Crystal in form of solvate of (R)-2-amino-3-phenylpropylcarbamate hydrochloride, preparation method, composition and use thereof

Abstract

The invention relates to a crystal in the form of a solvate of (R)-2-amino-3-phenylpropyl carbamate hydrochloride, and a preparation method, a composition and application thereof. The present invention relates to newly discovered solvate forms of (R)-2-amino-3-phenylpropylcarbamate (APC) hydrochloride, methods of making APC hydrochloride, and methods of using the same in the treatment of disorders. The invention also relates to a method for preparing APC hydrochloride with improved purity.

Description

[0001] This application is a divisional application of the patent application with application number 201780065192.6, application date September 6, 2017, and invention name “solvate form of (R)-2-amino-3-phenylpropylcarbamate”.

[0002] Claim priority

[0003] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 383,822, filed on September 6, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present invention relates to the field of crystals, and more particularly to crystals of a solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride, methods for preparing the same, compositions, and uses thereof, as well as solvates of (R)-2-amino-3-phenylpropylcarbamate (APC) hydrochloride, methods for preparing APC hydrochloride, and methods for using the same to treat disorders. The present invention also relates to methods for preparing APC hydrochloride with improved purity. Background Art

[0005] APC is a phenylalanine analog that has been shown to be useful in treating a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, and fibromyalgia. For example, see 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. Publication Nos. 2012 / 0004300 and 2015 / 0018414. Methods for preparing 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 patents and applications are incorporated herein by reference for all purposes.

[0006] The present invention will overcome the shortcomings of the art by providing new solvate forms of APC and methods for preparing APC with minimal contamination. Summary of the Invention

[0007] The present invention relates to the identification of novel solvated forms of APC, which are hemihydrate forms. The present invention also relates to methods for preparing APC with minimal contamination. The present invention also relates to the use of the novel solvated forms and / or APC of increased purity for treating disorders responsive to APC.

[0008] Therefore, the present invention relates to a solvate form of APC hydrochloride, characterized in that Figure 1 A powder X-ray diffraction pattern substantially identical to the form shown and / or a powder X-ray diffraction pattern having peaks at approximately 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.

[0009] The present invention also relates to a method for preparing a solvate form of APC hydrochloride, comprising the steps of slurrying APC hydrochloride in acetonitrile / water (95% / 5% v / v) and collecting the solvate by vacuum filtration.

[0010] The present invention also relates to a composition comprising APC, wherein less than about 10% of the APC in the composition is in the form of a solvate of the present invention.

[0011] The present invention also relates to a composition comprising APC, wherein at least about 30% of the APC in the composition is in the form of a solvate of the present invention.

[0012] The present invention also relates to a method for treating a disorder treatable with APCs, 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 for promoting smoking cessation in a subject in need thereof, comprising administering to the subject a dosage form comprising a solvate form of the present invention.

[0013] The present invention also relates to a method for preparing APC hydrochloride, which minimizes contamination caused by 2-chloropropane. The method comprises the steps of crystallizing APC in an aqueous HCl solution to prepare APC hydrochloride crystals.

[0014] The present invention further relates to compositions comprising APCs prepared to enhanced purity according to the methods of the present invention.

[0015] The present invention also relates to a method for treating disorders that can be treated with APCs, such as for 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 of the method, or for promoting smoking cessation in a subject in need of the method, the method comprising the step of administering to the subject a dosage form comprising APCs prepared with increased purity according to the method of the present invention.

[0016] Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings and the description of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The X-ray pattern diffraction (XRPD) of the APC crystalline form is shown.

[0018] Figure 2 Shown is a thermogram according to differential scanning calorimetry (DSC) of hemihydrate Form B of APC.

[0019] Figure 3 A comparison of the DSC thermograms of Forms A and B of APC is shown.

[0020] Figure 4 A comparison of the thermogravimetric (TG) thermographs of Forms A and B of APC is shown.

