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Keywords:

  • alprazolam;
  • crystal engineering;
  • co-crystal;
  • triazole;
  • pharmaceuticals;
  • drugs

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

A series of molecular complexes, both co-crystals and salts, of a triazole drug—alprazolam—with carboxylic acids, boric acid, boronic acids, and phenols have been analyzed with respect to heterosynthons present in the crystal structures. In all cases, the triazole ring behaves as an efficient hydrogen bond acceptor with the acidic coformers. The hydrogen bond patterns exhibited with aromatic carboxylic acids were found to depend on the nature and position of the substituents. Being a strong acid, 2,6-dihydroxybenzoic acid forms a salt with alprazolam. With aliphatic dicarboxylic acids alprazolam forms hydrates and the water molecules play a central role in synthon formation and crystal packing. The triazole ring makes two distinct heterosynthons in the molecular complex with boric acid. Boronic acids and phenols form consistent hydrogen bond patterns, and these are seemingly independent of the substitutional effects. Boronic acids form noncentrosymmetric cyclic synthons, while phenols form O[BOND]Hequation imageN hydrogen bonds with the triazole ring. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3743–3753, 2010


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Pharmaceutical co-crystals are multicomponent molecular crystals formed by the co-crystallization of active pharmaceutical ingredients (APIs) with small organic molecules, called coformers. They constitute a novel class of crystalline forms ideally with improved physico-chemical properties, when compared to the parent API.1–4 In recent times, the study of pharmaceutical co-crystals has become an integral part of crystal engineering.5–7 Due to the availability of several potential organic coformers, there exists tremendous scope for identifying a large number of possible co-crystal forms for a particular API. The literature provides several examples of co-crystals with a proven track record in achieving better stability, solubility, dissolution rates, and improved mechanical properties when compared with the parent APIs.8–12 The formation of a co-crystal is generally achieved as a result of recognition established between the complementary functional groups present on the two molecular species. Of the several interactions present in any crystal structure, combinations of a few significant ones actually determine the stable crystal structure; these combinations are referred to as supramolecular synthons.13–15 Because the constituents of a pharmaceutical co-crystal are distinct molecules (API and coformer), the synthons formed are typically unsymmetrical and have been termed as heterosynthons.16, 17 An understanding of the possible heterosynthons and their consistency in appearance is important for the effective design of co-crystals. In this context, carboxylic acid–amide, carboxylic acid–pyridine, and phenol–pyridine are among the best studied of heterosynthons.18–20

Triazoles constitute a major building block in the crystal structures of several drug molecules but their intermolecular interactions are not well studied. The pKa of 1,2,4-triazole is 2.2, making it a weaker base than pyridine (5.14). It is interesting to note that the N-rich pyridazine ring with a similar pKa value (2.10) is also not well studied in crystal engineering. This may be due to the weaker hydrogen bonds formed by less basic heterocyclics. For the 1421 hits for 1,2,4-triazoles in the Cambridge Structural Database (CSD), only a very few neutral co-crystals are reported.21 A detailed analysis of the supramolecular synthons present in the crystal structures of triazoles (with the number of chemical units >1) was carried out. The molecular complexation of 1,2,4-triazoles with carboxylic acids and phenols is infrequent. However, hydrated forms of triazole with various hydrogen bond patterns are numerous.a One of the best examples of a pharmaceutical co-crystal involving a 1,2,4-triazole and a carboxylic acid is the 2:1 molecular complex of the antifungal drug itraconazole with succinic acid (SA); this complex reportedly achieves a higher solubility when compared to the crystalline drug.22 Thus, a systematic evaluation of heterosynthons present in the co-crystals of 1,2,4-triazoles is interesting from both academic and commercial viewpoints. This is the aim of the present work.

