(S)-Afollana Crystalline Form

Abstract

The present invention provides a crystalline form of a compound of formula (la) and a method for preparing the crystalline form. Also provided are a composition comprising the crystalline form and a crystalline form for treating or preventing parasitic infections in animals.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to US Provisional Application No. 62 / 482,175, filed on April 5, 2017, which is incorporated herein by reference. Field of the Invention

[0003] The present disclosure generally relates to solid forms of compounds of formula (Ia)

[0004] Background of the Invention

[0006] Polymorphs can have different physical and chemical (i.e. physicochemical) properties such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility and dissolution rate, and biological properties such as biological availability. It is still impossible to predict the physicochemical properties of one or more crystalline forms that can exist in a compound's solid state.

[0007] In addition, interest in single enantiomers of pharmacologically active compounds has increased in recent years due to their improved pharmacokinetic and biological properties. Therefore, there is a need for a method that can be used to prepare single enantiomers of afoxolan on a large scale. Generally, asymmetric processes for obtaining chiral molecules provide optically active molecules in enantiomerically enriched form rather than pure single enantiomers unless the process includes a resolution method. Therefore, there is also a need for a method that can be used to increase the enantiomeric purity of optically active (S)-afoxolan on a large scale.

[0008] Afoxolamide can exist as two enantiomeric configurations, namely the (S)-enantiomer, which is a compound of formula (Ia):

[0009]

[0010] and the (R)-enantiomer, which is a compound of formula (Ib):

[0011]

[0012] Furthermore, it is impossible to even predict whether the solid state of a compound may exist in more than one crystalline form.

[0013] US Patent Application No. 62 / 319,207, the priority document of US Patent Application No. 15 / 480,316, published as US 2017 / 0311601 A1 (incorporated herein by reference in its entirety), discloses compounds of formula (Ia) and methods thereof, as well as the use of the compounds as invertebrate pest control agents. A new solid form of the compound has now been discovered.

[0014] US Patent No. 8,410,153 (incorporated herein by reference) describes Afoxolana as being effective in treating or preventing parasitic infections or infestations in or on animals.

[0015] Join by reference

[0016] Any of the foregoing applications and all documents cited therein or during the prosecution thereof ("application cited documents") and all documents cited or referenced therein, and all documents cited or referenced herein ("herein cited documents") and all documents cited or referenced therein, as well as any manufacturer's guides, instructions, product manuals, and product leaflets for any products mentioned therein or in any document incorporated by reference herein, are incorporated herein by reference and may be used in the practice of the present invention. Citation or identification of any such document in this application is not an admission that the document may serve as prior art to the present invention. SUMMARY OF THE INVENTION

[0017] The present invention relates to solid forms of the compound of formula (Ia). More particularly, the present invention relates to crystalline forms of the compound of formula (Ia) designated Form I and Form II, and methods of preparing these crystalline forms.

[0018] The present invention also relates to a composition containing a solid form of a compound of formula (Ia); and a method for controlling invertebrate pests, comprising contacting the invertebrate pests or their environment with a biologically effective amount of a solid form of a compound of formula (Ia) or a composition containing a solid form of a compound of formula (Ia).

[0019] The specific features of the present invention will become more apparent from the following detailed description with reference to the accompanying examples. The following description will continue to discuss the problems and solutions provided by the present invention with respect to antiparasitic applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Shown is a powder X-ray diffraction pattern of Form I of the compound of Formula (Ia) showing absolute intensity counts plotted against 2θ reflection positions.

[0021] Figure 2 The differential scanning calorimetry thermogram of Form I of the compound of formula (Ia) is shown.

[0022] Figure 3 Shown is a powder X-ray diffraction pattern of Form II of the compound of Formula (Ia) showing absolute intensity counts plotted against 2θ reflection positions.

[0023] Figure 4 The differential scanning calorimetry thermogram of Form II of the compound of formula (Ia) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0025] The term "about" as used herein means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the described numerical value. Typically, the term "about" is used herein to modify a numerical value to be 10% above and below the value. Therefore, about 50% means a range of 45%-55%. The numerical range described herein by endpoints includes all numbers and fractions covered by the range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It should also be understood that all numbers and fractions thereof are presumed to be modified by the term "about".

[0026] The term "administering" as used herein refers to any method that delivers the compound or composition used in the present invention to the subject to be treated in a reasonable veterinary practice in a manner that allows effective prevention or treatment of parasitic infestation. For example, the compound or composition is administered via oral, parenteral, transdermal or topical routes. Topical administration includes, among other things, skin solutions (pour-ons or smears), sprays, baths, showers, splashes, powders, ointments, shampoos, creams, etc. Pour-on type skin solutions can be designed to deliver actives transdermally or distribute actives on the outside of the animal.

[0027] The term "anhydrate" or "anhydrous polymorph" or "anhydrous crystalline form" refers to a crystalline form that does not have water bound in the crystal lattice. However, the crystals may contain trace amounts of water or other solvents that are not bound in the crystal lattice.

[0028] The term "amorphous" as used herein for afoxolane refers to a solid state in which the afoxolane molecules exist in a disordered arrangement and do not form a recognizable lattice or unit cell. Amorphous afoxolane does not produce any characteristic crystalline peaks when subjected to X-ray powder diffraction.

[0029] The term "chemical purity" refers to the total level of the desired product. If a compound exists in enantiomeric form, "chemical purity" as used herein will include both enantiomeric forms when calculating the total level of the desired product. If a compound exists in the form of a solvate, "chemical purity" as used herein will include the solvate when calculating the total level of the desired product. Impurities can exist in the form of, for example, undesirable process reagents, process intermediates, degradation products, or oxidation products. In a specific embodiment, high chemical purity refers to a chemical purity greater than 90%, particularly greater than 92.5%, 95%, 96%, 97%, 98%, 99%, 99.9% and including 100%. Purity can be measured by various techniques including HPLC analysis.

[0030] The term "effective amount" as used herein refers to a sufficient amount of a crystalline form of a compound of formula (Ia) to eradicate or reduce the number of parasite infestations in an animal. In certain embodiments, the effective amount of the active agent achieves at least 70% efficacy against the target parasite. In other embodiments, the effective amount of the crystalline form of the present invention achieves at least 80%, or at least 90% efficacy against the target pest. Preferably, the effective amount of the crystalline form of the present invention will achieve at least 95%, at least 98% or 100% efficacy against the target parasite.

[0031] The terms "enantiomer" and "enantiomeric" refer to molecules that are non-superimposable on their mirror images and are therefore optically active wherein an enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light by the same degree in the opposite direction.

[0032] The term "enantiomeric excess" or "ee" as used herein refers to the difference between the amount of one enantiomer and the amount of the other enantiomer present in the product mixture. The enantiomeric excess values ​​in each of the examples provided below indicate the relative amounts of each enantiomer. This value is defined as the difference in the relative percentages of the two enantiomers. Thus, for example, in the case where the percentage of the (S)-enantiomer of the compound of the invention is 97.5% and the percentage of the (R)-enantiomer is 2.5%, the enantiomeric excess of the (S)-enantiomer is 95%.

[0033] The term "enantiomerically pure" or "enantiomeric purity" as used herein is a measure of the extent to which one enantiomer is present in excess over the other in a mixture of enantiomers. For example, a mixture of 99% (S)-enantiomer and 1% (R)-enantiomer has an enantiomeric purity of 99% of the (S)-enantiomer. Enantiomeric purity is preferably at least 95% or at least 98%, more preferably at least about 99% enantiomeric purity. In yet another embodiment enantiomeric purity is from about 99.90% to about 100% enantiomeric purity.

[0034] The term "isolated" as used herein in reference to the solid state forms of afoxolane of the present disclosure corresponds to the solid state form of afoxolane being physically separated from the solution from which the solid state form was formed.

[0035] The term "solvent volume" as used herein refers to the volume of solvent expressed in liters at ambient temperature used to dissolve 1 kg of solid material. For example, 5 volumes of solvent used for 1 kg of feedstock in a process would be equivalent to 5 liters of solvent.

[0036] As used herein, "lower alkyl alcohol" refers to a branched or straight-chain C1-C6 alkyl group containing one hydroxyl group, such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, hexanol, etc.; preferred lower alkyl alcohols include ethanol, propanol and isopropanol; most preferred is ethanol.

[0037] As used herein, "aliphatic solvent" refers to a linear, branched or cyclic aliphatic solvent containing up to 9 carbon atoms. Aliphatic solvents include alkane, alkene or alkyne solvents. Non-limiting examples of aliphatic solvents include pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc.

