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. 2019 May 1;4(5):7938–7943. doi: 10.1021/acsomega.9b00603

Solubility Studies of Cyclosporine Using Ionic Liquids

Paula Berton †, Manish Kumar Mishra ‡, Hemant Choudhary ‡, Allan S Myerson §, Robin D Rogers ‡,*
PMCID: PMC6649182  PMID: 31459882

Abstract

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Six ionic liquids (ILs) were selected based on their chemical and physical properties to study the solubility of cyclosporine A. Of these, cyclosporine exhibited higher room temperature solubility in 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) than in acetone, an effective molecular solvent used to solubilize and purify cyclosporine. The solubility of cyclosporine in the ILs dramatically increased at higher temperatures, a critical factor that cannot be varied in a wide range with low boiling molecular solvents. The differences in solubility were explored for cyclosporine purification. Cyclosporine was purified up to ∼93% with n-butylammonium acetate ([C4NH3][OAc]) and could be further purified to 95% using an IL/organic solvent biphasic system. After purification, cyclosporine was recovered as an amorphous solid using the ILs.

Introduction

Cyclosporine A (hereafter cyclosporine) is a neutral, lipophilic, cyclic endecapeptide with a molecular weight of 1202.635 g/mol and low aqueous solubility (Figure 1). It is widely used as an immunosuppressive agent to prevent rejection in organ and tissue transplantation during surgery by reducing the activity of the patient’s immune system.1−3 Cyclosporine is generally isolated as a complex in a nutrient medium by the cultivation of the strain of Tolypocladium inflatum fungus species.4 In comparison with cyclosporine B and cyclosporine C, the production of higher concentrations of cyclosporine depends on the type of the selected fungus.

Figure 1.

Figure 1

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Chemical structure of cyclosporine.

The development of strategies to solubilize poorly water-soluble active pharmaceutical ingredients (APIs) has been of great interest in order to facilitate their purification and establish better drug delivery systems.5−7 In this case, the solubility of the hydrophobic, non-ionizable cyclosporine is determined by its crystallinity and its interactions with the solvent. The structural conformation of this drug depends on the solvent, which in turn affects its solubility; when in an apolar environment, intramolecular hydrogen bonds stabilize the β-sheet structure, while the addition of polar solvents exposes its hydrogen bonding groups and breaks such 3D structures.8,9 These conformational changes are reflected in the differences in solubility. Cyclosporine is soluble in methylene chloride (10 mg/mL—clear, colorless to faint yellow solution), >100 mg/g in ethanol, methanol, acetone, ether, acetonitrile, or chloroform; while it is slightly soluble in water (0.04 mg/g) and saturated hydrocarbons (solubility in hexane: 5.5 mg/g).8 Interestingly, its solubility in water decreases with temperature (from 101.5 to 7.3 μg/L at 5 and 37 °C, respectively10), mainly due to dehydration of amino acid residues, affecting the conformation and solubility of the drug.9

Several attempts have been made toward the isolation and purification of cyclosporine. In an earlier report, cyclosporine was extracted from a biomass broth (after inactivating the enzymes) by incubating overnight with methanol in the first step, then further extracting with ethyl acetate (EtOAc) in the second step, and finally the residue from the second step was purified chromatographically in two stages: (1) silica gel column (mobile phase: hexane/chloroform/methanol; 10:9:1) and (2) resin column (mobile phase: methanol).11 Other reports purified cyclosporine through crystallization with PEG-400 by slow temperature reduction combined with seeding.12,13 Cyclosporine can also be purified by two-stage continuous mixed-suspension, mixed-product removal, and cooling crystallization with acetone.14,15 Still, a possible route to improvement in cyclosporine separation is to enhance the solubility and purity of cyclosporine at room temperature.

