Solvate form of (r)-2-amino-3-phenylpropyl carbamate

Abstract

To provide a solvate form of (R)-2-amino-3-phenylpropyl carbamate (APC) hydrochloride, a method of preparing APC hydrochloride, and methods of using the same to treat disorders.SOLUTION: The present invention provides a solvate form of (R)-2-amino-3-phenylpropyl carbamate hydrochloride, characterized by a specific powder X-ray diffraction pattern and / or a powder X-ray diffraction pattern having peaks at about 7.0, 13.6, 16.2, 17.4, 17.8, 18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3±0.2° 2θ. The invention further provides methods of producing APC hydrochloride with increased purity.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Priority claim This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 383,822, filed September 6, 2016, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a newly identified solvate form of (R)-2-amino-3-phenylpropylcarbamate (APC) hydrochloride, a method for preparing APC hydrochloride, and its use in the treatment of disorders. The present invention further relates to a method for preparing APC hydrochloride with increased purity. [Background technology]

[0003] APC is an analog of phenylalanine that has been proven effective in treating various disorders including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, etc. See, for example, U.S. Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290; and see U.S. Patent Application Publication Nos. 2012 / 0004300 and 2015 / 0018414. Methods for producing APC (also known by other names) and related compounds can be found in U.S. Patent Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of the above mentioned patents and applications are incorporated herein by reference in their entirety for all purposes. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention overcomes the deficiencies in the art by providing new solvated forms of APC and methods for producing APC with minimal contamination. [Means for solving the problem]

[0005] The present invention relates to the identification of novel solvate forms of APC, which are hemihydrate forms. The present invention further relates to methods for producing APC with minimal contamination. The present invention also relates to the use of APC with increased purity and / or novel solvate forms for the treatment of disorders responsive to APC.

[0006] Accordingly, the present invention relates to solvate forms of APC hydrochloride characterized by an X-ray powder diffraction pattern substantially identical to that shown in FIG. 1 and / or an X-ray powder diffraction pattern having peaks at about 7.0, 13.6, 16.2, 17.4, 17.8, 18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3±0.2 degrees 2θ.

[0007] The present invention also relates to a method for preparing a solvate form of APC hydrochloride, comprising slurrying APC hydrochloride in acetonitrile / water (95% / 5% v / v) and collecting the solvate by vacuum filtration.

[0008] The present invention further relates to compositions comprising APC, wherein less than about 10% of the APC in the composition is a solvate form of the present invention.

[0009] The present invention further relates to compositions comprising APC, wherein at least about 30% of the APC in the composition is a solvate form of the present invention.

[0010] The present invention also relates to a method of treating an APC-treatable disorder, such as narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder or obesity in a subject in need thereof, or promoting smoking cessation in a subject in need thereof, comprising administering to the subject a dosage form comprising the solvate form of the present invention.

[0011] The present invention also relates to a method for producing APC hydrochloride while minimizing contamination with 2-chloropropane, the method comprising the step of crystallizing APC in the presence of an aqueous HCl solution to produce crystals of APC hydrochloride.

[0012] The present invention further relates to compositions comprising APCs of increased purity produced by the methods of the invention.

[0013] The present invention also relates to methods of treating disorders treatable with APC, such as treating narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention-deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity in a subject in need thereof, or promoting smoking cessation in a subject in need thereof, comprising administering to the subject a dosage form comprising APC of increased purity produced by the methods of the invention.

[0014] The invention is explained in more detail in the drawings herein and the specification set forth below. [Brief description of the drawings]

[0015] [Figure 1] 1 shows the X-ray pattern diffraction (XRPD) of a crystalline form of APC. [Diagram 2] 1 shows a differential scanning calorimetry (DSC) thermogram of hemihydrate Form B of APC. [Diagram 3] FIG. 1 shows a comparison of DSC thermograms for APC forms A and B. [Figure 4] 1 shows a comparison of thermogravimetric (TG) thermograms for APC forms A and B. [Diagram 5] 1 shows the XRPD pattern for the conversion of APC form A to form B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention may be embodied in other forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features described in connection with one embodiment can be incorporated in other embodiments, and features described in connection with a particular embodiment can be deleted from that embodiment. Moreover, numerous modifications and additions to the embodiments proposed herein will be apparent to those skilled in the art in light of this disclosure without departing from the invention.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used in the description herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the invention.

