On the Formation and Desolvation Mechanism of Organic Molecule

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On the formation and desolvation mechanism of organic molecule solvates: a structural study of methyl cholate solvates Agris B#rzi#š, Aija Trimdale, Artis Kons, and Dace Zvani#a Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00657 • Publication Date (Web): 25 Sep 2017 Downloaded from http://pubs.acs.org on September 26, 2017

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Crystal Growth & Design

On the formation and desolvation mechanism of organic molecule solvates: a structural study of methyl cholate solvates Agris Bērziņš*, Aija Trimdale, Artis Kons, Dace Zvaniņa Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia

Solvate formation and desolvation mechanism of 25 obtained methyl cholate solvates were rationalized using crystal structure analysis and study of the phase transformations. The facile solvate formation was determined to be associated with the possibility for more efficient packing in structures containing solvent molecules. Most of the obtained solvates crystallized in one of the six isostructural solvate groups, with solvent selection based on the solvent capability to provide particular intermolecular interactions along with appropriate size and shape. In crystal structures several different methyl cholate conformers were observed, as apparently more efficient packing could be achieved by diversifying the molecule conformation and even adopting energetically quite unfavorable conformations. Nevertheless, the packing was generally controlled by the steroid ring system, particularly employing hydrogen bonding of the attached hydroxyl groups. Study of the desolvation mechanism showed that the primary desolvation product is determined by the structure similarity with the solvate, with thermodynamic stability of the desolvate having no directly identifiable effect. In case of the absence of acceptable structurally similar desolvate, desolvation produced an amorphous phase.

* Telephone: +(371)-67033903. E-mail: [email protected]

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On the formation and desolvation mechanism of organic molecule solvates: a structural study of methyl cholate solvates Agris Bērziņš*, Aija Trimdale, Artis Kons, Dace Zvaniņa Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia * Telephone: +(371)-67033903. E-mail: [email protected]

ABSTRACT Solvate formation and desolvation mechanism of 25 obtained methyl cholate solvates were rationalized using crystal structure analysis and study of the phase transformations. The facile solvate formation was determined to be associated with the possibility for more efficient packing in structures containing solvent molecules. Most of the obtained solvates crystallized in one of the six isostructural solvate groups, with solvent selection based on the solvent capability to provide particular intermolecular interactions along with appropriate size and shape. In crystal structures several different methyl cholate conformers were observed, as apparently more efficient packing could be achieved by diversifying the molecule conformation and even adopting energetically quite unfavorable conformations. Nevertheless, the packing was generally controlled by the steroid ring system, particularly employing hydrogen bonding of the attached hydroxyl groups. Study of the desolvation mechanism showed that the primary desolvation product is determined by the structure similarity with the solvate, with thermodynamic stability of the desolvate having no directly identifiable effect. In case of the absence of acceptable structurally similar desolvate, desolvation produced an amorphous phase. 2 ACS Paragon Plus Environment

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INTRODUCTION Exploration of a solid form landscape is an essential step during the drug development process, as different polymorphs and, particularly, solvates have different stability1, mechanical properties2-4, and bioavailability (linked to the different solubility5). Such studies are of particular importance as pharmaceutical molecules tend to form a range of different phases6,7, e.g., up to 10 polymorphs for ROY1 and flufenamic acid8, even more for aripiprazole9,10, and dozens (for olanzapine11 and axitinib12,13) or even more than 100 solvates (for sulfathiazole7). Experimental solid form screening will always involve crystallization from multiple solvents to find all accessible polymorphs and solvates to ensure that solid form with the best compromise of physical and chemical properties are selected for development as well as to prevent unexpected solid form appearance after the approval of a drug14,15. The discovery of solvates is important in several aspects: 1) formation of solvate can limit selection of solvents for crystallization of the polymorphs, 2) solvates can be used as intermediates for producing the necessary polymorphs, as specific polymorphs can sometimes be only obtained via desolvation of particular solvates16-19, and 3) particularly stable solvates, typically but not exclusively hydrates, can be used as the marketed form. Two main structural driving forces responsible for incorporation of solvent molecules in the structure have been identified6 and are a) ability of solvents to compensate unsatisfied potential intermolecular interactions between the molecules20, and b) ability to decrease the void space and/or lead to more efficient packing21. Both the formation of extensive hydrogen bond network established by the solvent molecules22 as well as increase of the packing efficiency23,24 has been showed to be the main contributing factor for the solvate formation of pharmaceutical molecules. Most of the solvates, however, include contributions from both of these driving forces6, and the solvate formation thus is due to a lowering of the crystal free energy. Only in the first scenario the solvate selectivity is based purely on their functionality. This principle is well demonstrated by isostructural solvates, which can form only with solvents having some specific interactions25,26 or 3 ACS Paragon Plus Environment


