Packing Interactions and Physicochemical Properties of Novel

Article pubs.acs.org/crystal

Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X‑ray and Solid-State NMR Inês C. B. Martins,† Mariana Sardo,‡ Sérgio M. Santos,‡ Auguste Fernandes,† Alexandra Antunes,† Vânia André,† Luís Mafra,*,‡ and M. Teresa Duarte*,† †

CQE − Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

‡

S Supporting Information *

ABSTRACT: The reactivity of the active pharmaceutical ingredient azelaic acid (AA) with carboxylic acid, alcohol, amine, and amide based co-formers was screened. Five new multicomponent crystal forms of AA were obtained by liquid assisted grinding and conventional solution methods. The obtained forms: (i) a co-crystal with 4,4′-bipyridine (AA:BIP, 1), (ii) an anhydrous and an hydrated molecular salt with piperazine (AA:PIP, 2 and 3), and (iii) two anhydrous molecular salts with morpholine (AA:MORPH, 4) and 1,4diazobicyclo[2.2.2]octane (AA:DABCO, 5), were fully characterized by X-ray diffraction and solid-state (SS) NMR. In all new forms the carboxylic-carboxylic R22(8) homosynthon present in AA is broken, and NH2···OCOOH or +NH2···OCOOhydrogen bonds (HBs) become the fundamental pillars in the new supramolecular arrangements. The X-ray structure of 4 exhibits a static disorder in the hydrogen atoms engaged in an HB between two COOH moieties of AA. Density functional theory geometry optimization of the hydrogen positions followed by GIPAW-DFT calculations of 1H chemical shifts showed that such disordered atoms refer to O···H···O hydrogens, roughly equidistant from both proton acceptor and donor atoms. 1H SSNMR detected unusually strong HBs associated with such disordered hydrogens through the presence of 1H resonances shifted to very high frequencies (up to ca. 20.1 ppm). These results clearly show the advantageous use of both X-ray diffraction and SSNMR techniques for structural elucidation. We concluded that the hydrated piperazine salt 3 readily converted to 2 at ambient RH and that their thermal behavior is strongly determined by both the supramolecular arrangement and strength of HB network. Piperazine salt 2 presents an improved aqueous solubility bestowing a promising opportunity to avoid the use of alcoholic solutions in the final formulations.

1. INTRODUCTION

salts, solvates, hydrates, and salts) that can be obtained using a variety of inexpensive and readily available small molecules.6 API multicomponent crystal forms have been prepared using solution and mechanochemical processes, the latter one presenting a “greener” alternative, due to the absence or limited use of solvents.2,7 Liquid assisted grinding (LAG), using a catalytic small amount of solvent, is a mechanochemical approach that, in general, favors the migration and rearrangement of the constituent molecules outperforming the neat grinding method.7,8 Solid APIs are easily engaged in hydrogen bond (HB) networks and other intermolecular interactions in their supramolecular structure, largely due to the presence of several functional groups. Their crystal packing arrangements thus play

Crystal engineering has emerged as an important crossdisciplinary field having evolved from designing structures to designing properties. Nowadays, this field describes a planned synthesis of an organic or metal−organic crystal structure associated with a particular predesired property.1 Solid-state and the structure−activity relationships are particularly relevant in the pharmaceutical industry. The majority of active pharmaceutical ingredients (APIs) occur as solids (∼98%),2−4 and their crystalline forms are highly preferred over the amorphous ones due to physicochemical stability considerations.5 However, most of the problems related with the use of crystalline APIs are due to their poor solubility and/or bioavailability. Current approaches to modify physicochemical properties of APIs, without impacting its pharmacological behavior, include the development of new multicomponent crystalline solid forms (co-crystals, molecular © XXXX American Chemical Society

