Salt Forms of Amides: Protonation and Polymorphism of

Oct 7, 2013 - Sensors that selectively detect glycolipids—molecules that are involved in infection, inflammation, and... BUSINESS CONCENTRATES ...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/crystal

Salt Forms of Amides: Protonation and Polymorphism of Carbamazepine and Cytenamide Amanda R. Buist,† Alan R. Kennedy,*,† Kenneth Shankland,‡ Norman Shankland,§ and Mark J. Spillman‡ †

WestCHEM Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland School of Pharmacy, University of Reading, Reading RG6 6AD, England § Crystallografx Ltd, 2 Stewart Street, Milngavie, Glasgow G62 6BW, Scotland ‡

S Supporting Information *

ABSTRACT: In situ generation of HCl or HBr in alcohol leads to O-protonation of the amide group of carbamazepine. Six salt phases have been produced using this method and their crystal structures determined by single crystal diffraction. A new polymorph of carbamazepine hydrochloride is described as are two polymorphs of carbamazepine hydrobromide. All are protonated at the amide O atom to give RC(OH)NH2 cations. Prolonged exposure to air results in addition of water to the solid salt forms. Such hydration of carbamazepine hydrobromide simply gives a monohydrated phase, but similar treatment of the equivalent hydrochloride results in partial loss of HCl and the transfer of the remaining proton from the amide group to water to give [carbamazepine][H3O]0.5[Cl]0.5·H2O. A similar hydronium chloride species is the only product isolated after reaction of the carbamazepine analogue cytenamide with HCl generated in methanol.

■

INTRODUCTION The pharmaceutical industry utilizes salt formation and salt selection techniques as simple and effective routes to changing the solid-state and physicochemical properties of active pharmaceutical ingredients (APIs).1 The properties typically of interest include aqueous solubility and dissolution rate, mechanical hardness, crystal morphology, and hygroscopicity, but other commercial considerations also come into play. For basic APIs, hydrochloride salts are the most common salt form to go to market.1,2 This is because chloride is generally regarded as a nontoxic counterion and because the parent hydrochloric acid is a strong acid that can be expected to react with most basic groups yet is relatively inexpensive and plentiful. In 2012, Perumalla and Sun pointed out that overfamiliarity with hydrochloric acid has perhaps produced a blind spot with respect to hydrochloride salt formation.3 What is commonly referred to as hydrochloric acid is in fact an aqueous solution of HCl; the interaction of H+ with water stabilizes the proton and hence lessens its reactivity toward putative bases. It was shown that in situ generation of HCl in nonaqueous solvents gave HCl salts of carbamazepine (CBZ) and paracetamol, both of which are amides and nonbasic in aqueous media. The mechanical properties of the paracetamol salts were then further investigated.3,4 No other protonated form of either API has been reported. Structural studies of other protonated amides have recently been surveyed by Nanubolu et al.,5 who showed the relative rarity of such structures. Despite the widespread occurrence of amide functionalities throughout organic chemistry, few structures of other pharmaceutically relevant amide salts are known. Most crystallographic examples of © 2013 American Chemical Society

protonated amides are simple uronium or methyl uronium ions,6 though structures of more complicated species are known,7 as is the structure of an HCl salt of the API, dutasteride.5 CBZ is an amide-containing anticonvulsant used in the treatment of epilepsy (Scheme 1). However, it is better known to the crystal growth community as the API at the heart of many studies on polymorphism,8 preparation and prediction of solvate and cocrystal forms,9 the mechanism of crystal formation,10 and the comparative structural analysis of systematic series of structures.11 This latter analysis is aided by the presence of structures of five polymorphs of CBZ and over forty solvated forms of CBZ in the Cambridge Structural Database (CSD).12 Our interest in crystal forms of CBZ and the structures of salt forms of organic materials in general9a,c,e,13 led us to revisit Perumalla and Sun’s hydrochloride salt of CBZ (CBZHCl).3 Herein, phase changes in the CBZHCl salt system are reported and the work is expanded to include bromide as a counterion and cytenamide (CYT), a structural analogue of CBZ.14 Six structures of new salt forms of CBZ and CYT are reported and their occurrence and structural similarities discussed.

