Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate

May 30, 2014 - Here, the solid form selection of TAK-441, a highly solvating ... which immediately desolvated upon harvesting, and that TAK-441 crysta...
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Solid Form Selection of Highly Solvating TAK-441 Exhibiting SolvateTrapping Polymorphism Kentaro Iwata,* Takashi Kojima, and Yukihiro Ikeda Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan S Supporting Information *

ABSTRACT: Solid form selection of active pharmaceutical ingredients is essential for pharmaceutical development. Solvates, except for hydrates, are rarely selected because of their physical instability and the potential toxicity of solvent. Here, the solid form selection of TAK-441, a highly solvating compound, was conducted. Anhydrate form I and 12 solvates were obtained from solution. The solvates showed isomorphism and could be placed into three categories. Anhydrate forms II, III, and IV were obtained via the desolvation of different type solvates, and anhydrate form V crystallized following thermal conversion of solvates. Equilibrium solubility analysis suggested that certain thermodynamic relationships between anhydrates were enantiotropic in nature. Moreover, form I was more stable than other polymorphs at ambient temperature, and was thus selected for further development. Finally, crystal structure analyses revealed that form I was an isomorphic desolvate of another solvate type (type 4), which immediately desolvated upon harvesting, and that TAK-441 crystallized only via solvate formation. Notably, types 2 and 3 solvates possessed unique channel structures, and pores of type 4 solvate were much larger than those of other types. This large pore size may cause extreme instability of type 4 solvate.

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INTRODUCTION Active pharmaceutical ingredients (APIs) in the crystalline state are often formulated with excipients in most pharmaceutical products. The use of crystalline APIs in various dosage forms is generally preferred from the perspectives of stability1 and manufacturability.2 However, APIs frequently exhibit polymorphism and form solvates and hydrates,3 and each crystal form has its own physicochemical properties. For example, solubility,4 hygroscopicity,5 tablettability,6 and chemical and physical stabilities7 vary for different polymorphs of the same compound. These differences may profoundly influence the product’s performance, including its bioavailability, manufacturability, and shelf life.8 Developing an appropriate form is crucial for the pharmaceutical industry, because the need to withdraw a drug from the market due to the unexpected appearance of a new stable form will result in a change in performance and lead to product shortage, which can significantly affect both patients and the overall pharmaceutical market negatively.9,10 It is not uncommon, however, to encounter cases where obtaining a given crystal form is difficult, even though previously it was routinely stable over a long period.11,12 Pharmaceutical companies prefer to develop the most stable form whenever possible to minimize unexpected changes. Therefore, the investigation of various thermodynamic relationships of crystal forms is essential for the determination of the development form. © 2014 American Chemical Society

To explore crystal forms, polymorph screening is often performed once the chemical entity of the API is determined.13,14 Screening often involves several solventbased techniques (e.g., slow and fast cooling precipitation from a saturated solution, crystallization via solvent evaporation, antisolvent crystallization, and formation of a slurry of API solids).13,15 Such screening provides various crystal forms and their solvent preferences, which are useful for designing the manufacturing process.13 It should be noted that crystallization of an individual polymorph from a certain solvent does not necessarily mean that this form nucleates directly in the solvent. The polymorph may have formed during an isolation procedure by the desolvation of short-lived, unstable solvates, which are often overlooked.16 The development form is typically an anhydrate or a hydrate; solvates are rarely selected because of their physical instability and the potential toxicity of the solvent. Typically and unfortunately, there are several compounds identified during the screening process that exhibit a high tendency to form solvates with various organic solvents.12,17−20 Such a solvating tendency often makes it difficult to determine appropriate candidates21 and limits the solvents available for use during manufacturing. Received: February 16, 2014 Revised: May 15, 2014 Published: May 30, 2014 3335

