Salts, solvates and hydrates of the multi-kinase inhibitor drug pazopanib with hydroxybenzoic acids†

Sunil K. Rai *^a, Debjani Baidya ^a and Ashwini K. Nangia *^ab
aDivision of Organic Chemistry, CSIR – National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India. E-mail: sunilbhu28@gmail.com; ashwini.nangia@gmail.com; ak.nangia@ncl.res.in
^bSchool of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India

First published on 29th July 2021

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1. Introduction

Extensive research in the field of crystal engineering has advanced our understanding of supramolecular synthons which direct crystal packing and in a retrosynthetic sense provide strategies for the design of pharmaceutical solids with tailored physicochemical properties.^1–5 To improve the physicochemical performance of active pharmaceutical ingredients (APIs), usually drug molecules are screened to obtain the optimal salt (ionic), cocrystal (neutral) or polymorph (different forms of the same molecule)^2,6–8 Due to stability problems during tableting, processing and storage and unpredictable changes of physical properties, polymorphs are generally not preferred unless it is the stable thermodynamic form.⁹ Further complications can arise from disappearing polymorphs.¹⁰ In contrast, the design of salts and cocrystals by utilizing the supramolecular synthon approach^1,3,5 and the proton state using the ΔpK_a rule (pK_a of conjugate acid of base – pK_a of acid)^11–13 is more consistent with the experimental outcomes. Salt and cocrystal screens not only provide crystal forms with enhanced physicochemical properties of the API but also give more stable multicomponent solids and open opportunities for fixed dose combinations (FDCs) for drugs.^14–17 A few FDCs are in clinical testing phases with promising leads.^17,18 Several salt-cocrystal multi-drug combinations were approved in the past 5–6 years. Entresto, for the treatment of chronic heart failure, contains sacubitril monosodium or valsartan disodium as the hemipentahydrate structure.¹⁹ A cocrystal of TAK-020-gentisic acid is formulated for solid dose administration.^20,21 Steglatro (ertugliflozin and pyroglutamic acid 1:1 cocrystal)^22–24 and Suglat (ipragliflozin and L-proline 1:1 cocrystal)^25,26 were approved as SGLT2 (sodium glucose co-transporter 2) inhibitor drugs for the treatment of type-II diabetes.

Pazopanib (trade name VOTRIENT®) is a multi-kinase inhibitor drug approved in 2009 by the US FDA for the treatment of advanced renal cell carcinoma (RCC). This drug was selected because it exhibits very poor solubility at pH 1.1 (gastric environment 0.65 mg mL⁻¹) and insoluble above pH 4 in aqueous medium (below 0.1 mg mL⁻¹).^27,28 Pazopanib (PAZ) is a Biopharmaceutics Classification System (BCS) class II drug wherein poor aqueous solubility and slow dissolution rate limit bioavailability. The main constituents of the PAZ structure are an indazole ring, 2-aminopyrimidine ring and benzenesulfonamide ring. The three basic functional groups of different pK_a values are 2-aminopyridine (pK_a 6.4 for N1), indazole (pK_a 2.1 for N2), and sulfonamide NH (pK_a 10.2) (Scheme 1).²⁹ The indazole ring has an aromatic nitrogen atom which can act as a hydrogen bond acceptor (pK_a 2.1). The 2-aminopyrimidine moiety has a strong hydrogen bond acceptor nitrogen atom with a pK_a value of 6.4. In general, the 2-aminopyrimidine moiety shows a centrosymmetric homosynthon of N–H⋯N hydrogen bonds as an R²₂(8) motif in single component crystals. The same motif is also observed in multicomponent crystals with a heterosynthon interaction.^30–34 The sulfonamide group has a weakly acidic proton as a hydrogen bond donor; however, the oxygen atoms can behave as hydrogen bond acceptors and the centrosymmetric sulfonamide N–H⋯N homosynthon of R²₂(8) motif is expected.^35–38 Other hydrogen bond patterns for the sulfonamide group have been reported.^36,39–47

