Pharmaceutical Crystal Engineering Using Ionic Liquid AnionâSolute

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Pharmaceutical crystal engineering using ionic liquid anion-solute interactions Manishkumar Ramesh Shimpi, Sitaram P. Velaga, Faiz Ullah Shah, and Oleg N. Antzutkin Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01698 • Publication Date (Web): 10 Feb 2017 Downloaded from http://pubs.acs.org on February 13, 2017

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Crystal Growth & Design

Pharmaceutical crystal engineering using ionic liquid anion-solute interactions Manishkumar R. Shimpi,†a,b Sitaram P. Velaga,†a,* Faiz Ullah Shahb and Oleg N. Antzutkinb,* a

Department of Health Sciences, Luleå University of Technology, Luleå, Sweden, SE-971 87 Chemistry of Interfaces, Luleå University of Technology, Luleå, Sweden, SE-97 187. * Corresponding authors, [email protected] and [email protected] †Equal contribution

b

Abstract: The main purpose of this work was to investigate the potential of ionic liquids (ILs) in crystal engineering. We have employed ILs with different combinations of cations and anions to study their role in directing crystal structure formation of a nicotinamide (NIC) and oxalic acid (OXA) system. A new crystal form of NIC-OXA salt (2:1) was identified and characterised using standard solid state tools such as powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Raman and Infrared spectroscopy. The crystal structure of the 2:1 salt was elucidated using single-crystal X-ray diffraction. The NIC-OXA 2:1 salt form revealed a two-dimensional layered structure while the known 1:1 salt had a perpendicular “tape-like” structure. The 2:1 salt form could only be crystallised from the ILs possessing hydrogen bond acceptor functionality. We demonstrated that specific ILs could be selected as solvents for altering the solid-state structure of organic and inorganic materials. Introduction: Pharmaceutical solids can be classified into single and multicomponent systems. Salts and cocrystals are important among multicomponent systems, which offer exciting opportunities for product development in the material science and pharmaceutical industries.1 A distinction between the salt and cocrystal is the location of the proton between the acid and base in the crystal, and a continuum is thought to exist between these extremes.2 These structural changes are the reason for altered or improved 1

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physicochemical properties of active pharmaceutical ingredients (APIs) such as solubility, structural stability, dissolution rate, density, melting point, etc.3 Crystallisation is one of the most important purification methods in the pharmaceutical industry. The solubility and bioavailability of a crystalline material is strongly dependent on its crystalline form, morphology, particle size distribution, etc.4 The physicochemical properties of a crystalline product are highly dependent on its solvent characteristics. A change in the crystallisation solvent and conditions can significantly alter the resulting crystal and powder properties, such as particle shape, flow properties, compaction, agglomeration followed by their thermodynamic properties. In solvent-based crystallisation methods, a range of conditions or factors like solvent, solution composition, temperature, additive, supersaturation, cooling rate, agitation, and composition affect molecular recognition events, nucleation and crystal growth and, thereby, the outcomes of the solid form.5 A number of studies have been reported in the literature exploiting these process factors to direct the crystallisation of a desired polymorph and/or morphologies and size of particles (i.e., to engineer crystals to particles).6 Sabiruddin et al.7 and Naser et al.8 have shown how changing the polarity of the solvent and water activity in an organic solvent controls the crystal formation or morphology of erythromycin and lysine, respectively. More recent studies have demonstrated the role of organic solvents and solvent compositions on the supramolecular host-guest networks in cocrystals.9,10 It is, therefore, apparent that different crystallisation media can generate different polymorphs, stoichiometries or morphologies in solution-based crystallisation. These crystal structures or solid forms have been explained to be a result of specific interactions between solute (API or API-co-former) and solvent molecules. In this context, functionalised ionic liquids (ILs) may offer exciting potential in crystal engineering, as 2


