Isostructurality Among Solvates of Cabazitaxel: X-ray Structures and New Solvates Preparation

RESEARCH ARTICLE – Drug Discovery-Development Interface

Isostructurality Among Solvates of Cabazitaxel: X-ray Structures and New Solvates Preparation WEI XU,1 NINGBO GONG,1 SHIYING YANG,1 NA ZHANG,2 LAN HE,2 GUANHUA DU,3 YANG LU1 1

Beijing City Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China 2 National Institutes for Food and Drug Control, Beijing 100050, China 3 Beijing City Key Laboratory of Drug Target and Screening Research, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China Received 17 November 2014; revised 3 January 2015; accepted 12 January 2015 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24374 ABSTRACT: Cabazitaxel is an anticancer drug and its marketed product (form A) is acetone solvate (1:1) (Didier E, Perrin MA. 2005. Patent WO2005/028462 A1). This work describes three crystal structures of cabazitaxel 1:1 solvates with isopropyl alcohol (B), 2-butanol (C), and dioxane (D). These solvates are isostructural with cabazitaxel forming a host framework through hydrogen bonds and the guest solvent molecules located in channels from which they can escape. The host is hydrogen bonded to each other through hydroxyl O1 and sec-amide N3  , whereas the hydroxyl O2  plays an important role in connecting the host to the guest. Moreover, because of the existence of channels in the crystal structure, the solvent-replacement method was established to prepare four new solvates of cabazitaxel with dimethyl formamide (E), cyclohexane (F), n-hexane (G), and ethyl ether (H). All the seven solvates involved in this work were proven to be isostructural by methods of X-ray crystallography and contain the same amount of solvents by thermogravimetric analysis. The single-crystal structures of C 2015 Wiley Periodicals, solvate C–E and the solvates prepared by solvent-replacement method have been reported for the first time.  Inc. and the American Pharmacists Association J Pharm Sci Keywords: cabazitaxel; isostructurality; solvate; crystal structure; X-ray powder diffractometry; thermogravimetric analysis; pseudopolymorph

INTRODUCTION Cabazitaxel (2",5$,7$,10$,13")-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylprop anoyl}oxy)-1hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate, CASRN:183133-96-2) is a semisynthetic taxane that uses a precursor molecule extracted from yew tree needles.1–3 Its antitumor activity has been shown to promote assembly and stabilization of microtubules, blocking tumor cell division,4 and inhibiting tumor cell trafficking.5,6 Furthermore, it can effectively inhibit cell lines with acquired resistance against docetaxel7,8 and is potentially active in patients with cerebral or leptomeningeal metastatic disease.9 Cabazitaxel (Jevtana@ ; Sanofi–Aventis) has been approved in the USA in June 201010 and in Europe in January 201111 in combination with prednisone for the treatment of patients with castration-resistant metastatic prostate cancer whose disease progresses after docetaxel treatment. Molecular structure of cabazitaxel with atomic numbering is shown in Figure 1. The marketed product (form A) of cabazitaxel is acetone solvate (1:1),12 and other solid forms such as the amorphous form,13–17 anhydrates, and18–22 solvates21–27 of nearly 30 different kinds of organic solvents have been reported earlier. Almost all the literature references focus on the preparations and identifications of polymorphs, little is known about the crystal strucCorrespondence to: Yang Lu (Telephone: +86-10-63165212; Fax: +86-1063165212; E-mail: [email protected]); Guanhua Du (Telephone: +86-10-63165184; Fax: +86-10-63165184; E-mail: [email protected]) Journal of Pharmaceutical Sciences

 C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association

tures except the isopropyl alcohol (IPA) solvate.24 However, this IPA solvate is not available in the CSD (version 1.8) and only the unit cell parameters were published in the relevant patent. Therefore, the crystal structure of IPA solvate was investigated in this work and deposited with CCDC, which has the same unit cell parameters with the reported one. As the marketed product (form A) was identified simply by X-ray powder diffraction analysis (XRPD) in the relevant patent,1 single-crystal X-ray diffraction (SCXRD) was used to further characterize form A. Although the crystallographic data of form A is not good enough to be deposited with CCDC, the basic structure information is ˚ b = 17.406(2) A, ˚ c clear: space group is P21 with a = 11.891(4) A, ˚ $ = 109.927(6)°, which is obviously isostructural = 12.535(4) A, with all the seven solvates described in this work. As structural information derived from an X-ray diffraction study of a single crystal is the most fundamental description of a polymorph or solvatomorph, and helps to explain formation reasons for polymorphism or solvatomorphism at the atomic scale, three crystalline forms of cabazitaxel with IPA (B), 2butanol (C), and dioxane (D) are described in this present work. Isostructurality occurs among these solvates with cabazitaxel molecules forming a framework and solvent molecules residing in the channels. The hydroxyl O1 , O2  , and sec-amide N3  play an important role in the hydrogen-bonding interactions. Moreover, according to the channels existing in the crystal lattice, the solvent-replacement method was established to prepare four new solvates of cabazitaxel with DMF (E), cyclohexane (F), n-hexane (G), and ethyl ether (H). X-ray crystallography and thermogravimetric analysis (TGA) were introduced into the characterizations of these new solvates, which prove Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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Figure 1. Molecular structure of cabazitaxel with atomic numbering.

