Method of preparing a highly pure crystalline form

Abstract

Disclosed herein is a novel method for preparing a highly pure crystalline form of a compound from an efflorescent solvate form of the compound. The method comprises submitting the efflorescent solvate to a specific catalytic vapor solvent.

Description

Attorney Docket No. 01183-0348-00PCT-PRNMETHOD OF PREPARING A HIGHLY PURE CRYSTALLINE FORMFIELD

[0001] Disclosed herein is a novel one-step method to obtain a highly pure crystalline form of a compound in a quantitative yield from an efflorescent solvate form of the compound.BACKGROUND

[0002] Obtaining a crystalline form of a pharmaceutical compound with a high structural purity can be a difficult process if the compound has several competing non-solvated polymorphs. The solvate intermediate of the compound often plays a crucial role in the structural purity of the crystalline product as the evaporation of the solvent can generate new polymorphs that are only accessible via preliminary formation of the said solvates. The efflorescence phenomena (i.e., when a solvate, a chemical that has a solvent associated with its molecules, is exposed to air and spontaneously loses the solvent molecules through evaporation) is not always sufficient to directly obtain the desired stable pure crystalline form with a good crystallinity.

[0003] Therefore, it would be highly desirable to have a one-step desolvation step to produce the expected stable crystalline form in a quantitative manner with a good structural purity and crystallinity.

[0004] One illustration of the instant invention is the preparation of a crystalline form of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile starting from a solvate form. 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]-pent-2-enenitrile, known as rilzabrutinib, is also referred to herein as the compound of Formula (I), having the following structure:(I).Attorney Docket No. 01183-0348-00PCT-PRN

[0005] The compound described by Formula (I) is an inhibitor of Bruton’s tyrosine kinase (BTK) and is useful in the treatment of disorders and conditions mediated by BTK activity. BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells, and has been implicated in multiple signaling pathways across a wide range of immune-mediated diseases. BTK activity has been also implicated in the pathogenesis of several disorders and conditions, such as B cell-related hematological cancers (e.g., non Hodgkin lymphomia and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, pemphigus, inflammatory bowel disease, lupus, and asthma).

[0006] The compound of Formula (I) is disclosed in Example 31 of WO2014 / 039899. The synthesis of the compound of Formula (I) that is disclosed in WO2014 / 039899, requires purification by column chromatography and affords a foam upon removal of solvent, which can be crushed to a powder. Crystalline solid forms characterized as Form A, Form B, and an acetonitrile solvate (referred to also as crystalline Form C) of the compound of Formula (I), as well as processes of preparation thereof, are disclosed in WO2021 / 150723.

[0007] It has been found that some solvates of rilzabrutinib, more specifically ester solvates and carbonate solvates, or more specifically the methylacetate solvate of rilzabrutinib or the dimethylcarbonate solvate of rilzabrutinib, have the remarkable property to be efflorescent and can be desolvated at ambient temperature and ambient pressure to lead to non-solvated crystalline solid forms, including Form A, Form B, and a mixture of Form A and Form B of the compound of Formula (I). This efflorescence property linked to the volatility of the solvents allows the final crystalline form to have a low residual solvent content post-desolvation. A polishing step using a class II or a class III solvent can be applied to obtain Form B of the compound of Formula (I). This polishing step selectively dissolves the crystalline Form A over Form B and improves the crystallinity, the crystalline purity, and the stability of the obtained crystalline Form B of the compound of Formula (I).

[0008] Another illustration of the instant invention is the preparation of a crystalline form of modafinil starting from a modafinil solvate, in particular, starting from modafinil acetonitrile solvate. Modafinil (C15H15NO2S), also referred to herein as the compound of Formula (II), 2-(benzhydrylsulfinyl) acetamide, or 2- [(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide derivative with wake-promoting activity, and the structure of which has been described in U.S. Patent No. 4,177,290 ("the '290 patent"). The racemate of modafinil has been approved by the United States Food and Drug Administration for use in the treatment of narcolepsy.Attorney Docket No. 01183-0348-00PCT-PRN"Modafinil has been described as a compound that has an interesting neuropsychopharmacological potential in mice (US Patent No. 4,177,290). Modafinil also induces an important increase in night activity in monkeys (Y. Duteil et al., Eur. J. Pharmacol., 1990; 180: 49). Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuropsyc. Biol. Psych., 1988; 12: 695).

[0009] Another illustration of the instant invention is the preparation of a crystalline form of the levorotatory (R) enantiomer of modafinil, also referred to herein as armodafmil or the compound of Formula R-(II), starting from the acetonitrile solvate of armodafmil.

[0010] A method of preparation of a racemic mixture of modafinil is described in the '290 patent. A method of preparation of the levorotary isomer of modafinil, or armodafmil, as well as its use as an antidepressant or stimulant agent in the treatment of hypersomnia and disorders related to Alzheimer's disease are further described in U.S. Patent No. 4,927,855. Method of preparation of an acetonitrile solvate of modafinil is described in W02004 / 014846. Method of preparation of acetonitrile solvate of armodafmil is disclosed in W02004 / 060858.

[0011] For a compound to be suitable for use as a therapeutic agent, its synthesis should be amenable to large scale manufacturing, isolation, and drying, and the physical properties of the compound should be such that they do not negatively impact the effectiveness or costs of the formulated active ingredient. The present disclosure addresses such needs.SUMMARY

[0012] Disclosed herein is an efficient one-step method to obtain a highly pure crystalline compound directly from an efflorescent solvate form thereof. This one-step process involves a low quantity of a single solvent used as vapor. Moreover, the process is performed at near room temperature, for example, in a facility with temperatures ranging from 0°C to 40°C, or from 10°C to 30°C, and is efficient in time.

[0013] Disclosed herein is an efficient one-step method to obtain a highly pure crystalline compound of Formula (I), (II), or R-(II) directly from an efflorescent solvate form.Attorney Docket No. 01183-0348-00PCT-PRN

[0014] It has been found that submitting an efflorescent solvate form in the presence of a specific catalytic vapor solvent at room temperature and at 1 atmosphere allows obtaining a highly pure crystalline form of a compound of Formula (I), (II), or R-(II) in a quantitative yield.

