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The Phase Transformation and Formation Mechanism of Isostructural Solvates: A case study of Azoxystrobin Haiyan Yang, Yang Yang, Lina Jia, Weiwei Tang, Shijie Xu, Shichao Du, Mingchen Li, and Junbo Gong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01144 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 3, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Crystal Growth & Design

The Phase Transformation and Formation Mechanism of Isostructural Solvates: A case study of Azoxystrobin Haiyan Yang†, Yang Yang†, Lina Jia †, Weiwei Tang†, Shijie Xu†, Shichao Du†, Mingchen Li†, Junbo Gong*, †, ‡, § †State

Key Laboratory of Chemical Engineering, School of Chemical

Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China ‡ Collaborative

Innovation Center of Chemistry Science and Engineering, Tianjin

300072, P. R. China § Key Laboratory Modern Drug Delivery and High Efficiency in Tianjin University, P. R. China Abstract: Azoxystrobin has one amorphous form and two solvent-free forms. A series of new solvates were obtained by crystallization experiments in 40 solvents. Among these solvates, four of them were successfully determined by single crystal X-ray diffraction and analyzed in terms of molecular conformation, intermolecular interaction, and crystal packing motifs. In addition, the physiochemical properties of all solvates were further studied and presented with comprehensive characterization. It was found that both properties and the size of solvent molecules attribute to the formation of isostructural azoxystrobin solvates. Isostructural solvates can be formed when the solvents have particular molecular size (molar volume ranging from 56.1-88.5 cm3 / mol) and solvent properties which could make weak interactions with azoxystrobin. Desolvation and formation mechanism of isostructural solvates were investigated through the phase transformations and crystal structure analysis. The desolvation of solvates first forms form B, then form B melts and recrystallizes into a stable form A. A possible mechanism for the formation of isostructural solvates was proposed.

Keywords: Azoxystrobin; Isostructural solvate; phase transformation; formation

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Introduction Solvate is a common solid form that may be formed during the preparation and storage of organic crystal products. It differs substantially from the solvent-free forms in regard to critical properties such as stability, mechanical properties, solubility and dissolution rate (sometimes leading to bioavailability problems).1,

2

Desolvation

processes of solvate can be applied to prepare new polymorphic forms which are complicated or cannot be obtained via conventional crystallization methods.2 Stable solvates could be used as marketed form. Studies on desolvation pathways can prevent undesired solvates phase transformation and reduce the residual of solvents in pharmaceutical industry.3 Nowadays, solvates have been extensively studied from perspectives of the crystal structure, desolvation kinetics and phase (thermal or moisture) stability.4-6 However, little is known about their crystallization mechanism. Isostructural solvates, a special kind of solvates, are compounds of identical packing motifs with similar related molecules. Literature7-12 on isostructural solvates has focused on structure characterization, formation and desolvation. Intermolecular interactions13 and the increase of packing efficiency14, 15 can lead to the formation of isostructural solvates. To gain a better understanding of the isostructural solvate formation mechanism, it is necessary to evaluate the properties of solvent and active pharmaceutical ingredient, and possible intermolecular interactions. Desolvation conditions can have an effect on the polymorph obtained in the desolvation.16-18 The gap in the mechanism of the isomorphism has caused a lack of practical guidance for isostructural solvates researches. Studying the mechanism of phase transformation and formation of isostructural solvates really makes sense for not only academic research but also solving problems in drug industrial crystallization. The model compound studied in this work is azoxystrobin (AZO, the formula is C22H17N3O5 and the corresponded chemical structure is shown in Scheme 1) which is a broad-spectrum fungicide with protectant and curative properties that can control and prevent fungi grown on agricultural and horticultural crops.19 Azoxystrobin has low acute and chronic toxicity to humans and mammals.20, 21 Many studies22-24 have focused on the resistance mechanism of azoxystrobin against diseases and the residue behaviors of azoxystrobin in plants. This material is known to have one amorphous form and two solvent-free forms.25, 26 The crystal structure of form A was determined by Chopra27 in 2007 and the solubility of it was studied recently.28 However, no related solvates have been reported in literature.


