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Solid-State Characterization and Insight into Transformations and Stability of Apatinib Mesylate Solvates Bin Zhu, Qi Zhang, GuoBin Ren, and Xuefeng Mei Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01123 • Publication Date (Web): 03 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017

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Crystal Growth & Design

Solid-State

Characterization

and

Insight

into

Transformations and Stability of Apatinib Mesylate Solvates Bin Zhu, a Qi Zhang, b Guobin Ren,*a,c and Xuefeng Mei*b a

Laboratory of Pharmaceutical Crystal Engineering & Technology, School of

Pharmacy, East China University of Science and Technology, Shanghai, 200237, China b

Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai

Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China c

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China

University of Science and Technology, Shanghai, 200237, China Shanghai Key Laboratory of New Drug Design

ACS Paragon Plus Environment


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

Abstract: Two types of solvates for the anti-angiogenesis drug apatinib mesylate

(ATM) were obtained and their crystal structures were determined by single-crystal X-ray diffraction. The properties of these solvates were fully characterized by powder X-ray diffraction, dynamic vapor sorption, differential scanning calorimetry, and thermogravimetric analysis. Experimental and theoretical studies were performed on the solvates to understand the phase transitions induced by heat and humidity. An irreversible humidity-induced single-crystal-to-single-crystal (SCTSC) transformation from ethanol solvate (type II) to monohydrate (type I) was elucidated. Stability of these solvates, including moisture-dependent and thermal stability, was studied. The comprehensive investigation of the solvates and hydrate provided essential knowledge about quality control of the important drug. INTRODUCTION

Many active pharmaceutical ingredients (APIs) were known to have various crystal forms such as polymorphs or solvates/hydrates.1-3 These polymorphs and solvates/hydrates have different stabilities,4 mechanical properties,5-7 solubility,8 dissolution rate,9 and bioavailability,10 when compared to their original forms and, as such, demand a thorough investigation of the solid form landscape during drug development.1,

11-13

Solvates and hydrates could be potentially formed during the

manufacturing and storage process.14 The accidental formation of undesired solvates could prove costly, as these transformations are often unpredictable and can cause changes in the physiochemical properties of a product. However, there are also a handful of valuable solvate drugs on the market, such as trametinib dimethyl sulfoxide


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solvate,15 dapagliflozin propanediol monohydrate,16 indinavir sulfate ethanolate,17 and darunavir ethanolate18. Moreover, solvate desolvation processes can be applied to discover and prepare new polymorphic forms that may have been previously inaccessible via conventional crystallization techniques.19, 20 ATM (Scheme 1) is an orally effective small-molecule anti-angiogenesis drug21-23 that inhibits the vascular endothelial cell growth factor receptor 2 (VEGFR-2) of tyrosine kinase.24-27 ATM came into to market under the brand name AiTan®, approved to provide targeted chemotherapy in advanced gastric cancer by the Chinese State Food and Drug Administration (SFDA) in 2014.28,

29

Previously, we have

reported two ATM polymorphic forms I and II, a monohydrate HA, and a hemihydrate HB.8 However, the formation conditions of ATM solvates and their transition relationship with polymorph and hydrates haven’t been reported. Fully identifying solvate modifications, understanding and rationalizing their characteristics, especially solid state stability and transition behaviors, can bring crucial insights for consistent and safe drug manufacturing.30-32 In this work we reported two types of ATM solvates and acetonitrile solvate. All their crystal structures were determined by single-crystal X-ray diffraction. Differences in physiochemical properties of solvates were characterized by TGA, DSC, and DVS. The moisture-dependent and thermal stability of these solvates were rationalized based on the phase transitions associated with crystal structures and solvent molecular properties. The comprehensive investigation of the solvates and hydrate provided essential knowledge about quality control of the important drug in



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favor of preventing undesired solvates phase transitions and reducing the residual solvent during the manufacturing and storage process. HA: monohydrate S1: ATM- N,N-dimethylformamide (1:1) S2: ATM- nitromethane (1:1) S3: ATM- ethanol (1:1) S4: ATM- acetic acid (1:1) S5: ATM- 1, 2-dichloroethane (1:1) S6: ATM- tetrahydrofuran (1:1) S7: ATM- acetonitrile (1:1)

Scheme 1. Molecular structure of ATM with labeled flexible torsion angles and its solvates. EXPERIMENTAL SECTION

Materials. Apatinib mesylate was obtained from BioChemPartner Company, Ltd. (Zhangjiang Road, Pudong New Area, Shanghai, China) with purity greater than 98%. All analytical grade organic solvents were purchased from the Sinopharm Chemical Reagent Company and were used after further removing water with molecular sieves. Preparation of HA (monohydrate). ATM HA was prepared by fast cooling saturated ATM methanol solution from 70 °C to 5 °C. Preparation of S1 (N,N-dimethylformamide solvate). 20mg of ATM HA was dissolved in 1 mL N,N-dimethylformamide (DMF) at 60 °C. Then the mixture was filtered. After adding 4 mL of Acetone into the filtrate, it was left under ambient conditions for 3h to get trapezoid-shaped S1 crystals. Preparation of S2 (nitromethane solvate). 20mg ATM HA was added into 5 mL of