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molecular shapes27, although it is common that such solvates form with different solvent molecules located in structural channels28-30. While computational structure prediction tools are successful in prediction of polymorphs and their relative stability17,31-35, prediction of solvates and particularly their stability is more challenging, although successfully accomplished for some relatively simple hydrate36-39 and solvate40,41 systems with predefined stoichiometry. Alternatively, prediction of guest-free higherenergy structures have been employed for solvate prediction and identification of formation driving forces42-44. Although several algorithms for prediction of solvate formation based on fluid-phase thermodynamics computations45,46 as well as knowledge based models47 have been proposed, they are still unable to take into account all of the factors contributing in solvate formation. Therefore when considering solvate formation possibilities it is reasonable to evaluate the solvent and host properties and possible intermolecular interactions48-50. Although systematic and comprehensive studies of solvate formation23,24,48 and their properties30,51-53 have been published recently, a general understanding to achieve theoretical prediction of solvate formation based on the molecular structure, and prediction of solvate properties based on the crystal structure data have not yet been achieved. Similarly, there is no generally known method for prediction of the desolvation mechanism and structure of the desolvation product in particular. Often structurally similar non-solvated phases54-56 are obtained in the desolvation process indicating that escape of the solvent have caused limited molecule rearrangements57,58. Frequently, however, the solvate and its desolvate shares no similar structure features, particularly if the solvent have a significant role in stabilization of the molecular packing59, or the desolvation results in recrystallization or melting60,61. Moreover, in numerous cases sample properties and preparation, or desolvation conditions alter the polymorph obtained in the desolvation19,53,62. Methyl cholate MC (3α,7α,12α-trihydroxy-5β-cholan-24-oic acid methyl ester, see Figure 1) is water-insoluble white crystalline substance with applications in the pharmaceutical industry. It is 4 ACS Paragon Plus Environment

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used as an intermediate in synthesis of bile acids used to prevent and dissolve gallstones, as well as can be used as an intermediate for the production of corticosteroid structure drugs used in treatment of inflammation and tumor.

Figure 1. Molecular structure of MC with the numbering of non-hydrogen atoms and labeling of flexible dihedral angles. MC is reported to exist in one polymorphic form (designated here as polymorph I) as well as

solvates with methanol (SMe), ethanol (SEt), isopropanol (SIPA) and acetonitrile (SACN), first three of which are isostructural63-66. Additionally, MC is reported to form inclusion compounds with over fifty different organic substances, such as aliphatic and/or aromatic alcohols, ketones, aldehydes, ethers, carboxylic acids, esters, nitriles, halides, and nitro compounds63 and therefore can be characterized as very keen solvate former. However, no structural information about these have been presented, and only ten specific solvents (including methanol and acetonitrile) together with the stoichiometry and solvent release temperature are mentioned. Therefore, in this study we systematically investigated the solid form landscape of MC by performing crystallization experiments from numerous different solvents, analyzing stability and phase transformations of the obtained phases at elevated temperature and relative humidity. The aims of this study were 1) to rationalize the driving force for the solvate formation of MC, 2) to use the structural information for rationalization of the solvate formation with the particular solvent molecules, 3) to rationalize the formation of the obtained different isostructural solvate groups, and 4) to use the structural and thermodynamic stability information for rationalization of the observed phase transformations and mechanism during the desolvation of MC solvates. 5 ACS Paragon Plus Environment


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EXPERIMENTAL SECTION Materials Methyl cholate (purity >98%) was obtained from JSC Grindeks (Riga, Latvia). Inorganic compounds and organic solvents of analytical grade were purchased from commercial sources and used without further purification.