[0018] It is specifically intended that the various features of the invention described herein can be used in any combination, unless the context indicates otherwise.

[0019] Furthermore, it is anticipated that in some implementations of the present invention, any feature or combination of features described herein may be excluded or omitted.

[0020] For purposes of explanation, where the specification describes a composite containing components A, B, and C, specifically either A, B, or C, or any combination thereof, singly or in any combination, may be omitted or disclaimed.

[0021] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes.

[0022] As used herein, "a," "an," or "the" can mean one or more. For example, "a cell" can mean a single cell or multiple cells.

[0023] Additionally, as used herein, "and / or" refers not only to any and all possible combinations of one or more of the associated listed items, but also to the absence of a combination when interpreted as the alternative ("or").

[0024] Additionally, the term "about" as used herein when referring to a measurable value such as an amount, dosage, time, temperature, etc., of a compound or formulation of the present invention is meant to include variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the particular amount.

[0025] The term "consisting essentially of" (and grammatical variations) as applied to compositions of the invention means that the composition may include additional components so long as the additional components do not materially modify the composition. The term "materially modified" as applied to a composition indicates an increase or decrease in the therapeutic efficacy of the composition by at least about 20% or more as compared to the therapeutic efficacy of a composition consisting of the recited components.

[0026] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of a composition, compound, or agent of the invention that confers a modulating effect, which can be a beneficial effect on a subject suffering from a disorder, disease, or condition, including, for example, improving the subject's condition (e.g., in one or more symptoms), reducing or slowing the progression of the condition, delaying the onset of the disorder, and / or changing clinical parameters in the disease or condition, as known in the art. For example, a therapeutically effective amount or effective amount can refer to an amount of a composition, compound, or agent that improves the subject's condition by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0027] "Treat" or "treating" or "treatment" refers to any type of action that imparts a modifying effect, which can be, for example, a beneficial effect on a subject suffering from a disorder, disease or condition, including improving the subject's condition (e.g., in one or more symptoms), reducing or slowing the progression of a condition, and / or changing clinical parameters of the disease or illness, as known in the art.

[0028] "APC-treatable disorder" means any disorder in which administration of APC to a patient treats one or more symptoms of the disorder in the patient. Examples of such disorders include, but are not limited to, narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention-deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity.

[0029] As used herein, "pharmaceutical acceptable" includes a substance that is not biologically or otherwise objectionable. That is, it means that the substance can be administered to an individual together with the composition of the present invention without causing substantial adverse biological effects or interacting in a harmful manner with any other components contained in the composition. As is well known to those skilled in the art, the substance is naturally selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject (see, for example, Remington's Pharmaceutical Science; 21st Edition, 2005).

[0030] "Concurrently" means sufficiently short in time to produce a combined effect (i.e., concurrently can be simultaneously together or can be two or more events occurring within a short time period before and after each other). In some implementations, administering two or more compounds "concurrently" means that the two compounds are administered within a short enough time period that the presence of one alters the biological effect of the other. The two compounds can be administered in the same or different formulations, or sequentially. Concurrent administration can be accomplished by mixing the compounds prior to administration, or by administering the compounds in two different formulations, for example, at the same time but at different anatomical sites or using different routes of administration.

[0031] The present invention relates to the identification and characterization of a new solvate form of APC hydrochloride, designated Form B. The solvate form is a hemihydrate form, which is a more stable form of the compound at high humidity levels compared to anhydrous Form A.

[0032] The structure of APC free base is represented by Formula I below.

[0033] JPEG2024178291000002.jpg77166

[0034] Accordingly, one aspect of the present invention relates to a solvate form of APC hydrochloride characterized by an X-ray powder diffraction pattern substantially identical to that shown for Form B in Figure 1 and / or an X-ray powder diffraction pattern having peaks at about 7.0, 13.6, 16.2, 17.4, 17.8, 18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3±0.2 degrees 2θ. In some embodiments, the solvate is further characterized by having a broad endotherm with an onset at a temperature of 69.1°C and a peak at a temperature of 71.7°C by differential scanning calorimetry, and a sharp endotherm with an onset at a temperature of 182.5°C and a peak at a temperature of 183.6°C. In some implementations, the solvate is further characterized by having a buffer solubility of about 700-750 mg / ml at pH 1-6.5, hi certain implementations, the solvate form is a hemihydrate.

