Expanding the pool of multicomponent crystal forms of the antibiotic 4

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Expanding the pool of multicomponent crystal forms of the antibiotic 4-aminosalicylic acid: the influence of crystallization conditions Vania Andre, Oleksii Shemchuk, Fabrizia Grepioni, Dario Braga, and M. Teresa Duarte Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01075 • Publication Date (Web): 25 Oct 2017 Downloaded from http://pubs.acs.org on October 27, 2017

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Crystal Growth & Design

Expanding the pool of multicomponent crystal forms of the antibiotic 4aminosalicylic acid: the influence of crystallization conditions

Vânia Andréa*, Oleksii Shemchukb, Fabrizia Grepionib*, Dario Bragab, M. Teresa Duartea a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1,

1049-001 Lisbon, Portugal; bDipartimento di Chimica “Giacomo Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy

* [email protected], [email protected]

ABSTRACT Finding new multicomponent crystal forms of commercially available pharmaceuticals is important, as they represent a straightforward way to drastically influence the solidstate properties of a drug. The antibiotic 4-aminosalicylic acid (ASA) is known to exist in several multicomponent crystal forms, and in this work we expand the world of ASA cocrystals

and

salts

by

reporting

new

crystalline

forms

comprising

diazabicyclo[2.2.2]octane (DABCO), and caffeine. All species were characterized by Xray single crystal, powder diffraction and thermal behaviour. This study contributes to the rationalization of preferred functional groups for the synthesis of 4-aminosalicylic acid new multicomponent crystal forms and highlights the relevance of the reaction conditions in the achievement of those forms.

INTRODUCTION The non-steroid anti-inflammatory drug (NSAID) 4-aminosalicylic acid (ASA) has been used as an antibiotic in the treatment of tuberculosis since the 1940s.1 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 Several prodrugs of this active pharmaceutical ingredient (API) have been exploited to slow down its absorption in the upper intestinal tract in order to make it suitable for the treatment of active ulcerative proctitis or left sided ulcerative colitis.2, 5 Azo6 and phenol-class azo derivatives7 have 1

ACS Paragon Plus Environment


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been synthesized in the quest for a better ASA prodrug against inflammatory bowel disease; additionally ASA conjugates of EDTA (ethylenediaminetetraacetic acid) chelating to Cu(II) were reported not only as potential anti-inflammatory prodrugs but also as promising drugs with anti-cancer properties, due to their proteolytic attack resistance.4 Also worth mentioning are ASA:α-cyclodextrins complexes that have shown an improvement in ASA solubility (up to 100 mM),8 and the novel ASA:konjac glucomannan (KGM) pH-sensitivity complex synthesized based on the advantage of the biodegradability of KGM,9,

10

a high-molecular weight polysaccharide known for

reducing the risk of developing diabetes and heart diseases.11 To the best of our knowledge only one crystal form of this API has been reported (Figure 1),12,

13

whose crystal packing is characterized by an intramolecular synthon

between the hydroxyl and carboxyl groups, the carboxyl···carboxyl homosynthon and a N-H···OOH interaction promoting a 3-dimensional network.

a

b

c

Figure 1 (a) 4-aminosalicylic acid (ASA), and its crystal packing showing (b) a detailed view of the hydrogen-bonds and (c) a global arrangement in a view along a. Several multicomponent crystal forms of ASA have been reported in recent years. Chloride,13 sulfate and methanesulfonate14 salts have been synthesized. Cocrystals and molecular salts with 3,5-dinitrobenzoic acid,15 4,4’-bipiridine,16, pyridyl)ethane,17,

18

3-hydroxypiridine,

4-aminopiridine,17

17

1,2-bis(4-

nicotinamide,19

isonicotinohydrazide, isoniazid, pyrazine-2-carboxamide,20 cystosine, nicotinamide,14 sulfadimidine21 and with a codified compound reported as VX-95022 are described in the literature. Also two private communications by Callear and co-workers with 2aminopyridine (one salt and one cocrystal) are available at Cambridge Structural Database.23 We have further reported multicomponent crystal forms with morpholine, dioxane and piperazine24 as well as three polymorphs of its ammonium salt.25 A ternary 2


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multicomponent crystal was prepared in 2013 by Seaton and co-workers, involving ASA, 3,5-dinitrobenzoic acid and 4,4’-bipyridine.26 Very recently also drug-drug cocrystals involving ASA have also been reported.27,