[0038] The term "ansolvate polymorph" or "ansolvate crystalline form" refers to a crystalline form that has no solvent bound in the crystal lattice, such as an anhydrous polymorph. However, the crystals may contain trace amounts of solvent that is not bound in the crystal lattice.

[0039] The term "or" as used herein and unless expressly described to the contrary, refers to an inclusive or rather than an exclusive or. For example, any of the following situations satisfies the condition A or B: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0040] The term "pharmaceutically acceptable carrier" as used herein may include any of a variety of solvents, diluents, or other liquid or solid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., which are suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, Eighteenth Edition, EW Martin (Mack Publishing Co., Easton, PA 1990) discloses various carriers used in the preparation of pharmaceutical compositions and known techniques for preparing them. Except for any conventional carrier medium that is incompatible with compound (Ia) such as producing any undesirable biological effect or interacting with any other component of the pharmaceutical composition in a harmful manner, it is expected to be used within the scope of the present invention. Some examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycerol, glycerides, glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; ethanol, and phosphate buffered solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0041] The term "polymorph" as used herein refers to the different crystal structures (solvated or unsolvated forms) in which a compound is able to crystallize.

[0042] The terms "racemic" or "racemate" and other similar terms refer to generally equimolar proportions of (S)-afoxolane and (R)-afoxolane.

[0043] The term "seed" as used herein can be used as a noun to describe one or more crystals of crystallized afoxolane (e.g., polymorph Form I). For example, if it is desired to produce crystallized (S)-afoxolane polymorph Form I, the seed crystals to be used to enhance the crystallization process can be (S)-afoxolane polymorph Form I crystals. The term "seed" or "seeding" can also be used as a verb to describe the introduction of the one or more afoxolane crystals (e.g., polymorph Form I) into an environment (including but not limited to, for example, a solution, mixture, suspension or dispersion) thereby causing the formation of more identical afoxolane crystals (e.g., polymorph Form I).

[0044] The terms "solvate," "solvate polymorph" or "solvate crystal form" refer to a crystalline form having a solvate bound in the crystal lattice.

[0045] The phrase "substantially pure crystalline form" is understood to mean a material that does not contain detectable amounts of other crystalline forms or amorphous forms by typical analytical methods, i.e., contains less than 10% of other crystalline forms, unless otherwise specified, such as X-ray powder diffraction and / or solid-state infrared absorption. Preferably, there is less than 5%, more preferably less than 2%, and even more preferably less than 1% of any other crystalline form or amorphous form of the compound.

[0046] When used to describe the data in a diffraction pattern, spectrum or figure, the term "substantially similar" means that the diffraction pattern, spectrum or figure data encompasses all diffraction patterns, spectra or figure data that vary within acceptable experimental boundaries, which are known to those skilled in the art. The experimental boundaries vary depending on the type of data in the diffraction pattern, spectrum or figure, but are still known to those skilled in the art.

[0047] The term "treating" or "treatment" or "therapy" as used herein contemplates that the compounds or compositions of the present invention are applied or administered to an animal having a parasitic infestation for the purpose of eradicating the parasite or reducing the number of parasites infecting the animal being treated. It should be noted that the compositions of the present invention can be used to prevent the above-mentioned parasitic infestations.

[0048] It should also be noted that in this disclosure and particularly in the claims or paragraphs, terms such as "comprising," "containing," "including," etc. can have the meanings assigned to them by US patent law; for example, they can mean "covering," "containing," "having," etc.; and terms such as "consisting essentially of..." and "consisting essentially of..." have the meanings assigned to them by US patent law, for example, they allow for elements not expressly described but exclude elements that exist in the prior art or that affect the basic or novel characteristics of the invention.

[0049] As described herein, the compound of formula (Ia) can be in a crystalline form that can exist as one or more polymorphs, including solvate forms. Generally speaking, polymorphs (also known in the art as polymorph forms, polymorphic forms or crystalline forms) differ in their X-ray powder diffraction patterns, spectra, physicochemical and pharmacokinetic properties, and thermodynamic stability. In addition, as is known for polymorphs, polymorphs can exhibit different physical properties such as crystal shape, chemical stability, dissolution rate, and bioavailability. Accordingly, a specific polymorph can represent the most suitable form for a given application, including but not limited to use in a specific administration form such as a suspension, ointment, tablet or capsule, or for preparing a pharmaceutical form having excellent pharmacokinetic properties.

[0050] Depending on the desired use of the (S)-afolan solid form, the processing conditions may tend to select a specific solid form or a specific combination of the solid forms. Using a solvated crystalline form instead of Form I or Form II in the composition eliminates the processing step of the process, i.e., desolvation, which would otherwise be performed by desolvation of the solvated crystalline form. However, in the pharmaceutical or veterinary fields, certain solvents are not allowed to exceed a threshold level for toxicity considerations and must be removed in order to be used in products administered to humans or animals. Accordingly, it is not possible to use certain solvates in these fields. In addition, it is difficult to remove solvents from a compound crystalline form in which the solvent is part of the crystal lattice. The desolvation step can be eliminated in the case of a non-solvated crystalline solid form of the compound, resulting in an improved compound preparation process. For example, if Form I or Form II is directly crystallized from an appropriate solvent without the need for the preparation of an intermediate solvated crystalline form and the intervening step of desolvation, a significant cost saving and more efficient process is achieved. See, e.g., E. Shefter and T. Higuchi, who have measured the relative dissolution rates of several crystalline solvated and non-solvated forms of important drugs, J. Pharm. Sci., 52 (8), (1963), 781-91. In the case of the compound of formula (Ia) as shown below, it was found that the crystallization of the compound from common process solvents, including aromatic solvents such as toluene, made it difficult to separate the compound as a solvate and the non-solvated form of the compound of formula (Ia). However, the solvate cannot be used directly in pharmaceutical or veterinary applications without significantly reducing the solvent level, which is commercially unfeasible. Therefore, it was found that the non-solvated forms I and II of the compound of formula (Ia) represent a significant improvement in the development of effective parasiticidal compositions for the treatment or prevention of parasiticidal infestations in animals.

[0051] In another embodiment of the present invention, the exact molar ratio of the components of the solvate, including the hydrate, has some variability, which depends on various conditions understood by those skilled in the art. For example, the molar ratio of the components in the solvate provides information to those skilled in the art that the general relative amounts of the components of the solvate and that the molar ratios can vary from the stated range by about plus or minus 20% in many cases. For example, a molar ratio of 1:1 is understood to include ratios of 1:0.8 and 1:1.2 and all individual ratios therebetween.

[0052] The present invention provides (S)-afollana Form I substantially free of bound organic solvent and free of bound water, as characterized by X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC) as described in Example 3.

[0053] The present invention also provides (S)-afollana Form II substantially free of bound organic solvent and free of bound water, as characterized by X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC) as described in Example 3.

[0054] Furthermore, the present invention provides a process for preparing (S)-afoxane Form I and / or (S)-afoxane Form II or a mixture thereof, comprising crystallizing the compound from a solvent mixture comprising an aliphatic solvent and a co-solvent.

[0055] Embodiments of the invention described in the Summary of the Invention include those described below.

[0056] Embodiment (1): A crystal of a compound of formula (Ia), designated as Form I,

[0057]

[0058] wherein the crystals are characterized in having an X-ray powder diffraction pattern comprising 3, 4, 5, 6, 7 or more peaks selected from the group consisting of 10.03°, 10.48°, 13.16°, 15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52°, and 28.13° 2θ ± 0.2 as measured on a diffractometer using Cu-Kα radiation.

[0059] Embodiment (2): According to the crystal of the compound of formula (Ia) according to embodiment (1), it is characterized in that it has an X-ray powder diffraction pattern, which contains 3 or more peaks selected from the following: 10.03°, 10.48°, 13.16°, 20.16°, and 22.15°2θ±0.2, as measured on a diffractometer using Cu-Kα radiation.

[0060] Embodiment (3): A crystal of the compound of formula (Ia) according to embodiment (1), characterized in that it has substantially similar Figure 1 X-ray powder diffraction pattern of .

[0061] Embodiment (4): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (3), characterized in that it has a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 146°C and starting at about 143°C, measured with a heating rate of 5°C / min.

[0062] Embodiment (5): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (4), characterized by having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 61.7 J / g.