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The aim of this work is: (a) to explore the factors for the formation of isostructural AZO solvates based on crystal structure and various solvent physicochemical properties; (b) to understand the mechanism of phase transformation and the isostructural solvate formation through comprehensive characterization.

Scheme 1: Chemical structure of AZO. Experimental section Materials The raw material, azoxystrobin (form A), was supplied by Changshuhengrong Commercial and Trading Co., Ltd. with purity larger than 0.998 (mass fraction purity). Solvents were all purchased from Hengshan Chemical Science and Technology Co., Ltd., Tianjin, China, and were employed without any further purification. Preparation of the Crystal Forms The crystallization experiments of AZO were performed in a series of solvents selected among different solvent classes. The crystallization experiment started by addition of the selected solvent into a crystallizer at 10−60 °C (regulated by the thermostat water bath) depending on its boiling point, then excess amount of AZO was added into the crystallizer and agitated for 12 hours by magnetic stirring at 220 rpm to reach the solid-liquid equilibrium.6 After equilibrium, the excess solute was allowed to settle with no agitation for some time and then the suspended solids were filtered and dried at room temperature for further collection and characterization. Apart from the two known forms, A and B, and amorphous form, eight new solvates were obtained from acetone (SDMK), dioxane (SDIOX), N,N-dimethylformamide (SDMF), tetrahydrofuran (STHF), dichloromethane (SDCM), acetic acid (SAA), chloroform (STCM), and butyl acetate (SBAC). Among the obtained solvates, four single crystals (SDMK, SDMF, STHF, SAA,) were prepared by slow evaporation.



Powder X-ray Diffraction Analysis Powder X-ray diffraction (PXRD) was used to measure samples on a Rigaku D/max-2500 (Rigaku, Japan) using Cu Kα radiation (0.15405 nm) in the 2-theta range of 2-35° and scanning rate of 8°/min. Variable temperature powder X-ray diffraction (VT-PXRD) patterns were recorded after it reached the target temperature at heating rate of 2°C/min. Spectroscopy Analysis Fourier transform infrared (FTIR) spectra was collected by a Bruker Alpha FT-IR 750 spectrometer in the range of 4000 to 400 cm−1, with a resolution of 4 cm−1 and 16 scans per spectrum at ambient conditions. The Raman spectra were measured at room temperature by ThermoFisher DXR Raman Microscope spectrometer with a resolution of 1.496 cm−1 and a range of 3450-50 cm−1. Scanning Electron Microscope (SEM) A HITACHI TM-1000 scanning electron microscope (SEM) was used to investigate the morphology of the crystals. Single Crystal X-ray Diffraction (SCXRD) Single crystal X-ray diffraction measurements were conducted on a Rigaku 007HF XtaLAB P200 diffractometer using Mo-Kα radiation (λ = 0.71073 Å) with a graphite monochromator. Integration and scaling of the intensity data were accomplished using the SAINT program. The structures were solved using SHELXS-97, and refinement was conducted using SHELXL-2014.29 Data was corrected for the effects of absorption using SADABS. Differential Scanning Calorimetry (DSC) Differential scanning calorimeter (DSC 1/500, Mettler Toledo, Switzerland), calibrated by indium and zinc, was used to characterize solvates. Samples weighting 5-10 mg were transferred into standard pinhole DSC aluminum pans and an empty pinhole pan was used as reference. Each sample was heated from 25 °C to 160 °C at a rate of 2 °C/min under a nitrogen gas flow of 50 mL/min. Thermogravimetric Analysis (TGA) Thermogravimetric analysis was conducted in a Mettler TGA/DSC 1 STARe System, using a nitrogen gas flow of 20 mL/min and a heating rate of 2 °C/min from 25 °C to 160 °C.


