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Inconvenient Truths about Solid Form Landscapes Revealed in the Polymorphs and Hydrates of Gandotinib Doris E. Braun, Jennifer A McMahon, Rajni M. Bhardwaj, Jonas Nyman, Marcus A. Neumann, Jacco van de Streek, and Susan M. Reutzel-Edens Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00162 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 14, 2019

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Crystal Growth & Design

Inconvenient Truths about Solid Form Landscapes Revealed in the Polymorphs and Hydrates of Gandotinib Doris E. Braun,†* Jennifer A. McMahon,§ Rajni M. Bhardwaj,§ Jonas Nyman,#§ Marcus A. Neumann,ǂ Jacco van de Streekǂ and Susan M. Reutzel-Edens§*

†Institute §Small

of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.

Molecule Design & Development, Eli Lilly and Company, Indianapolis, Indiana 46285,

United States. #School

of Pharmacy, University of Wisconsin – Madison, 777 Highland Ave, Madison,

Wisconsin 53705, United States. ǂAvant-garde

Materials Simulation Deutschland GmbH, Alte Str. 2, 79249 Merzhausen,

Germany.

KEYWORDS gandotinib, hydrate, polymorph, crystal structure prediction, thermodynamic and kinetic stability, interconversion pathways.

ACS Paragon Plus Environment

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ABSTRACT

Elucidating the structure relationships and transformation pathways of the solid forms of gandotinib was an enormous challenge. Only seven of the 11 experimentally observed forms crystallized directly from solution: a neat form (I), a tetrahydrate (Hy4), a 3.0-3.7-hydrate (HyY) and four solvates (methanol, n-propanol, n-butanol and N-methyl-2-pyrrolidone). The four remaining forms (II, Hy2.2, Hy1.3 and HyX) were produced by dehydration and/or rehydration processes. Interconversion of the anhydrates and hydrates of gandotinib with small changes in the relative humidity complicated identifying and characterizing the crystalline forms to such an extent that some experiments conducted in the humidity of summer could not be reproduced in the winter, and vice versa. Thus, with solid-state transformations being the only route to four of the solid forms, elucidating the crystal structural relationships underpinning the dehydration-rehydration pathways as a function of temperature and humidity required not only complementary experimental and computational methods, but also extreme patience. A key feature of this system is that the chlorofluorophenyl ring of gandotinib in the various neat and hydrated forms is disordered, but to different extents. Tetrahydrate Hy4 dehydrates to form II in a process that sees the disordered rings nearly completely reorder; rehydration of form II does not return Hy4 to the original, thermodynamic ratio of ring orientations, instead kinetically trapping the conformations in a disorder ratio close to that of form II. A crystal structure prediction of gandotinib showed that stable form I belongs to a large family of very similar low energy structures, all higher in lattice energy than the global minimum structure on the computed crystal energy landscape. By taking into account the contribution of disorder to the total free energy, form I is calculated to be energetically competitive with the global lattice energy minimum structure, suggesting that the thermodynamically most stable form has been found.


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1. Introduction Crystalline forms are essential to all industries that rely on fine-tuning material properties for optimal product performance. For the pharmaceutical industry, the selection of a solid-state form is frequently the first step in the process of transforming a drug molecule to a medicine.1-3 This means that every compound entering into development is normally subjected to extensive crystal form screening in order to discover as many polymorphs, hydrates and solvates as possible. The hope, of course, is that at least one form will surface with properties (stability, solubility, etc.) suitable for use in a drug product.4-6 Careful exploration of solid form landscapes, in addition to finding crystalline forms, will inevitably deepen the understanding of solid form properties and uncover nuances in crystallization behavior that can guide process and product design.7-8 At a minimum, solid form screens aim to find the thermodynamically most stable crystalline form so as to avoid the potentially catastrophic consequences of having it appear for the first time in a marketed product (cf. ritonavir9, rotigotine10). It is now more than 50 years ago that Walter McCrone famously stated, “every compound has different polymorphic forms and, in general, the number of forms known is proportional to the time and money that has been spent in research on that compound”.11 Statistical analysis of polymorphism and hydrate formation has since shown that 90% of compounds purposely screened for solid forms crystallize in multiple forms. Of these, up to 75% exhibit true polymorphism,12-13 and on average, 35% form hydrates.14-15 As the thermodynamically most stable form of a drug could be neat (non-solvated) or a hydrate at typical product storage conditions, solid form screens are generally designed to promote the nucleation and growth of these types of crystalline forms. For hydrates, experimental form screening must also consider the various ways in which water