[0063] Embodiment (6): A crystal of a compound of formula (Ia) according to any one of Embodiments (1) to (5), characterized in that it has substantially similar Figure 2 Differential scanning calorimetry thermogram of .

[0064] Embodiment (7): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (6), wherein the crystalline form is isolated.

[0065] Embodiment (8): The crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (7), wherein the crystalline form is non-solvated.

[0066] Embodiment (9): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (8), which is enantiomerically pure.

[0067] Embodiment (10): A crystal of a compound of formula (Ia) according to any one of Embodiments (1) to (9), having a chemical purity of at least about 95%.

[0068] Embodiment (11): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (10), having a chemical purity of at least about 98%.

[0069] Embodiment (12): A crystal of a compound of formula (Ia) according to any one of Embodiments (1) to (10), having a chemical purity of at least about 99%.

[0070] Embodiment (13): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (12), having a chemical purity of about 98.00% to about 99.00%.

[0071] Embodiment (14): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (13), having a chemical purity of about 99.00% to about 99.95%.

[0072] Embodiment (15): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (13), having a chemical purity of about 99.00% to about 100%.

[0073] Embodiment (16): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (15), having a chemical purity of about 99.90%.

[0074] Embodiment (17): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (16), having an enantiomeric purity of about 98.0 to about 99.0%.

[0075] Embodiment (18): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (17), having an enantiomeric purity of about 99.0 to about 100%.

[0076] Embodiment (19): A crystal of the compound of formula (Ia) according to any one of embodiments (1) to (18), having a chemical purity of about 99.00% to about 99.95% and an enantiomeric purity of about 99.0 to about 100%.

[0077] Embodiment (20): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (19), having a chemical purity of about 99.90% and an enantiomeric purity of about 99.90%.

[0078] Embodiment (21): A crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (20) in a substantially pure crystalline form.

[0079] Embodiment (22): A crystalline form of (S)-afoxolamide that is biologically equivalent to the crystal of the compound of formula (Ia) according to any one of Embodiments (1) to (21).

[0080] Embodiment (23): A pharmaceutical composition comprising a crystal of a compound of formula (Ia) according to any one of Embodiments (1) to (22), and at least one pharmaceutically acceptable excipient.

[0081] Embodiment (24): A composition comprising a crystal of a compound of formula (Ia) according to any one of embodiments (1) to (22), wherein the crystal of the compound of formula (Ia) is mixed with one or more different polymorphic forms or amorphous forms of the compound of formula (Ia).

[0082] Embodiment (25): A composition according to embodiment (24), wherein the different polymorphic form is Form II.

[0083] Embodiment (26): A composition according to embodiment (24), wherein the crystal of the compound of formula (Ia) is mixed with the amorphous form of the compound of formula (Ia).

[0084] Embodiment (27): A pharmaceutical composition according to any one of embodiments (23) to (26), wherein the composition comprises at least about 50.0% by weight of crystals of the compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0085] Embodiment (28): A pharmaceutical composition according to any one of embodiments (23) to (27), wherein the composition comprises at least about 70% by weight of crystals of a compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0086] Embodiment (29): A pharmaceutical composition according to any one of embodiments (23) to (28), wherein the composition comprises at least about 80% by weight of crystals of a compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0087] Embodiment (30): A pharmaceutical composition according to any one of embodiments (23) to (29), wherein the composition comprises at least about 90% by weight of crystals of a compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0088] Embodiment (31): A pharmaceutical composition according to any one of embodiments (23) to (28), wherein the composition comprises at least about 95% by weight of crystals of a compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0089] Embodiment (32): A pharmaceutical composition according to any one of embodiments (23) to (31), wherein the composition comprises at least about 99.0% by weight of crystals of the compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0090] Embodiment (33): A method for preparing a crystal of a compound of formula (Ia) according to any one of embodiments (1) to (22), comprising:

[0091] (a) heating a mixture of toluene solvate of (S)-afoxanal in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic aliphatic solvent (e.g., pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc.) or an alcohol, or a combination thereof, until dissolution has occurred;

[0092] (b) optionally adding a co-solvent;

[0093] (c) lowering the temperature of the solvent system to induce nucleation;

[0094] (d) maintaining the mixture at a temperature below the temperature at which nucleation begins; and

[0095] (e) isolating crystals of the compound of formula (Ia) thus precipitated.

[0096] Embodiment (34): A method according to embodiment (33), wherein the co-solvent is isobutyl ketone or acetone.

[0097] Embodiment (35): A method according to embodiment (33), wherein the aliphatic solvent is a C1-C8 linear, branched or cyclic alkane solvent.

[0098] Embodiment 36: A method according to any one of embodiments (33) to (35), wherein the alcohol is a lower alkyl alcohol.

[0099] Embodiment (37): A method according to any one of embodiments (33) to (36), wherein the alcohol is ethanol.

[0100] Embodiment (38): A method according to any one of embodiments (33) to (37), wherein the solvent is a mixture comprising ethanol and cyclohexane.

[0101] Embodiment (39): A method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 10:90 to about 99:1 (v / v) ethanol:cyclohexane.

[0102] Embodiment 40: A method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 1:99 to about 25:75 (v / v) ethanol:cyclohexane.

[0103] Embodiment 41: A method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 3:97 to about 10:90 (v / v) ethanol:cyclohexane.

[0104] Embodiment (42): A method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 5:95 to about 10:90 (v / v) ethanol:cyclohexane.

[0105] Embodiment (43): A method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 8:92 (v / v) ethanol:cyclohexane.

[0106] Embodiment (44): The method according to any one of embodiments (33) to (43), comprising seeding with enantiomerically pure (S)-afoxolane Form I crystals.

[0107] Embodiment (45): A method according to any one of embodiments (33) to (44), wherein the heating is to about 50 to about 80 degrees Celsius.

[0108] Embodiment (46): A method according to any one of embodiments (33) to (45), wherein the temperature is reduced to about 10 degrees Celsius or less.

[0109] Embodiment (47): A method according to any one of embodiments (33) to (46), wherein the temperature is reduced to a temperature of about 5 degrees Celsius or less.

[0110] Embodiment (48): A method according to any one of embodiments (33) to (47), wherein the rate of reducing the temperature is about 3 degrees Celsius per hour.

[0111] Embodiment (49): A method for preparing the (S)-Afollana Form I of Embodiment 1, comprising:

[0112] (a) heating a mixture of toluene solvate of (S)-afoxolane having an enantiomeric purity of ≥ 97% in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic alkane solvent or an alcohol or a combination thereof, until dissolution has occurred;

[0113] (b) optionally adding a co-solvent;

[0114] (c) lowering the temperature of the solvent system to induce nucleation;

[0115] (d) maintaining the mixture at a temperature below the temperature at which nucleation begins; and

[0116] (e) isolating the (S)-afollana Form I thus precipitated.

[0117] Embodiment (50): A method according to any one of embodiments (33) to (49), wherein the isolated crystals of the compound of formula (Ia) are enriched in the (S)-afoxanal enantiomer.

[0118] Embodiment (51): (S)-Afollana crystalline form prepared by the method according to any one of Embodiments (33) to (50).

[0119] Embodiment (52): The (S)-Afollana crystalline form disclosed in any embodiment.

[0120] Embodiment (53): A method for treating or preventing a parasitic infection or infestation in an animal, comprising administering to the animal an effective amount of the (S)-afoxanol crystalline form of any one of embodiments (1) to (22) or embodiment (52) or a composition of any one of embodiments 23-32.

[0121] Embodiment (54): A crystal of a compound of formula (Ia), designated Form II,

[0122]

[0123] wherein the crystals are characterized by having an X-ray powder diffraction pattern comprising 3, 4, 5, 6, 7 or more peaks selected from the group consisting of 5.99°, 12.99°, 15.80°, 18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11° and 29.00° 2θ±0.2 as measured on a diffractometer using Cu-Kα radiation.

[0124] Embodiment (55): A crystal of a compound of formula (Ia) according to embodiment (54), wherein the crystal is characterized in having an X-ray powder diffraction pattern comprising 3 or more peaks selected from the following: 5.99°, 12.99°, 15.80°, 22.17°, 26.11° 2θ±0.2, as measured on a diffractometer using Cu-Kα radiation.

[0125] Embodiment (56): A crystal of a compound of formula (Ia) according to any one of embodiments (54) or (55), characterized in that it has substantially similar Figure 3 X-ray powder diffraction pattern of .

