Crystalline forms of (s)-alfalana

Abstract

The present invention provides crystalline forms of a compound of formula (1a) (crystalline forms of (S)-arfampanaga) and methods of making the crystalline forms. Also provided are compositions comprising the crystalline forms and crystalline forms for use in the treatment or prevention of parasite infections in animals. # imgabs0 #

Description

[0001] This application is a divisional application of the parent application Chinese Patent Application No. 201880033276.6.

[0002] Cross - reference to related applications

[0003] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 482,175, filed on April 5, 2017, which is incorporated herein by reference. Technical field

[0004] This disclosure generally relates to solid forms of compounds of formula (Ia)

[0005] Background art

[0006] Polymorphs can have different physical and chemical (i.e., physicochemical) properties such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, and dissolution rate, as well as biological properties such as bioavailability. It remains impossible to predict the physicochemical properties of one or more crystal forms in which a compound can exist in the solid state.

[0007] In addition, the interest in individual enantiomers of pharmacologically active compounds has been increasing in recent years due to their improved pharmacokinetic and biological properties. Therefore, methods are needed that can be used on a large scale to prepare the individual enantiomers of afoxolaner. Generally, asymmetric processes for obtaining chiral molecules provide enantiomer - enriched forms rather than optically active molecules in the form of pure individual enantiomers, unless the process includes a resolution method. Therefore, methods are also needed that can be used on a large scale to increase the enantiomeric purity of optically active (S) - afoxolaner.

[0008] Afoxolaner 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] In addition, it is impossible even to predict whether a compound can exist in more than one crystal form in the solid state.

[0013] The priority document US Patent Application No. 62 / 319,207 of US Patent Application No. 15 / 480,316, published as US2017 / 0311601 A1 (incorporated herein by reference in its entirety), discloses compounds of formula (Ia) and methods thereof, and the use of such compounds as agents for controlling invertebrate pests. New solid forms of such compounds have now been discovered.

[0014] US Patent US8410153 (incorporated herein by reference) describes that afoxolaner is effective in treating or preventing parasite infections or infestations in or on animals.

[0015] Incorporation 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 in the application cited documents, and all documents cited or referenced herein ("herein cited documents") and all documents cited or referenced in the herein cited documents, as well as any manufacturer's guides, instructions, product specifications, and product description sheets for any products mentioned in any document herein or incorporated herein by reference, are incorporated herein by reference and may be used in the practice of the present invention. The citation of any such document in the present application does not admit that such document can serve as prior art for the present invention. Summary of the invention

[0017] Abstract of the invention

[0018] The present invention relates to solid forms of compounds of formula (Ia). More particularly, the present invention relates to crystalline forms of compounds of formula (Ia) designated as Form I and Form II, and methods for preparing these crystalline forms.

[0019] The present invention also relates to compositions containing solid forms of compounds of formula (Ia); and methods for controlling invertebrate pests, including contacting an invertebrate pest or its 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).

[0020] 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 regarding antiparasitic applications of the present invention and the solutions provided. Brief description of the drawings

[0021] Figure 1 A powder X-ray diffraction pattern of crystalline Form I of the compound of formula (Ia) is shown, which shows plotting the absolute intensity counts against the 2θ reflection positions.

[0022] Figure 2 A differential scanning calorimetry thermogram of crystalline Form I of the compound of formula (Ia) is shown.

[0023] Figure 3 Powder X-ray diffraction pattern of polymorph II of the compound of formula (Ia), showing the plot of absolute intensity counts against 2θ reflection positions.

[0024] Figure 4 Differential scanning calorimetry thermogram of polymorph II of the compound of formula (Ia). DETAILED DESCRIPTION OF THE INVENTION

[0026] 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 that range by extending the upper and lower boundaries of the described values. Generally, the term "about" is used herein to modify a value to within 10% of the variance of the stated value. Thus, about 50% means a range of 45% - 55%. Numerical ranges described herein by endpoints include all numbers and fractions subsumed within that 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 their fractions are presumed to be modified by the term "about".

[0027] The term "administer" as used herein refers to any method that, in a reasonable veterinary practice, delivers a compound or composition used in the present invention to a subject to be treated in such a manner that a parasitic infestation can be effectively prevented or treated. For example, the compound or composition is administered via oral, parenteral, percutaneous or topical routes. Topical administration particularly includes dermal solutions (pour-ons or spot-ons), sprays, bath agents, shower agents, splashes, powders, ointments, shampoos, creams, etc. Pour-on type dermal solutions can be designed to deliver the active ingredient transdermally or distribute the active ingredient over the exterior of the animal.

[0028] The term "anhydrate" or "anhydrous polymorph" or "anhydrous crystal form" refers to a crystal form that does not have water bound in the crystal lattice. However, the crystal may contain trace amounts of water or other solvents not bound in the crystal lattice.

[0029] The term "amorphous" as used herein for afoxolaner refers to the solid state in which afoxolaner molecules are present in a disordered arrangement and do not form a recognizable crystal lattice or unit cell. In the case of performing X-ray powder diffraction, amorphous afoxolaner does not produce any characteristic crystal peaks.

[0030] The term "chemical purity" refers to the total level of the desired product. If the 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 the compound exists in solvate form, "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, undesired process reagents, process intermediates, degradation products, or oxidation products. In a specific embodiment, high chemical purity means greater than 90%, particularly higher than 92.5%, 95%, 96%, 97%, 98%, 99%, 99.9% and including 100% chemical purity. Purity can be measured by various techniques including HPLC analysis.

[0031] The term "effective amount" as used herein refers to an amount of the crystalline form of the compound of formula (Ia) sufficient to eradicate a parasite infestation in an animal or reduce its number. 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.

[0032] The terms "enantiomer" and "enantiomeric" refer to molecules that cannot be superimposed on their mirror images and are thus optically active, where 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.

[0033] The term "enantiomeric excess" or "e.e." as used herein refers to the difference between the amount of one enantiomer present in a product mixture and the amount of the other enantiomer. The enantiomeric excess values in the examples provided below indicate the relative amounts of the respective enantiomers. 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 present invention is 97.5% and the percentage of the (R)-enantiomer is 2.5%, the enantiomeric excess of the (S)-enantiomer is 95%.

[0034] The term "enantiomerically pure" or "enantiomeric purity" as used herein is a measure of the extent to which one enantiomer is present in excess of the other in an enantiomeric mixture. For example, a mixture of 99% (S)-enantiomer and 1% (R)-enantiomer has 99% enantiomeric purity of the (S)-enantiomer. Enantiomerically pure is preferably at least 95% or at least 98%, more preferably at least about 99% enantiomeric purity. In yet another embodiment, enantiomerically pure is from about 99.90% to about 100% enantiomeric purity.

[0035] The term "separation" as used herein in connection with the disclosed afoxolaner solid forms corresponds to the physical separation of the solid form of afoxolaner from a solution, where the solid form is formed from the solution.

[0036] The term "solvent volume" as used herein refers to the volume of solvent in liters at ambient temperature required to dissolve 1 kg of a solid substance. For example, 5 volumes of solvent used for 1 kg of starting material in a process would be equal to 5 liters of solvent.

[0037] 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.

[0038] 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.

[0039] The term "non-solvate polymorph" or "non-solvate crystal form" refers to a crystal form that does not have solvent incorporated in the crystal lattice, such as an anhydrous polymorph. However, the crystal may contain trace amounts of solvent not incorporated in the crystal lattice.

[0040] The term "or" as used herein and unless explicitly stated to the contrary, refers to an inclusive or rather than an exclusive or. For example, any of the following cases satisfies condition A or B: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both A and B are true (or present).

