An unusual ionic cocrystal of ponatinib hydrochloride: characterization by single-crystal X-ray diffraction and ultra-high field NMR spectroscopy

Abstract

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon·HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a “square” arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A ¹³C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D ¹H and 2D ¹H–¹H DQ–SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D ³⁵Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and H⋯Cl⁻ hydrogen bonding arrangements. A 2D ³⁵Cl → ¹H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions.

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1. Introduction

A significant body of research has been devoted to relating the crystal structures of active pharmaceutical ingredients (APIs) to their physicochemical properties.^1–4 Various classes of solid forms of APIs exist, including polymorphs, salts, hydrates/solvates, cocrystals, amorphous phases (including amorphous solid dispersions), and various combinations of these forms. Each solid form of an API can have divergent physicochemical properties, and can sometimes be marketed as distinct pharmaceutical products.^5,6 Because of the integral relationship between molecular-level structure and the properties of each solid form, there is significant interest in developing methods for the structural characterization of APIs. Full structural characterization provides useful information for rational design of novel solid forms, which can lead to improvements in drug efficacy, safety, and protection of intellectual property.^7,8

Two common ways of modifying the physicochemical properties of an API are through the synthesis of salts (i.e., solids exhibiting complete charge transfer between two or more molecular components) and cocrystals (i.e., solids that are composed of two or more molecular and/or ionic components in the same crystal lattice, which are neither solvates or simple salts). Consequently, there is significant interest in studying the salt/cocrystal continuum,^9–11 especially as it relates to multicomponent crystals that are difficult to classify.¹² One uncommon group of API solid forms is those that contain an API with mixed charges on the counterion/coformer molecules. An example of this is the oxalate/oxalic acid salt cocrystal of escitalopram.¹³ The crystal structure contains two escitalopram cations balanced by an oxalate dianion. Also included in the structure, hydrogen bonded to each side of the oxalate, are neutral molecules of oxalic acid, which produce linear supramolecular chains. Other examples include the hydrogen oxalate salt of ritonavir that cocrystallizes with oxalic acid,¹⁴ and the tiotropium fumarate salt that cocrystallizes with fumaric acid,¹⁵ both of which feature linear hydrogen oxalate/oxalic acid and/or fumarate/fumaric acid supramolecular chains. To the authors' knowledge, there are no examples of solid forms featuring mixed charges on API molecules. Although some progress has been made in the study of these materials, a more complete understanding of the structures of materials falling within the salt/cocrystal continuum would benefit from the advancement of spectroscopic methods for the structural characterization of API solid forms.^8,16–21

Solid-state NMR (SSNMR) spectroscopy is a powerful technique for the structural characterization of APIs, as it can greatly augment the understanding of molecular-level structure obtained by other methods such as X-ray diffraction (XRD).²² In this regard, NMR crystallography has the potential to provide insight into crystal structures in the absence of high-quality diffraction data,^23–34 making the analysis of NMR spectra in terms of structural features a topic of considerable recent investigation.^35–40 1D and/or 2D ¹³C SSNMR experiments are among the most commonly used, that when paired with quantum chemical calculations using density functional theory (DFT), provide site-specific chemical information that can be linked directly to molecular-level structure.^38,41 However, these methods have limited applications for large molecules with many carbon atoms, where definitive spectral assignments often cannot be made. Furthermore, measurement of the isotropic chemical shifts alone may not provide rich structural information related to intermolecular bonding arrangements (although this could be obtained through measurement of the principal values of chemical shift tensors or through other 2D techniques).²²¹³C SSNMR also has limited applicability for the study of API dosage forms where interfering signals arise from excipient molecules (especially for those of low API wt%). ¹H SSNMR techniques also suffer from similar disadvantages, which are compounded by the smaller chemical shift range and the common presence of strong homonuclear dipolar coupling, which broadens spectral lines, even under conditions of moderate or fast magic angle spinning (MAS).⁴²

When an API is formulated as a hydrochloride (HCl) salt (which accounts for nearly half of oral dosage forms),⁴³³⁵Cl (nuclear spin, I = 3/2) SSNMR spectroscopy is invaluable for characterizing the local hydrogen bonding environments of chloride ions.^44–55 This sensitivity results from the fact that electric field gradients (EFGs) at the chlorine nucleus are extremely sensitive to ground-state electron density, as reflected in the appearance of the corresponding ³⁵Cl SSNMR central transition (CT, +1/2 ↔ −1/2) powder patterns, which are typically influenced by the second-order quadrupolar interaction. Furthermore, the number of magnetically distinct chloride ions in an API solid form is typically small, meaning that spectra can be readily assigned and interpreted in terms of their local H⋯Cl⁻ hydrogen bonding environments.^44–5035Cl SSNMR methods also have the ability to identify chemical changes that occur within dosage forms (e.g., the uptake of atmospheric water or the disproportionation of ions due to interactions with excipients),^56,57 quantify the wt% API in dosage forms,^46,56 and even characterize static and/or dynamic disorder in solids.⁵⁸ Various 2D SSNMR techniques that exploit (ultra)fast MAS and indirect detection of low-γ nuclides have been developed in recent years,^59–63 which could enhance understanding of H⋯Cl⁻ hydrogen bonding arrangements and their complex relationships with ³⁵Cl EFG tensors. Finally, the advent of ultra-high field NMR (e.g., using fields up to 35.2 T), possibly augmented through use of MQMAS techniques,^64–66 is expected to advance applications of ³⁵Cl SSNMR spectroscopy for the study of complex API solid forms with multiple overlapping patterns, including heterogeneous mixtures and amorphous solid dispersions.

