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Mar 4, 2015 - Road, Nankai District, Tianjin, 300072, People's Republic of China. ‡. Collaborative Innovation Center of Chemical Science and Chemica...
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Solid−Liquid Phase Equilibrium and Ternary Phase Diagrams of Ibuprofen−Nicotinamide Cocrystals in Ethanol and Ethanol/Water Mixtures at (298.15 and 313.15) K Xiaowei Sun,† Qiuxiang Yin,†,‡ Suping Ding,† Zhiming Shen,† Ying Bao,† Junbo Gong,†,‡ Baohong Hou,†,‡ Hongxun Hao,†,‡ Yongli Wang,†,‡ Jingkang Wang,†,‡ and Chuang Xie*,†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin, 300072, People’s Republic of China ‡ Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin 300072, People’s Republic of China

ABSTRACT: The phase diagrams for ibuprofen (IBU) and nicotinamide (NCT) in both ethanol and ethanol/water mixtures were constructed at (298.15 and 313.15) K under atmospheric pressure using static method. It is revealed that employing solvent mixtures in cocrystallization could significantly affect the symmetry of phase diagrams. In pure ethanol, the two solutes dissolve incongruently and the diagrams are asymmetric, so excessive IBU is needed to isolate cocrystals. However, in ethanol/water mixtures (mass fraction of water was 0.30), the solubility difference between the two components can be leveled out, resulting in more symmetric phase diagrams which can enlarge the processing space for cocrystallization. The solubility of the 1:1 IBU−NCT cocrystal was evaluated as a function of NCT concentration based on the solubility product. These findings are of great importance to develop the cocrystallization process for manufacturing IBU−NCT cocrystal.

1. INTRODUCTION Pharmaceutical cocrystals are stoichiometric molecular complexes that contain an active pharmaceutical ingredient (API) and coformer in a crystal lattice via noncovalent interactions1,2 and can change the thermal behaviors, physical and chemical stabilities, solubility, dissolution rates, and bioavailabilities of APIs.3 Different techniques have already been developed to screen and prepare cocrystals, such as evaporation, grinding, sonication-combined spray drying, and slow cooling cocrystallization from solution, among which solution cocrystallization remains the most preferred process in industry but suffers from the risk of crystallizing the individual component solid in solvents where API and coformer present high asymmetry in molar solubilities.4 A complete solute−solute−solvent phase diagram is necessary to decide the starting point for cooling cocrystallization because it can identify the stability domains for different crystalline phases and indicate the crystallization outcomes.5 A typical ternary phase diagram for 1:1 cocrystal AB is shown in Figure 1. Points a and b are the solubilities of © XXXX American Chemical Society

component A and B in the solvent, respectively; c and d are invariant points where cocrystals and pure crystalline component coexist in equilibrium with the solution. The different equilibrium regions are: (L), unsaturated solution; (A + L), A + solution; (B + L), B + solution; (AB + L), cocrystal + solution; (A + AB + L), cocrystal + A + a solution of the same composition as point c; (B + AB + L), cocrystal + B + a solution of the same composition as point d. Ibuprofen (IBU, IUPAC name (RS)-2-(4-(2-methylpropyl)phenyl) propanoic acid) is a nonsteroidal anti-inflammatory drug widely used for their anti-inflammatory, antipyretic, and analgesic properties in the treatment of arthritis, fever, and analgesia.6 It presents high permeability but poor aqueous solubility and thus belongs to class II drugs under the Biopharmaceutical Classification System (BCS).7 IBU has been reported to be capable of forming 1:1 cocrystals with Received: December 18, 2014 Accepted: February 26, 2015

A

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Figure 1. Schematic ternary phase diagram for a system forming 1:1 cocrystal AB; the stability regions for different crystalline phases are illustrated.

Figure 2. Powder X-ray diffraction (PXRD) patterns for IBU, NCT, and IBU−NCT cocrystal.

nicotinamide (NCT, IUPAC name pyridine-3-carboxamide),8 and the solubility tests indicated that the aqueous solubility of IBU−NCT cocrystals is 7.5 times higher than that of pure IBU,9 but to our knowledge, there is a lack of publication on specific phase diagrams for the IBU−NCT cocrystal. In this work, phase diagrams of IBU−NCT cocrystals in ethanol and ethanol/water mixtures (mass fraction of water is 0.30) at (298.15 and 313.15) K were constructed considering that ethanol and water are two of the cheapest, safest, and most commonly used solvents and the IBU−NCT cocrystal can be produced in either of them.6,10 The effect of employing solvent mixtures on the symmetry of the phase diagrams was analyzed. Furthermore, the solubility behavior of IBU−NCT cocrystals was investigated based on the solubility product.

