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<p>Cocrystals and Salts of Gabapentin: pH Dependent Cocrystal</p><p>Stability and Solubility</p><p>L. Sreenivas Reddy,† Sarah J. Bethune,† Jeff W. Kampf,‡ and Naı́r Rodrı́guez-Hornedo*,†</p><p>Department of Pharmaceutical Sciences and Department of Chemistry, UniVersity of Michigan, Ann</p><p>Arbor, Michigan, 48109-1065</p><p>ReceiVed June 6, 2008; ReVised Manuscript ReceiVed September 19, 2008</p><p>ABSTRACT: Thirteen new multicomponent crystals (cocrystals and salts) of an anticonvulsant drug gabapentin with various</p><p>carboxylic acid coformers have been discovered using the reaction crystallization method (RCM). These new forms are characterized</p><p>by X-ray powder diffraction (XRPD), Raman and infrared spectroscopy, and differential scanning calorimetry (DSC). Crystal structures</p><p>with 3-hydroxybenzoic acid (3HBA) 1, 4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy-2-napthoic acid (1H2NA) 4,</p><p>and RS-mandelic acid 5 are also determined. While there is proton transfer from coformer to gabapentin in crystals 3-5, no proton</p><p>transfer occurs in 1. Partial proton transfer is observed in crystal structure 2. Multicomponent crystals 1-5 are thermodynamically</p><p>stable and do not transform to gabapentin hydrate in water suggesting that the multicomponent phases have equal or lower solubility</p><p>than the components. pH has been shown to be an important variable in controlling solubility and stability. A mathematical model</p><p>that describes the pH dependent solubility profile of a cocrystal with a zwitterionic drug and an acidic coformer is derived based on</p><p>cocrystal dissociation and ionization solution equilibria. Predicted pH dependent cocrystal solubility and stability are in good agreement</p><p>with experimental measurements. An important capability of these models is that it allows one to generate the solubility and stability</p><p>dependence on pH from the knowledge of pKa values and solubility measurement at a single pH. Comparison of pH-solubility</p><p>profiles of cocrystal and components establishes the pH-dependent stability regions for cocrystal and components.</p><p>Introduction</p><p>Physicochemical properties of a solid form depend on the</p><p>arrangement of molecules in the crystal lattice.1 The majority</p><p>of active pharmaceutical ingredients (APIs) exist in a variety</p><p>of crystalline forms such as polymorphs, salts, and solvates.2</p><p>A recent analysis of 245 APIs showed that 89% had multiple</p><p>solid forms. Approximately 50% of the compounds showed</p><p>polymorphism, 37% were hydrates, and 31% were solvates.3</p><p>Choosing the best crystalline form of an API is an essential</p><p>step in drug development, as it has significant impact on its</p><p>performance.4 Salt formation is commonly employed to improve</p><p>API properties such as solubility and stability.5 Crystal engi-</p><p>neering approach to tailor the physiochemical properties of APIs</p><p>by cocrystallization is emerging as an important area of</p><p>research.6 Cocrystallization has been shown to improve impor-</p><p>tant pharmaceutical properties such as solubility,7 bioavailabil-</p><p>ity,8 moisture uptake,9 and physical and chemical stability10 of</p><p>a drug. Some of these aspects are highlighted in a special issue</p><p>dedicated to pharmaceutical cocrystals in Molecular Pharma-</p><p>ceutics.11</p><p>There has been great interest in pharmaceutical cocrystal</p><p>design and screening in the past few years, but in most cases</p><p>the API is uncharged.12 There are very few reports on cocrys-</p><p>tallization of charged APIs.12a,13 In this contribution we present</p><p>screening, synthesis, and properties of multicomponent crystals</p><p>of gabapentin which exists as a zwitterion in the solid state</p><p>(Scheme 1). The term “multicomponent crystals” is used to</p><p>describe both cocrystals and salts in this paper.14</p><p>Gabapentin, an analogue of the neurotransmitter gamma-</p><p>aminobutyric acid (GABA), is used as an anticonvulsant to treat</p><p>partial seizures.15 It crystallizes as three anhydrous polymorphs</p><p>and a monohydrate.16 Gabapentin also forms coordination</p><p>polymers with Cu and Zn.17 Very recently, Bernstein and co-</p><p>workers carried out a high throughput screening for cocrystals</p><p>with oxalic acid and reported a 2:1 gabapentin-oxalic acid</p><p>salt.18</p><p>Carboxylic acids are chosen as potential cocrystal or salt</p><p>formers by analyzing the way carboxylic acids interact with</p><p>zwitterionic compounds such as amino acids within the Cam-</p><p>bridge Structural Database (CSD).19 A CSD search for com-</p><p>ponds with +NH3, COO-, and C-COOH functional groups</p><p>resulted in 99 entries.20 Analysis of crystal structures reveals</p><p>that in 86 out of 99 compounds the carboxyl · · · carboxylate</p><p>synthon II (Scheme 2) is present. There is proton transfer in</p><p>some structures but the carboxyl · · · carboxylate synthon II is</p><p>still present as the carboxyl group becomes carboxylate. In the</p><p>remaining 13 structures, the carboxyl group is involved in either</p><p>intramolecular hydrogen bonding or hydrogen bonds to itself.