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Crystal Forms of Enzalutamide and a Crystal Engineering Route to Drug Purification Lucia Maini, Dario Braga, Francesco Farinella, Elisa Melotto, Massimo Verzini, Roberto Brescello, Ivan Michieletto, and Ilaria Munari Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01613 • Publication Date (Web): 31 May 2018 Downloaded from http://pubs.acs.org on May 31, 2018
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Crystal Growth & Design
Crystal forms of Enzalutamide and a Crystal Engineering Route to Drug Purification Lucia Maini,a * Dario Braga,a Francesco Farinella, ¥a Elisa Melotto §b Massimo Verzini, †b Roberto Brescello, ‡b Ivan Michieletto, ‡b Ilaria Munari. ‡b Università di Bologna, Dipartimento di Chimica "Giacomo Ciamician", Via F. Selmi 2, 40126 Bologna, Italy Zach System SpA, Italy Dedicated to Giorgio Soriato ABSTRACT.
The crystal forms of the API enzalutamide, a drug used for the treatment of metastatic prostate cancer, have been investigated by X-ray, TGA and DSC techniques. The single crystal structure of the anhydrous form R1 (marketed by Astellas) has been determined and compared with the powder diffraction data. Upon crystallization from MeOH and formic acid a new solvate form called R2 has been discovered and characterized. The crystal structure of R2 contains voids that can host other small molecules such as formic acid, methanol or water. Form R2 loses solvent at ca. 120-140°C and re-crystallize into the stable unsolvated form R1. In the case of isopropyl alcohol a solvate form R3 has also been obtained. R1 converts into R3 under slurry condition in isopropyl alcohol. The structure of R3 has been determined from powder diffraction data. Importantly, while form R1 is easily contaminated with O-enzalutamide (the substitution impurity of S-enzalutamide) by forming 1 ACS Paragon Plus Environment
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stable solid solutions up to 50%, form R3 does not and can be used to easily purify the raw Senzalutamide.
INTRODUCTION Crystal polymorphism, namely the existence of more than one crystal form for the same molecule,1 is being actively investigated in both academic and industrial laboratories for its implications on bioavailability, production, administration and distribution control and also for intellectual property protection.2 The literature on the discovery and characterization of novel crystal forms of previously known APIs is very large and still growing. Some historical cases are represented by Ritonavir® and Neupro®.3,4 Enzalutamide is an oral androgen receptor (AR) signaling inhibitor that was specifically engineered to overcome castration-resistant prostate cancer (CRPC) harboring AR amplification or overexpression.5–7 Presently, it is marketed by Medivation Inc. and Astellas Pharma with the brand name Xtandi®. The patent describing the drug substance expires in 2027,8 but the exclusive marketing right was granted to Astellas until the 30 August 2017.9 The possibility to enter in the market with the enzalutamide has prompted nine pharmaceutical industries to fill the drug master file10 and new patent applications on the crystal forms have been recently published.11–13 The CHMP assessment report declares that only one anhydrous form has been observed, while four solvates are known but no other information is reported.14 In this paper we report the crystal structures of three enzalutamide forms (hereafter called Senzalutamide, see scheme 1), the anhydrous R1 and the solvate forms R2 described in the Dr. Reddy’s patent12 and R3 (called also form B)13 and two anhydrous crystal forms of O-enzalutamide (see scheme 1) called form I and II. O-enzalutamide contains the group C=O in place of the group C=S and it is one of the impurities formed during the synthetic process.15 We also demonstrate that the investigation of crystal polymorphism can lead to discovery of new methods of purification by
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Crystal Growth & Design
exploiting the selective preference of form R1 with respect to the solvated polymorph (R3) to form solid solutions with the O-enzalutamide. O N H
F
N
O
N
S N O
F F
F
N H
N
O N
N
F
F O
F
F