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nitromethane (NM), then the mixture was heated to 70 °C, followed by stirring, and filtering. 5 mL of cyclehexane was added to the filtrate and the mixed solution was rested for 2 hours under ambient conditions to get S2 as prism-shaped crystals. Preparation of S3 (ethanol solvate). 20mg of ATM HA was dissolved in 2 mL of ethanol (EtOH) by sonicating at 70 °C. The clear mixed solution was filtered and the filtrate was vapored at 50 °C to obtain needle S3 crystals. Preparation of S4 (acetic acid solvate). 20mg of ATM HA was dissolved in 0.4 mL acetic acid (HAc) at 50 °C and filtered into a vial. The vial was kept in a vessel containing ethyl acetate for a week to get S4 as prism-shaped crystals.

S1

S2

S3

S4

S5 S6 S7 Figure 1. Polarizing microscopy images of ATM solvate forms. Preparation of S5 (1, 2-dichloroethane solvate). 20mg of ATM HA was dissolved in 5 mL of nitromethane (NM). Then the mixture was heated to 70 °C, followed by stirring and filtering. 15 mL of 1, 2-dichloroethane (DCE) was added to the filtrate. The prism-shaped S5 crystals were obtained after quiescence under ambient conditions for 6 days. Preparation of S6 (tetrahydrofuran solvate). 20mg of ATM HA was added into 1 mL of ethanol. Then the mixture was heated to 70 °C, with stirring and filtering. 10



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mL of tetrahydrofuran was added to the settled solution and the mixed solution was filtered after quiescence under ambient conditions for 4 days to get S6 as needle-shaped crystals. Preparation of S7 (acetonitrile solvate). 20mg of ATM HA was added into 10 ml of acetonitrile (ACN). The mixture was heated to 70 °C and stirred until the solution was clear. S7 shaped as virgulate crystals were obtained via vaporing the settled solution at 50 °C. Powder X-ray diffraction (PXRD). PXRD patterns were measured at ambient temperature on a D8 Advance (Bruker) diffractometer equipped with a LynxEye position sensitive detector. Data over the range 3-40° 2θ was collected with a scan rate of 5°·min-1 at ambient temperature using copper radiation (Cu-Kα) at the wavelength of 1.54180 Å. The tube voltage and current were set to 40 kV and 40 mA, respectively. The data was imaged and integrated with RINT Rapid and peak-analyzed with Jade 6.0 from Rigaku. To prevent the atmospheric humidity effect and decomposition of the solvates, the samples were covered with a polyethylene film when necessary during the analysis. Single Crystal X-ray Diffraction (SCXRD). X-ray diffractions of all single crystals were performed at 100 or 173 K on a Bruker Apex II CCD diffractometer using Mo-Kα radiation (λ = 0.71073 Å). The collected data integration and reduction was processed with SAINT software,33 and multi-scan absorption corrections were performed using the SADABS program.34 The structures were solved by direct methods using SHELXTL35 and were refined on F2 by the full-matrix least-squares


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technique using the SHELXL-97 and SHELXL-2014 program package.36 All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms of O-H and N-H were found from a Fourier difference map, and refined with a fixed distance of 0.86 (0.01) Å and isotropic displacement parameters of 1.50 times Ueq of the parent atoms. The remaining hydrogen atoms were placed in calculated positions and refined with a riding model with distance of 0.95 Å (sp2) and 0.98 Å (sp3) with isotropic dis-placement parameters set to 1.20 (sp2) and 1.50 (sp3) times Ueq of the parent atom. Thermogravimetric analysis (TGA). Thermogravimetric analysis was carried out on a Netzsch TG 209F3 equipment. The samples were placed in open aluminum oxide pans and heated at 10 °C·min-1 from 30 to 350 °C. Nitrogen was used as the purge gas at 20 mL·min-1. Differential scanning calorimetry (DSC). DSC experiments were performed on a DSC TA Q2000 instrument under a nitrogen gas flow of 50 mL·min-1 purge. Ground samples weighing 1-3 mg were equilibrated at 25 °C and heated in sealed aluminum pans from 25 to 210 °C at a heating rate of 10 °C·min-1. Each sample was analyzed in triplicate with RSD < 2%. Dynamic vapor sorption (DVS). Dynamic vapor sorption experiments were performed on an Intrinsic DVS instrument from Surface Measurement Systems, Ltd. Samples were studied over a humidity range of 0 to 95% RH at 25 °C. Each humidity step was made if less than a 0.02% weight change occurred over 10 min, with a maximum hold time of 360 min.



