Unexpected Single Crystal Growth Induced by a Wire and New

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Unexpected single crystal growth induced by a wire and new crystalline structures of lapatinib Gabriel Lima Barros de Araujo, Matthias Zeller, Daniel Smith, Haichen Nie, and Stephen R. Byrn Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01271 • Publication Date (Web): 06 Sep 2016 Downloaded from http://pubs.acs.org on September 7, 2016

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Crystal Growth & Design

Unexpected single crystal growth induced by a wire and new crystalline structures of lapatinib Gabriel L. B. de Araujo * † ‡, Matthias Zeller§, Daniel Smith‡, Haichen Nie‡, Stephen R. Byrn‡ †

Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of Sao Paulo, SP,

Brazil §

Department of Chemistry, Purdue University, West Lafayette, IN, United States

‡

Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN,

KEYWORDS. crystal growth; crystal structure; crystal polymorphism; hydrates/solvates; phase transition;

ABSTRACT. Single crystal growth of lapatinib free base was induced by immersion of a copper wire into a supersaturated methanolic aqueous solution yielding monoclinic anhydrous plates (space group P21/c, Form 1) and needles of a previously unknown channel hydrate (in P42212). Also, a new method has been developed herein to obtain anhydrous Form 1 via acid-base reaction of lapatinib ditosylate and sodium methoxide, avoiding the usage of an aqueous solution and hydrate formation. Anhydrous Form 2 as well as new solvates were produced via solution

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mediated transformation experiments; including a dichloromethane solvate with a powder X-ray diffraction (XRPD) pattern similar to that of anhydrous Form 2. Differential scanning calorimetry (DSC) and solution equilibrium experiments helped to elucidate the interconversion pathways between Form 1, Form 2 and the solvates.

INTRODUCTION In spite of the innumerous advances in many fields of the crystallization science, the success of unexpected approaches reveals why single crystal growth and the finding of new polymorphs of organic entities are uncertain1–3 and sometimes considered more as a mixture of science and art with a pinch of creativity and luck.1,3–5 Vapor-diffusion6, gels7, high-pressure8, laser beam9, electric10 and magnetic fields11 are examples of interesting and creative methods to promote crystal growth. Also, the presence of seeds that allow a primary surface to the first nucleation are recognized to play a primordial role and can vary from highly engineered approaches as the use of gold islands with self-assembled monolayers surfaces12 or polymers13,14, unintentional impurities like airborne particles3 and byproducts or degradation products15,16 to the simplest classical procedure of scratching the glassware. Braga et al.2 stated that crystal makers need “sagacity and readiness of mind”, so they “will be ready to pick new avenues as the crystal experiments will yield something unplanned for”. One curious episode was reported by Bucar et al.3 After two years trying to repeat the growth of a specific polymorph of a dimethyl analogue of the dichlorobenzylideneaniline, they succeed only after moving to a new laboratory operated by a new student hired by phone, using new reagents and new glassware to avoid the presence of unknown seeds from other polymorphs.3 For a crystal engineer faced with this wide-range of


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possibilities only two things are certain: for while there is no universal method2,17 and it is a compound specific problem.6 Herein, we report the investigation of new crystalline forms of lapatinib free base (LP) and the unplanned discovery of an unusual approach to promote single crystal growth of two of these forms. Lapatinib (Figure 1) is an effective and selective oral tyrosine kinase inhibitor first approved by the FDA in 2007 for the treatment of metastatic HER2-positive breast cancer. Recently, Lapatinib has been reported to shrink a metastatic brain lesion resulting from HER-2 positive breast cancer.18 In the case of lapatinib, the marketed salt lapatinib ditosylate (Tykerb®, GlaxoSmithkline, here abbreviated as LPDS) has more than twenty reported polymorphs that can be obtained from a wide range of conditions under thermodynamic and kinetic experimental control (Table 1). Lapatinib free base is of interest because it can form salts with acidic polymers such as HPMCP and HPMCAS and these amorphous salts are rather stable in the amorphous state.19 However, lapatinib free base has been reported to form only four crystalline polymorphs named Form 1, Form 2, Form X and Form Y with very limited thermodynamic or structural data available.20,21 To the best of our knowledge, no single crystal structure or interconversion studies have been reported for any of the polymorphs that have been described so far. After months of unsuccessful trials using classical procedures for growth of single crystals, in a moment of inspiration (or despair since we were running out of material), we decided to offer a different surface to promote a site for nucleation. Since at that time, we had only an old piece of copper wire available on hand, it was introduced in the drug solution and left to slowly evaporate yielding the new structures here described in the first attempt. Since that time we have repeated the experiment with the same results.


