An Investigation of Indomethacin–Nicotinamide Cocrystal Formation Induced by Thermal Stress in the Solid or Liquid State

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

An Investigation of Indomethacin–Nicotinamide Cocrystal Formation Induced by Thermal Stress in the Solid or Liquid State HONG-LIANG LIN, GANG-CHUN ZHANG, YU-TING HUANG, SHAN-YANG LIN Department of Biotechnology and Pharmaceutical Technology, Yuanpei University, Hsin Chu 30015, Taiwan, Republic of China Received 4 April 2014; revised 19 May 2014; accepted 29 May 2014 Published online 17 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24056 ABSTRACT: The impact of thermal stress on indomethacin (IMC)–nicotinamide (NIC) cocrystal formation with or without neat cogrinding was investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) microspectroscopy, and simultaneous DSC– FTIR microspectroscopy in the solid or liquid state. Different evaporation methods for preparing IMC–NIC cocrystals were also compared. The results indicated that even after cogrinding for 40 min, the FTIR spectra for all IMC–NIC ground mixtures were superimposable on the FTIR spectra of IMC and NIC components, suggesting there was no cocrystal formation between IMC and NIC after cogrinding. However, these IMC–NIC ground mixtures appear to easily undergo cocrystal formation after the application of DSC determination. Under thermal stress induced by DSC, the amount of cocrystal formation increased with increasing cogrinding time. Moreover, simultaneous DSC–FTIR microspectroscopy was a useful one-step technique to induce and clarify the thermal-induced stepwise mechanism of IMC–NIC cocrystal formation from the ground mixture in real time. Different solvent evaporation rates induced by thermal stress significantly influenced IMC–NIC cocrystal formation in the liquid state. In particular, microwave heating may promote IMC–NIC cocrystal formation in a short C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2386–2395, 2014 time.  Keywords: indomethacin; nicotinamide; co-crystals; thermal stress; DSC; FTIR; DSC-FTIR; physicochemical properties; physical characterization

INTRODUCTION In the pharmaceutical industry, it is commonly recognized that approximately 40% of the available active pharmaceutical ingredients (APIs) in conventional oral products are classified as practically water insoluble, and more than 70% of newly discovered drug candidates prepared through combinatorial screening technique are poorly water soluble, which could result in insufficient absorption in the gastrointestinal tract.1–4 To improve the physicochemical and biopharmaceutical characteristics of drugs during pharmaceutical development without changing the chemical composition of their APIs, the use of cocrystal technology in API preparation is an attractive approach to bring improved pharmaceutical products into the market.5–8 Cocrystals have gained increasing attention and interest in the pharmaceutical and chemical industries in recent years. Pharmaceutical cocrystals are multicomponent systems composed of an API and a coformer in a crystal lattice with a defined stoichiometry. Cocrystals are also recognized as molecular complexes or solid-state complexes formed through a variety of different intermolecular interactions, such as hydrogen bonds, aromatic B-stacking, or van der Waals forces, in which hydrogen bonding is the most important interaction.5–8 Pharmaceutical cocrystals not only provide new opportunities to enhance the physicochemical properties, dissolution rate, and bioavailability of APIs but also allow pharmaceutical companies to strengthen their intellectual property rights and extend the life cycle of their products with new patents for APIs.8–11

Correspondence to: Hong-Liang Lin (Telephone: +886-3-5381183, x8152; Fax: +886-03-6102312; E-mail: [email protected]); Shan-Yang Lin (Telephone: +886-3-6102439; Fax: 886-03-6102328; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 2386–2395 (2014)  C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

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The US Food and Drug Administration (FDA) recently issued industry guidance for the use of pharmaceutical cocrystals named “Regulatory Classification of Pharmaceutical Co-Crystals.”12 FDA recommends that a cocrystal should be considered as a drug product intermediate and not a new API. This regulation may have a major impact on the application of cocrystals in the pharmaceutical industry, paving the way for the use of cocrystals of APIs for new chemical entities and generic products. This guidance requires applicants for new drug applications (NDAs) and abbreviated NDAs to submit data to support the appropriate classification of a cocrystal, as well as the regulatory implications of the classification. This strongly implies that pharmaceutical cocrystals may emerge as new drug substitutes.8–12 Currently, several methods are used to screen and prepare cocrystals from solution or a solid state.6–11,13,14 The solution-based methods involve slurry conversion, solvent evaporation, cooling crystallization, and antisolvent addition, whereas the solid-based methods primarily involve neat and solvent-assisted grinding processes. To quickly screen for potential cocrystal formation, many methodologies have been attempted.10,13–15 In our previous studies, the stepwise formation mechanism of indomethacin (IMC)–saccharin or theophylline–citric acid cocrystal was successfully investigated using a neat cogrinding process,16–18 whereas the cocrystal formation of metaxalone with succinic acid, fumaric acid, and maleic acid was explored through a solvent-assisted cogrinding process.19 Among these preparation methods, thermal screening methods have been used as alternatives to solution-based or solid-based methods, but investigations of these methods are limited.20–24 Indomethacin is a typical poorly water-soluble biopharmaceutical classification system class II drug.25 Several IMC cocrystals have been extensively investigated,26 in which

