Cocrystals and Salts of Gabapentin: pH Dependent Cocrystal Stability

Dec 5, 2008 - Synopsis. Thirteen new multicomponent crystals of an anticonvulsant zwitterionic drug gabapentin with various carboxylic acid coformers ...
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Cocrystals and Salts of Gabapentin: pH Dependent Cocrystal Stability and Solubility L. Sreenivas Reddy,† Sarah J. Bethune,† Jeff W. Kampf,‡ and Naı´r Rodrı´guez-Hornedo*,† Department of Pharmaceutical Sciences and Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan, 48109-1065

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 1 378–385

ReceiVed June 6, 2008; ReVised Manuscript ReceiVed September 19, 2008

ABSTRACT: Thirteen new multicomponent crystals (cocrystals and salts) of an anticonvulsant drug gabapentin with various carboxylic acid coformers have been discovered using the reaction crystallization method (RCM). These new forms are characterized by X-ray powder diffraction (XRPD), Raman and infrared spectroscopy, and differential scanning calorimetry (DSC). Crystal structures with 3-hydroxybenzoic acid (3HBA) 1, 4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy-2-napthoic acid (1H2NA) 4, and RS-mandelic acid 5 are also determined. While there is proton transfer from coformer to gabapentin in crystals 3-5, no proton transfer occurs in 1. Partial proton transfer is observed in crystal structure 2. Multicomponent crystals 1-5 are thermodynamically stable and do not transform to gabapentin hydrate in water suggesting that the multicomponent phases have equal or lower solubility than the components. pH has been shown to be an important variable in controlling solubility and stability. A mathematical model that describes the pH dependent solubility profile of a cocrystal with a zwitterionic drug and an acidic coformer is derived based on cocrystal dissociation and ionization solution equilibria. Predicted pH dependent cocrystal solubility and stability are in good agreement with experimental measurements. An important capability of these models is that it allows one to generate the solubility and stability dependence on pH from the knowledge of pKa values and solubility measurement at a single pH. Comparison of pH-solubility profiles of cocrystal and components establishes the pH-dependent stability regions for cocrystal and components. Introduction Physicochemical properties of a solid form depend on the arrangement of molecules in the crystal lattice.1 The majority of active pharmaceutical ingredients (APIs) exist in a variety of crystalline forms such as polymorphs, salts, and solvates.2 A recent analysis of 245 APIs showed that 89% had multiple solid forms. Approximately 50% of the compounds showed polymorphism, 37% were hydrates, and 31% were solvates.3 Choosing the best crystalline form of an API is an essential step in drug development, as it has significant impact on its performance.4 Salt formation is commonly employed to improve API properties such as solubility and stability.5 Crystal engineering approach to tailor the physiochemical properties of APIs by cocrystallization is emerging as an important area of research.6 Cocrystallization has been shown to improve important pharmaceutical properties such as solubility,7 bioavailability,8 moisture uptake,9 and physical and chemical stability10 of a drug. Some of these aspects are highlighted in a special issue dedicated to pharmaceutical cocrystals in Molecular Pharmaceutics.11 There has been great interest in pharmaceutical cocrystal design and screening in the past few years, but in most cases the API is uncharged.12 There are very few reports on cocrystallization of charged APIs.12a,13 In this contribution we present screening, synthesis, and properties of multicomponent crystals of gabapentin which exists as a zwitterion in the solid state (Scheme 1). The term “multicomponent crystals” is used to describe both cocrystals and salts in this paper.14 Gabapentin, an analogue of the neurotransmitter gammaaminobutyric acid (GABA), is used as an anticonvulsant to treat partial seizures.15 It crystallizes as three anhydrous polymorphs and a monohydrate.16 Gabapentin also forms coordination * Corresponding author. Phone: 734-763-0101. Fax: 734-615-6162. E-mail: [email protected]. † Department of Pharmaceutical Sciences. ‡ Department of Chemistry.

Scheme 1. Compounds Used in Cocrystallization

polymers with Cu and Zn.17 Very recently, Bernstein and coworkers carried out a high throughput screening for cocrystals with oxalic acid and reported a 2:1 gabapentin-oxalic acid salt.18 Carboxylic acids are chosen as potential cocrystal or salt formers by analyzing the way carboxylic acids interact with zwitterionic compounds such as amino acids within the Cambridge Structural Database (CSD).19 A CSD search for componds with +NH3, COO-, and C-COOH functional groups resulted in 99 entries.20 Analysis of crystal structures reveals that in 86 out of 99 compounds the carboxyl · · · carboxylate synthon II (Scheme 2) is present. There is proton transfer in some structures but the carboxyl · · · carboxylate synthon II is still present as the carboxyl group becomes carboxylate. In the remaining 13 structures, the carboxyl group is involved in either intramolecular hydrogen bonding or hydrogen bonds to itself. This suggests that synthon II is robust and can be transferable from one crystal structure to the other. The strength of

10.1021/cg800587y CCC: $40.75  2009 American Chemical Society Published on Web 12/05/2008

