Piracetam Co-Crystals with OH-Group ... - ACS Publications

Apr 3, 2009 - Piracetam Co-Crystals with OH-Group Functionalized Carboxylic. Acids. Martin Viertelhaus, Rolf Hilfiker,* and Fritz Blatter*. SolVias AG...
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Piracetam Co-Crystals with OH-Group Functionalized Carboxylic Acids Martin Viertelhaus, Rolf Hilfiker,* and Fritz Blatter* SolVias AG, Klybeckstrasse 191, P.O. Box, CH-4002 Basel, Switzerland

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 5 2220–2228

Markus Neuburger UniVersity of Basel, Department of Chemistry, Spitalstrasse 51, CH-4056 Basel, Switzerland ReceiVed August 26, 2008; ReVised Manuscript ReceiVed January 30, 2009

ABSTRACT: We report the synthesis, crystal structures, and basic physicochemical properties of six co-crystals of piracetam. Co-crystals of piracetam with L-tartaric acid, with citric acid in a 1:1 and 3:2 ratio, with racemic mandelic acid, and with L-mandelic acid, as well as a piracetam-citric acid ethanol solvate were found in a focused screening approach. Sample amounts of up to several hundred milligrams of each co-crystal were obtained from either solvent-drop grinding, solution evaporation, or crystallization from solution. Crystal structure analysis revealed that the often observed amide-carboxylic acid R22(8) synthon is rarely found in the herein reported crystal structures. The mentioned motif can be used as a target for hydrogen bonds; however, in presence of a multitude of hydrogen bond donors and acceptors it cannot serve for an anticipation of co-crystals. Compared to piracetam the piracetam-L-tartaric acid co-crystal shows improved hygroscopic properties.

1. Introduction Quinhydrone was recently mentioned in the literature as an example from the co-crystal “hall of fame”, as it seems to be the first co-crystal for which a synthesis was presented in the literature more than 150 years ago.1 F. Wo¨hler described it in 1844 using approximately the following words: “the most enigmatic formation of the “green quinone” (quinhydrone) is through the interaction of colorless quinone (hydroquinone) and yellow quinone. Upon mixing of their solutions green crystals are immediately produced while no other product is formed.”2 The first patents on “pharmaceutical co-crystals”, in which at least one compound of a multicomponent crystal is an active pharmaceutical ingredient, seem to have appeared in 1924 and 1934, both originating from F. Hoffmann-La Roche.3 However, drug products with pharmaceutical co-crystals have remained a very rare phenomenon until now. One of the few more recent examples is the itraconazole-succinic acid co-crystal, which was first disclosed in 2001.4 As in Wo¨hler’s paper a considerable amount of serendipity led to the discovery of these co-crystals. Later, several itraconazole-carboxylic acid co-crystals were investigated by TransForm Pharmaceuticals.5 Various definitions of co-crystals are currently being discussed in the literature.6 Recently, Childs et al.7 discussed the distinction of salts and co-crystals by the location of the hydrogen between the acid and the base. Whereas at the salt end of the spectrum proton transfer is complete, proton transfer is absent in cocrystals on the opposite end, and both categories are connected by a salt-co-crystal continuum. Here a co-crystal is defined as a multicomponent crystal containing a stoichiometric ratio of at least two components that are solid at room temperature.8 Moreover, at least one component has to be in an un-ionized state. The latter implies that a salt with two ionized components needs a third un-ionized component to comply with the definition of a co-crystal, thus constituting a co-crystal of a salt.9 * Corresponding authors: (F.B.) Phone: +41 686 62 41. E-mail: fritz.blatter@ solvias.com; (R.H.) Phone: +41 61 686 60 21. E-mail: [email protected].

More recently, pharmaceutical co-crystals have attracted considerable attention from the pharmaceutical industry and the scientific community because they can enhance the space of potentially usable solid-state forms for a given drug substance (either ionizable or neutral). It has been recognized that the solidstate form of a new drug substance can be critical to the developability of a new drug product. Two interesting co-crystals have recently been presented by researchers of Merck & Co: one of a phosphodiesterase IV inhibitor with tartaric acid10 showing enhanced bioavailability, and one with phosphoric acid,11 which seems to be the single accessible crystalline solidstate form. Because of the increasing structural complexity of many new chemical entities, it is not uncommon that a crystalline form of a neutral API is inaccessible at ambient temperature. Considering that a given API in the amorphous form is chemically and physically less stable than in the crystalline state, finding suitable crystalline salts or co-crystals can determine whether a drug substance can be developed efficiently.12 The co-crystals of carbamazepine have been extensively studied, and it was shown that the carbamazepine-saccharin co-crystal may indeed exhibit physicochemical properties that would allow formulation of an improved drug product.13 There are various situations wherein the selection of a co-crystal might offer the best solution for developing a drug product. Probably the most important cases when co-crystals should be considered are (a) when the free drug substance exhibits a complex polymorphism, and some of the potential solid-state transformations are difficult to control (e.g., an enantiotropic system of two polymorphs with a transition temperature in ambient range); (b) when salts cannot be produced due to the neutrality of the compound (e.g., carbamazepine and piracetam); or (c) when acid/base groups are present but a crystalline salt can still not be found; and (d) when the required bioavailability to obtain a therapeutic effect cannot be achieved with any known solidstate form of the free drug or a salt thereof. The most important aspects and the relevance of polymorphism, hydrates, solvates, and pharmaceutical salts are described in several monographs.14

10.1021/cg800942n CCC: $40.75  2009 American Chemical Society Published on Web 04/03/2009

Piracetam Co-Crystals

Figure 1. Top: two examples of typical R22(8) synthons observed for amide and carboxylic acid groups, and bottom: two typically expected synthons of an amide group with a hydroxyl group that can be part of a chain or finite element structure (graph set D if part of a finite element or graph set C(x) if part of a chain).

