Ibrutinib Polymorphs: Crystallographic Study - Crystal Growth

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Ibrutinib Polymorphs: Crystallographic Study Vít Zvoní#ek, Eliška Sko#epová, Michal Dusek, Pavel Žvátora, and Miroslav Soos Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00923 • Publication Date (Web): 12 Feb 2018 Downloaded from http://pubs.acs.org on February 13, 2018

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Crystal Growth & Design

Ibrutinib Polymorphs: Crystallographic Study Vít Zvoníček✻1,2, Eliška Skořepová1, Michal Dušek3, Pavel Žvátora2, Miroslav Šoóš#1 1

Department of Chemical Engineering, University of Chemistry and Technology Prague, Technická 3, 16628, Prague 6, Czech Republic. 2 Zentiva, k.s., U kabelovny 130, 10237, Prague 10, Czech Republic 3 Institute of Physics of the Czech Academy of Sciences, Na Slovance 2, 182 21 Praha 8, Czech Republic

*[email protected]; #[email protected] Abstract In this paper, we present a comprehensive crystallographic study of Ibrutinib polymorphs and their behavior. Three neat polymorphs (A, B and C) and a methanol solvate (F) were obtained and characterized. The structures of forms A, C and F were solved from single-crystal diffraction data. Form B has only ever been prepared as powder and its structure solution has, so far, not been successful. Polymorph C is a desolvate of the methanol solvate F and its structure was solved via the single-crystal to single-crystal transformation. The analysis of the solved structures revealed significant differences in the crystal packing of form A in comparison with the previously described ibrutinib structures, enabling it to crystallize in a higher symmetry space group (monoclinic vs. triclinic). The structures also revealed a high similarity between forms C and F, explaining their mutual transformability. To further analyze the solids, we performed DSC, long-term slurry transformations, intrinsic dissolution experiments and DVS. FT-Raman spectroscopy was used for the preliminary characterization and fast distinction between the forms. We have also performed basic energy calculations to estimate the strength of the various present H-bonds. All methods confirmed the polymorph A to be the thermodynamically most stable form.

Address of the corresponding authors Department of Chemical Engineering, University of Chemistry and Technology Prague, Technicka 3, 16628, Prague 6, Czech Republic.

*,#

Telephone: +420 220 443 251

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Ibrutinib Polymorphs: Crystallographic Study Vít Zvoníček✻1,2, Eliška Skořepová1, Michal Dušek3, Pavel Žvátora2, Miroslav Šoóš#1 1

Department of Chemical Engineering, University of Chemistry and Technology Prague, Technicka 3, 16628, Prague 6, Czech Republic. 2 Zentiva, k.s., U kabelovny 130, 10237, Prague 10, Czech Republic 3 Institute of Physics of the Czech Academy of Sciences, Na Slovance 2, 182 21 Praha 8, Czech Republic

*[email protected]; #[email protected] Abstract In this paper, we present a comprehensive crystallographic study of Ibrutinib polymorphs and their behavior. Three neat polymorphs (A, B and C) and a methanol solvate (F) were obtained and characterized. The structures of forms A, C and F were solved from single-crystal diffraction data. Form B has only ever been prepared as powder and its structure solution has, so far, not been successful. Polymorph C is a desolvate of the methanol solvate F and its structure was solved via the single-crystal to single-crystal transformation. The analysis of the solved structures revealed significant differences in the crystal packing of form A in comparison with the previously described ibrutinib structures, enabling it to crystallize in a higher symmetry space group (monoclinic vs. triclinic). The structures also revealed a high similarity between forms C and F, explaining their mutual transformability. To further analyze the solids, we performed DSC, long-term slurry transformations, intrinsic dissolution experiments and DVS. FT-Raman spectroscopy was used for the preliminary characterization and fast distinction between the forms. We have also performed basic energy calculations to estimate the strength of the various present H-bonds. All methods confirmed the polymorph A to be the thermodynamically most stable form. Introduction A study of an API’s polymorphism is a crucial part of a current drug development1. Generally, new drug formulations are approved only if they contain a particular polymorph (solid form), or a defined mixture of polymorphs (solid forms), of the API2,3. Therefore, it is absolutely necessary to control the crystallization conditions in such a way that only the particular solid form crystallizes. To achieve such a control of the crystallization process, we need to obtain as much information about the possible solid forms of the API, as we can4–7, for example through a polymorphic screening3. The more information we get, the easier we can avoid problems like concomitant crystallization of an undesired solid form8, or even crystallization of a new and unexpected form9. Those are very serious problems in the pharmaceutical industry, which can hinder successful production of the desired product. Cases are known, where the whole production had to be moved into a different building (or even a different continent) in order to produce the desired polymorph again and even that did not help in some cases10,11. Pure (neat) polymorphs are the solids of choice for the final drug product formulation. Their use is not limited by a content of any undesirable crystallization partner, as it may be in case of multicomponent


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solids, such as solvates, hydrates, salts and co-crystals. That may also improve the stability, as they cannot be subject of a desolvation or a reactive interaction9,12,13 with their partner molecule. The selection of a proper polymorphic form also helps to improve the pharmacokinetic profile of the drug product3, without using excessive excipients. It can also improve the processing of the drug product by e.g. a better flowability or compressibility of the crystals14. For the here described polymorphic study, we selected an oncology API 1-[(3R)-3-[4-amino-3-(4phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-prop-2-en-1-one, also known as Ibrutinib (Figure 1). As an irreversible Bruton’s tyrosine kinase inhibitor, Ibrutinib is used to treat several types of leukemia, namely Waldentrom’s macroglobulinemia15, mantle cell lymphoma and chronic lymphocytic leukemia16–20. Furthermore, it was just recently approved for the indication of marginal zone lymphoma21,22.

