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Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720)

Journal of Pharmaceutical and Biomedical Analysis, Volume 109, 10 May 2015, Pages 45-51

Graphical abstract




  • Three polymorphic forms of the immunomodulatory drug, fingolimod hydrochloride (FTY 720), are highly temperature dependent.
  • The reversible single-crystal to single-crystal transformations were studied using different analytical techniques (XRD, DSC, and Raman).
  • Form I is stable at ambient condition, while II and III could change to I when appropriate temperature applied.


Single-crystal structures of fingolimod hydrochloride (FTY 720), a block-buster multiple sclerosis drug, were revealed for the first time in this study. Three different conformational polymorphs (designated as forms I–III) were characterized using a variety of analytical techniques, including single-crystal XRD, VT-PXRD, DSC, HSM, and VT-confocal Raman spectroscopy. A temperature-dependent solid–solid transformation between different conformational polymorphs was observed to be reversible, and the transition process was studied using both VT-PXRD and VT-Raman techniques. Structural analysis revealed that the FTY 720 molecules adopt distinctive conformations in different polymorphs. Single-crystal to single-crystal transformation from form I to II was observed and was closely monitored by X-ray diffraction.

Keywords: Fingolimod hydrochloride, Conformational polymorphism, Single-crystal to single-crystal, Thermal analysis, Polymorph transformation.

1. Introduction

Polymorphism, the existence of more than one crystalline form of a chemically distinct solid, has received particular attention in the pharmaceutical industry and academia. It is widely accepted that different polymorphs may possess different physicochemical properties, such as different physical and chemical stabilities, manufacturabilities, apparent solubilities, dissolution rates and bioavailabilities[1], [2], [3], [4], and [5]. A comprehensive understanding of the polymorphic landscape and corresponding phase transformation mechanism that controls the stability of a particular solid-state form is of fundamental importance in terms of manufacturing, formulation development and drug quality control[6] and [7]. The origin of polymorphism may arise from different packing configurations or conformational differences within a single molecular structure. Accordingly, polymorphs are generally classified as packing polymorphs or conformational polymorphs. Conformational polymorphism is often observed among active pharmaceutical ingredients with alkyl chains composed of four or more atoms [8] . These organic long-chain compounds appear in a variety of conformational structures, depending on environmental conditions as well as on the thermal histories the compounds have experienced [9] . More importantly, such a complexity in structure is closely related to the compounds’ functional activities and physicochemical properties [10] . Conformational polymorphism provides an ideal system for the study of structure–property relationships [11] .

Fingolimod hydrochloride (FTY 720, Scheme 1 ) is an oral immunomodulatory drug for multiple sclerosis, which is believed to be the most common inflammatory disorder of the central nervous system [12] . The drug is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs. FTY 720 has been sold on the market under the brand name Gilenya®since 2010, and world sales reached nearly US $2 billion in 2013 (sales data from IMS Health). FTY 720 has already become the second largest selling immunomodulatory drug to date.


Scheme 1 Chemical structure of FTY 720.

Three different polymorphs (I–III) were disclosed in a patent published in 2010 based on powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) data [13] . To the best of our knowledge, the single-crystal structure of FTY 720 has not yet been reported; moreover, the polymorphic transition behaviors of the drug have not been fully investigated. In this contribution, single-crystal structures of FTY 720 were revealed for the first time to establish the origin of the three polymorphs of the drug. The physicochemical properties of FTY 720 were fully investigated by employing a variety of analytical techniques. The polymorphic phase transformation was observed to be reversible and highly temperature-dependent. The single-crystal to single-crystal transformation process was monitored under HSM and analyzed by single-crystal XRD. The polymorphic origin of each phase was attributed to the conformational flexibility of FTY 720 molecules.

2. Materials and methods

2.1. Materials

The raw material of FTY 720 (form I) was obtained from Shanghai Growingchem Company Limited, with greater than 99% purity. All analytical-grade solvents were purchased from Sinopharm Chemical Reagent Company Limited and were used without further purification.

