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Crystal structure of pomalidomide Form I, C13H11N3O4

Published online by Cambridge University Press:  16 February 2021

James A. Kaduk Open the ORCID record for James A. Kaduk [Opens in a new window] ,
Amy M. Gindhart  and
Thomas N. Blanton Open the ORCID record for Thomas N. Blanton [Opens in a new window]
James A. Kaduk*
Affiliation:
North Central College, 131 S. Loomis St., Naperville, Illinois 60540, USA Illinois Institute of Technology, 3101 S. Dearborn St., Chicago, Illinois 60616, USA
Amy M. Gindhart
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania 19073-3273, USA
Thomas N. Blanton
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania 19073-3273, USA
*
a)Author to whom correspondence should be addressed. Electronic mail: kaduk@polycrystallography.com

Abstract

The crystal structure of pomalidomide Form I has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Pomalidomide Form I crystallizes in the space group P-1 (#2) with a = 7.04742(9), b = 7.89103(27), c = 11.3106(6) Å, α = 73.2499(13), β = 80.9198(9), γ = 88.5969(6)°, V = 594.618(8) Å3, and Z = 2. The crystal structure is characterized by the parallel stacking of planes parallel to the bc-plane. Hydrogen bonds link the molecules into double layers also parallel to the bc-plane. Each of the amine hydrogen atoms acts as a donor to a carbonyl group in an N–H⋯O hydrogen bond, but only two of the four carbonyl groups act as acceptors in such hydrogen bonds. Other carbonyl groups participate in C–H⋯O hydrogen bonds. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™ (PDF®).

Keywords

pomalidomidePomalystRietveld refinementdensity functional theory

Information

Type
New Diffraction Data
Information
Powder Diffraction , Volume 36 , Issue 2 , June 2021 , pp. 114 - 119
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press on behalf of International Centre for Diffraction Data

I. INTRODUCTION

Pomalidomide, marketed under the brand names Pomalyst® and Imnovid®, is a derivative of thalidomide. It is used as a treatment for relapsed and refractory multiple myeloma. Pomalidomide belongs to a class of medications called immunomodulating agents. First, pomalidomide functions by helping the bone marrow to produce normal blood cells, and second, it enhances the ability of immune cells to kill abnormal cells in the bone marrow. The IUPAC name (CAS Registry Number 19171-19-8) is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione. The molecular structure of pomalidomide is illustrated in Figure 1.

Figure 1.

The molecular structure of pomalidomide (occurs as a racemic mixture).

Crystalline forms A, B, C, D, E, F, G, and H of pomalidomide were claimed in International Patent Application WO 2005/023192 A2 (Chen et al., Reference Chen, Muller, Jaworsky, Saindane and Cameron2005), and powder diffraction data were provided. An additional unnamed crystalline dihydrate is claimed by Celgene in US Patent 10,093,647 B1 (Atwood, Reference Atwood2017). A process for the preparation of crystalline Form I of pomalidomide is claimed by Hetero Research Foundation (Reddy et al., Reference Reddy, Reddy, Reddy, Reddy and Krishna2017) in US Patent Application 2017/0088537 A1, and a powder pattern is reported; however, there was no report of a crystal structure. The International Patent Application WO 2014/170909 A2 (Reddy et al., Reference Reddy, Reddy, Reddy, Reddy and Krishna2014) is an equivalent description of Form I.

This work was carried out as part of a project (Kaduk et al., Reference Kaduk, Crowder, Zhong, Fawcett and Suchomel2014) to determine the crystal structures of large-volume commercial pharmaceuticals and include high-quality powder diffraction data for these pharmaceuticals in the Powder Diffraction File (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019).

II. EXPERIMENTAL

The sample was a commercial reagent, purchased from Sigma (Lot #71284), and was used as received. The white powder was packed into a 1.5-mm diameter of Kapton capillary and rotated during the measurement at ~50 Hz. The powder pattern was measured at 295 K at beamline 11-BM (Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Kurtz, Antao, Jiao and Toby2008; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.457899 Å from 0.5 to 50° 2θ with a step size of 0.001° and a counting time of 0.1 s step−1.