Received: July 24, 2015 Revised: November 3, 2015

A

DOI: 10.1021/acs.cgd.5b01057 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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isonicotinamide,22 pyridone,23 1,4-diazobicyclo[2.2.2]octane (DABCO),17 nicotinamide,24 bis(N-(2-pyridyl)acetamide),25 2-methylimidazolium,26 4,4′-ethane-1,2-diilodipyridone,27 N(pyridin-2-yl)isonicotinamide, 28 and N-(pyridin-2-yl)nicotinamide.28 Herein we have used AA and several co-formers, namely, amides, amines, carboxylic acids, hydroxyl and dioxane compounds (Figure 1) to produce five novel systems (1 cocrystal and 4 salts) with improved solubility and thermal stability. The most successful co-formers were 4,4′-bipyridine (BIP), piperazine (PIP), morpholine (MORPH), and DABCO (Figure 1), and an explanation addressing the nonreactivity of certain co-formers is provided in the discussion section. The thermal characterization of the compounds was performed using hot stage microscopy (HSM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), and preliminary solubility studies in water were also performed. The identification and characterization of the multicomponent solid forms were performed by solution NMR, FTIR, XRD, and SSNMR. The combined use of XRD and SSNMR was particularly important to identify specific interactions between the API and co-formers. Geometry optimization of hydrogens followed by calculations of 1H chemical shifts (CS) was performed by DFT and compared with the experimental CSs to solve ambiguities between salt and co-crystals. Such distinction is associated with the proton location within a given synthon, and 1H CSs are very sensitive to the chemical environment of 1H. 15N NMR studies also provided further confirmation of the proton position as many nitrogen-based synthons are involved in the reported cocrystal/salt systems. In addition, SSNMR combined with DFT calculations allowed clarification of some issues related to static disorder of hydrogen atoms present in the AA:MORPH salt.

Figure 1. Compounds used in the synthesis of new solid crystalline forms: (AA) azelaic acid (pKa1 = 4.55, pKa2 = 5.49); (TA) trimesic acid (pKa1 = 3.12, pKa2 = 3.89, pKa3 = 4.70); (OXA) oxalic acid (pKa1 = 1.25, pKa2 = 4.14); (TPA) terephthalic acid (pKa1 = 3.51, pKa2 = 4.82); (PA) phthalic acid (pKa1 = 2.98, pKa2 = 5.28); (IPA) isophthalic acid (pKa1 = 3.46, pKa2 = 4.46); (L-Asc) L-ascorbic acid (pKa1 = 4.10, pKa2 = 11.6); (L-Glu) L-glutamine (pKa(acid) = 2.17, pKa(amine) = 9.13); (DABCO) DABCO (pKa = 8.2); (PIP) piperazine (pKa = 9.8); (MORPH) morpholine (pKa = 8.34); (BIP) 4,4′-bipyridine (pKb = 9.67). Coformers in green−unsuccessful reactions; coformers in blue− successful reactions.

2. EXPERIMENTAL SECTION Synthesis. All reagents (Scheme 1) were purchased from Sigma and used without further purification.

an important role defining physicochemical properties of solid dosage forms.2 The structural characterization of solids is usually obtained using X-ray diffraction (XRD) techniques, and a full detailed description of the intra- and intermolecular distances and angles is usually obtained.9,10 However, XRD may present limitations in probing local interactions involving light atoms such as hydrogens.11 Solid-state NMR (SSNMR) spectroscopy is a well-established technique in pharma science, highly sensitive to the local environment of a given nucleus often used in tandem with XRD.12−17 SSNMR is particularly useful to study the strength and nature of HBs as well as other packing interactions having the potential to discriminate between salts and co-crystals mostly by means of 15N NMR in nitrogencontaining compounds.15,18 In this work we focus on the preparation of novel azelaic acid (AA) multicomponent crystal forms and their characterization by SSNMR and XRD. This compound is commonly used to treat skin disorders, like acne and rosacea.19,20 Usually it is incorporated in creams or gels (20% and 15% respectively) using alcohols as formulation solvent. As these can cause adverse effects in the lipid layer of the skin, such as dehydration, and also seem to promote some instability of AA at room temperature,19,21 increasing aqueous solubility of the API is of great importance. Other crystalline solid forms of AA have been reported, such as AA co-crystalized with different amines and amides:

Scheme 1. Experimental Conditions and Products Obtained with the Stoichiometric Ratio in the Reactions between AA and BIP, PIP, MORPH, and DABCO

Synthesis of Co-Crystal [C9H16O4]·[C10H8N2] (1) in Ethanol Solution. AA (0.0661 g, 0.3512 mmol) and BIP (0.0562 g, 0.3598 mmol) were dissolved in 3 mL of ethanol and left to crystallize by slow evaporation at room temperature. Colorless needle crystals were formed over 2 days. Synthesis of 1 by Liquid Assisted Grinding (LAG). AA (0.1621 g, 0.8607 mmol) and BIP (0.1350 g, 0.8644 mmol) were ground in a B



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Table 1. Crystallographic Details for Compounds 1−5 1