Figure 2. Molecular structure of piracetam.

Piracetam (2-oxo-1-pyrrolidinyl-acetamide) was marketed in 1972 as Nootropil by UCB, and used to treat memory and balance problems.15 The polymorphism of piracetam is well understood, and single crystal structures of all important forms are available. Fabbiani et al. have recently published an overview of the various crystalline forms:16 Five polymorphic forms and one hydrate are known, whereas form III seems to be the thermodynamically most stable form at ambient conditions. The objective of this study was to obtain further insights into the formation and structural nature of co-crystals. Here piracetam was chosen as a model compound for a co-crystal screening because of its structural simplicity, because of its acid/base neutrality, and because it offers two different amide configurations both representing suitable synthons for co-crystal formation with carboxylic acids and hydroxyl groups in particular. Graph sets are useful tools to describe structural features in co-crystals and to visualize compositions of various synthons. A detailed description is presented in Bernstein et al.17 Figure 1 presents some of the possible synthons (most obvious combinations of functional groups) with their graph set assignments.

2. Experimental Section Screening Experiments. High-throughput screening experiments were based on slow evaporation of mixed solutions under nitrogen using a flow rate of about 40 mL/min.18 The resulting solids were investigated by Raman microscopy. The most important elements of the applied screening methods are described in Solvias’s patent applications.19 The following 22 compounds were investigated as potential co-crystal formers in the performed screening experiment: citric acid, fumaric acid, maleic acid, saccharin, succinic acid, L-tartaric acid, L-arginine, imidazole, piperazine, 2-amino-5-methylbenzoic acid, mannitol, methyl4-hydroxybenzoate, urea, L-proline, glycine, 4-acetamidobenzoic acid, (+)-camphoric acid, D-glucuronic acid, glutaric acid, hippuric acid, L-mandelic acid, and gentisic acid (as reference because the gentisic acid co-crystal was known). The investigated co-crystal formers were selected to cover a broad range of functional groups while being suitable for pharmaceutical use. Generally, each co-crystal former was tested with four or five different solvents, which were acetone, acetonitrile, DMSO, 1-, or 2-propanol, and methanol. For the amino acids aqueous solutions were added to equimolar solutions of piracetam in the respective solvents, thus leading to water solvent mixtures.

Crystal Growth & Design, Vol. 9, No. 5, 2009 2221 The evaporation screening experiments were supplemented with solvent-drop grinding experiments on laboratory scale, that is, with about 50 mg of substance. Equimolar amounts of piracetam and cocrystal former were mixed and thoroughly ground with addition of a small amount of ethyl acetate and water. At first 1:1 stoichiometries were explored; however, once an identified lead to for co-crystal was confirmed, the 1:2 and 2:1 stoichiometries for the same coformer were tested in a further solvent drop grinding experiment. Raman spectra of the resulting solids were recorded and evaluated. Starting Materials. Piracetam was obtained from Sigma Aldrich Fluka (Sigma No. P5295) and identified as form III by powder X-ray diffraction (PXRD). L-Tartaric acid (Fluka No. 95310), citric acid (Fluka No. 27488), L-mandelic acid (Fluka No. 63460), and racemic mandelic acid (Fluka No. 63470) were also obtained from Sigma Aldrich Fluka and used without further purification. Piracetam-L-TartaricAcidCo-Crystal1:1(PLT).Thepiracetam-Ltartaric acid co-crystal (PLT) can be prepared by several methods. Evaporation of an equimolar mixture of solutions of piracetam and L-tartaric acid in acetonitrile led to co-crystals with a plate-like morphology. By solvent-drop grinding of equimolar amounts of L-tartaric acid and piracetam with acetonitrile or water (e.g., 600 mg total amount of L-tartaric acid and piracetam) were mixed with 20 µL of water). Crystals with a quality sufficient for single-crystal diffraction were obtained from a supersaturated acetonitrile solution by seeding with plates from the screening experiment. The powder X-ray diffraction (PXRD) pattern of the product of the solvent-drop grinding experiment corresponds to the single crystal structure and it confirms that the reaction went to completion. Piracetam-Citric Acid Co-Crystal 1:1 (PCI-1). The 1:1 co-crystal of piracetam and citric acid (PCI-1) was synthesized by solvent-drop grinding of an equimolar amount of piracetam and citric acid (e.g., 600 mg total amount of citric acid and piracetam were mixed with 200 µL of ethyl acetate and 20 µL of water). The grinding process was continued until complete conversion to the co-crystal occurred as monitored by Raman spectroscopy. Crystals suitable for single crystal X-ray diffraction were obtained from mild solvothermal synthesis. Piracetam and citric acid (ratio 1:2 or 1:3) were stirred at 90 °C in ethyl acetate in a closed vessel. Excess piracetam could be separated easily as the piracetam crystals were found at the cooler part of the vessel. Interestingly, experiments performed with equimolar reaction mixtures of piracetam and citric acid resulted in formation of amorphous material. Piracetam-Citric Acid Co-Crystal 3:2 (PCI-2). The piracetam citric acid co-crystal with a molar ratio 3:2 (PCI-2) was synthesized by solvent-drop grinding of piracetam and citric acid in the given stoichiometric ratio. The process is essentially the same as described for PCI-1. Crystals suitable for single crystal X-ray diffraction could be crystallized by a mild solvothermal reaction when the ratio of the reagents piracetam-citric acid was greater than 1. The same conditions as for PCI-1 were applied. Piracetam-Citric Acid Co-Crystal Ethanol Solvate 1:1:1 (PCI-EtOH). Suspension equilibration of various mixtures of both citric acid co-crystals PCI-1 and PCI-2 in ethanol resulted in the ethanol solvate. Piracetam-Mandelic Acid Co-Crystal 2:1 (PMA). The piracetam co-crystal with racemic mandelic acid with a molar ratio of 2:1 was synthesized by solvent-drop grinding of piracetam and mandelic acid in the given stoichiometric ratio. The process is essentially the same as described for PCI-1. Crystals suitable for single crystal X-ray diffraction were crystallized by suspension equilibration of an equimolar mixture of piracetam and mandelic acid in a 1:1 mixture of water and methanol between 22 and 50 °C. Piracetam-L-Mandelic Acid Co-Crystal 2:1 (PLMA). The cocrystal of piracetam and L-mandelic acid was synthesized using the same procedure as for PMA. Raman Microscopy. High-throughput experiments were analyzed using a Renishaw RM 1000 Raman microscope equipped with a 785 nm diode laser for excitation and an NIR-enhanced Peltier-cooled CCD camera as the detector. Measurements were carried out with a long working distance 20× objective on a measurement range of 100-2000 cm-1. FT-Raman Spectroscopy. Bulk Raman spectra were recorded using a Bruker RFS100 Raman spectrometer equipped with a germanium detector and a Nd:YAG laser with an excitation wavelength of 1064

