An Alternate Crystal Form of Gabapentin: A Cocrystal with Oxalic Acid Mazal Wenger and Joel Bernstein* Department of Chemistry, Ben-Gurion UniVersity of the NegeV, P.O. Box 653, Be’er SheVa, Israel, 84105
CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 5 1595–1598
ReceiVed September 11, 2007; ReVised Manuscript ReceiVed October 23, 2007
ABSTRACT: A cocrystal of gabapentin and oxalic acid has been prepared employing a strategy based on a hydrogen-bonded synthon described by the graph set notation R42(8). High throughput techniques and solvent drop grinding were used along with traditional crystallization methods, including crystallization in aqueous solutions at various pH. A number of new solid forms have been detected. The cocrystal of gabapentin and oxalic acid was fully characterized including single crystal structure analysis, which revealed the R42(8) synthon. Introduction Preparation of cocrystals in the pharmaceutical industry over the last 3 years has gained much attention in addition to efforts to obtain polymorphs, salts, and solvates of an active pharmaceutical ingredient (API).1–3 API’s are potentially valuable chemical entities; therefore, the diversity of the crystal forms of those molecules is of great interest for the variability of properties and potential intellectual property.4–6 Until recently, salts have been the preferred crystal form for API’s that exhibit poor aqueous solubility. Crystal engineering and cocrystallization of the API has a number of potential advantages over salt formation.7,8 Cocrystallization of pharmaceutical compounds may potentially be employed with all APIs including acidic, basic, and nonionizable molecules. Second, a large number of pharmaceutically acceptable cocrystal formers exist, which potentially increase the scope of cocrystallization over salt formation. Two important aspects exist in the design of cocrystallization experiments based on hydrogen bonding between the API and the potential cocrystal former. The first is the hydrogen-bonded synthon. Because of their higher energy and directionality, hydrogen bonds are among the most important intermolecular interactions. It has been observed that the strength of these directional forces, and consequently their ability to control the formation of intermolecular synthons, depends on the nature and polarity of the donor and acceptor groups and is significantly increased when the hydrogen bond is assisted by resonance9 or by charge;10 Second is the robustness of the synthon. The evaluation of the synthon’s structural robustness may be carried out by analysis of structural trends in the Cambridge Structural Database (CSD). Our present strategy consists of investigating the potential for utilizing the hydrogen-bond synthon described by the R42(8) graph set, as shown in Scheme 1. A survey of the CSD (November 2005) has identified more than 12000 instances of the R24(8) synthon, virtually all of which involve four individual and nonconnected (but not necessarily chemically different) moieties in the solid state. Many of these cases involve two chemically different moieties, often resulting in a pattern that is crystallographically centrosymmetric or pseudocentrosymmetric. As evidenced from Scheme 1, one way to achieve the R42(8) motif is through cocrystallization of molecules with an amino * Corresponding author. E-mail:
[email protected].
Scheme 1. Possible Acceptors (A) and Donors (D) for the R42(8) Synthon
Scheme 2. Molecules in the Obtained Cocrystal
group (-NH2) that will participate as a donor (D) and molecules with a carbonyl group (CdO) that will participate as an acceptor (A). A CSD survey revealed 918 hits for structures with these particular donors and acceptors that exhibit the R42(8) synthon. The CSD search also indicated a statistical preference for the ionized species -NH3+ and COO- in the formation of the desired R42(8) synthon. The combined species increase the stabilization energy of the synthon by approximately an order of magnitude over that of the isolated natural species.11 In a previous report on the preparation of cocrystals of γ-aminobutyric acid (GABA) with oxalic acid, and GABA with benzoic acid12 a strategy to design the cocrystal from aquous solution by controling pH was demonstrated.12 In the present work, cocrystallization attempts were initiated with high throughput (HT) screening13 and through solvent drop grinding (SDG)14 followed by traditional crystallization experiments (e.g., slow evaporation at room temperature). The API selected for cocrystallization is gabapentin Scheme 2, which was initially synthesized to mimic the structure of GABA for the treatment of epilepsy.15 Gabapentin is currently widely used as an alleviator especially of neuropathic pain. There are three reported crystal forms of gabapentin in the CSD (version 1.9, 2007): (1) the hydrochloride hemihydrate [AWUWIY], (2) the molecule crystallizing as a zwitterions [QIMKIG], and (3) as a zwitterions hydrate [QIMKOM]. The first two forms of gabapentin exhibit the R42(8) motif in their structures (Figure 1). Apparently additional forms of gabapentin have been found16 (structures have not been published yet). No
10.1021/cg7008732 CCC: $40.75 2008 American Chemical Society Published on Web 03/20/2008
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Figure 1. Hydrogen bond motif R42(8) in two out of the three reported gabapentin structures (a) [QIMKIG] gabapentin zwitterion and (b) [AWUWIY] gabapentin hydrochloride (chloride ions drawn as green spheres).