The pattern was indexed on a primitive triclinic unit cell with a = 7.04711, b = 7.89086, c = 11.31211 Å, α = 73.236, β = 80.933, γ = 88.609°, V = 594.6 Å3, and Z = 2 using N-TREOR (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013). Since pomalidomide is marketed as a racemate, the space group was assumed to be P-1, which was confirmed by successful solution and the refinement of the structure. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) yielded two hits, but no structures for pomalidomide derivatives.

A pomalidomide molecule was downloaded from PubChem (Kim et al., Reference Kim, Chen, Cheng, Gindulyte, He, He, Li, Shoemaker, Thiessen, Yu, Zaslavsky, Zhang and Bolton2019) as Conformer3D_CID_134780.sdf. It was converted into a .mol2 file using Materials Studio (Dassault, 2020) and a Fenske-Hall Z-matrix using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). The structure was solved by Monte Carlo simulated annealing (parallel tempering) techniques as implemented in FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002).

Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 2.2–27.0° portion of the pattern was included in the refinement (d min = 0.981 Å). All non-H-bond distances and angles were subjected to restraints based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011) of the model. The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 2.7% to the final χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2020). A common U iso was refined for the non-H atoms. The U iso of the hydrogen atoms were constrained to be 1.3× those of the heavy atoms to which they are attached. The background was modeled using a six-term shifted Chebyshev polynomial, along with a peak at 5.95° to model the scattering from the Kapton capillary and any amorphous component of the sample. The peak profiles were described using the generalized microstrain model, and a second-order spherical harmonic preferred orientation model was included.

The final refinement of 92 variables using 24 840 observations and 55 restraints yielded the residuals of R wp = 0.0849 and GOF = 1.75. The largest peak (0.32 Å from C15) and hole (1.95 Å from C9) in the difference Fourier map were 0.27 and –0.23(6) eÅ−3, respectively. The largest errors in the fit (Figure 2) are in the shapes of some of the low-angle peaks.

Figure 2.

The Rietveld plot for the refinement of pomalidomide Form I. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale is multiplied by a factor of 10× for 2θ > 10.0°.

A density functional geometry optimization (fixed experimental unit cell) was carried out using CRYSTAL14 (Dovesi et al., Reference Dovesi, Orlando, Erba, Zicovich-Wilson, Civalleri, Casassa, Maschio, Ferrabone, De La Pierre, D-Arco, Noël, Causà and Kirtman2014). The basis sets for the H, C, N, and O atoms were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994). The calculation was run on eight 2.1 GHz Xeon cores (each with 6 GB RAM) of a 304-core Dell Linux cluster at IIT, using eight k-points and the B3LYP functional, and took ~21 h.

III. RESULTS AND DISCUSSION

This synchrotron powder pattern of pomalidomide does not match the patterns of Celgene's Forms A through H (Figure 3; Chen et al., Reference Chen, Muller, Jaworsky, Saindane and Cameron2005) but does match that of Hetero's Form I (Figure 4; Reddy et al., Reference Reddy, Reddy, Reddy, Reddy and Krishna2017) well enough to conclude that they represent the same material. The commercial product studied here was thus apparently crystallized from a mixed solvent at T > 70 °C during its manufacture. The refined atom coordinates of pomalidomide Form I and the coordinates from the DFT optimization are reported in the Crystallographic Information Framework (CIFs) deposited with the ICDD.

Figure 3.

Comparison of the synchrotron pattern from this study of pomalidomide to the experimental patterns of Forms A through H reported by Chen et al. (Reference Chen, Muller, Jaworsky, Saindane and Cameron2005). The published patterns were digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.457899 Å using MDI JADE Pro (MDI, 2020). The synchrotron data are in front, and the patent patterns range from Form A to Form H toward the rear.

Figure 4.

Comparison of the synchrotron pattern from this study (black) of pomalidomide to the experimental pattern (green) of Form I reported by Reddy et al. (Reference Reddy, Reddy, Reddy, Reddy and Krishna2017). The published pattern was digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.457899 Å using MDI JADE Pro (MDI, 2020).

The root-mean-square Cartesian displacement of the non-hydrogen atoms in the Rietveld-refined and DFT-optimized structures is 0.067 Å (Figure 5), well within the normal range for correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion concentrates on the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 6, and the crystal structure is presented in Figure 7. The crystal structure (Figure 7) is characterized by the parallel stacking of planes parallel to the bc-plane. Hydrogen bonds link the molecules into double layers also parallel to the bc-plane. All of the bond distances, angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).