With the presence of basic N functional groups and SO₂NH in PAZ we selected hydroxybenzoic acids (HBAs) and dihydroxybenzoic acids (DHBAs) as complementary acidic partner coformers with possibility of proton transfer to give the salt of the cocrystal.^48–50 Furthermore, several HBAs/DHBAs are in Generally Recognized As Safe (GRAS) food substances⁵¹ and benzoic acid derivatives are present in several drugs (currently more than 450 marketed drugs have the carboxylic acid group).⁵²HBAs/DHBAs were selected as conformer molecules.^{31,32,53–55} Computational studies in combination with single crystal X-ray diffraction (SC-XRD) suggest that the OH group in benzoic acid can be a stronger donor than COOH and that the COOH group bonds with the second-best acceptor.⁵⁰ When a potential acceptor assists in hydrogen bonding of the CO group in COOH with an additional hydrogen-bond donor (e.g. an amine proton in the 2-aminopyridine moiety), then the COOH group is the preferred donor.^50,56 These studies show that mere consideration of the ΔpK_a between the donor and acceptor is not the correct way to predict the outcome of acid–base complexes. The prediction by using the ΔpK_a rule between donor–acceptor complexes is the formation of salt (ΔpK_a > 3, preferably 4) and cocrystal (ΔpK_a ≤ 0, preferably −1) or a continuum hybrid state (0 < ΔpK_a < 3, the expanded scale is −1 < ΔpK_a < 4).¹³ ΔpK_a determination is associated with the equilibrium phenomenon in solution that depends on factors such as the nature of the solvent, measurement technique, temperature during the measurement, and so forth.¹² Therefore, the salt or cocrystal not only depends on acid–base systems but sometimes is determined by the hydrogen bonds and supramolecular interactions in donor–acceptor pairs in a crystal structure. ΔpK_a in solution or gas phase serves as a guide but the actual state of proton transfer in the solid state can be quite different. Acid–base systems and salt–cocrystal equilibrium are important topics in the crystal engineering of pharmaceutical cocrystals and salts.⁵⁷

2. Results and discussion

We succeeded in co-crystallizing eight benzoic acid derivatives (Scheme 2) with the PAZ molecule and also reported the crystal structure of PAZ and a tetrahydrofuran solvate (PAZ·THF). All these ten crystal structures are novel and characterized by single crystal X-ray diffraction (Table 1), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). A detailed supramolecular synthon analysis of all the crystal structures was carried out for crystal engineering of related salts/cocrystals in the future. Dissolution analysis of the neat PAZ molecule and HBA/DHBA salts was carried out in a 1:1 water–methanol mixture (because of insolubility of PAZ in aqueous medium) at pH 4 buffer to know the relative dissolution rate of different salts.

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2.1 Cocrystal screening and preparation

Crystallization of PAZ was attempted in various solvents which showed that it is practically insoluble in aprotic solvents, except dipolar solvents like DMSO and DMF. Methanol and ethanol showed marginally better solubility at elevated temperature (>50 °C) but diffraction quality single crystals were not obtained. THF showed significantly better results and a solvated crystalline form PAZ·THF was crystallized. The neat form of PAZ was harvested in a slightly acidic medium, by using 2-propylpentanoic acid in acetonitrile. Initially 2-propylpentanoic acid (common name valproic acid, which is a drug) was used for cocrystallization as a drug–drug but cocrystallization was not observed. When excess valproic acid was added for cocrystallization the crystals were found to be PAZ single crystals suitable for single crystal X-ray diffraction (SC-XRD). Attempts with the more common acid acetic acid gave poor quality crystals. Slow evaporation in the presence of higher boiling acid could be a factor for better quality crystals with valproic acid. Further attempts were not made to optimize this crystallization. Next co-crystallization of PAZ was attempted with a wide range of carboxylic acid derivatives. In the initial experiments, it was observed that crystal growth was faster and diffraction quality crystals were obtained within aromatic carboxylic acids compared to aliphatic carboxylic acids (observation under ambient conditions). One of the most important steps in co-crystallization of multicomponent systems is the selection of solvent or a mixture of solvents which determines the kinetics of crystal nucleation and thus the crystal growth (due to the solubility difference in each component in that solvent). The solvent screening for combinations of PAZ and HBA/DHBA systems suggested that their solubility was significant in methanol/ethanol but again no single crystals could be obtained. To obtain good quality crystals, solvent system optimization of a mixture of methanol/ethanol solvents was used with several aprotic solvents, and it was found that acetonitrile gave the best combination with methanol in a 1:1 ratio. Subsequently, most of the co-crystallizations were carried out in a 1:1 ratio of methanol and acetonitrile. The poor growth of PAZ and 24DHBA crystals from methanol led to an ethanol–acetonitrile mixture. The crystal structures showed that PAZ·23DHBA and PAZ·26DHBA do not contain any solvent or water molecules in the crystal packing. The other structures contain solvent/water stoichiometry, e.g.PAZ·2HBA·MeOH, PAZ·4HBA·H₂O, PAZ·24DHBA·EtOH, PAZ·25DHBA·4H₂O, PAZ·35DHBA·MeOH·H₂O and PAZ·CFA·CH₃CN.