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Results and Discussion PXRD Analysis The PXRD patterns of all newly discovered solvates are presented in Figure S1. The PXRD diagrams of solvates (SDMK, SDIOX, SDMF, STHF, SDCM, SAA, STCM, SBAC) were found to be similar to each other, indicating they are isostructural.12 Very minor differences in the PXRD fingerprint can be identified by analyzing the characteristic peaks. For clarity, the PXRD of SDMK was selected to represent AZO solvates (Figure 1). Unlike the solvates, forms A and B can be easily distinguished in the PXRD patterns. FTIR and Raman spectra of AZO crystals are presented in Figure S2-S3. The FTIR spectra of eight solvates are nearly identical, confirming their isostructurality. Scanning electron microscope (SEM) images of eight solvates show similar rod-like crystal habits of them (Figure S4).

Intensity / counts

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


SDMK

B

A

5

10

15

20

25

30

35

2-Theta / deg

Figure 1. Comparison of the PXRD patterns of AZO polymorphs and solvate. Azoxystrobin Crystal Structures Analysis. The crystal structures of AZO solvates and form A (comparing with the reported results27) were solved by SCXRD, and the crystallographic data are summarized in Table 1. AZO solvates exhibit similar unit cell parameters suggesting they are isostructural solvates. They all crystallized in the monoclinic crystal system of P21/n space group. The asymmetric units for the four solvates all consist of one AZO molecule and one corresponding solvent molecule. Through analyzing these solvates, the main contribution to stabilize these crystal structures comes from π···π, C-H···π and a series of weak hydrogen bonding interactions, such as C-H···O and C-H···C.



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Meanwhile, only weak hydrogen bonding interactions exist between AZO molecules and solvent molecules due to the C-H hydrogen bond donors. For instance, in SDMK crystal structure, π···π interactions between the pyrimidyl rings with an inter-centroid distance of 3.581 Å (Figure 2a) and two kinds of C-H···π interactions, C11-H···π (2.975 Å), and C15-H···π (3.009 Å), connect two AZO molecules (Figure 2b and 2c). Other weak and complicated interactions between AZO molecules are shown in Figure S5. Further, solvent molecules serve as fillers in channel of solvate structure and can be removed from solvate structure easily due to the weak interaction feature between AZO and DMK molecules. They can be visualized by means of Hirshfeld surface analysis and discussed later. Table 1. Crystallographic Data of AZO form A and solvates. Form A

Form A16

C22H17N3O5

C22H17N3O5

Crystal system

Monoclinic

Space group Formula weight

SDMK

SDMF

STHF

SAA

C22H17N3O5·

C22H17N3O5

C22H17N3O5

C22H17N3O5·

C3 H6 O

·C3 H7 NO

·C4 H8 O

C2 H4 O2

Monoclinic

Monoclinic

Monoclinic

Monoclinic

Monoclinic

C2/c

C2/c

P21/n

P21/n

P21/n

P21/n

403.38

403.39

461.46

476.49

475.49

463.44

113(2)

292(2)

113(2)

113(2)

113(2)

113(2)

a (Å)

28.305(6)

28.946 (6)

12.512(3)

12.613(3)

12.4986(5)

12.435(3)

b (Å)

10.533 (2)

10.803 (2)

7.7153(15)

7.5625(15)

7.6236 (3)

7.6802(15)

c (Å)

13.099(3)

13.302 (3)

24.478(5)

25.214(5)

24.4225(9)

23.984(5)

α(Å)

90.00

90.00

90.00

90.00

90.00

90.00

β (Å)

95.13(3)

94.61(3)

98.86(3)

101.67(3)

98.782(4)

97.32(3)

γ(Å)

90.00

90.00

90.00

90.00

90.00

90.00

3889.9(14)

4146.1(15)

2334.7(8)

2355.3(8)

2299.8(16)

2271.9(8)

1.378

1.289

1.313

1.344

1.373

1.355

Formula

Temperature (K)

Cell volume (Å3) Calc.

density

(mg/m3)


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Z

8

Rint

0.0388

4

4

4

4

0.0500

0.0455

0.0906

0.0478

0.0544

0.0492

0.079

0.0547

0.0699

0.0399

0.0529

wR2

0.1124

0.220

0.1379

0.1586

0.0994

0.1452

GOF (S)