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(EtOAc), toluene (TLN), isopropyl acetate (IPrOAc), anisole (ANS), and isobutyl acetate (IBuOAc), and filtered through a 0.22μm plastic filter. The solutions or solutions mixed with water or heptane (HEP) as an antisolvent were slowly cooled to 5 °C,24 and the precipitates were isolated via filtration and characterized using powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Desolvation Study. A desolvation study was conducted using the solvates obtained from the polymorph screening. The solvates were maintained at reduced pressure at 80 °C and characterized using PXRD, TGA, and DSC. The solvates that failed to desolvate were heated at higher temperatures and monitored using PXRD until crystal transformation occurred. Powder X-ray Diffraction. PXRD patterns were collected using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Cu−Kα radiation generated at 50 mA and 40 kV. A sample was placed on a silicon plate at room temperature. Data were collected from 2° to 35° (2θ) at a step size of 0.02° and a scanning speed of 6°/min. Thermogravimetric Analysis and Differential Scanning Calorimetry. TGA was performed using a Mettler-Toredo TGA/ DSC1 (Greifensee, Switzerland). TGA thermograms were obtained in an open aluminum pan using approximately 3 mg of sample and a heating rate of 5 °C/min from 25 to 300 °C under a 100 mL/min flow of nitrogen. DSC analyses were performed using a Mettler-Toredo DSC1 (Greifensee, Switzerland). Approximately 3 mg of powder was placed in a closed aluminum pan and heated at 5 °C/min from 25 to 200 °C under a 40 mL/min flow of nitrogen. Equilibrium Solubility Determination. The anhydrate forms were gently ground with a pestle and sieved using a 500-μm mesh to reduce the particle size prior to use. At each temperature, an excess amount of solids was added to a 10% (v/v) solution of ACN in JP2 (pH 6.8; described in the Japanese Pharmacopoeia disintegration test) and shaken in a water bath using a vibratory shaker for 3 h. During shaking, the sample was vigorously suspended at 30 min intervals. After shaking, the samples were centrifuged, and then the supernatant was filtered through a 0.22-μm membrane filter. An aliquot (0.5 mL) was then withdrawn from the filtrate solution and diluted to 1.0 mL with ACN to prevent precipitation. The crystal form of the dried precipitate was confirmed via PXRD. Quantitative analysis was conducted using a high-performance liquid chromatography system (W2695, Waters, Milford, MA, USA) and a photodiode array detector

TAK-441 (Figure 1) is an oncology drug candidate as an inhibitor targeting the hedgehog signaling pathway for the

Figure 1. Chemical structure of TAK-441.

prevention of cancer cell growth.22,23 TAK-441 is soluble in most organic solvents and forms solvates with common solvents. Furthermore, TAK-441 anhydrous polymorphs showed enantiotropic relationships. Therefore, determination of its development form is challenging. Slurry competition experiment, which is the most common approach for the determination, is not applicable to the determination, even though at high temperature where solvate did not crystallize. Herein, we describe the solid form selection process for the development and report the characteristics of the solvates.

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EXPERIMENTAL SECTION

Materials. TAK-441 was synthesized in the Takeda Pharmaceutical Company (Osaka, Japan). All solvents were purchased from Wako Pure Chemical Industries (Osaka, Japan). Form I crystal was obtained from an ethanol (EtOH) solution with slow cooling. EtOH solvate form A crystallized when API was dissolved at 55 °C in EtOH and cooled at −20 °C. Form II crystal was prepared via desolvation of the EtOH solvate form A at 80 °C in a vacuum. Anhydrate forms III and IV were obtained via the desolvation of acetone (DMK) solvate form A and 2-propernol (IPA) solvate form A, respectively, at 80 °C in a vacuum. Form V crystal was obtained via the thermal conversion of the DMK solvate in the solid state at 140 °C. Solvent-Based Polymorph Screening. TAK-441 was dissolved in 12 solvents, methanol (MeOH), acetonitrile (ACN), EtOH, DMK, IPA, tetrahydrofuran (THF), 2-butanone (MEK), ethyl acetate

