Diversity in Itraconazole Cocrystals with Aliphatic Dicarboxylic Acids of


Sep 11, 2013 - ABSTRACT: The cocrystal formation potential of itraconazole, a potent antifungal drug, with C2−C10 aliphatic dicarboxylic acids has b...
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Diversity in Itraconazole Cocrystals with Aliphatic Dicarboxylic Acids of Varying Chain Length Anna Shevchenko,*,†,‡ Inna Miroshnyk,†,§ Lars-Olof Pietila,̈ ‡ Jorma Haarala,‡ Jukka Salmia,‡ Kai Sinervo,‡ Sabiruddin Mirza,†,§ Bert van Veen,‡ Erkki Kolehmainen,∥ Nonappa,∥ and Jouko Yliruusi† †

Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland Research and Development, Orion Corporation, P.O. Box 65, FI-02101 Espoo, Finland § School of Engineering and Applied Sciences, Harvard University, 9 Oxford Street, Cambridge, Massachusetts 02138, United States ∥ Laboratory of Organic Chemistry, Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland ‡

S Supporting Information *

ABSTRACT: The cocrystal formation potential of itraconazole, a potent antifungal drug, with C2−C10 aliphatic dicarboxylic acids has been investigated. Using two experimental screening techniques (solvent-assisted grinding and evaporation-based crystallization), the cocrystals of itraconazole with C2−C7 dicarboxylic acids have been successfully synthesized and characterized by powder X-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, and thermal analysis. The characterized multicomponent compounds include anhydrous cocrystals (malonic, succinic, glutaric, and pimelic acids), a cocrystal hydrate (adipic acid), and cocrystal solvates with acetone and tetrahydrofuran (oxalic acid). This study is the first to demonstrate the diversity in itraconazole cocrystals with a range of aliphatic dicarboxylic acids of variable carbon chain lengths.

1. INTRODUCTION Poor physicochemical properties of pharmaceutical solids significantly restrain both preclinical development and clinical translation of investigational new drugs.1,2 Scientific studies that disclose more solid-state forms of a given drug compound are therefore vital for the pharmaceutical industry.1,3 Cocrystals are a recently emerged, outstanding class of pharmaceutical solids in the context of accelerating drug product development.4,5 This is due to the fact that these multiple component crystalline forms make it possible to address several pharmaceutically relevant issues simultaneously, including poor solubility and bioavailability, inadequate physical stability, and manufacturability.6 Cocrystals of itraconazole (ITZ, Figure 1), a potent antifungal drug, are among the most successful examples of physicochemical properties improvement via cocrystal formation. For instance, the cocrystals being formed from a poorly watersoluble ITZ and a freely water-soluble dicarboxylic acid (cocrystal former) have shown a significant increase in solubility, as compared to that of the neat crystalline drug substance.7 Furthermore, it has been demonstrated that the cocrystals of ITZ can have an enhanced physical stability and a more controllable hygroscopicity compared to ITZ hydrochlorides.8 ITZ has been reported to form cocrystals with a number of C4 dicarboxylic acids, including fumaric, succinic, L-malic, L-, D-, and 7 DL-tartaric. The trimer formed by two molecules of ITZ and one molecule of succinic acid is considered as a valuable example of a molecular fitting mechanism in crystal engineering.4,9 It is remarkable that the expected interaction between succinic acid © XXXX American Chemical Society

and the strongest basic group of itraconazole (piperazine moiety) was not realized in the cocrystal structure. Surprisingly, the COOH group of succinic acid was found to be connected to a 1,2,4-triazole group.7,10 More importantly, since 2003 when the first cocrystals of ITZ were discovered, the formation of a multimolecular compound between a C3 or C5 dicarboxylic acid and ITZ has been considered to be unachievable.7 Most recently, however, we were able to discover and characterize a new cocrystal of itraconazole with malonic acid, which is a C3 dicarboxylic acid.8 Against this background, this study is designed to systematically investigate the possibility of ITZ cocrystal formation with dicarboxylic acids of varying carbon chain length, in particular with C2−C10 aliphatic dicarboxylic acids (Figure 1). To maximize the probability of discovering new cocrystals, we have chosen to use a combined approach that involves mechanochemical synthesis by grinding and crystallization by slow evaporation.6,11 These two techniques have been shown to be the most successful among the others.12 In addition, the screens are designed to include the experiments with two molar ratios, 1:1 and 2:1 (ITZ:coformer), of the components. Received: July 12, 2013 Revised: September 7, 2013

