Fenamate Cocrystals with 4,4â²-Bipyridine ... - ACS Publications

Article pubs.acs.org/crystal

Fenamate Cocrystals with 4,4′-Bipyridine: Structural and Thermodynamic Aspects Published as part of the Crystal Growth & Design Mikhail Antipin Memorial virtual special issue Artem O. Surov,† Anna A. Simagina,† Nikolay G. Manin,† Lyudmila G. Kuzmina,‡ Andrei V. Churakov,‡ and German L. Perlovich*,† †

G.A. Krestov Institute of Solution Chemistry RAS, 153045, Ivanovo, Russia Kurnakov Institute of General and Inorganic Chemistry RAS, Leninskii Prospect 31, 119991 Moscow, Russia

‡

S Supporting Information *

ABSTRACT: Cocrystallization of nonsteroidal anti-inflammatory drug fenamates (N-phenylanthranilic acid (N-PA), niflumic acid0 (NFA), flufenamic acid (FFA), tolfenamic (TFA) and mefenamic acids (MFA)) with 4,4′-bipyridine (BP) has resulted in the formation of cocrystals with a 2:1 molar ratio. Crystal Packing Similarity analysis has revealed that the packing arrangement of the [N-PA+BP], [TFA+BP], and [MFA+BP] cocrystals consists of discrete fragments of the crystal structures of initial APIs connected to each other by BP molecules. In the case of [FFA+BP], the cocrystal contains a previously unseen packing arrangement of FFA molecules which may be a fragment of a new polymorphic FFA form. Differential scanning calorimetry studies show a good correlation between the cocrystal melting temperature and the melting points of the corresponding pure APIs. The enthalpies of cocrystal formation are small, which indicates that the packing energy gain only originates from weak van der Waals interactions between the API and BP molecules.

1. INTRODUCTION Fenamates (N-phenylanthranilic acid, niflumic acid, flufenamic acid, tolfenamic, and mefenamic acids) belong to an important class of nonsteroidal anti-inflammatory drugs (NSAIDs), widely used as potent analgesics (Figure 1). According to the Biopharmaceutics Classification System (BCS),1 fenamates belong to class II drugs with low solubility, which restricts their bioavailability and leads to side effects.2 The fenamates primarily possess antiinflammatory activity as well as some analgesic and antipyretic properties and are non-cyclooxygenase selective.3 It has also been demonstrated that fenamates modulate a variety of neuronal ion channels4 and show neuroprotective action.5 It is well-known that fenamates are highly polymorphic compounds, and many of them exhibit the so-called conformational polymorphism.6 For mefenamic acid (MFA), three polymorphic forms have been currently established.7 Five polymorphs of tolfenamic acid (TFA) have been reported,8 whereas flufenamic acid (FFA), with nine polymorphic forms, is one of the most polymorphic drugs ever known.9 However, © 2014 American Chemical Society

niflumic acid (NFA) and N-phenylanthranilic acid (N-PA) are two exceptions. Recently, a new form II of NFA was obtained by Bag and Reddy who used the fast evaporation method, although its crystal structure was not determined.10 For unsubstituted N-PA, only one form is known so far. Uzoh et al. have shown that it is the phenyl ring substituents that determine the variety of fenamate crystal structures, and their relative energies. In the case of N-PA, the known and the closely related structure are thermodynamically favored above other alternatives, limiting the range of potential polymorphism.11 A range of cocrystals, salts, and solvates of fenamates are also described in the literature. Pharmaceutical cocrystals of fenamates (except N-PA) with nicotinamide have been reported by Fábián et al.12 For MFA, DMF solvate and cytosine salt have been isolated during preparation of its different polymorphic Received: August 25, 2014 Revised: November 6, 2014 Published: November 12, 2014 228

dx.doi.org/10.1021/cg5012633 | Cryst. Growth Des. 2015, 15, 228−238

Crystal Growth & Design

Article

quality single crystals of [FFA+BP], and its crystal structure was refined. All the fenamate cocrystals are characterized by singlecrystal X-ray diffraction, differential scanning calorimetry (DSC), and solution calorimetry. In addition, a Cambridge Structural Database (CSD)19 (Version 5.35, 2013 Release with Nov 2013 update) survey was applied to examine the conformational preferences and the fenamate crystal packing similarity, and intermolecular interaction energies were calculated.

2. MATERIAL AND METHODS 2.1. Compounds and Solvents. All the fenamates, 4,4′bipyridine and solvents (>99% purity) were available commercially and were used without further purification. Before cocrystallization experiments, all the substances were characterized by X-ray powder diffraction (XRPD) and compared with the XRPD patterns calculated based on their single crystal structure data (see Figure S1−S3 of the Supporting Information). Mefenamic acid and tolfenamic acid were identified as form I (ref codes XYANAC and KAXXAI01). The experimental XRPD pattern of flufenamic acid was found to be in well agreement with form I (FPAMCA11). 2.2. Crystallization Procedure. The fenamates and 4,4′bipyridine in a 2:1 molar ratio were dissolved in a small amount of solvent and stirred at room temperature. The resulting clear solution was filtered into a 2 mL test tube, covered by parafilm perforated with a few small holes, and allowed to evaporate slowly. For N-phenylanthranilic acid, mefenamic acid, and tolfenamic acid crystallization, acetone was used. In the case of niflumic and flufenamic acids, diffraction quality crystals were obtained from methanol solution. 2.3. Solvent-Drop Grinding. Solvent-drop grinding experiments were performed using a Fritsch planetary micro mill, model Pulverisette 7, in 12 mL agate grinding jars with 10 5-mm agate balls at a rate of 600 rpm for 60 min. The

Figure 1. Molecular structures of fenamates and 4,4′-bipyridine. For fenamates, the most widely varying torsion angle is indicated by τ1.