</p><p>This suggests that synthon II is robust and can be transferable</p><p>from one crystal structure to the other. The strength of</p><p>* Corresponding author. Phone: 734-763-0101. Fax: 734-615-6162. E-mail:</p><p>nrh@umich.edu.</p><p>† Department of Pharmaceutical Sciences.</p><p>‡ Department of Chemistry.</p><p>Scheme 1. Compounds Used in Cocrystallization</p><p>CRYSTAL</p><p>GROWTH</p><p>& DESIGN</p><p>2009</p><p>VOL. 9, NO. 1</p><p>378–385</p><p>10.1021/cg800587y CCC: $40.75  2009 American Chemical Society</p><p>Published on Web 12/05/2008</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-000.png&w=239&h=177</p><p>carboxyl · · · carboxylate synthon II is exploited in designing</p><p>multicomponent forms of gabapentin with various carboxylic</p><p>acid coformers (Scheme 1).</p><p>Experimental Section</p><p>Gabapentin and carboxylic acids were purchased from Spectrum</p><p>Chemicals and Aldrich Chemicals, respectively. All chemicals were</p><p>used without further purification. Gabapentin was analyzed by XRPD</p><p>and DSC before cocrystallization experiments. ACS reagent grade</p><p>acetonitrile or ethanol and deionized water were used in screening and</p><p>stability studies, respectively.</p><p>Screening and Scale Up. Screening and scale up experiments were</p><p>performed using reaction crystallization method (RCM) at room</p><p>temperature. Yield of the multicomponent crystals (cocrystal/salt) by</p><p>RCM was 85-95% depending on the solubility and solution concentra-</p><p>tion of components (drug and coformers). X-ray diffraction quality</p><p>single crystals were grown by slow evaporation. Both RCM and slow</p><p>evaporation experiments were carried out at room temperature.</p><p>Reaction Crystallization Method (RCM).21 In screening experi-</p><p>ments, 50-75 mg of gabapentin was added to 1 mL of presaturated</p><p>acetonitrile or ethanol solutions of coformers. In most cases cocrys-</p><p>tallization was observed within minutes. Solids were filtered, dried,</p><p>and characterized by XRPD and DSC. Appropriate quantities of</p><p>gabapentin and coformers were used for scale up.</p><p>Slow Evaporation. Single crystals of 1-5 were obtained by slow</p><p>evaporation of solutions containing gabapentin and coformer (1:3 molar</p><p>ratio) in appropriate solvents. Solvents used were acetonitrile, ethanol,</p><p>or water.</p><p>X-ray Diffraction. X-ray powder diffraction (XRPD) was collected</p><p>using a Rigaku MiniFlex diffractometer (The Woodlands, TX) with a</p><p>copper target X-ray tube. Data was collected at a scan rate of 2.5°/min</p><p>over a 2θ range of 2.5° to 40°. The accelerating voltage was 30 kV,</p><p>and the current was 15 mA.</p><p>Single crystal X-ray diffraction data on compounds 1-5 was</p><p>collected on a Bruker SMART APEX CCD-based X-ray diffractometer</p><p>(Mo KR radiation, λ ) 0.71073 Å) equipped with a low temperature</p><p>device. Empirical absorption corrections using SADABS22a were</p><p>applied. Structure solution and refinement were performed with</p><p>SHELXTL (version 6.12).22b All non-hydrogen atoms were refined</p><p>anisotropically with the hydrogen atoms placed in idealized positions</p><p>except for those involved in hydrogen bonding which were allowed to</p><p>refine isotropically.</p><p>Differential Scanning Calorimetry (DSC). Thermal analysis of</p><p>samples was carried out using a TA 2590 DSC (TA instruments, New</p><p>Castle, DE) which was calibrated for temperature and cell constants</p><p>using indium and n-dodecane.</p><p>Samples (5-7 mg) crimped in aluminum</p><p>pans were analyzed in the DSC from 25 to 220 °C with heating rate of</p><p>10 °C/min. Samples were continuously purged with nitrogen at 50 mL/</p><p>min.</p><p>pH Dependent Stability and Solubility of Gabapentin-3HBA</p><p>Cocrystal. Stability and solubility studies were performed by suspend-</p><p>ing excess cocrystal in aqueous solutions of different pH at room</p><p>temperature. pH was adjusted with either 1 M hydrochloric acid or 1</p><p>M sodium hydroxide. Solid phases and solution concentrations were</p><p>analyzed at 72 and 96 h to confirm that equilibrium was attained. pH</p><p>at equilibrium was measured. Solid phases were analyzed by XRPD,</p><p>and solution concentration was measured by HPLC.</p><p>High Performance Liquid Chromatography (HPLC). Gabapentin-</p><p>3HBA is a 1:1 cocrystal and its solubility is equal to either total</p><p>gabapentin or 3HBA solution concentration. 3HBA solution concentra-</p><p>tion was measured with a Waters system (Bedford, MA) equipped with</p><p>a photodiode array UV/vis detector. Gabapentin concentration was</p><p>calculated by mass balance. A 45% water/55% methanol with 0.1%</p><p>trifluoroacetic acid mobile phase was used at flow rate of 1 mL/min</p><p>through an Atlantis C18 column (Waters, Bedford, MA). 