28

The most recurrent hydrogen

bonding interaction in these multicomponent crystal forms is between the OHCOOH/COOof ASA and the Npyridine groups of the coformers. The work reported herein integrates our previous results24,25 and, along with all the published data, intends to clearly show the great propensity of this API to form multicomponent crystal forms with amines via O-H···N and/or N-H···O interactions. Novel forms of this API were synthesized with diazabicyclo[2.2.2]octane (DABCO) and caffeine. Valuable information can be drawn from this work on the type of interactions favouring the formation of solvates/cocrystals/salts of this API and will now be applied into the search of more GRAS co-formers, including possible excipients, having in perspective a potential application in the pharmaceutical field.29-31

RESULTS AND DISCUSSION Synthesis of the new multicomponent crystal forms was based on the supramolecular synthon approach, on datamining and our previous experience with the system. Multiple salts, cocrystals and ionic cocrystals were analysed in this search (Table I). Table I – List of multicomponent crystal forms of ASA CSD code ASALAC BEYZAI COLKUL CUKVIO CUKVOU CUKVAG CUKVEK ICEBOK ISIFUM KEBGAB KEBGAB01 KEBGAB02 MOYYOQ MOYZUX OBOVAF OFUYIZ PEXNOX PEXNUD PEXPAL PEXPEP

Crystal form Salt Ionic cocrystal Cocrystal Salt Salt Salt Cocrystal Cocrystal solvate Ionic cocrystal Salt Salt Salt Salt Cocrystal Cocrystal Cocrystal Salt Salt Salt Cocrystal

Coformer/counterion Chloride 4,4’-bipyridine; 3,5-dinitrobenzoic acid 3,5-dinitrobenzoic acid Piperazine Piperazine Morpholine Dioxane Caffeine; methanol 4,4’-bipyridine Ammonium Ammonium Ammonium 2-aminopyridine 2-aminopyridine Isonicotinamide Nicotinamide 1,2-bis(4-pyridyl)ethane 3-hydroxypiridine 4-aminopiridine 4,4’-bipyridine

Reference 13 26 15 32 32 32 32 27 16 25 25 25 23 23 27 19 17 17 17 17

3



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PEXNAJ PEXPIT URUDER01-10 URUGIY YUJLOG01 VATXOF VATXOF01 VATXOF02 VUGMOZ XICRIM XICROS XICQOR XICRAE XICREI

Cocrystal Cocrystal Cocrystal Cocrystal Cocrystal Cocrystal Cocrystal Cocrystal Cocrystal Ionic cocrystal Salt Ionic cocrystal Cocrystal Salt

1,2-bis(4-pyridyl)ethane 4,4’-bipyridine Isoniazid Pyrazine-2-carboxamide Theophylline 1,2-bis(4-pyridyl)ethane 1,2-bis(4-pyridyl)ethane 1,2-bis(4-pyridyl)ethane Sulfadimidine Cytosine Cytosine Sulfate Nicotinamide Methanesulfate

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17 17 20 20 27 16 17 17 21 14 14 14 14 14

Results show that the acid···pyridine synthon is the most recurrent synthon; for this reason, we have further explored mainly N-containing heterocyclic coformers that we expected to interact with ASA as shown in Scheme I. GRAS coformers containing carboxylic acids were also tested.

Scheme I Predicted synthons containing neutral and charged groups, characteristic of possible cocrystals (I) or molecular salts (II) of ASA with DABCO. New forms of ASA were obtained with DABCO and caffeine (Scheme II). The crystal structure of three different forms with DABCO and one with caffeine are reported herein and, as observed in most of the crystal forms previously reported, they confirm the ability of ASA to interact via O-H···N and/or N-H···O hydrogen bonds.