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Scheme 2. Hydrogen Bonded Synthons Discussed in This Paper

carboxyl · · · carboxylate synthon II is exploited in designing multicomponent forms of gabapentin with various carboxylic acid coformers (Scheme 1). Experimental Section Gabapentin and carboxylic acids were purchased from Spectrum Chemicals and Aldrich Chemicals, respectively. All chemicals were used without further purification. Gabapentin was analyzed by XRPD and DSC before cocrystallization experiments. ACS reagent grade acetonitrile or ethanol and deionized water were used in screening and stability studies, respectively. Screening and Scale Up. Screening and scale up experiments were performed using reaction crystallization method (RCM) at room temperature. Yield of the multicomponent crystals (cocrystal/salt) by RCM was 85-95% depending on the solubility and solution concentration of components (drug and coformers). X-ray diffraction quality single crystals were grown by slow evaporation. Both RCM and slow evaporation experiments were carried out at room temperature. Reaction Crystallization Method (RCM).21 In screening experiments, 50-75 mg of gabapentin was added to 1 mL of presaturated acetonitrile or ethanol solutions of coformers. In most cases cocrystallization was observed within minutes. Solids were filtered, dried, and characterized by XRPD and DSC. Appropriate quantities of gabapentin and coformers were used for scale up. Slow Evaporation. Single crystals of 1-5 were obtained by slow evaporation of solutions containing gabapentin and coformer (1:3 molar ratio) in appropriate solvents. Solvents used were acetonitrile, ethanol, or water. X-ray Diffraction. X-ray powder diffraction (XRPD) was collected using a Rigaku MiniFlex diffractometer (The Woodlands, TX) with a copper target X-ray tube. Data was collected at a scan rate of 2.5°/min over a 2θ range of 2.5° to 40°. The accelerating voltage was 30 kV, and the current was 15 mA. Single crystal X-ray diffraction data on compounds 1-5 was collected on a Bruker SMART APEX CCD-based X-ray diffractometer (Mo KR radiation, λ ) 0.71073 Å) equipped with a low temperature device. Empirical absorption corrections using SADABS22a were applied. Structure solution and refinement were performed with SHELXTL (version 6.12).22b All non-hydrogen atoms were refined anisotropically with the hydrogen atoms placed in idealized positions except for those involved in hydrogen bonding which were allowed to refine isotropically. Differential Scanning Calorimetry (DSC). Thermal analysis of samples was carried out using a TA 2590 DSC (TA instruments, New Castle, DE) which was calibrated for temperature and cell constants using indium and n-dodecane. Samples (5-7 mg) crimped in aluminum pans were analyzed in the DSC from 25 to 220 °C with heating rate of 10 °C/min. Samples were continuously purged with nitrogen at 50 mL/ min. pH Dependent Stability and Solubility of Gabapentin-3HBA Cocrystal. Stability and solubility studies were performed by suspending excess cocrystal in aqueous solutions of different pH at room temperature. pH was adjusted with either 1 M hydrochloric acid or 1 M sodium hydroxide. Solid phases and solution concentrations were analyzed at 72 and 96 h to confirm that equilibrium was attained. pH at equilibrium was measured. Solid phases were analyzed by XRPD, and solution concentration was measured by HPLC. High Performance Liquid Chromatography (HPLC). Gabapentin3HBA is a 1:1 cocrystal and its solubility is equal to either total gabapentin or 3HBA solution concentration. 3HBA solution concentration was measured with a Waters system (Bedford, MA) equipped with a photodiode array UV/vis detector. Gabapentin concentration was calculated by mass balance. A 45% water/55% methanol with 0.1%

Figure 1. XRPD patterns of new forms of gabapentin discovered by the reaction crystallization method (RCM). trifluoroacetic acid mobile phase was used at flow rate of 1 mL/min through an Atlantis C18 column (Waters, Bedford, MA). 3HBA absorbance was analyzed at 272 nm.

Results and Discussion Thirteen new multicomponent crystals of gabapentin with various carboxylic acid coformers were discovered by the reaction crystallization method (RCM) (Table 1).21 RCM is based on solution chemistry and proved to be an efficient method for cocrystal screening.6a These new solid phases were characterized by XRPD, Raman and IR spectroscopy, and DSC. Crystal structures with 3-hydroxybenzoic acid (3HBA) 1, 4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy2-napthoic acid (1H2NA) 4, and RS-mandelic acid 5 were also determined. A comparison of experimental XRPD patterns with those calculated from relevant single crystal data of 1-5 indicates that the crystalline products obtained from both reaction crystallization and slow evaporation are structurally homogeneous (Figure S1, Supporting Information). XRPD patterns of all new forms are shown in Figure 1. Crystallographic data is listed in Table 2 for 1-5. Simulated XRPD patterns (Figure S1), ORTEP diagrams (Figure S2), and important hydrogen bond geometries (Table S1) for 1-5, simulated XRPD patterns of gabapentin forms (Figure S3), and Raman and IR spectra along with DSC thermograms for all new forms are included in the Supporting Information. Graphics were generated in X-seed trial version.23 Table 1. New Multicomponent Crystals of Gabapentin Obtained by RCM with Various Carboxylic Acid Coformers (melting point of most stable r-gabapentin16a is 160-162 °C) multicomponent crystal

coformer

1 2 3 4 5 6 7 8 9 10 11 12 13

3-hydroxybenzoic acid 4-hydroxybenzoic acid salicylic acid 1-hydroxy-2-napthoic acid RS-mandelic acid S-mandelic acid R-mandelic acid DL-tartaric acid L-tartaric acid D-tartaric acid malic acid (+)-camphoric acid gallic acid

multicomponent coformer crystal, mp (°C) mp (°C) 132 166 131 126 125 129 129 157 132 132 112 149 150

