Application and Comparison of Cocrystallization Techniques on

Article pubs.acs.org/crystal

Application and Comparison of Cocrystallization Techniques on Trospium Chloride Cocrystals Veronika Sládková,*,† Jana Cibulková,‡ Václav Eigner,† Antonín Šturc,§ Bohumil Kratochvíl,† and Jan Rohlíček∥ †

Department of Solid State Chemistry, Institute of Chemical Technology Prague, Technicka 5, 16628, Prague 6, Czech Republic Central Laboratories, Institute of Chemical Technology Prague, Technicka 5, 16628, Prague 6, Czech Republic § Interpharma Praha, a.s., Komoranska 955, 14300, Prague 4, Czech Republic ∥ Institute of Physics AS CR, v.v.i., Na Slovance 2, 182 21 Prague 8, Czech Republic ‡

S Supporting Information *

ABSTRACT: To identify as many solid forms of active pharmaceutical ingredient (API) as possible and to monitor their cocrystallization potential, synthetic methods are needed. According to API properties (solubility, melting point, stability), suitable screening methods have to be considered. In this study, the performance of most of the commonly available cocrystallization techniques such as neat grinding, liquid-assisted grinding, slurrying, co-melting, and slow evaporation was compared. We applied them to four pharmaceutical cocrystals of trospium chloride (TCl, a muscarinic antagonist urinary antispasmodic) with adipic (AD), glutaric (GA), oxalic (OX), and salicylic acids (SA), which were identified as hits from previous slow evaporation experiments. Their structures were determined by single-crystal X-ray diffraction (TCl-SA and TCl-OX cocrystals) or from powder X-ray diffraction data (TCl-AD and TCl-GA cocrystals). Other methods to characterize the cocrystal phases were applied (1H NMR, DSC, IR, and Raman spectroscopy). Comparison of cocrystallization methods and of the prepared cocrystals was discussed.

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INTRODUCTION Cocrystal screening has recently become a part of the solid form development of an active pharmaceutical ingredient (API). The choice of cocrystallization techniques in the screening influences not only the number of experiments but also the number of potential hits. Nevertheless, only a few studies compare and evaluate the efficiency of each method.1 We decided to compare five most common techniques: neat grinding,2 liquid-assisted grinding,3 slurrying,4−6 co-melting,7 and slow evaporation.8 We applied them on four cocrystals of trospium chloride which are also presented in this paper. The new forms with trospium chloride which were previously prepared by simple slow evaporation of ethanol represent stable (well-behaved) cocrystals as well as unstable (ill-behaved) cocrystals. Therefore, they serve as examples of phases differing in stability. Trospium chloride (Figure 1), a muscarinic antispasmodic drug, used for the treatment of overactive bladder, exhibits high solubility in water, but low oral bioavailability.9 By cocrystalliza-

tion, its dissolution rate could be altered. Its chloride ion could be engaged in a hydrogen bond interaction with a carboxylic acid as described, e.g., for fluoxetine hydrochloride.10 Recently, new polymorph of trospium chloride has been described,11,12 but, to the best of our knowledge, no crystal structure data of cocrystals have been mentioned except in patent literature, where a complex of trospium chloride and saccharin is described.13 Its interaction character is not studied in detail, and no data presented in the patent exclude the possibility of cocrystal formation. Therefore, trospium chloride deserves our attention and requires further crystallographic investigation.

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Materials. Trospium chloride was obtained from the Interpharma Praha, a.s. company (Prague, Czech Republic) and used without further purification. Solvents and cocrystal formers were purchased from various suppliers and were used as received. Screening Techniques. The first cocrystal screening of trospium chloride (TCl) was conducted with 12 coformers: adipic acid, camphoric acid, citric acid, fumaric acid, glutaric acid, hippuric acid, maleic acid, malonic acid, oxalic acid (dihydrate), salicylic acid, succinic acid, and tartaric acid. Mixtures of API and acid (40 mg) in a molar ratio 1:1, 1:2, and 2:1, which were homogenized using a mortar and pestle, were placed in 50-mL round-bottomed flasks, dissolved in Received: February 13, 2014 Revised: April 23, 2014

Figure 1. Molecular structure of trospium chloride. © XXXX American Chemical Society

EXPERIMENTAL SECTION

A

dx.doi.org/10.1021/cg500226z | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Table 1. Cocrystal Screening Resultsa LAG stoichiometry of the samples TCl:AD TCl:AD TCl:AD TCl:GA TCl:GA TCl:GA TCl:OX TCl:OX TCl:OX TCl:SA TCl:SA TCl:SA