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Figure 2. Flowchart for the cocrystal screening applied in the study. mL) while dicarboxylic acids have lower (100 mg/mL), whereas ITZ is only sparingly soluble (27 mg/mL) in THF.14 Initially, solutions of pure ITZ in chloroform and a coformer in THF were mixed in 20 mL glass bottles to obtain 1:1 and 2:1 molar mixtures of ITZ and coformer, respectively. If needed, an excess solvent was then added to produce a 1:1 (chloroform:THF) solvent mixture. The prepared solutions were heated to 60 °C with continuous stirring to ensure complete dissolution of the solids. Thereafter, the bottles were sealed with a perforated film to allow for a slow solvent evaporation. Once the first crystals were observed, the film was removed to accelerate the evaporation. Finally, the solids were dried in a vacuum oven at 50 °C for 24 h. 2.4. Physical and Chemical Analysis. Identification and physicochemical characterization of the solids obtained was accomplished using a multitude of complementary analytical techniques, including powder X-ray diffractometry (PXRD), solution and solid-state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), mass spectroscopy (MS), Raman spectroscopy, and high-performance liquid chromatography (HPLC). The experimental details are provided in the Supporting Information.

Figure 1. Molecular structures for itraconazole and the aliphatic dicarboxylic acids used in the study.

2. EXPERIMENTAL SECTION In this section, we introduce the experimental protocol and decision tree (Figure 2) of our cocrystal screening approach. The physical and chemical analyses of the solids harvested follow the same methodology and are focused on disclosing and thorough investigation of the nature of new crystalline phases. 2.1. Materials. Itraconazole (ITZ, purity 99.7%, Apotecnia S.A.) was purchased from Apotecnia. Dicarboxylic acids, which are anhydrous oxalic acid anhydrate, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, and sebatic acids, were purchased from Sigma-Aldrich (ACS reagent > 99%). The analytical-grade solvents used for the studies were obtained from the commercial sources. 2.2. Molecular Modeling. The crystal structure data for the pure ITZ and ITZ-SUC cocrystal was obtained from the authors of ref 10, and molecular modeling was performed using Molecular Operating Environment program [MOE, Chemical Computing Group Inc., (v. 2012.10) (REF)].13 The force field used was MMF94x, as implemented into MOE. 2.3. Screening Experiments. A. Solvent-Assisted Milling. The mechanochemical synthesis of cocrystals was performed using a planetary ball mill (Pulverisette 6, Fritsch GmbH, Germany). The neat ITZ and a coformer were weighted in the desired ratios to obtain a batch size of 1 g and transferred in to an 80 mL stainless steel milling bowl with four milling balls. The synthesis was assisted with acetone (200 μL) and accomplished in four milling cycles (500 rpm) of 5 min duration, with a 5 min cooling interval in between each cycle. The resulting powder was removed from the bowl into a glass vial followed by vacuum drying at 50 °C for 24 h. B. Slow Evaporation. The slow evaporation experiments were completed using a 1:1 mixture of tetrahydrofuran (THF) with chloroform due to the suitable solubilities of cocrystal components in these solvents. Namely, ITZ is highly soluble in chloroform (363 mg/

3. RESULTS AND DISCUSSION 3.1. Preliminary Molecular Modeling. Complementarities between functional groups and a host−guest geometric fit are the key prerequisites for a successful cocrystal formation.15 The crystal structure of ITZ-SUC, a representative example of ITZ cocrystal with a C4 dicarboxylic acid, is dominated by supramolecular trimers consisting of two ITZ molecules with head-to-tail orientation and a succinic acid molecule (Figure 3 a).7,10 The guest molecule of succinic acid is located in a pocket formed by two itraconazole molecules and H bonded with the 1,2,4-triazole groups, serving as a bridge between the two host molecules. We assume that similar supramolecular motifs can exist in other cocrystals of ITZ with C4 dicarboxylic acids. From the crystal engineering perspective, it is of great practical interest to establish precise conformational and geometrical features that would allow forming similar supramolecular trimers. For this B

