Article pubs.acs.org/molecularpharmaceutics
Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study Palash Sanphui,† Manish Kumar Mishra,† Upadrasta Ramamurty,*,‡,§ and Gautam R. Desiraju*,† †
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India Department of Materials Engineering, Indian Institute of Science, Bangalore 560 012, India § Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia ‡
S Supporting Information *
ABSTRACT: Crystals of voriconazole, an antifungal drug, are soft in nature, and this is disadvantageous during compaction studies where pressure is applied on the solid. Crystal engineering is used to make cocrystals and salts with modified mechanical properties (e.g., hardness). Cocrystals with biologically safe coformers such as fumaric acid, 4-hydroxybenzoic acid, and 4-aminobenzoic acid and salts with hydrochloric acid and oxalic acid are prepared through solvent assisted grinding. The presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals is unambiguously confirmed with single crystal X-ray diffraction. All the cocrystals have 1:1 stoichiometry, whereas salts exhibit variable stoichiometries such as HCl salt (1:2) and oxalate salts (1:1.5 and 1:1). The nanoindentation technique was applied on single crystals of the salts and cocrystals. The salts exhibit better hardness than the drug and cocrystals in the order salts ≫ drug > cocrystals. The molecular origin of this mechanical modulation is explained on the basis of slip planes in the crystal structure and relative orientations of the molecules with respect to the nanoindentation direction. The hydrochloride salt is the hardest solid in this family. This may be useful for tableting of the drug during formulation and in drug development. KEYWORDS: crystal engineering, cocrystals, elastic modulus, hardness, nanoindentation, salts
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INTRODUCTION Crystal engineering1 is widely utilized in designing active pharmaceutical ingredients (APIs) so as to obtain materials that exhibit optimum combinations of important physicochemical properties such as solubility, dissolution rate, and bioavailability.2 In the context of industrial-scale pharmaceutical manufacturing, it can also be used to tune mechanical properties such as grindability and tabletability, which often determine the processing steps that are adopted. For example, voriconazole (VOR, Scheme 1), which is the compound examined in the current study, is so soft that it becomes a paste during grinding and/or milling3processes that are commonly employed during the production stages of APIsconsequently making it unwieldy. To circumvent this problem, regelatinized starch maize is being used to make compressed tablets during formulation of the drug. In this paper, we demonstrate that the mechanical properties of VOR cocrystals, especially hardness, a property that captures a material’s resistance to plastic deformation, can be varied systematically, and to the desired levels, by varying the coformer content. Although prior studies on the mechanical properties of cocrystals4 are available, most of those are performed on polycrystalline aggregates. The key feature of the current paper is the utilization of the nanoindentation technique to study the © 2015 American Chemical Society
properties of single crystals of VOR and its salts and cocrystals. This technique allows for measuring the mechanical response of materials that are available only in small sizes; this has been exploited in the recent past to study structure−property correlations in molecular crystals.5 In particular, fundamental understanding of the influence exerted by structural features such as crystal packing,5a strength of intermolecular interactions,5d domain coexistence,5b,h polymorphism,5f layer migration,5e and solid state reactivity on mechanical properties such as stiffness and strength5c,g can be explored through nanoindentation studies. In the current context, employing nanoindentation not only allows us to study mechanical properties of cocrystals but (and more importantly) also allows us to correlate the measured changes in properties with the underlying structural features in the context of cocrystal engineering. It is expected that such an understanding will enhance the predictability of powder processing steps such as milling and compaction, which otherwise require large Received: Revised: Accepted: Published: 889
October 27, 2014 January 5, 2015 January 14, 2015 January 14, 2015 DOI: 10.1021/mp500719t Mol. Pharmaceutics 2015, 12, 889−897
Article
Molecular Pharmaceutics Scheme 1. Voriconazole (VOR) and Coformers in This Studya
a
The most basic sites are marked with an asterisk (*).
The crystals were harvested and then washed with paraffin oil to remove any small crystallites that might have stuck to the surface of larger crystals. Subsequently, they were firmly mounted on a metallic stud using cyanoacrylate glue for nanoindentation experiments. Four to five crystals were examined for each case. The indentation experiments were performed on the (100) faces of VOR, VOR-OXA2, VOR− FUM, VOR−PAB, and VOR−PHB and (011) face of VORHCl and VOR-OXA1 with the Triboindenter of Hysitron, Minneapolis, MN, USA with an in situ imaging capability. The machine continuously monitors and records the load, P, and displacement, h, of the indenter with force and displacement resolutions of 1 nN and 0.2 nm, respectively. The loading and unloading rates were 0.5 mN/s, and the hold time at the peak load of 5 mN was 30 s. A three-sided pyramidal Berkovich diamond indenter (Poisson’s ratio = 0.07) with a tip radius of ∼100 nm was used. Around 20 indentations were performed on each crystal. The indentation impressions were captured immediately after unloading. The P−h curves were analyzed using the standard Oliver−Pharr method10 to extract the elastic modulus, E, and hardness, H, of the crystal in that orientation. In the absence of data on the Poisson’s ratio of VOR or its multicomponent crystals, we have assumed their Poisson’s ratio to be 0.3 for the purpose of the analysis.
quantities of powders for pilot plant studies, typically several tens of kilograms.3b,6 VOR (chemical name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) is a weakly basic, nonhygroscopic API and is classified as a moderately soluble (1 g/L) and highly permeable drug that is generally used to treat chronic, invasive fungal infections (antifungal drug). In VOR, both triazole and pyrimidine N atoms are capable of O−H···N heterosynthon formation with coformers containing carboxylic acids and phenols. We have chosen both aliphatic and aromatic coformers (Scheme 1), which are not toxic and hence are biologically safe.
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EXPERIMENTAL SECTION Commercially obtained VOR and coformers were used without further purification. Methods such as solid state grinding, solution crystallization, and slurry methods in polar solvents such as MeOH and MeCN were carried out to make the cocrystals and salts (see Supporting Information). Melting points (mp) of these materials were measured on a Büchi melting point apparatus. Water filtered through a double distilled water purification system (Siemens, Ultra Clear, Germany) was used in all the experiments. Powder X-ray diffraction (PXRD) data was recorded using a Philips X’pert Pro X-ray powder diffractometer equipped with an X’cellerator detector. All scans were performed at room temperature with the scan range 2θ = 5 to 40° and step size 0.017°. The X’Pert HighScore Plus software was used to compare the experimental PXRD pattern with the calculated lines from the crystal structure (see Figure S1, Supporting Information). Single Crystal X-ray Diffraction. Single crystal X-ray data of all the salts and cocrystals were collected on a Rigaku Mercury 375/M CCD (XtaLAB mini) diffractometer using graphite monochromated Mo Kα radiation at 150 K. The data were processed with the Rigaku Crystal clear software.7 Structure solution and refinements were executed using SHELX-978 using the WinGX9 suite of programs. Refinement of coordinates and anisotropic thermal parameters of nonhydrogen atoms were performed with the full-matrix leastsquares method. Positions of the hydrogen atoms were either located from difference Fourier map or calculated using the riding model. Crystallographic cif files (CCDC Nos. 984147− 984151) are available at www.ccdc.cam.ac.uk/data_request/cif. Nanoindentation. Large single crystals (average size: 1 × 1 × 0.5 mm3) of voriconazole and its salts and cocrystals were grown by slow evaporation at room temperature for a week.
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RESULTS AND DISCUSSION Crystal Structures. The crystal structures of VOR, its camphorsulfonate salt, oxalate salt, and fumaric acid cocrystals (without the 3D coordinates) are already reported in the literature,11 while Kumar et al.12 have recently reported the crystal structures of VOR cocrystals with 4-hydroxybenzoic acid, 4-aminobenzoic acid, and 3-nitrobenzoic acid, and also that of dinitrate salt. In view of this, we only report the new crystal structures of VOR-HCl (1:2), VOR-OXA1 (1:1.5), VOR-OXA2 (1:1) salts, and VOR−FUM (1:1) cocrystal in this paper. A brief summary of the crystallographic information on the reported salts and cocrystals is provided in Table S1, Supporting Information. The VOR molecule has the same chirality (2R, 3S) as the parent compound VOR in all the crystal structures. Mulliken atomic charges of the nitrogen atoms in the VOR molecule (Figure S2, Supporting Information) indicate that the N3 nitrogen of the triazole ring possesses a greater negative charge (−0.3217 au) than the N5 nitrogen of the pyrimidine ring (−0.1757 au). The N4 nitrogen of the pyrimidine ring (−0.3236 au) is highly negatively charged and donates a strong intramolecular 890
DOI: 10.1021/mp500719t Mol. Pharmaceutics 2015, 12, 889−897
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Molecular Pharmaceutics
Figure 1. Molecular packing and hydrogen bonded networks in the crystal structure of (a) VOR and its salts (b) VOR-HCl, (c) VOR-OXA1, and (d) VOR-OXA2.