forms.7b A comprehensive study of the crystal structures of various complexes of MFA with cyclic and acyclic amines has been reported by Antipin and co-workers.13 In turn, cocrystals of FFA with the asthma-therapy drug theophylline and 2-pyridone were obtained by Aitipamula et al.14 In the present paper we focus on the structures and physicochemical properties of cocrystals of fenamates, shown in Figure 1, with 4,4′-bipyridine (BP). 4,4′-Bipyridine is one of coformers most frequently chosen for cocrystallization trials. Co-crystals with 4,4′-bipyridine have been reported for a variety of well-known drugs, including paracetamol,15 aspirin,16 ibuprofen,16 and felodipine.17 It should be noted that crystal structures of the N-PA and FFA cocrystals with BP have been published previously.14,18 For [FFA+BP], however, the crystallographic data are found to be of poor quality (R1 = 19.85%). In this work, we were able to obtain diffraction Table 1. Crystallographic Data for the Fenamates Cocrystals [N-PA + BP] CCDC chemical formula crystal system space group a/Å b/Å c/Å α/° β/° γ/° unit cell volume/Å3 temperature/K no. of formula units per unit cell, Z absorption coefficient, μ/mm−1 no. of reflections measured no. of independent reflections Rint no. of variables final R1 values (I > 2σ(I)) final wR(F2) values (all data) goodness of fit on F2 largest diff. peak and hole, e·Å−3

1017637 2(C13H11NO2)· C10H8N2 triclinic P1̅ 7.7606(5) 9.7575(6) 20.0638(12) 98.2930(10) 92.4230(10) 104.5940(10) 1450.01(16) 183(2) 2 0.088 16156 7681 0.0216 517 0.0438 0.1084 1.017 0.143/−0.185

[NFA + BP]

[TFA + BP]

1017636 2(C13H9F3N2O2)· C10H8N2 monoclinic C2/c 26.000(4) 6.7394(10) 19.854(3) 90.00 111.386(2) 90.00 3239.3(8) 173(2) 4 0.122 13319 3523 0.0384 288 0.0423 0.1115 1.031 0.357/−0.299

1017633 2(C14H12ClNO2)· C10H8N2 monoclinic P21/c 4.7315(12) 45.263(12) 7.929(2) 90.00 106.911(3) 90.00 1624.6(7) 183(2) 2 0.249 13525 3508 0.0216 281 0.0493 0.1086 1.142 0.230/−0.235

229

[MFA + BP] 1017635 2(C15H15NO2)· C10H8N2 triclinic P1̅ 7.3302(4) 8.6992(5) 13.6719(8) 106.276(1) 99.368(1) 98.738(1) 807.55(8) 183(2) 1 0.086 8341 3878 0.0151 293 0.0406 0.1137 1.050 0.237/−0.210

[FFA + BP] 1017634 2(C14H10F3NO2)· C10H8N2 triclinic P1̅ 9.8384(11) 10.3962(11) 25.015(3) 84.632(2) 81.353(2) 71.679(2) 2398.3(5) 153(2) 3 0.122 19730 8504 0.0421 751 0.0583 0.1669 1.019 0.419/−0.535



Article

Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1017633−1017637. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: + 44-1223-336033; e-mail: [email protected]]. 2.5. Solution Calorimetric Experiments. Solution enthalpies were measured by using an ampule-type isoperibolic calorimeter with a titanium reaction vessel volume of 50 cm3.22 The automated control scheme allowed the temperature to be maintained with an accuracy over 6 × 10−4 K. The temperature and thermal sensitivities of the calorimeter measuring cell were 10−4 K and 10−3 J, respectively. The instrumental errors were 0.6−1%. The accuracy of weight measurements corresponded to ±10−5 g. Because of small values of the solution heat effects, a correction (q(T)) was introduced to account for the heat of ampule breaking and solvent evaporation in the ampule free volume: q(293.15 K) = 0.034 J, q(303.15 K) = −0.018 J, q(318.15 K) = −0.059 J. Other corrections were negligibly small. The calorimeter was calibrated using KCl (Merck analysis grade >99.5%) in water over a wide concentration interval with more than 20 measurements made. The obtained standard value of

experiments were carried out with the fenamates and 4,4′bipyridine in a 2:1 molar ratio and a few drops of solvent (methanol or acetone) added with a micropipette. 2.4. X-ray Diffraction Experiments. Single-crystal X-ray diffraction data were collected on a Bruker SMART APEX II diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Absorption correction based on measurements of equivalent reflections was applied.20 The structures were solved by direct methods and refined by full matrix leastsquares on F2 with anisotropic thermal parameters for all nonhydrogen atoms (except disordered −CF3 groups in [FFA +BP]).21 In [FFA+BP] structure, all hydrogen atoms were placed in calculated positions and refined using a riding model. In the other four structures, all H atoms were found from the difference Fourier synthesis and refined isotropically. In [FFA +BP], all three trifluoromethyl groups (C27, C47, and C67) are rotationally disordered over three positions with the occupancy ratios being equal to 0.51/0.25/0.24, 0.50/0.27/0.23, and 0.47/ 0.33/0.20, respectively. They were refined with restrained C−F and F···F distances (SADI). X-ray powder diffraction data were recorded under ambient conditions in Bragg−Brentano geometry with Bruker D8 Advance diffractometer with CuKα1 radiation (λ = 1.5406 Å).