3HBA</p><p>absorbance was analyzed at 272 nm.</p><p>Results and Discussion</p><p>Thirteen new multicomponent crystals of gabapentin with</p><p>various carboxylic acid coformers were discovered by the</p><p>reaction crystallization method (RCM) (Table 1).21 RCM is</p><p>based on solution chemistry and proved to be an efficient method</p><p>for cocrystal screening.6a These new solid phases were char-</p><p>acterized by XRPD, Raman and IR spectroscopy, and DSC.</p><p>Crystal structures with 3-hydroxybenzoic acid (3HBA) 1,</p><p>4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy-</p><p>2-napthoic acid (1H2NA) 4, and RS-mandelic acid 5 were also</p><p>determined. A comparison of experimental XRPD patterns with</p><p>those calculated from relevant single crystal data of 1-5</p><p>indicates that the crystalline products obtained from both</p><p>reaction crystallization and slow evaporation are structurally</p><p>homogeneous (Figure S1, Supporting Information). XRPD</p><p>patterns of all new forms are shown in Figure 1. Crystallographic</p><p>data is listed in Table 2 for 1-5. Simulated XRPD patterns</p><p>(Figure S1), ORTEP diagrams (Figure S2), and important</p><p>hydrogen bond geometries (Table S1) for 1-5, simulated XRPD</p><p>patterns of gabapentin forms (Figure S3), and Raman and IR</p><p>spectra along with DSC thermograms for all new forms are</p><p>included in the Supporting Information. Graphics were generated</p><p>in X-seed trial version.23</p><p>Scheme 2. Hydrogen Bonded Synthons Discussed in This</p><p>Paper</p><p>Table 1. New Multicomponent Crystals of Gabapentin Obtained by</p><p>RCM with Various Carboxylic Acid Coformers (melting point of</p><p>most stable r-gabapentin16a is 160-162 °C)</p><p>multicomponent</p><p>crystal coformer</p><p>multicomponent</p><p>crystal, mp (°C)</p><p>coformer</p><p>mp (°C)</p><p>1 3-hydroxybenzoic acid 132 204</p><p>2 4-hydroxybenzoic acid 166 214</p><p>3 salicylic acid 131 159</p><p>4 1-hydroxy-2-napthoic acid 126 192</p><p>5 RS-mandelic acid 125 134</p><p>6 S-mandelic acid 129 130</p><p>7 R-mandelic acid 129 130</p><p>8 DL-tartaric acid 157 205</p><p>9 L-tartaric acid 132 166</p><p>10 D-tartaric acid 132 170</p><p>11 malic acid 112 131</p><p>12 (+)-camphoric acid 149 187</p><p>13 gallic acid 150 250</p><p>Figure 1. XRPD patterns of new forms of gabapentin discovered by</p><p>the reaction crystallization method (RCM).</p><p>Cocrystals and Salts of Gabapentin Crystal Growth & Design, Vol. 9, No. 1, 2009 379</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-001.png&w=172&h=49</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-002.jpg&w=210&h=189</p><p>Gabapentin-3-hydroxybenzoic Acid (1:1), 1. Gabapentin-</p><p>3-hydroxybenzoic acid 1 crystallizes in orthorhombic space</p><p>group Pccn with one molecule of each in asymmetric unit. In</p><p>the crystal structure, gabapentin exists as a zwitterion. Both</p><p>carboxylic and phenolic OH donors of 3HBA form O-H · · ·O-</p><p>interactions (synthon II, D ) 2.541 Å, θ ) 178°; synthon III,</p><p>2.672 Å, 175°) with gabapentin to form a crown ether-like cyclic</p><p>tetramer, and these tetramers are in turn connected by charge</p><p>assisted N+-H · · ·O- (2.702 Å, 153°) hydrogen bonds to result</p><p>in a layered structure (Figure 2). Other N-H donors of the</p><p>ammonium group are involved in intra- and intermolecular</p><p>N+-H · · ·O- hydrogen bonds (Table S1, Supporting Informa-</p><p>tion).</p><p>Gabapentin-4-hydroxybenzoic Acid (1:1), 2. The crystal</p><p>structure of 1:1 gabapentin and 4-hydroxybenzoic acid (4HBA)</p><p>2 is interesting both chemically and crystallographically. Asym-</p><p>metric unit contains one molecule each of gabapentin and 4HBA</p><p>(triclinic, P1j). The carboxyl proton of 4HBA is disordered over</p><p>two positions with split occupancy of 50% on 4HBA and 50%</p><p>on gabapentin carboxylate. However, the partial proton transfer</p><p>is not through hydrogen bonding because both carboxyl and</p><p>carboxylate groups are not in close proximity. Moreover, both</p><p>these disordered protons are sitting on a crystallographic special</p><p>position, the inversion center. 4HBA interacts with gabapentin</p><p>through O-H · · ·O (2.759 Å, 178°) and N+-H · · ·O (2.779 Å,</p><p>167°) to form a tetrameric motif and these tetrameric motifs</p><p>are connected by N+-H · · ·O tetramer synthon18 leading to a</p><p>layered structure (Figure 3). One of the ammonium N-H donors</p><p>is involved in an intramolecular N+-H · · ·O (2.689 Å, 160°)</p><p>hydrogen bond.</p><p>Gabapentin-Salicylic Acid (1:1), 3. Asymmetric unit con-</p><p>tains two symmetry independent molecules each of gabapentin</p><p>and salicylic acid (monoclinic, P21/n). There is proton transfer</p><p>from the carboxyl group of salicylic acid to the basic gabapentin</p><p>carboxylate. As shown in Figure 4 gabapentin and salicylic acid</p><p>interact with each other via carboxyl · · · carboxylate synthon II</p><p>(2.553 Å, 174°; 2.547 Å, 173°) and ammonium · · · carboxylate</p><p>synthon I (2.949 Å, 146°; 2.841 Å, 156°). Phenolic group is</p><p>involved in an intramolecular O-H · · ·O- (2.529 Å, 153°; 2.505</p><p>Å, 156°) hydrogen bonding. Unlike other structures, gabapentin</p><p>molecule does not form an intramolecular N+-H · · ·O- hydro-</p><p>gen bond.