This study focuses on a novel solid form of the API ponatinib hydrochloride, 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride (Scheme 1), a tyrosine-kinase inhibitor used for the treatment of leukemia.^67,68 At least eight different solid forms of ponatinib have been reported,^69–71 including one form that is used in the branded drug product Iclusig.^72–74 We report the synthesis and characterization of a ionic cocrystal of ponatinib HCl, (hereafter referred to as pon·HCl),⁷⁵ which features an unusual stoichiometry with an asymmetric unit containing both a monocation and a dication of the ponatinib molecule, three water molecules, and three chloride ions. The crystal structure is obtained through single-crystal X-ray diffraction, and the uncommon structural features are verified through multinuclear and multidimensional SSNMR spectroscopy, with an emphasis on ³⁵Cl NMR spectra acquired at fields up to 35.2 T. DFT calculations are used to refine the crystal structure, assign peaks in the complex ¹H and ¹³C SSNMR spectra, and provide relationships between the molecular-level structure and ³⁵Cl SSNMR spectra. We emphasize that this is the only solid form of ponatinib to be characterized by either XRD or SSNMR methods to date. Finally, we discuss the significance of the discovery of this unusual ionic cocrystal, its wider implications to the crystal engineering and pharmaceutical communities, and the utility of high-field SSNMR spectroscopy for the characterization of such materials.

Scheme 1 Molecular structure of ponatinib, showing the two possible sites of protonation. The ponatinib monocation is protonated at the position of N6, whereas the dication is protonated at N6 and N1.

2. Experimental

2.1. Synthesis

Synthesis of pon·HCl on from ponatinib monohydrochloride. Ponatinib monohydrochloride (501 mg, 0.88 mmol) was weighed into a round bottom flask, to which was added acetonitrile (5.0 mL) and formic acid (0.35 mL). The resulting suspension was placed in an oil bath at 50 °C. After stirring for 1 h, water (0.50 mL) was added. Immediate dissolution was observed, the resulting yellow solution was filtered while hot, and subsequently allowed to cool to room temperature (RT) over a 1.5 h period. Precipitation was observed after 2 h at RT. The suspension was stirred for an additional 16 h. The solids were collected by filtration, washed with cold acetonitrile (2.0 mL), and dried in a vacuum oven at RT to give pon·HCl as a yellow solid (248 mg, 50% yield).

Synthesis of pon·HCl from the freebase. Ponatinib freebase (83.8 g) was suspended in acetone (314 mL) and water (70 mL) at RT. HCl (aq) (19.17 g, 1.0 mol eq.) was added to the mixture. After stirring at RT for 30 min, the suspension was heated to 45–50 °C for 30 min, leading to complete dissolution. Formic acid (29.3 mL) was added, and the solution was stirred for 30 min. The solution was cooled to 20 °C, held at that temperature for 1 h, further cooled to 0–5 °C, and stirred for 16 h. The resulting precipitate was filtered and washed with cold acetone (168 mL). The yellow solid was dried in a vacuum oven at 55 °C for 3 h, to give pon·HCl (69.63 g, 83% yield).

Single crystal growth. Crystals of pon·HCl suitable for analysis by single-crystal X-ray diffraction (SCXRD) were grown in an unconventional manner. Ponatinib freebase was added to a 4 mL vial, and acetonitrile was added on top of the solid material until covered. 1 mL of a solution prepared from acetonitrile (10 mL), formic acid (0.7 mL), water (0.8 mL), and hydrochloric acid (concentrated, 0.2 mL) was then layered over the first acetonitrile solution in the vial. After two days at RT, both white needle and yellow block crystals were seen in the vial. The crystals were carefully separated using the Pasteur method, and PXRD data were acquired for each type of crystal. The yellow block crystals were found to be pon·HCl, and the white needles were found to be the previously reported ponatinib monohydrochloride.^69,70

2.2. Single crystal X-ray diffraction

SCXRD studies were conducted at the MAX facility at McMaster University (Hamilton, ON, Canada). A suitable crystal fragment was selected and frozen on a MiTeGen loop using n-paratone oil on a Bruker APEX-II CCD diffractometer with a Mo Kα radiation source. The temperature was kept at 100 K during data collection. Using OLEX2,⁷⁶ the structure was solved with the XT⁷⁷ structure solution program using intrinsic phasing and refined with the XL⁷⁸ refinement package using least squares minimization. The structure has been deposited in the Cambridge Structural Database under the deposition number 2302285 with database identifier PONLOX.

2.3. Solid-state NMR spectroscopy

Overview. Preliminary low-field SSNMR experiments were conducted at the University of Windsor (Windsor, ON, Canada) using a 9.4 T wide-bore Oxford magnet and a Bruker Avance III HD spectrometer with Larmor frequencies of ν₀(¹H) = 400.24 MHz and ν₀(³⁵Cl) = 39.22 MHz, and a revolution 5.0 mm HX static probe with the sample packed into 5.0 mm o.d. glass tubes. All high-field SSNMR spectra were acquired at the National High Magnetic Field Laboratory (NHMFL, Tallahassee, FL). Spectra obtained at 18.8 T used medium-bore Oxford magnets and a Bruker Avance III HD console for which ν₀(¹H) = 800.12 MHz, ν₀(¹³C) = 201.19 MHz, and ν₀(³⁵Cl) = 78.39 MHz, or a Bruker Avance NEO console with ν₀(¹H) = 799.74 MHz and ν₀(³⁵Cl) = 78.36 MHz. Static and MAS experiments were conducted using a Low-E 3.2 mm HXY MAS probe (designed and constructed at the NHMFL) with the sample packed into a 3.2 mm o.d. pencil-style zirconia rotor. Ultrafast MAS experiments used a Bruker 1.3 mm HCN MAS probe (with the ¹⁵N channel tuned to ³⁵Cl), or a NHMFL-built 1.3 mm HXY MAS probe with the sample packed into a 1.3 mm o.d. Bruker-style rotor. Spectra obtained at 35.2 T used the series-connected hybrid (SCH) magnet⁷⁹ and a Bruker Avance NEO console for which ν₀(¹H) = 1500.21 MHz and ν₀(³⁵Cl) = 146.98 MHz. Experiments used a NHMFL-built Low-E 3.2 mm HX MAS probe with the sample packed into a 3.2 mm o.d. pencil-style rotor. A summary of all acquisition parameters is provided in the ESI† (Tables S1–S4).