1.121

1.062

1.110

1.058

1.107

0.29/-0.24

0.29 /-0.28

0.23/- 0.23

0.27/-0.23

0.24/-0.25

1858783

1858784

1858782

1858781

R1

8

(I>2sigma

(I))

Largest diff. peak/hole / e Å-3 CCDC

1858780

(a)

667485

(b)

(c)

Figure 2. Single crystal structure of SDMK. (a) π-π interactions between the pyrimidyl rings. (b) C-H···π interaction (C11-H···π). (c) C-H···π interaction (C15-H···π). Similar intermolecular interactions and molecular arrangements can be found in SDMF, STHF and SAA. The four network packing patterns are demonstrated in Figure 3. In addition to the elaboration of intermolecular interaction and crystal packing motifs in crystal structure, conformational differences among these forms in asymmetric units also lead to minor differences among solvates.10 To evaluate and compare the molecular conformations of form A and solvates, we have chosen the molecules of form A with higher occupancies (details of disordered form A are presented in Figure S6 and Table S1). As illustrated in Figure 4 and Table S2, solvates show different conformation features compared with form A on account of



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solvent molecules being restricted in crystal structure channel. The molecular conformation of the asymmetrically units among four solvates are similar, which further illustrates that they are isostructural solvates.

(a)

(b)

(c)

(d)

Figure 3. Similar packing diagram of SDMK, SDMF, STHF, and SAA (a-d) viewed along the b-axis.

Figure 4. The conformation overlays diagram of AZO (form A) and AZO solvates. form A (magenta), SDMK (blue), SDMF (green), STHF (yellow) and SAA (red).


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XPac analysis The structural similarity relationship analysis of the four solvates is quantitatively implemented by using the XPac program30-33 which traditionally can interpret for whole 3D structures. Structure fragments were defined based on the best figure of merit and lowest filter. The results obtained from the XPac analysis are listed in Table S3 and the corresponding relevant plots are shown in Figures S7-S9. The comparison clearly suggests that there is a 3D similarity among the four solvates, which is consistent with crystal structure analysis. Thus the four solvates are isostructural. Thermal Analysis Thermal behaviors of AZO polymorphs and all eight solvates were investigated34 by TGA and DSC. The superimposed DSC and TGA profiles are summarized in Figure 5 and Figure S10. To achieve comprehensive understandings of phase transformation of the solvates, DSC and TGA were employed at 2°C/min. Form A displayed higher melting point (114.7°C) compared to that of the form B (105.0°C). Two polymorphs are related monotropically because the higher melting form A shows the higher enthalpy of fusion according to the heat of fusion (HFR) rule.35, 36 It can be found that form A is the thermodynamically stable form on the basis of slurry experiments (discussed later). In the TGA thermograms, a stage of desolvation was observed for each solvate before the decomposition. The weight loss data determined by TGA analysis agree well with the calculated values based on chemical structure analysis (listed in Table 2). All solvates show similar DSC and TGA analyses results except SDMF and the two typical results were discussed. Desolvation of SDIOX was observed at 64.3°C and the process produced metastable polymorph form B with a VT-PXRD detection (more details of VT-PXRD analysis are given after the results of TGA and DSC analyses). With the temperature increasing, the endothermic and exothermic peaks between 103.8 °C and 106.7 °C revealed the melting of form B and then recrystallized into form A, respectively. Under continuous heating, form A melted and presented a sharp endothermic peak at Tonset of 116.4°C. The phase transformation process is shown in Figure 5.