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Figure 1. Structural formula of lapatinib. Table 1. Some of the crystal forms related to lapatinib free base and its salts. Salts and Polymorphs of Lapatinib Lapatinib anhydrate Form 1, Form 2 and solvates (1,4 dioxane, pyridine and N-methyl-2pyrrolidinone solvates)20 Polymorphs of lapatinib ditosylate (Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX)22 Lapatinib monotosylate (Form M1) and other salt forms of lapatinib in crystalline and amorphous states (maleate, tartrate, fumarate, succinate, sulfate, di-hydrochloride, dihydrobromide, phosphate)23

Amorphous and crystalline lapatinib free base polymorphs (Forms X and Y)21

Lapatinib ditosylate anhydrous and hydrate (Form A and Form B) and amorphous ditosylate form24


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Table 1 continued Salts and Polymorphs of Lapatinib Lapatinib ditosylate forms APO-I and APO-II (isopropanol solvate)25 Lapatinib ditosylate N-methylpyrrolidinone solvate26 Co-crystals of lapatinib monoacid salts27


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EXPERIMENTAL SECTION Materials High-purity (>99%) lapatinib free base and lapatinib ditosylate were obtained from LC Laboratories (Woburn, MA) and used as received. Sodium carbonate and sodium methoxide (25% by wt. in methanol) were procured from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO) as were high purity solvents (HPLC grade): acetonitrile, 1,4-dioxane, toluene, ethyl acetate, tetrahydrofuran, dichloromethane, 2-propanol, acetone, methanol, heptane, methyl-tert butyl ether (MTBE). Copper wire induced single crystal growth from methanol LP free base was dissolved in methanol (0.5 mg/mL) under stirring and filtered through a 0.22 µm PVDF filter (Grace Davidso, Dearfield, IL). A 6 mL volume of this solution was transferred to a 20 mL glass vial; then RO water (ca. 3 mL) was added dropwise until a slightly blue turbidity was observed (Tyndall effect). An additional 3 mL of the methanolic LP solution was added to the colloidal dispersion to yield a transparent solution. The vial was left partially covered and a copper wire was immersed in the solution to promote crystallization. The solution was allowed to slowly evaporate under ambient condition for one week. Another sample, prepared the same way, but without the wire, and was kept under the same conditions. The crystals obtained from the vial with the copper wire were collected by filtration and kept in a sealed glass vial at 2 – 8 °C. No crystals were observed in the vial without the copper wire.


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Preparation of crystalline forms Polymorphism screening was performed using three approaches: acid base reactions of LPDS with either sodium carbonate or sodium methoxide and slurries of LP free base. For all approaches the drug was suspended in 10 solvents selected preferentially from different groups according to their properties as categorized by C.-H. Gu et al..28 The acid base reaction was conducted using ditosylate salt and a selected base (sodium carbonate or sodium methoxide). LPDS was suspended in the selected solvent and stirred for 30 minutes at room temperature. Either aqueous sodium carbonate or methanolic sodium methoxide was added dropwise to the suspension and the resulting mixture stirred for 3 hours in a sealed vial at room temperature. The resulting suspension was filtered and the powder was dried for 48 h under vacuum. Slurry experiments were conducted by suspending LP free base in selected solvents and stirring for one week in a sealed glass scintillation vial. The solids were collected by filtration and the powder was dried for 48 h under vacuum. Additional solvent mediated transformation studies were performed according to conditions described in Table 2. Single crystal X-ray diffraction Single crystal X-ray measurements were conducted on a Rigaku Rapid II curved image plate diffractometer with a Cu-Kα X-ray microsource (λ = 1.54178 Å) with a laterally graded multilayer (Goebel) mirror for monochromatization. Single crystals were mounted on Mitegen microloop mounts using a trace of mineral oil and cooled in-situ to 100(2) K for data collection. Data were collected using the dtrek option of CrystalClear-SM Expert 2.1 b32.29 Data sets were processed using HKL300030 and data were corrected for absorption and scaled using Scalepack.31 The space groups were assigned and the structures were solved by direct methods


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using XPREP within the SHELXTL suite of programs 31,32 and refined by full matrix least squares against F2 with all reflections using Shelxl2014 33 with the graphical interface Shelxle. 34 H atoms attached to carbon and nitrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with carbon hydrogen bond distances of 0.95 Å for aromatic and alkene H atoms, 0.99 for CH2, and 0.98 for CH3 moieties, respectively. Methyl H atoms were allowed to rotate but not to tip to best fit the experimental electron density. N-H distances in the plate (monoclinic) polymorph were freely refined and N-H distances restrained to 0.86(2) Å. In the tetragonal hydrate polymorph, the amine H atom attached to N3 was set to 0.88 Å. That at N4 is 1:1 disordered (see below) and the N-H distances were set to 0.91 Å. Water H atoms were freely refined and their positions restrained based on hydrogen bonding considerations. Uiso(H) values were set to a multiple of Ueq(C/N) with 1.5 for OH and CH3, and 1.2 for NH2+, C-H and CH2 units, respectively. For the needle shaped crystals (tetragonal polymorph) several types of disorder are observed. The SO2Me group is disordered over two orientations with the two moieties being in general positions. Its disorder induces disorder of the water molecule of O8, and is correlated with presence or absence of the water molecule of O11. Parallel to this general disorder there is systematic disorder across symmetry elements and due to incompatible hydrogen bonds across symmetry elements, causing 1:1 disorder of large sections of the solvate regions and for the amine hydrogens of N4. Systematic disorder: Hydrogen bonded to the amine atom N3 is the water molecule of O6, which is in turn hydrogen bonded to its own counterpart across a twofold axis, causing 1:1 disorder of the H atoms of water molecule of O6. In its alternative position the second H atom of O6 is H-bonded to the lone pair of the amine of N4. When the H atom is engaged in a hydrogen