204 214 159 192 134 130 130 205 166 170 131 187 250

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Table 2. Crystallographic Data and Structure Refinement Parameters for Multicomponent Crystals of Gabapentin

emp. formula formula wt crystal system space group a, Å b, Å c, Å R, deg β, deg γ, deg Z V, Å3 T, K Dcalcd, g cm-3 reflns collected Unique reflns. observed reflns R1 (I > 2σ(I)) wR2 goodness-of-fit

1

2

3

4

5

C16H23NO5 309.35 orthorhombic Pccn 12.8276(12) 25.380(2) 9.5029(9) 90 90 90 8 3093.8(5) 85(2) 1.328 73413 3874 3585 0.0371 0.0966 1.069

C16H23NO5 309.35 triclinic P1j 6.0648(4) 11.0825(8) 12.5727(9) 66.3550(10) 83.4020(10) 85.7140(10) 2 768.60(9) 85(2) 1.337 27729 3843 3430 0.0366 0.0931 1.035

C16H23NO5 309.35 monoclinic P21/n 10.5813(9) 10.3920(9) 28.659(3) 90 96.573(1) 90 8 3130.6(5) 85(2) 1.313 67350 7813 6801 0.0504 0.1248 1.126

C20H25NO5 359.41 monoclinic P21/c 7.3565(6) 18.4929(15) 13.7524(11) 90 101.855(1) 90 4 1831.0(3) 85(2) 1.304 40063 3801 3320 0.0834 0.1959 1.147

C17H25NO5 323.38 triclinic P1j 6.1129(10) 9.3483(15) 14.879(2) 90 101.855(1) 90 2 811.9(2) 85(2) 1.323 24634 4070 3889 0.0424 0.1075 1.101

Gabapentin-3-hydroxybenzoic Acid (1:1), 1. Gabapentin3-hydroxybenzoic acid 1 crystallizes in orthorhombic space group Pccn with one molecule of each in asymmetric unit. In the crystal structure, gabapentin exists as a zwitterion. Both carboxylic and phenolic OH donors of 3HBA form O-H · · · Ointeractions (synthon II, D ) 2.541 Å, θ ) 178°; synthon III, 2.672 Å, 175°) with gabapentin to form a crown ether-like cyclic tetramer, and these tetramers are in turn connected by charge assisted N+-H · · · O- (2.702 Å, 153°) hydrogen bonds to result in a layered structure (Figure 2). Other N-H donors of the ammonium group are involved in intra- and intermolecular N+-H · · · O- hydrogen bonds (Table S1, Supporting Information). Gabapentin-4-hydroxybenzoic Acid (1:1), 2. The crystal structure of 1:1 gabapentin and 4-hydroxybenzoic acid (4HBA) 2 is interesting both chemically and crystallographically. Asymmetric unit contains one molecule each of gabapentin and 4HBA (triclinic, P1j). The carboxyl proton of 4HBA is disordered over two positions with split occupancy of 50% on 4HBA and 50% on gabapentin carboxylate. However, the partial proton transfer is not through hydrogen bonding because both carboxyl and carboxylate groups are not in close proximity. Moreover, both these disordered protons are sitting on a crystallographic special position, the inversion center. 4HBA interacts with gabapentin through O-H · · · O (2.759 Å, 178°) and N+-H · · · O (2.779 Å, 167°) to form a tetrameric motif and these tetrameric motifs

Figure 2. Hydrogen bonding pattern in gabapentin-3HBA. Tetramers form between gabapentin and 3HBA through O-H · · · O- hydrogen bonds. These tetramers are connected by N+-H · · · O- hydrogen bonds to form a layered structure. There is no proton transfer from 3HBA to gabapentin.