Solvent-based polymorph and solvate screening The most popular solvents chosen from different solvent classes67,68 (grouped according to physical and physicochemical properties) were selected for the crystallization of MC. Saturated or concentrated solutions of MC in all of the solvents were prepared at 40–80°C, depending on the boiling point of the solvent (see Table S1, Supporting Information). The obtained solutions were then cooled down to –10°C. In the cases when no crystallization was observed, the solutions were slowly evaporated at 25°C. The obtained products were collected by filtration, air-dried, and characterized. Type 1 and Type 2 (see below) solvates obtained as crystals were slightly grounded in the mortar.

Preparation of solvate samples For studying the phase transitions and stability all solvates were prepared as in the solvate screening experiments by obtaining crystals (for Type 1 and Type 2 solvates) or powders. Alternatively, non-solvated MC was suspended for 24 h in the corresponding solvent at 50°C, producing powdered SEt, SMe, SACN and SNM samples.

Study of solvate stability and phase transitions Stability and phase transitions of the solvates were determined by storing the solvate samples at elevated temperatures in air thermostats and at 30 °C in 22% and 68% relative humidity (using saturated solutions of CH3CO2K and KI respectively). The heating temperature was selected based on the recorded DSC/TG curves. Hydrate samples were also stored at 30°C in desiccator over P2O5 and saturated solutions of salts providing specific RH (LiBr (6%), LiCl (11%), MgCl2 (32%), NaBr (56%), NaCl (75%), KCl (84%), BaCl2 (92%), K2SO4 (97%)). Phase transformations were identified using PXRD and, if necessary, DSC/TG. 6 ACS Paragon Plus Environment

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Single crystal X-ray diffraction (SCXRD) The single-crystal X-ray diffraction data for MC nitromethane solvate were collected at 173 K on a Nonius Kappa CCD (Bruker) diffractometer, using Mo-Kα radiation (graphite monochromator, λ=0.71073Å) and Oxford Cryostream (Oxford Cryosystems) open-flow nitrogen cryostat for sample temperature control. The structure weas solved by direct method and refined by full-matrix least squares on F2 for all data using SHELX-97 suite69. All nonhydrogen atoms were refined anisotropically. The hydrogen atoms were located in difference Fourier maps and freely refined, except for the methyl H atoms which were refined in riding positions. The isotropic thermal factor of hydrogen atoms Uiso(H) = 1.2Ueq(C/O) or 1.5Ueq(C) for methyl H atoms was used.

Powder X-ray diffraction (PXRD) The PXRD patterns were measured at ambient temperature on a D8 Advance (Bruker) diffractometer using copper radiation (CuKα) at the wavelength of 1.54180 Å, equipped with a LynxEye position sensitive detector. The tube voltage and current were set to 40 kV and 40 mA. The divergence slit was set at 0.6 mm and the antiscatter slit was set at 8.0 mm. The diffraction patterns were recorded using a 0.2s/0.02° scanning speed from 3° to 35° on 2θ scale. To prevent the phase transformations, the samples were covered during the analysis with a 10 µm polyethylene film, when necessary. For crystal structure determination, PXRD patterns were measured on a D8 Discover (Bruker) diffractometer at transmission geometry using Göbel Mirrors and a capillary sample stage with upper and lower knife edges. Other settings and equipment were identical to those used for D8 Advance. Samples were sealed in rotating (60 rpm) borosilicate glass capillaries of 0.5 mm outer diameter (Hilgenberg glass No. 10), and data were collected using 36s/0.01° scanning speed from 3.0° (2.5° for V, VI, STOL and H1) to 70° (52° for IV) on 2θ scale. Variable-temperature PXRD (VT-PXRD) patterns were measured on a D8 Discover (Bruker) diffractometer equipped with MRI temperature chamber and Ansyco temperature controller. The



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diffraction patterns were recorded using a 0.5s/0.02° scanning speed from 3° to 30° on 2θ scale. Other settings and equipment were identical to those used for D8 Advance.

Crystal structure determination from PXRD data The PXRD patterns were indexed for the first 20-25 peaks, using DICVOL0470 (implemented in WinPLOTR software71) and SVD indexing algorithms72 (implemented in TOPAS v4.2). Space group determination was carried out using a statistical assessment of systematic absences, and Z’ was determined based on density considerations. Structure solutions were performed by Monte Carlo/Simulated annealing technique implemented in Expo201473,74, using a rigid model, flexible about the dihedral angles τ1–5 by also determining the center of mass location and molecular orientation. The initial geometries of MC molecule were used as in crystal structures of polymorph I, SMe and SACN. The initial geometry of DMSO and toluene molecules were taken from the CSD (Refcodes DAVGIS75 and TOLUEN76), that of dichloromethane was taken from the COD (COD ID 810084177) and that of tert-butanol from the literature78. The final refinements were carried out in Expo2014 by the Rietveld method using soft constraints on bond distances and angles. The background was modelled by a 20th-order polynomial function of the Chebyshev type; peak profiles were described by the Pearson VII function and a common (refinable) isotropic thermal factor was attributed to all non-hydrogen atoms, while that of hydrogen atoms was assumed to be 1.2 times higher.