2

chemical formula

C9H16O4·C10H8N2

C9H14O4·C4H12N2

Mr temp/K wavelength (Å) morphology, color

344.40 150 0.71069 plates, colorless

crystal size/mm crystal system space group a/Å b/Å c/Å α/deg β/deg γ/deg V/Å3 Z calc density/mg·cm−3 absorption coefficient/ mm−1 Θ min (deg) Θ max (deg) reflections collected/ unique Rint GOF threshold expression R1 (obs) wR2 (all)

3

4

5

274.36 150 0.71069 needles, colorless

2(C9H14O4)·C4H12N2· 2(H2O) 498.61 150 0.71069 plates, colorless

C9H15O4·C9H14O4· 2(C4H10NO) 549.67 150 0.71069 plates, orange

0.42 × 0.02 × 0.01 monoclinic C2/c 25.395(9) 5.0430(17) 27.771(10) 90.00 96.397(12) 90.00 3534.4(2) 8 1.294 0.091

0.21 × 0.04 × 0.02 monoclinic P2/c 5.706 (9) 9.274(2) 14.059(3) 90.000(0) 98.052(7) 90.000(0) 736.6(12) 2 1.237 0.091

0.22 × 0.13 × 0.02 triclinic P1̅ 8.024(2) 9.472(2) 17.545(4) 96.603(10) 98.893(7) 93.006(8) 1305.3(5) 2 1.269 0.099

0.30 × 0.03 × 0.02 triclinic P1̅ 5.4707(13) 11.3917(24) 23.9974(54) 102.811(8) 93.137(9) 99.602(10) 1431.32(43) 2 1.280 0.097

C9H15O4· 0.5(C6H14N2) 244.3 150 0.71069 parallelipipedic, colorless 0.33 × 0.05 × 0.05 orthorhombic Pnma 10.3635(18) 7.6322(18) 33.6490(61) 90.000(0) 90.000(0) 90.000(0) 2661.51(9) 8 1.220 0.091

1.50 25.70 13499/3283

3.66 25.36 5020/1347

1.20 25.70 7929/4742

2.6 25.5 9660/5154

1.20 25.4 9577/2629

0.1819 0.9030 >2σ(I) 0.0828 0.2330

0.0689 0.9520 >2σ(I) 0.0528 0.1389

0.0652 0.8680 >2σ(I) 0.0727 0.1795

0.0434 0.9740 >2σ(I) 0.0560 0.1320

0.1082 0.8930 >2σ(I) 0.0946 0.2874

ball mill with 50 μL of ethanol during 15 min at 29.8 Hz. AA (0.2172 g, 1.1501 mmol) was ground with BIP (0.1880 g, 1.2037 mmol) in an agate mortar, during 60 min with 90 μL of ethanol. X-ray powder diffraction (XRPD) analysis, confirmed that both techniques lead to the same product. Synthesis of Molecular Salt [C9H16O4]·[C4H10N2] (2) and Molecular Salt Hydrate [C9H16O4]·[C4H10N2]·[H2O] (3) in Ethanol:Water (4:1) Solution. AA (0.0850 g, 0.4516 mmol) and PIP (0.0381 g, 0.4423 mmol) were dissolved in a mixture of 4 mL of ethanol and 1 mL of water and left to crystallize by slow evaporation at room temperature. After 3 days, colorless needles and plate crystals were formed. Synthesis of 2 by LAG. AA (0.2059 g, 1.0939 mmol) and PIP (0.0942 g, 1.0935 mmol) were ground together with 50 μL of ethanol in a ball mill (15 min, 29.8 Hz). The same reagents (0.2747 g, 1.4595 mmol of AA and 0.1249 g, 1.4499 mmol of PIP) were ground in an agate mortar along with 150 μL of ethanol during 65 min. The products obtained by these two methods were confirmed by XRPD. Synthesis of Molecular Salt Hydrate [C9H16O4]·[C4H10N2]· [H2O] (3) in Water Solution. In order to obtain more quantities of molecular salt hydrate and confirm the conclusions presented herein, 82.6 mg (0.4388 mmol) of AA and 39.30 mg (0.4562 mmol) of PIP were dissolved in 4 mL of water and left to crystallize at room temperature by slow evaporation in a Petri dish. After 1 day colorless plate crystals start to appear. The analysis of those plates was carried out by SCXRD, and the thermal stability was evaluated by HSM. Synthesis of [C9H16O4]·[C4H9NO] (4) in Ethanol Solution. AA (0.1854 g, 0.9850 mmol) was dissolved in 4 mL of MORPH and left to crystallize by slow evaporation at room temperature. Orange needles crystals were formed after 3 days. Synthesis of 4 by LAG. AA (0.2038 g, 1.0828 mmol) and MORPH (25 μL, 0.2857 mmol) were ground in a ball mill during 15 min at 28 Hz. In an agate mortar AA (0.2731 g, 1.4510 mmol) and MORPH (75 μL, 0.8571 mmol) were mixed and ground during 30

