Understanding Polymorphic Control of Pharmaceuticals Using

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Understanding polymorphic control using imidazoliumbased ionic liquid mixtures as crystallization directing agents Inês C. B. Martins, José R. B. Gomes, Maria Teresa Teresa Duarte, and Luis Mafra Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01798 • Publication Date (Web): 04 Jan 2017 Downloaded from http://pubs.acs.org on January 6, 2017

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Crystal Growth & Design

Understanding polymorphic control of pharmaceuticals using imidazolium-based ionic liquid mixtures as crystallization directing agents Inês C. B. Martins, † ‡ José R. B. Gomes,‡ M. Teresa Duarte†* and Luís Mafra‡* †

CQE – Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa,

Portugal. ‡

CICECO – Aveiro Institute of Materials, Departmento de Química, Universidade de Aveiro, 3810-193 Aveiro,

Portugal.

ABSTRACT: Imidazolium-based RTILs were tested to assess their ability to control molecular polymorphic behavior. Mixtures of RTILs with distinct cation/anion combinations revealed promising capabilities in directing the crystallization process towards less stable polymorphs. In our tests gabapentin neuroleptic drug (GBP) was used as case study, as it is a well know polymorphic active pharmaceutical ingredient (API). For the first time, pure “bulk” GBP Form IV, a highly unstable polymorph, was isolated through RTILs. Forms were maintained over time, once they were kept soaked, opening new perspectives for the method presented here. Molecular dynamics simulations clearly supported the results.

Polymorphism,± a fascinating solid-state phenomenon, has been studied for decades both in the organic and inorganic fields. However, despite the huge efforts on exploiting the phenomenon, knowledge

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is still lacking. Understanding, predicting or controlling it, is quite a challenge!1 Controlling polymorphism in APIs is a topic of even higher importance as 9 out of 10 marketed drugs are distributed as solid dosage forms, preferably crystalline, due to their purity and thermal stability.2 As it is well known, the physicochemical properties of a given polymorph can vary drastically, being evident the impact in public health and turning its control urgent in pharmaceutical industry.3 Among the several factors influencing the crystallization process, the nature of the solvent is of major importance due to specific solvent-solute interactions.4 In the last decade, room temperature ionic liquids (RTILs), also known as ‘designer solvents’, have gained a new role in the crystallization process, due to the wide range of properties5 (conductivity, viscosity, density, polarizability and hydrogen bond energies (EHB))6 that can be fine-tuned by varying the constituent ions.7-9 The most common crystallization techniques involving RTILs, include solvothermal, thermal shift, solvent-antisolvent, and the use of organic co-solvent techniques.7-9 In particular, imidazolium-based RTILs have been used as crystallization medium for coordination compounds10 and its application is currently being extended to materials11, biological12 and pharmaceutical sciences.13 In the latter, techniques such as solvent-antisolvent,14 cooling crystallization or drowning-out15 were successfully applied in adefovir dipivoxil (design of polymorphs), paracetamol (inducing new particle size), and clopidogrel bisulfate (improving solubility).16-18 Despite the growing interest on applying RTILs as crystallization solvents, a systematic investigation on the influence of the nature of RTIL cations and anions in polymorphic control is still lacking. Recently, the use of RTIL mixtures has attracted the attention of the scientific community, especially due to their solvent capabilities.19,

20

Thermodynamic studies, focused on understanding the

physicochemical properties of RTIL mixtures, have shown that the cation ability to form bonds with anions becomes better satisfied for RTIL mixtures (containing the same cation but different anions) than in pure RTILs.19, 20 On the other hand, for RTIL mixtures containing different cations, but the same anion, the opposite effect is observed, i.e., disruption of interactions.19, 20


