First Crystal Structures of Pharmaceutical Ibrutinib: Systematic Solvate

Article pubs.acs.org/crystal

First Crystal Structures of Pharmaceutical Ibrutinib: Systematic Solvate Screening and Characterization Vít Zvoníček,*,†,‡ Eliška Skořepová,† Michal Dušek,§ Martin Babor,‡,∥ Pavel Ž vátora,‡ and Miroslav Šoós*̌ ,† †

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

ABSTRACT: A search for new solid forms of an active pharmaceutical ingredient (API) is an integral part of the drug product development process. The studied compound, Ibrutinib, is a recently approved anticancer drug. The main aim of this study was to search for new solvates of Ibrutinib and to perform their structural characterization. To do so, we performed a tailor-made systematic solvate screening and tested several solution and slurry based methods in the solvate screening for their suitability and success rate. The phase composition of the screening samples was analyzed by Raman spectroscopy and powder X-ray diffraction. From the 11 tested solvents, eight solvates were prepared (with 4-hydroxy-4methylpentan-2-on, dioxolane, α,α,α-trifluorotoluene, ortho-xylene, meta-xylene, para-xylene, anisole, and chlorobenzene). The crystal structures of all eight solvates were successfully solved from single-crystal X-ray diffraction data, and, to our best knowledge, this work is the first ever crystal structure study of Ibrutinib. The desolvation behavior of the prepared Ibrutinib solvates was studied by thermal methods (differential scanning calorimetry, thermogravimetric analysis, and hot-stage microscopy), and stability tests were performed to determine the strength of the API−solvent interaction. Dissolution experiments showed that the solvate formation can improve the dissolution rate by as much as 8.5 times, compared to the most stable nonsolvated form.

1. INTRODUCTION

On the other hand, solvates are more predictable in many aspects that are problematic for the nonsolvated polymorphs. In particular, the frequency of polymorphism itself is quite reduced in solvates.4,5 In addition, the bioavailability of the drug is often enhanced, because the solvates generally have a higher dissolution rate and, therefore, achieve higher supersaturation compared to the nonsolvated polymorphs.6 Furthermore, solvates can also be used for the preparation of various polymorphs through desolvation4,7−9 or to control the particle size distribution in the product in cases in which the nonsolvated forms are difficult to crystallize.10 Overall, the rationalization of the solvate formation is one of the important topics in the current crystal engineering.11−13 Limitations for the use of solvates in pharmaceutical production are given by the toxicity of solvents they contain. Permitted solvents and the limits of their content are provided by the regulatory authorities in the pharmacopoeias.14

The search for new solid forms of active pharmaceutical ingredients (APIs) is nowadays in the focus of many academic researchers as well as pharmaceutical companies. These new solid forms include nonsolvated polymorphs, solvates, salts, cocrystals, or even their combinations. Different solid forms may offer improved properties, such as increased bioavailability, higher solubility, and better chemical and physical stability or melting point.1,2 It is, therefore, of a great importance to search for the new API forms. Another benefit of the new solid forms, mostly of industrial relevance, is the opportunity to prepare the solid product with desired properties during the production scale-up,2 which can significantly reduce the time needed for the production process development. The nonsolvated polymorphs are the number one choice for the formulation of a drug, but there can be many problems with the production of the desired polymorph and the reproducibility of the production process.3 Because the energy differences between polymorphs are often quite small,4 they can undergo solid state transformations or even concomitantly crystallize to form phase mixtures. © 2017 American Chemical Society

Received: January 10, 2017 Revised: April 17, 2017 Published: May 1, 2017 3116

DOI: 10.1021/acs.cgd.7b00047 Cryst. Growth Des. 2017, 17, 3116−3127

Crystal Growth & Design

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a dissolution rate almost an order of magnitude higher than the nonsolvated form A.

Ibrutinib, also known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one (see Figure 1), is an irreversible Bruton’s

2. EXPERIMENTAL SECTION 2.1. Materials. Ibrutinib was kindly provided by Zentiva, k.s. The pure polymorphic forms A and C were prepared by recrystallization according to the procedures described in the patent literature.24 The used solvents of analytical purity were obtained from various commercial suppliers and were used as received. 2.2. Reproduction of the Known Solid Forms. Ibrutinib polymorphs A and C, as well as the solvated forms ANI (anisole solvate) and CBZ (chlorobenzene solvate), MOE (4-methylpentan-2one solvate), TOL (toluene solvate) and DME (1,2-dimethoxy ethane solvate), were prepared according to the patent procedure description.24,25 In particular, polymorph A was prepared from a methanol solution of Ibrutinib by adding water as an antisolvent. To the stirred solution of Ibrutinib in methanol (120 mL with temperature 45 °C and Ibrutinib concentration 0.1 g/L), 72 mL of water was added dropwise over 45 min. The prepared mixture became cloudy over the course of 3 h, and the slurry was stirred for additional 12 h. The solid was filtered and dried in the vacuum chamber (100 mbar, 40 °C) for 12 h. Polymorph C was prepared by a recrystallization of Ibrutinib polymorph A in methanol. In particular, form A of Ibrutinib was suspended in methanol and heated on a magnetic heater to 50 °C. The prepared solution (concentration 80 mg/mL) was then stirred and cooled to 0 °C, slowly turning cloudy. Prepared solid was filtered and then dried under a vacuum (100 mbar) at 40 °C overnight. The solvated forms were prepared similarly. To prepare the CBZ and ANI solvates, Ibrutinib was dissolved in the corresponding solvent at 70 °C, and the prepared solution with concentration 200 mg/mL was then stirred by a magnetic stirrer and allowed to cool to the laboratory temperature. The obtained solid was filtered and dried under 200 mbar and 40 °C. The rest of the previously described solvates were prepared by slurry experiments from Ibrutinib form C, which was suspended in the corresponding solvent, and the slurry was agitated for a week at room temperature. The obtained solid was then filtered and dried under 200 mbar and 40 °C. 2.3. Solvate Screening. The solvents used in the solvate screening were chosen according to the similarity with the solvents that have already been reported to form solvates with Ibrutinib. The screened solvents included 4-hydroxy-4-methylpentan-2-on (SMPO), 2methyltetrahydrofuran (SMHF), 1-chlorbutane (SCBU), dioxolane (SDOX), cyclopentyl-methyl ether (SCME), α,α,α-trifluorotoluene (STFT), ortho-xylene (SOXY), meta-xylene (SMXY), and para-xylene (SPXY) (Figure 1). Two of the known solvents, anisole and chlorobenzene, were also added to the study, making the final number of the tested solvents equal to 11. For the purpose of this study, we will use the following notation. For example, for 4-hydroxy-4-methylpentan-2-on, the solvent will be denoted as “SMPO” and the resulting solvate as “MPO”. 2.3.1. Solvate Screening in Solution. A total of 200 mg of Ibrutinib form A was weighed into a glass vial, which was consequently tempered near the boiling temperature of the particular solvent, and the solvent was added gradually until all the solids dissolved or to the maximum volume of 3 mL. If the solution remained cloudy, it was filtered through the syringe filter with a 200 nm cutoff size. The prepared solution was divided into four vials and every part was treated differently. The first part was allowed to cool to room temperature (RT) and slowly evaporateslow evaporation (SE). The second part was capped and allowed to cool to the RTslow cooling (SC). The third part was quickly evaporated on the rotary evaporatorquick evaporation (QE). The fourth part was immediately cooled to −5 °C and then stored in the freezer at −20 °Cquick cooling (QC). The precipitated solid was filtered and dried under 200 mbar and 40 °C. 2.3.2. Solvate Screening in Slurry. A particular polymorph of Ibrutinib (either A or C) was suspended in the corresponding solvent, and the slurry was agitated for a week at room temperature. The obtained solid was then filtered and dried under 200 mbar and 40 °C.