[0015] It has been found that submitting a wet cake of an efflorescent solvate form containing residual solvent at a quantity lower than 30% w / w, lower than 20% w / w, or lower than 10% w / w in the presence of the vapor of a class III or class II solvent that exhibits a boiling temperature between 30 and 105°C at 1 atmosphere provides a highly pure crystalline form.

[0016] In another aspect, disclosed herein is the preparation of a highly pure Form B of rilzabrutinib (for example, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°) from an ester solvate or a carbonate solvate. In some embodiments, the highly pure Form B of rilzabrutinib (the compound of Formula (I-(E))) prepared from an ester solvate or a carbonate solvate is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.2° ± 0.2°, 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°.

[0017] In another aspect, disclosed herein is the preparation of a highly pure Form 1 of modafinil (for example, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.03 ± 0.10, 10.18 ± 0.10, 11.20 ± 0.10, 12.89 ± 0.10, 15.77 ± 0.10, and 19.31 ± 0.10) from an acetonitrile solvate.

[0018] In another aspect, disclosed herein is the preparation of a highly pure Form 1 of armodafmil (for example, characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 6.66 ± 0.10, 10.40 ± 0.10, 13.35 ± 0.10, and 14.05 ± 0.10) from an acetonitrile solvate.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of the methylacetate (MAC) solvate of the compound of Formula (I-(E)).

[0020] Figure 2 shows an XRPD pattern of the dimetylcarbonate (DMC) solvate of the compound of Formula (I-(E)).

[0021] Figure 3A shows an XRPD pattern of crystalline Form B of the compound of Formula (I-(E)) obtained after drying the methylacetate (MAC) solvate of the compound of Formula (I-(E)) in the presence of methanol vapor (static or dynamic mode).

[0022] Figure 3B shows an XRPD pattern of a mixture of two phases of the compound of Formula (I-(E)) obtained after exposing the methylacetate (MAC) solvate of the compound ofAttorney Docket No. 01183-0348-00PCT-PRN Formula (I-(E)) to air at room temperature and room pressure. The peaks at the two-theta range between 4°-6° from left to right each indicate the presence of crystalline Form B and crystalline Form A, respectively, of the compound of Formula (I-(E)).

[0023] Figure 4 shows an XRPD pattern of crystalline Form B of the compound of Formula (I-(E)) obtained after drying the dimethylcarbonate (DMC) solvate of the compound of Formula (I-(E) in the presence of acetonitrile vapor in dynamic mode.

[0024] Figure 5 shows, from the bottom to the top, an XRPD pattern of crystalline Form 1 of the compound of Formula (II), or modafinil, obtained after drying the acetonitrile solvate of modafinil in the presence of methanol vapor in static mode; a reference (calculated) XRPD pattern of crystalline Form 1 of modafinil; a reference (calculated) XRPD pattern of crystalline Form 3 of modafinil; an XRPD pattern of the acetonitrile solvate of modafinil just after filtration; and an XRPD pattern of modafinil solid after efflorescence at room temperature for lOh.

[0025] Figure 6A shows the optical microscopy images of the initial particles (acetonitrile solvate and crystalline Form VI) and Figure 6B shows the optical microscopy images of the final particles (pure crystalline Form 1 after drying the acetonitrile solvate of modafinil in the presence of methanol vapor at room temperature) of the compound of Formula (II)

[0026] Figure 7 shows, from the top to the bottom, an XRPD pattern of crystalline Form 1 of modafinil obtained after drying the acetonitrile solvate of modafinil in the presence of acetone vapor at RT in static mode; and a reference (calculated) XRPD pattern of crystalline Form 1 of modafinil.

[0027] Figure 8 shows, from the bottom to the top, an XRPD pattern of the acetonitrile solvate of armodafmil; an XRPD pattern of crystalline Form 1 of armodafinil, or the compound of Formula R-(II), obtained after drying the acetonitrile solvate of armodafmil in the presence of methanol vapor such as p(MeOH): MeOH + e Caprolactam in static mode; an XRPD pattern of crystalline Form 1 of armodafmil obtained after drying the acetonitrile solvate of armodafmil in the presence of methanol vapor in static mode at 5°C, and the reference (calculated) XRPD pattern of crystalline Form 1 of armodafmil.

[0028] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.Attorney Docket No. 01183-0348-00PCT-PRN

[0029] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.

[0030] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description, serve to explain the principles described herein.DETAILED DESCRIPTIONDefinitions

[0031] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meaning.

[0032] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.

[0033] As used herein, the term “about” means approximately, in the region of, roughly or around. When the term “about” is used in conjunction with a numerical range it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%.

[0034] As used herein, the term “highly pure crystalline form” of a compound means the compound comprises at least 90% or more of a single crystalline form. “Highly pure crystalline form” can be used interchangeably with “structural purity,” / .< ., a compound that exhibits the same 3D molecular arrangement for every particle, rather than a mixture of polymorphic forms, as measured by X-ray powder diffraction (XRPD) (see, for example, G. Coquerel, Chemical Engineering and Processing, 2006; 45(10): 857-862). In some embodiments, the compound comprises at least 91% or more of a single crystalline form. In some embodiments, the compound comprises at least 92% or more of a single crystalline form. In some embodiments, the compound comprises at least 93% or more of a single crystalline form. In some embodiments, the compound comprises at least 94% or more of a single crystalline form. In some embodiments, the compound comprises at least 95% or more of a single crystalline form. In some embodiments, the compound comprises at least 96% or more of a single crystalline form. In some embodiments, the compound comprises at least 97% or more of a single crystalline form. In some embodiments, the compound comprises at least 98% or more of a single crystalline form. In some embodiments, the compound comprises at least 99% or more ofAttorney Docket No. 01183-0348-00PCT-PRN a single crystalline form. In some embodiments, the compound comprises at least 99.5% or more of a single crystalline form. In some embodiments, the compound comprises at least 99.9% or more of a single crystalline form. In some embodiments, the compound comprises 100% of a single crystalline form.

