LenalidomideâGallic Acid Cocrystals with Constant High Solubility

Article pubs.acs.org/crystal

Lenalidomide−Gallic Acid Cocrystals with Constant High Solubility Jia-Xi Song,† Jia-Mei Chen,*,‡ and Tong-Bu Lu*,†,‡ †

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China ‡ School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

Downloaded by FLORIDA ATLANTIC UNIV on August 29, 2015 | http://pubs.acs.org Publication Date (Web): August 28, 2015 | doi: 10.1021/acs.cgd.5b00699

S Supporting Information *

ABSTRACT: Pharmaceutical cocrystals are an efficient approach to improve the solubility of insoluble active pharmaceutical ingredients (APIs), while the dissolution profiles of pharmaceutical cocrystals usually exhibit a type of “spring and rapid parachute” effect that influences stability and pharmacodynamic sustainability, in which the high apparent solubility induced by the formation of cocrystals can only be maintained for a short time (usually minutes) in the metastable zone and then decreases rapidly afterwords. Herein we reported the preparation and structures of two lenalidomide cocrystals with gallic acid (1, 2). After the formation of cocrystals, the intrinsic dissolution rate and apparent solubility of lenalidomide were found to be enhanced. The high solubility of cocrystals can keep for 48 h without dropping. The result of phase solubility study indicates gallic acid (GA) forms a 1:1 complex with lenalidomide (Rev) in aqueous solution, with a stability constant of 1713.2 L/mol. The multiple hydrogen bonding interactions between GA and Rev are attributed to the formation of GA-Rev complex in aqueous solution and subsequently the constant high solubility of cocrystals.

■

INTRODUCTION Pharmaceutical cocrystals have been defined as multiple component crystals composed of an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable neutral coformers (CCFs) with a well-defined stoichiometry through noncovalent interactions.1−3 Formation of cocrystals could modulate the physicochemical properties of APIs, such as solubility, dissolution rate, moisture sorption, and stability, without affecting their intrinsic bioactivity.4−7 Recently, pharmaceutical cocrystals have been proven to be an efficient approach to enhance the solubility of APIs with solubilitylimited bioavailability,8−11 and the concept of the “spring and parachute” effect is used to explain the solubility advantage of pharmaceutical cocrystals,12 in which the cocrystal dissolves quickly in aqueous solution at the early stage to achieve high apparent solubility for insoluble drugs (spring), and the high apparent solubility can be maintained for a long time (usually hours) in the metastable zone (parachute). However, the application of cocrystals is usually limited by the “rapid parachute” effect of the cocrystals, in which the high apparent solubility can only be maintained for a short time in the metastable zone, and then decreases rapidly afterwords.13−21 In © XXXX American Chemical Society

a cocrystal, API and CCF are usually connected by hydrogen bonds, which tend to be broken once dissolving in water if the hydrogen bonding interactions between API and CCF are weak; thus it rapidly dissolves and reaches supersaturation (“spring”), and API and CCF will be separated by water within a short time due to the weak hydrogen bonding interactions between API and CCF, leading to quickly precipitation of API in solution (“rapid parachute”), and the cocrystal will quickly decompose to API and CCF in solution before it is adsorbed into blood. It is important to overcome the “rapid parachute” dissolution behavior for the development of a cocrystal drug to increase its solubility-limited bioavailability. Lenalidomide, with a trade name Revlimid (Rev, see Scheme 1), is an immunomodulatory agent with antineoplastic properties, and it has been used for the treatment of transfusion-dependent anemia and multiple myeloma.22 Revlimid hemihydrate (Rev·0.5H2O) is the commercially available form and belongs to class II (high permeability and Received: May 21, 2015 Revised: August 21, 2015