Thermal analysis The differential scanning calorimetry/thermogravimetry (DSC/TG) analysis was performed with TGA/DSC2 (Mettler Toledo). Open 100 µL aluminum pans were used. Heating of the samples from 25 to 200°C was performed at a 10°·min–1 heating rate (in few cases also 1°·min– 1

). Samples of 5–10 mg mass were used, and the nitrogen flow rate was 100±10 mL·min–1. Most

of the solvates were analyzed three times and polymorphs two times using samples obtained in different crystallization or phase transition experiments, see details in Table 2 and Table S11. The differential thermal analysis/thermogravimetry (DTA/TG) analysis was performed to study the effect of particle size on the phase transformations of Type 1 and Type 2 solvates using 8 ACS Paragon Plus Environment

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Exstar6000 TG/DTA6300 (SII). Open aluminum pans were used. Heating of the samples from 30 to 200°C was performed at a 5°·min–1 or 1°·min–1 heating rate. Samples of 5–10 mg mass were used, and the nitrogen flow rate was 100±10 mL·min–1. Each sample was analyzed once.

Water vapor sorption and desorption studies Dynamic vapor sorption experiments were performed on the DVS Advantage (Surface Measurement Systems). Sample weight was 7 – 12 mg. The samples were studied over a humidity range from 0 - 90% or 95% RH at 25 °C by starting with RH similar to that used for preparing the sample (except for H2III which was initially dried under a 200 mL stream of N2 to establish the equilibrium dry mass). Each humidity step was taken with equilibration set to dm/dt 0.002%/min on a 5 min time frame (with the minimum hold time of 10 min and the maximum of 300 min). Changes in the PXRD pattern were examined by storing samples in the desiccators with RH controlled by saturated solutions of salts or P2O5, see above.

Theoretical calculations Relaxed potential energy surface (PES) scans were performed in Gaussian 0979 at the B3LYP/6-311G(d,p) level by scanning all five flexible torsion angles (see Figure 1) of MC with the step size of 10°. Initial geometry of MC molecule was taken from the crystal structure of polymorph I (molecule B). The geometry optimization and the resulting calculation of total energy of MC polymorphs and solvates was performed in Quantum ESPRESSO80 by either relaxing positions of all atoms (relax) or positions of all atoms and unit cell parameters (vc-relax). All calculations were performed using the PBE functional using ultra-soft pseudopotentials from the original pseudopotential library and a 44 Ry plane-wave cut-off energy with vdW interactions treated according to the D2 method of Grimme81. The selection of the pseudopotentials as well as parameters of convergence and the k-point grid were done using the already published suggestions for structure optimizations of pharmaceutical molecules82.



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The lattice energy calculations were performed using semi-empirical PIXEL83 methodology developed by Gavezzotti. Crystal structures were used after geometry optimization in Quantum ESPRESSO.

Crystal structure comparison and analysis Mercury 3.8 software84 was used for crystal structure analysis and simulation of PXRD patterns based on crystal structure data. The Crystal Explorer 3.185 was used for generation and analysis of 2D fingerprint plots of Hirshfeld surfaces summarizing the information about intermolecular interactions86,87. Detailed analysis of the molecular packing was performed using XPac code88,89. The packing coefficients and void space in crystal structures were calculated by PLATON90.