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Hot stage microscope (HSM). All HSM examinations were performed on an XPV-400E Polarizing microscope and an XPH-300 hot stage coupled with a JVC TK-C9201 EC digital video recorder (Shanghai Chang Fang Optical instrument Co. Ltd.). The samples were heated over a temperature range of 20 to 160 °C at a constant heating rate of 10 °C·min-1. Computational procedures. The molecular structures of distinct species (anion, cation and solvent molecule) in the asymmetric unit were directly extracted from the experimental crystal structure. Then a HF/3-21G calculation have been performed for molecular structures. The charges obtained by a Mulliken population analysis after the ab initio calculation were used in the PIXEL37 for calculation of intermolecular energies including the Coulomb-polarization term, a dispersion term and a repulsion term. The PIXEL will calculate the different contributions and sum it up as the lattice energies. The Interactions Solvent Molecules in Solvates. The analysis of intermolecular interactions were performed through the analysis of weak interactions and 2D fingerprint plots of Hirshfeld surfaces calculated by Program Crystal Explorer 3.1 (isovalue: 0.5, quality: high standard),38-40 which accepts a structure input file in CIF format.

Results and discussion Solvate Screening and Classification. A crystal form screening of ATM was performed by selecting the most commonly used solvents of various solvent classes and mixed solvents. Besides the already known crystalline forms, six new solvates


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were

obtained

from

acetonitrile,

nitromethane,

ethanol,

acetic

acid,

1,

2-dichloroethane, and tetrahydrofuran. Polarizing microscope images of single crystals show their different crystal habits (mostly plate or prism shapes) (Figure 1). Their crystal structures were solved by SCXRD, and the crystallographic data was summarized in Table 1. Table 1. The crystallographic data of the apatinib mesylate monohydrate8 and seven organic solvates. Form

/

Solvate Radiction Formula

Temperature （K） Crystal

HA

S1

S2

S3

S4

S5

S6

S7

MoKα

MoKα

MoKα

MoKα

MoKα

MoKα

MoKα

MoKα

C25H29

C28H34

C26 H29

C27 H33

C27 H30

C29H35

C27H30

N5O5S

N6O5S

N7O4 S

N5 O5 S

N5 O6 S

N5O5S

N6O4S

100(2)

173(2)

173(2)

100(2)

173(2)

173(2)

173(2)

173 (2)

triclini

monocl

monocl

monocl

monocl

monocl

monocl

c

inic

inic

inic

inic

inic

inic

triclinic

system Space group a/(Å) b/(Å)

c/(Å)

C27H31 Cl2N5O 4S

P-1

P-1

Cc

Cc

Cc

Cc

Cc

C2/c

8.6361(

8.9476(

8.7891

9.0304(

8.7239(

8.7131(

8.9227(

16.392

5)

5)

(4)

9)

10)

6)

5)

0(5)

9.4346(

9.4601(

16.025

15.990

16.877

16.749

16.512

8.8029(

5)

5)

0(3)

1(15)

7(16)

7(12)

0(9)

3)

17.086

19.522

19.203(

18.983

18.599

19.457

19.211

38.765

2)

3(19)

2(19)

9(13)

1(10)

3(14)

90

90

90

90

90

90

3(10)

6(10)

79.507(

76.528(

3)

3)

85.010(

84.240(

98.628(

99.722(

97.572(

98.784(

98.584(

101.83

3)

3)

9)

8)

9)

4)

4)

1(2)

64.790(

61.991(

3)

3)

90

90

90

90

90

90

1238.4

1418.7

2674.1(

2701.8

2714.7

2806.4

2798.7

volume(Å )

3(13)

2(14)

7)

0(5)

0(5)

0(3)

0(3)

Z

2

2

4

4

4

4

4

5474. 9(3) 8

1.356

1.327

1.363

1.327

1.352

1.402

1.343

1.297

4619

4982

5009

4115

6268

4833

5362

6254

Rint

0.0425

0.0831

0.0593

0.0698

0.0971

0.0383

0.0381

0.0334

R(sigma)

0.0536

0.0565

0.0892

0.0966

0.1671

0.0379

0.0688

0.0471

α/(°)

β/(°)

γ/(°) Cell 3

Clac. density (g·cm−3)) unique reflection



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S(=1)

1.071

1.073

1.011

0.955

0.967

1.08

1.052

1.029

R

0.0556

0.086

0.0545

0.0511

0.065

0.0476

0.0552

0.0585

wR2

0.162

0.2466

0.1120

0.0952

0.1247

0.1305

0.1103

0.1429

Based on the crystallographic data and crystal structures, three types of solvates can be determined. Type I isostructural solvates include HA and S1, and type II isostructural solvates contain S2, S3, S4, S5, and S6. S7 is different form the two types of solvates. The crystalline forms of bulk samples are highly consistent with the single crystal. The PXRD patterns obtained experimentally and simulated from crystal structure data were identified (Figure 2).

