Exploration of Solid Forms of Crisaborole: Crystal Engineering

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Exploration of Solid Forms of Crisaborole: Crystal Engineering Identifies Polymorphism in Commercial Sources and Facilitates Cocrystal Formation Gonzalo Campillo-Alvarado, Tighe Didden, Shalisa Oburn, Dale C. Swenson, and Leonard R. MacGillivray Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00375 • Publication Date (Web): 15 May 2018 Downloaded from http://pubs.acs.org on May 16, 2018

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Crystal Growth & Design

Exploration of Solid Forms of Crisaborole: Crystal Engineering Identifies Polymorphism in Commercial Sources and Facilitates Cocrystal Formation Gonzalo Campillo-Alvarado, Tighe D. Didden, Shalisa M. Oburn, Dale C. Swenson and Leonard R. MacGillivray* Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA. KEYWORDS Pharmaceutical cocrystals; polymorphism; benzoxaborole; boron pharmaceutics; crystal engineering

ABSTRACT

We report the discovery of three polymorphs of the very recently FDA-approved boroncontaining API Crisaborole. Crisaborole displays polymorphism based on the syn– (Form I) and anti– (Form II) conformations of the hydroxyl group of the oxaborole ring as shown by singlecrystal X-ray analysis. Forms I and II were discovered based on the availability from two

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different commercial suppliers, while Form III was obtained upon heating of Form I or II. A cocrystal based on 4,4’-bipyridine was also obtained.

Boron-based (B-based) active pharmaceutical ingredients (APIs) have emerged as a highlypromising platform for the development of new therapies. To date, the FDA has approved three B-containing APIs; namely, Bortezomib, Tavaborole, and Crisaborole. Crisaborole (AN2728, trade name: Eucrisa®), a non-steroidal topical agent used for the treatment of atopic dermatitis, is the latest addition to an emerging library.1,2 The mechanism of action includes inhibitory activity against the phosphodiesterase 4 and inflammation-related cytokine release.3 Crisaborole shares with B-containing therapeutic agents a benzoxaborole skeleton (i.e. boronic acid hemi-ester) that confers unique bioactivities and low toxicity.4,5 However, the design of dosage forms has been limited to topical and intravenous administrations; moreover, the development and study of solid forms has been relatively unexplored.6 Recently, our group embarked in studies to design solid forms of B-pharmaceutics by the generation of cocrystals of the antifungal agent Tavaborole.7 As part of our efforts to explore crystalline forms of boron APIs, we report the first solid forms of AN2728. Specifically, we describe the discovery of three polymorphs of AN2728 and the generation of a cocrystal of composition 2(AN2728)·(bpy) (where: bpy = 4,4’-bipyridine) (Scheme 1). The discovery of the initial two polymorphs of AN2728 originates from each polymorph being sold from two different commercial suppliers. Specifically, Forms I and II of AN2728 are available and packaged by the quantity discount fine chemical suppliers ArkPharm, Inc. and ComiBlocks, Inc., respectively.8,9 Form III was elucidated by thermal studies.


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Scheme 1. Structures and functionalities: (a) Crisaborole (AN2728) and (b) oxaborole conformations (e.g. syn– and anti–) and supramolecular synthons solid forms (c) I and (d) II of AN2728, and (e) cocrystal with bpy.

In our initial experiments, we crystallized AN2728 (20 mg) (ArkPharm, Inc., white solid, 250 mg bottle) in diethyl ether (3 mL) by slow evaporation. The crystallization experiment afforded colorless plates (Form I). A single-crystal X-ray diffraction (SCXRD) analysis revealed AN2728 to crystallize in the triclinic space group P-1 (Fig. 1). AN2728 self-associates into dimers sustained by (B)O– H⋯O(H)B hydrogen bonds (O1⋯O2’: 2.7825(3) Å). The hydrogen-bond synthon of Form I is based on two benzoxaborole molecules in a syn-conformation, which compares favorably to


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reported benzoxaboroles (Fig. 1a).10-12 The dimers assemble to generate one-dimensional (1D) tapes along the a-axis sustained by bifurcated C–H⋯N≡C forces. The bifurcated interaction is regarded as a robust synthon in crystal engineering.13,14 Adjacent molecules interact by weak C– H⋯O hydrogen bonds along the c-axis (Fig. 1b).

Sheets perpendicular to the b-axis are

sustained by edge-to-face π-interactions involving a benzoxaborole ring and 4-cyanophenyl group (Fig. 1c). Short B(sp2)⋯π and B(sp2)⋯O contacts are also present as with benzoxaborole analogs.15

Figure 1. X-ray structure of Form I of AN2728: (a) syn-dimer with (B)O–H⋯O(H)B hydrogen bonds, (b) 1D chains along a-axis sustained by C–H⋯N contacts, and (c) sheets oblique to baxis.