■

EXPERIMENTAL SECTION

Crystallographic measurements were made with Oxford Diffraction Xcalibur and Gemini instruments. Structural solution and refinement Received: September 6, 2013 Revised: October 6, 2013 Published: October 7, 2013 5121

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

Scheme 1. Carbamazepine (CBZ, Top) and Cytenamide (CYT, Bottom)

Table 2. Selected Crystallographic and Refinement Parameters for CBZ Hydrobromide Structures

against F2 to convergence were performed using programs from the SHELX suite.15 Hydrogen atoms bound to carbon were placed in idealized positions and refined in riding modes, but those bound to nitrogen or oxygen were placed as found in difference Fourier syntheses and refined isotropically. For CBZHBr·H2O, it was found necessary to impose bond length restraints on the NH2 and water protons. For both hydronium species, it was necessary to impose bond length and geometry restraints on all water and hydronium O−H groups. Selected details are given in Tables 1 and 2, and full data has been deposited in CIF format as CCDC 959637−959643. This data can be obtained free of charge from the Cambridge Crystallographic Data center via www.ccdc.cam.ac.uk/data_request/cif. Samples were prepared by the acetyl halide route described previously.3 All reagents were used as purchased and no further drying of reagents or solvents was carried out. Multiple batches of CBZHCl and CBZHBr were prepared. For each batch, approximately 0.23 g of CBZ was dissolved in 4 cm3 of ethanol or methanol and the

compound

CBZHBr (I)

CBZHBr (II)

CBZHBr H2Oa

formula formula weight crystal system space group λ (Å) a (Å) b (Å) c (Å) β (deg) volume (Å3) temperature (K) Z D (g cm−3) reflections collected reflections unique reflections observed Rint goodness of fit R[I > 2σ(I)], F Rw, F2 Flack

C15H13BrN2O 317.18 orthorhombic P212121 0.71073 5.3472(2) 10.3235(3) 49.6238(17) − 2739.32(16) 123(2) 8 1.538 12544 6342 5364 0.0514 1.110 0.0589 0.0860 −0.022(9)

C15H13BrN2O 317.18 orthorhombic P212121 0.71073 7.8120(2) 9.5016(3) 18.0400(7) − 1339.05(8) 123(2) 4 1.573 6015 3043 2721 0.0349 1.042 0.0376 0.0739 −0.017(11)

C15H15BrN2O2 335.20 monoclinic P21/n 1.5418 5.0943(11) 11.110(2) 26.065(5) 91.646(19) 1474.6(5) 123(2) 4 1.510 a

5159 2864 a

1.011 0.0670 0.1624 −

a

Crystal twinned by a 180° rotation about 1 0 0. Application of the appropriate twin matrix gave a new, hklf 5 formatted reflection file and final refinement against this data is reported. The twin scale parameter refined to 0.088(3).

solution placed in a narrow tube. Dropwise, 1 cm3 of either acetyl chloride or acetyl bromide was slowly added. After the vigorous reaction had subsided, the tube was sealed with Parafilm and a few holes were pricked into this seal to allow evaporation. Large crystals were typically visible in the mother liquor after 5 days. The hydronium chloride salt of CYT was prepared by dissolving 0.03 g of CYT in 0.5 cm3 of methanol and then adding 0.25 cm3 of acetyl chloride. The reaction mixture was then left to evaporate and crystallize as above.

