Enhancing adamantylamine solubility through salt formation: novel

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Enhancing adamantylamine solubility through salt formation: novel products studied by X-ray diffraction and Solid-state NMR Inês C. B. Martins, Mariana Sardo, Edith Alig, Lothar Fink, Martin U. Schmidt, Luis Mafra, and M. Teresa Duarte Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01830 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 30, 2019

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Crystal Growth & Design

Enhancing adamantylamine solubility through salt formation: novel products studied by X-ray diffraction and Solid-state NMR Inês C. B. Martins,1,2,3 Mariana Sardo,2 Edith Alig,3 Lothar Fink,3 Martin U. Schmidt,3 Luís Mafra2*, M. Teresa Duarte1* 1CQE

– Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal 2CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal 3Institut fuer Anorganische und Analytische Chemie, J. W. Goethe Universitaet, Frankfurt am Main, Germany *e-mail: [email protected], [email protected]

ABSTRACT

The reactivity of the neuroleptic drug adamantylamine (ADA) towards aliphatic carboxylic acids, sulfone derivatives and aromatic amino-acids, was screened for the first time using simple mechanochemical methods. Seven new molecular salts structures were reported exhibiting improved physicochemical properties. To carefully characterize these compounds, multiple complementary techniques were combined: single crystal and powder X-ray diffraction, 13C / 15N solid-state NMR and FTIR-ATR spectroscopies, employed to solve co-crystal/salt ambiguities. In all molecular salts, the crystal packing is supported on a common synthon, a N-H+(ADA)⋯O-(coformer)

charge assisted hydrogen bond. Different supramolecular arrangements were obtained

induced by the size of the counter-ions as well as their complementary functional groups. Two salts, with glutaric and methanesulfonic acids, presented higher solubility than the commercially available pharmaceutical product.

1. Introduction Launching new pharmaceutical products in the market is expensive and time consuming, even when hundreds of new chemicals can be produced and identified by means of combinatorial chemistry and high-throughput screening.1 Selecting the lead compound and ultimately isolate suitable active pharmaceutical ingredients (APIs), is a long process and several issues regarding solubility, dissolution profiles and thus bioavailability, can still arise.1, 2 An alternative to the pharmaceutical industry has been the development of new strategies to improve the efficacy of “old” APIs, enhancing their physicochemical properties without changing pharmacological behavior.1 Among these strategies, the synthesis of API multicomponent forms, such as cocrystals and salts, is widely used.3-7 Understanding API physicochemical behavior and of their multicomponent crystal forms, relies on the available information of their supramolecular arrangement.7,

ACS Paragon Plus Environment

8

For that, structural

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

information is needed recurring to X-ray diffraction analysis, both single crystal (SCXRD) and powder. The use of X-ray powder diffraction powder (XRPD) for structure determination, is a powerful structural tool and its potential in the pharmaceutical field has been exploited in several works, although it is not a trivial assignment.8, 13-16 Solid-state NMR (SSNMR) has been used as a complementary technique to probe the short-range local structure, helping in defining the position of light atoms, such as hydrogens16-19 and study packing interactions such as hydrogen bonds (HBs). In addition, 15N and 13C SSNMR has also been used for unambiguous confirmation of proton-transfer thus helping to discriminate between co-crystals and salts in compounds containing nitrogen atoms.7, 19 Adamantylamine (ADA, Figure 1) is a low-affinity non-competitive N-methyl-D-aspartate receptor antagonist widely used in the treatment of Parkinson’s disease.20, 21 Some studies indicate that ADA can also be used to treat influenza (H5N1) as well as depression, alone or combined with other drugs.22, 23 ADA free base exhibits low water solubility (1.03 mg/mL) and is currently used in its hydrochloride form (ADA.HCl), in Europe and USA, with the trade name Virosol®, Virofral®, Symadine® or Symmetrel®.19 When administrated in this form, high concentration levels in blood plasma are achieved rapidly.24 This observation has been associated with some toxic effects on the central nervous system, causing hallucinations and nervousness.24 For that reason, in Central Europe, a different ADA salt (ADA sulfate) was synthesized and tested, revealing some advantages, such as slow concentration increase in blood plasma. This effect allowed the possibility to increase the daily dosage for treating long-term Parkinson’s disease.25 Very recently, a work published by Roy and co-workers, reported the combination of ADA with peptides, containing a non-steroidal anti-inflammatory drug (indomethacin), to produce supramolecular gels with potential biomedical applications.26 Furthermore, these gels may be used as injectable self-delivery systems for improving drug biological properties. Until today, no other works reporting the synthesis of ADA salts to improve physicochemical/biological properties were published.26 Taking this into account, and considering the low ADA aqueous solubility, as well as the limitations of the commercially available hydrochloride form, we present herein the synthesis and characterization of seven new ADA molecular salts with improved solubility and thermal stability properties. For this purpose, we combined ADA with four different groups of GRAS (generally recognized as safe) co-formers composed by aliphatic carboxylic acids – oxalic (OXA), glutaric (GLUTA), glycolic (GLY) and tartaric (TART) acids; sulfone derivatives – methanesulfonic (METHA) and sulfanilic (SULFA) acids, and saccharin (SAC); aromatic amino-acids – 3- and 4-aminobenzoic acids (3-AMINO and 4-AMINO respectively) and non-aromatic amino-acids – aspartic (ASPA) and glutamic (GLUTAM) acids; insaturated aliphatic acids – maleic (MALA) and trans-aconitic acids; and aromatic acids – homophtalic (HOMA) and gallic (GALLA) acids (Figure 1).