Scheme 1 left: S-enzalutamide, right: O-enzalutamide impurity EXPERIMENTALS Enzalutamide was provided by Zach (Zambon chemical), solvents were purchased from SigmaAldrich and used without further purification. Slurry experiments. Slurry experiments were carried with 100 mg of sample and 0.1-0.3 mL of solvent. Solvent used: methanol, isopropyl alcohol, formic acid. The slurries were kept under stirring for 7 days at room temperature. Thermal gravimetric analysis (TGA). TGA measurements were performed using a PerkinElmer TGA7 in the temperature ranges 40-400 °C, under N2 gas flow, at a heating rate of 5°C min-1. Differential scanning calorimetry (DSC). DSC measurements were performed with a PerkinElmer Diamond. Samples (3-10 mg) were placed in open aluminum pans. Heating was carried out in the temperature range 25-200°C. The scanning rate is reported in the figure caption. X-ray powder diffraction (XRPD) experiments. For phase identification purposes, X-ray powder diffractograms in the 2θ range 3-40° (step size 0.02°; time/step 20 s; 0.04° rad soller; VxA 40 kV x 40mA) were collected on a Panalytical X’Pert PRO automated diffractometer equipped with a X’Celerator detector in Bragg-Brentano geometry, using CuKα radiation without a monochromator. For variable temperature measurements the Panalytical X’Pert PRO automated diffractometer was equipped with an Anton Paar TTK 450 system. For structure determination purposes, a X-ray powder diffractometer Panalytical X’Pert PRO equipped with Pixcel detector in transmission geometry with CuKα radiation without a 3 ACS Paragon Plus Environment
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monochromator was used. The samples were placed in 0.05mm capillaries, the 2θ range 3-70° (step size 0.007°, time/step 75 s, VxA 40x40) was collected three times and the measurements were merged. Structure determination from single crystal X-ray data. All single crystal data were collected on an Oxford Xcalibur S instrument with MoKα radiation (λ=0.71073 Å) and graphite monochromator at room temperature. SHELX9716 was used for structure solution and refinement based on F2. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were added in calculated positions. Since it was not possible to describe the disordered solvent in form R2 of S-enzalutamide R2, the SQUEEZE17 method was used to remove the diffuse electron density present in the voids. CCDC 1586495-1586499 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Structure determination from XRPD data. The cell parameters were determined with TOPAS18. The asymmetric unit contains one molecule of enzalutamide and half molecule of isopropanol. Space group determination resulted in space group P21/c. The structure was solved by simulated annealing using one enzalutamide molecule. The torsion angles C8-C6-N1-C1, C13-C7N4-C1, N22-C21-C10-C9 were let free to rotate during the solution while the torsion angle F25C24-C14-C13 were allowed to change only during the Rietveld refinement (see figure SI 12 for the numbering scheme). The isopropanol molecule has only half occupancy since it is placed on the inversion center. The best solution was chosen for Rietveld refinements, which were performed with the software TOPAS.18 A shifted Chebyshev function with 9 parameters and a Pseudo-Voigt function were used to fit background and peak shape, respectively. An overall thermal parameter was adopted for all atoms of non hydrogen atoms. All the hydrogen atoms were fixed in calculated positions. Refinement converged with χ2 = 5.55 and Rwp = 8.99 (Table 2). The program Mercury19 was used for all graphical representations.
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Crystal Growth & Design
Table 1. Crystallographic data of S-enzalutamide R1, R2, R3 and O-enzalutamide I and II Form
R1
R2
R3
I
II
Formula
C21H16F4N4O2S
C21H16F4N4O2.5S (CH3OH)0.5
C21H16F4N4O2.5S (CH3CHOHCH3)0.5
C21H16F4N4O3
C21H16F4N4O3
Mol wt
464.44
479.45
502.48
448.38
448.38
System
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Space group
P21/n
P21/c
P21/c
P21/n
P21/c
a (Å)
8.4972(4)
18.366(1)
19.7065(4)
8.0639(5)
7.3747(5)
b (Å)
26.963(1)
15.203(1)
15.1867(3)
25.701(2)
27.606(2)
c (Å)
9.5571(5)
8.0136(8)
7.9159(2)
9.9640(6)
9.9128(7)
β (°)
93.739(4)
90.049(7)°.