[0021] Figure 5 The XRPD pattern of APC from Form A to Form B is shown. DETAILED DESCRIPTION

[0022] The present invention can be implemented in different forms and should not be construed as being limited to the examples set forth in the present invention. On the contrary, these examples are provided to make this disclosure thorough and complete and to fully convey the scope of the present invention to those skilled in the art. For example, features described with respect to one example can be incorporated into other examples, and features described with respect to a particular example can be deleted from that example. In addition, it will be apparent to those skilled in the art, based on this disclosure, that various modifications and additions can be made to the examples mentioned herein without departing from the present invention.

[0023] 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 the invention belongs. The purpose of the terms used in the description of the present invention is only to describe specific examples and is not intended to limit the present invention.

[0024] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.

[0025] Furthermore, it is also contemplated that in some examples of the present invention, any feature or combination of features described herein may be excluded or omitted.

[0026] For purposes of illustration, if the specification states a compound comprising components A, B, and C, any one or combination of components A, B, and C is specifically intended and may be omitted or disclaimed, individually or in any combination.

[0027] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference for all purposes.

[0028] As used herein, "a" or "an" or "the" can mean more than one. For example, "a" or "an" unit can mean a single unit or a plurality of units.

[0029] Furthermore, as used herein, “and / or” refers not only to any or all possible combinations of more than one of the relevant listed items, but also includes the absence of combinations when interpreted as alternatives (“or”).

[0030] In addition, when referring to measurable values ​​such as the amount of a compound or formulation of the present invention, dosage, time, temperature, etc., the term "about" is used herein to include variations of ±10%, ±5%, ±1%, ±0.5% or ±0.1% of the specified amount.

[0031] When applied to the compositions of the present invention, the term "consisting essentially of" (and grammatical variations) means that the composition may include additional components as long as the additional components do not materially alter the composition. As applied to a composition, the term "materially altered" means that the therapeutic effectiveness of the composition is increased or decreased by at least about 20% or more compared to the effectiveness of a composition consisting of the listed components.

[0032] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of a composition, compound, or agent of the present invention that imparts a modulating effect, which is known in the art, for example, an effect that is beneficial to a subject suffering from a disorder, disease, or condition, including (for example, in one or more symptoms) an improvement in the subject's symptoms, a reduction or delay in symptom progression, a delay in the onset of a disorder, and / or a change in a clinical parameter of the disorder or disease. For example, a therapeutically effective amount or effective amount can mean an amount of a composition, compound, or agent that improves the subject's condition by at least 5%, for example, 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%.

[0033] "Treat" or "treating" or "treatment" means any type of action that imparts a modulatory effect, which, as is known in the art, can be an effect that is beneficial to a subject suffering from a disorder, disease or condition, including, for example, improvement in the subject's symptoms (in one or more symptoms), reduction or delay in symptom progression, delay in the onset of a disorder, and / or a change in a clinical parameter of the disorder or disease.

[0034] "APC-treatable disorder" refers to any disorder in which administration of an APC to a patient results in treatment of one or more symptoms of the patient's disorder. 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.

[0035] As used herein, "pharmaceutically acceptable" refers to a substance that is not biologically or otherwise unsuitable, i.e., the substance can be administered to an individual with the compositions of the present invention without causing adverse biological effects or interacting in a harmful manner with any other ingredients contained in the composition. As is well known to those skilled in the art, the substance will necessarily be selected to minimize any degradation of the active ingredient and to minimize any side effects that are detrimental to the subject (e.g., see Remington's Pharmaceutical Science; 21st edition, 2005).

[0036] "Simultaneously" means close enough in time to produce a combined effect (i.e., concurrently can be synchronous (simultaneously), or two or more events that occur within a short period of time). In some examples, "simultaneous" administration of two or more compounds means that the two compounds are administered at a sufficiently close time, and the presence of one of the compounds changes the biological effect of the other. The two compounds can be administered in the same or different formulations, or can be administered sequentially. Simultaneous administration can be performed by mixing the compounds before administration, or by administering two different formulations, for example, at the same time point but in anatomically different locations or using different routes of administration.

[0037] 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 and is a more stable form of the compound at high humidity levels compared to anhydrous Form A.

[0038] The structure of APC free base is shown in Formula I below.