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The use of SCXRD and XRPD with SSNMR data, was employed to validate the formation of molecular salts and identify specific interactions between the API and co-formers.

Figure 1. General experimental conditions and products obtained in the reactions between ADA and aliphatic acids, sulfone derivatives, aromatic and non-aromatic amino-acids, unsaturated aliphatic acids and aromatic acids.

2. Experimental section Synthesis. All reagents were purchased from Sigma and used without further purification. Compounds were mechanochemically synthesized either using LAG with methanol or neat grinding. Compound ADA:SAC (VI) was isolated as a di-hydrate and other hydrated phases were detected in the freshly ground salts of ADA:OXA (I), ADA:METHA (V) and ADA:SULFA (VII). A detailed description of the experimental conditions can be found in the Supplementary Information (ESI). For ADA:OXA (I), ADA:METHA (V), ADA:SAC (VI), ADA:SULFA (VII), and ADA:4-AMINO (IX), SCXRD analysis was used for structural characterization as good single crystals were obtained, after recrystallization in a methanol solution. For ADA:GLUTA (II) and ADA:3-AMINO (VIII), no crystals grew and hence structure solution was obtained using XRPD.



Single Crystal X-ray Diffraction (SCXRD). X-ray diffraction data for I, V, VI, VII and IX were collected on a Bruker AXS-KAPPA APEX II diffractometer with graphite-monochromated radiation (Mo K,  = 0.17069 Å) at 296 K or 150 K. The X-ray generator was operated at 50 kV and 30 mA and the X-ray data collection was monitored using APEX2 program. All data were corrected for Lorentzian, polarization and absorption effects using SAINT27 and SADABS28 programs. Crystals were mounted on a loop with Fomblin© protective oil. Data collection and refinement details are listed in Table 1. SIR97,29 SHELXS-9730 and SHELXT were used for structure solution and SHELXL-9749 was used for full matrix least-squares refinement on F2. These three programs are included in the program packages WINGX-Version 1.80.0531 and Olex2.32 Non-hydrogen atoms were refined anisotropically. For compounds I and VI, hydrogen atoms were inserted in idealized positions, whereas for V, VII and IX were located from electron density map. All hydrogen atoms were allowed to refine in the parent heteroatom. MERCURY 3.933 was used for packing diagrams. Table S1 shows details on the HB distances and angles, obtained using PLATON.34 X-ray powder Diffraction (XRPD). Data was collected in a D8 Advance Bruker  – 2 diffractometer, with copper radiation (Cu K 1,  = 1.5406 Å) and a secondary monochromator, operated at 40 kV and 40 mA. For temperature variation, the diffractometer was equipped with an Anton Paar chamber HTK 16N and a temperature control unit Anton Paar TCU 2000N. MERCURY 3.933 was used to obtain the calculated diffraction patterns from SCXRD data. Bulk purity was ascertained comparing experimental XRPD patterns with the calculated ones obtained from SCXRD data (Figures S1 to S5). For compounds VI and IX the experimental and theoretical XRPD patterns overlap proving that, not only the reactions were complete, but also that the bulk is representative of the chosen crystal. In compounds I, V, VII and VIII, a second phase, present in small quantities, was detected. For compounds I, V and VII the secondary component was identified as the hydrated one, confirmed by DSC-TGA (Figures 14, S10 and S11). Structure solution with XRPD. For compounds II and VIII data collection was performed at room temperature on a STOE Stadi-P diffractometer equipped with a focussing Ge(111) monochromator and a linear position-sensitive detector, using Cu K 1 radiation ( = 1.5406 Å). Sample was contained in a rotating glass capillary with 0.7 mm diameter. Data was collected from 2 to 80 in 2θ with a step width of 0.01. Software WinXPOW was used for data acquisition. Powder patterns of compounds II and VIII were indexed using DICVOL.35 Structure solution was achieved by the real-space method using simulated annealing routine implemented in DASH.36 The starting models of ADA, GLUTA and 3-AMINO molecules were obtained from the cif files of Cambridge Structural Database37 with the entries DIGDOM10,38 GLURAC0239


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and AMBNZA01 respectively.40 During the simulated annealing, no restriction in the degrees of freedom of each molecule was applied. Rietveld refinement was carried out using TOPAS41, 42 for the full 2θ range. A Pawley fit was first performed and in the following refinement steps, the scale factor, background, atom positions and isotropic displacement parameters were refined. For II, three different isotropic displacement parameters were refined: one for the non-hydrogen (non-H) atoms of the ADA molecule, another for the carbon and nitrogen atoms of the GLUTA moiety and a parameter for the oxygen atom of GLUTA moiety. For the hydrogen atoms of both ADA and GLUTA, the values were set as Biso(H)=1.2*Biso(non-H) respectively. Two different isotropic displacement parameters were refined for VIII: one for the non-H atoms of each ADA and 3-AMINO molecules, and another one for the hydrogen atoms of ADA and 3AMINO (Biso(H)=1.2*B(non-H)). For both compounds II and VIII, no preferred orientation was found and hence no correction was required. Restrains were applied for all bond lengths, angles and planar rings/groups. Data collection and structure refinement details are summarized in Table S2. Table S3 contains all the information about HB distances and angles for all the salts. Thermal stability Studies. Combined TG-DSC measurements were carried out on a SETARAM TG-DTA 92 thermobalance under nitrogen flow with a heating rate of 10 C.min-1. The samples weights were in the range 5-10 mg. Hot-Stage Microscopy (HSM). Hot-stage experiments were carried out using a Linkam TP94 device connected to a Linkam LTS350 platinum plate. Images were collected, via the imaging software Cell, with an Olympus SZX10 stereomicroscope. Crystals were placed on an oil drop to allow a better visualization of solvent or decomposition products release. Solid-state Nuclear Magnetic Resonance (SSNMR). The magic-angle spinning (MAS) solidstate NMR spectra were acquired on Bruker Avance III 400 and 700 spectrometers operating at a B0 field of 9.4 and 16.4 T, respectively. The 1H/13C/15N Larmor frequencies were 400.1/100.6/40.6 and 700.1/176.1/70.9 for the 400 and 700 spectrometers, respectively. All

