Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic Acid

Article pubs.acs.org/crystal

Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic Acid Vânia André,† M. Teresa Duarte,*,† Dario Braga,‡ and Fabrizia Grepioni‡ †

Centro de Química Estrutural, DEQ, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal ‡ Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy S Supporting Information *

ABSTRACT: Reaction of the antibiotic 4-aminosalicylic acid with ammonia yields three polymorphic forms of the ammonium 4-aminosalicylate salt [NH4][C6H3NH2OH(COO)]. When the reaction is conducted in solution, the three polymorphs are obtained concomitantly, while liquidassisted grinding and solid−gas reaction result in the formation of pure Form II. The three polymorphs are characterized by different patterns of hydrogen bonding interactions between the structurally rigid anions and the ammonium cations. Solid products were characterized by single-crystal and powder X-ray diffraction, variable temperature powder diffraction, calorimetric techniques (DSC and TGA), and hot-stage microscopy (HSM).

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INTRODUCTION 4-Aminosalicylic acid (ASA), a nonsteroid anti-inflammatory drug (NSAID),1 is an antibiotic that has been used since the 1940s in the treatment of tuberculosis. It has also shown to be safe and effective in the treatment of inflammatory bowel diseases, namely, distal ulcerative colitis2,3 and Crohn’s disease.4 After oral administration, ASA is rapidly absorbed in the upper intestinal tract before it reaches the colonic sites, decreasing its suitability for the treatment of active ulcerative proctitis or left sided ulcerative colitis.2,5 To overcome this problem, azo6 and phenol-class azo derivatives7 have been synthesized in the pursuit of a better ASA prodrug against inflammatory bowel disease. ASA conjugates of ethylenediaminetetraacetic acid (EDTA) chelating to Cu(II) were reported as potential antiinflammatory pro-drugs and as promising drugs with anticancer properties, due to proteolytic attack resistance.4

Only one crystal form of this active pharmaceutical ingredient has been reported in the literature, for which single crystal data were extracted from the CSD.11,12 The crystal packing of this form is characterized by a S(6) intramolecular synthon between the hydroxyl and carboxyl groups [O− HOH···OCOOH], the R22(8)·carboxyl−carboxyl homosynthon [O−HCOOH···OCOOH], and a N−H···OOH interaction that gives rise to a three-dimensional (3D) network (Figure 1). Organic carboxylic acids have received considerable attention in crystal engineering owing to their potential for the formation of hydrogen bonds and their predisposition to form a dimeric carboxyl···carboxyl homosynthon that generates self-complementary hydrogen-bonding interactions in their crystal structures.13,14 However, in the presence of an N-containing heterocyclic moiety, a robust O−HCOOH···Npyridine heterosynthon is preferentially shaped in the resultant multicomponent crystal form (co-crystal, salt, molecular salt, solvate).15−17 Two ASA co-crystals have been reported with sulfadimidine18 and with a codified compound reported as VX-950,19 as well as a solvate with dioxane and molecular salts with morpholine and piperazine.20 Moreover, copper(II)-p-aminosalicylate complexes with diamine ligands21 and ASA metalcoordination and hydrogen-bonded networks with silver22 were reported. In 2011, new supramolecular networks, more specifically, a hydrated molecular salt and a complex with Co(II) have been disclosed involving ASA and 4,4′-bipyridine.23 The formation of a complex with polystyrene for application in

A novel ASA−konjac glucomannan (KGM) pH-sensitivity complex was synthesized based on the advantage of the biodegradability of KGM.8 KGM is a high-molecular weight polysaccharide extracted from the tubers of the amorphophallus konjac plants that has received recognition for reducing the risk of developing diabetes and heart diseases.9 The binding number indicates a 1:1 complexation of the drug ASA with the sugarring of the KGM chain.10 © XXXX American Chemical Society