[0039]

[0040] Therefore, one aspect of the present invention relates to a solvate form of APC hydrochloride, characterized in that Figure 1The solvate may have a substantially identical powder X-ray diffraction pattern to Form B and / or a powder X-ray diffraction pattern having peaks at approximately 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 instances, the solvate is further characterized by a broad endotherm starting at 69.1°C and having a peak at 71.7°C, and a sharp endotherm starting at 182.5°C and having a peak at 183.6°C, according to differential scanning calorimetry. In some instances, the solvate is further characterized by a solubility in buffered solutions at pH 1 to pH 6.5 of about 700 mg / ml to 750 mg / ml. In certain instances, the solvate is a hemihydrate.

[0041] In some instances, the solvate form is further characterized by being prepared by slurrying APC in acetonitrile / water (95% / 5% v / v).

[0042] As used herein, the term "hemihydrate" refers to a hydrate in which one water molecule is bound to two APC molecules.

[0043] As used herein, the term "crystalline" refers to a material containing a particular compound that is hydrated and / or solvated and has sufficient crystalline content to exhibit a discernible diffraction pattern by XRPD or other diffraction techniques.

[0044] The solvate form can be prepared by a method comprising a slurrying step of slurrying APC hydrochloride in a suitable solvent system (e.g., acetonitrile / water (95% / 5% v / v)), and a step of collecting the solvate crystals using a suitable technique, such as vacuum filtration. In some examples, for example, the above process is performed at room temperature of about 20° C. to 28° C. and about 5-10 (e.g., 10) volumes of solvent. In some examples, the slurrying step is performed for a sufficient time to allow the solvate to form, for example, for at least about 10 hours, for example, for at least about 10, 15, 20, 25, 50, 75, or 100 hours or more.

[0045] In some examples, the process is performed at a temperature of about 20° C. and in about 5 volumes of solvent. In some examples, the slurrying step is performed for a time sufficient to form the solvate, such as for about 1-2 hours.

[0046] The wet Form B prepared by the methods described herein can be dried by any method suitable for maintaining Form B and limiting dehydration to Form A. In some examples, drying is carried out at a temperature of about 20° C. to about 25° C. In some examples, drying is carried out under reduced pressure, for example, at about 600 mbar to 950 mbar, for example, at about 700 mbar to 750 mbar. In some examples, drying is carried out for a suitable time to achieve complete drying, for example, about 4-40 hours, for example, about 10-24 hours. In some examples, drying is carried out at high humidity, for example, at a relative humidity of 80% to 100%.

[0047] Another aspect of the present invention relates to a composition comprising APC, e.g., to a dosage form, wherein less than about 10% of the APC in the composition is in solvate Form B. In some examples, less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the APC is in solvate Form B. In some examples, the dosage form is an oral dosage form, e.g., including an immediate-release dosage form such as a tablet or capsule.

[0048] Another aspect of the present invention relates to a composition comprising APC, e.g., a composition in a dosage form, wherein at least about 30%, e.g., about 30% to about 99% or more of the APC in the composition is in solvate Form B. In some examples, at least about 40%, 50%, 60%, 70%, 80%, or 90% of the APC is in solvate Form B. In some examples, the dosage form is an oral dosage form, e.g., including an immediate-release dosage form such as a tablet or capsule.

[0049] In one example, the dosage form is an immediate-release dosage form that releases at least 85%, e.g., 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 less than 15 minutes after administration to a subject. Such immediate-release dosage forms are disclosed, e.g., in U.S. Provisional Application No. 62 / 383,818, which is incorporated herein by reference in its entirety.

[0050] The formulation of APCs in an immediate-release dosage form can be processed into unit dosage forms suitable for oral administration, such as filled capsules, compressed tablets or caplets, or other dosage forms suitable for oral administration using conventional techniques. The immediate-release dosage form prepared as described above can be suitable for oral administration so as to achieve and maintain therapeutic levels of APCs within a preselected time interval. In specific examples, the immediate-release dosage form as described herein can be a solid oral dosage form of any desired shape and size, including circular, oval, oblong, or polygonal. In one such example, the surface of the immediate-release dosage form can be flat, round, concave, or convex.