Figure 2. Molecular units in (a) [N-PA+BP]; (b) [NFA+BP]; (c) [TFA+BP]; (d) [MFA+BP]; (e) [FFA+BP]. Displacement ellipsoids are shown at 50% probability. For [FFA+BP], all −CF3 groups are rotationally disordered over three positions. 230



Article

solution enthalpy was 17240 ± 36 J·mol−1, which was in good agreement with the value 17241 ± 18 J·mol−1 recommended by IUPAC.23 A minimum of four measurements were made for each of the analyzed samples. The enthalpy of formation, ΔHTf (AB), of a cocrystal with (1:1) stoichiometry can be calculated as24

(99.999%), and bismuth (99.9995%). The accuracy of the weighing procedure was ±0.01 mg. 2.7. Computational Procedures. Intermolecular interaction energies were calculated using the Coulomb−London− Pauli (CLP) model developed by Gavezzotti.25 The crystal structures of the fenamate cocrystals and their polymorphic forms were compared using the Crystal Packing Similarity module26 implemented in Mercury.27 The size of molecular cluster that can be overlaid between two different structures when all non-hydrogen atom−atom distances were n ≤ 20 within a 20% distance tolerance and angles within 20°. The smallest molecular components were ignored. The calculated rmsdn is the root-mean-square deviation of all nonhydrogen atom positions in the clusters of n molecules. The program allows comparing crystal structures of different molecules with the rmsdn calculated from only the common non-hydrogen atoms.

T T T ΔHfT(AB) = ΔHsol (A)B + ΔHsol (B)A − ΔHsol (AB)B

(1)where ΔHTsol(A)B and ΔHTsol(B)A are the solution heat values for solid A in a solution containing B and for solid B in a solution containing A, respectively. It is essential to consider that the solution enthalpy of one of the pure solid coformers may be affected by the presence of the other coformer in the solution. Thus, solution heat measurements taken in the presence of the second coformer are required. This ensures that the same solute A−solute B interactions that occur during cocrystal dissolution are taken into account in the calculation of the formation enthalpy. For [API+BP] (2:1), the formation enthalpy was calculated in a similar manner with a proper account of the cocrystal stoichiometry. All experiments were conducted at 298.15 K. Methanol was chosen as a solvent as the cocrystals dissolve well with a large endothermic heat effect. 2.6. DSC Experiments. Thermal analysis was carried out employing DSC 204 F1 Phoenix differential scanning heat flux calorimeter (NETZSCH, Germany) with a high sensitivity μ-sensor. The sample was heated at the rate of 10 K·min−1 in an argon atmosphere and cooled with gaseous nitrogen. The temperature calibration of the DSC was performed against six high-purity substances, cyclohexane (99.96%), mercury (99.99+%), biphenyl (99.5%), indium (99.999%), tin

3. RESULTS AND DISCUSSION 3.1. Crystal Structures. Crystallographic data are summarized in Table 1, and the molecular units of the cocrystals are shown in Figure 2. In the [N-PA+BP] structure, the 4,4′-bipyridine molecules occupy general positions, while in [MFA+BP], [NFA+BP], and [TFA+BP] they possess crystallographically imposed symmetry. As for specific case of [FFA+BP], one independent BP molecule occupies general position, and another lies on an inversion center resulting in 1.5 crystallographically unique BP fragments. In each structure, fenamate and BP molecules connected by O−H···N hydrogen bonds involving API carboxylic acid and pyridine N atoms of BP to form a

Table 3. Selected Torsion Angle, τ1, and the Dihedral Angle between Planes of Phenyl Rings, β, of the Fenamate Molecules in Different Crystal Formsa [N-PA+BP] N-PA [NFA+BP] NFA [NFA+Nicotinamide] [TFA+BP] TFA form I TFA form II TFA form III TFA form IV TFA form V [TFA+Nicotinamide] [MFA+BP] MFA form I MFA form II MFA form III [MFA+DMF] [MFA+Nicotinamide] [FFA+BP] FFA form I FFA form II FFA form III [FFA+Nicotinamide] [FFA+Theophylline]13 [FFA+2-pyridone]13 a

τ1, °

β, °

−139.5 (A′); −69.8 (B′) −136.6 (A); −70.5 (B) −154.4 −176.3 11.6 −76.3 −74.9 −142.6 −138.4 (A); 126.8 (B) −115.9 (A); −125.9 (B); −134.1 −125.1 (50% of occupancy) 133.7 77.2 −119.9 68.2 (55% of occupancy) −80.2 −75.6 137.1 155.3(A′); 148.3 (B′); −44.1 (C′) −130.1 141.3 8.7 135.4 37.3 54.4

47.9 (A′); 70.1 (B′) 52.9 (A); 72.6 (B) 22.0 8.8 9.0 69.9 72.7 44.5 54.3 (A); 53.5 (B) 61.5 (A); 63.8 (B); 58.1 (C) 76.9 46.9 79.3 62.4 77.8 80.3 75.3 50.4 40.8(A′); 43.2(B′); 47.2(C′) 53.0 50.8 43.0 54.8 47.8 53.4

rmsd 0.081(A′A); 0.081(B′B) 0.250 2.072 0.101 0.905 0.756(A); 1.840(B) 0.674(A); 0.624(B); 0.699(C) 0.445 1.807 1.787 0.121 1.813 1.788 0.664 1.128(A′); 1.488(B′); 1.252(C′) 0.427(A′); 0.326(B′); 2.095(C′) 1.538(A′); 1.487(B′); 0.384(C′) 0.537(A′); 0.346(B′); 2.050(C′) 1.437(A′); 1.311(B′); 0.473(C′) 1.343(A′); 1.249(B′); 0.290(C′)

ref. code this work QQQBTY02 this work NIFLUM10 EXAQEA this work KAXXAI01 KAXXAI KAXXAI02 KAXXAI03 KAXXAI04 EXAQIE this work XYANAC XYANAC02 XYANAC03 ZAZGAK EXAQOK this work FPAMCA11 FPAMCA17 FPAMCA EXAQAW