cocrystal with gabapentin has been reported. Many pharmaceutical cocrystals have been obtained with carboxylic acids as cocrystal formers.17 Among them, oxalic acid provides a number of examples, including Therapoline,8 caffeine,18 and GABA.12 Experimental Section Cocrystallization of gabapentin and oxalic acid was attempted using 16 different solvents in SDG and 13 different solvents in the high throughput screen. (A) Traditional Crystallization Methods. Materials. Gabapentin (Transform Pharmaceuticals) and oxalic acid dihydrate 99+% (Aldrich) were used for the preparation of the cocrystal as obtained from aqueous solution of distilled water. Gabapentin and oxalic acid were dissolved in a 1:1 molar ratio in water. The pH of the resulting solution was in the range of 2–3. Upon slow evaporation at room temperature, colorless crystals appeared after 1 week. (B) Solvent-Drop Grinding (SDG) and HT (high throughput) Experiments. Gabapentin and oxalic acid were used as received for the preparation of the cocrystal. Sixteen solvents were used for the grinding experiments (methanol, dichloromethane, ethylacetate, nitromethane, chlorobenzene, ethanol, DMSO, DMF, NMP, pyridine, water, water adjusted to pH 10 using 1N NaOH, acetone, toluene, chloroform, and N-propylacetate). The first 12 of these were also used for the high throughput experiments, in addition to aqueous NaOH at pH 13. All organic solvents were purchased from Sigma-Aldrich, generally as HPLC grade. HPLC-grade distilled water (at pH >5) was obtained from Fisher. (C) Methods. Solvent-Drop Grinding Crystallization. Mechanical grinding experiments were conducted by adding one or two drops of solvent to solid mixtures of gabapentin and oxalic acid. Typical experiments contained 10 mg of each of the solids (gabapentin and oxalic acid). A total of 16 solvents (10 µL) were used as additives in experiments designed to identify new cocrystaline powders. The samples were ground for 20 min using a mechanical shaker, and the resulting powders were characterized using XRPD. (D) HT Crystallization. Attempted cocrystallization of gabapentin and oxalic acid was carried out in a 96-well aluminum block holding borosilicate tubes containing the crystallization mixtures, which were rendered supersaturated by heating to 75 °C for 2 h followed by a 0.5 °C/min cooling ramp to 5 °C. Each tube in a 96-tube array was sealed within 15 s of a combinatorial dispensing with a Teflon-coated crimp top to avoid evaporation of organic solvents. A selection of 13 diverse solvents was used. The samples were incubated at 5 °C and monitored for crystallization over a 1 week period. The crystallization events are identified by an optical scanning station using automated image analysis. Samples that crystallized were removed from the original array. (E) Powder X-ray Diffraction (XRPD). X-ray powder data were collected on the following: (1) a Philips 1050 diffractometer, Cu KR radiation (λ ) 1.5406 Å), graphite monochromator on diffracted beam, operated at 40 kV and 30 mA; (2) a Bruker AXS D8 Discover X-ray
Wenger and Bernstein
Figure 2. Overlay of representative XRPD data for nine samples obtained by SDG of gabapentin and oxalic acid with various solvents: acetone, dichloromethane, toluene, ethylacetate, nitromethane, chlorobenzene, water, pyridine, and chlorobenzene, marked A-I, respectively, on the plot. diffractometer. This instrument was equipped with GADDS (general area diffraction detection system), a Bruker AXS HI-STAR area detector at a distance of 15.05 cm as per system calibration, a copper source (Cu KR1 radiation, λ ) 1.5406 Å), automated x-y-z stage, and 0.5 mm collimator. The sample was compacted into pellet form and mounted on the x-y-z stage. A diffractogram was acquired under ambient conditions at a power setting of 40kV and 40 mA in reflection mode while the sample remained stationary. The diffractogram obtained underwent a spatial remapping procedure to account for the geometrical pincushion distortion of the area detector, then integrated along chi from -118.8 to -61.8 and 2.1-37° 2θ at a step size of 0.02° with normalization set to bin normalize. (F) Single-Crystal X-ray Diffraction. Single-crystal intensity data of the cocrystal were collected on a Bruker SMART 1000K diffractometer using Mo KR radiation (λ ) 0.71073 Å) with a graphite monochromator. The data were reduced by SAINT,19 solved with SHELX,20 and then refined with SHELXL.21 (G) Hot Stage Microscopy (HSM). HSM examinations were performed on a Wagner and Munz Kofler hot stage equipped with digital video recorder facilities. (H) Differential Scanning Calorimetry (DSC). DSC measurements were performed using a Q1000 differential scaning calorimeter (TA Instruments, New Castle, DE). Heating and cooling rates of 0.5 °C/ min were employed under dry N2 with a flow rate of 50 mL/min. The analysis software used was Universal Analysis 2000 for Windows 95/98/2000/NT, version 3.1E.
