The Devil is in the Detail: A Rare H-Bonding Motif in New Forms of

Sep 10, 2013 - We also report the crystal structures of two docetaxel hydrates (the new monohydrate DOW and the full structural details, including ato...
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The Devil is in the Detail: A Rare H‑Bonding Motif in New Forms of Docetaxel Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju. Liana Vella-Zarb,†,‡ Robert E. Dinnebier,† and Ulrich Baisch*,§ †

Max Planck Institute for Solid State Research, Heisenbergstrasse 1, D-70596 Stuttgart, Germany Department of Chemistry, Durham University, South Road, Durham DH1 3LE, United Kingdom § School of Chemistry, Newcastle University, Bedson Building, Newcastle-upon-Tyne NE1 7RU, United Kingdom ‡

S Supporting Information *

ABSTRACT: Docetaxel is a semisynthetic analog of the taxane paclitaxel, pivotal for the treatment of various types of cancer. Minor differences in its chemical structure give docetaxel a slightly better water solubility profile when compared to paclitaxel. An understanding of the hydrogenbonding network in docetaxel is therefore imperative if an explanation for its improved solubility over its predecessor is to be sought. New crystalline forms for solvated (ethanol), hydrated, and anhydrous docetaxel are reported. The crystal structures were determined by single crystal synchrotron and laboratory powder X-ray diffraction experiments on crystalline materials resulting from polymorph screening tests in various solvents. Variable-temperature experiments were carried out over ranges between 20 and 130 °C, with subsequent loss of crystal water at 70 and 90 °C. The resulting structures are discussed in terms of their intermolecular interactions, molecular conformations, and packing motifs. A rare hydrogen-bonding motif, observed between carbamate and tetracyclic ether groups, was found in the packing of all phases of docetaxel. Subtle but significant changes in structural hydrogen bonding motifs are discussed and their differences supported and visualized by Hirshfeld surface calculations and related two-dimensional fingerprint plots.

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INTRODUCTION Docetaxel is a semisynthetic analog of the antineoplastic drug paclitaxel, a taxane originally extracted from the bark of the Pacific Yew tree.1,2 Like its predecessor, it exerts its antitumor activity via the promotion of microtubular stability and disruption of microtubule disassembly3,4 and is indicated for use in breast, non-small-cell lung, ovarian, and head and neck cancers.5 It differs from paclitaxel at two positions in its chemical structure, having a hydroxyl group rather than an acetate ester on carbon 10 and a tert-butyl carbamate ester instead of a benzyl amide on the phenylpropionate side chain (Scheme 1). Although it remains largely insoluble in water, docetaxel shows a slightly better water solubility profile when compared to paclitaxel.5 While the differences in the chemical structure are important, they do not constitute the only reason for a better dissolution profile of the solid; a distinctly different packing arrangement of the molecules can also have a considerable impact on its solubility. Changes in intermolecular interactions and packing arrangements have a direct influence on the physical properties of a solid. In compounds of pharmaceutical relevance, this may translate into the alteration of solubility, bioavailability, toxicity, and chemical stability or shelf life, among others.6 Hydrogen bonds are among the most important intermolecular © XXXX American Chemical Society

Scheme 1. Docetaxel Molecule and the Numbering Scheme Applied in This Paper

interactions, not only because of their high energy but also because of their directionality.7 The nature and polarity of the donor and acceptor groups within a hydrogen bond affect the strength and ability of these forces to control intermolecular synthon formation. Therefore, an understanding of the hydrogen-bonding network in docetaxel is imperative if an explanation for its improved solubility over paclitaxel is to be Received: May 26, 2013 Revised: September 5, 2013

A

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Table 1. Chemical, Crystallographic, And Refinement Parameters of DOWEt, DOW2Et, and DOW3 Obtained by Single-Crystal Diffraction Using Synchrotron Radiation identification code empirical formula formula moiety formula weight (g mol−1) temperature (°C) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z ρcalc (mg/mm3) m (mm−1) F(000) crystal size (mm3) 2Θ range for data collection index ranges

reflections collected independent reflections data/restraints/parameters goodness-of-fit on F2 final R indexes [I ≥ 2σ(I)] final R indexes [all data] largest diff. peak/hole (e Å−3) flack parameter