Received: February 27, 2012 Revised: April 23, 2012

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dx.doi.org/10.1021/cg300284z | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Crystal packing of ASA11,12 showing (a) the pattern of intra- and intermolecular hydrogen bonds at work in the crystal and (b) a view of the packing along the crystallographic a-axis. that were added whenever the previous drops had dried. This synthetic method yielded pure Form II, as determined by XRPD. Grinding of HCl and Ammonium Salts (1:1). 0.091 mmol of ASA·HCl salt obtained as previously described12 were manually ground for 5 min with 0.102 mmol of a mixture of the three forms of [NH4][C6H3NH2OH(COO)]. This resulted in the formation of pure ASA in its known form and NH4Cl, as established by XRPD. Single Crystal X-ray Diffraction. Data collection for polymorphs I and II was carried out with an Oxford X’Calibur S CCD diffractometer equipped with a graphite monochromator (Mo−Kα radiation, λ = 0.71073) and operated at room temperature. For polymorph III, data collection was carried out in a Bruker AXSKAPPA APEX II diffractometer with graphite-monochromated radiation (Mo Kα, λ = 0.71073 Å), at room temperature. The X-ray generator was operated at 50 kV and 30 mA, and the X-ray data collection was monitored by the APEX2 program. All data were corrected for Lorentzian, polarization, and absorption effects using SAINT32 and SADABS33 programs. Crystals suitable for X-ray diffraction study were mounted on a loop with Fomblin protective oil. SIR9734 and SHELXS-97 were used for structure solution, and SHELXL-9735 was used for full matrix least-squares refinement on F2. These three programs are included in the package of programs WINGX-Version 1.80.05.36 MERCURY 2.237 was used for packing diagrams. PLATON38 was used to calculate hydrogen bonding interactions. All non-hydrogen atoms were refined anisotropically. HCH and HOH atoms were added in calculated positions and refined riding on their respective C and O atoms. Crystals of ASA−ammonium salt form III were of bad quality; the ratio reflections/variables is rather low, hindering a better refinement of the crystal structure. X-ray Powder Diffraction (XRPD). XRPD data for solution and gas−solid diffusion experiments were collected with a Panalytical X’Pert Pro instrument equipped with an X’Celerator detector and an Anton Paar TTK 450 low temperature camera. A Cu anode was used as X-ray source at 40 kV and 40 mA. Data for grinding experiments were collected in a D8 Advance Bruker AXS θ-2θ diffractometer, with a copper radiation (Cu Kα, λ = 1.5406 Å) and a secondary monochromator, operated at 40 kV and 30 mA. The program Mercury 2.223 was used for calculation of X-ray powder patterns on the basis of the single crystal structure determinations. The identity of single crystals and the bulk material obtained from solution and grinding/kneading experiments was always verified by comparison of the calculated and observed X-ray powder diffraction patterns. Hot-Stage Microscopy (HSM). Hot stage experiments were carried out using a Linkam TMS94 device connected to a Linkam LTS350 platinum plate. Images were collected, via the imaging software Cell, with an Olympus BX41 stereomicroscope. Crystals were placed within an oil drop to allow a better visualization of solvent or decomposition products release. Differential Scanning Calorimetry (DSC). Calorimetric measurements were performed using a Perkin-Elmer Diamond equipped with a model ULSP90 intracooler. Temperature and enthalpy calibrations were performed by using high purity standards (n-decane,

the analysis of natural water samples was also recently published.24 Very recently, two drug−drug multicomponent crystal forms of ASA have been disclosed with the antituberculosis active pharmaceutical ingredients (APIs) isoniazid and pyrazinamide. With isoniazid, a 1:1 co-crystal was formed and with pyrazinamide a 1:1 monohydrate molecular salt was synthesized. In both systems the O−HCOOH···Npyridine hydrogen bond is found, as expected.25 In this paper we report the preparation and characterization of three polymorphic modifications, which we call forms I, II, and III, of the molecular salt [NH4][C6H3NH2OH(COO)]. Form II was obtained by liquid-assisted grinding (LAG)26,27 and solid vapor diffusion, while conventional solution methods yielded mixtures. Polymorphism is a widespread phenomenon observed in most pharmaceutical ingredients, and it is well established that different polymorphs frequently display different physical, chemical, mechanical, and thermal properties that can deeply affect the bioavailability, stability, and other performance characteristics of the drug.28 These studies aim to rationalize a path for the development of new acceptable pharmaceutical species of ASA, by using different synthetic techniques and different experimental conditions. The knowledge of the type of interactions favoring the formation of salts of this API can then be applied in a future work to the synthesis of crystal forms with other generally recognized as safe (GRAS) co-formers, with the intent of obtaining formulations characterized by better performance.29−31