[0126] Embodiment (57): Crystals of a compound of formula (Ia) according to any one of embodiments (54) to (56), characterized in that it has a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 149°C and starting at about 146°C, measured with a heating rate of 5°C / min.

[0127] Embodiment (58): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (57), characterized by having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 65.7 J / g.

[0128] Embodiment (59): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (58), characterized in that it has substantially similar Figure 4 Differential scanning calorimetry thermogram of .

[0129] Embodiment (60): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (59), wherein the crystalline form is isolated.

[0130] Embodiment (61): The crystal of the compound of formula (Ia) according to any one of embodiments (54) to (60), wherein the crystalline form is non-solvated.

[0131] Embodiment (62): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (61), which is enantiomerically pure.

[0132] Embodiment (63): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (62), having a chemical purity of at least about 95%.

[0133] Embodiment (64): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (63), having a chemical purity of at least about 98%.

[0134] Embodiment (65): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (64), having a chemical purity of at least about 99%.

[0135] Embodiment (66): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (65), having a chemical purity of about 98.00% to about 99.00%.

[0136] Embodiment (67): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (66), having a chemical purity of about 99.00% to about 99.95%.

[0137] Embodiment (68): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (67), having a chemical purity of about 99.00% to about 100%.

[0138] Embodiment (69): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (68), having a chemical purity of about 99.90%.

[0139] Embodiment (70): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (69), having an enantiomeric purity of about 98.0 to about 99.0%.

[0140] Embodiment (71): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (70), having an enantiomeric purity of about 99.0 to about 100%.

[0141] Embodiment (72): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (70), having a chemical purity of about 99.00% to about 99.95% and an enantiomeric purity of about 99.0 to about 100%.

[0142] Embodiment (73): A crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (72), having a chemical purity of about 99.90% and an optical purity of about 99.90%.

[0143] Embodiment (74): A crystal of the compound of formula (Ia) according to any one of embodiments (54) to (73) in a substantially pure crystalline form.

[0144] Embodiment (75): A (S)-afollana crystalline form that is biologically equivalent to the crystal of the compound of formula (Ia) according to any one of embodiments (54) to (74).

[0145] Embodiment (76): A pharmaceutical composition comprising a crystal of a compound of formula (Ia) according to any one of embodiments (54) to (75), and at least one pharmaceutically acceptable excipient.

[0146] Embodiment (77): A composition comprising a crystal of a compound of formula (Ia) according to embodiment (76), wherein the crystal of the compound of formula (Ia) is mixed with one or more different polymorphic forms or amorphous forms of the compound of formula (Ia).

[0147] Embodiment (78): A composition according to embodiment (77), wherein the different polymorphic form is Form I.

[0148] Embodiment (79): A composition according to embodiment (77), wherein the crystal of the compound of formula (Ia) is mixed with the amorphous form of the compound of formula (Ia).

[0149] Embodiment (80): A pharmaceutical composition according to any one of embodiments (76) to (79), wherein the composition comprises at least 50.0% by weight of crystals of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0150] Embodiment (81): A pharmaceutical composition according to any one of embodiments (76) to (80), wherein the composition comprises at least about 70% by weight of crystals of a compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0151] Embodiment (82): A pharmaceutical composition according to any one of embodiments (76) to (81), wherein the composition comprises at least about 80% by weight of crystals of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0152] Embodiment (83): A pharmaceutical composition according to any one of embodiments (76) to (80), wherein the composition comprises at least about 90% by weight of crystals of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0153] Embodiment (84): A pharmaceutical composition according to any one of embodiments (76) to (83), wherein the composition comprises at least about 95% by weight of crystals of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0154] Embodiment (85): A pharmaceutical composition according to any one of embodiments (76) to (84), wherein the composition comprises at least 99.0% by weight of crystals of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0155] Embodiment (86): A method for preparing a crystal of a compound of formula (Ia) according to embodiment (54), comprising:

[0156] (a) heating a mixture of toluene solvate of (S)-afoxanal in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic aliphatic solvent (e.g. pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc.) or an alcohol or a mixture thereof until dissolution has occurred;

[0157] (b) optionally adding a co-solvent;

[0158] (c) lowering the temperature of the solvent system to induce nucleation;

[0159] (d) maintaining the mixture at a temperature below the temperature at which nucleation begins; and

[0160] (e) isolating crystals of the compound of formula (Ia) thus precipitated.

[0161] Embodiment (87): A method according to embodiment (86), wherein the co-solvent is isobutyl ketone or acetone.

[0162] Embodiment (88): A method according to any one of embodiments (86) to (87), wherein the alcohol is ethanol.

[0163] Embodiment (89): A method according to any one of embodiments (86) to (88), wherein the solvent is a mixture comprising ethanol and cyclohexane.

[0164] Embodiment (90): The method of embodiment 89, wherein the mixture of ethanol and cyclohexane is about 15:85 to about 99:1 (v / v) ethanol:cyclohexane.

[0165] Embodiment 91: A method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is about 1:99 to about 25:75 (v / v) ethanol:cyclohexane.

[0166] Embodiment 92: A method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is about 3:97 to about 10:90 (v / v) ethanol:cyclohexane.

[0167] Embodiment (93): A method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is about 5:95 to about 10:90 (v / v) ethanol:cyclohexane.

[0168] Embodiment (94): A method according to any one of embodiments (89) to (91), wherein the mixture of ethanol and cyclohexane is about 15:85 (v / v) ethanol:cyclohexane.

[0169] Embodiment (95): The method according to any one of embodiments (86) to (94), comprising seeding with enantiomerically pure (S)-afoxolane Form II.

[0170] Embodiment (96): A method according to any one of embodiments (86) to (95), wherein the heating is to about 50 to about 80 degrees Celsius.

[0171] Embodiment (97): A method according to any one of embodiments (86) to (96), wherein the temperature is reduced to a temperature of about 10 degrees Celsius or less.

[0172] Embodiment (98): A method according to any one of embodiments (86) to (97), wherein the temperature is reduced to a temperature of about 5 degrees Celsius or less.

[0173] Embodiment (99): A method according to any one of embodiments (86) to (98), wherein the rate of reducing the temperature is about 3 degrees Celsius per hour.

[0174] Embodiment (100): A method for preparing (S)-Afollana Form II according to embodiment (54), comprising:

[0175] (a) heating a mixture of a toluene solvate of (S)-afoxanal having an enantiomeric purity of about 97% to about 100% in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic alkane or alcohol, or a mixture thereof, until dissolution has occurred;

[0176] (b) optionally adding a co-solvent;

[0177] (c) lowering the temperature of the solvent system to induce nucleation;

[0178] (d) maintaining the mixture at a temperature below the temperature at which nucleation begins; and

[0179] (e) isolating the thus precipitated (S)-afollana Form II.

[0180] Embodiment (101): (S)-Afollana crystalline form prepared by the method according to any one of embodiments (86) to (100).

[0181] Embodiment (102): A method for treating or preventing a parasitic infection or infestation in an animal, comprising administering to the animal an effective amount of a crystalline form of formula (Ia) according to any one of embodiments (54) to (75) or a composition according to embodiments 76 to 85.

[0182] In yet another embodiment, the present invention provides (S)-Afollana Form I, which exhibits one or more of the characteristic peaks shown in Table 1 below, the peaks being expressed as 2-theta (2θ) ± 0.2 degrees.

[0183] In yet another embodiment, the present invention provides (S)-Afollana Form I, which exhibits at least 7 of the characteristic peaks shown in one or more positions in Table 1 below, the peaks being expressed as 2-theta (2θ) ± 0.2 degrees.

[0184] In another embodiment, the present invention provides (S)-Afollana Form I, which is described in the Examples and shown in Figure 2 endothermic curve.

[0185] In another embodiment, the present invention provides (S)-Afoxolana Form I and (S)-Afoxolana Form II and / or amorphous (S)-Afoxolana in combination therewith. In another embodiment, the present invention provides a pesticide composition or a parasiticidal composition comprising (S)-Afoxolana Form I alone or (S)-Afoxolana Form I in combination with one or more additional active agents, and an agriculturally or pharmaceutically acceptable carrier or diluent, wherein at least 80% of the (S)-Afoxolana solid form is Form I.

[0186] In one embodiment, the present invention provides (S)-Afollana Form II, which exhibits one or more of the characteristic peaks shown in Table 1 below, wherein the peaks are expressed as 2-theta (2θ) ± 0.2 degrees.