Table 1. Selected Crystallographic and Refinement Parameters for CBZ and CYT Chlorides compound

CBZHCl (I)

CBZHCl (II)

CBZCl· Hydronium

CYTCl· Hydronium

formula formula weight crystal system space group λ (Å) a (Å) b (Å) c (Å) β (deg) volume (Å3) temperature (K) Z D (g cm−3) reflections collected reflections unique reflections observed Rint goodness of fit R[I > 2σ(I)], F Rw, F2 Flack

C15H13ClN2O 272.72 orthorhombic Pna21 0.71073 14.1099(3) 17.4778(3) 5.3403(2) − 1316.97(6) 123(2) 4 1.375 7785 3083 2857 0.0218 1.047 0.0303 0.0714 −0.03(5)

C15H13ClN2O 272.72 orthorhombic P212121 0.71073 7.6241(3) 9.5476(4) 17.8401(7) − 1298.61(9) 123(2) 4 1.395 4111 2570 2267 0.0314 1.061 0.0454 0.0813 0.08(8)

C15H15.5Cl0.5N2O2.5 281.52 monoclinic C2/c 1.5418 29.4803(17) 4.9462(2) 21.6558(13) 119.462(8) 2749.4(3) 123(2) 8 1.360 10286 2686 2274 0.0289 1.040 0.0368 0.1044 −

C16H16.6Cl0.4NO2.6 278.73 monoclinic C2/c 0.71073 20.2651(9) 5.8463(3) 23.8489(9) 95.724(4) 2811.4(2) 123(2) 8 1.317 6661 3293 2027 0.0357 1.062 0.0558 0.1293 −

5122

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

Table 3. Formation of Polymorphic and Hydrated Phases of CBZ Salts from Ethanol-Derived Solutions CBZHCl CBZHBr

initial form isolated

in mother liquor (sealed vial, >2 weeks)

in mother liquor (vial open to air)

isolated solid II kept in sealed vial

I I

II II

hydronium hydrate with small amount of II present

hydroniuma II

a All samples characterized were high quality single crystals and were identified by SXD, except for the hydronium chloride formed from the isolated solid of CBZHCl(II). This was poorly crystalline, and the phase was determined by comparison of IR spectra.

■

RESULTS AND DISCUSSION Phase Speciation. Freshly prepared crystals from the reaction of CBZ with acetyl halide in both ethanol and methanol were found to be the salt forms CBZHCl(I) and CBZHBr(I) (Tables 1 and 2). In the case of the chloride, this is the same form as that described previously.3 Addition of water to the isolated crystals gave an immediate conversion to CBZ dihydrate, as confirmed by IR spectroscopy.8e After storage of these salts for several weeks in mother liquor, capillary powder diffraction studies (PXRD) showed that the hydrochloride and the hydrobromide forms had both undergone phase transformations. These changes were complete and the PXRD data were of sufficiently high quality to allow the structures of the new CBZHCl(II) and CBZHBr(II) forms to be solved and refined, using DASH and TOPAS, respectively.16 To investigate the possibility that these phase changes were caused by the sample preparation steps required for PXRD analysis (drying and light grinding), further samples of both the hydrochloride and the hydrobromide were synthesized in ethanol, stored under various conditions, and the resultant crystals were characterized by single crystal diffraction (SXD, Table 3). It was found that the I → II phase transformations for both salts occurred in the mother liquor and were thus independent of the PXRD sample preparation. The SXD structures CBZHCl(II) and CBZHBr(II) were in excellent agreement with those determined from PXRD data and only the SXD structures are reported fully herein. CBZHBr(II) appears to be stable once isolated as a dry solid and does not phase transform if kept in mother liquor in a sealed vial. However, a darkening of solution color is associated with chemical decomposition. CBZHCl(II) appears stable in sealed vials in mother liquor but not as an isolated solid. A hydronium form of CBZ chloride and a hydrated CBZ hydrobromide were also discovered as shown in Table 3. Good quality single crystals of these hydrated forms were obtained by leaving solutions to evaporate in air over a period of 6 to 8 weeks and identified by SXD as CBZCl·hydronium and CBZHBr·H2O. A similar hydronium chloride form of the CBZ analogue, CYT, was the only product isolated from the CYT reaction mixture. This was identified as CYTCl·hydronium. The Protonated Amide. In each of the four anhydrous salt forms [i.e., the hydrochloride salts CBZHCl(I) and CBZHCl(II) and the hydrobromide salts CBZHBr(I) and CBZHBr(II)], the position of the acidic proton is clearly identified in the crystal structure through difference synthesis. These proton positions are well behaved under free refinement. In each case, the proton resides on the O atom of the amide, giving a hydroxyl tautomer with enhanced CN double bond character and the charge formally partially residing on the nitrogen atoms (see Scheme 2 and Figure 1). The protonation is accompanied by a significant lengthening (ca. 0.060−0.070 Å) of the C to O bond and by a shortening of both the C to N bonds (ca. 0.016−0.038 Å for the primary amine and ca. 0.038−0.050 Å for the tertiary amine; see Table 4 for details). This suggests