Figure 1 Ibrutinib molecule Ibrutinib has three polymorphic forms described in patent literature23 and several other multicomponent solid forms described in the patents23,24 or in the peer-reviewed journals, such as our previous article25. Pure Ibrutinib polymorphs are called form A, form B and form C and no structural characterization was available in the literature until now. A particularly interesting multicomponent solid mentioned in the patents is the methanol solvate (form F), as it is the precursor of a particular polymorph (form C), and therefore we describe its properties here as the only multicomponent solid involved in this study. Here, we will present a comprehensive study focused on a detailed structural characterization and description of ibrutinib polymorphs as well as of the methanol solvate. Further, we will also focus on the energetic properties of the solids as well as their thermal behavior and stability and also discuss their pharmaceutical usability according to their dissolution properties.

Experimental section Materials Ibrutinib was kindly provided by Zentiva, k.s. The pure polymorphic forms A, B and C were prepared by recrystallization according to patent literature23, though some modification of the proposed procedures turned out to be necessary (details below). The solvents used were obtained from various commercial suppliers and were used as received.



Preparation of the Solid Forms Ibrutinib polymorphs A, B and C, as well as solvated form F were prepared based on the patent procedure description (ref.23). However, as is often the case with patent literature, some modifications of the crystallization processes were necessary to obtain the pure polymorphs. The particular optimized procedures are as follows: Polymorph A was prepared from methanol solution of ibrutinib by adding water as an antisolvent. In particular, to the stirred solution of ibrutinib in methanol, 120 ml, 45 °C warm and with concentration 0.1 g/l, 72 ml of water was dropped over 45 minutes. The prepared mixture became cloudy in the course of 3 hours and the slurry was stirred for additional 12 hours. The solid was filtered and dried in the vacuum chamber (100 mbar, 40 °C) for 12 hours. Polymorph B was prepared by the fast addition of water into the methanol solution of ibrutinib followed by ripening of the obtained slurry. In particular, 1 g of Ibrutinib form C was suspended in 8 ml of methanol and then dissolved by heating to 50 °C with overhead stirring. The obtained solution was cooled down to 30 °C and 4 ml of water were added in steps (1 ml per step). The obtained cloudy solution was further cooled to 20 °C and stirred for 2 h. The resulting slurry was transferred to the fridge (5 °C) and let ripen for seven days. Polymorph C was prepared by recrystallization of ibrutinib in methanol. In particular, Ibrutinib polymorph A was suspended in methanol and heated on magnetic heater to 50 °C. Prepared solution (concentration 80 mg/ml) was then stirred and cooled to 0 °C, slowly turning cloudy. The prepared solid was filtered and then dried under vacuum (100 mbar) at 40 °C overnight. Form F was prepared similarly to form C. Ibrutinib form A was dissolved in methanol at 50 °C and a prepared solution with concentration 100 mg/ml was then stirred by a magnetic stirrer and allowed to cool to the laboratory temperature. The obtained solid was stored as a slurry in a remaining saturated solution to prevent a subsequent desolvation. For every performed measurement, the needed part of the solid was quickly filtered and used without further drying. Polymorphic Screening For the screening purposes, 17 solvents (16 pure plus one mixture) were chosen according to their different chemical and physical properties. The used solvents included water, dimethyl sulfoxide , acetonitrile, ethanol, propan-2-ol, acetone, butan-2-one, 4-methylpentan-2-one, dichloromethane, tetrahydrofuran, ethyl acetate, butyl acetate, chloroform, toluene, xylene, dioxane and a mixture of ethanol and water in ratio of 3:1. Ibrutinib form A with the admixture of amorphous ibrutinib was used as a starting material. For every experiment, roughly 100 mg of Ibrutinib was weighed to the vial, which was heated up close to the boiling temperature of the particular solvent or to the maximum temperature of 100 °C. The solvent was then added with 100 µl step until all the solid has dissolved or until the maximum volume of 1 ml was reached. In case the solid have not completely dissolved, the obtained slurry was filtered through the syringe filter to get a clear solution. The obtained solution was divided into four different vials and every vial was treated differently. The four treatments were slow cooling (SC), quick cooling (QC), slow evaporation (SE) and quick evaporation (QE), meaning: SC - the solution was closed with a lid and let to cool to room temperature in the fume hood; QC - the solution was immediately transferred to the cooling bath (0 °C) and then to the freezer (-20 °C); SE the solution was let to cool and evaporate at the laboratory conditions in a fume hood; QE - the samples were put to the vacuum chamber and evaporated under lowered pressure at 1 kPa.


