Study of Crystal Structures, Properties, and Form Transformations

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Study on Crystal Structures, Properties and Form Transformations between Polymorph, Hydrates, and Solvates of Apatinib Bin Zhu, Xiaoxue Fang, Qi Zhang, Xuefeng Mei, and Guobin Ren Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00397 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 10, 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

Study

on

Crystal

Transformations

Structures,

between

Properties

Polymorph,

and

Hydrates,

Form and

Solvates of Apatinib Bin Zhu,a Xiaoxue Fang,a Qi Zhang,b Xuefeng Mei,*b and Guobin Ren*a,c 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 Chemical Biology, School of Pharmacy, East China

University of Science and Technology, Shanghai, 200237, China

ACS Paragon Plus Environment

Crystal Growth & Design 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: Apatinib (APA) is a targeted antineoplastic drug by inhibiting the vascular endothelial cell growth factor receptor of tyrosine kinase. Its therapeutic solid form, apatinib mesylate (ATM), is dissociated to APA neutral form instantaneously in aqueous solution. Hereby, we undertook a form screen of APA. A polymorph, two hydrates, and three solvates of APA were discovered and characterized by SCXRD, PXRD, FTIR, and RAMAN. The relationships of phase transformation were assessed by DSC, TGA, and DVS. Their thermal and hygroscopic stability were elaborated and found to be dependent on intermolecular interaction and crystal packing. Form A with superior solubility and stability appeared to be a promising alternative form to overcome the disproportionation of ATM. Introduction Solid forms of active pharmaceutical ingredients (APIs) are critical to its physicochemical properties,1-3 such as solubility,4 dissolution rate, and stability5, which have an effect on the bioavailability and efficacy of orally insoluble drugs.6 The stability of API, such as thermodynamic and hygroscopic stability, need be noted and investigated to make sure no undesired phase transition occurred in the formulation process or storage stages.7-9 Crystal engineering technology has been utilized to design and prepare the solid forms with optimum physicochemical properties, such as polymorphs, solvates, salts, and cocrystals.10-13 Apatinib (APA) is an orally small-molecule antiangiogenesis drug, which can selectively inhibit the vascular endothelial cell growth factor receptor (VEGFR-2) of tyrosine kinase.14 In the clinical targeted chemotherapy treatment of advanced gastric


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cancer,15 APA is the first agent to prolong survival effectively in the third-line chemotherapy.16 We have reported that polymorphs and hydrates of apatinib mesylate (ATM).9 ATM was observed to convert to the neutral form in aqueous solution, which is defined as disproportionation. The optional cocrystals of apatinib were reported to overcome the disproportionation.17 However, the amplification of synthesizing cocrystals are challenging. To our knowledge, there is no literature about the polymorph of APA. We have reported patents about the polymorphs of apatinib. The form A and C in patents are corresponding to APA form A and 1.5H respectively. It is noticeable that the resulted APA forms have effect on the drug dissolution and absorption. Therefore, it is essential to investigate the physicochemical properties of the neutral form. In this study, we disclosed the solid-state landscape of APA. An anhydrous form A, a hemihydrate (HH), a sesquihydrate (1.5H), and three solvates were obtained for the first time (Scheme 1). The structures of form A, 1.5H, methanol solvate (FS1), dichloromethane solvate (FS2), and tetrahydrofuran solvate (FS3) were elucidated by SCXRD. FTIR, RAMAN, DSC, TGA, and DVS were used to characterize the physiochemical properties of new forms. The relationships of phase transformation and stability were elaborated and explained based on intermolecular interaction and crystal packing. The powder dissolution experiment shows that form A had the improved solubility in vitro compared to 1.5H, which makes it a superior candidate and alternative form for drug development.