[0035] As used herein, “2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4[4-(oxetan-3 -yl)piperazin-l-yl]-pent-2-enenitrile”, “rilzabrutinib” and “the compound of Formula (I),” are used interchangeably to refer to a compound having the following structure:which is also known as 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4[4-(oxetan-3 -yl)piperazin- 1 -yl]-(E and Z)-pent-2-enenitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile, 1 -piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]-a-[2-methyl-2-[4-(3-oxetanyl)-l-piperazinyl]propylidene]-P-oxo-, (3R)-; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, and also by the International Nonproprietary Names for Pharmaceutical Substances (INN) as published by the World Health Organization https: / / cdn.who.int / media / docs / default-source / international-nonproprietary-names-(inn) / pll21.pdf?sfyrsn=69617906_ 15&download=true) having the following structure:The compound of Formula (I) includes E and Z isomers, as indicated by the wavy bond in the structure shown above. The compound of Formula (I) may be present as a salt form.Attorney Docket No. 01183-0348-00PCT-PRN

[0036] A dose of the (E) isomer of the compound of Formula (I) may contain the corresponding (Z) isomer as an impurity in less than about 5% by weight, for example less than about 2% by weight, such as less than 1% by weight; a dose of the (Z) isomer of the compound of Formula (I) may contain the corresponding (E) isomer as an impurity in less than about 5% by weight, for example less than about 2% by weight, such as less than 1% by weight. When the compound of Formula (I) is denoted as a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, it means that the amount of (E) or (Z) isomer in the mixture is greater than about 2% by weight.

[0037] In some embodiments, the compound of Formula (I) is provided as the (E) isomer. In some embodiments, the compound of Formula (I) is provided as the (Z) isomer. In some embodiments, the compound of Formula (I) is provided as a mixture of (E) and (Z) isomers.

[0038] In some embodiments, the compound of Formula (I) is a compound of Formula (I-(E)), the E isomer of the compound of Formula (I). In some embodiments, the compound of Formula (I-(E)) has the following structure:(I-(E)).In some embodiments, the compound of Formula (I-(E)) is 95% or more pure, such as 96% pure, 97% pure, 98% pure, 99% pure, or 100% pure.

[0039] In some embodiments, the compound of Formula (I) is a compound of Formula (I-(Z)), the Z isomer of the compound of Formula (I). In some embodiments, the compound of Formula (I-(Z)) has the following structure:Attorney Docket No. 01183-0348-00PCT-PRN(I-(Z))- In some embodiments, the compound of Formula (I-(Z)) is 95% or more pure, such as 96% pure, 97% pure, 98% pure, 99% pure, or 100% pure.

[0040] As used herein, “2-(diphenylmethanesulfinyl)acetamide”, “modafinil,” and “the compound of Formula (II)” are used interchangeably to refer to a compound having the following structure:which is known as a racemic mixture of the two enantiomers” armodafinil” or “R(-)modafinil” and “esmodafinil” or “S(+)modafinil.” “R(-)modafinil” or “(-)-2-[(R)-(diphenylmethyl)sulfinyl]acetamide” is a compound having the following structure:

[0041] The compounds described herein, e.g., the compound of Formula (I), the compound of Formula (II), or the compound of Formula R-(II), may also exist in the form of solvates, in other words, in the form of associations or combinations with one or more molecules of solvent. These solvates include more particularly hydrates, where the solvent is water. As used herein, the terms “solvate form” and “solvate” interchangeably refer to a physical association of a compound with one or more solvent molecules. Solvate forms can be identified and distinguished from each other by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and therm ogravimetric (TG) analysis.Attorney Docket No. 01183-0348-00PCT-PRN

[0042] As used herein, a “pharmaceutically acceptable excipient” refers to a carrier or an excipient that is useful in preparing a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use.

[0043] As used herein, the term “treat”, “treating” or “treatment”, when used in connection with a disorder or condition, includes any effect e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0044] As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0045] As used herein, "desolvating" and "desolvation" mean the elimination of most or all solvent molecules, preferably greater than or equal to 90%, more preferably greater than or equal to 95%, even more preferably greater than or equal to 99%, most preferably 100% from the solvate that leads to the conversion of the solvate into the polymorph.

[0046] As used herein, “wet cake” refers to a solvate, where the amount of solvent exceeds the maximum amount that the crystal lattice can contain. For example, a wet cake can refer to a solvate that was dried until it has traces of solvent, wherein the molar ratio between the solvent and the compound is between 1 : 1 and 1 :3, e.g., a dihydrate wet cake can have 2 to 6 molecules of water per a molecule of solute. This molar ratio can also be expressed in percentage, in which case the wet cake can contain residual solvent at, e.g., a quantity lower than 30% w / w, lower than 20% w / w, or lower than 10% w / w.

[0047] As used herein, “Class III solvents” refer to solvents with low toxic potential and of relatively low risk to human health, as determined by FDA guidance. Available data indicate that those solvents are less toxic in acute or short-term studies and negative in genototoxicity studies.

[0048] As used herein, “Class II solvents” refer to solvents that should be limited in pharmaceutical products because of their inherent toxicity.

[0049] As used herein, “closed system” refers to a physical system that allows the transfer of energy (e.g., heat) but not the transfer of mass in or out of the system.

[0050] As used herein, “open system” refers to a physical system that allows the transfer of energy (e.g., heat) and mass in or out of the system.Attorney Docket No. 01183-0348-00PCT-PRN

[0051] As used herein, “static mode” refers to a process, wherein a wet cake that comprises a certain level of residual solvent is exposed to an inert atmosphere saturated with vapor of a chosen solvent in a closed system for Ih or up to several days. The closed system is maintained at a constant temperature close to RT (i.e., isothermal mode). In some embodiments, the inert atmosphere comprises an intert gas selected from nitrogen and monoatomic gas. In some embodiments, the monoatomic gas is selected from argon, krypton, helium, neon, and xenon.

[0052] As used herein, “dynamic mode” refers to a process, wherein a wet cake is dried in an open system. The dynamic mode consists in flushing the solvate form with inert gas saturated with the vapor of a class III or class II solvent. The dynamic mode can be performed with a dryer, such as a conical dryer or paddle dryer. In some embodiments, the inert gas is selected from nitrogen and monoatomic gas. In some embodiments, the monoatomic gas is selected from argon, krypton, helium, neon, and xenon.

[0053] As used herein, an “atmosphere saturated with vapor of a solvent” refers to an atmosphere where there is an equilibrium between the liquid phase and the gas phase. It is possible to depart from that equilibrium point by up to 20% (supersaturation) or down to 50% (under saturation). The undersaturation can be obtained by dissolving a solid that is soluble in the solvent to be used in the desolvation step, such as s-Caprolactam in the case of methanol, and thereby preparing a catalytic solvent in the vapor phase.