Scheme II ASA, DABCO, and caffeine

4


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In this work, we also underline the fact that different forms could be synthesized by slightly modifying the crystallization conditions. This concept is extremely important in the synthesis of the DABCO new forms, where the evaporation area of the crystallization vessels proved to be crucial. Three new forms [HDABCO]+2⋅[C6H3NH2OH(COO)]-2⋅DABCO⋅7H2O (1), [HDABCO]+⋅[C6H3NH2OH(COO)]-⋅2H2O (2) and [HDABCO]+⋅[C6H3NH2OH(COO)]-

⋅DABCO⋅H2O (3), were obtained with ASA and DABCO upon distinct evaporating conditions. Scheme III reports the chemical formulae of the compounds under discussion. It is noteworthy that in compound 1 and 3 DABCO participates both as counterion and neutral coformer, while 2 is a salt.33 The synthetic pathways to selectively obtain ASA:DABCO multicomponent crystal forms are not straightforward and are not easy to rationalize. While liquid-assisted grinding lead34, 35 to the formation of 1, traditional crystallization by slow solvent evaporation results in mixtures of the three forms (1-3). The prevalence of one form over the others obtained by solution techniques is highly dependent on the evaporation area of the crystallization vessel, with the crystalline form characterized by the lowest water content being favoured by wider evaporation areas. Slurries also resulted in mixtures of the three forms. Even though the different forms have different formulae, the ratio between [HDABCO]+ and [C6H3NH2OH(COO)]- is the same, the difference arising from the presence of neutral DABCO and by the hydration degree. All attempts to influence the composition by changing the reagents ratio were unsuccessful, and mixtures were the recurrent result. The structural and thermal characterization of these forms (1-3) will be presented and discussed. With caffeine, a new hydrate (4) was obtained by solution methods but it was not possible to determine its crystal structure, and an anhydrous cocrystal (5) is obtained by recrystallization of the hydrate in methanol, even though in very low yields for this method. The crystal structure of the anhydrous form 5 was determined, [C6H3NH2OH(COOH)].[C8H10N4O2], and its structural and thermal characterization are also discussed herein.

5



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Scheme III Representation of 1, 2, 3 and 5.

Crystal structure analysis for 1, 2 and 3 The

asymmetric

2 ⋅DABCO ⋅7H 2 O

(1)

unit

of

consists

the of

salt

two

[HDABCO]+2⋅[C6H3NH2OH(COO)]ASA,

three

DABCO

and

seven

crystallographically independent water molecules. Both ASA moieties are deprotonated ([C6H3NH2OH(COO)] - [C-O distances are 1.251(4) and 1.267(5) Å; 1.236(5) and 1.294(4) Å in the two anions, respectively]), while of the three DABCO molecules two are protonated, i.e. they are [HDABCO]+ cations, as confirmed by the location of the hydrogen atom next to the nitrogen of cationic nature, and the third is neutral. The crystallographically independent [C6H3NH2OH(COO)]- anions still maintain the intramolecular bond, now reinforced by charge assistance [O(H)···OCOO- 2.528(5) and 2.480(6) Å]. One of the anions connects with three water molecules, while the second anion links with a fourth water molecule [N(H)anion···OW 2.690(5) Å] and one of the [HDABCO]+ cations [N(H)anion···N+cation 3.005(6) Å and N+(H)cation···O-COO2.690(5) Å] (see Figure 2.a). The neutral DABCO and one of the cations interact one with the other [N+(H)cation···NDABCO 2.647(5) Å] and with water molecules, thus forming 6


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hydrogen bonded zig-zag chains (Figure 2.b). The interaction of these chains with the motifs previously described is established via a water molecule, giving rise to an extended hydrogen bonded network (Figure 2.c).

a

b Figure 2 Crystal packing of 1 (a) hydrogen bonded zig-zag chains formed by [HDABCO]+ cations (yellow and violet), neutral DABCO (red), ASA anions (blue and light green) and water molecules (dark green and white); (b) overall packing in a view along b. This form was never obtained as a single phase in any of the experiments carried out and most frequently appears concomitantly with 2 (Figure S1). The asymmetric unit of [HDABCO]+⋅[C6H3NH2OH(COO)] -⋅2H2O, 2 consists of two [C6H3NH2OH(COO)]- anions, two [HDABCO]+ cations and four water molecules. The salt nature of this form was assessed by the C-O distances in the [C6H3NH2OH(COO)] - anions (1.247(14) and 1.278(14); 1.252(10) and 1.292(9) Å) and the proton location from the electron density map on the [HDABCO]+ cations. Once again the intramolecular bonds in [C6H3NH2OH(COO)]- anions are maintained [O-HOH···O-COO- 2.537(7) and 2.504(10) Å]. Wavy chains of alternating anions and water molecules are shown in Figure 3.a. The second independent anion interacts via hydrogen bonds with water molecules and one of the two independent 7