2222

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Table 1. Molecular Structures of Co-Crystal Formers and Overview on Piracetam Co-Crystals

Table 2. Crystallographic Data for Co-crystals PLT, PCI-1, PCI-2, PMA, and PLMA co-crystal structural formula formula weight crystal system space group (no.) T (K) a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z Fcalc (g/cm3) µ (mm-1) R1 wR2 (all data) goodness-of-fit reflns collected θmax unique reflns observed reflns cryst size (mm3) largest diff peak and hole (e Å-3)

piracetam-L-tartaric acid

piracetam-citric acid 1:1

piracetam-citric acid 3:2

piracetam-mandelic acid 2:1

piracetam-L-mandelic acid 2:1

PLT (C6H10N2O2) (C4H6O6) 292.25 orthorhombic P212121 (19) 173 6.2437(1) 9.2921(1) 22.2291(3) 90 90 90 1289.67(3) 4 1.505 0.132 0.0269; [I > 2σ(I)] 0.0600 0.9265 15400 32.03 2585 2564 0.08 × 0.21 × 0.40 0.32/-0.20

PCI-1 (C6H10N2O2) (C6H8O7) 334.28 monoclinic P21/a (14) 173 11.1234(2) 9.7575(2) 13.8054(3) 90 98.4480(11) 90 1482.13(5) 4 1.498 0.130 0.0354; [I > 3σ(I)] 0.0763 1.1157 15758 32.04 4336 2371 0.13 × 0.30 × 0.34 0.25/-0.21

PCI-2 (C6H10N2O2)3 (C6H8O7)2 810.72 monoclinic P21/a (14) 173 11.6397(1) 9.3631(1) 33.3734(4) 90 95.4384(5) 90 3620.78(7) 4 1.487 0.126 0.0646; [I > 3σ(I)] 0.0801 0.9305 30030 27.52 8322 6422 0.04 × 0.24 × 0.31 0.36/-0.31

PMA (C6H10N2O2)2 (C8H8O3) 436.47 monoclinic C2/c (15) 173 21.9754(10) 9.3204(4) 10.5208(5) 90 90.939(2) 90 2154.58(17) 4 1.345 0.103 0.0636; [I > 0.5σ(I)] 0.0481 1.0272 17155 27.47 2464 1925 0.11 × 0.16 × 0.20 0.27/-0.29

PLMA (C6H10N2O2)2 (C8H8O3) 436.47 orthorhombic P212121 (19) 173 9.0811(2) 9.4231(2) 25.3265(6) 90 90 90 2167.24(8) 4 1.338 0.102 0.0418; [I > 0.5σ(I)] 0.0484 1.0584 16371 27.76 2902 2422 0.08 × 0.23 × 0.44 0.21/-0.17

nm. Typically, 300 mW was used as the laser power. Measurements were carried out by accumulation of 64 scans over the range of 50-3500 cm-1 with a 2 cm-1 resolution. Several milligrams of each sample were pressed into aluminum sample holders. Powder X-ray Diffraction (PXRD). PXRD patterns were recorded on a Bruker D8 Advance X-ray diffractometer equipped with a

VANTEC-1 detector using 360 ( 10 active channels operated with Cu KR-radiation. Typically, the X-ray tube was run at 35 kV/45 mA. A step size of 0.017° (2θ) and a step time of 105 ( 5 s over a scanning range of 2-50° in 2θ were applied. The divergence slit was set to variable V12 and the opening angle at 3°. A few milligrams of powder was pressed into a silicon single crystal sample

Piracetam Co-Crystals

Crystal Growth & Design, Vol. 9, No. 5, 2009 2223

Table 3. Geometric Parameters of the Hydrogen Bonds in Co-crystals PLT, PCI-1, PCI-2, PMA, and PLMA d(A · · · H)/Å

d(D · · · A)/Å

θ(∠D-H · · · A)/°

d(A · · · H)/Å

d(D · · · A)/Å

θ(∠D-H · · · A)/°

O7-H7 · · · O2 N2-H1 · · · O8 N2-H2 · · · O1

1.73 2.18 2.12

2.587(2) 2.924(2) 2.963(2)

175 146 173

O3-H3 · · · O1 O5-H5 · · · O4 O6-H6 · · · O4

1.75 2.07 2.05

2.586(2) 2.899(2) 2.844(2)

168 167 156

O7-H5 · · · O6 O5-H4 · · · O7 O8-H6 · · · O1

2.38 1.80 1.56

2.923(2) 2.666(2) 2.582(2)

119 155 164

O3-H3 · · · O2 N2-H2 · · · O1 N2-H1 · · · O9

1.63 2.02 2.06

2.595(2) 2.967(2) 3.003(2)

167 170 174

O19-H14 · · · O5 N6-H5 · · · O19 O18-H13 · · · O17 N6-H6 · · · O6 O14-H11 · · · O4 N4-H4 · · · O15 O16-H12 · · · O6 N6-H5 · · · O17 N6-H6 · · · O17