All spectra were processed and fit using the ssNake v1.3 software package.⁸⁰ Uncertainties in the EFG and chemical shift tensor parameters and Euler angles were assessed via bidirectional variation of each parameter, and visual comparison of experimental and simulated spectra.

¹³C NMR spectra. A ¹H → ¹³C{¹H} ramped-amplitude cross polarization (CP)/MAS sequence^81–84 was used to obtain the ¹³C SSNMR spectra, featuring a ¹H π/2 pulse of 3.33 μs, SPINAL-64 ¹H decoupling with ν₂ = 75 kHz,⁸⁵ a spinning rate of ν_rot = 18 kHz, a contact time of 2.0 ms with a Hartmann–Hahn matching field (50 kHz on the H channel, and matched on the X channel),⁸⁶ and a recycle delay of 30 s. Chemical shifts were referenced to neat TMS at δ_iso(¹³C) = 0.0 ppm using the high-frequency peak of α-glycine at δ_iso(¹³C) = 176.5 ppm as a secondary reference.⁸⁷

¹H NMR spectra. ¹H spectra were acquired at 18.8 T using ν_rot = 50 kHz, π/2 pulse widths of 2.5 μs, and a relaxation delay of 6.5 s. The 1D spectrum was collected using a Hahn-echo sequence with 8 coadded transients. The ¹H DQ–SQ spectrum was acquired using one rotor period of back-to-back (BABA) recoupling,^88,89 48 t₁ increments, and 16 coadded transients per increment. Chemical shifts were referenced to neat TMS at δ_iso(¹H) = 0.0 ppm, using the high-frequency peak in L-histidine HCl·H₂O at δ_iso(¹H) = 17.2 ppm.⁶¹

³⁵Cl NMR spectra. The ³⁵Cl spectra acquired at 9.4, 18.8, and 35.2 T used a Hahn-echo sequence with CT-selective π/2 pulses, with ¹H decoupling used for experiments at 9.4 and 18.8 T. The MAS experiment at 35.2 T used a spinning rate of ν_rot = 16 kHz. Chemical shifts were referenced to 0.1 M NaCl in D₂O at δ_iso(³⁵Cl) = 0.0 ppm using NaCl(s) at δ_iso(¹³C) = 41.1 ppm as a secondary reference.

³⁵Cl → ¹H D-RINEPT Spectrum. A 2D ³⁵Cl → ¹H spectrum was obtained at 18.8 T using the dipolar-mediated refocused insensitive nuclei enhanced by polarization transfer (D-RINEPT) sequence.^60,90 The spectrum was obtained with ν_rot = 50 kHz, a recycle delay of 0.5 s, 64 t₁ increments, and 4096 scans per increment. A 5.0 μs CT-selective π/2 pulse was applied on the ³⁵Cl channel. Rotor-synchronized dipolar recoupling was applied on the ¹H channel using symmetry-based SR4₁² recoupling⁹¹ with an rf field equivalent to two times ν_rot to fulfill the second-order R³ condition, which was calibrated through a separate ¹H π/2 pulse-spin lock pulse experiment.⁹² Enhanced CT-polarization was achieved through WURST pulse blocks applied on the ³⁵Cl channel prior to the D-RINEPT transfer step, using WURST-80 pulses with a 38.0 μs duration (followed by a 2.0 μs delay), a maximum rf of 30 kHz, a 50 kHz sweep width, and an optimized transmitter offset frequency of 300 kHz.^93,94

2.4. Additional characterization techniques

Additional characterization techniques, including powder XRD (PXRD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), potentiometric titrations, and solution-state ¹H NMR spectroscopy, are described in the ESI† S1.

2.5. Density functional theory calculations

Geometry optimizations. Plane-wave DFT calculations were performed using the CASTEP module within BIOVIA Materials Studio 2020 (ref. 95) using the single-crystal X-ray diffraction data for pon·HCl as an initial structural model. These calculations used the RPBE functional,⁹⁶ ultrasoft pseudopotentials generated on-the-fly,⁹⁷ a plane-wave cutoff energy of 800 eV, and a Monkhorst–Pack grid with a k-point spacing of 0.05 Å⁻¹.⁹⁸ Structural refinements employed the LBFGS energy-minimizing scheme,⁹⁹ with convergence thresholds including a maximum change in energy of 5 × 10⁻⁶ eV per atom, a maximum displacement of 5 × 10⁻⁴ Å per atom, and a maximum Cartesian force of 10⁻² eV Å⁻¹. Dispersion corrections were introduced using the semi-empirical two-body dispersion force field correction of Grimme (DFT-D2),^100,101 or a reparametrized version of this method introduced by the authors for applications in NMR crystallography (DFT-D2*).^102–104 These calculations used a two-step geometry optimization in which all atoms were first relaxed at the RPBE-D2 level (s₆ = 1.0; d = 20.0), followed by a second optimization in which only atoms involved in X–H⋯Cl⁻ (X = N, O) hydrogen bonding were relaxed at the RPBE-D2* level (s₆ = 1.0; d = 3.5), while all other atoms remained in fixed positions. This refined crystal structure was used in all subsequent computational analyses.