DOW3

DOW2Et

DOWEt

C43H59NO17 C43H53NO14·3H2O 861.91 −153(2) orthorhombic P212121 8.594(2) 12.644(3) 39.717(10) 90 90 90 4315.8(18) 4 1.327 0.094 1840.0 0.1 × 0.1 × 0.001 4.318 to 52.93° −8 ≤ h ≤ 11 −15 ≤ k ≤ 16 −51 ≤ l ≤ 51 39684 9563 [R(int) = 0.0886] 9563/3/558 1.034 R1 = 0.0635, wR2 = 0.1331 R1 = 0.0900, wR2 = 0.1414 0.44/−0.27

C44H58.5NO16 C43H53NO14(CH3.5O)·H2O 857.41 −123(2) monoclinic P21 10.287(2) 32.938(8) 12.780(3) 90 90.213(3) 90 4330.2(17) 4 1.315 0.100 1830.0 0.05 × 0.05 × 0.002 3.088 to 42.514° −10 ≤ h ≤ 10 −34 ≤ k ≤ 34 −13 ≤ l ≤ 13 10423 10423 [R(int) = 0.0843] 10423/33/1139 0.936 R1 = 0.0642, wR2 = 0.1341 R1 = 0.1390, wR2 = 0.1558 0.26/−0.23 unreliable λ = 0.6889 Å

C45H60NO16 C43H53NO14(C2H6O)·H2O 870.94 −153(2) monoclinic P21 12.608(3) 8.6626(19) 20.353(4) 90 98.942(2) 90 2196.0(8) 2 1.317 0.100 930.0 0.1 × 0.1 × 0.001 2.026 to 65.374° −19 ≤ h ≤ 18 −11 ≤ k ≤ 7 −30 ≤ l ≤ 30 26748 11926 [R(int) = 0.0219] 11926/1/594 1.041 R1 = 0.0499, wR2 = 0.1396 R1 = 0.0531, wR2 = 0.1428 0.69/−0.51

translate into the subtle variations observed among these crystal structures, thus gaining insight into the nature of their cohesive energies.

sought. To date, two crystal structures of docetaxel (CSD REF DARGOT and DARGOT01,8 both reported to be trihydrates) and two derivatives (CSD REF IVIGID9 and XESVAT10) have been reported, although no atomic coordinates are available for the trihydrates. In this paper, we present a variable temperature PXRD (powder X-ray diffraction) study of docetaxel carried out to determine whether loss of water of hydration occurs in a manner similar to that described for paclitaxel.11 This is supplemented by single crystal synchrotron data and thermogravimetric analysis. We also report the crystal structures of two docetaxel hydrates (the new monohydrate DOW and the full structural details, including atomic coordinates of the trihydrate DOW3), as well as the anhydrous form DOCE, and two ethanol hydrates DOWEt and DOW2Et for the first time. The structure of docetaxel was solved from both powder (DOW3P) and single-crystal (DOW3) data in order to confirm that both bulk powder and single crystal forms show the same structure. Despite their molecular similarity, significant differences in the hydrogen-bonding networks between paclitaxel and docetaxel were observed. The formation of a particular carbamate−cyclic ether synthon in almost all the crystal forms of the latter is discussed in this context. The appearance of different hydrogen bond motifs in docetaxel and the inherent similarity between the various forms prompted calculation of the Hirshfeld surfaces12 of the anhydrous and hydrated forms. This was done in an effort to better understand the differences in electron distribution that

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EXPERIMENTAL SECTION

Docetaxel was purchased from Carbosynth Ltd. and used without any further purification. Reagent grade THF (tetrahydrofuran) and ethanol were purchased from Fisher Scientific, and distilled water was generated in-house. Recrystallization from THF. 40 mg of docetaxel were placed as bought in a 30 mL glass container with a plastic cap equipped with a stirring bar. 5 mL of THF were used to dissolve the powder under rapid stirring at room temperature. After complete dissolution (ca. 10 min), 20 mL of distilled water were added carefully, and precipitation occurred again. The resulting white solid was filtered and dried in air. In order to obtain suitable single crystals, one spatula of docetaxel was dissolved in ca. 10 drops of THF, and 10 drops of water were added carefully, so that docetaxel remained completely dissolved. Slow evaporation of the solvent mixture (over three days) resulted in the formation of tiny colorless crystals of docetaxel trihydrate (DOW3), suitable for data collection. Recrystallization from Ethanol. One spatula of docetaxel was dissolved in ca. 0.5 mL of ethanol, and 0.5 mL of water were added carefully to ensure that docetaxel remained completely dissolved. Slow evaporation of the solvent mixture over four days resulted in the formation of tiny colorless crystals of docetaxel monohydrate ethanol solvate (DOWEt). These were suitable for data collection. Similarly, 50 mg of docetaxel were dissolved in ca. 1 mL of ethanol and heated up in order to increase the dissolution of the solid. 2 mL of water were added carefully into the hot solution and slow evaporation B