are connected by N+-H · · · O tetramer synthon18 leading to a layered structure (Figure 3). One of the ammonium N-H donors is involved in an intramolecular N+-H · · · O (2.689 Å, 160°) hydrogen bond. Gabapentin-Salicylic Acid (1:1), 3. Asymmetric unit contains two symmetry independent molecules each of gabapentin and salicylic acid (monoclinic, P21/n). There is proton transfer from the carboxyl group of salicylic acid to the basic gabapentin carboxylate. As shown in Figure 4 gabapentin and salicylic acid interact with each other via carboxyl · · · carboxylate synthon II (2.553 Å, 174°; 2.547 Å, 173°) and ammonium · · · carboxylate synthon I (2.949 Å, 146°; 2.841 Å, 156°). Phenolic group is involved in an intramolecular O-H · · · O- (2.529 Å, 153°; 2.505 Å, 156°) hydrogen bonding. Unlike other structures, gabapentin molecule does not form an intramolecular N+-H · · · O- hydrogen bond. Gabapentin-1-hydroxy-2-napthoic acid (1:1), 4. A multicomponent crystal, 4, crystallizes in monoclinic P21/c space group with one molecule each of gabapentin and 1-hydroxy2-napthoic acid (1H2NA) in an asymmetric unit. There is proton transfer from the acidic 1H2NA to the basic carboxylate of gabapentin. Gabapentin molecules interact with 1H2NA through carboxyl · · · carboxylate synthon II (2.592 Å, 170°) and ammonium · · · carboxylate synthon I (2.841 Å, 165°) to form a tetrameric unit (Figure 5). These tetrameric units are connected by N+-H · · · O- (2.804 Å, 154°) hydrogen bonds (not shown in the figure). The phenolic group is involved in an intramolecular O-H · · · O- (2.510 Å, 170°) hydrogen bond. Gabapentin-RS-Mandelic Acid (1:1), 5. There is proton transfer from RS-mandelic acid to gabapentin carboxylate in the crystal structure. It crystallizes in triclinic space group P1j with one molecule each of gabapentin and mandelic acid in the asymmetric unit. Gabapentin interacts with mandelic acid via carboxyl · · · carboxylate synthon II (2.574 Å, 163°) and phenolic O-H · · · O hydrogen bonds (2.814 Å, 147°) to form a tetrameric motif. These tetrameric motifs in turn are connected by charge assisted N+-H · · · O- (2.812 Å, 168°) hydrogen bonds leading to formation of a layered structure (Figure 6). These layers are connected by N+-H · · · O- hydrogen bonds in the other direction. One of the ammonium N-H donors of gabapentin molecule is involved in an intramolecular N+-H · · · O hydrogen bond. Crystal structures show proton transfer with salicylic acid, 1-hydroxy-2-napthoic acid, and RS-mandelic acids but not with 3-hydroxybenzoic acid. The extent of proton transfer in the crystalline phase can be determined by analyzing proton location or position and bond lengths of atoms involved, for example, C-O distances of carboxyl groups.24 In carboxylic acids, the average C-O distance is 1.31 Å, whereas the CdO distance average is 1.21 Å. On the other hand, the average C-O distance in the carboxylate moiety is 1.25 Å.25 In crystal 1, the C-O bond distances in the gabapentin carboxylate moiety are 1.27 and 1.26 Å while in 3HBA the C-O and CdO bond distances are 1.32 and 1.22 Å. This suggests that there is no proton transfer from 3HBA to gabapentin; thus, 1 is a cocrystal. Similar analysis of C-O bond distances (Table 3) in forms 3-5 show that there is proton transfer from the coformer to gabapentin suggesting salt formation. Multiple protonation states with partial occupancy and C-O bond distances in 2 suggest a partial proton transfer. This could be due to disorder, and neither the salt nor the cocrystal can be labeled to accurately describe this structure. Analysis of multicomponent crystal structures of amino acids in the CSD also shows a similar trend. A CSD search for

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Crystal Growth & Design, Vol. 9, No. 1, 2009 381

Figure 3. Hydrogen bonding pattern in the crystal structure of gabapentin-4HBA. 4HBA interacts with gabapentin through O-H · · · O and N+-H · · · O to form a tetrameric motif and these tetrameric motifs are connected by N+-H · · · O hydrogen bonds. Carboxyl hydrogen atom is disordered over two positions and not participating in hydrogen bonding.

Figure 4. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxylate synthon I in gabapentin-salicylic acid tape structure. There is proton transfer from salicylic acid to gabapentin carboxylate.

compounds with +NH3, COO-, and COOH groups excluding other hydrogen bonding competing groups such as water, pyridine moiety, urea, and carbonyl resulted in 47 entries.26 In 29 out of 47 structures there is proton transfer from carboxylic acid to the basic carboxylate of amino acid whereas in 16 instances there is no proton transfer. In two crystal structures both protonation and unprotonation are observed. It is interesting to note that proton transfer from coformer to gabapentin carboxylate is observed with salicylic acid, 1-hydroxy-2napthoic acid, and RS-mandelic acid with pKa values of 2.97, 4.17, and 3.41, respectively, but not in the case of 3-hydroxybenzoic acid with pKa 4.06. It is difficult to rationalize the proton transfer in these structures based on pKa values. Other factors such as crystal structures and reaction conditions are also known to play an important role in the extent of proton transfer.14,27 Another interesting observation is that the melting points of most of the multicomponent crystals of gabapentin discovered in this study are lower than that of the individual components (Table 1). Although there is proton transfer in 3, 4,and 5 and no proton transfer in 1, gabapentin interacts with the acid coformers via carboxyl · · · carboxylate synthon II. Similar hydrogen bonding can be expected in multicomponent crystals 6-13, irrespective of whether there is proton transfer or not in crystalline state. In multicomponent crystals 8-12, where the coformer is a dicarboxylic acid, there may be competition between the carboxyl and carboxylate groups of gabapentin and coformer in synthon II formation depending on stoichiometry.