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nicotinamide (NIC) has been widely utilized as a coformer for IMC–NIC cocrystal formation because of its propensity to form intermolecular hydrogen bonds via its carboxamide and pyridine moieties.27–34 These IMC–NIC cocrystals have been prepared by several preparation methods, such as slurry crystallization, spray drying, solvent evaporation, and solventassisted cogrinding. In the present study, IMC and NIC were selected as a drug candidate and coformer, respectively. An investigation of the impact of thermal stress and different solvent evaporation methods on IMC–NIC cocrystal formation with or without neat cogrinding was conducted to evaluate the thermalinduced stepwise mechanism of IMC–NIC cocrystal formation in the solid or liquid state.

EXPERIMENTAL Materials Indomethacin ((-form) and NIC were purchased from Sigma– Aldrich Chemical Company (St. Louis, Missouri) and identified by infrared microspectroscopy. The chemical structures of IMC and NIC are shown in Figure 1. Both raw materials were used without further purification but were vacuum dried at 40◦ C for 24 h to remove water adsorbed before use. The KBr crystals were obtained from Jasco Company (Tokyo, Japan). Preparation of Pure IMC–NIC Cocrystals by a Solvent Evaporation Method Pure IMC–NIC cocrystals were prepared by evaporation of an ethyl acetate solution containing a 1:1 molar ratio of IMC and DOI 10.1002/jps.24056

NIC in a water bath at 50◦ C, as modified from the Alhalaweh and Velaga method.28 After complete evaporation of the solvent, the precipitates were vacuum dried for 24 h and stored at 25◦ C for further examination. Preparation of IMC–NIC Ground Mixture by Neat Cogrinding A physical mixture of IMC and NIC (molar ratio = 1:1) was ground in an oscillatory ball mill (Mixer Mill MM301; Retsch GmbH & Company, Haan, Germany) with an oscillation frequency of 20 Hz. First, equimolar physical mixtures of IMC with NIC were prepared by gentle mixing of the accurately weighed components in a mortar with a spatula. Then, approximately 0.2 gm of the mixture was transferred into 25-mL stainless steel grinding jars containing two 10-mm diameter stainless steel balls by neat cogrinding for 40 min at ambient temperature.16–18 In the cogrinding process, the ground sample was withdrawn at prescribed intervals and immediately vacuum dried at 25◦ C for further examination. The infrared spectrum of each ground powder was determined by Fourier transform infrared (FTIR) microspectroscopy (IRT-5000-16/FTIR6200; Jasco Company, Tokyo, Japan) with a mercury cadmium telluride detector using a transmission mode. All FTIR spectra were generated by the coaddition of 256 interferograms collected at 4 cm−1 resolution. Effect of Thermal Stress on IMC–NIC Mixtures Differential Scanning Calorimetry Investigations Approximately 8 mg of a physical or ground mixture of IMC and NIC were directly stressed via differential scanning calorimetry Lin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2386–2395, 2014