Form A HH (APA : H2O = 2:1) 1.5H (APA : H2O = 1:1.5) FS1 (APA : MeOH = 1:1) FS2 (APA : CH2Cl2 = 2:1) FS3 (APA : THF = 2:1) Scheme 1. The molecular structure with labeled atoms and flexible torsion angles of APA polymorph, hydrates, and solvates. Experimental Section Materials. Amorphous apatinib with purity greater than 98 % was obtained from BioChemPartner Company, Ltd. (Pudong New Area, Shanghai, China). All analytical grade organic solvents were purchased from the Sinopharm Chemical Reagent Company. Preparation of form A. 20 mg of APA was dissolved in 1 mL of dimethylsulfoxide (DMSO) at 50 °C. Then the mixture was filtered. After adding 1 mL of H2O into the filtrate, it was left under ambient conditions for 12 h to get column-shaped crystals. Preparation of hemihydrate (HH). 20 mg of APA was added into 2 mL of tetrahydrofuran (THF), and the mixture was heated to 50 °C, followed by stirring and filtering. 5 mL of H2O was added to the filtrate and the mixed solution was rested for 24 h under ambient conditions to get plate-shaped crystals. Preparation of sesquihydrate (1.5H). 20 mg of ATM was added into 2 mL of N,Ndimethylformamide (DMF). The mixture was heated to 50 °C and stirred until the solution was clear. 6 mL of H2O was added to the filtrate and the mixed solution was rested for 8 h under ambient conditions to get block-shaped crystals.


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Preparation of methanol solvate (FS1). 20 mg of APA was added into 2 mL of methanol (MeOH). The mixture was stirred at 50 °C for 2 h. The solution was filtered and volatilized slowly at room temperature to get needle-shaped crystals. Preparation of dichloromethane solvate (FS2). 20 mg of APA was added into 2 mL of dichloromethane (CHCl2). The mixture was stirred at 40 °C until the solution was clear and filtered. 1 mL of H2O was added to the filtrate and the mixed solution was rested for 24 h under ambient conditions to get plate-shaped crystals. Preparation of tetrahydrofuran solvate (FS3). 40 mg of APA was added into 2 mL of tetrahydrofuran (THF). Then the mixture was heated to 60 °C, followed by stirring, and filtering. The plate crystals were prepared by cooling the filtrate from 70 to 20 °C. Powder X-ray diffraction (PXRD). PXRD patterns were measured at ambient temperature on a D8 Advance diffractometer (Bruker) 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. The copper (Cu-Kα) radiation (λ = 1.54180 Å) was used and 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, Rigaku. To prevent decomposition of the solvates caused by the atmospheric humidity, the samples were covered with a polyethylene film when necessary. Single Crystal X-ray Diffraction (SCXRD). X-ray diffractions of all single crystals were performed at 173 or 206 K using Mo-Kα radiation (λ = 0.71073 Å) on a Bruker Apex II CCD diffractometer. The collected data integration and reduction was processed with SAINT software,18 and multi-scan absorption corrections were



performed using the SADABS program.19 The structures were solved by direct methods using SHELXTL20 and were refined on F2 by the full-matrix least-squares technique using the SHELXL-97 and SHELXL-2014 program package.21 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 displacement parameters set to 1.20 (sp2) and 1.50 (sp3) times Ueq of the parent atoms. Fourier-Transform Infrared (FTIR) Spectroscopy. FTIR spectra were collected by a Nicolet-Magna FTIR 750 spectrometer in the range from 4000 to 400 cm−1, with a resolution of 4 cm−1 at ambient conditions. Raman Spectroscopy. Raman spectra were recorded with a Thermo Scientific DXR Raman microscope equipped with a 780 nm laser. The Raman scans ranged from 3500 to 400 cm−1. The samples were analyzed directly on a glass sheet using a 100 mW laser power with a resolution of 2 cm-1 and a 50 μm slit spectrograph aperture. Calibration of the instrument was performed using a standard polystyrene film. Thermogravimetric analysis (TGA). TGA 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 - 400 °C. Nitrogen was used as the purge gas at 20 mL·min-1. Differential scanning calorimetry (DSC). DSC experiments were performed on a TA Q2000 instrument under a nitrogen gas flow of 50 mL·min-1 purge. Ground samples


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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). DVS experiments were performed on an Intrinsic DVS instrument from Surface Measurement Systems, Ltd. Samples were studied over a humidity range of 0 - 95% or 40 - 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. In Vitro Powder Dissolution. To minimize the size effect of bulk samples on dissolution behaviors, each of APA forms was sieved through 100- mesh sieves. Accurately weighed powders of 30 mg of APA were added to dissolution vessels containing 15 mL of pH 2.0 hydrochloric acid (HCl) buffer at 37 °C. The dissolution studies were conducted at a rotation speed of 100 rpm. Sampling was performed at 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 min. Then the suspensions were centrifuged at 14000 rpm for 5 min, and the supernatant was diluted appropriately with pH 2.0 HCl buffer prior to HPLC analysis. The solubility measurements were done in replicates of three. High Performance Liquid Chromatography (HPLC) Analysis. The contents of APA were determined by an Agilent 1260 series HPLC (Agilent Technologies), equipped with a quaternary pump (G1311C), diode-array detector (G1315D) set at 260 nm. The analytes were separated on a 4.6 × 75 mm, 3.5 μm particle size Agilent Eclipse plus C18 column. A mobile phase consisting of solvent A (water) and solvent B