1:1 1:2 2:1 1:1 1:2 2:1 1:1 1:2 2:1 1:1 1:2 2:1

slurry

slow evaporation

EtOH

iPrOH

EtAc

EtOH

iPrOH

EtAc

EtOH

iPrOH

neat grinding

co-melting

− − − − − − + + + + + +

− − − − − − + + + + + +

− − − − − − + + + + + +

− − − − − − + + + + + +

− − − − − − ◼ + + + + +

− − − − − − + + + + + +

+ + ◼ ◼ + + + + + ◼ + +

+ + + − − − + + + + + +

− − − − − − + + + − − −

− − − − − − + + + + + +

a

Symbol (−) stands for no cocrystal formation, (+) for cocrystal. The samples which yielded cocrystals suitable for structure solution from SCXRD or PXRD data are indicated by filled square. ground in an agate mortar and stacked on a Si holder (zero background). Data evaluation was performed in the software package HighScore Plus. X-ray powder diffraction data at room temperature which were used for crystal structure determination of cocrystals TCl-GA and TCl-AD as well as data measured at different temperatures were collected on the Empyrean PANalytical diffractometer with Debye-Sherrer geometry using Cu Kα radiation (λ = 1.54184 Å, focusing mirror and PIXCel3D detector with 255 active channels). Each sample was ground and placed into a 0.3 mm borosilicate glass capillary. Room temperature measurement: scan type 2θ, range 4−80° 2θ, step 0.013° 2θ, counting time 3000 s step−1. Temperature resolved measurements: Oxford Cryosystem Coldhead 700, scan type 2θ, range 3−50° 2θ, step 0.013° 2θ, counting time 60 s step−1, measurements at constant temperatures 50 °C, 100 °C, 150 °C, 160 °C, 170 °C, 180 °C, 190 °C, 200 °C, 210 °C, and 220 °C, heating rate of 6 °C min−1 between scans. Single Crystal X-ray Diffraction (SCXRD). Data were collected using an Xcalibur PX four-circle diffractometer with OnyxCCD area detector and graphite monochromated Cu Kα radiation. Infrared (IR) Spectroscopy. ATR (ZnSe−single reflection) infrared spectra of the solids were obtained using an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS detector and KBr beam splitter. A total of 12 scans per spectrum were acquired in the range 4000−600 cm−1. Spectral resolution was 2 cm−1. The data were acquired and interpreted using Omnic 6.2. Raman Spectroscopy. Raman spectroscopic analyses were carried out on a FT-Raman RFS100/S spectrometer equipped with a germanium detector (Bruker Optics, Germany). Spectra were collected using an excitation wavelength of 1064 nm of Nd:YAG laser radiation (power 250 mW). Each sample was analyzed in a HPLC glass vial. A total of 64 scans per spectrum were acquired from 4000 to −2000 cm−1. Spectral resolution was 4 cm−1. The data were acquired and interpreted using Opus 5.5. NMR. 1H NMR spectra were obtained using Varian Gemini 300 HC spectrometer with 300 MHz frequency. Differential Scanning Calorimetry (DSC). DSC measurements were performed on a PerkinElmer Pyris 1 DSC. The sample were weighed in aluminum pans and covers (20 μL) and measured in a nitrogen flow (20 mL/min). Investigations were performed in a temperature range of 50−300 °C with a heating rate of 10 °C/min. The temperatures specified in relation to DSC analyses are onset temperatures of peaks. The specific heat is given in J/g. The weight sample was about 3 mg.