96.200(2)
95.005(6)
91.527(6)
V (ų)
2184.96(19)
2237.5(3)
2355.2(2)
2057.1(2)
2017.4(2)
Z/Z’
4/1
4/1
4/1
4/1
4/1
Density (g cm-3)
1.412
1.423
1.448
1.476
F(000)
952
972
920
920
µ(MoKα)(mm-1)
0.207
0.206
0.123
0.126
Measured reflns
9828
10790
15110
9537
Unique reflns
5007
4835
4824
4603
Refined parameters
292
307
294
340
GOF on F²
1.077
1.070
1.066
0.835
R1 (F,I >2σ(I)
0.08
0.09
0.07*
0.09
0.07
WR2 (F², all data)
0.22
0.22
0.09**
0.24
0.27
* Rp **Rwp
RESULTS AND DISCUSSION Crystal forms of Enzalutamide 5 ACS Paragon Plus Environment
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The anhydrous form of Enzalutamide was provided by Zach (Zambon chemical) and was identified as form R1 (see SI) on the basis of the powder diffraction pattern.20 The crystal structure has been determined on crystals grown from isopropyl alcohol. A view of the crystal structure is shown in Figure 1. The molecules are paired by π-stack interactions; the distance between the cyanophenyl rings is 3.390(3) Å with centroid shift of about 1.856(3)Å. The thio group is involved in a weak hydrogen bond with the amide group (N—S distance 3.583(3)Å and N-H---S angle of 135.5°).21 Form R1 has a melting point of 201°C (see supporting information).
a
b
Figure 1. a) The structure of enzalutamide R1, ellipsoids drawn at the 50% of probability; b) packing view along the c-axis. Form R2 was obtained by slurry experiments in formic acid and methanol. The XRPD patterns measured on the polycrystalline product were consistent with the peaks reported in Dr. Reddy Patent.12 The XRPD patterns measured on the crystalline compounds obtained from methanol and from formic acid are very similar with some differences only at high θ value (see figure 2). The solvated nature of the two compounds was ascertained by DSC and TGA with evolved gas, and the nature of the solvent of the slurry, respectively formic acid and methanol, was confirmed by the gas analysis. The amount of solvent determined by TGA is slightly less than what would be expected based on the chemical composition Enzalutamide·½ solvent (see SI).
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Intensity (counts)
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6000
5000
4000
3000
2000
* 1000
0 5
10
15
20
25
30
35 2Theta (°)
Figure 2. Powder patterns of the precipitate obtained in the slurry experiments in methanol and formic acid. The peak indicated with the (*) is due to the sample holder. Slow crystallization of enzalutamide in methanol allowed the formation of single crystals suitable for the structure determination. The asymmetric unit consists of one molecule of enzalutamide with fluorine atom of the benzyl ring disordered over two positions with occupancy 80:20 and a solvent molecule placed on the inversion center (see Figure 3a). Unfortunately, it was not possible to determine the solvent atom positions, which suggests that the solvent is disordered inside the cavity, which is large enough to accommodate different kinds of molecules such as methanol, formic acid and water. The empty space in the cell, without taking into account the solvent, corresponds to 105Å3 (calculated with Voids in Mercury; not disordered molecules, probe radius 1.2 Å, grid spacing 0.7Å),19 which corresponds to 2 molecules of methanol or formic acid (volume MeOH = 45.6 Å3, volume HCOOH = 46.8 Å3).23 We did not observe the formation of the hydrate form, also in presence of high concentration of water, but we do not exclude that R2 could contains a mixture of MeOH/H2O or HCOOH/H2O. Hence, R2 can be described as a clathrate with the possibility of trapping different solvents (see Figure 3b), the nature of the solvent can slightly change the position and the intensity of the peaks in the diffraction pattern. 7 ACS Paragon Plus Environment
Crystal Growth & Design
a b Figure 3. a) The structure of R2 (hydrogen atoms omitted for sake of clarity, ellipsoids drawn at 50% probability); b) The crystal packing of Form R2 showing the cavities occupied by the solvent molecules. Van der Waals interactions stabilize the structure, while more specific interactions such as Hbond or π-stack are not present. Upon heating at 140° C R2 loses the solvent molecules, regardless of their nature, and converts to R1 as shown by the variable temperature XRPD patterns reported as a function of the temperature in Figure 4. Intensity (arbitrary units)
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10000
6400
3600
1600
400
0 5
10
15
20
25
30
35 2Theta (°)
Figure 4. XRPD patterns reported as a function of the temperature showing how desolvation of R2 leads to R1 . Slurry of R1 in isopropyl alcohol leads to formation of a third crystal forms R3 within 72h. Interestingly, it is possible to speed up quantitative transformation into R3 by seeding the slurrying 8 ACS Paragon Plus Environment