13C

and

15N

NMR

experiments were performed on the 9.4 T spectrometer and recorded at a spinning rate of 12 and 5 kHz using a double-resonance 4 mm and 7 mm Bruker MAS probes, respectively. 1H NMR experiments were recorded on the 16.4 T spectrometer, using a 1.9 mm double-resonance Bruker MAS probe with a spinning rate of 40 kHz. 1H, 13C and 15N chemical shifts are quoted in ppm from TMS (0 ppm) and glycine (C=O at 176.03 and NH3+ at −347.6 ppm), respectively. The 1H, 13C and 15N 90° pulses to optimize 1D cross-polarization (CP) MAS NMR experiments were set to 2.4, 5.1 and 4.4 μs corresponding to radio frequency (RF) field strength of 104, 49 and 57 kHz, respectively.



The 1H-13C CPMAS NMR spectra were acquired using a contact time of 2 ms, recycle delay (RD) of 4 s, 1H and 13C RF field strength of 79 (50−100% RAMP-CP shape) and 49 kHz, respectively. The CP step for 1H-15N CPMAS experiment was performed with a contact time of 2 ms, RD 4 s, 1H

and

15N

RF of 90 (50−100% RAMP-CP shape) and 57 kHz, respectively. During the

acquisition of 13C and 15N CPMAS NMR experiments, a SPINAL-6443 1H decoupling with a pulse length of 4.75 and 5.5 μs at a RF field strength of 80 and 83 kHz was employed, respectively. Fourier Transform Infrared spectroscopy with Attenuated Total Reflectance (FTIR-ATR). The FTIR spectra were obtained in absorbance mode using a FTIR Bruker Tensor 27 instrument with a Golden Gate ATR (Attenuated Total Reflectance). The measurements were recorded in the range of 350-4000 cm-1, 4.0 cm-1 of resolution, 256 scans and applying atmosphere and background correction. Data are presented in Table 4 and Figures S6 to S9. Solubility studies. Preliminary solubility studies were carried out by dissolving ~10 mg of each molecular salt in water, gradually added until complete dissolution. The amount of added water allowed the determination of empiric solubility values and ADA was used for comparison.

3. Results and discussion In this work we intended to obtain safe salts of ADA, so co-former selection was based in its biological safety (GRAS) and in the ΔpKa rule (if ΔpKa ≥ 3 salts are obtained, for ΔpKa ≤ 1 cocrystals).44-48 ADA is a strong base (Figure 1), possessing only one functional group, so combining it with strong to moderate acids yielded salts in a 1:1 stoichiometry. Compound IV was isolated as a di-hydrate, hence a 1:1:2 salt. New compounds were obtained in all the synthetic procedures (see ESI) referred in Figure 1. Here we will only present results for the seven products we could isolate and identify. The packing features of the seven new crystalline forms of ADA (I, II, V – IX), together with their solubility and thermal stability properties, are presented and thoroughly discussed. A combination of SCXRD, XRPD SSNMR and FTIR-ATR studies were performed for all compounds in order to confirm and validate the formation of molecular salts. In addition, a set of XRPD analysis with temperature variation (XRPD-VT) was performed for the samples whose thermal behavior, observed by DSC-TGA, has shown extra thermal events. Structural Analysis


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ADA:OXA (I). The supramolecular arrangement in ADA:OXA (2:1) molecular salt, is based on N-H+(ADA) ⋯O-(OXA) HBs with distances in the range dH···O = 1.89 to 2.05 Å, responsible for creating a mosaic-like pattern within bc plane (Figure 2a). Each hydrogen atom of ADA protonated primary amine is interacting with different OXA carboxylate groups. A lamellar packing is observed with two layers of ADA aliphatic moiety (apolar domain), facing each other, alternating with a polar domain containing an extended network of HBs between OXA carboxylate group and ADA protonated primary amine (Figure 2b). The distances found for CO bonds, dC-O = 1.242(3) and 1.257(2) Å, are typical of carboxylate groups indicating that the proton transfer occurred, confirmed by FTIR-ATR and SSNMR analysis (see below).

Figure 2. a) view along a evidencing N-H+(ADA)⋯O-(OXA) interactions in a mosaic-like fashion mode; b) view along b showing the lamellar effect. Aliphatic hydrogen atoms were omitted for clarity.

ADA:GLUTA (II). The powdered sample was indexed as an orthorhombic unit cell, using DICVOL41 in DASH42 program, without ambiguity (see Table 2). Using Hofmann’s volume increments,49 the expected molecular volume was 392.4 Å3, corresponding to 4 molecules per unit cell (Z = 4) for a unit-cell volume of 1541.5(1) Å3. The structure was solved by the real-space method and refined by the Rietveld method (Figure 3).



Figure 3. Rietveld refinement plot displaying the measured powder pattern (grey dots), the calculated powder pattern (red solid line), the difference curve (blue) and the reflection positions (vertical black dashes).