Figure 1. Structural formula of Ibrutinib with highlighted interaction sites.

tyrosine kinase inhibitor recently approved15 as an anticancer drug for the treatment of chronic leukocytic leukemia, mantle cell lymphoma,16−20 and Waldenström’s macroglobulinemia.21 Ibrutinib is produced in the form of capsules (120 mg per capsule) with the highest dosage of 560 mg per day. The high dosing is due to its extremely low solubility in water (this API belongs to the BCS (Biopharmaceutical Classification System) class II22). The overall bioavailability of Ibrutinib is only about 3%,23 so there is an obvious need for new solid forms of this API, which would allow lowering of the daily intake and improved utility of the drug. Decreasing the daily dose may lower the risk of the drug’s side effects and also lower the environmental pollution by the nonmetabolized drug. To the best of our knowledge, there has, so far, not been published any peer reviewed study dealing with the solid forms of Ibrutinib. In the patent literature, three polymorphs (A, B, C) and several other solid forms have been described.24,25 Those mentioned solid forms were identified as solvates with 4methylpentan-2-one (form D in patent, here MOE), toluene (form E, TOL here), anisole (form VII, ANI in this paper), chlorobenzene (from VIII, CBZ here), and 1,2-dimethoxy ethane (form III, here DME).24,25 While three of the solid forms have the unit cell parameters described in the corresponding patents,24,25 none of them was published in the Cambridge Structural Database (CSD), nor were the atomic coordinates made publicly available otherwise. In this study, we have performed a tailor-made systematic solvate screening of Ibrutinib. Starting from the known solid forms,24 we have prepared additional six new solvates and solved eight crystal structures of the solvated forms using single crystal X-ray data. Unfortunately, we were not able to prepare the single crystals of the nonsolvated polymorphs yet. All of the solved structures were compared in terms of their packing. For all the prepared solvates, we tried a desolvation experiment, which led in most cases to the formation of the most stable polymorphic form of Ibrutinib, form A.24 The solvated forms were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) as well as by Raman spectroscopy; the latter also turned out to be very helpful for fast distinguishing between solid forms of Ibrutinib. In addition, the dissolution rate was measured for some of the solvates and compared with that of the most stable form A. Results show that the solvates can have 3117



