Simultaneous Improvement of Epalrestat Photostability and Solubility

Dec 19, 2017 - In this study, we attempt to simultaneously improve the photostability and solubility of epalrestat (a drug used for neuropathy treatme...
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Simultaneous Improvement of Epalrestat Photostability and Solubility via Cocrystallization: A Case Study Published as part of a Crystal Growth and Design virtual special issue Honoring Prof. William Jones and His Contributions to Organic Solid-State Chemistry Okky Dwichandra Putra,†,‡,§ Daiki Umeda,† Yuda Prasetya Nugraha,‡ Kazuya Nango,‡ Etsuo Yonemochi,*,† and Hidehiro Uekusa*,‡ †

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8551, Japan § Pharmaceutical Development, AstraZeneca Gothenburg, Pepparedsleden 1, Mölndal S-431 83, Sweden ‡

S Supporting Information *

ABSTRACT: In this study, we attempt to simultaneously improve the photostability and solubility of epalrestat (a drug used for neuropathy treatment) by preparing epalrestat−betaine zwitterionic cocrystals and characterize the physicochemical property alterations accompanying their formation. Notably, we reveal that the strong hydrogen bonds between epalrestat and betaine molecules in the above cocrystals and the reduced size of the reaction cavity around epalrestat molecules prevent the E,Z to Z,Z photoisomerization of the latter, resulting in improved photostability. Furthermore, the prepared cocrystals exhibit a higher solubility and larger dissolution rate than pure epalrestat crystals due to featuring a layered structure with alternately arranged epalrestat and betaine coformer molecules.

1. INTRODUCTION The study of solid active pharmaceutical ingredients (APIs) not only encompasses numerous scientific disciplines but is also becoming an intriguing phenomenon due to the broadly variable physicochemical properties of these APIs, e.g., solubility, stability, tabletability, color, and hygroscopicity.1−9 Recently, the formation of solid cocrystals has attracted increased attention due to its numerous beneficial effects on the properties of constituent APIs. Cocrystals are crystalline single-phase materials comprising two or more different molecular entities, generally in a stoichiometric ratio, and are neither solvates nor simple salts.10,11 Specifically, pharmaceutical cocrystals have found diverse applications such as remedying the deficiencies of certain drugs, allowing the delivery of live-saving APIs to patients.12,13 In addition, cocrystallization also offers some advantages from the regulatory point of view, since it does not require the registration of a new active substance or chemical entity, which is needed in the case of pharmaceutical salts.14 A common strategy of producing pharmaceutical cocrystals utilizes the so-called pKa rule,15−18 which states that in order to produce neutral cocrystals instead of ionic salts, the difference between the pKa’s of the base and its conjugate should be negative or at least as low as possible. However, the occurrence of proton transfer is sometimes unavoidable even in systems with low ΔpKa ( 2σ(I)]

755.91 triclinic P1̅ 8.0392 (2) 8.1821 (2) 29.5097 (5) 88.743 (6) 85.164 (6) 64.052 (4) 1738.94 (9) 2, 1 93(2) 6210 5797 (Rint = 0.033) 462 1.07 R1 = 0.045

P1̅ space group. The asymmetric unit of these crystals contained two EPR molecules (EPR I and II) and one BET molecule, as shown in Figure 2. As expected, the utilization of a

Figure 2. Thermal ellipsoid structures of EPR and BET molecules drawn at a 50% probability level. The asymmetric unit contained two EPR molecules (I and II) and one BET molecule. C

DOI: 10.1021/acs.cgd.7b01371 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 3. (a) Hydrogen bond architectures and (b) packing view along the b-axis of a zwitterionic EPR−BET cocrystal, with blue and orange lines representing conventional and unconventional hydrogen bonds, respectively. In the packing view, the BET molecules are drawn in a space-fill setting, with hydrogen atoms omitted for clarity.