[0041] The term "pharmaceutically acceptable carrier" as used herein can include any of a variety of solvents, diluents, or other liquid or solid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., which are suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Eighteenth Edition, E.W. Martin (Mack Publishing Co., Easton, PA 1990) discloses various carriers used in formulating pharmaceutical compositions and the known techniques for preparing them. It is contemplated for use within the scope of the present invention except where any conventional carrier medium is incompatible with compound (Ia), such as producing any undesirable biological effects or interacting in a detrimental manner with any other component of the pharmaceutical composition. 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil, and soybean oil; glycerol, glycerol esters, diols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; ethanol, and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring and aromatic agents, preservatives, and antioxidants can also be present in the composition according to the judgment of the formulator.

[0042] The term "polymorph" as used herein refers to the different crystal structures (solvated or non-solvated forms) in which a compound can crystallize.

[0043] The terms "racemic" or "racemate" and other similar terms refer to an approximately equimolar ratio of (S)-afloqualone and (R)-afloqualone.

[0044] The term "seed crystal" as used herein can be used as a noun to describe one or more crystals of crystalline afloqualone (e.g., polymorphic form I). For example, if it is desired to produce crystalline (S)-afloqualone polymorphic form I, the seed crystal to be used to enhance the crystallization process can be (S)-afloqualone polymorphic form I crystals. The terms "seeding" or "inoculating" can also be used as verbs to describe the introduction of said one or more afloqualone crystals (e.g., polymorphic form I) into an environment (including but not limited to, for example, a solution, mixture, suspension, or dispersion) thereby causing the formation of more of the same afloqualone crystals (e.g., polymorphic form I).

[0045] The terms "solvate", "solvate polymorph", or "solvate crystal form" refer to a crystal form having a solvate incorporated in the lattice.

[0046] The phrase "substantially pure crystal form" is understood to mean, unless otherwise specified, a substance that does not contain amounts of other crystal forms or amorphous forms detectable by typical analytical methods, i.e., contains less than 10% of other crystal forms, the methods being 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 crystal form or amorphous form of the compound.

[0047] When used to describe data in a diffraction pattern, spectrum, or graph, the term "substantially similar" means that the data in the diffraction pattern, spectrum, or graph encompasses all data in diffraction patterns, spectra, or graphs that vary within acceptable experimental bounds, the variations being known to those skilled in the art. The experimental bounds vary depending on the type of data in the diffraction pattern, spectrum, or graph, but are still known to those skilled in the art.

[0048] The terms "treat" or "treatment" or "therapy" as used herein are intended to mean the administration or giving of a compound or composition of the invention to an animal having a parasite infestation for eradicating the parasite or reducing the number of parasites infesting the treated animal. It should be noted that the compositions of the invention can be used to prevent the above-mentioned parasite infestations.

[0049] 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 given by U.S. patent law; for example, they can mean "encompassing", "having", etc.; and terms such as "consisting essentially of" and "consisting substantially of" have the meanings given by U.S. patent law, for example, they allow elements not explicitly described but exclude elements that are present in the prior art or affect the basic or novel features of the invention.

[0050] As described herein, the compounds of formula (Ia) can be crystal forms that can exist as one or more polymorphs, including solvate forms. Generally speaking, the X-ray powder diffraction patterns, spectra, physicochemical and pharmacokinetic properties, and thermodynamic stabilities of polymorphs (also known in the art as polymorphic forms, polymorphic shapes, or crystal forms) are different. Additionally, 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, the applications including but not limited to for a specific dosage form such as a suspension, ointment, tablet, or capsule, or for preparing a pharmaceutical form having excellent pharmacokinetic properties.

[0051] Depending on the desired use of the (S)-afoxolaner solid form, the processing conditions can be inclined to select a particular solid form or a particular combination of the solid forms. Using a solvated crystal form in a composition instead of Form I or Form II eliminates the processing step of the process, i.e., desolvation, which would otherwise be carried out for the solvated crystal form. However, in the pharmaceutical or veterinary fields, certain solvents are not allowed to exceed a threshold level due to 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. Additionally, it is difficult to remove the solvent from a crystalline form of a compound where the solvent is part of the crystal lattice. The elimination of the desolvation step is possible in cases where a non-solvated crystalline solid form of the compound can be prepared, resulting in an improved compound preparation process. For example, if Form I or Form II is directly crystallized from a suitable solvent without the intervening steps of preparation and desolvation of an intermediate solvated crystal form, a significantly cost-saving and more efficient process is achieved. See, for example, E. Shefter and T. Higuchi, The relative dissolution rates of several crystalline solvated and non-solvated forms of important drugs have been measured, J. Pharm. Sci., 52(8), (1963), 781-91. In the case of the compound of formula (Ia) shown below, it has been found that the crystallization of the compound from common process solvents including aromatic solvents such as toluene, etc. results in the compound being separated as a solvate and the separation of the non-solvated form of the compound of formula (Ia) is very difficult. However, the solvate cannot be directly used in pharmaceutical or veterinary applications without significantly reducing the solvent level, which is not commercially viable. Accordingly, the non-solvated Forms I and II of the compound of formula (Ia) represent a significant improvement in the development of effective antiparasitic compositions for the treatment or prevention of parasitic infestations in animals.

[0052] In yet another embodiment of the present invention, the exact molar ratio of the components of the solvate including the hydrate has some variability, depending 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 about the general relative amounts of the solvate components and in many cases the molar ratio can vary from the stated range by about plus or minus 20%. For example, a molar ratio of 1:1 is understood to include ratios of 1:0.8 as well as 1:1.2 and all individual ratios therebetween.

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

[0054] The present invention also provides crystalline form II of (S)-afloqualone substantially free of bound organic solvent and free of bound water, characterized by X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC) as described in Example 3.

[0055] Furthermore, the present invention provides a method for preparing form I and / or form II of (S)-afloqualone or a mixture thereof, comprising crystallizing the compound from a solvent mixture comprising an aliphatic solvent and a co-solvent. Detailed Description

[0056] Embodiments of the present invention described in the Summary of the Invention include those described below.

[0057] Embodiment (1): A crystal of a compound of formula (Ia), designated as form I,

[0058]

[0059] wherein said crystal is characterized by having an X-ray powder diffraction pattern that comprises 3, 4, 5, 6, 7 or more peaks selected from the following: 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.

[0060] Embodiment (2): A crystal of a compound of formula (Ia) according to Embodiment (1), characterized by having an X-ray powder diffraction pattern that comprises 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.

[0061] Embodiment (3): A crystal of a compound of formula (Ia) according to Embodiment (1), characterized by having a substantially similar Figure 1 X-ray powder diffraction pattern.

[0062] Embodiment (4): A crystal of a compound of formula (Ia) according to any one of Embodiments (1) to (3), characterized by having a differential scanning calorimetry (DSC) thermogram with a peak located at a temperature of about 146 °C and starting at about 143 °C, measured at a heating rate of 5 °C / min.

[0063] 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 with a heat of fusion of about 61.7 J / g.

[0064] Embodiment (6): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (5), characterized by having a substantially similar Figure 2 differential scanning calorimetry thermogram.

[0065] Embodiment (7): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (6), wherein the crystal form is isolated.

[0066] Embodiment (8): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (7), wherein the crystal form is non-solvated.

[0067] Embodiment (9): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (8), which is enantiomerically pure.

[0068] 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%.

[0069] Embodiment (11): 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 98%.

[0070] 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%.

[0071] Embodiment (13): A crystal of a 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%.

[0072] Embodiment (14): A crystal of a 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%.

[0073] Embodiment (15): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (13), having a chemical purity of about 99.00% to about 100%.

[0074] Embodiment (16): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (15), having a chemical purity of about 99.90%.