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(acetonitrile) was run at 1.0 mL·min-1 with the ratio of 65/35 (v/v) for 0-5 min, 50/50 (v/v) for 5-10 min, 40/60 (v/v) for 10-10.01 min, and 65/35 (v/v) for 10.01-12 min. The column temperature was set at 30 °C and the injection volume was 15 μL.

Results and discussion Solid Forms Screening and Classification. The screening of APA forms was performed by selecting the most commonly used solvents and their mixed solvents. One anhydrous form, two hydrates and three solvates were unambiguously identified by PXRD and SCXRD. Polarizing microscope images of the various solid states show their different crystal habits (Figure 1).

Form A

HH

FS2

FS3

1.5 H

FS1

Figure 1. Polarizing microscopy images of APA polymorph, hydrates, and solvates. Microcrystalline powder samples of APA solid phases were characterized by PXRD. All the peaks displayed in the measured patterns closely matched those in the simulated patterns generated from SCXRD data (Figure S1, Supporting Information), confirming the formation of highly pure phases. FTIR and Raman spectra of crystalline


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powder samples of APA polymorph, hydrates, and solvates are shown in the Figure S2 and S3. Crystal Structure Analysis. Growing suitable single crystals of APA for structure determination was challenging due to the propensity of solid phases to form small crystals with poor crystal quality. Their crystal structures were solved by SCXRD, and the crystallographic data was summarized in Table 1. All APA solid forms crystallize in the monoclinic crystal system. The space groups of form A and FS1 are P21/c, 1.5H and FS2 are in the space group of C2/c, whereas FS3 is in the space group Cc. Table 1. The crystallographic data of APA polymorph, hydrates, and solvates Form

A

1.5H

FS1

FS2

FS3

Radiation

MoKα

MoKα

MoKα

MoKα

MoKα

Stoichiometry

---

1:1.5

1:1

2:1

2:1

Empirical Formula

C24H23N5O

C24H26N5O2.5

C25H27N5O2

C49H48Cl2N10O2

C52H53N10O3

Formula weight

397.47

424.50

429.51

879.87

866.04

Temperature/K

173(2)

173(2)

206(2)

206(2)

173(2)

Crystal system

monoclinic

monoclinic

monoclinic

monoclinic

monoclinic

Space group

P21/c

C2/c

P21/c

C2/c

Cc

a/Å

15.1777(5)

15.9721(7)

8.4584(12)

15.6562(15)

15.602(3)

b/Å

16.9101(5)

8.8817(4)

28.719(4)

9.3884(10)

9.3406(18)

c/Å

15.7193(5)

29.7712(12)

9.8709(14)

29.558(3)

30.749(5)

α/°

90

90

90

90

90

β/°

97.604(10)

93.028(2)

112.989(3)

92.860(2)

97.771(4)

γ/°

90

90

90

90

90

Cell volume/Å3

3999.0(2)

4217.4(3)

2207.4(5)

4339.3(8)

4440.0(14)