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they might provide a solvent medium (or environment) with unique polarity, a high ionic strength, solvation energy and specific interactions with the solute. ILs are salts of organic cations and inorganic or organic anions with low melting points (< 100 °C). ILs are often fluids at ambient conditions, thus, called room-temperature ILs (RT-ILs) and can be used as solvents in many applications including crystallisation. Interestingly, the physicochemical properties of ILs can be tuned by selecting a combination of cations and anions, which is not possible in molecular organic solvents.11 Since a decade ago ILs have received special attention, as green solvents12 and co-solvents for crystallisation of organic,13 inorganic14 and biological molecules.15 Shah et al. have recently introduced novel classes of halogen-free and hydrolytically stable orthoboratebased RTILs.16 The negligible vapor pressure, non-flammability and non-toxic nature of these ILs have resulted in their increasing popularity as lubricants11,16 and alternative solvent media as reported in this work. Recent studies have used ILs for designing polymorphs of the dipivoxil and adefovir dipivoxil in anti-solvent and drowning-out crystallisation, respectively.17,18 In other studies, Garlitz et al.19 and Li et al.20 have employed ILs to modify the crystal morphology and crystal structure of lysozyme. Furthermore, in the area of material processing, ILs have been applied to produce and stabilise nanoparticles of ZnS and Au.21,22 However, to the best of our knowledge the potential of ILs in cocrystallisation has not been fully explored so far. Our initial investigation in this area focuses on the acidbase reaction between oxalic acid and nicotinamide as a model system and manipulation of intermolecular interactions to tailor its stoichiometry using the ionic liquids’ anionsolute interactions. This communication reports the formation of a new stoichiometric salt 3



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form of nicotinamide (NIC) and oxalic acid (OXA) using various ionic liquids possessing a hydrogen bond acceptor (Figure 1) as a crystallisation medium. Experimental: Synthesis and characterisation data: All chemicals and solvents (purity >99%) were purchased from Sigma-Aldrich or Acros Organics and were used without further purification. [P6,6,6,14][BOB] and [P4,4,4,8][BOB] were prepared as per reported in the literature.23,24 [P6,6,6,14][BMB]16 and [EMIm][BMB]25 were prepared as per reported by Shah et al.16,25 [P6,6,6,14][B(TMP)P], [P6,6,6,14][DCA], [P4,4,4,8]Cl, [P6,6,6,14]Cl and [P6,6,6,14]Br were purchased from Cytec and Solvionic. [P6,6,6,14][BF4] was prepared from an equimolar ratio of [P6,6,6,14]Cl and NaBF4 in dichloromethane with overnight stirring. A liquid product, [P6,6,6,14][BF4] was isolated by solvent evaporation. A mixture of nicotinamide (0.05 mmol) and oxalic acid (0.05 mmol) was added to the premixed solvent mixture of [P6,6,6,14][BOB] and toluene (6:4 v:v ratio) in 50 mL conical flask. A clear solution was kept for evaporation at room temperature. The colourless blocks were crystallised out in 48 hours. Crystalline materials were separated by filtration and washed with toluene. The single crystal X-ray diffraction structure data of the crystalline phase is given in Table S1 in the Supporting Information. For the crystallisation reaction, a 4-mL glass vial was charged with 244.1 mg (1 mmol) of nicotinamide and 180 mg (1 mmol) of oxalic acid. About 2 mL of ionic liquids or organic solvents were added to form a slurry. The reaction was allowed to stir for a total of 8 days, at which time the solids present were isolated by vacuum filtration and air dried at room temperature. X-ray diffraction structure determination The single-crystal X-ray diffraction data of the crystals was collected on a Bruker Nonius Kappa CCD. The data sets for compounds were collected at room temperature (293 K). The crystals 4