2. EXPERIMENTAL SECTION 2.1. Materials. IBU was purchased from Tianjin Chemical the Sixth Co. (Tianjin, China). NCT was purchased from Shanghai Chemical Co. (Shanghai, China). Ethanol was purchased from Kewei Chemical Co. Ltd. (Tianjin, China). Deionized water was prepared by Thermo Scientific Barnstead Pacific TII (Wuzhou Technology, Beijing) in our laboratory. All chemicals were used as received and are described in Table 1.

Figure 3. Differential thermal analysis (DSC) curves for IBU, NCT, and IBU−NCT cocrystal.

2.3. Determination of the Phase Diagrams. The phase diagrams were determined by suspension equilibration method.11−15 Excess IBU and NCT were added into the solvent, varying NCT/IBU ratio from 0 to 1. The suspensions were stirred magnetically in a water bath at constant temperature for at least 24 h to reach equilibrium. The temperature of water bath was controlled by a thermostat (model 501 A, Shanghai Laboratory Instrument Works Co., Ltd., China), and the system temperature variation for all the measurements was found to be less than ± 0.1 K. Then, aliquots were withdrawn using syringe with a 0.45 μm nylon filter. The concentrations of IBU and NCT in the solution were analyzed by HPLC, and the solid phase was examined by PXRD. 2.4. Analytical Methods. Powder X-ray diffraction (PXRD) patterns were recorded on a powder diffractometer (D/MAX 2500) with a Cu Kα radiation (1.54 Å), tube voltage of 40 kV, and current of 100 mA. Powder diffraction patterns were collected with 2θ increasing at a continuous scan rate of 8°/min. The patterns were recorded from 2° to 50° at 2θ values with steps of 0.05°. Differential scanning calorimetry (DSC) measurements were performed on a DSC 821 (1/500, Mettler Toledo, Switzerland) under protection of nitrogen atmosphere (flow rate 50 mL/ min). Prior to measurement, the DSC was calibrated using

Table 1. Description of Materials Used in This Paper chemical IBU NCT ethanol a

source Tianjin Chemistry the Sixth Co. (China) Shanghai Chemical Co. (China) Kewei Chemical Co. Ltd. (China)

mass fraction purity

purification method

analysis method

>0.990

none

GCa

>0.990

none

GCa

>0.995

none

GCa

Gas−liquid chromatography.

2.2. Preparation of the IBU−NCT Cocrystal. Stoichiometric amounts of IBU (1.0314g) and NCT (0.6107g) were mixed in a mortar. The mixture was ground by hand for 30 min with a pestle in the presence of two drops of ethanol. The powders obtained were characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The PXRD patterns and DSC curves are presented in Figures 2 and 3, suggesting IBU−NCT cocrystal formation.8 B

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Table 2. Experimental Solid−liquid Equilibrium Data (Mass Fraction) for IBU + NCT + Ethanol and IBU + NCT + Ethanol/ Water at (298.15 and 313.15) K and Pressure p = 101.3 kPaa IBU

a

NCT

ethanol

equilibrium solid

0.0000 0.0491 0.0818 0.1287 0.1801 0.2197 0.2142 0.2472 0.3082 0.4202 0.4545 0.5430 0.5294 0.5040

0.1075 0.1163 0.1129 0.1143 0.1155 0.1239 0.1170 0.0976 0.0783 0.0546 0.0483 0.0422 0.0348 0.0000

0.8925 0.8346 0.8053 0.7570 0.7044 0.6564 0.6688 0.6552 0.6135 0.5252 0.4972 0.4148 0.4358 0.4960

NCT NCT NCT NCT NCT NCT + cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal + IBU IBU IBU

0.0000 0.0314 0.0735 0.1260 0.1988 0.2511 0.3182 0.3401 0.3721 0.4417 0.5503 0.5982 0.6822 0.6430 0.6545