The present study focuses on synthon preferences of the 1,2,4-triazole ring by examining the hydrogen bonds in co-crystals of a 1,2,4-triazole containing drug, alprazolam (ALP). This drug belongs to the benzodiazepine class and is used to treat moderate to severe anxiety disorders, panic attacks, and depression.23, 24 ALP works by slowing down the movement of chemicals in the brain that may become unbalanced, which in turn results in a reduction in nervous tension (anxiety). Alprazolam is marketed under the trade names Xanax, Xanor, Alprax, and Niravam and these are among the most marketed drugs in the United States and Europe. To develop a better understanding of the supramolecular synthons involving the triazole fragment, we carried out several co-crystallization experiments of ALP with carboxylic acids, boric acid, boronic acids, sulfonic acids, and phenols. Of the several combinations tried we were successful in obtaining single crystals of molecular complexes in 20% of the cases. These complexes have been analyzed to identify novel and robust heterosynthons between the 1,2,4-triazole moiety and various complementary functional groups. In this article, we report the recognition patterns in co-crystals of alprazolam with the following coformers: benzoic acid (BA), 4-aminobenzoic acid (ABA), 2,6-dihydroxybenzoic acid (26DHB), 3,5-dihydroxybenzoic acid (35DHB), 2,6-difluorobenzoic acid (26DFB), 3,5-difluorobenzoic acid (35DFB), oxalic acid (OA), fumaric acid (FA), succinic acid (SA), boric acid (BORA), 1,4-benzenediboronic acid (BDBA), 4-hydroxyphenylboronic acid (HPBA), hydroquinone (HQ), and 2,4,6-trichlorophenol (TCP). Some of the binary compounds isolated crystallized as neutral molecules. These are referred to here as “co-crystals.” In some cases, proton transfer occurs across a hydrogen bond. These compounds are referred to as “salts.” Taken together, the co-crystals and salts are referred to as “molecular complexes.”

The motivation of the present work is structural. It is hoped that with the information obtained in this work, further studies can be undertaken with the aim of using co-crystal forms of alprazolam in formulation technologies.

EXPERIMENTAL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Materials

Alprazolam was obtained from Lupin Ltd., Pune, India and was used without further purification. All the coformers were obtained from either Aldrich, Bangalore or SD Fine Chem. (India). Reagent grade solvents were used for the co-crystallization experiments. Equimolar mixtures were ground, using a mortar and pestle, for 15 min followed by the addition of two drops of methanol. The resulting mixture was ground further for another 10 min. The mixture was analyzed using powder X-ray diffraction for the possible formation of new phases. The mixtures were dissolved in various solvents and solvent mixtures and the clear solution was kept for slow evaporation. Crystals formed over a period of a fortnight were analyzed using single crystal X-ray diffraction.

Powder X-Ray Diffraction (PXRD)

X-ray powder diffraction data were collected in the Indian Institute of Science on a Philips X'pert Pro X-ray powder diffractometer equipped with X'cellerator detector. The scan range, step size, and time per step were 2θ = 5.00 to 40°, 0.02°, and 25 s, respectively.

Single Crystal Diffraction (SXRD)

Single crystals were carefully chosen after viewing through an Olympus microscope supported by a rotatable polarizing stage and a CCD camera. The crystals were cleaned thoroughly and glued to a thin glass fiber using an adhesive (cyanoacrylate) and mounted on a diffractometer equipped with an APEX CCD area detector. Data were collected both in the University of Hyderabad and in the Indian Institute of Science. Normal methods were employed for crystal handling and data collection, except that the crystals were smeared in cyanoacrylate to protect them from ambient laboratory conditions. The intensity data were processed using the Bruker suite of data processing programs (SAINT), and absorption corrections were applied using SADABS.25 The structure solution was carried out by direct methods, and refinements were performed by full-matrix least-squares on F2 using the SHELXTL-PLUS suite of programs.26 All the structures converged to reasonable R factors. All the nonhydrogen atoms were refined anisotropically, and the hydrogen atoms were refined isotropically. Intermolecular interactions were computed with the PLATON program.27

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Co-Crystals of Alprazolam with Benzoic Acid and 4-Aminobenzoic Acid, 1 and 2