An emerging research field of interest is the utilization of ionic liquids (ILs, salts with melting points below 100 °C16) in pharmaceutical applications. ILs have been exploited in the pharmaceutical industry, used in organic transformations, either as catalysts and/or solvents,17−20 to turn solid drugs into liquids, or as drug delivery systems,21 and even to control the polymorphism of an API,22,23 to name a few of their applications. ILs as potential pharmaceutical solvents to dissolve poorly soluble APIs have been investigated for a range of ILs and APIs.24,25

The goal of this work was to evaluate the solubility of cyclosporine in ILs and to develop strategies for purification at room temperature. To accomplish this goal, we chose six different ILs based on their chemical and physical properties to force interactions with cyclosporine at the molecular level.

Results and Discussion

Cyclosporine is a hydrophobic branched aliphatic connected via amido linkages into a cyclic structure.26 We, therefore, chose ILs with varied lengths of alkyl chains bearing functional groups with potential to form hydrogen bonding to (a) regulate the hydrophobicity of the medium and (b) facilitate hydrogen bonding with the amido moieties of the cyclosporine. The ILs chosen for study include n-butylammonium acetate ([C4NH3][OAc]), n-octylammonium acetate ([C8NH3][OAc]), choline acetate ([Cho][OAc]), trihexyltetradecylphosphonium chloride ([P66614]Cl), 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]), and 1-ethyl-3-methylimidazolium bistriflimide ([C2mim][NTf2]).

The crude cyclosporine was obtained as an amorphous powder (Figure S1, Supporting Information) with purity of 90.8% and ca. 38 impurities as determined by high performance liquid chromatography (HPLC) (Figure S7, Supporting Information). It decomposed at 336.3 °C as determined by TGA (Figure S2, Supporting Information). In order to investigate cyclosporine’s solubility in the ILs chosen for their different physical and chemical properties (Table 1), an attempt to prepare saturated solutions was made as described in the Methods section. Saturation was achieved for [C4NH3][OAc] and [C2mim][NTf2] at 25 and 100 °C; however, solutions of [P66614]Cl and [C2mim][OAc] became too viscous to stir after reaching a certain concentration (Figure 2, right) and saturation was not achieved. Also, due to the higher melting point of [C8NH3][OAc] (mp 48 °C27) and [Cho][OAc] (mp 80–85 °C28), these ILs were studied only at 100 °C. Each final solution was filtered (hot if at elevated temperature) and a known amount of the filtrate was dissolved in acetonitrile for HPLC analysis. The cyclosporine concentrations are reported in Table 1.

Table 1. ILs Chosen for Study and Cyclosporine Solubilities.

graphic file with name ao-2019-00603z_0005.jpg

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a

Values without parenthesis represent “wt %”; values in parenthesis represent mmol/L.

b

Solubility at 53 °C.

c

These are partial solubilities, as these solutions became too viscous to stir at higher concentrations (Figure 2, right).

d

NA: not applicable; these ILs have melting points above 25 °C.

Figure 2.

Figure 2

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Left: Cyclosporine solubility at 25 (gray) and 100 °C (black). Right: Solutions of (a) 24.8 wt % cyclosporine in [C2mim][OAc] after stirring at 25 °C and (b) 60.2 wt % cyclosporine in [P66614]Cl after stirring at 100 °C.

The solubility results (Table 1, Figure 2, left) indicate that, at 25 °C, cyclosporine was most soluble in [C2mim][OAc] where it reached 24.8 wt % before the solution became too viscous to stir. This is remarkably high in comparison with the rest of the evaluated ILs and similar to its solubility in acetone (20.3 wt %), a well-known molecular solvent for the drug.12,13 The overall trend in solubility at 25 °C followed the order [C2mim][OAc] ≈ acetone > [C4NH3][OAc] (12.3 wt %) > [P66614]Cl (5.2 wt %) > [C2mim][NTf2] (<0.1 wt %). When the molar solubility of the drug per mol of IL/solvent is compared, the differences between [C2mim][OAc] and the rest of ILs and acetone are even higher. In this case, the order is [C2mim][OAc] (46.5 mmol/mol IL) > [P66614]Cl (25.3 mmol/mol IL) > [C4NH3][OAc] (15.5 mmol/mol IL) > acetone (12.3 mmol/mol acetone) > [C2mim][NTf2] (negligible).