</p><p>Gabapentin-1-hydroxy-2-napthoic acid (1:1), 4. A multi-</p><p>component crystal, 4, crystallizes in monoclinic P21/c space</p><p>group with one molecule each of gabapentin and 1-hydroxy-</p><p>2-napthoic acid (1H2NA) in an asymmetric unit. There is</p><p>proton transfer from the acidic 1H2NA to the basic carboxy-</p><p>late of gabapentin. Gabapentin molecules interact with</p><p>1H2NA through carboxyl · · · carboxylate synthon II (2.592</p><p>Å, 170°) and ammonium · · · carboxylate synthon I (2.841 Å,</p><p>165°) to form a tetrameric unit (Figure 5). These tetrameric</p><p>units are connected by N+-H · · ·O- (2.804 Å, 154°) hydro-</p><p>gen bonds (not shown in the figure). The phenolic group is</p><p>involved in an intramolecular O-H · · ·O- (2.510 Å, 170°)</p><p>hydrogen bond.</p><p>Gabapentin-RS-Mandelic Acid (1:1), 5. There is proton</p><p>transfer from RS-mandelic acid to gabapentin carboxylate in</p><p>the crystal structure. It crystallizes in triclinic space group P1j</p><p>with one molecule each of gabapentin and mandelic acid in the</p><p>asymmetric unit. Gabapentin interacts with mandelic acid via</p><p>carboxyl · · · carboxylate synthon II (2.574 Å, 163°) and phenolic</p><p>O-H · · ·O hydrogen bonds (2.814 Å, 147°) to form a tetrameric</p><p>motif. These tetrameric motifs in turn are connected by charge</p><p>assisted N+-H · · ·O- (2.812 Å, 168°) hydrogen bonds leading</p><p>to formation of a layered structure (Figure 6). These layers are</p><p>connected by N+-H · · ·O- hydrogen bonds in the other</p><p>direction. One of the ammonium N-H donors of gabapentin</p><p>molecule is involved in an intramolecular N+-H · · ·O hydrogen</p><p>bond.</p><p>Crystal structures show proton transfer with salicylic acid,</p><p>1-hydroxy-2-napthoic acid, and RS-mandelic acids but not with</p><p>3-hydroxybenzoic acid. The extent of proton transfer in the</p><p>crystalline phase can be determined by analyzing proton location</p><p>or position and bond lengths of atoms involved, for example,</p><p>C-O distances of carboxyl groups.24 In carboxylic acids, the</p><p>average C-O distance is 1.31 Å, whereas the CdO distance</p><p>average is 1.21 Å. On the other hand, the average C-O distance</p><p>in the carboxylate moiety is 1.25 Å.25 In crystal 1, the C-O</p><p>bond distances in the gabapentin carboxylate moiety are 1.27</p><p>and 1.26 Å while in 3HBA the C-O and CdO bond distances</p><p>are 1.32 and 1.22 Å. This suggests that there is no proton transfer</p><p>from 3HBA to gabapentin; thus, 1 is a cocrystal. Similar analysis</p><p>of C-O bond distances (Table 3) in forms 3-5 show that there</p><p>is proton transfer from the coformer to gabapentin suggesting</p><p>salt formation. Multiple protonation states with partial occupancy</p><p>and C-O bond distances in 2 suggest a partial proton transfer.</p><p>This could be due to disorder, and neither the salt nor the</p><p>cocrystal can be labeled to accurately describe this structure.</p><p>Analysis of multicomponent crystal structures of amino acids</p><p>in the CSD also shows a similar trend. A CSD search for</p><p>Table 2. Crystallographic Data and Structure Refinement</p><p>Parameters for Multicomponent Crystals of Gabapentin</p><p>1 2 3 4 5</p><p>emp. formula C16H23NO5 C16H23NO5 C16H23NO5 C20H25NO5 C17H25NO5</p><p>formula wt 309.35 309.35 309.35 359.41 323.38</p><p>crystal system orthorhombic triclinic monoclinic monoclinic triclinic</p><p>space group Pccn P1j P21/n P21/c P1j</p><p>a, Å 12.8276(12) 6.0648(4) 10.5813(9) 7.3565(6) 6.1129(10)</p><p>b, Å 25.380(2) 11.0825(8) 10.3920(9) 18.4929(15) 9.3483(15)</p><p>c, Å 9.5029(9) 12.5727(9) 28.659(3) 13.7524(11) 14.879(2)</p><p>R, deg 90 66.3550(10) 90 90 90</p><p>�, deg 90 83.4020(10) 96.573(1) 101.855(1) 101.855(1)</p><p>γ, deg 90 85.7140(10) 90 90 90</p><p>Z 8 2 8 4 2</p><p>V, Å3 3093.8(5) 768.60(9) 3130.6(5) 1831.0(3) 811.9(2)</p><p>T, K 85(2) 85(2) 85(2) 85(2) 85(2)</p><p>Dcalcd, g cm-3 1.328 1.337 1.313 1.304 1.323</p><p>reflns collected 73413 27729 67350 40063 24634</p><p>Unique reflns. 3874 3843 7813 3801 4070</p><p>observed reflns 3585 3430 6801 3320 3889</p><p>R1 (I > 2σ(I)) 0.0371 0.0366 0.0504 0.0834 0.0424</p><p>wR2 0.0966 0.0931 0.1248 0.1959 0.1075</p><p>goodness-of-fit 1.069 1.035 1.126 1.147 1.101</p><p>Figure 2. Hydrogen bonding pattern in gabapentin-3HBA. Tetramers</p><p>form between gabapentin and 3HBA through O-H · · ·O- hydrogen</p><p>bonds. These tetramers are connected by N+-H · · ·O- hydrogen bonds</p><p>to form a layered structure. There is no proton transfer from 3HBA to</p><p>gabapentin.</p><p>380 Crystal Growth & Design, Vol. 9, No. 1, 2009 Reddy et al.