ethanol at ambient temperature, and left until crystalline material was formed. Powders were then analyzed by powder X-ray diffraction (PXRD). Four hits with diffraction patterns differing from starting material were obtained. The identities of the newly prepared phases were verified by indexing of the diffraction patterns, including mixtures. The physical mixtures of TCl with adipic (AD), glutaric (GA), oxalic (OX), and salicylic (SA) acid were then used for further experiments. Slow Evaporation. In the slow evaporation experiments, the physical mixtures of TCl with AD, GA, OX, and SA in 1:1, 1:2, and 2:1 molar ratios were placed in 50-mL round-bottomed flasks and dissolved in ethanol (EtOH) and similarly in isopropylalcohol (iPrOH) at ambient temperature and left until crystalline material was formed. Slurry Screening. Approximate solubilities of the acids and TCl in the solvents were measured. Slurries were prepared by dissolving more soluble component in a solvent while leaving approximately half of the solid undissolved and adding less soluble component in a 1:1, 1:2, and 2:1 ratio. EtOH, iPrOH, and EtAc were used as solvents. Slurries in glass vials with screw caps and polytetrafluorethylene-coated septa were placed in an orbital shaker (IKA MS 3 digital, 500 rpm) for 48 h at ambient temperature, then filtered and analyzed. Neat Grinding. The neat grinding experiments were performed in Retsch MM 200 ball mill. The physical mixtures of TCl with AD, GA, OX, and SA in a 1:1, 1:2, or 2:1 ratio was placed in 3 mL volume stainless steel jars, along with one stainless steel grinding ball of 5 mm diameter. The samples were ground for 30 min at an operating frequency of the mill of 25 Hz. Liquid-Assisted Grinding (LAG). The LAG experiments were performed in Retsch MM 200 ball mill. The physical mixtures of TCl with AD, GA, OX, and SA in a 1:1, 1:2, or 2:1 ratio with two drops of EtOH, iPrOH, or EtAc were ground for 30 min (at an operating frequency of the mill of 25 Hz). After grinding, the samples were dried by standing in air. Co-melting. The physical mixtures of TCl with AD, GA, OX, and SA were prepared at 1:1, 1:2, and 2:1 molar ratios. The mixtures were heated, at 10 °C per min under nitrogen purge, in non-hermetically crimped DSC aluminum pans, from room above eutectic temperature. The mixtures were then cooled to room temperature at a cooling rate 10 °C per min. After the mixtures stood at 30 °C for 60 min, the heating was repeated, and the obtained solid was investigated by PXRD. Analytical Methods. Powder X-ray Diffraction (PXRD). Fast Xray powder diffraction data for screening experiments were collected at room temperature with laboratory X́ PERT PRO MPD PANalytical diffractometer with parafocusing Bragg−Brentano geometry, using Cu Kα radiation (λ = 1.54184 Å), measurement range 2−40° 2θ, a step size of 0.01° 2θ and a counting time of 0.5 s step−1. Samples were B



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results are provided in Table 1. According to the measured diffraction patterns, the cocrystals obtained were always the same regardless of the stoichiometry ratio of the input mixtures. Neat grinding provided only cocrystal TCl-OX, although the conversion to cocrystal could have been facilitated by the presence of crystal water in oxalic acid dihydrate. LAG gave cocrystals TCl-OX and TCl-SA in all solvents, but the preparation of cocrystals with AD and GA was not successful. The slurries gave cocrystals with OX and SA. In comparison with the other four methods where preprepared physical mixtures were used, our preparation method of slurries of the samples was impractical as we wanted to ensure that both starting crystalline phases are present and the components of the samples were weighed separately. On the other hand, by slurrying we were able to prepare single crystals of TCl-OX from iPrOH on the sides of the vials which were suitable for SCXRD. The link between LAG and slurrying was aptly described by Frišcǐ c using parameter η.14 Therefore, we tried to maximally differentiate between the methods: LAG (small η, less solvent used) vs slurry (larger η, more solvent used). Nevertheless, in our screening both methods provided the same results. By slow evaporation, all cocrystals were prepared, and single crystals for SCXRD structure determination of cocrystal TClSA were obtained from EtOH. It seems that the successful preparation of all four cocrystals by slow evaporation was due to (1) the good choice of solvents where both cocrystallized components have similar solubility and (2) sufficient time (weeks) given to the samples to recrystallize. As trospium chloride is thermally stable until its melting point, heating together with coformers was applied. Soon after reaching its melting temperature trospium chloride quickly decomposes; therefore, heating experiments were halted below melting of TCl. By co-melting in DSC pans, the cocrystal phases TCl-SA and TCl-OX were obtained directly during the first heating. Above the eutectic endotherm, a new endotherm was observed, which was later identified as corresponding to the cocrystal melt. New samples were prepared and heated below those new endotherms, and the powders collected from DSC pans were identified by PXRD as cocrystals. The powders from DSC pans which were heated above two endotherms (eutectic and melt of the cocrystals) were identified as trospium chloride. No exotherms of recrystallization were observed, and yet the cocrystals were prepared. With GA no cocrystal phase was prepared by heating. It was not surprising, as its cocrystal phase with TCl was found to be unstable under ambient conditions and prone to decompose to starting components while heating or measuring by PXRD. Cocrystal TCl-AD was not prepared. Only one endotherm was observed, probably eutectic, and the powders heated above or below the endotherm were identified as physical mixtures of starting components. Cocrystals’ Characterization. All obtained crystalline phases were analyzed by PXRD. The reference diffractograms of starting physical mixtures were compared with the screening diffractograms, which were, in the case of new phase formation, completely different. As samples were prepared with a different stoichiometry, the phase purity of powders differed. For further analyses, the purest powders of new phases were used. The presence of cocrystallized compounds in the phases was affirmed by 1H NMR spectroscopy, and the possibility of solvate formation of the starting material was dismissed.