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EXPERIMENTAL SECTION

Synthesis. All reagents were purchased from Sigma (pa reagent grade) and used without further purification. Solution Technique. 200 mg of ASA were dissolved in 4 mL of a 1:1 (v/v) basic solution of acetone and ammonia 25%, heated to boiling temperature, and left to cool and crystallize at room temperature. Crystals were formed after 1 day, corresponding to a mixture of Forms II and III of [NH4][C6H3NH2OH(COO)], as proven by X-ray powder diffraction (XRPD). Similar results were attained using solutions of ammonia/ethanol and ammonia/chloroform in analogous conditions. A room temperature solution of ammonia and acetone left to crystallize yielded a mixture of the three polymorphic forms reported herein, from which a single crystal of Form I was selected for X-ray structural determination. Furthermore, 100 mg of ASA were dissolved in 2 mL of ammonia 25% and left to crystallize at room temperature. Crystals of the three forms were obtained after 3 days. Gas−Solid. 200 mg of solid ASA were placed inside a covered box with ammonia 25% in the bottom, not in direct contact with the solid. After 3 days pure Form II was obtained, as shown by XRPD. Liquid-Assisted Grinding. 200 mg of ASA was manually ground for 10 min in an agate mortar with a few drops (40 μL) of ammonia 25% B



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Table 1. Crystallographic Details for ASA/Ammonium Salts Forms I, II, and III I chemical formula Mr T (K) morphology, color crystal size/mm crystal system space group a (Å) b (Å) c (Å) β (°) V (Å3) Z d (mg·m−3) μ (mm−1) θmin (°) θmax (°) reflections collected/ unique Rint GOF threshold expression R1 (obsd) wR2 (all)

II

III

C7H6NO3·NH4 170.17 293 plate, colorless 0.15 × 0.08 × 0.03 orthorhombic P212121 4.7638(5) 6.2178(5) 26.844(3) 90 800.15(13) 4 1.413 0.112 3.03 28.50 3060/1047

C7H6NO3·NH4 170.17 293 block, colorless 0.24 × 0.18 × 0.06 orthorhombic P212121 4.8050(4) 12.0290(7) 14.5230(9) 90 839.42(10) 4 1.347 0.106 2.80 25.34 2858/1452

C7H6NO3·NH4 170.17 293 plate, colorless 0.10 × 0.06 × 0.02 monoclinic P21/n 8.736(6) 3.7600(8) 29.484(8) 94.97(1) 964.8(5) 4 1.172 0.093 4.01 25.34 7094/1636

0.0595 0.906 >2σ(I)

0.0388 0.863 >2σ(I)

0.1568 1.202 >2σ(I)

0.0564 0.0556

0.0341 0.0639

0.1805 0.4694

Figure 3. Melting and recrystallization experiments conducted for polymorphic screening: (top) slow cooling after melting; (middle) quenching after melting; (bottom) 3-aminophenol pattern calculated from SCXRD.

fast (quenching) or slow recrystallization. Most experiments were conducted under ambient conditions, but also high and low temperature conditions were tested. In the solvent screening at ambient conditions a new dioxane solvate and a morpholine molecular salt were obtained, and their full characterization was previously reported by us.20 In all the other solvents no new forms of ASA were detected (Figure 2). Slurry experiments with water, THF, and acetonitrile yielded the known form of ASA, indicating that this is the thermodynamically stable form at ambient conditions. There is no evidence of the formation of crystalline hydrates, but mainly amorphous forms were obtained in DMSO, water, and water/ethanol solutions. Additional polymorph screening was performed using melting and recrystallization experiments. Two different approaches were used: slow cooling to room temperature after melting and fast cooling by quenching in liquid nitrogen. In both experiments, decomposition of ASA into 3-aminophenol was observed, in agreement with what has been previously reported (Figure 3).39 Salt Screening: Three Polymorphic Modifications of the Molecular Salt [NH4][C6H3NH2OH(COO)]. The preparation of salts was attempted using hydrochloric acid, sodium hydroxide, and ammonia. The experiments with the acid resulted in the formation of the already reported hydrochloride salt;12 experiments with NaOH were done in ethanol or water solutions and in both cases the sodium salt was detected as an amorphous phase. After waiting for 1 day to 1 week, HCl was added to the previous solutions and precipitation took place; the precipitate was filtered off and always checked by XRPD and proved to be the ASA hydrochloride salt. On the other hand, experiments with ammonia were successful, and three new polymorphic forms of the molecular salt [NH4][C6H3NH2OH(COO)] were obtained. All forms appeared concomitantly from solution, and the solid mixtures, after solvent evaporation, were stable and the proportion of forms in the mixture was maintained over time. On the other hand, pure Form II was obtained when the reaction was conducted in the solid state (solid−gas and liquid-assisted grinding). Forms I and II crystallize in the P212121 orthorhombic space group, and both asymmetric units contain one ammonium cation and one [C6H3NH2OH(COO)]− anion. Form III has a