(a) S1

(d) S4

(b) S2

(c) S3

(e) S5

(f) S6

(g) S7

Figure 2. The PXRD patterns obtained experimentally and simulated from crystal structure data. Analysis of ATM Solvates Single Crystal Structure.


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The asymmetric units for all solvates consist of one ATM molecule and one corresponding solvent molecule. The conformations of asymmetric units were analyzed on the basis backbone of Ring A (Figure S1). The τ1-τ3 (τ1, τ2, and τ3 representing the torsion angles along C1-N2-C6-C7, C13-N4-C12-C2, and C17-C18-C19-C21 respectively) were compared (Table S1), revealing that the conformations in different solvents are similar. The similarities between the different types of solvate structures were quantified (Table S2) via crystal packing similarity tool in Mercury 3.8. The same type solvates such as S1 and HA or S2 and S3 revealed high crystal packing similarity (26 out of 30, 20 out of 20 respectively). Crystal packing similarity between S1 and S2 was only 9 out of 20, suggesting type I and II solvates have obvious packing discrepancy. Crystal packing similarity between S1 and S7 (17 out of 30 molecules) suggested that S1 (type I solvates) and S7 presented obvious difference. The H-bonding parameters for the different solid forms are summarized in Table S3. ATM molecules are connected via an ionic bond generated between a mesylate anion O(3) in methylsulfonic acid and a planar protonated N(3) pyridine cation in free base (N(3)−H···O(3)). For type I solvates and S7, 2D network layer packing patterns were displayed in Figure 3. Two adjacent ATM molecules form a R 22 (18) supramolecular synthon dimer via hydrogen bonds between N(5) in the cyano-group and N(4) in amide group (N(4)−H(4)···N(5)). The dimers as the basic building block are further linked as a bimolecular chain by hydrogen bonds N(2)−H(2)···O(3) along a-axis (for HA and S1), or b-axis (for S7). Their discrepant symmetry elements give



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rise to different packing motifs. The dimers in S1 are lined into an oblique line shape (Figure 3b), while S7 forms a zigzag skeleton (Figure 3c).

R22 (18) dimer (a)

c b a

o

(b)

c

o

b

a (c) Figure 3. (a)H-bonding interactions, (b)1D bimolecular chain along the a-axis, and (c) 2D network layer packing of S1 and S7 (hydrogen atoms without strong hydrogen-bond interaction were omitted).


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The discrepancy of motifs viewing along the c-axis is obvious. S1 motif consisting of two ATM molecules is ring-shaped, and two DMF solvent molecules are contained in the ring (Figure 4a). In contrast, S7 motif is a cage-like structure as a result of the cross arrangement of four ATM molecules (Figure 4b), and four ACN molecules are restricted in the cage.

(a) (b) Figure 4.The discrepancy of (a) S1 and (b) S7 motifs along the c-axis (the mesylate anion is ignored for convenience). Type II solvates are isostructural solvates crystallizing in the monoclinic crystal system and the Cc space group with four asymmetric units in the unit cell. One ATM molecule is linked with the adjacent ATM molecules to form a chain via hydrogen interactions with the O(3) in the sulfonyl group and the N(2) in the amino group (N(2)−H···O(3)) in the a-axis direction, which form a 2D planar network via the N(4) in the amide group and the O(4) in the sulfonyl group (N(4)−H(4)···O(4)) (Figure 5). Solvent molecules in S3 and S4 form strong H-bonds with ATM molecules (Figure S2), while no strong H-bond is formed between host and guest molecules for the other type II solvates. The guest molecules in S3 and S4 solvates are associated with host molecules via O(5)−H(5A)···O(2) and O(6)−H(6)···O(2). The lengths of host-guest



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hydrogen bonds for S3 and S4 are 2.903 and 2.662 Å respectively. Correspondingly, the Elatt of S4 is stronger than that of S3, suggesting that the interaction between host and guest in S4 is stronger than that in S3.

(a)

c

a

o (b)

(b) Figure 5. (a) H-bonding patterns, (b) the 2D network packing of S3 solvates viewing along the b-axis (hydrogen atoms without strong hydrogen-bond interaction were omitted). According to the void occupied by solvent molecule is continuous or not, solvates can be classified into channel or isolated-site solvates. ATM solvates seem to

be segregated by API molecules (Figure S3). To display and analyze the solvent distribution, solvent molecules were removed from ATM solvates and the void volume maps were generated in Mercury depending on contact surface (probe radius: 1.2 Å, Grid spacing: 0.7 Å).19 The void volume distribution occupied by solvent molecules show discontinuous in void volume maps, therefore all solvates were