[0187] In another embodiment, the present invention provides (S)-Afollana Form II, which exhibits at least 7 of the characteristic peaks shown in one or more positions in Table 1 below, wherein the peaks are expressed as 2-theta (2θ) ± 0.2 degrees.

[0188] In another embodiment, the present invention provides (S)-Afollana Form II, which is described in the Examples and shown in Figure 4 endothermic curve.

[0189] In another embodiment, the present invention provides (S)-Afoxolana Form II and (S)-Afoxolana Form I and / or amorphous (S)-Afoxolana in combination therewith. In another embodiment, the present invention provides a pesticide composition or a parasiticidal composition comprising (S)-Afoxolana Form II alone or (S)-Afoxolana Form II in combination with one or more additional active agents, and an agriculturally or pharmaceutically acceptable carrier or diluent, wherein at least 80% of the (S)-Afoxolana solid form is Form II.

[0190] In other embodiments, the polymorph may contain impurities. Non-limiting examples of impurities are residual organic and inorganic molecules such as solvents, water or salts. In one embodiment, the polymorph contains less than 10% by weight total impurities.

[0191] In yet another embodiment, the polymorph contains less than 5%, less than 4%, less than 3%, less than 2% total impurities by weight. In yet another embodiment, the polymorph contains less than 1% total impurities by weight. In yet another embodiment, the polymorph is substantially free of impurities.

[0192] In yet another embodiment, the present invention provides (S)-Afollana Form I, wherein at least 90% of the solid form is in Form I form.

[0193] In yet another embodiment, the present invention provides crystalline (S)-afoxolane, wherein at least 80% of the solid form is in the crystalline toluene solvate form.

[0194] In yet another embodiment, the present invention provides (S)-Afoxanal Form II, wherein at least 90% of the solid form is in the Form II form.

[0195] In a specific embodiment, polymorph Form I is in a substantially pure crystalline form. In another embodiment, polymorph Form I has less than 10% of other crystalline forms. Preferably, there is less than 5%, more preferably less than 2%, and even more preferably less than 1% of any other crystalline form or amorphous form of the compound.

[0196] Similarly, in a specific embodiment, polymorph Form II is a substantially pure crystalline form. In another embodiment, polymorph Form II has less than 10% of other crystalline forms. Preferably, there is less than 5%, more preferably less than 2%, and even more preferably less than 1% of any other crystalline form or amorphous form of the compound.

[0197] In one embodiment, the crystalline form I and / or crystalline form II of (S)-Afolan can be prepared as follows: (S)-Afolan can be crystallized from a combination of a lower alcohol solvent and an aliphatic solvent according to methods known in the art. In another embodiment, the form I and / or form II of (S)-Afolan can be prepared as follows: the compound is crystallized from an alkyl ester solvent or a solvent mixture containing an alkyl ester solvent. The alkyl ester solvent includes but is not limited to acetic acid alkyl ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, etc. In yet another embodiment, the form I and / or form II of (S)-Afolan can be prepared as follows: the compound is crystallized from a nitrile solvent or a solvent mixture containing a nitrile solvent. The nitrile solvent includes but is not limited to acetonitrile. In yet another embodiment, the form I and / or form II of (S)-Afolan can be prepared as follows: the compound is crystallized from a combination of an aliphatic solvent and an alkyl ester solvent. In yet another embodiment, the form I and / or form II of (S)-Afolan can be prepared as follows: the compound is crystallized from a nitrile solvent including acetonitrile.

[0198] In another embodiment, (S)-Afoxolane Form I and / or (S)-Afoxolane Form II can be crystallized from water, ethanol, isopropanol, methanol, toluene, dichloromethane, hexane, cyclohexane, diisopropyl ether or butyl chloride or a mixture thereof.

[0199] Aliphatic solvents are linear, branched, cyclic primary, secondary or tertiary hydrocarbons and include, but are not limited to, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc. In another embodiment, (S)-Afoxolane Form I and / or Form II can be prepared by crystallizing (S)-Afoxolane from a solvent combination of a lower alcohol solvent and a cycloalkyl solvent. In another embodiment, (S)-Afoxolane Form I and / or Form II can be prepared by crystallizing (S)-Afoxolane from a solvent combination of an alkyl ester solvent and an aliphatic solvent. In yet another embodiment, (S)-Afoxolane Form I and / or Form II can be prepared by crystallizing (S)-Afoxolane from a solvent combination of a nitrile solvent and an aliphatic solvent.

[0200] In one embodiment of the method, the ratio of lower alcohol solvent to aliphatic solvent is about 1:99 (v / v) to about 25:75 (v / v) of lower alcohol: aliphatic solvent. In another embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 2:98 (v / v) to about 20:80 (v / v). In yet another embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 4:96 to about 15:85. In yet another embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 5:95 to about 10:90. In one embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 6:94 (v / v). In yet another embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 7:93 (v / v). In yet another embodiment, the ratio of lower alcohol solvent to aliphatic solvent is about 8:92 (v / v).

[0201] The total volume of solvent can vary during the process. However, using too much solvent can affect the process yield. In contrast, using too little solvent can result in a lower quality product because co-crystals or impurities in another solid form are more likely to appear. In one embodiment, about 7 volumes to about 30 volumes of total solvent or solvent mixture can be used. In another embodiment, about 10 volumes to about 25 volumes of total solvent or solvent mixture can be used for crystallization. In another embodiment, about 12 volumes to about 20 volumes of solvent or solvent mixture can be used. In other embodiments, about 12 volumes to 18 volumes, about 13 volumes to about 17 volumes or about 14 volumes to about 16 volumes can be used. In one embodiment, about 15 volumes of total solvent or solvent mixture can be used to crystallize (S)-Afolan Form I or Form II.

[0202] The source of (S)-Afoxolana may be amorphous (S)-Afoxolana or other solid forms of the compound. Alternatively, a solution of (S)-Afoxolana in another solvent may be used. In one embodiment, the enantiomeric purity of the (S)-Afoxolana used in the process is at least about 90% (e.g., a 90:10 ratio of (S)-enantiomer:(R)-enantiomer). In another embodiment, the enantiomeric purity of the (S)-Afoxolana is at least about 95%. Preferably, the enantiomeric purity of the (S)-Afoxolana used in the process is at least about 98%. In one embodiment, the (S)-Afoxolana is dissolved in a suitable solvent at a concentration such that the mixture is a suspension at or below ambient temperature and a solution at an elevated temperature, and then slowly cooled to induce crystallization from the solvent. In another embodiment, the (S)-Afoxolana is dissolved in a solvent in which it is suitably soluble, and then a second solvent in which the compound is less soluble is slowly added to induce crystallization.

[0203] Optionally, seed crystals can be added to promote crystallization. The seed crystals should be enriched in the desired enantiomer to direct crystallization to that enantiomer. The enantiomeric excess of the seed crystals can be the same or different from the afoxol solution to which it is added, but a high enantiomeric excess is preferred, such as at least 90% ee or higher. Similarly, the seed crystals can be the desired racemic compound to direct crystallization to that racemic compound.

[0204] In an embodiment of the present invention, seed crystals may be added to induce crystallization of (S)-Afolan. The amount of (S)-Afolan seed crystals added is such that it exceeds the saturation amount in the solvent used, so that undissolved seed crystals are present in the solution. Those skilled in the art will appreciate that the seeding temperature depends on the solvent used, and also on the solvent ratio if a solvent mixture is used. In one embodiment using a solvent mixture comprising an aliphatic solvent and a lower alcohol solvent, seeding may be performed at a temperature range of about 50°C to about 60°C. In another embodiment, seeding may be performed at a temperature of about 52°C to about 58°C. In yet another embodiment, seeding may be performed at a temperature of about 53°C to 57°C. In yet another embodiment, seeding may be performed at a temperature of about 55°C.