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resulted in tiny colorless crystals of DOW2Et in the shape of plates, suitable for data collection. Sample Preparation. A few milligrams of the crystalline powder obtained by recrystallization from THF were ground gently in an agate mortar and immediately filled into borosilicate glass capillaries (Hilgenberg Glass no. 50) of diameter 0.4 mm, which were later sealed. For the temperature-resolved measurements, the capillaries were left open-ended. Single Crystal X-ray Diffraction. Single crystal X-ray diffraction data were collected at Station I19 at Diamond Light Source on a Rigaku Saturn724+ diffractometer at a temperature of 120 K (DOWEt, DOW2Et) and 150 K (DOW3). SADABS-2008/113 was used for absorption correction. The structure was solved by direct methods and refined on all unique F2 values, with anisotropic non-H atoms and constrained riding isotropic H atoms. Disordered solvent molecules that could not be modeled as discrete atoms were treated by the SQUEEZE14 procedure of PLATON.15 The software used was Rigaku CrystalClear for data collection, APEX213 for integration and absorption corrections, OLEX216 or SHELXTL17 for structure solution and refinement, and DIAMOND18 for graphics. Final agreement factors (R values) are listed in Table 1, and full crystallographic experimental details are provided as Supporting Information, together with a list of bond distances and angles.19 X-ray Powder Diffraction. An X-ray powder diffraction pattern of the trihydrate was initially recorded at room temperature on a Bruker D8 ADVANCE high-resolution laboratory X-ray powder diffractometer using Cu Kα1 radiation from a primary Ge(111)-Johanson-type monochromator and a Våntec position-sensitive detector (PSD) in Debye−Scherrer geometry. Data collection spanned over 15 h, covering a range of 5° to 52° along 2θ in steps of 0.008° with a 6° opening of the PSD. To ensure better particle statistics, the sample was spun during measurement. Temperature-resolved measurements were subsequently carried out on a STOE Stadi P diffractometer equipped with a position sensitive detector. Temperatures ranged from 50 to 130 °C at 20° increments, and data collection at each stage commenced after the desired temperature was reached. The time span for these measurements was shorter, with each measurement covering a range of 2° to 70° along 2θ in steps of 0.010° over 6 h. Structure determination and refinement of powder data were carried out using the programs ENDEAVOR,20 TOPAS 4.1,21 and DASH 3.3.1.22 Powder diffraction patterns were indexed independently with the singular value decomposition method as implemented within TOPAS,23 resulting in orthorhombic unit cells for all the hydrated and anhydrous forms; Z′ was determined to be 1 for all structures. The peak profile and precise lattice parameters were determined by Le Bail fits24 using the fundamental parameter (FP) approach of TOPAS,25 allowing for the determination of microstructural properties such as domain size and microstrain. For the modeling of the background, third order Chebychev polynomials were employed. The crystal structures of the hydrated and anhydrous forms of docetaxel were solved from powder data by the global optimization method of simulated annealing (SA) in real space as implemented by DASH22 and ENDEAVOR.20 The same molecular model with standard bond lengths and angles was used for the simulated annealing runs of both structures, allowing for three rotations, three translations, and six torsion angles in either case. Slack bond length, bond angle, and planarity restraints were introduced to stabilize the subsequent Rietveld refinement.26 For the final Rietveld refinement, all profile and lattice parameters were released and all atomic positions were subjected to refinement using soft bond and angle constraints (Rietveld plots are included in the Supporting Information). Hydrogen atoms were added in calculated positions based on geometrical assumptions and were refined using restraints. Final agreement factors (R values) are listed in Table 2. The full list of atomic coordinates for all structures, together with intramolecular distances and angles, can be found in the Supporting Information.17 The crystallographic data for all six crystal structures discussed herein have been deposited with the Cambridge Crystallographic Data

Table 2. Chemical, Crystallographic and Refinement Parameters of DOW3P, DOW, and DOCE Obtained by Laboratory Powder Diffraction Using Cu Kα Radiation identification code empirical formula formula moiety formula weight (g mol−1) temperature (°C) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Ztaxane, Z′taxane ρcalc (mg/mm3) wavelength (Å) F(000) R-exp (%)a R-p (%)a R-wp (%)a R_Bragg χ2 starting angle (deg 2θ) final angle (deg 2θ) step width (deg 2θ) a