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bond to the counterpart of O6 across the two fold axis, the lone pair of O6 acts as an acceptor for the amine H atom of N4, thus causing 1:1 disorder of the H atoms on amine N4. This disorder in turn causes disorder of H atoms at the water molecule of O8, which is H bonded to N4. To refine this disorder, O6 and its H atoms were split into two half occupied moieties nearly related by the two fold axis. O6 and O6B were constrained to have identical anisotropic displacement parameters, ADPs. The disordered SO2Me group moieties were restrained to have similar geometries and Uij components of ADPs of their atoms were restrained to be similar if closer than 1.7 Å. The SO2Me disorder is correlated with disorder of the water molecule of O8 and with presence or absence of the water molecule of O11. O8 was split into two positions with the same occupancy ratios as the SO2Me group. The distance of O8 and O8B to N4 was restrained to be similar. Both the major moiety of O8 as well as the minor moiety of O8B show additional disorder of their hydrogen atoms, induced by the H atom disorder at N4, see above. The water molecule of O11 is incompatible with O8B, with no indication of disorder as for O8 and the SO2Me group visible. O11 was thus refined as partially occupied and absent when O8B is present. Both O11 as well as neighboring O7 are 1:1 disordered across two fold axes. Hydrogen atoms of O8, O11 and O7 were placed in positions compatible with the expected hydrogen bonding interactions. One of the H atoms of O7 was additionally split due to hydrogen bonding across another two fold axis to a symmetry created copy of O7. H atoms were placed in positions compatible with the expected hydrogen bonding interactions and were refined with a damping factor and distance restraints based on H-bonding considerations. In the final refinement cycles the damping factor was removed and H atoms were set to ride on their carrier oxygen atoms. A mild anti-bumping restraint was applied during H atom refinement and was retained in the final refinement steps.


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Subject to these conditions, the occupancy ratio of the SO2Me moieties and O8 refined to 0.810(7) to 0.190(7).

X-ray powder diffraction X-Ray powder diffraction patterns were measured on a Siemens/Bruker D5000 diffractometer, using Ni filtered Cu Kα radiation (λ = 1.5418 Å) with an acceleration voltage of 40 kV and a tube current of 40 mA, step size of 0.02, step time 5 s with an angular range of 4° < 2Θ < 40°.

Thermal analysis Differential Scanning Calorimetry (DSC) curves were obtained using a DSC Q10 cell (TA Instrument, USA). About 2 mg of sample were weighed into aluminum crucibles and hermetically sealed. The samples were scanned at a heating rate of 10 °C/min, under a dynamic N2 atmosphere (100 mL/min), in a temperature range of 25 °C to 200 °C.

RESULTS AND DISCUSSION Single crystal growth experiments Conventional approaches such as room temperature evaporation from solution, boiling and cooling of a supersaturated solution and vapor diffusion were not successful in inducing the growth of single crystals of lapatinib free base. However, introduction of a copper wire into a supersaturated methanol/water solution of LP induced the nucleation and growth of single


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crystals with two different morphologies, plates and thin needles; both of which adhered to the wire (Figure 2-a and 2-b). No crystal growth was observed using the same solution and conditions in the absence of the wire. Crystals with regular shape were selected for single-crystal X-ray diffraction analysis. Structures with atomic labels and crystal packing are shown in Figures 3 and 4. Crystallographic data are reported Table 2. Calculated X-ray powder patterns are presented in Figures 8-d and Fig.9-f.

Figure 2. Single crystal growth induced by copper wire: (a) lapatinib free base crystal growth in a scintillation vial using a copper wire; (b) closeup view of needles attached in the copper wire;


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(c) optical microscopy photomicrographs (10x) of plates under polarized light and (d) a needle under nonpolarized light.