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2.4. Single Crystal Preparation. To determine the crystal structure of the newly prepared as well as the known solvates, single crystals were prepared to be measured by X-ray diffraction. All single crystals were prepared by the same method. Ibrutinib was suspended in a particular solvent, and the mixture was agitated for 2 h at room temperature to reach saturation. Next, the suspension was filtered through a syringe filter with 200 nm cutoff size, and the saturated solution was allowed to very slowly evaporate in the vial with a lid perforated by a needle. 2.5. Single Crystal X-ray Diffraction (SC-XRD). Single crystal Xray diffraction (SC-XRD) was measured either on a four-circle diffractometer Gemini of Oxford Diffraction with a mirror-collimated Cu Kα radiation (1.5418 Å) of a classical sealed X-ray tube, with the CCD detector Atlas S1 (CBZ, OXY, PXY, and DOX solvates), or on a four-circle diffractometer SuperNova of Rigaku Oxford Diffraction with a mirror-collimated Cu Kα radiation (1.5418 Å) form a microfocus X-ray tube, detected by the CCD detector Atlas S2 (ANI, MPO, MXY, and TFT solvates). The single crystal X-ray diffraction analysis was carried out at a temperature of 120 K (Gemini) and 95 K (SuperNova). The data collection and reduction were done by a program 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 Jana2006.28 All non-hydrogen atoms were refined anisotropically (except for DOX). The simulated PXRD patterns were calculated using the Mercury software (version 3.3).29 Illustrations of the crystal structures were done in Mercury29 and Discovery studio.30 For structures’ refinement details, see Supporting Information, S1. 2.6. Powder X-ray Diffraction (PXRD). The diffraction patterns were obtained using a powder diffractometer X’PERT PRO MPD PANalytical equipped with X-ray beam Cu Kα (λ = 1.542 A) working at the excitation voltage of 45 kV with the anodic current of 40 mA. Measurements were realized over the range of angles between 2° and 40° 2Θ with a step size of 0.01° 2Θ and time remaining at the reflection of 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 antiscattering 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 antiscattering slits were used to correct the secondary beam. 2.7. Raman Spectroscopy. The samples were measured in glass HPLC vials in a spectrometer FT-Raman RFS100/S, with a germanium detector (Bruker Optics, Germany) equipped with a Nd:YAG laser operated at the wavelength of 1064 nm, covering a measurement range from 4000 to −2000 cm−1 with a spectral resolution of 4.0 cm−1. Data were obtained at 64 or 128 accumulations of spectra. The software OMNIC was applied in processing the spectra. 2.8. 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 to 300 °C with the heating rate of 5 °C/min (amplitude = 0.8 °C; period = 60s). The peak maximum temperature (Tpeak) and the peak onset temperature (Tonset) were specified in the DSC result. The enthalpy was given in the unit J/ g. The sample weight was about 3−5 mg. 2.9. Thermogravimetric Analysis (TGA). TGA measurements were performed on PerkinElmer TGA 6. About 20 mg of the sample was weighed into a ceramic pan and measured in a nitrogen flow. The TGA investigations were performed in the temperature range of 20− 300 °C with a heating rate of 10 °C/min. 2.10. Hot-Stage Microscopy (HSM). HSM measurements were performed on a Nikon Eclipse E400 (Nikon, Japan) thermomicroscope, with a Linkam heating unit and a Nikon Coolpix 5400 digital camera (Nikon, Japan). Samples were placed on an object plate and covered. Investigations were performed in the temperature range of 20−180 °C with a heating rate of 5 °C/min.

3. RESULTS The main aim of this study was to search for new solvates of Ibrutinib and to perform their structural characterization. 3.1. Preparation of the Solvates. The first part of the study comprised the searching for new solvates of the used API. The first step was selection of the suitable solvents based on their properties. The amount of the solvent in the pharmaceutical product is strictly limited by official guidelines,14 and only a small part of all the possible liquids usable as a solvent can be present in the pharmaceutical product in a higher than trace amount. The specific amount of every allowed solvent is set mostly according its toxicity. For the purposes of our study, the solvents used were chosen according to their structural and chemical properties, while we put less emphasis on the aspect of their pharmaceutical acceptability. This is because many solvates can also be used in a crystallization process, followed by the preparation of the desired polymorph through a solvate desolvation. The most important potential benefits of this approach are higher robustness of the crystallization process, less amount of a solvent and cosolvents, better yields of the crystallization process, and possible control of the crystal size and shape.10 To maximize the outcome of the search, the second step, the solvates’ preparation, was performed by several methods, which were consequently compared according to their success of finding a new solvate. Two known solvates were also used for this study as a control sample. 3.1.1. Rational Selection of the Screened Solvents. As was already mentioned in the Introduction, some patent literature exists describing that Ibrutinib can form solvated solid forms. Those include ANI (anisole solvate) and CBZ (chlorobenzene solvate), MOE (4-methylpentan-2-one solvate), TOL (toluene solvate), and DME (1,2-dimethoxy ethane solvate).24,25 First, we reproduced the above-mentioned solvates and confirmed their existence by Raman spectroscopy (see an example in Figure 2). The existence of all five solvates was confirmed. On the basis of the results, we have chosen nine new solvents with the molecular structure and electronic properties similar to the solvents forming the known solvates. The selected solvents

Figure 2. An example of the screening results evaluation by Raman spectroscopy. The spectra of the nonsolvated forms of Ibrutinib A and C and of the prepared MXY (m-xylene) solvate. The regions with the most pronounced differences are highlighted. The MXY spectrum is clearly different from those of the nonsolvated forms. 3118



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Figure 3. Solvents, for which the existence of the solvates of Ibrutinib had been described in the patent literature (black), and those tested in our solvate screening (blue and red).

Table 1. Solvate Screening Results for Ibrutiniba

were 4-hydroxy-4-methylpentan-2-on (SMPO), 2-methyltetrahydrofuran (SMHF), 1-chlorbutane (SCBU), dioxolane (SDOX), cyclopentyl-methyl ether (SCME ), α,α,α-trifluorotoluene (STFT), ortho-xylene (SOXY), meta-xylene (SMXY), and paraxylene (SPXY) (see Figure 3). Those newly selected solvents were used in a systematic solvate screening of Ibrutinib. As a control, we also did the full screening with two of the solvents known to form solvates, namely, anisole (S ANI ) and chlorobenzene (SCBZ). For systematic purposes, we have divided the known solvates into two groups: oxo solvents and substituted benzenes. For the oxo-solvents group, SMPO was chosen for its close similarity to SMOE, while SDOX, SCME, and SMHF were selected for their (albeit looser) similarity to SDME. The last solvent in this group was SCBU. The selection of this solvent was driven by an electronegativity effect of the chlorine atom comparable to the oxygen atom in the oxo-solvents. In the other group of solvents, the substituted benzenes, STFT was chosen based on its clear similarity with SCBZ due to the comparability of their size as well as the electronic effect of their substituent on the benzene ring. The same is true for SOXY, SMXY, SPXY, and STOL; however, their steric requirements are slightly larger compared to the originally proposed solvents. Focusing on the pharmaceutical acceptability, the xylenes can be used in a drug product, but their amount is restricted (2170 ppm or 21.7 mg per day). SMPO is a chemical commonly used in food production, so, in our opinion, from all of the prepared Ibrutinib solvates, MPO would be the most pharmaceutically acceptable one. The other solvents are considered harmful, and they cannot be used in the final drug product. 3.1.2. The Solvate Screening. The solvate screening itself was carried out in a systematic way by six different methods that can be divided into two groups. The first group is comprised of the four solution based methods: quick cooling (QC), slow cooling (SC), quick evaporation (QE), and slow evaporation (SE), while the second one includes the slurry based methods starting with either the thermodynamically stable form (form A) or metastable form (form C). On the basis of the results from the previously mentioned screening experiments, single crystals were grown for the discovered solvates. For a detailed description, see the Experimental Section. Table 1 shows the complete results of the performed screening and single-crystal growth experiments. The phase composition of the samples was analyzed by both Raman

a

A: anhydrous form A. -: no crystalline material obtained.