Table 1. Summary of the Solvent-Based Polymorph Screening Results crystal form anhydrate form I EtOH solvate form A DMK solvate form A EtOAc solvate form B TLN solvate form A IPrOAc form B IBuOAc solvate form A IPA solvate form A THF solvate form A MEK solvate form A EtOAc solvate form A IPrOAc form A ANS solvate form A

TGA weight loss (%)

crystallization solvents

stoichiometric proportion

MeOH, ACN, EtOH, MeOH/water (1/1,v/v), ACN/water (2/5,v/v), EtOH/HEP (1/9,v/v), DMK/water (1/9,v/v), DMK/HEP (1/9,v/v) EtOH

0 7.2

1.0

DMK

5.1

0.5

EtOAc/HEP (5/17,v/v)

2.3

0.2

TLN, TLN/HEP (25/36,v/v)

7.4

0.5

IPrOAc/HEP (13/20,v/v) IBuOAc, IBuOAc/HEP (10/17,v/v)

8.6 9.8

0.5 0.5

IPA, IPA/HEP (1/5,v/v)

7.0

0.7

THF THF/HEP (1/4,v/v)

11.3

1.0

MEK, MEK/HEP (1/9,v/v)

10.7

1.0

EtOAc

7.2

0.5

IPrOAc ANS, ANS/HEP (5/8,v/v)

9.4 8.7

0.6 0.5

3336

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(W2996, Waters) operating at 220−400 nm. The concentration of TAK-441 in the solutions was determined using the absorbance at 240 nm. The system operation and data analysis were performed using Empower 2 workstation software (Waters). The YMC PackPro packed column (5 μm, 4.6 × 150 mm, YMC, Kyoto, Japan) operated at 40 °C, and a 20-mM phosphate buffer (pH 7.0):ACN (55:45, v/v) solution was used as the mobile phase at a flow rate of 1.0 mL/min. Each determination was performed twice. Single Crystal X-ray Diffraction. Single crystal X-ray diffraction (SCXRD) data were recorded on a Rigaku R-AXIS RAPID (Rigaku, Tokyo, Japan) with graphite-monochromated Cu−Kα radiation. The crystal structures were solved via direct methods and refined using a full-matrix least-squares procedure. The non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were located geometrically and refined using a riding model. All calculations were performed using the Crystal Structure crystallographic software package (Rigaku, Tokyo, Japan), except for the direct solution and refinement calculations, which were performed using SHELXL-97.25 To determine the structure of IBuOAc solvate form A, EtOAc solvate form A, and EtOH solvate form B, the residual electron density resulting from disorder in the solvent molecules was adjusted using the SQUEEZE option in PLATON,26 and thus not recorded in the formula and formula weights. The solvent accessible voids per unit cell (Vsolvent, Å3) were calculated using SOLV in PLATON. Assuming that channels are smooth cubes and that VSA is the inner volume of the channel, the average cross-sectional area of the channels (Across, Å2) was calculated using the following formula to estimate their pore sizes:

Table 2. Summary of the Desolvation Study Results solvate type

desolvate form (desolvation condition)

EtOH solvate form A DMK solvate form A EtOAc solvate form B TLN solvate form A IPrOAc form B IBuOAc solvate form A IPA solvate form A THF solvate form A

Type Type Type Type Type Type

1 2 2 2 2 2

anhydrate form II (80 °C in a vacuum) anhydrate form III (80 °C in a vacuum) anhydrate form III (80 °C in a vacuum) anhydrate form V (140 °C) anhydrate form V (140 °C) anhydrate form V (140 °C)

Type 3 Type 3

MEK solvate form A EtOAc solvate form A IPrOAc form A ANS solvate form A

Type Type Type Type

anhydrate form IV (80 °C in a vacuum) anhydrate form IVa (80 °C in a vacuum) anhydrate form V (130 °C) anhydrate form IV (80 °C in a vacuum) anhydrate form V (140 °C) anhydrate form V (130 °C)

crystal form

a

3 3 3 3

Tiny amount of form I was also detected.