2.2 Molecular geometry analysis

The 2-aminopyrimidine functional group of PAZ participates in strong hydrogen bonding with the COOH group of HBAs/DHBAsvia O–H⋯N and N–H⋯O interactions; therefore COOH and 2-aminopyrimidine participate in the most preferred heterosynthon shown in Scheme 3.^50,56 The ΔpK_a values¹³ between the acceptor group of PAZ (pyrimidine ring nitrogen)²⁹ and the hydrogen bond donor of HBAs/DHBAs (COOH) (Table 2)⁵⁸ predict the proton location in the acid–base systems.^57,59 In the case of a cocrystal the cyclic ring motif R²₂(8) will have O–H⋯N and N–H⋯O hydrogen bonds (synthon I in Scheme 3) such that one donor and one acceptor are present on each functional group of the heterosynthon. After proton transfer from COOH to pyrimidine N1, the ionic bonding will be N⁺–H⋯O and N–H⋯O (or a delocalized structure with the positive and negative charges distributed on the aminopyridinium and carboxylate groups, synthon II in Scheme 3).^{30,31,33,50,59} In the reported set of crystal structures, the acid–base pairs show calculated ΔpK_a ≥ 3.00, and ionic salt formation through heterosynthon II. Predicting the proton transfer in the ΔpK_a range −1 to 4, typical for organic acids and bases, is a probabilistic outcome depending on a number of structural and experimental factors, and Cruz-Cabeza¹³ suggested based on an extensive CSD analysis that the likelihood of salt formation is 60%, 80% and 90% when ΔpK_a > 2, >3 and >3.75, respectively.

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The hydrogen atom position refinement in the X-ray crystal structures shows that the acidic proton is transferred from COOH to the aromatic nitrogen N1 of 2-aminopyrimidine (Fig. 1). Direct visualization of the electron density of hydrogen atoms within the 2-aminopyrimidine and COOH heterosynthon was performed by using Fourier difference maps (Fig. 2). The electron density of the hydrogen atom (bright red circular spots) is well localized near the pyrimidine ring nitrogen atom in all the complexes which is corroborated by the complete transfer of the hydrogen atom from COOH to the N1 of the 2-aminopyrimidine ring. In the case of PAZ·4HBA·H₂O, the difference electron density map shows a slight smearing out of the electron density along the hydrogen bond as a second peak with distributed intensity peaks suggesting that the hydrogen atom is partially occupied near the oxygen atom of the COOH group.⁶⁰ In the present situation it is reasonably clear that the major proton position in the PAZ·4HBA·H₂O complex is indicative of a salt rather than a cocrystal. High resolution X-ray or neutron diffraction at variable temperature measurements will answer this question unambiguously.