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(DSC, Q 20; TA Instruments, Inc., New Castle, Delaware) at a heating rate of 3◦ C/min with an open pan system in a stream of N2 gas over a temperature range of 30◦ C–200◦ C. The instrument was calibrated for temperature and heat flow using indium as the standard. Simultaneous DSC–FTIR Microspectroscopic Investigations Each IMC–NIC ground mixture was also sealed into two pieces of KBr pellets (without grinding with KBr powder) by direct compression with an IR spectrophotometric hydraulic press (Riken Seiki Company, Tokyo, Japan) under 400 kg/cm2 for 15 s to form a compressed KBr disc. The compressed KBr disc was directly placed onto a micro hot stage (DSC microscopy cell; FP 84; Mettler, Greifensee, Switzerland). This DSC microscopy cell was then set in an FTIR microspectroscope (IRT-5000-16/FTIR6200, Jasco Company). The temperature of the DSC microscopy cell was monitored with a central processor (FP 80HT, Mettler). The heating rate of the DSC assembly was maintained at 3◦ C/min under ambient conditions. The compressed KBr disc was previously equilibrated to the starting temperature (30◦ C) and then heated from 30◦ C to 200◦ C. At the same time, the thermal-responsive IR spectra were recorded when the sample disc was heated on the DSC microhot stage. The operation was performed in the transmission mode.19,21,35 Comparison of Different Thermal Evaporation Methods for Preparing IMC–NIC Cocrystals A comparison of different evaporation techniques for preparing IMC–NIC cocrystals was performed. The preparation method of IMC–NIC cocrystal was modified by slow or fast evaporation of an ethyl acetate solution containing the same molar ratio of IMC and NIC. Five different evaporation methods were applied, including slow evaporation with or without stirring at ambient temperature, fast evaporation at 50◦ C, solvent-assisted cogrinding for 20 min in a ceramic mortar after adding three drops of ethyl acetate, and microwave-assisted evaporation. The domestic microwave oven (TMO-202; Tatung Company, Taipei, Republic of China) used in this study had full power of 800 W to heat the sample to approximately 78◦ C after 3 min of irradiation. After the solvent had been completely evaporated, the different precipitates were vacuum dried for 24 h and stored at 25◦ C for further FTIR and DSC examinations.

RESULTS AND DISCUSSION Nicotinamide, a well-known potent hydrotropic agent, is used to increase the aqueous solubility of many hydrophobic drugs.36–38 The most commonly proposed and accepted mechanism of solubilization for NIC is complexation through a B-donor–Bacceptor mechanism.39 It has also been proposed that stacking of the pyridine ring, because of its planarity, may promote complexation.38 NIC molecules have three donor sites for easily enabling cocrystal formation through intermolecular hydrogen bonding with other drugs: (a) pyridine ring nitrogen, (b) carbonyl oxygen, and (c) amino nitrogen. Identification of IMC, NIC, a Physical Mixture, and a Solvent-Evaporated Sample of IMC–NIC The FTIR spectra and DSC curves of IMC (1), NIC (2), a physical mixture (3), and a solvent-evaporated sample of IMC–NIC (4) are displayed in Figure 1. The data clearly revealed several Lin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2386–2395, 2014