DOW3P

DOW

DOCE

C43H59NO17 C43H53NO14· 3H2O 861.91

C43 H55NO15 C43H53NO14· H2O 825.88

C43 H53NO14 C43H53NO14

20 orthorhombic P212121 8.6619(8) 12.7429(9) 39.838(4) 90 90 90 4397.4(5) 4, 1 1.270 1.5406 1758 1.822 2.497 3.321 1.305 1.823 5

70 orthorhombic P212121 8.625(2) Å 12.910(2) Å 38.764(11) Å 90 90 90 4316.7(18) 4, 1 1.288 1.5406 1752 3.543 3.245 4.131 1.283 1.166 5

110 orthorhombic P212121 8.6078(8) Å 12.9231(16) Å 38.421(5) Å 90 90 90 4273.9(9) 4,1 1.251 1.5406 1720 3.142 2.866 3.673 1.438 1.169 5.0

60 0.017

60.0 0.017

60.0 0.017

807.86

As defined in TOPAS (Bruker-AXS, Karlsruhe, Germany).

Centre, deposition no. CCDC 940077−940082. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; Fax: (+44) 1223-336-033; or [email protected]). Thermal Analysis. Thermal analyses of two docetaxel samples (as bought and recrystallized from THF) were carried out using a Netzsch STA 449C instrument. Samples were placed in corundum crucibles with lids in a helium stream flowing at 30 mL min−1 over a temperature range of 303−403 K. A heating rate of 2° min−1 ensured the detection of subtle changes in the structure. At 10° intervals, the temperature was kept constant for 20 min before heating was resumed. A short discussion of the thermal analysis can be found as Supporting Information. Hirshfeld Surface Analysis. Important intermolecular interactions within the crystal structures of the hydrated and anhydrous forms of docetaxel were identified via analysis of their Hirshfeld surfaces, which were calculated using CRYSTALEXPLORER 3.1.27 The normalized contact distance dnorm is based on both the distances from the surface to the nearest nucleus inside and outside the surface (di and de, respectively) as well as on the van der Waals radii (rvdw) of the atoms (eq 1).28 dnorm =

d i − ri vdw ri

vdw

+

de − re vdw re vdw

(1)

2D fingerprint plots, derived from the Hirshfeld surface by plotting the fraction of points on the surface as a function of di and de, provide a visual summary of the intermolecular contacts within the crystal.12c,27 C

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Figure 1. Molecular structure of docetaxel showing the intramolecular distances discussed (blue dotted lines) and the carbamate−cyclic ether hydrogen bond interaction (red dotted line). Only fragments of the neighboring molecules are shown (orange), and hydrogen atoms as well as the acetoxy group on C4 were removed for clarity.

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> 8 Å) are reported to be typical for T-taxols,30 whereas angles between 50° and 30° (d = 4−6 Å) are more typical for other more common taxol conformations. Figure 1 shows the molecule and the two distances discussed above. In the trihydrate DOW3P, the distance between the centroids of the two phenyl rings measures at 10.797 Å, and the torsion angle H45−C45−C47−H47 and the improper torsion angle C25−C2−C47−N54 are 59.6° and 64.2°, respectively. At 7.150 Å, the C2−C47 distance lies within the typical 7−9 Å range for the T-taxol side chain conformation. In all three structures, intermolecular interactions between the cyclic ether oxygen of the backbone and either the amino group of the side chain (DOW3P and DOCE) or the alcohol oxygen of the side chain (DOW) result in linear onedimensional chains. A particular carbamate−cyclic ether motif (see also Figure 1) is created by the tetracyclic ether O21 and the carbamate N(H)54 on the C13 side chain. The O(H)···O interaction in the monohydrate is stronger than in all other docetaxel structures, with d = 2.843 Å. A significant change to the side ring arrangement occurs upon loss of water. In the monohydrate form, DOW, the distance between the carbon atoms to which both phenyl rings are attached decreases to 6.976 Å, and the corresponding torsion angle in the side chain H45−C45−C47−H47 increases slightly to 62.5°. The improper torsion angle between the two phenyl rings shows the largest difference compared to all other crystal forms at only 47.3°, a clear indication that the molecule has now adopted a more common taxol conformation. However, the distance between the centroids of the phenyl rings remains stable at 10.190 Å, almost the same value as that observed in all other room temperature structures. In the anhydrous form, DOCE, the complete lack of water has a strong influence on the structure and brings some additional conformational changes to the side chain in anhydrous docetaxel (DOCE). Both the C2 to C47 distance and the distance between the centroids between the phenyl rings decrease further to d = 6.856 and 8.933 Å, respectively. The decrease of these distances provides additional evidence