Scheme 2. Neutral (Left) and O-Protonated (Middle and Right) Resonance Forms of the Amide Functionality of CBZ. Note that the O-Atom Is More Susceptible to Protonation than the Amide N-Atom5

Figure 1. Ion pair structure of CBZHCl(II), highlighting the protonation of the amide group. Nonhydrogen atom thermal ellipsoids here and elsewhere are drawn at the 50% probability level.

that the tertiary amine (and hence tautomer B) has a significant influence here. The hydrated salt CBZHBr·H2O is subtly different in character. It can be seen from Table 4 and the Supporting Information that the C−O and C−N bond lengths lie between those of neutral CBZ and those of the four anhydrous forms. Although difference synthesis suggests that the amide O atom in CBZHBr·H2O is protonated, the data quality does not allow all the proton positions to be independently refined. Thus only the position of the O−H proton of the CBZ cation is refined free of restraints. This gives a rather long O−H bond and a very short H···OH2 hydrogen-bonded contact [2.481(6) and 1.43(6) Å for O···O and H···O, respectively) (see Figure 2). Taken together with the intermediate C−O and C−N bond lengths, this hydrogen-bond geometry suggests that the proton position in crystalline CBZHBr·H2O may be dynamic and that the equilibrium is between the protonated amide and hydronium ion, H3O+. A very short O−H···OH2 hydrogen bond is also seen in the protonated amide salt structure of dutasteride.5 5123

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

Table 4. Geometric Details of the Amide Group bond length (Å) a

CBZ neutral CBZCl·H3O+ CBZHBr· H2O CBZHCl(I) CBZHCl(II) CBZHBr(I)′ CBZHBr(I)″ CBZHBr(II) CYT neutralb CYTCl·H3O+

bond angle (deg)

C−O

C−NH2

C−Xc

OCN

OCX

NCX

1.242 1.250(2) 1.280(7) 1.302(2) 1.308(3) 1.309(5) 1.311(5) 1.312(4) 1.238 1.243(2)

1.342 1.331(2) 1.331(8) 1.318(2) 1.322(3) 1.326(6) 1.316(6) 1.304(4) 1.325 1.323(3)

1.373 1.373(2) 1.338(8) 1.332(2) 1.329(3) 1.323(5) 1.324(6) 1.335(4) 1.534 1.531(3)

122.2 121.2(1) 122.0(7) 120.7(1) 120.5(2) 120.5(4) 120.7(5) 121.0(3) 122.1 121.4(2)

120.3 120.7(1) 118.3(7) 116.9(1) 117.1(2) 117.6(4) 116.5(4) 116.3(3) 120.1 120.7(2)

117.4 118.1(1) 119.7(6) 122.4(1) 122.4(2) 121.9(4) 122.9(5) 122.6(3) 117.7 117.8(2)

a

Average values from 47 nondisordered, well-modeled, SXD-determined fragments present in the CSD. bAverage values from 8 nondisordered, wellmodeled, SXD-determined fragments present in the CSD. cFor CBZ, XN; for CYT, XC.

Figure 3. Structure of CBZCl·hydronium with partially present H2O molecules omitted for clarity. These disordered solvent molecules lie close to the partially occupied Cl and H3O sites shown.

Figure 2. Asymmetric unit contents of CBZHBr·H2O highlighting the ROH to water interaction.