Molecules corresponding to a cocrystal are indicated by stroke, ′. 231



Article

Figure 3. Overlay of the fenamate molecules conformations in different crystal forms shown in Table 3: (a) N-PA: [N-PA+BP] mol. A′ − blue, mol. B′ − red, QQQBTY02 mol. A − green, mol. B − yellow; (b) NFA: [NFA+BP] − blue, NFA − red, EXAQEA − green; (c) TFA: [TFA+BP] − blue, KAXXAI01−red, KAXXAI − green; KAXXAI02 mol. A − orange, mol. B − yellow, KAXXAI03 mol. A − cyan, mol. B − purple, mol. C − light blue, KAXXAI04−light green (50% of occupancy), EXAQIE − magenta; (d) MFA: [MFA+BP] − blue, XYANAC − red, XYANAC02−green (55% of occupancy), XYANAC03−yellow, ZAZGAK − purple, EXAQOK − orange; (e) FFA: [FFA+BP] mol. A′ − blue, mol. B′ − red, mol. C′ − green (50% of occupancy), FPAMCA11−orange, FPAMCA17 − yellow, FPAMCA − cyan, EXAQAW − purple, [FFA+Theophylline] − light blue, [FFA+2-pyridone] − light green.

Table 2. Dihedral Angle in BP Molecules, α, and the Angle between the Fenamate Anthranilic Fragment and the BP Hydrogen-Bonded Pyridine Ring, θ

heterotrimer unit (Figure 2). In addition, BP forms C−H···O contacts with the neighboring API molecules. Despite similar organization of the cocrystals asymmetric units, the BP molecule shows considerable conformational variations and a different orientation relative to the anthranilic fragment of the fenamate molecule. The angles between the least-squares planes of the pyridine rings of BP (α) and the angles between the fenamate anthranilic fragment and the hydrogen-bonded pyridine ring of BP (θ) in the cocrystals are summarized in Table 2. These angles are illustrated in Figure S4 of the Supporting Information. We have recently reported that BP planar conformation in two-component cocrystals is the most frequent one, despite the fact that it is a relatively higher-energy state.17 A similar trend is also observed for fenamate cocrystals with BP. The molecular conformation of BP is considerably twisted from planarity only

cocrystal

α, °

θ, °

[N-PA+BP] [NFA+BP] [TFA+BP] [MFA+BP] [FFA+BP] Molecule A Molecule B Molecule C

14.83(6) 26.65(3) 0.0 0.0

23.80(5), 39.43(4) 23.39(3) 24.6(1) 5.07(7)

0.0 0.0 0.9(1)

30.86(9) 31.78(9) 32.33(9)

in two structures, namely, [N-PA+BP] and [NFA+BP]. It should be noted that conformational diversity of the API molecule in [FFA+BP] has only a minor effect on BP conformation. 232



Article

Figure 4. Distributions of the torsion angle, τ1, and the dihedral angle, β, in all known crystal forms of FFA. Conformations of A′, B′, and C′ molecules in [FFA+BP] are indicated by blue lines.

[MFA+BP], the rmsd parameter indicates a large similarity between molecular conformation in the cocrystal and form II of pure MFA. The [FFA+BP] structure is interesting as it contains three crystallographically independent molecules with distinct conformations According to Cruz-Cabeza and Bernstein,28 a new conformation is considered to be a new conformer only if it corresponds to distinct energy minima of the gas-phase potential energy surface. Therefore, the asymmetric unit of [FFA+BP] contains two different conformers of FFA molecule, where one of the conformers adopts two conformations (Table 3, Figure 3e). It should be noted that similar phenomenon was found only in metastable polymorphic forms IV, VI, VIII of pure FFA.9 Table 3 shows a comparison of the FFA conformations in the cocrystal with the most stable polymorphs I−III and the known cocrystals. The conformation of the molecules A′ and B′, which are two conformations of the first conformer, is comparable to that in FFA form II. Whereas the second conformer (molecule C′) corresponds to the most thermodynamically stable form III of FFA. Figure 4 shows the distributions of the torsion angle, τ1, and the dihedral angle, β, in all known crystal forms of FFA. Apparently, τ1 values are distributed into two tight regions corresponding to two energy minima of the potential energy surface. Molecules A′ and B′ belong to the high-angle region, while the molecule C′ is located in the low-angle region. Conformational analysis clearly shows that the fenamate conformations are not influenced significantly by cocrystal formation. It might be reasonable to assume that a similar trend may be observed in the packing arrangement of the API molecules in the cocrystals. In order to test this assumption, the crystal structures of the fenamate cocrystals and their polymorphic forms were compared using the Crystal Packing Similarity module26 implemented in Mercury.27 Figure 5a shows the results of the Crystal Packing Similarity analysis between [N-PA+BP] and the only known form of pure N-PA (QQQBTY02). The crystal structures overlay 20 molecules with rmsdn of 0.377 Å. Therefore, a considerable similarity in

In all other cases the BP molecules hold planar conformation. In contrast to α, angle θ, which characterizes orientation of the fenamate anthranilic fragment and the hydrogen-bonded pyridine ring of BP, is considerably greater than 0° for all the cocrystals. The least value of angle θ is observed in [MFA+BP]. Probably, it is a consequence of the π···π interactions between BP and the neighboring molecules of mefenamic acid. For the rest of the cocrystals, the θ value varies within a ca. 20° range, and it does not correlate with the BP conformation. It is evident that both angles (α and θ) reflect the influence of supramolecular surroundings on the BP orientation in a cocrystal. It is difficult, however, to highlight the influence of certain factors on the mentioned angles. 3.2. Conformational Analysis and Crystal Packing Similarity. Considering a diversity of polymorphic forms and a variety of conformational states of fenamates, it would be interesting to compare molecular conformations of fenamates in the cocrystals with BP and different polymorphs, the known cocrystals and solvates (Table 3). The conformational state of the fenamate molecules can be described in terms of the most widely varying torsion angle, τ1, (Figure 1) and the angle between the least-squares planes of phenyl rings, β (see Figure S4 of the Supporting Information). For quantitative comparison of conformations, we used the rmsd parameter, which is the rootmean-square deviation of all non-hydrogen atom positions in two molecules, calculated in Mercury.27 The overlay of conformations of the fenamate molecules in different crystal forms is shown in Figure 3. The results shown in Table 3 reveal that conformations of the fenamate molecules in the cocrystals with BP are similar to those in different polymorphs of pure fenamates. Moreover, for [N-PA+BP], both asymmetric molecules of N-PA show almost identical conformations to the ones in the pure compound. In [NFA+BP], the conformation of NFA is in good agreement with the known form of NFA, while the alternative conformer is observed in the nicotinamide cocrystal (EXAQEA). For the [TFA+BP] cocrystals, the conformation of the API molecule corresponds to form I of TFA. In the case of 233