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RTIL mixtures have been applied as solvents in catalysis,21 CO2 capture,22 metal organic framework synthesis,23 enzymatic synthesis,24 electrochemical process25 and chromatography.26 Herein we attempt to rationalize the effects of various pure and mixed structurally related RTILs on GBP polymorphic behavior (the API used as our case study), by tuning the nature of their anions and cations. GBP a neuroleptic drug used to treat epilepsy, anxiety and tardive dyskinesia, is known in three different conformational polymorphs: Forms II, III and IV,27 and a hydrated form, known as Form I.28 Form II is thermodynamically stable (commercially available) whereas Forms III and IV are unstable polymorphs.29 These latter two are usually obtained through crystallization in ethanol at room or high temperature,27 respectively, and easily convert into Form II after grinding.30 Although III can be isolated, IV is always obtained as a mixture of Forms (III+IV).30 Here we demonstrate that it is possible to isolate the less stable Form IV, using a mixture of RTILs at different temperature conditions. The present work reports the influence of pure and mixed imidazolium-based RTILs (Tables 1 and S1) on GBP crystallization. These RTILs were selected according to their different EHB values.5 A procedure based on different crystallization conditions was followed as depicted in Figure 1. Four different combinations of crystallization temperatures were applied in each assay: i) RT (in black); ii) RT→LT→RT (in green); iii) RT→HT→RT (in blue) and iv) RT→HT→LT→RT (in orange). RT, HT and LT are defined as room, high and low temperatures, respectively. RT and HT transitions to LT were done by quenching using ice (0°C).


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Figure 1. Schematic representation of the complete process followed to obtain GBP crystals. Conditions steps are represented with different colored arrows: RT (black); RT→LT→RT (green); RT→HT→RT (blue) and RT→HT→LT→RT (orange). RT, LT and HT stand for 24°C, 0°C and 80°C respectively.

To assess the influence of RTILs in GBP crystallization, we have compared the four above-mentioned temperature assays (Tables 1 and S1) for two distinct cases. First, we carried out a set of experiments where 50 mg of GBP were dissolved in 2 mL of pure/mixed RTILs (1:1 proportion), in the presence of methanol (co-solvent, 1 mL) added to promote dissolution and crystallization in RTIL medium. Second, a control experiment was performed where GBP was dissolved in pure methanol. After complete crystallization of GBP (in the different experimental conditions illustrated in Figure 1), isolated crystals were characterized by single crystal and powder X-ray diffraction (SCXRD and PXRD), (Table S2 and Figures S1-S13) and optical microscopy. Tables 1 and S1 summarize GBP forms obtained in the presence of selected RTILs having distinct EHB. Form II always crystalizes either in control sample or in the presence of C2mimBF4 and C4mimPF6 (Cnmim = 1-n-alkyl-3-methylimidazolium). At RT, pure Form II was invariably obtained, except for the three assays employing C4mimCH3CO2, C4mimCF3CO2 and a mixture of C4mimN(CF3SO2)2 +C6mimN(CF3SO2)2.


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It appears that under RT conditions, GBP polymorphic trans-formations are rather insensitive to the use of RTILs with very distinct EHB (Tables 1 and S1, column 3). However, when different temperature sequences are applied (Figure 1 and Tables 1 and S1), the use of distinct RTILs completely changed the type of polymorph obtained. Below, we describe the obtained GBP Forms at the three distinct temperature sequences: 1) In the RT→LT→RT sequence, the metastable Form III appeared either in its pure form or mixed with Form II. Interestingly, only the C4mimN(CF3SO2)2 was able to induce the crystallization of the kinetic Form IV. 2) Regarding the RT→HT→RT sequence, Forms II and III were either obtained in their isolated or mixed forms. In this case, Form IV could only be obtained mixed with Form II (using C6mimBF4). 3) As for the RT→HT→LT→RT sequence, using C6mimBF4 favored the formation of pure Form IV. It is interesting to note that in all temperature sequences, Form IV (the most thermodynamically unstable polymorph) was only obtained when RTILs with intermediate EHB values were used (Tables 1 and S1, entries 3-6 and entry 6, respectively).