benzene, and indium). Samples (3−5 mg) were placed in aluminum open pans. Calorimetric measurements were performed using a Setaram DSC121. Thermogravimetric Analysis (TGA). TGA analyses were performed with a Perkin-Elmer TGA-7. Each sample, contained in a platinum crucible, was heated in a nitrogen flow (20 cm3 min−1) at a rate of 5 °C min−1, up to decomposition. Sample weights were in the range 5−10 mg. Combined TG-DSC measurements were carried out on a SETARAM TG-DTA 92.

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RESULTS AND DISCUSSION Polymorph Screening. After a careful characterization of the starting material, a thorough polymorphic screening was performed for 4-aminosalicylic acid using different techniques: grinding, solvent screening, slurrying, and melting followed by

Figure 2. XRPD patterns for the products of solvent screening at ambient conditions. C



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Table 2. Hydrogen Bond Details for [NH4][C6H3NH2OH(COO)] Forms I, II, and III structure I

II

III

sym op

D−H···A

d(D−H) (Å)

d(D···A) (Å)

(DĤ A) (deg)

x, y, z 1/2+ x, 1/2 − y, −z 1 + x, 1 + y, z −x, −1/2+ y, 1/2 − z x, y, z 1 + x, y, z 1 − x, 1/2 + y, 1/2 − z x, y, z 1/2 − x, 1 − y, 1/2 + z 1/2+x, 1/2-y, 2-z 1 − x, y, z 3/2 − x, 1 − y, 1/2 + z 1/2 − x, 1 − y, 1/2 + z 1/2 − x, 1 − y, 1/2 + z 1 − x, 1/2 + y, 3/2 − z x, y, z 3/2 − x, 1/2 + y, 1/2 − z −1 + x, 1 + y, z 1 − x, 1 − y, −z x, y, z x, 1 + y, z 1 − x, −y, −x −1 + x, y, z

O−HOH···OCOON−HASA···OOH N−HASA···OOH N+−Hcation···OCOON+−Hcation···OCOON+−Hcation···OCOON+−Hcation···OCOOO−HOH···OCOON−HASA···OCOON−HASA···NASA N+−Hcation···OOH N+−Hcation···OCOON+−Hcation···OCOON+−Hcation···OCOON+−Hcation···OCOOO−HOH···OCOON−HASA···NASA N+−Hcation···OCOON+−Hcation···OCOON+−Hcation···OOH N+−Hcation···OOH N+−Hcation···OCOON+−Hcation···OCOO-

0.82 0.88(3) 0.88(3) 0.92(2) 0.94(4) 0.90(3) 0.94(3) 0.82 0.92(2) 0.89(2) 0.91(2) 0.96(2) 0.95(3) 0.95(3) 0.95(2) 0.82 0.86 0.90(4) 0.90(4) 0.90(8) 0.90(8) 0.9(1) 0.9(1)

2.552(4) 3.221(5) 3.476(6) 2.849(5) 2.839(6) 2.798(6) 2.749(5) 2.518(2) 3.004(2) 3.151(3) 2.855(2) 2.792(3) 3.167(2) 2.911(3) 2.775(2) 2.51(1) 3.27(1) 3.07(1) 3.06(2) 3.13(2) 2.99(2) 2.99(2) 2.888(19)