Article

Figure 5. (a) Overlay of the [N-PA+BP] crystal structure (gray) and the only known form of N-PA (green) (n = 20, rmsdn = 0.377); (b) molecular packing projection for [N-PA+BP]. Hydrogen atoms are omitted.

Figure 6. (a) Overlay of the [TFA+BP] crystal structure (gray) and form I of TFA (green) (n = 20, rmsdn = 0.426); (b) molecular packing projection for [TFA+BP]. Hydrogen atoms are omitted.

the cocrystal structure is MFA form II, which is thermodynamically less stable than form I under ambient conditions. The fragments are segregated so that there are clear regions with interactions between API and BP and regions where only API or BP molecules interact. It should be pointed out that the [FFA+BP] crystal structure consists of distinct alternating fragments, which contain either FFA or BP molecules (Figure 8a). This packing arrangement is essentially similar to that of [N-PA+BP], [TFA+BP], and [MFA+BP]. On the basis of the packing similarity analysis described above, it might be reasonable to assume that the packing arrangement of the FFA molecules in the cocrystal also corresponds to a stable or metastable configuration of molecules in a crystal of the pure compound. However, the Crystal Packing Similarity search does not show any satisfactory match between the cocrystal structure and the known crystal forms of FFA. Considering the highly polymorphic nature of FFA we speculate that the [FFA+BP] structure contains

large clusters of molecules between those two structures is observed. Comparison of the crystal structures of [TFA+BP] and TFA form I (KAXXAI01) resulted in a 20 molecule overlay with rmsdn of 0.426 Å (Figure 6a). For [MFA+BP] (Figure 7a,b), the best results were obtained in MFA form II (XYANAC02) (n = 16, rmsdn = 0.703) and DMF solvate (ZAZGAK) (n = 13, rmsdn = 0.670). However, for [NFA+BP] and [FFA+BP], the Crystal Packing Similarity search has not revealed clusters of molecules with n > 10 and rmsdn < 1. In the case of [FFA+BP], crystal structures of all currently established polymorphic forms were considered. Therefore, the packing arrangement of the NFA and FFA molecules in the cocrystals with BP is unique, and it is not seen in any of the APIs polymorphs. The Crystal Packing Similarity analysis indicates clearly that the packing arrangement of the [N-PA+BP], [TFA+BP], and [MFA+BP] cocrystals consists of discrete fragments of the crystal structures of initial APIs connected to each other by BP molecules (Figures 5b, 6b, and 7c). In [MFA+BP], the basis of 234



Article

Table 4. Sums of the Intermolecular Interaction Energies (kJ mol−1) between the Different Types of Molecules Calculated Using the CLP Method API-API [N-PA+BP] [MFA+BP] [TFA+BP] [NFA+BP]

−59.4 (50.6%) −61.0 (47.3%) −64.7 (52.9%) −58.7 (46.9%)

API-BP −44.1 (37.5%) −57.7 (44.8%) −43.0 (35.2%) −65.6 (52.4%)

BP-BP

totala

−14.0 (11.9%) −10.2 (7.9%)

−117.5

−14.6 (11.9%) −1.0 (0.8%)

−128.9 −122.3 −125.3

a

The total corresponds to the calculated energy change for formation of one mole of [API+BP] crystal from 2 mol of API and 1 mol of BP separated in the gas phase.

are summarized in Table 4. For [FFA+BP], the calculations were not performed due to complex disorder of CF3 group. In [N-PA+BP], [MFA+BP], and [TFA+BP], the API-API interactions provide the largest contribution to the lattice energy (≈ 50%), while the BP-BP interactions comprise ca. 8−12% of the total energy. This energy distribution reflects the alternation of the API and the BP molecular fragments in a crystal lattice of the cocrystals. The energy distribution of the intermolecular interactions for [NFA+BP] is substantially different compared to the other cocrystals. In this case, the API-BP interactions provide the largest contribution to the lattice energy. In addition, API-API and API-BP interactions comprise more than 99% of the total energy, while the BP molecules do not seem to interact with each other. It turns out that the packing fragment segregation phenomenon in a cocrystal is observed not only in fenamates. As an example, we used a BP cocrystal with carbamazepine (XAQQUC). Carbamazepine (CBZ) is an important drug in treatment of epilepsy and trigeminal neuralgia and is famous for its ability to form solvates,29 cocrystals,30 and polymorphs.31 The Crystal Packing Similarity analysis of the [CBZ+BP] cocrystal shows a close resemblance in large clusters of molecules between this structure and form III of pure CBZ (CBMZPN01) (n = 12, rmsdn = 0.684), DMSO solvate (UNEYIV) (n = 12, rmsdn = 0.495), and acetone solvate (CRBMZA01) (n = 12, rmsdn = 0.370) (Figure S5 of the Supporting Information). 3.3. Thermal Analysis. The thermal data for all the cocrystals and pure components are represented in Table 5. The DSC curves of the cocrystals and pure components are shown in Figure S6 of the Supporting Information. We have recently reported that the increase in the melting temperature of BP cocrystals with different APIs is accompanied by an increase in the melting temperature of the corresponding pure APIs.17 Figure 9 shows the melting temperature of the fenamate cocrystals with BP as a function of the melting points of the corresponding pure fenamates. In the temperature range considered, the increase in Tfus of the cocrystals is accompanied by an increase in the melting temperature of the pure API. It indicates that the intermolecular interactions, which are responsible for the thermal stability of the pure API crystals, are partially conserved in the fenamate cocrystal. This fact is consistent with the Crystal Packing Similarity analysis. The average value of fusion heat for most of the cocrystals is found to be ca. 81 kJ mol−1, while [NFA+BP] is an exception. The increase in ΔHfus in this case is probably caused by the difference in the energy distribution of the