[0051] In particular, when the immediate-release dosage form is prepared as a tablet, the immediate-release tablet contains a relatively large percentage and absolute amount of APC, and thus can be 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 taken orally, for example, administered closely spaced, to provide a therapeutically effective dose of APC to a subject in a shorter period of time.

[0052] If desired or necessary, the exterior surface of the immediate-release dosage form can be coated, for example, with a color coating or with a moisture barrier using materials and methods well known in the art.

[0053] The dosage form can contain an amount of any APC or a pharmaceutically acceptable salt thereof suitable for administration as a unit dosage form. In some examples, the dosage form contains about 1 mg to about 1000 mg of the drug, or any range or value therein, such as about 10 mg to about 500 mg, such as about 37.5 mg, about 75 mg, about 150 mg, or about 300 mg.

[0054] APC or a pharmaceutically acceptable salt thereof can be obtained or synthesized by methods known in the art and as described herein. Detailed reaction schemes for synthesizing APC are described in U.S. Patent Nos. 5,705,640, 5,756,817, 5,955,499, and 6,140,532, the contents of which are incorporated herein by reference in their entirety.

[0055] During the development of a process for the preparation of APC, it was discovered that unacceptable levels of the impurity 2-chloropropane (i.e., isopropyl chloride) may be present during the crystallization of APC hydrochloride. Because it is a potentially genotoxic impurity, it is preferable to minimize the presence of 2-chloropropane. Therefore, one aspect of the present invention relates to an improved process for the preparation of APC hydrochloride that minimizes contamination by 2-chloropropane. By employing this improved process, the 2-chloropropane content in the final product can be less than about 10 ppm, for example, less than about 9, 8, 7, 6, 5, 4, 3, 2, or 1 ppm.

[0056] Thus, one aspect of the present invention relates to an improved process for preparing APC hydrochloride that minimizes contamination by 2-chloropropane, comprising the step of crystallizing APC from aqueous HCl to produce APC hydrochloride crystals. Crystallization can be carried out using a suitable solvent, for example, the free base of APC in isopropyl alcohol.

[0057] In some examples, the HCl aqueous solution is a 37% HCl aqueous solution. In some examples, the crystallization is carried out at a temperature of about 15°C to about 40°C, for example, at a temperature of about 25°C to about 35°C, and then cooled to a temperature below 0°C, for example, to a temperature below about -5°C to about -25°C, for example, to a temperature below about -15°C. In some examples, the crystallization is dried at a temperature below about 45°C, for example, at a temperature below about 40°C, 35°C or below 30°C. In some examples, the crystallization is carried out at a temperature of about 25°C to about 35°C in the presence of about 1 mole to about 1.2 molar equivalents (e.g., about 1.05 molar equivalents) of a 37% HCl aqueous solution, and then carried out at a temperature of about -15°C.

[0058] As described herein, methods for treating conditions treatable with APCs by administering an effective amount of one or more dosage forms are disclosed. For example, the dosage forms of the present invention can be administered to a subject in need of treatment for 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 a subject in need of facilitating smoking cessation. For example, see 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. Publication Nos. 2012 / 0004300 and 2015 / 0018414, which relate to the conditions to be treated and are incorporated herein by reference in their entirety.

[0059] The dosage forms disclosed herein can also be provided as a kit comprising, for example, a container containing a plurality of immediate-release tablets or capsules, for example, which can be individually packaged, such as in foil envelopes or blister packs. The tablets or capsules can be packaged in a variety of configurations, regardless of the presence or absence of desiccants or other substances to prevent water ingress. Instructional materials or means, such as printed labels, can also be included for administration, for example, for sequential administration at preselected time periods and / or at preselected time intervals, in order to produce the desired level of APCs in vivo at a preselected time period and to treat a preselected condition.

[0060] A daily dose of about 1 mg to about 2000 mg of APC or a pharmaceutically acceptable salt thereof can be administered to achieve the therapeutic results disclosed herein. For example, a daily dose of about 10 mg to 1000 mg, such as about 20 mg to 500 mg, can be administered in a single dose or divided doses. In some examples, the daily dose can be about 0.01 mg to about 150 mg / kg weight, such as about 0.2 mg to about 18 mg / kg weight.