</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-003.jpg&w=238&h=137</p><p>compounds with +NH3, COO-, and COOH groups excluding</p><p>other hydrogen bonding competing groups such as water,</p><p>pyridine moiety, urea, and carbonyl resulted in 47 entries.26 In</p><p>29 out of 47 structures there is proton transfer from carboxylic</p><p>acid to the basic carboxylate of amino acid whereas in 16</p><p>instances there is no proton transfer. In two crystal structures</p><p>both protonation and unprotonation are observed. It is interesting</p><p>to note that proton transfer from coformer to gabapentin</p><p>carboxylate is observed with salicylic acid, 1-hydroxy-2-</p><p>napthoic acid, and RS-mandelic acid with pKa values of 2.97,</p><p>4.17, and 3.41, respectively, but not in the case of 3-hydroxy-</p><p>benzoic acid with pKa 4.06. It is difficult to rationalize the proton</p><p>transfer in these structures based on pKa values. Other factors</p><p>such as crystal structures and reaction conditions are also known</p><p>to play an important role in the extent of proton transfer.14,27</p><p>Another interesting observation is that the melting points of most</p><p>of the multicomponent crystals of gabapentin discovered in this</p><p>study are lower than that of the individual components (Table</p><p>1).</p><p>Although there is proton transfer in 3, 4,and 5 and no proton</p><p>transfer in 1, gabapentin interacts with the acid coformers via</p><p>carboxyl · · · carboxylate synthon II. Similar hydrogen bonding</p><p>can be expected in multicomponent crystals 6-13, irrespective</p><p>of whether there is proton transfer or not in crystalline state. In</p><p>multicomponent crystals 8-12, where the coformer is a dicar-</p><p>boxylic acid, there may be competition between the carboxyl</p><p>and carboxylate groups of gabapentin and coformer in synthon</p><p>II formation depending on stoichiometry.</p><p>Multicomponent crystals 6-13 are characterized by their</p><p>unique XRPD (Figure 1) and Raman and IR spectra (Supporting</p><p>Information) when compared to all known individual component</p><p>forms. They exhibit melting points different from components</p><p>except for crystals 6 and 7, whose melting points are very close</p><p>to that of coformers. However, the XRPD patterns and Raman</p><p>and IR spectra are different from all reported forms of</p><p>gabapentin and mandelic acids. Furthermore, crystallization of</p><p>single components is unlikely under RCM conditions, because</p><p>precipitation occurs in solutions at or below saturation of</p><p>reactants and there is no solvent evaporation or temperature</p><p>change.21</p><p>Ionization state or proton transfer in solids can be determined</p><p>by single crystal X-ray diffraction or spectroscopic techniques</p><p>such as IR and solid-state NMR.28 In multicomponent crystals</p><p>1-5, the ionization state of gabapentin was determined by</p><p>crystal structure determination. IR spectra of 6-13 were</p><p>analyzed and compared with 1-5 to gain information about</p><p>ionization state of gabapentin. It suggests that while gabapentin</p><p>ionization state can be evaluated with aromatic carboxylic acids</p><p>by following the carbonyl absorption region, it is difficult in</p><p>multicomponent crystals with aliphatic carboxylic acids. The</p><p>carbonyl group of aromatic carboxylic acids absorbs at lower</p><p>frequencies (1710-1680 cm-1) than aliphatic of carboxylic</p><p>acids (1750-1700 cm-1) due to resonance.29 Anhydrous</p><p>gabapentin exhibits an IR band at 1610 cm-1 corresponding to</p><p>carboxylate stretching. If there is proton transfer from coformer</p><p>to gabapentin, the gabapentin carboxylate group would have a</p><p>carbonyl peak at frequency >1700 cm-1 similar to aliphatic</p><p>carboxylic acid. In multicomponent crystal 13 appearance of a</p><p>strong IR band in at 1719 cm-1 suggests that there is proton</p><p>transfer from gallic acid to gabapentin (Supporting Information).</p><p>Similar analysis cannot be applied to multicomponent crystals</p><p>with aliphatic carboxylic acids as their carbonyl absorption band</p><p>appears in same region as protonated gabapentin. Although it</p><p>is not very clear from IR spectra, in 6 and 7 (with S/R-mandelic</p><p>acids), one can expect salt formation as there is proton transfer</p><p>from RS-mandelic acid to gabapentin in 5.</p><p>pH-Dependent Stability and Solubility of Gabapentin-</p><p>3HBA Cocrystal. Thermodynamic stability and solubility of</p><p>multicomponent crystalline drug forms in aqueous media are</p><p>important to understand and control transformations in order</p><p>to achieve the desired dissolution and bioavailability. In general,</p><p>thermodynamic stability and solubility are inversely related; as</p><p>Figure 3. Hydrogen bonding pattern in the crystal structure of gabapentin-4HBA. 4HBA interacts with gabapentin through O-H · · ·O and N+-H · · ·O</p><p>to form a tetrameric motif and these tetrameric motifs are connected by N+-H · · ·O hydrogen bonds. Carboxyl hydrogen atom is disordered over</p><p>two positions and not participating in hydrogen bonding.