Table 1. GBP polymorphic forms identified by single crystal XRD data. Hydrogen bond energies (EHB) of single RTILs are also provided. Entry 1 2 3 4 5 6 7

EHB (kJ.mol-1)6 -9.86 -9.79 -9.35 [a]

RTIL in methanol Control sample[a] C4mimN(CF3SO2)2 C4mimBF4 C6mimBF4 C4mimBF4+C6mimBF4 C4mimN(CF3SO2)2+C6mimN(CF3SO2)2 C6mimN(CF3SO2)2+C6mimBF4

RT Form II Form II Form II Form II Form II Forms II+III Form II

RT→ →LT→ →RT Form II Form IV Forms II+III Form III Form III Forms II+III+IV Form II

RT→ →HT→ →RT Form II Form III Form II Forms II+IV Form IV Form III Form II

RT→ →HT→ →LT→ →RT Form II Form III Forms II+IV Form IV Form IV Form IV Form II

This control sample does not contain RTIL and was used for comparison purposes with respect to the assays containing RTILs

Considering that we have successfully crystallized the highly unstable Form IV employing RTILs with intermediate EHB (e.g., C4mimN(CF3SO2)2 [EHB = -9.86 kJ·mol-1] and C6mimBF4 [EHB = -9.35 kJ·mol-1]) we found this result intriguing and decided to explore the possible influence of their mixtures in inducing


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polymorphic crystallization. Different mixtures of selected RTILs were used, essentially the anion was maintained while the cation was changed (Tables 1 and S1, entries 5, 6 and 9, 10, respectively). For example, C4mimBF4+C6mimBF4 and C4mimN(CF3SO2)2+C6mimN(CF3SO2)2 were the only pairs of RTILs leading to the isolation of Form IV, which suggest that the differences in the alkyl chain length of cations (e.g., C4mim+ and C6mim+) might play a relevant role in directing polymorphic transformations. Indeed, Form IV was tendentiously obtained for “both” mixtures regardless the anion employed (BF4- and N(CF3SO2)2-) in “each” RTIL mixture. Interestingly, when a mixture of RTILs comprises the same cation (C4mim+) but distinct anions (BF4- and N(CF3SO2)2-) no Form IV was attained, instead, stable Form II appeared in all the temperature sequences. From literature it is known that in a RTIL mixture comprising a common anion, increasing the alkyl chain length of the imidazolium enhances cation⋯cation dispersion interactions, which can be disrupted upon addition of a second cation bearing shorter alkyl chains.19, 20 For this case (analogous to the situation in Table 1, entries 5 and 6), Navia et al. claimed that a net destruction of interactions between the present ions occurs;20 this can be an advantage as the cations and anions become more disperse and hence more available for possible interactions with GBP molecules. However, according to the same authors, using mixtures containing a common cation (Table 1, entry 7) leads to a net creation of interactions among ions, therefore decreasing possible RTIL⋯API intermolecular interactions.19, 20 In this case, we believe that the RTIL mixture behaves as a spectator in the presence of methanol. This seems to be supported by the fact that Form II is always obtained in both entries 1 and 7 from Table 1. As reported elsewhere, Form IV is extremely difficult to isolate; and it has been only obtained in polymorphic mixtures.30 In order to analyze the bulk crystallization where Form IV was obtained (Table 1, entries 5 and 6), powder XRD analysis (Figure 2) was performed without grinding the samples, as Form IV easily converts into II upon milling.30 Our results show that the bulk of the product obtained is indeed Form IV. To the best of our knowledge, this is the first time that pure Form IV was obtained through crystallization process.


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Figure 2. Experimental powder XRD diffractograms of GBP polymorph IV obtained in: a) C4mimBF4+C6mimBF4 (RT→HT→RT) and b) C4mimN(CF4SO2)+C6mimN(CF4SO2) (RT→HT→LT→RT). The theoretical diffractogram of Form IV is presented in c).