0.1720 0.1670 0.1742 0.1740 0.1766 0.1817 0.1887 0.1647 0.1469 0.1120 0.0815 0.0752 0.0696 0.0604 0.0000

0.8280 0.8016 0.7523 0.7000 0.6246 0.5672 0.4931 0.4952 0.4810 0.4463 0.3682 0.3266 0.2482 0.2966 0.3455

NCT NCT NCT NCT NCT NCT NCT + cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal + IBU IBU IBU

IBU 298.15 K 0.0000 0.0639 0.0870 0.1034 0.1387 0.1786 0.2625 0.2923 0.3273 0.3777 0.3528 0.3363 0.3199 0.3200 313.15 K 0.0000 0.0799 0.1525 0.1623 0.2230 0.2869 0.3192 0.3544 0.4366 0.5312 0.5982 0.6240 0.6035 0.5619 0.5450

NCT

ethanol/water

equilibrium solid

0.3300 0.3436 0.2917 0.2448 0.1916 0.1584 0.1234 0.1148 0.1043 0.0939 0.0696 0.0498 0.0210 0.0000

0.6700 0.5925 0.6213 0.6518 0.6697 0.6630 0.6141 0.5929 0.5684 0.5284 0.5776 0.6139 0.6591 0.6800

NCT NCT + cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal + IBU IBU IBU IBU IBU

0.4405 0.4255 0.4009 0.3842 0.3081 0.2546 0.2307 0.2098 0.1715 0.1347 0.1180 0.1078 0.0894 0.0369 0.0000

0.5595 0.4946 0.4466 0.4535 0.4689 0.4585 0.4501 0.4358 0.3919 0.3341 0.2838 0.2682 0.3071 0.4012 0.4550

NCT NCT NCT + cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal + IBU IBU IBU IBU

Standard uncertainty u is u(T) = 0.05 K, u(p) = 10 kPa; the relative standard uncertainty of mass fraction ur(x) = 0.05.

indium. Samples (5 mg to 10 mg) were crimped in aluminum DSC pans and scanned at a heating rate of 10 K/min over the range from 303.15 K to 473.15 K. The detecting temperature deviation of DSC is ± 0.3 K. The composition of the solution was analyzed by HPLC equipped with a UV−vis spectrophotometer detector. IBU and NCT were separated over a C18 column (4.6 mm × 250 mm, 5 μm, Extend, Agilent). The analysis was conducted at 299.15 K with a flow rate of 1.0 mL/min. The mobile phase consisted of methanol and buffer (0.04 mol/L NaH2PO4 brought to pH 3.00 with H3PO4), in proportions of 75:25. Absorbance of IBU and NCT was monitored at 220 nm. The injection sample volumes were 20 μL.

The position of the regions for solid state in a cocrystal system relies closely on the nature of solvent. Choosing solvents where the API and coformer manifest similar solubility is expected to yield a more symmetric phase diagram (e.g., to present in both the left and right sides of the diagram). In such a case, it is possible to produce single cocrystals from the solvent using a stoichiometric coformer/API ratio.16 Otherwise, the phase diagrams are highly asymmetric when the solubilities of the API and coformer are of different order of magnitude.11 The solubilities of IBU and NCT in ethanol, water, and ethanol/water mixtures17,18 are shown in Table 3. In ethanol and water, there is a significant solubility difference between the two components, while in ethanol/water mixtures, the difference becomes relatively smaller, so the phase diagrams become much more symmetric. To yield pure IBU−NCT cocrystals in solution, the composition for the starting point should be determined based on the ternary phase diagrams. Taking the end temperature of 298.15 K as an example, the initial NCT/IBU ratio should be confined in the range from 0.131 to 0.952 to remain in the safe operation region (region 4 in Figure 4a). It means that an excess of IBU is needed compared with the stoichiometric ratio, which is unfavorable because API is more expensive than coformer in most cases. By employing ethanol/ water mixtures, the range of the initial NCT/IBU ratio becomes much wider from 0.428 to 9.00 (region 4 in Figure 4c),