[0075] Embodiment (17): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (16) has an enantiomeric purity of from about 98.0 to about 99.0%.

[0076] Embodiment (18): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (17) has an enantiomeric purity of from about 99.0 to about 100%.

[0077] Embodiment (19): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (18) has a chemical purity of from about 99.00% to about 99.95% and an enantiomeric purity of from about 99.0 to about 100%.

[0078] Embodiment (20): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (19) has a chemical purity of about 99.90% and an enantiomeric purity of about 99.90%.

[0079] Embodiment (21): A crystal of a compound of formula (Ia) according to any one of embodiments (1) to (20) is in a substantially pure crystal form.

[0080] Embodiment (22): A crystal form of (S)-afloqualone that is biologically equivalent to a crystal of a compound of formula (Ia) according to any one of embodiments (1) to (21).

[0081] 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.

[0082] 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 an amorphous form of the compound of formula (Ia).

[0083] Embodiment (25): The composition according to embodiment (24), wherein the different polymorphic form is form II.

[0084] Embodiment (26): The composition according to embodiment (24), wherein the crystal of the compound of formula (Ia) is mixed with an amorphous form of the compound of formula (Ia).

[0085] Embodiment (27): The pharmaceutical composition according to any one of embodiments (23) to (26), wherein the composition comprises at least about 50.0% by weight of the crystal of the compound of formula (Ia) according to embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0086] 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 the compound of formula (Ia) according to Embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0087] 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 the compound of formula (Ia) according to Embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0088] 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 the compound of formula (Ia) according to Embodiment 1, based on the total weight of the compound of formula (Ia) in the composition.

[0089] 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 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 (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.

[0091] Embodiment (33): A method for preparing crystals of the compound of formula (Ia) according to any one of embodiments (1) to (22), which comprises: —

[0092] (a) Heating a mixture of the (S)-afloqualone toluene solvate in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic aliphatic solvent (such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc.) or an alcohol, or a combination thereof, until dissolution has occurred;

[0093] (b) Optionally adding a co-solvent;

[0094] (c) Lowering the temperature of the solvent system to induce nucleation;

[0095] (d) Maintaining the mixture at a temperature below the temperature at which nucleation has commenced; and

[0096] (e) Separating the crystals of the compound of formula (Ia) so precipitated.

[0097] Embodiment (34): The method according to embodiment (33), wherein the co-solvent is isobutyl ketone or acetone.

[0098] Embodiment (35): The method according to embodiment (33), wherein the aliphatic solvent is a C1-C8 linear, branched or cyclic alkane solvent.

[0099] Embodiment 36: The method according to any one of embodiments (33) to (35), wherein the alcohol is a lower alkyl alcohol.

[0100] Embodiment (37): The method according to any one of embodiments (33) to (36), wherein the alcohol is ethanol.

[0101] Embodiment (38): The method according to any one of embodiments (33) to (37), wherein the solvent is a mixture comprising ethanol and cyclohexane.

[0102] Embodiment (39): The method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 10:90 to about 99:1 (v / v) ethanol:cyclohexane.

[0103] Embodiment 40: The method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 1:99 to about 25:75 (v / v) ethanol:cyclohexane.

[0104] Embodiment 41: The method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 3:97 to about 10:90 (v / v) ethanol:cyclohexane.

[0105] Embodiment (42): The method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 5:95 to about 10:90 (v / v) ethanol:cyclohexane.

[0106] Embodiment (43): The method according to embodiment (38), wherein the mixture of ethanol and cyclohexane is about 8:92 (v / v) ethanol:cyclohexane.

[0107] Embodiment (44): The method according to any one of embodiments (33) to (43), comprising the enantiopure (S)-afloqualone form I seed crystal.

[0108] Embodiment (45): The method according to any one of embodiments (33) to (44), wherein it is heated to about 50 to about 80 degrees Celsius.

[0109] Embodiment (46): The method according to any one of embodiments (33) to (45), wherein the temperature is lowered to about 10 degrees Celsius or lower.

[0110] 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 lower.

[0111] Embodiment (48): A method according to any one of embodiments (33) to (47), wherein the rate of temperature reduction is about 3 degrees Celsius per hour.

[0112] Embodiment (49): A method for preparing crystalline form I of (S)-afoxolaner according to Embodiment 1, comprising: —

[0113] (a) Heating a mixture of a toluene solvate of (S)-afoxolaner having an enantiomeric purity ≥ 97% in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic alkane solvent or alcohol or a combination thereof, until dissolution has occurred;

[0114] (b) Optionally adding a co-solvent;

[0115] (c) Lowering the temperature of the solvent system to induce nucleation;

[0116] (d) Maintaining the mixture at a temperature below the temperature at which nucleation has started; and

[0117] (e) Separating the thus-precipitated crystalline form I of (S)-afoxolaner.

[0118] Embodiment (50): A method according to any one of embodiments (33) to (49), wherein the crystals of the compound of formula (Ia) separated are (S)-afoxolaner enantiomer-enriched.

[0119] Embodiment (51): A crystalline form of (S)-afoxolaner prepared by a method according to any one of embodiments (33) to (50).

[0120] Embodiment (52): A crystalline form of (S)-afoxolaner disclosed in any example.

[0121] Embodiment (53): A method for treating or preventing parasitic infection or infestation in an animal, comprising administering to the animal an effective amount of a crystalline form of (S)-afoxolaner according to any one of embodiments (1) to (22) or Embodiment (52) or a composition according to any one of embodiments 23 - 32.

[0122] Embodiment (54): Crystals of the compound of formula (Ia), designated as Form II,

[0123]

[0124] Wherein the crystal is characterized by having an X-ray powder diffraction pattern that includes 3, 4, 5, 6, 7 or more peaks selected from the following: 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.

[0125] Embodiment (55): A crystal of a compound of formula (Ia) according to embodiment (54), wherein the crystal is characterized by having an X-ray powder diffraction pattern that includes 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.

[0126] Embodiment (56): A crystal of a compound of formula (Ia) according to any one of embodiments (54) or (55), characterized by having a substantially similar Figure 3 X-ray powder diffraction pattern.

[0127] Embodiment (57): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (56), characterized by having a differential scanning calorimetry (DSC) thermogram that has a peak located at a temperature of about 149 °C and starting at about 146 °C, measured at a heating rate of 5 °C / min.

[0128] 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 that has a heat of fusion of about 65.7 J / g.

[0129] Embodiment (59): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (58), characterized by having a substantially similar Figure 4 differential scanning calorimetry thermogram.

[0130] Embodiment (60): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (59), wherein the crystal form is isolated.

[0131] Embodiment (61): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (60), wherein the crystal form is non-solvated.

[0132] Embodiment (62): A crystal of a compound of formula (Ia) according to any one of embodiments (54) to (61), which is enantiomerically pure.

[0133] Embodiment (63): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (62) has a chemical purity of at least about 95%.

[0134] Embodiment (64): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (63) has a chemical purity of at least about 98%.

[0135] Embodiment (65): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (64) has a chemical purity of at least about 99%.

[0136] Embodiment (66): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (65) has a chemical purity of about 98.00% to about 99.00%.

[0137] Embodiment (67): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (66) has a chemical purity of about 99.00% to about 99.95%.

[0138] Embodiment (68): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (67) has a chemical purity of about 99.00% to about 100%.

[0139] Embodiment (69): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (68) has a chemical purity of about 99.90%.

[0140] Embodiment (70): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (69) has an enantiomeric purity of about 98.0 to about 99.0%.

[0141] Embodiment (71): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (70) has an enantiomeric purity of about 99.0 to about 100%.