Table S3 summarizes the shelf stability of GBP polymorphs, in RTIL media, during a period of time spanning over 4 months. The results obtained show that: i) Form II persists once it is formed (this is true whether Form II is or not present in a mixture); ii) an initial mixture not containing Form IV (e.g., II+III) is always maintained; iii) either pure or mixed Form IV converts to a different mixture of polymorphs or to pure Form II. It is worth emphasizing that under certain conditions, RTILs prevent the rapid conversion of Form IV into Form II because after 4 months Form IV is still present in major proportion (e.g., Figure 3 and Table S3, entries 3, 4 and 6, RT→HT→LT→RT). Figure 3, illustrates the shelf stability results, for C4mimBF4+C6mimBF4 mixture, Forms II or III are maintained over time while Form IV slowly converts into Form II, leading to a mixture (II+IV). It is well known that this conversion occurs: after grinding; during slurry in ethanol or at higher humidity conditions.30


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II

III

I

III

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IV

Figure 3. Crystal images of GBP polymorphic forms obtained in C4mimBF4+C6mimBF4 after crystallization and after 4 months.

In order to explain our experimental results, and show the high importance of solvent-solute interactions, classical molecular dynamics (MD) simulations were performed for four selected crystallization conditions, GBP with methanol, C4mimBF4, C6mimBF4 and C4mimBF4+C6mimBF4 – interaction parameters and atomic charges are presented in Tables S4-S7. The GBP’s CCCC dihedral angle (DA) depicted in Figure 4 was selected to analyze the conformation of the Forms during the simulation runs. GBP has conformational polymorphs and therefore this would be the best way to determine the stabilized one in the different liquid media. The chosen DA has different values for each Form; from experimental crystallographic structures: II, 51.21°; III, 63.47°; and IV, -46.39° (Figure 4 and Table S4). Figures 4 and S14 illustrate the variation of DA with the type of solvent (methanol or RTILs) used. As Forms II and III exhibit similar DAs, the discrimination between the two was impossible due to peak overlap and hence the study focused on the formation of Form IV, which displays a DA with opposite sign.


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MD simulations (Figure 4) show that, the use of RTILs favors the formation of Form IV. The changes observed in the DA can be justified by GBP⋯RTIL interactions as evident from the radial distribution functions (RDF). Results point towards a strong influence of H(acidic (C4/C6mim))⋯O(carboxylate) interaction on driving the formation of Form IV, as the RDF intensity is higher in C6mimBF4 and C4mimBF4+C6mimBF4 than in C4mimBF4 (Figure S15). This agrees with experimental results, Form IV was isolated in these solutions (Table 1, entries 4 and 5). As the O(carboxylate)⋯H(primary

amine)

interaction

between GBP molecules is stronger in methanol and C4mimBF4 (RDF more intense (Figure S16)), this corroborates the tendency for the formation of Forms II/III observed experimentally (Table 1, entries 1 and 3). Illustrations of the specified interactions are presented in Figures S18-S23, in the Supporting Information, as well as a detailed description of experimental conditions and theoretical approaches.

Figure 4. Evolution of dihedral angle formation in polymorphs II/III and IV at RT for GBP in methanol (green), C4mimBF4 (red), C6mimBF4 (pink) and C4mimBF4+C6mimBF4 mixture (blue). % values correspond to the relative areas of peaks for Forms IV or Forms II/III.