the feasibility of the solvent-replacement method applying to the new solvates preparation of cabazitaxel. The single-crystal structures of solvate C–E and the solvates prepared by solventreplacement method have been reported for the first time.

EXPERIMENTAL Materials Cabazitaxel with the purity value greater than 98.5% was purchased from Dalian Melone Biotechnology Inc. (batch number: MB14031303; Liaoning, China) and proven to be anhydrous by TGA. Analytical grade solvents purchased from Sinopharm Chemical Reagent Company Ltd. (Shanghai, China) were used for the experiments. Single crystals of samples were obtained by slow evaporation of cabazitaxel-saturated solutions from IPA– ethanol mixture (3:2, v/v), 2-butanol–THF mixture (2:1, v/v), and dioxane–water mixture (1:1, v/v), respectively, at 10°C over 20 days. X-ray Powder Diffraction Analysis Powder samples were identified using a Rigaku D/MAX-2550 diffractometer with Cu K" radiation (Rigaku, Tokyo, Japan) at room temperature. The voltage and current applied were 40 kV and 150 mA, respectively. Diffraction patterns were collected over a range of 3°–80° 22 at a scan rate of 8° 22/min. Samples were placed on the quartz glass sample holder that has 0.1 mm thickness and 2.0 cm diameter. Samples were ground into fine powders to eliminate preferred orientation, but vigorous grinding was avoided to minimize potential phase transformations or solvent loss at room temperature. The JADE software (Rigaku) and OriginPro 8 (OriginLab Corporation, Northampton, Massachusetts) were used for further processing and plotting the XRPD patterns, respectively. Single-Crystal X-ray Diffraction X-ray diffraction patterns were collected on a Rigaku MicroMax-002+ diffractometer using Cu K" radiation (8 = ˚ Rigaku Americas, The Woodlands, Texas) with a 1.54187 A; CCD detector. Data were processed using the CrystalClear software package (Rigaku Americas) with structure solution and Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

refinement using SHELXS.28 The structures were solved by direct methods and refined by full-matrix least-squares on F2 . For each structure, the nonhydrogen atoms were refined anisotropically, whereas the hydrogen atoms were refined isotropically. Hydrogen atoms were placed in idealized positions and refined in a riding model with Uiso values 1.2–1.5 times those of their parent atoms. Elongated anisotropic displacement parameters (ADPs) were found in the terminal methyl groups and solvent molecules; thus, suitable restraints were applied to the refinement of disorders to help data convergence.29 The volume of the channels in which the solvent molecules reside, was carried out ˚ 30 using the program PLATON with probe size of 1.2 A. Thermogravimetric Analysis Thermogravimetric analysis was performed using a Mettler Toledo DSC/TGA 1 instrument (Mettler Toledo, Greifensee, Switzerland), which confirmed the stoichiometry of host and guest for solvates. Mass losses were recorded using 6–10 mg samples heated from 30°C to 500°C at 10°C/min in open aluminum crucibles purged with a nitrogen flow of 50 mL/min. Solvent-Replacement Method According to the single-crystal structure analysis of solvates B–D, cabazitaxel has a considerable ability to form a framework with solvent molecules residing in the channels, which suggests that a variety of solvent molecules could be accommodated. Thus, the solvent-replacement method was established to obtain new solvates of cabazitaxel. The operating steps of this method are as follows: first of all, excess amounts of cabazitaxel were suspended in single solvent. DMF, cyclohexane, nhexane, and ethyl ether are chosen as target solvents in consideration of eliminating all the reported solvates. Then, the suspension was slurried for a day at room temperature with a constant stirring rate. At last, the suspension was filtered and the wet filter cake was the target solvate that needs to be airdried before further identification. The filtrate was stored at 10°C and crystalline samples with prism shaped were obtained from DMF and ethyl ether, respectively. The new solvates prepared by solvent-replacement method are named as E (DMF), DOI 10.1002/jps.24374