[0061] In one example of the present invention, APC is administered to the subject as needed to treat the disease. The compound can be administered continuously or intermittently. In one example, the compound is administered more than once a day, for example, 2, 3 or 4 times a day, or every day, every two days, every three days, every four days, every five days, every six days or every seven days. In another example, the compound is administered only once a week to the subject, for example, only once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months or longer. In a further example, the compound uses two or more different schemes, for example, more frequently administered than in the early stage (for example, formed to a specific level, for example, more than once a day), and then less frequently used (for example, less than once a week). In other examples, the compound can be administered by any discontinuous dosing regimen. For example, the compound can be administered only once every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days or every ten days or longer. Administration can be continued for one week, two weeks, three weeks, or four weeks, or one month, two months, three months, or longer. Alternatively, after a rest period, the compound can be administered under the same or a different regimen. Depending on the pharmacodynamic effects of the compound on the subject, the rest period can be one week, two weeks, three weeks, or four weeks, or longer. In another example, the compound can be administered until a specific level is formed, and then after maintaining the level, a tailing dose can be maintained.

[0062] According to one aspect of the present invention, APCs are delivered to a 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 in a different regimen or by a different route than the compound. The additional therapeutic agent can be any agent that provides a benefit to the subject. Additional agents include, but are not limited to, stimulants, antipsychotics, antidepressants, neurological disorder agents, and chemotherapeutic agents. One of the therapeutic agents that can be administered at the same time is commercially sold by Jazz Pharmaceuticals. It is used to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0063] The present invention can be used not only in the fields of veterinary medicine and medicine, but also in the field of research. Suitable subjects are generally mammalian subjects. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, and rodents (e.g., rats or mice). Human subjects include neonates, infants, adolescents, adults, and elderly subjects.

[0064] In specific examples, the subject is a human subject having a condition that can be treated with APCs. In other examples, the subject useful in the methods of the present invention is an animal model of a condition that can be treated with APCs.

[0065] A subject can be a subject "in need" of the methods of the present invention, e.g., a subject in need of the therapeutic effects of the methods of the present invention. For example, the subject can be a subject experiencing a condition treatable with APCs, a subject suspected of having a condition treatable with APCs, and / or a subject anticipated to experience a condition treatable with APCs, and the methods and compositions of the present invention are used for therapeutic and / or prophylactic treatment.

[0066] The present invention will be explained in more detail in the following non-limiting examples.

[0067] Example 1

[0068] Solvate form of (R)-2-amino-3-phenylpropylcarbamate

[0069] A polymorph and solvate screen of APC was performed to assess its propensity to exist in 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.

[0070] Polymorph and solvate screening of APC was performed using different crystallization techniques to vary the nucleation and growth conditions for both thermodynamic and kinetic investigations. Solvent systems with a variety of chemical properties were used, with selected experiments specifically focusing on process solvents. Selected experiments were also performed using salt formation experiments targeting the monohydrochloride salt using the free base.

[0071] A crystalline hemihydrate form was identified and designated Form B. Form B was prepared at room temperature from a slurry in acetonitrile:water (95%:5% v:v). Form B was also prepared at subambient temperature from a slurry in dioxane:water (95%:5% v:v). Form B was also observed to be 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).

[0072] The XRPD pattern of Form B is shown in Figure 1 The differential scanning calorimetry (DSC) thermogram of Form B showed broad endotherms at 69.1°C (onset), 71.7°C (maximum peak) ( Figure 2 ). An endotherm is associated with a corresponding weight loss of 3.5% on the TG thermogram calculated for about 0.5 moles of water. This phenomenon is likely due to dehydration. A sharp endotherm was observed at 182.5°C (onset), 183.6°C (peak maximum), followed by exotherm at 185.2°C (peak maximum) likely due to recrystallization. This was followed by an endotherm at 190.1°C (peak maximum). A comparison of the DSC and thermogravimetric (TG) thermograms of Form A and Form B is shown in Figure 3 and Figure 4 middle.

[0073] According to Karl Fischer analysis, Form B contains about 3.71 wt% water, or about 0.5 mol. This data is consistent with the weight loss observed in the TG thermogram.