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were quite stable and hence no special precautions were necessary for collection of the intensity data. All the data sets were collected using Mo Kα radiation (λ = 0.71073 Å), and crystal structures were solved by direct methods using SIR-92 and refined by full-matrix least-squares refinement on F2 with anisotropic displacement parameters for non-H atoms using SHELXL2013. Hydrogen atoms were placed on their expected chemical positions using the HFIX command. All the non-hydrogen atoms were refined anisotropically. The structural solution, refinement and generation of material for publication, were performed by using shelXLe, V623 software. All packing diagrams are generated using Diamond software. Differential scanning calorimetry (DSC) Thermal analyses of samples were performed on a TA Instruments DSC Q1000. The sample was placed into an aluminium DSC pan, and the weight accurately recorded. The pan was crimped and the contents heated under nitrogen atmosphere. Indium was used as the calibration standard. The data was collected in triplicate for each sample. Thermogravimetric (TG) analysis TG analyses were performed using a TA Instruments 2950 thermogravimetric analyser. Each sample was placed in an aluminium sample pan and inserted into the TG furnace. Nickel and Alumel™ were used as the calibration standards. The data was collected in triplicate for each sample. Infrared spectroscopy Infrared spectra were recorded on a Bruker Vertex 80v FTIR spectrometer equipped with a DLaTGS detector and a Platinum-ATR accessory with a diamond crystal as the ATR element. Both a single-beam background without sample and single-beam spectra of the powered samples were obtained by averaging 128 scans with an optical resolution of 4 cm−1. The resulting 5



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interferograms were Fourier transformed using the Mertz phase correction mode, a Blackman– Harris 3-term apodisation function, and a zero-filling factor of 2. All spectra were recorded under vacuum using the double-side forward-backward acquisition mode. Raman spectroscopy Raman spectra were recorded on a Chromex Sentinel dispersive Raman unit equipped with a 785 nm, 70 mW excitation laser and a TE cooled CCD. Each spectrum is a result of twenty co-added 20 s scans. The unit has continuous automatic calibration using an internal standard. The data was collected by SentinelSoft data acquisition software and processed in GRAMS AI. Powder X-ray Diffraction (PXRD) PXRD patterns for the samples were collected using an Empyrean X-ray diffractometer (PANalytical, The Netherlands) equipped with a PIXel3D detector and a monochromatic Cu Kα radiation X-ray tube (1.54056). The tube voltage and amperage were set at 45 kV and 40 mA, respectively. Samples were prepared for analysis by pressing a thin layer of the sample onto a metal sample holder. Instrument calibration was performed using a silicon reference standard. Each sample was scanned in the 2θ range of 5° to 40°, increasing at a step size of 0.02° 2θ. The data was processed using HighScore Plus Version 3.0 software (PANalytical, The Netherlands).

6


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C6H13 C6H13

P

O

O

O

O B

C14H29

C6H13

C6H13 O

O

O

C6H13

O

C6H13

P

O

[P6,6,6,14][B(TMP)P] O

O

O

O

O

C6H13

O

N

B

N

O

[P6,6,6,14][BMB]

C4H9

P

O

C4H9

O

O

B O

O

O

O

[EMiM][BMB]

O

C8H17

O

O

B

C14H29

C4H9

P O 2

C6H13

[P6,6,6,14][BOB]

C6H13

O

P C14H29

C6H13 C6H13

O

O

P

C14H29

NC

N

CN

C6H13

[P4,4,4,8][BOB]

[P6,6,6,14][DCA]

Figure 1. Structures and abbreviations of the various ionic liquids possessing hydrogen bond acceptor-anions used as crystallisation solvents in this study.