Z

8

8

4

4

4

ρcalc/g·cm−3

1.320

1.337

1.292

1.347

1.296

Unique reflns

9148

3711

5092

5023

7121



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Rint

0.0181

0.0287

0.0558

0.0523

0.0608

S

1.036

1.071

1.027

1.040

0.966

R1

0.0398

0.0496

0.0484

0.0528

0.0586

wR2

0.1055

0.1368

0.1162

0.1273

0.1307

The asymmetric units for all solid states show significant difference (Figure S4, Supporting Information). The crystal structures show that two independent APA molecules (A_co1 and A_co2) exist in the asymmetric unit of form A, one APA and two water molecules in the asymmetric unit of 1.5H, in which one water molecule H2O(A) in the symmetrical position is counted as half occupancy. Both FS1 and FS2 include one APA host molecule and one guest solvent molecule in their asymmetric units. The difference is that the MeOH solvent molecule in FS1 and CH2Cl2 molecule is in the general and symmetrical position respectively. Therefore, the stoichiometric ratios of the host and guest molecule in FS1 and FS2 are 1:1 and 2:1, respectively. In contrast, two independent APA molecules (FS3_co1 and FS3_co2) and one THF solvent molecule exist in the asymmetric unit of FS3. The different conformations of APA molecule in asymmetric units were analyzed on the basis backbone of Ring A (Figure 2). The τ1-τ3 (τ1, τ2, and τ3 representing the torsion angles along C1-N2-C6C7, C13-N4-C12-C2, and C17-C18-C19-C21 respectively) show substantial difference (Table S1). A_co1 (red) and A_co2 (green) show difference in the τ1 and τ3, resulting in terminal rings B and D in the opposite direction. The τ2 and τ3 in 1.5H (blue) is similar to the FS3_co2 (orange), while τ1 is in the opposite direction. The conformation of FS1 (yellow), FS2 (cyan), and FS3_co1 (magenta) are highly consistent. The τ2 and


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τ3 in A_co1 is consist with FS1, while the τ1 corresponding to ring D is in the opposite direction.

Figure 2. Overlays of unique molecule in crystal structure of A_co1 (red), A_co2 (green), 1.5H (blue), FS1 (yellow), FS2 (cyan), FS3_co1 (magenta), and FS3_co2 (orange). The H-bonding parameters for the different solid forms are summarized in Table S2. In the case of form A, APA A_co1 molecules are connected as a chain-like structure along b-axis direction via H-bonds generated between N(4) in amide groups and N(3) in pyridine groups (N(4)−H···N(3)) (red molecules in the figure 3a). APA A_co2 molecules (green molecules in the figure 3a) are attached on either side of the chain to form a dendritic structure via hydrogen bonds between N(9) in amide groups of A_co2 and N(5) in the cyano-groups of A_co1 (N(9)−H(4)···N(5)). The dendritic structures are arranged parallelly along the a-axis direction in the aob plane (Figure 3b). The dendritic structures in the adjacent planar array were stacked and staggered (Figure S5, Supporting Information).



(a)

(b) Figure 3. (a) The molecular chain linked with hydrogen bond and (b) 2D packing patterns along the c-axis direction in APA form A 1.5H has two independent H2O molecules (H2O(A) and H2O(B)). H2O(A) is linked with another adjacent H2O(A) via H-bonds (O(1S)−H···O(1S). The two H2O(A) molecules are connected with two APA molecules via H-bonds generated between O(1) in carbonyl groups and O(1S) in H2O(A) respectively to form the APA–H2O(A)–


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H2O(A)–APA structure. The structure is connected with H2O(B) via H-bonds generated between N(3) in pyridine groups and O(2S) in H2O(B) to form a 1D helix chain (– [APA–H2O(A)–H2O(A)–APA–H2O(B)]n–) along the a-axis direction (Figure 4). The APA molecules in two neighbouring helix chains are connected to form a R2 2(18) dimer via H-bonds generated between N(4) in amide groups and N(5) in the cyanogroups (N(4)−H(4)···N(5)). The helix chains are linked as a 2D network structure along the c-axis direction in the aoc plane. Along b-axis direction, two neighbouring helix chains are connected and cross via H-bonds generated between N(3) in pyridine groups and O(1S) in H2O(A) in the Figure S6.

c a (a)

b

(b)



(c)

(d)

Figure 4. (a) The helix molecular chain linked with hydrogen bond, (b) the helix molecular chain along the vertical direction, (c) 2D network combined by three helix molecular chains via H-bond along the a-axis, (d) 2D network combined by three helix molecular chains via H-bond perpendicular to the a-axis. The basic building blocks in the three APA solvates are similar (Figure 5). In FS1 and FS2, two adjacent APA molecules form a R2 2(18) supramolecular synthon dimer via H-bonds between N(5) in the cyano-group and N(4) in amide group (N(4)−H(4)···N(5)) in FS1 and FS2. In FS3, two molecular conformations FS3_co1 and FS3_co2 formed a R2 2(18) dimer via H-bonds between N in the cyano-group and N in amide group (N(4)−H(4)···N(10) and N(9)−H(4)···N(5)). The dimer in FS1 is contacted to MeOH via H-bonds generated between N(3) in pyridine groups and O(2) in MeOH (O(2)–H···N(3)). The MeOH is also contacted to the adjacent dimer via H-