1.86 2.27 2.16 2.20 1.74 2.22 1.82 2.71 2.61

2.563(2) 2.919(3) 2.846(2) 2.999(2) 2.562(2) 3.009(3) 2.637(2) 2.978(3) 2.978(3)

144 131 140 154 176 153 166 99 107

O18-H13 · · · O15 N4-H3 · · · O20 N2-H1 · · · O13 N2-H2 · · · O1 O12-H10 · · · O1 N2-H1 · · · O13 O7-H7 · · · O2 O9-H8 · · · O3 O11-H9 · · · O10

2.44 2.20 2.13 2.15 1.74 2.13 1.82 1.79 2.14

3.079(3) 2.999(3) 2.972(2) 2.997(2) 2.559(2) 2.972(2) 2.620(2) 2.610(2) 2.800(2)

134 154 169 177 174 169 163 164 136

N1-H2 · · · O1 N1-H1 · · · O7 N1-H1 · · · O5

2.02 1.86 2.20

2.899(2) 2.726(2) 3.048(2)

177 170 162

O5-H5 · · · O2 O6-H6 · · · O2

2.07 1.74

2.851(2) 2.577(2)

156 176

O6-H6 · · · O2 N3-H3 · · · O5 N1-H1 · · · O7

1.70 2.11 2.08

2.526(2) 2.955(2) 2.939(2)

167 167 176

PLMA O5-H5 · · · O4 N3-H4 · · · O1 N1-H2 · · · O3

1.89 2.08 2.05

2.666(2) 2.925(2) 2.889(2)

153 168 173

PLT

PCI-1

PCI-2

PMA

holder with a depth of 0.1 mm and samples were rotated during the measurement. Single Crystal X-ray Diffraction (SC-XRD). Crystal structures were measured on a Nonius KappaCCD diffractometer20 at 173 K using graphite-monochromated Mo KR radiation with a wavelength of λ ) 0.71073 Å; measurements were carried out to a θmax of 27.47 to 32.04°. The collect suite was used for data collection and integration. Structures were solved by direct methods using the program SIR92.21 Least-square refinement against F and F2 was carried out on all non-hydrogen atoms using the program CRYSTALS.22 Hydrogen atoms bonded to nitrogen or oxygen atoms were localized in the difference Fourier map and refined isotropically using restraints for bond length and temperature parameters. The remaining hydrogen atoms are in calculated positions. Structure graphics shown in the figures were created using the Mercury23 software package version 1.4. Dynamic Vapor Sorption (DVS). DVS measurements were performed with an SPS11-100n “Sorptions Pru¨fsystem” of Projekt Messtechnik“, D-89077 Ulm (Germany). About 10 mg of sample was put into an aluminum sample pan. Humidity change rates of 5%/h were used. The applied measurement program is visualized in Figure 12. Thermogravimetry Coupled with Fourier Transform Infrared Spectroscopy (TG-FTIR). TG-FTIR was performed on a Netzsch Thermo-Microbalance TG 209, which is coupled with a Bruker FT-IR Spectrometer Vector 22. The aluminum crucibles used were either open or with a (micro) pinhole and the measurements were carried out under a nitrogen atmosphere and at a heating rate of 10 °C/min over the range 25-250 °C. Differential Scanning Calorimetry (DSC). DSC measurements were carried out on a Perkin-Elmer DSC-7. Samples were placed in closed gold crucibles. The heating rate was either 10 or 20 °C min-1 over the range -50 to 250 °C. Solubility Determination. Saturated aqueous solutions of the cocrystal samples were prepared by equilibration of an excess of cocrystal and agitation of the produced suspension for at least 24 h at room temperature (22 ( 2 °C). The solid-state form from the resulting suspension after equilibration was investigated by Raman spectroscopy. The concentrations of piracetam and the carboxylic acids in the solution were determined by high performance liquid chromatography.

3. Results Two co-crystals of piracetam, namely, with gentisic acid and p-hydroxybenzoic acid, have been described by Vishweshwar et al.24 Since these co-crystals were known at the beginning of these investigations, it was an intriguing question whether a co-

crystal screen would reveal additional piracetam co-crystals. Of further interest is the frequency and predictability of the wellknown heterosynthon [R22(8)] between the amide and the carboxylic acid in new co-crystals. Six new co-crystals with piracetam were found by focused co-crystal screening employing various experimental techniques. An evaporation screening experiment produced leads for new co-crystals with L-tartaric acid, and mandelic acid. A subsequently performed solventdrop grinding screen delivered leads for co-crystals with citric acid. No positive screening hits were obtained from any of the other investigated co-crystal formers. All obtained co-crystals were reproduced on a laboratory scale (i.e., at least about 50 mg of each co-crystal was successfully prepared) and characterized in terms of their physicochemical properties. In the case of piracetam solvent-drop grinding turned out to be a very efficient method to obtain about 50-600 mg of a given cocrystal. The co-crystal with L-mandelic acid was found in a solvent drop grinding experiment after the co-crystal with racemic mandelic acid was known. New co-crystals were found with L-tartaric acid (PLT), citric acid 1:1 (PCI-1), citric acid 3:2 (PCI-2), citric acid 1:1 ethanol solvate (PCI-EtOH), Lmandelic acid (PLMA), and racemic mandelic acid (PMA). The ethanol solvate of the co-crystal with citric acid was obtained from suspension equilibration of either PCI-1 or PCI-2 in ethanol. Crystals of adequate quality for single crystal X-ray diffraction (SC-XRD) were obtained in all cases except the ethanol solvate (PCI-EtOH), and the single crystal structures were determined. In Figure 2 the structure of piracetam is shown. The structure of the co-crystal formers and basic information on the co-crystals are presented in Table 1. Crystallographic data for the solvent-free co-crystals are displayed in Table 2. Piracetam-L-Tartaric Acid Co-Crystal 1:1 (PLT). Cocrystal PLT can be obtained either by evaporation from an equimolar solution in acetonitrile or by solvent-drop grinding with acetonitrile or water. Single crystal X-ray diffraction shows that PLT crystallizes in the orthorhombic space group P212121 with cell parameters a ) 6.2437(1) Å, b ) 9.2921(1) Å, and c ) 22.2291(3) Å. The asymmetric unit contains one piracetam and one L-tartaric acid molecule. Surprisingly, the [R22(8)]