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Table 1. Crystallographic Data and Experimental Details for Solvates of Cabazitaxel Empirical formula Formula weight (Da) Crystal form Color Crystal size (mm3 ) Temperature (K) Crystal system Space group ˚ a (A) ˚ b (A) ˚ c (A) " (°) $ (°) ( (°) Z ˚ 3) Volume (A dcalcd (g/cm3 ) F (0 0 0) Abs coeff (mm−1 ) Theta range for data collection (°) Reflections collected Independent reflections Goodness-of-fit on F2 Rint Final R, wR(F2 ) values [I>2F(I)] Final R, wR(F2 ) values (all) Flack parameter Completeness (%) CCDC deposition number

B (IPA) C45 H57 NO14 ·C3 H8 O

C (2-Butanol) C45 H57 NO14 ·C4 H10 O

D (Dioxane) C45 H57 NO14 ·C4 H8 O2

E (DMF) C45 H57 NO14 ·C3 H7 NO

896.01 Prism Colorless 0.60 × 0.64 × 0.96 295(2) Monoclinic P21 11.807(4) 17.339(5) 12.610(4) 90 108.121(10) 90 2 2453.5(13) 1.213 960 0.741 3.69–72.40 24,026 6654 1.046 0.0478 0.0443, 0.1186 0.0460, 0.1214 0.01(14) 97.1 1,032,507

910.04 Prism Colorless 0.20 × 0.28 × 0.81 295(2) Monoclinic P21 11.834(3) 17.330(9) 12.614(3) 90 107.360(5) 90 2 2469.1(15) 1.224 976 0.744 3.67–72.31 21,822 6887 1.050 0.0474 0.0451, 0.1194 0.0483, 0.1250 0.02(14) 96.8 1,032,525

924.02 Prism Colorless 0.14 × 0.40 × 0.95 295(2) Monoclinic P21 11.950(3) 17.399(9) 12.573(3) 90 109.800(5) 90 2 2459.6(15) 1.248 988 0.771 3.74–72.34 21,570 6942 1.011 0.0719 0.0520, 0.1250 0.0580, 0.1334 0.10(17) 96.6 1,032,535

909.01 Prism Colorless 0.23 × 0.42 × 0.59 295(2) Monoclinic P21 11.951(5) 17.393(6) 12.509(5) 90 108.649(7) 90 2 2463.7(17) 1.225 972 0.752 3.73–72.43 20,892 7999 1.079 0.0406 0.0462, 0.1253 0.0495, 0.1311 0.07(14) 98.3 1,032,536

F (cyclohexane), G (n-hexane), and H (ethyl ether) following the alphabet sequence of solvates B–D.

RESULTS AND DISCUSSION Crystal Structure Analysis Cabazitaxel is a large (molecular formula C45 H57 NO14 and formula weight 835.95 Da), conformationally flexible molecule and consists of 11 chiral centers. The molecule contains two hydroxyls, one sec-amide NH conventional hydrogen bond donor and a variety of oxygen acceptors, which are available for hydrogen-bonding interaction. Chemical, crystallographic, and refinement parameters of solvates B–D are listed in Table 1. Isostructurality is obvious among solvates B–D with the same cabazitaxel–solvent ratio (1:1), monoclinic P21 space group, formula units per cell (Z = 2), and similar unit cell parameters.31 The density of solvates B–D are relatively low (1.2 g/cm3 ), which suggest that voids may exist in the crystal lattices. The absolute structures of solvates B–D were confirmed with the flack parameters refined as 0.01(14), 0.02(14), and 0.10(17), respectively.32 The taxane skeleton ring A–B–C of cabazitaxel shows a boat, chair–boat, and envelope conformation. The carbon atoms of the oxetan ring (D) almost lie in a plane with an oxygen atom O20 lying out of the theoretical calculating plane ˚ (solvate B) and the minwith the maximal deviation of 0.167 A ˚ imum deviation of −0.182 A (solvate D). Ring B and C is transconnected, whereas C and D is cis-connected. The C13 side chain is folded with the tert-butyl group positioned closer to the taxane skeleton while the phenyl group placed farthest from the DOI 10.1002/jps.24374