Figure 7. (a) Overlay of the [MFA+BP] crystal structure (gray) and form II of MFA (green) (n = 16, rmsdn = 0.703); (b) overlay of the [MFA+BP] crystal structure (gray) and DMF solvate of MFA (green) (n = 13, rmsdn = 0.670); (c) molecular packing projection for [MFA +BP]. Hydrogen atoms are omitted.

fragments of new polymorphic form of FFA stabilized by the BP molecules due to weak van der Waals interactions. The [NFA+BP] structure is found to be different compared to the other fenamate cocrystals. In this structure the API and BP molecules are distributed uniformly in the bulk of the crystal, although the discrete fragments of the crystal structures of the components are not seen (Figure 8b). In addition, the Crystal Packing Similarity search does not show any satisfactory match between the cocrystal structure and the known NFA crystal forms. In order to highlight the difference between the [NFA+BP] crystal structure and the other fenamate cocrystals, the CLP calculations were carried out.25 The calculation results 235



Article

Figure 8. Molecular packing projection for (a) [FFA+BP]; (b) [NFA+BP]. Hydrogen atoms are omitted.

3.4. Solution Calorimetry. The results of solution calorimetry experiments and calculated enthalpies of formation for the cocrystals are summarized in Table 6 (see Tables S1 and S2 in the Supporting Information for the full data set). Table 6 shows that the enthalpies of formation of the cocrystals are small. Moreover, for [MFA+BP], the ΔH0f value is of the same order of magnitude as the experimental error. It should be noted that enthalpy of formation is an integral parameter which indicates the difference between the crystal lattice energy of a cocrystal and individual components at certain stoichiometry. Therefore, for [MFA+BP], almost all intermolecular interactions (including hydrogen bonds) present in the crystals of pure components are energetically comparable to those in the cocrystal. As mentioned above, the basis of the [MFA+BP] crystal structure is form II of MFA, which is found to be ca. 3.6 kJ mol−1 less stable than form I.32 Considering the difference in crystal lattice energy between MFA polymorphs, the formation enthalpy of [MFA+BP] from MFA form II as the

Table 5. Thermophysical Data for the Fenamate Cocrystals, Pure APIs and 4,4′-Bipyridine Tfus, °C (onset) [N-PA+BP] [NFA+BP] [TFA+BP] [MFA+BP] [FFA+BP] N-PA NFA TFA (form I) MFA (form II) FFA (form III) 4,4′-bipyridine

145.7 153.8 157.0 163.5 128.0 186.6 202.9 212.1 230.4 133.9 111.8

± ± ± ± ± ± ± ± ± ± ±

0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.2 0.2 0.2

ΔHfus, kJ mol−1

ΔSfus, J mol−1K−1

± ± ± ± ± ± ± ± ± ± ±

198.1 225.1 201.2 179.2 190.3 86.4 76.7 84.5 76.8 65.6 64.1

83.0 96.1 77.1 83.1 84.6 39.7 36.5 41.0 38.7 26.7 24.7

0.9 1.1 0.7 0.9 0.5 0.5 0.4 0.4 0.5 0.5 0.5

intermolecular interactions for [NFA+BP] compared to the other cocrystals. The melting temperature of this cocrystal, however, is consistent with the general correlation. 236



Article

Screening for [FFA+BP] polymorphs was performed by a solution cocrystallization of FFA and BP in 2:1 molar ratio using 12 different solvents at room temperature. For the experiment, a wide range of the most frequently used organic solvents for polymorph screening was taken:35 acetone, acetonitrile, chloroform, dioxane, DMSO, ethyl formate, ethyl acetate, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, and toluene. All dry samples were analyzed by XRPD (see Figure S7 in the Supporting Information). The results indicate clearly that in all cases cocrystallization of FFA and BP leads to formation of only one structure. Therefore, the previously unseen packing arrangement of FFA molecules in the cocrystal is found to be quite stable. A considerable role in the structure stabilization is probably played by weak van der Waals interactions between the FFA and BP molecules.

4. CONCLUSIONS Co-crystals of fenamates with 4,4′-bipyridine were obtained, and their crystal structures were determined by the singlecrystal X-ray diffraction method. The asymmetric unit of the [FFA+BP] cocrystal contains two distinct conformers of FFA molecule, where one of the conformers adopts two different conformations. For most cocrystals, the conformations of the fenamate molecules are similar to those in various polymorphs of pure fenamates. The Crystal Packing Similarity analysis indicates that the packing arrangement of the [N-PA+BP], [TFA+BP], and [MFA+BP] cocrystals consists of discrete fragments of the crystal structures of initial APIs connected to each other by BP molecules. In the case of [FFA+BP], the cocrystal contains a previously unseen packing arrangement of FFA molecules which may be a fragment of new polymorphic form of FFA stabilized by the BP molecules due to weak van der Waals interactions. In [NFA+BP], the API and BP molecules are distributed uniformly in the bulk of the crystal, although the discrete fragments of the crystal structures of the components are not formed. The DSC studies show that for the structurally related fenamate cocrystals, a good correlation between Tfus of the cocrystals and Tfus of the pure API is observed. The enthalpies of formation for the cocrystals are small. The [FFA+BP] cocrystal shows the largest ΔH0f value which may be caused by additional interactions between the API molecules in the crystal. Considering the high propensity of FFA to polymorphism, we assumed that the [FFA+BP] cocrystal may be also polymorphic. However, the results of screening for [FFA+BP] polymorphs indicate that in all cases cocrystallization of FFA and BP leads to formation of only one structure.