Multicomponent crystals 6-13 are characterized by their unique XRPD (Figure 1) and Raman and IR spectra (Supporting Information) when compared to all known individual component forms. They exhibit melting points different from components except for crystals 6 and 7, whose melting points are very close to that of coformers. However, the XRPD patterns and Raman and IR spectra are different from all reported forms of gabapentin and mandelic acids. Furthermore, crystallization of single components is unlikely under RCM conditions, because precipitation occurs in solutions at or below saturation of reactants and there is no solvent evaporation or temperature change.21 Ionization state or proton transfer in solids can be determined by single crystal X-ray diffraction or spectroscopic techniques such as IR and solid-state NMR.28 In multicomponent crystals 1-5, the ionization state of gabapentin was determined by crystal structure determination. IR spectra of 6-13 were analyzed and compared with 1-5 to gain information about ionization state of gabapentin. It suggests that while gabapentin ionization state can be evaluated with aromatic carboxylic acids by following the carbonyl absorption region, it is difficult in multicomponent crystals with aliphatic carboxylic acids. The carbonyl group of aromatic carboxylic acids absorbs at lower frequencies (1710-1680 cm-1) than aliphatic of carboxylic acids (1750-1700 cm-1) due to resonance.29 Anhydrous gabapentin exhibits an IR band at 1610 cm-1 corresponding to carboxylate stretching. If there is proton transfer from coformer to gabapentin, the gabapentin carboxylate group would have a carbonyl peak at frequency >1700 cm-1 similar to aliphatic carboxylic acid. In multicomponent crystal 13 appearance of a strong IR band in at 1719 cm-1 suggests that there is proton transfer from gallic acid to gabapentin (Supporting Information). Similar analysis cannot be applied to multicomponent crystals with aliphatic carboxylic acids as their carbonyl absorption band appears in same region as protonated gabapentin. Although it is not very clear from IR spectra, in 6 and 7 (with S/R-mandelic acids), one can expect salt formation as there is proton transfer from RS-mandelic acid to gabapentin in 5. pH-Dependent Stability and Solubility of Gabapentin3HBA Cocrystal. Thermodynamic stability and solubility of multicomponent crystalline drug forms in aqueous media are important to understand and control transformations in order to achieve the desired dissolution and bioavailability. In general, thermodynamic stability and solubility are inversely related; as

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Figure 5. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxylate synthon I in gabapentin-1H2NA tape structure. There is proton transfer from 1H2NA to gabapentin.

Figure 6. Carboxyl · · · carboxylate synthon II and ammonium · · · carboxylate synthon I in gabapentin-RS-mandelic acid. Two molecules each of gabapentin and RS-mandelic acid form a tetramer and these tetramers are connected by N+-H · · · O- hydrogen bonds. There is proton transfer from RS-mandelic acid to gabapentin. Table 3. Distribution of C-O Bond Lengths for Gabapentin and Carboxylic Acid Coformers in New Forms multicomponent crystal

gabapentin, d(C-O), Å

coformer, d(C-O), Å

nature of multicomponent crystal

1 2

1.266, 1.258 1.245, 1.280

1.222, 1.319 1.251, 1.287

cocrystal H-atom disordered

3

1.21, 1.329, 1.21, 1.328

1.259, 1.262, 1.254, 1.267

salt

4 5

1.219, 1.301 1.212, 1.329

1.293, 1.245 1.266, 1.234

salt salt

solubility of multicomponent crystal increases and surpasses the solubility of individual components, there is greater potential for transformation. Multicomponent crystals 1-5 were found to be thermodynamically stable when suspended in pure water at room temperature and did not transform to component solid phases suggesting that the multicomponent phases have equal or lower solubility than the drug or coformer. Stability of gabapentin-3HBA 1 was further studied in aqueous solutions at several pH values (Figure 7). Results show

Figure 7. pH dependent stability of gabapentin-3HBA cocrystal. Cocrystal is thermodynamically stable at pH 4.0 and 5.7 and transforms to 3HBA at pH 2.6.

that cocrystal is stable at pH 4.0 and 5.7 but transforms to 3HBA at pH 2.6. This indicates that gabapentin-3HBA cocrystal is less

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solubility behavior is challenged with experimental measurements of 1:1 gabapentin-3HBA cocrystal. A zwitterionic drug such as gabapentin is expressed as ABH+, and the diprotic acidic coformer such as 3HBA is expressed as H2X. The equilibrium reactions and equilibrium constants for dissociation of cocrystal and ionization of components in solution (assuming no complexation) are as follow: + ABH+H2Xsolid h -ABHsoln +H2Xsoln

-

Ksp ) [-ABH+][H2X]

(1)

HABH+ h -ABH++H+ Kal,-ABH+ )

[-ABH+][H+] [HABH+]

(2)

-

ABH+ h -AB + H+

Ka2,-ABH+ )

[-AB][H+]

(3)

[-ABH+]

H2X h HX-+H+ Figure 8. Calculation of gabapentin-3HBA cocrystal Ksp according to eq 11, using measured cocrystal solubility as a function of pH. Slope is the Ksp (0.0147 M2).