[0142] Embodiment (72): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (70) has a chemical purity of about 99.00% to about 99.95% and an enantiomeric purity of about 99.0 to about 100%.

[0143] Embodiment (73): The crystal of the compound of formula (Ia) according to any one of Embodiments (54) to (72) has a chemical purity of about 99.90% and an optical purity of about 99.90%.

[0144] Embodiment (74): The crystal of the compound of formula (Ia) according to any one of embodiments (54) to (73) is in a substantially pure crystal form.

[0145] Embodiment (75): A crystal form of (S)-afloqualone that is biologically equivalent to the crystal of the compound of formula (Ia) according to any one of embodiments (54) to (74).

[0146] Embodiment (76): A pharmaceutical composition comprising the crystal of the compound of formula (Ia) according to any one of embodiments (54) to (75), and at least one pharmaceutically acceptable excipient.

[0147] Embodiment (77): A composition comprising the crystal of the 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 an amorphous form of the compound of formula (Ia).

[0148] Embodiment (78): The composition according to embodiment (77), wherein the different polymorphic form is Form I.

[0149] Embodiment (79): The 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).

[0150] Embodiment (80): The pharmaceutical composition according to any one of embodiments (76) to (79), wherein the composition comprises at least 50.0% by weight of the crystal of the compound of formula (Ia) according to embodiment 53, based on the total weight of the compound of formula (Ia) in the composition.

[0151] Embodiment (81): The pharmaceutical composition according to any one of embodiments (76) to (80), wherein the composition comprises at least about 70% by weight of the crystal 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 (82): The pharmaceutical composition according to any one of embodiments (76) to (81), wherein the composition comprises at least about 80% by weight of the crystal 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 (83): The pharmaceutical composition according to any one of embodiments (76) to (80), wherein the composition comprises at least about 90% by weight of the crystal 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 (84): A pharmaceutical composition according to any one of embodiments (76) to (83), wherein the composition comprises at least about 95% by weight of the 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 (85): A pharmaceutical composition according to any one of embodiments (76) to (84), wherein the composition comprises at least 99.0% by weight of the 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.

[0156] Embodiment (86): A method for preparing crystals of the compound of formula (Ia) according to embodiment (54), comprising: —

[0157] (a) Heating a mixture of the toluene solvate of (S)-afloqualone in a solvent, wherein the solvent is acetonitrile, ethyl acetate, a linear, branched or cyclic aliphatic solvent (such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc.) or an alcohol or a mixture thereof, until dissolution has occurred;

[0158] (b) Optionally adding a co-solvent;

[0159] (c) Lowering the temperature of the solvent system to induce nucleation;

[0160] (d) Maintaining the mixture at a temperature below the temperature at which nucleation has started; and

[0161] (e) Separating the crystals of the compound of formula (Ia) so precipitated.

[0162] Embodiment (87): The method according to embodiment (86), wherein the co-solvent is isobutyl ketone or acetone.

[0163] Embodiment (88): The method according to any one of embodiments (86) to (87), wherein the alcohol is ethanol.

[0164] Embodiment (89): The method according to any one of embodiments (86) to (88), wherein the solvent is a mixture comprising ethanol and cyclohexane.

[0165] 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.

[0166] Embodiment 91: The method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is about 1:99 to about 25:75 (v / v) ethanol:cyclohexane.

[0167] Embodiment 92: The method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is ethanol: cyclohexane in a ratio of about 3:97 to about 10:90 (v / v).

[0168] Embodiment (93): The method according to embodiment (89), wherein the mixture of ethanol and cyclohexane is ethanol: cyclohexane in a ratio of about 5:95 to about 10:90 (v / v).

[0169] Embodiment (94): The method according to any one of embodiments (89) to (91), wherein the mixture of ethanol and cyclohexane is ethanol: cyclohexane in a ratio of about 15:85 (v / v).

[0170] Embodiment (95): The method according to any one of embodiments (86) to (94), comprising the enantiopure (S)-afloqualone form II crystalline.

[0171] Embodiment (96): The method according to any one of embodiments (86) to (95), wherein it is heated to about 50 to about 80 degrees Celsius.

[0172] Embodiment (97): The method according to any one of embodiments (86) to (96), wherein the temperature is reduced to a temperature of about 10 degrees Celsius or lower.

[0173] Embodiment (98): The method according to any one of embodiments (86) to (97), wherein the temperature is reduced to a temperature of about 5 degrees Celsius or lower.

[0174] Embodiment (99): The method according to any one of embodiments (86) to (98), wherein the rate of temperature reduction is about 3 degrees Celsius per hour.

[0175] Embodiment (100): A method for preparing the (S)-afloqualone crystalline form II according to embodiment (54), which comprises: —

[0176] (a) Heating a mixture of a toluene solvate of (S)-afloqualone 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;

[0177] (b) Optionally adding a co-solvent;

[0178] (c) Lowering the temperature of the solvent system to induce nucleation;

[0179] (d) Maintaining the mixture at a temperature below the temperature at which nucleation has started; and

[0180] (e) Separating the thus-precipitated (S)-afloqualone crystalline form II.

[0181] Embodiment (101): A crystalline form of (S)-afoxolaner prepared by the method according to any one of embodiments (86) to (100).

[0182] Embodiment (102): A method of treating or preventing a parasite 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.

[0183] In yet another embodiment, the present invention provides crystalline form I of (S)-afoxolaner, which exhibits one or more of the characteristic peaks shown in Table 1 below, said peaks being expressed as 2-θ (2θ) ± 0.2 degrees.

[0184] In yet another embodiment, the present invention provides crystalline form I of (S)-afoxolaner, which exhibits at least 7 of the characteristic peaks at one or more of the positions shown in Table 1 below, said peaks being expressed as 2-θ (2θ) ± 0.2 degrees.

[0185] In yet another embodiment, the present invention provides crystalline form I of (S)-afoxolaner, which exhibits the endothermic curve described in the examples and shown in Figure 2 the endothermic curve.

[0186] In yet another embodiment, the present invention provides crystalline form I of (S)-afoxolaner and crystalline form II of (S)-afoxolaner and / or amorphous (S)-afoxolaner in combination therewith. In yet another embodiment, the present invention provides a pesticidal composition or a parasiticide composition comprising crystalline form I of (S)-afoxolaner alone or crystalline form I of (S)-afoxolaner and one or more additional active agents in combination therewith, and an agriculturally or pharmaceutically acceptable carrier or diluent, wherein at least 80% of the solid form of (S)-afoxolaner is crystalline form I.

[0187] In one embodiment, the present invention provides crystalline form II of (S)-afoxolaner, which exhibits one or more of the characteristic peaks shown in Table 1 below, said peaks being expressed as 2-θ (2θ) ± 0.2 degrees.

[0188] In yet another embodiment, the present invention provides crystalline form II of (S)-afoxolaner, which exhibits at least 7 of the characteristic peaks at one or more of the positions shown in Table 1 below, said peaks being expressed as 2-θ (2θ) ± 0.2 degrees.

[0189] In yet another embodiment, the present invention provides crystalline form II of (S)-afoxolaner, which exhibits the endothermic curve described in the examples and shown in Figure 4 the endothermic curve.

[0190] In yet another embodiment, the present invention provides crystalline form II of (S)-afoxolaner, in combination with crystalline form I of (S)-afoxolaner and / or amorphous (S)-afoxolaner. In yet another embodiment, the present invention provides a pesticidal or antiparasitic composition comprising crystalline form II of (S)-afoxolaner alone or crystalline form II of (S)-afoxolaner in combination with one or more additional active agents, and an agriculturally or pharmaceutically acceptable carrier or diluent, wherein at least 80% of the solid form of (S)-afoxolaner is crystalline form II.