At 100 °C, the solubilities of cyclosporine in all the ILs increased dramatically. As a result of the lower viscosity as the temperature was raised, more cyclosporine could be dissolved in [C2mim][OAc] (24.8–56.4 wt % or 46.5–183.4 mmol/mol IL) before the viscosity became too high to continue. An even more dramatic increase was observed for [P66614]Cl where the amount which could be dissolved before viscosity became an issue jumped from only 5.2 wt % at 25 °C to 60.2 wt % at 100 °C (23.5 vs 652.3 mmol/mol IL, respectively). A measurable amount of cyclosporine (1.2 wt %, 3.9 mmol/mol IL) could be dissolved in the hydrophobic [C2mim][NTf2] at this temperature, while the solubility in [Cho][OAc] remained negligible (<0.1 wt %), and using [C8NH3][OAc] the solubility was 25.7 wt % (54.3 mmol/mol IL). The low solubility in [Cho][OAc] can be related to its poor hydrogen bond donor ability due to the strong interionic hydrogen bond, resulting in low reactivity, also observed when used for biomass dissolution.29 It is worth noting that a reduction in cyclosporine solubility was observed with a longer alkyl chain in the alkylammonium acetate ILs (67.1 vs 54.3 mmol/mol IL for [C4NH3][OAc] and [C8NH3][OAc], respectively).

Using ILs allows performing studies at high temperatures in comparison to traditional solvents such as acetone, due to the low boiling points of the latter. The solubility of cyclosporine in acetone at 53 °C was reported to be ca. 30 wt % (20.7 mmol/mol acetone), a solubility much lower than in [C2mim][OAc], [P66614]Cl, or [C4NH3][OAc] at higher temperatures.

In some of our previous efforts to enhance the solubility of APIs, we have demonstrated the influence on solubility of ibuprofen free acid and lidocaine free base when excess parent amine or acid is present in a protic IL.30 An increase in solubility of ibuprofen (in its free acid form, insoluble in [C4NH3][OAc] or in acetic acid, HOAc) was observed in mixtures of [C4NH3][OAc] and HOAc. Likewise, the solubility of free lidocaine was increased in mixtures of [C4NH3][OAc] and n-butylamine (C4NH2), likely by weakening the strength of C4NH2 as a hydrogen bond donor.30

We therefore studied the solubility of cyclosporine in the protic IL [C4NH3][OAc] in the presence of excess acid (HOAc) or base (C4NH2). Solutions with 1:2, 1:1, and 1:0.5 molar ratios of IL/acid and IL/base were prepared by direct addition. Following the same procedures noted in the Methods section, saturated solutions of cyclosporine were prepared and analyzed at 25 °C. As shown in Figure 3, the solubility of cyclosporine in [C4NH3][OAc] was improved with the addition of either excess acid or base, where the addition of base had a pronouncing effect compared to acid. This is in agreement with our observations that cyclosporine solubilities were higher in the IL with the stronger basic acetate anions, that is, [C2mim][OAc].

Figure 3.

Figure 3

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Cyclosporine solubility in [C4NH3][OAc] solutions containing excess HOAc (IL/acid = 1:2, 1:1, and 1:0.5 molar ratios) or C4NH2 (IL/base = 1:2, 1:1, and 1:0.5 molar ratios) at 25 °C. *Partial solubility of cyclosporine, no more cyclosporine was added to the solution after 45.5 wt %.

The results from the solubility studies were used to assess the usefulness of ILs in purifying cyclosporine from its impure form (here called “crude cyclosporine, CC*”) with both antisolvent and liquid–liquid extraction strategies. The antisolvent strategy was explored using the water soluble ILs [C2mim][OAc], [C4NH3][OAc], and the [C4NH3][OAc] systems with excess HOAc or C4NH2. The usage of the latter systems (i.e., [C4NH3][OAc] with excess HOAc or C4NH2) were previously reported to induce crystallization of acidic and free base forms of APIs.19 EtOAc was studied for comparison.