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bonds generated between N(3) in pyridine groups and O(2) in MeOH (N(2)–H···O(2)), which result in a bimolecular chain in FS1. Their discrepant symmetry elements give rise to different packing motifs. The dimers in FS1 form a zigzag skeleton (Figure 6a) via van der Waals' interaction, while FS2 and FS3 are lined into an oblique line shape (Figure 6b and c). N3 O2 N4 N5

N5 N4

(a)

(b)

(c)

Figure 5. The dimeric building block in (a) FS1, (b) FS2, and (C) FS3. O2

N2

c a

b

(a)



c

a

b

(b)

b a

c

(c) Figure 6. The 2D layer packing patterns in (a) FS1, (b) FS2, and (c) FS3. Thermal analysis. TGA and DSC were performed to distinguish and determine the molten nature and desolvation process, as shown in Figure 7. Thermal analysis for form A show its melting point exists at Tonset of 160.3 °C and little weight loss. The single crystal of HH was defective, in which the moisture content was identified by the thermal analysis. HH have a 1.57% of weight loss, which confirms the stoichiometric


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ratio of APA and H2O 2:1. The desolvation temperature is at Tonset of 88.5 °C. On basis of the weight loss, the stoichiometry ratios of host and guest in 1.5H, FS1, FS2, and FS3 are determined as 1:1.5, 1:1, 2:1, and 2:1 respectively. DSC of 1.5H shows three endothermic peaks, which suggests H2O solvent molecules at different sites have distinct interaction. Tonset of the first dehydration peak is 86.2 °C, which is close to that of HH dehydration behavior. Tonset of the second dehydration peak is 125.8 °C. Tonset of the last endothermic peak is 159.6 °C, which is corresponding to the melting point of form A, suggesting 1.5H transforms to form A via heating. The VT-PXRD patterns for APA 1.5H also evidence the transformation (Figure S7, Supporting Information). According to the endothermic behavior, all solvates and hydrates transform to form A.

(a)

(b)

(c)

(d)



(e) (f) Figure 7. DSC and TGA figures of APA polymorph, hydrates, and solvates. Moisture Sorption Analysis. Moisture uptake has a profound impact on the physicochemical stability of solid forms. The moisture-dependent phase transition of drug affects the crystallization process development, formulation selection, and storage conditions. The isothermal DVS profiles of APA polymorph, hydrates, and solvates were investigated at 25 °C (Figure 8). Form A, HH, 1.5H, and FS1 shown the reversible sorption and desorption behavior in two cycles, which suggest they are stable. Along with the RH was increased to 40-80%, the water content of form A, HH, 1.5H, and FS1 increased by 1.1, 0.6, 1.5, and 0.47%, respectively. The water content of FS2 and FS3 changed in the cycle, indicating the solid states have transformed. The mass changed more quickly in the desorption stage than sorption stage. At the end of cycle 2 desorption, the mass decreased by 6.5 and 1.3% for FS2 and FS3, respectively. PXRD measurements of power after DVS (Figure S8, Supporting Information) also demonstrate the solid states of form A, HH, 1.5H, and FS1 remain unchanged. FS2 has changed to 1.5H. PXRD characteristic peaks of 1.5H were found in the resulted FS3 powder, revealing FS3 transformed to 1.5H partly. By keeping FS3 at RH = 60% dryer for a month, PXRD of the resulted powder has converted to 1.5H.


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Figure 8. DVS figures of APA polymorph, hydrates, and solvates. Phase transition and stability analysis. According to the thermoanalysis, all hydrates and solvates transformed to form A. The thermal stability order of solvates is FS3 < FS1 < FS2, this heat-induced desolvation is reported to be dependent on the intermolecular interactions of solvent molecules.22 2D finger print plots of Hirshfeld surfaces for the selected solvent molecules were plotted in the Figure S9. The contribution percentages of different element reciprocal contacts were demonstrated in Figure 9, which were varied with the component feature and intermolecular interaction



of solvent molecules. The order of O···H reciprocal close contacts (%) is FS1 (20.6%) > FS2 (9.1%) > FS3 (3.9%), resulting in that FS1 and FS2 are more thermostable than FS3. For FS2, the percentage of unique Cl···H interactions is up to 58.9%. The strong intermolecular interactions contribute to the superior stability of FS2. On the basis of moisture sorption measurement and PXRD, the solid phases of form A, HH, 1.5H, and FS1 were stable. In contrast, FS2 and FS3 transformed to 1.5H at last. The moisture-dependent stability of different solvates was dependent on the packing efficiency and free void of solvent molecules.23 The packing efficiencies of APA solvates were calculated in the Table S3, and the relationship is FS2 < FS3 < FS1. The order of packing efficiencies is consistent with that of hygroscopic stability of these solvates, suggesting the higher packing efficiency benefits hygroscopic stability of solvates.