taxane skeleton. The C2 benzoate extends away from the taxane ring structure in opposite direction approximately perpendicular to the direction of the C13 side chain, and the C4 acetate points away from the C2 benzoate group with the acetate carbonyl oxygen positioned over the U-shaped pocket formed by the rigid taxane ring structure. A careful analysis of the conformational differences revealed that all the conformers found in the solvates show similar conformations with each other. The orientation of tert-butyl and methoxyl may be slightly varying because of single-bonding rotations, which contributes to the relatively high thermal motion observed in these corresponding groups. In all the three solvates, the cabazitaxel molecules form a host framework through hydrogen bonds and the guest solvent molecules occupy the channels along the [010] direction. The adduction of various solvents does not affect the packing arrangement, with the solvent molecules serving merely to fill the channels between the drug molecules. These similarities indicate isostructurality among the various solvates. The hydrogen-bonding interactions in these solvates consist of weak hydrogen bonds and conventional hydrogen bonds. The weak hydrogen bonds via C–H . . . O have relatively long D . . . A distances and narrow D–H . . . A angles (110°), which only contribute to fairly weak intramolecular interactions; thus, they are not considered as effective forces in the structure stabilization. The conventional hydrogen bonds via O–H . . . O and N–H . . . O contribute significantly to sustain the architecture, so we make a detailed description of them in the following. Geometric parameters of conventional hydrogen bonds are given in Table 2. Packing diagrams with hydrogen-bonding motifs Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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˚ °) of Hydrogen Bonds for Solvates B–D of Cabazitaxel Table 2. Geometric Parameters (A, Solvate

D–H . . . A

˚ d(D–H) (A)

˚ d(H . . . A) (A)

˚ d(D . . . A) (A)

(DHA) (°)

B (IPA)

N3  –H3  A . . . O5 a O1 –H1A . . . O41 b O2  –H2  A . . . O1I c O1I –H1IA . . . O7 N3  –H3  A . . . O5 d O1 –H1A . . . O41 e O2  –H2  A . . . O1B f O1B –H1BA . . . O7 N3  –H3  . . . O5 g O1 –H1 . . . O41 h O2  –H2  . . . O1 

0.86 0.82 0.82 0.82 0.86 0.82 0.82 0.82 0.86 0.82 0.82

2.275 2.264 2.084 2.025 2.255 2.260 2.079 2.038 2.273 2.323 2.175

3.10 2.99 2.86 2.83 3.09 2.98 2.86 2.84 3.09 3.05 2.64

160.72 147.99 158.96 168.57 165.09 147.48 159.29 165.40 158.99 147.27 116.36

C (2-butanol)

D (dioxane)

a

x, y, z+1. −x, y−1/2, −z. x, y, z+1. d x, y, z−1. e −x−2, y−1/2, −z. f x, y, z−1. g x, y, z−1. h −x, y−1/2, −z+2. b c

Figure 2. Part of the crystal structure for solvates B–D showing the chain along [001] and the chain along [010] with hydrogen-bonding motifs. Solvent molecules are shown as wireframe model for clarity and hydrogen bonds are indicated with blue broken lines. Left to right: (a) solvate B—IPA; (b) solvate C—2-butanol; and (c) solvate D—dioxane.

viewed along crystallographic a-axis are shown in Figure 2. The frameworks formed by cabazitaxel molecules are similar among all the solvates, which are assembled with the same hydrogen-bonding interactions. In one direction, the sec-amide N3  –H3  A donor is involved in N3  –H3  A . . . O5 hydrogen bond˚ with cyclic ether oxygen of translated cabazitaxel ing (3.10 A) chain along [001]. This increased hydrogen-bonded distance is likely associated with the distortions caused by the proximity of the tert-butoxycarbonyl on the C13 side chain and C2 benzoate substituent on the taxane ring between the adjacent cabazitaxel molecules.33 In another direction, the hydroxy O1 acts as a hydrogen-bond donor to carbonyl O41 , which produce a simple spiral chain along [010] that is generated by the 21 screw axis. The propagation of these hydrogen-bonding interactions leads to the formation of an infinite two-dimensional network of sheets running parallel to [011] plane. Neither hydrogen bonds nor aromatic B–B stacking interactions are identified between these sheets; thus, the van der Waals interactions contribute most to the sheets accumulation. The channels formed by the molecular framework of cabazitaxel are embedded between these sheets. Layered structures of the solvates with Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