Results and Discussion Weber et al.26 tailored the solubility of acetaminophen within ILs and engineered its crystallisation through the use of strong hydrogen-bond-donating anti-solvents. Interestingly, it was reported that only hydrophilic ILs (possessing coordinating anions which are strong hydrogen bond acceptors) can dissolve drug molecules whereas hydrophobic

ILs

having

non-coordination

anions

could

not.27,28

We

therefore

hypothesised that an IL with hydrogen bond acceptor capability could strongly interact with solute such as oxalic acid (possessing hydrogen bond donating groups) and direct the intermolecular interactions leading to crystal formation. A known salt of NIC-OXA (1:1) (I) has been crystallised using the water-based solvent evaporation crystallisation method.29 It exists in the monoclinic P21/c space group with 7



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one nicotinamide cation and one oxalate anion (singly deprotonated). Oxalic acid forms a catameric chain and interacts with nicotinamide in a chelating mode, forming “tape-like” packing along the c-axis in three dimensions (Figure 2). The morphologies of these crystals were found to be plate-like. To investigate our hypothesis, nicotinamide (NIC) and

oxalic

acid

(OXA)

were

crystallised

in

trihexyl(tetradecyl)phosphonium

bis(oxalato)borate, [P6,6,6,14][BOB], an ionic liquid possessing hydrogen bond acceptor anions. Interestingly, co-crystallisation of NIC and OXA (1:1) in [P6,6,6,14][BOB] : toluene (60:40), resulted in block-shaped crystals (Figure S1 in the Supporting Information, SI) upon solvent evaporation at room temperature (ca 22 °C).

Figure 2. 1:1 salt of nicotinamide-oxalic acid (I): hydrogen bonds present between NIC and OXA (a) and perpendicular type packing along the c-axis (b). The resulting solid form was subjected to extensive thermal and solid-state characterisation. TGA analysis revealed that the new solid form II was non-solvated and had a significantly lower degradation temperature (ca 180 °C) as compared to I (see Fig. 3a). The DSC thermogram of salt I showed a melting endotherm at 206.6 °C (∆Hf = 236.33 J/g) (Figure 3b), while the new solid form II had an endothermic transition at 178.78 °C (∆Hf = 101.93 J/g) attributed to melting, followed by degradation at ca 180 °C

8


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in line with the TGA result (Figure 3b). The substantial difference in the melting enthalpies suggests differences between the packing energies of these two forms. (a)

(b)

Figure 3. (a) TGA and (b) DSC thermograms of nicotinamide-oxalic acid salts I and II. The powder X-ray diffraction patterns of these two solid phases were distinctly different, confirming that they exist in different crystal forms (see Fig. 4). In fact, significant shifts in vibrational frequencies were also observed in the Raman and FTIR spectra of these two solid forms (see SI) indicating differences in the intra- and supramolecular environment leading to crystal structural differences. Single-crystal X-ray diffraction studies were performed on II to elucidate the crystal structure and arrangement of the molecules and to draw some comparisons with the known structure of the 1:1 salt of NIC-OXA. We found that II crystallises as a 2:1 salt in the centrosymmetric orthorhombic Pbca space group with one nicotinamide cation and a half oxalate ion in the asymmetric unit (see Fig. 5). Important crystallographic parameters of II are given in Table S1 in the SI.‡ Crystal structure analysis reveals that the 2:1 salt forms a two-dimensional layered structure, while the known 1:1 salt has a perpendicular “tape-like” structure. In contrast to

9



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the 1:1 salt, the amide group of nicotinamide in II is not coplanar with the pyridine ring [N(9)–C(7)–C(8)–C(6); ∠= 152.98o].

Figure 4. PXRD patterns of salts of nicotinamide-oxalic acid forms I and II.

The two pyridinium N+–H groups of the two nicotinamide cations interact with one oxalate ion with bifurcated N+–H…O¯ interactions [N1+…O2-; D…A = 2.974 Å, ∠= 122o; N1+…O4-; D…A = 2.579, ∠ = 158o]. These two nicotinamide cations further interact with another two NIC+ forming amide homodimer synthons with N–H…O hydrogen bonds [N9…O3; D…A = 2.897 Å, ∠= 179o]. Further, these dimers interact with the oxalate anion with N–H…O¯ interactions [N9…O4; 2.902 Å, ∠= 162°] resulting in a one-dimensional, sheet-like structure (see Fig. 5a). These sheets form a two-dimensional, layered structure along the crystallographic b-axis (200 plane) (see Fig. 5b). The characteristics of the hydrogen bonds are mentioned in Table S2 in the SI.‡ These layers are

10


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further stabilised by weak C–H…O and π…π (3.6628 Å) interactions formed by the glide-related nicotinamide cations.