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Single Crystal X-Ray Diffraction (SC-XRD) To determine the crystal structures of the Ibrutinib polymorphs A, C and the MeOH solvate form F, single crystals were prepared to be measured by X-ray diffraction. To prepare a suitable single crystal of the form A, a vapor diffusion technique was used. Roughly 100 mg of Ibrutinib was dissolved in 3 ml of methanol and transferred to a vial. The opened vial was then transferred to a bigger flask, some water was added to the bigger flask and the whole system was tightly closed and let to equilibrate for seven weeks. Single crystal of the methanol solvate F was prepared by crystallization of the oversaturated solution of ibrutinib in methanol. Ibrutinib form C in amount of 100 mg was charged into a vial and suspended in 1 ml of methanol. Prepared slurry was heated up to 50 °C in an agitator to dissolve all the solid. The obtained solution was allowed to cool down to a room temperature and let crystallize. Single crystal of the form C was prepared by careful desolvation of the single crystal of the methanol solvate F at room temperature and atmospheric pressure. Single crystal X-ray diffraction (SC-XRD) was measured on a diffractometer Xcalibur, Atlas, Gemini ultra with a mirror-monochromator and a CCD detector, Cu Kα radiation with a wavelength of 1.5418 Å. The single crystal X-ray diffraction analysis was carried out at a temperature of 120 K. Collection and data reduction program was CrysAlisPro, Rigaku Oxford Diffraction, 2015, version 1.171.38.41q. An empirical correction for absorption was done by a scaling algorithm SCALE3 ABSPACK. The structure was solved by direct methods (program SIR9226) and refined in the programs CRYSTALS 14.40b2427 and Jana200628. All non-hydrogen atoms were refined anisotropically. The simulated XRPD patterns were calculated using the Mercury software (version 3.3)29. The figures concerning crystal structures were prepared in Mercury29 and Discovery studio30. Structures’ refinement details can be found in Supporting information S1. X-Ray Powder Diffraction (XRPD) The diffraction patterns were obtained using a powder diffractometer X'PERT PRO MPD PANalytical; X-ray beam Cu Kα (λ =1.542 A), excitation voltage: 45 kV, anodic current: 40 mA, measured range: 2 - 40° 2Θ, step size: 0.01° 2Θ, remaining at a step for 0.05 s. The measurement was performed on a flat sample of area/thickness 10/0.5 mm. 0.02 rad Soller slits, 10 mm mask and 1/4° fixed anti-scattering slits were used to correct the primary beam. The irradiated area of the sample was 10 mm; programmable divergent slits were used. 0.02 rad Soller slits and 5.0 mm anti-scattering slits were used to correct the secondary beam. Raman Spectroscopy The samples were measured in glass HPLC vials in a spectrometer FT-Raman RFS100/S, with germanium detector (Bruker Optics, Germany), at wavelength of Nd: YAG laser 1064 nm, in the measuring range from 4000 to -2000 cm-1, with spectral resolution 4.0 cm-1. Data were obtained at 64 or 128 accumulations of spectra. The software OMNIC was applied in processing the spectra. Differential Scanning Calorimetry (DSC) DSC measurements were performed on the TA Instruments Discovery DSC. The sample was weighed in the aluminum pan (40 µL), covered and measured in the flow of a nitrogen gas. The investigation was performed in the temperature range from 0°C to 300°C with the heating rate 5°C/min (amplitude = 0.8°C; period = 60s). The peak maximum temperature (Tpeak) and the peak onset temperature (Tonset), for the crystalline form, and the glass transition temperature (Tg), for the amorphous form, were specified in the DSC result. The enthalpy was given in the unit J/g. The sample weight was



about 3-5 mg. Dynamic Vapor Sorption (DVS) Gravimetric moisture sorption analysis was carried out using a humidity and temperature controlled microbalance DVS apparatus, DVS Advantage 1 (Surface Measurement Systems, U.K.) with a Cahn D200 recording ultra-microbalance with a mass resolution of ±0.1 µg. Samples of approximately 20 mg were dried at 0% RH under a nitrogen stream at 25 °C. Moisture uptake (reported relative to the dry weight) was monitored over a sorption/desorption range of 0–90% RH in increments of 10%. Relative Stability Testing The relative stabilities of the polymorphs were tested in long term (3 weeks) slurry experiments in ethanol. Four different mixtures, particularly: A and B, A and C, B and C, and A, B and C and all three pure polymorphs were used for the experiments. The ratio of the polymorphs in the mixtures was 1:1 or 1:1:1 respectively. 200 mg of the solid was slurried in 1.5 ml of ethanol in HPLC vial and agitated for three weeks in a laboratory agitator at RT. Resulting solids were filtered, dried under vacuum and measured by XRPD. Dissolution The dissolution properties of the prepared materials were characterized using intrinsic dissolution rate (IDR) measurements. IDR describes, how fast different solid phases release a molecule from the crystal lattice into a solution, while the influence of particle size is eliminated. IDR were determined using Sirius inForm (Sirius Analytical, Forest Row, UK). Disc compacts were prepared by compressing approximately 40 mg of material in a 6 mm diameter dye under a constant load of 120 kg maintained for 2 minutes. Measurements were performed using 40 mL of solution at constant pH 2.0 and ionic strength of 160 mM adjusted by sodium chloride and hydrochloric acid. UV spectra were recorded every 30 seconds. Absorbance values between wavelength 250 and 350 nm were used to evaluate the amount released at a given time point. IDR was calculated using zero order linear fit through the experimental data. All measurements were performed in duplicate. Molecular Packing Similarity Calculation To quantify the level of packing similarity between the solved crystal structures, the calculation in CrystalCMP31 (CIT) was performed. The resulting tree diagram/dendrogram is used for a clear analysis of similarity in the crystal packing of a group of structures. It can compare the crystal packing of only the largest molecule in the structure and therefore, can easily analyze a family of polymorphs, hydrates, solvates, salts and co-crystals. The similarity is calculated on the basis of the distance and rotation of the respective molecules.