The reaction of ADA with GLUTA yielded a molecular salt with Z’=1. The HB network is based on N-H+(ADA)⋯O-(GLUTA), dH···O = 1.914 (11) and 1.975 (12) Å, complemented by bifurcated NH+(ADA) ⋯O-(GLUTA), dH···O = 2.252 (12) and 2.329 (12) Å, enabling the formation of a 𝑅24(8) synthon50 (Figure 4a). An additional O-H(GLUTA)⋯O-(GLUTA) HB, dH···O = 1.620 (11) Å, acts as a bridging interaction, completing a 𝑅68(40) synthon cage, where the aliphatic domains of two ADA molecules are pointing towards each other (Figure 4b). The C-O distances found in GLUTA molecules, dC-O = 1.247 (5), 1.249 (5) Å and 1.209 (4), 1.277 (4) Å, are typical of carboxylate and carboxylic groups respectively. FTIR-ATR and SSNMR data support the formation of a molecular salt in a 1:1 stoichiometry. The overall packing arrangement presents a zeolite-like structure, with the ADA molecules occupying the pores.

Figure 4. a) view of the HB network in II, based on 𝑅24(8) synthons; b) view along c detailing the relative positioning of the two ADA molecules. Aliphatic hydrogen atoms were omitted for clarity.


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ADA:METHA (V). The 1:1 molecular salt packing arrangement, is supported by strong NH+(ADA)⋯O-(METHA) HB interactions, dH···O = 1.883(16), 1.917(17) and 1.994(14) Å, best described as 𝑅66(18) synthons, in which three oxygen atoms of METHA are interacting with three N-H hydrogen atoms of ADA (Figure 5a). The synthon framework extends along the bc plane. Similar to compound I, a lamellar packing is observed and again the ADA aliphatic domains face each other. These apolar domains alternate with domains containing the extended HB network, based on METHA sulfonate oxygen atoms interacting with ADA protonated amine (Figure 5b).

Figure 5. a) formation of the 𝑅66(18) synthon between ADA and METHA molecules through N-H+(ADA)⋯O-(METHA) HB interaction; b) lamellar packing, in a view along c, evidencing the polar and apolar domains. Aliphatic hydrogen atoms were omitted for clarity.

ADA:SAC (VI). A 1:1 di-hydrated salt was obtained. In the supramolecular arrangement of compound VI, water molecules play an important role defining the HB network based on NH+(ADA)⋯Oamide(SAC) [dH···O = 1.89 Å], N-H+(ADA)⋯O(water) [dH···O = 1.93 and 1.96 Å], O-Hwater⋯ Oamide(SAC) [dH···O = 1.91 Å], and O-Hwater⋯OSO2N(SAC) [dH···O = 1.99 and 2.12 Å] interactions (Table S3). Water molecules act as bridging blocks between ADA and SAC generating 𝑅35(10) and 𝑅44 (12) synthons, centred in one water molecule (Figure 6a). In a view along b, (Figure 6b) an alternated packing of apolar and polar domains is observed. Here the polar domains face each other while in the apolar domain ADA aliphatic residues are interpenetrated. The alternation is best seen in a view along c, evidencing the sigmoidal arrangement of the polar domain, extending along a (the HB network runs in ac plane). The crystal packing is further reinforced by π-π interactions among SAC molecules, dπ···π = 3.404 (12) Å (Figure 6b), as well as by C-H⋯π interactions between ADA and SAC molecules, dH···π = 2.788 (8) Å (Figure 6d).



Figure 6. a) 𝑅44(12) and 𝑅35(10) synthons formed between ADA, SAC and water molecules; b) packing assembly evidencing the HB among ADA, SAC and water molecules, emphasizing π-π interactions between SAC molecules; c) packing interactions along c, evidencing the sigmoidal arrangement of SAC and water molecules; d) C-H⋯π interaction between ADA and SAC molecules. Some aliphatic hydrogen atoms were omitted for clarity.

ADA:SULFA (VII). The reaction of ADA with SULFA yields a molecular salt, in a 1:1 stoichiometry, as depicted in Figure 7a. ADA is alternately interacting with SULFA molecules, in a zig-zag mode, through N-H+(ADA)⋯O-(SULFA) HB, dH···O = 1.931(1), 1.940(1) and 1.963(2) Å, forming 𝑅44(12) and 𝑅24(8) synthons (Figure 7b). An additional N-HNH2(SULFA)⋯O-(SULFA) HB interaction, dH···O = 2.280(2) and 2.340(2) Å (Table 3), allows the formation of a 𝑅68(40) synthon, where ADA aliphatic domains are pointing to each other. This structure arrangement is further supported by C-H⋯π interaction, dH···π = 2.953(2) and 2.787(1) Å, between ADA hydrogen atoms and the aromatic rings of SULFA molecules (Figure 7c). Similar to compound II, the overall packing arrangement presents a zeolite-like structure, with ADA molecules occupying the pores. The pores have similar dimensions (both based on 𝑅68(40)) but in this case ADA molecules are more tightly held, due to the referred C-H⋯π interaction.


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Figure 7. a) zig-zag arrangement of ADA and SULFA, evidencing the formation of 𝑅44(12) and 𝑅24(8) synthons; b) crystal packing showing the formation of the 𝑅68(40) synthon and C-H⋯π interactions (red and green) involving SULFA and ADA molecules. Some aliphatic hydrogen atoms were omitted for clarity.

ADA:3-AMINO (VIII). Similar to compound II, structure solution was successfully obtained using XRPD. A phase transition at Tmax = 188.1 ᵒC (Figure 17, section 3.5), was detected in the DSC trace (see below). This led us to compare the experimental XRPD patterns obtained for the “freshly ground” ADA:3-AMINO (Figure 8a) and for the sample heated at 213 ºC for 1h. Although it was impossible to index the diffractogram of the former, the powder pattern of the latter was easily indexed (Figure 8b and c).