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cations [N+(H)cation···O-COO- 2.626(8) Å] (Figure 3.b). [HDABCO]+ cations are at close distance [N+(H)cation···N+cation 2.754(9) Å] and one of them is hydrogen bonded to a water molecule [O(H)W ···N+cation 2.805(9) Å], giving rise to [C6H3NH2OH(COO)]- – water – [HDABCO]+ – [HDABCO]+ – [C6H3NH2OH(COO)]- chains (Figure 3.c).

a

b

c Figure 3 Crystal packing of 2 in views along b: (a) showing the wavy chains formed by one of the ASA anions (blue) and water (orange); (b) depicting the hydrogen bonding between one of the ASA anions (green) with a water molecule (dark green) and their contacts with both DABCO cations (yellow and red), giving rise to chains (c) showing the overall packing, where the interaction between both type of chains is established by water molecules (light blue and pink). Form 2 was possible to obtain as a single phase (Figure S2) when crystallization vessels with a medium evaporation area, such as beakers, were used. The asymmetric unit of [HDABCO]+⋅[C6H3NH2OH(COO)]-⋅DABCO⋅H2O 3 consists of one ASA anion, one [HDABCO]+ cation, one neutral DABCO and one water molecule. The anionic nature of ASA was determined by the C-O distances in the carboxylate moiety (1.253(2) and 1.282(2) Å) and the cationic nature of one DABCO was assessed by the proton location from the electron density map. In

this

system,

as

observed

in

the

previously

described

structures,

-

[C6H3NH2OH(COO)] anions maintain the intramolecular interaction [O-HOH···O-COO2.459(2) Å]. The only intermolecular interactions in which [C6H3NH2OH(COO)]8


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anions are involved is established through the amine and carboxylate moieties [NHASA···O-COO- 2.932(3) Å]. These interactions along with three hydrogen bonds with the water molecules [N-HASA···OW 2.935(2) Å, O-HW···O-COO- 2.795(3) Å and OHW···OOH 2.815(3) Å] give rise to sheets in the bc plane (Figure 4.a). DABCO molecules form isolated dimers through N+-HDABCO···NDABCO hydrogen-bonds [N+HDABCO···NDABCO 2.721(3) Å] and pack in between the [C6H3NH2OH(COO)]- anionswater sheets (Figure 4.b).

a

b Figure 4 Crystal packing of 3 in views (a) along a showing the sheets formed by ASA and water in the bc plane; (b) along b showing the alternated layers of [C6H3NH2OH(COO)]- - water sheets and DABCO dimers. (colour code: light blue – [HDABCO]+ cation; dark blue – DABCO molecule; purple – [C6H3NH2OH(COO)]anion; green – water) This form is obtained as the only bulk product (Figure S3) if crystallization vessels with a large evaporation area are used.

Thermal behaviour of the crystalline forms 1-3 DSC, TGA and HSM studies were performed on crystalline forms 1-3 to assess their thermal stability. The thermal analysis is not straightforward, like it would be expected as these crystal forms are highly hydrated. In all the three forms water is released before melting, but in none of them this process is carried out in a single step 9



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and therefore several thermal events with corresponding water loss are detected below 150°C. The melting point of the three forms is similar and occurs at approximately 163165°C. For 1, which contains seven water molecules, several sequential events are detected indicating that the water loss slowly starts at approximately 50°C and is more intense above 119°C. The melting peak is detected at 165.2°C and is followed by decomposition (Figure S4). This data is also supported by HSM observations (Figure 5).

Figure 5 HSM for 1, showing the melting and decomposition at 162°C. The two water molecules per formula unit in crystalline 2 leave the structure between 50 and 110°C, and the melting, followed by decomposition, is detected at 164.8°C (Figures 6 and S5).

Figure 6 HSM for 2, showing the water release between 50 and 110°C (images at 87 and 105 °C) and the melting and decomposition (image at 170°C). Crystalline 3 contains only one water molecule per asymmetric unit, and this is lost in the 60-120°C range. Melting is detected at 165.4°C and is once again followed by decomposition (Figures 7 and S6).

Figure 7 HSM for 3 showing the water release between 60 and 120°C (images at 80 and 102°C) and the melting and decomposition (image at 166°C).