Energy Frameworks Energy frameworks were calculated using software CrystalExplorer1732, version 17.5, revision f4e298a. Molecular wavefunctions were obtained using build-in Tonto utility33 at “accurate” setting using B3LYP/6-31G(d,p) level of theory. The pictures of the energy frameworks were created using CrystalExplorer17.

Results Polymorphic screening To search for possible new polymorphic forms of Ibrutinib, we performed a thorough crystallization screening. For these experiments, we selected 17 solvents and four experimental procedures (see the details in the Experimental section). Unfortunately, the screening did not reveal any new solid forms. Form A was the resulting solid for almost all of the samples. The only exceptions were QC and QE


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samples in which the ethanol-water (3:1) mixture was used. In both cases, form B was the resulting solid, pure in QC sample and with admixture of form A in QE. Polymorph C was not detected in any of the samples. Solid Forms and Their Crystal Structures The polymorphs were prepared according to the patent literature23. However, it was found that proposed methods were not robust, therefore to resolve this issue, we modified the experimental approaches as mentioned in the text above. Furthermore, our extensive polymorphic screening lead to additional improvements of the proposed methods. The identity and purity of the prepared solid forms was verified by powder X-ray diffraction (see Figure 2).

Figure 2. XRPD patterns of all here described solid forms of Ibrutinib The crystal structures of forms A, C and F were successfully solved from the single-crystal diffraction data. For the details about the measurement and structure refinement, see Table 1. The structure solution of form B was, despite all our efforts, not successful. As a polymorph obtained only by shock precipitation it was not possible to grow its single-crystals. Furthermore, the low crystallinity made the structure solution from powder data impossible. The thermal properties of the solids were also studied and will be described further in a dedicated section. Here, it is enough to say that form A is the most stable polymorph according to the melting point (m.p. 155 °C), while form C (m.p. 133 °C) and form B (m.p. 115 °C) are metastable forms.

Table 1. Single crystal measurement and structure refinement details Ibrutinib Polymorph A

Ibrutinib Polymorph C


Ibrutinib MeOH Solvate


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Formula

4C25H24N6O2

2C25H24N6O2

2C25H24N6O2 . 3CH3OH

Formula weight

1762.02

880.99

977.14

Color

colorless

white

colorless

Crystal. Morphology

block

lath

lath

T (K)

120

120

120

Radiation

Cu Kα

Cu Kα

Cu Kα

Crystal System

Monoclinic

Triclinic

Triclinic

Space Group

P 21

P1

P1

a (Å)

14.2459(10)

9.7764(10)

9.6578(3)

b (Å)

10.1261(10)

10.0551(11)

9.8034(3)

c (Å)

30.8586(10)

13.459(2)

15.0204(5)

α (°)

90

90.959(11)

105.705(3)

β (°)

96.908(10)

110.369(12

95.072(2)

γ(°)

90

112.917(10)

111.523(3)

V (Å3)

4419.2(6)

1124.5(3)

1245.28(8)

Z

2

1

1

Z’

4

2

5

ρcalc (g/cm3)

1.324

1.301

1.303

Reflns. Collected

69765

8561

19815

Indept. Reflns.

15586

4667

8431

No. of Params.

1190

463

675

R(int)

0.0400

0.0653

0.037

R1, wR2 [I > 2σ(I)]

0.0356, 0.0909

0.0711, 0.0718

0.0415, 0.103


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R1, wR2 (all data)

0.0377, 0.0931

0.2316, 0.0979

0.0456, 0.1074

∆ρmin, ∆ρmax (e Å−3)

-0.30, 0.90

-0.45, 0.35

-0.2, 0.26

GOF

1.0086

1.81

1.0040

CCDC number

1559244

1559242

1559243

Form A The preparation of form A did not present any challenges. As it is the thermodynamically stable polymorph (with the highest melting point), it was obtained as a resulting solid in the most of our screening experiments. Its single-crystal structure has a monoclinic symmetry with space group P 21 (see Figure 3).

Figure 3. ORTEP image of Ibrutinib polymorph A Form A is a pure crystalline solid of Ibrutinib, lacking any solvation or hydration often seen in ibrutinib solids. It contains 4 unique conformations of ibrutinib molecule in asymmetric part of the unit cell (see Figure 34).