Thermochemistry. Single-point energy calculations were performed using the Amsterdam Modeling Suite (AMS 2021.106), in which a dimer of ponatinib molecules was used as a structural model to calculate the potential energy as a function of the intermolecular NH⁺⋯N hydrogen bond distance. These calculations employed the double-hybrid PBE0-2 functional,¹⁰⁵ which combines a 79% admixture of Hartree–Fock exchange and a 50% admixture of Møller–Plesset correlation with the PBE functional. Semiempirical dispersion was introduced through the three-body B3(BJ) model (s₆ = 0.540; s₈ = 0.515; a₁ = 0; a₂ = 8.345).^106,107 These calculations employed the TZ2P basis set with Becke integration set to “very good”.^108,109

Magnetic shielding and EFG tensors. Magnetic shielding tensors were calculated in CASTEP using the gauge-including projector-augmented wave (GIPAW) method¹¹⁰ and AMS using the gauge-including atomic orbital (GIAO) method.^111–115 CASTEP calculations used structural models consisting of the fully periodic crystal structure or an isolated molecule, whereas AMS calculations were performed on isolated molecules only. CASTEP calculations of EFG and magnetic shielding tensors used the RPBE functional,⁹⁶ ultrasoft pseudopotentials generated on-the-fly,⁹⁷ a plane-wave cutoff energy of 800 eV, and a Monkhorst–Pack grid with a k-point spacing of 0.05 Å⁻¹.⁹⁸ AMS calculations of magnetic shielding tensors used the TZ2P basis set, with Becke integration set to “very good”,^108,109 along with the hybrid PBE0 functional,¹¹⁶ which includes a 25% admixture of Hartree–Fock exchange.

³⁵Cl EFG and magnetic shielding tensors were calculated through a single periodic calculation using CASTEP. In contrast, ¹H and ¹³C magnetic shielding tensors were obtained from three separate calculations: (i) a RPBE calculation in CASTEP using the periodic crystal lattice as a structural model; (ii) a RPBE calculation in CASTEP using only an isolated molecule, which was approximated using a P1 unit cell with a size of 25 × 25 × 25 Å; and (iii) a final PBE0 calculation in AMS using an isolated molecule as the structural model. The difference between the first two calculations provides the intermolecular contributions to the ¹H and ¹³C chemical shifts, which are added to the higher level PBE0 calculation performed in AMS. The advantage of this method rests on the fact that magnetic shielding is largely a local phenomenon, meaning that the influences of weak noncovalent interactions on magnetic shielding tensors can be calculated at a tractable lower level.

¹H, ¹³C, and ³⁵Cl magnetic shielding constants were converted to their respective chemical shift scales through additional calculations on small organic molecules and comparison with previously published experimental chemical shifts (ESI† S2).^62,117–120 Euler angles describing the relative orientation of the chemical shift and EFG tensors, according to the ZY′Z′′ convention for rotation, were extracted from the CASTEP output files using EFGShield 4.1.¹²¹

3. Results and discussion

3.1. Synthesis and preliminary characterization

A novel solid form of the API ponatinib hydrochloride (pon·HCl) was synthesized from both ponatinib monohydrochloride and freebase ponatinib as reagents, with the former yielding powder samples, and the latter yielding either powders or large crystals, depending on the experimental conditions. All three synthetic pathways led to formation of the same novel product, as indicated by PXRD (Fig. 1). It was initially assumed that pon·HCl was simply a novel polymorph or hydrate of ponatinib monohydrochloride; however, subsequent analyses demonstrated that this was not the case.

Fig. 1 Experimental PXRD patterns of ponatinib monohydrochloride form I (red), the novel form pon·HCl (blue), and a simulated pattern based on the crystal structure of pon·HCl. There are some systematic differences in the peak positions in the experimental powder pattern of pon·HCl and the simulated pattern based on its crystal structure (especially at high 2θ angles), because the two datasets were obtained at 298 K and 100 K, respectively.

The structure of pon·HCl was determined by SCXRD, and found to be a complex multicomponent crystal featuring a ponatinib monocation, a ponatinib dication, three chloride ions, and three water molecules (vide infra). However, prior to the determination of the crystal structure and the precise establishment of the stoichiometry of various molecular and ionic components, several analytical techniques indicated that pon·HCl is a hydrate, and does not feature the anticipated 1.0 eq. of Cl⁻ to 1.0 eq. of ponatinib for a monohydrochloride salt. Powder samples of pon·HCl appear to be stable under ambient conditions and are unaffected by humidity. The DSC thermogram shows a broad, major endotherm with an onset at 175.4 °C, further indicating the stability of pon·HCl near RT (Fig. S1†). Analysis by TGA indicates a gradual reduction in mass of 4.4% during heating from ca. 30–175 °C, which is consistent with a loss of 1.5 eq. of H₂O relative to the 1.0 eq. of ponatinib (Fig. S2†). A potentiometric titration for Cl⁻ ions showed 8.50% Cl⁻ in the material, which is close to the 8.66% that would indicate 1.5 eq. of Cl⁻ with respect to the 1.0 eq. of ponatinib. The ¹H NMR (acetic acid-d₃) spectrum showed that ca. 0.06 wt% formic acid was retained in the final solid products (Fig. S3†) (N.B.: the role of formic acid in crystal nucleation is unknown, except for the fact that without it, pon·HCl is not formed. It may be that interactions involving formic acid, ponatinib, and other constituents play key roles in pre-organization, nucleation, and/or crystallization).