min. The products from both methods were analyzed by XRPD and proven to be the same as obtained in the solution methodology. Synthesis of [C9H16O4]·[C6H12N2] (5) in Ethanol Solution. AA (0.0760 g, 0.4038 mmol) and DABCO (0.0461 g, 0.4110 mmol) were dissolved in 2 mL of ethanol and left to crystallize by slow evaporation at room temperature. Colorless parallelipipedic crystals were formed over 2 days. Synthesis of 5 by LAG. AA (0.1871 g, 0.9941 mmol) and DABCO (0.1142 g, 1.0181 mmol) in 50 μL of ethanol were ground in a ball mill during 15 min at 28 Hz. In an agate mortar AA (0.2570 g, 1.3654 mmol) and DABCO (0.1501, 1.3381 mmol) were introduced with 40 μL of water and ground during 45 min. The products obtained were analyzed by XRPD and proved to be the same as obtained from the method previously described. Solubility Studies. Preliminary solubility studies were carried out by dissolving 10 mg of each multicomponent form obtained in water, gradually added until complete dissolution. The amount of water added allowed the determination of empiric solubility values. AA was used for comparison. Single Crystal X-ray Diffraction (SCXRD). X-ray diffraction data of 1−5 were collected on a Bruker AXS-KAPPA APEX II diffractometer with graphite-monochromated radiation (Mo Kα, λ = 0.17069 Å) at 150 K. 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 SAINT and SADABS programs. Crystals suitable for X-ray diffraction study were mounted on a loop with Fomblin© protective oil. Data collection and refinements details are listed in Table 1. SIR9725 and SHELXS-97 were used for structure solution, and SHELXL-97 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. Non-hydrogen atoms were refined anisotropically. All the hydrogen atoms were inserted in calculated positions and allowed to refine in the parent carbon atom, except for C



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1D 1H MAS NMR spectra were recorded using the high-resolution 1.3 mm Bruker MAS probe at a 700 MHz spectrometer, using a spinning rate of 60 kHz, and RF of 125 kHz. Because of temperature sensitivity issues, the 1H MAS spectrum of compound 4 was recorded on a 2.5 mm probe spinning at 30 kHz at low temperature ( 2.7 for salt).8 The pKa value for AA is around 4.5 and for PIP is 9.8 (the difference is 5.3), which means that PIP is a moderate base and can remove an acidic hydrogen atom to form a molecular salt. Molecular Salt 3. This compound was obtained in the same bulk of 2 when a 4:1 ethanol/water solution was used. Compound 3 is readily obtained in water solution but easily converts into 2 as water evaporates. Figure 5 shows a sequence of micrographs which follow the conversion rate of 3 (plates) → 2 (needles). Molecular salt 3 presents a 2:1:2 (AA:PIP:water) stoichiometry. There is a single deprotonation in each AA molecule, with C−O distances of 1.240(4), 1.274(4), and 1.241(4), 1.277(5) Å, imposing the complete protonation of PIP molecule (Figure 6). The packing, illustrated in Figure 7a, is based on four main types of interactions: (i) bifurcated +N−H···OCOO- [1.75(5) and 1.86(3) Å (blue dashed lines), Table 2]; (ii) O−HCOOH··· OCOO- [1.70 and 1.74 Å (pink dashed lines), Table 2]; (iii) O− HH2O···OCOO- [1.82(5) and 1.94(4) Å] and O−HH2O···OCOOH [2.05(4) and 2.03(4) Å] (orange dashed lines) and (iv) +N− H···OH2O [1.91(3) and 1.84(3) Å (brown dashed lines), Table 2] HB. The multiple intermolecular interactions promote the formation of alternated AA:PIP chains extending along b through hydrogen bonded water molecules. This can be better described using Etter’s graph set terminology42 where four R34(13) rings result in the formation of a R46(12) synthon

Figure 6. Representation of the unit cell content of 3.

