.821 Å, 162.8°). Using the melting point and bond length theory, it was judged that IBU-INA was cocrystal rather than salt. Bioavailability can be verified by subsequent experiments and may reduce the dosage of IBU in clinical application in the near future.

  
  
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• 

  Figure 1  Molecular structures of (a) Ibuprofen and (b) Isonicotinamide

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  Figure 2  PXRD patterns of IBU, INA and IBU-INA

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  Figure 3  (a) Molecular structure chart of IBU-INA, (b) The simplest hydrogen bond connection pattern and (c) The self-assembly expansion of hydrogen bond pattern generating one-dimensional zigzag chain structure. Hydrogen bonds are purple red

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  Figure 4  DSC thermograms of IBU-INA, IBU and INA

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  Figure 5  DSC and TGA thermograms of IBU-INA

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  Figure 6  IR spectra of IBU-INA, IBU and INA

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  Figure 7  Solubility curves of IBU and IBU-INA

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  Figure 8  Stability in simulated gastric fluid of IBU and IBU-INA

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  Table 1.  Selected Bond Lengths (Å) and Bond Angles (°)

  Bond	Dist.		Bond	Dist.		Bond	Dist.
  C(1)–O(1) C(1)–C(2) C(3)–C(4) C(7)–O(2) C(8)–C(12) C(9)–C(11) C(12)–C(15) C(16)–C(17)	1.234(5) 1.491(6) 1.376(6) 1.190(5) 1.326(8) 1.363(9) 1.358(10) 1.240(2)		C(1)–N(2) C(2)–C(3) C(5)–N(1) C(7)–O(3) C(8)–C(90 C(10)–C(14) C(13)–C(15) C(17)–(19)	1.327(5) 1.370(5) 1.300(6) 1.289(5) 1.383(8) 1.376(9) 1.387(12) 1.220(2)		C(2)–C(6) C(4)–N(1) C(5)–C(6) C(7)–C(10) C(8)–C(10) C(11)–C(13) C(13)–C(16) C(17)–C(18)	1.387(6) 1.317(6) 1.372(6) 1.522(7) 1.524(8) 1.354(10) 1.842(17) 1.495(17)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–C(1)–N(2) C(3)–C(2)–C(6) C(2)–C(3)–C(4) C(5)–C(6)–C(2) O(3)–C(7)–C(10) C(9)–C(8)–C(10) C(14)–C(10)–C(8) C(8)–C(12)–C(15) C(15)–C(13)–C(16) C(19)–C(17)–C(16) C(5)–N(1)–C(4)	121.6(4) 115.7(4) 119.4(4) 120.9(4) 111.6(5) 121.0(6) 119.1(6) 122.5(7) 119.0(9) 125.0(2) 117.7(4)		O(1)–C(1)–C(2) C(3)–C(2)–C(1) N(1)–C(4)–C(3) O(2)–C(7)–O(3) C(12)–C(8)–C(9) C(11)–C(9)–C(8) C(7)–C(10)–C(8) C(11)–C(13)–C(15) C(12)–C(15)–C(13) C(19)–C(17)–C(18)	120.6(4) 124.9(4) 123.8(4) 123.3(4) 117.2(6) 121.1(6) 108.9(5) 116.7(8) 120.9(7) 110.0(2)		N(2)–C(1)–C(2) C(6)–C(2)–C(1) N(1)–C(5)–C(6) O(2)–C(7)–C(10) C(12)–C(8)–C(10) C(14)–C(10)–C(7) C(13)–C(11)–C(9) C(11)–C(13)–C(16) C(17)–C(16)–C(13) C(16)–C(17)–C(18)	117.8(4) 119.3(4) 122.5(4) 125.1(5) 121.8(7) 117.9(6) 121.3(8) 121.4(10) 99.1(14) 119.7(19)

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  Table 2.  Selected Hydrogen Bond Lengths (Å) and Bond Angles (°) for IBU-INA

  Hydrogen bonds	Distancea,	Distanceb,	Anglec,
  O(3)–H(3A)···N(1)#1 C(3)–H(3)···O(2)#2 N(2)–H(2B)···O(2)#2	1.821(4) 2.495(4) 2.287(3)	3.111(4) 3.397(6) 2.615(6)	160.5(2) 163.4(3) 162.8(2)
  a Distance between donor and acceptor. b Distance between hydrogen and acceptor. c Angle of acceptor-hydrogen-donor.

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•