RESULTS AND DISCUSSION Crystal Structures and Hirshfeld Analysis of Anhydrous Docetaxel (DOCE), Docetaxel Monohydrate (DOW), and Docetaxel Trihydrate (DOW3P) Derived from Variable Temperature Powder X-ray Diffraction Experiments. Docetaxel has shown to undergo dehydration upon heating, and although heating beyond 150 °C resulted in structure decomposition, the water loss occurring before this temperature is not associated with any sample degradation. Analysis of the powder X-ray diffraction data collected at 20, 50, 70, 90, 110, and 130 °C revealed three distinct crystal forms: docetaxel trihydrate (DOcetaxel Water 3 times and P for Powder data, DOW3P) at 20 and 50 °C, docetaxel monohydrate (DOW) at 70 °C, and the anhydrous form of docetaxel (DOCE) at 90, 110, and 130 °C. Structure solution and refinement from powder data was carried out on all diffraction patterns obtained. However, only the structure for the 20 °C data collection and the ones where the occurrence of a new form was observed (the 70 and 110 °C data collection) will be discussed. The backbone of the molecule shows almost exactly the same configuration in all crystal forms. All crystallographically independent molecules in the docetaxel structures reported here show a C13 side chain conformation that is very different to the one observed in the solid state structures of paclitaxel;11 a typical T-taxol conformation is adopted in which the phenyl ring attached to C2 has a distance between 7 and 9 Å from C47 on the phenyl ring of the side chain. This conformation is wellknown for its particularly high biological activity.29,30 In some of the crystal structures reported here, the torsion angles H45− C45−C47−H47 show typical values for this T-shaped or butterfly conformation with angles ranging between 60(1) and 61(1)°. Another often-mentioned29 parameter for the conformation of taxanes is the improper torsion angle O25−C2−C47−N54 (O125−C102−C147−N154), which can be taken as a measure of the distance (between centroids) and inclination of the two phenyl rings attached to C2 and C47. High angles (>80° and d D

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Figure 2. Layered structure of docetaxel trihydrate DOW3 (left), monohydrate DOW (center), and anhydrous docetaxel DOCE (right). Water molecules are represented by spheres corresponding with the van der Waals radii of the respective atoms. Hydrogen atoms of solvent molecules which are not part of a water molecule are omitted for clarity.

that these molecules no longer adopt the T-shape conformation but one of the more common forms of taxols instead. At 56.1°, the improper torsion angle O25−C2−C47−N54 lies between those of DOW3P and DOW, whereas the torsion angle in the side chain (H45−C45−C47−H47) deviates significantly from all equivalent torsion angles measured in the other structures, with the two hydrogen atoms lying almost opposite each other at an angle of 142.0°. It is not surprising that the loss of water, and thus also the source of strong hydrogen bonding, has a marked influence on the way the phenyl rings and the side chain can orientate and pack in the dehydrated structures. In fact, whereas DOW3P exhibits hydrogen bonding to a similar extent as that in the ethanol solvate structures, there is very limited but strong hydrogen bonding detected between the molecules in the docetaxel monohydrate and anhydrous forms. Figure 2 shows packing diagrams of DOW3, DOW, and DOCE, respectively, whereas Table 3 summarizes and compares the intermolecular hydrogen bond interactions in all structures discussed in this paper. DOW3P shows the same kind of medium H-bond interaction between O(H)22 and O36 (d = 2.878 Å) and O(H)38 and O44 (d = 2.941 Å) as that observed in DOW3. Conversely, DOW shows a relatively strong intermolecular hydrogen bond interaction between the alcohol group and the phenyl ring on the side chain between neighboring molecules (d = 2.543 Å). The strongest intermolecular interaction among all docetaxel structures with nonsolvent moieties can be measured in the anhydrous form DOCE, between an alcohol group of the taxane backbone and a carbonyl oxygen of the side chain (d = 2.347 Å). Other torsion angles and distances are in accordance with the conformations of other derivatives or crystal forms of docetaxel reported in the literature. Lists of hydrogen bond interactions, as well as bond distances and angles for all three structures, can be found in the Supporting Information files. Examination of the Hirshfeld surfaces of the taxane molecules in DOCE, DOW, and DOW3P (Figure 3) demonstrates the significance of the slight changes in taxane conformation, as influenced by the amount of crystal water present in the system. Areas of close contact are mapped in red on the Hirshfeld surface. The 2D fingerprint plots (Figure 4) provide a visual summary of intermolecular contacts in the three structures, and although they have distinctly different