The consistent observation of 1.5 eq. of Cl⁻ (indicated by potentiometric titrations) and 1.5 eq. of H₂O (indicated by TGA) relative to the 1.0 eq. of ponatinib that would be anticipated for a monohydrochloride salt led us to reconsider the optimal synthetic conditions for preparing pon·HCl. To rule out the possibility that the excess Cl⁻ arises from interstitial sources (e.g., aqueous HCl), additional efforts were made to remove the excess chloride. Syntheses using <1.5 eq. of Cl⁻ resulted in lower yields, but still with 1.5 eq. of Cl⁻. Attempts to dry the material further using higher temperatures and stronger vacuum resulted in a reduction to 1.3 eq. of Cl⁻ in the final solid product, but with significant decreases in crystallinity (as indicated by PXRD). In the end, it was clear that the excess 0.5 eq. of chloride could not be removed without compromising the crystallinity of the solid form, and that a novel solid form had been produced with a stoichiometry distinct from that of a monohydrochloride salt. Therefore, an effort was made to characterize pon·HCl through the combination of SCXRD and multinuclear SSNMR spectroscopy.

3.2. Crystal structure and refinement

Pon·HCl crystallizes in the triclinic space group P1̄ (Table 1) with a structure that is composed of one ponatinib monocation, one ponatinib dication, three chloride anions, and three water molecules in the asymmetric unit (Fig. 2; see Fig. S4† for an overlay of the two ponatinib molecules), which is consistent with the preliminary observations made through TGA and potentiometric titrations. Both the mono- and dications of the ponatinib molecule are protonated on the methyl piperazine nitrogens (N6B and N6A, respectively), each forming a hydrogen bond with the nearby chloride ions (Cl1B and Cl1A, respectively). The dication molecule features an additional protonated nitrogen atom (N1A) within the imidazopyridazine moiety, with the associated hydrogen atom (H1A) found to be hydrogen bonded to the equivalent nitrogen atom (N1B) in the monocation (Fig. 3A). H1A was located in the difference map with a strong diffraction peak and refined as an isotropic hydrogen atom, causing a subsequent R₁ drop, casting no doubt as to which nitrogen atom is protonated (N1A).

Table 1 Single-crystal X-ray diffraction data and refinement parameters for pon·HCl

CCDC no.	2302285	V (Å^3)	2907.9(3)
Formula	C58H63Cl3F6N12O5	Z	2
Formula weight (g mol^−1)	1228.55	ρ calc (g cm^−3)	1.403
Crystal system	Triclinic	μ (mm^−1)	0.237
Space group	P1̄ (no. 2)	Reflections collected	97 752
T (K)	100.0(1)	Independent reflections	14 060 (Rint = 0.0692, Rσ = 0.0588)
a (Å)	12.4408(7)	Restraints/parameters	0/790
b (Å)	15.1905(8)	R 1[I > 2σ(I)]	0.0599
c (Å)	16.5411(9)	R 1 (all data)	0.0894
α (°)	92.864(3)	wR1 (all data)	0.1724
β (°)	102.624(3)	GoF on F^2	1.096
γ (°)	106.246(3)	Largest diff. peak/hole (e Å^−3)	0.67/−0.40

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Fig. 2 The structure of pon·HCl, as determined by single-crystal X-ray diffraction.

Fig. 3 (A) The hydrogen bonding motif of the two imidazopyridazine rings, with atom labels indicated. (B) The hydrogen bonding motif of Cl1 and three H₂O molecules.

Unusually, the third chloride ion (Cl1) was not located in the vicinity of hydrogen atoms associated with the positively charged protonated imidazopyridazine, charged amine, or amide moieties. In fact, Cl1 does not form hydrogen bonds with any organic moiety within the ponatinib molecules, with only a weak noncovalent interaction involving the aromatic proton H1AA at r(CH⋯Cl⁻) = 2.573 Å. However, Cl1 forms hydrogen bonds with two of the H₂O molecules, which each hydrogen bond with a third H₂O molecule, forming a “square” arrangement (Fig. 3B). The hydrogen atoms of the H₂O molecules were added in calculated positions, with the rigid H₂O groups oriented as indicated by the difference map peaks. The final electron density difference map gave no indication that any of the three H₂O molecules are protonated to form H₃O⁺ ions.

The crystal structure of pon·HCl was subjected to a dispersion-corrected plane-wave DFT geometry optimization in which all atomic positions were refined in a two-step process (vide supra), with the unit cell parameters fixed at their experimental values. All interatomic distances and calculated NMR interaction tensors reported in this work are determined from this refined crystal structure. Additionally, double-hybrid PBE0-2/D3(BJ) DFT calculations were used to confirm the position of H1A by varying its position along the bonding axis of the intermolecular NH⁺⋯N hydrogen bond (Fig. 4). These calculations indicate a double-well potential energy surface, with an activation barrier of 18.5 kJ mol⁻¹ with respect to the global energy minimum.

Fig. 4 Potential energy curve describing the position of the hydrogen atom within the intermolecular NH⁺⋯N hydrogen bond in pon·HCl, as predicted using DFT calculations at the double-hybrid PBE0-2/D3(BJ) level. The value of Δ(N⁺–H) designates the distance of the hydrogen atom with respect to the global energy minimum at Δ(N⁺–H) = 0 Å.

3.3. SSNMR spectroscopy

¹H → ¹³C{¹H} SSNMR spectra. The ¹H → ¹³C{¹H} spectrum acquired at 18.8 T and a ν_rot = 18 kHz features many overlapping peaks (Fig. 5A), consistent with the 54 crystallographically distinct carbon atoms observed in the crystal structure. A preliminary assignment of the peaks is made through DFT calculations (Fig. 5B), with a complete listing of all DFT calculated ¹³C chemical shifts provided in Table S5.† In general, it is only possible to assign the carbon sites to specific structural moieties, rather than to signals arising from crystallographically and magnetically distinct sites. Nonetheless, the observation of pairs of peaks (i.e., peak doubling in some cases) is evidence for the two crystallographically distinct ponatinib molecules in the crystal structure of pon·HCl. Additional experiments involving dipolar dephasing, or other spectral editing techniques, or possibly 2D techniques, could potentially lead to the assignments of a larger number of ¹³C peaks to chemically similar but magnetically distinct sites.