Table 2. Hydrogen Bond Geometries in Zwitterionic EPR− BET Cocrystals D−H···A

D−H (Å)

H···A (Å)

O3−H···O8a C5−H···O2a O6−H···O7b C35−H···O8b C32−H···O5c C34−H···O1d C1−H···O5e C2−H···O2f C16−H···O8g C6−H···O8

0.81 (3) 0.95 0.90 (3) 0.98 0.99 0.98 0.95 0.95 0.95 0.95

1.76 (3) 2.5 1.68 (3) 2.57 2.53 2.55 2.58 2.53 2.41 2.56

D···A (Å)

D−H···A (deg)

2.550 3.396 2.573 3.533 3.461 3.509 3.406 3.196 3.204 3.469

164 (3) 158 167 (3) 166 156 167 145 128 141 160

(2) (2) (2) (3) (3) (3) (2) (3) (2) (2)

a Symmetry codes: −x + 1, −y + 1, −z + 1. bx − 1, y, z. cx, y + 1, z. d− x + 1, − y, − z + 1. ex + 1, y, z. f−x + 2, − y, − z + 1. g−x + 1, − y + 1, − z.

as a coformer due to its inherent ability to form charge-assisted hydrogen bonds. The photostability of zwitterionic EPR cocrystals was qualitatively examined by 1H NMR measurements to detect the E,Z to Z,Z photoisomerization. In addition, to reduce the influence of experimental conditions, sample preparation was conducted within 5 min or less, with the NMR spectra recorded immediately afterward. As illustrated in Figure 4, solid-state EPR underwent E,Z to Z,Z isomerization after 24-h irradiation at 6000 lx, as indicated by the appearance of new peaks in the 1 H NMR spectra of irradiated samples (see the small black dots corresponding to the Z,Z isomer). This isomerization induced a

Figure 4. 1H NMR spectra of EPR and EPR−BET before and after irradiation, with black dots indicating peaks of the Z,Z EPR isomer.

color change from orange to pale yellow (Figure 5a), being in good agreement with previous reports.27,38 Interestingly, the EPR−BET cocrystal did not undergo isomerization under the same conditions, as indicated by the absence of the above color change (Figure 5b). The observed photostability alteration was explained by changes of intermolecular interactions and the reaction cavity D

DOI: 10.1021/acs.cgd.7b01371 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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structure47 indicating whether or not a given solid-state reaction will occur.48−50 Herein, the reaction cavity was characterized for both the whole EPR molecule and its olefin part, reflecting molecular mobility. It should be noted that intact crystals of EPR form I contained two different EPR molecules, namely, EPR A and B. The reaction cavity volumes of EPR A and B of intact-crystal EPR form I and EPR I and II of EPR−BET cocrystals were calculated as 103.4, 108.6, 84.1, and 85.5 Å3, respectively (Figure 6). Thus, the reaction cavities of EPR in the cocrystal were significantly smaller (by ∼ 30 Å3) than those of intactcrystal EPR. In addition, the reaction cavity volumes of the olefin parts of intact-crystal EPR A and B and EPR I and II of EPR−BET cocrystals equaled 26.6, 18.0, 15.0, and 17.3 Å3, respectively, with cocrystal values again being smaller than those of EPR form I crystals. The above-mentioned reaction cavity decrease was correlated with the ease of E,Z to Z,Z isomerization; i.e., smaller reaction cavities did not allow molecular motion and thus hindered isomerization. According to the BCS, EPR is a class II drug molecule exhibiting poor solubility and slow dissolution. 26 The equilibrium solubilities of EPR, BET, and EPR−BET were determined as 2.956, 1.346 × 103, and 5.561 mg mL−1, respectively, i.e., the equilibrium solubility of zwitterionic cocrystals was almost two times higher than that of EPR form I crystals. Intrinsic dissolution rate measurements were performed in such a way as to minimize the influence of experimental conditions such as particle orientation, size uniformity, and agglomeration. Figure 7 shows that zwitterionic cocrystals showed a dissolution rate almost 3.5 times higher than that of the parent drug. All solid forms remained unchanged at the end of solubility and intrinsic dissolution rate experiments, as confirmed by PXRD measurements. On the basis of the obtained results, we rationalized the observed solubility and intrinsic dissolution rate improvement

Figure 5. Visual appearance of (a) EPR and (b) EPR−BET before and after irradiation. (For interpretation of color in this figure, the reader is referred to the web version of this article.)

size. It is generally known that the number and strength of intermolecular interactions constrain EPR molecules in the lattice and prevent their E,Z to Z,Z isomerization. As described above, EPR and BET molecules in the cocrystal were connected by abundant hydrogen bonds including two O···O strong hydrogen bonds (DO···O = 2.550 (2) and 2.573 (2) Å) and other weak ones (EPR−EPR and EPR−BET), which were expected to restrain EPR molecules and therefore prevent their isomerization. The observed photostability improvement can also be rationalized using the concept of a “reaction cavity”, which is defined as the space around the reactive group in the crystal

Figure 6. Whole (a−d) and partial (e−h) reaction cavities (drawn as blue translucent spaces) of EPR molecules. EPR form I comprised EPR A (a and e) and B (b and f) molecules, and EPR−BET cocrystals contained EPR I (c and g) and II (d and f) molecules. E

DOI: 10.1021/acs.cgd.7b01371 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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DSC and TGA measurements and solid state UV-Vis spectra (PDF) Accession Codes

CCDC 1576381 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (E.Y.). *E-mail: [email protected] (H.U.). ORCID

Okky Dwichandra Putra: 0000-0002-6968-1858 Daiki Umeda: 0000-0001-5815-8220 Etsuo Yonemochi: 0000-0001-5255-5129

Figure 7. Intrinsic dissolution rate curves of EPR (yellow) and EPR− BET(green).

