Polymorphs and Hydrates of Apatinib Mesylate: Insight into the Crystal

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Polymorphs and Hydrates of Apatinib Mesylate: Insight into the Crystal Structures, Properties and Phase Transfomations Bin Zhu, Jian-Rong Wang, GuoBin Ren, and Xuefeng Mei Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01230 • Publication Date (Web): 14 Oct 2016 Downloaded from http://pubs.acs.org on October 16, 2016

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Crystal Growth & Design

Polymorphs and Hydrates of Apatinib Mesylate: Insight into the

Crystal

Structures,

Properties

and

Phase

Transformations Bin Zhu,a Jian-Rong Wang,b Guobin Ren,*a 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

ACS Paragon Plus Environment


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ABSTRACT: Apatinib mesylate (ATM) is an orally administrated anticancer agent for the treatment of advanced gastric cancer. Single-crystal structures of four ATM solid forms, including two anhydrous polymorphs (I and II), hydrates (HA and HB) were elucidated by single-crystal X-ray diffraction. The properties of these various forms were fully characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform-infrared spectroscopy, and Raman spectroscopy. The discrepant molecule conformations, H-bonding interactions and packing arrangements in the crystal structures were analyzed associated with the hygroscopicity of forms I and II. Various form transformations induced by either moisture or solution conditions were examined, and the relative stability was established. The results revealed that HA is the most thermodynamically stable form and is superior to the currently marketed form. INTRODUCTION Many drugs on the market exist in the crystalline solid state due to the advantages of stability and ease of handling during the various stages of drug development.1, 2 Polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community.3 Crystalline solids can exist in the forms of polymorphs,4-6 solvates7 or hydrates8. The various solid forms generally present different physicochemical properties9 and are closely related to the bioavailability and manufacture of active pharmaceutical ingredients (APIs).3 Phase transitions, such as polymorph interconversion,10 solvate desolvation,11 hydrate formation,12 and crystalline conversion,13, 14 may occur during various pharmaceutical processes, which may alter the dissolution rate and transport characteristics of the


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drug.1, 15, 16 Hence, it is desirable to understand the solid-state behavior of the drug and to investigate phase transformation mechanism to judiciously select the optimal solid form for development. Apatinib mesylate (ATM, Scheme 1) is a safe and orally effective small-molecule antiangiogenesis drug,17-19 which was developed by JiangSu HengRui Medicine Co. Ltd. ATM was approved to market under the brand name AiTan® by the Chinese State Food and Drug Administration (SFDA) in 2014. ATM is the first agent to show a clear survival benefit in the third-line chemotherapy setting compared with a placebo and is the second antiangiogenic drug, following the approval of ramucirumab.20 ATM provides targeted chemotherapy treatment in advanced gastric cancer by selectively inhibiting the vascular endothelial cell growth factor receptor (VEGFR-2) of tyrosine kinase,21,

22

which transduces signals critical for cell

proliferation, especially for patients suffering failure of the standard treatment.23-27 ATM is insoluble in water and has low oral bioavailability in male dogs (9.24%) and female dogs (15.4%) after a single oral administration.28 ATM was first reported as white needle crystals, as described in the patent, with a melting point of 193.5-195 °C.27 Previously, the five solid states A, B, C, D, F, and N, N-dimethylformamide solvate in the patents,29-34 whereas there is no information regarding their crystal structures and properties. The crystal purity of the drug is critical to its quality and effects due to the discrepant solubility, dissolution rate, and bioavailability associated with different crystal forms. Thus, it is urgent to research



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the solid-state landscape and to select the superior form for drug quality control and development. In this study, the solid-state landscape of this important medicine is disclosed after an extensive solid-state form screening protocol. Single crystals of four ATM solid forms were obtained for the first time, including two anhydrous polymorphs (I and II), and one monohydrate HA (referred to as A in the patent29, for clarity), and one hemihydrate HB. Their structures were elucidated by single-crystal X-ray diffraction (SXRD). Forms I, II, and HA were characterized by PXRD, thermal analysis (TGA and DSC), dynamic vapor sorption (DVS), Fourier transform-infrared (FTIR)

spectroscopy,

and

Raman

spectroscopy.