Table 3. (A) Hydrogen Bonds for DOWEt, DOW2Et, and DOW3 and (B) Hydrogen Bonds for DOW3P, DOW, and DOCEa D

H

A

d(D− H) (Å)

d(H− A) (Å)

D−H−A (deg)

d(D-A) (Å)

Part A: Hydrogen Bonds for DOWEt, DOW2Et, and DOW3 N54 O22 O23

H54 H22 H23

N54 N154 O38 O138 O46

H54 H154 H38 H138 H46

N54 O22 O38 O38

H54 H22 H38 H38

Hydrogen Bonds for DOWEtb O213 0.88 2.34 3.084(2) O361 0.84 2.10 2.862(3) 0.84 2.10 2.740(2) O382 Hydrogen Bonds for DOW2Etc O211 0.88 2.11 2.989(12) 0.88 2.08 2.961(13) O1212 O24 0.84 2.14 2.563(12) O124 0.84 2.07 2.562(11) O123 0.84 1.89 2.718(11) Hydrogen Bonds for DOW3d O211 0.88 2.39 3.147(4) O362 0.83 2.09 2.856(4) O24 0.84 2.05 2.553(4) O443 0.84 2.48 2.934(4)

D

H

A

d(D−H) (Å)

d(H−A) (Å)

d(D−A) (Å)

143.0 151.4 132.9 176.8 177.3 111.0 117.1 166.7 144.1 152.5 118.1 115.0 D−H−A (deg)

Part B: Hydrogen Bonds for DOW3P, DOW, and DOCE N54 O22 O38

H54 H22 H38

O46

H281

N54 O38

H49 H38

Hydrogen Bonds for DOW3Pe O211 0.88 2.41 3.171(6) O362 0.84 2.11 2.878(6) O443 0.85 2.49 2.941(8) Hydrogen Bonds for DOWf O211 0.85 N/A 2.852(4) Hydrogen Bonds for DOCE O21 0.91 2.28 3.126(3) O441 0.87 N/A 2.347(3)

144 153 115 N/A 156 N/A

a

Although structures of DOW3 and DOW3P are identical, the data are still provided to prove that both determination methods (from single crystal and powder) show the same geometry and accuracy at two different temperatures. b11 + X, −1 + Y, +Z; 21 − X, 1/2 + Y, 1 − Z; 3−1 + X, +Y, +Z. c1+X, +Y, 1 + Z; 2+X, +Y, −1 + Z. d 1+X, 1 + Y, +Z; 21 + X, +Y, +Z; 31 − X, −1/2 + Y, 1/2 − Z. e1X, 1 + Y, Z; 21 + X, Y, Z; 31 − X, −1/2 + Y, 1/2 − Z. f1X, −1 + Y , Z. g1X, −1 + Y , Z.

shapes, it is clear that the structures are strongly related to one another. Areas of marked similarity exist between the trihydrate E

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Figure 3. Hirshfeld surface of docetaxel trihydrate DOW3P at 20 °C (left), docetaxel trihydrate DOW at 70 °C (center), and anhydrous docetaxel DOCE at 110 °C. The carbamate−cyclic ether motif is shown in the blue dotted lines and is highlighted further with green arrows.

Figure 4. Hirshfeld global fingerprints of DOW3P (left), DOW (center), and DOCE (right) at 20, 70, and 110 °C.

Figure 5. Hirshfeld N···A fingerprint plots of DOW3P (left), DOW (center), and DOCE (right) at 20, 70, and 110 °C.

Figure 6. Hirshfeld O···A fingerprint plots of DOW3P (left), DOW (center), and DOCE (right) at 20, 70, and 110 °C.

each molecule give a more in-depth indication of the nature and mode of interaction within the structure. Figure 5 illustrates the similarity between the trihydrate and anhydrous forms through the fingerprint plots of a selection of interactions. Whereas, DOW3P and DOCE show a very similar curved nature of the N···A plots, the more distributed and inversely curved pattern

and anhydrous forms, such as the clear spikes pertaining to the carbamate−cyclic ether hydrogen-bonding motif between de = 1.0 and 1.2 and di = 0.6 and 0.8 Å. This lies in contrast to the monohydrate DOW in which this motif does not exist but a new O(H)···O interaction exists (vide supra). The Hirshfeld surface area percentage of N···A and O···A contacts observed in F