characteristic IR absorption bands and their assignments of IMC or NIC as follows (in cm−1 ): 1718 [<(C=O) of carboxylic acid dimer], 1691 [benzoyl <(C=O)], 1625–1575 and 1480 (C=C of aromatic rings), 1308 (C–O of acidic group), 1270–1200 (=C–O of ether group), 1068 (C–Cl) for IMC40–42 ; 1679 with a shoulder at 1698 [<(C=O)], 1618 *(NH2 ), 1592–1422 (pyridine ring stretching), 1395 [<(C–N)], 1201 [<(C–C)], and 1028 (ring deformation vibration) for NIC.43,44 In addition, the IR spectrum of a physical mixture of IMC–NIC contains the superimposed spectrum of each mixture component (c). However, the IR spectrum for the solvent-evaporated coprecipitate of IMC–NIC was markedly different from that of the physical mixture of IMC– NIC. Several new unique IR absorption peaks at 1706, 1663 with shoulder at 1680, 1621, 1466, 1440, 1362, 1325, 1288, 1231, 1177, 1147, 1071, 1035, 914, and 842 cm−1 were observed in the IR spectrum of the solvent-evaporated sample (d) of IMC– NIC. The appearance of these new IR peaks was because of cocrystal formation via the intermolecular interaction between IMC and NIC, which was almost consistent with that of the IR spectrum of IMC–NIC cocrystals.31 It is apparent that the physical mixture of IMC–NIC can easily form IMC–NIC cocrystals after solvent evaporation. Once the raw materials of IMC and NIC were determined by DSC analytical technique, one endothermic peak at 163◦ C for IMC (a) and one endothermic peak at 131◦ C for NIC (b) were observed in the DSC curves, which were attributed to the fusion of IMC and NIC. It has been reported that NIC possesses four polymorphic forms, and the melting points of forms I, II, III, and IV are 124◦ C–134◦ C, 112◦ C–117◦ C, 107◦ C–111◦ C, and 102◦ C, respectively.45 The appearance of endothermic peak at 131◦ C suggests that stable form I NIC was used in the present study. However, a broad endothermic peak at 110◦ C was also found in the DSC curve of the physical mixture of IMC–NIC (c). This peak may be because of the fusion of the eutectic mixture between IMC and NIC.20,46 The solvent-evaporated coprecipitate displayed a clear sharp endothermic peak at 126◦ C (d), which was near the melting point at 128◦ C of IMC–NIC cocrystals reported by Kojima et al.47 From the results of FTIR and DSC studies, the solvent-evaporated IMC–NIC sample may be confirmed as an IMC–NIC cocrystal. Thermal Stress via DSC Figure 2 shows the cogrinding effect on the FTIR spectra and DSC curves of IMC–NIC physical mixtures. It is evident that with an increased cogrinding time, the IMC–NIC ground mixture exhibited similar FTIR spectra. The FTIR spectra for all IMC–NIC ground mixtures were superimposed on the FTIR spectra of IMC and NIC, suggesting that there was no interaction between IMC and NIC even after mechanical grinding. On the contrary, the DSC curves of the ground mixtures displayed different thermal characteristics. After cogrinding the IMC–NIC physical mixture for 0.5 min, its DSC trace exhibited a single sharp endothermic peak near 101◦ C, shifted from the broad peak at 110◦ C observed for the IMC–NIC physical mixture without grinding. This may be because of the compactness of fine particles created by cogrinding, resulting in an early-onset temperature for this DSC endothermic peak near 110◦ C with a sharper pattern. Upon increasing the cogrinding time, the DSC traces exhibited an initial endothermic peak at 100◦ C, followed by a second smaller exothermic peak at 124◦ C and a third endothermic peak at 126◦ C. The appearance of DOI 10.1002/jps.24056

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Thermal Stress via DSC–FTIR Microspectroscopy A powerful DSC–FTIR combined system has been extensively applied to simultaneously and rapidly screen and identify the cocrystal formation of API coformer in real time.16,21,35 This unique simultaneous DSC–FTIR microspectroscopy had been considerably applied to rapidly examine the thermal-induced characterization of solid-state chemical stability, Maillard reaction, and polymorphic interconversion processes of drugs in the solid state.48–50 A three-dimensional plot of the FTIR spectrum of IMC as a function of temperature is shown in Figure 4. The thermalrelated changes in peak intensity for several specific bands are DOI 10.1002/jps.24056

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continuous exothermic and endothermic peaks was because of IMC–NIC cocrystal formation via thermal stress, which was also confirmed by FTIR spectral determination. The appearance of this exothermic peak was attributed to the molecular interaction of IMC and NIC.16,21 With a further increase in the cogrinding time, the initial endothermic peak near 100◦ C shrank and shifted to 96◦ C, but the second endothermic peak at 126◦ C was enlarged. In particular, an exothermic peak at 98◦ C–99◦ C shifted from 124◦ C was also observed, corresponding to the mechanical cogrinding effect. Moreover, the enthalpy of both endothermic peaks near 96◦ C–100◦ C and 126◦ C were changed with increased cogrinding time, implying grinding time-dependent IMC–NIC cocrystal formation under thermal stress (Fig. 3). This strongly suggests that thermal stress can easily promote solid-state cocrystal formation between IMC and NIC after cogrinding.

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also displayed. The image clearly indicates that the thermaldependent IR spectral contour and peak intensity of IMC were markedly changed near 154◦ C, which was near the onset temperature of the DSC endothermic peak at 163◦ C for IMC. Before 154◦ C, the three-dimensional FTIR spectral map maintained an almost constant contour. However, the wave number ranges of 2900–3400 (carboxylic O–H and C–H stretching) and 1500–1800 cm−1 (carboxylic and benzoyl groups C=O Lin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2386–2395, 2014

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

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Figure 5. Three-dimensional plot of FTIR spectra of NIC as a function of temperature and its changes in peak intensity of several specific peaks.

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Figure 6. Thermal-dependent three-dimensional FTIR plot of physical mixture of IMC–NIC (molar ratio = 1:1) after cogrinding for 3 min and its changes in peak intensity of several specific peaks.