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determined to be isolated-site solvates.41 The effect of crystal packings and void volume on the stability of ATM solvents was further discussed. Thermal analysis and Hot stage microscope. Solvates were subjected to thermal analysis and the DSC/TGA curves of all solvates were measured under the same heating rate (see Figure 6 and Figure S4). The temperature range of desolvation process identified in DSC and TGA were concurrent. Two endothermic peaks occurred on the DSC patterns. Combined with TGA, the first endothermic peak was identified as desolvation process. According to the weight loss, the stoichiometry of the solvates was determined as 1:1 ratio. The onset temperatures of desolvation were summarized in Table 2. The thermal stability order of solvates is HA< S3< S2< S6< S1< S4< S5 < S7. The second endothermic peaks were corresponding to melting point of ATM form I, suggesting all solvates transformed to form I. The desolvation processes and the phase transitions were further confirmed using hot stage microscopy (HSM) (Figure S5) by heating solvates to their corresponding desolvation temperatures. The temperatures of solvent loss in HSM were consistent with the onset temperature calculated by DSC. According to PXRD analysis, the resulted solids were also verified as ATM form I (Figure S6).



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Figure 6. Thermal analysis and the overlaid DSC and TGA profiles of S1, S2, S3, and S7. Table 2. Thermal and DVS analysis Solvates

HA

S1

S2

S3

S4

S5

S6

S7

Guest Molecule Mw Properties

H2O 18.02 Isolated

Stoichiometry Cal. Weight loss (%) Obs. Weight loss in TGA (%) Obs. Weight loss in DVS (%) Guest loss Tem (± 0.3°C) ∆H for Guest loss (J/g) Resulted phase via heating Resulted phase via moisture absorption

1：1 3.5 3.4

DMF 73.09 Isolat ed 1：1 12.9 11.8

NM 61.04 Isolate d 1：1 11.0 10.5

EtOH 46.07 Isolat ed 1:1 8.5 8.5

HAc 60.05 Isolat ed 1：1 10.8 10.8

DCE 98.97 Isolat ed 1：1 16.7 15.2

THF 72.11 Isolat ed 1:1 12.8 11.9

ACN 41.05 Isolat ed 1：1 7.7 6.2

3.6

12.0

10.7

8.5

10.7

14.4

11.5

5.6

45

122

117

104

131

132

120

137

89.39

86.59

82.96

80.20

122.7

94.25

80.80

69.85

I

I

I

I

I

I

I

I

HA

HA

HA

HA

HA

HA

HA

HA

Dynamic vapor sorption (DVS). Moisture uptake has a profound impact on the physicochemical stability of solvates. The moisture-dependent phase transition of drug solvates affects the crystallization process development, formulation selection, and storage conditions. The hydration and dehydration profiles of ATM solvates were investigated using DVS (0–95% relative humidity) at 25 °C (Figure 7). A critical relative humidity (CRH) existed for these solvates obviously, except


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for S1. The mass of solvates was stable over a wide humidity range from RH=0 to the CRH. A sharp descending step occurred when the RH was reached the CRH. The decreased mass was calculated as the mass difference between the solvent molecule and water molecule. According to PXRD (Figure S7) and the following DVS cycles of the resulted phase, guest solvent molecules were replaced by water molecules during CRH and solvates was transformed to HA. From the mass change, the quantity of solvent content and stoichiometry (Table 2) can be calculated and determined as 1:1, consistent with SCXRD and TGA results. The resulted phase HA which was transformed from S3 and S5 continued to adsorb water after RH exceeded 90%. The phase at high moisture range (60 to 95% RH) of sorption/desorption processes was already determined as HA via VRH-PXRD (Figure S8). ATM monohydrate (HA) with different DVS behaviors (Figure S9) has been pointed out in our previous report,8 VRH-PXRD for HA suggested no form changed during the DVS process. The added water taken up on the surface of HA may affected by morphology and size differences of powders.8, 42 The CRHs order for different solvates are S3= S2< S4= S6< S1< S5, representing the moisture-dependent stability of solvates. DVS curve of S7 is different from the other solvates, and shows no mass loss during the cycle 1 water sorption. S7 increased by 2.68% (correspond to one water molecule) when RH increase from 0 to 90%, which suggesting water incorporated into the S7. The VRH-PXRD and single crystal unit cell test determined that S7 crystal structure did not change from 0 to 60% RH (Figure S10). While RH was added



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up to 70%, the PXRD revealed the crystal structure began to change to HA. The unique water sorption behavior for S7 was mainly caused by its unique cage-like crystal structure as the result of the mentioned zigzag packing pattern, in which water molecules can reserve and coexist with acetonitrile solvent molecules when RH% was lower than 60%. The single crystal of SA was also placed in the 58% RH container to measure SCTSC. The daughter single crystal was measured by single crystal X-ray diffraction. Unit cell parameters of S7 single crystal at RH=58% were listed in the Table S4.The crystal structure refinement result showed co-existence of water and acetonitrile molecules (Figure S11).