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DSC curve of SDMF indicated that SDMF appeared to transform into amorphous during desolvation due to the absence of crystallinity of the desolvation product (Figure S10a). However, form B seemed to be obtained after desolvation according to VT-PXRD patterns. In order to further understand this phase transformation phenomenon, SDMF was heated from 25°C to 70°C, and cooled to 25°C, then reheated to 160°C. In the recycle process (Figure S10b), three endothermic peaks were found and the desolvation of SDMF first produced form B, then form B melted and recrystallized into a stable form A. These results suggest that the desolvation product of SDMF may be amorphous phase, which then might transforms into form B with enough time. The desolvation and phase transformation processes were in situ monitored by VT-PXRD during the thermo treatment and plotted in Figure 6 and Figure S11. Among eight solvates, SDIOX solvate was chosen as an example to illustrate the phase transformation process (Figure 6). The heating conditions applied in the VT-PXRD experiments are similar to those used in the DSC and TGA experiments. The characteristic peaks at 8.40°, 17.80° and 18.62°of SDIOX gradually weaken and eventually disappeared, which may indicate the removal of solvents.15 On the contrary, the appearances of peaks at 10.06°, 10.54° and 15.46° demonstrated the formation of form B.

Table 2 Thermal analysis data for AZO solvates Solvate

Calculated

Observed

Tdesolvation in DSC

Boiling points of

weight loss, %

weight loss, %

(onset), °C

included solvents, °C

Azo:solvent

SDMK

1:1

12.6

13.1

54.8

56.5

SDIOX

1:1

17.9

16.3

64.3

101.3

SDMF

1:1

15.3

14.3

61.6

153.0

STHF

1:1

15.2

12.4

61.2

66.0

SDCM

1:1

17.4

16.1

55.3

39.8

SAA

1:1

12.9

11.6

79.7

118.1


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STCM

1:1

22.8

22.0

46.6

61.3

SBAC

2:1

12.6

11.5

78.9

126.1

0.0 100

metling of B and transition to A

-0.2 desolvation

-0.4 -0.6

90

-0.8

TG / %

Heat Flow / Wg

-1

95

-1.0 -1.2

85

melting of A

-1.4 40

60

80

100

120

140

80

160

°

T/ C

Figure 5. DSC and TGA curves at 2 °C/min of SDIOX.

Form B °

90 C

Intensity / counts

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


°

70 C °

60 C °

50 C °

40 C SDIOX 5

10

15

20

2-Theta / deg

25

30

35

Figure 6. VT-PXRD curves at 2 °C/min of SDIOX (the peaks that show a significant variation are highlighted in grey with arrows pointing to the trends).

Correlation of the Solvent and Isostructural Solvate Formation Solvent properties involving the hydrogen bond donor (α) and acceptor abilities (β)



and the dipolar-polarizability (π*) play important roles in solvate formation.37 By evaluating the properties of solvents used in this work, a classification scheme38 based on various physical and physicochemical properties is given in Table S4. Isostructural AZO solvates were obtained from solvents belonging to groups 2, 5, 6, 7, 8, 11 after crystallization experiments in 13 different solvent groups. As known, Hirshfeld Surface analysis (HS) can display the short contacts features. In order to correlate the solvent properties with isostructural solvate formation clearly, the intermolecular interaction is analyzed via HS. HS is performed based on crystal geometries using CrystalExplorer 3.1.39 The 2D fingerprint plots of these solvates based on solvents show that interactions between AZO and solvents exist indeed (Figure S12). Then the Hirshfeld Surface is calculated in high resolution to recognize the close contact. In Figure 7, the dnorm surface is shown as transparent, which allows solvents to be visible. The area highlighted with bright red spots means that close contacts are formed.40 The upper left part of Figure 7 shows one red spot in SDMK, indicating the close contact H⋯O1S (C14−H···O1S) between AZO and solvent with a distance (dH…A) of 2.636 Å and an angle (θDHA) of 142o. Similarly, close bond between H and O1S in SDMF (C16−H···O1S, d and θ are 2.457 Å and 147o, respectively.) is associated with one slightly larger red spot. There are two kinds of C-H···O interactions between AZO and solvent in STHF. The two kinds of weak interactions are characterized by two red spots, corresponding to C14−H···O1S and C12−H···O1S. In the lower right part of Figure 7, the faint red spot visible on the surface is associated with a H⋯O1S contact of 2.716 Å (C11−H···O2S in SAA) supporting the existence of relatively weak interactions. While two large red spots show significant hydrogen bonds of SAA, common acetic acid homodimer O1S–H⋯O2S with a distance (dH⋯O) of 1.845 Å. According to all available interactions observed in solvates with solved structures, solvents which have particular properties from those groups could provide weak interactions (e.g. C−H···O) between AZO and solvents, and form isostructural solvates.