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typical polar conformation observed in other taxane crystal structures.29,30 The different amount of water/ethanol in the crystal structure of docetaxel has the structural data of DOW3 and is very similar to that of DOW3P, the trihydrate obtained from powder data, with comparable torsion angles and distances between centroids. Moderate hydrogen bonds are observed between O22(H) and O36 [d = 2.856(4) Å]. Stronger bonds are either intramolecular H bonds or contacts with water molecules [2.632(3)Å < d < 2.828(4)Å]. Through the O22(H)···O36 interactions, the docetaxel molecules form layers of infinite linear chains with the nonpolar t-butyl and phenyl groups of the molecule fitting into each other on one side and water molecules forming a network via interactions with various keto and alcohol oxygen atoms on the other side (Figure 2). A second dimension is added by considering relatively weak N54(H)···O21 interactions [d = 3.147(4) Å] which connect docetaxel molecules using the carbamate−cyclic ether motif. In this manner, a perfect 2D layer is formed in the (001) plane of the crystal structure. DOWEt shows very similar hydrogen bond interactions compared to DOW3. The O22(H)···O36 is slightly longer with d = 2.862(3) Å, whereas a moderately stronger N54(H)···O21 interaction with d = 3.084(2) Å is observed between the tetracyclic ether and the carbamate group on the side chain. An additional moderate interaction was formed between O23(H) and O38 [d = 3.147(4) Å], which is unique so far among all crystal structures of docetaxel. Stronger bonds are formed either between ethanol and water molecules or between the solvent molecules and docetaxel. In DOW2Et, a different intramolecular H-bond interaction between O22 and O36 is observed. Here, the alcohol groups O46(H) and O123, as well as O146(H) and O23, form moderate interactions of 2.718(11) Å. The same intramolecular pattern is observed between the cyclic ether oxygen O21 and the carbamate group N54(H) as well as O121 and N154(H), with stronger H-bonding compared to DOW3 at distances of 2.989(12) Å and 2.961(13) Å, respectively. It is interesting to note that the two molecules present in the asymmetric unit are not connected to each other by this very special H-bond motif, thus forming layers consistent of only molecule 1 and layers of only molecule 2 (Figure 7). Each molecule is connected to another infinitely by N(H)····O interactions. Molecules 1 and 2

in DOW differs appreciably. Similarly, plots of the O···A interactions further highlight the difference in hydrogen bonding arising from the different molecular taxol conformation adopted by docetaxel in its monohydrated form (Figure 6). Crystal Structures of Docetaxel Trihydrate (DOW3), Monohydrate Ethanol Solvate (DOWEt), and Dihydrate Ethanol Solvate (DOW2Et) Solved from Single Crystal Data. The docetaxel ethanol solvates DOWEt (docetaxel monohydrate ethanol solvate) and DOW2Et (docetaxel dihydrate ethanol solvate) and docetaxel trihydrate (DOW3) were determined from single crystal synchrotron data, the latter serving as a confirmation of the crystal structure obtained from laboratory powder diffraction data. The crystal structures of the two ethanol solvates determined in the present study show significant differences in unit cell dimensions (see Table 1) compared to the trihydrate. Both structures crystallize in a monoclinic cell setting (P21). DOW2Et shows a similar cell volume but different cell lengths compared to DOW3 (i.e., there are two molecules of docetaxel in the asymmetric unit). The DOWEt parameters differ significantly, with a unit cell volume half the size and consequently having just one docetaxel molecule in the asymmetric unit. In DOW2Et, ethanol and water oxygen share one position in the crystal structure and, thus, it is difficult to determine the exact content of both solvents in the crystal structure. However a 2:1 ratio between water and ethanol gave the best refinement factors. The lattice parameters of DOW3 and DOWEt match the two different phases published by Zaske et al.8 (DARGOT, P212121, DARGOT01, P21, see Table 1), respectively, and are the only entries for docetaxel shown in the CCDC database to date. No exact comparison between these published structures and DOW3/DOWEt could be carried out, due to the lack of atom coordinates in both the publication and the corresponding CCDC database entries. However, while DARGOT and DOW3 have the same chemical composition, DARGOT01 is again reported to be the trihydrate, whereas DOWEt is a different solvated form of docetaxel. Both DARGOT structures have been determined from recrystallizations in ethanol/water.8 It is therefore difficult, in absence of atomic coordinates, to determine with absolute certainty whether DOWEt and DARGOT01 are truly different solvated crystal forms of docetaxel having very similar cell parameters or whether the published DARGOT01 actually contained some solvated ethanol. Both structures DOWEt and DOW3 derive from more complete and precise single-crystal data. Significant positional disorder of water and ethanol molecules which fill up the cavities between the taxane molecules was observed, and for DOW2Et, the best refinement was achieved with some water oxygen atoms sharing the same position as the oxygen atoms in ethanol. Overall, this results in one molecule of ethanol and two molecules of water filling up the cavities created by docetaxel molecules in DOW2Et. The two docetaxel structures reported herein differ quite significantly from each other. DOW2Et shows improper torsion angles O25−C2−C47−N54 (O125−C102−C147−N154 for the other independent molecule in the asymmetric unit) of 95.2(8)° and 96.1(7)° and C2−C47 distances of 8.95(2) Å and 9.55(2) Å, and DOW3 shows the same angle at a much lower value of 64.0(2)Å but a distance between the two phenyl rings of 10.721(2)Å. These values clearly show that there are additional intermolecular interactions present in the crystal structure that prevent the phenyl rings from adopting the