Figure 2. Molecular packing and hydrogen bonded networks in the crystal structure of (a) VOR−FUM, (b) VOR−PHB, and (c) VOR−PAB cocrystals.
group P212121, and the asymmetric unit contains protonated triazole and pyrimidine N atoms in VOR and two chloride anions. The crystal packing of the dihydrochloride and dinitrate salts (reported)12 are quite different. There is a common intramolecular O−H···N hydrogen bond between pyrimidine N1 atom and hydroxyl group. Two VOR cations and two Cl− anions form a tetramer ring with C−H···Cl−and N+−H···Cl− interactions, and this is extended along the crystallographic a axis (Figure 1b). The Cl− anions are present in the channel
hydrogen bond. Below, we describe the relevant and necessary aspects of the crystal structures of each of the compounds. Voriconazole. The reported crystal structure of VOR (P21, Z = 2)11a consists of strong O−H···N intramolecular hydrogen bond and auxiliary weaker C−H···O (OH) and C−H···N hydrogen bonds forming a layered structure (Figure 1a). The layers are extended via even weaker C−H···F interactions (Figure S3a, Supporting Information). Voriconazole Dihydrochloride Salt (VOR-HCl, 1:2). VOR-HCl (1:2) salt crystallizes in the orthorhombic space 891
DOI: 10.1021/mp500719t Mol. Pharmaceutics 2015, 12, 889−897
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Figure 3. (a) Torsional flexibility in VOR. (b, c) Structural overlay of VOR in the API, cocrystals and salts. Pyrimidine and triazole rings are anti in the API and the salts, while they are in syn positions in cocrystals.
(viewed down the b axis) between the two layers of VOR cations (Figure S3b, Supporting Information). Voriconazole Oxalate Salt (VOR-OXA1, 1:1.5). VOROXA1(1:1.5) salt crystallizes in the orthorhombic space group C2221, and the PXRD pattern is different from the prior art (WO 2009/053993 A2).11d The asymmetric unit consists of one VOR cation, one oxalic acid (neutral), and a half equivalent of oxalate anion. Proton transfers from oxalic acid to triazole N of VOR and one oxalate dianion bind two VOR cations. Oxalic acid and oxalate anion form 1D O−H···O/O−H···O− hydrogen bonds along the crystallographic b axis (Figure 1c). Auxiliary (sp2) C−H···O hydrogen bonds further stabilize the packing. Similar to the HCl salt, oxalic acid and oxalate anions are sandwiched between the double layers of VOR cations (Figure S3c, Supporting Information). Voriconazole Oxalate Salt (VOR-OXA2, 1:1). VOROXA2 salt crystallizes in the monoclinic space group P21, and the PXRD pattern is also different from the prior art (WO 2009/053993 A2).11d The crystal structure contains one VOR cation and one oxalate monoanion in the asymmetric unit. Proton transfer from oxalic acid to triazole N of VOR confirms its ionic nature. Similar to the 1:1.5 salt, oxalate monoanions form 1D chains via O−H···O− ionic hydrogen bonds along the b axis and further interact with the API through N+−H···O− interactions, see Figure 1d. However, the 3D packing is quite different in the two cases. In VOR-OXA1, API and coformers are well separated, whereas they are partially overlapped over each other in VOR-OXA2, viewed down the a axis, Figure S3d, Supporting Information. Voriconazole Fumaric Acid Cocrystal (VOR−FUM, 1:1). Unlike oxalic acid, fumaric acid forms a cocrystal with VOR, and the crystal structure (P21, Z = 2) consists of one VOR and one FUM molecule in the asymmetric unit. Recently, VOR− FUM cocrystal is reported in a patent, WO 2013/084130 A1,11e with PXRD characterization. We were not able to locate
the hydrogen atom of the hydroxyl group in VOR. Fumaric acid interacts with both the triazole and pyrimidine N atoms via (CO2H) O−H···N hydrogen bond in a helical pattern (Figure 2a).The trimer units are extended to the next trimer via auxiliary C−H···F interactions. Three dimensional packing diagram of the cocrystal indicates that the layers of VOR and FUM are not well separated (Figure S3e, Supporting Information). Voriconazole 4-Hydroxybenzoic Acid Cocrystal (VOR−PHB, 1:1). The reported cocrystal VOR−PHB (1:1) crystallizes in the monoclinic space group P21 (Z = 2).12 The single crystal X-ray data was re-collected at 150 K for better comparison purposes. Mulliken atomic charges of the OH group (−0.6707 au) and the CO2H group (−0.5032 and −0.6248 au) indicate stronger donor capacity of hydroxyl group compared to carboxyl (Figure S2, Supporting Information). Hence, hydroxyl and carboxyl groups form hydrogen bonds with triazole and pyrimidine N atoms and a helical motif similar to the one in the VOR−FUM cocrystal is observed; see Figure 2b. The helical arrangement of VOR and PHB molecules is further stabilized by auxiliary (sp2) C−H···O interactions between triazole ring CH and carboxylic acid. The trimer units of two VOR and one PHB molecules are extended to the next unit via (sp3) C−H···F bonds. Voriconazole 4-Aminobenzoic Acid Cocrystal (VOR− PAB, 1:1). The reported cocrystal VOR−PAB (1:1) crystallizes in the monoclinic space group P21 (Z = 2).12 The only difference is that the −OH group is replaced by the isoelectronic −NH2 in PAB. Both VOR−PHB (1:1) and VOR−PAB (1:1) are 3D isostructural. In PAB, the NH2 group is more electronegative (−0.7839 au) than CO2H (−0.5019 and −0.6798 au) and hence similar to VOR−PHB cocrystals, amine NH2 and −CO2H groups forming hydrogen bonds with the triazole and pyrimidine nitrogen atoms via N−H···N and O−H···N hydrogen bonds (Figure 2c). The other amine N−H 892
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Figure 4. Representative P−h curves obtained on VOR and its (a) salts and (b) cocrystals.
relatively easy. Likewise, H is a particularly important mechanical property in the context of compressibility and tabletability. Since these are physical properties that depend on intrinsic structural features, they can also be correlated to functional properties as well. For example, we have recently shown that H and solubility of the APIs are inversely correlated, with polymorphs of APIs with low H values being more amenable to dissolution than those with high H.17 Salts. All the nanoindentation experiments were carried out on structurally similar major faces of VOR, its salts, and its cocrystals. Representative P−h curves of VOR and its salts are displayed in Figure 4a. The P−h responses obtained on VOR crystals are smooth, indicating homogeneous plastic deformation. In contrast, the loading parts of the P−h curves obtained on all the salts showed discrete displacement bursts, referred to as “pop-ins”18 in the literature, indicating that the plastic deformation in these crystals occurs intermittently. The pop-ins in VOR-HCl were found to be integer multiples of ∼10 nm, which is close to the interplanar spacing of (011), d011 (0.98 nm). Likewise, the pop-ins on the P−h curves of VOR-OXA1 and VOR-OXA2 are ∼10.2 and 9 nm in magnitude respectively, which again are integer multiples of d010 (2.5 nm) and d100 (0.87 nm) in respective crystals. The AFM images of the indents made on the salts showed material pile-up along the edges of the impressions, whereas no such pile-up was observed in VOR (Figure S4, Supporting Information). The average values of E and H of VOR and its salts extracted from the P−h curves are listed in Table 1. As seen here, all the salts are
fragment interacts with the carboxylic acid via N−H···O hydrogen bonds. Molecular Conformations. The voriconazole molecule contains flexible triazole and pyrimidine rings (Figure 3a). The torsional flexibility is observed in this drug and its cocrystal and salts, also reported by Kumar et al.12 The orientation of the triazole ring of VOR in the cocrystals with FUM, PHB, and PAB is syn with respect to the pyrimidine moiety of VOR, but anti in the salts with HCl, OXA1, and OXA2, see Figure 3b,c. It seems that the coformers with two functional groups, which can interact with both the triazole and pyrimidine moiety, exhibit the syn conformation. Mechanical Properties. Before presenting results of the nanoindentation experiments and discussing the structural origins of the material-to-material variations in the mechanical properties, elastic modulus (E) and hardness (H) that can be measured with nanoindentation, it may be useful to highlight the physical significance of these properties. For a given material, E and H are measures of the resistance offered by it to elastic and plastic deformations respectively, and depend on a number of structural factors.13 E depends upon parameters such as the structural packing efficiency, type and number of interactions between molecules, and also the relative orientation of the molecules with respect to the loading (indentation) direction. Typically, high packing efficiency, strong intermolecular interactionsand a multitude of them, and alignment of them along the indentation direction lead to high E.14 In contrast, H depends strongly on the relative ease with which molecular layers can slide past each other on specific crystallographic planes. Typically, slip planes are the ones with the least attachment energy, Eatt.15 Likewise, the slip directions are those along which the lattice translation is the shortest. Together, the slip planes and directions are referred to as the slip system. Thus, variations in H can be rationalized by taking recourse to the identification of the slip system and its relative orientation with the indentation direction. Additionally, weak nondirectional π···π and van der Waals interactions facilitate easy shearing of the molecular planes as they can be broken relatively easily. In contrast, strong directional interactions like hydrogen bonds influence elasticity because of their restorative character. Typically, high values of both E and H would imply that the material is resistant to deformation and hence is brittle; ceramics are classical examples of such materials.6,16 In the pharmaceutical manufacturing context, such materials would be easy to comminute (or mill) as fragmentation would be
Table 1. Elastic Modulus (E), Hardness (H), and Slip System of VOR and Its Salts and Cocrystals indented face
hardness, H (MPa)
elastic modulus, E (GPa)
H/E
VOR
{100}
366.9 ± 2.8
3.79 ± 0.17
0.097
VOR-HCl (1:2) VOR-OXA1 (1:1.5) VOR-OXA2 (1:1) VOR−FUM (1:1) VOR−PAB (1:1) VOR−PHB (1:1)
{011}
870.0 ± 6.0
19.41 ± 0.13
0.045
{010}
426.1 ± 5.8
5.95 ± 0.10
0.072
{100}
628.4 ± 2.0
8.29 ± 0.25
0.076
{100}
292.7 ± 3.4
5.79 ± 0.26
0.051
{100}
264.5 ± 5.0
5.63 ± 0.35
0.047
{100}
262.8 ± 1.6
5.64 ± 0.21
0.046
compound
893
slip system {001} [110] {001} [112] {001} [021] {001} [010] {001} [110] {001} [110] {001} [110]
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Figure 5. Molecular packing of VOR and its salts. Red lines represent the planes on which indentations were performed (the major face), and black dotted lines represent possible slip planes. Projection of crystal structure along (a) (010) of VOR, indentation along [100], (b) (100) of VOR-HCl, indentation along [011], (c) (010) of VOR-OXA2, indentation along [100], and (d) (100) of VOR-OXA1, indentation along [010].