A

DOI: 10.1021/acs.cgd.5b00699 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

needle-shaped crystals of 1. IR data (KBr, cm−1): 3571, 3362, 3227, 2986, 2661, 1714, 1672, 1605, 1541, 1200, 1031, 878, 756, 722, 607. Rev/GA Cocrystal (1:1), 2. This cocrystal was obtained by a similar procedure to that of 1, except using absolute ethanol instead of water. A mixture of 100 mg of the resulting solid and 2 mL of ethyl acetate was allowed to stir at room temperature for 30 min. The suspension was filtered and dried under a vacuum for 24 h, and the filtrate was evaporated slowly in a sealed glass desiccator containing P2O5 to get needle-shaped crystals of 2. IR data (KBr, cm−1): 3578, 3381, 3252, 3089, 1720, 1622, 1444, 1330, 1175, 1037, 882, 777, 746, 695, 609. Cocrystal 2 can be also obtained by heating 1 at 150 °C for 1 h to remove the crystalline water in 1. Single Crystal X-ray Diffraction. Single-crystal X-ray diffraction data for 1 and 2 were collected on an Agilent Technologies Gemini A Ultra system with graphite monochromated Cu Kα radiation (λ= 1.54178 Å). The structures were solved by the direct methods using the SHELX-97 program29 and refined by the full-matrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were placed in calculated positions with fixed isotropic thermal parameters and included in the structure factor calculations in the final stage of fullmatrix least-squares refinement. Crystallographic data and details of refinements of 1 and 2 are given in Table 1, and the hydrogen bonding distances and angles are listed in Table 2.


Scheme 1. Structures of Rev (left) and GA (right)

low solubility) of the biopharmaceutics classification system (BCS). Its oral bioavailability is very low (below 33%) due to its poor aqueous solubility, and we consider that its low bioavailability could be improved by the formation of cocrystals to increase its solubility. We have previously prepared two cocrystals of Rev with 3,5-dihydroxybenzoic acid,23 and their dissolution profiles exhibit “rapid parachute” effect within a few hours. We consider that the “rapid parachute” dissolution behavior may be improved by increasing the hydrogen bonding interactions between API and CCF. Gallic acid (GA, Scheme 1) is present in many plants and is known to induce apoptosis in the human myelongenous leukemic cell line.24,25 In addition, GA contains multiple hydrogen bonding donors and acceptors, and thus it can form multiple hydrogen bonds with APIs.26,27 Therefore, GA was chosen as a CCF to interact with Rev to get two new cocrystals; powder dissolution profiles show that the solubility of Rev·0.5H2O increased after the formation of two cocrystals with GA. Interestingly, the high solubility of cocrystals can be kept constantly within 48 h, and “rapid parachute” dissolution behavior was not observed; these results are important for the development of cocrystal drugs to increase its solubility-limited bioavailability.

■

Table 1. Crystallographic Data for 1 and 2 formula formula weight temperature/K crystal system space group a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Z Dc/g·cm−3 F(000) crystal size/mm range of indices Rint GOF R1 [I > 2σ(I)] wR2 [all data]

EXPERIMENTAL SECTION

Materials and General Methods. Rev·0.5H2O was obtained from Zhejiang Taizhou Chemical Co. Ltd. Anhydrous gallic acid (GA) was obtained from Aladdin reagent Inc. The other chemicals and solvents were commercially available and used without further purification. The infrared spectra were performed using a Bruker Equinox 55 spectrometer (KBr pellets). X-ray powder diffraction (XRPD) patterns were measured by a Bruker D2 Advance with Cu Kα radiation (30 kV, 10 mA). Variable temperature X-ray powder diffraction patterns (VT-XRPD) were measured by a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA). Thermogravimetric analyses (TGA) were performed using a Netzsch TG-209 instrument. Samples were loaded into aluminum oxide pans and heated in a nitrogen purge, with a heating rate of 10 °C/min. Scans were carried out within the temperature range of 30−300 °C. Differential scanning calorimetry (DSC) was recorded on a Netzsch DSC 200 F3 instrument. Samples were loaded into aluminum sample pans in nitrogen atmosphere, with a heating rate of 10 °C/min in the 30−200 °C temperature range. Electrospray ionization mass spectrometry (ESI-MS) measurement was performed using a Thermo Finnigan LCQ DECA XP ion trap mass spectrometer. UV−vis spectra were obtained on a Cary 50 UV−vis spectrophotometer. Grinding. The liquid-assisted grinding (LAG) method28 was used to prepare Rev/GA cocrystal at ambient temperature, in which the stoichiometric amount of Rev·0.5H2O and anhydrous GA with appropriate solvent was mixed in a 25 mL stainless steel grinding jar, and ground by a stainless steel grinding ball (15 mm in diameter) at a frequency of 20 Hz using a Retsch Mixer Mill model MM200. Rev/GA Cocrystal Monohydrate (1:1:1), 1. A mixture of Rev (259 mg, 1 mmol), anhydrous GA (170 mg, 1 mmol), and two drops of water was ground for 30 min. The resulting solid was suspended in 2 mL of mixed solution of water and ethyl acetate (v/v = 1/9) and allowed to stir for 20 min at room temperature. The suspension of 1 was filtered and dried under a vacuum for 24 h at room temperature. The filtrate was evaporated slowly at ambient temperature to get