Across = Vsolvent /Lchannel where Lchannel (Å) is the channel length in the crystal lattice. The channel length was equal to the length of a particular crystallographic axis in this study, because the channels in the crystal structures ran along the crystallographic axes. The program Mercury was used to depict the crystal structures.27

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RESULTS AND DISCUSSION Solution Crystallization of Anhydrate Form I. The crystallization of TAK-441 from organic solvents, including mixtures of solvents with water or HEP, was studied. Table 1 summarizes the TAK-441 solid forms obtained from various solutions. TAK-441 formed 12 solvates, including EtOAc and IPrOAc solvate polymorphs or pseudopolymorphs. In this

Figure 3. TGA thermograms of TAK-441 solvates. Type 1 solvate (red): (a) EtOH solvate form A. Type 2 solvates (green): (b) DMK solvate form A, (c) EtOAc solvate form B, (d) TLN solvate form A, (e) IPrOAc solvate form B, and (f) IBuOAc solvate form A. Type 3 solvates (blue): (g) IPA solvate form A, (h) THF solvate form A, (i) MEK solvate form A, (j) EtOAc solvate form A, (k) IPrOAc solvate form A, and (l) ANS solvate form A.

Figure 2. PXRD patterns of TAK-441 solvates. Type 1 solvate (red): (a) EtOH solvate form A. Type 2 solvates (green): (b) DMK solvate form A, (c) EtOAc solvate form B, (d) TLN solvate form A, (e) IPrOAc solvate form B, and (f) IBuOAc solvate form A. Type 3 solvates (blue): (g) IPA solvate form A, (h) THF solvate form A, (i) MEK solvate form A, (j) EtOAc solvate form A, (k) IPrOAc solvate form A, and (l) ANS solvate form A.

Figure 4. PXRD patterns of anhydrate forms. (a) Form I, (b) form II, (C) form III, (d) form IV, and (e) form V.

research, anhydrate forms were labeled with Roman numerals (I, II, ...), while each solvate forms were described by Roman letters (A, B, ...). Anhydrate form I was the only anhydrate 3337

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hand, TLN solvate form A, IPrOAc solvate form B, and IBuOAc solvate form A were stable (Figure 3). The TGA thermograms of these solvates indicated that their desolvation occurred above 120 °C. As components in organic crystals excluding organometallic crystals, solvents can serve as participants in hydrogen-bonding networks or act as space fillers with weak interactions.30 Stability of type 2 solvates was correlated to molecular weight (Mw) of guest solvents. The TLN (Mw: 92.14), IPrOAc (Mw: 102.14), and IBuOAc (Mw: 116.16) were more stable than the DMK (Mw: 58.08) and EtOAc (Mw: 88.11) solvates. Since Mw is roughly proportional to molecular size, solvent size was important for solvate stability. Furthermore, TLN cannot form hydrogen-bonding network because it has no donors or acceptors that can form hydrogen bonds. Thus, the solvents in type 2 solvates most likely function as space fillers. Type 3 solvates also exhibited isomorphism and had characteristic peaks at 6.5°, 8.4°, and 10.6° (2θ). IPA (Mw: 60.10) solvate form A and THF (Mw: 72.11) solvate form A readily lost their solvent molecules in an air atmosphere, while the MEK (Mw: 72.11), EtOAc, IPrOAc, and ANS (Mw: 108.14) solvates were stable. Stability of type 3 solvates was dominated by other factors such as the guest geometry as well as the guest Mw, because THF and MEK have same Mw but their solvates showed different stability. Desolvated Forms of Various Solvates. Desolvation of solvates is sometimes the pathway for generating particular crystal forms.31 It has been reported in one case that the thermodynamically most stable anhydrate form was generated via the desolvation of solvates.32 Thus, the solvates of TAK-441 were desolvated, and the results are presented in Table 2. Four new anhydrate forms were obtained. EtOH solvate form A yielded anhydrate form II, while anhydrate forms III and IV were obtained from volatile type 2 (DMK solvate form A and EtOAc solvate form B) and type 3 (IPA solvate form A, THF solvate form A, and EtOAc solvate form A) solvates, respectively. A small amount of form I was also detected in the solid obtained from the THF solvate. A tiny amount of form I would also crystallize in the THF and THF/HEP solutions. The other solvates remained in the solvated state after drying. These solvates were then heated to 130−140 °C for achieving desolvation, which was accompanied by the transformation to anhydrate form V. The solvates that yielded anhydrates forms II, III, and IV also converted to form V at 130−140 °C. Characterization of Anhydrate Polymorphs. The obtained anhydrate forms had unique PXRD patterns (Figure 4). Forms II, III, and IV, which were the desolvated forms from different solvates, were expected to have different crystal structures than those of the original solvates because the PXRD patterns changed after desolvation. Anhydrate form V also had unique PXRD patterns, and their crystal structures were completely different from those of the corresponding solvates. DSC thermograms of these polymorphs are shown in Figure 5. Anhydrate forms I and V each exhibited only one endothermic peak at 161 and 170 °C with heats of fusion (Hf) of 32 and 31 kJ/mol, respectively. Anhydrate form II exhibited a broad and small endothermic peak at 127 °C (Hf = 14 kJ/mol) and a tiny endothermic peak at 161 °C, while anhydrate forms III and IV exhibited an endothermic peak at approximately 120 °C and an exothermic peak at 144 °C, with calculated Hf values of 17 and 14 kJ/mol, respectively. The exothermic peak and a second sharp endothermic peak near 170 °C indicated that these forms crystallized as anhydrate form V after melting.