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Crystal Growth & Design, Vol. 9, No. 5, 2009

Figure 3. The structure of PLT is built up from hydrogen-bonded piracetam chains in the b-direction and L-tartaric acid chains in the a-direction.

amide-carboxylic acid heterosynthon is not present in PLT. The most striking structural feature observed consists of the piracetam ring carbonyl oxygen which forms a hydrogen bond with the amide proton of a neighboring piracetam, whereas both are connected to the same carboxylic acid group of L-tartaric acid (Figure 3). This H-bonding motif results in a 15-membered ring involving two piracetam molecules and one L-tartaric acid [R33(15)]. Both piracetam molecules in this structural element are furthermore part of a hydrogen bonded piracetam chain. Zigzag chains of head to tail hydrogen bonded piracetam molecules run along the b-axis [C(7)]. Both hydroxyl groups of L-tartaric acid form hydrogen bonds to one carboxylic acid oxygen of a neighboring L-tartaric acid molecule [R12(7)]. This formation of a seven-membered double hydrogen bonded ring results in tartaric acid-chains running along the a-direction [C(5)]. The proton of the carboxylic acid group, of which the free carboxyl oxygen is part of the sevenmembered ring, is directed toward the ring amide oxygen of piracetam (O1) which serves as proton-acceptor for two protons. Piracetam and tartaric acid chains are arranged in separate layers parallel to the ab-plane. Alternating layers are stacked up along the c-direction. Piracetam-Citric Acid Co-Crystal 1:1 (PCI-1). PCI-1 was obtained either from solvent-drop grinding or mild solvothermal synthesis in water-saturated ethyl acetate at 90 °C. PCI-1 crystallizes in the monoclinic space group P21/a with cell parameters a ) 11.1234(2) Å, b ) 9.7575(2) Å, c ) 13.8054(3) Å and β ) 98.4480(11)°. The asymmetric unit contains one piracetam and one citric acid molecule. Again, the [R22(8)] amide-carboxylic acid heterosynthon is not present in PCI-1 (Figure 4). In this co-crystal piracetam molecules form head to tail zigzag chains along the b-direction [C(7)]. The proton of one citric acid carboxylic acid group forms a hydrogen bond to the hydroxyl group of the next citric acid [C(6)] to form chains in the same direction. The hydroxyl proton is directed to the carbonyl group of the symmetry equivalent carboxylic group resulting in a six-membered ring through an intramolecular hydrogen bond [S(6)]. As in the case of the co-crystal PLT, piracetam and citric acid are organized in layers of chains of each component which are stabilized by hydrogen bonds between the piracetam and citric acid chains [R34(20); R44(26)]. Piracetam-Citric Acid Co-Crystal 3:2 (PCI-2). PCI-2 can be prepared by solvent-drop grinding or solvothermal synthesis

Viertelhaus et al.

Figure 4. Zig-zag chains of piracetam and citric acid run parallel to the b-direction of PCI-1.

Figure 5. One citric acid molecule (both shown citric acid molecules are CIT1) in PCI-2 forms hydrogen bonded chains via the hydroxyl hydrogens. One of these hydrogens is involved in the amide-carboxylic acid heterosynthon with a piracetam molecule (PIR1). The carboxylic group at the other end of the molecule bridges the amide homosynthon between two piracetam molecules (PIR2, around an inversion center).

under mild conditions. Co-crystal PCI-2 crystallizes in the monoclinic space group P21/a with cell parameters a ) 11.6397(1) Å, b ) 9.3631(1) Å, c ) 33.3734(4) Å and β ) 95.4384(5)°. Three piracetam and two citric acid molecules occupy the asymmetric unit. In this co-crystal all three piracetam molecules show individual hydrogen bonding patterns. This structure is the only one described in this paper that shows the often observed [R22(8)] amide - carboxylic acid heterosynthon. One piracetam is hydrogen bonded to a carboxylic acid group of citric acid in this pattern (PIR1). The amide homosynthon is observed for a second piracetam [R22(8)] (PIR2, around an inversion center). The third piracetam PIR3 forms a head to tail hydrogen bond which was already found for PLT and PCI1. Piracetam zigzag chains [C(7)] which are formed by this hydrogen bond are directed along the b-axis. Neighboring chains arranged in parallel form a piracetam layer in the ab-plane. Nevertheless there are no direct interchain hydrogen bonds between the piracetam chains. The noncarboxylic acid hydroxyl protons of both citric acid molecules form intramolecular hydrogen bonds with carbonyl groups as observed in co-crystal PCI-1 [S(6)]. For CIT1 the same hydroxyl proton is additionally directed to a carboxyl oxygen of a symmetry-equivalent citric acid molecule (Figure 5). The resulting chain [C(6)] is oriented along the a-direction. The second citric acid CIT2 is surrounded by four piracetam molecules (Figure 6). The crystal structure of PCI-2 is apparently

Piracetam Co-Crystals

Figure 6. The hydroxyl group of the citric acid molecule (CIT2) forms an intramolecular hydrogen bond. All further hydrogen bond acceptors and donors are saturated by four different piracetam molecules (PIR1 and three times PIR3).