It is well known that the C–C–O parameters of carboxylic acid in neutral and anionic forms will be different.⁶¹ Therefore, one can know salt/cocrystal formation by measuring the C–O and CO bond distances of the carboxyl group in the crystal structures. Based on CSD analysis of benzoic acid derivatives, it has been found that the C–O and CO distances in neutral carboxylic acid are 1.31(2) Å and 1.21(2) Å, and for the delocalized carboxylate ion the average C–O distance is 1.25(2) Å (intermediate value between double and single bonds).⁶² The C–C–O distances/angles of HBAs and DHBAs in multicomponent crystals lie in the range d₁/d₂ 1.25–1.28 Å and θ₁/θ₂ 122.7–123.7° (Table 3). These values are consistent with a carboxylate group and salt formation. As the C–O bond distance of the carboxyl group decreases the corresponding C–C–O angle increases in benzoic acids with near coplanarity.⁶¹ In present cases, all PAZ·HBA/DHBA complexes follow the latter pattern except PAZ·4HBA·H₂O and PAZ·CFA·CH₃CN. Furthermore, protonated pyridine/pyrimidine rings (pyridinium group) show larger C–N–C bond angles than those in neutral form (pyridine ring).^32,61,62 The C–N–C bond angle in PAZ and PAZ·THF is ∼114.3–114.5°, while in PAZ·HBA/DHBA complexes the angle is 119.0–119.6°, expanded by about 5° (Table 3), suggesting again the protonated pyrimidine ring (CNH⁺–C) of PAZ. These pieces of evidence prove that salt formation takes place in the crystal structures of PAZ·HBA/DHBA complexes with N⁺–H⋯O and N–H⋯O hydrogen bonded cyclic heterosynthons. A secondary question is: does the best donor–best acceptor rule follow in the heterosynthon R²₂(8) ring motif, wherein the 2-hydroxy group of HBA/DHBA attenuates the hydrogen bond acceptor strength of one of the carboxylate oxygen atoms due to intramolecular hydrogen bonding? It was observed that the oxygen atom engaged the intramolecular hydrogen bond in HBAs/DHBAs interacts with the weaker neutral N–H(amine) in the heterosynthon motif (compared to the stronger N⁺–H(pyridine) donor) except for PAZ·23DHBA. In PAZ·23DHBA, there is non-planarity of the participating atoms/groups in hydrogen bonding (torsion angle = 33.66°) (Table 3, Scheme 4).

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2.3 Crystal structure analysis

2.4 Thermal analysis

Differential scanning calorimetry (DSC) analysis and thermal gravimetric analysis (TGA) of PAZ and its salts were carried out to understand the thermal behavior (samples were air-dried). DSC of PAZ free base (used as received from the vendor) shows a single endotherm at 312 °C. The THF solvate shows a broad endotherm at ∼190 °C with a weight loss of ∼14% (between 100 and 200 °C), followed by a sharp melting endotherm at ∼314 °C, corresponding to the free drug (Fig. 13a). The continuous weight loss from 40 °C to 100 °C in TGA of PAZ·THF is due to desorption of unbound surface water. In several solvated/hydrated salts, desorption of unbound water was observed to the extent of ∼1–2% weight loss. The uptake of moisture by the salts will pose problems in the scale up and drug formulation. Desolvation/dehydration of crystallized solvent/water is characteristic of the occupancy and binding through hydrogen bonds to the crystal structure. PAZ·2HBA·CH₃OH undergoes a phase transition at ∼55 °C (before desolvation) followed by loss of methanol at ∼80–140 °C during the DSC temperature scan (Fig. 13b). However, in PAZ·4HBA·H₂O the water molecules appear to be very tightly bound to the crystal because in DSC there is no endotherm and TGA does not show any weight loss below 200 °C (Fig. 13c). Desolvation of PAZ·24DHBA·EtOH is observed at ∼45–120 °C with a single broad endotherm (Fig. 13e), and PAZ·25DHBA·4H₂O shows an overlap of two endotherms between 40 and 100 °C (Fig. 13f). TGA confirms that dehydration of PAZ·25DHBA·4H₂O occurs in two steps, where two water molecules escape rapidly (the channel water molecules) below 100 °C and the remaining two (tightly hydrogen bonded water molecules) are released slowly after 100 °C up to 240 °C. The mixed solvate hydrate PAZ·35DHBA·MeOH·H₂O shows a complex DSC thermogram but analysis in conjugation with TGA suggests that methanol loss occurs at ∼50–100 °C and water escapes between 100 and 170 °C. The loss of both methanol and water results in phase transitions, as seen in multiple endotherms of DSC (Fig. 13h). Similar to PAZ·4HBA·H₂O, desolvation of PAZ·CFA·CH₃CN occurs with melting of the solid above 200 °C (Fig. 13i).