</p><p>Figure 4. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxy-</p><p>late synthon I in gabapentin-salicylic acid tape structure. There is proton</p><p>transfer from salicylic acid to gabapentin carboxylate.</p><p>Cocrystals and Salts of Gabapentin Crystal Growth & Design, Vol. 9, No. 1, 2009 381</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-004.jpg&w=359&h=173</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-005.jpg&w=132&h=119</p><p>solubility of multicomponent crystal increases and surpasses the</p><p>solubility of individual components, there is greater potential</p><p>for transformation. Multicomponent crystals 1-5 were found</p><p>to be thermodynamically stable when suspended in pure water</p><p>at room temperature and did not transform to component solid</p><p>phases suggesting that the multicomponent phases have equal</p><p>or lower solubility than the drug or coformer.</p><p>Stability of gabapentin-3HBA 1 was further studied in</p><p>aqueous solutions at several pH values (Figure 7). Results show</p><p>that cocrystal is stable at pH 4.0 and 5.7 but transforms to 3HBA</p><p>at pH 2.6. This indicates</p><p>that gabapentin-3HBA cocrystal is less</p><p>Figure 5. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxylate synthon I in gabapentin-1H2NA tape structure. There is proton transfer</p><p>from 1H2NA to gabapentin.</p><p>Figure 6. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxylate synthon I in gabapentin-RS-mandelic acid. Two molecules each of</p><p>gabapentin and RS-mandelic acid form a tetramer and these tetramers are connected by N+-H · · ·O- hydrogen bonds. There is proton transfer</p><p>from RS-mandelic acid to gabapentin.</p><p>Table 3. Distribution of C-O Bond Lengths for Gabapentin and</p><p>Carboxylic Acid Coformers in New Forms</p><p>multicomponent</p><p>crystal</p><p>gabapentin,</p><p>d(C-O), Å</p><p>coformer,</p><p>d(C-O), Å</p><p>nature of</p><p>multicomponent</p><p>crystal</p><p>1 1.266, 1.258 1.222, 1.319 cocrystal</p><p>2 1.245, 1.280 1.251, 1.287 H-atom disordered</p><p>3 1.21, 1.329,</p><p>1.21, 1.328</p><p>1.259, 1.262,</p><p>1.254, 1.267</p><p>salt</p><p>4 1.219, 1.301 1.293, 1.245 salt</p><p>5 1.212, 1.329 1.266, 1.234 salt</p><p>Figure 7. pH dependent stability of gabapentin-3HBA cocrystal.</p><p>Cocrystal is thermodynamically stable at pH 4.0 and 5.7 and transforms</p><p>to 3HBA at pH 2.6.</p><p>382 Crystal Growth & Design, Vol. 9, No. 1, 2009 Reddy et al.</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-006.jpg&w=339&h=194</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-007.jpg&w=339&h=185</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-008.jpg&w=239&h=156</p><p>soluble or as soluble as gabapentin hydrate and 3HBA, between</p><p>pH 4.0 and 5.7, while cocrystal is more soluble than 3HBA at</p><p>pH 2.6. The narrow pH range under which the cocrystal is stable</p><p>motivated the development of mathematical models that allow</p><p>for the prediction of the cocrystal solubility-pH dependence from</p><p>limited solubility data and knowledge of pKa values of cocrystal</p><p>components.</p><p>We have previously shown that solubility and stability of</p><p>cocrystals with a nonionizable drug and acidic or basic coformer</p><p>are controlled by solution pH, coformer pKa, and cocrystal</p><p>Ksp.9b,30 In the present study, we extend the thermodynamic</p><p>models to describe the pH-dependent solubility of 1:1 cocrystals</p><p>with a zwitterionic drug and a diprotic acidic coformer. Predicted</p><p>solubility behavior is challenged with experimental measure-</p><p>ments of 1:1 gabapentin-3HBA cocrystal.</p><p>A zwitterionic drug such as gabapentin is expressed as</p><p>-ABH+, and the diprotic acidic coformer such as 3HBA is</p><p>expressed as H2X. The equilibrium reactions and equilibrium</p><p>constants for dissociation of cocrystal and ionization of com-</p><p>ponents in solution (assuming no complexation) are as follow:</p><p>-ABH+H2Xsolidh</p><p>-ABHsoln</p><p>+ +H2Xsoln</p><p>Ksp ) [-ABH+][H2X] (1)</p><p>HABH+h -ABH++H+</p><p>Kal,-ABH+ )</p><p>[-ABH+][H+]</p><p>[HABH+]</p><p>(2)</p><p>-ABH+h -AB+H+</p><p>Ka2,-ABH+ )</p><p>[-AB][H+]</p><p>[-ABH+]</p><p>(3)</p><p>H2XhHX-+H+</p><p>Kal,H2X )</p><p>[HX-][H+]</p><p>[H2X]</p><p>(4)</p><p>HX-hX2-+H+</p><p>Ka2,H2X )</p><p>[X2-][H+]</p><p>[HX-]</p><p>(5)</p><p>where Ksp is the cocrystal solubility product and Ka represents</p><p>ionization constants of components. The total drug concentration</p><p>or analytical concentration ([AB]T) is the sum of all the ionized</p><p>species and is given by</p><p>[AB]T)[-ABH+]+ [HABH+]+ [-AB] (6)</p><p>The total coformer concentration ([X]T) is a sum of ionized and</p><p>un-ionized species and is given by</p><p>[X]T)[H2X]+ [HX-]+ [X2-] (7)</p><p>Substituting the equilibrium constants from eqs 1, 2, and 3 into</p><p>eq 6 gives</p><p>[AB]T )</p><p>Ksp</p><p>[H2X]</p><p>R</p><p>where R) (1+ [H+]</p><p>Kal,-ABH+</p><p>+</p><p>Ka2,-ABH+</p><p>[H+] )</p><p>(8)</p><p>Rewriting eq 7 to express [H2X] in terms of [X]T results in</p><p>[H2X])</p><p>[X]T</p><p>�</p><p>where �) (1+</p><p>Kal,H2X</p><p>[H+]</p><p>+</p><p>Kal,H2XKa2,H2X</p><p>[H+]2 )</p><p>(9)</p><p>Substituting eq 9 into eq 8 gives the total drug concentration</p><p>[AB]T )</p><p>Ksp</p><p>[X]T</p><p>R� (10)</p><p>For a 1:1 cocrystal, cocrystal solubility (Scocrystal) equals total</p><p>drug or total coformer concentration:</p><p>Figure 8. Calculation of gabapentin-3HBA cocrystal Ksp according to</p><p>eq 11, using measured cocrystal solubility as a function of pH. Slope</p><p>is the Ksp (0.0147 M2).