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Powder X-ray diffraction of acalabrutinib dihydrate Form III, C26H23N7O2(H2O)2

Published online by Cambridge University Press:  27 May 2024

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

Abstract

The crystal structure of acalabrutinib dihydrate Form III has been refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Acalabrutinib dihydrate Form III crystallizes in space group P21 (#4) with a = 8.38117(5), b = 21.16085(14), c = 14.12494(16) Å, β = 94.5343(6)°, V = 2497.256(20) Å3, and Z = 4 (Z′ = 2) at 295 K. The crystal structure consists of herringbone layers parallel to the ac-plane. Hydrogen bonds between the acalabrutinib and water molecules generate a three-dimensional framework. Each water molecule acts as a donor in two hydrogen bonds and as an acceptor in at least one hydrogen bond. Amino groups and pyridine N atoms link the acalabrutinib molecules into dimers. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Keywords

acalabrutinibCalquencecrystal structureRietveld refinementdensity functional theory

Information

Type
Data Report
Information
Powder Diffraction , Volume 39 , Issue 4 , December 2024 , pp. 283 - 286
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Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited
Copyright
Copyright © The Author(s), 2024. Published by Cambridge University Press on behalf of International Centre for Diffraction Data

Acalabrutinib (sold under the brand name Calquence) is used to treat various types of non-Hodgkin lymphoma like chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Acalabrutinib is a kinase inhibitor used for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior cancer therapy. The systematic name (CAS Registry Number 1420477-60-6) is 4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide. The crystal structures of Forms I (anhydrous) and III (dihydrate, CAS Registry Number 2648852-74-6) of acalabrutinib, as well as powder data for several other forms and derivatives, are reported in US Patent 9,796,721 B2 (Blatter et al., Reference Blatter, Ingallinera, Barf, Aret, Krejsa and Evarts2017; Acerta Pharma B.V.). 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 them in the Powder Diffraction File (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019).

The synchrotron X-ray powder diffraction pattern (Figure 1) of a commercial reagent (purchased from TargetMol, lot #119209) was measured at 11-BM at APS (Antao et al., Reference Antao, Hassan, Wang, Lee and Toby2008; 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) using a wavelength of 0.459744(2) Å. The pattern was indexed using JADE Pro (MDI, 2023). The unit cell matched that reported for the single-crystal structure of Form III dihydrate by Blatter et al. (Reference Blatter, Ingallinera, Barf, Aret, Krejsa and Evarts2017), which is not in the Cambridge Structural Database. Only the major component of a disordered portion of the molecule was included in the model. The structure was refined (Figure 2) using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013), and optimized using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996). A single-point density functional calculation (fixed experimental cell) and population analysis was carried out using CRYSTAL23 (Erba et al., Reference Erba, Desmarais, Casassa, Civalleri, Donà, Bush, Searle, Maschio, Daga, Cossard, Ribaldone, Ascrizzi, Marana, Flament and Kirtman2023).

Figure 1.

The synchrotron X-ray powder diffraction pattern of acalabrutinib dihydrate Form III. The y-axis is the square root of the intensity. The inset shows a ball-and-stick drawing of the asymmetric unit of acalabrutinib dihydrate. Image generated using JADE Pro (MDI, 2023) and Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).

Figure 2.

The Rietveld plot for the refinement of acalabrutinib dihydrate Form III. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The vertical scale has been multiplied by a factor of 10× for 2θ > 9.2°.

The crystal structure (Figure 3) consists of herringbone layers parallel to the ac-plane, or alternatively as slightly wavy layers parallel to the bc-plane. Hydrogen bonds between the acalabrutinib and water molecules generate a three-dimensional framework. Each water molecule acts as a donor in two hydrogen bonds (Table I) and as an acceptor in at least one hydrogen bond. The amino groups N19 and N54 of the two independent molecules, with the pyridine N atoms N15 and N50, link the acalabrutinib molecules into dimers. The amino groups N25 and N60 form hydrogen bonds to water molecules. The energies of the O–H⋯O hydrogen bonds were calculated using the correlation of Rammohan and Kaduk (Reference Rammohan and Kaduk2018), and the energies of the N–H⋯O hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). A variety of C–H⋯O and C–H⋯N hydrogen bonds also contribute to the lattice energy.

Figure 3.

The crystal structure of acalabrutinib dihydrate Form III, viewed down the a-axis. Image generated using Diamond (Crystal Impact, 2023).

TABLE I.

Hydrogen bonds (CRYSTAL23) in acalabrutinib dihydrate Form III.

a Intramolecular.

I. DEPOSITED DATA

The powder pattern of acalabrutinib dihydrate Form III from this synchrotron data set has been submitted to ICDD for inclusion in the Powder Diffraction File. 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 pdj@icdd.com.

ACKNOWLEDGMENTS

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 Saul Lapidus for his assistance in the data collection.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

References

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Figure 0

Figure 1. The synchrotron X-ray powder diffraction pattern of acalabrutinib dihydrate Form III. The y-axis is the square root of the intensity. The inset shows a ball-and-stick drawing of the asymmetric unit of acalabrutinib dihydrate. Image generated using JADE Pro (MDI, 2023) and Mercury (Macrae et al., 2020).

Figure 1

Figure 2. The Rietveld plot for the refinement of acalabrutinib dihydrate Form III. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The vertical scale has been multiplied by a factor of 10× for 2θ > 9.2°.

Figure 2

Figure 3. The crystal structure of acalabrutinib dihydrate Form III, viewed down the a-axis. Image generated using Diamond (Crystal Impact, 2023).

Figure 3

TABLE I. Hydrogen bonds (CRYSTAL23) in acalabrutinib dihydrate Form III.