[0054] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the compounds and / or methods disclosed herein.

[0055] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0056] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.Attorney Docket No. 01183-0348-00PCT-PRN

[0057] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated.

[0058] It is understood that, independently of stereoisomerical or isotopic composition, each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereoisomerical composition of each compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective compound or salt thereof disclosed herein, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective compound.

[0059] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0060] Although various features of the compounds and methods disclosed herein may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the compounds and methods disclosed herein may be described in the context of separate embodiments for clarity, the compounds and methods disclosed herein may also be implemented in a single embodiment.Methods of preparing a highly pure crystalline form

[0061] In accordance with the current disclosure, a method of preparing a highly pure crystalline form of a compound from an efflorescent solvate form of the compound comprises a drying step, or a desolvation step, wherein the drying step consists of submitting the wet cake of the efflorescent solvate to an atmosphere saturated with the vapor of a solvent selected from the groups of class III and class II solvents, wherein the solvent has a boiling temperature that ranges from about 30 to about 105°C.

[0062] In some embodiments, the wet cake contains a residual quantity of solvent below 30% w / w. In some embodiments the residual quantity of solvent is below 20% w / w. In some embodiments the residual quantity of solvent is below 10% w / w or below 5% w / w or below 1% w / w.

[0063] In some embodiments, the drying step is carried out at room temperature. In some embodiments, the drying step is carried out at about 40°C. In some embodiments, the dryingAttorney Docket No. 01183-0348-00PCT-PRN step is carried out at about 25°C. In some embodiments, the drying step is carried out at about 20°C. In some embodiments, the drying step is carried out at about 5°C.

[0064] In some embodiments, the organic solvent is selected from the group of class III solvents with a boiling temperature that ranges from about 30 to about 105°C comprising acetone, methylethyl ketone, ethyl ether, tert-butylmethyl ether, pentane, heptane, ethanol, 1-propanol, 2-propanol, 2-butanol, ethyl formate, methyl acetate, ethylacetate, isopropyl acetate, propyl acetate, formic acid, and triethylamine.

[0065] In some embodiments, the organic solvent is selected from the group of class II solvents with a boiling temperature that ranges from about 30 to about 105°C comprising acetonitrile, hexane, cyclohexane, methylcyclohexane, di chloromethane, chloroform, 1,2-di chloroethene, 1,2-dimethoxy ethane, 1,4-di oxane, methanol, and nitromethane.

[0066] In some embodiments the vapor pressure is saturated. In some embodiments the vapor pressure ranges from about 50% to about 120% of the equilibrium between the liquid and gas phase. In some embodiments the vapor pressure is close to 100% of the equilibrium between the liquid and gas phase.

[0067] In some embodiments, the drying step is carried out in static mode. In some embodiments the drying step is carried out in dynamic mode.

[0068] In some embodiments, the efflorescent solvate is an acetate solvate or an ester carbonate solvate of the compound of Formula (I).

[0069] In some embodiments, the efflorescent solvate is a methylacetate solvate of the compound of Formula (I) or a dimethylcarbonate solvate of the compound of Formula (I).

[0070] In one embodiment, the efflorescent solvate is an acetonitrile solvate of modafinil (the compound of Formula (II)) or an acetonitrile solvate of armodafinil (the compound of Formula R-(II)).

[0071] In some embodiments, the class III organic solvent with a boiling temperature that ranges from about 30 to about 105°C is acetone.

[0072] In some embodiments, class II the organic solvent with a boiling temperature that ranges from about 30 to about 105°C is acetonitrile or methanol.

[0073] In some embodiments, the efflorescent solvate comprises molecules of a first solvent co-ordinated to said compound.

[0074] In some embodiments, the efflorescent solvate is desolvated, or dried, by submitting the efflorescent solvate form of the compound to an inert atmosphere saturated with a vapor of a second solvent.

[0075] In some embodiments, the first solvent and the second solvent are different.Attorney Docket No. 01183-0348-00PCT-PRN

[0076] In some embodiments, an efflorescent solvate of the compound is prepared. In some embodiments, the efflorescent solvate comprises molecules of a first solvent co-ordinated to said compound. In some embodiments, the efflorescent solvate is desolvated by submitting the efflorescent solvate of the compound to an inert atmosphere saturated with a vapor of a second solvent. In some embodiments, the first solvent and the second solvent are different. In some embodiments, the efflorescent solvate of the compound and the vapor of a second solvent are submitted to or stand together in a closed system until the highly pure crystalline form is obtained. In some embodiments, a continuous flow of the vapor of a second solvent is submitted to the efflorescent solvate of the compound through an open system until the highly pure crystalline form is obtained. In some embodiments, the second solvent has a boiling point that ranges from about 30 °C to about 105 °C. In some embodiments, the second solvent is a class III solvent. In some embodiments, the class III solvent is selected from acetone, methylethyl ketone, ethyl ether, tert-butylmethyl ether, pentane, heptane, ethanol, 1 -propanol, 2-propanol, 2-butanol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, formic acid, and triethylamine. In some embodiments, the class III solvent is selected from acetone and ethyl acetate. In some embodiments, the class III solvent is acetone. In some embodiments, the second solvent is a class II solvent. In some embodiments, the class II solvent is selected from acetonitrile, hexane, cyclohexane, methylcyclohexane, di chloromethane, chloroform, 1,2-di chloroethene, 1,2-dimethoxy ethane, 1,4-di oxane, methanol, and nitromethane. In some embodiments, the class II solvent is selected from acetonitrile, chloroform, and methanol. In some embodiments, the class II solvent is selected from acetonitrile and methanol. In some embodiments, the pressure of the atmosphere is about 1 atm. In some embodiments, the temperature of the atmosphere ranges from about 0 to about 40 °C. In some embodiments, the temperature of the atmosphere is selected from about 5, about 20, and about 25 °C. In some embodiments, the inert atmosphere comprises an inert gas selected from nitrogen, argon, xenon, helium, krypton, and neon.