spectroscopy (see Figure 2) and PXRD (see Figure 4); the single-crystals were analyzed by SC-XRD (structures are discussed in detail later in the text). From the obtained results, it can be seen that from 11 tested solvents, new solvates were prepared for eight of them (see Figure 3). Out of those, seven were newly discovered solvates of Ibrutinib (MPO, DOX, TFT, OXY, MXY, PXY, and PXY2). Interestingly, two solvates with different stoichiometry were prepared from SPXY. The PXY was, so far, prepared only as a powder sample under slurry conditions, while the PXY2 emerged only during the single crystal preparation in SPXY. The 3119



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significant impact on the solvate formation. The results of the experiments were either the formation of a solvate, the transformation to, or preservation of the thermodynamically stable nonsolvated form A or even, for some of the experiments, no crystallization occurred at all. The most successful method, in this study, turned out to be the slurry based experiment with the metastable nonsolvated form C as the starting material. All of the prepared solvates were prepared by this method as well (8 out of 8 = 100% success rate at discovering the solvates, if we presume that our screening gave no false negative results). The worst method proved to be the other slurry based experiment, the one in which the thermodynamically stable nonsolvated form A of Ibrutinib was used as the starting material. None of the solvates were observed by this method (0 out of 8 = 0% success rate). The solution based experiments gave mixed results: slow cooling (5 out of 8 = 62.5% success rate), quick evaporation (2 out of 8 = 25% success rate), quick cooling, and slow evaporation (for both of them 1 out of 8 = 12.5% success rate). The results of the slurry based experiments may somehow be rationally derived from the thermodynamics. As the activation energy for a recrystallization is higher for the more stable polymorph, form A (the most thermodynamically stable polymorph) remained unchanged under slurry conditions, while form C (the metastable polymorph) recrystallized in the slurry in every studied case, yielding the appropriate solvate. These results show how important the choice is of an appropriate starting material for the solid form screening. 3.2. Crystal Structures. To get insight into the crystal packing and interactions of Ibrutinib and solvent molecules in the solvates, the prepared single crystals (Table 1) were measured by SC-XRD, with a subsequent structure solution. Brief results are given in Table 2 (for more information, see Table S1 in the Supporting Information) While the host API molecules in the crystal structures were held rigidly, the solvent molecules were less so, which is reflected by their bigger atomic displacement parameters (ADPs) in all cases. ORTEP diagrams for all the solved structures can be found in the Supporting Information as Figure S4. As a chiral molecule, Ibrutinib is limited to only certain, socalled chiral or enantiomorphic, space groups for crystallization. All of the here described Ibrutinib solvates crystallize in the triclinic system with the space group P1. Most of the solvates,

Figure 4. Powder diffraction patterns of Ibrutinib nonsolvated forms A and C and of the described solvates. *For PXY2, the diffractogram was calculated from the crystal structure.

growth of the higher-solvated crystals may be caused by the high solvent content in the system for single crystals preparation and relatively low supersaturation, and thus low crystal growth rate in comparison with the conditions in the solvate screening. The remaining two solvates (ANI and CBZ) were the successfully reproduced forms already mentioned in the patent literature that were included as a control to our screening. 3.1.3. Evaluation of the Screening Methods. As can be seen from Table 1, the preparation conditions have quite a Table 2. Basic Crystallographic Data of Ibrutinib Solvatesa empirical formula formula weight crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z CCDC no. a

MPO

DOX

TFT

OXY

MXY

PXY2

ANI

CBZ

C31H36N6O4 556.67 triclinic P1 10.7491(2) 11.6814(2) 13.4100(3) 75.3769(17) 69.4688(17) 64.9843(17) 1418.14(3) 2 1525561

C28H30N6O4 514.59 triclinic P1 9.9709(2) 14.8343(2) 17.4937(2) 80.5116(11) 78.5650(13) 74.3710(14) 2425.30(7) 4 1525560

C32 H29 F3 N6 O2 586.54 triclinic P1 10.9962(2) 11.9991(2) 12.0896(2) 79.7179(16) 71.7985(18) 69.0665(19) 1411.29(2) 2 1525565

C33 H34 N6 O2 546.64 triclinic P1 11.3206(2) 15.6063(3) 16.6997(3) 87.2953(13) 76.7525(15) 79.8121(15) 2826.52(5) 4 1525563

C58H58N12O4 987.18 triclinic P1 10.1055(2) 10.4590(2) 13.8796(2) 95.3990(12) 100.2221(15) 116.7545(18) 1263.623(18) 1 1525562

C33H34N6O2 546.68 triclinic P1 10.1530(3) 10.7810(2) 14.5247(3) 82.5381(19) 71.019(2) 77.858(2) 1466.54(3) 2 1525564

C57H56N12O5 989.15 triclinic P1 9.9939(2) 10.2957(2) 13.9251(3) 94.7775(17) 100.3620(17) 116.113(2) 1243.99(3) 1 1525558

C31 H29 Cl1 N6O2 553.05 triclinic P1 11.0598(4) 11.8540(4) 11.9400(4) 81.279(3) 67.786(3) 72.096(3) 1377.89(5) 2 1525559

For more details see Table S2. 3120



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Figure 5. Comparison of molecular conformations of Ibrutinib in the presented structures.