The

discrepant

molecule

conformations, H-bonding interactions and packing arrangements in the crystal structures were analyzed associated with the hygroscopicity difference between I and II. Various form transformations induced by either moisture or solution conditions were examined, and the relative stability was established. The results reveal that HA is not sensitive to humidity change in the range of 40-80% relative humidity and HA is the most stable form under ambient conditions, which makes it a superior candidate for drug development.


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Scheme 1. Chemical structure of ATM.

Form I

Form II

HA

Figure 1. Polarizing microscopy images of forms I, II, and HA. EXPERIMENTAL SECTION Materials. The sample of ATM used in the present work was purchased from BioChemPartner Company, Ltd. (Zhangjiang Road, Pudong New Area, Shanghai, China) with purity greater than 98%. All analytical grade solvents were purchased from Sinopharm Chemical Reagent Company, Ltd. and were purified by dehydration. Preparation of Various Forms. ATM (20 mg) was dissolved in isopropanol (10 mL) in a glass vial at 50 °C. The saturated solution was filtered through a 0.45 µm organic membrane filter, and the solution was left to slowly concentrate in a fuming hood at 50 °C. Single crystals of form I were harvested after three days. The single crystals of form II were prepared by dissolving 40 mg ATM in 8 mL isopropanol at 70 °C, filtering through a 0.45 µm organic membrane filter, and volatilizing at 50 °C. Form II was prepared by cooling the saturated isopropanol solution of ATM from 70 °C to 25 °C at a cooling rate between 0.5 and 1 °C/min. HA can be prepared by several methods, such as volatilizing a saturated ethanol solution of ATM at room temperature. Moreover, cooling or slurrying in most organic solvents, e.g., methanol, acetonitrile or their mixture, can produce HA with high phase purity. Single crystals suitable for X-ray diffraction analysis were carefully selected from the corresponding



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bulk samples. HB single crystals were obtained by volatilizing a saturated acetone solution of ATM at 50 °C. Powder X-ray Diffraction (PXRD). PXRD patterns were obtained using a Bruker D8 Advance X-ray diffractometer (Cu Kα radiation). The voltage and current of the generator were set to 40 kV and 40 mA, respectively. Data over the range 3−40° 2θ were collected at a scan rate of 5 °/min at ambient temperature. The data were imaged and integrated with RINT Rapid and the peaks were analyzed with Jade 6.0 from Rigaku. Fourier Transform-Infrared (FTIR) Spectroscopy. Fourier transform-infrared (FTIR) spectra were collected with a Nicolet-Magna FT-IR 750 spectrometer in the range from 4000 to 350 cm−1 with a resolution of 4 cm−1 under 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 50 cm−1. The samples were analyzed directly on a glass sheet using a 60 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 polystyrene film standard. Differential Scanning Calorimetry (DSC). DSC experiments were performed on a DSC TA Q2000 instrument under a nitrogen gas flow of 50 mL/min. Ground samples weighing 1−3 mg were heated in sealed aluminum pans from 25 to 210 °C at a heating rate 10 °C/min. The instrument was calibrated against the melting properties of indium.


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Thermogravimetric Analysis (TGA). Thermogravimetric analysis was performed on a Netzsch TG 209F3 instrument. The samples were placed in open aluminum oxide pans and heated at 10 °C/min to 350 °C. Nitrogen was used as the purge gas at 20 mL/min. Two-point calibration of the temperature was performed with ferromagnetic materials (Alumel and Ni, Curie-point standards, PerkinElmer). Dynamic Vapor Sorption (DVS). The water sorption and desorption processes were measured on an Intrinsic DVS instrument from Surface Measurement Systems, Ltd. The samples were mounted on a balance, and the water sorption was analyzed over a humidity range from 0% to 95% RH for forms I and II and from 40% to 95% RH for HA. Then, the RH was decreased to 0% for desorption at 25 °C, and two cycles were performed with RH changes setting to 5% for all cycles. Each humidity step 5% was made if less than a 0.02% weight change occurring over 10 mins and a maximum time limit of 360 min for each step. Solubility Measurement by Dynamic Laser Scattering. The dynamic laser scattering monitoring technique is performed to determine the solubility in transparent vessels.35-37 The vessels equipped with a stir bar rotate at speed of 700 rpm and contained 20 mL ultrapure water at 37 ± 0.5 °C. The initial transmittance of laser scattering through the vessels was recorded as 100% by Avantium Crystalline. Adding a small amount of ATM sample in the solution, the intensity of laser beam was decreased. As the particles of the solute dissolved quickly, the intensity of the laser beam increased gradually. When the laser intensity reached 80% of the maximum, the solution was thought as clear. Then additional solute was introduced into the vessel.