Kal,H2X )

[HX-][H+] [H2X]

(4)

HX- h X2- + H+ [X2-][H+] Ka2,H2X ) [HX-]

(5)

where Ksp is the cocrystal solubility product and Ka represents ionization constants of components. The total drug concentration or analytical concentration ([AB]T) is the sum of all the ionized species and is given by

[AB]T)[-ABH+] + [HABH+] + [-AB]

(6)

The total coformer concentration ([X]T) is a sum of ionized and un-ionized species and is given by

[X]T)[H2X] + [HX-] + [X2-]

(7)

Substituting the equilibrium constants from eqs 1, 2, and 3 into eq 6 gives

[AB]T ) Figure 9. Gabapentin-3HBA cocrystal solubility dependence on pH. Symbols (b) represent experimental solubility values. Predicted solubility curve was generated from eq 11 using the Ksp value of 0.0147 M2.

Ksp R [H2X]

(

where R ) 1 +

[H+] Kal,-ABH+

+

Ka2,-ABH+ [H+]

)

(8)

Rewriting eq 7 to express [H2X] in terms of [X]T results in soluble or as soluble as gabapentin hydrate and 3HBA, between pH 4.0 and 5.7, while cocrystal is more soluble than 3HBA at pH 2.6. The narrow pH range under which the cocrystal is stable motivated the development of mathematical models that allow for the prediction of the cocrystal solubility-pH dependence from limited solubility data and knowledge of pKa values of cocrystal components. We have previously shown that solubility and stability of cocrystals with a nonionizable drug and acidic or basic coformer are controlled by solution pH, coformer pKa, and cocrystal Ksp.9b,30 In the present study, we extend the thermodynamic models to describe the pH-dependent solubility of 1:1 cocrystals with a zwitterionic drug and a diprotic acidic coformer. Predicted

[H2X] )

[X]T β

(

where β ) 1 +

Kal,H2X +

[H ]

+

Kal,H2XKa2,H2X [H+]2

)

(9)

Substituting eq 9 into eq 8 gives the total drug concentration

[AB]T )

Ksp Rβ [X]T

(10)

For a 1:1 cocrystal, cocrystal solubility (Scocrystal) equals total drug or total coformer concentration:

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Scocrystal ) [AB]T ) [X]T Therefore, cocrystal solubility can be expressed as Scocrystal ) √KspRβ

(11)

which relates cocrystal solubility to cocrystal Ksp, components pKa values, and solution pH. If Ksp is known, one can calculate the solubility of cocrystal (Scocrystal) at any given pH. Alternatively, if cocrystal solubility is known at given pH, Ksp can be calculated from eq 11. Because gabapentin-3HBA cocrystal is stable at pH 4.0 and 5.7 (Figure 7), equilibrium solubility was measured at pH values in this range and equation 11 was used to calculate Ksp. As shown in Figure 8, the Ksp for gabapentin-3HBA was evaluated to be 0.0147 M2 from a plot of (Scocrystal)2 against KspRβ. Reported pKa values 3.68 and 10.70 for gabapentin and 4.06 and 9.92 for 3HBA were used in solubility and Ksp calculations.31 Figure 9 shows that the experimentally measured solubilities of gabapentin-3HBA cocrystal are in good agreement with the predicted solubility from eq 11. The model predicts a minimum cocrystal solubility at a pH between the two pKa values of the components (3.68 and 4.06). A pH-solubility plot for all three phases (cocrystal, gabapentin, and 3HBA) is valuable to predict phase stability and transformations. Because accurate values of 3HBA and gabapentin solubility dependence on pH were not reported in the literature, the solubility of each component was measured at a single pH at room temperature: gabapentin hydrate 150 mg/ mL (0.88 M) at pH 7.3 and 3HBA 8 mg/mL (0.06 M) at pH 2.8. The Henderson-Hasselbalch relationship was used to calculate pH dependent solubility of each component. Figure 10 shows the pH-solubility plot for all three phases: cocrystal and individual components. Solid lines represent the pH range over which the respective component is predicted to be thermodynamically stable. Dashed lines represent component solubility and pH ranges over which the respective component may transform to the most thermodynamically stable phase. The cocrystal solubility and component solubilities plotted in Figure 10 provide reasonable estimates of the cocrystal