The asymmetric unit of the alprazolam–benzoic acid co-crystal, 1, consists of one molecule each of the API and the acid. In the crystal, two molecules of BA interact with two ALP units through O[BOND]Hequation imageN (Hequation imageN, 1.74 Å) hydrogen bonds at N1 (see Scheme 1 for atom numbering). A cyclic tetramer results from bifurcated C[BOND]Hequation imageO (Hequation imageO, 2.46 and 2.84 Å) hydrogen bonds to the carbonyl group of the acid (Fig. 1A). This tetramer extends in three-dimensions through centrosymmetric C[BOND]Hequation imageN (Hequation imageN, 2.68 Å) hydrogen bonds between the methyl group and N7 (Fig. 1B). The Cl atom is not involved in hydrogen bonding. This is unsurprising given the fact that one is dealing with “organic” chlorine.28, 29

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Scheme 1. Chemical structures of alprazolam and coformers.

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Figure 1. The characteristic synthons (A and B) present in ALP–BA co-crystal, 1.

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ABA forms a 1:1 co-crystal, 2, with ALP. The acid molecules form an undulated molecular chain, stabilized by N[BOND]Hequation imageO (Hequation imageO, 2.12 Å) hydrogen bonds between the amino and carboxyl functionalities. The ALP molecules are pendant on the acid chains and are attached with O[BOND]Hequation imageN (Hequation imageN, 1.74 Å) hydrogen bonds between N1 and the acid (Fig. 2a). These recognition units are extended with centrosymmetric C[BOND]Hequation imageN (CH3equation imageN7) bonds between two ALP units (Fig. 2b). Thus, molecular complexes 1 and 2 display similar recognition patterns (synthon I) and in the propagation of these interactions in the crystal through centrosymmetric C[BOND]Hequation imageN hydrogen bonds. But unlike the undulated chains observed in the molecular complex of ABA, a cyclic network is formed in the BA complex, possibly due to the absence of a functional group on the tail end to carry forward the recognition events.

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Figure 2. Co-crystal, 2. (a) Recognition patterns in the molecular complex and the corresponding synthon. (b) Centrosymmetric C[BOND]Hequation imageN hydrogen bonds between adjacent ALP molecules.

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Molecular Complexes of Alprazolam with Dihydroxybenzoic Acids, 3 and 4

26DHB is a strong acid because both hydroxyl groups form intramolecular hydrogen bonds with the carboxylic functionality.30 This is reflected in the fact that molecular complex, 3, of 26DHB and ALP exists as a salt, stabilized by ionic N+[BOND]Hequation imageO/C[BOND]Hequation imageO (Hequation imageO, 1.42 and 2.48 Å) pairwise interactions (synthon III) (Fig. 3a). This primary synthon is extended with C[BOND]Hequation imageO, C[BOND]Hequation imageN hydrogen, and Clequation imageN halogen bonds. So, while strong ionic interactions hold the two hetero functionalities together, their further elaboration in the crystal is mediated by weaker interactions.

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Figure 3. Molecular complexes 3 and 4 with respective synthons.

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In the 35DHB co-crystal, 4, the asymmetric unit consists of two molecules of ALP and a molecule each of 35DHB and water. Each 35DHB bridges two symmetry-independent molecules of ALP through O[BOND]Hequation imageN hydrogen bonds, making use of its carboxyl and hydroxyl functionalities. Whilst the carboxyl end forms O[BOND]Hequation imageN/C[BOND]Hequation imageO pairwise interactions with N2 and the methyl group of the first ALP molecule, one of the hydroxyl groups builds an O[BOND]Hequation imageN (Hequation imageN, 1.96 Å) hydrogen bond with N1 of the second ALP unit (Fig. 3b). The second hydroxyl group make O[BOND]Hequation imageO (Hequation imageO, 1.84 Å) hydrogen bonds with a water molecule, which in turn interacts with two symmetry independent ALP molecules through O[BOND]Hequation imageN (Hequation imageN, 2.07 Å) hydrogen bonds. Thus, lattice water plays a major role in hydrogen bond formation, acting as a two-donor one-acceptor fragment. This basic unit extends in the crystal through centrosymmetric C[BOND]Hequation imageO (Hequation imageO, 2.62 Å) hydrogen bonds formed between adjacent acid units. Thus, the three hydrogen bond donor functionalities (carboxyl, hydroxyl, and water) generate two distinct synthons (II and IV).