past each other; see Figure 5b. This is the reason for the high H for this salt. The large force required to shear the planes is also the raison d’être for intermittent plastic flow, which is seen as prominent serrations in the loading part of the measured P−h responses (Figure 4a). Mechanical properties of VOR-OXA1 and VOR-OXA2 salts, which have different stoichiometry, i.e., 1:1.5 and 1:1 respectively, as well as different crystal structure and packing (see Figures 5c and 5d), fall between those of VOR and VORHCl, as seen from Table 1. In VOR-OXA1, two strong ionic N+−H···O−and O−H···O− interactions are skew-inclined to the indentation direction, whereas auxiliary and weak C−H···O interactions and one O−H···F H bond are parallel to it. In VOR-OXA2, two strong ionic interactions, O−H···O−, N+− H···O−, and one N−H···O interaction are almost normal to the indentation direction [100], whereas secondary weak C−H···O interactions and a few C−H···F interactions are inclined oblique to it. The interlocked molecular packing on {100} in VOR-OXA2 results in a higher H than VOR-OXA1, whose slip planes are almost parallel to the indentation direction, and hence exhibits lower E and H than VOR-OXA2. Cocrystals. Representative P−h curves obtained on the major faces of the VOR cocrystals are shown in Figure 4b. In contrast to the salts, all the loading segments of the P−h curves obtained on cocrystals are smooth. No significant pile-up around the indentation impressions was seen either (Figure S5, Supporting Information). These featuressmooth indentation responses and no pile-up around the indentsare similar to those observed in VOR. However, the values of E and H, as seen from Table 1, indicate that all three cocrystals have similar E values and are considerably stiffer than VOR. Interestingly, however, they are softer (by about 20%) than VOR. The higher E of cocrystals is possibly due to the fact that the number of
substantially stiffer and harder than VOR. In particular, the VOR-HCl salt is ∼80% and ∼58% stiffer and harder respectively than VOR. For VOR and its salts, Eatt values were estimated using the Dreiding force field in Materials Studio 6.019 (Table S2, Supporting Information), and in turn, possible slip systems for each of them were identified and are listed in Table 1. With the aid of these and the intermolecular interactions, we discuss below the structural origins for the observed variations in E and H. In VOR, strong intermolecular hydrogen bonds are absent and an intramolecular O−H···N interaction is present in the crystal structure. While two auxiliary C−H···N interactions (see Table S3, Supporting Information) and a few C−H···O interactions exist, they are at an oblique angle to the indentation direction. The observed low E value in VOR is a consequence of these factors. The slip planes are nearly parallel to the indentation direction (Figure 5a) and are attached to each other only with the weak C−H···F interactions (Figure S3a, Supporting Information). This arrangement facilitates easy shearing of the molecular layers during nanoindentation on the {100} face of VOR, which, in turn, results in low hardness. Since the planes can slide past each other without much resistance, a smooth P−h curve is obtained. In the VOR-HCl salt, in contrast, two strong ionic interactions like C−H···Cl− and N+−H···Cl− are present, and are almost normal to the indentation direction [011]. Various other weak intermolecular interactions like C−H···O, C−H··· N, and C−H···F are also present, but are inclined obliquely to the indentation direction. These strong ionic interactions and other auxiliary interactions are the reasons for the measured high E value of this salt. Further, the presence of two Cl− ions, which form strong ionic intermolecular interactions between the slip planes, resists the shearing of the crystallographic planes 894
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Figure 6. Molecular packing of voriconazole cocrystals. Red lines represent the plane on which indentation is made (the major face), and black and orange dotted lines represent possible slip planes. Projection of crystal structure along (010) and indentation along [011] of (a) VOR−FUM, (b) VOR−PHB, and (c) VOR−PAB.
indentation along [100], see Figures 6b and 6c. This similarity is the reason for the near-identical E and H values of these two cocrystals. The availability of two possible slip planes makes it even easier for slip to occur as compared to VOR, and hence the H values in the two cocrystals are lower than that of the VOR. In contrast, only one slip plane (black dotted line in Figure 6a) is present in VOR−FUM, causing it to exhibit a slightly higher H value as compared to VOR−PAB and VOR− PHB. In VOR salts, the molecular orientation of the triazole ring of VOR is anti with respect to the pyrimidine moiety, see Figures 3b and 3c. This anti or twisted conformation provides higher friction for shear sliding of molecular layers, which results in higher H as compared to that of the cocrystals, in which the syn conformation facilitates easy shearing resulting in a lower H even when compared to VOR. Nanoindentation and Compaction Properties. Tableting properties of an API depend upon the ability of its crystals to undergo plastic deformation. It is important to note that two contrasting demands are placed on this feature. On one hand, plasticity in the crystal is absolutely essential so as to increase the interparticulate contact area and binding during compaction. On the other hand, if the plastic deformation occurs too readily, i.e., too low a value of H, one may end up with a pasty solid that would be extremely difficult to mill. While a brittle material would be easy to mill, as it would be easy to fragment, it would lack the plastic deformability, making compaction difficult.3b,6 Thus, a judicious selection of properties is essential to achieve both millability and tabletability. While the plastic deformation resistance of an API can be gauged by measuring H during nanoindentation, measuring brittleness may not
intermolecular interactions in all of them is higher than that in VOR, but less than those in the salts. While stronger ionic interactions are present in the salts compared to the weaker noncovalent interactions in the cocrystals, the degrees of isotropic character in these two types of crystals may also be important in determining elastic character. In VOR−FUM cocrystal, two strong O−H···N interactions are inclined oblique to the indentation direction [100], whereas two very weak C− H···F interactions are normal and one weak C−H···O H bond is parallel to the indentation direction [100]. The molecular packing on the {100} of VOR−PAB and VOR−PHB is similar because of 3D isostructurality, while the interactions are different though equal in numbers and strength. In VOR−PAB, a strong N−H···O interaction and a weak C−H···N interaction are present such that they are normal to the indentation direction [100], whereas several strong O−H···N and N−H···N interactions and a few weak interactions like C−H···O and C− H···F are inclined oblique to the indentation direction [100]. In VOR−PHB also, two strong interactions like O−H···N are less skewed and several weak interactions like C−H···O, C−H···N, and C−H···F are more skewed to the indentation direction [100]. The equal number of similar interactions in VOR− FUM, VOR−PHB, and VOR−PAB are the reason for similar E. The lower stiffness of VOR vis-á-vis the cocrystals is possibly due to the smaller number of interactions in it, as well as to the fact that they are inclined oblique to the indentation direction. The presence of ionic interactions and prominent hydrogen bonds in salts imparts high E values to them as compared to the cocrystals. The molecular packing of VOR−PHB and VOR−PAB is similar to two possible slip planes (orange dotted line) for 895