stability. Gabapentin-3HBA cocrystal is predicted to be the most thermodynamically stable phase between pH 4.7 and 5.8. Experimental stability results (Figure 7) show that cocrystal was unstable at pH 2.6 and was stable at pH values between 4.0 and 5.7. The lack of agreement at pH 4.0 between predicted and experimental solubility and stability (Figures 9 and 7) may be due to slow transformation kinetics or transformation levels below the detection limit of XRPD. The role of solute activity on the accuracy of predicted solubilities using the HendersonHasselbalch equation has not been considered in our study but has been reported to be important in the case of cationic drugs.32 Because cocrystal is the most thermodynamically stable phase between pH 4.7 and 5.8, gabapentin-3HBA can be synthesized from aqueous solutions in this pH range. At pH values higher than 5.8, the solution pH was determined by solute concentrations and could not be controlled independently. Therefore, experimental solubility and stability measurements are not reported at pH values higher than 5.8. Comparison of pHdependent stability and solubility of salts and cocrystals of gabapentin is currently under investigation and will be presented in a future manuscript. Conclusions A crystal engineering approach aided by information retrieved from CSD was successfully used to design multicomponent crystalline forms of gabapentin. In all, 13 new multicomponent crystalline forms were discovered and characterized. Crystal structures of five multicomponent forms were determined by single crystal X-ray diffraction. Gabapentin is shown to form cocrystal with 3HBA and salts with salicylic acid, 1-hydroxy2-napthoic acid, and RS-mandelic acid. There is partial proton transfer from 4HBA to gabapentin. However, the expected carboxyl · · · carboxylate synthon II is present in all crystal structures of 1, 3, 4, and 5. Carboxyl · · · carboxylate synthon II is absent in 2 because the carboxyl proton is disordered and located at multiple sites. Multicomponent crystals 1-5 are thermodynamically more stable and equal or less soluble than gabapentin hydrate and carboxylic acid coformers in pure water. Stability and solubility of gabapentin-3HBA cocrystal were shown to be pH dependent. A theoretical model that describes the experimental 1:1 cocrystal solubility dependence on pH and pKa was derived. This model enables one to generate a complete pH-solubility profile, define stability domains with a minimum number of experiments, and estimate cocrystal solubilities that are experimentally inaccessible. Acknowledgment. We gratefully acknowledge partial funding from the Purdue-Michigan Consortium on Supramolecular Assemblies and Solid-State Properties of Pharmaceuticals, Boehringer Ingelheim, American Foundation for Pharmaceutical Education, GM07767 National Institute of General Medical Sciences, and Warner Lambert/Park Davis fellowship College of Pharmacy, University of Michigan. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of funding sources. Supporting Information Available: X-ray crystallographic files (CIF), simulated XRPD, and ORTEP diagrams for 1-5 and DSC thermograms, and Raman and IR spectra for all multicomponent crystals. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 10. Predicted pH-dependent solubility of gabapentin-3HBA cocrystal (black) and individual components of drug and coformer (redgabapentin hydrate, blue-3HBA). Equation 11 was used to calculate cocrystal solubility, and the Henderson-Hasselbalch relationship was used to calculate gabapentin hydrate and 3HBA solubilities.

References (1) (a) Datta, S.; Grant, D. J. W. Nat. ReV. Drug DiscoVery 2004, 3, 42– 57. (b) Byrn, S. R. Solid State Chemistry of Drugs; Academic Press:

Cocrystals and Salts of Gabapentin

(2) (3) (4) (5)

(6)

(7)

(8)

(9)

(10) (11) (12)

(13) (14)

¨ New York, 1982. (c) Gardner, C. R.; Walsh, C. T.; Almarsson, O Nat. ReViews 2004, 3, 926–34. Rodríguez-Spong, B.; Price, C. P.; Jayasankar, A.; Matzger, A. J.; Rodríguez-Hornedo, N. AdV. Drug DeliVery ReV. 2004, 56, 241–74. Stahly, P. G. Cryst. Growth Des. 2007, 7, 1007–26. (a) Huang, L. F.; Tong, W. Q. AdV. Drug DeliVery ReV. 2004, 56, 321–34. (b) Singhal, D.; Curatolo, W. AdV. Drug DeliVery ReV. 2004, 56, 335–47. (a) Serajuddin, A. T. M. AdV. Drug DeliVery ReV. 2007, 59, 603–16. (b) Serajuddin, A. T. M.; Pudipeddi, M. Salt-selection strategies. In Handbook of Pharmaceutical Salts: Properties, Selection, and Use; Stahl, P. H., Wermuth, C. G., Eds.; Wiley-VCH: Weinheim, 2002; pp 135-160. (a) Childs, S. L.; Rodrı´guez-Hornedo, N; Sreenivas Reddy, L.; Jayasankar, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, ¨ .; ZaworotB. C. CrystEngComm 2008, 10, 856–64. (b) Almarsson, O ko, M. J. Chem. Commun. 2004, 1889–96. (c) Babu, N. J.; Reddy, L. S.; Nangia, A. Mol. Pharm. 2007, 4, 417–34. (d) Vishweshwar, P.; McMahon, J. A.; Zaworotko, M. J. In Frontiers in Crystal Engineering; Tiekink, E. R. T., Vittal, J. J., Eds.; Wiley: Chichester, 2006; pp 2549. (e) Aakero¨y, C. B.; Salmon, D. J. Cryst EngComm 2005, 439–48. (a) Nehm, S. J.; Rodrı´guez-Spong, B.; Rodrı´guez-Hornedo, N. Cryst. Growth Des. 2006, 6, 592–600. (b) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335–42. (c) Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. J. Am. Chem. Soc. 2003, 125, 8456–57. (a) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; Donnell, E. O.; Park, A. Pharm. Res. 2006, 23, 1888–97. (b) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Sunita, T.; Rashid, S.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. J. Pharm. Sci. 2008, 97, 3942–56. (a) Rodrı´guez-Spong, B. Ph.D thesis, the University of Michigan, 2005. (b) Rodrı´guez-Hornedo, N.; Nehm, S. J.; Jayasankar, A. Cocrystals: Design, Properties, and Formation Mechanisms. In Encylopedia of Pharmaceutical Technology; Swarbrick, J., Ed.; Informa Healthcare Inc: 2006; pp 615-35, (a) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320, 114–123. (b) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013–21. Mol. Pharm. 2007, 4, Issue No. 3. (a) Childs, S. L.; Hardcastle, K. I. Cryst. Growth Des. 2007, 7, 1291– 304. (b) Frisˇcˇicˇ, T.; Trask, A. V.; Jones, W.; Motherwell, W. D. S. Angew. Chem., Int. Ed. 2006, 45, 7546–50. (c) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodrı´guez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003, 186– 87. (d) Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D. B.; Rodrı´guez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909–19. (e) Basavoju, S.; Bostrom, D.; Velaga, S. P. Pharm. Res. 2007, 25, 530–41. (a) Wenger, M.; Bernstein, J. Angew. Chem., Int. Ed. 2006, 45, 7966– 69. (b) Samas, B.; Wang, W.; Godrej, D. B. Acta Crystallogr. 2007, E63, o3938. Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharm. 2007, 4, 323–38.