Table 2. Crystallographic data of lapatinib plates and needles obtained from recrystallization in methanol/water seeded with a copper wire. Crystalline Modification

Anhydrous (plates)

3.4 Hydrate (needles)

Form 1

Solvate A (3.4 hydrate)

Formula

C29H26ClFN4O4S

C29H26ClFN4O4S . 3.4H2O

Temperature

100 K

100 K

Space group

P21/c

P42212

Cell parameters

a = 38.752(3) Ǻ

a/b = 26.2160 (4) Ǻ

b = 5.3361(4) Ǻ

c = 8.6021 (2) Ǻ

c = 12.5021(8) Ǻ β = 90.447 ° Cell volume (Ǻ3)

2585.16

5912.04

Z

4

8

R-factor ([F2 > 2σ(F2)], %)

7.91

5.58


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Figure 3. Crystal structures from single crystal X-ray diffraction (ORTEP view, thermal ellipsoids at the 50% probability level) showing atoms labeling: a) LP anhydrous (Form 1); b) LP 3.4 hydrate.


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Figure 4. (a) Intermolecular H-bonding interactions and (b) crystal packing view along the b axis in anhydrous LP obtained by recrystallization from methanol/water with copper wire.


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The plate like crystals obtained are anhydrous and the X-ray powder pattern calculated from the single crystal corresponds very well to the anhydrous Forms 1 and X claimed by different patents (Support Information Table S1 and Figure 6-f). Form 1 is reported to be an anhydrate obtained from the reaction between lapatinib ditosylate suspended in ethyl acetate and sodium carbonate in aqueous solution.20 Form X is described to be formed when the salt is suspended in acetonitrile and equilibrated at 40 °C, followed by reaction with sodium carbonate in an aqueous solution yielding LP free base.21 Normalized X-ray powder diffraction patterns of Form 1 and Form X are practically the same as can be observed in Tablet S1 and shown in Figure 5.

Figure 5. Comparison of Form X and Form 1 X-ray powder data extracted from patents.20,21 The LP needle shaped crystals, on the other hand, have a characteristic channel hydrate structure, solvate A, with several types of disorders (vide infra), with ca. 3.4 water molecules for every molecule of lapatinib free base. Figure 6 shows a comparison of the conformation of lapatinib in the plates (Form1) and needles (solvate A). The two forms can be regarded as conformational polymorphs, if the solvate water molecules of the hydrate are ignored. In Form


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1, the quinzaolinamine ring and the appended furan ring as well as the aminomethylsulfonyl side chain are nearly coplanar. The phenyl rings bearing the chlorine and the fluorine atoms, on the other hand, are not coplanar with the quinzaolinamine ring. In the solvate A, the quinzaolinamine ring, the appended furan ring and the two phenyl rings bearing the Cl and F atoms are nearly coplanar. Here, the aminomethylsulfonyl side chain is not coplanar with the larger ring system with the C-N bond being oriented nearly perpendicular to the ring system (Figures 3).

Figure 6. Overlay of the conformations of lapatinib motif:(blue) in hydrate structure and (red) anhydrous.

The four molecules in the unit cell in Form 1 are held together in pairs by one N-H---O hydrogen bond (2.21 Å) and one N-H---N hydrogen bond (2.16 Å). In the solvate, the nearly planar ring systems of the eight molecules in the unit cell are arranged in two types of stacks along the z axis. The stacks form the channels (Figure 7) that accommodate the solvent water molecules. The stacks of planar rings are held together by van der Waals contacts as well as one


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hydrogen bond connecting a nitrogen atom of the quinzaolinamine ring to a water molecule which in turn is hydrogen bonded to an adjacent quinzaolinamine ring. The estimated solvent accessible volume is 570 Å3 (9.6% of the unit cell volume), with a probe radius of 1.4 Å, (calculated using the contact surface approach of the Mercury software). Substantial disorder is observed in the solvate: The SO2Me group in solvate A is disordered over two orientations in general positions. Its disorder induces disorder of one of the water molecules (O8), and is correlated with presence or absence of another water molecule (O11). Parallel to this general disorder there is systematic disorder across symmetry elements due to incompatible hydrogen bonds across symmetry elements, causing 1:1 disorder of large sections of the solvate regions and for the amine hydrogens (N4).

Figure 7. Water channels in LP 3.4 hydrate structure.


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Crystal space of lapatinib Although complex, demanding and often not possible to achieve, the single crystal growth and structure determination are still fundamental steps to map the crystal space, obtain a standard for powder diffraction and understand the structural aspects of polymorphism phenomena like solvatation and interconversions. 6,35 In order to explore the crystal space of lapatinib free base polymorphism screening and interconversion studies were carried out and results were summarized in Table 3 and Scheme 1.


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Scheme 1. Overview of polymorphic conversions in LP crystal forms.