1

2

C20H21N3O9 447.40 150.00(10) Triclinic P1̅ 10.2719(9) 10.3488(6) 10.8229(9) 107.583(6) 100.840(7) 109.819(7) 976.16(13) 2 1.522 468 0.10 × 0.08 × 0.04 −8.11; −12.11; −12,11 0.0312 1.034 0.0496 0.1365

C20H19N3O8 429.38 150.01(10) Triclinic P1̅ 7.4961(7) 8.3257(9) 16.3618(12) 92.217(7) 90.992(7) 115.549(10) 919.95(15) 2 1.550 448 0.10 × 0.06 × 0.02 −8.8; −9.9; −18.14 0.0471 1.015 0.0438 0.1093

a R1 = Σ∥ Fo| − | Fc∥/Σ| Fo|. wR2 = [Σ[w(Fo2 − Fc2)2]/Σw(Fo2)2]1/2, w = 1/[σ2 (Fo)2 + (aP)2 + bP ], where P = [(Fo2) + 2Fc2]/3.

Dynamic Vapor Sorption (DVS) Measurement. DVS was measured by a DVS Intrinsic instrument (Surface Measurement Systems, UK) at 25 ± 0.1 °C. The samples were dried under a stream of nitrogen to establish the equilibrium dry mass before measurements. The relative humidity (RH) was first increased from 10% RH to 95% RH and then decreased for the desorption phase. The sorption/ desorption isotherms were obtained from the equilibrium mass values. High Performance Liquid Chromatography (HPLC) Analysis. A Shimadzu LC-20A HPLC was used to analyze the contents of Rev, with a UV detection wavelength of 304 nm and a C18 column (Inertsil ODS-3, 5 μm × 4.6 mm × 150 mm column, GL Sciences Inc., Japan), using acetonitrile/0.1% phosphoric acid (90/10, v/v) as a mobile phase, with a flow rate of 1.0 mL/min, and peak area values were related to solution concentrations using a calibration curve. B



Article

where G is the intrinsic dissolution rate (mg/min/cm2); dw is the change in drug dissolved (mg); dt is the change in time (min); S is the surface area of the compact (cm2); D is diffusion coefficient (cm2/s); Cs is the solubility (mg/cm3) and h is the stagnant layer thickness (cm).32

Table 2. Hydrogen Bonding Distances and Angles for 1


D−H···A 1a N1−H1···O3#1 N1−H2···O6A#2 N3−H3···O5A#3 O5A−H5A···O1 O7A−H7A···O8A#4 O6A−H6A···O10#5 O4A−H4A···N1#6 O10−H10A···O1 2b O4−H4···O1#1 O5−H5···O8#2 O6−H6···O1 O7−H7···O3#3 N3−H3···O8#4 N1−H1···O6#5 N1−H1···O4#5

D···A (Å)

D−H···A (deg)

2.968(3) 3.041(3) 2.952(3) 2.688(3) 2.610(3) 2.722(3) 2.778(3) 2.838(3)

161(3) 147(4) 165(3) 130.0 172.2 157.1 165(4) 175(5)

2.670(2) 3.001(3) 2.724(2) 2.609(2) 3.279(3) 3.121(3) 3.264(3)