[0035] In some implementations, the solvate form is further characterized by being produced by slurrying the APC in acetonitrile / water (95% / 5% v / v).

[0036] As used herein, the term "hemihydrate" refers to a hydrate in which one molecule of water is associated with two molecules of APC.

[0037] As used herein, the term "crystalline" refers to a material containing a particular compound, which is hydrated and / or solvated, and has sufficient crystalline content to exhibit a discernible diffraction pattern by XRPD or other diffraction techniques.

[0038] The solvate form can be prepared by a process that includes slurrying APC hydrochloride in a suitable solvent system (e.g., acetonitrile / water (95% / 5% v / v)) and collecting the solvate crystals using a suitable technique, e.g., vacuum filtration. In some implementations, the above process is carried out at room temperature, e.g., about 20° C. to 28° C., and in about 5 to 10 (e.g., 10) volumes of solvent. In some implementations, the slurrying step is carried out for a sufficient time for the solvate to form, e.g., at least about 10 hours, e.g., at least about 10, 15, 20, 25, 50, 75, or 100 hours or more.

[0039] In some implementations, the above process is carried out at a temperature of about 20° C. and in about 5 volumes of solvent. In some implementations, the slurrying step is carried out for a time sufficient for the solvate to form, for example, about 1-2 hours.

[0040] Wet Form B produced by the methods described herein may be maintained as Form B, and Form A may be dried by any method suitable to limit dehydration. In some implementations, drying is performed at a temperature of about 20° C. to about 25° C. In some implementations, drying is performed at reduced pressure, e.g., about 600-950 mbar, e.g., about 700-750 mbar. In some implementations, drying is performed for a suitable time to achieve complete drying, e.g., about 4-40 hours, e.g., about 10-24 hours. In some implementations, drying is performed at high humidity, e.g., 80-100% relative humidity.

[0041] Yet another aspect of the invention relates to compositions, e.g., dosage forms, comprising APC, wherein less than about 10% of the APC in the composition is solvate form B. In some implementations, less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the APC is solvate form B. In some implementations, the dosage form is an oral dosage form, e.g., a tablet or capsule, including, e.g., an immediate release dosage form.

[0042] A further aspect of the invention relates to compositions, e.g., dosage forms, comprising APC, wherein at least about 30%, e.g., about 30% to about 99% or more, of the APC in the composition is solvate Form B. In some implementations, at least about 40%, 50%, 60%, 70%, 80%, or 90% of the APC is solvate Form B. In some implementations, the dosage form is an oral dosage form, e.g., a tablet or capsule, including, e.g., an immediate release dosage form.

[0043] In some implementations, the dosage form is an immediate release dosage form that releases at least 85%, for example at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the APC HCl contained therein within a period of less than 15 minutes after administration of the tablet to a subject. Such immediate release dosage forms are disclosed, for example, in U.S. Provisional Patent Application No. 62 / 383,818, the entire contents of which are incorporated herein by reference.

[0044] APC preparations, including immediate release formulations, can be processed into unit dosage forms suitable for oral administration, such as, for example, filled capsules, compressed tablets or caplets, or other dosage forms suitable for oral administration using conventional techniques. The immediate release dosage forms prepared as described can be adapted for oral administration to achieve and maintain therapeutic levels of APC for a preselected interval. In certain implementations, the immediate release dosage forms as described herein can include solid oral dosage forms of any desired shape and size, including round, elliptical, oblong cylindrical, or polygonal. In one such implementation, the surface of the immediate release dosage form can be flat, round, concave, or convex.

[0045] In particular, when the immediate release dosage form is manufactured as a tablet, the immediate release tablet contains a relatively high percentage and absolute amount of APC, which is expected to improve patient compliance and convenience by replacing the need to ingest large amounts of liquid or liquid / solid suspensions. One or more immediate release tablets as described herein can be administered, for example, by oral ingestion, closely spaced apart to provide a therapeutically effective dose of APC to a patient within a relatively short period of time.