Co-Crystals of Alprazolam with Difluorobenzoic Acids, 5 and 6

26DFB and ALP co-crystallize to give a 1:1 molecular complex, 5, with a heterosynthon (synthon II) similar to that observed in the case of co-crystal 4. This synthon is further extended with C[BOND]Hequation imageN (Hequation imageN, 2.76 and 2.71 Å) C[BOND]Hequation imageF (Hequation imageF, 2.56 Å) hydrogen bonds (Fig. 4).31

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Figure 4. Heterosynthons present in co-crystal 5 between ALP and 26DFB.

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The co-crystal of 35DFB and ALP, 6, exhibits recognition patterns similar to those seen in 1 (Fig. 5a). Surprisingly, even the unit cell parameters match. This cyclic entity extends in the crystal of 6 through centrosymmetric C[BOND]Hequation imageN (Hequation imageN, 2.66 Å) and C[BOND]Hequation imageCl (Hequation imageCl, 2.93 Å) interactions (Fig. 5b).

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Figure 5. Co-crystal 6. (a) Major recognition pattern. (b) Centrosymmetric C[BOND]Hequation imageN and C[BOND]Hequation imageCl hydrogen bonds between adjacent ALP units.

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From a comparative analysis of binary crystals formed by ALP with five aromatic carboxylic acids it can be inferred that though the N-heteroatoms of the triazole ring act as efficient hydrogen bond acceptors, the heterosynthons present between the acid and triazole fragments cannot be predicted at least based on recognition patterns observed in other similarly substituted acids. Clearly the structural divergences are too high. In the molecular complexes of BA and ABA, the synthon consists of the interaction formed between N1 and the carboxyl functionality. While 26DHB makes a salt with ALP, an entirely different recognition pattern is observed with its fluorinated analogue, 26DFB. A nonsolvated co-crystal is obtained in the case of 35DFB as against a hydrated form for 35DHB. Thus, a very minor shift in the acidity and substituents present on the coformers yields co-crystals with entirely different heterosynthons. To find some supramolecular similarity among the ALP co-crystals, we extended our studies to aliphatic acids.

Co-Crystals of Alprazolam with Aliphatic Dicarboxylic Acids, 7–9

The asymmetric unit of the OA and ALP molecular complex, 7, consists of one molecule each of ALP, OA, and water. Of the two carboxylic acid functionalities of OA, one exhibits a syn conformation with respect to the carbonyl functionality, while the other is in the anti orientation. Unlike the aromatic acids, the carboxylic acid functionality in 7 does not interact directly with the triazole heteroatoms. Instead, a series of hydrogen bonds are formed with water molecules, which act as linkers between ALP and OA. A tetramer supramolecular entity (synthon V) is generated by the interactions of two molecules each of water molecules and the API through O[BOND]Hequation imageN (Hequation imageN, 1.72 and 1.91 Å) hydrogen bonds at N1 and N2 (Fig. 6A). Two such entities are bridged by two OA molecules. One of the carboxylic acid functionalities, with syn conformation, interacts with lattice water through an O[BOND]Hequation imageO (Hequation imageO, 1.43 Å) hydrogen bond. The second acid group, with an anti conformation, makes an O[BOND]Hequation imageN (Hequation imageN, 1.72 Å) hydrogen bond with N7 (Fig. 6B). Thus, an extended network of hydrogen bonds exists with the water molecule, acting as a two-donor one-acceptor hydrogen bond species.

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Figure 6. Oxalic acid co-crystal, 7 with a representation of hydrated synthon V.

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A similar water assisted recognition pattern was observed in co-crystal, 8, formed by FA with ALP. The acid molecules are disordered over the ethylene bridge with a population of 51:49. As observed in the OA–ALP co-crystal, a cyclic tetramer is established by two molecules each of water and ALP. In a unique cyclic entity, water molecules act as two-donor hydrogen bond centers and form O[BOND]Hequation imageN (Hequation imageN, 1.86 and 1.91 Å) hydrogen bonds with the N1 and N2. These tetramer units interact with two other lattice water molecules, forming a cyclic water cluster, which in turn interact with two FA molecules, through O[BOND]Hequation imageO (Hequation imageO, 1.85 Å) hydrogen bonds (Fig. 7b).