3. RESULTS AND DISCUSSION 3.1. Effects of Solvent Mixtures and Temperatures on Ternary Phase Diagrams. Experimental liquid−solid equilibrium data for IBU and NCT in ethanol or ethanol/water mixtures (mass fraction of water is 0.30) at (298.15 and 313.15) K at atmospheric pressure are given in Table 2. The ternary phase diagrams generated from these experimental data are given in Figure 4. It turned out that in pure ethanol, the phase diagrams are asymmetric, stretching toward more soluble IBU. On the contary, the diagrams become much more symmetric in ethanol/water mixtures. C

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Figure 4. Ternary phase diagrams for: IBU + NCT + ethanol at 298.15 K (a) and 313.15 K (b), and IBU + NCT + ethanol/water at 298.15 K (c) and 313.15 K (d). ▲, the experimental data; the numbered points refer to various regions: 1, unsaturated region; 2, IBU + solution; 3, NCT + solution; 4, IBU-NCT cocrystal + solution; 5, IBU−NCT cocrystal + IBU + solution (saturated with both cocrystal and IBU); 6, IBU−NCT cocrystal + NCT + solution (saturated with both cocrystal and NCT). The dashed line represents the 1:1 stoichiometric composition of NCT and IBU. Compositions are in mole fractions (/%) of the total mixture, and only the upper parts are shown for clarity.

indicating the solubilities of the corresponding solid phases increase and the unsaturated region becomes larger. It should be noticed that the symmetry of the phase diagrams does not change significantly with temperature in the investigated range. This is probably because the solubilities of the two components increase by a similar amount with increasing temperature. 3.2. Solubility Behavior of the IBU−NCT Cocrystal. Knowledge of cocrystal solubility behavior is important for cocrystal screening and preparation. In the region where the IBU−NCT cocrystal is the only stable solid phase (related to region 4 in Figure 4), the solubility of IBU−NCT cocrystals depended intimately on the coformer (NCT) concentration, as shown in Figures 5 and 6. In all cases, the solubility of the cocrystal decreased when the NCT concentration increased. There have already been models derived to interpret the solubility behavior of cocrystals in terms of the solubility product and solution complexation.5,14,20−24 Here the specific explanation of the solubility behavior of IBU−NCT cocrystals was given.

Table 3. Solubility of IBU and NCT in Ethanol, Water, and Ethanol/Water Mixtures (Mass Fraction of Water is 0.30) at 298.15 K at Atmospheric Pressure solubility/(mol/L) components IBU NCT

ethanol 2.56 0.80

water 7.54 × 10 4.06

ethanol/water −4

1.76 2.75

including the stoichiometric ratio, so an excess of IBU can be avoided. There are also disadvantages of using solvent mixtures. One of them is that evaporation cocrystallization is not applicable anymore because it is hard to control the composition of the solvents.19 Still, there is no reason why solvent mixtures could not be employed in cooling or suspension cocrystallization. Temperatures can also alter the position and size of the regions in the phase triangle. When the temperature rises from 298.15 K to 313.15 K, the wedges 2, 3, and 4 move downward, D

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[NCT] is a straight line across the origin of coordinates with a slope given by KSP. To explain the solubility behavior of the cocrystal, it is also necessary to assess the magnitude of solution complexation. If the 1:1 complexation is considered, written as eq 4: K11

IBUsolution + NCTsolution ↔ IBU − NCTsolution

(4)

where K11 is the complexation constant for the 1:1 complex. Then, the dependence of the IBU−NCT cocrystal solubility on NCT concentration can be expressed by eq 5: KSP [IBU] = + K11KSP [NCT] (5) According to eq 5, the plot of [IBU] versus 1/[NCT] yields a straight line with a slope given by KSP, as well as a y-intercept given by the product of K11 and KSP. The straight lines that best fitted eq 5 are given in Figure 7. In this case, the y-intercepts are

Figure 5. Dependence of solubility of IBU−NCT cocrystals on the concentration of NCT in ethanol. Symbols ■ and ▲ represent experimental values at (298.15 and 313.15) K, respectively. Solid lines are the best fit curves according to eq 3; the functions are y = 0.725/x, y = 1.66/x, respectively.

Figure 7. Plots of [IBU] versus 1/[NCT] based on eq 5. ■ and ▲ represent experimental values in ethanol at (298.15 and 313.15) K; ◆ and ▼ represent experimental values in ethanol/water at (298.15 and 313.15) K, respectively. Solid lines are the best fit according to eq 5. The dashed lines are the extension of the straight lines. R2 is the linear correlation coeffcient.

