Polymorphic Anhydrous Cocrystals of Gallic Acid and Acetamide from

May 21, 2012 - Polymorphic Anhydrous Cocrystals of Gallic Acid and Acetamide from Methanol: Pointers toward a Stable Cocrystal Form. Ramanpreet Kaur a...
8 downloads 20 Views 2MB Size
Download PDF
Communication pubs.acs.org/crystal

Polymorphic Anhydrous Cocrystals of Gallic Acid and Acetamide from Methanol: Pointers toward a Stable Cocrystal Form Ramanpreet Kaur and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *

ABSTRACT: Polymorphic anhydrous cocrystals generated from a methanolic solution of gallic acid monohydrate and acetamide are shown to convert to the stable form II on complete drying, and the pathway to the stable form is explained on the basis of the variability in the hydrogen bonding patterns followed by theoretical calculations.

T

pharmaceuticals. In most cases, the polarity associated with the solvent9−11 of crystallization appears to dictate the packing motifs and the conformational preferences of the participating molecules. Indeed, the multimorphic cocrystals reported so far in the literature are from different polarity solvents, and most of these are conformationally guided. So far to our knowledge there has been no report of multimorphic modifications of anhydrous cocrystals generated from the same solvent of crystallization. In this Communication, we report five anhydrous cocrystal forms of gallic acid and acetamide obtained from the same solvent system (laboratory methanol) and we address issues related to their stability. Since there is no conformational flexibility associated with the coformers, the polymorphism is entirely governed by variations in the hydrogen bonding schemes of the coformers in the crystal lattice. It is noteworthy that none of the five forms are hydrated though one of the participating coformers; gallic acid is monohydrated. All structures are determined at 110 K by single crystal XRD, and the residual densities do not indicate any significant unaccounted density (Supporting Information TS1). The two components gallic acid monohydrate and acetamide (1:1 w/w %) were ground into a fine powder, and methanol was used as a solvent of crystallization. In general, slow evaporation resulted in concomitant crystals with different morphologies identified as form I and form III which could be separated under a polarizing microscope from the mother

he importance of identifying cocrystal formers in terms of the functionalities which offer intra- and intermolecular building blocks has been recognized and categorized in recent years. The outcome of such an analysis becomes complicated with the occurrence of polymorphism and the presence of hydration in either or both components. Several recent examples in the literature1,2 address these issues, but there is no clear indication toward the identification of a stable polymorphic cocrystal. Gallic acid (3,4,5-trihydroxybenzoic acid; Scheme1) monohydrate, with its multifunctional groups Scheme 1. (a) Gallic Acid (3,4,5-Trihydroxybenzoic Acid) and (b) Acetamide

represented by carboxylic acid and phenols, displays several polymorphic modifications.3 Indeed, at least four polymorphic forms have been identified so far3−5 of gallic acid monohydrate, whereas acetamide (Scheme1), the coformer, displays two polymorphic modifications.6,7 The potential hydrogen bonding patterns dominating the cocrystal formation may vary with the polarity of the solvents used in crystallization, the pKa values, and other crystallization conditions.8 However, in cases where cocrystallization results in various polymorphs, identification of the stable form becomes crucial, particularly in the context of © 2012 American Chemical Society

Received: April 19, 2012 Revised: May 21, 2012 Published: May 21, 2012 2744

dx.doi.org/10.1021/cg300536n | Cryst. Growth Des. 2012, 12, 2744−2747

Crystal Growth & Design

Communication

Figure 1. (a) Route map of the formation of all forms with pathways leading to the final stable 1:3 complex; morphologies of (b) forms I (blue circle) and III (red circle) and of (c) form II.