Figure 8. XRPD patterns of VIII obtained from samples a) freshly ground; b) heated at 213 ºC (collected at room temperature); c) heated at 213 ºC (data collected at -50 ºC).

XRPD data collected at -50 °C (Figure 8c) was used for indexing and solving the structure. The sample was indexed as a monoclinic unit cell, using DICVOL41 in DASH42 program, without ambiguity (Figure 9). Lattice parameters are described in Table 2. The estimated volume of the molecules, calculated using Hofmann’s volume increments,49 is 404.1 Å3 which corresponds to 2 molecules per unit cell (Z = 2) considering the obtained unit cell volume of 769.65(1) Å3.



Figure 9. Rietveld refinement plot displaying the measured powder pattern (grey), the calculated powder pattern (red), the difference curve (blue) and the reflection positions (vertical black lines).

Compound VIII is a 1:1 molecular salt with a Z’ = 1. C-O distances found in 3-AMINO molecule are typical of carboxylate groups, dC-O = 1.268(4) and 1.269(3) Å, supported by FTIR-ATR and SSNMR data. The crystal packing is essentially characterized by strong N-H+(ADA)⋯O-(3-AMINO) [dH···O = 1.880 (10), 1.882 (9) and 1.976 (10) Å] HB interactions (Table S3), driving the formation of a 𝑅24(8) synthon defined by a tetramer (Figure 10a). This fragment expands in the 3 directions generating an alternated packing of polar and apolar domains (Figure 10b). The polar domains encompass not only the extended HB network, expanding along the ac plane, but also contain the planar 3-AMINO molecules. The alternated packing is reinforced by C-H⋯π interactions (ADA – 3-AMINO), dH···π = 2.941 (4) Å. The design is further reinforced by a N-H⋯π interaction, dH···π = 2.951 (9) Å, between two 3-AMINO molecules, leading to a face to face stacking.

Figure 10. a) packing interactions along b evidencing the 𝑅24(8) synthon formed between ADA and 3-AMINO molecules (N-HNH3+(ADA)⋯OCOO-(3-AMINO)) as well as the C-H⋯π and N-H⋯π interactions; b) packing along a with alternated polar and apolar domains. Aliphatic hydrogen atoms were omitted for clarity.


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ADA:4-AMINO (IX). From the reaction of ADA with 4-AMINO, a molecular salt in a 1:1 stoichiometry with a Z’ = 1 was obtained (Figure 11a). Again, salt formation is revealed by C-O distances, dC-O = 1.267(1) and 1.266(1) Å and further supported by FTIR-ATR and SSNMR data. Similarly to what was observed in salt VIII, both ADA and 4-AMINO molecules are interacting through 3 N-H+(ADA)⋯O-(4-AMINO) [dH···O = 1.802(18), 1.955(19) and 1.976(18) Å] forming a 𝑅24(8) synthon (Figure 11). But here, an additional N-H(4-AMINO)⋯O-(4-AMINO) [dH···O = 2.243(15) Å] HB, controls the arrangement leading to a very different packing and generating an 𝑅68(40) synthon, within which, the aliphatic domains of ADA molecules face each other, similar to the obtained for compounds II and VII. The different position of the amine group in 4-AMINO molecule (para position), with respect to the metha position in 3-AMINO, dictates the design, a zeolite-like structure, with the ADA molecules occupying the pores. Moreover, CH⋯π interactions, dH···π = 2.663 (4) Å, between ADA and 4-AMINO favor the specific orientation of ADA molecules.

Figure 11. Packing interactions highlighting the 𝑅24(8) synthon between ADA and 4-AMINO molecules (N-H+(ADA)⋯ O-(4-AMINO) HB). The presence of the N-H(4-AMINO)⋯O-(4-AMINO) HB interaction allows the formation of a 𝑅68(40) synthon, where ADA aliphatic domains are facing each other. Some aliphatic hydrogen atoms were omitted for clarity.

Solid-state NMR and FTIR studies Unambiguous confirmation of proton-transfer was performed using SSNMR and FTIR-ATR analysis. 15N NMR is a valuable source of information and often used to detect proton transfer in salt/co-crystal systems. Amine protonation is known to shift 15N NMR resonances towards more shielded chemical shift (CS) regions (lower CSs).19, 51, 52 In a recent contribution, 2D 15N NMR methods have also been used to measure N-H distances between the two individual components of a salt, co-crystal or continuum, enabling a clear distinction between the different forms.53 In this work, although 15N CPMAS NMR spectra show the nitrogen resonance (NH3+) shifting to



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lower CS values (ca. 5-8 ppm), compared to the NH2 group in pure ADA (Figure 12, Table 4), it is often difficult to assure that such differences provide an unambiguous proof of amine protonation regarding the wide range of CSs in which 15N nuclei resonate. Fortunately, quaternary carbons, directly bonded to a primary amine, are very sensitive to amine protonation. Batchelor et al.54 found that the 13C CS of quaternary carbons directly attached to an amine are shifted by ca. 5 ppm, towards higher CS values, upon protonation of an adjacent amine group. This is exactly what is observed in this work (Figure 13, Table 4). For all salts, the