[0191] 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 of total impurities.

[0192] In yet another embodiment, the polymorph contains less than 5%, less than 4%, less than 3%, less than 2% by weight of total impurities. In yet another embodiment, the polymorph contains less than 1% by weight of total impurities. In still yet another embodiment, the polymorph is substantially free of impurities.

[0193] In yet another embodiment, the present invention provides crystalline form I of (S)-afoxolaner, wherein at least 90% of the solid form is in crystalline form I.

[0194] In yet another embodiment, the present invention provides crystalline (S)-afoxolaner, wherein at least 80% of the solid form is in the crystalline toluene solvate form.

[0195] In yet another embodiment, the present invention provides crystalline form II of (S)-afoxolaner, wherein at least 90% of the solid form is in crystalline form II.

[0196] In a specific embodiment, polymorphic form I is in a substantially pure crystalline form. In yet another embodiment, polymorphic 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 or amorphous form of the compound.

[0197] Similarly, in a specific embodiment, polymorphic form II is in a substantially pure crystalline form. In yet another embodiment, polymorphic 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 or amorphous form of the compound.

[0198] In one embodiment, crystalline form I and / or crystalline form II of (S)-afloqualone can be prepared as follows: (S)-afloqualone is crystallized from a combination of a lower alcohol solvent and an aliphatic solvent according to methods known in the art. In another embodiment, form I and / or form II of (S)-afloqualone can be prepared as follows: the compound is crystallized from an alkyl ester solvent or a solvent mixture containing an alkyl ester solvent. Alkyl ester solvents include, but are not limited to, alkyl acetate solvents such as ethyl acetate, isopropyl acetate, methyl acetate, etc. In yet another embodiment, form I and / or form II of (S)-afloqualone can be prepared as follows: the compound is crystallized from a nitrile solvent or a solvent mixture containing a nitrile solvent. Nitrile solvents include, but are not limited to, acetonitrile. In another embodiment, form I and / or form II of (S)-afloqualone 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, form I and / or form II of (S)-afloqualone can be prepared as follows: the compound is crystallized from a nitrile solvent including acetonitrile.

[0199] In another embodiment, crystalline form I of (S)-afloqualone and / or crystalline form II of (S)-afloqualone can be crystallized from water, ethanol, isopropanol, methanol, toluene, dichloromethane, hexane, cyclohexane, diisopropyl ether or chlorobutane or a mixture thereof.

[0200] Aliphatic solvents are straight-chain, branched, cyclic primary, secondary or tertiary hydrocarbons and include, but are not limited to, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, etc. In another embodiment, crystalline form I and / or crystalline form II of (S)-afloqualone can be prepared as follows: (S)-afloqualone is crystallized from a solvent combination of a lower alcohol solvent and a cycloalkyl solvent. In another embodiment, crystalline form I and / or crystalline form II of (S)-afloqualone can be prepared as follows: (S)-afloqualone is crystallized from a solvent combination of an alkyl ester solvent and an aliphatic solvent. In yet another embodiment, crystalline form I and / or crystalline form II of (S)-afloqualone can be prepared as follows: (S)-afloqualone is crystallized from a solvent combination of a nitrile solvent and an aliphatic solvent.

[0201] In one embodiment of the method, the ratio of the lower alcohol solvent to the aliphatic solvent is from about 1:99 (v / v) to about 25:75 (v / v) of lower alcohol:aliphatic solvent. In another embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is from about 2:98 (v / v) to about 20:80 (v / v). In yet another embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is from about 4:96 to about 15:85. In another embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is from about 5:95 to about 10:90. In one embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is about 6:94 (v / v). In another embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is about 7:93 (v / v). In another embodiment, the ratio of the lower alcohol solvent to the aliphatic solvent is about 8:92 (v / v).

[0202] The total volume of the 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 it is more likely to form another solid form of the eutectic or impurities. In one embodiment, about 7 volumes to about 30 volumes of the total solvent or solvent mixture can be used. In another embodiment, about 10 volumes to about 25 volumes of the total solvent or solvent mixture can be used for crystallization. In yet another embodiment, about 12 volumes to about 20 volumes of the 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 the total solvent or solvent mixture can be used to crystallize (S)-afloqualone form I or form II.

[0203] (S)-afloqualone can be sourced from amorphous (S)-afloqualone or other solid forms of the compound. Alternatively, a solution of (S)-afloqualone in another solvent can be used. In one embodiment, the enantiomeric purity of (S)-afloqualone 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 (S)-afloqualone is at least about 95%. Preferably, the enantiomeric purity of (S)-afloqualone used in the process is at least about 98%. In one embodiment, (S)-afloqualone is dissolved in a suitable solvent at a concentration such that the mixture is a suspension at ambient temperature or below and a solution at elevated temperature, and then slowly cooled to induce crystallization from the solvent. In another embodiment, (S)-afloqualone 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.

[0204] Optionally, seeds can be added to promote crystallization. The seeds should be enriched in the desired enantiomer to direct crystallization towards that enantiomer. The enantiomeric excess of the seeds can be the same as or different from the amodiaquine solution to which they are added, but preferably a high enantiomeric excess, such as at least 90% ee or higher. Similarly, the seeds can be the desired racemic compound to direct crystallization towards that racemic compound.

[0205] In an embodiment of the invention, seeds can be added to induce crystallization of (S)-amodiaquine. The amount of (S)-amodiaquine seeds added is such that it exceeds the saturation amount in the solvent used, such that undissolved seeds are present in the solution. Those skilled in the art will understand that the seeding temperature depends on the solvent used and, if a solvent mixture is used, also on the solvent ratio. In one embodiment using a solvent mixture comprising an aliphatic solvent and a lower alcohol solvent, seeding can be carried out in the temperature range of about 50 °C to about 60 °C. In another embodiment, seeding can be carried out at a temperature of about 52 °C to about 58 °C. In yet another embodiment, seeding can be carried out at a temperature of about 53 °C to 57 °C. In yet another embodiment, seeding can be carried out at 55 °C.

[0206] Allow the mixture 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 for further aging, and subsequently further cooled to separate the crystallized product. This cycle can be repeated. The heating / cooling cycle can be used to increase the size of the crystals formed; however, this 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 sufficient to achieve the 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. In one embodiment, the mixture is aged at the desired temperature for about 2 hours to about 27 hours. Then the crystallization mixture is further cooled to a temperature below about 20 °C and aged, and subsequently the crystals are separated 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, and then the crystals are separated.

[0207] The cooled mixture is aged for a sufficient time and then separated. The length of aging before separation can vary without significantly affecting the 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 and then separated. In yet 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.

[0208] In yet another embodiment of the present invention, the crystals can be collected by filtration or centrifugation and optionally washed to remove residual ethanol. Drying can also be carried out if desired. Appropriate drying conditions should be selected to avoid melting of the compound of formula (Ia). For example, overheating should be avoided during the drying conditions.

[0209] The present invention also relates to enantiopure (S)-afloqualone in crystalline form. The crystalline form can be more stable, easier to handle and store, and easier to purify and synthesize in a reproducible manner.

[0210] In one aspect, there is provided a pharmaceutical composition comprising a compound of formula (Ia) such as polymorphic form I or polymorphic form II or a mixture thereof, and a pharmaceutically acceptable carrier or diluent. For example, in one embodiment, there is provided a pharmaceutical composition comprising polymorphic form I and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a pharmaceutical composition comprising polymorphic form II and a pharmaceutically acceptable carrier or diluent. In still another embodiment, the present invention provides a pharmaceutical composition comprising a mixture of polymorphic form I and polymorphic form II and a pharmaceutically acceptable carrier or diluent.