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may be introduced, intentionally or otherwise, during processing (e.g. crystallization, wet granulation, or freeze-drying) or simply storage at atmospheric humidity.16-17 Industry has at its disposal many ‘standard’ techniques and platforms to crystallize drug molecules under diverse conditions. Frustratingly, the process by which forms are found continues to this day to be a trial-and-error exercise with an infinite number of possible experiments and no clear end point.18 This has fueled considerable interest across the pharmaceutical industry in crystal structure prediction (CSP) methods, capable of predicting thermodynamically feasible crystal structures from a chemical diagram of the molecule. A sufficiently reliable prediction showing which crystal structure is thermodynamically most stable (albeit as a lattice energy minimum) could give confidence in having found the stable form or justify expanding the experimental search.18-19 Under favorable circumstances, putative polymorphs would also appear on the crystal energy landscape, presumably within ~10 kJ mol–1 of the global energy minimum structure.12, 20 With capable methods to generate crystalline forms and emerging computational tools to assess the completeness of the experimental search, industry-standard solid form screens would seem poised to consistently deliver on the promise of finding all important solid forms. However, many questions remain unanswered regarding the extent of screening required and the appropriate time to discontinue a given search for forms. For example, with no guarantee that the thermodynamically most stable crystal structure of a molecule will crystallize, what happens when CSP shows that a more stable structure exists than has been found for an extensively screened molecule? It is important to know about metastable polymorphs, especially in cases of enantiotropy, so that their properties can be exploited or processes can be designed around them. But how high in energy should CSP structures be considered as putative polymorphs? With detailed investigations into solid form landscapes showing the ease with which molecules make


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mistakes during crystal growth, to what extent should disorder be factored into the determination that all important solid forms have been found? In this work, we survey the solid form landscape of gandotinib [GAN, LY2784544, (3-(4-chloro2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine)], Figure 1. GAN is a selective Janus kinase 2 (JAK-2) inhibitor, that has been investigated for the treatment of myeloproliferative disorders, such as polycythemia vera, essential thrombocythemia and mutant myeloid metaplasia.21-22 Our exploration of the structural features, stabilities and interconversion pathways of the neat and hydrated forms decorating the solid-state landscape of GAN has revealed many inconvenient truths about the challenges that must sometimes be overcome to generate solid forms and establish structure-property relationships. We use state-of-the-art experimental methods, in combination with developing computational tools, to paint a molecular picture that captures the extent to which disorder can affect form appearance and stability. We also describe a post-CSP analysis that may enable the completeness of experimental form screens to be meaningfully assessed for systems with dynamically-disordered polymorphs.

Figure 1. The molecular structure of gandotinib, GAN.


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2. Materials and Methods 2.1. Preparation of Gandotinib Solid Forms GAN (form I, purity > 99%) was obtained from Lilly Research Laboratories. All solvents used for crystallization screening were reagent grade (purity > 99%). Highly crystalline form I was prepared by slurrying GAN in ethanol for 24 hours at 25 °C. Hy4 was obtained by suspending form I (600 mg) in 3:1 isopropyl alcohol-H2O (10 mL), stirring the suspension for 48 to 72 hours at 10 to 30 C, isolating the solid product by filtration using a waterjet vacuum pump at room temperature and drying at 75% relative humidity (RH). Form II was prepared by drying Hy4 over P2O5 for ≥ 72 hours. Storing form II at 22% RH (saturated KOAc solution), 43% RH (sat. K2CO3 solution), and either 84% RH (sat. KCl solution) or 98% RH (sat. K2SO4 solution) at room temperature (RT) resulted within 2 days in Hy1.3, Hy2.2 and Hy4*, respectively. HyX was observed concomitantly with Hy1.3 or Hy2.2 upon drying Hy4 at RH < 30%. HyY was prepared by heating a suspension of form I in 3:1 tetrahydrofuran-H2O to 50 °C, then syringe-filtering the hot solution into a flask containing chilled (approx. 5 °C) H2O. The solid product was isolated by vacuum filtration, air dried for less than 30 minutes, then stored in a 53% RH (sat. MgNO3 solution) humidity chamber. 2.2. Gravimetric Moisture (De)sorption Analysis Moisture sorption and desorption studies were performed with the automatic multisample gravimetric moisture sorption analyzer SPS23-20µ (ProUmid, Ulm, Germany). The moisture sorption analyzer was calibrated with saturated salt solutions according to the supplier’s recommendations. Approximately 150 to 250 mg of sample was used for each analysis. The measurement cycles were started at either 60 or 94% RH with an initial stepwise desorption (decreasing humidity) to 0% RH, followed by a sorption cycle up to 94% RH and back, and a final