DOI: 10.1021/mp500719t Mol. Pharmaceutics 2015, 12, 889−897
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(b) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm. Res. 2006, 23, 1888−1897. (c) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Cocrystals of quercetin with improved solubility and oral bioavailability. Mol. Pharmaceutics 2011, 8, 1867−1876. (d) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Salt and cocrystals of sildenafil with dicarboxylic acids: Solubility and pharmacokinetic advantage of the glutarate salt. Mol. Pharmaceutics 2013, 10, 4687−4697. (3) (a) Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org. Process Res. Dev. 2001, 5, 28−36. (b) Taylor, L. J.; Papadopoulos, D. G.; Dunn, P. J.; Bentham, A. C.; Dawson, N. J.; Mitchell, J. C.; Snowden, M. J. Predictive milling of pharmaceutical materials using nanoindentation of single crystals. Org. Process Res. Dev. 2004, 8, 674− 679. (4) (a) Sun, C. C.; Hou, H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst. Growth Des. 2008, 8, 1575−1579. (b) Karki, S.; Frišcǐ č, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Improving mechanical properties of crystalline solids by cocrystal formation: New compressible forms of paracetamol. Adv. Mater. 2009, 21, 3905−3909. (5) (a) Kiran, M. S. R. N.; Varughese, S.; Reddy, C. M.; Ramamurty, U.; Desiraju, G. R. Mechanical anisotropy in crystalline saccharin: Nanoindentation studies. Cryst. Growth Des. 2010, 10, 4650−4655. (b) Varughese, S.; Kiran, M. S. R. N.; Solanko, K. A.; Bond, A. D.; Ramamurty, U.; Desiraju, G. R. Interaction anisotropy and shear instability of aspirin polymorphs established by nanoindentation. Chem. Sci. 2011, 2, 2236−2242. (c) Karunatilaka, C.; Bučar, D. K.; Ditzler, L. R.; Frišcǐ ć, T.; Swenson, D. C.; MacGillivray, L. R.; Tivanski, A. V. Softening and hardening of macro- and nano-Sized organic cocrystals in a single-crystal transformation. Angew. Chem., Int. Ed. 2011, 50, 8642−8646. (d) Mishra, M. K.; Varughese, S.; Ramamurty, U.; Desiraju, G. R. Odd−even effect in the elastic modulii of α,ω-alkanedicarboxylic acids. J. Am. Chem. Soc. 2013, 135, 8121−8124. (e) Varughese, S.; Kiran, M. S. R. N.; Ramamurty, U.; Desiraju, G. R. Nanoindentation as a probe for mechanically-induced molecular migration in layered organic donor−acceptor complexes. Chem.Asian J. 2012, 7, 2118−2125. (f) Ghosh, S.; Mondal, A.; Kiran, M. S. R. N.; Ramamurty, U.; Reddy, C. M. The role of weak interactions in the phase transition and distinct mechanical behavior of two structurally similar caffeine cocrystals polymorphs studied by nanoindentation. Cryst. Growth Des. 2013, 13, 4435−4441. (g) Sahoo, S. C.; Sinha, S. B.; Kiran, M. S. R. N.; Ramamurty, U.; Dericioglu, A. F.; Reddy, C. M.; Naumov, P. Kinematic and mechanical profile of the self-actuation of thermosalient crystal twins of 1,2,4,5-tetrabromobenzene: A molecular crystalline analogue of a bimetallic strip. J. Am. Chem. Soc. 2013, 135, 13843−13850. (h) Mishra, M. K.; Desiraju, G. R.; Ramamurty, U.; Bond, A. D. Studying microstructure in molecular crystals with nanoindentation: Intergrowth polymorphism in Felodipine. Angew. Chem., Int. Ed. 2014, DOI: 10.1002/anie.201406898. (6) Taylor, L. J.; Papadopoulos, D. G.; Dunn, P. J.; Bentham, A. C.; Mitchell, J. C.; Snowden, M. J. Mechanical characterisation of powders using nanoindentation. Powder Technol. 2004, 143−144, 179−185. (7) RigakuMercury375R/M CCD, CrystalClear-SM Expert 2.0 rc14; Rigaku Corporation: Tokyo, Japan, 2009. (8) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr. 2008, A64, 112−122. (9) Farrugia, L. J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837−838. (10) (a) Oliver, W. C.; Pharr, G. M. An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments. J. Mater. Res. 1992, 7, 1564−1583. (b) Oliver, W. C.; Pharr, G. M. Measurement of hardness and elastic modulus by instrumented indentation: Advances in understanding and refinements to methodology. J. Mater. Res. 2004, 19, 3−20.
always be possible. The indentation toughness of the crystal can only be measured if it cracks during indentation. In the absence of such, the ratio of H/E can be considered. Hewitt measured mechanical properties of a few APIs and proposed that a low H/E value yields better compaction behavior.20 Taking a cue from this, we computed the H/E values for all the crystals examined in this work, which are tabulated in Table 1. As seen, VOR has the highest H/E ratio and is known to exhibit poor compaction behavior.3b,6 The HCl salt’s H/E is almost half that of VOR, and hence can be expected to offer better tableting properties.
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CONCLUSIONS This work shows that the device of making salts and cocrystals of an API can modulate mechanical properties effectively. Voriconazole (VOR) is a drug wherein the pure API is too soft for tableting and compacting. A number of salts and cocrystals of VOR are studied with single crystal X-ray diffraction and nanoindentation. Stronger ionic interactions, other noncovalent interactions, and lack of slip planes in salts make them harder than VOR, whereas the presence of a critical number of slip planes and a smaller number of interactions makes cocrystals softer than VOR. Salts offer the dual advantage21 of improved mechanical properties and expected higher solubility (as in the reported nitrate salt11) in a single dose form. While correlation of mechanical properties with the crystal structure may help a chemist to obtain better formulation during drug development, it is also worth noting that pharmaceutical cocrystals need not always offer better pharmaceutically relevant properties. For example, piroxicam−saccharin and theophylline−methyl gallate cocrystals exhibit lower plasticity (poor tableting) than the drug molecule itself.22 In the context of the present study, the hydrochloride salt of VOR may be preferred as the best solid form in terms of handling and better tableting.
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ASSOCIATED CONTENT
S Supporting Information *
Details of attachment energy calculations, PXRD patterns, crystallographic and hydrogen bonding parameters, and AFM images of nanoindentation indents for VOR cocrystals and salts. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS P.S. thanks the University Grants Commission for a Dr. D. S. Kothari Fellowship. M.K.M thanks CSIR for a Senior Research Fellowship. G.R.D. and U.R. thank the Department of Science and Technology for their respective J. C. Bose Fellowships.
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REFERENCES
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Growth Des. 2014, 14, 3864−3874. (b) Chattoraj, S.; Shi, L.; Sun, C. C. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1:1 co-crystal. CrystEngComm 2010, 12, 2466−2472.