RESULTS AND DISCUSSION Solvate screening and characterization MC was crystallized from 34 solvents selected to represent different solvent classes based on

classification according to statistical analysis of four molecular descriptors67, as well as hydrogen bond acceptor and donor propensity, polarity/dipolarity, dipole moment, and dielectric constant68. In these experiments 21 new MC solvates (n-propanol SnPA, nitromethane SNM, dichloromethane SDCM, toluene STOL, o-xylene SXYL, 3-pentanone SPEN, dimethyl carbonate SDMC1 and SDMC2, isopropyl acetate SiPrOAc, 1,3-dioxolane SDXLN, THF STHF, DMSO SDMSO and SDMSO2, DMF SDMF, isobutanol SiBA1 and SiBA2, tert-butanol StBA, dimethylacetamide SDMA, and

benzyl alcohol SBA solvates as well as hydrates H1 and H3VII, a non-stoichiometric hydrate with structure related to MC polymorph VII) were obtained, while crystallization from ethanol, methanol, isopropanol and acetonitrile produced in the literature described SEt, SMe, SIPA and SACN, see Table S1, Supporting Information. In crystallization experiments where solvate was

not obtained, typically already reported polymorph I formed, although in some of the crystallization experiments from butyl acetate, 1,4-dioxane and butanone a new MC polymorph VI was obtained. In phase transition studies two additional hydrates H4 and H2III (a non-


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stoichiometric hydrate with structure related to MC polymorph III) as well as six polymorphs (II, III, IV, V, VII and VIII) were discovered. From part of the solvents, however, no crystallization was observed, and complete evaporation was not possible (due to formation of high-viscosity liquid because of very high solubility of MC in these solvents) or produced amorphous solid.

In this study all of the obtained solvates (including the already reported but not well explored SEt, SMe, SIPA and SACN) were characterized using PXRD patterns and DSC/TG analysis. Solvate

stability and phase transformations upon desolvation were studied by identifying the desolvation routes and products. Crystals suitable for SCXRD measurements were obtained for SNM. Additionally, attempts were made to solve the crystal structures of the rest of the new phases by using the PXRD patterns collected in transmission mode at ambient temperature, with success for polymorphs II, III and IV as well as solvates SDCM, STOL, StBA, SDMSO, and H3VII. The obtained crystallographic

data are given in Table 1, with more details available in Table S2, Supporting Information. Based on the similarity of the solvate PXRD patterns most of the MC solvates can be classified into six solvate groups designated as Type 1 – Type 6, see Table 2 and Figure S1 in the Supporting Information. Solvates within the same group are isostructural, which besides the similarity of the PXRD patterns is also confirmed by their crystal structures (if available) or results from the indexing of the respective PXRD patterns, see Table S3, Supporting Information.



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Table 1. Crystallographic Data for the MC Phases II, III, IV, SDCM, SDMSO, STOL, StBA, H3VII, and SNM. II

III

IV

SDCM

SDMSO

StBA

STOL

H3VII

SNM

Empirical formula

C25H42O5

C25H42O5

C25H42O5

C26H44O5Cl2

C27H48O6S

C54H94O11

C57H92O10

C50H86O11

C26H45O7N

Formula weight

422.59

422.59

422.59

507.51

500.71

919.29

937.31

863.19

483.63

Sample type

Powder

Powder

Powder

Powder

Powder

Powder

Powder

Powder

Single crystal

Crystal system

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Triclinic

Space group

P21

C2

P21

P21

P21

P21

P21

P21

P21

a/Å

20.607(5)

27.987(12)

8.888(3)

9.9186(13)

14.744(8)

15.975(4)

21.6671(12)

18.748(11)

9.7246(3)

b/Å

12.435(2)

7.846(3)

8.131(2)

8.3570(10)

8.449(5)

21.682(4)

7.7659(4)

16.407(6)

8.3056(2)

c/Å

9.2732(18)

24.692(11)

17.372(5)

16.376(2)

11.471(6)

7.6682(14)

16.56390(100)

7.687(3)

16.2848(6)

α/°

90

90

90

90

90

90

90

90

90

β/°

101.756(14)

114.17(2)

104.633(14)

99.863(9)

106.40(2)

99.734(14)

105.297(4)

93.06(4)

99.1489(10)

90

90

90

90

90

90

90

90

90

2326.3(8)

4947(4)

1214.8(6)

1337.3(3)

1370.9(13)

2617.9(9)

2688.4(3)

2361

1298.57(7)

ρcalc / g·cm

1.207

1.135

1.155

1.26

1.213

1.166

1.158

1.214

1.237

Z/ Z′

4/2

8/2

2/1

2/1

2/1

4/2

4/2

4/2

2/1

Temperature / K

293(2)

293(2)

293(2)

293(2)

293(2)

293(2)

293(2)

293(2)

173(2)

3–70/0.01

3–52/0.01

3–70/0.01

3–70/0.01

3–70/0.01

2.5–70/0.01

3–70/0.01

-

γ/° 3

V/Å

-3

2θmin–2θmax /increment / 3–70/0.01 ° Rwp / %

4.032

6.792

2.737

4.049

8.965

4.750

3.335

4.586

-

Rp / %

2.904

4.639

1.967

2.889

5.302

3.570

2.472

3.617

-

R1 (wR2) / %

-

-

-

-

-

-

-

-

5.47 (11.57)

Packing coeff.