Five of the eight salt forms (PAZ·2HBA·CH₃OH, PAZ·4HBA·H₂O, PAZ·23DHBA, PAZ·25DHBA·4H₂O and PAZ·26DHBA) display two sharp endotherms between 200 and 320 °C. The first peak between 200 and 280 °C is due to melting of HBAs/DHBAs (accompanied with decomposition of the hydroxy acids visible as weight loss in TGA) and the second endotherm at 300–320 °C is attributed to the melting of PAZ. The DSC thermogram of the remaining three salt forms PAZ·24DHBA·EtOH, PAZ·35DHBA·MeOH·H₂O and PAZ·CFA·CH₃CN showed one melting endotherm after the loss of the crystallization solvent/water molecule. TGA indicated weight loss arising from the dissociation of CCFs during the melting process between 200 and 280 °C (calculated and observed weight loss are given in Table S2, ESI†). These data indicate that unlike disproportionation in the previous five salts, these three salts show melting with decomposition.

2.5 Dissolution study

The dissolution rate and solubility of a solid drug substance in aqueous medium are important to understand its bioavailability. Equilibrium solubility is a thermodynamic parameter defined as the maximum concentration of a solute in the solvent at fixed temperature. Solution mediated phase transformation of the residual solids after the equilibrium measurements can result in a new solid phase, e.g. a hydrate.⁶⁸ Most of the PAZ salts are either solvates or hydrates, which indicates that there is possibility of change in the solid phase in the solubility measurement medium. The dissolution rate is a surface kinetic phenomenon where mass transfer occurs on the solid–liquid interface and these processes are directly related to the measurement of the intrinsic dissolution rate of the drug substance. The dissolution profile of PAZ and only two of its salts which are non-solvated/non-hydrated could be determined, namely PAZ·23DHBA and PAZ·26DHBA, because the remaining salts did not exhibit a stable consistent phase behavior due to additional solvent and water molecules. Dissolution experiments were carried out in 1:1 aqueous phosphate buffer (pH 4) and methanol mixture (methanol is used to increase the solubility to measurable values) (Fig. 14). Both salts exhibit faster solubility kinetics compared to the reference drug over a 3 h period, which is long enough time for most tablets and oral powders to dissolve. The PAZ salts with HBAs in this study and the recent report⁶⁹ on the dissolution and solubility of pazopanib hydrochloride at different pH conditions opens opportunity to modulate the pharmacokinetics of this important cancer drug.

3. Conclusions

Cocrystallization of PAZ with HBAs/DHBAs and their single crystal X-ray structural analysis presents the supramolecular synthon hierarchy in their salt forms. The structural information obtained from this family of salts shows that the best hydrogen bond donor (acidic COOH) in CCFs bonds to the best hydrogen-bond acceptor (basic 2-aminopyrimidine) of PAZ in all crystal forms analyzed. The predominant and sole primary heretosynthon is the N–H⋯O⁻ pyridinium⋯carboxylate heterosynthon II. The functional group pK_a guides the selectivity and preference for hydrogen bonding with differential acidity of donors and basicity for acceptors. The second-best hydrogen-bond acceptor (indazole N) of PAZ interacts with the OH groups of water or alcohol or CCFs. The formation of hydrates and solvates is quite frequent in these cocrystals/salts (6/8) which makes further processing for drug formulation somewhat problematic because of issues in stability and volatile components in the crystal structure. The sulfonamide group participates in hydrogen bonding at the third level of hierarchy after COOH and OH groups of HBA/DHBA and aminopyridine and indazole groups of PAZ are paired up. The consistent formation of salt with PAZ at the 2-aminopyrimidine ring with HBA/DHBA acids in ΔpK_a >3 is a positive outcome for pharmaceutical development. The complication of solvent/water inclusion needs to be overcome using solvent-less cocrystallization techniques such as dry grinding, milling, hot-melt extrusion and twin-screw feeds.

4. Experimental section

4.1 Materials

Pazopanib free base (PAZ) was purchased from Swapnroop Drugs & Pharmaceuticals (Aurangabad, Maharashtra, India). All coformers (purity >99.0%) were purchased from TCI Chemicals and solvents (AR grade, purity >99.0%) were purchased from either Finar or Thomas Baker Chemicals, and used without further purifications.