10


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Crystal structure analysis for 5 The preparation of new ASA-caffeine cocrystals was attempted by both solution and grinding. By neat-grinding and LAG, only a mixture of both starting materials is obtained. In solution, a new compound (4) is always formed, but no single crystals suitable for X-ray diffraction could be grown. To ascertain that we were working with a new form we further checked the diffraction data against all the reported polymorphs and hydrates of caffeine (Figure S7). Several recrystallization attempts using different solvents (acetone, ethanol, methanol, acetonitrile, water), as well as different crystallization temperatures (RT and low temperature), were carried out. Single crystals suitable for diffraction experiments could only be obtained from methanol, which permitted

the

characterization

of

the

anhydrous

cocrystal

[C6H3NH2OH(COOH)]·[C8H10N4O2], 5. The asymmetric unit of 5 consists on one ASA and one caffeine molecules, without any proton transfer, and therefore this form corresponds to a cocrystal. Once again the intramolecular interaction [O-HOH···OCOOH 2.605(7) Å] is maintained in ASA. Each ASA moiety interacts with three different caffeine molecules via hydrogen bonds [OHCOOH···NCAF 2.702(8) Å, N-HASA···OC=O,CAF 2.927(8) and 2.975(8) Å], giving rise to a 3D crystal packing with alternated ASA and caffeine molecules (Figure 8.a), in which similar molecules do not interact directly among them. In this crystal structure the crystal packing is further reinforced by π··· π interactions (Figures 8.b and 8.c).

a

b

c

Figure 8 Crystal packing of 5, depicting (a) the ASA (blue) ˗ caffeine (green) alternated arrangement, (b) π··· π distances, in Å, between aromatic rings centers of ASA and caffeine molecules, and (c) π··· π interactions between ASA (blue) and caffeine (green) molecules in a view along the a axis. 11



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Thermal behaviour of crystalline 4 DSC data for the compound initially obtained with ASA and caffeine, 4, (Figure S8) reveals two endothermic peaks: the first one corresponding to a 7% mass loss in the TGA, the second to melting followed by decomposition, overlapping with a small exothermic peak. The mass loss between 50 and 70°C suggests that this form is likely to be a solvate. As the same form is obtained with different solvents, this is most probably a hydrate: the 7% mass loss would therefore correspond to the loss of 1.5 water molecules per formula unit, i.e. crystalline 4 should be a sesquihydrated 1:1 cocrystal. Figure S-9 shows VT-XRPD measurements on crystalline 4. A change in the diffraction pattern is indeed detected in the diffractogram collected at 80°C, in agreement with the results from DSC and TGA. The new pattern does not change, but for small shifts due to temperature variations, when the sample is cooled down to room temperature. Similarities can be found with the pattern calculated for crystalline 5 on the basis of single crystal data (Figure S-9); unfortunately, in spite of numerous attempts at recrystallizing the dehydrated product or at determining the structure from powder data, we have not been able, so far, to characterize it.

CONCLUSIONS The discovery of new solid forms of old drugs is an important research field not only in modern solid-state and materials chemistry, but also in the pharmaceutical field. These new forms include polymorphs, solvates, salts, and cocrystals, all of them with distinct structural and physicochemical properties, which may be very useful to overcome several issues (such as stability, solubility and bioavailability) of the drug forms currently used.36-58 The tendency of ASA to form solvates and molecular salts had already been proven and this is reinforced in this study. We have also demonstrated herein the importance of reaction conditions to yield different forms with a single co-former. Based on a Cambridge Structural Database23 survey, we have investigated the possibility of forming new crystal forms between ASA and cyclic lone-pair containing heterocycles such as DABCO. These coformers carry nitrogen atoms that can act as proton acceptors or hydrogen bonding acceptors thus being able to be engaged in 12


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extended hydrogen bonded networks, suitable for the study of synthon competition and cooperation established in this type of structures. Carboxylic acids are known for their potential in the formation of hydrogen bonds and their predisposition to form dimeric carboxyl···carboxyl homosynthons that generate self-complemented hydrogen-bonding interactions in their crystal structures.59,