0.719

0.637

0.659

0.681

0.713

0.667

0.697

0.687

0.687

12

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DSC/TG analysis provided information about solvent stoichiometry (from the observed weight loss) as well as rapid and rough evaluation of their stability. Solvates within the same group have nearly identical DSC/TG traces because of the identical desolvation pathway. DSC/TG traces for SEt, SACN, SPEN, SiPrOAc, H1 and StBA (representing desolvation of Type 1 – Type 6 solvates,

respectively), SDMSO, SiBA1, SDMA, H2III, H3VII, and H4 are given in Figure 2, while data for all solvates are given in Table 2. Type 1 and Type 2 solvates are all monosolvates and crystallize as single crystals (except for SDCM which crystallize as a powder). All other solvates crystallize as powder. Stoichiometry of Type 3 and Type 6 solvates are close to the 1:0.5. The observed stoichiometry of Type 4 and Type 5 solvates are typically below 1:0.5 (except for the H1), explained by the fact that these solvates apparently are non-stoichiometric, which is also confirmed by their desolvation products being isostructural desolvates, as discussed further. SiBA is hemisolvate. SDMSO appears to be monosolvate and SDMA – hemisolvate, although DSC/TG analysis is complicated by slow evaporation of the solvent. All of the hydrates appear to be nonstoichiometric, with maximum stoichiometry being 1:0.5 for H2III and H3VII, 1:1 for H4 and more than 1:2 for H1, which is also confirmed using DVS measurements, see the Supporting Information.

Table 2. Weight loss observed during the desolvation of MC solvates and information about the desolvation temperature and products. Solvate

Solvate group

Obtained in crystallization Type 1 SMe Type 1 SEt Type 1 SIPA Type 1 SnPA Type 2 SACN Type 2 SNM Type 2 SDCM Type 3 STOL Type 3 SXYL Type 3 SPEN Type 3 SDMC2 Type 4 SiPrOAc

ratio

calculated weight loss / %

observed weight loss / %a

Tdes / °Cb

Desolvation product

1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:0.5 1:0.5 1:0.5 1:0.5 1:0.5

7.0 9.8 12.5 12.5 8.8 12.6 16.7 9.8 11.2 9.2 9.6 10.8

6.2 – 7.5 7.2 – 10.5 9.7 – 12.3 10.9 – 12.5 7.5 – 9.0 10.0 – 13.0 12.5 – 14.5 7.0 – 9.0 9.0 – 11.1 5.7 – 8.4 N/Dc 5.8 – 6.6

70 (p: 112) 70 (p: 107) 60 (p: 94) 60 (p: 90-93) 60-70 (p: 106) 60-70 (p: 99) p: 67 80 80 50 N/D 60-70d

III III III III IV / amorphous IV / amorphous IV + unid. phase V V V V ISDT4



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Type 4 1:0.5 8.1 SDXLN Type 4 1:0.5 7.9 STHF – 1:1 15.6 SDMSO Type 5 1:0.5 8.5 SDMSO2 Type 5 1:0.5 8.0 SDMF Type 5 1:1 4.1 H1 Type 5 1:0.5 9.6 SDMC1 – 1:0.5 2.1 H3VII Type 6 1:0.5 8.1 SiBA2 Type 6 1:0.5 8.1 StBA – 1:0.5 11.3 SBA – 1:0.5 8.1 SiBA1 – 1:0.5 9.3 SDMA Obtained in phase transformation experiments – 1:0.5 2.1 H2III – 1:1 4.1 H4

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3.5 – 4.6 4.5 - 6.6 15.5 5.0 – 9.0 6.2 – 7.8 4.5 – 5.5e 5.0 – 6.0 1.8 – 2.2e 7.6 – 7.8 7.8 – 8.1 N/Df 9.0 – 10.0 10.0 – 12.5