Figure 2. Final Rietveld plot of TCL-AD showing the measured data (red line), calculated data (black thin-cross), and difference curve (blue line). Calculated Bragg positions are shown by vertical bars (top row: TCl, bottom row: TCl-AD).

Table 2. Melting Points (Onsets on DSC) of Cocrystals, API, and Coformersa melting points of single component crystals cocrystal

Mp (°C)

TCl Mp (°C)

coformer Mp (°C)

TCl-SA TCl-OX TCl-AD TCl-GA

205.7 176.3 114.7* 56.6*

267.7 267.7 267.7 267.7

158.6 (ref 21) 101.5 (ref 21) 151.5 (ref 21) 97.3 (ref 21)

a The melting of TCl-AD and TCl-GA (values with asterisk) is affected by the presence of other phases (TCl and coformer).

Figure 3. Supramolecular unit in the asymmetric unit of TCl-SA.

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RESULTS AND DISCUSSION Cocrystal Screening of Trospium Chloride. In the homologous series of dicarboxylic coformers OX (C2), GA (C5), and AD (C6), the capacity to form cocrystals decreased with increased carbon number. Although the early screen with more coformers including members of the homologous series malonic (C3) and succinic (C4) acid did not provide new phases, it could be interesting to put more effort into the search and complete the homologous cocrystal series. But we doubt it would bring new insight. All the samples with crystalline material were analyzed by PXRD, and their diffraction patterns were compared with diffractograms of physical mixtures, which were measured before any treatment. The preparation of the cocrystals by the cocrystallization techniques was reproduced, and the detailed C



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Figure 4. Similar packing of (a) TCl-OX, (b) TCl-GA, and TCl-AD (c) shown in the c−a plane.

Table 3. Crystallographic Data for TCl-SA and TCl-OX Cocrystals formula Mr color cryst morphology cryst size (mm) temperature (K) radiation wavelength (Å) cryst system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z density (g/cm3) μ (1/mm) F(000) θ (min, max) no. unique reflns no. of params hmin,max kmin,max lmin,max R_all, wR2_all R_obs, wR2_obs Δρmin, Δρmax (e·Å−3) GOF CCDC number

Figure 5. Packing of TCl-SA.

The collected single crystal data were used for single crystal X-ray structure solution in the case of new phases with SA and OX. The structures of new cocrystals with GA and AD were determined from powders. The structures are discussed and compared later in the results section (Tables 3 and 4). Cocrystal Structures Determination and Refinement of TCl-SA and TCl-OX from SCXRD. The cocrystal structures were solved by direct methods15 and refined anisotropically using Crystals suite of programs.16 The hydrogen atoms were refined using riding constraints. The theoretical diffraction patterns were generated using Mercury 3.017 and compared with experimental ones. Both diffractograms were in good agreement. Cocrystal Structures Determination and Refinement of TCl-GA and TCl-AD from PXRD. Several attempts to find single crystals of sufficient quality failed, and only polycrystalline mixtures containing various amounts of starting phases were prepared. Hence we used powder samples with the highest amount of supposed cocrystal phases for the crystal structure determination process. The sample containing cocrystal TCl-AD was a mixture of two phasestrospium chloride11 (in form P21) and TCl-AD cocrystal and the sample with TCl-GA cocrystal also contained trosium choride and GA phases. Unit cells of new cocrystals were found by Dicvol software,18 and consequent Le Bail refinements with space group test, including, of course, impurity phases, were performed in

TCl-SA

TCL-OX

C25H30NO3·C7H6O3· Cl 566.09 colorless plate 0.61 × 0.37 × 0.07 180 Cu Kα 1.54184 monoclinic P21/c 20.0561 (5) 19.5073 (2) 9.6398 (2) 90 130.671 (4) 90 2860.5 (2) 4 1.314 1.56 1200.0 4.53, 76.50 5862 361 −25, 21 −24, 24 −6, 11 0.055, 0.129 0.045, 0.111 −0.27, 0.25 0.97 941640