The hydrochloride salt of CBZ is also hygroscopic and incorporates water into the crystal structure both as an isolated solid and when still in contact with its mother liquor. Unlike the bromide case, above, this is accompanied both by partial loss of HCl and by complete transfer of the remaining acidic proton to water to give the mixed hydronium chloride species with formula [CBZ]2[H3O][Cl]·2H2O, CBZCl·hydronium (Figure 3). The structure has disordered hydronium/water sites, but the identification of the cation as protonated water and not protonated CBZ is supported by (a) the amide group’s C−O and C−N bond distances, which are consistent with other neutral CBZ species and (b) by the isolation of a similar hydronium/chloride species, which was the only product isolated upon attempted protonation of cytenamide. CYTCl· hydronium has stochiometry [CYT]2[H3O]0.8[Cl]0.8·2.4H2O and thus contains somewhat less chloride than its CBZ equivalent. Within the limited scope of the crystallizations performed, no CYT(H) cation species has been detected. The bond length analysis discussed above and summarized in Table 4 shows that for CBZ(H), the ring N atom plays a major role in stabilizing the positive charge. Similar stabilization is obviously not possible for CYT. Note that while not overly common, solid state structures of organic hydronium chlorides are known and are accessible from aqueous hydrochloric acid.17 However, the conversion of a solid organic HCl salt to a solidstate hydronium species through interaction with air, as seen for

CBZHCl, is unusual. Protonation of the amide can also be detected by IR spectroscopy. The simple halide salts have obvious absorption bands (e.g., at 2285, 2393, and 2378 cm−1 for the Cl, Br, and Br hydrate forms, respectively) at frequencies not seen for the various polymorphs of CBZ8c or in the IR spectra of the hydronium chloride species, further confirming the neutral nature of the CBZ and CYT molecules in these latter complexes. Supramolecular Motifs and Packing. Analyses of the structures of CBZ and CYT solvates and cocrystals have commented on the common occurrence of a hydrogen-bonded motif, featuring an R22(8) amide−amide dimer. This frequently has two additional solvent molecules that accept hydrogen bonds from the anti positioned amine groups (Scheme 3).9c,e,14 This dimeric motif is a variation on the hydrogen-bonded dimers seen in the polymorphic structures of these and similar amides and which is often discussed with comparison to the alternative arrangement of a hydrogen-bonded catemeric chain.5,18 In the salt forms presented here, the proton on the amide O atom prevents the normal CBZ-to-CBZ hydrogen bonds from occurring. However, the two hydronium salts again show their fundamental difference to the CBZ(H) containing salts as both of these do form dimer structures similar to those seen for CBZ and CYT solvates. Thus, in the structure of CYTCl·hydronium, a variation of the classic hydrogen-bonding 5124

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

of dimers are offset from one another (compare Figures 5 and 4).

Scheme 3. Most Common Hydrogen-Bonded Motif Found in Cocrystals of CBZ, S = Solvent or Cocrystal Former

Figure 5. Packing in CBZCl·hydronium as viewed down the b direction. Note that unlike Figure 4, each stack of dimeric pairs is offset with respect to its neighbors.

motif of Scheme 3 is seen. The amide−amide dimer is retained, but now the amide NH2 and carbonyl groups are both involved in hydrogen bonding to the disordered solvent and ion sites (see Figure 4). The solvent/ion sites also interact with