13C

CS of the ADA

quaternary carbon (C1) bound to the primary amine (Figure 1a) increases between 4-5 ppm, compared to the C1 CS in neutral ADA compound, hence providing a strong evidence of amine protonation and the presence of salts. In the 13C CPMAS NMR spectrum collected on a “freshly ground” VIII, an additional carbonyl signal was observed (Figure 13). No NMR data was obtained for the high temperature phase, as it could not be obtained in sufficient quantity to fill the NMR sample holder. Table 4. Comparison of 13C and 15N NMR CSs for ADA and the multicomponent ADA salts (I, II, V – IX) along with the asymmetric stretching vibrational bands (υas) of the carboxylate moieties arising from five co-formers. Compound ADA ADA:OXA (I) ADA:GLUTA (II) ADA:METHA (V) ADA:SAC (VI) ADA:SULFA (VII) ADA:3-AMINO (VIII) ADA:4-AMINO (IX)

13C (ppm) Quaternary carbon 48.0 52.2 53.03 53.0 52.2 53.0 52.5 53.1

15N

(ppm)

-317.2 -324.1 -323.6 -* -324.1 -323.3 -323.5 -322.6

υas (cm-1) NA 1612.1 1714.8; 1614.3 1619.0 1624.2

*Signal not observed from the 15N CPMAS NMR spectrum.

FTIR-ATR analysis confirms the presence of carboxylate groups due to the presence of vibrational bands at ca. 1610-1620 cm-1, therefore supporting that proton transfer has occurred. For compounds I, VIII and IX, all carboxylic acids moieties are deprotonated (Figures S6, S8, S9 and Table 4). In the case of II, the FTIR spectrum (Table 4, Figure S7) shows two signals at 1714.2 cm-1 and 1614.3 cm-1, corresponding to the carboxylic and carboxylate asymmetric stretching bands, respectively.55


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Figure 12. 15N CPMAS NMR spectra for all salts. Red, blue and green rectangles highlight the 15N CS associated with ADA protonated amine, SAC and SULFA, respectively.



Figure 13. 13C CPMAS NMR spectra for all salts, showing the CS range for C1 (right side) and carboxylic/carboxylate resonances (left side). Filled circles in ADA structure indicate the position of the C1 quaternary carbon.

Thermal stability studies: DSC-TGA, XRPD-VT and HSM As mentioned, molecular salt I was never isolated as a bulk, hence, thermal stability studies were performed starting with the as-synthesized mixture. In the DSC-TGA trace, presented in Figure 14a, a phase transition, with a mass loss of 6.2%, was detected at Tmax=92.4 ºC and a second event (Ton=186.5ºC, Tmax=223.3 ºC), was observed. The first phenomenon was attributed to the release of two water molecules, corresponding to the percentage of mass loss, while the second involves amorphization followed by melting. Both events were ascertained by XRPD-VT (Figure 14b) as compound I was isolated at ca 90 ºC and amorphization was detected at ca 200, followed by


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melting. With these evidences, we can hypothesize that a mixture containing both anhydrous and hydrated forms was firstly obtained.

Figure 14. a) DSC-TGA of the mixture evidencing the transition to pure compound I; b) Experimental XRPD-VT; c) HSM images.

Compound II presented a phase transition at Tmax = 183.0 ºC (Figure 15, left) and, for this first event, the XRPD-VT analysis shows a complete amorphization, followed by melting. A second occurrence, involving a mass loss, at Ton = 191.4 ºC, Tmax = 205.3 ºC, corresponds to a recrystallization process observed in the XRPD-VT analysis. (Figure 15, right). The new crystalline phase is probably a decomposition product and melts above 300 ºC.



Figure 15. DSC-TGA of compound II evidencing two phase transitions, and the presence of moisture. Both events were detected by XRPD-VT, in the 1st and 2nd events, left and right respectively.

Compound V is a wet powder and by the DSC-TGA data, presented in Figure S10, there is an endothermic peak between 75 ºC and 120 ºC, along with mass loss (more evident ~95 ºC) that probably corresponds to moisture. The second endothermic peak at Tmax = 152.8 ºC corresponds to the melting of the compound, along with decomposition. This value was in accordance with the one obtained by glass capillary (Table 5). Figure 16a shows the DSC-TGA of molecular salt VI evidencing the release of two water molecules, 9.7 % mass loss, at Tmax = 81.4 ºC. XRPD-VT powder patterns collected up to 160 ºC, Figure 16b, indicate that possibly the final crystalline obtained, whose structure is maintained after cooling to RT, corresponds to the anhydrous form of this salt. Due to overlapping diffraction peaks and quality of the XRPD data, the indexing process was unsuccessful. HSM images corroborate the results obtained from DSC-TGA and XRPD-VT.


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Figure 16. a) DSC-TGA evidencing a transition at Tmax = 81.42 °C; b) experimental XRPD-VT; and c) HSM images. of VI.

Compound VII exhibits an endothermic peak, with mass loss, between 100 ºC and 150 ºC (Figure S11), that might correspond to water release of the secondary hydrated phase. At temperatures above 250 ºC there are complex endothermic behaviors, with sample melting around 345 ºC. This value also compares with the one obtained from glass capillary (Table 5). For compound VIII, the “bulk” of the final synthesized compound was a mixture. Despite several unsuccessful attempts to prepare a pure phase, isolation of VIII was only achieved after heating the sample at 213 ºC. The phase transition observed at Tmax = 188.1 ºC (Figure 17) refers to the formation of the characterized compound, that melts at Tmax = 244.2 ºC.



Figure 17. DSC-TGA of VIII evidencing a transition at Tmax= 188.12 °C, without mass loss.

DSC-TGA analysis for molecular salt IX (Figure 18a), shows the melting point (MP) of the sample at Tmax = 245.9 ºC, also detected in the HSM images (Figure 18b). This compound exhibits a better thermal stability profile when compared with the previous salts.

Figure 18. a) DSC-TGA of IX evidencing the melting point at Tmax = 245.9 °C; b) HSM images.