2.2. Single-crystal X-ray diffraction

X-ray diffraction of a single-crystal was performed on a Bruker Apex II CCD diffractometer using Mo Kα radiation (λ = 0.71073 Å) at 296(2) K. The structures were determined by direct methods and refined via full-matrix least-squares difference Fourier analysis using SHELX-97 software. Nonhydrogen atoms were refined using anisotropic displacement parameters, and all hydrogen atoms were placed in calculated positions and refined with a riding model. Data were corrected for the effects of absorption using SADABS. Crystallographic data have been deposited with the Cambridge Crystallographic Data Center, CCDC 942684 and 942685. Essential crystal data are summarized in Table 1 .

Table 1 Crystallographic data for I and II.

FTY 720 Form I Form II
Formula C19H34ClNO2 C19H34ClNO2
Formula weight 343.92 343.92
Crystal system Monoclinic Monoclinic
Space group P21/n P21/n
Temperature (K) 296(2) 296(2)
a (Å) 7.1370(3) 57.158(4)
b (Å) 5.9623(2) 5.9602(5)
c (Å) 49.4475(18) 51.005(4)
α (°) 90 90
β (°) 91.231(2) 102.439(4)
γ (°) 90 90
Cell volume (Å3) 2103.65(14) 16968(2)
Calc. density (g/cm3) 1.073 1.077
Z 4 32
Z 1 8
μ 0.190 0.189
Independent reflections 4829 23681
S 1.008 1.089
R 1 0.079 0.179

2.3. Powder X-ray diffraction

PXRD patterns were obtained using a Bruker D8 Advance X-ray diffractometer (Cu Kα radiation). The voltage and current applied were 40 kV and 40 mA, respectively. Samples were measured in reflection mode over the 2θrange 3–40° at a scan speed of 1.2°/min (step size 0.025°, step time 1.0 s) using a LynxEye detector. Data were imaged and integrated with RINT Rapid, and the peaks are analyzed with Jade 6.0 software from Rigaku. Calibration of the instrument was performed using a corindon (Bruker AXS Korundprobe) standard.

2.4. Variable-temperature powder X-ray diffraction

Variable-temperature X-ray powder diffraction patterns were recorded with an Anton Paar TTK 450 low-temperature camera attached to a Bruker D8 Advance diffractometer. A heating and cooling rate of 5 °C/min was applied throughout the VT-PXRD experiment.

2.5. Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) was conducted in Tzero aluminum pans using a TA Instruments Q2000 unit under a nitrogen gas flow rate of 20 mL/min. Samples weighing 3–5 mg were heated in standard aluminum pans at scan rates ranging from 5 to 10 °C/min. Two-point calibration using indium and tin was carried out to check the temperature axis and heat flow of the equipment.

2.6. Variable-temperature Raman

Variable-temperature Raman spectra were recorded with an XPH-300 hot stage attached to a Thermo Scientific DXR Raman microscope equipped with a 532 nm laser. The Raman scans ranged from 3500 to 50 cm−1. A heating rate of 5 °C/min was used during all of these determinations. Samples were analyzed directly in a glass sheet using 10 mW of laser power and a 50 μm pinhole spectrograph aperture. Calibration of the instrument was performed using a polystyrene film standard.

3. Results and discussion

3.1. Thermal analysis

Differential scanning calorimetry experiments[7] and [14]were carried out to study the phase transitions of FTY 720 ( Fig. 1 ). In the first heating scan, three peaks (peaks 1, 2, and 3) were observed, corresponding to two solid–solid phase transitions and a solid–liquid melting transition. When the samples were subjected to further heating cycles after the first scan in which the samples were heated to 50 °C and then cooled, FTY 720 showed a solid phase transition (II–III transition) and a single sharp transition corresponding to the melting of the sample (III–liquid transition). Furthermore, when the samples were subjected to another cycle of heating after the first scan in which the samples were heated to 80 °C and then cooled, FTY 720 showed only a single sharp transition corresponding to the melting of the sample (form III melting). The third peak occurred at 107 °C in the first heating cycle, with a melting endotherm of 66.5 J/g, corresponding to the melting point of FTY 720. The melting process was visually monitored during the hot-stage microscope experiment. The observed melting point of FTY 720 is in agreement with previously published patent data [13] . Moreover, the other two endothermic peaks that occurred at temperatures below the melting (TI–IIat 40 °C andTII–IIIat 65 °C) correspond to two solid–solid phase transitions of form I to II and form II to III, respectively. This observation allowed for the identification of three distinct polymorphic forms (designated as I, II, and III) of FTY 720.