Fig. 5 (A) High-resolution ¹H → ¹³C{¹H} CP/MAS spectrum of pon·HCl acquired at 18.8 T with ν_rot = 18 kHz. Spinning sidebands are marked by asterisks (*). (B) Simulated ¹³C spectrum based on DFT calculations. (C) 1D ¹H Hahn echo spectrum of pon·HCl acquired at 18.8 T with ν_rot = 50 kHz. (D) Simulated ¹H spectrum based on DFT calculations.

¹H and ¹H–¹H DQ–SQ SSNMR spectra. The 1D ¹H SSNMR spectrum acquired at 18.8 T and ν_rot = 50 kHz features regions of strongly overlapping peaks, corresponding to the 63 crystallographically distinct hydrogen atoms in the asymmetric unit, most of which cannot be resolved or assigned definitively (Fig. 5C). A complete listing of all DFT calculated ¹H chemical shifts is provided in Table S6.† The resolved peak at δ_iso(¹H) = 18.8 ppm is assigned to the key imidazopyridazine proton (H1A), which is covalently bound to N1A in the ponatinib dication, and forms an intermolecular hydrogen bond with N1B in the monocation, leading to the high chemical shift that is indicative of a very deshielded proton (in agreement with DFT calculations, Fig. 5D).

A ¹H–¹H DQ–SQ spectrum, acquired at 18.8 T with ν_rot = 50 kHz and one rotor period of BABA recoupling, provides some additional resolution of ¹H spectral peaks (Fig. 6). In such an experiment, the ¹H–¹H homonuclear dipolar coupling is recoupled during the double quantum excitation and reconversion periods, leading to the observation of correlations between spatially proximate ¹H spins. Because the recoupling time is short, only the strongly coupled sites appear in the 2D spectrum. Peaks appear along the δ_DQ = 2δ_SQ diagonal line when (i) two crystallographically equivalent protons are close enough to produce through-space dipolar correlations or (ii) short-range correlations are observed between two nearby protons with the same chemical shift.¹²² Correlations between protons with different chemical shifts manifest as pairs of peaks that are equidistant from the diagonal line with a value of δ_DQ equal to the sum of the two distinct values of δ_SQ. The spectrum has clear off-diagonal peaks (marked with X) that demonstrate correlations between the well-resolved imidazopyridazine proton (H1A) and its nearest neighbor, H5A (δ_iso(¹H) = 10.6 ppm), which is predicted by DFT calculations to have the highest shift of the remaining protons. Additional off-diagonal peaks suggest correlations involving protons in the charged amine moieties, water molecules, and various species of aliphatic protons; however, clear features are not present that lend further insight into these relationships.

Fig. 6 A 2D ¹H–¹H DQ–SQ spectrum of pon·HCl acquired at 18.8 T with ν_rot = 50 kHz and one rotor period of BABA recoupling. The red diagonal line representing the relationship δ_DQ = 2δ_SQ is included as a visual aid. Connected off-diagonal peaks are indicated by blue horizontal lines and X's.

³⁵Cl and ³⁵Cl → ¹H D-RINEPT SSNMR spectra. ³⁵Cl SSNMR spectra were acquired under static conditions at 9.4 and 18.8 T, and under both static and MAS conditions at 35.2 T (Fig. 7). Of these, only the spectra acquired at 18.8 and 35.2 T were useful for determining the EFG and chemical shift tensors (vide infra). Spectra were acquired at multiple fields because the chemical shift interaction and second-order quadrupolar interaction (SOQI) have field-dependent manifestations in the CT patterns of half-integer quadrupolar nuclides (HIQNs) that scale in proportion to B₀ and B₀⁻¹, respectively. Typically, acquisition of spectra with sufficiently high MAS rates averages the chemical shift interaction and partially averages the SOQI, leading to CT powder patterns that are influenced by only three parameters: the isotropic chemical shift, δ_iso; quadrupolar coupling constant, C_Q; and asymmetry parameter, η_Q. Acquisitions of static spectra at two fields allows for the determination of additional parameters describing the chemical shift tensor (span, Ω; skew, κ) and the set of Euler angles (α, β, γ) defining the relative orientation of the principal axis systems of the EFG and chemical shift tensors (see Table 2 for definitions).

Fig. 7 Experimental ³⁵Cl SSNMR spectra of pon·HCl. Spectra of static samples were acquired at 9.4 T, 18.8 T, and 35.2 T, as well as under MAS (ν_rot = 16 kHz) conditions at 35.2 T. Spinning side bands are marked by asterisks (*).

Table 2 Summary of calculated and experimental ³⁵Cl EFG and chemical shift tensor parameters for pon·HCl^a,b,c,d,e

		C Q	η Q	δ iso	Ω	κ	α	β	γ
		(MHz)		(ppm)	(ppm)		(°)	(°)	(°)
a Theoretical EFG and chemical shift tensor parameters were obtained from calculations on XRD-derived structures and structures refined at the RPBE-D2* level. b The experimental uncertainties in the last digit for each value are indicated in parentheses. c The principal components of the EFG tensors are defined such that |V33| ≥ |V22| ≥ |V11|. The quadrupolar coupling constant and asymmetry parameter are given by CQ = eQV33/h, and ηQ = (V11 − V22)/V33, respectively. The sign of CQ cannot be determined from the experimental ^35Cl spectra. d The principal components of the chemical shift tensors are defined using the frequency-ordered convention, with δ11 ≥ δ22 ≥ δ33. The isotropic chemical shift, span, and skew are given by δiso = (δ11 + δ22 + δ33)/3, Ω = δ11 − δ33, and κ = 3(δ22 − δiso)/Ω, respectively. e The Euler angles α, β, and γ define the relative orientation of the EFG and chemical shift tensors using the ZY′Z′′ convention for rotation. The experimental angles derived from ssNake (which uses the ZX′Z′′ convention) are adjusted to match the calculated values extracted by EFGShield. f This parameter is not reported since has little effect on the appearance of simulated powder patterns.
Cl1	Exp.	2.21(4)	0.70(4)	52(2)	30(10)	—^f	—^f	100(20)	—^f
	DFT-D2*	2.51	0.47	84	26	0.65	181	80	98
ClA	Exp.	5.13(6)	0.40(5)	25(2)	80(10)	0.2(2)	90(10)	0(15)	10(5)
	DFT-D2*	−4.79	0.70	42	90	0.0	70	7	0
ClB	Exp.	5.66(6)	0.71(5)	70(2)	70(10)	—^f	—^f	0(5)	—^f
	DFT-D2*	−5.85	0.61	93	88	−0.10	98	40	1