Solubility studies Preliminary solubility studies were carried out for ADA and all the synthesized molecular salts (Table 5). Compound V is the most soluble salt, and together with II they present a higher solubility value than the commercially used hydrochloride salt. The behavior of salt V is in agreement with literature, attesting that API solubility, when combined with sulfonate derivatives, especially methanesulfonate, is remarkably improved due to the high solubility and low molecular weight of these counter-ions.56 However the very high value obtained is also due to its


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hygroscopicity. Salts II and V exhibit the lowest melting point (Table 5), in accordance with previous studies, albeit no general rule can be defined.57-66 Table 5. Solubility, thermal stability and supramolecular interactions of ADA, ADA.HCl and molecular salts (I to VII). Compound ADA ADA.HCl ADA:OXA (I) ADA:GLUTA (II) ADA:METHA (V) ADA:SAC (VI) ADA:SULFA (VII) ADA:3-AMINO (VIII) ADA:4-AMINO (IX)

Solubility (mg/mL) 1.03 50 0.81 58.8 200 14.3 5.6 9.1 0.96

Melting point (°C) 206-208 300 223 183 153.9* 242.6 347.3* 244.2 245.9

Melting point co-formers(°C) 189-191 95-98 17-19 228 288 178-180 187-189

*Melting point determined by glass capillary method and by DSC-TGA (Figures S9 and S10)

4. Conclusions Seven novel ADA molecular salts were mechanochemically prepared and structurally characterized combining X-ray diffraction and spectroscopic techniques. SCXRD data was used to determine the structure of five of the compounds, whereas the structure of compounds II and VIII was successfully obtained through XRPD data. SSNMR analysis of 15N and 13C CPMAS data was helpful in determining the protonation state of the ADA amine group, allowing unambiguous identification of the salt forms. From the

15N

CPMAS NMR spectra, a shift of

around 5-8 ppm was observed for the NH3+ resonance in all salts, compared to NH2 resonance from pristine ADA. Moreover, salt formation was also confirmed through the analysis of

13C

CPMAS NMR, with special emphasis on the chemical shift variation of the quaternary carbon directly attached to the amine of ADA, which is very sensitive to the protonation state of this amine group. The supramolecular arrangement of all molecular salts is based on strong N-H+(ADA) ⋯O-(co-former) HB interactions, between the protonated ADA amino moiety and the oxygen atom of either carboxylic/carboxylate or sulfonate derivatives. The full crystal packing depends on the size and functional groups of the counter-ions. For small ones, such as OXA and METHA (I and V), a lamellar-like packing of alternated polar and apolar domains is observed, where the polar ones are composed by N-H+(ADA)⋯O-OXA/METHA HB interactions and the apolar contain the aliphatic moiety of ADA molecules. In the case of hydrate VI, the presence of water molecules reinforces the hydrogen bonding network within the polar domains, leading to the formation of an alternated polar/apolar packing and π-π interactions among SAC aromatic rings also contribute to the stability of these domains. Apolar domains are composed of ADA aliphatic moieties. In salt VIII the polar domains are



defined by strong N-H+(ADA)⋯O-(3-AMINO), further reinforced by NH⋯π interactions between 3AMINO molecules, that extend within the layer. The apolar domains are further supported by CH(ADA)⋯π(3-AMINO) HB. Compounds II, VII and IX exhibit a similar zeolite-like packing, where the framework is defined by the strong N-H+(ADA)⋯O-(co-former) HB system. These have in common a 𝑅68(40) synthon, forming a “cage” where the aliphatic domains of ADA are pointing to each other. This design is further stabilized, in the case of compounds VII and IX, by additional weak CH⋯π interactions. Results point out that six of the seven synthesised salts present higher solubility than ADA, but only compounds II and V are more soluble than the commercially available ADA.HCl, even though the extremely high solubility of V might be due to its high hygroscopicity. These are also the ones with the lowest melting points. As previously suggested in the literature,58-66 when predicting the melting point of multicomponent forms from the melting point of their building blocks, if the melting point of the co-former is lower than that of the API, then the resulting product should also present a lower melting point and vice versa. Our compounds seem to follow the rule, as co-formers with lower melting point than ADA generate salts with lower melting point, while those with higher (VI and VII) also lead to higher melting point compounds, with the exception of the amino derivatives. These results confirm that the physicochemical properties strongly depend on the supramolecular structure and on the interplay of the HB network strength.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: XXXX Tables S1 – S3 contain the crystallographic details and hydrogen-bond distances and angles for all prepared compounds. Figures S1 – S4 present the powder diffractograms obtained for ADA salts. Figures S5 – S8 present FTIR data. Figures S9 and S10 show DSC-TGA data. Crystallographic files for I, II, V – IX (CCD deposit numbers 18819211881927) (CIF). 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 The work was financed by Fundação para a Ciência e a Tecnologia (FCT) through project PTDC/QEQ-QAN/6373/2014. This work was developed in the scope of the Projects PEstOE/QUI/UI0100/2013 (CQE-IST) and POCI-01-0145-FEDER-007679| UID/CTM/50011/2013 (CICECO), financed by national funds through the FCT/MEC and cofinanced by FEDER under the PT2020 Partnership Agreement. I. C. B. Martins also acknowledge FCT for Ph.D. Grant SFRH/BD/93140/2013. The authors are also grateful to Investigador FCT program and to the Portuguese NMR Network (RNRMN).