atom from diffraction data can lead to ambiguities, a thorough SSNMR analysis was performed. The 1H MAS NMR spectrum recorded at fast spinning (see Figure 11a, section 3.5) depicts the presence of an isolated resonance, highly shifted toward high frequencies, at 16.3 ppm, which is ascribed to a very strong O−H···N HB. Moreover, 13C CS of the carbonyl carbon are good indicators of the protonation state of the COOH group.39,40 Indeed, the 13C CPMAS spectrum (see Figure 12a, section 3.5) shows a 13C CS of 175.4 ppm which is in agreement with values previously found in similar compounds.17 To unambiguously assign the 1 H and 13C resonances, we usually compare experimental with calculated CSs. However, such a procedure was not possible for compound 1 as the size of the unit cell was substantially larger than the other three compounds (see calculations below). Comparing the 15N CS of compound 1 (see Figure 13, section 3.5) with the reference 15N CS of glycine zwitterion form (NH3+ at ca. −347.6 ppm), it is possible to confirm that 1 is in its neutral (co-crystal) form as the 15N CS is ca. −95.2 ppm (considerably far from protonated nitrogen groups) and consistent with nonprotonated aromatic nitrogen atoms for a pyridine derivative,41 suggesting the formation of a co-crystal through a HB network composed of O−HCOOH···NBIP bonds. Molecular Salt 2. Figure 4a shows compound 2. As in the previous example, the AA molecules present a torsion angle C3C4C5C4 of −60.9(1)° very different from its almost linear conformation in pure AA (176.78 and 169.96).28 The supramolecular packing is based on bifurcated +N−HPIP··· OCOO- interaction [1.76(3) and 2.51(3) Å] reinforced by further +N−HPIP···OCOO- [1.73(3) Å], turning one of the G



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Figure 7. (a) Packing structure of 3 highlighting (with different colors) the interactions formed between water, PIP and AA molecules; (b) detail on R34(13) synthon and (c) R46(12) synthon. Table 2 shows all the intermolecular distances depicted here.

Figure 8. View along a of the packing structure of 4 showing the supramolecular interactions. The atomic disorder in the hydrogen atoms of AA carboxylic group is highlighted with blue dashed lines.

the carboxylic/carboxylate groups as there are two molecules of AA in the asymmetric unit. Two of these resonances observed at ca. 175.7 and 176.5 ppm are ascribed to COOH carbons, while the other two resonances, found ca. 179.7 and 180.4 ppm, are associated with COO− carbons (Table S3, see Supporting Information). Note that COOH carbons are more shielded than COO− groups. The single carbonyl resonance found in 1 falls within the COOH region defined above thus evidencing that half the carbonyls in 3 are in their carboxylate form. 15N CPMAS spectrum (see Figure 13c) shows a CS at ca. −350 ppm, which again supports the existence of a molecular salt. Molecular Salt 4. Solid 4 is a molecular salt, with a 1:1 stoichiometry, where the protons from carboxylic acid of AA were transferred to the nitrogen atom of MORPH. The C−O distances [1.228(4), 1.278(4), 1.277(4), 1.239(4), 1.280(4) Å] are typical of carboxylate (COO−) groups.

(Figure 7b,c). The AA molecule adopts its almost linear conformation (∼178°), for which it is determinant the type of HB established. Compared to the SSNMR data obtained for compound 2 (anhydrous AA:PIP), the 1H MAS spectrum of the hydrate form (compound 3), displayed in Figure 11c, provides sufficient resolution to distinguish the four types of protons, described previously, involved in strong HB: hydrogen bonded water protons (7.3 ppm); one O−H···O− HB (16.1 ppm) and two +N−H···O/+N−H···O− (13.4 and 10.4 ppm). The unambiguous assignment of the different types of HB observed in the 1H MAS NMR spectra was assisted by using the GIPAWDFT 1H CS calculations and the results are summarized in Table S2 (see Supporting Information). 13C CPMAS spectrum (see Figure 12c) is more complex compared to its anhydrous counterpart (2) and shows four 13C resonances associated with H



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Figure 9. 1H GIPAW-DFT CSs shown on the asymmetric unit of 4. Only CSs pertaining to H-bond involved protons are shown (white spheres); remaining protons have been omitted. X−H···O H-bonds (X = N, O) are shown as yellow dashes, along with the corresponding bond lengths in Å. The annotated 1H CSs correspond to the theoretical CSs shown in Table S2. Figure 11. 1D 1H MAS NMR spectra of (a−d) compounds 1−4 recorded at B0 = 16.4 T. Spectra (a−c) were acquired with νr = 60 kHz and spectrum (d) at νr = 30 kHz.