Figure 5. DSC thermograms of anhydrate forms. (a) Form I, (b) form II, (C) form III, (d) form IV, and (e) form V.

Figure 6. van’t Hoff plots of TAK-441 anhydrous polymorphs in 10% (v/v) ACN in JP2.

directly obtained from the solution. Although TAK-441 formed solvates with DMK and THF, DMK/water, DMK/HEP, and THF/water solutions yielded form I. Mixing excess of water or HEP reduced the overall activity of the organic solvents below their critical levels where solvates were favored thermodynamically.28,29 Interestingly, both EtOH solvate form A and anhydrate form I competitively crystallized in EtOH solutions. Anhydrate form I was obtained from the solution slowly cooled. The EtOH solvate crystallized when the solution was rapidly cooled. In general, a solvate in its own solvent is more stable and thermodynamically preferred than an anhydrate. Under ambient pressure, anhydrates crystallize in the solvent above the temperature at which the solvate becomes less stable than the anhydrous phase.29 However, these results seemed to be a different situation from the general concept, because the EtOH solvate would be stable over the whole temperature range of the crystallization experiment. Solvate Isomorphism and Categorization. The obtained solvates were sorted into three categories on the basis of similarities in their PXRD patterns (Figure 2). Table 2 lists the categories of the solvates. EtOH solvate form A was categorized as type 1 and had unique peaks at 8.7° and 9.3° (2θ) in its PXRD pattern. Type 2 solvates exhibited isomorphism and had characteristic peaks at 11.6° and 14.5° (2θ). DMK solvate form A and EtOAc solvate form B were unstable and readily lost their solvent molecules in an air atmosphere. On the other 3338

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Table 3. Crystallographic Data for Anhydrate Form I and Its Various Solvates anhydrate form I empirical formula Mr temperature (K) crystal size (mm) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z F(000) μ (cm−1) ref collected/unique parameters final R indices [I > 2σ(I)] R indices (all data) goodness of fit on F2

C28H31F3N4O6 576.57 298 0.60 × 0.40 × 0.15 monoclinic C2/c 26.9301(5) 18.7690(4) 11.8275(3) 90.00 103.076(1) 90.00 5823.2(2) 8 2416.00 9.011 33684/5338 399 0.0700 0.2160 1.101 DMK solvate form A

empirical formula Mr temperature (K) crystal size (mm) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z F(000) μ (cm−1) ref collected/unique parameters final R indices [I > 2σ(I)] R indices (all data) goodness of fit on F2