solvent molecules located in the channels between the layers and space-filling representation of the molecules of cabazitaxel with the continuous channels are shown in Figure 3. The solvents incorporated in solvates B–D can be grouped into two categories based on their hydrogen-bonding properties: (1) alcohols—IPA and 2-butanol; (2) ethers—dioxane. In the former category, solvent molecules bridge the hydroxyl O2  of one cabazitaxel and methoxyl O7 of adjacent translated cabazitaxel along [001]. Whereas in the latter category, no hydrogen bond is observed between cabazitaxel and the solvent, the hydroxyl O2  gives its proton to carbonyl O1  to form intramolecular hydrogen bond so as to successfully make all the OH conventional donors to be involved in the hydrogen bonding. The analysis of intermolecular interactions between the host and guest molecules suggests that the hydroxyl O2  of cabazitaxel plays an important part in hydrogen bonding to the guest molecule. The additional hydrogen bonds imposed upon the cabazitaxel structures by the presence of solvent merely serve as supplementary binding forces, which do not lead to any intermolecular arrangement change. The adducted solvent is regarded as a space filler, which plays a vital role in stabilizing crystal lattices. The DOI 10.1002/jps.24374

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Figure 3. Upper row: layered structures of solvates B–D with solvent molecules located in the channels between the lays viewed down crystallographic c-axis. Solvent molecules are represented by spheres corresponding with the van der Waals radii of the respective atoms. Hydrogen atoms are omitted for clarity. Left to right: (a) solvate B—IPA; (b) solvate C— 2-butanol; and (c) solvate D—dioxane. Lower row: spacefilling representation of cabazitaxel showing the continuous channels along [010] viewed down crystallographic b-axis. Cabazitaxel molecules are represented by spheres corresponding with the van der Waals radii of the respective atoms. Solvents are omitted for clarity.

solvent atoms are disordered in these solvates, which may arise from the fact that the solvent does not fit tightly enough in the available void with poor host–guest interactions. The alteration of solvent molecules adducted in the crystal lattice brings about almost no volume distinctions. The calculated volume of solvent-accessible voids in solvates B–D is ˚ 3 , accounting for approximately 15.3%, 376.2, 384.4, and 380.7 A 15.6%, and 15.5% of the unit-cell volumes, respectively. The expected volumes of small solvent molecules (e.g., toluene) are ˚ 3 . Therefore, combined with the results of hydrogen100–300 A bonding interaction analysis, almost all the conventional solvents can be incorporated into the channels regardless of the capability to form hydrogen bonds with the host framework of cabazitaxel. Single crystals of solvate E and H were obtained by solventreplacement method. However, the crystal quality of solvate H did not allow a determination by SCXRD, only the structure data of solvate E was obtained. Chemical, crystallographic, and refinement parameters of solvate E are listed in Table 1. In comparison with solvates B–D, they are isostructural with the same P21 space group, cabazitaxel–solvent ratio (1:1), formula units per cell (Z = 2), similar unit cell parameters, comformation, crystal packing, hydrogen-bonding interactions, and channels in the respective unit cell. Parameters of hydrogen bonds DOI 10.1002/jps.24374

˚ for solvate E are as follows: N3  –H3  A . . . O5 (x, y, z−1): 3.05 A, ˚ O2  –H2  A . . . O1D : O1 –H1A . . . O41 (−x+1, y−1/2, −z+1): 3.05 A, ˚ Although DMF is lack of hydrogen-bonding donor atoms, 2.74 A. the carbonyl oxygen atom can perform as a proton acceptor accepting proton from hydroxyl O2  of cabazitaxel, which further demonstrates the significance of hydroxyl O2  in connecting the host to the guest. The calculated volume of solvent-accessible ˚ 3 , accounting for approximately voids in solvate E is 373.4 A 15% of the unit-cell volume as well as solvates B–D. XRPD Analysis The experimental XRPD patterns of all the seven solvates studied in this paper are compared with each other in Figure 4, which suggests that all the seven solvates are isostructural as they have several major peaks at very similar angular locations. Over the range of 5°–10° 22 of these solvates, the d-spacings of the three most intense peaks are nearly the same with approxi˚ corresponding to the lattice planes mately 11.9, 11.3, and 8.6 A (0 0 −1), (1 0 0), and (1 1 −1), respectively, which indicate the similarities in the a-dimension, b-dimension, and c-dimension of the unit cell in the various solvates. Therefore, the remarkably similar topologies of XRPD patterns imply that if the crystallographic data of solvates F–H can be obtained, they should Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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Figure 4. Comparison of the zoomed experimental XRPD patterns of solvates B–H. The experimental XRPD patterns of solvates B–H are indicated with gray, orange, pink, green, blue, red, and black, respectively. Top to bottom: solvate B—IPA, solvate C—2-butanol, solvate D—dioxane, solvate E—DMF, solvate F—cyclohexane, solvate G—nhexane, and solvate H—ethyl ether.