Crude cyclosporine (50 mg, 90.8% purity, see CC* in Figure 4) was added to a 15 mL glass vial with 1 g of each IL, mixture, or solvent. The mixture was stirred using a magnetic stir bar (350 rpm) for 1 h at room temperature (25 °C) for dissolution. Water (1 mL) was then added and the mixture was vortexed to induce the precipitation of the cyclosporine. The precipitates were filtered under vacuum and the filters were washed with extra water to remove any remaining IL/solvent. The cyclosporine was dissolved in acetonitrile and the percentages of cyclosporine and the impurities dissolved in the solutions (Figure 4, Table S1) were quantified using HPLC and calculated based on the peak areas, as noted in the Methods section.

Figure 4.

Figure 4

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Crude cyclosporine (CC*) purification using EtOAc, the ILs [C2mim][OAc] and [C4NH3][OAc], and mixtures of [C4NH3][OAc] containing excess HOAc or C4NH2 (IL/acid or IL/base = 1:2, 1:1, and 1:0.5 molar ratios). (Gray bar: cyclosporine; black bar: total impurities).

Although [C2mim][OAc] had higher solubility of cyclosporine than [C4NH3][OAc] at both 25 and 100 °C (Table 1, Figure 2), the purity of the recovered cyclosporine was much lower in the case of [C2mim][OAc] (72.9% pure) when compared to [C4NH3][OAc] (92.9% pure). The impurities observed when [C2mim][OAc] was used were even higher than the starting CC*. This might suggest that impurities were more soluble than the drug in [C2mim][OAc]. The addition of excess acid to [C4NH3][OAc] did not improve the purity of cyclosporine, instead the purity was observed to be 89.9% for two extra moles of acid per mole of IL. Excess base did not have any significant effect on purity unless the amount was increased to two extra moles. Overall, the high solubility of the drug into the hydrophilic ILs and mixtures resulted also in higher solubility of impurities, which are similar in structure to the drug.

Our next approach was to use liquid/liquid extraction rather than antisolvent precipitation to obtain higher purity cyclosporine. Two of the ILs with the high cyclosporine solubilities at 25 °C, [C2mim][OAc] and [C4NH3][OAc], were chosen for this study. To choose the best immiscible solvents to perform the extraction, we considered the solubility of cyclosporine in chloroform, toluene, dichloromethane, EtOAc, and ethyl ether which are all reported to be >50 mg/mL,31 and in hexane which is reported to be <5 mg/mL. Of these, [C4NH3][OAc] is immiscible with ethyl ether and hexane, while [C2mim][OAc] is immiscible with EtOAc and hexane, therefore these four biphasic systems were examined.

Crude cyclosporine (CC*, 50 mg) was added into a 15 mL glass vial containing 1 g of the two ILs and stirred at room temperature until complete dissolution. The organic solvents were then added to these solutions resulting in 1:1 weight ratios of the phases, sonicated for 60 min, and finally allowed to stand 30 min for phase separation. The upper, organic phases were separated, and a second portion of organic solvent was added to the IL phase, repeating the extraction step. All extracted volumes were combined and the solvent was allowed to evaporate at room temperature. No solids were detected after solvent evaporation of the organic phases (EtOAc, hexane) recovered from the biphasic systems with [C2mim][OAc], indicating preferential partitioning of the drug (and impurities) to the IL rather than the organic solvent. On the other hand, solids were obtained after the evaporation of the organic phases extracted from the systems [C4NH3][OAc]/organic solvents. All solids obtained after evaporation were redissolved in acetonitrile and subjected to HPLC analysis. The IL phases were dissolved in water to precipitate any cyclosporine, which was then filtered and dried before dissolving in acetonitrile for HPLC analysis (Table 2).

Table 2. Purification of Cyclosporine Using Biphasic Systems Based on [C4NH3][OAc] and [C2mim][OAc] with Organic Solvents.