[0205] The mixture is allowed to stand at a temperature of about 10°C to about 65°C, preferably about 10°C to about 60°C or about 10°C to about 30°C. In one embodiment, the mixture is aged at a temperature of about 25°C to about 45°C after seeding, then heated to a temperature of about 50°C to about 60°C and aged again, followed by further cooling to separate the crystallized product. This cycle can be repeated. The heating / cooling cycle can be used to increase the size of the formed crystals; however, the process is not absolutely required. In one embodiment, the mixture is aged at the desired temperature for at least about 15 minutes. In other embodiments, the mixture is aged for at least about 30 minutes or at least about 1 hour. In other embodiments, the mixture is aged at the desired temperature for at least about 2 hours, at least about 3 hours or longer. If the aging time is not enough to achieve equilibrium solubility at the aging temperature, the length of the aging time can affect the process yield; however, as long as the mixture is stable, the duration of the aging step is not critical and the mixture can be kept at the aging temperature for a longer period of time. In one embodiment, the mixture is aged at the desired temperature for about 2 hours to about 27 hours. The crystallization mixture is then further cooled to a temperature of about 20°C or less and aged, followed by separation of the crystals by filtration or centrifugation. In one embodiment, the mixture is cooled to a temperature of about 0°C to about 20°C. In another embodiment, the mixture is cooled to a temperature of about 0°C to about 15°C or about 5°C to about 20°C. In yet another embodiment, the mixture is cooled to a temperature of about 5°C to about 15°C or about 5°C to about 10°C and aged for a sufficient time, followed by separation of the crystals.

[0206] The mixture of cooling is aged enough time, then separated. The aging length before separation can vary and does not significantly affect yield. In one embodiment, the mixture is cooled for at least about 15 minutes. In another embodiment, the mixture is aged for at least about 30 minutes or at least about 1 hour, then separated. In another embodiment, the mixture is aged for at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours or longer. In other embodiments, the mixture can be aged for at least about 10 hours, at least about 15 hours, at least about 20 hours or at least about 24 hours or longer.

[0207] In another embodiment of the present invention, the crystal can be collected by filtration or centrifugation, and optionally washed to remove residual ethanol. If desired, it can also be dried. Appropriate drying conditions should be selected to avoid melting of the compound of formula (Ia). For example, overheating should be avoided during drying conditions.

[0208] The present invention also relates to enantiomerically pure (S)-afoxolane in crystalline form. The crystalline form may be more stable, easier to handle and store, and easier to purify and easier to synthesize in a reproducible manner.

[0209] In one aspect, a pharmaceutical composition is provided, comprising a compound of formula (Ia), such as polymorph Form I or polymorph Form II, or a mixture thereof, and a pharmaceutically acceptable carrier or diluent. For example, in one embodiment, a pharmaceutical composition is provided, comprising polymorph Form I and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a pharmaceutical composition, comprising polymorph Form II and a pharmaceutically acceptable carrier or diluent. In yet another embodiment, the present invention provides a pharmaceutical composition, comprising a mixture of polymorph Form I and polymorph Form II and a pharmaceutically acceptable carrier or diluent.

[0210] In the case where the compounds of the present invention are administered to animals such as mammals as drugs, they can be provided as is or as a pharmaceutical composition containing, for example, 0.1% to 99.9% (w / w) (more preferably 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier in combination therewith. In other embodiments, the pharmaceutical composition comprises about 0.5% to about 50% (w / w), about 0.5% to about 25% (w / w) of a compound of formula (Ia) as form I, form II, or a mixture thereof. In other embodiments, the pharmaceutical composition comprises about 0.5% to about 15% (w / w) or about 0.5% to about 10% (w / w) of form I, form II, or a mixture thereof. In yet another embodiment, the pharmaceutical composition comprises about 0.1% to about 5% (w / w) or about 0.1% to about 2.5% (w / w) of a compound of formula (Ia) as form I, form II, or a mixture thereof.

[0211] In another aspect of the present invention, compositions are provided, comprising a mixture of two or more forms of a compound of formula (Ia) or a mixture of a crystalline (e.g., form I and form II) and a non-crystalline form, which may have particular advantages in extended release formulations. Thus, the present invention also relates to a mixture of crystalline products of the compound of formula (Ia).

[0212] In another aspect of the invention, the crystals of the compound of formula (Ia) comprise a mixture of crystalline forms (e.g., Form I and Form II) and amorphous forms. For example, the % crystallinity of the compound of formula (Ia) can be at least about 10%, preferably at least about 20% (by weight) of the total compound of formula (Ia), preferably at least about 30%, at least about 40%, at least about 50%, at least about 60% (by weight) of the total compound of formula (Ia).

[0213] In one embodiment, the % crystallinity of the compound of formula (Ia) is present in the composition in an amount of about 10% to 70%, preferably about 30% to 50% by weight of the total compound of formula (Ia).

[0214] The crystalline forms described herein can be combined with pharmaceutically acceptable carriers according to conventional pharmaceutical mixing techniques. In addition, the carrier can be in a variety of forms, depending on the form of the preparation desired to be administered, such as oral (e.g., tablets, capsules or soft chews) or parenteral (including intravenous injections or infusions). In the preparation of oral dosage forms, any conventional pharmaceutical medium can be used. Conventional pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, surfactants, solvents, binders, humectants, etc. in the case of oral liquid preparations (such as suspensions, solutions, emulsions and elixirs); aerosols; or carriers such as starch (e.g., corn starch), sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders (e.g., povidone, solid polyethylene glycol, etc.), disintegrants, etc. in the case of oral solid preparations (such as powders, capsules, tablets and soft chews).

[0215] Wetting agents, emulsifiers, surfactants and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants can also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, tocopherols, etc.; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0216] Examples of suitable surfactants for use in pharmaceutical compositions include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate Polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide (e.g., poloxamers such as etc.), polyethylene glycol castor oil derivatives including polyethylene glycol 35 castor oil Macrogol 40 Hydrogenated Castor Oil Macrogol 60 hydrogenated castor oil Propylene glycol monolaurate Glycerides including Glyceryl Caprylate / Caprate Polyethylene glycol glycerides PEG 300 Caprylic / Capric Glycerides PEG400 Caprylic / Capric Glycerides PEG 300 Oleic Acid Glyceryl PEG300 Linoleic Acid Glyceryl Polyethylene glycol stearate and polyethylene glycol hydroxystearate include polyethylene glycol 8 stearate (PEG 400 monostearate), polyethylene glycol 40 stearate (PEG 1750 monostearate) etc. The surfactant may be present in the composition at a concentration of about 0.1% to about 10% (w / w), about 1% to about 10% (w / w) or about 5% to about 10% (w / w). More generally, the surfactant may be present at a concentration of about 0.1% to about 5% (w / w) or about 1 to about 5% (w / w).

[0217] Fillers that can be used in oral formulations include but are not limited to corn starch, pregelatinized corn starch, soy protein powder, corn cobs, and corn gluten meal, etc., or combinations thereof. Fillers are generally present in compositions at a concentration of about 5% to about 80% (w / w), about 10% to about 70% (w / w), about 10% to about 60%, about 10% to about 50% (w / w), or about 10% to about 40% (w / w). More generally, fillers can be present at a concentration of about 30% to about 70%, about 30% to about 60%, about 30% to about 50% or about 35% to about 55%.

[0218] Binders that can be used for oral administration in the compositions of the present invention include, but are not limited to, polyvinyl pyrrolidone (e.g., povidone), cross-linked polyvinyl pyrrolidone (crospovidone), various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000, PEG 8000 and even PEG 20,000, etc.; copolymers of vinyl pyrrolidone and vinyl acetate (e.g., copovidone) such as BASF sold under the trade name Products sold, etc.; starches such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and various types of sugar; or a combination of two or more binders. In one embodiment, the composition comprises a binder povidone K30LP and PEG 3350 or PEG 4000 or a combination thereof. The binder is generally present in the composition at a concentration of about 1% to about 30% (w / w). More generally, the composition includes a binder at a concentration of about 1% to about 20% (w / w), about 1 to about 15% (w / w), about 1% to about 10% (w / w), about 5% to about 15% (w / w) or about 5% to about 10% (w / w).

[0219] Solvents that can be used in the compositions of the present invention include, but are not limited to, various grades of liquid polyethylene glycol (PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylene carbonate; propylene glycol; triglycerides including, but not limited to, caprylic / capric triglyceride, caprylic / capric / linoleic triglyceride (e.g. and 812, caprylic / capric / succinic triglycerides, propylene glycol dicaprylate / dicaprate, etc.; water, sorbitol solution, glyceryl caprylate / caprate and polyglycolyzed glycerides 2-pyrrolidone, N-methylpyrrolidone (NMP), dimethylacetamide, or a combination thereof.

[0220] The solvent may be included in the composition at a concentration of about 1 to about 50% (w / w). In other embodiments, the solvent concentration is about 1 to about 40% (w / w), about 1 to about 30% (w / w), or about 1 to about 20% (w / w). More generally, the solvent concentration in the composition is about 5% to about 20% (w / w) or about 5% to about 15% (w / w).