Figure 5.

Comparison of the Rietveld-refined (red) and DFT-optimized (blue) structures of pomalidomide Form I.

Figure 6.

The asymmetric unit of pomalidomide Form I, with the atom numbering. The atoms are represented by 50% probability spheroids.

Figure 7.

The crystal structure of pomalidomide Form I, viewed down the b-axis.

Analysis of the contributions to the total crystal energy using the Forcite module of Materials Studio (Dassault, 2020) suggests that angle deformation terms are the dominant contributions to the intramolecular deformation energy, as expected for a molecule, which contains a fused ring system. The intermolecular energy is dominated by electrostatic attractions, which, in this force-field-based analysis, include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.

As might be expected, each of the amine hydrogen atoms acts as a donor to a carbonyl group in a N–H⋯O hydrogen bond (Table I), but only two of the four carbonyl groups act as acceptors in such hydrogen bonds. The energies of the N–H⋯O hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). These hydrogen bonds link the molecules into double layers. Chains and rings with graph set symbols (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000) R2,2(14), R2,2(8), C1,1(9), C1,1(11), C2,2(11), and larger patterns make up these layers. There are several C–H⋯O hydrogen bonds involving carbonyl groups.

Table I.

Hydrogen bonds (CRYSTAL14) in pomalidomide Form I.

a Intramolecular.

The volume enclosed by the Hirshfeld surface (Figure 8; Hirshfeld, Reference Hirshfeld1977; Turner et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) is 291.74 Å3, 98.12% of half of the unit cell volume. The molecules are thus not tightly packed. All of the significant close contacts (red in Figure 8) involve the hydrogen bonds. The volume/non-hydrogen atom is 14.9 Å3.

Figure 8.

The Hirshfeld surface of pomalidomide Form I. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.

The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect platy morphology for pomalidomide Form I, with {001} as the principal faces. A second-order spherical harmonic model for preferred orientation was incorporated into the refinement. The texture index was only 1.001(0), indicating that preferred orientation was slight in this rotated capillary specimen. The powder pattern of pomalidomide Form I from this synchrotron data set has been submitted to the ICDD for inclusion in the Powder Diffraction File™.

IV. DEPOSITED DATA

The Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement (including the raw data) and the DFT geometry optimization were deposited with the ICDD. The data can be requested at info@icdd.com.

ACKNOWLEDGEMENTS

The use of the Advanced Photon Source at Argonne National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-06CH11357. This work was partially supported by the International Centre for Diffraction Data. We thank Lynn Ribaud and Saul Lapidus for their assistance in the data collection, and Andrey Rogachev for the use of computing resources at IIT.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

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Figure 0

Figure 1. The molecular structure of pomalidomide (occurs as a racemic mixture).

Figure 1

Figure 2. The Rietveld plot for the refinement of pomalidomide Form I. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale is multiplied by a factor of 10× for 2θ > 10.0°.

Figure 2

Figure 3. Comparison of the synchrotron pattern from this study of pomalidomide to the experimental patterns of Forms A through H reported by Chen et al. (2005). The published patterns were digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.457899 Å using MDI JADE Pro (MDI, 2020). The synchrotron data are in front, and the patent patterns range from Form A to Form H toward the rear.

Figure 3

Figure 4. Comparison of the synchrotron pattern from this study (black) of pomalidomide to the experimental pattern (green) of Form I reported by Reddy et al. (2017). The published pattern was digitized using UN-SCAN-IT (Silk Scientific, 2013) and scaled to the synchrotron wavelength of 0.457899 Å using MDI JADE Pro (MDI, 2020).

Figure 4

Figure 5. Comparison of the Rietveld-refined (red) and DFT-optimized (blue) structures of pomalidomide Form I.

Figure 5

Figure 6. The asymmetric unit of pomalidomide Form I, with the atom numbering. The atoms are represented by 50% probability spheroids.

Figure 6

Figure 7. The crystal structure of pomalidomide Form I, viewed down the b-axis.

Figure 7

Table I. Hydrogen bonds (CRYSTAL14) in pomalidomide Form I.

Figure 8

Figure 8. The Hirshfeld surface of pomalidomide Form I. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.