50-60d 45-60d p: 67 100 90 40-50 50-60 60 90 90 N/D 80 80-90

ISDT4 ISDT4 SDMSO2 ISDT5 ISDT5 ISDT5 ISDT5 VII amorphous amorphous II amorphous + VI amorphous

0.1 – 1.5g 2.5 – 4.7g

50-60 30-40h

III VIII

a

– for Type 1, Type 2, Type 3, and Type 5 solvates, H2III and H3VII weight loss values are obtained from measurements of at least three different samples (except for SnPA where one sample was analyzed thrice), and for Type 4 and Type 6 solvates, SDMSO, SiBA1, SDMA, and H4 from measurements of at least two different samples. b

– desolvation temperature under the desolvation conditions in DSC/TG analysis; p: peritectic desolvation and/or melting temperature c

– solvate was very unstable and almost completely transformed into V during the drying

d

– desolvation of Type 4 solvates occurred without appearance of characteristic peak and only peak associated with the melting was present e

– water content is dependent on the RH. Typical water content for sample stored in ambient conditions is given f

– dry solvate sample was not obtained and instead of desolvation dissolution in benzyl alcohol occurred. g

– water content is dependent on the RH.

h

– no characteristic dehydration peak was observed


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Figure 2. DSC/TG traces of MC solvates. d – desolvation, dp – peritectic desolvation and/or melting, pt – phase transition, r – recrystallization, m – melting of the respective phase, and gt – glass transition. Traces for the remaining solvates are given in Figure S2, Supporting Information.

Desolvation pathway The primary desolvation products of MC solvates are given in Table 2. However, the phase transitions occurring during the desolvation were not always simple, thus detailed study of the desolvation process was performed by additionally exploring the stability of solvates in multiple environmental conditions. Summary of the observed phase transformations is given in Figure 3 15 ACS Paragon Plus Environment


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and described below, while more details and additional results are given in the Supporting Information.

Figure 3. Schematic summary of phase transformations of MC solvates and their desolvation products. Type 1 solvates. Desolvation of Type 1 solvates at 60-70 °C produced polymorph III, see Figure S14, Supporting Information. Despite the simple one-step desolvation process, results of the thermal analysis of Type 1 solvates were complicated by low thermal stability of the obtained polymorph III as well as slow desolvation of the solvates resulting in the appearance of endothermic peaks corresponding to (a) kinetically controlled desolvation and (b) peritectic desolvation and/or melting (see Figure 2 and Figure S2, Supporting Information). Heating of 16 ACS Paragon Plus Environment

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polymorph III at 100 °C produced MC polymorph II. This transformation, however, appeared to be complex process, see Supporting Information. In ambient conditions III fast transformed into phase with highly similar PXRD pattern designated as H2III. It was determined that H2III contains water (0.4 – 0.7%, see DSC/TG traces in Figure 2) and easily transforms back to III when heated at 60 °C. The highly similar PXRD patterns suggest on only slight structure changes during the incorporation of the water molecules. When H2III was exposed to relative humidity above 80% (at 30 °C), it transformed to MC hydrate H1, while exposure of Type 1 solvates themselves to 68% RH (at 30 °C) produced another hydrate H4. Type 2 solvates. A PXRD study of the desolvation of Type 2 solvates revealed that in the desolvation process a poorly crystalline polymorph IV is obtained at 60 °C. Further heating at 70-80 °C produced amorphous phase, while at 100 °C polymorph II was obtained, see Figure S19, Supporting Information. The results of the thermal analysis of SACN and SNM were complicated by recrystallization of amorphous phase, melting/amorphization of IV and following recrystallization, as well as by slow desolvation of the solvates resulting in the appearance of endothermic peaks corresponding to (a) kinetically controlled desolvation and (b) peritectic desolvation and/or melting (see Figure 2 and Figure S2, Supporting Information). For desolvation of SDCM only the peritectic desolvation and/or melting peak at 67 °C was observed. Type 3 solvates. Desolvation of Type 3 solvates at 60 °Cproduced polymorph V. Further heating at 130-140 °C produced polymorph VI (or a mixture of VI and II), see Figure S25, Supporting Information. Type 4 solvates. A PXRD study of the desolvation of Type 4 solvates revealed that upon heating at 60 °C slight changes of the PXRD pattern occurred (broadening and shift of some of the peaks), while the thermal analysis confirmed that the obtained phase does not contain any solvent. Therefore, Type 4 solvates apparently are non-stoichiometric (as also confirmed by the determined solvent content) and at 60 °C forms isostructural desolvate ISDT4, see Figure S27, 17 ACS Paragon Plus Environment