[0221] The humectants that can be used in the composition include, but are not limited to, glycerol (also referred to herein as glycerol), propylene glycol, cetyl alcohol, and glyceryl monostearate, etc. Various grades of polyethylene glycol can also be used as a humectant. The humectant can generally be present in the composition at a concentration of about 1% to about 25% (w / w). Generally, the concentration of the humectant in the composition of the present invention is 1% to about 20% (w / w), about 1% to about 15% (w / w), or about 5% to about 15% (w / w). More generally, the composition of the present invention contains about 1% to about 10% (w / w) humectant.

[0222] Pharmaceutical compositions comprising a crystalline form (eg, Form I and / or Form II) of a compound of Formula (Ia) may be formulated to have any desired concentration, preferably an amount that is therapeutically effective and does not cause one or more undesirable side effects.

[0223] Because of their ease in administration, tablets, soft chewable dosage forms and capsules may represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers may be employed. If desired, tablets and soft chewable dosage forms may be coated by techniques known to those skilled in the art.

[0224] In certain embodiments, the pharmaceutical composition comprises varying amounts of a crystalline form of the compound of formula (Ia), based on the total weight of the compound of formula (Ia) in the composition. In one embodiment, the pharmaceutical composition comprises less than 1% by weight of the crystalline form of polymorph Form I of the compound of formula (Ia). In another embodiment, the pharmaceutical composition comprises less than 1% by weight of the crystalline form of polymorph Form I of the compound of formula (Ia). In another embodiment, the pharmaceutical composition comprises less than 10% by weight of the crystalline form of polymorph Form I. In another embodiment, the pharmaceutical composition comprises less than 25% by weight of polymorph Form I of the compound of formula (Ia).

[0225] In yet another embodiment, the pharmaceutical composition comprises less than 50% by weight of polymorph Form I of the compound of Formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 99% by weight of polymorph Form I of the compound of Formula (Ia).

[0226] In other embodiments, the pharmaceutical compositions of the invention comprise at least about 30% (w / w), at least about 50% (w / w), or at least about 70% (w / w) of the compound of Formula (Ia) polymorph Form I. In yet another embodiment, the pharmaceutical compositions of the invention comprise at least about 80% (w / w), at least about 90% (w / w), or at least about 95% (w / w) of the compound of Formula (Ia) polymorph Form I. In yet another embodiment, the compositions of the invention comprise at least about 99% (w / w) of the compound of Formula (Ia) Form I.

[0227] In another embodiment, the pharmaceutical composition comprises less than 1% by weight of the crystalline form of polymorph Form II of the compound of formula (Ia). In another embodiment, the pharmaceutical composition comprises less than 1% by weight of the crystalline form of polymorph Form II of the compound of formula (Ia). In another embodiment, the pharmaceutical composition comprises less than 10% by weight of the crystalline form of polymorph Form II of the compound of formula (Ia). In another embodiment, the pharmaceutical composition comprises less than 25% by weight of the polymorph Form II of the compound of formula (Ia).

[0228] In yet another embodiment, the pharmaceutical composition comprises less than 50% by weight of polymorph Form II of the compound of Formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 99% by weight of polymorph Form II of the compound of Formula (Ia).

[0229] In other embodiments, the pharmaceutical compositions of the present invention comprise at least about 30% (w / w), at least about 50% (w / w), or at least about 70% (w / w) of the polymorph Form II of the compound of Formula (Ia). In yet another embodiment, the pharmaceutical compositions of the present invention comprise at least about 80% (w / w), at least about 90% (w / w), or at least about 95% (w / w) of the polymorph Form II of the compound of Formula (Ia). In yet another embodiment, the compositions of the present invention comprise at least about 99% (w / w) of the compound of Formula (Ia) Form II.

[0230] Pharmaceutical compositions include those suitable for oral, sublingual, nasal, rectal, vaginal, topical (e.g., smears or pour-ons), buccal, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but the most suitable route will depend on the nature and severity of the condition being treated. The composition can be conveniently provided in unit dosage form and prepared by any method known in the art of pharmaceutics. In certain embodiments, the pharmaceutical composition is formulated for oral administration in the form of a pill, capsule, soft chewable dosage form, lozenge, or tablet. In other embodiments, the pharmaceutical composition is in the form of a suspension.

[0231] A pharmaceutical composition comprising a specific crystalline form can be identified by comparing the X-ray powder diffraction pattern of the composition with the X-ray powder diffraction pattern of the pure specific crystalline form. It should be recognized that a pharmaceutical composition comprising a specific crystalline form may exhibit an X-ray powder diffraction pattern that is not completely identical to the X-ray powder diffraction pattern of the pure specific polymorph.

[0232] Also provided herein are crystalline forms that are biologically equivalent to any one or more of the (S)-afollana polymorphs Forms I and II described herein. In certain embodiments, biological equivalence between two crystalline forms means that the crystalline forms have substantially similar bioavailability, substantially similar potency, substantially similar safety profile, or a combination thereof.

[0233] In other embodiments, biological equivalence refers to that the crystal form displays substantially similar pharmacokinetic characteristics or therapeutic effects. Biological equivalence can be displayed by several in vivo and in vitro methods. These methods may include, for example, pharmacokinetics, pharmacodynamics, clinical and in vitro studies. In some embodiments, biological equivalence can be displayed by any suitable pharmacokinetic means known in the art or pharmacokinetic means combination, including loading dose, steady-state dose, initial or steady-state concentration of the drug, biological half-life, elimination rate, area under the curve (AUC), clearance rate, peak blood or plasma concentration (C), time to reach peak concentration (T), bioavailability and efficacy. In some embodiments, biological equivalence is realized with similar dosage amounts. In alternative embodiments, biological equivalence is realized with different dosage amounts.

[0234] In view of the pharmaceutical value of crystalline (S)-afoxolana, it is important to be able to obtain it by an efficient synthetic process that can be easily scaled up and obtains crystalline (S)-afoxolana in good yield and excellent enantiomeric and chemical purity.

[0235] The Applicant has now developed a new synthetic process which allows obtaining crystalline (S)-afoxolane in a reproducible manner and without laborious purification, in a purity consistent with its use as a pharmaceutical active ingredient.

[0236] The examples serve to further illustrate and explain the present invention and should not be considered limiting in any way. Unless otherwise specified in the examples and the remainder of the specification and claims, all parts and percentages are based on weight. Temperatures are based on degrees Celsius.

[0237] It should be appreciated that certain features of the present invention are described in the context of separate embodiments for the sake of clarity, which may also be provided in combination in a single embodiment. Conversely, various features of the present invention are described in the context of a single embodiment for the sake of brevity, which may also be provided separately or in any suitable sub-combination or in any other embodiment of the present invention described. Certain features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiment does not function without those elements.

[0238] Benefits, other advantages, and solutions to problems have been described above with respect to specific embodiments. However, the benefits, advantages, solutions to problems, and any features that may cause any benefit, advantage, or solution to occur or become more significant are not to be construed as key, required, or essential features of any or all of the claims.

[0239] It should be noted that the present invention is not intended to encompass within the scope of the present invention any pre-disclosed compositions, products, methods of making products, or methods of using products that meet the written description and enabling requirements of the USPTO (35 U.S.C. 112, paragraph 1) or the EPO (EPC Article 83), and applicants reserve the right and hereby disclose the exclusion of any pre-described products, methods of making products, or methods of using products. Example

[0240] Example 1: Synthesis of racemic afoxolane and (S)-afoxolane

[0241] Racemic afollana can be obtained by methods such as those disclosed in US Patent No. US8410153, which is incorporated herein by reference in its entirety. Enantiomerically enriched afollana enriched in the (S)-enantiomer can be obtained by methods such as those disclosed in US Application No. 62 / 319,207, which is the priority document of US 15 / 480,316 disclosed as US 2017 / 0311601 A1, which is incorporated herein by reference in its entirety.

[0242] Example 2 - Synthesis of Crystalline (S)-Afoxolane Toluene Solvate

[0243] (a) Synthesis of (S)-Afollana:

[0244]

[0245] 1. 1 kg of compound (IIA-1) (1 equivalent) and 9 volumes of dichloromethane (DCM) were added to a reactor and stirred to dissolve the compound.

[0246] 2. The mixture was cooled to about 0°C, 50 g (5% by weight of compound (IIA-1)) of chiral phase transfer catalyst (IIIa-13-1) and 1 L of DCM were added, and the resulting mixture was cooled to about -13°C.