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General experimental conditions and products obtained in the reactions between ADA and aliphatic acids, sulfone derivatives, aromatic and non-aromatic amino-acids, unsaturated aliphatic acids and aromatic acids. 298x225mm (96 x 96 DPI)



Figure 2. a) view along a evidencing N-H+(ADA)⋯O-(OXA) interactions in a mosaic-like fashion mode; b) view along b showing the lamellar effect. Aliphatic hydrogen atoms were omitted for clarity. 352x164mm (96 x 96 DPI)


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Figure 3. Rietveld refinement plot displaying the measured powder pattern (grey dots), the calculated powder pattern (red solid line), the difference curve (blue) and the reflection positions (vertical black dashes). 151x100mm (96 x 96 DPI)



Figure 4. a) view of the HB network in ADA:GLUTA, based on R_4^2(8) synthons; b) view along c detailing the relative positioning of the two ADA molecules. Aliphatic hydrogen atoms were omitted for clarity. 357x150mm (96 x 96 DPI)


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Figure 5. a) formation of the R_6^6(18) synthon between ADA and METHA molecules through NH+(ADA)⋯O-(METHA) HB interaction; b) lamellar packing, in a view along c, evidencing the polar and apolar domains. Aliphatic hydrogen atoms were omitted for clarity. 360x171mm (96 x 96 DPI)



Figure 6. a) R_4^4(12) and R_5^3(10) synthons formed between ADA, SAC and water molecules; b) packing assembly evidencing the HB among ADA, SAC and water molecules, emphasizing π-π interactions between SAC molecules; c) packing interactions along c, evidencing the sigmoidal arrangement of SAC and water molecules; d) C-H⋯π interaction between ADA and SAC molecules. Some aliphatic hydrogen atoms were omitted for clarity. 366x310mm (96 x 96 DPI)


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Figure 7. a) zig-zag arrangement of ADA and SULFA, evidencing the formation of R_4^4(12) and R_4^2(8) synthons; b) crystal packing showing the formation of the R_8^6(40) synthon and C-H⋯π interactions (red and green) involving SULFA and ADA molecules. Some aliphatic hydrogen atoms were omitted for clarity. 343x116mm (96 x 96 DPI)



Figure 8. XRPD patterns of VI obtained from samples a) freshly ground; b) heated at 213 ºC (collected at room temperature); c) heated at 213 ºC (data collected at -50 ºC). 149x93mm (96 x 96 DPI)


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Figure 9. Rietveld refinement plot displaying the measured powder pattern (grey), the calculated powder pattern (red), the difference curve (blue) and the reflection positions (vertical black lines). 149x104mm (96 x 96 DPI)



Figure 10. a) packing interactions along b evidencing the R_4^2(8) synthon formed between ADA and 3AMINO molecules (N-HNH3+(ADA)⋯OCOO-(3-AMINO)) as well as the C-H⋯π and C-H⋯π interactions; b) packing along a with alternated polar and apolar domains. Aliphatic hydrogen atoms were omitted for clarity. 348x137mm (96 x 96 DPI)


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Figure 11. Packing interactions highlighting the R_4^2(8) synthon between ADA and 4-AMINO molecules (NH+(ADA)⋯O-(4-AMINO) HB). The presence of the N-H(4-AMINO)⋯O-(4-AMINO) HB interaction allows the formation of a R_8^6(40) synthon, where ADA aliphatic domains are facing each other. Some aliphatic hydrogen atoms were omitted for clarity. 260x176mm (96 x 96 DPI)



Figure 12. 15N CPMAS NMR spectra for all salts. Red, blue and green rectangles highlight the 15N CS associated with ADA protonated amine, SAC and SULFA, respectively. 147x202mm (96 x 96 DPI)


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Figure 13. 13C CPMAS NMR spectra for all salts, showing the CS range for C1 (right side) and carboxylic/carboxylate resonances (left side). Filled circles in ADA structure indicate the position of the C1 quaternary carbon. 153x157mm (96 x 96 DPI)



Figure 14. a) DSC-TGA of the mixture evidencing the transition to pure compound I; b) Experimental XRPDVT; c) HSM images. 189x226mm (96 x 96 DPI)


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Figure 15. DSC-TGA of compound II evidencing two phase transitions, and the presence of some moiture. Both events were detected by XRPD-VT, in the 1st and 2nd events, left and right respectively. 235x202mm (96 x 96 DPI)



Figure 16. a) DSC-TGA evidencing a transition at Tmax = 81.42 °C; b) experimental XRPD-VT; and c) HSM images. of IV. 183x238mm (96 x 96 DPI)


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Figure 17. DSC-TGA of VI evidencing a transition at Tmax= 188.12 °C, without mass loss. 183x126mm (96 x 96 DPI)



Figure 18. a) DSC-TGA of VII evidencing the melting point at Tmax = 245.9 °C; b) HSM images. 205x126mm (96 x 96 DPI)


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Enhancing adamantylamine solubility through salt formation: novel products studied by X-ray diffraction and Solid-state NMR Inês C. B. Martins,1,2,3 Mariana Sardo,2 Edith Alig,3 Lothar Fink,3 Martin U. Schmidt,3 Luís Mafra2*, M. Teresa Duarte1* 1

CQE – Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal 2 CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal 3 Institut fuer Anorganische und Analytische Chemie, J. W. Goethe Universitaet, Frankfurt am Main, Germany *e-mail: [email protected], [email protected]

Novel adamantylamine salts with enhanced solubility were mechanochemicaly synthesized. Crystal packing is supported on a common synthon: a N-H+(ADA)⋯O-(co-former) charge assisted hydrogen bond. Small counter-ions induce lamellar-like packing structures whereas linear and aromatic counter-ions promote zeolite-like structures. X-ray diffraction and Solid-state NMR were used to solve co-crystal/salt ambiguities.


Enhancing adamantylamine solubility through salt formation: novel

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