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This procedure was repeated until the penetrated laser transmittance could not recover to 80% over 2 hours. The withdrawn suspension was filtered with a 0.22 µm filter. The sample concentration was determined using a UV-vis spectrophotometer (Varian CARY 50) compared with a standard sample. The same solubility experiment was conducted three times, and each time had good agreement. The estimated uncertainty of the solubility values based on error analysis and repeated observations was within 1.0 %. Computational Methods for Conformation Energy The conformation energy for different ATM conformers were calculated using the Gaussian 09 program.38 The geometries were optimized at the Becke's three-parameter hybrid DFT method39 with the Lee-Yang-Parr correlation functional40 (B3LYP) by using the 6-31G* basis set41 (denoted as B3LYP/6-31G*). By considering the energy as a function of the dihedral angles, the structure was optimized by fixing backbone dihedral angles, and the ab initio energy was obtained. Single-crystal X-ray Diffraction (SXRD). X-ray diffractions of all single crystals were performed at 173(2) K on a Bruker Apex II CCD diffractometer using Mo-Kα radiation (λ = 0.71073 Å) for forms I, II, and HA and Cu Kα radiation (λ = 1.54178 Å) for HB. The collected data integration and reduction were performed with SAINT software,42 and multi-scan absorption corrections were performed using the SADABS program.43 The structures were solved by direct methods using SHELXTL44 and were refined on F2 using the full-matrix least-squares technique in the SHELXL-97 and SHELXL-2014 program package.45 All non-hydrogen atoms were refined with


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anisotropic displacement parameters. The hydrogen atoms of N-H were found using a Fourier difference map and were refined with a fixed distance of 0.86 (0.01) Å and isotropic displacement parameters of 1.50 times the Ueq of the parent atoms. The remaining hydrogen atoms were placed in calculated positions and were refined with a riding model with distances of 0.95 Å (sp2) and 0.98 Å (sp3) with isotropic displacement parameters set to 1.20 (sp2) and 1.50 (sp3) times the Ueq of the parent atom. The crystallographic data and refinement details are summarized in Table 1. Table 1. Crystallographic Data and Structure Refinement Parameters Form I

Form II

HA

HB

C24H24N5O•CH3S

C24H24N5O•CH3 S

C24H24N5O•CH3S

C24H24N5O•CH3SO3

O3

O3

O3•H2O

•1/2 (H2O)

173(2)

173(2)

173(2)

173(2)

Crystal system

Triclinic

Triclinic

Triclinic

Monoclinic

Space group

P-1

P-1

P-1

Cc

a (Å)

9.0053(6)

5.4479(4)

8.6361(5)

8.8831(1)

b (Å)

9.4059(6)

12.8981(9)

9.4346(5)

16.8392(2)

c (Å)

16.4243(9)

17.6634(12)

17.0863(10)

19.2653(2)

α (°)

102.949(4)

74.743(3)

79.507(3)

90.00

β (°)

94.827(4)

81.344(4)

85.010(3)

99.048(10)

γ (°)

114.346(4)

80.495(3)

64.790(3)

90.00

1210.58(14)

1173.48(14)

1238.43(13)

2845.93(6)

Z

2

2

2

4

DClac (g•cm−3))

1.354

1.397

1.356

1.171

Unique reflns

4268

5459

4618

4070

Rint

0.0768

0.0393

0.0425

0.0182

Rsigma

0.0797

0.0371

0.0536

0.0379

S

1.030

1.092

1.071

1.136

R1

0.0846

0.0383

0.0556

0.0814

wR2

0.2560

0.1136

0.1642

0.2140

Formula

Temperature (K)

Cell volume (Å3)