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Table 3. Summary of results of LP polymorphism screening. Solvent

Acid-base reaction with Acid-base reaction with Slurry for one week sodium carbonate

sodium methoxide

at room temperature

Acetonitrile (condition 1 a)


***

***

Acetonitrile (condition 2 b)

Form 2

***

***

1,4-Dioxane

***

***

***

Toluene

***

***

Form 2 unchanged

Ethyl acetate

***

***

Form 2 unchanged

Tetrahydrofuran

***

***

***

Dichloromethane

***

***

Solvate B

Solvate C

***

Solvate C

Acetone


***

Form 1

Methanol

***

Form 1

Form 1

Heptane

***

Form 1

***

MTBE (methyl-tert butyl ether)

***

***

***

1-Octanol

a

condition 1: reaction was carried out in suspension at 25 °C, under stirring for 1 hour. Then, crystals were filtered and dried under vacuum for 48 hours at room temperature. b

condition 2: reaction was carried out in suspension at 40 °C, under stirring for 1 hour. The resulting yellow suspension was stirred at 5 °C for 2 hours. The product was filtered and dried under vacuum for 48 hours at room temperature. *** incomplete reaction or impurity profile inadequate.


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Figure 8. Normalized X-ray powder diffractogram of LP solvates: a) solvate obtained from slurry of Form 2 in octanol (one week at RT); b) solvate from acid-base reaction of LPDS with sodium carbonate in aqueous and acetone; c) solvate from acid-base reaction of LPDS with sodium carbonate in aqueous and acetonitrile; d) X-ray powder pattern calculated from LP 3.4 hydrate.


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Figure 9. Normalized X-ray powder diffractograms of non-solvate LP crystals obtained experimentally: a) LP crystals obtained from acid-base reaction of LP with sodium carbonate in water and acetonitrile (at 40 °C); b) LP crystals from slurry in methanol (one week at RT); c) LP crystals from slurry in acetone (one week at RT); d) LP crystals obtained from acid-base reaction of LPDS with sodium methoxide in methanol; e) LP crystals obtained from acid-base reaction of LPDS with sodium methoxide in heptane; f) X-ray powder pattern calculated from anhydrous LP Form 1 (100 K data, additional low angle peak at 4.612°).


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Figure 10. Normalized X-ray powder diffractogram LP crystals obtained experimentally: a) LP crystals obtained from acid-base reaction of LP with sodium carbonate in water and acetonitrile (at 40 °C); b) LP Form 2 from commercial source (arrows indicate presence of Form 1); c) solvate obtained from slurry of Form 2 in dichloromethane (one week at 25 °C).


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Figure 11. DSC curves obtained in dynamic N2 atmosphere (100 mL/min) at a heating rate of 10 °C/min: a) hydrate obtained from acid-base reaction of LPDS with sodium carbonate in water and acetonitrile (condition 1); b) hydrate from ethanol/water single crystal experiments; c) solvate obtained from slurry of Form 2 in octanol (one week at RT); d) solvate obtained from slurry of Form 2 in dichloromethane (one week at RT); e) Form 2 obtained from acid-base reaction of LP with sodium carbonate in aqueous and acetonitrile (at 40°C); f) LP Form 2 from commercial source; g) Form 1 obtained from acid-base reaction of LPDS with sodium methoxide in methanol.


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X-ray powder patterns of LP solvates and its anhydrous forms obtained in the screening are presented in Figures 8 and 9, respectively. Acid-base reactions of LPDS with sodium carbonate in acetronitrile/water or ethyl acetate/water had been described to produce LP Form X or Form 1, respectively. 20,21 By dissolving LP in heated dichloromethane and allowing the solution to cool gradually it is reported to crystallize into Form 2. 20 The same procedure when conducted in 1,4dioxane is claimed to lead to Form Y. 21 In our screening, however, reactions carried out in an acetonitrile/water environment were resulted in formation of a solvate and Form 2, depending on experimental conditions. No complete reaction was accomplished in ethyl acetate as solvent. To avoid the hydrate formation a reaction in absence of water was proposed with sodium methoxide. XRPD patterns of crystals from acid-base reaction of LPDS with sodium methoxide in methanol (Fig.9-d) and heptane (Fig. 9-f) and those obtained from slurry conversion of commercial Form 2 in methanol (Fig.9-b) and acetone (Fig. 9-c) showed a good match with the diffractogram calculated from the single crystal structure of the anhydrous plates (Fig.9-f), and with the previously reported Forms X and 1 (Table S1). Their DSC curves (Fig. 11-g) indicate that this crystal form has a well-defined melting endortherm at = 137 °C (Tonset) with an enthalpy of fusion of 76.2 J/g (Tpeak=144 °C). It is known that solvent mediated anhydrate/hydrate phase transformations are complex processes that depend on competition of kinetic and thermodynamic factors related to water activity in the surrounding solvent and temperature. 36 As the acetonitrile/water ratio was kept the same between both procedures, the hydrate/anhydrate transition temperature in this system seems to be an important factor to be explored in the crystallization methodologies described in literature. 20,21 XRPD patterns reveal that the solvates obtained are in good agreement to the channel hydrate structure obtained from the single crystal growth experiments (Fig.8-b, 8-c and