Figure 7. Layered structure of docetaxel hydrate ethanol solvate. Solvent molecules are represented by spheres corresponding with the van der Waals radii of the respective atoms. Hydrogen atoms which are not part of solvent molecules are omitted for clarity. G

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available. This material is available free of charge via the Internet at http://pubs.acs.org.

are weakly connected by the above-mentioned alcohol Oalcohol O interactions only for layers in which no ethanol molecules are present. H-bond interactions between NH of the carbamate groups and ether oxygens are rare in the literature. Linear onedimensional chains showing this particular motif have been reported five times in the CCDC database to the best of our knowledge.31−35 In addition, a literature search in the same database for H-bond interactions between tetracyclic ethers and amino groups resulted in only three hits, two of which were derivatives with a taxane backbone.36−39 In taxanes in particular, these hydrogen bonds have so far been overlooked because in the crystal structures of the derivatives reported, these bonds have shown distances B(H)···A of above 3.00 Å, thus being considered too weak to have a large influence. The intermolecular interactions in DOW2Et are the shortest ones reported so far in the literature.

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*E-mail: [email protected]. Tel: (+44) 191 222 8507. http://www.ncl.ac.uk/chemistry/staff/profile/ulrich. baisch. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a Marie Curie Reintegration Grant (U.B.) within the 7th European Community Framework Program of the European Commission. The authors thank Diamond Light Source for access to beamline I19, Prof. David Manning and Mr. Bernard Bowler (Newcastle University) for DTA/DSC measurements, and Christine Stefani (Max Planck Institute, Stuttgart) and Edith Alig and Lothar Fink (Johann Wolfgang Goethe Universität, Frankfurt) for the powder measurements. Furthermore, we would like to thank Prof. Dr. Martin Schmidt (Johann Wolfgang Goethe Universität, Frankfurt) for data collection using his instruments and helpful scientific discussion.

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CONCLUSIONS The present study involving five new crystal forms of docetaxel enabled detailed analysis of the intermolecular interactions between taxane molecules, highlighting motifs that are intrinsically unique to docetaxel in particular. The ability of docetaxel in forming such strong intermolecular interactions in the solid state at different temperatures and including different solvate molecules is a valuable discovery for the taxane community. It provides possible sterical and geometrical explanations for why docetaxel molecules show a different activity compared to other taxanes, even though the molecules are very similar. The existence of these different H-bond interactions may well be responsible for the improved solubility of this highly active anticancer drug when compared to its predecessor paclitaxel. Both the results of the variable temperature study and the identification of differently solvated crystal forms were ideally suited to afford observation of the interactions that persisted and those that were mainly attributable to the inclusion of solvent water. The carbamate−cyclic ether interaction is unique for docetaxel and certainly pertinent to the particular way molecules pack during the crystallization process. The only exception here being the monohydrated form DOW which shows a O(H)···O interaction instead. This suggests that this form is more of an intermediate in the dehydration process. All other hydrogen bonds were found to differ from one crystal form of docetaxel to another, thereby placing further emphasis on the specificity of the carbamate−cyclic ether interaction to the taxane molecule in docetaxel. Hirshfeld surface analysis provided supporting evidence to these observations. Furthermore, through more exact synchrotron radiation studies, we found evidence that, to our knowledge, the published structure DARGOT01 could also be a mixed, not stoichiometric ethanol hydrate. Finally, we were able to identify how the inclusion or exclusion of solvent water or ethanol can influence the side chain conformation of the taxane molecule; a conformational change known to influence the activity of the drug significantly.29,30

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AUTHOR INFORMATION

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic information files (CIF) are available for all crystal structures. Additionally, crystallographic data in table format as well as Rietveld plots and thermogravimetric data are H

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