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by Akeröy and co-workers.15 On the basis of these structural considerations, we have hypothesized that the geometries similar to that of the ITZ-SUC trimer can be realized with a variety of dicarboxylic acids. It should be noted, however, that the formation of such trimers with the odd-chain dicarboxylic acids requires a significant departure from their minimal energy conformation, as the latter is characterized by an angle of approximately 120° between the two −OH groups.15,16 In contrast, the even-chain dicarboxylic acids are known to have the minimum energy conformation with the −OH groups arranged in a collinear fashion15,16 As a result, the replacement by a dicarboxylic acid with an even number of carbon atoms allowed a trimer formation using the conformation of the acid with minimum energy. This suggests a higher probability of the cocrystal formation with these acids. We have recently revised the structure of the ITZ-SUC cocrystal as well as the neat itraconazole.10 The revised structures revealed the presence of weak halogen bonding as one of the important noncovalent interactions in the ITZ-SUC cocrystal (N···Cl) (Figure 4), as well as in neat itraconazole (O···Cl).10 Our geometrical considerations suggested that the length alteration of the carbon chain of acids forming the trimer leads to a shift of the relative position of the itraconazole molecules in opposite directions. This shift changes the outer size and the geometry of the supramolecular trimer and, as a result, may significantly alter the weak halogen-bonding network between the trimers in the ITZ cocrystals. Since, in addition to hydrogen bonds, weak van der Waals interactions and halogen bonds also participate in bonding17 and stabilizing the trimers in the cocrystal, it is difficult, if not impossible, to predict whether or not these virtual trimers would eventually form a periodic crystalline structure. 3.2. Experimental Cocrystal Screening. In accordance with the molecular modeling data, ITZ should be able to form cocrystals with dicarboxylic acids that have an even number of carbon atoms in the chain. To verify this hypothesis, we have

Figure 3. Examples of hypothetic trimers that can be formed between ITZ and dicarboxylic acids with varying carbon chain length. The structures were generated so that the hydrogen bond between the triazole ring and the −COOH moieties have the same geometry as in the ITZ-SUC cocrystal.

purpose, we have assessed the possibility to obtain analogous supramolecular structures between ITZ and other dicarboxylic acids by systematically replacing the SUC with dicarboxylic acids of varying carbon chain lengths. Initially, the succinic acid was replaced with one of the dicarboxylic acids and then the ITZ molecules were added to the acid so that the H-bonding and ITZ geometry stays the same as in the ITZ-SUC cocrystal. The conformations of dicarboxylic acids (Figure 3, panels b−e) used in this study were selected in a way that ensures the pocket geometry of ITZ-SUC in the model structures. Here, we exploited a mix and match strategy described

Figure 4. Illustration of weak halogen-bonding network between the ITZ-SUC trimers. View of the two neighboring trimers along the b axis (top) and the top view of these trimers (bottom). C

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Table 1. Solid-State Properties of ITZ Cocrystals and Cocrystal Solvates with C2−C7 Dicarboxylic Acids cocrystal/cocrystal solvate

number of carbons

stoichiometry

co-former mp (°C)

co-crystal mp (desolvation T) (°C)

weight loss on drying (%)

desolvation product

ITZ-MAL ITZ-SUC ITZ-GLU ITZ-PIM ITZ-ADI-H2O ITZ-OXA-ACE ITZ-OXA-THF

3 4 5 7 6 2 2

2:1 2:1 1:2 − 1:1:1.3 1:1:0.5 1:1:1

134 186 98 104 153 189 189

148 157 94 − (80) (81) (100)