(11) (a) Ravikumar, K.; Sridhar, B.; Prasad, K.; Rao, A. B. Voriconazole, an antifungal drug. Acta Crystallogr., Sect. E: Struct. Rep. Online 2007, 63, o565−o567. (b) Dickinson, R. P.; Bell, A. S.; Hitchcock, C. A.; Narayanaswami, S.; Ray, S. J.; Richardson, K.; Troke, P. F.Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against Aspergillus fumigates. Bioorg. Med. Chem. Lett. 1996, 6, 2031−2036. (c) Lopez, E. D.; Vilagran, M. C.; Lascorz, J. C. Process for the preparation of voriconazole. US 2010/ 0056784 A1, 2010. (d) Reddy, A. V.; Jaganmohan, G.; Kumari, S. A.; Mithra, S. L.; Reddy, B. S. Process for preparation of novel salt of voriconzole oxalate form C. WO 2009/053993 A2. (e) Andreas, H.; Tobias, H. M.; Fritz, B.; Eva, R. Multicomponent crystalline system of voriconazole with fumaric acid. WO2013/084130 A1. (12) Kumar, S. S.; Thakuria, R.; Nangia, A. Pharmaceutical cocrystals and a nitrate salt of voriconazole. CrystEngComm 2014, 16, 4722− 4731. (13) (a) Chou, P. C.; Pagano, N. J. ElasticityTensor, Dyadic and Engineering Approaches; Dover Publications: New York, 1992. (b) Hill, R. Theory of Plasticity; Oxford University Press: Oxford, 1950. (c) Varughese, S.; Kiran, M. S. R. N.; Ramamurty, U.; Desiraju, G. R. Nanoindentation in crystal engineering: Quantifying mechanical properties of molecular crystals. Angew. Chem., Int. Ed. 2013, 52, 2701−2712. (14) (a) Ghosh, S.; Reddy, C. M. Elastic and bendable caffeine cocrystals: Implication for the design of flexible organic materials. Angew. Chem., Int. Ed. 2012, 124, 10465−10469. (b) Mukherjee, A.; Desiraju, G. R. Halogen bonds in some dihalogenated phenols: Applications to crystal engineering. IUCrJ 2013, 1, 49−60. (15) Sun, C. C.; Kiang, Y.-H. On the identification of slip planes in organic crystals based on attachment energy calculation. J. Pharm. Sci. 2008, 97, 3456−3461. (16) (a) Basu, B.; Balani, K. Advanced Structural Ceramics; Wiley Publication: 2011. (b) Lawn, B. R.; Evans, A. G.; Marshall, D. B. Elastic/Plastic Indentation Damage in Ceramics: The Median/Radial Crack System. J. Am. Ceram. Soc. 1980, 63, 574−581. (c) Lawn, B. R.; Marshall, D. B. Hardness, Toughness, and Brittleness: An Indentation Analysis. J. Am. Ceram. Soc. 1979, 62, 347−350. (d) Lingyan, Z.; Fei, T.; Christopher, S.; Muhanna, A. K.; Fook, T. S.; David, K.; Rabih, A. O.; Bardeen, C. J. Improved Solid-State Photomechanical Materials by Fluorine Substitution of 9−Anthracene Carboxylic Acid. Chem. Mater. 2014, 26, 6007−6015. (17) Mishra, M. K.; Sanphui, P.; Ramamurty, U.; Desiraju, G. R. Solubility−hardness correlation in molecular crystals: Curcumin and sulfathiazole polymorphs. Cryst. Growth Des. 2014, 14, 3054−3061. (18) (a) Tromas, C.; Colin, J.; Coupeau, C.; Girard, J. C.; Woirgard, J.; Grilhé, J. Pop-in phenomenon during nanoindentation in MgO. Eur. Phys. J. Appl. Phys. 1999, 8, 123−128. (b) Lorenz, D.; Zeckzer, A.; Hilpert, U.; Grau, P.; Johansen, H.; Leipner, H. S. Pop-in effect as homogeneous nucleation of dislocations during nanoindentation. Phys. Rev. B 2003, 67, 172101−172104. (c) Jang, J. I.; Bei, H.; Becher, P. F.; Pharr, G. M. Experimental analysis of the elastic−plastic transition during nanoindentation of single crystal alpha-silicon nitride. J. Am. Ceram. Soc. 2012, 95, 2113−2115. (d) Jian, S. R.; Tseng, Y. C.; Teng, I. J.; Juang, J. Y. Dislocation energetics and pop-ins in AlN thin films by Berkovich nanoindentation. Materials 2013, 6, 4259−4267. (e) Ramamurty, U.; Jang, J. Nanoindentation for probing the mechanical behavior of molecular crystals−a review of the technique and how to use it. CrystEngComm 2014, 16, 12. (19) Materials Studio 6.0; Accelrys Inc.: San Diego, CA, 2011. (20) Duncan-Hewitt, W. C. Evaluating the hardness, Young’s modulus and fracture toughness of some pharmaceutical crystals using microindentation techniques. J. Mater. Sci. Lett. 1989, 8, 1350− 1352. (21) Perumalla, S. R.; Shi, L.; Sun, C. C. Ionized form of acetaminophen with improved compaction properties. CrystEngComm 2012, 14, 2389−2390. (22) (a) Chattoraj, S.; Shi, L.; Chen, M.; Alhalaweh, A.; Velaga, S.; Sun, C. C. Origin of deteriorated crystal plasticity and compaction properties of a 1:1 cocrystal between piroxicam and saccharin. Cryst. 897
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Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study Palash Sanphui,† Manish Kumar Mishra,† Upadrasta Ramamurty,*,‡,§ and Gautam R. Desiraju*,† †
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India Department of Materials Engineering, Indian Institute of Science, Bangalore 560 012, India § Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia ‡
S Supporting Information *
ABSTRACT: Crystals of voriconazole, an antifungal drug, are soft in nature, and this is disadvantageous during compaction studies where pressure is applied on the solid. Crystal engineering is used to make cocrystals and salts with modified mechanical properties (e.g., hardness). Cocrystals with biologically safe coformers such as fumaric acid, 4-hydroxybenzoic acid, and 4-aminobenzoic acid and salts with hydrochloric acid and oxalic acid are prepared through solvent assisted grinding. The presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals is unambiguously confirmed with single crystal X-ray diffraction. All the cocrystals have 1:1 stoichiometry, whereas salts exhibit variable stoichiometries such as HCl salt (1:2) and oxalate salts (1:1.5 and 1:1). The nanoindentation technique was applied on single crystals of the salts and cocrystals. The salts exhibit better hardness than the drug and cocrystals in the order salts ≫ drug > cocrystals. The molecular origin of this mechanical modulation is explained on the basis of slip planes in the crystal structure and relative orientations of the molecules with respect to the nanoindentation direction. The hydrochloride salt is the hardest solid in this family. This may be useful for tableting of the drug during formulation and in drug development. KEYWORDS: crystal engineering, cocrystals, elastic modulus, hardness, nanoindentation, salts
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INTRODUCTION Crystal engineering1 is widely utilized in designing active pharmaceutical ingredients (APIs) so as to obtain materials that exhibit optimum combinations of important physicochemical properties such as solubility, dissolution rate, and bioavailability.2 In the context of industrial-scale pharmaceutical manufacturing, it can also be used to tune mechanical properties such as grindability and tabletability, which often determine the processing steps that are adopted. For example, voriconazole (VOR, Scheme 1), which is the compound examined in the current study, is so soft that it becomes a paste during grinding and/or milling3processes that are commonly employed during the production stages of APIsconsequently making it unwieldy. To circumvent this problem, regelatinized starch maize is being used to make compressed tablets during formulation of the drug. In this paper, we demonstrate that the mechanical properties of VOR cocrystals, especially hardness, a property that captures a material’s resistance to plastic deformation, can be varied systematically, and to the desired levels, by varying the coformer content. Although prior studies on the mechanical properties of cocrystals4 are available, most of those are performed on polycrystalline aggregates. The key feature of the current paper is the utilization of the nanoindentation technique to study the © 2015 American Chemical Society
properties of single crystals of VOR and its salts and cocrystals. This technique allows for measuring the mechanical response of materials that are available only in small sizes; this has been exploited in the recent past to study structure−property correlations in molecular crystals.5 In particular, fundamental understanding of the influence exerted by structural features such as crystal packing,5a strength of intermolecular interactions,5d domain coexistence,5b,h polymorphism,5f layer migration,5e and solid state reactivity on mechanical properties such as stiffness and strength5c,g can be explored through nanoindentation studies. In the current context, employing nanoindentation not only allows us to study mechanical properties of cocrystals but (and more importantly) also allows us to correlate the measured changes in properties with the underlying structural features in the context of cocrystal engineering. It is expected that such an understanding will enhance the predictability of powder processing steps such as milling and compaction, which otherwise require large Received: Revised: Accepted: Published: 889
October 27, 2014 January 5, 2015 January 14, 2015 January 14, 2015 DOI: 10.1021/mp500719t Mol. Pharmaceutics 2015, 12, 889−897
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Molecular Pharmaceutics Scheme 1. Voriconazole (VOR) and Coformers in This Studya
a
The most basic sites are marked with an asterisk (*).
The crystals were harvested and then washed with paraffin oil to remove any small crystallites that might have stuck to the surface of larger crystals. Subsequently, they were firmly mounted on a metallic stud using cyanoacrylate glue for nanoindentation experiments. Four to five crystals were examined for each case. The indentation experiments were performed on the (100) faces of VOR, VOR-OXA2, VOR− FUM, VOR−PAB, and VOR−PHB and (011) face of VORHCl and VOR-OXA1 with the Triboindenter of Hysitron, Minneapolis, MN, USA with an in situ imaging capability. The machine continuously monitors and records the load, P, and displacement, h, of the indenter with force and displacement resolutions of 1 nN and 0.2 nm, respectively. The loading and unloading rates were 0.5 mN/s, and the hold time at the peak load of 5 mN was 30 s. A three-sided pyramidal Berkovich diamond indenter (Poisson’s ratio = 0.07) with a tip radius of ∼100 nm was used. Around 20 indentations were performed on each crystal. The indentation impressions were captured immediately after unloading. The P−h curves were analyzed using the standard Oliver−Pharr method10 to extract the elastic modulus, E, and hardness, H, of the crystal in that orientation. In the absence of data on the Poisson’s ratio of VOR or its multicomponent crystals, we have assumed their Poisson’s ratio to be 0.3 for the purpose of the analysis.
quantities of powders for pilot plant studies, typically several tens of kilograms.3b,6 VOR (chemical name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) is a weakly basic, nonhygroscopic API and is classified as a moderately soluble (1 g/L) and highly permeable drug that is generally used to treat chronic, invasive fungal infections (antifungal drug). In VOR, both triazole and pyrimidine N atoms are capable of O−H···N heterosynthon formation with coformers containing carboxylic acids and phenols. We have chosen both aliphatic and aromatic coformers (Scheme 1), which are not toxic and hence are biologically safe.