Figure 4. Molecular conformations of Ibrutinib in Form A. Form B Form B was prepared by fast addition of water into the methanol solution of Ibrutinib. The product is first obtained as a partially amorphous solid, which is then let to ripen in a mother liquor for several days at low temperature to get a solid with a higher crystallinity. The results of the polymorphic screening show that this polymorph can be also prepared using another solvent, namely ethanol, under similar kinetic conditions as with the methanol solution. Unfortunately, the kinetic conditions during the form B preparation allow to obtain the product only in the form of a very fine powder with low crystallinity. For this reason, we were unable to prepare a single crystal of the form B nor to solve the structure from the powder XRD data, despite multiple various trials to improve the crystallinity (e.g. temperature cycling). Without the full structure solution, we can only speculate about the crystal structure of form B. When we compared the Raman spectra with the other known crystal forms of ibrutinib, we saw the closest similarity to the spectra of p-xylene solvate25 (see Figure S1). Therefore, ibrutinib in form B might experience similar molecular interactions as in p-xylene solvate, but the crystal packing is probably significantly different, due the lack of any solvent molecules. Form C Preparation of form C is described in the patent23 as a cooling crystallization from the methanol solution of Ibrutinib followed by drying of the obtained solid under vacuum conditions. We found that the crystallization part of this process leads first to the methanol solvate F (described in the following section), which only subsequently, during the drying part, undergoes desolvation phase transition to form C. Further, we conducted several experiments trying to crystallize form C directly from either methanol or other solvent solution of ibrutinib using seeds of form C. All our trials were unsuccessful. The desolvation phase transition was used also for the preparation of the single crystal of form C, although using much milder conditions. Successful crystal structure solution revealed that form C crystallizes in the triclinic system with the space group P 1, with two molecules of ibrutinib in the asymmetric unit (Fig. 5).


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Figure 5. ORTEP image of Ibrutinib polymorph C Form F Form F was the only multicomponent solid form evaluated in this study. It is a highly unstable methanol solvate of Ibrutinib, desolvating fast even under ambient conditions. Form F is prepared by crystallization of Ibrutinib in pure methanol. For the crystallization, we tried both the cooling crystallization and the evaporative one. In the latter, the evaporation proceeded only until sufficiently sized crystals appeared in the solution and then it was stopped with the crystals still submerged in a remaining liquid. Both crystallization processes resulted into form F. The cooling process provided smaller crystals suitable only for XRPD, while the evaporative crystallization gave us crystals in millimeter size suitable for single crystal X-ray measurement.

Figure 6. ORTEP image of Ibrutinib methanol solvate, form F Form F was found to crystallize in the triclinic system in the space group P 1, with two molecules of ibrutinib and three molecules of methanol in the asymmetric unit (Fig. 6), making it ibrutinib methanol sesquisolvate. The solved structure of the form F showed some signs of a general similarity (the same symmetry, space group and similar molecular conformations and packing) with the previously described solvates25. From this point of view, methanol solvate belongs to the group of the Ibrutinib non-aromatic solvates (solvates containing non-aromatic solvent molecule as a crystallization partner)25. As the other solvates in the non-aromatic group do, it also contains the non-classical H-bonds (e.g. C-H…O bonds) between the solvent (methanol) and the Ibrutinib molecules. In addition, methanol also makes the classical H-bonds in this solvate, where its -OH groups are H-bonded either to the carbonyl group of ibrutinib or between themselves (see Figure 7). Even though methanol molecules create many Van der Waals interactions in the solvate structure, the overall strength of those interactions is somewhat low,



as shown in section Energy Calculations. That is in agreement with the high instability of this solvate and its easy desolvation.

Figure 7. Details of H-bond system in Ibrutinib methanol solvate As form F is a precursor of form C, structural changes between them were found to be sufficiently small to allow the preparation of form C single-crystal by a SC-SC transformation of F. Overlaying the molecular conformations found in form C with those of F shows that the conformation of the form C retains high similarity with the methanol solvate, as can be seen in Figure 8. .

Figure 8. Overlaid conformations of Ibrutinib in form C and form F. The main difference between the forms is the torsion of the terminal phenyl ring. Crystal Packing Molecular structure of Ibrutinib allows it to create many different intermolecular interactions including classical and non-classical H-bonds, π-π stacking and alkyl-π stacking34. As we have shown


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in our previous study25, the basic interaction motif in ibrutinib solvates is a dimerization of the planar core bicycles of the ibrutinib molecules and a following catemerization of those dimers, all formed by the classical H-bonds. Another highly pronounced interaction is the π-π stacking, which stabilized the solvent molecules in the crystal structures of aromatic solvates . Further, non-aromatic solvates have had the solvent molecules stabilized in the structure by non-classical H-bonds. Generally, the feature of Ibrutinib creating H-bonded dimers in the solids was preserved in all the here described structures (see Figure S2). The other structural feature, catemer-like chains made of the dimers, was preserved only in forms C and F. Form A, on the other hand, forms tetramers. The mentioned chains of ibrutinib molecules are then arranged in similar positions in parallel to each other. In the previous study of ibrutinib solvates, we found, in most cases, there is only one type of the chain, made of two Ibrutinib molecules of mutually complementary conformations, in one structure. Other possibilities included two chains made of two different conformations each and four conformations making only one type of chain.

Figure 9. Tetrameric (catemer-like) structure of form A (top) compared with catemers of forms C (middle) and F (bottom). All classic H-bonds are depicted.