171.7 148.2 156.3 150.6 175.2 147.5 146.9

■

RESULTS AND DISCUSSION Crystal Structures. The asymmetric unit of 1 contains one Rev, one GA, and one water molecule, in which Rev molecules link each other through the N1−H1···O3#1 hydrogen bonds to form a one-dimensional chain (Figure 1a), and two adjacent chains are connected by GA molecules through O5A−H5A··· O1 and N1−H2···O6A#2 hydrogen bonds to generate a 2D sheet (Figure 1a,b). The 2D sheets are further held together through N3−H3···O5A#3, O7A−H7A···O8A#4, and O4A− H4A···N1#6 hydrogen bonds to form the 3D structure of 1

Symmetry code: #1 x − 1, y − 1, z; #2 x − 1, y − 1, z − 1; #3 −x + 1, −y + 1, −z + 2; #4 −x + 2, −y + 3, −z + 3; #5 −x + 1, −y + 1, −z + 3; #6 −x, −y + 1, −z + 2; #7 −x + 1, −y + 2, −z + 3. bSymmetry code: #1 x + 1, y, z; #2 −x + 1, −y, −z + 2; #3 −x + 2, −y + 1, −z + 2; #4 −x + 1, −y + 1, −z + 2; #5 −x + 1, −y + 1, −z + 1 (D and A are hydrogen bond donors and acceptors). a

Powder Dissolution Experiments. The powders of 1, 2, and Rev·0.5H2O were milled and sieved by standard mesh sieves to obtain samples with approximate particle size ranges of 75−150 μm. To a round-bottom flask containing 134 mg (or equivalent amounts) of Rev·0.5H2O, 50 mL of 0.2 M phosphate buffer of pH 6.8 was added, and the above mixture solution was stirred at 37 °C and 500 rpm. An aliquot of the slurry was withdrawn from the flask at each time interval, filtered through a 0.22 μm nylon filter, diluted to appropriate concentration, and analyzed by HPLC. The pH value of the solution after the dissolution experiment was measured, and the remaining solid was collected by filtration, dried, and analyzed by XRPD. Phase Solubility Experiments. Phase solubility studies were carried out at 37 °C in 0.2 M phosphate buffer (pH 6.8) according to the method reported by Higuchi and Connors.30 An excess amount of drug, 13.4 mg of Rev·0.5H2O, was added to a test tube containing 5 mL of different concentrations of GA solution (phosphate buffer, pH 6.8). The suspensions were stirred at 500 rpm. After 48 h for equilibrium, the solutions were analyzed by HPLC after filtration through 0.22 μm nylon filter and appropriate dilution. The corresponding stability constant Ks is calculated by

Ks =

slope D0(1 − slope)

(1)

D0, solubility of Rev without GA; slope, slope of phase solubility diagram.31 Intrinsic Dissolution Measurements. The intrinsic dissolution rate (IDR) determinations were performed on a ZQY-2 Dissolution Tester (Shanghai Huanghai Yaojian instrument distribution Co., Ltd.). In a die of 5 mm diameter disk, approximate 80 mg of solid was compressed with a press at 0.5 t for 2 s. The paraffin wax was used to cover the disk, with the flat surface under investigation for dissolution uncovered. The above disk was dipped into 0.02 M phosphate buffer of pH 6.8 (900 mL) at 37 °C, with the paddle rotating at 100 rpm. Two milliliters of the dissolution medium was withdrawn at each time interval and constant volume was maintained by replacing an equal volume of fresh medium. The solutions were analyzed by HPLC after filtered through 0.22 μm nylon filter. IDR was calculated by G = (dw/dt )(1/S) = DC s/h

Figure 1. (a) 1D chain, (b) front view (up) and side view (down) of a 2D sheet, and (c) the 3D structure of 1.