The prominent features in the packing are the presence of acid−amide heterodimers formed by the carboxylic acid moiety with the amide moiety. The dimers are linked via hydrogen bonds involving phenolic groups, resulting in a tetrameric motif (Figure 2). An additional π−π interaction (distance = 3.455 Å) formed between the adjacent layers of the gallic acid motifs provides further stability to the overall packing.

liquor (methanol). However, in two separate crystallization experiments under similar conditions, two new polymorphs (forms IV and V) were harvested independently from a methanol solution. All these forms represent a 1:1 cocrystal of gallic acid and acetamide with no hydration. Crystals of all forms were dipped in paratone oil before mounting for data collection. These crystals remain stable and yield high quality diffraction data even after storage for over two weeks, except for form IV, whose data quality deteriorates. On complete evaporation of the solvent in all these cases, the resulting crystalline product is form II, which is a 1:3 cocrystal. However, in only one isolated experiment, form IV was obtained, and repeated attempts to reproduce form IV were not successful (hence the ? sign in Figure 1a). Interestingly, form II could be crystallized independently from a solution in THF. It must be mentioned that cocrystallization experiments using anhydrous gallic acid (generated on overnight heating of the monohydrate at 85 °C) with acetamide in methanol resulted in the formation of concomitant forms I and III. Figure 1a gives a route map to the formation of all forms of the cocrystal, and parts b and c of Figure 1 show the concomitant forms I and III and the crystals of the stable form II, respectively. Crystals of form I (Figure 1b) are block shaped and belong to a monoclinic space group P21/c with Z = 4. The asymmetric unit represents a 1:1 complex of gallic acid and acetamide with the water of hydration completely removed from the cocrystal.

Figure 2. Tetramer formation by acid−amide heterodimer in form I (formed between the gallic acid and acetamide moieties). 2745

dx.doi.org/10.1021/cg300536n | Cryst. Growth Des. 2012, 12, 2744−2747

Crystal Growth & Design

Communication

Figure 3. (a) Homodimer formation between gallic acid and acetamide molecules in form III; (b) homosynthons of gallic acid and acetamide (lie in one plane) in form IV.

Figure 4. Unusual phenolic dimer (circled) and the heterodimer formation between acid and amide moieties in form V.

Figure 5. Sheetlike structure in form II generated via homodimers (found in forms III, IV) and heterodimers (found in forms I, V).

Form III, crystallizing in a monoclinic space group P21/n, presents an entirely different packing motif with the formation of a carboxylic acid dimer synthon associated with the gallic acid moiety and an amide homodimer synthon formed between acetamide moieties (Figure 3a). Form IV, which also crystallizes in monoclinic space group P21/n, is similar to form III in all respects, except the assembly of homosynthons of gallic acid as well as acetamide lie in one plane (Figure 3b). It is of interest to note that this feature brings in the importance of dipolar interactions resulting in an antiparallel motif (II) type suggested by Allen et al.,12 leading to the further stabilization of the supramolecular assembly. The structure of form V represents an unusual homodimer formed by gallic acid motifs involving meta- and para-phenolic groups. Such a homodimer has not been observed in any of the earlier reported structures of gallic acid and its cocrystals (Figure 4). The dominance of heterodimer between gallic acid and acetamide in this form

appears to take preference over the formation of the carboxylic acid dimer. Form II is a 1:3 complex formed between acid−amide molecules consisting of both homo- and heterodimer synthons, resulting in a compact packing. The crystal structure is triclinic with the space group P1̅, Z = 2, and it contains three acetamide moieties and one gallic acid moiety in an asymmetric unit. Figure 5 shows the packing diagram of form II. The yellow, blue motifs of acetamide form homodimers (found in forms III and IV) while the red moiety links to the carboxylic acid unit of gallic acid (green) to form heterodimers (found in forms I and V). This generates a sheetlike structure represented by interlinked homodimers and heterodimers of acetamide sandwiched between the sheets. It is to be noted that the addition of two more units of acetamide in the stable form (form II) offers stability and allows for the variability in hydrogen bonding schemes depending on whether the packing motif in the intermediate phase is a 2746

dx.doi.org/10.1021/cg300536n | Cryst. Growth Des. 2012, 12, 2744−2747

Crystal Growth & Design

Communication

Table 1. Various Lattice Energy Values of All Five Forms comp

E(bulk)a (hartrees)

E(mol,bulk)a (hartrees)

E(mol,ghost)a (hartrees)

ΔE(cond)a (hartrees)

BSSEa (hartrees)

E(lattice energy)a (hartrees)

E(lattice energy)a (kcal/ mol)