While an X-ray powder diffraction study of the commercially-available powder AN2728 (ArkPharm, Inc.) showed peaks that matched Form I, there were a number of unidentifiable


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peaks also present in the diffractogram (Fig. 2). In particular, prominent peaks were located at 2θ = 16.6, 20.8, 21.8, and 22.6o (Fig. 2, arrows). We note that liquid-assisted grinding (LAG) of the commercial solid from ArkPharm, Inc. using diethyl ether16 resulted in the unidentified peaks to disappear and to give a powder pattern that matched Form I. The LAG experiment, thus, resulted in the solid converting entirely to the identified Form I.17

Figure 2. X-ray powder patterns of AN2728. Arrows indicate unidentifiable peaks in bulk commercial sample purchased from ArkPharm, Inc.

The unidentified peaks present in the diffractogram of the solid of AN2728 obtained from Arkpharm Inc. matched those from the material manufactured by CombiBlocks, Inc. (250 mg bottle, white solid). Repeated attempts to crystallize AN2728 (CombiBlocks, Inc.) from diethyl ether invariably afforded a polycrystalline powder. A diffractogram of the resulting powder


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revealed prominent peaks at 2θ = 16.6, 20.7, 22.6, and 27.8o. The peaks closely matched the unidentified peaks in AN2728 (ArkPharm, Inc.).

We managed to grow single crystals as

colorless plates (Form II) by slow evaporation of a toluene solution (3 mL) of AN2728 (CombiBlocks, Inc.) (20 mg). A SCXRD analysis of Form II revealed AN2728 to crystallize in the monoclinic P21/n space group with two full molecules in the asymmetric unit (Fig. 3a). Adjacent molecules of AN2728 Form II, similar to Form I, are sustained by two (B)O–H⋯O(H)B hydrogen bonds (O2⋯O4: 2.698(6) and O1⋯O5: 2.720(6) Å) (Fig. 3a). In contrast to Form I, however, the oxaborole moiety adopts an anti-conformation whereby the molecules self-assemble to form catamers parallel to the a-axis (Fig. 3b). C–H⋯O hydrogen bonds (C6⋯O5: 3.276(9) and C20⋯O2: 3.344(9) Å) contribute to the formation of the catamers. There are few reported examples of a benzoxaborole that adopts the anti-conformation in the solid state.18-20 As a consequence of the assembly process, the molecules of Form II form chains along the b-axis. Additional C–H⋯O forces extend the packing into sheets that stack approximately perpendicular to the c-axis (Fig. 3c).


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Figure 3. X-ray structure of Form II of AN2728: (a) anti-conformation, (b) catamer formed via (B)O–H⋯O hydrogen bonds, and (c) stacked organization of sheets.

Differential scanning calorimetry (DSC) indicated that Form I21 underwent a transformation to another solid phase at 129.1°C (5°C/min) and then melting at 176.9°C. The two events contrasted a DSC trace of Form II22 showed three thermal events at 125.6 oC, 131.8 o

C, and 179.8 oC.23,24

A competition slurry experiment (diethyl ether. room temperature)

containing a mixture of Form I and Form II showed a complete transformation to Form I in a period of three days, confirming Form I to be the most thermodynamically stable polymorph of the pair.25 The highest temperature endotherm present in both thermograms of Form I and Form II corresponds to melting of Form III of AN2728. Heating of either Form I or Form II to 145 oC for a period of 30 minutes resulted in an opaque, reddish solid. Further heating of the reddish solid showed a single endotherm at 177.2 oC. A PXRD analysis of revealed a solid phase showing prominent peaks at 2θ = 5.4, 17.2, 18.6, 19.9 and 26.3, absent in Form I and Form II. A combination of 1H NMR spectroscopy and HR-MS showed the composition of AN2728 to remain intact. We were unable to grow single crystals of Form III from diethyl ether, methanol, and toluene, among other solvents.


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Figure 4. DSC traces of Forms I, II and III of AN2728.

The ability of AN2728 to support cocrystal formation7 was realized with the cocrystal 2(AN2728)·(bpy). Single crystals of 2(AN2728)·(bpy) in the form of irregular prisms were obtained from slow solvent evaporation of AN2728 and bpy (9.33 mg, 0.060 mmol) in methanol (3 mL). 2(AN2728)·(bpy) crystallizes in the monoclinic space group C2/c (Fig. 5).

The

molecules form a discrete, three-component assembly, similar to AN2690, held together by two (B)O–H⋯Npyr hydrogen bonds (O2⋯N2: 2.7443(2), and O5⋯N3: 2.7729(2) Å) (Fig. 5a). The pendant hydrogen-bonded molecules of the API adopt an anti-conformation. The hydrogen bonding between the benzoxaborole and central linker of 2(AN2728)·(bpy) are characterized by different twist angles (36.8 and 75.0o). The pyridyl ring planes are also twisted from one another (37.4°). The three-component assembly adopts an overall zig-zag conformation.7

Adjacent

assemblies interact by –C≡N⋯H–C forces to form 1D chains along the b-axis.14 Edge-to-face π– stacking between Ar-CN rings organize the components into columns within the ac-plane (Fig. 5b).