have the same P21 space group, similar unit cell parameters, and crystal packing as well as solvates B–E. Several subtle peak shifts may arise from the minor differences in the a-dimension, b-dimension, c-dimension, and angle $ of the unit cells of the various solvates.34 Furthermore, the prism-shaped crystals obtained from crystallization were grinded before test. Then the fragmented samples were obtained after grinding, which may be of the same shapes as the original crystals and bring about several subtle peak shifts. Thermogravimetric Analysis The solvent ratios of all the seven solvates are obtained from weight loss measurements by TGA. The determined values of mass loss (w/w) are 6.56% (B), 7.26% (C), 8.28% (D), 7.05% (E), 8.47% (F), 8.62% (G), and 7.38% (H), corresponding to the calculated stoichiometric ratios (guest/host) of 1.0 (B), 0.9 (C), 0.9 (D), 0.9 (E), 0.9 (F), 0.9 (G), and 0.9 (H), respectively, which further demonstrates that the cabazitaxel–solvent ratio is 1:1 in all the seven solvates. TGA profiles are shown in Figure 5.

CONCLUSIONS Cabazitaxel exhibits great ability to form solvatomorphs and may be crystallized as a solvated form from a large number of polar or nonpolar solvents. So far, the solvated forms of cabazitaxel have been the only crystalline form suitable for crystal structure determination by means of SCXRD. Crystallization of cabazitaxel from different solvents results in the formation of three monosolvates with IPA, 2-butanol, and dioxane. All the three solvates are isostructural with the same P21 space group, similar unit cell parameters, and crystal packing in the respective unit cell. In all the three crystal structures, cabazitaxel molecules form a host framework and the solvent molecules are residing in the channels along [010]. The hydroxyl O1 , O2  , and sec-amide N3  play an important role in the hydrogen-bonding interactions. The calculated volumes of solvent-accessible voids Xu et al., JOURNAL OF PHARMACEUTICAL SCIENCES

Figure 5. Zoomed TG profiles of solvates B–H. Profiles of solvates B–H are indicated with gray, orange, pink, green, blue, red, and black, respectively. Top to bottom: solvate B—IPA, solvate C—2-butanol, solvate D—dioxane, solvate E—DMF, solvate F—cyclohexane, solvate G— n-hexane, and solvate H—ethyl ether.

in these solvates are nearly the same, and the crystal packing does not depend on the nature of the solvent molecules, which perhaps signifies that in the nucleation stage the channel is first formed by the molecular framework and the guest molecules have a simple space-filling role. On the basis of channels existing in the crystal structures, the solvent-replacement method was established to obtain new solvates of cabazitaxel with DMF, cyclohexane, n-hexane, and ethyl ether, respectively, and fortunately the crystallographic data of solvate with DMF were obtained. Characterizations by X-ray crystallography and TGA suggest the isostructurality among all the seven solvates and the feasibility of solventreplacement method in an attempt to discover novel solvates of cabazitaxel. As one of the taxane family members, docetaxel also shows remarkable ability to form solvatomorphs. Interestingly, the solvates of docetaxel are also isostructural with docetaxel molecules forming a host framework while solvent molecules residing in channels,35 which suggests that more solvates of docetaxel may be obtained by the solvent-replacement method as well as cabazitaxel. To sum up, the taxanes may all possess the power to form channels and take in solvents as a result of the rigid taxane skeleton and the flexible side chains. The research results in this paper can provide references for solvatomorphic investigations of compounds belonging to taxanes. Furthermore, compared with the marketed form A (acetone monosolvate) of cabazitaxel, some solvated forms may have less drug toxicity or better treating activities and have great potential to become the alternative drug in clinical treatment.

ACKNOWLEDGMENTS We thank the Ministry of Science and Technology of the People’s Republic of China for the National Science (grant no. 2012ZX0930101002-001-013), Technology Major Projects (grant no. 2013ZX09102110), and the General Administration of Quality Supervision, Inspection, and Quarantine of the DOI 10.1002/jps.24374

RESEARCH ARTICLE – Drug Discovery-Development Interface

People’s Republic of China for the Special Scientific Research Project of Public Welfare (grant no. 2012104008-1-14).

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