C28H31F3N4O6, C3H6O 634.65 100 0.30 × 0.30 × 0.05 triclinic P1̅ 9.8775(3) 13.1864(4) 13.4772(4) 64.134(2) 84.447(2) 74.764(2) 1523.69(7) 2 668.00 9.370 17955/5448 407 0.0737 0.1919 0.908

anhydrate form I C28H31F3N4O6 576.57 100 0.20 × 0.20 × 0.20 monoclinic P21/c 11.6230(2) 18.7138(4) 25.8604(5) 90.00 100.6201(7) 90.00 5528.6(2) 8 2416.00 9.491 89159/10107 741 0.0581 0.1793 1.138 IBuOAc solvate form A

100 0.40 × 0.10 × 0.05 triclinic P1̅ 9.9970(3) 13.0749(3) 13.4367(3) 63.551(2) 84.122(2) 75.542(2) 1522.61(7) 2 604.00 8.616 18015/5449 371 0.0803 0.2454 0.962

Thermodynamic Relationships of Anhydrate Polymorphs. Burger and Ramberger’s Heat of Fusion Rule33 is considered a rule of thumb for the classification of the relationship between two polymorphs as either monotropic or enantiotropic. However, the thermodynamic order of polymorphs is not completely determined at the temperature of interest, because the rule does not identify the transition temperature (Ttrans) for enantiotropically related systems.34 Therefore, the determination of the equilibrium solubility of polymorphs is the foremost experimental method for the estimation of these relationships and the values for Ttrans. The equilibrium solubility of the anhydrates was thus determined between 10 and 50 °C. The equilibrium solubility indicated that the relative order of thermodynamic stability for the anhydrates was forms I > II > V > III > IV between 10 and 30 °C (Figure 6), and the van’t Hoff plots showed linear

EtOH solvate form B

100 0.60 × 0.40 × 0.10 monoclinic C2/c 26.5176(5) 18.4139(4) 11.9808(3) 90.00 101.5000(7) 90.00 5732.7(2) 8 2416.00 9.153 33288/5229 398 0.0566 0.1592 1.063 MEK solvate form A C28H31F3N4O6, C4H8O 648.68 100 0.25 × 0.08 × 0.05 triclinic P1̅ 10.4172(2) 11.4906(3) 13.2190(3) 80.834(2) 80.647(2) 82.419(2) 1532.17(6) 2 684.00 9.437 18160/5509 415 0.0611 0.1871 1.070

EtOH solvate form A C28H31F3N4O6, C2H6O 622.64 100 0.60 × 0.10 × 0.05 monoclinic P21/n 13.1698(3) 12.1820(3) 18.9898(5) 90.00 97.260(1) 90.00 3022.2(2) 4 1312.00 9.329 34279/5522 411 0.0845 0.2632 1.035 EtOAc solvate form A

100 0.80 × 0.20 × 0.10 triclinic P1̅ 10.7573(3) 11.4193(4) 13.7386(4) 74.026(2) 83.878(2) 80.058(2) 1595.01(7) 2 604.00 8.225 18791/5722 371 0.0591 0.1602 1.000

relationships. Notably, the lines for forms I and II, forms II and V, and forms III and IV crossed each other, and thus these sets of anhydrate forms were enantiotropically related. The estimated values for Ttrans were calculated using the points of intersection for the lines in the van’t Hoff plots and determined to be 7, 46, and 36 °C for forms I and II, II and V, and III and IV, respectively. Therefore, form I was stable above 7 °C, and thus selected for further development. Anhydrate Form I: An Isomorphic Desolvate of a Transient Solvate. Next, the crystal structure of anhydrate form I was determined, and the crystallographic information is presented in Table 3. The SCXRD data of form I was collected at 25 °C because the crystal lattice shrank at −173 °C, and the patterns computed using the crystallographic data obtained at low temperatures did not agree with the PXRD pattern of form I at room temperature (Figure 7). In the crystal structure, it can 3339