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sorption step to 94% RH. The RH changes were set to 2% and the equilibrium condition for each step was set to a mass constancy of ± 0.001% over 60 minutes and a maximum time limit of 48 hours per step. The measurements were repeated at least three times. 2.3. Slurry Bridging Experiments Excess GAN was stirred in ≥ 5 mL of solvent/water mixtures, each containing a different mole fraction of water corresponding to a defined water activity (Section 5 of the ESI), at temperatures ranging from 23 to 70 ± 0.1 °C for Y < 3.0], Hy2.2, Hy1.3 and HyX [2.0 > X 200 by energy, 19.2 kJ mol–1 above the global energy minimum structure, occupies a higher energy region of the search space, where convergence is poorer. The experimental structure was therefore energy-minimized using PBE-NP and placed on the landscape (Figure 12). Form I, on the other hand, resembles many structures belonging to hydrogen bonding family #2 that are well within the energy range of the top 84 structures. In this case, the chlorofluorophenyl ring disorder, shown by ssNMR spectroscopy to be dynamic (Figure 3), was not well-accounted for by a simple two-site model in the SCXRD structure of form I (Figure 14). Given the large population of highly similar structures resembling form I on the crystal energy landscape, multiple structures needed to be considered to properly model this disordered structure. Interestingly, the global energy minimum structure, with an entirely different space group and hydrogen bonding configuration (family #1), is not among the form I candidate structures.

Figure 14. Left: ORTEP drawing of the GAN molecule in form I (H atoms omitted, ellipsoids drawn at 50% probability) at room temperature (~296 K) and right: GAN conformers in Z’=1 CSP structures 4, 11, 16, 29, 36, 53, 78, 81 and 83, all belonging to H-bond family 2 and having ≥ 15 out a 20 matching molecules from a crystal packing similarity search (Z’=2 structures meeting these criteria are not shown).


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3.7.

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Risk of a Late-Appearing More Stable Polymorph

The crystal structure prediction of GAN, in having found an appreciably more stable packing than any in the ensemble to which form I belongs (Figure 12), warrants consideration of the risk that this structure might pose to becoming a late-appearing thermodynamically more stable form (cf. ritonavir9). Of course, whether the global lattice energy minimum structure (rank 1) is also the free energy minimum must be considered before drawing any conclusions about the thermodynamically most stable form having been missed, attempting to provide a plausible explanation for not having seen it in the comprehensive polymorph screen or commissioning further work to find it. We therefore sought to calculate the free energy of disordered form I relative to the other low energy structures. In total, three corrections were applied to the PBE-NP lattice energy from the CSP in order to estimate the free energy: a hybrid functional (PBE0-MBD) that includes Hartree-Fock exchange and many body dispersion to improve the lattice energy, lattice dynamics to estimate the vibrational contribution, and SAET to evaluate the configurational free energy in disordered form I. The latter method has been shown to reproduce experimentallyobserved form stability relationships in other disordered systems (e.g., loratadine56). Modeling the disorder in form I was complicated by the fact that the chlorofluorophenyl ring atoms were not precisely located (dynamic disorder) in the experimental crystal structure. Furthermore, many predicted structures (red data points in Figure 12), with similar molecular conformations (Figure 14), hydrogen bonding patterns (Figure 13), and crystal packing similarity (Figure 15), if present as disorder components, could stabilize form I.66 To identify the disorder components in play, we first calculated the chlorofluorophenyl ring torsion energy profile in the crystal (ESI section 13) to investigate whether rapid ring flipping in the form I structure is sufficiently captured by the harmonic approximation. Two local minima, corresponding to