0 0 0 0 2.8 3.4 7

− − − − amorphous amorphous amorphous

performed an experimental screening that employs dicarboxylic acids of varying chain lengths (C2−C10), also including those that have an odd number of carbon atoms. The approach is schematically illustrated in Figure 2. The results of these screening experiments are described in detail in Table S1 of the Supporting Information. In the experiments, we have indeed obtained cocrystals of ITZ with oxalic (C2) and adipic (C6) dicarboxylic acids, of which two are cocrystal solvates (ITZ-OXA-ACE and ITZ-OXA-THF) and one is a hydrate (ITZ-ADI-H2O). Then, to our surprise, we have succeeded in obtaining the cocrystals of ITZ with the malonic (C3), glutaric (C5), and pimelic (C7) acids, which have an odd number of carbon atoms in the chain. These cocrystals are ITZMAL, ITZ-GLU, and ITZ-PIM. However, we could not obtain cocrystals of ITZ with the C8−C10 dicarboxylic acids. Also, the solvent-assisted milling of ITZ with azelaic (C9) acid resulted in a mixture of pure ITZ and alpha polymorphic form (form II) of azelaic acid reported by Housty.18 In terms of cocrystal generation, both screening methods, solvent-assisted milling and slow evaporation, were equally successful. The main difference between the methods is that they yielded different cocrystal solvates, which is solely attributed to the different solvents employed during the experiments, as in the case of ITZ cocrystals with oxalic acid. In addition, the slow evaporation experiments were able to produce ITZ-ADI-H2O, while the solvent-assisted milling resulted in a physical mixture of ITZ and ADI only. On the other hand, the solvent-assisted milling experiments of ITZ and the GLU acid in 1:1 and 2:1 ratios indicated the existence of a ITZ-GLU cocrystal of a different stoichiometry (1:2), which was not achieved in the crystallization experiments. Our results demonstrate that employing the combined screening approach, where the two most popular experimental techniques and various ratios of the components are used, is feasible in order to maximize the number of hits. Contrary to solvent-assisted milling, the outcome of evaporative crystallization strongly depends on the choice of solvents and the knowledge of the phase diagram.19 Hence, high-throughput screenings that exclusively utilize the later experimental technique, such as the study performed in ref 7, tend to have a lower success rate. 3.3. Solid-State Properties of Multicomponent Crystals of ITZ. The solid-state forms of ITZ discovered within these studies include anhydrous cocrystals, a cocrystal hydrate, and cocrystal solvates; their properties are summarized in Table 1. The solid phase and chemical purity of all these cocrystals was confirmed by PXRD and HPLC, respectively. The absence of the residual solvent was verified by TGA and NMR. 3.3.1. Anhydrous Cocrystals. Itraconazole:Malonic Acid (ITZ-MAL). The PXRD pattern of the ITZ-MAL cocrystal (Figure 5) differed substantially from a 2:1 physical mixture of ITZ and

Figure 5. PXRD patterns for physical mixtures (PM) of the ITZ and dicarboxylic acids and the new cocrystals and cocrystal solvates discovered in the present study.

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Figure 6. Raman spectra of the discovered cocrystals of ITZ and aliphatic dicarboxylic acids.

report.10 The absence of the residual solvent was confirmed by NMR. Itraconazole:Glutaric acid (ITZ-GLU). In this case, the first screening cycle failed to produce phase-pure ITZ-GLU cocrystals. In the subsequent screening cycle, where a 1:2 mixture of ITZ:GLU was used, both screening techniques yielded the same pure solid phase. The PXRD pattern shown in Figure 5 clearly differs from that of a physical mixture of the components, indicating the formation of a new crystalline phase. It is worth mentioning that there is an excellent match between the patterns of the latter form and the form initially identified in the 1:1 and 1:2 milling experiment (Supporting Information). No mass loss was revealed by TGA, confirming the unsolvated nature of this solid form. Finally, a unique melting point was observed in the DSC thermogram at 94 °C, further confirming the formation of the ITZ-GLU cocrystals. Itraconazole:Pimelic acid (ITZ-PIM). Interestingly, even though the formation of a new solid form (Figure 5) was seen in all experiments, including additional ones with the component

MAL and matched the pattern previously reported by us in ref 8. Nonsolvated nature of this solid form was confirmed by TGA, showing no weight loss between 25 and 148 °C. This is again consistent with our earlier report.8 The melting of the ITZ-MAL cocrystal (Tonset = 148 °C, according to the DSC thermogram) was accompanied by the decomposition of MAL, seen as a stepwise weight loss at the same temperature in the TGA thermogram. Finally, it should be noted that both experimental techniques, solvent-assisted milling, and slow evaporation, produced identical cocrystalline phases. Itraconazol:Succinic Acid (ITZ-SUC). It should be emphasized that the experimental PXRD pattern of ITZ-SUC (Figure 5) differed slightly from the one computed by using the singlecrystal data for IKEQEU (CSD refcode).7 However, there was an excellent correspondence with the theoretical pattern simulated from the refined single crystal data we recently reported (see the Supporting Information).10 The TGA showed no weight loss before the melting, and the melting point observed on the DSC thermogram was Tonset = 157 °C, consistent with our previous E

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Figure 7. 13C CPMAS spectra of neat ITZ and the ITZ cocrystals with aliphatic dicarboxylic acids.