Fig. 1 DSC curves for the heating scans of FTY 720: heating scans of forms I (a), II (b), and III (c) at a scan rate of 10 °C/min.

Fig. 2 shows that form I presents an endothermic peak (Cp = 12.6 J/g) in the DSC diagram at temperatureT = 40 °C, which corresponds to the conversion of form I to form II. Given that there is no other peak between this endothermic transition point and the melting point, according to the heat-of-transition rule[3] and [15], form I and form II should be enantiotropically related, with form I being the more stable form below the transition temperature. Following the same principles, forms II and III should also be enantiotropically related, with form II being the more stable form below the phase transition temperature. The derived thermodynamic relationship also agrees well with the fact that the polymorphic state is highly temperature-dependent and the phase inter-conversion is reversible.


Fig. 2 Hot-stage microscopy snapshots of the single-crystal to single-crystal transformation from form I to form II.

3.2. Single-crystal to single-crystal transformation analysis

Single-crystal to single-crystal transformation behavior was first observed during the hot-stage microscope experiments ( Fig. 2 ). The clear, prismatic single crystal of form I was first obtained by slowly evaporating the solvent from a saturated acetone solution. A suitable single crystal was selected and subjected to single-crystal X-ray diffraction measurement. The diffraction data were collected at ambient temperature due to the loss of crystallinity when the sample was placed at low temperature (e.g., 273 K or lower). The crystal was examined under a hot-stage microscope, with the temperature ramped up at 5 °C/min. No distinct shape change was observed over the temperature range examined. However, a slight color change was noticed when the sample was heated to approximately 40 °C ( Fig. 2 ). The sample was further heated to 50 °C, held at that temperature for 1 h, allowed to cool to room temperature and immediately subjected to another single-crystal X-ray diffraction analysis. Rapid cell determination showed that the unit cell was elongated along thea-axis. The crystal structure was later determined to be form II.

Form I crystallized in the monoclinicP21/n space group with unit cell dimensionsa = 7.1370(3),b = 5.9623(2),c = 49.4475(18) Å,β = 91.231(2)°. Details of data collection and structure refinement are summarized in Table 1 . There is one molecule in the asymmetric unit, resulting in four molecules in the monoclinic unit cell. The C8 hydrocarbon chain of FTY 720 molecule adopts an all-trans zig-zag conformation in form I ( Fig. 3 ). The polar amino hydrochloride heads line up in a head-to-head fashion to form a 1-D infinity train structure connected by multiple H-bonding interactions between hydroxyl groups and chloride anions. In addition, multiple hydrogen bonds were observed between the amino salt and hydroxyl groups in the crystal structure. The C8 hydrocarbon chain, as expected, is packed in a parallel fashion, and the molecules are organized in a tail-to-tail fashion, similar to the arrangement of molecules in a bilayer membrane ( Fig. 4 a)[9] and [16].


Fig. 3 Crystal structure of FTY 720 (form I).


Fig. 4 Molecular packing, as viewed down thea-axis, of forms I (a) and II (b).

Form II has the same crystal system and space group as form I, indicating the structural similarity between the two polymorphs. However, significant changes in the unit cell dimensions occurred; for form II,a = 51.005(4),b = 5.9602(5),c = 57.158(4) Å,β = 102.439(4)°. There are 8 molecules in the asymmetric unit, leading to 32 molecules in the monoclinic unit cell. Form II also adopts a tail-to-tail packing configuration, resembling that of form I but with distinct molecular structure changes in the FTY 720 molecule itself ( Fig. 4 b). Interestingly, a portion of FTY 720 adopts a different conformation in the crystal lattice.