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Supporting Information. By heating the obtained desolvate at 100 °C, polymorph I is obtained, which then transforms into polymorph II at 120 °C. SDMSO easily (even upon storage at ambient conditions) but slowly started to desolvate by

producing another crystalline phase, see Figure S28, Supporting Information. Complete transformation, however, was achieved only after weeks at 60 °C temperature. Thermal analysis confirmed that loss of the solvent occurs in two steps, with the first step (peritectic desolvation and/or melting peak at 67 °C, see Figure 2) being formation of lower stoichiometry DMSO solvate SDMSO2. Type 5 solvates. By heating Type 5 solvates at 50-60 °C reduction of the solvent content in the structure as well as significant loss of crystallinity and change of the peak positions was observed, see Figure S29, Supporting Information. Therefore, in these conditions a weaklycrystalline isostructural desolvate (ISDT5) was obtained. The melting of the isostructural desolvate or its mixture with the respective solvate (in case of SDMF and SDMSO2) was observed at 100-105 °C, and further recrystallization to polymorph II (or its mixture with VI) occurred. Type 6 solvates and SDMA. During the desolvation upon heating Type 6 solvates (at 80 – 90 °C) as well as SDMA (at 70 – 80 °C) slowly transformed into amorphous phase followed by coincident crystallization of polymorph II, see Figure S33 and S34, Supporting Information. The primary desolvation product was amorphous phase, which always latter started to recrystallize into II, followed by further desolvation into amorphous phase and simultaneous crystallization of II, or, less likely, desolvation into II in the presence of its nuclei. SiBA1 desolvated at 80 °C by producing amorphous phase always containing small amount of

weakly crystalline polymorph VI, see Figure S35, Supporting Information. In thermal analysis an endothermic peak appeared after the desolvation apparently corresponding to the glass transition (as no PXRD changes were observed during this phase transition), after which recrystallization into VI with commonly-observed crystallinity immediately followed.


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Hydrate H3VII. Dehydration of H3VII occurred at 70 – 80 °C by producing polymorph VII, associated with very limited changes of the PXRD pattern (suggesting only slight structure changes during the loss of the water molecules), see Figure S36, Supporting Information. Further heating of VII at 100 °C produced polymorph II. In ambient conditions VII immediately absorbed water by transforming back to H3VII. Hydrate H4 was determined to be non-stoichiometric hydrate, in 60 – 70% RH having approximately monohydrate stoichiometry, while its dehydration both by heating and exposure to 0% RH produced polymorph VIII. Further heating of VIII at 80 °C produced amorphous phase, which above 90 °C crystallized into polymorph II. SBA. Reliable characterization of SBA was not possible as it was not possible to obtain dry

sample even at elevated temperature. Prolonged heating at 60 °C resulted in very slow transformation into polymorph II, although it is possible that II formed in crystallization from benzyl alcohol solution or is in fact phase transition product of an undetected primary desolvated phase.

Characterization of MC crystal structures The obtained crystal structure information showed that polymorph III crystallize in the space group C2 with Z′ = 2 while II and IV crystallize in the space group P21 with Z′ = 2 and Z′ = 1, respectively. All of the solvates for which crystal structures were determined crystallize in the space group P21 with one MC and one solvent molecule (SNM, SDCM, and SDMSO, where the first two are isostructural) or two MC and one solvent molecule (STOL, H3VII, and StBA) in the asymmetric unit. The solvent stoichiometry determined was consistent with that determined from the TG analysis. An overlay of the experimental and PXRD pattern simulated from the crystal structure data (see Figure S3, Supporting Information) confirmed the identity of the polycrystalline SNM. The correctness of the structures calculated from the PXRD patterns was confirmed by the good agreement between experimental and calculated diffraction patterns (see 19 ACS Paragon Plus Environment


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Figure S4), as well as by the geometry optimization in Quantum ESPRESSO introducing only small changes (RMSD < 0.21 Å for all atoms and 1.8% of the unit cell volume) and the packing coefficients are quite low (

On the Formation and Desolvation Mechanism of Organic Molecule

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