Notes

The authors declare no competing financial interest.

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by considering the molecular arrangement in the crystal structure. As mentioned above, the prepared cocrystals featured a layered structure comprising alternating EPR and BET molecules. In this case, when the soluble BET coformer came in contact with the solvent and dissolved, both strong and weak BET−EPR interactions and the lattice structure collapsed, exposing EPR molecules to the dissolution medium. This mechanism was greatly emphasized in the layered structure, since the continuous and rapidly propagating loss of BET coformer and BET−EPR intermolecular interactions subsequently resulted in EPR dissolution. It should be noted that the solubility and intrinsic dissolution rate of layered structures are known to exceed those of discretely arranged ones such as that found in EPR form I intact crystals, as reported in numerous investigations aimed at improving the solubility of insoluble APIs via layered structure formation.33,51,52

ACKNOWLEDGMENTS We wish to thank Nagano Science for lending their photostability testing instrument. Y.P.R. acknowledges a scholarship from MEXT.

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ABBREVIATIONS API, active pharmaceutical ingredient; BET, betaine; EPR, epalrestat; PXRD, powder X-ray diffraction (1) Du, Q.; Xiong, X.; Suo, Z.; Tang, P.; He, J.; Zeng, X.; Hou, Q.; Li, H. RSC Adv. 2017, 7, 43151−43160. (2) Deng, J.; Lu, T.; Sun, C. C.; Chen, J. Eur. J. Pharm. Sci. 2017, 104, 255−261. (3) Chen, S.; Guzei, I. A.; Yu, L. J. Am. Chem. Soc. 2005, 127, 9881− 9885. (4) Putra, O. D.; Yonemochi, E.; Uekusa, H. Cryst. Growth Des. 2016, 16, 6568−6573. (5) Duggirala, N. K.; Perry, M. L.; Almarsson, Ö .; Zaworotko, M. J. Chem. Commun. 2016, 52, 640−655. (6) Smith, A. J.; Kavuru, P.; Arora, K. K.; Kesani, S.; Tan, J.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2013, 10, 2948− 2961. (7) Delori, A.; Eddleston, M. D.; Jones, W. CrystEngComm 2013, 15, 73−77. (8) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Int. J. Pharm. 2013, 453, 101−125. (9) Frišcǐ ć, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 1547−1559. (10) Grothe, E.; Meekes, H.; Vlieg, E.; ter Horst, J. H.; de Gelder, R. Cryst. Growth Des. 2016, 16, 3237−3243. (11) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper, R. K.; Thomas, S. P.; Tothadi, S. T.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Cryst. Growth Des. 2012, 12, 2147−2152. (12) Tao, W.; Chen, J.; Lu, T.; Ma, L. Cryst. Growth Des. 2012, 12, 3144−3152.

4. CONCLUSION Herein, we described the synthesis and structure of novel EPR−BET zwitterionic cocrystals, revealing that they exhibit better photostability and solubility than the parent drug. The increased photostability of these cocrystals was explained by their resistance to E,Z to Z,Z isomerization, which, in turn, was ascribed to the presence of strong intermolecular interactions and the decreased reaction cavity of EPR molecules resulting in effectively restrained molecular motion. In addition, the prepared cocrystals featured improved solubility and dissolution rate, which was attributed to their layered structure comprising alternately arranged EPR and BET molecules. Thus, we succeeded in simultaneously solving photoinstability and solubility problems of EPR via the formation of zwitterionic cocrystals, demonstrating the utility of crystal engineering in solving real-world problems in the pharmaceutical field. The fact that EPR−BET zwitterionic cocrystals show better photostability and solubility than the parent drug should be considered as important for future application of this important drug.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b01371. F

DOI: 10.1021/acs.cgd.7b01371 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.cgd.7b01371 Cryst. Growth Des. XXXX, XXX, XXX−XXX