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solution with seeds of R3 and, in a second experiment, the quantitative conversion was obtained in 9 hours. TGA measurements revealed that R3 is an isopropyl alcohol solvate. The weight loss observed at 120°C corresponds to the stoichiometric ratio enzalutamide:solvent 1:0.5. As observed in the case of R2 (see SI), desolvation of R3 leads to the conversion into R1. The DSC curve (fig SI 11) suggests the presence of amorphous compound after the desolvation, which readily crystallizes This phenomenon is not observed in the VTXRPD experiment which indicates the persistence of a crystalline compound up to the melting. In spite of the numerous efforts, growing single crystals of form R3 suitable for data collection proved impossible and the structure of form R3 was determined from powder diffraction data. The powder patterns of crystalline R3 and R2 (see figure 5) present similarities in keeping with an overall similar packing, the close cell parameters and same space group, and also in the same conformation of the molecules as shown in figure 6. Intensity (arbitray)
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Crystal Growth & Design
6000
5000
4000
3000
2000
1000
0 5
10
15
20
25
30
35 2Theta (°)
Figure 5. Powder pattern of R2 (red line up) and R3 (blue line bottom)
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Figure 6. Comparison of the geometry of the enzalutamide molecules in crystalline R2 (orange) and R3 (green). Disordered atoms and hydrogen omitted for sake of clarity. The benzamidyl groups take part in the formation of the large niche accommodating the solvent molecules (see Figure 7) while the benzonitrile groups interdigitate on the other side without forming π-stacking interaction. The difference in size and shape of the solvent molecules are responsible for the observed differences in the diffraction patterns.
a
b
c
d
Figure 7. A comparison of the crystal packings on R2 and R3. a) The molecules in R2 with solvent molecules presented as blue spheres; b) The molecules in R3 around the disordered isopropyl
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Crystal Growth & Design
alcohol molecules (in light green); c) Packing of R2 along the b axis; d) packing of R3 along the b axis. H atoms omitted for sake of clarity. Solid solutions of S-enzalutamide and the selective behaviour towards the ketonic impurity. Reducing impurities to specification is one of the major challenges in production lines. Batch conformity to specification is a prerequisite for marketing and distribution.24 Considerable efforts and large investments are necessary in order to adhere to requirements. One of the impurities, in the case
of
enzalutamide,
is
represented
by
the
ketonic
O-analogue
4-(3-(4-cyano-3-
(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide hereafter O-enzalutamide (see scheme 1, right).25 Importantly, the industrial process involves recrystallization of crude enzalutamide in isopropyl alcohol. It has been found that form R1 with the required impurity profile specification, needs three recrystallizations, whereas only one recrystallization of crude enzalutamide is needed to obtain the required specification of purification for form R3. These results prompted us to further investigate the relationship between the crystal structure of R1 and R3 and that of the most relevant impurity in the process, namely Oenzalutamide. The ketonic impurity O-enzalutamide forms crystals, called form I, that are isomorphous with R1 (see table 1 and figure 8); it is thus possible for the C=O and C=S derivatives to form solid solutions.26,27 It is known that the electrostatic potential around C=O is much more stabilizing than around C=S, so leading to stronger O···H−N hydrogen bonds, as compared to S···H−N hydrogen bonds.21 Hence the formation of an isomorphic structure and of a solid solution in a structure where the S atom replaces the O atom involved in a hydrogen bond should be disadvantaged if not impeded. In our case, the weak thio hydrogen bond is replaced by a O···H−N interaction. However, the long donor-acceptor distance (N---O distance 3.304(4) Å, N-H---O angle 142°) indicates a rather weak interaction that should not affect the possibility of the formation of a solid solution. In order to gain insight into this aspect we investigated the possibility of obtaining the solvate forms of 11 ACS Paragon Plus Environment
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O-enzalutamide by carrying out slurry experiments in methanol, ethanol and isopropyl alcohol. After 3 days the solid part was characterized and a new anhydrous crystal form was discovered but no solvate forms.