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EXPERIMENTAL SECTION Commercially obtained VOR and coformers were used without further purification. Methods such as solid state grinding, solution crystallization, and slurry methods in polar solvents such as MeOH and MeCN were carried out to make the cocrystals and salts (see Supporting Information). Melting points (mp) of these materials were measured on a Büchi melting point apparatus. Water filtered through a double distilled water purification system (Siemens, Ultra Clear, Germany) was used in all the experiments. Powder X-ray diffraction (PXRD) data was recorded using a Philips X’pert Pro X-ray powder diffractometer equipped with an X’cellerator detector. All scans were performed at room temperature with the scan range 2θ = 5 to 40° and step size 0.017°. The X’Pert HighScore Plus software was used to compare the experimental PXRD pattern with the calculated lines from the crystal structure (see Figure S1, Supporting Information). Single Crystal X-ray Diffraction. Single crystal X-ray data of all the salts and cocrystals were collected on a Rigaku Mercury 375/M CCD (XtaLAB mini) diffractometer using graphite monochromated Mo Kα radiation at 150 K. The data were processed with the Rigaku Crystal clear software.7 Structure solution and refinements were executed using SHELX-978 using the WinGX9 suite of programs. Refinement of coordinates and anisotropic thermal parameters of nonhydrogen atoms were performed with the full-matrix leastsquares method. Positions of the hydrogen atoms were either located from difference Fourier map or calculated using the riding model. Crystallographic cif files (CCDC Nos. 984147− 984151) are available at www.ccdc.cam.ac.uk/data_request/cif. Nanoindentation. Large single crystals (average size: 1 × 1 × 0.5 mm3) of voriconazole and its salts and cocrystals were grown by slow evaporation at room temperature for a week.
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RESULTS AND DISCUSSION Crystal Structures. The crystal structures of VOR, its camphorsulfonate salt, oxalate salt, and fumaric acid cocrystals (without the 3D coordinates) are already reported in the literature,11 while Kumar et al.12 have recently reported the crystal structures of VOR cocrystals with 4-hydroxybenzoic acid, 4-aminobenzoic acid, and 3-nitrobenzoic acid, and also that of dinitrate salt. In view of this, we only report the new crystal structures of VOR-HCl (1:2), VOR-OXA1 (1:1.5), VOR-OXA2 (1:1) salts, and VOR−FUM (1:1) cocrystal in this paper. A brief summary of the crystallographic information on the reported salts and cocrystals is provided in Table S1, Supporting Information. The VOR molecule has the same chirality (2R, 3S) as the parent compound VOR in all the crystal structures. Mulliken atomic charges of the nitrogen atoms in the VOR molecule (Figure S2, Supporting Information) indicate that the N3 nitrogen of the triazole ring possesses a greater negative charge (−0.3217 au) than the N5 nitrogen of the pyrimidine ring (−0.1757 au). The N4 nitrogen of the pyrimidine ring (−0.3236 au) is highly negatively charged and donates a strong intramolecular 890
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Figure 1. Molecular packing and hydrogen bonded networks in the crystal structure of (a) VOR and its salts (b) VOR-HCl, (c) VOR-OXA1, and (d) VOR-OXA2.
Figure 2. Molecular packing and hydrogen bonded networks in the crystal structure of (a) VOR−FUM, (b) VOR−PHB, and (c) VOR−PAB cocrystals.
group P212121, and the asymmetric unit contains protonated triazole and pyrimidine N atoms in VOR and two chloride anions. The crystal packing of the dihydrochloride and dinitrate salts (reported)12 are quite different. There is a common intramolecular O−H···N hydrogen bond between pyrimidine N1 atom and hydroxyl group. Two VOR cations and two Cl− anions form a tetramer ring with C−H···Cl−and N+−H···Cl− interactions, and this is extended along the crystallographic a axis (Figure 1b). The Cl− anions are present in the channel
hydrogen bond. Below, we describe the relevant and necessary aspects of the crystal structures of each of the compounds. Voriconazole. The reported crystal structure of VOR (P21, Z = 2)11a consists of strong O−H···N intramolecular hydrogen bond and auxiliary weaker C−H···O (OH) and C−H···N hydrogen bonds forming a layered structure (Figure 1a). The layers are extended via even weaker C−H···F interactions (Figure S3a, Supporting Information). Voriconazole Dihydrochloride Salt (VOR-HCl, 1:2). VOR-HCl (1:2) salt crystallizes in the orthorhombic space 891
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Figure 3. (a) Torsional flexibility in VOR. (b, c) Structural overlay of VOR in the API, cocrystals and salts. Pyrimidine and triazole rings are anti in the API and the salts, while they are in syn positions in cocrystals.
(viewed down the b axis) between the two layers of VOR cations (Figure S3b, Supporting Information). Voriconazole Oxalate Salt (VOR-OXA1, 1:1.5). VOROXA1(1:1.5) salt crystallizes in the orthorhombic space group C2221, and the PXRD pattern is different from the prior art (WO 2009/053993 A2).11d The asymmetric unit consists of one VOR cation, one oxalic acid (neutral), and a half equivalent of oxalate anion. Proton transfers from oxalic acid to triazole N of VOR and one oxalate dianion bind two VOR cations. Oxalic acid and oxalate anion form 1D O−H···O/O−H···O− hydrogen bonds along the crystallographic b axis (Figure 1c). Auxiliary (sp2) C−H···O hydrogen bonds further stabilize the packing. Similar to the HCl salt, oxalic acid and oxalate anions are sandwiched between the double layers of VOR cations (Figure S3c, Supporting Information). Voriconazole Oxalate Salt (VOR-OXA2, 1:1). VOROXA2 salt crystallizes in the monoclinic space group P21, and the PXRD pattern is also different from the prior art (WO 2009/053993 A2).11d The crystal structure contains one VOR cation and one oxalate monoanion in the asymmetric unit. Proton transfer from oxalic acid to triazole N of VOR confirms its ionic nature. Similar to the 1:1.5 salt, oxalate monoanions form 1D chains via O−H···O− ionic hydrogen bonds along the b axis and further interact with the API through N+−H···O− interactions, see Figure 1d. However, the 3D packing is quite different in the two cases. In VOR-OXA1, API and coformers are well separated, whereas they are partially overlapped over each other in VOR-OXA2, viewed down the a axis, Figure S3d, Supporting Information. Voriconazole Fumaric Acid Cocrystal (VOR−FUM, 1:1). Unlike oxalic acid, fumaric acid forms a cocrystal with VOR, and the crystal structure (P21, Z = 2) consists of one VOR and one FUM molecule in the asymmetric unit. Recently, VOR− FUM cocrystal is reported in a patent, WO 2013/084130 A1,11e with PXRD characterization. We were not able to locate
the hydrogen atom of the hydroxyl group in VOR. Fumaric acid interacts with both the triazole and pyrimidine N atoms via (CO2H) O−H···N hydrogen bond in a helical pattern (Figure 2a).The trimer units are extended to the next trimer via auxiliary C−H···F interactions. Three dimensional packing diagram of the cocrystal indicates that the layers of VOR and FUM are not well separated (Figure S3e, Supporting Information). Voriconazole 4-Hydroxybenzoic Acid Cocrystal (VOR−PHB, 1:1). The reported cocrystal VOR−PHB (1:1) crystallizes in the monoclinic space group P21 (Z = 2).12 The single crystal X-ray data was re-collected at 150 K for better comparison purposes. Mulliken atomic charges of the OH group (−0.6707 au) and the CO2H group (−0.5032 and −0.6248 au) indicate stronger donor capacity of hydroxyl group compared to carboxyl (Figure S2, Supporting Information). Hence, hydroxyl and carboxyl groups form hydrogen bonds with triazole and pyrimidine N atoms and a helical motif similar to the one in the VOR−FUM cocrystal is observed; see Figure 2b. The helical arrangement of VOR and PHB molecules is further stabilized by auxiliary (sp2) C−H···O interactions between triazole ring CH and carboxylic acid. The trimer units of two VOR and one PHB molecules are extended to the next unit via (sp3) C−H···F bonds. Voriconazole 4-Aminobenzoic Acid Cocrystal (VOR− PAB, 1:1). The reported cocrystal VOR−PAB (1:1) crystallizes in the monoclinic space group P21 (Z = 2).12 The only difference is that the −OH group is replaced by the isoelectronic −NH2 in PAB. Both VOR−PHB (1:1) and VOR−PAB (1:1) are 3D isostructural. In PAB, the NH2 group is more electronegative (−0.7839 au) than CO2H (−0.5019 and −0.6798 au) and hence similar to VOR−PHB cocrystals, amine NH2 and −CO2H groups forming hydrogen bonds with the triazole and pyrimidine nitrogen atoms via N−H···N and O−H···N hydrogen bonds (Figure 2c). The other amine N−H 892
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Figure 4. Representative P−h curves obtained on VOR and its (a) salts and (b) cocrystals.