In comparison with the previously known Ibrutinib solids, the structure of form A was found to have the most significant deviation from the usual catemeric structure. In the structure of form A, the bicyclic cores in the Ibrutinib dimers have the highest deviation from the co-planar arrangement: torsion angles of the bicycles of 156.5° and 156.7° compared to 168.9° in C and 177.4° in F (see Figure 9), giving the dimers a wave-like structure. This packing allows the H-bonds NH…N to have the N-H-N angle closer to its ideal value of 180°, while on the other hand, the H-bonds are generally longer in form A (see Table 2). The second pair of H-bonds, between the amino group and carbonyl, is also effected in the form A. Two of the Ibrutinib molecule conformations in form A have the carbonyl, particularly groups C(19)=O(20) and C(101)=O(100), in such a position, where they cannot interact with other molecules through H-bonding. All those effects result in a tetrameric structure of ibrutinib molecules in form A (for details see Figure 9), which are further arranged into pseudochains. The mentioned pseudo-chains have the parallel arrangement in only one direction, making a plane. Those planes are further stacked together, with every second plane rotated by 73° (see Figure 10). The rotation allows forms A to better express π-π interaction. The space left between the aromatic rings of one plane is filled by those of the other plane, locking the rotated planes together through the interacting aromatics and terminal double bonds. Combination of all these effects allows more efficient packing (density 1.324 g/cm3 in A versus 1.301 g/cm3 in C or 1.304 g/cm3 in F) and



higher crystallographic symmetry of form A (P 21 as opposed to P 1, which is the space group of every other up-to-date published ibrutinib structure).

Figure 10. Rotated planes of the Ibrutinib form A, highlighted with red and blue (left top), their side view (right top) and the packing of the form A with the displayed unit cell axes (bottom)

Main H-bonds angles and lengths

N117 N48 N81 N15

H1172 H482 H812 N151

N46 N115 N12 N79

N48 N81

H481 H811

O67 O34

N61 N59 N12

Form A dist (D…A; Å) 3.111(2) 2.923(2) 2.919(2) 2.958(2)

angle (DH…A; °) 171.4 176.4 179.8 177.6

H612 H121 H122

3.147(2) 2.972(2) Form C N13 2.932(4) N12 2.946(4) O34 2.889(4)

167.0 146.8 126.4

N61

H611

O23

114.1

N5 N15 N5 N13 O60

H51 H131 H52 H132 H601

N2 N13 O1 O6 O11

2.828(3) Form F 2.918(2) 3.090(2) 3.055(3) 2.939(3) 2.801(4)

135.4 127.0

174.5 172.5 127.1 141.6 135.0


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O11 O6

H111 H611

O1 O61

2.765(4) 2.798(6)

172.0 79.7

Table 2 Lengths and angles of the H-bonds in polymorphs A, C and MeOH solvate F The structures of forms C and F were found to contain the most common Ibrutinib chain, consisting of two different Ibrutinib conformations. Hydrogen bonds lengths and angles are also of typical values in comparison with the previously published structures (compare Tab. 2 with our previous study25). Furthermore, form F was found to be a channel solvate. This feature probably contributes to its instability, as the channel solvates are generally more prone to desolvation35–37. To further compare the 3D molecular structures of the described Ibrutinib solids, we constructed packing similarity tree diagrams using CrystalCMP software. The resulting diagram clearly shows the similarity between form C and F, and very high dissimilarity to form A (see Figure 11).

Figure 11. Packing similarity tree diagram of the here-presented Ibrutinib structures produced by CrystalCMP softwar. A part of the diagram between 3 and 33 was deleted to make the figure shorter and more readable; this is indicated by the curved line. Energy Calculations Calculated energy frameworks show that all the structures are based primarily on dispersive interactions (see Figure 2). This is in agreement with the observed ability of Ibrutinib to interact via ππ interactions. Coulombic interactions contribute mostly at the sites of H-bonding, while, elsewhere, they are rather small or negligible.



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Figure 12 Energy frameworks for forms A (top), C (middle) and F (bottom) of Ibrutinib. Different colored tubes represent different type of energy increment: coulombic (red), dispersion (green) and total energy of the interaction (blue). Thickness of the tube is proportional to the strength of the interaction. Scaling of the tubes is the same in all pictures. To improve the clarity of the pictures, interactions of less than 15 kJ/mol were omitted. The most energetic interaction between Ibrutinib molecules is their stacking into pairs bonded by NH…O=C hydrogen bond with the energy of more than -100 kJ/mol (see Table 3). This stacking benefits from both the electrostatic and dispersive energy increment and its energy is significantly lower for the pair that lacks this H-bond in form A. Furthermore, even the second pair in form A has lower energy of this particular interaction compared to forms C and F. The energy of the interaction between NH…N homodimers is very similar for forms A and F with a value of around -60 kJ/mol, while it is lower for C, -47.6 kJ/mol. On the other hand, form A creates generally more high-energetic interactions (8, from approx. -50 kJ/mol up) than forms C (3) and F (3), which further supports its stability. For details see Table S1 in Supporting Information.