[0211] In the case where the compounds of the present invention are administered to an animal such as a mammal as a medicine, they can be provided as such or as a pharmaceutical composition containing, for example, 0.1% to 99.9% (w / w) (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier combined therewith. In other embodiments, the pharmaceutical composition comprises from about 0.5% to about 50% (w / w), from about 0.5% to about 25% (w / w) of the compound of formula (Ia) in the form of form I, form II or a mixture thereof. In other embodiments, the pharmaceutical composition comprises from about 0.5% to about 15% (w / w) or from about 0.5% to about 10% (w / w) of form I, form II or a mixture thereof. In still another embodiment, the pharmaceutical composition comprises from about 0.1% to about 5% (w / w) or from about 0.1% to about 2.5% (w / w) of the compound of formula (Ia) in the form of form I, form II or a mixture thereof.

[0212] In yet another aspect of the present invention, there are provided compositions comprising a mixture of two or more forms or crystals (e.g., Form I and Form II) and an amorphous form of the compound of formula (Ia), which may have particular advantages in extended release formulations. Accordingly, the present invention also relates to mixtures of the crystalline products of the compound of formula (Ia).

[0213] In yet another aspect of the present invention, the crystals of the compound of formula (Ia) comprise a mixture of crystalline forms (e.g., Form I and Form II) and an amorphous form. 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), with preferred amounts being 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).

[0214] 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).

[0215] The crystalline forms described herein can be combined with pharmaceutically acceptable carriers according to conventional pharmaceutical mixing techniques. Additionally, the carrier can be in a wide variety of forms, depending on the dosage form desired for administration, e.g., oral (e.g., tablets, capsules or soft chewables) or parenteral (including intravenous injections or infusions). In preparing compositions for oral dosage forms, any conventional pharmaceutical medium can be used. Conventional pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, surfactants, solvents, binders, humectants, etc. in the case of oral liquid formulations (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 glycols, etc.), disintegrating agents, etc. in the case of oral solid formulations (such as powders, capsules, tablets and soft chewables).

[0216] Wetting agents, emulsifying agents, surfactants and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and aromatic agents, 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 chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0217] Examples of suitable surfactants for pharmaceutical compositions include glyceryl 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 polyethylene glycol 40 hydrogenated castor oil polyethylene glycol 60 hydrogenated castor oil propylene glycol monolaurate glycerides including glycerol caprylate / caprate polyethylene glycolated glycerides PEG 300 caprylic / capric glyceride PEG 400 caprylic / capric glyceride PEG 300 oleic glyceride PEG 300 linoleic glyceride polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyethylene glycol 8 stearate (PEG 400 monostearate), polyethylene glycol 40 stearate (PEG1750 monostearate), etc. The surfactant can 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 can be present at a concentration of about 0.1% to about 5% (w / w) or about 1 to about 5% (w / w).

[0218] Fillers that can be used in oral formulations include, but are not limited to, corn starch, pregelatinized corn starch, soy protein isolate, corn cob, and corn gluten meal, etc., or combinations thereof. Fillers are generally present in the composition 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%.

[0219] Binders for which the composition of the present invention can be used for oral administration include, but are not limited to, polyvinylpyrrolidone (e.g., povidone), cross-linked polyvinylpyrrolidone (crospovidone), various grades of polyethylene glycol including PEG 3350, PEG4000, PEG 6000, PEG 8000 and even PEG 20,000, etc.; copolymers of vinylpyrrolidone and vinyl acetate (e.g., copovidone) such as the product sold by BASF under the trade name VA 64, etc.; starches such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and various types of sugars; or combinations of two or more binders. In one embodiment, the composition comprises the binders povidone K30 LP 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 comprises 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).

[0220] Solvents that can be used in the composition 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., 810 and 812, caprylic / capric / succinic triglyceride, propylene glycol dicaprylate / dicaprate, etc.; water, sorbitol solution, glyceryl caprylate / caprate and polyethylene glycolated glycerides 2-pyrrolidone, N-methylpyrrolidone (NMP), dimethylacetamide, or combinations thereof.

[0221] The solvent can 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 concentration of the solvent in the composition is about 5% to about 20% (w / w) or about 5% to about 15% (w / w).

[0222] Humectants that can be used in the composition include, but are not limited to, glycerol (also referred to herein as glycerin), propylene glycol, cetyl alcohol, and glyceryl monostearate, etc. Various grades of polyethylene glycol can also be used as humectants. 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.

[0223] A pharmaceutical composition comprising a crystalline form of a compound of formula (Ia) (such as Form I and / or Form II) can be formulated to have any desired concentration, preferably a therapeutically effective amount that does not cause one or more undesirable side effects.

[0224] Because of the convenience of administration, tablets, soft chewable dosage forms, and capsules can represent the most advantageous oral dosage unit forms, and in this case, solid pharmaceutical carriers can be used. If desired, tablets and soft chewable dosage forms can be coated by techniques known to those skilled in the art.

[0225] In certain embodiments, the pharmaceutical composition contains varying amounts of the 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 contains less than 1% by weight of the crystalline form of the polymorphic form I of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition contains less than 1% by weight of the crystalline form of the polymorphic form I of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition contains less than 10% by weight of the crystalline form of the polymorphic form I. In yet another embodiment, the pharmaceutical composition contains less than 25% by weight of the polymorphic form I of the compound of formula (Ia).

[0226] In yet another embodiment, the pharmaceutical composition contains less than 50% by weight of the polymorphic form I of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition contains less than 99% by weight of the polymorphic form I of the compound of formula (Ia).

[0227] In other embodiments, the pharmaceutical composition of the present invention contains at least about 30% (w / w), at least about 50% (w / w), or at least about 70% (w / w) of the polymorphic form I of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition of the present invention contains at least about 80% (w / w), at least about 90% (w / w), or at least about 95% (w / w) of the polymorphic form I of the compound of formula (Ia). In still yet another embodiment, the composition of the present invention contains at least about 99% (w / w) of the form I of the compound of formula (Ia).

[0228] In yet another embodiment, the pharmaceutical composition comprises less than 1% by weight of the polymorphic form II crystal form of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 1% by weight of the polymorphic form II crystal form of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 10% by weight of the polymorphic form II crystal form of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 25% by weight of the polymorphic form II of the compound of formula (Ia).

[0229] In yet another embodiment, the pharmaceutical composition comprises less than 50% by weight of the polymorphic form II of the compound of formula (Ia). In yet another embodiment, the pharmaceutical composition comprises less than 99% by weight of the polymorphic form II of the compound of formula (Ia).

[0230] 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 polymorphic 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 polymorphic form II of the compound of formula (Ia). In still yet another embodiment, the compositions of the present invention comprise at least about 99% (w / w) of the form II of the compound of formula (Ia).

[0231] Pharmaceutical compositions include those suitable for oral, sublingual, nasal, rectal, vaginal, topical (e.g., creams or drenches), 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 compositions may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical art. In certain embodiments, the pharmaceutical composition is formulated for oral administration in the form of pills, capsules, soft chewable dosage forms, lozenges or tablets. In other embodiments, the pharmaceutical composition is in the form of a suspension.

[0232] A pharmaceutical composition comprising a particular crystal 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 particular crystal form. It should be recognized that a pharmaceutical composition comprising a particular crystal form may exhibit an X-ray powder diffraction pattern that is not exactly the same as that of the pure particular polymorphic X-ray powder diffraction pattern.

[0233] Also provided herein are crystal forms that are biologically equivalent to any one or more of the (S)-afranol polymorphic forms I and II described herein. In certain embodiments, biological equivalence between two crystal forms means that the crystal forms have substantially similar bioavailability, substantially similar potency, substantially similar safety profiles, or combinations thereof.