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structures #16 and #36, were observed, and separated by an energy barrier of 13 kT, ring flipping is a rare event. Structures #16 and #36, which qualitatively agreed with the main disorder components observed by SCXRD, were used to construct a symmetry-adapted ensemble theory model to calculate the configurational free energy. Combining the PBE0-MBD-Fvib energy of the major component (#16) with the SAET configurational free energy, form I becomes the rank 3 structure, 0.88 kJ mol–1 above the global minimum structure. Given the errors in PBE0-MBD-Fvib relative energies (1-2 kJ mol-1),49, 51-53, 67 it is no longer obvious that the thermodynamically most stable form of GAN has been missed in the experimental solid form screen, and if it has, the most stable polymorph is unlikely to be appreciably more stable than form I. 82 75

72

80 3

74 71 79 69

52 41 51

2 54

76,77

1 31 28 32 33 20 24 8 7 18 17 57 48 35

HB family #1 HB family #2 HB family #3

55 60 46 12 34 13 81 53 11 67 83

HB family #4 HB family #5 HB #6

66 6

39

84

5

23

59

50

30 15

25,27,38,42,43 9,56 4,10,36,49,64,78 14,21,22,37,62,70,73 16,19,26,29,47 45,63 44,61 40 65,68 58

Figure 15. GAN structure family tree, showing crystal packing and hydrogen bonding similarity between the 84 lowest energy crystal structures from the CSP. Structures are colored according to their hydrogen bonding family in Figure 12. Disordered form I belongs to the large ensemble of structures in hydrogen bond family 2 (red).


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3.8.

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Inconvenient Truths about Solid Form Landscapes

The exploration of solid form landscapes can be relatively straightforward. Even for large, flexible pharmaceutical-like molecules, it is not unusual to find systems with few, relatively easily crystallized forms, each with clearly distinguishable structures and well-defined properties.68 However, gandotinib shows just how complicated surveying solid form landscapes can be in practice. GAN crystallized in many different forms (neat polymorphs, hydrates and solvates), oftentimes concomitantly, and not always in the most highly crystalline form. This complicated the process of establishing just how many forms were produced by the screen, their solvent composition and stoichiometry, and structural purity (disorder). The physical stability of the forms was highly dependent on the relative humidity of the environment, with form II and some hydrates existing over relatively narrow RH ranges. In some cases, the solid-state transformation kinetics were so rapid that even minimal exposure to laboratory RH conditions induced form conversions, frustrating efforts to keep forms long enough to characterize them during the winter and summer months. Slow transformation kinetics, on the other hand, thwarted efforts to rapidly assess the stoichiometry of certain GAN hydrates, as some forms produced by solid-state humidification required weeks of storage to attain their equilibrium water content. The observation of fractional hydrate stoichiometries for Hy2.2 and Hy1.3, though not unprecedented,17,69 required confirmatory studies to gain confidence in the determination of their hydration states, given all of the problems in securing and maintaining phase pure samples. Finally, all of the neat and hydrated forms of GAN were plagued by disorder, in some cases thermodynamic and in others frozen in, depending on the method of preparation. A range of experimental and computational methods was ultimately required to identify the unique forms decorating the solid form landscape of GAN, to establish their stability relationships


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and interconversion pathways (Figure 16), and to assess the likelihood of having missed a more stable form. Generating stable forms is, of course, a goal of every solid form screen. However, the observation of a second, high energy polymorph, form II, which melts nearly 100 °C lower in temperature than form I and is 10-11 kJ mol–1 higher in energy, attests to the ease with which high energy forms can appear. It is imperative that such high-energy forms not be overlooked or disregarded. Metastable form II is unlikely to crystallize directly from solution, i.e., its appearance rests on first crystallizing Hy4, and it is not appreciably stable in the solid state. Still, the structural characterization of this desolvate polymorph was essential for understanding the source of property variation in Hy4 materials, helping to show that different levels of disorder are possible in the same structure and ensure disorder was not mistaken for polymorphism.

Figure 16. Solid form landscape of GAN, showing routes of production and transformation pathways as a function of temperature (T) and relative humidity (RH)/water activity (aw). Solid lines show which forms can be crystallized directly from solution; forms in dashed lines are accessible only via solid-state phase transformations. Thermodynamically stable forms (under certain conditions) are shaded. Scryst = solvent of crystallization.