1 2 3 4 5

−3421.33026 −2547.17417 −3421.31969 −3421.32701 −3421.33121

−855.24632 −1273.47959 −855.24495 −855.23894 −855.24274

−855.25464 −1273.48768 −855.25365 −855.24728 −855.25149

−0.08625 −0.10749 −0.08497 −0.092813 −0.09006

0.00832 0.00809 0.00870 0.00834 0.00875

−0.07793 −0.09941 −0.07627 −0.08447 −0.08131

−48.90182 −62.37759 −47.86016 −53.00574 −51.04176

a

See the Supporting Information

■

homodimer or a heterodimer. Thus, both setsform I, V and forms III, IVare amenable for a facile conversion to form II. A confirmation to these conversion pathways has been provided from powder diffraction studies which represent the bulk of the material (see Supporting Information S1). The conversion of the concomitant forms to form II on complete evaporation of the solvent is a clear indication of the metastable nature of forms I and III. It may be conjectured that forms IV and V also might follow a similar pathway. Further support to this observation is provided on the basis of lattice energy calculations carried out using CRYSTAL0913 package 45 at the DFT(B3LYP) level of theory using the 6-31G** basis set. The calculations were performed using the coordinates from the experimental structures determined at 110 K. The coordinates of hydrogen atoms were fixed on the basis of the average neutron bond lengths14 in all these calculations. Table 1 clearly establishes that form II is the energetically most favored form. The lattice energy values of form I and form III (−48.90182 and −47.86016 kcal/mol, respectively) are close, indicating their preference to crystallize concomitantly. In conclusion, the formation of several polymorphs resulting from the same solvent which convert to a stable configuration with a different stoichiometry is indicative of pathways for the formation of a final stable form. Crystallization proceeds through intermediate metastable forms either via the heterodimers dominant forms I and V or the homodimers dominant forms III and IV, eventually being driven toward the formation of form II, containing both homo- and heterodimers.

■

REFERENCES

(1) Varughese, S.; Desiraju, G. R. Cryst. Growth Des. 2010, 10, 4184− 4196. (2) Clarke, H. D.; Arora, K. K.; Bass, H.; Kavuru, P.; Ong, T. T.; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 2152−2167. (3) Clarke, H. D.; Arora, K. K.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2011, 11, 964−966. (4) Jiang, R. W.; Ming, D. S.; But, P. P. H.; Mak, T. C. W. Acta Crystallogr. 2000, C56, 594−595. (5) Okabe, N.; Kyoyama, H.; Suzuki, M. Acta Crystallogr. 2001, E57, 0764−0766. (6) Hamilton, W. C. Acta Crystallogr. 1965, 18, 866. (7) Frederic, S.; Harker, D. J. Am. Chem. Soc. 1940, 62, 2008−2019. (8) Braga, D.; Palladino, G.; Polito, M.; Rubini, K.; Grepioni, F.; Chierotti, M. R.; Gobetto, R. Chem.Eur. J. 2008, 14, 10149−10159. (9) Marlena, G.; Krawczuk, A.; Stadnicka, K. Acta Crystallogr. 2008, B64, 623−632. (10) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2009, 11, 1823−1827. (11) Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K. Cryst. Growth Des. 2012, 12, 485−494. (12) Allen, F. H.; Baalham, C. A.; Lommerse, J. P. M.; Raithby, P. R. Acta Crystallogr. 1998, B54, 320−329. (13) Saunders, V. R.; Dovesi, R.; Roetti, C.; Orlando, R.; Wilson, C. M. Z.; Harrison, N. M.; Doll, K.; Civalleri, B.; Bush, I.; D’Arco, P.; Llunell, M. User’s Manual; University of Torino: Torino, 2009. (14) Allen, F. H.; Bruno, I. J. Acta Crystallogr. 2010, B66, 380−386.

ASSOCIATED CONTENT

S Supporting Information *

Additional figures; table of crystallographic data; table of intraand intermolecular interactions; and crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS R.K. thanks IISc for a fellowship. T.N.G.R. thanks DST for the award of a J.C. Bose fellowship. We thank the DST, India, for the funding under DST-FIST (Level II) for the X-ray diffraction facility at SSCU, IISc, Bangalore, and Rumpa Pal for a discussion related to lattice energy calculations using CRYSTAL09. 2747

dx.doi.org/10.1021/cg300536n | Cryst. Growth Des. 2012, 12, 2744−2747