[0046] If desired or necessary, the exterior surface of the immediate release dosage form can be coated, for example with a color coating or moisture barrier layer, using materials and methods known in the art.

[0047] The dosage form can contain an amount of APC or a pharma- ceutically acceptable salt thereof suitable for administration as a unit dosage form. In some implementations, the dosage form contains about 1 mg to about 1000 mg of drug, or any range or value thereof, such as about 10 mg to about 500 mg, for example, about 37.5 mg, about 75 mg, about 150 mg, or about 300 mg.

[0048] APC or a pharma- ceutically acceptable salt thereof can be obtained or synthesized by methods known in the art and described herein. Detailed reaction schemes for synthesizing APC are described in U.S. Patents 5,705,640; 5,756,817; 5,955,499; and 6,140,532, all of which are incorporated by reference in their entireties.

[0049] During the development of the manufacturing process for APC, it was found that unacceptable levels of the impurity 2-chloropropane (i.e., isopropyl chloride) can appear during crystallization of APC hydrochloride. Because this is a potential genotoxic impurity, it is preferable to minimize 2-chloropropane. Accordingly, one aspect of the present invention relates to an improved method for producing APC hydrochloride with minimal contamination by 2-chloropropane. Such improved methods result in levels of 2-chloropropane in the final product that are less than about 10 ppm, e.g., less than about 9, 8, 7, 6, 5, 4, 3, 2, or 1 ppm.

[0050] Thus, one aspect of the present invention relates to a method for producing APC hydrochloride with minimal contamination by 2-chloropropane, the method comprising the step of crystallizing APC in the presence of aqueous HCl to produce crystals of APC hydrochloride. Crystallization can be carried out using the free base of APC in a suitable solvent, for example, isopropanol.

[0051] In some embodiments, the aqueous HCl solution is a 37% aqueous HCl solution. In some embodiments, the crystallization is carried out at a temperature of about 15°C to about 40°C, for example, about 25°C to about 35°C, followed by cooling to a temperature below 0°C, for example, about -5°C to about -25°C, for example, about -15°C. In some embodiments, the crystals are dried at a temperature below about 45°C, for example, below about 40°C, 35°C, or 30°C. In some embodiments, the crystallization is carried out in the presence of about 1 to about 1.2 molar equivalents (for example, about 1.05 molar equivalents) of a 37% aqueous HCl solution at a temperature of about 25°C to about 35°C, followed by cooling to a temperature of about -15°C.

[0052] As described herein, the present specification discloses a method for treating conditions treatable by APC by administering an effective amount of one or more dosage forms.For example, the dosage form of the present invention can be administered to treat subjects who need to treat narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity, or to subjects who need to promote smoking cessation. See, for example, U.S. Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290, and U.S. Patent Publication Nos. 2012 / 0004300 and 2015 / 0018414, each of which is incorporated by reference in its entirety with respect to the disorders treated.

[0053] The dosage forms disclosed herein can also be provided as a kit that includes a container containing a plurality of immediate release tablets or capsules, such as tablets or capsules that can be individually packaged, such as in foil envelopes or blister packs. The tablets or capsules can be packaged in a number of conformations to prevent ingress of water, with or without a desiccant or other material. Instructional materials or means, such as printed labels, for administration, e.g., sequential administration for a preselected period of time and / or at preselected intervals, can further be included to calculate a desired level of APC in vivo for a preselected time and treat a preselected condition.

[0054] The therapeutic results disclosed herein can be achieved by administering a daily dose of about 1 to about 2000 mg of APC or a pharma- ceutically acceptable salt thereof. For example, a daily dose of about 10 to 1000 mg, e.g., about 20 to 500 mg, is administered in a single or divided dose. In some implementations, the daily dose can be about 0.01 to about 150 mg / kg body weight, e.g., about 0.2 to about 18 mg / kg body weight.