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RESULTS AND DISCUSSION Preparation of Various Forms. A comprehensive crystallization screening protocol, including slurry, evaporation, and cooling in various single or mixed solvents, was conducted to study the polymorphic behavior of ATM (Table S1, Supporting Information). Two anhydrous forms and two hydrates were unambiguously identified by single-crystal diffraction. Polarizing microscope images showed the various polymorphs with different crystal habits (Figure 1). Form I is prism-shaped crystal, whereas form II is trapezoid-shaped and HA is needle-like. Unfortunately, single crystals of HB were obtained by accident, and a powder sample of HB in pure phase could not be obtained because HB transforms to HA promptly under ambient conditions. Microcrystalline samples of the ATM phases were characterized by PXRD to ensure phase identity (Figure 2, characteristic peaks are marked). Form I has characteristic peaks at 10.7, 16.8, 18.6, 20.2, 21.2, 23.1, 24.4, 27.1, and 32.3°, and the characteristic peaks of form II are at 2θ 5.0, 13.7, 15.4, 18.2, 18.9, 21.6, 20.3, 22.2 and 25.0°. HA has characteristic peaks at 10.4, 15.9, 17.4, 20.3, 21.2, 21.9, 25.0, 27.2 and 28.9°, and the characteristic peaks of HB simulated PXRD are at 2θ 9.3, 10.5, 11.3, 14.0, 17.5, 18.8, 20.2, 21.7, 24.6, and 25.4°. All the peaks displayed in the measured patterns of the bulk powder closely matched those in the simulated patterns generated from the single-crystal diffraction data (Figure S1, Supporting Information), confirming the formation of highly pure phases.


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Figure 2. PXRD patterns of the various solid forms of apatinib mesylate. Spectroscopic Analysis. FTIR spectroscopy was used to demonstrate the differences in the N−H···O and C−H···O hydrogen bonding in the solid state. The differences observed in the FTIR spectra of forms I, II, and HA (Figure 3) are in the O−H bond vibration stretching (3072, 3083, and 3079 cm−1 for I, II, and HA, respectively) and in the region of 800-1400 cm−1, corresponding to S=O bond stretching (1027, 1033, and 1029 cm−1 for I, II, and HA, respectively). In addition, HA presents an obvious difference in the O−H bond vibration stretching position at 3438 cm−1. The broad peak indicates the presence of hydrogen-bonding interactions between solvent water molecules and the methanesulfonate ion in HA. The amide NH stretching bands (3342, 3334 and 3342 cm−1 for I, II, and HA) and C≡N stretching bands (2233, 2229, and 2233 cm−1 for I, II, and HA) were identified with similar hydrogen interactions between the amide and cyano groups in forms I and HA, whereas a remarkable difference was found in form II. Characterization of the different solid forms was



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performed by Raman spectroscopy (Figure S2, Supporting Information).46 There is also a distinguishable difference in the carbonyl C=O stretching band, with form I at 1520 cm−1, form II at 1539 cm−1, and HA at 1519 cm−1. Moreover, the peak at 1585 cm−1 in form II splits into two peaks at 1574 and 1595 cm−1 in form I. Meanwhile, forms I and HA show similar Raman signal patterns throughout the frequency range due to the structural similarity. Raman spectroscopy was not as sensitive as FTIR for differentiating the different solid forms of ATM, especially when considering the changes in hydrogen-bonding interactions.

Figure 3. FTIR patterns of ATM forms I, II, and HA. Thermal Analysis. TGA and DSC were performed on the hydrous and anhydrous ATM forms (Figure S3, Supporting Information). The TGA analysis shows a negligible mass loss prior to decomposition for forms I and II, confirming that there is no solvent or water molecules involved. The TGA weight loss of HA is 3.4%, which confirms the ATM and H2O stoichiometric ratio of 1:1 (calculated value: 3.5%). As shown in Figure 4, the melting of form I is observed as a pronounced endothermic


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peak at Tonset of 196.4 °C. The single endothermic peak of form II indicates melting at Tonset of 189.7 °C. However, HA displays two endothermic events, the first broad endothermic peak is at 80 °C due to dehydration. The second endothermic melting peak at 197.7 °C corresponds to the melting onset temperature. PXRD confirmed that HA transforms to form I after dehydration (Figure S4, Supporting Information).