IL solvent phase solid obtained from cyclosporine purity, %
[C4NH3][OAc] ethyl ether IL 91.0
    organic 95.0
[C4NH3][OAc] hexane IL 94.3
    organic 70.3
[C2mim][OAc] EtOAc no solids were observed after evaporation of organic phases. cyclosporine purity recovered from IL phase is comparable with the anti-solvent approach (ca. 72%).
[C2mim][OAc] hexane  
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In the case of the [C4NH3][OAc]/ethyl ether system, the cyclosporine purity reached 95% in the organic phase, while its purity in the IL phase reached 91%. In the case of the [C4NH3][OAc]/hexane system, higher affinity of cyclosporine was observed for the IL than the hexane phase (94.3 vs 70.3%, respectively), possibly due to the low solubility of the drug in hexane. Independent of the strategy or IL selected to purify the CC*, the recovered cyclosporine remained in its amorphous form.

Conclusions

In summary, we employed ILs as alternative solvents to dissolve cyclosporine. At 25 °C among all ILs employed, [C2mim][OAc] had a higher solubility of cyclosporine than that of acetone, a known molecular solvent for cyclosporine solubility. The solubility can be enhanced more than 11X for [P66614]Cl and more than 2X for [C2mim][OAc] by increase of temperature from 25 to 100 °C. The ILs were also used to purify cyclosporine from its crude form. The strategies evaluated allowed purification of an amorphous cyclosporine up to ca. 95%. Although simple strategies such as IL–organic solvents biphasic systems can be used to improve the purity of cyclosporine, future work should focus on the crystallization of the drug from highly concentrated IL solutions, if possible at room temperature.

Methods

Chemicals

Crude cyclosporine was supplied by Novartis-Massachusetts Institute of Technology (USA) with purity of 90.8%. Purified cyclosporine (95.0% purity, crystalline form), n-butylamine, n-octylamine, choline hydroxide, and glacial acetic acid were purchased from Sigma-Aldrich (Oakville, ON, Canada). Acetonitrile (HPLC grade), ethyl ether, EtOAc, hexane, phosphoric acid, and tert-butyl methyl ether were purchased from Fisher Scientific (Ottawa, ON, Canada). The water used in the experiments was obtained from a Millipore purified water system (resistivity 18.2 MΩ cm, 25 °C, Milli-Q Academic, Millipore, USA).

[Cho][OAc], [C4NH3][OAc], and [C8NH3][OAc] were synthesized by following reported procedures (see Supporting Information for complete description and characterization).32,33 [P66614]Cl was kindly donated by Cytec-Solvay (Niagara Falls, ON, Canada). [C2mim][OAc] and [C2mim][NTf2] were purchased from IoLiTec (Tuscaloosa, AL, USA).

Solubility Studies

Purified cyclosporine (0.05 g) was added to a vial loaded with ca. 0.7 g of pure [C4NH3][OAc], [C8NH3][OAc], [Cho][OAc], [P66614]Cl, [C2mim][OAc], or [C2mim][NTf2] and the mixtures were stirred at 25 or 100 °C for 6 h. Also, mixtures containing 0.7 g [C4NH3][OAc] with an excess of acetic acid or n-butylamine (0.33, 0.5, 1, or 2 molar excess) and 0.05 g of cyclosporine were prepared in a glass vial and the solutions were stirred at 25 °C for 6 h. For all the solutions prepared above, if no solids were observed after mixing, another 5 mg of cyclosporine was added to the solutions and further stirred for 30 min. The addition of cyclosporine and stirring steps were repeated until solid precipitation was observed after mixing. The solutions were then filtered using a syringe filter (0.45 μm) to separate the undissolved particles. The filtered homogeneous solution was weighed and dissolved in acetonitrile in a 10 mg solution:1 mL acetonitrile ratio for cyclosporine quantification using HPLC.