2(C25H30NO3)·C2H2O4· 2Cl 945.98 colorless plate 0.53 × 0.41 × 0.09 190 Cu Kα 1.54184 monoclinic C2/c 43.4462 (7) 6.61949(10) 16.5083 (2) 90 99.7909(19) 90 4678.51 (12) 4 1.343 1.76 2008.0 5.44, 77.25 4939 298 −54, 54 −8, 8 −14, 20 0.043, 0.122 0.040, 0.117 −0.29, 0.26 0.92 941641

JANA2006.19 Both crystal structures were found ab initio by direct space methods as implemented in the software FOX,20 which also allowed us to define impurity phases occurring in powder patterns. The starting model for direct space methods has to be a content of the asymmetric part of the unit cell. We D



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cell parameters, background, overall scale factor and phase fraction factor. See results in Figure 2 and in Table 4. All cocrystals were characterized by IR and Raman spectrometry. Both infrared and Raman spectra of the cocrystals differed from the starting materials. The resulting spectra were not a simple superposition of the initial materials’ spectra; shifts in absorption maxima positions and their relative intensity were observed, which could be explained by the interactions between the API and coformers. Both Raman and infrared spectra affirmed the interactions between API and the carboxylic groups of coformers. While shifts in the bands assigned to carboxylic groups of coformers were significant, only minor changes of the positions of bands assigned to TCl were observed. That is not surprising as trospium cation is not engaged in the API−coformer interaction. The chloride anion is the most involved in the interaction between API and coformer. These interactions were also observed in the cocrystal structures solved from single crystals as well as from powders. The melting points of pure cocrystals were measured by DSC (Table 2). As cocrystals TCl-AD and TCl-GA were obtained with phase impurities, the melting points of their phases were affected. The DSC curves showed endotherms corresponding to melting of cocrystals as well as melting of recrystallized TCl. The onset of melting of TCl was shifted to lower temperature probably due to the presence of melted acid. The explanation of each endotherm was confirmed by temperature resolved PXRD. The melts of TCl-SA and TClOX were in agreement with endotherms obtained from comelting experiments. Structures of Cocrystals. TCl-SA contains a trospium cation, a chloride anion, and a molecule of salicylic acid in the asymmetric unit. These three residua are held together by strong classical hydrogen bonds, forming a supramolecular block (Figure 3). These blocks engage in “head to tail” interactions where chloride anion and acidic hydrogen atoms of spiro-cycles of trospium form three non-classical hydrogen bonds. These interactions lead to formation of supramolecular chains in direction of the c axis. The chains are further connected by C−H−π interactions between phenyl rings of trospium cation. Cocrystals TCl-OX and TCl-AD contain trospium cation, a chloride anion, and a half of dicarboxylic acid in the asymmetric unit cell; hence the final ratio between TCl and dicarboxylic acid is 2:1. The ratio between TCl and GA in the TCl-GA cocrystal is 1:1, because the asymmetric part of the unit cell contains trospium cation, a chloride anion, and one molecule of GA. Even if there is a different ratio between TCl and dicarboxylic acids in these three cocrystals, the packing is similar. Trospium cations and chloride anions are ordered in layers which are parallel to the c−b plane. Trospium cations in these layers are connected by C−H−π interactions between phenyl rings. Chloride anion is connected by H-bond to the trospium cation. Dicarboxylic acids are formed in the space between TCl layers. In the case of TCl-OX and TCl-AD one dicarboxylic acid is connecting TCl layers by two hydrogen bonds to chloride anions. In the case of TCl-GA, two glutaric acids are connecting TCl layers by two hydrogen bonds to chloride anions and one hydrogen bond between acids; see (Figure 4). In the case of TCl-SA, the formation of these “dimers” is not possible since SA is just a monohydric acid, creating a completely different crystal packing (Figure 5).