ratio of 1:2 (ITZ:PIM), the phase-pure cocrystals could not be isolated within this study. Since TGA revealed no weight loss upon heating, the new solid form was confirmed to be unsolvated. However, further studies are needed to establish stoichiometry of the ITZ-PIM cocrystals. 3.3.2. Cocrystal Hydrate (ITZ-ADI-H2O). The PXRD pattern of ITZ-ADI-H2O (Figure 5) does not reproduce that of the ITZADI physical mixture, signifying the formation of a unique crystal structure. The TGA trace for ITZ-ADI-H2O yielded a 2.8% weight loss in the temperature range of 50−150 °C, with the onset at 80 °C (peak at 100 °C). Furthermore, the TGA/MS run revealed ion 18 (H2O) escaping from the sample at the same temperature (see the Supporting Information). The latter result leads to the conclusion that ITZ-ADI-H2O is a hydrate. From the weight loss value, it can be calculated that stoichiometry of the complex is 1:1:1.3. Presumably, water was absorbed by the sample from the atmosphere during slow evaporation under a hood. Finally, it should be indicated that the attempts to remove water from the sample by drying at elevated temperatures resulted in a loss of crystallinity (data not shown). 3.3.3. Cocrystal Solvates. ITZ-OXA-ACE. The ternary cocrystal ITZ-OXA-ACE was identified in the milling experiments. As the PXRD pattern for ITZ-OXA-ACE (Figure 5) clearly differs from that of the 1:1 physical mixture, the formation of a new solid phase can be deduced. A stepwise weight loss of 3.4% was detected by TGA at 81 °C, suggesting the solvent evaporation from the crystals. The following TGA/MS and NMR confirmed that the escaping solvent is acetone (ion 43, see the Supporting Information). Hence, taking into account the TGA weight loss value, a stoichiometric ratio of the cocrystal formers is 1:1:0.5. To remove acetone from the sample, we tried (1) drying the sample at elevated temperatures and (2) replacing the solvent with water molecules by keeping the solvate at 100% relative humidity and ambient temperature. Both attempts led to a collapse of the crystalline structure, which was seen as a halo in

the PXRD pattern, typical for amorphous samples (data not shown). ITZ-OXA-THF. In the slow evaporation experiments, another cocrystal solvate of ITZ and OXA was discovered. According to PXRD, the new solid form (Figure 5) was crystallized from the 1:1 solution of ITZ and OXA. TGA showed a 7% stepwise weight loss at 100 °C, which confirms the solvated nature of the form. The TGA-MS confirmed THF (ion 42, see the Supporting Information) escaping at the same temperature. In addition, the THF was clearly seen in the NMR spectra (data not shown). No evidence of chloroform was revealed by either NMR or TGA/ MS analysis. This new form can consequently be referred to as ITZ-OXA-THF solvate having (1:1:1) stoichiometry, consistent with the TGA weight loss value. Similar to ITZ-OXA-ACE, the attempts of solvent removal and replacing with water were not successful. 3.4. Molecular Insight into ITZ Cocrystal Formation with Carboxylic Acids. In order to gain an insight into the structure of new nonsolvated crystalline forms, an experimental analysis combining 13C cross-polarization magic angle spinning (CPMAS), solid-state NMR (SSNMR), and Raman spectroscopy was performed.20 In this study, 13C CPMAS NMR and Raman spectra of the cocrystals were compared with those of the pure itraconazole and dicarboxylic acids. In solid forms, most dicarboxylic acids appear as H-bonded chains, where the carboxyl groups of one molecule are H-bonded to the carboxyl groups of the neighboring molecules, so that C O groups act as acceptors and −OH groups as donors.16 In the known ITZ-SUC cocrystal, the supramolecular trimer consists of two ITZ molecules that are H-bonded to succinic acid in such a way that the CO group of the acid is free of H bonds, but the −OH group is connected to the 1,2,4,-triazol group of ITZ.7,10 This implies that, in the Raman spectrum of the cocrystal, the CO stretching vibration must be shifted to a higher wavenumber.21 Indeed, the CO peak observed in the Raman spectra of SUC at 1653 cm−1 is shifted to 1719 cm−1 in the ITZSUC spectrum (Figure 6). F