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Figure 7. Hirshfeld surface for four solvates mapped with dnorm. Neighbouring molecules associated with close contacts are shown along with distances and angles between the atoms involved. Nevertheless, it can be seen that not all solvents from the solvent groups 2, 5, 6, 7, 8, and 11 can form solvates. According to molar volumes (Vm) of solvents, relatively small molecules from the solvent groups 2, 5, 6, 7, 8, and 11 can form isostructural solvates. To clarify this, all molar volumes of the selected solvents are ranked in Table 3. Solvate can be formed with Vm at a range of 56.1-88.5 cm3/mol, while it should be assumed that all of the potentially existing solvates have been identified. The largest solvent molecule forming an isostructural solvate with azoxystrobin is BAC (the size of which is even higher than that of some solvents not able to form isostructural solvates). It can be explained that the solvent content in the SBAC observed by TG measurements is about 0.5 stoichiometry. In other words, two AZO molecules share one solvent molecule as a result of the long linear shape of BAC.15 It is worth noticing that another important factor for the formation of isostructural solvates is the size of solvent molecules.



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Table 3. Different Solvents ranked by Molar Volume.a,b,c Solvent

Molar Volume

Group37

Formic acid

39.8

12

Methanol

42.5

3

Acetonitrile

54.9

9

Acetic acid

56.1

8

Nitrotoluene

57.8

9

Ethanol

59.0

3

Dichloromethane

69.8

7

Glycerol

70.9

14

Acetone

75.1

5

1-propanol

75.5

3

2-propanol

75.9

3

Chloroform

79.5

7

Tetrahydrofuran

79.7

2

N,N-dimethylformamide

82.6

6

1,4-dioxane

88.5

11

Benzene

89.4

4

Carbon tetrachloride

90.6

1

Butanone

91.6

5

1-butanol

92

3

2-methyl-2-propanol

92.1

3

2-methyl-1-propanol

92.4

3

2-butanol

92.4

3

N-methyl-2-pyrrolidone

96.2

6

Ethyl acetate

98

2

N,N-dimethylacetamide

98.9

6

Cyclohexanone

102.9

5

Toluene

105.7

4


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Cyclohexane

106.4

1

1-pentanol

108.5

3

N-pentane

111

1

Methyl tertiary - butyl ether

117.4

2

P-xylene

121.9

4

4-methyl-2-pentanone

125

5

N-hexane

127.5

1

Butyl acetate

131

2

Diisopropyl ether

134.6

2

Triethylamine

134.8

11

N-heptane

144

1

1-octanol

158

3

N-octane

160.5

1

aSolvents bMolar

that can form isostructural solvates are highlighted in red colour.

Volume is calculated using Advanced Chemistry Development (ACD/Labs)

Software V11.02 (© 1994-2018 ACD/Labs) in condition of 20℃ and 101 KPa. cGroups

are based on cluster analysis of following solvent parameters: hydrogen bond acceptor

propensity, hydrogen bond donor propensity, polarity/dipolarity, dipole moment, and dielectric constant, and contain various solvents with similar properties (except for: group 13 = diethylamine, and group 14 = glycerol).