[0077] Also disclosed herein is a method of desolvating efflorescent solvates comprising exposing the efflorescent solvate to an inert atmosphere saturated with the vapor of a different solvent.EXAMPLES

[0078] The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.Attorney Docket No. 01183-0348-00PCT-PRN

[0079] Unless specified otherwise, all procedures were carried out at ambient pressure, i.e., at about 1 atm.

[0080] The following abbreviations are used herein.AbbreviationsACN: acetonitrileAcOMe or MAC: methylacetateatm: atmospheric pressureDMC: dimethylcarbonateEtOH: ethanolh or hr: hour(s)K: kelvinMeOH: methanolRT or rt: room temperatureXRPD: X-ray powder diffraction

[0081] The following analytical methods were used herein.Analytical methodsX-Ray Powder Diffraction (XRPD)

[0082] XRPD measurements were carried out at ambient temperature on a Bruker D8 Discover apparatus using the following conditions: Cu Ka radiation (1.54 A), Ni Kp filter, divergent slit 0.6 mm, and high-performance detector (Lynx-eye).

[0083] The samples were scanned from 3-30° or 3-40° 29 angles, with a 0.04° step (1 s duration per step). 40 kV - 40 mA.

[0084] The software used to process the data was Bruker DIFFRAC.EVA V4.1.Optical Microcopy

[0085] Nikon Eclipse LV100 optical binocular microscope equipped with a Nikon Digital sight DS-Ril camera was used for microscopy studies.

[0086] The software used to analyze the results was Nikon NIS Elements D V3.1.

[0087] The device was controlled with the software Linksys 32 v2.4.3.Calculated X-Ray Powder Diffraction (XRPD)

[0088] Calculated” XRPD or “reference” XRPD was obtained by calculation from crystallographic data of the resolved structure: lattice parameters, space group and reduced coordinates, and anisotropic motion parameters for all the atoms except hydrogen. TheAttorney Docket No. 01183-0348-00PCT-PRN crystallographic data was extracted from the Cambridge Structural Datatbase via ConQuest (version 2024.1.0), which was then put in the software Mercury (version 2024.1.0) to provide the calculated XRPD pattern of reference. The X-ray wavelength used for the calculation was the wavelength produced by a copper anticathode, i.e., 1.54 A.Example 1. Preparation of the methylacetate solvate of the compound of Formula (I-(E))

[0089] The methylacetate solvate of the compound of Formula (I-(E)) was obtained from the acetonitrile solvate of the compound of Formula (I-(E)) (or crystalline Form C of the compound of Formula (I-(E))), the crystalline Form B of the compound of Formula (I-(E)), or the amorphous form of the compound of Formula (I-(E)).Example 1.1. Methylacetate solvate of the compound of Formula (I-(E)) from crystalline Form C

[0090] 10.35 g of the acetonitrile solvate of the compound of Formula (I-(E)) (or crystalline Form C of the compound of Formula (I-(E))) was completely dissolved in 31 g of methylacetate (MAC) at RT. Dissolution was fast and the medium remained turbid. After 20 minutes, crystallization of methylacetate solvate of the compound of Formula (I-(E)) started to progress. After 4 h, thick white slurry was observed.Example 1.2. Methylacetate solvate of the compound of Formula (I-(E)) from crystalline Form B

[0091] Crystalline Form B of the compound of Formula (I-(E)) was dissolved in 5 V of methylacetate. The mixture was heated to 40 °C and maintained at 40 °C for 1 h. The mixture was cooled to a temperature between 0 and 10 °C.Example 1.3. Methylacetate solvate of the compound of Formula (I-(E)) from amorphous form

[0092] 32.82 g of the amorphous form of the compound of Formula (I-(E)) was dissolved into 60 mL of methylacetate at RT. The solution was seeded with 150 mg of crystalline Form B of the compound of Formula (I-(E)), prepared according to the methods described in PCT / US2024 / 040259. The suspension was maintained at RT for 24 h under magnetic stirring. The methylacetate solvate of the compound of Formula (I-(E)) was obtained.Exemple 1.4. XRPD analysis of the methylacetate solvate of the compound of Formula (I-(E))

[0093] The XRPD pattern was measured on Bruker D8 advance diffractometer following the method described above, which is shown in Figure 1.Example 2. Preparation of the dimethylcarbonate solvate of the compound of Formula (I-Attorney Docket No. 01183-0348-00PCT-PRN (E))

[0094] Dimethylcarbonate solvate of the compound of Formula (I-(E)) was obtained from the acetonitrile solvate of the compound of Formula (I-(E)), the crystalline Form B of the compound of Formula (I-(E)), or the amorphous form of the compound of Formula (I-(E)). Example 2.1. Dimethylcarbonate solvate of the compound of Formula (I-(E)) from crystalline Form C of the compound of Formula (I-(E))

[0095] 0.7191 g of crystalline Form C of the compound of Formula (I-(E)) was completely dissolved in 5.0961 g of dimethylcarbonate. The solution was placed in a freezer for several hours until the completion of solidification. The vial was then placed at RT. After melting of the solvent, a foggy medium was obtained. This light suspension was stirred for hours at RT to give a white thick suspension.Example 2.2. Dimethylcarbonate solvate of the compound of Formula (I-(E)) from amorphous form of the compound of Formula (I-(E))

[0096] 7 g of amorphous form of the compound of Formula (I-(E)) was dissolved in 21 mL of dimethylcarbonate solvent. The solution was seeded with few milligrams of crystalline Form B of the compound of Formula (I-(E)), prepared according to the methods described in PCT / US2024 / 040259, and frozen at -18 °C. After 12h, the mixture was thawed and stirred at RT and crystallization was observed. The solid obtained was dimethylcarbonate solvate of the compound of Formula (I-(E)).Example 2.3. XRPD analysis of the dimethylcarbonate solvate of the compound of Formula (I-(E))

[0097] The dimethylcarbonate solvate of the compound of Formula (I-(E)) was analyzed by XRPD following the method described above. The pattern recorded and peak positions are presented in Figure 2 (having signals at two-theta values 4.7° ± 0.2°, 9.5° ± 0.2°, 10.7° ± 0.2°, 10.8° ± 0.2°, 14.2° ± 0.2°, and 16.9° ± 0.2°).

[0098] Based on peak positions, the XRPD pattern of the dimethylcarbonate solvate of the compound of Formula (I-(E)) was comparable to that of the methylacetate solvate of the compound of Formula (I-(E)).