(a)

(b)

(c)

(d)


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(e)

(f)

(g) Figure 7. DVS diagrams of various solid forms of ATM: (a) S1, (b) S2, (c) S3, (d) S4 (e) S5, (f) S6, and (g) S7. Solid-state transitions and SCTSC of ATM solvates. According to thermal analysis for all solvates, the resulting solid phases via heat-induced desolvation were identified as form I. DVS of solvates revealed all solvates transformed to HA at high relative humidity, especially over their CRH. SCTSCs were the unique phase transitions, where a precursor single crystal can be used to resolve the converted single crystal structure.43, 44 A single crystal usually loses its integrity during a phase transition, often becoming opaque due to scattering by defects, and brittle because of the stresses inherent to the molecular motion.45 A SCTSC was observed from S3 crystallizing in the monoclinic space group Cc (type II) to HA crystallizing in the triclinic space group P-1 (type I), via standing a typical S3 single crystal [a = 9.0196(7) Å, b = 15.8620(12) Å, c = 18.9559(14) Å, β =



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99.471(3) °, V = 2675.0(4) Å3 at 100 K] in a humidity-controlled dryer with RH=68% for one week. The following crystal retained its original size and shape (Figure S12) and its crystal structure was determined by SCXRD. The resulting orientation matrix [a = 8.672(3) Å, b = 9.360(4) Å, c = 17.001(7) Å, α = 80.126(17) °, β = 85.462(18) °, γ = 64.504(17) °, V = 1227.2(9) Å3 at 100 K] was consistent with a single orientation of the daughter HA crystal (Table S4). This irreversible moisture-induced SCTSC between S3 and HA belong to non-topotactic relationship,43 in which the crystallographic orientations between daughter and parent phase are different. As described in the above section, the ATM in S3 is linked to be a monomolecular chain. In contrast, ATM molecules in HA are linked by the dimers to form a bimolecular chain. Although S3 and HA differ with respect to molecular packings, the transition pathway may be explained from their packing patterns observed along the a-axis (Figure 8). The SCTSC was likely to be established by the rotation of molecular chains of S3. The half of monomolecular chains of S3 shows similarity to one of bimolecular chain in HA (green chains in figure 8). The other half of monomolecular chains (blue chains in figure 8) of S3 and HA are in the different orientation. This half of molecule chains of S3 rotated along the b-axis direction (blue background) when the ethanol molecules were replaced by water molecules induced by humidity.


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RH=58%

b o (a)

b c

o (a)

c

(a)

(b)

Figure 8. The irreversible humidity-induced SCTSC transformation from S3 to HA: (a) crystal packing pattern of S3 along a-axis and (b) crystal packing pattern of HA along opposite a-axis. Rationalization of Thermal Stability of Solvates. The different ATM solvates show diverse thermal stabilities in their desolvation processes. The thermal stability in the heat-induced transition may be dependent on the intermolecular interaction, crystal packing structures, and solvent molecular properties of solvates. In order to rationalize the thermal stability of solvates, guest solvent molecular volume, solvent Mw, solvent boiling points, and Elatt were calculated and summarized in Table S5. The thermal stability order of the solvates is HA< S3< S2< S6< S1< S4< S5< S7. There is no obvious and direct relationship between these properties and thermal stability order. The Intermolecular Interactions of Solvent Molecules in Solvates. The intermolecular interaction differences focusing on the solvent molecules were analyzed via Hirshfeld surfaces analysis by selecting solvent molecules as the object. 2D fingerprint plots of Hirshfeld surfaces were plotted in the Figure S13. The contribution percentages of different element reciprocal contacts correlated with the



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component feature of solvent molecules were demonstrated in Figure 9.

Figure 9. Highlight reciprocal close contacts from elements in selected solvent molecule of ATM solvates. For type I solvates, the water molecule of HA has a smaller area than the DMF solvent molecule of S1 in nearest atoms distance (di and de) of 2D fingerprint plots, suggesting S1 possess stronger interaction than HA. Corresponding to the interaction intensity, S1 has a better thermal stability than that of HA. For type II solvates, the 2D fingerprint plots of solvent molecules of S4, S5, and S6 have shorter diameters than those of S2 and S3, which suggesting solvent molecules of S4, S5, and S6 have stronger intermolecular interaction. Corresponding to the interaction intensity, thermal stabilities of S4, S5, and S6 were better than that of S2 and S3. In addition, S3 and S4 exhibit a sharp pattern corresponding to O-H hydrogen bonds interaction between solvent guest and ATM host molecules. The different kinds of reciprocal close contacts percentage also determine the interaction intensity. The relative percentage ratio between O-H reciprocal close contacts and H-H contacts for S2 is much higher than S3, suggesting S2 is more thermostable than