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Figure 7. Crystal structures of co-crystals 8 and 9. (a) Interaction of lattice water with ALP units. (b) Linear chain formed by FA and water molecules. (c) Representation of the perpendicular orientation of the SA with respect to the plane containing the ALP units.

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As in co-crystal 7, water plays a major role in synthon formation and structure stabilization in 8. But, water acts both as a two-donor two-acceptor as well as a two-donor one-acceptor molecule. SA, which has similar dimensions to FA, forms a co-crystal, 9, isostructural to co-crystal 8. Thus, unlike aromatic acids, the association of aliphatic dicarboxylic acids with ALP is mediated by water molecules. Although the basic tetramer unit involving the drug molecule and water is similar in the assemblies, the interaction of the acid functionalities with the tetramer unit varies in each case. OA, being a small molecule, is inserted between two cyclic tetramer units. But, with larger dicarboxylic acids steric factors might have contributed to the observed perpendicular orientation of the acid molecules. Further, the tetramer observed in these molecular complexes 79 is entirely different from the synthons present in alprazolam dihydrate.32

Co-Crystal of Alprazolam with Boric Acid, 10

Boric acid is a weak acid, often used as antiseptic and also as precursor of other chemical compounds. This molecule has not been utilized effectively in crystal engineering as suggested by a CSD analysis, which revealed only 32 hits of BORA co-crystals. Although a small molecule, the flexibility of the three hydroxy functionalities and their various orientational possibilies (syn, anti) make this molecule a strong contender in crystal engineering strategies. This prompted us in selecting this molecule for co-crystallization experiments with ALP.

The asymmetric unit of the co-crystal of BORA with ALP consists of a disordered water and two molecules each of the API and BORA. A noncentrosymmetric dimer is established between two symmetry independent boric acid molecules through O[BOND]Hequation imageO (Hequation imageO, 1.87 and 1.89 Å) hydrogen bonds. This dimer in turn interacts with neighboring units through O[BOND]Hequation imageO (Hequation imageO, 1.83 Å) hydrogen bonds to form a BORA tape, as shown in Figure 8. ALP molecules on both sides are held to the BORA tape through two distinct recognition patterns (Fig. 8A). The API in turn interacts with a symmetry related unit via a water molecule, making use of N2 (Fig. 8B). Thus, two distinct recognition patterns (synthon VI and VII) exist on the two sides of the acid tapes. The orientations of the hydroxy functionalities of the BORA units seem to play a key role in synthon formation and structure stabilization. Compared with the threefold symmetry observed in its native structure, the BORA units lack any symmetry.33

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Figure 8. Crystal structure of co-crystal, 10 and the representation of synthons VI and VII.

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Co-Crystals of Alprazolam with Boronic Acids, 11 and 12

The utility of boronic acids in noncovalent synthesis has not been studied extensively, although this class of compounds have been efficiently employed in organic synthesis as chemical building blocks and intermediates.34, 35 Further, pharmaceutical co-crystals involving boronic acids are unknown in the literature. To evaluate the utility of boronic acids in the preparation of pharmaceutical co-crystals, ALP was taken for co-crystallization with BDBA and HPBA.

In the co-crystal of BDBA with ALP, 11, the boronic acid group exhibits a syn–syn conformation. The boronic acid bridges symmetry independent ALP units through noncentrosymmetric O[BOND]Hequation imageN (Hequation imageN, 2.01, 2.05, and 2.13 Å) hydrogen bonds (synthon VIII), resulting a three-membered supramolecular aggregate (Fig. 9).

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Figure 9. Three-molecule supramolecular ensemble formed by BDBA and ALP in co-crystal, 11.