---

The 1D ³⁵Cl SSNMR spectra indicate the presence of three overlapping patterns, corresponding to the three crystallographically and magnetically distinct chloride ions in the crystal lattice of pon·HCl (see Fig. 8 for a deconvolution of the 35.2 T MAS spectrum and Table 2 for NMR tensor parameters). The three overlapping patterns in the ³⁵Cl SSNMR spectra are readily assigned to their respective crystallographic sites through use of plane-wave DFT calculations due to the substantial differences in the EFG and chemical shift tensors (vide infra). In the 35.2 T MAS spectrum, the three patterns have relative integrated intensities of 1.0 : 1.0 : 0.9, which is close to the anticipated ratio of 1 : 1 : 1 (Cl1 : Cl1A : Cl1B). The spectra show no evidence of impurity phases, including the products of disproportionation reactions; this conclusion is further supported by the absence of any sharp peaks in Bloch decay spectra acquired at 9.4 T, using relaxation delays of 1.0 and 8.0 s (Fig. S5†).

Fig. 8 Experimental ³⁵Cl spectrum of pon·HCl acquired at 35.2 T with a spinning rate of ν_rot = 16 kHz, along with a total simulated pattern representing the three overlapping chloride sites, and deconvolutions of the three underlying patterns.

The comparison of ³⁵Cl static Hahn-echo spectra acquired at 9.4, 18.8, and 35.2 T demonstrates a striking example of the utility of ultra-high field SSNMR for the analysis and structural characterization of APIs with unusual crystal structures and correspondingly complex SSNMR spectra. Only the spectra acquired at 18.8 and 35.2 T have patterns of high enough quality from which EFG and chemical shift tensor parameters could be derived (Fig. 7). In contrast, the spectrum acquired at 9.4 T shows clear evidence of the narrow feature corresponding to the chloride ion Cl1, but only low signal-to-noise features with no apparent discontinuities corresponding to the broader patterns of Cl1A and Cl1B.

The local environments of chloride ions, especially number, types, and spatial arrangements of H⋯Cl⁻ hydrogen bonds, influence ³⁵Cl EFG tensors, with the strongest effects exerted by those featuring r(H⋯Cl⁻) of 2.2 Å or less.^44–47 Our previous work on qualitatively identifying these relationships is briefly summarized in ESI† S3. The three ³⁵Cl patterns for pon·HCl can be definitively assigned from DFT calculations of the ³⁵Cl chemical shift and EFG tensors on a model of the refined crystal structure (Fig. 9, Table 3). Of the three overlapping patterns evident in the ³⁵Cl spectra, the narrow pattern (C_Q = 2.21 MHz; η_Q = 0.70) corresponds to Cl1; this is one of only a handful of examples of a chloride ion in an organic crystalline solid that forms hydrogen bonds exclusively with water molecules to be characterized by ³⁵Cl SSNMR spectroscopy.¹²³ This site features two hydrogen bonds with water molecules at distances of r(H⋯Cl⁻) = 2.234 and 2.235 Å. DFT calculations demonstrate that the sign of C_Q is positive, and V₃₃ is not oriented in the direction of any hydrogen bonding axis and does not appear to be constrained by any obvious symmetry or pseudo-symmetry element. However, V₁₁ and V₂₂ reside approximately within the plane of the three water molecules, indicating positive EFGs within this plane and negative EFGs perpendicular to the plane. The two broader patterns correspond to chloride ions that form hydrogen bonds with both water molecules and the charged tertiary amine moieties, and have correspondingly larger magnitudes of C_Q. Cl1A (C_Q = 5.16 MHz; η_Q = 0.41) features hydrogen bonds with a charged amine moiety at r(H⋯Cl⁻) = 2.151 Å and a water molecule at r(H⋯Cl⁻) = 2.208 Å. Similarly, Cl1B (C_Q = 5.66 MHz; η_Q = 0.71) features hydrogen bonds with a water molecule at r(H⋯Cl⁻) = 2.327 Å, a charged amine moiety at r(H⋯Cl⁻) = 2.335 Å, and an amide contact at r(H⋯Cl⁻) = 2.507 Å. For both sites, DFT calculations predict the sign of C_Q to be negative, with V₃₃ oriented in the general direction of charged tertiary amine moiety, and approximately perpendicular to the hydrogen bond with the water molecule.

Fig. 9 ³⁵Cl EFG tensor orientations for the three chloride ions in pon·HCl. H⋯Cl⁻ hydrogen bonds (<2.6 Å) are shown as dotted blue lines. The three yellow vectors represent the orientations of the principal components of the EFG tensors (V₁₁, V₂₂, and V₃₃), with one principal components perpendicular to the page in each case.