(2) C



Article


(Figure 1c). The H2O molecules locate in the crystal lattice of 1 and connect to Rev and GA molecules through O10−H10A··· O1 and O6A−H6A···O10#5 hydrogen bonds. The structure of 2 is different from that of 1, in which the GA molecules in 2 are alternately linked by the Rev molecules through O4−H4···O1#1 and O6−H6···O1 intermolecular hydrogen bonds, generating a chain along the a axis (Figure 2a). The adjacent chains are connected through multiple

Figure 3. Variable temperature XRPD patterns for 1.

Figure 4. TGA and DSC curves for 1. Figure 2. (a) 1D chain and (b) 3D structure of 2.

XRPD analysis was performed on the resulted solid (Figure S2), indicating that 1 has indeed transformed into 2. The influence of humidity on the stability of 1 and 2 was studied by the DVS measurement. 1 and 2 adsorbed 0.12% and 0.4% of water respectively at 95% RH (Figure 5), and the

interchain hydrogen bonds (O5−H5···O8#2, O7−H7···O3#3, N3−H3···O8#4, N1−H1···O6#5, and N1−H1···O4#5) to generate the 3D structure of 2 (Figure 2b). XRPD, TG, and DVS Analyses. The crystalline phase purity of 1 and 2 was checked by XRPD, in which the patterns of the products are different from either that of Rev or GA (Figure S1), demonstrating the formation of new crystalline phases. In addition, all the peaks displayed in the measured patterns for 1 and 2 closely match those in the simulated patterns generated from single crystal diffraction data (Figure S1), demonstrating the single phases of 1 and 2 were formed. The VT-XRPD patterns of 1 show that its crystallinity can be remained up to 105 °C and then begins to transform to 2 at 110 °C (Figure 3). After being cooled to 30 °C, 2 cannot convert back to 1 (Figure 3), indicating water molecules in 1 was removed during heating process, and 2 does not adsorb moisture from air to transform to 1. Figure 4 shows the TGA and DSC curves for 1. The TGA curve of 1 shows a weight loss of 3.9% from 118 to 153 °C, with the consistent loss of one H2O molecule (calcd 4.0%). An endothermic peak at 145 °C, followed an exothermic peak at 153 °C are shown in the DSC curve of 1, corresponding to the dehydration and phase transition from 1 to 2. The sample after DSC measurement was cooled to ambient temperature, and

Figure 5. Water sorption/desorption isotherms for 1 and 2 at 25 °C. D



Article


Scheme 2. Cocrystal Transformation Reaction

absorbed water was lost slowly along with the decrease of RH. The crystalline water in 1 did not lose even at 0% RH. The XRPD measurements for 1 and 2 after DVS experiment demonstrated that both 1 and 2 are stable (Figure S3), and their crystal forms remained after the DVS measurements. Transformation from 1 to 2. Cocrystal 2 can be obtained by heating 1 at 150 °C for 1 h. When the solids of 1 were stirred in anhydrous acetonitrile containing saturated GA for 30 min, 1 transforms to 2 as evidenced by the XRPD measurements (Figure S4a). Slowly evaporating the filtrate of the above acetonitrile solution in a sealed glass desiccator containing P2O5 generated the crystals of 2. However, when the solids of 2 was stirred in water containing saturated GA for 48 h, 2 cannot transform to 1 as evidenced by the XRPD measurements (Figure S4b). The feasible ways of the transformation from 1 to 2 are illustrated in Scheme 2. Powder Dissolution Studies, ESI-MS, and UV Spectra. Powder dissolution profiles for Rev·0.5H2O, 1 and 2 are shown in Figure 6. The dissolution profile of Rev·0.5H2O display a “spring and parachute” effect, which can be attributed to the slow transformation from Rev·0.5H2O to less soluble Rev· 2H2O, as evidenced by the XRPD measurement (Figure S5). It can be found that maximum solubility (Smax) values of both cocrystals are increased approximately 40% than Rev·0.5H2O. It is interesting to note that the higher concentration of Rev in 1 and 2 can remain constant for 48 h, and no “rapid parachute” effect was observed in the powder dissolution profiles of 1 and 2 (Figure 6). The results of XRPD analyses for 1 and 2 indicate that all the undissolved solids have transformed to Rev·2H2O34 after the dissolution experiments (Figures S5 and S6). The pH values of the resulting solutions for 1 and 2 were 6.67 after the powder dissolution experiments. Such profiles are different from those of previously reported cocrystals of Rev with 3,5-dihydroxybenzoic acid,23 in which a “rapid parachute” effect was observed in Rev/3,5-dihydroxybenzoic acid cocrystals. The measured solubility of Rev· 0.5H2O in 0.2 M phosphate buffer of pH 6.67 is 0.471 ± 0.005 mg/mL; this value is lower than those of 1 and 2 (Figure 6), indicating the increased solubility of 1 and 2 is not caused by the decrease of pH value (from initial 6.8 to final 6.67). To understand the above dissolution behavior of 1 and 2, the powder dissolution profile of a 1:1 (mol ratio) physical mixture of Rev·0.5H2O (134 mg) and GA (85 mg) was measured (Figure 6), and it was found that the apparent solubility of Rev in the physical mixture slowly increased from 0.26 to 0.69 mg/ mL within 500 min, and the high solubility was maintained within 48 h. The result of XRPD analysis of the undissolved solids indicates that the physical mixture transformed to Rev· 2H2O (Figure S7). Indeed, 1 was formed when the physical mixture of Rev and GA (1:1) was slurried in 0.2 M phosphate