[0234] In other embodiments, biological equivalence means that the crystalline forms exhibit substantially similar pharmacokinetic characteristics or therapeutic effects. Biological equivalence can be demonstrated by several in vivo and in vitro methods. These methods can include, for example, pharmacokinetics, pharmacodynamics, clinical, and in vitro studies. In certain embodiments, biological equivalence can be demonstrated using any suitable pharmacokinetic means or combination of pharmacokinetic means known in the art, 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, peak blood or plasma concentration (C), time to reach peak concentration (T), bioavailability, and efficacy. In certain embodiments, biological equivalence is achieved with similar dose administrations. In alternative embodiments, biological equivalence is achieved with different dose administrations.

[0235] Given the pharmaceutical value of crystalline (S)-afloqualone, it is important to be able to obtain it by an efficient synthetic process that can be easily scaled up and that gives crystalline (S)-afloqualone in good yield and with excellent enantiomeric and chemical purity.

[0236] The Applicant has now developed a new synthetic process that gives crystalline (S)-afloqualone in a reproducible manner and without laborious purification, the purity being consistent with its use as a pharmaceutical active ingredient.

[0237] Examples are used to further illustrate and explain the invention and should in no way be regarded as limiting. Unless otherwise specified in the examples and elsewhere in the specification and claims, all parts and percentages are by weight. Temperatures are in degrees Celsius.

[0238] It should be appreciated that certain features of the invention that are described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable sub-combination or in any other suitable embodiment of the invention as described. Certain features that are described in the context of various embodiments are not to be considered essential features of those embodiments unless the embodiment cannot function without those elements.

[0239] Benefits, other advantages, and solutions to problems have been described above with respect to specific embodiments. However, such benefits, advantages, solutions to problems, and any features that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features of any or all of the claims.

[0240] It should be noted that the present invention is not intended to cover within the scope of the present invention any pre - disclosed composition, product, method of making a product, or method of using a product that meets the written description and enablement requirements of the USPTO (35 U.S.C. 112, paragraph 1) or the EPO (Article 83 of the EPC), and thus the applicant reserves the right and hereby discloses the exclusion of any pre - described product, method of making a product, or method of using a product.

[0241] Examples

[0242] Example 1: Synthesis of racemic afloqualone and (S)-afloqualone

[0243] Racemic afloqualone can be obtained by methods such as those disclosed in U.S. Patent No. US8410153, which is hereby incorporated by reference in its entirety. Enantiomerically enriched afloqualone, which is enriched in the (S)-enantiomer, can be obtained by methods such as those disclosed in U.S. Application No. 62 / 319,207, which is the priority document of U.S. 15 / 480,316 published as U.S. 2017 / 0311601 A1, and is hereby incorporated by reference in its entirety.

[0244] Example 2 - Synthesis of the toluene solvate of crystalline (S)-afloqualone

[0245] (a) Synthesis of (S)-afloqualone:

[0246]

[0247] 1. Add 1 kg of compound (IIA - 1) (1 equivalent) and 9 volumes of dichloromethane (DCM) to a reactor and stir to dissolve the compound.

[0248] 2. Cool the mixture to about 0 °C, add 50 g (5% by weight of compound (IIA - 1)) of chiral phase - transfer catalyst (IIIa - 13 - 1) and 1 L of DCM, and cool the resulting mixture to about - 13 °C.

[0249] 3. Simultaneously add a 19% (w / w) hydroxylamine sulfate solution (prepared with 294 g of (NH2OH)H2SO4 and 141 g of NaCl in 1112 mL of water, 1.1 equivalents) and a 4.4 - equivalent 17.6% (w / w) NaOH solution (prepared with 286 g of NaOH and 158 g of NaCl in 1180 mL of water) to the reaction mixture.

[0250] 4. Vigorously mix the resulting reaction mixture at about - 13 °C for about 20 hours, and then check the reaction conversion by HPLC (target ≤ 0.5% area);

[0251] 5. After completion of the reaction, water (3 volumes) is added at about 0 °C. Then, an aqueous solution of 709 g of KH2PO4 in 4.2 liters is added to the mixture to adjust the pH (target 7 - 8), and the resulting mixture is stirred at about 20 °C for 30 minutes.

[0252] 6. Allow the layers to settle, remove the aqueous layer, and wash the organic layer twice with 3 liters of water to afford (S)-afloqualone in the organic layer.

[0253] b) Crystallization of the toluene solvate

[0254] 1. After the extraction / washing step of Example 2(a)(6) above, dichloromethane is removed by distillation under reduced pressure to about 1 - 2 volumes, and toluene (about 5 - 10 volumes) is added.

[0255] 2. Adjust the volume by further distillation under reduced pressure and / or add more toluene to about 5 - 6 volumes. Further distill the mixture and maintain the volume to substantially remove the dichloromethane reaction solvent.

[0256] 3. Then cool the mixture to about 10 °C and seed with afloqualone (racemic compound), and stir at the same temperature for at least 2 hours;

[0257] 4. Heat the mixture to about 55 - 65 °C and age (in one embodiment for at least 17 hours), then filter off the solid racemate. Wash the filtered solid with toluene;

[0258] 5. Adjust the combined filtrate and washings to about 5 - 6 volumes by distillation under reduced pressure and / or addition of toluene;

[0259] 6. Cool the resulting mixture to about 10 °C and age for at least 5 hours, then filter. Wash the cake with toluene.

[0260] 7. Dry the cake under reduced pressure at 50 °C to obtain the crystalline (S)-afloqualone toluene solvate, which is rod-shaped crystals.

[0261] Example 3: Formation of (S)-afloqualone polymorph I from ethanol / cyclohexane

[0262] In a 25 L jacketed vessel at 20 °C, add the following:

[0263] (S)-afloqualone toluene solvate (e.e. 96%) 591 g

[0264] EtOH (ethanol) 709 ml

[0265] Cyclohexane 1773 ml

[0266] After addition of the substance, the reaction mixture was 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 was added, the stirring speed was adjusted to 100 rpm (0.04 W.L-1) and cooled to 55 °C. The mixture can be seeded at this stage to promote crystal formation. The mixture was then subjected to the following procedural steps twice:

[0267] Cooled to 30 °C (-10 °C / h)

[0268] Stirred at 30 °C for 30 minutes

[0269] The stirring power was increased to 0.13 W.L-1

[0270] Heated to 60 °C (15 °C / h)

[0271] Stirred at 60 °C for 1 h

[0272] After completion of 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 5 h. The suspension was then filtered at 10 °C and washed twice with cyclohexane at 10 °C (i.e., 2 x 1.2 L). The filtered crystals were then dried under reduced pressure (50 mbar) at 50 °C for 20 h, giving 453.7 g of unsolvated crystalline (S)-afloqualone, with a chemical purity greater than 94% (e.e. ≥96%). Thermogravimetric analysis (TGA) showed no weight loss, indicating the presence of a solvate crystal form. The unsolvated crystalline (S)-afloqualone was confirmed by XRPD to be Form I.

[0273] Example 4: Formation of (S)-afloqualone Crystal Form II from Ethanol / Cyclohexane

[0274] Using a method similar to Example 3 but with 100% optically pure (S)-afloqualone toluene solvate and 15 / 85% v / v ethanol / cyclohexane as the crystallization solvent gave (S)-afloqualone Form II. Thermogravimetric analysis (TGA) showed no weight loss, indicating the presence of a solvate crystal form. The unsolvated crystalline (S)-afloqualone was confirmed by XRPD to be Form II.