Figure 4. Comparison of the DSC figures of ATM forms I, II, and HA (10 °C/min). The downward peaks represent endothermic behavior. Moisture Sorption Analysis. The dynamic vapor sorption (DVS) isotherms for forms I, II and HA were studied at 25 °C, and the results are summarized in Figure 5. Form transformation was observed during the DVS experiments. The identities of the resulting solid forms were further verified by PXRD under each related humidity condition (Figure S5, Supporting Information). For the two anhydrous polymorphic forms, the moisture content is markedly different with the increment of the relative humidity from 0 to 95% RH. Form I has a water sorption stage between 0% and 30% RH, and the amount of absorbed water (3.59 ± 0.03%) is approximately one molecule



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of water per molecule of ATM, which implies the transformation of form I to HA, as verified by PXRD (Figure S5a, Supporting Information). The DVS of form II shows no pronounced increment in the water content over a relative humidity range from 0 to 75% RH, revealing better hygroscopic stability than form I. As the RH is further increased to 75-80%, the water content of form II increases to 3.52 ± 0.03%, converting to HA. The desorption and sorption curves indicate form II irreversibly transforms to HA depending on the RH (Figure S5b, Supporting Information). The increase in mass at highest RH values (> 80%) should be caused by surface sorption concerning on the size and morphology of powders. HA has very low hygroscopicity throughout the investigated room humidity range. The uptake of water content slightly increases by 0.3 ± 0.02% from 40 to 80% RH and decreases by 3.57 ± 0.03% when the RH is less than 20%, revealing the reversible transition between I and HA depending on humidity level (Figure S5c, Supporting Information). According to DVS, HA is insensitive to humidity change, with a superior stability under ambient conditions (40-80% RH).


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Figure 5. DVS diagrams of various solid forms of ATM: (a) I, (b) II, and (c) HA. Crystal Structures and Mechanism of the Hygroscopicity Difference. Growing suitable single crystals of ATM for structure determination was challenging due to the propensity of both the anhydrate and hydrate phases to form small crystals with poor crystal quality. To overcome these challenges, all single crystals were obtained under precise conditions of solvent and temperature, and the structures were determined at 173(2) K. Forms I, II, and HA crystallized in a triclinic crystal system and space group P-1, whereas HB was in the monoclinic crystal system and space group Cc (Table 1). The crystal structures show that one independent molecule exists in the asymmetric unit of all four solid forms (Figure S6, Supporting Information). The H-bonding parameters of different solid forms are summarized in Table S2 (Supporting Information). 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)). Due to the molecular structure arrangement, intramolecular hydrogen bonding between the O(1) of the sulfonyl


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group and N(2) of the amino group to form a 6-membered ring structure is observed in all four crystal structures (Figure S7, Supporting Information). The basic building block of I is an R22 (18) supramolecular synthon dimer (D1) formed by hydrogen bonds between N(5) in the cyan-group and N(4) in the amide group (N(4)−H(4)···N(5) distance of 3.0757 Å) of adjacent ATM molecules (Figure 6a). The dimer (D1) is linked by the O(3) in mesylate and the N(2) in the amino group (N(2)−H···O(3) distance of 3.1326 Å) to form a one-dimensional (1D) bimolecular layer chain (BLC1) along the a-axis, as shown in Figure 6b. The adjacent BLC1 are held together layer-by-layer in a parallel pyridine ring (B) through weak π···π stacking (centroid–centroid distance of 3.9913 Å) along the c-axis, leading to a two-dimensional (2D) network layer (Figure 6c). The layers are further stacked layer-by-layer via van der Waals interactions along the b-axis (Figure S8, Supporting Information).

(a)



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(b)

(c) Figure 6. (a) The structure of the ATM dimer in form I, (b) 1D bimolecular layer chain (BLC1) along the a-axis, (c) 2D network layer along the c-axis. Form II displays distinctly different packing arrangements to form I. In form II, ATM molecules are linked via S=O···H−N hydrogen bonds between the O(2) in the sulfonyl group and the N(4) in the amide group (N(4)−H···O(2) distance of 2.9731 Å), which develop into a 1D chain (C1) along the b-axis (Figure 7a). Two centrosymmetric C1 chains are hold together and crossed to form a bimolecular layer chain (BLC2) (Figure 7b). Then, BLC2 overlap to form a parallel and dense 2D network along the c-axis (Figure 7c). The complicated 2D networks are stacked layer-by-layer along the a-axis in 3D space (Figure S9, Supporting Information).