the proximities to their respective proton acceptor/donor oxygen atoms after DFT geometry optimization. In fact, these hydrogen atoms are approximately equidistant from the proton acceptor and donor oxygen O···H···O showing O···H and H··· O distances of 1.21 and 1.22 Å for O5···H···O5 and 1.23 Å for O3···H···O3 (Figure 9). The fact that such hydrogen atoms are placed in-between both oxygen atoms may justify their strong downfield shifts and the observed crystallographic atomic static disorder mentioned above (50%). Harris et al. reported the evolution of calculated 1H CS as a function of the O−H distance18 and showed that the highest predicted 1H CS is at ∼20−21 ppm for a O−H crystallographic distance of ∼1.2−1.3 Å, which is in excellent agreement with our results (i.e., 1.22− 1.23 Å in Figure 9). Figure 9 shows the asymmetric unit of 4 highlighting the HB network in dashed lines. A “normal” location (closer to one of the oxygen atoms involved in the HB) of the 1H resonance associated with this proton would necessarily appear at much lower CS as confirmed for the remaining O−H···O HB resonance (Figure 11d) observed at 15.6 ppm. Two additional HB are assigned to N−H···O (13.1 and 9.4 ppm). The full assignment of 1H CSs performed by comparing experimental and calculated 1H CSs is presented in Table S2 (see Supporting Information). The large difference between exp. and calc. 1H CSs values (ca. 1.5 ppm) for the peaks at 13.1 and 9.4 ppm (ascribed to NH2 protons) may be due to the dynamic behavior of such protons that is not considered in the DFT calculations performed in this work and which usually has an important effect in the theoretical determination of 1H CSs.43 From the 13C CPMAS spectrum (Figure 12d) of 4, four carbonyl resonances (between 175 and 180 ppm) clearly show that two AA molecules are present in the asymmetric unit. In

Figure 10. (a) Packing structure of 5 evidencing the interactions between AA and DABCO molecules. Oxygen atom (O4) disorder is highlighted with blue dashed lines; (b) representation showing the mirror plane (blue) containing the AA molecule.

As shown in Figure 8 the packing of 4 is based on +N−H··· OCOOH and OHCOOH···OCOO− HB giving rise to R44(28) synthon defined by two MORPH and two AA molecules. This synthon, repeated along the (120) plane, is based on OHCOOH···OCOO− interactions, coupled with the additional simple and bifurcated + N−H···OCOO− interactions. The hydrogen atomic static disorder in AA carboxylic groups (highlighted) is represented with a 50% occupation factor. To determine unequivocally the exact position of the hydrogen atoms, we employed GIPAW-DFT geometry optimization of protons followed by 1H CS calculations, which were then compared with experimental ones. The former uses a quantum mechanical approach instead of empirical methods to locate adequately the hydrogen positions (Figure 9). Compound 4 shows several high-frequency shifted 1H CSs above 12 ppm. Unusually strong HBs appear at ca. 19.3 (O3··· H···O3) and 20.1 (O5···H···O5) ppm (Figure 11d), which correspond to the acidic protons engaged in HB involving two carboxylic acid moieties. These two exceptionally highfrequency 1H CSs can be explained through the analysis of I



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Figure 12. 1D 13C CPMAS NMR spectra of (a−d) compounds 1−4. All spectra were acquired at B0 = 9.4 T, using νr = 10 kHz with the exception of compound 3 (B0 = 16.4 T and νr = 12 kHz).

Figure 10 shows the crystal packing of the obtained 2:1 molecular salt with two carboxylic groups of different AA deprotonated molecules (the C−O bond distances are 1.195(9) and 1.309(10), 1.214(13), and 1.147(10) Å) resulting in double protonation of DABCO molecules. In contrast to what was reported by Braga and co-workers,17 i.e., the crystal packing of their co-crystal is based on a chain of alternated AA with DABCO; in our form (5) the packing (Figure 10a) involves a AA dimer alternated with one DABCO molecule along the c-axis. These chains, based on two chargeassisted HB, O−HCOOH···OCOO−, and +N−H···OCOO− interact among them through a O−HCOOH···OCOOH HB, forming a sheet (010). Because AA molecules are within a symmetry plane and three of the oxygen atoms also belong to the plane, atom O4 is represented in the two possible positions (50% occupation) (Figure 10b).