built-up by blocks of the single components wherein the piracetam layer divides the unit cell into two compartments. Both compartments consist of one piracetam and one citric acid block (both approximately a quarter of the unit cell). Figure 7 is drawn along the a-direction and shows the piracetam and citric acid rods that run along this direction. Piracetam-Citric Acid Co-Crystal Ethanol Solvate 1:1:1 (PCI-EtOH). Suspension equilibration of either PCI-1 or PCI-2 in ethanol leads to a new solid-state form that was found to be an ethanol solvate of a piracetam-citric acid cocrystal. The single crystal structure of PCI-EtOH has not been elucidated. However, the obtained co-crystal is characterized by a new powder X-ray diffraction pattern as shown in Figure 11. Thermogravimetry coupled with infrared spectroscopy readily identifies PCI-EtOH as a monosolvate of ethanol. Upon mild drying in air at ambient temperature PCI-EtOH was found to transform into PCI-1. Therefore, the instability of the obtained co-crystal solvate and its conversion into PCI-1 essentially establishes that the solvate contains a 1:1 ratio of piracetam to citric acid. Piracetam-Mandelic Acid Co-Crystal 2:1 (PMA). PMA is prepared by solvent-drop grinding or by evaporation from an equimolar solution of both components in methanol. The piracetam mandelic acid 2:1 cocrystal crystallizes in the monoclinic space group C2/c with cell parameters a ) 21.9754(10) Å, b ) 9.3204(4) Å, c ) 10.5208(5) Å, and β ) 90.939(2)°. The asymmetric unit contains one piracetam and one mandelic acid molecule, the latter with a 50% occupancy. The mandelic acid molecule is disordered along the 2-fold axis that passes through the molecule. With an occupancy of 0.5

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the piracetam/mandelic acid ratio is 2:1. The hydrogen bonds can be satisfied for both orientations of the mandelic acid. The hydrogen atoms of mandelic acid from both the hydroxylic and the carboxylic acid group are directed toward the piracetam ring amide oxygen (Figure 8). The oxygen atoms of mandelic acid (both carbonyl and hydroxyl) form hydrogen bonds with the piracetam amide group. Therefore, one mandelic acid molecule establishes four hydrogen bond contacts with four piracetam molecules. Piracetam dimers formed around an inversion center are arranged into individual layers of piracetam alternating with mandelic acid layers piled up in the a-direction. R44(24) rings are formed by two alternating piracetam and mandelic acid molecules. With this pattern a three-dimensional network is established. Piracetam-L-Mandelic Acid Co-Crystal 2:1 (PLMA). After the discovery of co-crystal PMA the existence of a cocrystal with enantiomerically pure mandelic acid with similar synthons was readily hypothesized. Indeed, co-crystal PLMA was obtained via solvent-drop grinding with water-saturated ethyl acetate or seeded precipitation from aqueous solutions supersaturated with respect to the co-crystal. From a structural viewpoint, a chiral space group (C2) with a similar arrangement would be conceivable. However, the PLMA co-crystal crystallizes in the orthorhombic space group P212121 with cell parameters a ) 9.0811(2), b ) 9.4231(2), and c ) 25.3265(6) Å. The obtained crystal structure indeed shows the same hydrogen bonding pattern as PMA (Figure 9). Yet, the different orientation of the piracetam molecules surrounding the mandelic acid results in a new structure. One L-mandelic acid and two piracetam molecules are present in the asymmetric unit. Here, the L-mandelic acid is not disordered. Both symmetry inequivalent piracetam molecules form an amide homosynthon. Apart from the first shell hydrogen bonding pattern, this structure cannot be related to the previously described racemic one. The three-dimensional network is best explained with R55(23) rings. Physicochemical Characteristics. All co-crystals obtained were further characterized by differential scanning calorimetry (DSC), by thermogravimetry coupled with Fourier transform infrared spectroscopy (TG-FTIR), by dynamic vapor sorption (hygroscopicity), by powder X-ray diffraction, and by measurement of their aqueous solubility. TG-FTIR allowed the identification of PCI-EtOH as an ethanol monosolvate; all other cocrystals were found to be essentially free of residual solvents according to the same method. Table 1 compares the obtained DSC and aqueous solubility data for the described co-crystals with the data for the single compounds. Although piracetam is known in a hydrated crystal form, tests of the solid residue of

Figure 7. The packing diagram of PCI-2 shows the division of the unit cell into piracetam and citric acid compartments. Hydrogen-bonded piracetam chains (PIR3) running in the a-direction divide the unit cell in the middle.

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Viertelhaus et al.

Figure 8. The mandelic acid in PMA is disordered along the 2-fold axis which passes through the molecule. For simplicity only one occupational situation is drawn. The second orientation would satisfy the hydrogen bonds in the same manner. Additionally the amide homosynthon can be seen.

Figure 10. This figure shows the powder X-ray diffraction patterns of the co-crystals with racemic mandelic acid (PMA, trace A), L-mandelic acid (PLMA, trace B), and L-tartaric acid (PLT, trace C).

Figure 9. The first-order hydrogen-bonding system in PLMA is like that in PMA. Nevertheless, the different orientation of the molecules results in a different crystal structure.

the performed solubility experiments showed that the co-crystal was retained during the solubility experiment which lasted for 24 h. The only exception was PCI-1 which was found to convert into PCI-2, but piracetam hydrate was not found. It is beyond the scope of this paper to investigate the advantages and disadvantages of each new co-crystal as compared with the stable form III of piracetam or any of the other forms. In the case of piracetam, which is highly soluble in water, a lower aqueous solubility would be acceptable, if not desirable, in exchange for improved properties in terms of large-scale production, powder processing, granulation, or other operations of pharmaceutical technology. In terms of physical properties, it is interesting to note that PLT is the only co-crystal that exhibits a higher melting point (171 °C) than piracetam form III (∼152 °C). Lower melting points were found for all other