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8-d); it is also supported by DSC curves (Figure 11-a and 11-b) which show a similar dehydratation event in the range of 40-80 °C. This unusual water loss behavior at low temperatures with a broad endothermal peak is characteristic of channel solvates and has been observed for sodium ibruprofen dihydrate and carbamazepine dehydrate. 36–39 The LP crystals obtained from acid-base reaction of LPDS with sodium carbonate in water and acetonitrile at 40 °C with subsequent cooling to 5 °C yielded crystals with XRPD patterns in good agreement with Form 2 described in patent WO 2009/079547. 20 Nevertheless, DSC curves reveal a different thermal behavior from experimental Form 2 and the commercial sample. Both samples present a first endothermal event assigned to melting of Form 2 in the range of 85-115 °C, 25 °C lower than for Form 1. Nevertheless, in the commercial sample there is evidence of a Form 1 impurity and/or a phase transition with an additional endothermic peak in agreement with melting of Form 1. This can be explained by the presence of small amounts Form 1, as indicated by small peaks in the XRPD pattern (Fig. 7b – indicated by arrows). The small amounts of Form 1 might also act as crystallization seeds from the melt of Form 2. The DSC results in association with stability studies involving solvent equilibration of mixtures of both polymorphs (Table 4) indicate that Form 1 is the stable form from 25 up to 150 °C.


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Table 4. Stability of polymorphs formed by slurry methods in different solvents. Initial Composition

Condition

Final Composition

Mixture 1:1 (w/w) Slurry in methanol at 25°C for 1 Form 1 (Form 1 and Form 2)

week.

Mixture 1:1 (w/w) Suspension in toluene at 70 °C Form 1 Form 1 and Form 2

for 48 hours.

Mixture 1:1 (w/w) Slurry in dichloromethane at 25 Solvate B Form 1 and Form 2

°C for 1 week.

Form 1

Suspension heated to reflux in Solvate B dichloromethane

(39.6

°C)

according to procedure described in patent (14) to obtain Form 2. Form 1

Slurry in dichloromethane at 25 Solvate B °C for 24 hours.

The dichloromethane solvate also has a structure similar to that of Form 2 as evidenced by its XRPD and DSC curve (Figs 7 and 8d). After loss of solvent this structure changes into Form 2. An 1-octanol solvate was obtained via a slurry method and presents a XRPD pattern different from any of the other forms. DSC curves indicate three events in the range of 45-150 °C: the first transition, a endothermic event, is assigned to solvent loss in the range of 45-114 °C, followed by an exothermic event assigned to a crystallization of Form 1 at 113 °C with subsequent melting between 123-140 °C. It is noteworthy that Form Y could not be obtained in any of our screening experiments, or even by reproducing the literature procedure. 21


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CONCLUSION The immersion of a copper wire into a methanol/water solution of lapatinib free base was able to induce the nucleation and growth of single crystals with two different morphologies, plates and thin needles. Structural refinement indicates that the needles are a 3.4 hydrate with a channel structure and the plates correspond to an anhydrous form that corresponds to previously reported forms 1 and X. A new acid-base reaction between lapatinib ditosylate and sodium methoxide in methanol or heptane can successfully be used to produce this last form avoiding the presence of the hydrate. Form 2 can selectively be formed by desolvation of the hydrate, or from several other solvates with structures similar to the hydrate. The combination of thermal analysis, solvent equilibrium studies and X-ray diffraction allowed the identification of new solvates and the establishment of Form 1 as the most stable form in a wide range of temperature.


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ASSOCIATED CONTENT Supporting Information. Table S1. Comparison of X-ray diffraction data of lapatinib free base anhydrous polymorphs reported in patents 18,19 and calculated pattern from single crystal data (anhydrous plates). This material is available free of charge via the Internet at http://pubs.acs.org. Accession Codes Complete crystallographic data, in CIF format, have been deposited with the Cambridge Crystallographic Data Centre. CCDC 1501183-1501184 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. AUTHOR INFORMATION Corresponding Author *Email:[email protected] Funding Sources This project was funded by the São Paulo Research Foundation (FAPESP) [grant#2015/15456-5 and grant#2015/05685-7, SP, Brazil]. Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENT The authors acknowledge the São Paulo Research Foundation (FAPESP) for financial support. ABBREVIATIONS LP, lapatinib free base; LPDS, lapatinib ditosylate; XRPD, X-ray powder diffraction; DSC, differential scanning calorimetry.

REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16)

Laird, T. Org. Process Res. Dev. 2010, 14 (1), 1–1. Braga, D.; d’Agostino, S.; Dichiarante, E.; Maini, L.; Grepioni, F. Chem. Asian J. 2011, 6 (9), 2214–2223. Bučar, D.-K.; Lancaster, R. W.; Bernstein, J. Angew. Chem. Int. Ed. 2015, 54 (24), 6972– 6993. Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28 (4), 193–200. Pamplin, B. R. Crystal Growth: International Series on the Science of the Solid State; Elsevier, 2013. Spingler, B.; Schnidrig, S.; Todorova, T.; Wild, F. CrystEngComm 2012, 14 (3), 751–757. Hektisch, H. K.; Dennis, J.; Hanoka, J. I. J. Phys. Chem. Solids 1965, 26 (3), 493–496. Neumann, M. A.; Van De Streek, J.; Fabbiani, F. P. A.; Hidber, P.; Grassmann, O. Nat. Commun. 2015, 6. Garetz, B. A.; Aber, J. E.; Goddard, N. L.; Young, R. G.; Myerson, A. S. Phys. Rev. Lett. 1996, 77 (16), 3475. Charron, C.; Didierjean, C.; Mangeot, J. P.; Aubry, A. J. Appl. Crystallogr. 2003, 36 (6), 1482–1483. Potticary, J.; Terry, L. R.; Bell, C.; Collins, A. M.; Fontanesi, C.; Kociok-Kohn, G.; Crampin, S.; Da Como, E.; Hall, S. R. ArXiv Prepr. ArXiv150904120 2015. Lee, A. Y.; Lee, I. S.; Dette, S. S.; Boerner, J.; Myerson, A. S. J. Am. Chem. Soc. 2005, 127 (43), 14982–14983. Kawaguchi, A.; Okihara, T.; Katayama, K. J. Cryst. Growth 1990, 99 (1), 1028–1032. Curcio, E.; López-Mejías, V.; Di Profio, G.; Fontananova, E.; Drioli, E.; Trout, B. L.; Myerson, A. S. Cryst. Growth Des. 2014, 14 (2), 678–686. Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W. Org. Process Res. Dev. 2000, 4 (5), 413–417. Blagden, N. Powder Technol. 2001, 121 (1), 46–52.


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(17) Bučar, D.-K.; Lancaster, R. W.; Bernstein, J. Angew. Chem. Int. Ed. 2015, 54 (24), 6972– 6993. (18) Park, Y.; Kim, H.; Kim, E.-H.; Suh, C.-O.; Lee, S. Cancer Res. Treat. Off. J. Korean Cancer Assoc. 2016, 48 (1), 403. (19) Song, Y.; Yang, X.; Chen, X.; Nie, H.; Byrn, S.; Lubach, J. W. Mol. Pharm. 2015, 12 (3), 857–866. (20) Craig, A. S.; Crowe, D. M.; Millan, M. Quinazoline anhydrate forms; Google Patents, 2009. (21) Metsger, L.; Mittelman, A.; Yurkovski, S. Forms of crystalline lapatinib and processes for preparation thereof; Google Patents, 2009. (22) Metsger, L.; Mittelman, A.; Yurkovski, S. Forms of lapatinib ditosylate and processes for preparation thereof; Google Patents, 2009. (23) Metsger, L.; Mittelman, A.; Yurkovski, S. Forms of lapatinib compounds and processes for the preparation thereof; Google Patents, 2010. (24) Huang, H. M. H.; Yang, H. Preparation of polymorphic form of lapatinib ditosylate; Google Patents, 2011. (25) Zetina-Rocha, C.; Cammisa, E. G.; Weeratunga, G. Polymorphic forms of lapatinib ditosylate and processes for their preparation; Google Patents, 2011. (26) Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof; Google Patents, 2014. (27) Tesson, N.; SEGADE, R. A. Co-crystals of lapatinib monoacid salts; Google Patents, 2015. (28) Gu, C.-H.; Li, H.; Gandhi, R. B.; Raghavan, K. Int. J. Pharm. 2004, 283 (1), 117–125. (29) CrystalClear-SM Expert 2.1 b32; Rigaku Corp.: The Woodlands, Texas, USA. (30) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307–326. (31) Sheldrick, G. M. SHELXTL: v. 6.14, Structure Determination Software Suite,; Bruker AXS Inc.: Madison, WI, 2000. (32) Sheldrick, G. M. Acta Crystallogr. A 2008, 64 (1), 112–122. (33) Sheldrick, G. M. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71 (1), 3–8. (34) Hübschle, C. B.; Sheldrick, G. M.; Dittrich, B. J. Appl. Crystallogr. 2011, 44 (6), 1281– 1284. (35) Braga, D.; Grepioni, F.; Maini, L.; Polito, M. In Molecular Networks; Springer, 2009; pp 87–95. (36) Tian, F.; Qu, H.; Zimmermann, A.; Munk, T.; Jørgensen, A. C.; Rantanen, J. J. Pharm. Pharmacol. 2010, 62 (11), 1534–1546. (37) Byrn, S. R. Solid-state chemistry of drugs; Academic Press Inc, 1982. (38) Kawakami, K.; Ida, Y.; Yamaguchi, T. Pharm. Res. 2005, 22 (8), 1365–1373. (39) Censi, R.; Martena, V.; Hoti, E.; Malaj, L.; Di Martino, P. J. Therm. Anal. Calorim. 2013, 111 (3), 2009–2018.