4. DETERMINATION OF PHYSICOCHEMICAL PROPERTIES In this section we present and discuss the thermal stability and preliminary solubility studies determined for all the synthesized compounds. From DSC-TGA (Figures 14 and 16) data compounds 1 and 2, show a higher melting point (MP) (145 and 144 °C respectively) when compared with pure AA (109− 111 °C). HSM analysis (Figures 15 and 17) confirms DSCTGA results and no other transformations or alterations were detected. DSC-TGA analysis was not performed for compound 3 because it was not stable enough (see Figure 5) to perform the analysis. However, according to HSM data (Figure 18) using one single crystal protected in fombolin oil, the measured melting point was approximately 81−82 °C, i.e., about 64 °C lower than 1 and 2 (Figures 15 and 17). According to the DSC-TGA and HSM data (Figures 19−22), melting points determined for compounds 4 and 5 (85.6 and 89.9 °C) are also lower than that of AA. HSM confirmed these results. The results determined here do not follow the melting point rule: co-crystals whose co-formers have a high MP than the API should lead to higher MP multicomponent forms.27 This

Figure 13. 1D 15N CPMAS NMR spectra of (a−d) compounds 1−4. All spectra were acquired at B0 = 9.4 T, using νr = 10 kHz with the exception of compound 3 (B0 = 16.4 T and νr = 12 kHz).

addition, the 15N CPMAS spectrum (Figure 13d) also shows two resonances, consistent with the existence of two molecules of MORPH in the asymmetric unit. Therefore, SSNMR confirms a 1:1 stoichiometry of AA:MORPH with Z′ = 2. Analyzing the 15N CPMAS spectrum of this compound (Figure 13d), the CS is similar to the ones obtained for compounds 2 and 3, around −350 ppm, also supporting that 4 is in its molecular salt state. Molecular Salt 5. Braga and co-workers had already reported the formation of a co-crystal between AA and DABCO under similar conditions to the ones tested in this work. The authors reported that the co-crystal form was obtained in a mixture with an unknown phase.17 According to the ΔpKa rule one would expect the formation of a molecular salt rather than a co-crystal (ΔpKa = 3.65). In our study, however, we have isolated the same phase as Braga et al. plus another crystalline phase (possibly the unknown phase reported by the authors), here reported as molecular salt 5. J



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Figure 19. DSC (at black curve) and TGA (at blue curve) for 4, in which melting point is observed at 85.6 °C.

Figure 14. DSC (black) and TGA (blue) for 1, in which melting point is observed at 144.6 °C.

Figure 15. HSM for 1 at (a) 21 °C; (b) 141 °C − starting of the melting process; (c) 145 °C − melting.

Figure 20. HSM for 4 at (a) 21 °C; (b) 85.4 °C − start of the melting process; (c) 87.6 °C − melting.

Figure 16. DSC (at black curve) and TGA (at blue curve) for 2, in which melting point is observed at ca. 144.1 °C.

Figure 21. DSC (at black curve) and TGA (at blue curve) for 5, in which melting point is observed at 89.9 °C.

Figure 17. HSM for 2 at (a) 29 °C; (b) 141 °C − start of the melting process; (c) 145 °C − melting.

Figure 22. HSM for compound 5 at (a) 21.6 °C; (b) 90.9 °C − start of the melting process; (c) 91.2 °C − melting.

145 °C, and with DABCO (MP ≈ 156 °C) we obtain a salt with a MP of ∼90 °C. It is also important to notice that the sole introduction of a water molecule in compound 2, obtaining 3, completely alters the HB network, changing drastically the MP from 144.1 to 81.3°. Preliminary solubility studies were carried out for AA, compounds 1, 2, and 4. However, it was not possible to test the solubility for compounds 3 and 5 once; as explained before, the hydrate 3 is very unstable and converts readily to the anhydrate

Figure 18. HSM of 3 at (a) 24 °C; (b) 81 °C − start of the melting process; (c) 82 °C − melting.

principle is, as we know, highly debatable,44 and we tend to agree with these authors, our results being a proof of that when using BIP (MP ≈ 114 °C) we obtain a co-crystal with MP = K



Article

Table 3. Solubility, Thermal Stability, and Supramolecular Interactions of Pure AA and Products 1−5 compound AA 1 2

solubility in water

solubility in methanol

10 mg in 7.5 mL 10 mg in 8.0 mL 10 mg in 0.5 mL

10 mg in 0.3 mL 10 mg in 0.3 mL 10 mg in 1.1 mL

3 4 5 a

10 mg in 3.5 mL

10 mg in 0.5 mL

melting point ( °C)

filled space (%)

density

109−111

68.3

1.260

OHCOOH···OCOOH

144.6

70.1

1.294

OHCOOH···N

144.1

69.0

1.237

NH···OCOO−

81.3

70.0

1.269

OHCOOH···OCOO−, OH(H2O)···OCOO-, OH(H2O)···OCOOH, NH2+···OCOO−, NH2+···OH(H2O)

85.6

70.3

1.270

NH2−···OCOO−, OHCOOH···OCOO−

89.9

68.1a

1.220

OHCOOH···OCOO−, NH+···OCOO−

supramolecular interactions

Filled space considering a completely occupied position for oxygen atom of carboxylic group.