</p><p>Figure 9. Gabapentin-3HBA cocrystal solubility dependence on pH.</p><p>Symbols (b) represent experimental solubility values. Predicted solubil-</p><p>ity curve was generated from eq 11 using the Ksp value of 0.0147 M2.</p><p>Cocrystals and Salts of Gabapentin Crystal Growth & Design, Vol. 9, No. 1, 2009 383</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-009.png&w=227&h=233</p><p>http://pubs.acs.org/action/showImage?doi=10.1021/cg800587y&iName=master.img-010.png&w=218&h=212</p><p>Scocrystal ) [AB]T ) [X]T</p><p>Therefore, cocrystal solubility can be expressed as</p><p>Scocrystal ) √KspR� (11)</p><p>which relates cocrystal solubility to cocrystal Ksp, components</p><p>pKa values, and solution pH. If Ksp is known, one can calculate</p><p>the solubility of cocrystal (Scocrystal) at any given pH. Alterna-</p><p>tively, if cocrystal solubility is known at given pH, Ksp can be</p><p>calculated from eq 11.</p><p>Because gabapentin-3HBA cocrystal is stable at pH 4.0 and</p><p>5.7 (Figure 7), equilibrium solubility was measured at pH values</p><p>in this range and equation 11 was used to calculate Ksp. As</p><p>shown in Figure 8, the Ksp for gabapentin-3HBA was evaluated</p><p>to be 0.0147 M2 from a plot of (Scocrystal)2 against KspR�.</p><p>Reported pKa values 3.68 and 10.70 for gabapentin and 4.06</p><p>and 9.92 for 3HBA were used in solubility and Ksp calcula-</p><p>tions.31 Figure 9 shows that the experimentally measured</p><p>solubilities of gabapentin-3HBA cocrystal are in good agreement</p><p>with the predicted solubility from eq 11. The model predicts a</p><p>minimum cocrystal solubility at a pH between the two pKa</p><p>values of the components (3.68 and 4.06).</p><p>A pH-solubility plot for all three phases (cocrystal, gabap-</p><p>entin, and 3HBA) is valuable to predict phase stability and</p><p>transformations. Because accurate values of 3HBA and gaba-</p><p>pentin solubility dependence on pH were not reported in the</p><p>literature, the solubility of each component was measured at a</p><p>single pH at room temperature: gabapentin hydrate 150 mg/</p><p>mL (0.88 M) at pH 7.3 and 3HBA 8 mg/mL (0.06 M) at pH</p><p>2.8. The Henderson-Hasselbalch relationship was used to</p><p>calculate pH dependent solubility of each component. Figure</p><p>10 shows the pH-solubility plot for all three phases: cocrystal</p><p>and individual components. Solid lines represent the pH range</p><p>over which the respective component is predicted to be</p><p>thermodynamically stable. Dashed lines represent component</p><p>solubility and pH ranges over which the respective component</p><p>may transform to the most thermodynamically stable phase.</p><p>The cocrystal solubility and component solubilities plotted</p><p>in Figure 10 provide reasonable estimates of the cocrystal</p><p>stability. Gabapentin-3HBA cocrystal is predicted to be the most</p><p>thermodynamically stable phase between pH 4.7 and 5.8.</p><p>Experimental stability results (Figure 7) show that cocrystal was</p><p>unstable at pH 2.6 and was stable at pH values between 4.0</p><p>and 5.7. The lack of agreement at pH 4.0 between predicted</p><p>and experimental solubility and stability (Figures 9 and 7) may</p><p>be due to slow transformation kinetics or transformation levels</p><p>below the detection limit of XRPD. The role of solute activity</p><p>on the accuracy of predicted solubilities using the Henderson-</p><p>Hasselbalch equation has not been considered in our study but</p><p>has been reported to be important in the case of cationic drugs.32</p><p>Because cocrystal is the most thermodynamically stable phase</p><p>between pH 4.7 and 5.8, gabapentin-3HBA can be synthesized</p><p>from aqueous solutions in this pH range. At pH values higher</p><p>than 5.8, the solution pH was determined by solute concentra-</p><p>tions and could not be controlled independently. Therefore,</p><p>experimental solubility and stability measurements are not</p><p>reported at pH values higher than 5.8. Comparison of pH-</p><p>dependent stability and solubility of salts and cocrystals of</p><p>gabapentin is currently under investigation and will be presented</p><p>in a future manuscript.