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Moreover, in the SSNMR, the 13C signal from carbonyl (C O) in succinic acid (180.0 ppm) showed an upfield shift (175.0 ppm) of 5.0 ppm (Figure 7). The neat malonic acid displayed a doublet resonance pattern (CO at 174.7 and 174.3 ppm) due to the presence of two nonequivalent H-bonding schemes in the crystal: an intramolecular and an intermolecular one. Similarly, in the Raman spectra of the neat malonic acid, two peaks attributed to the CO vibrations are seen at 1650 and 1680 cm−1 (Figure 6). Interestingly, the ITZ-MAL cocrystal resulted in a singlet resonance pattern with the carbonyl signal showed an upfield shift (169.0 ppm) of 5.7 ppm. Also, in the Raman spectra of ITZMAL, there is a shift of the CO vibration to a higher wavenumber (1730 cm−1). In addition, the neat itraconazole shows a doublet resonance pattern in its solid state NMR attributed to the presence of two nonequivalent molecules in an asymmetric unit of the crystal lattice.10 The cocrystal with succinic acid (ITZ:SUC) shows a significant change in the SSNMR spectra exhibiting a singlet resonance pattern that indicates the presence of one molecule of itraconazole in an asymmetric unit. These results are consistent with the single crystal X-ray diffraction studies.10 The cocrystals obtained with malonic acid also showed a similar change in the SSNMR. Overall, the 13C CPMAS spectra of ITZ-MAL are very similar to ITZ-SUC. This clearly illustrates a similarity of the ITZ:SUC and ITZ:MAL cocrystal structures, which is a remarkable result. Furthermore, we have noticed the peak shifts of the CO vibration to a higher wavenumber and upfield shifts of the 13C signal from the carbonyl (CO) of the carboxylic acids in Raman and CPMAS NMR spectra of all cocrystals and cocrystal solvates discovered in this work (Figures 6 and 7). This is an indication of the absence of the H bonding between the CO and OH groups due to formation of a complex with itraconazole. However, the other cocrystals and cocrystal solvates has the SSNMR spectra that are distinctive from the ITZ-SUC and ITZMAL due to a different stoichiometry. For instance, the cocrystal derived from glutaric acid, ITZ-GLU (1:2), displayed two sets of 13 C resonances corresponding to carbonyl carbons (CO, 184.0 and 176.7 pm). The neat glutaric acid is known to exhibit a singlet resonance pattern.22 The nonshifted resonance of the CO at 184.0 ppm implies that, in this complex, the molecules of glutaric acid are still connected to each other with a single −COOH end. On the other hand, the other −COOH end of the acid is hydrogen bonded to the itraconazole, which is revealed by an upfield shift of 7.4 ppm. Since the dicarboxylic acid has two −COOH groups, such arrangement in the complex of 1:2 stoichiometry is theoretically possible. Furthermore, the SSNMR of pimelic acid cocrystal resembles that of the glutaric acid and also shows two resonance peaks for carbonyl (182.0 ppm and 171.0 ppm). The cocrystal solvates derived from the oxalic acid in acetone, resulting in a solvate, is evident from the 13C resonance signal of acetone at 206.0 ppm. However, due to the low degree of crystallinity of the samples, it is difficult to extract more information both from acetone and from the THF solvates. The ITZ-ADI cocrystal hydrate showed a better crystallinity. Its behavior, in terms of its SSNMR spectra, is similar to that of ITZPIM, ITZ-GLU, and ITZ-OXA. These experimental observations are in agreement with the powder X-ray diffraction patterns. These results demonstrate that a preliminary molecular modeling, with the only conformation (the one that is realized in ITZ-SUC) of itraconazole being considered, is not enough for a reliable prediction of obtainable cocrystals of itraconazole and aliphatic dicarboxylic acids, as these molecules are rather complex and conformationally flexible.

4. CONCLUSIONS We have systematically studied cocrystallization of ITZ with a range of aliphatic dicarboxylic acids by employing a combination of two experimental techniques, solvent-assisted milling and evaporation-based crystallization. This combined experimental approach for cocrystal screening enabled us to expand the screening landscape and resulted in a number of novel multicomponent crystalline phases of ITZ. Most importantly, C7 was identified as the maximum carbon atom number of the aliphatic chain for the successful cocrystallization reaction between ITZ and a dicarboxylic acid. In terms of supramolecular structures, two families of the ITZ cocrystals were recognized: (1) the cocrystals built of the trimer characteristic of ITZ-SUC and (2) the cocrystals that are not able to form similar synthons. Overall, our work demonstrates a wide diversity of itraconazol cocrystals with aliphatic dicarboxylic acids having a variety of the carbon chain lengths. This finding alone has a considerable conceptual and also practical value in the field of crystal engineering, suggesting importance of the weak intermolecular interactions in the crystal structure cohesion.