60

But in the presence of N-containing

heterocyclic moieties, the homosynthon is commonly disrupted by the robust OHCOOH···Npyridine heterosynthon that is preferentially shaped in the resultant multicomponent crystal form (cocrystal, salt, molecular salt, solvate).61, 62 The ASA molecule is sufficiently acidic to transfer the carboxylic proton to DABCO molecules,31 as expected based on the ∆pka rule and by analyzing studies of similar structures with other salicylic acid derivatives and these co-formers.15, 63-66 The strong homomeric carboxylic acid synthon observed in ASA cannot occur in the molecular salts studied herein due to the proton transfer from the API carboxylic group to the amine moiety of the co-former. This disruption gives rise to charge-assisted N+-Hcation···O-COO- supramolecular interactions, originating different ring and chain synthons in the molecular salts studied. On the other hand, in the anhydrous form of caffeine there is no proton transfer and this form corresponds to a cocrystal. In this case, the strong homomeric carboxylic acid synthon observed in ASA is also disrupted, but the charge-assisted interactions previously mentioned are replaced by O-HCOOH···NCAF and N-HASA···OC=O,CAF hydrogen bonds, with π··· π further reinforcing the crystal packing. The N-HASA···OOH interaction is maintained in two of the crystal structures discussed herein.

Experimental All reagents were purchased from Sigma and used without further purification. SYNTHESIS OF MULTICOMPONENT CRYSTAL FORMS

Solution synthesis of [HDABCO]+2⋅[C6H3NH2OH(COO)] -2⋅DABCO⋅7H2O (1): A solution was prepared in a flask with ASA (0.0339 g, 0.2214 mmol) and DABCO (0.05059 g, 0.4502 mmol) and dissolved in 5 mL of ethanol. The solution was heated at boiling temperature for 5 minutes and left to crystallize at room temperature. Crystals were formed after 2 days. 13



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Solution synthesis of [HDABCO]+⋅[C6H3NH2OH(COO)]-⋅2H2O (2): A solution was prepared in a beaker with ASA (0.0406 g, 0.2651 mmol) and DABCO (0.0302 g, 0.2692 mmol) and dissolved in 5 mL of ethanol. The solution was heated at boiling temperature for 5 minutes and left to crystallize at room temperature, but covered with parafilm. Crystals were formed after 2 days.

Solution synthesis of [HDABCO]+⋅[C6H3NH2OH(COO)]-⋅DABCO⋅H2O (3): A solution was prepared in a crystallization vessel with a very wide evaporation area with ASA (0.0340 g, 0.2220 mmol) and DABCO (0.0432 g, 0.3851 mmol) and dissolved in 4.3 mL of ethanol. The solution was heated at boiling temperature for 5 minutes and left to crystallize at room temperature. Crystals were formed over night.

Synthesis of 1-3 by slurry: Two preparations were attempted. ASA and DABCO in two different stoichiometric ratios (3:2 and 1:2) were suspended in ethanol and stirred in a closed vessel for six days. In both cases the final bulk consists of a mixture of the three forms previously obtained by solution technique but other forms different, in each case, are additionally present. No crystals suitable for single crystal X-ray diffraction of a new form were obtained from the recrystallization of these experiments.

Solution synthesis of the ASA·caffeine cocrystal (4): equimolar amounts of ASA and caffeine were dissolved in water/ethanol solutions that were left to crystallize at room temperature. Powder formed after 3 days and was identified by XRPD as a powder pattern distinct from any form of the starting materials. Alternatively, similar solution was left at 5°C for crystallization and a similar result was obtained. Both acetone and acetonitrile, as well as just water, were tested as solvents and once again the new powder pattern was obtained. The same result was obtained by joining two different solutions: an ASA solution in ethanol and a caffeine solution in acetonitrile, and leave them to crystallize at room temperature. Despite the many recrystallization attempts carried out using different techniques, single crystals suitable for SCXRD were never obtained. Whenever higher percentage of ASA was used in the preparations, this reagent was detected in the final XRPD analysis, along with form 4, showing that changes in the starting ratio of the reagents do not affect the final form obtained.

Synthesis of the ASA·caffeine cocrystal (4) by mechanochemistry: equimolar amounts of ASA and caffeine were manually ground in an agate mortar for 30 minutes. 14


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No conversion into new forms was detected by XRPD data. Reaction occurred by adding a few drops of solvent (water, ethanol or acetone) before grinding the mixture.

Crystal growth of [C6H3NH2OH(COOH)]·[C8H10N4O2] (5) from solution: equimolar quantities of ASA and caffeine were dissolved in methanol and were left to crystallize at 5°C. After 5 days a couple of crystals suitable for single crystal X-ray diffraction were formed. However, the majority of the obtained material was powder. Its XRPD diffraction analysis showed that the majority of the obtained material corresponded to the hydrated form 4.