Figure 6. Powder dissolution profiles for Rev·0.5H2O, 1, 2 and the mixture of Rev·0.5H2O and GA in 0.2 M phosphate buffer of pH 6.8 at 37 °C after (a) 240 min and (b) 48 h.

buffer (pH 6.8) containing saturated GA for 4 h (Figure S8). The above results indicate the interactions between Rev and GA are relatively strong so they can form the cocrystal of 1 even in phosphate buffer (pH 6.8); in other words, the hydrogen bonding linked Rev and GA in 1 and 2 is not separated by water in aqueous solution due to the relatively strong hydrogen bonding interactions between Rev and GA. From the structure of 1 it can be found that there are a large number of hydrogen bonds formed between Rev and GA, in which each Rev molecule forms six hydrogen bonds, and each GA molecule forms seven hydrogen bonds (Figure 7). The E



Article


Figure 7. Hydrogen bonding motifs for each Rev (a) and GA (b) molecules in the structure of 1.

GA concentration with a slope of 0.74988 (R2 = 0.99958), indicating the formation of 1:1 stoichiometric complex of Rev and GA in aqueous solution, with the calculated stability constant Ks of 1713.2 L/mol. The quantitative information on the dissolution rates of Rev· 0.5H2O, 1 and 2 were obtained by dissolution rate (IDR) experiments, and the intrinsic dissolution profiles within the first 20 min are shown in Figure 9. The calculated IDR values

multiple hydrogen bonding interactions between Rev and GA will generate the stable Rev-GA complex in aqueous solution, and thus the high solubility of Rev in 1 and 2 can remain constant without dropping. To get the evidence for the formation of the cocrystals in solution, ESI-MS for 1 and UV−vis spectra for 1, 2, Rev and GA were measured. The ESI-MS spectrum shows an m/z of 429.3 (Figure S9), corresponding to the formation of 1:1 adduct of Rev and GA, demonstrating the formation of cocrystal 1 in solution. In addition, the UV−vis spectra for 1 and 2 are similar in 0.2 M phosphate buffer of pH 6.8, which are different from those of Rev and GA (Figure S10a), also demonstrating the formation of cocrystals 1 and 2 in solution. When the solution of 1 was diluted from 0.02 to 0.004 mg/mL, 1 still survives in solution (Figure S10b), demonstrating the interactions between Rev and GA in aqueous solution are relatively strong, and the hydrogen bonding linked Rev and GA in 1 is not separated by water at such concentration. Phase Solubility and IDR Studies. To further understand the interactions between Rev and GA in aqueous solution, phase solubility, which is commonly used to explore the inclusion interactions between β-cyclodextrin and API,35−37 was measured in 0.2 M phosphate buffer of pH 6.8 at 37 °C. The phase solubility diagram for Rev and GA is presented in Figure 8. With the increase of concentration of GA in solution, the solubility of Rev increases from 1.75 to 2.67 mmol/L, indicating the presence of GA can indeed improve the solubility of Rev. There is a linear relationship between Rev solubility and