[0055] In one embodiment of the present invention, APC is administered to a subject as needed to treat a disorder. The compound can be administered continuously or intermittently. In one embodiment, the compound is administered more than once a day, for example, 2, 3 or 4 times a day, or once every 1, 2, 3, 4, 5, 6 or 7 days. In another embodiment, the compound can be administered to a subject only once a week, for example, once every 2 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, or more. In a further embodiment, the compound can be administered using two or more different schedules, for example, more frequently at first (for example, once a day or more to build up to a certain level), and then less frequently (for example, once a week or less). In another embodiment, the compound can be administered by any discontinuous administration regimen. As an example, the compound can be administered once every 3, 4, 5, 6, 7, 8, 9 or 10 days or more. Administration can last for 1, 2, 3 or 4 weeks, or for 1, 2 or 3 months or longer. Optionally, after a rest period, the compound can be administered under the same or different schedule. Depending on the pharmacodynamic effects of the compound on the subject, the rest period can be 1, 2, 3 or 4 weeks or more. In yet another implementation, the compound can be administered to build up to a certain level, and then maintained at a certain level before being maintained at a tailing dose.

[0056] In one aspect of the present invention, the APC is delivered to the subject simultaneously with an additional therapeutic agent. The additional therapeutic agent can be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent can be delivered to the subject by a different schedule or a different route compared to the compound. The additional therapeutic agent can be any agent that can provide a benefit to the subject. Additional agents include, but are not limited to, stimulants, antipsychotics, antidepressants, neuropathic agents, and chemotherapeutic agents. One therapeutic agent that can be administered during the same period is Xyrem™, commercially available from Jazz Pharmaceuticals, which is used to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0057] The present invention is used in the veterinary and medical fields as well as in research fields. Suitable subjects are generally mammals. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and the like. Human subjects include neonates, infants, adolescents, adults, and geriatrics.

[0058] In certain embodiments, the subject is a human having an APC-treatable disorder, hi other embodiments, the subject used in the methods of the invention is an animal model of an APC-treatable disorder.

[0059] The subject can be a subject "in need" of the methods of the invention, e.g., a subject in need of the therapeutic effect of the methods of the invention. For example, the subject can be a subject suffering from an APC-treatable disorder, suspected of having an APC-treatable disorder, and / or predicted to experience an APC-treatable disorder, and the methods and compositions of the invention are used for therapeutic and / or prophylactic treatment.

[0060] The invention is explained in more detail in the following non-limiting implementation examples.

[0061] Example 1 (R)-2-Amino-3-phenylpropylcarbamate hydrochloride solvate form

[0062] A polymorph and solvate screen was performed on APC to assess its propensity to exist as various solid forms and to determine the stable form of the compound. Four lots of APC were partially characterized. All lots were found to be the same anhydrous, crystalline material, which was designated Form A.

[0063] A polymorph and solvate screen of APC was performed using different crystallization techniques to vary the conditions of crystal nucleation and growth, exploring both thermodynamic and kinetic conditions. Solvent systems with different chemical properties were used, and selected experiments were specifically focused on process solvents. Selected experiments were also performed using the free base, via salt formation experiments targeting the monohydrochloride salt.

[0064] A crystalline hemihydrate form was identified and designated Form B. Form B was prepared from a slurry in acetonitrile:water (95%:5% v:v) at room temperature. Form B was also prepared from a slurry in p-dioxane:water (95%:5% v:v) at subambient temperatures. Form B was also observed as a mixture with Form A or other crystalline material from various experiments such as crash precipitation and evaporation in ethanol, hexafluoroisopropanol, methanol, and / or water. Partial conversion to Form B was also observed after stressing Form A at approximately 75% humidity (RH).

[0065] The XRPD pattern of Form B is shown in FIG. 1. The differential scanning calorimetry thermogram of Form B showed a broad endotherm at temperatures of 69.1° C. (onset) and 71.7° C. (peak maximum) (FIG. 2). The endotherm is associated with a corresponding 3.5% weight loss in the TG thermogram that accounts for about 0.5 moles of water. Such a phenomenon is believed to be due to dehydration. The sharp endotherms observed at temperatures of 182.5° C. (onset), 183.6° C. (peak maximum), and the subsequent exotherm observed at a temperature of 185.2° C. are believed to be due to a recrystallization phenomenon. An endotherm was then observed at a temperature of 190.1° C. (peak maximum). A comparison of the DSC and thermogravimetric (TG) thermograms of Form A and Form B is shown in FIG. 3 and FIG. 4.

[0066] Karl Fischer analysis showed that Form B contained ~3.71 wt% water or approximately 0.5 moles, which is consistent with the weight loss observed in the TG thermogram.