Table 4. Crystallographic Data for TCl-GA and TCl-AD cocrystals TCl-GA formula Mr color temperature (K) radiation wavelength (Å) cryst. system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z density (g/cm3) μ (1/mm) F(000) θ (min, max) no. of params no. of restraints no. of constrains Rp, Rwp Robs, wRobs Rall, wRall Δρmin, Δρmax (e·Å−3) GOF CCDC number amount of the cocrystal (wt %) amount of TCl/coformer (wt %)

TCl-AD

C25H30NO3· C5H8O4·Cl 560.1 white powder 293 Cu Kα1,2 1.54184 monoclinic P21/c 25.4311(5) 6.66631(12) 16.7131(3) 90 95.0570(17) 90 2822.38(9) 4 1.317 1.60 1192.0 4, 80 161 99 189 0.015, 0.020 0.085, 0.074 0.113, 0.079 −0.49, 0.32 1.56 984 370 0.73

C25H30NO3· 0.5(C6H10O4)·Cl 501.0 white powder 293 Cu Kα1,2 1.54184 monoclinic P21/c 24.2324(6) 6.76298(12) 16.5907(3) 90 107.6063(9) 90 2591.58(9) 4 1.284 1.616 1072.5 4, 80 144 92 173 0.021, 0.0282 0.048, 0.051 0.069, 0.057 −0.12, 0.11 2.81 984 371 0.98

0.22/0.05

0.02/0

estimated it from the unit cell’s volume and from the volume of each supposed molecule in the crystal structure. The starting model of TCl-AD cocrystal was one trospium cation, one chloride anion, and a half molecule of AD. The starting model of TCl-GA phase was one trospium cation, one chloride anion, and one molecule of GA. Molecular models were built from cif files of TCl, GA, and AD, which were found in the Cambridge Structural Database (CSD). Rietveld refinement of TCl-AD and TCl-GA was performed in JANA2006 as a multiphase refinement, and the procedure was almost identical for both cocrystals. Atomic parameters of impurity phases were fixed, and only unit cell and profile parameters were refined. Refinement of cocrystal structures was complicated due to the large number of atoms in the asymmetric part of the unit cell. We used bond and bond angles restraints to keep the correct shape of molecules. This allowed each molecule to move and also to change its shape (free torsion angles). Hydrogen atoms were kept in their theoretical positions with isotropic ADPs calculated as a 1.2*ADP of the parent atom. Hydrogen atoms participating in hydrogen bonds were set in the direction of these bonds. At the final stage we refined atomic coordinates, still restrained by bonds and bond angles restraints, two overall isotropic ADP for each molecule and one isotropic ADP for chloride anion, unit E



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CONCLUSIONS While most of the studies discussing cocrystallization techniques favor one method over the others, studies trying to evaluate the performance of such methods on the example of a few cocrystals are not numerous. We have tried to focus on the preparation of novel forms of trospium chloride by five common cocrystallization techniques, and the comparison between them showed that some phases were not obtainable by all means. On the other hand, stable cocrystals were prepared practically always, so the parameters mostly concerned in the choice of optimal method would be material consumption and the convenience and automation of experiments. For well-soluble substances such as TCl, slurrying and LAG demanded higher amounts of material. On the other hand comelting experiments were advantageously used where small amounts (4 mg) of material were sufficient. Slow evaporation experiments gave the highest number of cocrystals, but similar solubility had to be achieved, and, of course, cocrystallization took much longer time in comparison to other methods. Regardless, we suggest that more cocrystallization techniques during screening should be applied. The screening results also show that trospium chloride’s cocrystallization potential has not been fully exploited and that its new solid forms could be possibly used for enhancement of its physicochemical properties.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

* Supporting Information S

X-ray crystallographic information files (CIF) for all cocrystals, PXRD pattern fits of TCl-SA, TCl-OX, and TCl-GA, DSC, IR, and Raman spectra of all the cocrystals are available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail: [email protected]. Author Contributions

All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Tomas Pekarek for assistance with IR and Raman spectroscopy and interpretation of the spectra, Lukas Krejcik for assistance with DSC analyses, and Ondrej Dammer for consultation and helpful comments. We acknowledge financial support from specific university research (MSMT No. 20/2014 and No. 604 613 7302).

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REFERENCES

(1) Fucke, K.; Myz, S. A.; Shakhtshneider, T. P.; Boldyreva, E. V.; Griesser, U. J. How good are the crystallisation methods for cocrystals? A comparative study of piroxicam. New J. Chem. 2012, 36 (10), 1969−1977. (2) Trask, A. V.; van de Streek, J.; Motherwell, W. D. S.; Jones, W. Achieving polymorphic and stoichiometric diversity in cocrystal formation: Importance of solid-state grinding, powder X-ray structure determination, and seeding. Cryst. Growth Des. 2005, 5 (6), 2233− 2241. (3) Karki, S.; Friscic, T.; Jones, W. Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the F


Application and Comparison of Cocrystallization Techniques on

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