Purification of Cyclosporine

Antisolvent Strategy

Crude cyclosporine (50 mg) was added to a 15 mL glass vial containing 1 g of [C4NH3][OAc], [C2mim][OAc], and [C4NH3][OAc] systems with excess HOAc, or C4NH2, or EtOAc. The mixtures were stirred at room temperature using a magnetic stir bar (350 rpm) to complete dissolution (ca. 1 h). After dissolution, 1 mL of water was added to precipitate the cyclosporine. The precipitates were filtered under vacuum and the filters were washed with extra water to remove any remaining IL/solvent. The precipitates were redissolved in acetonitrile and analyzed using HPLC.

Liquid–Liquid Extraction Strategy

Crude cyclosporine (50 mg) was added to 15 mL glass vials containing a magnetic stir bar and 1 g of [C4NH3][OAc] or [C2mim][OAc]. The mixtures were stirred at room temperature, 350 rpm until complete dissolution (ca. 1 h). After dissolution, hexane or EtOAc was added to cyclosporine in [C2mim][OAc] solution, while hexane or ethyl ether was added to cyclosporine in [C4NH3][OAc] solutions, resulting in 1:1 (IL/organic solvent) mass ratio biphasic systems. The mixtures were vortexed for 10 s, sonicated in an ultrasonic bath for 60 min, and left on the bench for 30 min until phase separation was completed. The upper, organic phase was separated using a glass Pasteur pipet. A second portion of organic solvent was added to the IL phase and the extraction and separation steps were repeated. Both organic phases were mixed and left on the bench for evaporation. If solids appeared, these were dissolved in acetonitrile and analyzed using HPLC. The IL phase was dissolved in water and the precipitated cyclosporine was filtered, dried, and dissolved in acetonitrile for HPLC analysis.

HPLC Analysis

The IL-cyclosporine solutions produced from the solubility studies and the powders recovered from the cyclosporine purification experiments were dissolved in acetonitrile, filtered through a 0.45 μm filter membrane, and injected into an Agilent 1260 series HPLC system (Agilent Technologies, Santa Clara, CA, USA). The HPLC system was equipped with a quaternary pump, an autosampler, and a multiwavelength UV–vis detector. HPLC separations were carried out on a Zorbax Eclipse XDB-C18 LC Column (250 mm × 4.6 mm, 5 μm, Agilent Technologies) at 75 °C. The flow rate was 1.5 mL/min, and the injection volume was 20 μL. Following a previously reported method,34,35 an isocratic elution was selected, using a mobile phase of 52.1% acidified H2O (0.1% phosphoric acid), 43% acetonitrile, and 4.9% tert-butyl methyl ether, with a runtime of 80 min and a detection wavelength at 210 nm.

Cyclosporine calibration curves were prepared for quantitative analysis of cyclosporine dissolved and/or purified. A stock solution of cyclosporine was obtained by dissolving ∼40 mg (purified cyclosporine, 95%) in 2 mL of acetonitrile. The standard solutions were obtained by subsequent dilutions of stock solutions with acetonitrile to obtain five different concentrations in the range of 0.6–6 mg/mL. A linear calibration curve was obtained by plotting the areas of the chromatogram peak against the concentration to obtain R2 > 0.99 (Figure S6, Supporting Information). For purification studies, impurities were treated as one “dummy” impurity, and the purity of cyclosporine was calculated as in eq 1

graphic file with name ao-2019-00603z_m001.jpg 1

where % area is the area under the chromatograph peak observed by HPLC.

Acknowledgments

This work was initiated at The University of Alabama and continued in part at McGill University. We thank the Novartis-Massachusetts Institute of Technology (MIT, 5710003948) Center for Continuous Manufacturing (CCM) and Novartis International AG for financial support.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00603.

  • Crude cyclosporine characterization (TGA, PXRD, and HPLC chromatograms), synthesis of ILs and characterization (NMR spectra), and HPLC calibration curves for cyclosporine quantification (PDF)

Author Present Address

∥ Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, MN 55455, United States.

Author Present Address

⊥ Joint BioEnergy Institute, 5885 Hollis St, Emeryville, CA 94608, United States.

The authors declare no competing financial interest.

Supplementary Material

ao9b00603_si_001.pdf (530.7KB, pdf)

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