Single-crystal structure analysis suggests that no molecular displacement takes place during the phase transition process. A close analysis of the single-crystal structures of I and II revealed that the conformation of FTY 720 molecules is significantly different in form II. The conformational diversity was highlighted by an overlay of conformers extracted from both I and II. The results show that the structural difference mainly arises from the rotation of the single bonds C12[glyph: sbnd]C13. Although only one conformer was observed in the single-crystal structure of form I, three distinctive conformers were observed with a fixed ratio of 5 (red): 1 (green): 2 (blue) in the crystal structure of polymorph II. The torsion angles C8[glyph: sbnd]C9[glyph: sbnd]C12[glyph: sbnd]C13of the three conformations are 20.3, 75.2, and 115.6, respectively. Single-crystal analysis indicates that the phase transition from I to II mainly arises from the rearrangement of the alkyl chain upon heating.

Although the determination of the single-crystal structure of forms I and II was feasible, attempts to resolve the single-crystal structure of form III failed due to the unstable nature of form III at ambient temperature.

3.3. Variable temperature powder X-ray crystallographic studies

Form I was the most thermodynamically stable form at ambient temperature. Form II could remain stable for a few days at room temperature; however, form III was unstable at ambient condition, and the XRPD measurements had to be conducted at elevated temperature (e.g.,T > 65 °C). Distinctive PXRD patterns were recorded immediately after a proper treatment of form I to yield the corresponding forms I (25 °C), II (50 °C), and III (80 °C), as shown in Fig. 3 . Form I presented characteristic peaks at 2θ = 3.6°, 7.1°, 10.7°, 15.4°, 17.9°, 20.5°, 21.5°. Form II presented XRPD peaks at 2θ = 3.5°, 7.1°, 8.7°, 9.3°, 10.6°, 19.3°, 20.0°, 20.9°, 21.5°, and the XRPD pattern of form III closely resembles that of form I, but subtle differences can be observed at 2θ = 3.5°, 6.9°, 10.4°, 14.7°, 19.4°, 20.9° for form III. The differences in the PXRD data clearly indicate the presence of three distinct polymorphs.

To further analyze the phase transformation properties of the different solid-state forms of FTY 720, variable-temperature powder X-ray diffraction was performed, starting with form I, at ambient condition. The temperature-dependent measurement obtained by PXRD for FTY 720 is shown in Fig. 4 . The graph shown on the right depicts the DSC results obtained for the same experiment cycle (temperature, DSC curve), and the graph shown on the left depicts PXRD profiles obtained throughout the temperature ramping process. One temperature cycle was set from 10 °C to 80 °C and back to 10 °C (at 5 °C/min) (Fig 5 and Fig 6).


Fig. 5 Overlay of molecules in crystal structure of FTY 720 form I (black) and three different molecules, 5 (red): 1 (green): 2 (blue), in form II. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)


Fig. 6 PXRD patterns of crystal forms I–III.

As the temperature was ramped up, the powder patterns corresponding to form I (green lines) transformed into to a new powder pattern corresponding to form II (blue lines) at approximately 40 °C. An endothermic event also occurred during the phase transformation process. With the further increase in temperature, the PXRD pattern of form II was broadened and weakened until it fully converted to the PXRD pattern of form III (bright blue) at approximately 65 °C. In conjunction with the form II to III phase transition, a pronounced and sharp endothermic event was observed in the DSC diagram. In the subsequent lowing-temperature cycle controlled at 5 °C/min, two exothermic events were observed, corresponding to the solid–solid phase transformations of III to II and II to I. Accordingly, during the cooling cycle, changes in the PXRD pattern were also observed at 47 °C and 36 °C, echoing the two reversed solid–solid form transitions. Overall, the variable-temperature PXRD analysis demonstrated that the interconversion of the three polymorphs (I–III) is reversible and that form I is thermodynamically stable at room temperature ( Fig. 8 ). It is worth pointing out that forms III, once formed in the heating cycles, can be stable when the sample was cool down to room temperature quickly. However, when the cooling down process is slow (e.g. 5 °C/min), The conversion of form III to II and then I can be captured as shown in Fig. 7 .


Fig. 7 VT-PXRD analysis of FTY 720. The colored lines of the powder XRD patterns (left) correspond to the same colored areas of the DSC thermogram (right). (For interpretation of the reference to color in this figure legend, the reader is referred to the web version of this article.)


Fig. 8 Reversible interconversion of FTY 720 polymorphs.