relatively easy. Likewise, H is a particularly important mechanical property in the context of compressibility and tabletability. Since these are physical properties that depend on intrinsic structural features, they can also be correlated to functional properties as well. For example, we have recently shown that H and solubility of the APIs are inversely correlated, with polymorphs of APIs with low H values being more amenable to dissolution than those with high H.17 Salts. All the nanoindentation experiments were carried out on structurally similar major faces of VOR, its salts, and its cocrystals. Representative P−h curves of VOR and its salts are displayed in Figure 4a. The P−h responses obtained on VOR crystals are smooth, indicating homogeneous plastic deformation. In contrast, the loading parts of the P−h curves obtained on all the salts showed discrete displacement bursts, referred to as “pop-ins”18 in the literature, indicating that the plastic deformation in these crystals occurs intermittently. The pop-ins in VOR-HCl were found to be integer multiples of ∼10 nm, which is close to the interplanar spacing of (011), d011 (0.98 nm). Likewise, the pop-ins on the P−h curves of VOR-OXA1 and VOR-OXA2 are ∼10.2 and 9 nm in magnitude respectively, which again are integer multiples of d010 (2.5 nm) and d100 (0.87 nm) in respective crystals. The AFM images of the indents made on the salts showed material pile-up along the edges of the impressions, whereas no such pile-up was observed in VOR (Figure S4, Supporting Information). The average values of E and H of VOR and its salts extracted from the P−h curves are listed in Table 1. As seen here, all the salts are
fragment interacts with the carboxylic acid via N−H···O hydrogen bonds. Molecular Conformations. The voriconazole molecule contains flexible triazole and pyrimidine rings (Figure 3a). The torsional flexibility is observed in this drug and its cocrystal and salts, also reported by Kumar et al.12 The orientation of the triazole ring of VOR in the cocrystals with FUM, PHB, and PAB is syn with respect to the pyrimidine moiety of VOR, but anti in the salts with HCl, OXA1, and OXA2, see Figure 3b,c. It seems that the coformers with two functional groups, which can interact with both the triazole and pyrimidine moiety, exhibit the syn conformation. Mechanical Properties. Before presenting results of the nanoindentation experiments and discussing the structural origins of the material-to-material variations in the mechanical properties, elastic modulus (E) and hardness (H) that can be measured with nanoindentation, it may be useful to highlight the physical significance of these properties. For a given material, E and H are measures of the resistance offered by it to elastic and plastic deformations respectively, and depend on a number of structural factors.13 E depends upon parameters such as the structural packing efficiency, type and number of interactions between molecules, and also the relative orientation of the molecules with respect to the loading (indentation) direction. Typically, high packing efficiency, strong intermolecular interactionsand a multitude of them, and alignment of them along the indentation direction lead to high E.14 In contrast, H depends strongly on the relative ease with which molecular layers can slide past each other on specific crystallographic planes. Typically, slip planes are the ones with the least attachment energy, Eatt.15 Likewise, the slip directions are those along which the lattice translation is the shortest. Together, the slip planes and directions are referred to as the slip system. Thus, variations in H can be rationalized by taking recourse to the identification of the slip system and its relative orientation with the indentation direction. Additionally, weak nondirectional π···π and van der Waals interactions facilitate easy shearing of the molecular planes as they can be broken relatively easily. In contrast, strong directional interactions like hydrogen bonds influence elasticity because of their restorative character. Typically, high values of both E and H would imply that the material is resistant to deformation and hence is brittle; ceramics are classical examples of such materials.6,16 In the pharmaceutical manufacturing context, such materials would be easy to comminute (or mill) as fragmentation would be
Table 1. Elastic Modulus (E), Hardness (H), and Slip System of VOR and Its Salts and Cocrystals indented face
hardness, H (MPa)
elastic modulus, E (GPa)
H/E
VOR
{100}
366.9 ± 2.8
3.79 ± 0.17
0.097
VOR-HCl (1:2) VOR-OXA1 (1:1.5) VOR-OXA2 (1:1) VOR−FUM (1:1) VOR−PAB (1:1) VOR−PHB (1:1)
{011}
870.0 ± 6.0
19.41 ± 0.13
0.045
{010}
426.1 ± 5.8
5.95 ± 0.10
0.072
{100}
628.4 ± 2.0
8.29 ± 0.25
0.076
{100}
292.7 ± 3.4
5.79 ± 0.26
0.051
{100}
264.5 ± 5.0
5.63 ± 0.35
0.047
{100}
262.8 ± 1.6
5.64 ± 0.21
0.046
compound
893
slip system {001} [110] {001} [112] {001} [021] {001} [010] {001} [110] {001} [110] {001} [110]
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Figure 5. Molecular packing of VOR and its salts. Red lines represent the planes on which indentations were performed (the major face), and black dotted lines represent possible slip planes. Projection of crystal structure along (a) (010) of VOR, indentation along [100], (b) (100) of VOR-HCl, indentation along [011], (c) (010) of VOR-OXA2, indentation along [100], and (d) (100) of VOR-OXA1, indentation along [010].
past each other; see Figure 5b. This is the reason for the high H for this salt. The large force required to shear the planes is also the raison d’être for intermittent plastic flow, which is seen as prominent serrations in the loading part of the measured P−h responses (Figure 4a). Mechanical properties of VOR-OXA1 and VOR-OXA2 salts, which have different stoichiometry, i.e., 1:1.5 and 1:1 respectively, as well as different crystal structure and packing (see Figures 5c and 5d), fall between those of VOR and VORHCl, as seen from Table 1. In VOR-OXA1, two strong ionic N+−H···O−and O−H···O− interactions are skew-inclined to the indentation direction, whereas auxiliary and weak C−H···O interactions and one O−H···F H bond are parallel to it. In VOR-OXA2, two strong ionic interactions, O−H···O−, N+− H···O−, and one N−H···O interaction are almost normal to the indentation direction [100], whereas secondary weak C−H···O interactions and a few C−H···F interactions are inclined oblique to it. The interlocked molecular packing on {100} in VOR-OXA2 results in a higher H than VOR-OXA1, whose slip planes are almost parallel to the indentation direction, and hence exhibits lower E and H than VOR-OXA2. Cocrystals. Representative P−h curves obtained on the major faces of the VOR cocrystals are shown in Figure 4b. In contrast to the salts, all the loading segments of the P−h curves obtained on cocrystals are smooth. No significant pile-up around the indentation impressions was seen either (Figure S5, Supporting Information). These featuressmooth indentation responses and no pile-up around the indentsare similar to those observed in VOR. However, the values of E and H, as seen from Table 1, indicate that all three cocrystals have similar E values and are considerably stiffer than VOR. Interestingly, however, they are softer (by about 20%) than VOR. The higher E of cocrystals is possibly due to the fact that the number of
substantially stiffer and harder than VOR. In particular, the VOR-HCl salt is ∼80% and ∼58% stiffer and harder respectively than VOR. For VOR and its salts, Eatt values were estimated using the Dreiding force field in Materials Studio 6.019 (Table S2, Supporting Information), and in turn, possible slip systems for each of them were identified and are listed in Table 1. With the aid of these and the intermolecular interactions, we discuss below the structural origins for the observed variations in E and H. In VOR, strong intermolecular hydrogen bonds are absent and an intramolecular O−H···N interaction is present in the crystal structure. While two auxiliary C−H···N interactions (see Table S3, Supporting Information) and a few C−H···O interactions exist, they are at an oblique angle to the indentation direction. The observed low E value in VOR is a consequence of these factors. The slip planes are nearly parallel to the indentation direction (Figure 5a) and are attached to each other only with the weak C−H···F interactions (Figure S3a, Supporting Information). This arrangement facilitates easy shearing of the molecular layers during nanoindentation on the {100} face of VOR, which, in turn, results in low hardness. Since the planes can slide past each other without much resistance, a smooth P−h curve is obtained. In the VOR-HCl salt, in contrast, two strong ionic interactions like C−H···Cl− and N+−H···Cl− are present, and are almost normal to the indentation direction [011]. Various other weak intermolecular interactions like C−H···O, C−H··· N, and C−H···F are also present, but are inclined obliquely to the indentation direction. These strong ionic interactions and other auxiliary interactions are the reasons for the measured high E value of this salt. Further, the presence of two Cl− ions, which form strong ionic intermolecular interactions between the slip planes, resists the shearing of the crystallographic planes 894
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Figure 6. Molecular packing of voriconazole cocrystals. Red lines represent the plane on which indentation is made (the major face), and black and orange dotted lines represent possible slip planes. Projection of crystal structure along (010) and indentation along [011] of (a) VOR−FUM, (b) VOR−PHB, and (c) VOR−PAB.