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S3. The similar discrepancy existed in S4 and S6. What is the most outstanding the percentage of Cl-H interactions in S5 is up to 49.4%. The Cl-H interactions result in the broadest interaction area, suggesting that S5 with strong intermolecular interactions possess a superior stability. As for S7, the weak interactions contact areas occupy longer distance area due to the relaxed 3D packing. However, unique and noticeable N-H weak interactions (up to 36.1%) for the acetonitrile solvent molecule determine S7 may possess stronger weak interaction than other solvates. In summary, the thermal stability in the heat-induced desolvation is dependent on the intermolecular interactions of solvent molecules, which can be presented by the Hirshfield surface analysis. The smaller contact distance, a broader interaction area and higher relative percentage ratio of strong contacts is positive to the intermolecular interactions and the thermal stability. Rationalization of Hygroscopic Stability of Solvates. The different types of the ATM solvates show diverse moisture-dependent stabilities in their phase transition processes. As for the moisture-dependent stability, the humidity-induced solvates phase transition is a solvent replacement process, which is dependent on the solvent molecular size properties, crystal structures, and packing patterns. The different crystal structures and packing patterns of ATM solvates were elaborated. The resulted packing efficiency of the molecule polymorph or the solvates was reported to be correlated to the stability.46 The packing efficiencies of ATM were calculated in the Table 3. However, the relationship between packing efficiencies and



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the moisture-dependent stability is weak. Therefore, further investigations into the moisture-dependent stability from other aspects should be considered. The Free Void of Solvent Molecules in Solvates. The free void for solvent is critical to constrain the guest molecule and hinder the inclusion of outside water vapor. Furthermore, solvent molecule sizes had to be considered. Herein, the ratio of solvent molecular surface volumes to void volumes of solvent accessible surface (Rs-v) in crystals was given out, representing the relative free space accessible for solvent molecules. Rs-v, calculated in Table 3, was supposed to indicate and account for the moisture-dependent stability order.41 The trend of Rs-v (S3≈ S2≈ S4< S5< S1≈ S6) is highly consistent with the trend of CRH (S3= S2< S4< S6< S1< S5) (Figure 10), which suggests Rs-v has an effect on the moisture-dependent stability of these solvates. Table 3. The humidity stability analysis of ATM solvates. Form

CRH (%)

HA S3 S2 S4 S6 S1 S5

20 40 40 45 45 55 60

Packing Efficiency (%) 72.42 71.52 72.24 71.48 72.47 74.14 71.61

Vvoid (Å3)

Vsol (Å3)

Rs-v

206.3 424.66 408.92 446.56 430.97 194.48 424.53

26.6 80.06 74.67 78.97 105.85 101.49 107.75

0.26 0.75 0.73 0.7 0.98 1.04 1.02

Rs-v = Z Vsol/ Vvoid, where Vsol is the solvent molecule surface volume (Å3), Vvoid is the void volume (Å3) of solvent accessible surface in the unit cell, calculated using Mercury 3.8 (probe radius 0.2 Å and approx. Grid spacing 0.4 Å), and Z is the molecule number in the unit cell.


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Figure 10. Plot of relationship between Rs-v and CRH. Additionally, intermolecular interactions also affect the replacement of initial solvent molecules during a humidity-induced transition. For example, S4 is more stable than S2 and S3, which is mainly because of the acetic acid molecules of S4 have stronger host-guest interactions. In addition, the higher moisture-dependent stability for S5 is also benefited from its excess Cl-H intermolecular interactions. In conclusion, the main and direct factor on the moisture-dependent stability of ATM solvates was found to be Rs-v. In addition, the strong intermolecular interactions enhanced the moisture-dependent stability. Conclusions Crystallization of ATM from various solvents produced seven solvates. According to their crystal structures, all solvates were classified into three types: type I (with H2O and DMF), type II (with NM, EtOH, HAc, DCM and THF) and S7 (with ACN). The formation of various ATM solvates crystal structures was resulted from the diverse possibilities of molecular packing induced by different intermolecular interactions. A comparison of the crystal structures of ATM phases showed that type I solvates and S7 have a similar dimer chain. S7 lies in a zigzag packing compared to



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the parallel packing of type I solvates. Type II solvates have a completely different mono-molecular chain packing. Strong host-guest intermolecular interactions were observed in S3 and S4. The phase transformation relationships and desolvation pathways were determined. Notably, S3 (type II) can transform to HA (type I) via SCTSC induced by humidity, which was infrequent for discrepant crystal structures. Desolvation studies of ATM solvates showed that the solvates had different moisture-dependent and thermal stability based on different phase transitions. The factors affecting the stability of the solvates were analyzed and the results show that the main and direct factor on thermal stability of ATM solvates was found to be the intermolecular interaction of solvent molecules. Rs-v, the index of free void for solvent molecules, was identified to affect the moisture-dependent stability of the solvates mainly. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Crystallographic information files are also available from the Cambridge Crystallographic Data Center (CCDC) upon request (http://www.ccdc.cam.ac.uk, CCDC deposition numbers 1480501-1480506, 1576630). AUTHOR INFORMATION Corresponding Author E-mail address: [email protected] (X. F. Mei); fax: +86-21-50807088; tel.: +86-21-50800934, [email protected]. Fax: +86 (0)21-64253406 Notes