than could be expected. All of the Ibrutinib solvates hold the cyclohexyl in the chair conformation, with the only exception being MPO, which has a chair/boat disorder in this part of the molecule. Again, the cyclohexyl has a very similar rotational position in the structures, although it is bonded by a single bond. Interesting is the situation of the acrylate part, which adopts an eclipsing conformation that holds one of the acrylate hydrogens in close proximity with another hydrogen on cyclohexyl. Although this situation should be energetically unfavored, the energy penalty of the eclipse is probably compensated by other more energetically advantageous effects allowed by this conformation. The acrylic group is almost perfectly planar due to the conjugation of the double bonds. Because the carbonyl on the acrylate has to be in the proper position to accept the H-bond of the main structure motif formed by Ibrutinib molecules, the whole acrylic group stays in the same position across all the structures (the OC−CC torsion of around 0°). The opposite conformation is also possible (the OC−CC torsion of around 180°); however, according to CSD,31 it is much less probable. This assumption is supported by a quite often disorder of this part of the molecule. 3.2.1. Molecular Packing. The following discussion on the molecular packing of Ibrutinib solvates will be divided based on the dimensionality of the described motifs. 3.2.1.1. Zero-Dimensional Motif - Ibrutinib Homodimer. Similar to the molecular conformation, the crystal packing of Ibrutinib in the solvates also follows quite rigid patterns. The main motif is a homodimer of Ibrutinib molecules H-bonded into a homosynthon N−H···N(arom.) in plane of the bicycle (see Figure 6). The bond between the nitrogen atoms is the strongest bond in the structure system; its angle is close to 180°, which is the theoretically ideal angle for H-bonds,32 with

namely, ANI, CBZ, MPO, MXY, PXY, and TFT, have two Ibrutinib molecules in the unit cell, while OXY and DOX have four. In our Ibrutinib structures, the different number of molecules in the asymmetric unit corresponds to the different number of conformations of Ibrutinib molecules. Generally, Ibrutinib molecule adopts four main conformations arranged into pairs in the crystal structures. There is only a small divergence between the different solvates with the same pair of conformations. For ANI, CBZ, MPO, MXY, PXY, and TFT, it was possible to adopt only one conformational pair in the structure, while for the OXY and DOX, both conformational pairs are mixed in their structures. The conformations in one pair are almost perfect mirror images (within one solvate) but for the difference caused by the chirality of Ibrutinib. The four different conformations arise from the variation in both ends of the molecule (A and B), each having either two or four conformations (1−4), see Figure 5. The four general conformations can be described as A1B1, A2B2, A1B3, and A2B4, see bottom of Figure 5. To evaluate and compare the crystal structures and molecular conformations of the disordered solvates, we have chosen the molecules with higher occupancies. As can be seen in Figure 5, the most mobile part of Ibrutinib is the terminal phenyl ring (region B), which adopts a different position in each solvate (with the exception of the isostructural ones). The other phenyl ring holds almost the same position in the structures with only a slight misalignment of its plane, even though it could theoretically rotate around the single bonds to which it is attached. This rigidity is induced partly by the intermolecular H-bonding between carbonyl and amino groups between the Ibrutinib molecules. The other end of the molecule, the six-membered ring with acrylamide (region A), is also conformationally more stable 3121



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weaken the nearest covalent C−H bonds, making the hydrogen more prone to H-bonding. Similar bonds can be observed even in some of the substituted benzenes group solvates, namely, CBZ and TFT (see text below). Detailed images showin, that there is no standard hydrogen bonding between the solvent and Ibrutinib molecule can be found as Figure S5 at the Supporting Information. 3.2.1.3. Two-Dimensional Motif - Arrangement of the Chains. Overall, the crystals consist of one, or in the case of OXY, two symmetrically independent chains of Ibrutinib molecules combined with the solvent. An interesting phenomenon can be observed in the case of DOX and OXY solvates. Both of these solvates have four different conformations of Ibrutinib in their crystal structure (the other structures contain only two). The largest difference between DOX and OXY is the way that those four molecules are packed in the structure. Both of them preserve the main motif of the Ibrutinib chain, but, while the OXY contains two different chains of Ibrutinib with 2 + 2 molecular conformations, the DOX structure combines all four conformations into one chain. Within the meaning of 2D packing, the DOX is more similar to the other solvates, because it contains only one type of chain repeating in the structure. On the other hand, OXY is more similar to the other solvates from a 1D point of view, because it has two different conformations in each chain. This peculiar behavior might be influenced by the particular solvent molecule. 3.2.1.4. Three-Dimensional Motif - Crystal Packing. In general, even if the molecular shape or the conformation is highly similar, it does not necessarily mean that the packing or the long-range order of the molecules in the crystal will be very similar, nor that the crystals will be isostructural. As we showed in Figure 5, Ibrutinib molecules have quite similar conformations in all of the prepared structures. In spite of the conformational similarity, further analysis of the structures showed that they are not so similar within the meaning of the crystal packing. In fact, we have only found two highly similar (isostructural) structure pairs, namely, CBZ + TFT and ANI + MXY. Between the other structures’ long-range order, no significant similarities were found. In order to quantify the similarities of the complete structures in a long-range order, we have used the software CrystalCMP.33 This software overlaps the structures (without solvent molecules) and returns figures of merit indicating the similarity of the crystal packing and molecular conformations. The values are then used to construct a similarity tree diagram.