Form A Coulombic Polarization Dispersive Repulsion Total term term term term Energy (kJ/mol) (kJ/mol) (kJ/mol) (kJ/mol) (kJ/mol)

Atomic labels

N117 N48 N81 N15 N48 N81 N117

H1172 H482 H812 N151 H481 H811 H1171

N46 N115 N12 N79 O67 O34 O20

-74.8

-16.7

-17.7

80.7

-57.0

-88.0

-20.3

-18.9

101.3

-62.0

-47.7

-13.4

-114.4

81.3

-109.8

-18.6

-2.4

-98.0

57.7

-71.1


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N15

H152

O100

N61 N59 N12 N61

H612 H121 H122 H611

N13 N12 O34 O23

Form C -70.4

-16.8

-19.3

90.8

-47.6

-58.2

-14.5

-132.0

103.9

-123.0

Form F N5 H51 N2 -77.4 -17.6 -17.9 83.1 -59.1 N15 H131 N13 N5 H52 O1 -55.3 -14.4 -121.9 85.2 -122.6 N13 H132 O6 O60 H601 O11 -21.0 -5.3 -8.6 26.4 -17.3 O11 H111 O1 -43.9 -10.4 -11.3 50.3 -32.9 O6 H611 O61 -5.0 -1.2 -16.4 10.8 -13.8 Table 3 Interaction energies of H-bonded molecules of ibrutinib and their particular terms In addition, Figure 12 shows some similarity of Ibrutinib structural packing, even between form A and the other two forms. The molecules of Ibrutinib in all here described structures tend to make strongly bonded chains/pseudochains which are further adhered to each other by less strong dispersive forces, mostly between aromatic rings. For forms C and F, those bonds are ordered around the channels of methanol such that they make a rectangular net, while, in form A, these bonds are more evenly distributed over the whole structure. In summary, these results confirm our observations about Ibrutinib, and particularly form A, having highly pronounced π-π interactions, and they also agree with our previous study, where we found several solvates of ibrutinib with aromatic solvents. Scanning Electron Microscopy The morphology of ibrutinib polymorphs was studied by SEM. Whenever possible, the observed crystal shape was compared to the theoretical morphology from the crystal structure (BFDH model). For details see Figure 13. Form A crystallizes as platelets, which corresponds very well to the predicted shape. As for the form B, we can see small crystallites on the surface of an irregular, possibly amorphous, material. The crystallites resemble the shape of the Form C crystals, which may point to possible structural similarity, but without the solved structure this is just a speculation. As we have shown above that form C is always the desolvation product of form F (MeOH solvate), the SEM image actually represents both. There was not observed any macroscopic recrystallization or morphology change upon drying. Form C/F crystallizes as prolonged tiles. The shape of the particles corresponds to the ones calculated for forms C and F both, but the observed crystals have different aspect ratio. This is probably caused by the crystallization conditions, i.e. that the (100), (-100), (10-1) and (-101) set of crystal planes for form F grow slower, than would be predicted solely based on the crystal structure (only information about the unit cell parameters and the space group are considered for the BFDH morphology calculation).



Figure 13. SEM photos of all here described Ibrutinib forms with comparison to the BFDH model (where possible).

Thermal Behavior To evaluate the stability and thermal behavior of the prepared solids, we first performed DSC measurements. The results confirmed that form A is the most stable polymorph, having the melting point of 155 °C. For form C, the measured melting point was 133 °C and, for the least stable form B, it was 115 °C. It is obvious from the DSC diagrams that forms A and C are much better crystalline with a narrower endothermic peak and with a straightforward progress of the change during the melting (see Figure 14). Forms A and C show only one endothermic process (melting), while form B shows two peaks. The first is one very broad, connected by a recrystallization phase to the second peak, which was recognized as the melting of form A. Despite our greatest efforts, we were not able to measure DSC of the form F properly, because of its high instability.


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Figure 14. DSC diagrams of all Ibrutinib polymorphs The relative stability of the polymorphs was further confirmed by applying Burger-Ramberger rules on the measured thermodynamic properties. According to the heats of fusion (∆H) obtained from DSC, the highest melting polymorph A has the highest value of ∆HA = 62,22 J/g. In addition, it also has the highest density of ρA = 1.324 g/cm3 in comparison with form C. On the other hand, the middle melting polymorph C has ∆HC = 59.23 J/g and density ρC = 1.301 g/cm3 and the lowest melting polymorph B has ∆HB = 41.99 J/g. In summary, all these results correspond to the rules well and further confirm form A as the most stable polymorph. To further confirm the relative stability of the polymorphs, we conducted several long-term (3 weeks) slurry experiments. In particular, we prepared seven experiments containing different mixtures of polymorphs as well as the pure polymorphs to obtain the stabilities in all possible cases. The results measured by XRPD confirmed the stability of form A, as it was the resulting solid found in all four experiments. Interestingly, during the long-term experiments, we discovered some possible problems



with chemical stability of the Ibrutinib molecule. Therefore, we performed an experiment focused on this phenomenon, resulting in partial decomposition of the molecule. For further details, please refer to Supplementary Information.

Water sorption and solubility To study the hygroscopicity of the Ibrutinib polymorphs, DVS measurements were performed. Dry powders were introduced in a humidity controlled chamber and a mass weight change was observed with the changing relative humidity. The formation of a possible stoichiometric hydrate was not observed for any of the forms. In all forms, the water uptake corresponded to surface sorption. For details see Figure S2 in Support Material. In form A, the sorption was reasonably smooth and at 90% RH, the water uptake was 0.45 % (molar ratio of 0.1). In form B, the sorption was very smooth and was 2 wt.% (molar ratio of 0.5). In form C, a step-like hysteresis was observed, however, the amount of the water uptake (0.45 wt.%, molar ratio of 0.1) was too low to indicate a hydrate formation. The IDR results for ibrutinib polymorphs A, B and C can be found in Figure 17. IDRs were 17, 48 and 52 ug . min-1 . cm-2, for forms A, B and C, respectively. Therefore, form A had the lowest dissolution rate and forms B and C were 2.8 and 3.1 times more soluble. This supports all other experimental results, that form A is the most thermodynamically stable and the other forms are metastable.