[0074] Images of Form B were taken using a microscope and showed elongated plates (approximately 50 μm-100 μm) and smaller fragments.

[0075] The aqueous solubility of Form B is shown in Table 1 and is above 700 mg / ml as measured in various pH buffers.

[0076] [Table 1]

[0077]

[0078] A crystal of APC was submitted for single crystal structure analysis. The structure was determined by single crystal X-ray diffraction. The monoclinic cell parameters and calculated volume are as follows: β=94.404(5)°(α=γ-90°); The formula weight of the asymmetric unit in the crystal structure of APC form B is 239.70 g mol -1 , Z = 4, 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 were consistent with the previously obtained XRPD indexing of Form B.

[0079] When the appropriate relative RH is reached, Form A converts to Form B. Interconversion slurry experiments with Form A and Form B indicate that Form B is the more stable form at room temperature at about 50% RH or higher.

[0080] Slurry experiments were performed at various water activities starting with Form A alone and interconverting slurries or pre-saturated solutions with APC, and then proceeded by adding equal amounts of Form A and Form B. When slurrying of Form A alone was achieved, conversion to Form B occurred at room temperature at 67% RH, and additional conversion to Form B occurred at 40% RH at 2° C.-8° C. Form B was isolated from all experiments with relative humidities between 50% and 70% using interconverting slurries.

[0081] Two small-scale experiments were conducted in acetonitrile:water (95%:5% v:v) to evaluate whether Form A could be converted to Form B overnight. The experiments were conducted at approximately 98 mg / ml and approximately 51 mg / ml. In both experiments, Form B was produced after approximately 24 hours of slurrying, indicating that the kinetics of the conversion of Form A to Form B can occur within 24 hours ( Figure 5 ).

[0082] Drying studies were performed on Form B. Drying experiments were performed at various temperatures, regardless of vacuum. Milling, storage under desiccant, and low RH stress were additionally performed. In all experiments, Form B partially or completely dehydrated to Form A. After vacuum drying for 1 day at ambient temperature, heating at 40°C for 1 day, storage under desiccant for 1 day, and pressurization at 33% RH for 2 weeks, partial conversion to Form A occurred. After vacuum drying at 50°C for 1 day, heating at 80°C for 1 day, and milling, complete dehydration to Form A occurred. The results of the drying studies on Form B indicate that Form B is unstable at low RH or increased temperature.

[0083] A scaled-up process for producing Form B was developed. APC was slurried in acetonitrile:water (95%:5% v:v) while maintaining the temperature at 22°C. Subsamples of the slurry were periodically removed, vacuum filtered, and analyzed by XRPD. A mixture of Form B with trace amounts of Form A was observed from approximately 20 hours to 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 was likely due to dehydration caused by vacuum filtration and low atmospheric humidity. The slurry was stirred for an additional 3 days, and another subsample was taken. XRPD analysis indicated that the subsample taken at approximately 91 hours was Form B. The slurry was separated by vacuum filtration after approximately 121.5 hours of slurrying, and the wet cake was washed with two cake volumes of acetonitrile:water (95%:5% v:v). XRPD analysis indicated that the wet cake consisted of Form B. The wet cake was vacuum dried at ambient temperature for approximately 16 hours. XRPD analysis showed that the dried material dehydrated slightly to Form A, with approximately 5% of the mixture containing Form A. Dehydration could be avoided by drying without vacuum or at high RH (approximately 75%).

[0084] The mixture of Form B and trace amounts of Form A was determined by Karl Fischer calorimetry for water content and solvent content (convent). 1 H NMR solution specific Karl Fischer analysis indicated 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 a trace amount of acetonitrile (0.003 mol / mol APC) were also observed in the spectrum.

[0085] An alternative scale-up method for producing Form B was developed that reduced reaction time and volume and improved yield. Form B was isolated from Form A in 5 volumes of solvent (acetonitrile:water (95%:5% v:v)) at approximately 20°C for approximately 1-2 hours. Drying was performed at an oven temperature of 20°C-25°C and low vacuum (700-750 mbar). Under these drying conditions, Form B was stable, and no detectable Form A was formed. This method was used on a 4.5 kg batch of APC, producing a 93.7% yield of Form B.