(a)

(b)

Figure 5. 2:1 salt of nicotinamide-oxalic acid (II). Nicotinamide cations form dimers and four such dimeric units interact with oxalic acid through N–H…O hydrogen bonds (a). II shows stacked layer packing along the c-axis (b). Single deprotonation of oxalic acid is involved in the crystallisation of 1:1 salt (I). Association and complete deprotonation of oxalic acid with [P6,6,6,14][BOB], through intermolecular hydrogen bonds, due to sufficient hydrogen bond acceptor capacity of the ILs explains the formation of the 2:1 salt (II). To further investigate the role of the anion, other ionic liquids were chosen (see Fig. 1) as they feature anions of different hydrogen bond acceptors. In this regard, solution crystallisation or reaction crystallisation methods have been successfully employed in the screening of salts. The reaction crystallisation method

creates

a

thermodynamic

driving

force

towards

the

formation

of

a

multicomponent system, independent of reactant molar ratio.30 As anticipated, reaction crystallisation of NIC and OXA in the presence of these ionic liquids (see Fig. 1) had always led to the formation of salt II (confirmed by PXRD, see Figs. S4-S5 in the SI). Eigen had discussed three reaction routes of acid-based reactions that involve proton transfer, namely: i) direct proton exchange, ii) proton dissociation to solvent, protolysis and iii) solvent proton scavenging by the base, hydrolysis.31 Additional reaction crystallisation using [P6,6,6,14][BMB], [P4,4,4,8][BOB], [P6,6,6,14][B(TMP)P], [EMiM][BMB] 11



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and [P6,6,6,14][DCA] (see Fig. 1) indicate that the anion plays an important role in the formation of salt II. The reaction could be governed by complete deprotonation of oxalic acid to the solvent (specific to the anion) and subsequent proton scavenging by the base, NIC. To investigate further, the hydrogen bond acceptor, the anions in ILs, were replaced by halogenated anions to disrupt the process of protolysis. In this respect, four ionic liquids possessing halogenated anion were tested: trihexyl(tetradecyl)phosphonium chloride,

[P6,6,6,14]Cl;

tributyloctylphosphonium

trihexyl(tetradecyl)phosphonium chloride

[P4,4,4,8]Cl

and

bromide,

[P6,6,6,14]Br;


tetrafluoroborate, [P6,6,6,14][BF4]. It was observed that the halogen-containing ionic liquids lead to the formation of only salt I as shown in Figure. S6 in the SI). The outcome of the reaction crystallisation was unchanged even if the reactions were carried out for prolonged time periods (12-14 days) to avoid any kinetic issues. These results also suggest that halogenated ILs do not really influence or alter the formation of salt I, which was originally generated from aqueous medium. Further, reaction crystallisation was performed in the presence of other organic solvents like 2-propanol, methanol, ethanol, acetonitrile, ethyl acetate, toluene, etc. However, the resulting solid form was always salt I (see Fig. S7 in the SI), suggesting a very strong driving force for the reaction (salt, I formation) by the favourable acid-protonated base ∆pKa difference.32 There was also no evidence of the formation of different polymorphs or stoichiometry (for the XRD analysis, see Figs. S4-S8 in the SI). Moreover, solid-state grinding (without any solvent) of NIC and OXA indicates the formation of salt I (see Fig. S8 in the SI). Hence, the acid-base reaction of OXA and NIC was found to be spontaneous, independent of solvent (organic or halogenated ILs) and is consistent with the ∆pKa difference. 12


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Conclusions: In summary, crystal engineering and multicomponent systems offer exciting opportunities in pharmaceutical product development. Ionic liquids are an emerging class of solvents whose potential has not yet been fully explored in pharmaceutical crystallisation. We have shown that novel classes of ILs can be employed as solvents for crystallisation. A new salt form of nicotinamide-oxalic acid was obtained from halogenfree ionic liquids as a crystallisation solvent. Importantly, ILs can replace conventional solvents and, due to their unique properties, have the potential to generate exciting new discoveries. Thus, we can conclude that a unique crystallisation environment can be created to engineer solute-solvent interactions. Further, the reaction mechanism, with a specific focus on proton transfer and the role of ILs has yet to be investigated.