Crystal Growth & Design, Vol. 9, No. 1, 2009 385 (15) Satzinger, G.; Hartenstein, J.; Hermann, M.; Heldf, W. U.S. Patent 4024175, 1977. (16) (a) Reece, H. A.; Levendis, D. C. Acta Crystallogr. 2008, C64, o105– 8. (b) Ibers, J. A. Acta Crystallogr. 2001, C57, o641–3. (17) Braga, D.; Grepioni, F.; Maini, L.; Brescello, R.; Cotarca, L. CrystEngComm 2008, 10, 469–71. (18) Wenger, M.; Bernstein, J. Cryst. Growth Des. 2008, 8, 1595–98. (19) (a) Allen, F. H. Acta Crystallogr. 2002, B58, 380–8. (b) Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. New J. Chem. 1999, 25–34. (20) CSD Version 5.29 + January 2008 update. Search parameters were defined as follows: 3D-coordinates present, no polymeric, no disorder, no powder structures, only organics with R < 5%. (21) Rodrı´guez-Hornedo, N.; Nehm, S. J.; Seefeldt, K. F.; Pagan-Torres, Y.; Falkiewicz, C. J. Mol. Pharm. 2006, 3, 362–67. (22) (a) Sheldrick, G. M. SADABS, v. 2.10, Program for empirical absorption correction of area detector data; University of Gottingen: Gottingen, Germany, 2003. (b) Sheldrick, G. M. SHELXTL, v. 6.12; Bruker Analytical X-ray: Madison, WI, 2001. (23) (a) Barbour, L. J. J. Supramol. Chem. 2001, 1, 189–191. (b) Atwood, J. L.; Barbour, L. J. Cryst. Growth Des. 2003, 3, 3–8. (24) (a) Aakero¨y, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharm. 2007, 4, 317–22. (b) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm 2005, 7, 551–62. (25) Bis, J. A.; Zaworotko, M. J. Cryst. Growth Des. 2005, 5, 1169–79. (26) Refcodes of multicomponent forms in the CSD search with ammonium, carboxylate, and carboxylic acid groups. Cocrystals: BEYVAD, EWOZIZ, GALPIT, GEFAEF, GEJLEN, HAGYEU, IREKAR, JAXZIS, LAWKIE, NONZOF, NONZUL, OJEPEY, RAZPUE, SILFEZ, VIKLOR and VIKLUX. Salts: AHERAG, AMTBUB, BANPUL, BOQTEG, DIKSUM, EDASUX, EDAXIQ, ETEYOR, FACXUD, FETNEY, HAGZUL, HESXUY, IYEBIX, MOCXUX, MUVXAC, NELPUR, QURSUR, RENBAN, REPFEX, TRYPTB, VAGVEF, VAGVIJ, WEHZAL, WERLAH, WERLEL, WOVYOV, YEJYIV, YIFLOP, ZAJHAT. Both ionized and unionized forms in JOTKIM and RALKUS. (27) Santra, R.; Ghosh, N.; Biradha, K. New J. Chem. 2008, 32, 1673–6. (28) (a) Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74–86. (b) Aakeroy, C. B.; Hussain, I.; Desper, J. Cryst. Growth Des. 2006, 6, 474–80. (c) Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V. J. Am. Chem. Soc. 2006, 128, 8199–210. (29) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric identification of organic compounds, 7th ed.; John Wiley & Sons, Inc.: New York, 2005; pp 72-126. (30) (a) Nehm, S.; Jayasankar, A.; Rodrı´guez-Hornedo, N. AAPS J. 2006, 8, 52. (b) Bethune, S. J. Ph.D thesis, The University of Michigan, September, 2008. (31) (a) The Merck Index, an encyclopedia of chemicals, drugs, and biological, 13th ed.; Merck & Co. Inc.: 2001. (b) Serjeant, E. P.; Dempsey, B. Ionization Constants of Organic Acids in Aqueous Solution; Pergamon: Oxford, 1979. (32) Bergstrom, C. A. S.; Luthman, K.; Artursson, P. Eur. J. Pharm. Sci. 2004, 22, 387–98.

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