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Table 4. Vsolvent and Across in TAK-441 Channel-Type Solvates IBuOAc solvate form A EtOAc solvate form A EtOH solvate form B

type

Vsolvent (Å3)

Across (Å2)

2 3 4

236 338 430

24 30 36

the computed pattern for the solvate was quite similar to the PXRD pattern observed for form I at 25 °C. This similarity indicates that form I is an isomorphic desolvate35 of the EtOH solvate that is assumed to crystallize via desolvation of the solvate. This result is consistent with the competitive crystallization between anhydrate form I and EtOH solvate form A during the solution crystallization. The competitive crystallization must occur not between form I and the EtOH solvate form A, but between the EtOH solvate forms A and B in fact. Anhydrate form I is obtained upon harvesting only when EtOH solvate form B crystallizes. Isomorphic solvates of the transient solvate must also crystallize in MeOH and ACN, because anhydrate form I was also harvested from these solutions. It should be noted that in this study, TAK-441 crystallized only via solvate formation. Crystal Structure of Types 1, 2, and 3 Solvates. Crystal structures of other solvate types were also obtained. The computed patterns for the solvates were in good agreement with the PXRD patterns obtained during the screening process; therefore, it was concluded that the crystal structures obtained at −173 °C were the same as those formed at 25 °C. In all crystal structures of TAK-441, intramolecular hydrogen bonds similar to those observed for form I were present. EtOH solvate form A (type 1), however, was not a channeltype solvate. Each EtOH molecule was isolated from other EtOH molecules and formed intermolecular hydrogen bonds with the API molecule. In addition, the solvate consisted of head-to-tail dimers in which the API molecules were connected via hydrogen bonds between the hydroxyl substituent of the

Figure 7. Experimental PXRD pattern of form I and the computed patterns of form I and EtOH solvate form B. (a) Experimental PXRD pattern of form I, (b) computed pattern of form I at 25 °C, (c) computed pattern of EtOH solvate form B at −173 °C, and (d) computed pattern of form I at −173 °C.

be seen that the amide group and the oxygen of the trifluoroethoxy group participate in an intramolecular N−H··· O hydrogen bond. Furthermore, an intermolecular O−H···O C hydrogen bond connects a glycolyl group and two API molecules (Figure 8). As a result, a channel accessible from the crystal exterior exists along the crystallographic c axis in the crystal structure of form I. The channels in form I trap solvents when it crystallizes, as indicated by the crystal structure of a new EtOH solvate obtained via SCXRD at −173 °C using a fresh crystal isolated from an EtOH solution. This new EtOH solvate was designated as EtOH solvate form B and categorized as a fourth solvate type (type 4). The EtOH molecules were highly disordered in the channel, and therefore determining the electron density was not possible. Interestingly, the crystal structure of this EtOH solvate was nearly the same as that of form I at 25 °C because

Figure 8. Hydrogen-bond patterns and packing diagrams of TAK-441 form I and its solvates. Panels (a) and (b) form I at 25 °C, (c) and (d) EtOH solvate form A (type 1), (e) DMK solvate form A (type 2), and (f) and (g) MEK solvate form A (type 3). The solvent molecules in the solvates are highlighted in space-filling mode. Solid lines and light blue dot lines indicate the crystal lattices and hydrogen bonds, respectively. The arrows and dots indicate crystallographic axes directions. 3340

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size of the channel in type 4 solvate was much larger than those of the channels in the other types and may contribute to its extreme instability. Finally, anhydrate forms II, III, and IV were obtained via the desolvation of type 1, type 2, and type 3 solvates, respectively, while anhydrate form V crystallized following thermal conversion of solvates at 130−140 °C. The equilibrium solubility analysis suggested that forms I and II, forms II and V, and forms III and IV were related enantiotropically. Form I was more stable than the other polymorphs above 7 °C and was thus selected for further development.