ASSOCIATED CONTENT

* Supporting Information S

Supporting Information including the details of analytical techniques, tables containing the results of experimental solvent-assisted grinding, slow-evaporation crystallization, and concentrations of itraconazole and coformers in solutions, selected results of PXRD analysis and TGA/MS, and solution NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]fi. Tel:+ 358 509662624. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS Dr. Miroshnyk and Dr. Mirza acknowledge financial support from the Finnish Cultural Foundation and the Academy of Finland (decision no. 132726), respectively. A.S. acknowledges the supervising support of Ms. Sanna Peltoniemi, Dr. Juha Kiesvaara, Prof. Veli-Pekka Tanninen, and Dr. Jaakko Aaltonen, as well as the stuff of the Laboratory of Physics (Orion Corporation) for their friendly attitude.



REFERENCES

(1) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. In Solid-State Chemistry of Drugs; SSCI, Inc: West Lafayette, IN, 1999. (2) (a) Gardner, C. R.; Walsh, C. T.; Almarsson, Ö . Nat. Rev. Drug Discovery 2004, 3, 926−934. (b) Balbach, S.; Korn, C. Int. J. Pharm. 2004, 275, 1−12. (c) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Morris, J. Pharm. Res. 2001, 18, 859−866. (d) Huang, L.; Tong, W.-Q. Adv. Drug Delivery Rev. 2004, 56, 321−334. (e) Lipinski, C. A. J. Pharmacol. Toxicol. Methods 2000, 44, 235−249. (f) Wassvik, C. M.; Holmen, A. G.; Bergstrom, C. A. S.; Zamora, I.; Artursson, P. Eur. J. Pharm. Sci. 2006, 29, 294−305. (3) (a) Byrn, S. R.; Henck, J.-O. Optimizing the physical form opportunities and limitations. Drug Discovery Today: Technol. 2012, 9, e73−e78. (b) Byrn, S. R.; Zografi, G.; Xiaoming, C. Accelerating proof of concept for small molecule drugs using solid-state chemistry. J. Pharm. Sci. 2010, 99, 3665−3675. (c) Stahly, G. P. Cryst. Growth Des. 2007, 7, 1007−1027. G