147 153(4) 173(2) 162(3) 164(4) 171(3) 176(2) 148 173(2) 163(2) 160(2) 162(2) 143(3) 156(3) 161(2) 146 162 127(10) 114(10) 134(15) 116(14) 147(10) 107(9)

Figure 4. Hydrogen bonding interactions in [NH4][C6H3NH2OH(COO)] Form I: (a) the double chain formed by the [C6H3NH2OH(COO)]− anions in a view along the a-axis; (b) anionic chains in a view along the b-axis, intercalated by cations (blue spheres); (c) packing in a view along the c-axis showing the rotation of the [C6H3NH2OH(COO)]− lines (ammonium cations and hydrogen atoms not involved in the represented hydrogen bonds have been omitted for clarity); (d) detailed view of the hydrogen bonds between the anion and the ammonium cations (intramolecular O− H···O bond in blue).

interactions); X-ray single crystal and powder X-ray diffraction data are compared for a characterization of the bulk material in all cases. Thermal characterization of each form was performed and will be discussed. Crystal Structure of [NH4][C6H3NH2OH(COO)] Form I. The amino group on the [C6H3NH2OH(COO)]− anion is

similar content in the asymmetric unit but displays a monoclinic symmetry crystallizing in the P21/n space group. The intramolecular hydrogen bond observed in the crystal structure of ASA is maintained in all the salt structures. The supramolecular arrangement of the three forms is described (see Table 2 for a list of relevant hydrogen bonding D



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Figure 5. Supramolecular arrangements in [NH4][C6H3NH2OH(COO)] Form II: (a) hydrogen bonded chains extending along the c-axis direction, (b) ammonium cations environment, and (c) a view of the packing down the c-axis.

Figure 6. Supramolecular arrangements for [NH4][C6H3NH2OH(COO)] Form III depicting: (a) the Nanion···Nanion interactions (b) the ladder-like arrangement showing the planes formed by pairs of [C6H3NH2OH(COO)]− anions, and (c) the R44(12) synthon identified by the pink circle, the R46(12) in the purple circle, and a void indicated by the blue circle.

view along the c-axis, it is clear that the lines that give rise to the double chains are rotated by 81.77° (Figure 4c). Each ammonium cation is linked to four different anions via charge-assisted N+−H···O hydrogen bonds with oxygen atoms belonging to carboxylate groups [N+cation···O−COO- 2.849(5), 2.839(6), 2.798(6), and 2.749(5) Å]; in turn, each anion is connected to four different ammonium cations: the oxygen atom involved in the intramolecular O−−H···OOH hydrogen bond is connected to one ammonium cation, while the second

involved exclusively in two hydrogen bonds with the hydroxyl groups of two adjacent anions [N−HASA···OOH 3.221(5) and 3.475(6) Å] (see Figure 4a). Thus the hydroxyl groups work both as acceptors from the amino group and donors in the intramolecular hydrogen bond [OOH···OCOO- 2.552(4) Å]. The N−HASA···OOH interactions are responsible for the formation of double chains along a and b directions; ammonium cations work as spacers between these double chains (Figure 4a,b). In a E



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Figure 7. Overlap of structures of [NH4][C6H3NH2OH(COO)] Form I (blue), II (magenta), and III (green). a) for the asymmetric unit; b) crystal packing. Figure 10. DSC and TGA for pure form II of [NH4][C6H3NH2OH(COO)].