[0067] Microscopic images of Form B showed elongated plates (~50-100 μm) and smaller fragments.

[0068] As shown in Table 1, the aqueous solubility of Form B was measured to be greater than 700 mg / ml in different pH buffers.

[0069] JPEG2024178291000003.jpg102166

[0070] Crystals of APC were submitted for single crystal structure analysis. The structure was determined by single crystal X-ray diffraction. The monoclinic cell parameters and calculated volumes are: a = 15.9491(8) Å; b = 5.8431(6) Å; c = 12.7663(12) Å; β = 94.404(5)° (α = γ-90°); V = 1186.21(18) Å. 3In the crystal structure of APC Form B, the formula weight of the asymmetric unit is Z=4, 239.70 g mol -1 and the calculated density is 1.342 g cm -3 The space group was determined to be C2 (no. 5). The space group and unit cell parameters are consistent with the previously obtained XRPD indexing of Form B.

[0071] When the appropriate relative RH is achieved, Form A converts to Form B. Interconversion slurry experiments performed on Form A and Form B suggest that Form B is the more stable form at about 50% RH or above at room temperature.

[0072] Slurry experiments can be performed by starting with only Form A and running slurries or pre-saturated solutions that are interconverted with APC, then adding identical amounts of Form A and Form B. When only Form A is slurried, conversion to Form B at room temperature occurs at 67% RH, and at temperatures between 2 and 8° C. it occurs at 40% RH. With the interconverting slurries, Form B was isolated from all experiments that had relative humidity between 50% and 70%.

[0073] To assess whether conversion of Form A to Form B is possible overnight, two small scale experiments were performed in acetonitrile:water (95%:5% v:v). Experiments were performed at about 98 mg / ml and about 51 mg / ml. After slurrying for about 24 hours, Form B appeared in both tests. This indicates that conversion kinetics from Form A to Form B can occur within 24 hours (Figure 5).

[0074] Drying studies were conducted on Form B. Drying experiments were conducted at various temperatures with and without vacuum. Milling, storage under desiccant, and low RH stressing were further conducted. In all experiments, Form B partially or completely dehydrated to Form A. Partial conversion to Form A occurred after 1 day of vacuum drying at ambient temperature, 1 day of heating at 40° C., 1 day of storage under desiccant, and 2 weeks of stressing at 33% RH. Complete dehydration to Form A occurred after 1 day of vacuum drying at 50° C., 1 day of heating at 80° C., and milling. The drying study results for Form B suggest that Form B is not stable under low RH or elevated temperatures.

[0075] A scaled-up process was developed to produce Form B. APC was slurried in acetonitrile:water (95%:5% v:v) while maintaining the temperature at 22°C. Subsamples of the slurry were periodically taken, vacuum filtered, and analyzed by XRPD. It was found that a mixture of Form B and traces of Form A were observed at approximately 20-28.5 hours. An increase in Form A was observed in the subsample taken at 24 hours compared to the subsample taken at 20 hours. This is believed to be due to dehydration caused by vacuum filtration and low atmospheric humidity. The slurry was stirred for an additional 3 days and further subsamples were taken. XRPD analysis indicated that the subsample taken at approximately 91 hours was Form B. After slurried for approximately 121.5 hours, the slurry was separated by vacuum filtration and the wet cake was washed with two filter cake volumes of acetonitrile:water (95%:5% v:v). XRPD analysis indicated that the wet cake consisted of Form B. The wet cake was dried under vacuum at ambient temperature for about 16 hours. XRPD analysis showed that the dried material was slightly dehydrated to Form A, with about 5% Form A in the mixture. Dehydration can be avoided by drying without vacuum or drying under high RH (about 75%).

[0076] Mixtures of Form B and traces of Form A were also analyzed by Karl Fischer for the determination of water content and by HPLC for the determination of solvent content. 1 The solution was characterized by H NMR. Karl Fischer analysis showed that the mixture contained 0.47 moles of water per mole of APC or approximately 3.52% water. 1 The H NMR spectrum was consistent with the structure of APC. Water and traces of acetonitrile (0.003 moles per mole of APC) were also observed in the spectrum.