</p><p>Conclusions</p><p>A crystal engineering approach aided by information retrieved</p><p>from CSD was successfully used to design multicomponent</p><p>crystalline forms of gabapentin. In all, 13 new multicomponent</p><p>crystalline forms were discovered and characterized. Crystal</p><p>structures of five multicomponent</p><p>forms were determined by</p><p>single crystal X-ray diffraction. Gabapentin is shown to form</p><p>cocrystal with 3HBA and salts with salicylic acid, 1-hydroxy-</p><p>2-napthoic acid, and RS-mandelic acid. There is partial proton</p><p>transfer from 4HBA to gabapentin. However, the expected</p><p>carboxyl · · · carboxylate synthon II is present in all crystal</p><p>structures of 1, 3, 4, and 5. Carboxyl · · · carboxylate synthon II</p><p>is absent in 2 because the carboxyl proton is disordered and</p><p>located at multiple sites.</p><p>Multicomponent crystals 1-5 are thermodynamically more</p><p>stable and equal or less soluble than gabapentin hydrate and</p><p>carboxylic acid coformers in pure water. Stability and solubility</p><p>of gabapentin-3HBA cocrystal were shown to be pH dependent.</p><p>A theoretical model that describes the experimental 1:1 cocrystal</p><p>solubility dependence on pH and pKa was derived. This model</p><p>enables one to generate a complete pH-solubility profile, define</p><p>stability domains with a minimum number of experiments, and</p><p>estimate cocrystal solubilities that are experimentally inaccessible.</p><p>Acknowledgment. We gratefully acknowledge partial fund-</p><p>ing from the Purdue-Michigan Consortium on Supramolecular</p><p>Assemblies and Solid-State Properties of Pharmaceuticals,</p><p>Boehringer Ingelheim, American Foundation for Pharmaceutical</p><p>Education, GM07767 National Institute of General Medical</p><p>Sciences, and Warner Lambert/Park Davis fellowship College</p><p>of Pharmacy, University of Michigan. The contents of this</p><p>publication are solely the responsibility of the authors and do</p><p>not necessarily represent the official views of funding sources.</p><p>Supporting Information Available: X-ray crystallographic files</p><p>(CIF), simulated XRPD, and ORTEP diagrams for 1-5 and DSC</p><p>thermograms, and Raman and IR spectra for all multicomponent</p><p>crystals. This material is available free of charge via the Internet at</p><p>http://pubs.acs.org.</p><p>References</p><p>(1) (a) Datta, S.; Grant, D. J. W. Nat. ReV. Drug DiscoVery 2004, 3, 42–</p><p>57. (b) Byrn, S. R. 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Search parameters were</p><p>defined as follows: 3D-coordinates present, no polymeric, no disorder,</p><p>no powder structures, only organics with R < 5%.</p><p>(21) Rodrı́guez-Hornedo, N.; Nehm, S. J.; Seefeldt, K. F.; Pagan-Torres,</p><p>Y.; Falkiewicz, C. J. Mol. Pharm. 2006, 3, 362–67.</p><p>(22) (a) Sheldrick, G. M. SADABS, v. 2.10, Program for empirical</p><p>absorption correction of area detector data; University of Gottingen:</p><p>Gottingen, Germany, 2003. (b) Sheldrick, G. M. SHELXTL, v. 6.12;</p><p>Bruker Analytical X-ray: Madison, WI, 2001.</p><p>(23) (a) Barbour, L. J. J. Supramol. Chem. 2001, 1, 189–191. (b) Atwood,</p><p>J. L.; Barbour, L. J. Cryst. Growth Des. 2003, 3, 3–8.</p><p>(24) (a) Aakeröy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharm. 2007, 4,</p><p>317–22. (b) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm</p><p>2005, 7, 551–62.</p><p>(25) Bis, J. A.; Zaworotko, M. J. Cryst. Growth Des. 2005, 5, 1169–79.</p><p>(26) Refcodes of multicomponent forms in the CSD search with ammonium,</p><p>carboxylate, and carboxylic acid groups. Cocrystals: BEYVAD,</p><p>EWOZIZ, GALPIT, GEFAEF, GEJLEN, HAGYEU, IREKAR,</p><p>JAXZIS, LAWKIE, NONZOF, NONZUL, OJEPEY, RAZPUE, SIL-</p><p>FEZ, VIKLOR and VIKLUX. Salts: AHERAG, AMTBUB, BANPUL,</p><p>BOQTEG, DIKSUM, EDASUX, EDAXIQ, ETEYOR, FACXUD,</p><p>FETNEY, HAGZUL, HESXUY, IYEBIX, MOCXUX, MUVXAC,</p><p>NELPUR, QURSUR, RENBAN, REPFEX, TRYPTB, VAGVEF,</p><p>VAGVIJ, WEHZAL, WERLAH, WERLEL, WOVYOV, YEJYIV,</p><p>YIFLOP, ZAJHAT. Both ionized and unionized forms in JOTKIM</p><p>and RALKUS.</p><p>(27) Santra, R.; Ghosh, N.; Biradha, K. New J. Chem. 2008, 32, 1673–6.</p><p>(28) (a) Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74–86.</p><p>(b) Aakeroy, C. B.;</p><p>Hussain, I.; Desper, J. Cryst. Growth Des. 2006,</p><p>6, 474–80. (c) Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek,</p><p>A.; Trask, A. V. J. Am. Chem. Soc. 2006, 128, 8199–210.</p><p>(29) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric</p><p>identification of organic compounds, 7th ed.; John Wiley & Sons, Inc.:</p><p>New York, 2005; pp 72-126.</p><p>(30) (a) Nehm, S.; Jayasankar, A.; Rodrı́guez-Hornedo, N. AAPS J. 2006,</p><p>8, 52. (b) Bethune, S. J. Ph.D thesis, The University of Michigan,</p><p>September, 2008.</p><p>(31) (a) The Merck Index, an encyclopedia of chemicals, drugs, and</p><p>biological, 13th ed.; Merck & Co. Inc.: 2001. (b) Serjeant, E. P.;</p><p>Dempsey, B. Ionization Constants of Organic Acids in Aqueous</p><p>Solution; Pergamon: Oxford, 1979.</p><p>(32) Bergstrom, C. A. S.; Luthman, K.; Artursson, P. Eur. J. Pharm. Sci.</p><p>2004, 22, 387–98.</p><p>CG800587Y</p><p>Cocrystals and Salts of Gabapentin Crystal Growth & Design, Vol. 9, No. 1, 2009 385</p>