Figure 6. Homosynthon dimer of ibutinib molecules. This synthon appears in all described structures.

the highest deviation of 12.7° (PXY2) but only up to 7° in most of the reported structures. The mean D−A distance is 2.967 Å (see Table S2 in Supporting Information). 3.2.1.2. One-Dimensional Motif − Zig-Zag Chains. The other important H-bond is CO···H−N (see Figure 6). It adopts an angle of around 140°, and it is, therefore, probably less strong than the previously described bond. Still, it is one of the strongest nonbonding interactions in the structures. These bonds protrude out of the bicycle plane, and they link the Ibrutinib dimers into catemers with a zigzag structure (Figure 7). This chain-bonding system was never disrupted by any interaction from the solvents, which points to its high stability. In most cases, the solvent molecules sit in a discrete cavity in the structure, filling the space between the chains, without making highly specific or strong bonds. Only in the case of PXY2 structure, the solvent molecules form infinite channels. The solvent molecules are held in the structures only by weak interactions. For the group of substituted benzene solvents, the highest manifestation was observed for the π−π interaction, either the herringbone type or edge-to-face. In the MPO solvate, the SMPO makes weak H-bondlike interactions of CO···H−C type with Ibrutinib (both acting as donors and acceptors). This is made possible by the presence of electronegative atoms (O, N) in the carbon chain, which

Figure 7. “Zigzag” H-bonded chains in all of the structures of solvates of Ibrutinib. For OXY, only one chain is shown for illustrative reasons. 3122



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Figure 8. Packing similarity tree diagram of Ibrutinib solvates calculated by CrystalCMP. Parts of the tree diagram between 3 and 6 and between 6 and 13 were removed to make the figure shorter and more readable; the vertical curved lines indicate these deletions.

The results shown in Figure 8 clearly indicate the existence of the two perfectly isostructural groups (CBZ + TFT shown in Figure 9 and ANI + MXY shown in Figure 10). The

Figure 10. Both SANI (anisole, violet) and SMXY (m-xylene, yellow) have a similar “space requirements” (a) resulting in the same packing of the Ibrutinib molecules (b) and their similar interactions (c). Solvent surfaces were calculated by Discovery Studio (probe radius of 1.4 Å). The overlay was done by CrystalCMP. Hirshfeld surfaces and related fingerprint plots were generated by CrystalExplorer36 (high resolution).

Figure 9. Both SCBZ (chlorobenzene, left) and STFT (trifluorotoluene, right) have a similar molecular structure and “space requirements” (a) resulting in the same packing of the Ibrutinib molecules in the solvent (b) and their similar interactions (c). Solvent surfaces calculated by Discovery Studio (probe radius of 1.4 Å). The overlay was done by CrystalCMP. Hirshfeld surfaces and related fingerprint plots were generated by CrystalExplorer36 (high resolution).

Despite the described possible variability, two isostructural pairs can be identified among the prepared solvates, particularly pair 1 containing TFT and CBZ solvates and pair 2 containing ANI and MXY. For further investigation of the isostructures, we have used Hirshfeld fingerprint plots34,35 (high quality setting) of Ibrutinib molecules for studying the interactions and isosurfaces of solvent molecules to estimate the steric effects. This gave us information about the main N−H···N and N−H··· O interactions between the Ibrutinib molecules, but also about the interactions with the solvent molecules. The molecular similarity of the solvents in pair 1 (see Figure 9) is more visible than in pair 2 (see Figure 10). The similarity of the solvents is based on the electronic effects of the substituents as well as on the exact position and conformation

dissimilarities between the other groups (and the particular structures) are caused by the increasingly differing positions of the parallel infinite chains influenced by unit cell parameters. 3.3. Isostructural Solvates. Generally, the solvent molecules are held in the structures only by the weak interactions. In MPO, CBZ and TFT, weak H-bonds (e.g., C−H··· OC), π−π interactions, and dispersive forces play a role, while for the rest of the structures, only the last two types of interactions are relevant. This is probably the reason for the solvent position variability. 3123



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followed by a broad endothermic plateau up to the melting temperature of the form A of Ibrutinib (see Figure 11). The

of the solvent in the crystal structure. For both isostructural pairs (see Figures 9 and 10), it can be clearly seen that the fingerprint plots of the corresponding molecules with the same conformation from both solvates in each isostructural pair are more similar than the plots of the Ibrutinib molecules paired within one solvate. The main motif in all the plots of Ibrutinib are the four spikes, which describe the hydrogen bonding of Ibrutinib molecules into the chains. The longest outer spikes depict the main N−H···N bonds in the Ibrutinib homodimer. The shorter inner spikes show the interaction N−H···O of the Ibrutinib amino group with the carbonyl group of another Ibrutinib molecule. On the sides of the plots, there are typical “wings” which depict the C−H···π interactions. In pair 1, both α,α,α-trifluorotoluen and chlorobenzene are similar in size (see Figure 9) and have similar electronic properties. The trifluoromethyl group is sterically slightly more demanding than the chlorine, but the electronic effect of the substituents on the benzene ring is very similar. Both substituents are electron withdrawing, which makes the benzene ring electron deficient, enabling both solvents to interact similarly. Some other, rather weak, interactions may be recognized in both CBZ and TFT, specifically the interaction of the halogen atom with slightly acidic hydrogen on the cyclohexyl ring of Ibrutinib (C−H···X) and the interaction between aromatic C− H in the para-position to the substituent with both carbonyl and vinyl groups of the Ibrutinib molecule. The second pair of isostructural solvates, pair 2 (see Figure 10), containing MXY and ANI, has the main interaction of edge-to-face (E−F) π−π stacking37 type mixed with CH3−π interaction. The structures contain rows of solvent molecules surrounded by phenyl rings of Ibrutinib molecules rotated perpendicular to the plane of the solvent. In this manner, each solvent molecule interacts with four Ibrutinib molecules by E− F π−π stacking. Despite the previous, the pair of ANI and MXY contains a higher number of the longer contacts with high di and de in their fingerprint plots, in comparison with the pair of CBZ and TFT, which may indicate less efficient packing of the structures of ANI and MXY. To this pair of isostructural forms, actually, a third one could be addedPXY. For this form, the crystal structure has not been solved yet; however, a significant similarity of its powder diffraction pattern with those of ANI and MXY was observed (see Figure 4). In fact, there may be even a third isostructural pair of solvatesMPO and MOE. However, the crystal structure of MOE is not available; their possible isostructurality is only estimated according to the high similarity of their whole Raman spectra (Figure S1) as well as PXRD patterns (Figure S2). 3.4. Stability and Desolvation Properties. To get insight into the structural behavior and lattice stability of the Ibrutinib solvates, we used thermal methods DSC and TGA, which are commonly used for the characterization of the thermal behavior of the solids. In addition, hot-stage microscopy (HSM) was used for an explanation of the MPO unusual behavior. 3.4.1. Thermal Analyses. Overall, Ibrutinib solvates exhibit unusual and very interesting behavior during heating. The TGA and DSC data for all solvates are available in the Supporting Information, S3. None of the solvates have only one sharp endotherm, indicating the desolvation, and a second one for the melting of the desolvated phase, as would be usually expected. For example, MPO has the first sharp endotherm followed by a small exothermic peak (probably recrystallization), further