Results and Discussion In the experiments of SDG using acetone, dichloromethane, toluene, ethylacetate, nitromethane, chlorobenzene, pyridine, and chloroform, new forms were identified in 9 out of 16 experiments either as cocrystals, new crystal forms of the starting material, or solvates. As shown in Figure 2, 8 of the 9 are the same form. Pure water whose pH was measured to be 6 (no adjustment) as a solvent yielded a different crystal form. The high throughput experiments yielded in 12 (out of 13) experiments new phases that were different from the starting materials (Figure 3). One of the new forms was obtained from an aqueous solution adjusted to pH 14 with 1 N NaOH. The follow up experiments of the HT screen were carried out at pH 6, 8, and 14 in aqueous solutions. It is important to note that the addition of the two components (gabapentin and oxalic acid) results in changes of the pH from that of the starting solutions; therefore for the slow evaporation experiments measurements of the pH were carried out after mixing the crystallization
Alternate Crystal Form of Gabapentin
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Figure 5. Crystal structure of the 2:1 cocrystal of gabapentin oxalic acid. The R42(8) synthon is marked as a dark brown dashed line. Other hydrogen bonds have been deleted for clarity. Table 1. Hydrogen Bond Lengths of the Cocrystal of Gabapentin and Oxalic Acid; Graph Set Designators Correspond to Figure 5 and Table 2
Figure 3. Overlay of representative XRPD data for 12 samples obtained by HT on gabapentin and oxalic acid with various solvents: Nmethylpyrrolidine, chlorobenzene, methanol, dichloromethane, ethanol, N,N-dimethylformamide, ethylacetate, nitromethane, acetone, toluene, pyridine, and aqueous NaOH pH 14, marked A-L, respectively, on the plot.
a b c d e
a
b
c
d
e
D22(6) C22(12) C22(12) C22(12) C33(16)
D22(6) R42(8) R42(14) C33(14)
D22(6) R24(8) C33(14)
D22(6) C33(14)
C(7)
Table 2. Graph Set Matrix of the Cocrystal of Gabapentin and Oxalic Acid
Figure 4. Overlay of representative XRPD data for gabapentin and oxalic acid. From bottom to top: calculated from single-crystal solution of cocrystal; experimental on bulk of cocrystallization; experimental of HT, SDG, gabapentin + oxalic acid in water; oxalic acid; gabapentin.
solution. In situ determination of the pH was not feasible with the high throughput crystallization experiment. To obtain an estimate of the pH in the HT experiments, we carried out the following test: The pH of distilled water was measured and found to be 6, the two acids were added, and the pH was measured again and found to be 2. The acids were then added to an aqueous solution initially at pH 8 and the measured resulting pH was 5, whereas when the acids were added to an aqueous solution initially at pH 14, the resulting pH was 12. Comparison of the experimental XRPDs of the cocrystal obtained by traditional methods and in HT revealed two different forms (Figure 4). The calculated diffractogram of the cocrystal with the experimental bulk material from which the single crystal was selected are essentially identical (Figure 4), indicating that there is no additional form in the bulk. Considering the pH’s of the crystallization mixture, at pH of 2 and 5 the same cocrystal was obtained; at pH 12 a different form was obtained (by XRPD), but we have not yet obtained crystals suitable for structure determination.