Of the CBZ(H) cation containing species, none feature direct amide-to-amide hydrogen bonds. In the anhydrous salts, both the OH and NH2 groups of CBZ(H) donate hydrogen bonds only to the halide counterions. A 20 molecule overlay, in the program Mercury,20 confirmed significant packing similarity between the CBZHCl(I) and CBZHBr(I) crystal structures, with 15 out of 20 CBZ cations in common (RMSD = 0.858 Å, with the software option “Ignore smallest molecular components” selected and 30% geometric tolerances). The thermodynamically more favorable phases, CBZHCl(II) and CBZHBr(II), are mutually isostructural, with 20 out of 20 CBZ cations in common (RMSD = 0.170 Å; see Tables 1 and 2 for the dimensions of the CBZHCl(II) and CBZHBr(II) unit cells). The differences between these species and their respective polymorphs can best be illustrated by describing the interactions of the halide ions. In the form (II) structures, each halide accepts three classical hydrogen bonds, two each from a single CBZ(H) ion to form a [XHNCOH] (X = Cl or Br) six-membered ring and one from a second neighboring NH2 group that lies out of the [XHNCOH] ring plane. A fourth and final close contact of the halide is to a third CBZ(H) cation and to the ortho carbon atom of the aromatic ring syn to OH [Cl···C = 3.584; Br···C = 3.639 Å]. This interaction also lies significantly out of the [XHNCOH] ring plane, giving an approximately tetrahedral set of interactions about the halide ion (see Figure 6). The initially formed hydrochloride species, CBZHCl(I), displays the same types of short chloride interactions as the more favorable polymorph, but the geometry of these is now different with all the groups (2 NH2, OH, and sp2 C) forming the closest interactions to Cl lying approximately in plane (see Figure 7). A further difference is that the close C···Cl contact (3.596 Å) is now with the C atom para to the amide functionality rather than to the ortho C atom of the same ring. The structure of CBZHBr(I) contains two crystallographically independent bromide ions. One of these interacts as does that in CBZHBr(II), but the closest C···Br interaction (3.727 Å) now involves the C atom of the amide group and not one from the aromatic ring. The second bromide site is similar, but now the [BrHNCOH] ring contains two very asymmetric Br···H

Figure 4. Packing in CYTCl·hydronium, as viewed down the b direction. Hydrophobic and hydrophilic layers alternate along the c direction.

neighboring amide−amide dimers to give a hydrogen-bonded chain that propagates parallel to the crystallographic a direction. Similar intermolecular interactions are seen for the analogous compounds [CBZ][NH4][X], (X = Cl or Br), the only other known CBZ structures with charged species present.19 The chloride ions in CYTCl·hydronium also form hydrogen bonds that further link the above-described chains in the b direction, leaving a layered structure with alternating hydrophilic and hydrophobic zones along c (see Figure 4). The other hydronium salt, CBZCl·hydronium, has a similar amide− amide dimeric structure with further hydrogen bonds to water and the ionic species. However, the interwater and ion contacts now differ and give a packed structure where neighboring stacks 5125

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

Figure 8. One-Dimensional Hydrogen-Bonded Polymer in the Structure of CBZHBr·H2O. Figure 6. Close contacts with Cl in CBZHCl(II). The bromide species CBZHBr(II) is isostructural.

CBZ have been produced using this method and their crystal structures determined by SXD. Both CBZHCl and CBZHBr were initially isolated as metastable forms that subsequently spontaneously transformed to the more favorable forms, CBZHCl(II) and CBZHBr(II). These latter two forms are isomorphic. Prolonged exposure to air leads to hydration. In the case of the hydrobromide, this gives a hydrate, but the hydrochloride partially loses HCl and undergoes proton transfer to give a hydronium chloride species. A similar hydronium chloride species was the only product identified upon reaction of CYT with HCl. The phase transformation behavior of the CBZ salts and their instability on contact with liquid water indicates that they are unlikely candidates for further drug development. However, this rarely utilized approach to salt formation has a much wider industrial relevance, enabling poorly ionizable functional groups to become targets for halide salt formation.

Figure 7. Close contacts with Cl in CBZHCl(I). The Cl anion and the 4 H atoms of the hydrogen bond donors all lie in a more planar geometry than that seen for the phase (II) species.

■

ASSOCIATED CONTENT

■

AUTHOR INFORMATION

S Supporting Information *

Details of single crystal characterizations as cif files, a graphical representation of the geometrical difference between the amide groups of protonated and neutral CBZ, and overlay diagrams showing packing similarities. This material is available free of charge via the Internet at http://pubs.acs.org.