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Disorder, which is by no means uncommon in molecular crystals,56,70-74 is a key feature of the gandotinib system and its contribution to the free energy of the neat and hydrated forms could not be ignored. Whereas modelling the disorder in form II and Hy4 over two isolated sites was relatively straightforward, both the vibrational and configurational dynamics had to be modeled in form I to evaluate the risk of a more stable form having been missed in the solid form screen. The extent to which dynamics can stabilize molecular crystals is perhaps surprising, but for GAN, it is in line with experimental observations. Our experience shows that in order to meaningfully model properties, such as stability, the potential for disorder to stabilize certain polymorphs should be assessed. Finally, CSP continues to cement its place alongside experiments in solid form screening, helping scientists to structurally characterize polymorphs, rationalize crystallization behaviors, anticipate disorder and assess the risk of late-appearing more stable forms,19 yet neither form I nor form II were found per se in the structure search of GAN. Disordered form I was instead represented as a collection of lattice energy minima and form II was too high in energy. Clearly, until CSP studies move beyond the generation of static lattice energy landscapes and include the contributions of temperature and crystallization kinetics, it will remain impossible to know which calculated low energy structures are more likely to crystallize, let alone how to crystallize them.75 Anticipating which higher energy structures may be observable as desolvates is a whole other challenge to which new approaches are needed. 4. Conclusions Our survey of the crystal chemistry of gandotinib has revealed inconvenient truths about solid form landscapes and the effort that is sometimes required to identify solid forms, characterize their properties and determine when it is appropriate to discontinue screening. Disorder was a key


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feature of the GAN system, present to varying degrees in each of its neat and hydrated crystal forms. Whereas the chlorofluorophenyl ring disorder in Hy4 is a thermodynamic equilibrium property and crystallization of the tetrahydrate from solution yields Boltzmann-weighted populations, non-equilibrium disorder ratios are kinetically trapped in form II and tetrahydrate materials obtained by solid-state transformations. Modelling the dynamic disorder in form I was more complicated, with contributions from vibrational and configurational free energy, manybody dispersion and Hartree-Fock exchange needing to be considered. We have shown that disorder components, when present, can significantly enhance the stability of some polymorphs.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Crystallography (powder, single crystal), solid form screen details, crystal structure prediction study details ( including CIF files), solubility, solid form characterization (solid-state NMR spectroscopy, GVS, differential scanning calorimetry) Accession Codes. CCDC Accession Codes 1893103-1893106 contain the supplementary crystallographic data for this paper, all of which can be obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif, by emailing [email protected], or contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.


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AUTHOR INFORMATION Corresponding Authors * Dr. Doris E. Braun, Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria, Tel: +43(0)512 507 58653, Email: [email protected]. * Dr. Susan M. Reutzel-Edens, Small Molecule Design & Development, Eli Lilly and Company, Indianapolis,

Indiana

46285,

United

States,

Tel:

+1(317)260-1708,

Email:

reutzel-

[email protected]. ORCID Doris E. Braun: 0000-0003-0503-4448 Susan M. Reutzel-Edens: 0000-0003-0806-5565 Jonas Nyman 0000-0001-9011-3962 Rajni M. Bhardwaj 0000-0002-7402-9995 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources Austrian Science Fund (FWF), project V436-N34.

ACKNOWLEDGMENT We dedicate this work to honor the life and legacy of Prof. Joel Bernstein (1941-2019).


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The CASTEP calculations have been performed using the HPC infrastructure LEO of the University of Innsbruck. Anthony Reilly (CCDC) is acknowledged for the packing similarity dendrogram script.

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For Table of Contents Use Only

Inconvenient Truths about Solid Form Landscapes Revealed in the Polymorphs and Hydrates of Gandotinib Doris E. Braun, Jennifer A. McMahon, Rajni M. Bhardwaj, Jonas Nyman, Marcus A. Neumann, Jacco van de Streek and Susan M. Reutzel-Edens


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For Table of Contents Use Only

Inconvenient Truths about Solid Form Landscapes Revealed in the Polymorphs and Hydrates of Gandotinib Doris E. Braun*, Jennifer A. McMahon, Rajni M. Bhardwaj, Jonas Nyman, Marcus A. Neumann, Jacco van de Streek and Susan M. Reutzel-Edens*

Synopsis: This study reveals the experimental and computational effort that is sometimes required to identify solid forms, characterize their properties and determine when it is appropriate to stop solid form screening. Form interconversions with small changes in the relative humidity complicated identifying and characterizing the neat and hydrated forms of gandotinib. Disorder, present to varying degrees in each of the neat and hydrated forms, was shown to substantially enhance the stability of some polymorphs.


Inconvenient Truths about Solid Form Landscapes ... - ACS Publications

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