3.4. Variable-temperature Raman spectroscopic analysis

Along with X-ray diffraction, Raman spectroscopy provides a powerful tool for the investigation of polymorphism, especially for detecting polymorphic transformations[7], [10], [17], [18], and [19]. In the case of fatty acids and related compounds having a polar head group and a chain end, Raman peak shifts corresponding to the deformation, twisting, or rocking of methylene (1000–1500 cm−1), and C[glyph: sbnd]H stretching modes (2800–3000 cm−1) are the most commonly observed changes [20] . Significant changes in the VT-Raman spectra in the range of 1500–1200 cm−1corresponding to CH2wagging and the 2800–3000 cm−1region corresponding to C[glyph: sbnd]H stretches indicate the structural transformation of FTY 720 upon heating. The systematic Raman single changes suggest that the geometry of the C12[glyph: sbnd]C13bond of the molecule is affected during the polymorphic transition, which is correlated with the conformational changes that occur at the molecular level.

The typical conventions are used for labeling vibrational modes (v = stretch,δ = deformation,w = wag,t = twist,r = rock,s = symmetric,a = antisymmetric). Polymethylene modes are labeled CH2, and methyl modes are labeled CH3.

Raman spectra of FTY 720 were recorded between 3500 and 50 cm−1as a function of temperature. A partial view of those spectra is provided in Fig. 9 . During the course of polymorphic form I's transition to form II atTI–II = 40 °C, the 800–1500 cm−1region ( Fig. 9 a) presented the most marked changes. Specifically, the intensity atr(CH2) = 1298 diminished, whereas two sharp doublets (approximately 1200 cm−1) broadened as the temperature increased. Similarly, throughout the process of polymorphic form II's transformation into form III atTII–III = 65 °C, the 2800–3000 cm−1region ( Fig. 9 b) showed observable differences. The peak atva(CH2) = 2882 cm−1slowly disappeared as the temperature was ramped up from 45 °C to 68.5 °C. Finally, when form III melted atTIII–Liq = 107 °C, the main difference occurred in the 1100–1500 cm−1region ( Fig. 9 c). For example, the peak atδ(CH2) = 1473 cm−1disappeared andr(CH2) = 1300 cm−1decreased, whereas the band peak atr(CH2) = 1202 cm−1became sharp and the peak height increased significantly. The changes in this region correspond to the wagging mode of methylene.


Fig. 9 Temperature dependence of the Raman spectra of FTY 720 over different temperature ranges: 35.0–45.0 °C (a); 45.0–68.5 °C (b); and 105.0–108.5 °C (c).

The results of the Raman analysis reported here are closely related to the conformational changes that occur at the molecular level and that give rise to distinct conformational polymorphic forms. In particular, the observed changes related to the CH2group of the molecule during the polymorphic transitions suggest the rearrangement of the alkyl chain upon heating the crystals.

The existence of alternative crystal structures is a characteristic property of long chains compounds (fatty acids, triglycerides, etc.)[9] and [21]. Heating allows for a rearrangement of the flexible hydrocarbon chains into different conformations. The geometry of the polar heads should not be greatly affected by heating because they are held by a network of strong hydrogen bonding.

4. Conclusion

The thermodynamic properties and phase transition kinetics of each polymorph of a drug play a key role in establishing the drug's processing parameters, defining the drug's storage and transportation conditions, and establishing the specific conditions under which the drug can be administered. Based on a series of solid-state characterization techniques, including thermo-analysis, single-crystal XRD, VT-PXRD, and VT-Raman spectroscopy, evidence demonstrating that the immunomodulatory drug FTY 720 can exist in three distinctively polymorphic forms depending on temperature was obtained. A single-crystal to single-crystal transformation was observed under hot-stage microscopy and monitored by single-crystal X-ray diffraction. The solid–solid phase transformation was observed to be reversible under the appropriate conditions. The observed phase transition temperatures therefore serve to delineate temperature ranges of stability for the different polymorphic forms of the drug: below 40 °C for form I, between 40 and 65 °C for form II, and between 65 and 106 °C for form III.


We thank the National Natural Science Foundation of China (grants 81273479 and 81402898) and the Shanghai Institute of Materia Medica New-Star Plan B for funding.


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Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

lowast Corresponding author. Tel.: +86 21 50800934; fax: +86 21 50800934.

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