contacts. Indeed the longer Br···H−N contact of 2.71 Å is outside the range of what would normally be considered a significant Br···H hydrogen bond. There is a significant packing similarity between the CBZHBr(I) and CBZHBr·H2O crystal structures, with 13 out of 20 CBZ cations in common (RMSD = 0.729 Å). In hydrated CBZHBr·H2O, two water OH···Br interactions replace the amide OH···Br interaction and one of the NH··· Br interactions seen in the anhydrous structures. There are no Br···C interactions as short as those found in the anhydrous salts. As discussed above, the amide OH here donates a hydrogen bond to the water molecule in a very short interaction suggestive of an equilibrium with a hydronium species. Despite this potential hydronium-like character, this hydrate forms neither amide−amide dimers (as seen for the hydronium species and cocrystals and solvates of CBZ) nor does it form the six-membered [XHNCOH] ring seen in the anhydrous salts. Instead, the hydrogen bonds combine to give a one-dimensional motif that propagates along the crystallographic a direction (Figure 8).

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS M.J.S. is grateful to both the University of Reading and the STFC Centre for Molecular Structure and Dynamics for funding.

■

REFERENCES

(1) Handbook of Pharmaceutical Salts: Properties, Selection and Use; Stahl, P. H., Wermuth, C. G., Eds.; VHCA: Zurich, 2008. (2) (a) Gould, P. L. Int. J. Pharm. 1986, 33, 201. (b) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. J. Pharm. Sci. 1977, 66, 1. (c) Lam, K. W.; Xu, J. J.; Ng, K. M. Ind. Eng. Chem. Res. 2010, 49, 12503. (d) Paulekhun, G. S.; Dressman, J. B.; Saal, C. J. Med. Chem. 2007, 50, 6665. (3) Perumalla, S. R.; Sun, C. C. Chem.Eur. J. 2012, 18, 6462.

■

CONCLUSION In situ generation of HCl or HBr in methanol or ethanol leads to O-protonation of the amide group of CBZ. Six salt phases of 5126