[0275] (S)-afloqualone Forms I and II X-ray Powder Diffraction (XRPD) Analysis

[0276] Table 1 summarizes the peaks in the X-ray diffraction patterns of (S)-afloqualone Forms I and II, measured using the following equipment and parameters:

[0277] Equipment: Bruker D8 Advance diffractometer

[0278] Source

[0279] Generator: 40 kV - 30 mA

[0280] Detector: lynx Eye.

[0281] PMMA sample holder

[0282] Phi rotator:

[0283] Rotation speed: 30 rpm

[0284] Angle range: 2° to 40°, θ-θ

[0285] Variable dispersion slit: 12 mm (V12)

[0286] Step size: 0.02°

[0287] Step time 10.6 s

[0288] Form I shows the most prominent 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 prominent peaks at 2θ = 5.99°, 12.99°, 15.80°, 18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11°, 29°.

[0289] Table 1:

[0290]

[0291] (S)-Afloqualone Forms I and II differential scanning calorimetry thermal analysis

[0292] Forms I and II were measured using the following equipment and parameters:

[0293] Equipment: PerkinElmer Diamond DSC

[0294] Atmosphere: nitrogen 20 ml / min

[0295] Pan: 50 μl aluminum pan

[0296] Cover: drilled aluminum cover with 100 μm holes

[0297] Rate: 5 °C / min

[0298] Form I: The differential scanning calorimetry (DSC) thermogram has a peak located at a temperature of approximately 146 °C and starting at approximately 143 °C.

[0299] Form II: The differential scanning calorimetry (DSC) thermogram has a peak located at a temperature of about 149 °C and starting at about 146 °C.

[0300] Example 5: Formation of (S)-afloqualone polymorph I from ethyl acetate

[0301] The procedure of Example 3 was followed, but using ethyl acetate instead of the EtOH / cyclohexane mixture, and after completion of the second procedure, the mixture was cooled to 4 °C at a rate of -5 °C / h and stirred at 4 °C for 72 h to isolate (S)-afloqualone polymorph I.

[0302] Example 6: Formation of (S)-afloqualone polymorph I from acetonitrile

[0303] The procedure of Example 3 was followed, but using acetonitrile instead of the EtOH / cyclohexane mixture, and after completion of the second procedure, the mixture was cooled to 4 °C at a rate of -5 °C / h and stirred at 4 °C for 72 h to isolate (S)-afloqualone polymorph I.

Claims

1. Crystals of the compound of formula (Ia), designated as Form I, wherein said crystals are characterized by having an X-ray powder diffraction pattern that contains 3, 4, 5, 6, 7 or more peaks selected from the following: 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.

2. Crystals of the compound of formula (Ia) according to claim 1, characterized in that Having an X-ray powder diffraction pattern that includes 3 or more peaks selected from: 10.03°, 10.48°, 13.16°, 20.16° and 22.15° 2θ ± 0.2, as measured on a diffractometer using Cu-Kα radiation.

3. Crystals of the compound of formula (Ia) according to claim 1 or 2, characterized in that Having an X-ray powder diffraction pattern substantially similar to Figure 1.

4. Crystals of the compound of formula (Ia) according to any one of claims 1 to 3, characterized in that Having a differential scanning calorimetry (DSC) thermogram with a peak located at a temperature of about 146 °C and starting at about 143 °C, measured at a heating rate of 5 °C / min.

5. Crystals of the compound of formula (Ia) according to any one of claims 1 to 4, characterized in that Having a differential scanning calorimetry (DSC) thermogram with a heat of fusion of about 61.7 J / g.

6. Crystals of the compound of formula (Ia) according to any one of claims 1 to 5, characterized in that Having a differential scanning calorimetry thermogram substantially similar to Figure 2.

7. Crystals of the compound of formula (Ia) according to any one of claims 1 to 6, which are enantiomerically pure.

8. Crystals of the compound of formula (Ia) according to any one of claims 1 to 7, having a chemical purity of at least 97%.

9. Crystals of the compound of formula (Ia) according to any one of claims 1 to 8, having an enantiomeric purity of at least 98%.

10. Crystals of the compound of formula (Ia) according to any one of claims 1 to 9, in a substantially pure crystalline form.

11. Crystals of the compound of formula (Ia), designated as Form II, wherein said crystals are characterized by having an X-ray powder diffraction pattern that contains 3, 4, 5, 6, 7 or more peaks selected from the following: 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.

12. A crystal of a compound of formula (Ia) according to claim 11, wherein the crystal is characterized by 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.

13. A crystal of a compound of formula (Ia) according to claim 11 or 12, characterized in that Having an X-ray powder diffraction pattern substantially similar to Figure 3.

14. A crystal of a compound of formula (Ia) according to any one of claims 11 to 13, characterized in that Having a differential scanning calorimetry (DSC) thermogram with a peak located at a temperature of about 149 °C and starting at about 146 °C, measured at a heating rate of 5 °C / min.

15. A crystal of a compound of formula (Ia) according to any one of claims 11 to 14, characterized in that Having a differential scanning calorimetry (DSC) thermogram with a heat of fusion of about 65.7 J / g.

16. A crystal of a compound of formula (Ia) according to any one of claims 11 to 16, characterized in that Having a differential scanning calorimetry thermogram substantially similar to Figure 4.

17. A crystal of a compound of formula (Ia) according to any one of claims 11 to 16, which is enantiopure.

18. A crystal of a compound of formula (Ia) according to any one of claims 11 to 17, having a chemical purity of at least 97%.

19. A crystal of a compound of formula (Ia) according to any one of claims 1 to 9 or 11 to 18, wherein the compound of formula (Ia) is a mixture of crystalline form I and crystalline form II and / or an amorphous form of the compound of formula (Ia).

20. A pharmaceutical composition comprising crystalline form I of a compound of formula (Ia) according to any one of claims 1 to 10 and / or crystalline form II of a compound of formula (Ia) according to any one of claims 11 to 18, and at least one pharmaceutically acceptable excipient.

21. The composition according to claim 20, wherein the composition comprises a mixture of crystalline form I and / or crystalline form II of the compound of formula (Ia) and / or an amorphous form of the compound of formula (Ia).

22. The pharmaceutical composition of claim 21, wherein the composition comprises at least 90% by weight of crystalline form I of a compound of formula (Ia) according to any one of claims 1 to 10 or at least 90% by weight of crystalline form II of a compound of formula (Ia) according to any one of claims 11 to 18, based on the total weight of the compound of formula (Ia) in the composition.

23. A crystal form of (S)-afloqualone designated as form I or form II, prepared by the following method: The specified crystalline form of Form I is non-solvated and characterized by having an X-ray powder diffraction pattern that includes 7 or more peaks selected from the following: 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 The specified crystalline form of Form II is non-solvated and characterized by having an X-ray powder diffraction pattern that includes 7 or more peaks selected from the following: 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 (S)-afloqualone toluene solvate 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 has begun; and (d) Separating the crystals of the compound of formula (Ia) so precipitated.

24. The crystalline form of (S)-afoxolaner of claim 23, wherein the mixture of ethanol and cyclohexane is ethanol:cyclohexane in a ratio of 3:97 to 10:90 (v / v).

25. The crystalline form of (S)-afoxolaner of claim 23, wherein the mixture of ethanol and cyclohexane is ethanol:cyclohexane in a ratio of 8:92 (v / v).

26. The crystalline form of (S)-afoxolaner of any one of claims 23 to 25, comprising the enantiopure (S)-afoxolaner Form I seed crystal.

27. The crystalline form of (S)-afoxolaner of any one of claims 23 to 25, wherein the temperature is reduced to a temperature of 5 degrees Celsius..

Images