Figure 11. This figure shows the powder X-ray diffraction patterns of the co-crystals with the piracetam-citric acid ethanol monosolvate (PCIEtOH, trace A), citric acid 3:2 (PCI-2, trace B), and citric acid 1:1 (PCI-1, trace C).

co-crystals. While the aqueous solubility of the co-crystals in mg/mL is generally greater, due to the increased molecular

Piracetam Co-Crystals

Crystal Growth & Design, Vol. 9, No. 5, 2009 2227

Figure 12. This figure shows a comparison of dynamic vapor sorption measurements of piracetam form III and the piracetam-L-tartaric acid co-crystal. The left-hand y-axis corresponds to the water content (which is the same as the water uptake) of the co-crystal and the right-hand y-axis corresponds to the relative humidity over the sample according to the applied measurement program, which is reflected by the thin solid line.

weight, all the molar solubilities are smaller than the solubility of piracetam form III or piracetam hydrate, respectively. The most pronounced solubility decrease has been found for PLT. The powder X-ray diffraction patterns of all obtained cocrystals are shown in Figures 10 and 11. Comparison of the experimental powder X-ray diffraction patterns with those calculated from the single crystal X-ray data shows that the cocrystals were obtained in high phase purity (see Supporting Information). Hygroscopicity. The piracetam-L-tartaric co-crystal was found to exhibit the best properties of all co-crystals investigated in terms of hygroscopic behavior. The results obtained for PLT, as shown in Figure 12, revealed that in contrast to pure piracetam form III, for which deliquescence was observed at 95% relative humidity, the water uptake of PLT is dramatically decreased, when measured under the same conditions. A reversible water adsorption with a maximum water uptake of 3% was found for PLT, as compared with g40% for pure piracetam form III. Despite the fact that piracetam form III is deliquescent at 95% r.h. piracetam form III is classified as nonhygroscopic according to the European Pharmacopoeia,25 and the same classification applies for PLT. Using the same criteria for the other co-crystals results in the classification of PCI-2, PMA, and PLMA as slightly hygroscopic, and PCI-1 as hygroscopic. The results from dynamic vapor sorption measurements are included in the Supporting Information.

4. Discussion and Conclusions Hydrogen Bonding Network. A review of hydrogen bonding in the solid state was published by Steiner.26 Approximately 10% of the published structures with compounds that contain an amide and a carboxylic acid group are found to incorporate the R22(8) hydrogen bonded heterosynthon in the crystal

structure, and almost 50% of the structures which include a primary amide and a carboxylic acid do so.27 Only one of the co-crystals obtained in this study, namely, PCI-2, exhibits the above-mentioned heterosynthon for one-third of the molecules present. Both the amide and carboxylic acid homosynthons can compete with the corresponding heterosynthon; however, calculations support the thesis that the heterosynthon should be energetically slightly favored.28 Nevertheless, the amide homosynthon can be found in three out of the five structures, although in PCI-2 only one-third of the piracetam molecules participate. It is not surprising that the observed co-crystal structures represent complex three-dimensional networks of hydrogen bonds. The energetic stabilization of co-crystals originates from the summation of all hydrogen bonds plus other electrostatic interactions. Comparison of the bond lengths in the various cocrystals reveals that these numbers have similar magnitudes no matter which synthons are actually formed (Table 3). Both R22(8) synthons observed in the citric acid co-crystal PCI-2 seem to be sterically hindered. In these cases, the molecular planes of both components are tilted toward each other, resulting in angles significantly smaller than found for other co-crystals (homosynthon:N6-H6 · · · O6:153.9°;heterosynthon:N4-H4 · · · O15 and O14-H11 · · · O4 both 152.7°). The homosynthons of the mandelic acid co-crystals do not show this phenomenon. Three-dimensional hydrogen bond networks are generally well described by graph sets. The graph sets for the most prominent features of the five new co-crystals are listed in Table 4. Similarities and differences can be elucidated in this comparison. Head-to-tail catemers of hydrogen bonded piracetam molecules are found for PLT, PCI-1, and PCI-2 [C(7)]. This structural element is also present in piracetam polymorphs I, II, and III. In the high pressure form IV a similar arrangement forms rings of two piracetam molecules [R22(14)].29 For both mandelic acid co-crystals the amide homosynthon is the most prominent piracetam feature. This motif is observed in piracetam forms II, III, and the monohydrate.29 Co-crystal formers form chains when these are also observed for piracetam. The similarities in the first sphere of hydrogen bonds and the differences in the full three-dimensional network can easily be seen by the graph sets for PLMA and PMA: first-order graph sets are similar; graph sets in higher order differ (Table 4). The question of whether a similar crystal structure to PMA exists for L-mandelic acid and vice versa remains open. To date eight co-crystals of piracetam (including PCI-EtOH) have been described. Interestingly, all of the known co-crystal formers are carboxylic acids containing at least one additional hydroxyl group. The currently discussed crystal engineering approach can be helpful and provide leads to new co-crystals; however, pharmaceutical compounds, which often contain various hydrogen bond donors or acceptors, cannot be forced into a specific motif. Crystal packing and saturation of as many hydrogen bond donors and acceptors as possible lead to an energetically stabilized three-dimensional hydrogen bond network. Therefore, molecular recognition patterns and self-

Table 4. Graph Sets for Co-crystals PLT, PCI-1, PCI-2, PMA, and PLMA PLT

PCI-1 (1:1)

homomolecular piracetam

C(7)

C(7)

homomolecular co-crystal former

C(5) R17(7) R33(15)

C(6) S(6) R34(20) R44(26)

heteromolecular piracetam - co-crystal former

PCI-2 (3:2)

PLMA

PMA

R22(8) [PIR2] C(7) [PIR3] C(6) [CIT1] S(6) [CIT2] R22(8) [PIR1,CIT1] R12(4) R22(6)

R22(8)

R22(8) [PIR1, PIR2]

R55(23) C33(11)

R44(24) C33(11)