glycolyl group and the amide group. Furthermore, the API molecules in the structure were partially disordered at the ethyl groups. DMK solvate form A (type 2) and IBuOAc solvate form A (type 2) had very similar crystal structures that contained a channel along the crystallographic a axis. DMK was packed in the channel, and the crystal structure was constructed of only weak interactions, such as van der Waals interactions. On the other hand, IBuOAc was so disordered that it was not possible to identify its position in the crystal structure. The weight loss during the TGA analyses indicated that the stoichiometric ratio for the IBuOAc solvate was 0.5, while the DMK solvate was a mono-DMK solvate. It is likely that the DMK solvate was partly desolvated prior to the TGA analysis. DMK might be so small that it went through the pore of type 1 solvate, while IBuOAc was too large. MEK solvate form A (type 3) and EtOAc solvate form A (type 3) had nearly the same structures and consisted of headto-tail dimers in which the API molecules were connected via intermolecular hydrogen bonds between the hydroxyl substituent of the glycolyl group and the oxygen of 4oxopyloropyridine. The dimers formed pockets comprising phenyl and glycolyl groups that were stacked along the crystallographic b axis and created another type of channel. Although the location of EtOAc could not be specified due to disorder, MEK was found to be packed in the channel without hydrogen bonds. In addition, the MEK solvate was a monoMEK solvate, which was consistent with the TGA weight loss. Pore Sizes of Channels in Each Solvate Type. Types 2, 3, and 4 solvates had distinct channel structures with different pore sizes. The Vsolvent and Across of the solvates where the residual electron density resulting from disorder in the solvent molecules were adjusted are listed in Table 4. The values of Across for EtOH solvate form B (type 4) were 1.5 and 1.2 times larger than that of IBuOAc solvate form A (type 2) and EtOAc solvate form A (type 3), respectively. Larger pore size may contribute to the extreme instability of the type 4 solvate. In fact, the type 4 pore size was so large that solvents could not be efficiently packed within the channel but passed through it upon harvesting.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic data in CIF format (anhydrate form I at both 298 and 100 K, EtOH solvate form B, EtOH solvate form A, DMK solvate form A, IBuOAc solvate form A, MEK solvate form A, EtOAc solvate form A at 100 K), DSC curves of the solvates, TGA curves of the anhydrates and computed PXRD pattern of the solvates are shown in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org/.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +81-466-32-2855. Fax: +81-466-29-4432. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Keiichirou Nakaoka of the Chemical Development Laboratories for TAK-441 API supply. We also wish to thank the members of the Material Science & Physicochemical Profiling at Analytical Development Laboratory of Takeda Pharmaceutical Co., Ltd. for their kind assistance and discussions.

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REFERENCES

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CONCLUSIONS Polymorph screening of TAK-441 was conducted to optimize crystal form. Solution crystallization led to the isolation of anhydrate form I and 12 solvates. Notably, TAK-441 formed only solvates from solution because as indicated by the crystal structure analysis, form I was the only anhydrate directly obtained from the solution and was a desolvated form of unstable solvates that immediately desolvated upon harvesting. In this study, competitive crystallization occurs between EtOH solvate form A and anhydrate form I in EtOH solution. Actually, it must occur between EtOH solvate form A and a second EtOH solvate that leads to the formation of anhydrate form I. Several solvates showed isomorphism and were structurally categorized as type 4 solvates. Type 1 solvate, EtOH solvate form A (type 1), was a nonchannel-type solvate, while the others were channel-type solvates. Type 2 solvates were constructed of only weak interactions, such as van der Waals and dipolar interactions, while type 3 solvates consisted of API dimers connected via intermolecular hydrogen bonding that did not involve solvent participation. Type 4 solvate was a transient solvate that led to the formation of anhydrate form I. The pore 3341

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Crystal Growth & Design

Article

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