Figure 9. IDR profiles for Rev·0.5H2O, 1 and 2 in 0.02 M phosphate buffer of pH 6.8 at 37 °C.

for Rev·0.5H2O, 1, and 2 are 0.151, 0.226, and 0.243 mg·min−1· cm2, respectively, with the calculated R2 of 0.9966, 0.9975, and 0.9952 for Rev·0.5H2O, 1 and 2, respectively, indicating the IDR is increased after the formation of cocrystals 1 and 2.

■

CONCLUSIONS Two cocrystals of Rev with gallic acid were synthesized successfully, and their structures were assembled via multiple intermolecular hydrogen bonds. 1 can be converted to 2 by slurrying 1 in acetonitrile containing saturated GA, or by heating 1 to remove the crystalline water. After the formation of cocrystals 1 and 2, their solubility values increase approximately 40% in comparison with that of Rev·0.5H2O, and the high solubility of cocrystals can remain constant within 48 h, and “rapid parachute” dissolution behavior was not observed. The result of the phase solubility study demonstrates Rev and GA forms a 1:1 complex in aqueous solution, with a stability constant of 1713.2 L/mol, and the multiple hydrogen bonds

Figure 8. Phase solubility diagram for Rev with GA. F



Article

(18) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Mol. Pharmaceutics 2013, 10, 4687−4697. (19) Yan, Y.; Chen, J. M.; Lu, T. B. CrystEngComm 2013, 15, 6457− 6460. (20) Chadha, R.; Saini, A.; Jain, D. S.; Venugopalan, P. Cryst. Growth Des. 2012, 12, 4211−4224. (21) Geng, N.; Chen, J. M.; Li, Z. J.; Lu, T. B.; Jiang, L. Cryst. Growth Des. 2013, 13, 3546−3553. (22) Gandhi, A.; Shi, T.; Li, M.; Jungnelius, U.; Romano, A.; Tabernero, J.; Siena, S.; Schafer, P.; Chopra, R. PLoS One 2013, 8, e80437. (23) Song, J. X.; Yan, Y.; Yao, J.; Chen, J. M.; Lu, T. B. Cryst. Growth Des. 2014, 14, 3069−3077. (24) Kaur, R.; Guru Row, T. N. Cryst. Growth Des. 2012, 12, 2744− 2747. (25) Thomas, S. P.; Kaur, R.; Kaur, J.; Sankolli, R.; Nayak, S. K.; Guru Row, T. N. J. Mol. Struct. 2013, 1032, 88−92. (26) Braun, D. E.; Bhardwaj, R. M.; Florence, A. J.; Tocher, D. A.; Price, S. L. Cryst. Growth Des. 2013, 13, 19−23. (27) Clarke, H. D.; Arora, K. K.; Wojtas, Ł.; Zaworotko, M. J. Cryst. Growth Des. 2011, 11, 964−966. (28) (a) Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 2372− 2373. (b) Friscic, T.; Childs, S. L.; Rizvi, S. A. A.; Jones, W. CrystEngComm 2009, 11, 418−426. (c) Delori, A.; Friscic, T.; Jones, W. CrystEngComm 2012, 14, 2350−2362. (29) Sheldrick, G. M. SHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997. (30) Higuchi, T.; Connors, K. A. Adv. Anal. Chem. 1965, 4, 117−212. (31) Kou, W.; Cai, C.; Xu, S.; Wang, H.; Liu, J.; Yang, D.; Zhang, T. Int. J. Pharm. 2011, 409, 75−80. (32) Zakeri-Milani, P.; Barzegar-Jalali, M.; Azimi, M.; Valizadeh, H. Eur. J. Pharm. Biopharm. 2009, 73, 102−106. (33) Chen, R. S.; Muller, G. W.; Jaworsky, M. S.; Saindane, M. T.; Cameron, L. M. U.S. Patent, 2005/023192, 2005. (34) Higuchi, T.; Connors, K. A. Wiley-Interscience 1965, 4, 117. (35) Chen, A.; Liu, M.; Dong, L.; Sun, D. Fluid Phase Equilib. 2013, 341, 42−47. (36) Filippa, M. A.; Sancho, M. I.; Gasull, E. I. J. Inclusion Phenom. Macrocyclic Chem. 2013, 77, 223−230. (37) Shi, J.; Zhou, Y. Spectrochim. Acta, Part A 2011, 83, 570−574.