Figure 6. Dependence of solubility of IBU−NCT cocrystals on the concentration of NCT in ethanol/water. Symbols ◆ and ▼ represent experimental values at (298.15 and 313.15) K, respectively. Solid lines are the best fit curves according to eq 3; the functions are y = 1.12/x, y = 2.63/x, respectively.

not dramatically different from zero while one of them exceptionally has a negative y-intercept, which is physically meaningless. All these may suggest the solution complexation is negligible in the systems studied,25 probably because the solute−solvent interaction is preferred over the solute−solute interaction when the solubility of components is high. Regardless of the solution complexation, the plots of [IBU] versus 1/[NCT] based on eq 3 were shown as solid lines in Figure 8, showing good linearity. Linear analysis and the determined solubility product KSP are given in Table 4. The solubilities of IBU−NCT cocrystals as a function of NCT concentration in ethanol or ethanol/water mixtures were also given as the solid lines in Figures 5 and 6, which were in good agreement with the experimental data. It could be seen that the solubilities of cocrystals decrease with increasing coformer concentrations to maintain the solubility product constant, which is similar to the ion effect.26

The cocrystal is in equilibrium with a solution of IBU and NCT as the following reaction. KSP

IBU − NCT ←→ IBUsolution + NCTsolution

(1)

where KSP is the solubility product, defined as the product of the API and coformer activities. With the assumption that the activity for the solids in solution equals 1 or is constant, KSP could be simplified to eq 2: KSP = [IBU][NCT]

(2)

where [IBU] and [NCT] are the concentration of IBU and NCT, respectively. So the IBU solubility can be expressed as eq 3: KSP [IBU] = [NCT] (3)

4. CONCLUSIONS Phase diagrams for IBU−NCT cocrystals in ethanol or ethanol/water mixtures at (298.15 and 313.15) K were

Equation 3 explains the dependence of the IBU or cocrystal solubility on NCT concentration. The plot of [IBU] versus 1/ E

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Table 4. Linear Analysis and Solubility Product (KSP) Values at (298.15 and 313.15) K under Atmospheric Pressure (p = 101.3 kPaa) ethanol ethanol/water

T/K 298.15 313.15 298.15 313.15

equation of line y y y y

= = = =

0.725x 1.66x 1.12x 2.63x

R2 b

KSP/(mol/L)2

0.99 0.95 0.96 0.99

0.725 1.66 1.12 2.63

a

Standard uncertainty u is u(T) = 0.05 K, u(p) = 10 kPa. bR2 is the linear correlation coeffcient.

constructed by static method. In pure ethanol, the phase diagrams are asymmetric due to significant solubilty difference between the two components. Therefore, an excess of IBU is necessary, which is uneconomical. By employing ethanol/water mixtures, the diagrams became much more symmetrical, which is preferred in cooling or suspension cocrystallization. The solubility behavior of the IBU−NCT cocrystals was evaluated based on the solubility product. The correlation result indicates that the 1:1 solution complex was negligible in the systems. The solubility of IBU−NCT cocrystals as a function of coformer (NCT) concentration was also evaluated. These phase diagrams and solubility data are practical in cooling or suspension cocrystallization and essential to the IBU−NCT cocrystal manufacturing and scale-up process.

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Figure 8. Plots of [IBU] versus 1/[NCT] based on eq 3. ■ and ▲ represent experimental values in ethanol at (298.15 and 313.15) K; ◆ and ▼ represent experimental values in ethanol/water at (298.15 and 313.15) K, respectively. Solid lines are the best fit according to eq 3. R2 is the linear correlation coeffcient.

solvent

Article

AUTHOR INFORMATION

Corresponding Author

*Phone: 86-22-27405754. Fax: 86-22-27314971. E-mail: [email protected]. Funding

This research is financially supported by National Natural Science Foundation of China (nos. 21176173, 51202160), Tianjin Municipal Natural Science Foundation (no. 13JCZDJC28400), and Specialized Research Fund for the Doctoral Program of Higher Education (grant no. SRFDP20110032120016). Notes

The authors declare no competing financial interest. F

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