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Figure 5. X-ray structure of 2(AN2728)·(bpy): (a) three-component assembly via (B)O–H⋯Npyr hydrogen bonds and (b) organization of AN2728 and bpy molecules into chains.

In conclusion, we have described solid forms of Crisaborole (AN2728) that involve discoveries of three polymorphs and generation of a cocrystal. We show that the solid forms of commercially-available AN2728 differ based on availability from the chemical supplier. We suggest that while the growing market of Eucrisa®, and additional APIs in the drug pipeline, continue to demand approved APIs to be readily available commercially, crystal engineers will adopt a role to effectively monitor solid forms of APIs as related to quality control from increasing numbers of suppliers.

ASSOCIATED CONTENT


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Supporting Information Experimental information, DSC thermograms, PXRD patterns, and additional SCXRD data is provided in the ESI. X-ray crystallographic information files (CIF) are available for compounds AN2728-I AN2728-II, and 2(AN2728)·(bpy) (CCDC 1586479−1586481). All the supplemental information is available free of charge. Experimental conditions, 1H NMR spectra, powder X-ray diffractograms, and DSC thermograms (PDF) AUTHOR INFORMATION Corresponding Author *Leonard R. MacGillivray. E-mail: [email protected]. Fax: +1 319-335-1270. Tel: +1 319-335-3504. ORCID: 0000-0003-0875-677X Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. Additional note Crystal Data for AN2728-I (CCDC 1586479): (M =251.04 g/mol): triclinic, space group P-1 (no. 2), a = 6.4765(6) Å, b = 6.8814(7) Å, c = 14.9388(15) Å, α = 84.725(5)°, β = 78.179(5)°, γ = 64.672(5)°, V = 589.01(10) Å3, Z = 2, T = 190.15 K, µ(MoKα) = 0.099 mm-1,


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Dcalc = 1.415 g/cm3, 8482 reflections measured (5.572° ≤ 2θ ≤ 52.922°), 2409 unique (Rint = 0.0183, Rsigma = 0.0211) which were used in all calculations. The final R1 was 0.0341 (I > 2σ(I)) and wR2 was 0.0881 (all data). Crystal Data for AN2728-II (CCDC 1586480): (M =502.08 g/mol): monoclinic, space group P21/n (no. 14), a = 7.9862(8) Å, b = 18.1721(18) Å, c = 17.2488(17) Å, β = 102.788(5)°, V = 2441.2(4) Å3, Z = 4, T = 190.15 K, µ(MoKα) = 0.095 mm-1, Dcalc = 1.366 g/cm3, 24719 reflections measured (4.482° ≤ 2Θ ≤ 49.99°), 4308 unique (Rint = 0.2441, Rsigma = 0.2343) which were used in all calculations. The final R1 was 0.0838 (I > 2σ(I)) and wR2 was 0.2296 (all data). Crystal Data for 2(AN2728)·(bpy) (CCDC 1586481): (M =658.26 g/mol): monoclinic, space group I2/a (no. 15), a = 14.3073(18) Å, b = 9.2733(12) Å, c = 48.676(7) Å, β = 90.119(4)°, V = 6458.1(15) Å3, Z = 8, T = 170.7 K, µ(MoKα) = 0.092 mm-1, Dcalc = 1.354 g/cm3, 44574 reflections measured (5.494° ≤ 2Θ ≤ 53.116°), 6656 unique (Rint = 0.0622, Rsigma = 0.0536) which were used in all calculations. The final R1 was 0.0420 (I > 2σ(I)) and wR2 was 0.1051 (all data).

ACKNOWLEDGMENT We gratefully acknowledge financial support from the National Science Foundation (LRM DMR-1708673), CONACYT-COVEICYDET (GCA) and the University of Iowa Graduate College. TDD gratefully acknowledges the Belin-Blank Center of the University of Iowa. We also thank Brian Morrison and Jaclyn Wrona for assistance with IR spectroscopy and DSC analysis, respectively.


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For Table of Contents Use Only

SYNOPSIS We present the discovery of the first solid forms of the billion-dollar-drug Crisaborole (AN2728), which is a boron-containing API recently approved by the FDA for the treatment of atopic dermatitis (eczema). The results include a crystallographic analysis of two polymorphs of AN2728, and the formation of one cocrystal with 4,4’-bipyridine. The relevance of crystal engineering for the analysis of commercial materials is also highlighted.


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Exploration of Solid Forms of Crisaborole: Crystal Engineering

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