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(4) Almarsson, Ö .; Zaworotko, M. J. Chem. Commun. 2004, 1889− 1896. (5) (a) Miroshnyk, I.; Mirza, S.; Sandler, N. Expert Opin. Drug Delivery 2009, 6, 333−341. (b) Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Int. J. Pharm. 2011, 419, 1−11. (c) Steed, J. W. Trends Pharmacol. Sci. 2013, 34, 185−193. (d) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499− 516. (e) Brittain, H. G. J. Pharm. Sci. 2013, 102, 311−317. (f) Childs, S. L.; Zavorotko, M. J. Cryst. Growth. Des. 2009, 9, 4208−4211. (6) (a) Babu, N. J.; Nangia, A. Cryst. Growth. Des. 2011, 11, 2662− 2679. (b) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. J. Pharm. Sci. 2008, 97, 3942− 3956. (c) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. J. Pharm. Sci. 2008, 97, 3942− 3956. (d) Frišcǐ ć, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 1547− 1559. (e) Jones, W.; Motherwell, W. D. S.; Trask, A. V. MRS Bull. 2006, 31, 875−879. (f) Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617−630. (g) Gao, Y.; Zu, H.; Zhang, J. J. Pharm. Pharmacol. 2011, 63, 483−490. (h) Good, D. J.; RodríguezHornedo, N. Cryst. Growth. Des. 2009, 9, 2252−2264. (i) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888−1897. (j) Schultheiss, N.; Newman, A. Cryst. Growth. Des. 2009, 9, 2950−2967. (k) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; RodríguezHornedo, N. Int. J. Pharm. 2013, http://dx.doi.org/10.1016/j.ijpharm. 2012.10.043 . (l) Weyna, D. R.; Cheney, M. L.; Shan, N.; Hanna, M.; Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. Mol. Pharmaceutics 2012, 9, 2094−2102. (m) Xu, L.; Chen, J.-M.; Yan, Y.; Lu, T.-B. Cryst. Growth. Des. 2012, 12, 6004−6011. (7) Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzmán, H. R.; Almarsson, Ö . J. Am. Chem. Soc. 2003, 125, 8456−8457. (8) Shevchenko, A.; Bimbo, L. M.; Miroshnyk, I.; Haarala, J.; Jelínková, K.; Syrjänen, K.; van Veen, B.; Kiesvaara, J.; Santos, H. A.; Yliruusi, J. Int. J. Pharm. 2012, 436, 403−409. (9) (a) Sekhon, B. S. Ars Pharm. 2009, 50, 99. (b) Blagden, N.; Berry, D. J.; Parkin, A.; Javed, H.; Ibrahim, A.; Gavan, P. T.; De Matosa, L. L.; Seatona, C. C. New J. Chem. 2008, 32, 1659−1672. (c) Morissette, S. L.; Almarsson, Ö .; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56, 275−300. (10) Nonappa, N.; Lahtinen, M.; Kolehmainen, M.; Haarala, J.; Shevchenko, A. Cryst. Growth. Des. 2013, 13, 346−351. (11) (a) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41−70. (b) Fucke, K.; Myz, S. A.; Shakhtshneider, T. P.; Boldyreva, E. V.; Griesser, U. J. New J. Chem. 2012, 36, 1969−1977. (c) Myz, S. A.; Shakhtshneider, T. P.; Tumanov, N. A.; Boldyreva, E. V. Russ. Chem. Bull. 2012, 9, 1782−1793. (d) Losev, E. A.; Mikhailenko, M. A.; Boldyreva, E. V. Dokl. Phys. Chem. 2011, 439, 153−156. (e) Losev, E. A.; Mikhailenko, M. A.; Achkasov, A. F.; Boldyreva, E. V. New J. Chem. 2013, 37, 1973−1981. (12) Sheikh, A. Y.; Rahim, S. A.; Hammond, R. B.; Roberts, K. J. CrystEngComm 2009, 11, 501−509. (13) Molecular Operating Environment (MOE), 2012.10; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2012; http://www.chemcomp.com/ResearchCurrent_Journals.htm. (14) deChasteigner, S.; Fessi, H.; Devissaguet, J.-P.; Puisieux, F. Drug Develop. Res. 1996, 38, 125−133. (15) Aakeröy, C. B.; Panikkattu, S. V.; DeHaven, B.; Desper, J. Cryst. Growth Des. 2012, 12, 2579−2587. (16) (a) Gopalan, S. R.; Kumaradhas, P.; Kulkarni, G. U.; Rao, C. N. R. J. Mol. Struct. 2000, 521, 97−106. (b) Nguyen, T. H.; Hibbs, D. E.; Howard, S. T. J. Comput. Chem. 2005, 26, 1233−41. (17) Aakeröy, C. B.; Chopade, P. D.; Desper, J. Cryst. Growth. Des. 2011, 11, 5333−5336. (18) Housty, J. Acta Crystallogr. 1967, 22, 288−295.

(19) Chadwick, K.; Davey, R.; Sadiq, G.; Cross, W.; Pritchard, R. CrystEngComm 2009, 11, 412−414. (20) (a) Vogt, F. G.; Williams, G. R. Am. Pharm. Rev. 2011, 13 (7) (http://www.americanpharmaceuticalreview.com/Featured-Articles/ 37105-Advanced-Approaches-to-Effective-Solid-state-Analysis-X-RayDiffraction-Vibrational-Spectroscopy-and-Solid-state-NMR/). (b) Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. E.; Pham, T. N.; Watson, S. A. Cryst. Growth. Des. 2008, 9, 921−937. (21) Socrates, G. Infrared and Raman Characteristic Group Frequencies Tables and Charts, 3rd ed.; Wiley: Chichester, West Sussex, England, 2004. (22) Pogorzelec-Glaser, K.; Rachocki, A.; Ławniczak, P.; Pietraszko, A.; Pawlaczyk, C.; Hilczera, B.; Pugaczowa-Michalskaa, M. CrystEngComm 2013, 15, 1950−1959.

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dx.doi.org/10.1021/cg401061t | Cryst. Growth Des. XXXX, XXX, XXX−XXX