[0099] Example 3. Preparations of crystalline Form B of the compound of Formula (I-(E)) starting from the methylacetate solvate of the compound of Formula (I-(E)) using methanol vapor

[0100] The desolvation of the methylacetate solvate of the compound of Formula (I-(E)) in static mode was performed in saturated methanol atmosphere at two different temperatures, 5 or 25 °C. At 5°C, a wet cake with 25% w / w residual content of methylacetate was submitted toAttorney Docket No. 01183-0348-00PCT-PRN an atmosphere of nitrogen saturated with methanol vapor to rapidly give pure crystalline Form B of the compound of Formula (I-(E)) with high crystallinity in a quantitative yield (i.e., 100% of pure crystalline Form B was obtained). At 25°C, a wet cake with 20% w / w residual content of methylacetate was submitted to a saturated methanol atmosphere to give pure crystalline Form B of the compound of Formula (I-(E)), also with high crystallinity in a quantitative yield.

[0101] The XRPD pattern was measured on a Bruker D8 advance diffractometer following the method described above, which is shown in Figure 3.

[0102] The XRPD pattern in Figure 3(a) clearly demonstrated that the product obtained through the instant process of preparation was pure crystalline Form B of the compound of Formula (I-(E)), without any contaminants such as crystalline Form A or the MAC solvate of the compound of Formula (I-(E)). In contrast, the product obtained by simply exposing the MAC solvate of the compound of Formula (I-(E)) to air at room temperature and room pressure did not result in a pure crystalline form. Rather, it resulted in a mixture of crystalline forms, demonstrated by the XRPD pattern in Figure 3(b), which shows the presence of a mixture of crystalline forms, Form B and Form A, of the compound of Formula (I-(E)).

[0103] Example 4. Preparation of crystalline Form B of the compound of Formula (I-(E)) starting from dimethylcarbonate solvate using acetonitrile vapor

[0104] The desolvation of the dimethylcarbonate solvate of the compound of Formula (I-(E)) in dynamic mode was performed under nitrogen flux saturated with acetonitrile. The first part of the desolvation process was performed under vacuum and a 11% w / w residual content of dimethylcarbonate was achieved. The second part of the desolvation process was performed under a nitrogen flux saturated with acetonitrile vapor at a temperature of 35°C. The flow rate was 0.07L / min. After 1 Ih under the acetonitrile-saturated nitrogen flux, crystalline Form B of the compound of Formula (I-(E)) was obtained with a good structural purity.

[0105] The XRPD pattern was measured on a Bruker D8 advance diffractometer following the method described above, which is shown in Figure 4.

[0106] Example 5. Preparation of crystalline Form B of the compound of Formula (I-(E)) using methanol or acetonitrile vapor

[0107] A wet cake of methylacetate solvate of the compound of Formula (I-(E)) with 26% w / w residual content of methylacetate was submitted at room temperature to a saturated atmosphere of methanol or acetonitrile. Crystalline Form B of the compound of Formula (I-(E)) with good crystallinity was obtained in a quantitative yield in both static mode and dynamic mode. The experimental conditions used in Example 5 are shown below in Table 1.Attorney Docket No. 01183-0348-00PCT-PRN Table 1.

[0108] Example 6. Preparation of crystalline Form 1 of the compound of Formula (II) (modafinil)

[0109] 0.5 g of a wet cake of the acetonitrile solvate of modafinil with 22.6% w / w residual content of acetonitrile was submitted to static mode for 36 h at 1 atmosphere with a saturated atmosphere of MeOH vapor. Crystalline Form I of the compound of Formula (II) was obtained in a quantitative yield with a high purity and a good crystallinity.

[0110] The XRPD patterns of crystalline Form 1 of modafinil, or compound of Formula (II), are shown in Figure 5.

[0111] The optical microscopy image of the acetonitrile solvate of modafinil and the optical microscopy image of the crystalline Form 1 of modafinil are shown in Figures 6 A and 6B, respectively.

[0112] Example 7. Preparation of crystalline Form 1 of the compound of Formula (II) (modafinil)

[0113] 0.5 g of a wet cake of the acetonitrile solvate of modafinil with 22.6% w / w residual content of acetonitrile was submitted to static mode for 18 h at 1 atmosphere with a saturated atmosphere of acetone vapor at RT. Crystalline Form I of the compound of Formula (II) was obtained in a quantitative yield with a high purity and a good crystallinity.

[0114] The XRPD pattern of crystalline Form 1 of modafinil, or the compound of Formula (II), is shown in Figure 7 (plot on top).

[0115] Example 8. Preparations of crystalline Form 1 of the compound of Formula R-(II) (armodafinil)

[0116] Example 8.1. 0.5 g of a wet cake of the acetonitrile solvate of armodafinil with 25% w / w residual content of acetonitrile was submitted to static mode for 36 hours in 1 atmosphere with a saturated atmosphere of MeOH vapor at p(MeOH): MeOH + s-Caprolactam 57% m / m). Crystalline Form I of the compound of Formula R-(II) was obtained in aAttorney Docket No. 01183-0348-00PCT-PRN quantitative yield with a high purity and a good crystallinity. The XRPD patterns of crystalline Form 1 of armodafmil, or the compound of Formula R-(II), according to Example 8.1 are shown in Figure 8 (second plot from the bottom).

[0117] Example 8.2. 0.5 g of a wet cake of acetonitrile solvate of armodafmil with 25% w / w residual content of acetonitrile was submitted to static mode in 1 atmosphere with a saturated atmosphere with MeOH vapor for 2 days at 5°C. Crystalline Form I of the compound of Formula R-(II) was obtained in a quantitative yield with a high purity and a good crystallinity.

[0118] The XRPD patterns of crystalline Form 1 of armodafmil, or compound of Formula R-(II), according to Example 8.2 are shown in Figure 8 (third plot from the bottom).

[0119] Although the present disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.EMBODIMENTS

[0120] Non-limiting embodiments of the disclosure include:

[0121] Embodiment 1. A method of preparing a highly pure crystalline form of a compound from an efflorescent solvate form of the compound comprising:a) preparing an efflorescent solvate of the compoundb) submitting the efflorescent solvate form of the compound to an inert atmosphere saturated with a vapor of a solvent.