Our thermal stability results confirmed the hypothesis from different authors: there is no definitive rule when predicting the MP of the multicomponent form, co-crystals whose co-formers have a high MP than the API should lead to higher MP multicomponent forms.27 The thermal behavior strongly depends on the supramolecular structure and on the strength of HB network. Solubility tests led us to obtain a new form that presents higher solubility in water (compound 2) and thus could avoid the use of alcoholic solutions in the final formulations, presenting a promising insight in the search for safe secondary amine derivatives.

2, and compound 5 was obtained concomitantly with the respective co-crystal17 and all isolation attempts failed. Table 3 presents a brief summary of the determined physicochemical properties. The most soluble crystalline solid form in water is 2 (molecular salt) and the less soluble is 1 (cocrystal, ∼ to AA). Molecular salts are expected to be, in general, more soluble in water than the pure API due to their higher polarity. Crystalline form 4, another molecular salt, also exhibits a good improvement in the API water solubility. In contrast, AA and compounds 1 and 4 exhibit similar solubility in methanol, while compound 2 is much less soluble in methanol.

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5. CONCLUSIONS The purpose of this work was to test the reactivity of AA with different co-formers, based on crystal engineering principles, in order to obtain multicomponent forms with improved physicochemical properties. To attain our purpose, the complete structural characterization of the new synthesized solid forms of AA is of utmost importance and has been achieved using single crystal X-ray diffraction and SSNMR supported by GIPAW-DFT calculations. The new forms were obtained using “green” synthetic techniques. Crystal structures of the five new forms were obtained using X-ray diffraction and confirmed by SSNMR. In the case of compound 4 (AA:MORPH molecular salt) only the combined use of SSNMR with DFT geometry optimization allowed defining the exact position of the hydrogen atoms in O3 and O5. The high-resolution 1H SSNMR at very-fast magicangle spinning rates (up to 65 kHz) showed an unusuallly strong HB interaction associated with the hydrogen disorder and confirmed by the presence of 1H resonances shifted to very high frequencies (up to ca. 20.1 ppm). 13C CPMAS and 15N CPMAS analysis were used to confirm which type of multicomponent solid form (co-crystal or molecular salt) was obtained with AA. Structural results have shown that the formation of the charged assisted +N−H···OCOO− HB was the main cause for the disruption of R22(8) synthon (carboxylic-carboxylic), surpassing the formation of OHCOOH···OCOO− interactions, that when present were always between two API molecules and never with the co-former. From stability studies we can conclude that the hydrated piperazine salt 3, readily converted to 2 at ambient RH, and that even in controlled atmosphere (%RH = 75, 50, and 25%) there was always conversion as the bulk mixture was enriched in the anhydrous salt (slowly at 75% RH (∼4 days) and quite fast at 25%RH (∼1.5 day)).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01057. Figures S1−S5 present the powder diffractograms obtained for all the solid forms, Table S1 presents FTIR data, Tables S2−S3 present SSNMR data (PDF) Crystallographic files for 1−5 (CCDC 1415065− 1415069) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*(M.T.D.) E-mail: [email protected]. *(L.M.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors acknowledge Fundaçaõ para a Ciência e a Tecnologia (FCT) for funding: Projects PTDC/CTM-BPC/122447/2010, RECI/QEQ-QIN70189/2012; for the awarded development Grant (IF/01401/2013) to L.M., for the postdoc grants SFRH/ BPD/78854/2011, SFRH/BPD/65978/2009, and SFRH/ BPD/64752/2009 awarded to V.A, M.S., and S.M.S., respectively, to the Ph.D. Grant SFRH/BD/93140/2013 awarded to I.C.B.M. and the funded R&D project EXPL/ QEQ-QFI/2078/2013. This work was developed in the scope of projects CICECO-Aveiro Institute of Materials (UID/ ́ CTM/50011/2013) and Centro de Quimica Estrutural- IST (UID/QUI/00100/2013) financed by national funds through the FCT/MEC and when applicable cofinanced by FEDER under the PT2020 Partnership Agreement. The Portuguese NMR Network (RNRMN) is also acknowledged. L



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Article

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