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For Table of Contents Use Only GRAPHIC ENTRY FOR TABLE OF CONTENTS

SYNOPSIS For the first time single crystal growth was induced by a copper wire and lapatinib free base polymorphism, structure, solvate formation and phase transitions were addressed.


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Graphic Entry - Table of Contents 203x152mm (300 x 300 DPI)



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Figure 1. Structural formula of lapatinib Figure 1 9x3mm (600 x 600 DPI)


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Figure 2. Single crystal growth induced by copper wire: (a) lapatinib free base crystal growth in a scintillation vial using a copper wire; (b) closeup view of needles attached in the copper wire; (c) optical microscopy photomicrographs (10x) of plates under polarized light and (d) a needle under nonpolarized light. Figure 2 203x152mm (300 x 300 DPI)



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Figure 3. Crystal structures from single crystal X-ray diffraction (ORTEP view, thermal ellipsoids at the 50% probability level) showing atoms labeling: a) LP anhydrous (Form 1); b) LP 3.4 hydrate. Figure 3 203x152mm (300 x 300 DPI)


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Figure 4. (a) Intermolecular H-bonding interactions and (b) crystal packing view along the b axis in anhydrous LP obtained by recrystallization from methanol/water with copper wire. Figure 4 203x152mm (300 x 300 DPI)



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Figure 5. Comparison of Form X and Form 1 X-ray powder data extracted from patents.18, 19 Figure 5 208x159mm (300 x 300 DPI)


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Figure 6. Overlay of the conformations of lapatinib motif:(blue) in hydrate structure and (red) anhydrous Figure 6 203x152mm (300 x 300 DPI)



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Figure 7. Water channels in LP 3.4 hydrate structure Figure 7 203x152mm (300 x 300 DPI)


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Scheme 1. Overview of polymorphic conversions in LP crystal forms Scheme 1 203x152mm (300 x 300 DPI)



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Figure 8. Normalized X-ray powder diffractogram of LP solvates: a) solvate obtained from slurry of Form 2 in octanol (one week at RT); b) solvate from acid-base reaction of LPDS with sodium carbonate in aqueous and acetone; c) solvate from acid-base reaction of LPDS with sodium carbonate in aqueous and acetonitrile; d) X-ray powder pattern calculated from LP 3.4 hydrate. Figure 8 289x414mm (300 x 300 DPI)


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Figure 9. Normalized X-ray powder diffractograms of non-solvate LP crystals obtained experimentally: a) LP crystals obtained from acid-base reaction of LP with sodium carbonate in water and acetonitrile (at 40 °C); b) LP crystals from slurry in methanol (one week at RT); c) LP crystals from slurry in acetone (one week at RT); d) LP crystals obtained from acid-base reaction of LPDS with sodium methoxide in methanol; e) LP crystals obtained from acid-base reaction of LPDS with sodium methoxide in heptane; f) X-ray powder pattern calculated from anhydrous LP Form 1 (100 K data, additional low angle peak at 4.612ο) Figure 9 289x414mm (300 x 300 DPI)



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Figure 10. Normalized X-ray powder diffractogram LP crystals obtained experimentally: a) LP crystals obtained from acid-base reaction of LP with sodium carbonate in water and acetonitrile (at 40 °C); b) LP Form 2 from commercial source (arrows indicate presence of Form 1); c) solvate obtained from slurry of Form 2 in dichloromethane (one week at 25 °C) Figure 10 289x414mm (300 x 300 DPI)


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Figure 11. DSC curves obtained in dynamic N2 atmosphere (100 mL/min) at a heating rate of 10 °C/min: a) hydrate obtained from acid-base reaction of LPDS with sodium carbonate in water and acetonitrile (condition 1); b) hydrate from ethanol/water single crystal experiments; c) solvate obtained from slurry of Form 2 in octanol (one week at RT); d) solvate obtained from slurry of Form 2 in dichloromethane (one week at RT); e) Form 2 obtained from acid-base reaction of LP with sodium carbonate in aqueous and acetonitrile (at 40°C); f) LP Form 2 from commercial source; g) Form 1 obtained from acid-base reaction of LPDS with sodium methoxide in methanol Figure 11 203x152mm (300 x 300 DPI)


Unexpected Single Crystal Growth Induced by a Wire and New

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