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(a)

(b)

(c) Figure 7. (a) The one-dimensional chain structure of form II grows along the b-axis, (b) 1D bimolecular layer chain (BLC2) along the b-axis, (c) 2D network layer stacked with BLC2 along the c-axis. HA has similar conformation and packing patterns to form I. An R 22 (18) supramolecular synthon dimer (D2) is formed via two N···H−N hydrogen bonds between N(5) in the cyan-group and N(4) in the amide group (N(4)−H(4)···N(5) distance of 3.1045 Å). The dimer (D2) develops into BLC3 through hydrogen bonds



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between the O(3) in sulfonyl group and the N(2) in the amino group (N(2)−H···O(3) distance of 3.0554 Å) along the a-axis. However, due to the introduction of water molecules, more complicated H-bond interactions are involved in HA. The water molecules of HA are in a DD (D: donor) environment47 and form a tetrameric R44 (12) with adjacent mesylate moieties via hydrogen interactions with the O(2) and O(4) in two methanesulfonic acid molecules (O(1s)−H···O(2) distance of 2.8276 Å, O(1s)–H···O(4) distance of 2.8791 Å) (Figure 8c). The tetramers are embedded between the hydrophilic mesylate moieties of adjacent BLC3 to form a water channel. BLC3 and the water channel arrange alternately along the c-axis to form a 2D network (Figure 8c). The 3D packing of HA is the overlay of the 2D network through weak π···π stacking (centroid–centroid distance of 4.1795 Å) among parallel pyridine rings (B) along the b-axis, which suggested the water in HA is isolated (Figure S10, Supporting Information).

(a)


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(b)

(c) Figure 8. (a) The structure of the ATM dimer and tetramer in HA, (b) 1D bimolecular layer chain (BLC3) linked along the a-axis, and (c) 2D network layer inside the a-c plane. For HB, the ATM molecules are linked via S=O···H−N H-bonding between the O(4) in the sulfonyl group and the N(4) in the amide group (N(4)−H···O(4) distance of 2.905 Å), which develops into a 1D chain (C2) along the c-axis (Figure 9a). C2 forms a

2D network layer (L2) via hydrogen interactions with the O(3) in the sulfonyl group and the N(2) in the amino group (N(2)−H···O(3) distance of 2.981 Å) along the a-axis (Figure 9b). L2 overlaps along the a-axis in 3D space (Figure 9c). The closest distances between O1s in HB solvent water and N/O atoms are listed in Table S3



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(Supporting Information), which shows no strong H-bond interactions between ATM and solvent water molecules.

(a)

(b)

(c) Figure 9. (a) The 1D chain structure of HB grows along the c-axis. (b) The 2D network layer is linked by H-bond interactions along the a-axis. (c) The 3D layer-by-layer motif is stacked along the b-axis. For clarity, water solvent molecules in (a) and (b), and water hydrogen atoms in (b) are omitted.


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The

free rotation along C(2)−C(12) and C(6)−C(7) provides conformational

flexibility in the ATM molecular structure. Therefore, the overlays of the four symmetry-independent molecules from the crystal structures are shown in Figure 10, where solvate H2O, mesylate anions and hydrogens are removed. The structure overlays were based on the pyridine ring A plane, which revealed that the backbone N(1)-ring A-C(12)-N(4)-ring C of I, HA, and HB share similar conformations but with differences at both ends (Figure 10a). The torsion angles between the terminal pyridine rings B and A of forms I, HA, and HB are measured by N(2)–C(6)–C(7)–C(8) (approximately -151.73, 0.05, and -13.43°). Meanwhile, the torsion angle between the terminal 5-membered ring D and benzene ring C in the backbone is similar, as measured by C(21)–C(19)–C(18)–C(17) (approximately 94.05, 94.67, and 94.11°). The conformation of form II (blue) is evidently different from those of the three other states, and the substantial overlay figure of forms I and II is shown in Figure 10b. The torsion angles of forms I and II (approximately 22.52 and -22.40° along O(1)–C(12)– C(2)–C(1)) and the dihedral angle between rings A and C (approximately 56.63° for I, -53.39° for II) revealed the carboxamide group and ring C conformations in forms I and II are symmetrical with respect to ring A. The torsion angles between terminal rings B and A of forms I and II are measured by N(2)−C(6)–C(7)–C(9) (approximately 32.12 and 25.92°). The conformational energy for forms I and II were calculated using the Gaussian 09 program (EI, co= -801924.64 Kcal/mol for form I and EII, co = -801925.32 Kcal/mol for form II). Small energy difference was found between the conformers (∆EII-I, co = EII, co-EI, co= -0.68 Kcal/mol).2



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(a)

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(b)