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We performed a comprehensive study on the effect of using pure or mixtures of imidazolium-based RTILs, in the polymorphic control of GBP (pharmaceutical molecule used as our case study). Given the easiness in adjusting the nature of cations and anions in RTILs, we believe to have found the preferred experimental conditions where each GBP polymorphic Form can be isolated. In particular, kinetic Form IV, the most unstable, was successfully isolated. Not only isolated but also maintained, as the conversion to Form II was strongly delayed by RTILs. Our experimental results were corroborated by MD simulations in what may be understood as models of the early stages of the crystallization process, showing that GBP···RTIL interactions in solution, could be responsible for tuning the formation of specific polymorphs in solid-state. These are particularly promising and stimulating results as they open the possibility of “designing” RTILs that can specifically interact with the API and dictate its form, so full control of polymorphism is envisaged. In this work we applied general principles and approaches of crystallization process to control polymorphism using RTILs. Furthermore, we demonstrated the importance of using MD simulations in predicting the “designed” crystallization environment for the “desired” polymorph.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website Experimental details regarding the crystallization procedure as well as the molecular dynamics simulations are presented in Supporting Information. Tables S1-S3 present the single crystal Xray results, Figures S1-S13 present the X-ray powder diffraction results, Figures S14-S23 present the molecular dynamics simulations results (dihedral angle formation, radial distribution functions, and snapshots taken from the molecular dynamic simulation frames), Tables S4-S7 present

the

potential

parameters

obtained

for

each

molecule.


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] Funding Sources Investigator FCT and SFRH/BD/93140/2013 by Fundação para a Ciência e a Tecnologia and FEDER (PT2020 Partnership Agreement). Notes The authors declare no competing financial interests. ±

Ability of the molecules to adopt different packing arrangements, affecting the drug efficacy.

The authors declare no competing financial interest

ACKNOWLEDGMENT The authors acknowledge funding of the projects PTDC/QEQ-QAN/6373/2014, RECI/QEQQIN/0189/2012, UID/QUI/00100/ 2013(CQE), UID/CTM/50011/2013 (CICECO), Investigador FCT and SFRH/BD/93140/2013 by Fundação para a Ciência e a Tecnologia and FEDER (PT2020 Partnership Agreement). A special thanks to Dr. Mara Freire for all the fruitful discussions that greatly helped to understand and explain some of the results presented in this work.


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SYNOPSIS The method presented here proposes an approach to polymorphic control. Pure imidazoliumbased RTILs or mixtures, with distinct cation/anion combinations, revealed promising capabilities in directing the crystallization process of gabapentin (GBP). For the first time, pure “bulk” GBP Form IV, a highly unstable polymorph, was isolated. Molecular dynamics simulations clearly support the results.

ABSTRACT In this work the polymorphic behavior of gabapentin (GBP) is controlled recurring to the use of different pure imidazolium-based RTILs or mixtures, as crystallization solvents. Molecular dynamics

simulations

(C4/C6mim))⋯O(carboxylate)

clearly

supported

the

results

showing

that

specific

H(acidic

interaction between GBP and RTILs drives the formation of Form IV. For

the first time, pure “bulk” GBP Form IV, a highly unstable polymorph, was isolated. These results showed the importance of these ‘directing agents’ in the polymorphic process as well as the importance of using MD simulations in predicting the “designed” crystallization environment for the “desired” polymorph.


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Figure 1. Schematic representation of the complete process followed to obtain GBP crystals. Combinations of crystallization conditions are represented with different colored arrows: RT (black); RT→LT→RT (green); RT→HT→RT (blue) and RT→HT→LT→RT (orange).


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Figure 2. Experimental powder XRD diffractograms of GBP polymorph IV obtained in: a) C4mimBF4+C6mimBF4 (RT→HT→RT) and b) C4mimN(CF4SO2)+C6mimN(CF4SO2) (RT→HT→LT→RT). The theoretical diffractogram of Form IV is presented in c). 132x118mm (120 x 120 DPI)



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Figure 3. Crystal images of GBP polymorphic forms obtained in C4mimBF4+C6mimBF4 after crystallization and after 4 months. 170x76mm (120 x 120 DPI)


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Figure 4. Evolution of dihedral angle formation in polymorphs II/III and IV at RT for GBP in methanol (green), C4mimBF4 (red), C6mimBF4 (pink) and C4mimBF4+C6mimBF4 mixture (blue). % values correspond to the relative areas of peaks for Forms IV or Forms II/III. 151x112mm (120 x 120 DPI)