Figure 17. Intrinsic dissolution rate of ibrutinib polymorphs Solvation Continuum of Ibrutinib As we already described above, Ibrutinib has one desolvation dependent polymorph, form C. This polymorph is prepared by the desolvation of the Ibrutinib methanol solvate form F, which desolvates


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readily, even at ambient conditions. We found this transformation highly interesting and we performed several experiments to further analyze and understand this phase transition. First, we did a comprehensive study of the crystal structures, regarding the differences between the solvated and desolvated form. The study showed that the main difference between the methanol solvate and form C is a closure of the vacant channel in the form C that was left in the structure after the methanol molecules escape (see Figure 18). Otherwise, both structures retain high similarity with each other, which was also revealed by the molecular packing similarity calculation (see above).

Figure 18. Depiction of the structural changes that occur during the transformation of Form F (top) to Form C (bottom). After the desolvation, the terminal phenyl rings rotate to fill the vacant channel left after the methanol escape. In the following part of the study, FT-Raman spectra were measured, to get a better insight to the desolvation process. A freshly prepared form F was filtered and the Raman spectrum was immediately measured. Then the sample was left to desolvate for several minutes and Raman spectrum was measured again. After 14 minutes, the measured spectrum indicated that form C is the prevailing form in the sample. XRPD measurement of the sample confirmed the conversion. As a next step, we tried to resolvate form C back to form F. Small amount of the form C was wetted with methanol in a vial. The resolvation progress was observed by FT-Raman spectroscopy. Overall, the resolvation was successful, but it was so fast that the we were unable to measure its progress using Raman spectroscopy. After approximately one-minute acquisition of the Raman signals, the resulting spectrum contained only the signals of form F. For details see Figure S3.

Through a combination of the mentioned measurements with the solved crystal structures, we propose that the resolvation proceeds by a simple inflow of the methanol back into the structure, opening the channels closed after desolvation. The terminal phenyl rings, which close the channels, are free to move back to the starting position with the opened channels (see Figure 18, indicated by circles). The rest of the molecule of Ibrutinib needs to undergo only a minor conformational change during the



resolvation. As the methanol is in overwhelming molar excess, the whole transformation proceeds very fast. We are currently designing further experiments, which should give us a better insight into the kinetics and mechanism of the resolvation.

Conclusions In this work, we describe the crystal structures and solid state behavior of the polymorphs of Ibrutinib (A, B and C), together with its methanol solvate (F), for the first time in a peer-reviewed literature. The single-crystals of the forms A and F were prepared by standard methods, whereas the preparation of the form C proceeds by desolvation SC-SC transformation of F. Using the crystal structure data, we confirmed high similarity of the methanol solvate with polymorph C, along with its overall similarity with our previously described solvates. However, we found significant differences of the polymorph A with all the other structures. Calculated energy frameworks clearly show that form A prefers π-π interactions, even at the cost of the disruption of the H-bond system. According to DSC, form A is the most stable polymorph with melting point of 156 °C, monotropically related to the other polymorphs. Furthermore, we verified its stability by a long-term slurry experiment which resulted in form A in all cases, and by applying Burger-Ramberger rules on the obtained thermal and structural data. These findings are in agreement, and even support our claim from the previous study, that Ibrutinib prefers π-π interactions in its structures, such as when forming multicomponent solid forms utilizing aromatic coformers. Interestingly, in the experiments at temperatures over 40 °C, we found ibrutinib to be chemically unstable. This finding raises concerns about the stability of ibrutinib drug product during storage and it will be studied deeper. Finally, to assess a drug production usability, we performed intrinsic dissolution rate measurements. The results show forms B and C to have approximately 3 times higher dissolution rate than the most stable form A, which makes them good candidates for possible drug product development.

Acknowledgements We would like to acknowledge the Preformulation and Biopharmacy department of Zentiva, k.s. for the materials and all the help provided. Our great thanks go namely to Ondřej Dammer, Lukáš Krejčík and Josef Beránek. This work was supported by the Czech Science Foundation project, Grant No. 1723196S and received financial support from specific university research (MSMT No 20-SVV/2017). The equipment of ASTRA lab established within the Operation program Prague Competitiveness (project CZ.2.16/3.1.00/24510) was used in the crystallographic measurements.

Supporting Information Further details of the structures’ refinement Comparison of form B and PXY Raman spectra Crystal packing figure of forms A, B and C figures of DVS plots Stability of ibrutinib molecule Interconversion of forms C and F Table of all calculated interaction energies

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For Table of Contents Use Only

Ibrutinib Polymorphs: Crystallographic Study Vít Zvoníček, Eliška Skořepová, Michal Dušek, Pavel Žvátora, Miroslav Šoóš

Table of Contents Graphics

Synopsis Three polymorphs and one solvate of Ibrutinib, a recently approved oncological drug, were prepared and characterized. All four forms can be prepared using methanol solution. The crystal structures of three of the forms were solved and thoroughly assessed, regarding structural features. In addition, interaction energies were calculated for all the solids. Further, stability, thermal behavior, dissolution properties were measured and evaluated.


Ibrutinib Polymorphs: Crystallographic Study - Crystal Growth

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