Figure 8. a) The structure of O-enzalutamide form I (ellipsoid at the 50% of probability); b) overlaid molecules of Enzalutamide in R1 (green) and O- enzalutamide in form I (orange) The new form was called form II and its crystal structure was determined by single crystal X ray diffraction (see Figure 9). O-enzalutamide crystallizes in the monoclinic space group P21/c (see Table 1 for crystallographic data). The molecules present differently disordered functional groups: the position of the fluorine atoms of –CF3 was modelled over two sites with occupancies 60:40. The fluoride atom of the phenyl group is placed in three positions: two positions are located at the same side of the oxygen of the amide group with an overall occupancy of 80% while the third position is on the opposite side. Also the oxygen of the amide group is disordered over two positions.
a
b
Figure 9. a) The disordered structure of O-enzalutamide form II (ellipsoid at the 50% of probability; b) overlaid molecules of O-Enzalutamide in I (green) form II (orange). 12 ACS Paragon Plus Environment
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Crystal Growth & Design
A comparison of the structures of O-enzalutiamide in form I, and form II clearly shows that they are conformational polymorphs.28 The near co-planarity of the dioxoimidazolidin ring with the aromatic rings allows the formation of C-H---O intermolecular hydrogen bonds, which are sterically inhibited with the thio group. Moreover, the amide group is involved in a hydrogen bond (N---O distance 2.86(4) Å). These structural features suggest the impossibility of the S-enzalutamide to adopt the same packing arrangements. As a matter of fact, all attempts to induce the isomorphic crystallization of S-enzalutamide by heteroseeding, have failed. The DSC curves of Form I and II enable us to establish the thermodynamic relationship between the two polymorphs. Form I melts at 173°C while form II melts at 161°C followed by recrystallization into form I. Since the slurry experiments lead to form II, it is possible to conclude that form II is the thermodynamic stable form at room temperature. By drawing an energy/ temperature diagram (see SI) on the basis of the melting temperatures it is clear that the two polymorphs are enantiotropically related although no solid-solid transformation is observed for Form II. We have investigated the possibility of obtaining solid solutions between S-enzalutamide and Oenzalutamide by preparing slurry experiments in isopropyl alcohol with different percentages of enzalutamide R1 and O-enzalutamide form I (see Table 2) and characterizing the resulting products via XRPD and DSC. It is worth reminding that pure enzalutamide R1 in isopropanol converts into R3, while O-enzalutamide form I converts into form II. Our interest was to prove the possibility of contaminating R1 with O-enzalutamide, hence to be able to characterize the formation of solid solution the amount of O-enzalutamide in the solution was far higher than the amount present during the industrial purification process. In the presence of 10% (w/w) of O-enzalutamide the final pattern was indeed that characteristic of R3 and a Pawely refinement confirmed that the cell parameters were almost unchanged. The small extra peaks, not accounted for by R3, were attributed to the presence of the solid solution of the anhydrous forms since the cell parameters were in between the values of the O-enzalutamide form I and the S-enzalutamide form R1, (see Table 2). The DSC curve shows the endothermic peak due the release of solvent at 91°C and transformation 13 ACS Paragon Plus Environment
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in R1, a small endothermic peak at 177°C and the melting peak at 196°C which is close to the melting peak of pure R1 (200°C). Increasing the amount of O-enzalutamide increased the presence of the anhydrous form, in fact the XRPD of the starting mixture with 25% of O-enzalutamide, is consistent with the presence of two phases, one corresponding to the S-enzalutamide form R3 with its cell parameters almost unchanged and the second, the anhydrous phase, with cell parameters consistent with the presence of a solid solution (see Table 2). The DSC curve shows two melting points: the first one at 182°C, corresponding to the solid solution, and the second at 190°C, which is consistent with the melting point of the R1. It worth noting that the lower temperature observed in this sample with respect to pure R1 is due to the presence of O-enzalutamide. Unfortunately, it was not possible to estimate the relative quantities of the solid solution and of the compound R1 since the two melting points are not resolved.
Table 2. Cell parameters of the crystal phases observed in the slurry experiments.