c-axis direction, are interconnected through ammonium cations, each linked to four anions via N+−H···OOH [2.855(2) Å] and N+(H)···OCOO− [2.791(3), 2.911(3), and 2.775(2) Å] interactions. As always observed for these anions, also in Form II the intramolecular hydrogen bond is maintained [OOH···OCOO2.518(2) Å]. Crystal Structure of [NH4][C6H3NH2OH(COO)] Form III. In [NH4][C6H3NH2OH(COO)] Form III the amino group on the [C6H3NH2OH(COO)]− anion is exclusively involved in N−H···N hydrogen bonds with adjacent anions [Nanion···Nanion 3.27(1) Å]; therefore, its donor capacities are not completely fulfilled (Figure 6a). These contacts link each anion with two other equivalent anions, forming a ladder-like arrangement (Figure 6b). The hydroxyl and carboxylate moieties interact with ammonium cations via N+−H···OOH [3.13(2) and 2.99(2) Å] and N+−H···O−COO- [3.062(2), 2.99(2), 3.07(2), and 2.89(2) Å] contacts. The intramolecular hydrogen bond is again maintained [O−HOH···OCOO- 2.51(1) Å]. The combination of all these interactions gives rise to a supramolecular arrangement in which voids can be detected, in a view along the b, as well as the formation of R44(12) and R46(12) synthons (Figure 6c). Unlike what happens in ASA itself, both in I and II the amine moiety of ASA anion fulfils all its donor capacities. In I, the N− HASA···OOH interactions are similar to the N−HASA···OOH observed in ASA packing, but in I both hydrogens of NH2 are involved. On the other hand, in II none of the two interactions in which the amine moiety is involved is similar to the one observed in ASA. In III the amine moiety does not fulfill all its donor capacities, similar to what is observed in the ASA structure. The R22(8) synthon formed in ASA is disrupted in all these packings, due to formation of a carboxylate group and the competition with other active functions. In these structures the carboxylate moiety is mainly used to connect with the ammonium cations via charge-assisted N+−H···O−COO- hydrogen bonds, originating different synthons in the salts. The intramolecular synthon S(6) [O−H···OCOOH/COO-] is never disrupted in any of the salicylic acid derivatives and ASA crystal forms (ASA, ASA/sulfadimidine, and the multicomponent forms disclosed by our group) and, therefore, has shown once again to be the strongest synthon. Form III is the polymorph that presents a lower packing efficiency, with a packing coefficient of only 0.59. On the other

Figure 8. XRPD patterns for (from top to bottom) calculated Forms I, II, and III at 150 K; experimental acetone, chloroform, and ethanol solutions, gas−solid reaction and LAG with ammonia.

Figure 9. DSC and TGA results obtained for the bulk product containing the three forms of [NH4][C6H3NH2OH(COO)] obtained from solution.

oxygen atom takes part in a trifurcate hydrogen bond with three ammonium cations (Figure 4b). Ammonium cations alternate with anionic double chains (Figure 4d). Crystal Structure of [NH4][C6H3NH2OH(COO)] Form II. The hydrogen bonding pattern in crystalline Form II differs from the one observed for Form I, as each amine moiety on the anion is involved in interactions with only one carboxylate group on an adjacent anion and an amino group on a second anion [Nanion···OCOO- 3.004(2) Å, and Nanion···Nanion 3.151(3) Å] (Figure 5a); the resulting infinite chains, extending along the F



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Figure 11. Hot-stage microscopy images obtained with a crystal of Form I at 27, 109, 120, and 138 °C.

Figure 12. Hot-stage microscopy images obtained with a crystal of Form II at 25, 111, 123, and 134 °C.

Figure 13. Hot-stage microscopy images obtained with a crystal of Form III at 25, 109, 119, and 137 °C.

similar to the one observed in carbamazepine Form II.40 In the latter the VOID depended on the solvent used, while in ASA− ammonium salt Form III the VOID seems to be independent of the solvent (ethanol, acetone, chloroform). Crystallization might be induced by the presence of a solvent, not present in the structure and not detected in HSM (the only thermal characterization where isolated pure Form III was tested). Further comparisons of the three concomitant polymorphs point out that Forms I, II, and III have similar conformation, and their supramolecular arrangements are distinct due to the very different hydrogen bond patterns (Figure 7). Powder Diffraction, Grinding Experiments, and Thermal Behavior of [NH4][C6H3NH2OH(COO)] Forms I, II, and III. Crystallization from acetone and ethanol solutions systematically yielded concomitantly the three polymorphs, while from chloroform solutions only I and II were detected by XRPD. Only Form II was obtained as a pure phase, both by LAG and gas−solid reaction methods. Thermal Behavior of [NH4][C6H3NH2OH(COO)] Forms I, II, and III. Because of the impossibility of obtaining sufficient quantities of Forms I and II as pure forms, DSC and TGA measurements were performed on a mixture of the three forms and on pure Form II. Single crystals of the three forms were analyzed via hot stage microscopy. For a bulk mixture containing the three polymorphs, TGA data indicate the loss of ammonia between 75 and 120 °C. This loss is also observed in the DSC analysis that further shows an endothermic peak at approximately 138 °C, corresponding to the melting of ASA, immediately followed by decomposition. Pure II shows a similar behavior as do the mixtures of the three forms. HSM experiments were performed on single crystals of each of the three forms, revealing very similar behaviors. HSM is in agreement with DSC and TGA data, showing ammonia loss at temperatures around 100 °C and melting of pure ASA around 120−130 °C. To complete the thermal characterization of the bulk sample obtained from solution, -variable-temperature (VT)-XRPD was also performed on a mixture of the three forms. From this