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In co-crystal, 12, formed by HPBA and ALP, the co-operative influence of the boronic acid and hydroxyl functionalities, yields a four-membered cyclic recognition unit. The boronic acid group exhibits a syn–syn conformation and forms noncentrosymmetric O[BOND]Hequation imageN (Hequation imageN, 2.00 and 2.20 Å) hydrogen bonds with the triazole ring. The p-hydroxy group makes an O[BOND]Hequation imageN (Hequation imageN, 1.94 Å) hydrogen bond with N7 of the second ALP, which in turn interacts with another boronic acid, forming a cyclic aggregate (Fig. 10). Adjacent cyclic units are stabilized by a Type-I Clequation imageCl (Clequation imageCl, 3.57 Å) interaction.

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Figure 10. Co-crystal formed by HPBA with ALP to show the four-molecule ensemble of acid and hydroxyl functionalities and the Clequation imageCl interactions formed between these units.

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Thus, in co-crystals 11 and 12, the noncentrosymmetric cyclic recognition patterns formed by the boronic acid functionality and the triazole heteroatoms (synthon VIII) are the same confirming the reliability of this synthon.

Co-Crystals of Alprazolam with Phenols, 13 and 14

To evaluate the recognition patterns exhibited by hydroxyl groups, co-crystals of alprazolam with HQ and TCP were studied. With HQ, the API yielded a 2:1 co-crystal, 13, wherein, a three-membered centrosymmetric arrangement is formed with O[BOND]Hequation imageN (Hequation imageN, 1.99 Å) hydrogen bonds (synthon IX), as shown in Figure 11. The resulting unit is extended with centrosymmetric Clequation imageπ (Clequation imageπ, 3.35 Å) interactions.

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Figure 11. Co-crystal 13 to show the three-molecule recognition unit and Clequation imageπ interactions.

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In contrast to the three-molecule supramolecular aggregate in 13, a cyclic tetramer entity is formed in the co-crystal, 14 of ALP with TCP. The hydroxyl group of TCP makes O[BOND]Hequation imageN (Hequation imageN, 2.03 Å) and C[BOND]Hequation imageO (Hequation imageO, 2.50 Å) hydrogen bonds with two ALP units in a co-operative manner (Fig. 12a). The adjacent cyclic units are held together by Type-II Clequation imageCl interactions (Clequation imageCl, 3.49 Å) to form extended chains (Fig. 12b).36

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Figure 12. (a) Four-molecule cluster formed in the TCP and ALP co-crystal, 11. (b) Type-II Clequation imageCl interactions.

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A Comparative Evaluation of Synthons

From a collective evaluation of the supramolecular heterosynthons observed in the co-crystals of alprazolam with carboxylic acids, boric acid, boronic acids, and phenols, it is seen that the triazole ring plays a pivotal role in synthon formation. The aromatic carboxylic acids exhibit three distinct heterosynthons (I, II, and III) depending upon the substituent and its position. Co-crystals, 1, 2, and 6 (with BA, ABA, and 35DFB) exhibit synthon I, as against synthon II which is observed in co-crystals 4 and 5. A charged interaction (synthon III) is observed in the molecular complex of 26DHB and ALP. However, the reasons for the adoption of one or the other synthon are still elusive. A unique heterosynthon (synthon IV), linking the hydroxyl group and water molecule, exists in co-crystal 4.

In the co-crystals of ALP with aliphatic dicarboxylic acids, OA, FA, and SA, lattice water plays a key role in the cyclic tetramer (synthon V) formation and indeed in the entire crystal packing. While the tetramer units are established by making use of the donor–donor property of water molecules, the extended network is brought about by the versatile hydrogen bond donor–acceptor properties of the water molecule. Thus, multipoint hydrogen bonding is clearly a dominant factor that governs hydrate formation.37 A detailed analysis of synthons present in various 1,2,4-triazole hydrates have been carried out and a wide range of recognition patterns have been identified.a It is interesting to note that of the several hydrogen bond patterns possible, the hydrate structures of alprazolam complexes have selectively opted the donor–donor nature of the interaction in establishing the tetramer. Two distinct heterosynthons (VI and VII) are present in the co-crystal of BORA. Boronic acid based assemblies show noncentrosymmetric synthon VIII, while phenols hydrogen bond to N1, forming synthon IX. Thus, in the present series, aliphatic dicarboxylic acids, boronic acids, and phenols give more reliable supramolecular heterosynthons with the triazole ring while the patterns exhibited by aromatic carboxylic acids seem to be dependent on the position and the nature of the substituents.