Phase Transformation and Formation Mechanism of Isostructural Solvates According to all above desolvation data and results, it could be concluded that the desolvation of solvates first forms a metastable form B, and then the form B melts and recrystallizes into a stable form A. During the thermo treatment, the random molecular motion of solvent molecules filled in crystal lattice is more vigorous and solvents escape from crystal cell.12, 15 Removal of the solvents results in the formation of a metastable product, form B. Further heating produces a thermodynamically favorable polymorph form A. Based on thermal analysis given by DSC and TGA, the SDMF may transform into amorphous phase. The high boiling point of DMF attributes to this thermal analysis15 by hindering the conversion of solvates to form B. Solid-state amorphizations followed that the solvents escape from solvate crystal cell and the whole crystal structure frameworks collapse. Solute molecules could rearrange and transform to form B with enough time. In addition, form B can



transform to form A by slurrying in ethanol. Solvates can also be obtained when form B is suspended in DIOX, DMF, THF, DCM, AA, TCM, BAC and DMK. Details of slurry experiment and evidences are showed in Supporting Information (Figure S13 and S14). The phase transformation of the AZO solvates and polymorphs are summarized in Scheme 2.

Scheme 2: The phase transformation of the AZO solvates and polymorphs. To clearly clarify the formation mechanism of isostructural solvates, we firstly analyzed the structure of AZO form A to explore the possibility of absorption and penetration of solvent molecules. Recently, the breathing behavior of a Gemini surfactant (PMC) crystal structure was reported by Sheng et al.41 The rigid and flexible groups in PMC structure were interpreted to enable the specific adsorption of four VOCs (CHCl3, CH2Cl2, CH3OH, and C2H5OH). AZO bears a similar molecular and crystal structure, and it has both rigid pyrimidyl ring and aromatic rings and flexible methoxy group, which suggests the absorption of solvent into form A of AZO is possible. After examination of crystal structure of AZO form A, two types of channel structure could be found (Figure 8). As seen in Figure 8, The O2-linked pyrimidine ring and the benzene ring can be easily twisted to produce different conformations, and molecules of different conformations produce a channel structure with a diameter of around 9Å (highlighted in blue) in Figure 8. Another channel of around 3Å diameter highlighted in green (Figure 8) may be formed by aligning methoxy groups attached to a benzene ring. At the same time, the methoxy group


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gives the AZO molecule certain flexibility, providing a basis for solvent molecule adsorption and penetration. Phase transformation experiments (Figure S15) further reveal that form A adsorbs DMK solvent and transforms to SDMK gradually. During transformation process, the samples were taken at different times and analyzed by SEM. As shown in Figure S16, the crystal morphology of samples did not change significantly after solvent absorptions. Then the cracks were found to be formed in the crystal which is likely resulted from the stress produced within crystal structure. With this thought, we compare the conformation difference between form A and SDMK, and the significant difference can be observed (Figure S17). Moreover, we found other solvents including acetic acid, tetrahydrofuran, N, N-dimethylformamide and butyl acetate show similar results. On the basis of these thoughts, we thus propose a possible mechanism which involves the initial absorption or penetration of solvents into channel structure of form A, and then conformation changes and rearrangement of AZO molecules produce the stress causing cracks in the final crystal of AZO solvates. The details of underlying mechanism are still on-going and will be studied deeply in our future work.

Figure 8. Channel of form A. Conclusion Eight solvates of azoxystrobin (SDMK, SDIOX, SDMF, STHF, SDCM, SAA, STCM, and SBAC) were obtained by crystallization from 40 solvents with a quite wide



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range of physicochemical properties. The properties of all isostructural solvates were studied and presented with comprehensive solid-state characterization. To our knowledge, both properties and the size of solvent molecules contribute for the formation of azoxystrobin solvates. By analyzing the solvent classification, it is concluded that solvents with particular properties may provide weak interactions between AZO and solvents to promote solvate formation. Meanwhile, solvent whose size (Vm) are in the range of 56.1-88.5 cm3/mol can serve as filler in the channel of solvate structure to form isostructural solvate. Phase transformation and formation mechanism of isostructural solvate were discussed. The desolvation of solvates first forms metastable form B and then form B melts and recrystallizes into a stable form A. We propose a possible mechanism which involves sorption – conformation change and rearrangement for the formation of isostructural solvates. While more studies are indeed needed to fulfill the proposed molecular mechanism for the formation of isostructural solvates, this work shed some light to phase transformation and formation of solvates. Associated content Supporting Information The Supporting Information is available free of charge on the ACS Publications website.