CHARACTERIZATION

Single crystal X-ray diffraction (SCXRD) Data collection was carried out in an Oxford X’Calibur S CCD diffractometer equipped with a graphite monochromator (Mo-Kα radiation, λ = 0.71073Å) at room temperature and in a Bruker AXS-KAPPA APEX II diffractometer with graphitemonochromated radiation (Mo-Kα radiation, λ = 0.71073 Å) at 150 K. Refinement details are listed in the Table II. All non-hydrogen atoms were refined anisotropically. HOH atoms were added in calculated positions. HNH atoms were located from difference Fourier maps and refined. HCH and HOH atoms were added in calculated positions and refined riding on their respective C and O atoms. SHELX-9767 was used for all structure solutions and refinements on F2. Crystal data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or email: [email protected]). CCDC numbers 1561330-1561333.

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Table II Crystallographic details for 1-3 and 5 1

2

3

Mr

2(C7H6NO3).2(C6H13N2). C6H12N2.7(H2O) 768.91

C7H6NO3.C6H13N2 . 2(H2O) 301.34

C7H6NO3.C6H13N2.C6H12N2 C7H7NO3.C8H10N4O2 . H2O 395.5 347.33

T/K

150

150

150

293

Morphology, colour

Plate, brownish

Block, brownish

Plate, brownish

Prism, colourless

Crystal size / mm

0.10x0.08x0.03

0.08x0.05x0.05

0.17x0.16x0.10

0.12x0.11x0.09

Crystal system

Orthorhombic

Monoclinic

Monoclinic

Orthorhombic

Space group

Pca21

Cc

P21/n

P212121

a/Å

15.5430(15)

16.277(2)

11.3830(5)

7.5118(5)

b/Å

9.0140(8)

8.8488(11)

14.245(6)

7.8571(5)

c/Å

27.676(3)

21.007(2)

12.4480(5)

27.0495(19)

β/°

90

95.57(4)

91.908(2)

90

V / Å3

3877.5(6)

3011.4(6)

2017.3(9)

1596.49(18)

Z

4

8

4

4

d / mg.cm-3

1.317

1.329

1.302

1.445

µ / mm-1

0.102

0.102

0.093

0.111

θ min / °

1.47

2.68

2.17

3.5302

θ max / °

26.39

25.42

25.92

20.4550

25038/4052

5636/2681

22018/3925

6891/3673

Chemical formula

Reflections collected/unique Rint

5

0.0900

0.0439

0.0745

0.0373

GoF

1.019

1.024

1.015

1.053

Threshold expression

> 2σ(I)

> 2σ(I)

> 2σ(I)

> 2σ(I)

R1 (obsd) wR2 (all)

0.0527

0.0611

0.0463

0.0871

0.1506

0.1873

0.1204

0.1885

X-Ray Powder diffraction (XRPD) and variable-temperature X-Ray Powder diffraction (XRPD-VT) X-ray powder diffraction data were collected with a Panalytical X’Pert Pro and in a D8 Advance Bruker AXS θ-2θ diffractometer, with a copper radiation source (Cu Kα,

λ=1.5406 Å) and a secondary monochromator, operated at 40 kV and 40 mA

Hot-stage microscopy (HSM) Hot Stage experiments were carried out using a Linkam TMS94 device connected to a Linkam LTS350 platinum plate.

Differential Scanning Calorimetry (DSC) Calorimetric measurements were performed using a Perkin-Elmer Diamond.

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Thermogravimetric Analysis (TGA) TGA analysis was performed with a Perkin-Elmer TGA-7.