[0122] Embodiment 2. The method of embodiment 1, wherein the efflorescent solvate form of the compound and the vapor of a solvent are submitted to a closed system until the highly pure crystalline form is obtained.

[0123] Embodiment 3. The method of embodiment 1, wherein a continuous flow of the vapor of a solvent is submitted to the efflorescent solvate form of the compound through an open system until the highly pure crystalline form is obtained.

[0124] Embodiment 4. The method of embodiment 1, wherein the solvent has a boiling point that ranges from about 30 °C to about 105 °C.

[0125] Embodiment 5. The method of embodiment 1, wherein the solvent is a class III solvent.

[0126] Embodiment 6. The method of embodiment 5, wherein the class III solvent is selected from acetone, methylethyl ketone, ethyl ether, tert-butylmethyl ether, pentane, heptane,Attorney Docket No. 01183-0348-00PCT-PRN ethanol, 1 -propanol, 2-propanol, 2-butanol, ethyl formate, methylacetate, ethyl acetate, isopropyl acetate, propyl acetate, formic acid, and triethylamine.

[0127] Embodiment 7. The method of embodiment 6, wherein the class III solvent is selected from acetone and ethyl acetate.

[0128] Embodiment 8. The method of embodiment 7, wherein the class III solvent is acetone.

[0129] Embodiment 9. The method of embodiment 1, wherein the solvent is a class II solvent.

[0130] Embodiment 10. The method of embodiment 9, wherein the class II solvent is selected from acetonitrile, hexane, cyclohexane, methylcyclohexane, dichloromethane, chloroform, 1,2-di chloroethene, 1,2-dimethoxy ethane, 1,4-di oxane, methanol, and nitromethane.

[0131] Embodiment 11. The method of embodiment 10, wherein the class II solvent is selected from acetonitrile, chloroform , and methanol.

[0132] Embodiment 12. The method of embodiment 11, wherein the class II solvent is selected from acetonitrile and methanol.

[0133] Embodiment 13. The method of embodiment 1, wherein the pressure of the atmosphere is about 1 atm.

[0134] Embodiment 14. The method of embodiment 1, wherein the temperature of the atmosphere ranges from about 0 to about 40 °C.

[0135] Embodiment 15. The method of embodiment 1, wherein the temperature of the atmosphere is selected from about 5, about 20, and about 25 °C.

[0136] Embodiment 16. The method of embodiment 1, wherein the inert atmosphere comprises an inert gas selected from nitrogen, argon, xenon, helium, krypton, and neon.

[0137] Embodiment 17. The method of embodiment 1, wherein the compound is selected from:the compound of Formula (I) having the structurethe compound of Formula (I-(E)) having the structureAttorney Docket No. 01183-0348-00PCT-PRN(I-(E))the compound of Formula (I-(Z)) having the structure(I-(Z))the compound of Formula (II) having the structure(II) ; andthe compound of Formula R-(II) having the structureR-(II)

[0138] Embodiment 18. The method of embodiment 17, wherein the crystalline form of the compound is selected from:crystalline Form B of the compound of Formula (I-(E)) having the structureAttorney Docket No. 01183-0348-00PCT-PRN(i-(E)) ;crystalline Form 1 of the compound of Formula (II) having the structure(II) ; andcrystalline Form 1 of the compound of Formula R-(II) having the structureR-(II)

[0139] Embodiment 19. The method of embodiment 1, wherein the efflorescent solvate form of a compound is selected from the methylacetate solvate of the compound of Formula (I-(E)), the dimethylcarbonate solvate of the compound of Formula (I-(E)), the acetonitrile solvate of the compound of Formula (II), and the acetonitrile solvate of the compound of Formula R-(II)

[0140] Embodiment 20. The method of embodiment 18, wherein the X-ray powder diffraction (XRPD) pattern of crystalline Form B of the compound of Formula (I-(E)) comprises at least three characteristic peaks at two-theta values chosen from 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°.

[0141] Embodiment 21. The method of embodiment 20, wherein the X-ray powder diffraction (XRPD) pattern of crystalline Form B of the compound of Formula (I-(E)) comprises at least three characteristic peaks at two-theta values chosen from 5.2° ± 0.2°, 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°.

[0142] Embodiment 22. The method of any of the preceding embodiments, wherein the compound comprises at least 90% or more of a single crystalline form.Attorney Docket No. 01183-0348-00PCT-PRN

[0143] Embodiment 23. The method of any of the preceding embodiments, wherein the compound comprises at least 95% or more of a single crystalline form.

[0144] Embodiment 24. The method of any of the preceding embodiments, wherein the compound comprises 100% of a single crystalline form.

[0145] Embodiment 25. The method of any of the preceding embodiments, wherein in step a) the efflorescent solvate comprises molecules of a first solvent co-ordinated to said compound.

[0146] Embodiment 26. The method of any of the preceding embodiments, wherein in step b) the efflorescent solvate is desolvated by submitting the efflorescent solvate of the compound to an inert atmosphere saturated with a vapor of a second solvent

[0147] Embodiment 27. The method of embodiment 25 or 26, wherein the first solvent and the second solvent are different.

[0148] Embodiment 28. A method of preparing a highly pure crystalline form of a compound from an efflorescent solvate form of the compound comprising:a) preparing an efflorescent solvate of the compound, said efflorescent solvate comprising molecules of a first solvent co-ordinated to said compound; andb) desolvating said efflorescent solvate by submitting the efflorescent solvate form of the compound to an inert atmosphere saturated with a vapor of a second solvent;wherein the first solvent and the second solvent are different.

Claims

Attorney Docket No. 01183-0348-00PCT-PRN CLAIMSWhat is Claimed is:

1. A method of preparing a highly pure crystalline form of a compound from an efflorescent solvate form of the compound comprising:a) preparing an efflorescent solvate of the compoundb) submitting the efflorescent solvate form of the compound to an inert atmosphere saturated with a vapor of a solvent.

2. The method of claim 1, wherein the efflorescent solvate form of the compound and the vapor of a solvent are submitted to a closed system until the highly pure crystalline form is obtained.

3. The method of claim 1, wherein a continuous flow of the vapor of a solvent is submitted to the efflorescent solvate form of the compound through an open system until the highly pure crystalline form is obtained.