ASSOCIATED CONTENT Supporting Information Supporting Information (SI) is available free of charge on the ACS publication website at DOI:XXXXX. Synthesis and characterisation data, X-ray structure determinations, FTIR and Raman spectra, crystallographic data, hydrogen bonding data and XRD.

AUTHOR INFORMATION

Corresponding Authors E-mail: [email protected] E-mail: [email protected] ACKNOWLEDGMENT MRS thanks Luleå University of Technology and the Foundation in memory of J. C. and Seth M. Kempe for post-doctoral fellowships (Grant No. JCK-1205). This work was also 13



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partly supported by the Swedish Research Council (ONA and FUS, grant number 20135171).

ABBREVIATIONS Nicotinamide, NIC; oxalic acid, OXA; powder X-ray diffraction PXRD; trihexyl(tetradecyl)phosphonium bis(oxalato)borate, [P6,6,6,14][BOB]; trihexyl(tetradecyl)phosphonium bis(mandelato)borate, [P6,6,6,14][BMB];

tributyl(octyl)phosphonium bis(oxalato)borate, [P4,4,4,8][BOB];

trihexyl(tetradecyl)phosphonium bis(2,4,4-(trimethylpentyl))phosphinate, [P6,6,6,14][B(TMP)P]; 1ethyl-3-methylimidazolium phosphonium

dicyanamide,

bis(mandelato)borate, [P6,6,6,14][DCA];

[EMIM][BMB];

trihexyl(tetradecyl)-


chloride,

[P6,6,6,14]Cl; trihexyl(tetradecyl)phosphonium bromide, [P6,6,6,14]Br; tributyl(octyl)phosphonium chloride, [P4,4,4,8]Cl; trihexyl(tetradecyl)phosphonium tetrafluoroborate, [P6,6,6,14][BF4]. References (1) Brittain, H. G. J. Pharm. Sci. 2013, 2, 311-317. (2) Aakeröy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics 2007, 3, 317-322.

(3) Alhalaweh, A.; Roy, L.; Rodriguez-Hornedo, N.; Velaga, S. P. Mol. Pharmaceutics 2012, 9, 2605-2612.

(4) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 5, 2252-2264. (5) Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Adv. Drug Deliv. Rev. 2007, 7, 617-630.

(6) Desiraju, G. R. J. Am. Chem. Soc. 2013, 27, 9952-9967.

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For Table of Contents Use Only

Pharmaceutical crystal engineering using ionic liquid anion-solute interactions Manishkumar R. Shimpi,†a,b Sitaram P. Velaga,†a,* Faiz Ullah Shahb and Oleg N. Antzutkinb,* a

Department of Health Sciences, Luleå University of Technology, Luleå, Sweden, SE-971 87 Chemistry of Interfaces, Luleå University of Technology, Luleå, Sweden, SE-97 187. * Corresponding authors, [email protected] and [email protected] †Equal contribution

b

Ionic liquids (ILs) are unique tunable materials that appear to have potentially limitless applications in various disciplines. In this contribution, ILs are shown to promote the formation of unknown crystal form of a salt of nicotinamide-oxalate. Thus, ILs are promising solvents in pharmaceutical crystal engineering, and have the potential to generate exciting new discoveries.

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Pharmaceutical Crystal Engineering Using Ionic Liquid AnionâSolute

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Pharmaceutical Crystal Engineering Using Ionic Liquid AnionâSolute