Figure 7. Thermal-dependent three-dimensional FTIR plot of physical mixture of IMC–NIC (molar ratio = 1:1) after cogrinding for 40 min and its changes in peak intensity of several specific peaks. DOI 10.1002/jps.24056

Lin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2386–2395, 2014

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

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stretching) were significantly altered beyond 154◦ C.42,50 The peak position at 2927 cm−1 was shifted to 2933 cm−1 , but that at 1718 cm−1 , was shifted to 1741 cm−1 at temperatures of more than 154◦ C. The former peak at 1718 cm−1 corresponded to the hydrogen-bonded carboxylic cyclic dimers of IMC, but the latter peak near 1741 cm−1 corresponded to the nonhydrogen-bonded carboxylic acid.51 This may explain why the hydrogen-bonded dimers in the IMC structure dissociated into nonhydrogenbonded monomers under higher temperatures. The peak at 1308 cm−1 (C–O of acidic group) also exhibited the same thermal shifting behavior to 1317 cm−1 . Moreover, the peaks at 1360 and 1188 cm−1 were shifted to 1352 and 1176 cm−1 , respectively. It is evident that all of the peak intensities of IMC suddenly changed at temperatures exceeding 153◦ C, which was the melting point of IMC determined by DSC analysis. The thermal-dependent three-dimensional FTIR spectral plot and thermal-related changes in peak intensity for several specific spectra of NIC are displayed in Figure 5. Evidently, the thermal-dependent IR spectral contour and peak intensity of NIC were markedly changed near 123◦ C, but the three-dimensional FTIR spectral plot maintained a nearly constant contour at temperatures lower than 123◦ C. This temperature was prior lower than the onset temperature of fusion of 131◦ C. A possible explanation for this finding was that NIC after compression within KBr disc was more thermally sensitive than that of the DSC result of NIC powders in the course of thermal treatment, resulting in an easy and quick induction of FTIR spectral changes near 123◦ C. Once the heating Lin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2386–2395, 2014

temperature exceeded 123◦ C, several specific IR peak positions and peak intensities were markedly changed. Thermal-induced dissociation and liquefaction may be responsible for these results. The thermal-dependent three-dimensional FTIR plot of the IMC–NIC physical mixture after cogrinding for 3 min is displayed in Figure 6. The thermal-dependent IR spectral contour of this ground mixture was clearly changed near 87.5◦ C and 124◦ C. These temperatures were near the onset temperatures of DSC endothermic peaks of 100◦ C and 126◦ C, respectively. At temperatures less than 87.5◦ C, the three-dimensional FTIR spectral plot maintained a nearly constant contour. At higher temperatures over 87.5◦ C, two-step changes in several FTIR spectra were observed, namely, an increase or decrease in peak intensity or position. In particular, several new peaks at 1678, 1662, 1466, and 1440 cm−1 were found in the thermal-dependent IR spectral contour at temperatures exceeding 124◦ C, which were similar to the FTIR spectral peaks appearing at 1680, 1663, 1466, and 1440 cm−1 upon IMC– NIC cocrystal formation. These new IR peaks were because of cocrystal formation via intermolecular hydrogen bonding (C=O . . . H–C and C–O–H . . . N) between IMC and NIC under thermal stress.30,31 Beyond the fusion point of 126◦ C, the sample was liquefied, and it exhibited a broad FTIR spectral map. More evidence of IMC–NIC cocrystal formation was also revealed from the thermal-dependent three-dimensional FTIR plot of the IMC–NIC physical mixture after cogrinding for 40 min, as shown in Figure 7. It clearly indicates that DOI 10.1002/jps.24056