Figure 11. Overview of the changes of MPO sample with increasing temperature as observed by hot-stage microscopy (HSM) and compared with its DSC and TGA curves.

plateau phase is probably a desolvation combined with the recrystallization to the most stable form A. In addition, TGA also showed very interesting results indicating more than one mechanism of the desolvation for the most of the solvates. The explanation for this behavior is now our priority, and we plan to proceed with a more detailed study of the solvates’ thermal properties, particularly by measuring temperature dependent PXRD. According to the DSC results, we set up a desolvation experiments and let the solvates to desolvate at the temperature of their first endotherm. All forms, except DOX, provided the most stable polymorph A after desolvation. The DOX form desolvated to the metastable polymorph C. For MPO, we tried to understand the mechanism of the desolvation by introducing another thermal technique, HSM. As can be seen in Figure 11, the desolvation starts roughly at 82 °C and proceeds without a change of the macroscopic structure of the crystals up to 85 °C, where the crystals start to melt. Melting proceeds up to 95 °C with a complete melting of the smaller crystals and only partial melting of the big ones. During 3124



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Table 3. Summary of the Thermal Analyses of MPO temp range, °C

TGA

DSC

−2%

endotherm at 83 °C

95−100

inflection

weak exotherm

100−150

−19%

broad endotherm, maximum at 127 °C endotherm at 175 °Ca

155−163 a

HSM

78−95

explanation first stage of desolvation

crystals lose their transparency slight melting/phase transition recrystallization

beginning of structure rearrangement in the desolvated part of the sample main desolvation event with concomitant melting of the solvate and recrystallization to form A melting of form A

melting

The observed melting point of form A shifted probably because of a different heating rate.

Table 4. Thermal Behavior of Ibrutinib Solvates solvate

boiling point of the solvent (°C)

desolvation temperature (°C)

stoichiometry from TGA

stoichiometry from crystal structure

MPO DOX TFT OXY MXY PXY ANI CBZ

166 75 104 144 139 138 154 131

83 25c 88 90 95 99 115a 94

1:0.997 1:0.421 1:0.972 1:0.855 1:0.404 1:0.425 1:0.485b 1:0.928

1:1 1:0.5 1:1 1:1 1:0.5

a

Raman sp. of resulting powder Form Form Form Form Form Form Form Form

1:0.5 1:1

A C A A A A A A

On the basis of DSC. bOnset of desolvation, the sharpest part proceeds at around 120 °C. cTotal weight loss without sample decomposition.

Table 5. Stability and Desolvation Properties of Ibrutinib Solvatesa

a

solvate

MPO

DOX

TFT

OXY

MXY

PXY

ANI

CBZ

stability test A (12 h at 40 °C and 200 mbar) stability test B (3 months at ambient temperature and pressure)

OK OK

X

OK OK

OK OK

OK OK

OK OK

OK OK

OK OK

OK: stable. X: unstable.

and pressure for three months and measured again. The obtained results are summarized in Table 5. As can be seen, all of the solvates except DOX remained stable at both conditions. 3.5. Dissolution Enhancement. One of the main reasons for the solid state screening is the search for new forms with improved properties. As the dissolution is one of the most important properties of a pharmaceutical solid form, we have decided to test whether our solvates can differ from the nonsolvated form A. For our measurements, we used simulated stomach conditions (i.e., pH = 2) and measured the intrinsic dissolution, which is a method that is not influenced by particle sizes or shapes. An example of dissolution of TFT and MPO solvates is shown in Figure 12. For comparison, the data measured for form A are also included. It can be seen that solvates have a significantly higher dissolution rate, which increases by 3.5 times up to 8.5 times, respectively, relative to form A (see Figure 12).

further heating, no more melting, nor the crystallization occurred, up to 108 °C, where the melt started to recrystallize. The recrystallization was completed at about 120 °C. At 155 °C, another melting occurred, indicating that the newly crystallized form after the desolvation was the most stable form A. A summary for MPO thermal behavior is shown in Table 3. The results clearly indicate a very complex effect of the solvent−API interaction on the thermal behavior of the formed solvates, which will be part of our further research. Table 4 summarizes the thermal analysis of all the studied solvates. 3.4.2. Stability. Generally, the solvates are considered as a less stable solid forms than the other types of solids (e.g., pure polymorphs, cocrystals, salts, etc.) at ambient conditions. The reason for this assumption is the higher tendency of the solvent molecules to escape from the crystal lattice. The molecules are in an apparent liquid state, meaning that they would make a liquid if they were not trapped in the crystal lattice, under those conditions. Liquids generally tend to evaporate better than the solids (solid coformers), and this property is maintained also for the molecules of the solvent in the solvated crystal. For those reasons, the solvates tend to, at least slightly, desolvate during their storage. To assess the newly prepared solid forms, before they could be considered as a viable option for the solid form used for the pharmaceutical formulation, some stability tests were performed. The possible phase transitions were monitored by Raman spectroscopy. The prepared solids were first measured immediately after filtration, then they were put into the vacuum chamber with 200 mbar and 40 °C for 12 h and measured again. If no change was observed (they remained solvated), the samples were stored at the ambient temperature