4. The method of claim 1, wherein the solvent has a boiling point that ranges from about 30 °C to about 105 °C.

5. The method of claim 1, wherein the solvent is a class III solvent.

6. The method of claim 5, wherein the class III solvent is selected from acetone, methylethyl ketone, ethyl ether, tert-butylmethyl ether, pentane, heptane, ethanol, 1 -propanol, 2-propanol, 2-butanol, ethyl formate, methylacetate, ethyl acetate, isopropyl acetate, propyl acetate, formic acid, and triethylamine.

7. The method of claim 6, wherein the class III solvent is selected from acetone and ethyl acetate.

8. The method of claim 7, wherein the class III solvent is acetone.

9. The method of claim 1, wherein the solvent is a class II solvent.Attorney Docket No. 01183-0348-00PCT-PRN 10. The method of claim 9, wherein the class II solvent is selected from acetonitrile, hexane, cyclohexane, methylcyclohexane, di chloromethane, chloroform, 1,2-dichloroethene, 1,2-dimethoxy ethane, 1,4-di oxane, methanol, and nitromethane.

11. The method of claim 10, wherein the class II solvent is selected from acetonitrile, chloroform, and methanol.

12. The method of claim 11, wherein the class II solvent is selected from acetonitrile and methanol.

13. The method of claim 1, wherein the pressure of the atmosphere is about 1 atm.

14. The method of claim 1, wherein the temperature of the atmosphere ranges from about 0 to about 40 °C.

15. The method of claim 1, wherein the temperature of the atmosphere is selected from about 5, about 20, and about 25 °C.

16. The method of claim 1, wherein the inert atmosphere comprises an inert gas selected from nitrogen, argon, xenon, helium, krypton, and neon.

17. The method of claim 1, wherein the compound is selected from:the compound of Formula (I) having the structurethe compound of Formula (I-(E)) having the structureAttorney Docket No. 01183-0348-00PCT-PRN(I-(E)) ;the compound of Formula (I-(Z)) having the structure(i-(Z)) ;the compound of Formula (II) having the structure(II) ; andthe compound of Formula R-(II) having the structureR-(II)18. The method of claim 17, wherein the crystalline form of the compound is selected from: crystalline Form B of the compound of Formula (I-(E)) having the structureAttorney Docket No. 01183-0348-00PCT-PRN(i-(E)) ;crystalline Form 1 of the compound of Formula (II) having the structure(II) ; andcrystalline Form 1 of the compound of Formula R-(II) having the structure"R-(II)19. The method of claim 1, wherein the efflorescent solvate form of a compound is selected from the methylacetate solvate of the compound of Formula (I-(E)), the dimethylcarbonate solvate of the compound of Formula (I-(E)), the acetonitrile solvate of the compound of Formula (II), and the acetonitrile solvate of the compound of Formula R-(II).

20. The method of claim 18, wherein the X-ray powder diffraction (XRPD) pattern of crystalline Form B of the compound of Formula (I-(E)) comprises at least three characteristic peaks at two-theta values chosen from 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°.

21. The method of claim 20, wherein the X-ray powder diffraction (XRPD) pattern of crystalline Form B of the compound of Formula (I-(E)) comprises at least three characteristic peaks at two-theta values chosen from 5.2° ± 0.2°, 10.8° ± 0.2°, 15.3° ± 0.2°, 16.3° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, and 22.9° ± 0.2°.Attorney Docket No. 01183-0348-00PCT-PRN 22. The method of any of the preceding claims, wherein the compound comprises at least 90% or more of a single crystalline form.

23. The method of any of the preceding claims, wherein the compound comprises at least 95% or more of a single crystalline form.

24. The method of any of the preceding claims, wherein the compound comprises 100% of a single crystalline form.

25. The method of any of the preceding claims, wherein in step a) the efflorescent solvate comprises molecules of a first solvent co-ordinated to said compound.

26. The method of any of the preceding claims, wherein in step b) the efflorescent solvate is desolvated by submitting the efflorescent solvate form of the compound to an inert atmosphere saturated with a vapor of a second solvent.

27. The method of claim 25 or 26, wherein the first solvent and the second solvent are different.

28. A method of preparing a highly pure crystalline form of a compound from an efflorescent solvate of the compound comprising:a) preparing an efflorescent solvate of the compound, said efflorescent solvate comprising molecules of a first solvent co-ordinated to said compound; andb) desolvating said efflorescent solvate by submitting the efflorescent solvate of the compound to an inert atmosphere saturated with a vapor of a second solvent;wherein the first solvent and the second solvent are different; optionallywherein the efflorescent solvate of the compound and the vapor of a second solvent are submitted to a closed system until the highly pure crystalline form is obtained; optionallywherein a continuous flow of the vapor of a second solvent is submitted to the efflorescent solvate of the compound through an open system until the highly pure crystalline form is obtained; optionallywherein the second solvent has a boiling point that ranges from about 30 °C to about 105 °C; optionallyAttorney Docket No. 01183-0348-00PCT-PRN wherein the second solvent is a class III solvent; optionallywherein the class III solvent is selected from acetone, methylethyl ketone, ethyl ether, tert-butylmethyl ether, pentane, heptane, ethanol, 1 -propanol, 2-propanol, 2-butanol, ethyl formate, methylacetate, ethyl acetate, isopropyl acetate, propyl acetate, formic acid, and triethylamine; orwherein the class III solvent is selected from acetone and ethyl acetate; orwherein the class III solvent is acetone; optionallywherein the second solvent is a class II solvent; optionallywherein the class II solvent is selected from acetonitrile, hexane, cyclohexane, methylcyclohexane, di chloromethane, chloroform, 1,2-di chloroethene, 1,2-dimethoxy ethane, 1,4-di oxane, methanol, and nitromethane; orwherein the class II solvent is selected from acetonitrile, chloroform, and methanol; orwherein the class II solvent is selected from acetonitrile and methanol; optionallywherein the pressure of the atmosphere is about 1 atm; optionallywherein the temperature of the atmosphere ranges from about 0 to about 40 °C; orwherein the temperature of the atmosphere is selected from about 5, about 20, and about 25 °C; optionallywherein the inert atmosphere comprises an inert gas selected from nitrogen, argon, xenon, helium, krypton, and neon.

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