Figure 9. Plot of melting temperature of the fenamate cocrystals with BP vs the melting points of the corresponding pure fenamates.

Table 6. Solution Enthalpies, ΔH0sol, and Calculated Enthalpies of Formation, ΔH0f , at 298 K (kJ mol−1) ΔH0sol ΔH0f ([API + BP]) ΔH0sol(API)BP ΔH0sol(BP)Fel ([API + BP]) [N-PA+BP] [NFA+BP] [TFA+BP] [MFA+BP] [FFA+BP]

68.9 77.7 75.1 73.4 68.7

± ± ± ± ±

1.4 0.2 0.3 0.1 0.2

18.8 23.6 27.4 28.2 23.1

± ± ± ± ±

0.2 0.1 0.3 0.4 0.1

25.8 27.7 16.4 17.1 14.2

± ± ± ± ±

0.1 0.1 0.1 0.3 0.2

−5.6 −4.6 −3.9 0.2 −8.4

± ± ± ± ±

1.7 0.4 0.6 0.8 0.5

starting polymorph is ca. −7.0 ± 0.8 kJ mol−1. For [N-PA+BP] and [TFA+BP], which also contain large clusters of molecules of initial API, the enthalpies of formation are −5.6 ± 1.4 kJ mol−1 and −3.9 ± 0.6 kJ mol−1, respectively. In this case, the packing energy gain for the cocrystals is mainly caused by weak van der Waals API-BP and BP-BP interactions as the energy of API-API intermolecular interactions inside the clusters should be comparable to that of the pure APIs. The formation enthalpy of the [NFA+BP] cocrystal is close to that of [N-PA +BP] and [TFA+BP]. However, according to CLP calculations, the packing energy gain in [NFA+BP] is expected to be the result of the API-BP and API-API interactions, and the latter should be energetically comparable to those in the pure NFA crystal. The [FFA+BP] cocrystal shows the largest value of ΔH0f . However, the formation enthalpy of [FFA+BP] from the most thermodynamically stable FFA form III, which is ca. 2.7 kJ mol−1 more stable than form I, is calculated to be ca. −3.0 ± 0.6 kJ mol−1.32 This estimate does not exceed the average ΔH0f value for the fenamate cocrystals and equals ca. −5.2 kJ mol−1. It was established above that the packing arrangement of [FFA +BP] is essentially similar to that in [N-PA+BP], [TFA+BP], and [MFA+BP]. However, the [FFA+BP] structure does not contain any known fragments of the crystal forms of the pure compound. Therefore, the increase in the crystal lattice energy of the cocrystal compared to initial components may be caused by the API-BP, BP-BP interactions as well as additional interactions between the API molecules. 3.5. Screening for [FFA+BP] Polymorphs. Considering the high propensity of FFA to polymorphism, it might be possible to assume that the [FFA+BP] cocrystal may also be polymorphic.33 Polymorphism of 4,4′-bipyridine cocrystals with a 1:1 and 2:1 molar ratio has been reported previously.17,34

■

ASSOCIATED CONTENT

S Supporting Information *

The measured and calculated powder X-ray diffractograms, the experimental PXRD patterns of the [FFA+BP] cocrystals obtained from 12 different solvents, DSC curves of the fenamate cocrystals and pure components, illustration of different dihedral angles in the cocrystals, overlay of the crystal structures of carbamazepine cocrystals, the full data set of the solution calorimetry experiments. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Telephone: +7-4932-533784. Fax: +7-4932- 336237. E-mail [email protected]. 237



Article

Notes

(27) 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. (28) Cruz-Cabeza, A. J.; Bernstein, J. Chem. Rev. 2014, 114, 2170− 2191. (29) (a) Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909−919. (b) Johnston, A.; Johnston, B. F.; Kennedy, A. R.; Florence, A. J. CrystEngComm 2008, 10, 23−25. (c) Cruz-Cabeza, A. J.; Day, G. M.; Jones, W. Phys. Chem. Chem. Phys. 2011, 13, 12808−12816. (d) Delori, A.; Galek, P. T. A.; Pidcock, E.; Patni, M.; Jones, W. CrystEngComm 2013, 15, 2916−2928. (30) (a) McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340− 350. (b) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802−16803. (c) Seefeldt, K.; Miller, J.; Alvarez-Nunez, F.; Rodriguez-Hornedo, N. J. Pharm. Sci. 2007, 96, 1147−1158. (d) ter Horst, J. H.; Cains, P. W. Cryst. Growth Des. 2008, 8, 2537−2542. (e) Porter, W. W., III; Ellie, S. C.; Matzger, A. J. Cryst. Growth Des. 2008, 8, 14−16. (f) Childs, S. L.; Wood, P. A.; Rodriguez-Hornedo, N.; Reddy, L. S.; Hardcastle, K. I. Cryst. Growth Des. 2009, 9, 1869−1888. (g) Habgood, M.; Deij, M. A.; Mazurek, J.; Price, S. L.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 903−912. (31) (a) Lowes, M. M. J.; Cairo, M. R.; Lotter, A. P.; van der Watt, J. G. J. Pharm. Sci. 1987, 76, 744−752. (b) Lang, M.; Kampf, J. W.; Matzger, A. J. J. Pharm. Sci. 2002, 91, 1186−1190. (c) Fernandes, P.; Shankland, K.; Florence, A. J.; Shankland, N.; Johnston, A. J. Pharm. Sci. 2007, 96, 1192−1202. (d) Arlin, J.-B.; Price, L. S.; Price, S. L.; Florence, A. J. Chem. Commun. 2011, 47, 7074−7076. (32) Surov, A. O.; Terekhova, I. V.; Bauer-Brandl, A.; Perlovich, G. L. Cryst. Growth Des. 2009, 9, 3265−3272. (33) (a) Lemmerer, A.; Adsmond, D. A.; Esterhuysen, C.; Bernstein, J. Cryst. Growth Des. 2013, 13, 3935−3952. (b) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2014, 16, 3451−3465. (34) (a) Braga, D.; Palladino, G.; Polito, M.; Rubini, K.; Grepioni, R.; Chierotti, M. R.; Gobetto, R. Chem.Eur. J. 2008, 14, 10149−10159. (b) Halasz, I.; Rubčić, M.; Užarević, K.; Đilović, I.; Meštrović, E. New J. Chem. 2011, 35, 24−27. (c) Mukherjee, A.; Desiraju, G. R. Chem. Commun. 2011, 47, 4090−4092. (35) Miller, J. M.; Blackburn, A. C.; Macikenas, D.; Collman, B. M.; Rodríguez-Hornedo, N. Solvent Systems for Crystallization and Polymorph Selection. In Solvent Systems and Their Selection in Pharmaceutics and Biopharmaceutics; Augustijns, P., Brewster, M. E., Eds.; AAPS Press: New York, 2007.