Figure 9. Highlight reciprocal close contacts from elements in selected solvent molecule of APA polymorph, hydrates, and solvates.


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Solubility Measurement. The solubility and dissolution rate in the aqueous medium of API have an effect on its bioavailability and efficacy, which are influenced by solid forms. Therefore, the dissolution profiles of form A and 1.5H were determined, as seen in the Figure 10. HH is different to repeat, so that there are not enough samples to conduct the dissolution experiment for HH. 1.5H bulk samples dissolve faster than form A. However, the dissolution profile for 1.5H demonstrates a classical so-called “spring and parachute” behavior,24 which was used to describe the dissolution process of solid forms. The spring and parachute behavior of 1.5H dissolution profiles may be caused by 1.5H converted to HCl salt (Figure S10, Supporting Information). In the case of from A, there is no evident “spring” effect. After 300 min of dissolution, the apparent solubility of form A is higher by a factor of 2 compared with the concentration of 1.5H. The dissolution of ATM HA was reported in the literature.17 ATM HA start to dissolve faster than APA form A, then the concentration of ATM HA decreases and is lower than that of APA form A. It should be noted that the superior apparent solubility level of form A remains stable for quite a long time (the concentration at 24 h of dissolution is 750 μg/mL), which indicates a greater stability of form A in pH=2.0 buffer solution than 1.5H. The dissolution results suggest that form A is an advanced form with enhanced solubility and stability.



Figure 10. Powder dissolution profiles of APA polymorph and hydrate in pH=2.0 buffer solution. Conclusions An anhydrous form A, a hemihydrate (HH), a sesquihydrate (1.5H), and three solvates were discovered and identified via SCXRD, PXRD, FTIR, and RAMAN. Their physicochemical properties and phase transition were characterized through DSC, TGA, and DVS. It has been shown that all hydrates and solvates transformed to form A after the heat-induced desolvation. The thermodynamic stability is dependent on the discrepant intermolecular interaction on the basis of Hirshfeld surfaces analysis. As for hygroscopic stability, form A, HH, 1.5H, and FS1 remain stable. On the contrast, FS2 and FS3 transformed to 1.5H. The moisture-dependent phase transition appears to be controlled by packing efficiencies. Form A shows great thermodynamic stability, superior hygroscopic stability, and enhanced solubility. The combination of these advantages suggests it can be developed as a promising alternative to overcome the disproportionation of ATM. ASSOCIATED CONTENT Supporting Information.


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The Supporting Information is available free of charge on the ACS Publications website at DOI: Additional data and figures (PDF) Accession Codes CCDC 1857331, 1857332, 1857334, 1857335, and 1858734 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 *E-mail address: [email protected] (G. Ren); [email protected] (X. Mei). Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank the supports from the National Natural Science Foundation of China (Grant No. 21776073 and 21576080); Natural Science Foundation of Shanghai (grant No. 18ZR1447900). References (1) Berry, D. J.; Steed, J. W. Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv. Drug Delivery Rev. 2017, 117, 3-24. (2) Serajuddin, A. T. M. Salt formation to improve drug solubility. Adv. Drug Delivery Rev. 2007, 59, 603-616. (3) Higashi, K.; Ueda, K.; Moribe, K. Recent progress of structural study of polymorphic pharmaceutical drugs. Adv. Drug Delivery Rev. 2017, 117, 71-85. (4) Sanphui, P.; Devi, V. K.; Clara, D.; Malviya, N.; Ganguly, S.; Desiraju, G. R. Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug–Coformer