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organization ultimately form structural entities that go beyond the simple combination of functional groups into molecular synthons. When various hydrogen bond donors and acceptors are included in one system, interesting polymorphism can be supposed. Furthermore, it should be noted that variable stoichiometric ratios are not uncommon.30 With the increasing number of published co-crystal structures the diversity of existing synthons is enhanced continuously. Therefore, future discussions will likely be directed toward supramolecular retrosynthesis and screening approaches as major strategies for co-crystal discovery. Acknowledgment. The authors thank Dr. Susan M. De Paul for her helpful comments and for reviewing the manuscript. Supporting Information Available: The Supporting Information contains a list of the tested cocrystal formers along with the solvents used for the screening experiments, FT-Raman spectra, TG and DSC data, the dynamic vapor sorption results, comparison plots of the experimental powder X-ray diffraction patterns with the calculated powder patterns. In addition, the structures have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition numbers for PLT #717776, PCI-1 #717777, PCI-2 #717778, PMA #717779, and PLMA #717780. This information is available free of charge via the Internet at http://pubs.acs.org.

References (1) Zaworotko, M. J. Cryst. Growth Des. 2007, 7 (1), 4–9. (2) Wo¨hler, F. Ann. Chem. Pharm. 1844, 51, 153. (3) German Patent No. 562514 (December 07, 1924) and German Patent No. 605916 (November 01, 1934). (4) Baharatrajan, R.; Hegde, D.; Nerlekar, N. PCT publication No. WO 01/97853, 2001. (5) Remenar, F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Gusman, H. R.; Almarsson, Ö. J. Am. Chem. Soc. 2003, 125, 8456–8457. (6) (a) Desiraju, G. R. CrystEngComm 2003, 5, 466–467. (b) Dunitz, J. D. CrystEngComm 2003, 5, 506. (c) Bond, A. CrystEngComm 2007, 9, 833–834. (7) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharm. 2007, 4 (3), 323– 338. (8) The authors are aware that this definition of a co-crystal is scientifically not meaningful. The sole justification is its practical use to specify between various types of multicomponent crystals. (9) Co-crystals in the German literature have been also referred to as “Moleku¨lverbindungen,” which can also be translated as “[crystalline] molecular complexes”. The German term “Mischkristalle” is used for mixed crystals, which are generally non-stoichiometric, for example, the inorganic salts KMnO4 and KClO4. (10) Variankaval, N.; Wenslow, R.; Murry, J.; Hartman, R.; Helmy, R.; Kwong, E.; Clas, S-D.; Dalton, C.; Santos, I. Cryst. Growth Des. 2006, 6 (3), 690–700. Remark: The title of this “Preparation and solid-state characterization of nonstoichiometric co-crystals of a phosphodiesterase-IV inhibitor and L-tartaric acid”. Consequently, this system would in principle not qualify as a co-crystal according to the given definition. (11) Chen, A. M.; Ellison, M. E.; Perespykin, A.; Wenslow, R. M.; Variankaval, N.; Savarin, C. G.; Natishan, T. K.; Mathre, D. J.; Dormer, P. G.; Euler, D. H.; Ball, R. G.; Ye, Z.; Wang, Y.; Santos, I. Chem. Commun. 2007, 419–421. (12) Hilfiker, R.; Blatter, F.; von Raumer, M. In Polymorphism in the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH Verlag: Weinheim, 2006; Chapter 1, pp 1-19.

Viertelhaus et al. (13) Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; ¨ . Eur. J. Pharm. Biopharm. Haley, S.; Zaworotko, M. J.; Almarsson, O 2007, 87 (1), 112–119. (14) (a) Hilfiker, R. Polymorphism in the Pharmaceutical Industry; WileyVCH Verlag: Weinheim, 2006. (b) Bernstein, J., Polymorphism in Molecular Crystals; Oxford University Press: Oxford, 2002. (c) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs; SSCI, Inc., West Lafayette, IN, 1999. (15) The Merck Index, 13th ed.; Merck & Co., Inc.: Whitehouse Station, NJ, 2001; p 1342, and UCB homepage: http://www.ucbpharma.com/ about_ucb. (16) Fabbiani, F. P.; Allan, D. R.; David, W. I. F.; Davidson, A. J.; Lennie, A. R.; Parsons, S.; Pulham, C. R.; Warren, J. E. Cryst. Growth Des. 2007, 7 (6), 1115–1124. (17) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555–1573. (18) Hilfiker, R.; Berghausen, J.; Blatter, F.; Burkhard, A.; De Paul, S. M.; Freiermuth, B.; Geoffroy, A.; Hofmeier, U.; Marcolli, C.; Siebenhaar, B.; Szelagiewicz, M.; von Raumer, M. J. Therm. Anal. Calorim. 2003, 73, 429–440. (19) (a) Blatter, F.; Cron-Eckhardt, B.; Hofmeier, U. Ch.; Koller, P.; Marcolli, C.; Szelagiewicz, M. Sealing System with Flow Channels; PCT publication No. WO03/026797, 2003. (b) Szelagiewicz, M.; Marcolli, C.; Berghausen, J.; Cron-Eckhardt, B.; Hofmeier, U. Ch.; Blatter, F.; Multiple Sealing System for Screening Studies; PCT publication No. WO2004/045769, 2004. (c) Blatter, F.; Szelagiewicz, M.; von Raumer; M. Process for the Parallel Detection of Crystalline Forms of Molecular Solids; PCT publication No. WO2005/037424, 2005. (20) COLLECT Software, Nonius BV 1997-2001. (21) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435. (22) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487. (23) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453–457. (24) Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J. Chem. Commun. 2005, 4601–4603. (25) Hygroscopicity was classified according to the European Pharmacopoeia. By this definition, the mass gain of the sample after storage at 80% relative humidity (r.h.) for 24 h is used to classify samples according to their hygroscopicity: not hygroscopic (mass gain