Figure 14. XRPD-VT results for the bulk sample containing Forms I, II, and III obtained from an acetone solution.

hand, neutral ASA is the most efficient structure in terms of space filling, with a packing coefficient of 0.73. Forms I and II represent intermediate situations, with packing coefficients of 0.70 and 0.67, respectively. The low packing efficiency of Form III can be explained by a sort of a templating effect, somewhat

Figure 15. XRPD pattern resulting from manual grinding of ASA·NH4 and ASA·HCl salts (pink) compared with pure ASA (blue) and the NH4Cl pattern (gray). G



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Notes

technique it was possible to confirm the loss of ammonia and the transformation of all the salts into ASA. Grinding ASA Ammonium and Hydrochloride Salts. Using mechanochemistry26 to react the ASA ammonium salt with the ASA hydrochloride salt, the neutral API was obtained and the NH4Cl salt was formed (Figure 15). This is an example of a solid-state metathesis (SSM) process where the reaction was initiated by grinding. These fast solid state reactions that have been developed over the past two decades take advantage of the reaction enthalpy given out in a specific reaction, and the driving force behind them is the formation of stable byproducts. Typically in a SSM process a co-formed salt is obtained along with the desired product, the high lattice energy of the co-formed salt providing the driving force for the process.41,42

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge funding of the Project PTDC/QUI/ 58791/2004 and Ph.D. Grant SFRH/BD/40474/2007 to Fundaçaõ para a Ciência e Tecnologia. FG thanks MiUR for financial support (PRIN2008).

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CONCLUSIONS Preparation and characterization of, and control on crystal forms, i.e., solvates, salts, co-crystals and polymorphs, as well as of amorphous solid phases, has become one of the major issues of modern solid-state and materials chemistry.27,43−66 It is well-known that co-crystals and similar crystal derivatives are formed if the free-energy of the multicomponent system is lower than that of the crystalline components on their own.67 A large number of “extra” hydrogen bonding interactions, also reinforced by proton transfer and formation of molecular ions, helps in stabilizing the solid multi-component systems. As a result APIs are often commercialized as salts, with suitable counterions. ASA has been shown to be an API susceptible of forming solvates, co-crystals, and molecular salts. So far, only the hydrochloride ASA salt has been reported, in which the amino group on the API is protonated by HCl and becomes a cation. In the salts discussed herein, on the contrary, the proton transfer occurs from the carboxylic moiety of ASA to the base, resulting in formation of the [C6H3NH2OH(COO)]− anion. The proton transfer is reversible, as on heating ammonia is lost and the pure ASA is reobtained. This is also true for the chloride salt, but it has not been observed for the molecular salts previously reported by us with piperazine20 that show congruent melting. The three polymorphic modifications of [NH 4 ][C6H3NH2OH(COO)] are characterized by similar chargeassisted hydrogen bonds between the anions and the cations. The hydroxyl···carboxylate intramolecular interaction is a common feature in the three forms, but the assembly of the other donor/acceptor functions results in three distinct crystal packings, that is, three polymorphs. These forms appear concomitantly when acetone and ethanol solutions are used in the synthetic procedure, and only one of them, Form II, is obtained as a single phase by LAG and gas−solid reaction.

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ASSOCIATED CONTENT

* Supporting Information S

Crystallographic information files (CIF) are available for the three structures reported. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

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