Table 3 Structural information for the H⋯Cl⁻ hydrogen bonds in pon·HCl

Chloride site	Contact type^a	H⋯Cl^− distance^b	X⋯Cl^− distance^c	X–H⋯Cl^− angle^d
		(Å)	(Å)	(°)
a Indicates the functional group contributing to the H⋯Cl^− contacts (i.e., HOH⋯Cl^− signifies a water contact, RR′R′′NH^+⋯Cl^− signifies a charged tertiary amine contact, and CH⋯Cl^− signifies an aromatic contact). b The shortest H⋯Cl^− hydrogen bonds (<2.6 Å, X = N, O) as determined via energy minimization and geometry optimization with DFT plane wave calculations. c Distance between the chloride ion and the hydrogen-bond donor atom (X = N, O). d Angle between the hydrogen-bond donor atom (X = N, O), the hydrogen atom, and the chloride atom.
Cl1	HOH⋯Cl^−	2.234	3.142	164.4
	HOH⋯Cl^−	2.235	3.152	167.6
	CH⋯Cl^−	2.574	3.548	148.3
Cl1A	RR′R′′NH^+⋯Cl^−	2.151	3.124	166.4
	HOH⋯Cl^−	2.208	3.122	165.9
Cl1B	HOH⋯Cl^−	2.327	3.255	177.3
	RR′R′′NH^+⋯Cl^−	2.335	3.228	150.8
	RR'NH⋯Cl^−	2.507	3.452	166.3

---

In order to confirm the assignment of the chloride ions and their proximities with neighboring protons, a 2D ³⁵Cl → ¹H D-RINEPT spectrum was acquired with a spinning speed of ν_rot = 50 kHz and five rotor periods of SR4₁² recoupling (Fig. 10). Similar to the 1D ³⁵Cl MAS spectrum acquired at 35.2 T, the f₁ projection (i.e., the ³⁵Cl dimension) of the 2D D-RINEPT spectrum has an overall appearance that results from three overlapping ³⁵Cl patterns, corresponding to the three crystallographically distinct chloride ions. The f₂ projection (i.e., the ¹H dimension) features three groupings of peaks, resulting in a spectrum with more detail than observed in the 1D ¹H MAS spectrum. The 2D D-RINEPT spectrum features several cross peaks that result from dipolar interactions between the chloride ions and nearby protons. For instance, the strong peaks that occur at δ_iso(¹H) = 8.5 ppm for a broad range of ³⁵Cl frequencies are indicative of interactions between Cl1A and Cl1B and the hydrogen-bond donating charged tertiary amine moieties (H6A and H6B, respectively). The cross peak at δ_iso(¹H) = 3.8 ppm likely corresponds to water molecules that form hydrogen bonds with each of the chloride ion sites. Finally, the peak at δ_iso(¹H) = 9.9 ppm, which corresponds to the aromatic proton H1AA, has a cross peak indicating correlation to Cl1; this is in accordance with the crystal structure, where r(H1AA⋯Cl1⁻) = 2.507 Å.

Fig. 10 2D ³⁵Cl → ¹H D-RINEPT correlation spectrum of pon·HCl, acquired at 18.8 T with ν_rot = 50 kHz. Five rotor periods of recoupling was found to maximize the observed signal. A 1D ¹H spectrum is overlaid on top of the spectrum, whereas a simulated ³⁵Cl spectrum is overlaid on the left side.

4. Conclusion

The structure of a novel ionic cocrystal of ponatinib hydrochloride was determined by single crystal X-ray diffraction, and further characterized by SSNMR and DFT methods. The crystal structure contains both ponatinib monocations and dications, along with three chloride ions and three water molecules. The use of a variety of solid-state analytical techniques, including SCXRD and SSNMR in the present case, can uncover the nature of the noncovalent bonding interactions between the API molecules and other molecular or ionic components that constitute this multicomponent crystal, providing a detailed understanding of the key hydrogen bonds that serve to stabilize the structure.

SSNMR spectroscopy is invaluable for confirming the unusual crystal structure of pon·HCl. 1D ³⁵Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, which were assigned using plane-wave DFT calculations of their respective ³⁵Cl EFG and chemical shift tensors. The 2D ³⁵Cl → ¹H D-RINEPT spectrum confirms the spatial proximities between all three chloride ions and water molecules, amine protons, and even an aromatic proton. The ¹H → ¹³C{¹H} CP/MAS NMR spectrum confirms the presence of two crystallographically distinct ponatinib molecules in the asymmetric unit. 1D ¹H and 2D ¹H–¹H DQ–SQ spectra identify an unusually deshielded ¹H peak, which is assigned to the imidazopyridazine moiety that forms an intermolecular hydrogen bond from the ponatinib dication to the monocation. This all suggests future applications of multinuclear SSNMR spectroscopy at high and ultra-high fields to the study of complex HCl API materials for which SCXRD data is unavailable, including those exhibiting complex ¹H, ¹³C, and/or ³⁵Cl SSNMR spectra with overlapping patterns, with low wt% chlorine, and comprising heterogeneous mixtures or amorphous solid dispersions.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank the Florida State University and the National High Magnetic Field Laboratory for funding this research (materials, computers, spectrometer time, and NMR hardware). In addition, R. W. S and S. T. H. thank the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Award Number DE-SC0022310, for support of personnel involved in this work. The National High Magnetic Field Laboratory is supported by the National Science Foundation through NSF/DMR-1644779 and NSF/DMR-2128556, and the State of Florida. The Development of the 36 T Series-Connected Hybrid magnet and NMR instrumentation was supported by NSF (DMR-1039938 and DMR-0603042) and NIH (GM122698 and GM148766). The authors acknowledge the use of the MAX Diffraction Facility, McMaster University. The authors also thank the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery grant 2016-06642), the Canadian Foundation for Innovation, the Ontario Innovation Trust, the Ontario Research Fund, and the University of Windsor for supporting the initial stages of this project.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2302285. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ce01062g

‡ These authors have contributed equally.

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