graph set designator
hydrogen bond
H-O distance (Å)
a b c d e
O-H · · · O N-H · · · O N-H · · · O N-H · · · O N-H · · · O
1.618 1.903 2.29 + 7 1.824 2.411
The single-crystal sample of the cocrystal of gabapentin and oxalic acid Figure 5 was obtained by slow evaporation in triply distilled water at room temperature; the pH of the crystallization solution was 5. Colorless plates were obtained after 1 week. The asymmetric unit of the crystal structure contains one protonated molecule of gabapentin and half a molecule of doubly ionized oxalic acid leading to an overall stoichiometric ratio of 2:1 in the crystal structure. The hydrogen-bond distances are given in (Table 1). From a number of systematic studies of cocrystals,22 it has been recognized that, in general, the best hydrogen-bond donor tends to interact with the best hydrogen-bond acceptor in a given crystal structure. The rule is also obeyed in this structure, with the OH · · · O hydrogen bond (1.618 Å) between the carboxylic group of the gabapentin (best donor) and the O- of the oxalic acid (best acceptor). The second best donor would be any of the three hydrogens on the ammonium cation NH3+ · · · O(1.824, 1.903, 2.297 Å). The latter two hydrogen bonds comprise the centrosymmetric R42(8) hydrogen bond synthon as designed (Figure 5). The first and second level hydrogen bond motifs for the five hydrogen bonds in the structure were determined by PLUTO.23 They are summarized in matrix form24 in Table 2 and are illustrated in (Figure 6). It is clearly seen from the matrix and Figure 5 that the R42(8) synthon appears as a second level motif between the hydrogen bonds designated b and c. Thermal analysis was carried out to further characterize the cocrystal (Figure 7). Heating from ∼30 to 200 °C at 0.5 °C/ min revealed an endotherm at 137.6 °C for the melting point, which is compatible with the melting point observed by HSM.
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been achieved, along with additional crystal forms that are under continuing investigation. Acknowledgment. This work is supported by the U.S.-Israel Binational Science Foundation, Grant 2004118. We are grateful to Dr. Dmitry Mogilyanski for technical assistance and for the XRPD measurements on the powders obtained by traditional crystallization method (Figure 3). Supporting Information Available: (1) XRPD’s comparison of the crystal forms obtained in HT screening with all oxalic acid crystal forms and XRPD’s comparison of the crystal forms obtained in HT screening with all gabapentins crystal forms; (2) CIF of the cocrystal of gabapentin and oxalic acid. This information is available free of charge via the Internet at http://pubs.acs.org. Figure 6. Hydrogen bonds summarized in Tables 1 and 2. The bold lowercase designators refer to individual hydrogen bonds for which the graph set motif appears on the diagonal of Table 2. Individual hydrogen bonds are also color-coded. Single red spheres are oxygen atoms on molecules where remaining atoms have been deleted for clarity. Only a part of the C(7) chain motif for the hydrogen bond designated e has been shown, again for clarity.
Figure 7. DSC trace of the cocrystal. Heating rate 0.5 °C/min.
For reference the melting point of the starting materials are gabapentin 162–166 °C and oxalic acid dehydrate 101–102 °C. No other thermal events were observed. Continued heating of the melt led to an exotherm at 167.7 °C accompanied by bubbles escaping from the crystal at the melting point, which apparently is due to decomposition. Summary The possibility of the existence of multiple crystal forms can be manifested in the variability in the physicochemical profile of a substance. The ability to design those forms based on utilizing specific hydrogen-bond synthons suggests a strategy for gaining control of the physicochemical profile. The cocrystallization reported here resulted formally in the formation of a salt. There has been considerable discussion of the definition of a cocrystal with regard to the nature of both the starting components and the resultant molecules.25,26 As noted elsewhere27 we believe that the element of design should be taken into account in determining whether a product should considered a cocrystal or not, and that element of design is certainly present here. A combined approach to cocrystal design has been employed here to obtain a cocrystal of gabapentin and oxalic acid: CSD aided literature survey, high throughput experiments (solvent drop grinding and solution crystallization), and variation in pH. All the experiments were designed with the intent of obtaining a structure with the hydrogen bond synthon R42(8), which has
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