[0077] A further scaled up process was developed to produce Form B, decreasing the reaction time and volume and increasing the yield. Separation of Form A to Form B was carried out in 5 volumes of solvent (acetonitrile:water (95%:5% v:v)) at a temperature of about 20° C. for about 1-2 hours. The drying step was carried out at an oven temperature of 20-25° C. and low vacuum (700-750 mbar). Under these drying conditions Form B was stable and no detectable Form A was formed. This process was used on a 4.5 kg APC batch, producing a 93.7% yield of Form B.

[0078] Example 2 Synthesis of (R)-2-amino-3-phenylpropylcarbamate hydrochloride with minimal 2-chloropropane

[0079] Initially, large scale preparation of APC hydrochloride from the free base was carried out as follows: A solution of APC free base in isopropyl alcohol was diluted with isopropyl alcohol to a final concentration of 19% w / w. Water (37 g / mol) was added and the solution was heated to 70°C. Gaseous HCl (approximately 2 equivalents) was added to the headspace above the solution using a flow meter. The temperature rose to 75-80°C as the HCl dissolved. After addition of the clear supersaturated solution, it was quickly seeded within 15 minutes. APC hydrochloride crystallized. The suspension was stirred at 78°C and then allowed to cool to a temperature of 40°C for 10 hours. The suspension was cooled to 20°C and then further cooled to 3°C within 2 hours and stirred at this temperature for 1 hour. The solid was collected by filtration and washed with isopropyl alcohol. The wet cake was dried under reduced pressure for at least 16 hours.

[0080] This method produced unacceptable levels of the potential genotoxic impurity 2-chloropropane (2-CP), preferentially at levels below 5 ppm. These levels are believed to be due to the harsh crystallization conditions (HCl was charged close to the boiling point of the reaction mixture, stirred at 78°C for 1 hour, then cooled at a temperature of 40°C for 10 hours, followed by gradual cooling to a temperature of 3°C). Drying the crystals at elevated temperatures failed to reduce the amount of 2-CP. Reslurrying the crystals was also ineffective.

[0081] Given the difficulty in removing 2-CP once formed, it is necessary to modify the crystallization conditions to avoid the formation of 2-CP. Starting with APC free base in isopropyl acetate prevented the formation of 2-CP, but the conditions were not suitable because the crystallization was not well controlled, a thick crust formed in the reactor, and very small crystals were produced. Charging HCl gas at low temperatures (30-35°C) controlled the formation of 2-CP, but the conditions were not suitable because the crystallization was not well controlled, a thick crust formed in the reactor, and less crystalline material was produced.

[0082] Because charging HCl in gas form would cause unwanted spontaneous crystallization in the conditions evaluated, HCl was tested in the form of a 37% aqueous solution. This protocol increased the total amount of water by 1.76 times, from 37 g / mol to 65 g / mol, and the resulting suspension had to be cooled to a lower temperature to maximize the yield. However, the higher amount of water (1.05 molar equivalents compared to 2 molar equivalents) combined with the lower molar excess of acid and the lower temperature contribute to minimize the rate of formation of 2-CP.

[0083] The following general protocol was developed: APC free base solution was diluted with isopropyl alcohol to a final concentration of 19% by weight in isopropyl alcohol. The clear solution was warmed up to 25°C (20-30°C). 37% aqueous HCl was slowly added to the clear solution. The temperature was raised to 30°C. Seeding was applied immediately thereafter (within 15 minutes). The clear solution was stirred at a temperature of 30°C for 15 minutes, at which point APC hydrochloride slowly started to crystallize. Further 37% aqueous HCl was added to the suspension. The mixture was stirred at 30°C for 1 hour, then cooled to a temperature of -15°C within 2 hours and stirred at this temperature for 1 hour. The product was collected as a white crystalline solid and washed with isopropyl alcohol. The wet product was dried at 35°C (30-40°C) under a nitrogen stream.