formed between Rev and GA make the intermolecular interactions between Rev and GA become very strong; thus they can form a 1:1 complex in aqueous solution to increase the solubility of Rev. The above results open a new gate for overcoming the shortage of “rapid parachute” dissolution behavior of cocrystals and are important for the development of cocrystal drugs to increase the solubility-limited bioavailability.

■

ASSOCIATED CONTENT

S Supporting Information *


The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00699. XRPD patterns related to the preparation, DVS, powder and intrinsic dissolution experiments (PDF) Crystallographic information files (CIF1, CIF2)

■

AUTHOR INFORMATION

Corresponding Authors

*(J.-M.C.) Fax: +86-20-84112921. E-mail: chenjm37@mail. sysu.edu.cn. *(T.-B.L.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by NSFC (Grant No. 21331007), NSF of Guangdong Province (S2012030006240), and Guangzhou Pearl River New Star Fund Science and Technology Planning Project for J.M.C. (2013J2200054).

■

REFERENCES

(1) Desiraju, G. R. Crystal Engineering. The Design of Organic Solids; Elsevier: Amsterdam, 1989. (2) Childs, S. L.; Kandi, P.; Lingireddy, S. R. Mol. Pharmaceutics 2013, 10, 3112−3127. (3) Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952−9967. (4) Ma, W. J.; Chen, J. M.; Jiang, L.; Yao, J.; Lu, T. B. Mol. Pharmaceutics 2013, 10, 4698−4705. (5) Smith, A. J.; Kavuru, P.; Arora, K. K.; Kesani, S.; Tan, J.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2013, 10, 2948− 2961. (6) Yao, J.; Mo, Y. H.; Chen, J. M.; Lu, T. B. Cryst. Growth Des. 2014, 14, 2599−2604. (7) Tao, Q.; Chen, J. M.; Lu, T. B. CrystEngComm 2013, 15, 7852− 7855. (8) Shevchenko, A.; Bimbo, L. M.; Miroshnyk, I.; Haarala, J.; Jelínková, K. N.; Syrjänen, K.; van Veen, B.; Kiesvaara, J.; Santos, H. A.; Yliruusi, J. Int. J. Pharm. 2012, 436, 403−409. (9) Gao, Y.; Gao, J.; Liu, Z.; Kan, H.; Zu, H.; Sun, W.; Zhang, J.; Qian, S. Int. J. Pharm. 2012, 438, 327−335. (10) Alhalaweh, A.; Roy, L.; Rodriguez-Hornedo, N.; Velaga, S. P. Mol. Pharmaceutics 2012, 9, 2605−2612. (11) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311−335. (12) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662−2679. (13) Yan, Y.; Chen, J. M.; Geng, N.; Lu, T. B. Cryst. Growth Des. 2012, 12, 2226−2233. (14) Shan, N.; Perry, M. L.; Weyna, D. R.; Zaworotko, M. J. Expert Opin. Drug Metab. Toxicol. 2014, 10, 1255−1271. (15) Xu, L. L.; Chen, J. M.; Yan, Y.; Lu, T. B. Cryst. Growth Des. 2012, 12, 6004−6011. (16) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2011, 8, 1867−1876. (17) Chen, J. M.; Wang, Z. Z.; Wu, C. B.; Li, S.; Lu, T. B. CrystEngComm 2012, 14, 6221−6229. G


LenalidomideâGallic Acid Cocrystals with Constant High Solubility

Recommend Documents

LenalidomideâGallic Acid Cocrystals with Constant High Solubility