4. CONCLUSIONS The main goal of this study was the rational and systematic search for new solvates of Ibrutinib and the characterization of their structural features. Eleven solvents were tested and, for eight of them, solvates were prepared. Out of those, six solvates of Ibrutinib were newly discovered, in particular, solvates with 4-hydroxy-4-methylpentan-2-on, dioxolane, α,α,α-trifluorotoluene, ortho-xylene, meta-xylene, and two with para-xylene). The remaining two with anisole and chlorobenzene were the successfully reproduced forms mentioned in the patent literature that were included as a control to our screening. 3125



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ORCID

Vít Zvoníček: 0000-0002-4412-0894 Eliška Skořepová: 0000-0001-9753-2465 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to acknowledge the Solid State department of Zentiva, k.s. for the materials and all the help provided. Our ́ and great thanks go namely to Ondřej Dammer, Lukás ̌ Krejčik, Marek Schöngut. This work was supported by the Czech Science Foundation projects, Grant No. 17-23196S and received financial support from specific university research (MSMT No 20-SVV/2016). 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.

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Figure 12. Comparison of intrinsic dissolution rate for Ibrutinib nonsolvated form A and solvated forms TFT and MPO.

(1) Jia, L.; Zhang, Q.; Wang, J. R.; Mei, X. CrystEngComm 2015, 17, 7500−7509. (2) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: A Textbook; World Scientific: Singapore, 2011. (3) Bernstein, J.; Davey, R. J.; Henck, J. O. Angew. Chem., Int. Ed. 1999, 38, 3440−3461. (4) Minkov, V. S.; Beloborodova, A. A.; Drebushchak, V. A.; Boldyreva, E. V. Cryst. Growth Des. 2014, 14, 513−522. (5) Cruz-Cabeza, A. J.; Reutzel-Edens, S. M.; Bernstein, J. Chem. Soc. Rev. 2015, 44, 8619−8635. (6) Chi, Y.; Liu, C.; Ren, T.; Wang, X.; Yang, Q.; Yang, Z.; Yang, Y.; Yang, S.; Gu, J.; Hu, C. Cryst. Growth Des. 2016, 16, 3180−3189. (7) Sládková, V.; Skalická, T.; Skořepová, E.; Č ejka, J.; Eigner, V.; Kratochvíl, B. CrystEngComm 2015, 17, 4712−4721. (8) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2012, 14, 691−699. (9) Neville, G. A.; Beckstead, H. D.; Cooney, J. D. Fresenius' J. Anal. Chem. 1994, 349, 746−750. (10) Griesser, U. J. In Polymorphism in the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA, 2006; pp 211−233. (11) Tieger, E.; Kiss, V.; Pokol, G.; Finta, Z.; Rohlíček, J.; Skořepová, E.; Dušek, M. CrystEngComm 2016, 18, 9260−9274. (12) Tieger, E.; Kiss, V.; Pokol, G.; Finta, Z.; Dušek, M.; Rohlíček, J.; Skořepová, E.; Brázda, P. CrystEngComm 2016, 18, 3819−3831. (13) Braun, D. E.; Griesser, U. J. Cryst. Growth Des. 2016, 16, 6405− 6418. (14) In Residual Solvents, European Pharmacopoeia; Council of Europe, 2013; p 5967. (15) U.S. Food And Drug Administration. Drug Approval Package: Imbruvica http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2013/205552Orig1s000TOC.cfm (accessed January 6, 2017). (16) Rajabi, B.; Sweetenham, J. W. Ther. Adv. Hematol. 2015, 6, 37− 48. (17) Rozovski, U.; Hazan-Halevy, I.; Keating, M. J.; Estrov, Z. Cancer Lett. 2014, 352, 4−14. (18) Young, R. M.; Staudt, L. M. Cancer Cell 2014, 26, 11−13. (19) Puig de la Bellacasa, R.; Roué, G.; Balsas, P.; Pérez-Galán, P.; Teixidó, J.; Colomer, D.; Borrell, J. I. Eur. J. Med. Chem. 2014, 86, 664−675. (20) Veeraraghavan, S.; Viswanadha, S.; Thappali, S.; Govindarajulu, B.; Vakkalanka, S.; Rangasamy, M. J. Pharm. Biomed. Anal. 2015, 107, 151−158. (21) U.S. Food And Drug Administration. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm432123.htm (accessed December 28, 2016).

The most successful solvate screening method, in this case, turned out to be the slurry-based experiments with the metastable nonsolvated form C as the starting material. All of the solvates could be prepared by this method. Interestingly, with para-xylene, two forms with different stoichiometry were discovered as indicated by XRD. All of the solved structures were compared from various points of view. It was found that the Ibrutinib molecule crystallizes in four general conformation types. On the basis of molecular packing, two isostructural pairs (CBZ + TFT and ANI + MXY) were identified. The desolvation behavior of the prepared solvates turned out to be quite complex, and its full understanding will require further extensive study. Intrinsic dissolution experiments showed that, in the case of Ibrutinib solvates, the solvate formation could be an exciting option for dissolution rate enhancement, with the actual improvement of as much as 8.5 times.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00047. Further details of the structures’ refinement, extended crystallographic data table, figures comparing the MPO and MOE Raman spectra and PXRDs and a further description of their similarity, table of D−H···A distances for classical H-bonds, DSC and TGA data for all the solvates, ORTEP diagrams and hydrogen bonding figures for all the solvates (PDF) Accession Codes

CCDC 1525558−1525565 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*(V.Z.) Phone: +420 220 443 251. E-mail: vit.zvonicek@vscht. cz. *(M.S.) E-mail: [email protected]. 3126



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First Crystal Structures of Pharmaceutical Ibrutinib: Systematic Solvate

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