[0084] As an example, a solution of 16.9 g, 0.0871 moles of APC free base was diluted with isopropyl alcohol (43.8 g) and warmed to 30° C. 37% aqueous HCl (4.51 g, 0.0458 moles, 0.525 molar equivalents) was added dropwise while maintaining the temperature below 35° C. APC hydrochloride (22 mg) was added to the clear solution. The solution became cloudy almost immediately. After 15 minutes a suspension was obtained. No crystallization occurred around the walls of the reactor. Further 37% aqueous HCl (4.51 g, 0.0458 moles, 0.525 molar equivalents) was added dropwise while maintaining the temperature below 35° C. The suspension was charged and then stirred at 30° C. for 1 hour, cooled to a temperature of −15° C. within 2 hours and stirred at this temperature for 2 hours. The product was collected by filtration, washed with IPA (16.7 g) and dried under air flow at 30-50 mbar at 35° C. for 17 h. 16.87 g of product was recovered (yield 83.96%). Crystallization occurred very smoothly. The product was a white crystalline powder. No 2-CP was found.

[0085] Two additional batches were produced using the same protocol, both of which had levels of 2-CP in the product below 1 ppm.

[0086] The above is illustrative of the present invention and should not be construed as limiting thereof. The present invention is defined by the following claims, including equivalents thereof. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entirety for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

Claims

1. 1. A solvate form of (R)-2-amino-3-phenylpropyl carbamate hydrochloride characterized by a powder x-ray diffraction pattern substantially identical to that shown in form B of FIG. 1 and / or a powder x-ray diffraction pattern having peaks at about 7.0, 13.6, 16.2, 17.4, 17.8, 18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3±0.2 degrees 2θ.

2. 2. The solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride of claim 1, further characterized by having a broad endotherm with an onset at a temperature of 69.1° C. and a peak at a temperature of 71.7° C., and a sharp endotherm with an onset at a temperature of 182.5° C. and a peak at a temperature of 183.6° C. by differential scanning calorimetry.

3. The solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 1 or 2, wherein the solvate form is a hemihydrate.

4. The solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to any one of claims 1 to 3, further characterized by producing it by slurrying (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v).

5. A method for preparing a solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride comprising slurrying (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v) and collecting the solvate by vacuum filtration.

6. 6. The method for preparing the solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 5, wherein the slurrying step is carried out at room temperature.

7. 7. The method for preparing the solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 5 or 6, wherein the slurrying step is carried out for at least about 20 hours.

8. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein at least 30% of the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is in the solvate form of any one of claims 1 to 4.

9. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein less than 10% of the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is in the solvate form of any one of claims 1 to 4.

10. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 8 or 9, wherein the composition is in dosage form.

11. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride of claim 10, wherein the composition is an immediate release oral dosage form.

12. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 11, wherein the composition is a tablet or a capsule.

13. The present invention relates to a method for treating narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or a combination thereof, comprising administering to a subject the composition of any one of claims 8 to 11.

46. ​​A method for treating obesity or bronchitis, or promoting smoking cessation in a subject in need thereof.

14. 14. The method of claim 13, wherein the tablet is administered once daily.

15. 14. The method of claim 13, wherein the tablet is administered one or more times daily.

16. A method for producing (R)-2-amino-3-phenylpropylcarbamate hydrochloride while minimizing contamination by 2-chloropropane, comprising the step of crystallizing (R)-2-amino-3-phenylpropylcarbamate hydrochloride in the presence of aqueous HCl to produce (R)-2-amino-3-phenylpropylcarbamate hydrochloride crystals.

17. The method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 16, wherein the crystallization is carried out at a temperature of about 25°C to about 30°C.

18. The method for producing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 16 or 17, further comprising drying the crystals of (R)-2-amino-3-phenylpropylcarbamate hydrochloride at a temperature of about 35° C. or less.

19. The method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to any one of claims 16 to 18, wherein the content of 2-chloropropane in the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is less than about 5 ppm.

20. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride, the composition containing less than about 5 ppm of 2-chloropropane.

21. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 20, wherein the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is produced by the method according to any one of claims 16 to 19.

22. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 20 or 21, wherein the composition is in a dosage form.

23. 23. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride of claim 22, wherein the composition is an immediate release oral dosage form.

24. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to claim 23, wherein the composition is a tablet or a capsule.

25. 25. A method for treating narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or other conditions in a subject in need thereof, comprising administering to the subject the composition of any one of claims 20 to 24.

46. ​​A method for treating obesity or bronchitis, or promoting smoking cessation in a subject in need thereof.

26. 26. The method of claim 25, wherein the tablet is administered once daily.

27. 26. The method of claim 25, wherein the tablet is administered one or more times daily.

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