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

two-step changes in several unique FTIR spectral peaks were observed in the spectral map. At temperatures less than 67◦ C, the three-dimensional FTIR spectral plot maintained a nearly constant contour. Once the temperature exceeded 67◦ C, the peaks at 3367, 1717, 1692, 1309, and 1262 cm−1 displayed reduced intensity and shifts, but several new peaks at 3417, 3321, 3215, 1707, 1679, 1662, 1620, 1466, 1449, 1326, and 1177 cm−1 gradually appeared and grew in intensity. The new peaks were consistent with those of the FTIR spectrum of IMC–NIC cocrystals (Fig. 1d), suggesting the thermal-induced stepwise mechanism of IMC–NIC cocrystal formation occurred under thermal stress via DSC–FTIR microspectroscopy. It is interesting that the intensities of several peaks were increased or decreased over the temperature range of 67◦ C–90◦ C, whereas the intensities remained constant over the range of 90◦ C–122◦ C according to the three-dimensional FTIR spectral map. The temperatures of 90◦ C and 122◦ C corresponded to the onset temperatures of DSC endothermic peaks at 96◦ C (the fusion of eutectic mixture for 40 min IMC–NIC ground mixture) and 126◦ C (IMC–NIC cocrystal), respectively. At temperatures exceeding 126◦ C, the IMC–NIC cocrystals were liquefied, and they displayed broad FTIR spectral profiles. The marked changes in FTIR peak intensity and peak position for IMC–NIC cocrystals occurred earlier than those of a conventional DSC curve, suggesting that the thermally dependent IR spectral changes because of the induction of molecular vibration was more sensitive than those of conventional DSC. This implies that the simultaneous DSC–FTIR technique, which provides spectroscopic and thermodynamic information, is more useful for the easy induction and identification of IMC–NIC cocrystal formation than conventional DSC. Effect of Different Evaporation Methods for Preparing IMC–NIC Cocrystals For more efficient screening of pharmaceutical cocrystals, several methods are available, such as cooling, evaporation, the addition of a substance or solvent that reduces the solubility, and chemical reaction in the solution-based methods.5,6,10,15,52 Among them, the solvent evaporation method is the most popular method for preparing cocrystals. In this study, several different evaporation methods with various thermal evaporation rates were applied to prepare IMC–NIC cocrystals. Figure 8 illustrates the FTIR spectra and DSC curves of different IMC–NIC samples prepared using different thermal evaporation methods. IMC and NIC (molar ratio = 1:1) were completely dissolved in ethyl acetate and evaporated. When the IMC–NIC/ethyl acetate solution was slowly evaporated with or without stirring at ambient temperature, their FTIR spectra and DSC curves were similar (Figs. 8a and 8b). Unknown FTIR spectra were obtained; however, the DSC curves with two endothermic peaks at 105◦ C and 124◦ C–126◦ C were similar to the DSC curves of the IMC–NIC ground mixtures (Fig. 2). The unknown FTIR spectra should be further studied. However, based on the DSC curves, the unknown spectra may represent a mixture of IMC and NIC rather than a cocrystal. When the IMC–NIC/ethyl acetate solution was rapidly evaporated at 50◦ C, both the FTIR spectrum and DSC curve were identical to those of IMC–NIC cocrystals (Fig. 8c vs. Fig. 1d). This suggests that the fast thermal evaporation method could easily induce cocrystal formation between IMC and NIC. Once the solvent-assisted cogrinding process was applied after

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adding three drops ethyl acetate into the IMC–NIC mixture, the obtained FTIR spectrum was superimposable on the FTIR spectra of IMC and NIC, suggesting that there was no interaction between the components after solvent-assisted cogrinding in a ceramic mortar (Fig. 8d). Two endothermic peaks at 118◦ C and 126◦ C were obtained, implying that a physical mixture was presented in the ground mixture. This was contrary to the result of Alhalaweh’s report,29 in which IMC–NIC cocrystals were prepared by solvent-assisted cogrinding in a closed grinder chamber. The rapid evaporation of ethyl acetate during the present cogrinding process may be responsible for this result. When the microwave-assisted evaporation method was used, the FTIR spectrum and DSC curve of the sample (Fig. 8e) were identical to that of the IMC–NIC cocrystals (Fig. 1d). This was also consistent with the result of the heating condition alone, as shown in Figure 8c. This strongly suggests that IMC– NIC cocrystal formation would be accelerated and assisted by the thermal effect of microwave irradiation via the rapid evaporation of ethyl acetate.53,54

CONCLUSIONS The present study indicates that thermal stress can easily induce solid-state cocrystal formation between IMC and NIC after cogrinding. The amount of cocrystals formed is positively correlated with the cogrinding time. Furthermore, the simultaneous DSC–FTIR technique, in addition to providing spectroscopic and thermodynamic information, was more useful for the induction and identification of IMC–NIC cocrystal formation than conventional DSC. Different solvent evaporation rates induced by thermal stress may significantly influence IMC–NIC cocrystal formation. In particular, microwave heating may quickly result in IMC–NIC cocrystal formation.

ACKNOWLEDGMENT This work was supported by National Science Council, Taipei, Taiwan, Republic of China (NSC 100-2320-B-264-001-MY3).

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