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Table 1. GBP polymorphic forms identified by single crystal XRD data. Hydrogen bond energies (EHB) of single RTILs are also provided. 192x37mm (120 x 120 DPI)


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Figure S1. Experimental X-ray powder diffraction of GBP polymorphs obtained in methanol at a) RT – Form II, b) RT→LT→RT – Form II, c) RT→HT→RT – Form II and d) RT→HT→LT→RT – Form II. The theoretical diffractogram of Form II is presented in e). 137x114mm (120 x 120 DPI)



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Figure S2. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Form III, c) RT→HT→RT – Forms II+III and d) RT→HT→LT→RT – Form II. The theoretical diffractograms of Forms II and III are presented in e) and f) respectively, for comparison. 136x119mm (120 x 120 DPI)


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Figure S3. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Form III, c) RT→HT→RT – Form II and d) RT→HT→LT→RT – Form III. The theoretical diffractograms of Forms II and III are presented in e) and f) respectively, for comparison. 132x116mm (120 x 120 DPI)



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Figure S4. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Form III, c) RT→HT→RT – Form III and d) RT→HT→LT→RT – Form II. The theoretical diffractograms of Forms II and III are presented in e) and f) respectively, for comparison. 132x114mm (120 x 120 DPI)


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Figure S5. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, c) – RT→LT→RT – Form IV, e) RT→HT→RT – Form III, f) RT→HT→LT→RT – Form III. The theoretical diffractograms of Forms II, IV and III are presented in b), d) and g) respectively, for comparison. 131x115mm (120 x 120 DPI)



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Figure S6. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Form II, c) RT→HT→RT – Form II and d) RT→HT→LT→RT – Form II. The theoretical diffractogram of Form II is presented in e) for comparison. 133x115mm (120 x 120 DPI)


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Figure S7. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Forms II+III, b) – RT→LT→RT – Forms II+III and c) RT→HT→RT – Form III. The theoretical diffractograms of Forms II and III are presented d) and e) respectively, for comparison. 132x115mm (120 x 120 DPI)



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Figure S9. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Forms II+III and c) RT→HT→RT – Form II. The theoretical diffractograms of Forms II and III are presented in d) and e) respectively, for comparison. 136x115mm (120 x 120 DPI)



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Figure S10. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Form III, c) RT→HT→RT – Forms II+III and d) RT→HT→LT→RT – Form II. The theoretical diffractograms of Forms II and III are presented in e) and f) respectively, for comparison. 137x115mm (120 x 120 DPI)


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Figure S12. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Forms II+III, c) RT→HT→RT – Form II and d) RT→HT→LT→RT – Form II. The theoretical diffractograms of Forms II and III are presented in e) and f) respectively, for comparison. 145x126mm (120 x 120 DPI)


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Figure S13. Experimental X-ray powder diffraction of GBP polymorphs obtained at a) RT – Form II, b) – RT→LT→RT – Forms II+III, c) RT→HT→LT→RT – Form II. The theoretical diffractograms of Forms II and III are presented d) and e) respectively, for comparison. 148x127mm (120 x 120 DPI)



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Figure S14. Evolution of dihedral angle formation in polymorphs II/III and IV at RT for GBP in methanol (green), C4mimBF4 (red), C6mimBF4 (pink) and C4mimBF4+C6mimBF4 mixture (blue). % values correspond to the relative areas of peaks for Forms IV or Forms II/III. 137x124mm (120 x 120 DPI)


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Figure S15. RDF for the interactions between the acidic proton of C4mimBF4 and C6mimBF4 with the carboxylate group of GBP in C4mimBF4 (green), C6mimBF4 (red) and C4mimBF4+C6mimBF4 (blue) at T=298.15K. 145x108mm (120 x 120 DPI)