Additional

tables

and

figures

from

crystallization

experiments,

characterization, crystal structure analysis, and phase transformation studies, as well as information about the formation mechanism of AZO isostructural solvates (PDF). Accession Codes CCDC 1858780-1858784 contain the supplementary crystallographic data for this

paper.

These

data

can

be

obtained

free

of

charge

via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. Author information Corresponding Author *Tel.: 86-22-27405754. Fax: +86-22-27374971. E-mail: [email protected]. Notes


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The authors declare no competing financial interest. Acknowledgements The authors are grateful to the financial support of National Science Foundation of China (91634117 and 21676179), Major National Science and Technology Projects (2017ZX07402003 and 2017ZX09101001) and Innovative Group Project 21621004. We acknowledge Yifu Chen for his contribution in figure processing. Estevao Macaringue is thanked for language modification. References (1) Kachrimanis, K.; Griesser, U. J. Dehydration Kinetics and Crystal Water Dynamics of Carbamazepine Dihydrate. Pharm Res. 2012, 29, 1143-1157. (2) Jia, L.; Zhang, Q.; Wang, J.; Mei, X. Versatile solid modifications of icariin: structure, properties and form transformation. CrystEngComm. 2015, 17, 7500-7509. (3) Zhang, X.; Zhou, L.; Wang, C.; Li, Y.; Wu, Y.; Zhang, M.; Yin, Q. Insight into the Role of Hydrogen Bonding in the Molecular Self-Assembly Process of Sulfamethazine Solvates. Cryst. Growth Des. 2017, 17, 6151-6157. (4) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.; Wieser, J.; Griesser, U. J. Stability of Solvates and Packing Systematics of Nine Crystal Forms of the Antipsychotic Drug Aripiprazole. Cryst. Growth Des. 2009, 9, 1054-1065. (5) Zhu, B.; Zhang, Q.; Ren, G.; Mei, X. Solid-State Characterization and Insight into Transformations and Stability of Apatinib Mesylate Solvates. Cryst. Growth Des. 2017, 17, 5994-6005. (6) Zhou, L.; Yin, Q.; Du, S.; Hao, H.; Li, Y.; Liu, M.; Hou, B. Crystal structure, thermal crystal form transformation, desolvation process and desolvation kinetics of two novel solvates of ciclesonide. RSC Adv. 2016, 6, 51037-51045. (7) Stieger, N.; Liebenberg, W.; Wessels, J. C.; Samsodien, H.; Caira, M. R. Channel inclusion of primary alcohols in isostructural solvates of the antiretroviral nevirapine: an X-ray and thermal analysis study. Struct Chem. 2010, 21, 771-777. (8) Hosokawa, T.; Datta, S.; Sheth, A. R.; Brooks, N. R.; Young, V. G.; Grant, D. G. W. Isostructurality among Five Solvates of Phenylbutazone. Cryst. Growth Des. 2004, 4, 1195-1201. (9) Be̅rziņš, A.; Actiņš, A. Why Do Chemically Similar Pharmaceutical Molecules Crystallize in Different Structures: A Case of Droperidol and Benperidol. Cryst. Growth Des. 2016, 16, 1643-1653. (10) Be̅rziņš, A.; Hodgkinson, P. Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol. Solid State Nucl Mag. 2015, 65, 12-20.



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For Table of Contents Use Only The Phase Transformation and Formation Mechanism of Isostructural Solvates: A case study of Azoxystrobin Haiyan Yang†, Yang Yang†, Lina Jia †, Weiwei Tang†, Shijie Xu†, Shichao Du†, Mingchen Li†, Junbo Gong*, †, ‡, §

Synopsis: Eight isostructural solvates of azoxystrobin were obtained based on comprehensive solid-state screening experiments. Both properties and the size of solvent molecules attribute to the formation of isostructural azoxystrobin solvates. The desolvation of solvates first forms metastable form B and then form B melts and recrystallizes into stable form A. A possible mechanism for the formation of isostructural solvates was proposed.


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