Acknowledgements: Authors acknowledge Fundação para a Ciência e a Tecnologia for funding (PEst-OE/QUI/UI0100/2013, PTDC/CTM-BPC/122447/2010, RECI/QEQ-QIN/0189/2012 and SFRH/BPD/78854/2011) Supporting information: Supporting information is available containing information on powder X-ray diffraction, TGA and DSC data. REFERENCES: (1) Verreck, G.; Decorte, A.; Heymans, K.; Adriaensen, J.; Liu, D.; Tomasko, D.; Arien, A.; Peeters, J.; Van den Mooter, G.; Brewster, M. E., Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer. Int. J. Pharm. 2006, 327, 45-50. (2) Odonnell, L. J. D.; Arvind, A. S.; Hoang, P.; Cameron, D.; Talbot, I. C.; Jewell, D. P.; Lennardjones, J. E.; Farthing, M. J. G., Double-blind, controlled trial of 4-aminosalicylic acid and presnisolone enemas in distal ulcerative-colitis. Gut 1992, 33, 947-949. (3) Schreiber, S.; Howaldt, S.; Raedler, A., Oral 4-aminosalicylic acid versus 5aminosalicylic acid slow-release tablets - double-blind, controlled pilot-study in the maintenance treatment of Crohns ileocolitis. Gut 1994, 35, 1081-1085. (4) Bailey, M. A.; Ingram, M. J.; Naughton, D. P.; Rutt, K. J.; Dodd, H. T., Aminosalicylic acid conjugates of EDTA as potential anti-inflammatory pro-drugs: synthesis, copper chelation and superoxide dismutase-like activities. Transition Met. Chem. 2008, 33, 195-202. (5) Beeken, W.; Howard, D.; Bigelow, J.; Trainer, T.; Roy, M.; Thayer, W.; Wild, G., Controlled trial of 4-ASA in ulcerative colitis. Dig. Dis. Sci. 1997, 42, 354-358. (6) Zhao, Z. B.; Zheng, H. X.; Wei, Y. G.; Liu, J., Synthesis of azo derivatives of 4aminosalicylic acid. Chin. Chem. Lett. 2007, 18, 639-642. (7) Sheng, S. F.; Zheng, H. X.; Liu, J.; Zhao, Z. B., Synthesis of phenol-class azo derivatives of 4-aminosalicylic acid. Chin. Chem. Lett. 2008, 19, 419-422. (8) Lahiani-Skiba, M.; Youm, I.; Bounoure, F.; Skiba, M., Improvement in the water solubility and stability of 4ASA by the use of cyclodextrins. J. Inclusion Phenom. Macrocyclic Chem. 2011, 69, 327-331. (9) Xu, D. Y.; Li, G. J.; Liao, Z. F.; Chen, X. D., Synthesis and characterization of a novel pHsensitive complex for drug release. J. Wuhan Univ. Technol.-Mater. Sci. Ed. 2010, 25, 24-27. (10) Xu, D. Y.; Zhao, M. M.; Ren, J. Y.; Li, G. J.; Liao, Z. F., Investigation of interactions in 4aminosalicylic acid/polysaccharide in aqueous media. Food Res. Int. 2010, 43, 2077-2080. (11) Chen, H. L.; Cheng, H. C.; Liu, Y. J.; Liu, S. Y.; Wu, W. T., Konjac acts as a natural laxative by increasing stool bulk and improving colonic ecology in healthy adults. Nutr. 2006, 22, 11121119. (12) Bertinotti, F.; Giacomello, G.; Liquori, A. M., Crystal and molecular structure of paraaminosalicylic acid. Acta Crystallogr. 1954, 7, 808-812. (13) Lin, C. T.; Siew, P. Y.; Byrn, S. R., Solid-state dehydrochlorination and decarboxylation reactions. 1. Reactions of para-aminosalicylic acid hydrochoride and para-aminosalicylic acid, and revised crystal structure of para-aminosalicylic acid. J. Chem. Soc.-Perkin Trans. 2 1978, 957-962. (14) Cherukuvada, S.; Bolla, G.; Sikligar, K.; Nangia, A., 4-Aminosalicylic Acid Adducts. Cryst. Growth Des. 2013, 13, 1551-1557. 17



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For Table of Contents Use Only

Expanding the pool of multicomponent crystal forms of the antibiotic 4aminosalicylic acid: the influence of crystallization conditions

Vânia Andréa*, Oleksii Shemchukb, Fabrizia Grepionib*, Dario Bragab, M. Teresa Duartea a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1,

1049-001 Lisbon, Portugal; bDipartimento di Chimica “Giacomo Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy

* [email protected], [email protected]

TOC

The discovery of new solid forms of old drugs is an important research field in the pharmaceutical arena. The tendency of 4-aminosalicylic acid to form multicomponent crystal forms had already been proven and this is reinforced in this study. We have also demonstrated herein the importance of reaction conditions to yield different forms with a single co-former.

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Expanding the pool of multicomponent crystal forms of the antibiotic 4

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