The recognition patterns observed in the crystal structures were evaluated as a function of the pKa values of the heteroatoms present on ALP. Whilst N1 and N2 exhibit almost similar pKa values (1.35 and 2.01, respectively), N4 is the most acidic with a pKa value of −8.33 (Fig. 13).38 Of all the heteroatoms present, N7 with the highest pKa value (3.31) is not involved in any repeating synthon in the crystal structures. This can be due to its more sterically demanding environment and also due to the lack of any functional groups that can make auxiliary hydrogen bonds. A CSD analysis of the hydrogen bond preferences in the benzodiazepine core clearly indicates the lesser activity at N7 in hydrogen bond formation. Of the 124 hits observed for the core, only 16 were found to be involved in the formation of N[BOND]Hequation imageN or O[BOND]Hequation imageN hydrogen bonds at N7.a The O[BOND]Hequation imageN interactions are made by small molecules such as water, acetic acid, SA, and FA and hint towards the steric effect in realizing the interactions. The pKa values of the two heteroatoms in the triazole ring being almost similar, it is difficult to make a distinction or hierarchy in the hydrogen bond forming abilities of these N-atoms. This in turn is apparent from the variability of hydrogen bond patterns exhibited in the crystal structures. In addition to the stable and strong hydrogen bond patterns present in the assemblies, several weak (C[BOND]Hequation imageO, C[BOND]Hequation imageN, C[BOND]Hequation imageCl) hydrogen bonds and (Clequation imageCl and Clequation imageN) halogen bonds also contribute to structure stabilization.

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Figure 13. The pKa values of the N-atoms present in alprazolam.

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The prediction of a co-crystal/salt formation which is generally based on the difference in the pKa values is difficult in the case of alprazolam. While the carboxylic acid–alprazolam molecular adducts have too small a difference in pKa for a clear prediction of salt formation, BORA, boronic acid, and phenols are less prone to form the salt although the ΔpKa values is large (>3). Salt formation in the case of 2,6-dihydroxybenoic acid is not surprising as a CSD analysis revealed that in almost all the multicomponent systems of 26DHB, the salt form is preferred. In the case of aliphatic carboxylic acids, as the interactions between the acid and triazole are mediated by lattice water molecules, the ΔpKa values cannot be considered in predicting the salt/co-crystal formation. This is clearly evident in the case of OA–alprazolam molecular complex, as a carboxylic acid with pKa value similar to that of 26DHB has yielded a co-crystal.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

The structures of a series of co-crystals of the API alprazolam have been determined, and the heterosynthons present in the assemblies have been analyzed. The present study is the first systematic evaluation of heterosynthons of 1,2,4-triazole. The structures exhibit various hydrogen bond patterns depending upon the coformer used for the studies. Although the synthons existing in co-crystals of aromatic carboxylic acids can be understood on the basis of recognition between complementary functional groups, the observed deviations cannot be predicted. It may be assumed that the disparity in recognition patterns is a function of substitution and acidity of the substituents. A tetramer supramolecular synthon involving lattice water constitutes the primary recognition unit in the complexes of aliphatic dicarboxylic acids. Boronic acid, in a syn–syn conformation, provides an appropriate orientation for forming hydrogen bonds. In the phenol co-crystals, the hydroxyl group acts as a donor and forms hydrogen bonds with the triazole heteroatoms.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

S.V. and Y.A. thank the DST, New Delhi for the award of a Young Scientist fellowship. G.R.D. thanks the DST for the award of a J.C. Bose fellowship. We thank the Rigaku Corporation, Tokyo, for their support.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EXPERIMENTAL
  5. RESULTS AND DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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