Figure 10. Overlays of unique molecules in the crystal structures of (a) forms I (green), HA (red), and HB (yellow), (b) forms I (green) and II (blue). Solvate H2O, mesylate anions, and hydrogens were removed. According to DVS (Figure 5), forms I and II convert to HA at RH 25% and 75%, respectively. An analysis of the crystal structures of forms I, II and HA suggests the different hygroscopicity may be caused by the discrepant molecule conformations, interaction codes, and packing arrangements. Form I has similar conformation, interaction code, and packing arrangement to HA but is substantially different than II. The ability of the salt to absorb water appears to be due to the layered structure, which may permit the diffusion of water molecules into the crystal lattice.13 The hydration of form I to HA occurs via diffusion of water molecules through the hydrophilic anion layers of the crystal lattice, resulting from only minor reorientation of the BLC to maintain crystallinity (Figure 11). The hydration of form II to HA is more difficult than that of form I. The introduction of water molecules disrupting the hydrogen interactions12 promotes the conversion of form II to that of HA through the significant rotation of the C(1)−C(2) bond and N(4)−C(13) bond. Moreover, due to the stabilization of the H-bond (N(4)−H(4)···N(5)) to the inner hydrophobic moiety in BLC1, BLC1 is can easily compress and slide to provide enough voids in the


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hydrophilic moieties to contain water molecules (Figures 6c and 8c). In contrast, no H-bond interaction (N(4)−H(4)···N(5)) exists due to the conformation rotation, so a more close-packed arrangement in form II is found. The calculated density and packing efficiency of form II are 1.397 g•cm−3 and 73.13%, respectively. These values are higher than those of form I (1.354 g•cm−3 and 70.89%, respectively). The solid-state stability benefits from the higher density and packing efficiency; hence, II is more stable than I with respect to hygroscopicity. The density and packing efficiency of HA and HB were calculated as 1.356, 72.42% and 1.171, 63.05% respectively. The fact that HA is more stable than HB may be explained by the lager packing efficiency with HA crystals.

Figure 11. Molecular conformation and packing model in forms I (left), HA (middle), and II (right). Form I is easily transformed to HA due to their similar conformation and packing patterns, while obvious differences are observed with form II. Phase Transition between Different Forms. The thermodynamic data of forms I and II are summarized in Table S4 (Supporting Information). According to the Heat of Fusion Rule,48, 49 the relationship between forms I and II is enantiotropic polymorph. On the basis of Eq.1 (Supporting Information),48 the transition temperature (Ttr) was calculated as 135.3 °C. Although no distinguishable exothermic or endothermic transition peak occurred in the DSC diagram before the melting point, solvent



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mediated phase transition (SMPT)50 was performed to investigate the relative thermodynamic stability of forms I and II. The experiment result was consistent with the enantiotropic relationship of I and II. When slurrying a 1:1 physical mixture of forms I and II in isopropanol at 50 and 70 °C for three days, the PXRD results show the physical mixture transformed to form II under both conditions. As shown in Figure 12, the characteristic peaks of form I at 2θ = 10.7 and 16.8° disappeared, indicating form I transformed to II (characteristic peaks of form II at 2θ = 5.1, 18.2°). The transition experiment at elevated temperature (> 135 °C) was performed by holding physical mixture of forms I and II (1:1) at elevated temperatures ( e.g. 140 and 150 ℃) for 12 h using an oven (Figure S11, Supporting Information). Although new PXRD peaks were identified in the resulted material, they are not related to either form I or II, indicating potential new phase formed in the mixture. The PXRD patterns (Figure 13) also show that forms I and II transformed to HA at relative humidity of 20% and 80%, and HA transformed to form I, which confirmed the DVS results. After heating HA powder sample at 35 and 50 °C, the PXRD shows that HA transformed to form I via complete dehydration at 50 °C (Figure S4, Supporting Information). After slurrying HA powder sample in isopropanol at 50 °C, the PXRD shows that HA powders transform to form II after three days (Figure S12, Supporting Information). According to the enantiotropic relationship between I and II, form II is more stable at 50 °C. HA can transform to two anhydrous forms via different transformation pathways. The transition from HA to form I was dehydration upon SSPT as a result of dynamic priority. SSPT of HA to Form I may include a