4.2 Crystal preparation

The neat crystal form of PAZ was crystallized in acetonitrile solvent (∼20 mL) by dissolving PAZ free base (20 mg, 45.71 μmol) at 80 °C followed by addition of 2-propylpentanoic acid (0.5 mL, 3.2 mmol, ρ = 0.9 g mL⁻¹). The tetrahydrofuran solvate PAZ·THF was obtained by crystallization of PAZ in THF at room temperature (day and night temperature between 25 and 30 °C). Cocrystallization of PAZ (50 mg, 114.28 μmol) with an equimolar amount of CCFs (114.28 μmol) was done through the solvent-drop grinding method by adding acetonitrile solvent (0.5–1.0 mL). The change in the solid phase was confirmed by PXRD for the two stable anhydrate salts (Fig. S1, ESI†). The solids having new phases were dissolved in a minimum amount of 1:1 v/v ratio of methanol–acetonitrile (∼50 to 80 mL, depending on the solubility) in a 100 mL conical flask by stirring at 90–100 °C (in cases of 24DHBA, ethanol was used instead of methanol to obtain X-ray quality crystals). After seeing a clear solution, the conical flask was kept at room temperature (∼25–30 °C) by covering with parafilm and left slightly open to allow for solvent evaporation. X-ray quality single crystals appeared from this solution after one week which were characterized as neat salts, or solvated, hydrated crystals by X-ray diffraction.

4.3 Powder X-ray diffraction

Powder X-ray diffraction data were recorded on a Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA power. X-ray diffraction patterns were collected over the 2θ range 3–50° at a scan rate of 3.9° min⁻¹.

4.4 Single crystal X-ray crystallography

Single crystal X-ray diffraction data were collected on a Bruker SMART APEX II single crystal X-ray CCD diffractometer having graphite monochromatized (Mo-Kα, λ = 0.71073 Å) radiation at low temperature (100 K). The X-ray generator was operated at 50 kV and 30 mA. The data reduction was performed using APEX-II Software. Intensities were corrected for absorption using SADABS,⁷⁰ and the structure was solved and refined using SHELX97.⁷¹ All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were geometrically fixed with thermal parameters equivalent to 1.2 times that of the atom to which they are bonded, except those H atoms which are involved in strong hydrogen bonding. Molecular diagrams and packing for all the compounds were generated using Mercury version 4.10.⁷² PLATON was used for the analysis of bond lengths, bond angles, and other geometrical parameters.⁷³ X-ray crystal structures are deposited at CCDC, Cambridge, UK (No. 2050556–2050565).

4.5 Thermal analysis

Differential scanning calorimetry (DSC) analysis was performed on a Mettler Toledo DSC Q100 module and thermal gravimetric analysis (TGA) on a Mettler Toledo TGA Q5000 module. The sample size ranged from 2 to 5 mg for DSC and 5 to 10 mg for TGA. Samples were placed in sealed pin-pricked aluminum pans for DSC experiments and alumina pans for TGA experiments. A heating rate of 10 °C min⁻¹ in the temperature range 30–350 °C was applied for DSC and 30–900 °C for TGA. Samples were purged by a stream of dry nitrogen flowing at 80 mL min⁻¹ for DSC and 50 mL min⁻¹ for TGA.

4.6 Dissolution experiments

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

SKR thanks SERB, New Delhi, India for the financial support (N-PDF fellowship 2016/001632) and CSIR-NCL, Pune, India for providing the infrastructure to carry out this work. AKN acknowledges financial and infrastructure support from the University Grants Commission, New Delhi (through the UPE, CAS and NRC programs), the Department of Science and Technology, New Delhi (through the PURSE and FIST programs), and JC Bose Fellowship scheme (SR/S2/JCB-06/2009).

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Footnote

† Electronic supplementary information (ESI) available: Geometrical parameters of potential intra- and intermolecular interactions (Table S1); calculated and observed weight loss of salts in TGA (Table S2); and powder X-ray diffraction line profile of PAZ, DHBA coformer, and product salt to match with the single crystal X-ray structure of PAZ·23DHBA and PAZ·26DHBA. Crystallographic cif files are deposited at CCDC (No. 2050556–2050565). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ce00785h

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