[0247] 3. A 19% (w / w) hydroxylamine sulfate solution (294 g, 1.1 eq.) (prepared with 294 g (NH2OH)H2SO4 and 141 g NaCl in 1112 mL water) and 4.4 eq. of a 17.6% (w / w) NaOH solution (286 g NaOH and 158 g NaCl in 1180 mL water) were added simultaneously to the reaction mixture.

[0248] 4. The resulting reaction mixture was vigorously mixed at about -13°C for about 20 hours, and then the reaction conversion was checked by HPLC (target ≤ 0.5% area);

[0249] 5. After the reaction was complete, water (3 volumes) was added at about 0° C. Then, 709 g of KH2PO4 in 4.2 liters of water was added to the mixture to adjust the pH (target 7-8), and the resulting mixture was stirred at about 20° C. for 30 minutes.

[0250] 6. Allow the layers to settle, remove the aqueous layer, and wash the organic layer twice with 3 liters of water to provide (S)-afoxolane in the organic layer.

[0251] b) Crystallization of toluene solvate

[0252] 1. Following the extraction / washing step of Example 2(a)(6) above, dichloromethane was removed by distillation under reduced pressure to about 1-2 volumes and toluene (about 5-10 volumes) was added.

[0253] 2. Adjust the volume by further distillation under reduced pressure and / or add more toluene to about 5-6 volumes. The mixture is further distilled and the volume is maintained to substantially remove the dichloromethane reaction solvent.

[0254] 3. The mixture was then cooled to about 10°C and seeded with afoxol (racemic compound) and stirred at the same temperature for at least 2 hours;

[0255] 4. Heat the mixture to about 55-65°C and age (at least 17 hours in one embodiment) and then filter out the solid racemate. Wash the filtered solid with toluene;

[0256] 5. Adjust the combined filtrate and washings to about 5-6 volumes by distillation under reduced pressure and / or adding toluene;

[0257] 6. The resulting mixture was cooled to about 10°C and aged for at least 5 hours before filtering. The filter cake was washed with toluene.

[0258] 7. The filter cake was dried under reduced pressure at 50°C to obtain crystalline toluene solvate of (S)-afoxolane in the form of rod-shaped crystals.

[0259] Example 3: Formation of (S)-Afollana Form I from Ethanol / Cyclohexane

[0260] In a 25L jacketed vessel at 20°C, add the following:

[0261] (S)-Afoxolane toluene solvate (ee 96%) 591g

[0262] EtOH (ethanol) 709ml

[0263] Cyclohexane 1773ml

[0264] After the addition of the substances, the reaction mixture is heated to about 60°C at a rate of 20°C / h and stirred. The heating rate is not essential and depends on the equipment used. After about one hour, an additional 6.4 L of cyclohexane is added, the stirring speed is adjusted to 100 rpm (0.04 WL-1) and cooled to 55°C. At this stage the mixture can be seeded to promote crystal formation. The mixture is then subjected to the following procedure twice:

[0265] Cooling to 30℃(-10℃ / h)

[0266] Stir at 30°C for 30 minutes

[0267] Increase the stirring power to 0.13WL-1

[0268] Heating to 60℃(15℃ / h)

[0269] Stir at 60°C for 1 hour

[0270] After completing the second procedure, the mixture was cooled to 10°C at a rate of -5°C / h and stirred at 10°C for at least 5h. The suspension was then filtered at 10°C and washed twice with cyclohexane at 10°C (i.e., 2x1.2L). The filtered crystals were then dried under reduced pressure (50 mbar) at 50°C for 20h to provide 453.7g of non-solvated crystalline (S)-Afolan, with a chemical purity of greater than 94% (ee≥96%). Thermal imaging analysis (TGA) showed no weight loss, indicating the presence of a solvate crystalline form. Non-solvated crystalline (S)-Afolan was confirmed to be Form I by XRPD.

[0271] Example 4: Formation of (S)-Afollana Form II from Ethanol / Cyclohexane

[0272] A method similar to Example 3, but using 100% optically pure (S)-afoxolane toluene solvate and 15 / 85% v / v ethanol / cyclohexane as the crystallization solvent, provided (S)-afoxolane Form II. Thermal imaging analysis (TGA) showed no weight loss, indicating the presence of the solvate crystalline form. The non-solvated crystalline (S)-afoxolane was confirmed to be Form II by XRPD.

[0273] X-ray powder diffraction (XRPD) analysis of (S)-Afollana Forms I and II

[0274] Table 1 summarizes the peaks in the X-ray diffraction patterns of (S)-afollana Forms I and II, measured using the following equipment and parameters:

[0275] Equipment: Bruker D8Advance diffractometer

[0276] source

[0277] Generator: 40kV-30mA

[0278] Detector: lynx Eye.

[0279] PMMA Sample Holder

[0280] Phi Spinner:

[0281] Rotation speed: 30rpm

[0282] Angular range: 2° to 40°, θ-θ

[0283] Variable dispersion slit: 12mm (V12)

[0284] Step size: 0.02°

[0285] Step time 10.6s

[0286] Form I shows the most significant peaks at 2θ=10.03°, 10.48°, 13.16°, 15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52° and 28.13°. In contrast, Form II shows the most significant peaks at 2θ=5.99°, 12.99°, 15.80°, 18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11°, 29°.

[0287] Table 1:

[0288]

[0289]

[0290] Differential Scanning Calorimetry Thermogram Analysis of (S)-Afoxolane Forms I and II

[0291] Form I and Form II were measured using the following equipment and parameters:

[0292] Equipment: PerkinElmer Diamond DSC

[0293] Atmosphere: Nitrogen 20ml / min

[0294] Tray: 50μl aluminum tray

[0295] Cover: Drilled aluminum cover with 100μm holes

[0296] Rate: 5℃ / min

[0297] Form I: The differential scanning calorimetry (DSC) thermogram has a peak at a temperature of about 146°C with an onset at about 143°C.

[0298] Form II: The differential scanning calorimetry (DSC) thermogram has a peak at a temperature of about 149°C with an onset at about 146°C.

[0299] Example 5: Formation of (S)-Afollana Form I from Ethyl Acetate

[0300] Following the procedure of Example 3, but using ethyl acetate instead of the EtOH / cyclohexane mixture and cooling the mixture to 4°C at a rate of -5°C / h and stirring at 4°C for 72h after completion of the second procedure, (S)-afollana Form I was isolated.

[0301] Example 6: Formation of (S)-Afollana Form I from Acetonitrile

[0302] Following the procedure of Example 3, but using acetonitrile instead of the EtOH / cyclohexane mixture and after completion of the second procedure, cooling the mixture to 4°C at a rate of -5°C / h and stirring at 4°C for 72h, (S)-afollana Form I is isolated.

Claims

1. A method for preparing crystals of a compound of formula (Ia) designated as Form I or Form II, wherein the crystalline form designated Form I is unsolvated and is characterized by having an X-ray powder diffraction pattern comprising 7 or more peaks selected from the group consisting of: 10.03°, 10.48°, 13.16°, 15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52° and 28.13° 2θ±0.2 as measured on a diffractometer using Cu-Kα radiation; and wherein the crystalline form designated Form II is unsolvated and is characterized by having an X-ray powder diffraction pattern comprising 7 or more peaks selected from the group consisting of: 5.99°, 12.99°, 15.80°, 18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11° and 29.00° 2θ ± 0.2 as measured on a diffractometer using Cu-Kα radiation; The method comprises: (a) heating a mixture of toluene solvate of (S)-afoxanal in a solvent to about 50 to about 80 degrees Celsius until dissolution has occurred, wherein the solvent is acetonitrile, ethyl acetate, or a mixture of ethanol and cyclohexane, wherein the mixture of ethanol and cyclohexane is 1:99 to 25:75 (v / v) ethanol:cyclohexane; (b) lowering the temperature of the solvent system to induce nucleation; (c) maintaining the mixture at a temperature below the temperature at which nucleation begins; and (d) isolating crystals of the compound of formula (Ia) thus precipitated.

2. The process of claim 1, wherein the mixture of ethanol and cyclohexane is 3:97 to 10:90 (v / v) ethanol:cyclohexane.

3. The method of claim 1, wherein the mixture of ethanol and cyclohexane is 8:92 (v / v) ethanol:cyclohexane.

4. A process according to any one of claims 1 to 3, comprising seeding with enantiomerically pure (S)-afoxolane Form I.

5. The method of any one of claims 1 to 3, wherein the temperature is reduced to a temperature of 5 degrees Celsius.

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