indentation along [100], see Figures 6b and 6c. This similarity is the reason for the near-identical E and H values of these two cocrystals. The availability of two possible slip planes makes it even easier for slip to occur as compared to VOR, and hence the H values in the two cocrystals are lower than that of the VOR. In contrast, only one slip plane (black dotted line in Figure 6a) is present in VOR−FUM, causing it to exhibit a slightly higher H value as compared to VOR−PAB and VOR− PHB. In VOR salts, the molecular orientation of the triazole ring of VOR is anti with respect to the pyrimidine moiety, see Figures 3b and 3c. This anti or twisted conformation provides higher friction for shear sliding of molecular layers, which results in higher H as compared to that of the cocrystals, in which the syn conformation facilitates easy shearing resulting in a lower H even when compared to VOR. Nanoindentation and Compaction Properties. Tableting properties of an API depend upon the ability of its crystals to undergo plastic deformation. It is important to note that two contrasting demands are placed on this feature. On one hand, plasticity in the crystal is absolutely essential so as to increase the interparticulate contact area and binding during compaction. On the other hand, if the plastic deformation occurs too readily, i.e., too low a value of H, one may end up with a pasty solid that would be extremely difficult to mill. While a brittle material would be easy to mill, as it would be easy to fragment, it would lack the plastic deformability, making compaction difficult.3b,6 Thus, a judicious selection of properties is essential to achieve both millability and tabletability. While the plastic deformation resistance of an API can be gauged by measuring H during nanoindentation, measuring brittleness may not
intermolecular interactions in all of them is higher than that in VOR, but less than those in the salts. While stronger ionic interactions are present in the salts compared to the weaker noncovalent interactions in the cocrystals, the degrees of isotropic character in these two types of crystals may also be important in determining elastic character. In VOR−FUM cocrystal, two strong O−H···N interactions are inclined oblique to the indentation direction [100], whereas two very weak C− H···F interactions are normal and one weak C−H···O H bond is parallel to the indentation direction [100]. The molecular packing on the {100} of VOR−PAB and VOR−PHB is similar because of 3D isostructurality, while the interactions are different though equal in numbers and strength. In VOR−PAB, a strong N−H···O interaction and a weak C−H···N interaction are present such that they are normal to the indentation direction [100], whereas several strong O−H···N and N−H···N interactions and a few weak interactions like C−H···O and C− H···F are inclined oblique to the indentation direction [100]. In VOR−PHB also, two strong interactions like O−H···N are less skewed and several weak interactions like C−H···O, C−H···N, and C−H···F are more skewed to the indentation direction [100]. The equal number of similar interactions in VOR− FUM, VOR−PHB, and VOR−PAB are the reason for similar E. The lower stiffness of VOR vis-á-vis the cocrystals is possibly due to the smaller number of interactions in it, as well as to the fact that they are inclined oblique to the indentation direction. The presence of ionic interactions and prominent hydrogen bonds in salts imparts high E values to them as compared to the cocrystals. The molecular packing of VOR−PHB and VOR−PAB is similar to two possible slip planes (orange dotted line) for 895
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(b) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm. Res. 2006, 23, 1888−1897. (c) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Cocrystals of quercetin with improved solubility and oral bioavailability. Mol. Pharmaceutics 2011, 8, 1867−1876. (d) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Salt and cocrystals of sildenafil with dicarboxylic acids: Solubility and pharmacokinetic advantage of the glutarate salt. Mol. Pharmaceutics 2013, 10, 4687−4697. (3) (a) Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org. Process Res. Dev. 2001, 5, 28−36. (b) Taylor, L. J.; Papadopoulos, D. G.; Dunn, P. J.; Bentham, A. C.; Dawson, N. J.; Mitchell, J. C.; Snowden, M. J. Predictive milling of pharmaceutical materials using nanoindentation of single crystals. Org. Process Res. Dev. 2004, 8, 674− 679. (4) (a) Sun, C. C.; Hou, H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst. Growth Des. 2008, 8, 1575−1579. (b) Karki, S.; Frišcǐ č, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Improving mechanical properties of crystalline solids by cocrystal formation: New compressible forms of paracetamol. Adv. Mater. 2009, 21, 3905−3909. (5) (a) Kiran, M. S. R. N.; Varughese, S.; Reddy, C. M.; Ramamurty, U.; Desiraju, G. R. Mechanical anisotropy in crystalline saccharin: Nanoindentation studies. Cryst. Growth Des. 2010, 10, 4650−4655. (b) Varughese, S.; Kiran, M. S. R. N.; Solanko, K. A.; Bond, A. D.; Ramamurty, U.; Desiraju, G. R. Interaction anisotropy and shear instability of aspirin polymorphs established by nanoindentation. Chem. Sci. 2011, 2, 2236−2242. (c) Karunatilaka, C.; Bučar, D. K.; Ditzler, L. R.; Frišcǐ ć, T.; Swenson, D. C.; MacGillivray, L. R.; Tivanski, A. V. Softening and hardening of macro- and nano-Sized organic cocrystals in a single-crystal transformation. Angew. Chem., Int. Ed. 2011, 50, 8642−8646. (d) Mishra, M. K.; Varughese, S.; Ramamurty, U.; Desiraju, G. R. Odd−even effect in the elastic modulii of α,ω-alkanedicarboxylic acids. J. Am. Chem. Soc. 2013, 135, 8121−8124. (e) Varughese, S.; Kiran, M. S. R. N.; Ramamurty, U.; Desiraju, G. R. Nanoindentation as a probe for mechanically-induced molecular migration in layered organic donor−acceptor complexes. Chem.Asian J. 2012, 7, 2118−2125. (f) Ghosh, S.; Mondal, A.; Kiran, M. S. R. N.; Ramamurty, U.; Reddy, C. M. The role of weak interactions in the phase transition and distinct mechanical behavior of two structurally similar caffeine cocrystals polymorphs studied by nanoindentation. Cryst. Growth Des. 2013, 13, 4435−4441. (g) Sahoo, S. C.; Sinha, S. B.; Kiran, M. S. R. N.; Ramamurty, U.; Dericioglu, A. F.; Reddy, C. M.; Naumov, P. Kinematic and mechanical profile of the self-actuation of thermosalient crystal twins of 1,2,4,5-tetrabromobenzene: A molecular crystalline analogue of a bimetallic strip. J. Am. Chem. Soc. 2013, 135, 13843−13850. (h) Mishra, M. K.; Desiraju, G. R.; Ramamurty, U.; Bond, A. D. Studying microstructure in molecular crystals with nanoindentation: Intergrowth polymorphism in Felodipine. Angew. Chem., Int. Ed. 2014, DOI: 10.1002/anie.201406898. (6) Taylor, L. J.; Papadopoulos, D. G.; Dunn, P. J.; Bentham, A. C.; Mitchell, J. C.; Snowden, M. J. Mechanical characterisation of powders using nanoindentation. Powder Technol. 2004, 143−144, 179−185. (7) RigakuMercury375R/M CCD, CrystalClear-SM Expert 2.0 rc14; Rigaku Corporation: Tokyo, Japan, 2009. (8) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr. 2008, A64, 112−122. (9) Farrugia, L. J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837−838. (10) (a) Oliver, W. C.; Pharr, G. M. An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments. J. Mater. Res. 1992, 7, 1564−1583. (b) Oliver, W. C.; Pharr, G. M. Measurement of hardness and elastic modulus by instrumented indentation: Advances in understanding and refinements to methodology. J. Mater. Res. 2004, 19, 3−20.
always be possible. The indentation toughness of the crystal can only be measured if it cracks during indentation. In the absence of such, the ratio of H/E can be considered. Hewitt measured mechanical properties of a few APIs and proposed that a low H/E value yields better compaction behavior.20 Taking a cue from this, we computed the H/E values for all the crystals examined in this work, which are tabulated in Table 1. As seen, VOR has the highest H/E ratio and is known to exhibit poor compaction behavior.3b,6 The HCl salt’s H/E is almost half that of VOR, and hence can be expected to offer better tableting properties.
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CONCLUSIONS This work shows that the device of making salts and cocrystals of an API can modulate mechanical properties effectively. Voriconazole (VOR) is a drug wherein the pure API is too soft for tableting and compacting. A number of salts and cocrystals of VOR are studied with single crystal X-ray diffraction and nanoindentation. Stronger ionic interactions, other noncovalent interactions, and lack of slip planes in salts make them harder than VOR, whereas the presence of a critical number of slip planes and a smaller number of interactions makes cocrystals softer than VOR. Salts offer the dual advantage21 of improved mechanical properties and expected higher solubility (as in the reported nitrate salt11) in a single dose form. While correlation of mechanical properties with the crystal structure may help a chemist to obtain better formulation during drug development, it is also worth noting that pharmaceutical cocrystals need not always offer better pharmaceutically relevant properties. For example, piroxicam−saccharin and theophylline−methyl gallate cocrystals exhibit lower plasticity (poor tableting) than the drug molecule itself.22 In the context of the present study, the hydrochloride salt of VOR may be preferred as the best solid form in terms of handling and better tableting.
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ASSOCIATED CONTENT
S Supporting Information *
Details of attachment energy calculations, PXRD patterns, crystallographic and hydrogen bonding parameters, and AFM images of nanoindentation indents for VOR cocrystals and salts. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS P.S. thanks the University Grants Commission for a Dr. D. S. Kothari Fellowship. M.K.M thanks CSIR for a Senior Research Fellowship. G.R.D. and U.R. thank the Department of Science and Technology for their respective J. C. Bose Fellowships.
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