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The authors declare no competing financial interest. ACKNOWLEDGMENT We thank the National Natural Science Foundation of China (Grant Nos. 81273479 and 81402898), Youth Innovation Promotion Association CAS (Grant No. 2016257), CAS Key Technology Talent Program, and SANOFI-SIBS Scholarship for funding. References (1) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W., Adv. Drug Delivery Rev. 2001, 48, 3-26. (2) Hosokawa, T.; Datta, S.; Sheth, A. R.; Brooks, N. R.; Young, V. G.; Grant, D. J. W., Cryst. Growth Des. 2004, 4, 1195-1201. (3) Nangia, A.; R. Desiraju, G., Chem. Commun. 1999, 605-606. (4) Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G.; Byrn, S. R., J. Am. Chem. Soc. 2000, 122, 585-591. (5) Sun, C.; Grant, D. J. W., Pharm. Res. 2001, 18, 274-280. (6) Picker-Freyer, K. M.; Liao, X.; Zhang, G.; Wiedmann, T. S., J. Pharm. Sci. 2007, 96, 2111-2124. (7) Khomane, K. S.; More, P. K.; Bansal, A. K., J. Pharm. Sci. 2012, 101, 2408-2416. (8) Zhu, B.; Wang, J.-R.; Ren, G.; Mei, X., Cryst. Growth Des. 2016, 16, 6537-6546. (9) Surov, A. O.; Solanko, K. A.; Bond, A. D.; Bauer-Brandl, A.; Perlovich, G. L., CrystEngComm 2015, 17, 4089-4097. (10) Pudipeddi, M.; Serajuddin, A. T. M., J. Pharm. Sci. 2005, 94, 929-939. (11) Raw, A. S.; Furness, M. S.; Gill, D. S.; Adams, R. C.; Holcombe Jr, F. O.; Yu, L. X., Adv. Drug Delivery Rev. 2004, 56, 397-414. (12) López-Mejías, V.; Kampf, J. W.; Matzger, A. J., J. Am. Chem. Soc. 2012, 134, 9872-9875. (13) Hilfiker, R., Polymorphism in the Pharmaceutical Industry In ed.; Weinheim., W.-V., Ed. American Chemical Society: 2007. (14) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J., Pharm. Res. 2001, 18, 859-866. (15) Mekinist-Public assessment report, http://www.ema.europa.eu/docs/en_GB/document_library/E PAR_-_Public_assessment_report/human/002643/WC500169708.pdf (accessed 22, Jan 2017). (16) Forxiga-Public assessment report, http://www.ema.europa.eu/docs/en_GB/document_library/EP AR_-_Public_assessment_report/human/002322/WC500136024.pdf (accessed 22, Jan 2017). (17) Crixivan Scientific discussion, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR _-_Scientific_Discussion/human/000128/WC500035727.pdf (accessed 22, Jan 2017). (18) Prezista- Summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/docume nt_library/EPAR_-_Product_Information/human/000707/WC500041756.pdf (accessed 22, Jan 201 7). (19) Be̅rziņš, A.; Skarbulis, E.; Actiņš, A., Cryst. Growth Des. 2015, 15, 2337-2351. (20) Jia, L.; Zhang, Q.; Wang, J.-R.; Mei, X., CrystEngComm 2015, 17, 7500-7509. (21) Chen, P.; Iruela-Arispe, L.; Lou, L.; Sun, P.; Yuan, K., VEGFr inhibitor YN968D1 xenograft dose response studies against human colon cancer Ls174t and HT29. In ed.; AACR: 2006. (22) Yuan, K.-h.; Sun, P.; Zhou, Y.; Chen, Y. WO 2010/031266, 2010. (23) Yuan, K.; Sun, P.; Zhou, Y.; Chen, Y. US8362256 B2, 2013.



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For Table of Contents Use Only Solid-State

Characterization

and

Insight

into

Transformations and Stability of Apatinib Mesylate Solvates Bin Zhu, a Qi Zhang, b Guobin Ren,*a,c and Xuefeng Mei*b TOC GRAPHIC

SYNOPSIS Three types of ATM solvates were obtained and structurally elucidated by single-crystal X-ray diffraction. The phase formation relationships and desolvation pathways among these solid forms were revealed. Experimental and theoretical studies based on transitions mechanism were performed on the solvates to understand their thermal and moisture-dependent stability.


Solid-State Characterization and Insight into ... - ACS Publications

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