Interactions. Mol. Pharmaceutics 2015, 12, 1615-1622. (5) Wang, L.; Luo, M.; Li, J.; Wang, J.; Zhang, H.; Deng, Z. Sweet Theophylline Cocrystal with Two Tautomers of Acesulfame. Cryst. Growth Des. 2015, 15, 2574-2578. (6) Healy, A. M.; Worku, Z. A.; Kumar, D.; Madi, A. M. Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals. Adv. Drug Delivery Rev. 2017, 117, 25-46. (7) Anwar, J.; Zahn, D. Polymorphic phase transitions: Macroscopic theory and molecular simulation. Adv. Drug Delivery Rev. 2017, 117, 47-70. (8) Qi, M.-H.; Hong, M.-H.; Liu, Y.; Wang, E.-F.; Ren, F.-Z.; Ren, G.-B. Estimating Thermodynamic Stability Relationship of Polymorphs of Sofosbuvir. Cryst. Growth Des. 2015, 15, 5062-5067. (9) Zhu, B.; Wang, J.-R.; Ren, G.; Mei, X. Polymorphs and Hydrates of Apatinib Mesylate: Insight into the Crystal Structures, Properties, and Phase Transformations. Cryst. Growth Des. 2016, 16, 6537-6546. (10) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640-655. (11) Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv. Drug Delivery Rev. 2007, 59, 617-630. (12) Thakuria, R.; Nangia, A. Olanzapinium Salts, Isostructural Solvates, and Their Physicochemical Properties. Cryst. Growth Des. 2013, 13, 3672-3680. (13) Surov, A. O.; Manin, A. N.; Churakov, A. V.; Perlovich, G. L. New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility. Mol. Pharmaceutics 2015, 12, 4154-4165. (14) Li, J.; Zhao, X.; Chen, L.; Guo, H.; Lv, F.; Jia, K.; Yv, K.; Wang, F.; Li, C.; Qian, J.; Zheng, C.; Zuo, Y. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer 2010, 10, 1-8. (15) Roviello, G.; Ravelli, A.; Polom, K.; Petrioli, R.; Marano, L.; Marrelli, D.; Roviello, F.; Generali, D. Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. Cancer Lett. 2016, 372, 187-91. (16) Aoyama, T.; Yoshikawa, T. Targeted therapy Apatinib - new third-line option for refractory gastric or GEJ cancer. Nat. Rev. Clin. Oncol. 2016, 13, 268-270. (17) Zhu, B.; Wang, J.-R.; Zhang, Q.; Li, M.; Guo, C.; Ren, G.; Mei, X. Stable Cocrystals and Salts of the Antineoplastic Drug Apatinib with Improved Solubility in Aqueous Solution. Cryst. Growth Des. 2018, 18, 4701-4714. (18) Sheldrick, G., SAINT and XPREP. In ed.; Siemens Industrial Automation Inc. Madison, WI: 1995. (19) Sheldrick, G., SADABS, Empirical absorption correction program. In ed.; University of Göttingen: Göttingen, Germany: 1997. (20) Sheldrick, G., SHELXTL Reference Manual, version 5.1; Bruker AXS: Madison, WI, 1997. In ed.; 2005. (21) Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3-8. (22) Zhu, B.; Zhang, Q.; Ren, G. B.; Mei, X. F. Solid-State Characterization and Insight into Transformations and Stability of Apatinib Mesylate Solvates. Cryst. Growth Des. 2017, 17, 5994-6005. (23) Nauha, E.; Ojala, A.; Nissinen, M.; Saxell, H. Comparison of the polymorphs and solvates of two analogous fungicides-a case study of the applicability of a supramolecular synthon approach in crystal engineering. CrystEngComm 2011, 13, 4956-4964. (24) Babu, N. J.; Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals.


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Cryst. Growth Des. 2011, 11, 2662-2679.



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For the Table of Contents Only Study

on

Crystal

Transformations

Structures,

between

Properties

Polymorph,

and

Hydrates,

Form and

Solvates of Apatinib Bin Zhu,a Xiaoxue Fang,a Qi Zhang,b Xuefeng Mei,*b and Guobin Ren*a,c TOC GRAPHIC

SYNOPSIS An anhydrous form A, a hemihydrate (HH), a sesquihydrate (1.5H), and three solvates of the antineoplastic drug apatinib were obtained and determined by single-crystal Xray diffraction. APA form A shows superior solid-state stability with higher solubility, which make it a promising alternative to overcome the disproportionation of ATM.


Study of Crystal Structures, Properties, and Form Transformations

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