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127

Crystal Growth & Design

Article

(4) Perumalla, S. R.; Shi, L.; Sun, C. C. CrystEngComm 2012, 14, 2389. (5) Nanubolu, J. B.; Sridhar, B.; Ravikumar, K. CrystEngComm 2012, 14, 2571. (6) See for example, (a) Henschel, D.; Hamann, T.; Moers, O.; Blaschette, A.; Jones, P. G. Z. Naturforsch., B: J. Chem. Sci. 2002, 57, 113. (b) Chen, S.-P.; Hu, L.; Hu, X.-J.; Yuan, Y.-X.; Pan, L.-L.; Yuan, L.-J. Cryst. Growth Des. 2009, 9, 3835. (c) Goal, N.; Singh, U. P.; Singh, G.; Srivastava, P. J. Mol. Struct. 2013, 1036, 427. (7) Selected as especially interesting are (a) Stezowski, J. J. J. Am. Chem. Soc. 1977, 99, 1122. (b) Hasche, S.; Reich, O.; Beckmann, I.; Krebs, B. Z. Anorg. Allg. Chem. 1997, 623, 724. (c) Gubin, A. I.; Erkasov, R. S.; Nurakhmetov, N. N.; Buranbaev, M. Z. Krystallografiya 1990, 35, 1278. (d) Iliopoulos, P.; Fallon, G. D.; Murray, K. S. J. Chem. Soc., Dalton Trans. 1986, 437. (8) (a) Arlin, J.-B.; Price, L. S.; Price, S. L.; Florence, A. J. Chem. Commun. 2011, 47, 7074. (b) Lang, M.; Kampf, J. W.; Matzger, A. J. J. Pharm. Sci. 2002, 91, 1186. (c) Grzesiak, A. L.; Lang, M.; Kim, K.; Matzger, A. J. J. Pharm. Sci. 2003, 92, 2260. (d) Lui, W.; Wei, H.; Black, S. Org. Process Res. Dev. 2009, 13, 494. (e) Elqidra, R.; Ü nlü, N.; Ç apan, Y.; Sahin, G.; Dalkava, T.; Hincal, A. A. J. Drug Delivery Sci. Technol. 2004, 14, 147. (9) (a) Majumder, M.; Buckton, G.; Rawlinson-Malone, C.; Williams, A. C.; Spillman, M. J.; Shankland, N.; Shankland, K. CrystEngComm 2011, 13, 6327. (b) Musumeci, D.; Hunter, C. A.; Prohens, R.; Scuderi, S.; McCabe, J. F. Chem. Sci. 2011, 5, 883. (c) Johnston, A.; Johnston, B. F.; Kennedy, A. R.; Florence, A. J. CrystEngComm 2008, 10, 23. (d) Childs, S. L.; Rodriguez-Hornedo, N.; Reddy, L. S.; Jayasanker, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C. CrystEngComm 2008, 10, 856. (e) Florence, A. J.; Johnston, A.; Price, S. L.; Nowell, H.; Kennedy, A. R.; Shankland, N. J. Pharm. Sci. 2006, 95, 1918. (f) Arora, K. K.; Thakral, S.; Suryanrayanan, R. Pharm. Res. 2013, 7, 1779. (10) (a) Hunter, C. A.; McCabe, J. F.; Spitaleri, A. CrystEngComm 2012, 14, 7115. (b) O’Mahony, M. A.; Maher, A.; Croker, D. M.; Rasmuson, A. C.; Hodnett, B. K. Cryst. Growth Des. 2012, 12, 1925. (c) Diao, Y.; Whaley, K. E.; Helgeson, M. E.; Woldeyes, M. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L. J. Am. Chem. Soc. 2012, 134, 673. (d) Kelly, R. C.; Rodriguez-Hornedo, N. Org. Process Res. Dev. 2009, 13, 1291. (11) (a) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2006, 8, 448. (b) Cruz Cabeza, A. J.; Day, G. M.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2007, 7, 100. (12) (a) Allen, F. H. Acta Crystallogr. 2002, B58, 380. (b) The ubiquitous nature of CBZ in crystallographic research is even reflected in the choice of a hydrogen-bonded dimer of CBZ as part of the graphical logo of the database’s home page, http://webcsd.cds.rsc.org, accessed May 2013. (13) (a) Kennedy, A. R.; Morrison, C. A.; Briggs, N. E. B.; Arbuckle, W. Cryst. Growth Des. 2011, 11, 1821. (b) Arlin, J.-B.; Florence, A. J.; Johnston, A.; Kennedy, A. R.; Miller, G. J.; Patterson, K. Crystal Growth Des. 2011, 11, 1318. (c) Briggs, N. E. B.; Kennedy, A. R.; Morrison, C. A. Acta Crystallogr. 2012, B68, 453. (d) Kennedy, A. R.; Andrikopoulos, P. C.; Arlin, J.-B.; Armstrong, D. R.; Duxbury, N.; Graham, D. V.; Kirkhouse, J. B. A. Chem.Eur. J. 2009, 15, 9494. (14) Florence, A. J.; Bedford, C. T.; Fabbiani, F. P. A.; Shankland, K.; Gelbrich, T.; Hursthouse, M. B.; Shankland, N.; Johnston, A.; Fernandes, P. CrystEngComm 2008, 10, 811. (15) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112. (16) (a) David, W. I. F.; Shankland, K.; van de Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. J. Appl. Crystallogr. 2006, 39, 910. (b) Coelho, A. A. TOPAS User Manual, version 3.1; Bruker AXS GmbH: Karlsruhe, Germany, 2003. (17) For examples, see (a) Tessler, L.; Goldberg, I. Acta Crystallogr. 2005, C61, o738. (b) Hoser, A. A.; Dobrzycki, L.; Gutmann, M. J.; Wozniak, K. Cryst. Growth Des. 2010, 10, 5092. (c) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272. (18) (a) Florence, A. J.; Leech, C. K.; Shankland, N.; Shankland, K.; Johnson, A. CrystEngComm 2006, 8, 746. (b) Arlin, J.-B.; Johnston, A.;

Miller, G. J.; Kennedy, A. R.; Price, S. L.; Florence, A. J. CrystEngComm 2010, 12, 64. (19) Reck, G.; Thiel, W. Pharmazie 1991, 46, 509−512. (20) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466.

5127

dx.doi.org/10.1021/cg401341y | Cryst. Growth Des. 2013, 13, 5121−5127