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martensitic transformation processes, without diffusion of the molecular species, with a portion of the original phase information preserved in the final phase.51 The single-crystal structure of form I is isomorphic to that of HA, and form I can be viewed as related to HA by removing the water molecules. The transformation from HA to form II is a thermodynamic process via SMPT52 because form II is thermodynamically stable at 50 °C compared with form I. SMPT involves three steps: (1) dissolution of a metastable form, (2) nucleation of the stable form, and (3) growth of the stable form. Dissolution of HA and precipitation of form II via slurrying in isopropanol at 50 °C promoted the transformation of HA to form II completely when reaching a thermodynamic equilibrium state. HB is unstable in an atmospheric environment and transforms to HA. A stability study for various solid states under accelerated ICH conditions was performed to confirm their stability. Bulk powders were held at 40 °C and 75% RH for 10 weeks. The PXRD patterns indicated no form change for HA (Figure S13, Supporting Information), whereas forms I and II transformed to HA after ten weeks. The complicated phase transformation relationship among the two anhydrous polymorphs and monohydrate was established (Scheme 2), suggesting that HA is the most stable form under ambient conditions.



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Figure 12. PXRD patterns: a 1:1 physical mixture of forms I and II (black), transformation of a 1:1 physical mixture of forms I and II to form II by slurrying at 50 °C (red) and 70 °C (green) in isopropanol after three days, and form II (blue).

Figure 13. PXRD patterns of forms I and II at 30% and 80% RH converting to HA, respectively, and HA converting to form I at 10% RH.


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Scheme 2. ATM solid forms transition relationship. Solubility Measurement by Dynamic Laser Scattering. It was found that ATM is prone to convert to free base in aqueous solution. The various solid forms of ATM may also transfer to corresponding hydrate forms when slurred in water for extended amount of time. In order to access the differences in aqueous solubility for the new discovered solid forms, a maximum solubility was determined at 37 ± 0.5 °C, as described in the experimental section. A small amount of sample powder was added into the solution stepwise until no more solid can be dissolved. By keeping the least amount of solid in solution, this method provides a viable approach to determine a maximum solubility while avoiding complicate form transition may happen to the excess amount of metastable powder during solubility measurements. A standard curve of the ATM concentrations and UV absorbance was determined using a UV-vis spectrophotometer at 260 nm (Figure S14, Supporting Information). The solubility measurements conducted on forms I, II, and HA reveal that the anhydrate form I has better water solubility than forms II and HA (Figure S15, Table S5 in Supporting Information). The solubility of form I is 2.38 and 1.99 times as that of forms II and



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HA, respectively. This trend is consistent with the relative thermodynamic stability relationship among different polymorphs, where the least stable polymorph (form I) presents the highest solubility. CONCLUSIONS In the present study, two anhydrous polymorphs, a monohydrate and a hemihydrate of ATM were discovered. The crystal structures of all the solid forms were determined by single-crystal X-ray diffraction, and their physiochemical relationships were established. The transformation pathways among the two anhydrates and monohydrate were discussed in detail. The transitions from forms I and II to HA based on hygroscopicity were inferred from different transition mechanism due to the discrepant molecule conformations, H-bond interaction codes, and packing arrangements in the crystal structures. The transition pathways for the dehydration of HA to forms I and II were identified as SSPT and SMPT process, respectively. The results of the hygroscopic and thermodynamic stability tests revealed that HA is the most stable to humidity under ambient conditions; therefore, it is suitable for drug development. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: Additional data and figures (PDF) X-ray crystallographic data (CCDC 1480030) (CIF) X-ray crystallographic data (CCDC 1480067) (CIF)


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X-ray crystallographic data (CCDC 1480078) (CIF) X-ray crystallographic data (CCDC 1480088) (CIF) AUTHOR INFORMATION Corresponding Author *E-mail address: [email protected] (X. Mei); [email protected] (G. Ren). Notes 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), and CAS Key Technology Talent Program for funding. We also thank the supports from the National Natural Science Foundation of China (No. 21576080).

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For the Table of Contents Only Polymorphs and Hydrates of Apatinib Mesylate: Insight into the Crystal Structure, Properties and Phase Transformation Bin Zhu,a Jian-Rong Wang,b Guobin Ren,*a and Xuefeng Mei*b TOC GRAPHIC

SYNOPSIS Two anhydrates and two hydrates were discovered and were structurally elucidated by single-crystal X-ray diffraction. The transformation pathways among these solid forms were revealed and discussed.


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Polymorphs and Hydrates of Apatinib Mesylate: Insight into the Crystal

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