Form I O-enzalutamide
% O Enzalutamide (w/w) 100%
a (Å)
b(Å)
c(Å)
β°
8.0639(5)
25.701(2)
9.9640(6)
95.005(6)
Volume (Å3) 2057
Solid solution
10%
8.276(2)
26.18(1)
9.850(3)
94.87(2)
2126
Solid solution
25%
8.487(3)
26.916(6)
9.759(2)
93.03(3)
2226
Solid solution
50%
8.321(1)
26.259(1)
9.796(1)
94.57(1)
2133
R1 Enzalutamide
0%
8.4972(4)
26.93(1)
9.5571(5)
93.739(4)
2185
R3 Enzalutamide
0%
19.7065(4)
15.1867(3)
7.9159(2)
96.200(2)
2355
R3
10%
19.731(4)
15.199(2)
7.916(2)
96.29(2)
2359
R3
25%
19.715(2)
15.214(2)
7.918(1)
96.10(1)
2361
When the starting amount of O-enzalutamide was equal to the amount of S-enzalutamide the conversion into R3 was no longer observed and two anhydrous phases were found: the main phase with cell parameters of the solid solution and the minor phase with cell parameters close to the R1. The DSC curve presents only one the melting peaks at 179°C. The Rietveld refinement on this 14 ACS Paragon Plus Environment
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Crystal Growth & Design
sample suggests the presence of 95% of solid solution and 5% of R1. While in the previous experiments the O-enzalutamide was totally incorporated in the solid solution and the excess of Senzalutamide separated out as form R3, in 50:50 experiment we obtained two solid solutions: a main phase with the richest amount of O-enzalutamide and a minor phase rich in S-enzalutamide, therefore the presence of O-Enzalutamide in the structure prevents the conversion of Senzalutamide R1 into R3. To sum up, O-enzalutamide and S-enzalutamide yields solid solutions as the isomorphic anhydrous form, though with a miscibility gap, while S-enzalutamide recrystallizes as almost pure form R3 also in presence of O-enzalutamide.
CONCLUSIONS In this paper we have described three crystal forms of the API S-enzalutamide and investigated the relative stability. The single crystal structure of the anhydrous form R1 (marketed by Astellas) has been determined and compared with the powder diffraction data. The S-Enzalutamide is prone to form solvated crystal forms which possess almost the same crystal structure. In fact, form R2 can be obtained by slurry in methanol or formic acid, the XRPD patterns are almost identical while TGA experiments confirm the presence of methanol, or formic acid (or mixture of the solvent with water) depending on experimental the conditions. Form R2 loses solvent at ca. 120-140°C and recrystallizes into the stable unsolvated form R1. In the case of recrystallization or slurry experiments in isopropyl alcohol a new hemisolvate form R3 is obtained. The structure of R3 has been determined from powder diffraction data and appears to be almost isostructural with R2. Upon heating, R3 releases the solvent and converts to R1. It worth noting that recrystallization in isopropanol to obtain R1 is the last step in the industrial processes. Our study shows that the unexpected formation of the solvate form R3 of S-enzalutamide can be advantageous because, while the impurity of O-enzalutamide can form a solid solution with R1, it does not form a solvate. Hence form R3 is not contaminated by O-enzalutamide, while form R1 can form a solid solution
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with the keto impurity. The purification process by recrystallizing as R3 instead of R1 is therefore more efficient and requires less recrystallization steps.
Corresponding Author *Prof. Lucia Maini e.mail:
[email protected]. Present Addresses † Flamma S.p.A. Via Cascina Secchi, 217, 24040 Isso (BG), Italy. § Zambon
‡
Group SpA, Vicenza plant QC department, via della Chimixa 36100 Vicenza (VI) Italy
F.I.S. Fabbrica Italiana Sintetici SpA, Lonigo plant R&D department, Via Dovaro snc,
36045 Almisano di Lonigo, (VI) Italy ¥ NEWCHEM
SPA, Via Roveggia 47/43B, 37136 Verona, Italy
ACKNOWLEDGMENT This research is financially supported by ZACH Chemical (now acquired by FIS). We thank Dr. Katia Rubini for the TGA and DSC measurements.
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For Table of Contents Use Only
Crystal forms of Enzalutamide and a Crystal Engineering Route to Drug Purification Lucia Maini * Dario Braga, Francesco Farinella, Elisa Melotto, Massimo Verzini, Roberto Brescello, Ivan Michieletto, Ilaria Munari.
Recrystallization of S-enzalutamide is the final step to purify the API form impurities, but when S-enzalutamide precipitates as anhydrous form, a solid solution is obtained with the impurity Oenzalutamide, decreasing the effectiveness of the process. On the other hand, when S-enzalutamide recrystallizes as solvate form, the solid solution with O-enzalutamide is avoided.
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