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Figure S16. RDF for the interactions between oxygen of the carboxylate group and hydrogen of the primary amine of GBP in methanol (purple), C4mimBF4 (green), C6mimBF4 (red) and C4mimBF4+C6mimBF4 (blue) at T=298.15K. 145x108mm (120 x 120 DPI)


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Figure S17. RDF for the interactions between the primary amine proton of GBP and [BF4]- in C4mimBF4 (green), C6mimBF4 (red) and C4mimBF4+C6mimBF4 (blue) at T=298.15K. 148x109mm (120 x 120 DPI)



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Figure S18. MD frame showing the supramolecular interactions of GBP Form II (blue) in methanol: O(carboxylate)⋯H(primary amine) (intra and intermolecular) and O(carboxylate)⋯H(methanol) interactions. The dihedral angle corresponds to Form II/III. 119x120mm (120 x 120 DPI)


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Figure S19. MD frame showing the supramolecular interactions of GBP Form II (blue) in C4mimBF4: O(carboxylate)⋯H(primary amine) (intra and intermolecular) interaction. The dihedral angle corresponds to Form II/III. 123x106mm (120 x 120 DPI)



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Figure S20. MD frame showing the supramolecular interactions of GBP Form IV (blue) in C4mimBF4: O(carboxylate)⋯H(primary amine) (intramolecular) interaction; H(primary amine)⋯F(BF4) and O(carboxylate)⋯H(acidic(C4mim)). The dihedral angle corresponds to Form IV. 125x110mm (120 x 120 DPI)


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Figure S21. MD frame showing the supramolecular interactions of GBP Form II (blue) in C6mimBF4: O(carboxylate)⋯H(primary amine) (intermolecular) interaction and H(primary amine)⋯F(BF4). The dihedral angle corresponds to Form II/III. 131x102mm (120 x 120 DPI)



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Figure S22. MD frame showing the supramolecular interactions of GBP Form IV (blue) in C6mimBF4: O(carboxylate)⋯H(primary amine) (intramolecular) interaction; H(primary amine)⋯F(BF4) and O(carboxylate)⋯H(acidic(C6mim)). The dihedral angle corresponds to Form IV. 118x110mm (120 x 120 DPI)


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Figure S23. MD frame showing the supramolecular interactions of GBP Form IV (blue) in C6mimBF4: O(carboxylate)⋯H(primary amine) (intramolecular) interaction; H(primary amine)⋯F(BF4) and O(carboxylate)⋯H(acidic (C6mim)). The dihedral angle corresponds to Form IV. 128x102mm (120 x 120 DPI)



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Table S1. GBP polymorphic forms identified by single crystal XRD data. Detailed about hydrogen bond energy (EHB) of single RTILs is depicted. 203x52mm (120 x 120 DPI)


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Table S2. Cell parameters of GBP polymorphic forms identified by single crystal X-ray diffraction data. 193x26mm (120 x 120 DPI)



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Table S3. GBP polymorphs obtained after a period of 4 months in selected RTIL media. Blue color indicates the Forms present in the initial assays (see Table 1 in the communication). The obtained Forms were identified by single crystal XRD. 203x40mm (120 x 120 DPI)


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Table S4. Interaction parameters for GBP taken from the OPLS-AA force field. The CHelpG atomic charges were calculated at the B3LYP/6-311+G(d,p) level of theory. 120x119mm (120 x 120 DPI)



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Table S5. Interaction parameters for methanol taken from the OPLS-AA force field. Atomic charges are from the original OPLS-AA force field. 143x34mm (120 x 120 DPI)


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Table S6. Interaction parameters for C4mimBF4. The CHelpG atomic charges were calculated at the B3LYP/6-311+G(d,p) level of theory. 118x117mm (120 x 120 DPI)



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Table S7. Interaction parameters for C6mimBF4. The CHelpG atomic charges were calculated at the B3LYP/6-311+G(d,p) level of theory. The charges for [BF4]- anion are the same as described in table S6. 95x113mm (120 x 120 DPI)


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