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the Russian Scientific Foundation (No. 14-13-00640). We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with DSC and XRPD experiments.

■

REFERENCES

(1) Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. Mol. Pharmaceutics 2006, 3, 631−643. (2) Pedersen, S. B. Pharmacol. Toxicol. 1994, 75 (Suppl. 2), 22−32. (3) Nadendla, R. R. Principles of Organic Medicinal Chemistry; New Age International: New Delhi, 2005. (4) (a) Hill, K.; Benham, C. D.; McNulty, S.; Randall, A. D. Neuropharmacology 2004, 47, 450−460. (b) Coyne, L.; Patten, J.; Halliwell, R. F. Neurochem. Int. 2007, 51, 440−446. (c) Zhang, M.; Shi, W.; Xiao-Wei, F.; Ya-Rong, L.; Xi-Min, Z.; Yan-Ai, M. Toxicol. Appl. Pharmacol. 2008, 226, 225−235. (5) Khansari, P. S.; Halliwell, R. F. Neurochem. Int. 2009, 55, 683− 688. (6) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford, U.K., 2002. (7) (a) Lee, E. H.; Byrn, S. R.; Carvajal, M. T. Pharm. Res. 2006, 23, 2375−2380. (b) SeethaLekshmi, S.; Row, T. N. G. Cryst. Growth Des. 2012, 12, 4283−4289. (8) (a) Andersen, K. V.; Larsen, S.; Alhede, B.; Gelting, N.; Buchardt, O. J. Chem. Soc., Perkin Trans. 2 1989, 1443−1447. (b) López-Mejías, V.; Kampf, J. W.; Matzger, A. J. J. Am. Chem. Soc. 2009, 131, 4554− 4555. (9) López-Mejías, V.; Kampf, J. W.; Matzger, A. J. J. Am. Chem. Soc. 2012, 134, 9872−9875. (10) Bag, P. P.; Reddy, C. M. Cryst. Growth Des. 2012, 12, 2740− 2743. (11) Uzoh, O. G.; Cruz-Cabeza, A. J.; Price, S. L. Cryst. Growth Des. 2012, 12, 4230−4239. (12) Fábián, L.; Hamill, N.; Eccles, K. S.; Moynihan, H. A.; Maguire, A. R.; McCausland, L.; Lawrence, S. E. Cryst. Growth Des. 2011, 11, 3522−3528. (13) Fonari, M. S.; Ganin, E. V.; Vologzhanina, A. V.; Antipin, M. Yu.; Kravtsov, V. C. Cryst. Growth Des. 2010, 10, 3647−3656. (14) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2014, 16, 5793−5801. (15) Oswald, I. D. H.; Allan, D. R.; McGregor, P. A.; Motherwell, W. D. S.; Parsons, S.; Pulham, C. R. Acta Crystallogr., Sect. B 2002, 58, 1057−1066. (16) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Chem.Commun. 2003, 186−187. (17) Surov, A. O.; Solanko, K. A.; Bond, A. D.; Bauer-Brandl, A.; Perlovich, G. L. CrystEngComm 2014, 16, 6603−6611. (18) Kumaresan, S.; Seethalakshmi, P. G.; Kumaradhas, P.; Devipriya, B. J. Mol. Struct. 2013, 1032, 169−175. (19) Allen, F. H. Acta Crystallogr. B 2002, B58, 380−388. (20) Sheldrick, G. M. SADABS, Program for Scaling and Correction of Area Detector Data; University of Göttingen, 1997, Germany. (21) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (22) Manin, N. G.; Fini, A.; Perlovich, G. L. J. Therm. Anal. Calorim. 2011, 104, 279−289. (23) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and Organometallic Compounds; Academic Press: London, U.K., 1970. (24) Oliveira, M. A.; Peterson, M. L.; Davey, R. J. Cryst. Growth Des. 2011, 11, 449−457. (25) Gavezzotti, A. New J. Chem. 2011, 35, 1360−1368. (26) Chisholm, J. A.; Motherwell, S. J. Appl. Crystallogr. 2005, 38, 228−231. 238


Fenamate Cocrystals with 4,4â²-Bipyridine ... - ACS Publications

Recommend Documents

Fenamate Cocrystals with 4,4â²-Bipyridine ... - ACS Publications