[0086] Example 2

[0087] Synthesis of (R)-2-amino-3-phenylpropylcarbamate hydrochloride with minimal 2-chloropropane

[0088] Initially, the method for large-scale preparation of APC hydrochloride from free base is as follows. A solution of APC free base in isopropanol is diluted with isopropanol to a final concentration of 19% w / w. Water (37 g / mol) is added and the solution is heated to 70°C. Gaseous HCl (about 2 equivalents) is added in the headspace above the solution via a flow meter. As the HCl dissolves, the temperature is raised to 75°C-80°C. The clear supersaturated solution is quickly seeded within 15 minutes of addition. APC hydrochloride is crystallized. The suspension is stirred at 78°C and then cooled to 40°C over 10 hours. The suspension is further cooled to 20°C and then further cooled to 3°C over 2 hours and stirred at this temperature for 1 hour. The solid is recovered by filtration and washed with isopropanol. The wet cake is dried under reduced pressure for at least 16 hours.

[0089] This process produces unacceptable levels of the potentially genotoxic impurity 2-chloropropane (2-CP), which preferably does not exceed 5 ppm. This level is likely due to the harsh crystallization conditions (adding HCl near the boiling point of the reaction mixture, stirring at 78°C for 1 hour, then cooling to 40°C over 10 hours, and then gradually cooling to 3°C). Even drying the crystals at elevated temperatures does not reduce the amount of 2-CP. Reslurrying the crystals is also ineffective.

[0090] Given the difficulty in removing 2-CP once formed, it was necessary to modify the crystallization conditions to avoid 2-CP formation. Starting with APC free base in isopropyl acetate prevented 2-CP formation, but poor crystallization control resulted in a thick crust forming in the reactor and produced very small crystals, making the conditions inappropriate. Filling with HCl gas at lower temperatures (30°C-35°C) controlled 2-CP formation, but poor crystallization control resulted in a thick crust forming in the reactor and produced less crystalline material, making the conditions inappropriate.

[0091] The HCl of filling gas form can cause undesirable spontaneous crystallization under the conditions evaluated, so HCl is added with 37% aqueous solution form and tested.This scheme increases the total amount of water from 37g / mol to 65g / mol, has increased 1.76 times, therefore the gained suspension must be cooled to lower temperature to realize the maximization of yield.Yet, the acid of lower molar excess (comparing 1.05 molar equivalents of 2 molar equivalents) and the more a lot of water combined with lower temperature help to minimize the formation speed of 2-CP.

[0092] The following general protocol was developed. A solution of APC free base in isopropanol was diluted with isopropanol to a final concentration of 19 wt %. The clear solution was warmed up to 25°C (20°C-30°C). A 37% aqueous HCl solution was slowly added to the clear solution. The temperature was raised to 30°C. Inoculation was used immediately thereafter (within 15 minutes). The clear solution was stirred at 30°C for 15 minutes, whereby APC hydrochloride slowly began to crystallize. A 37% aqueous HCl solution was further added to the suspension. The mixture was stirred at 30°C for 1 hour, then cooled to -15°C within 2 hours and stirred at this temperature for 1 hour. The product was recovered as a white crystalline solid and washed with isopropanol. The wet product was dried at 35°C (30°C-40°C) under a stream of nitrogen.

[0093] In one embodiment, a 0.0871 mol solution of 16.9 g of APC free base was diluted with isopropyl alcohol (43.8 g) and warmed to 30° C. A 37% aqueous HCl solution (4.51 g, 0.0458 mol, 0.525 mol equivalent) was added dropwise, maintaining the temperature below 35° C. APC hydrochloride (22 mg) was added to the clear solution. The solution became turbid almost immediately. After 15 minutes, a suspension was obtained. No crystallization occurred around the reactor walls. A 37% aqueous HCl solution (4.51 g, 0.0458 mol, 0.525 mol equivalent) was further added dropwise, maintaining the temperature below 35° C. After the addition, the suspension was stirred at 30° C. for 1 hour, cooled to -15° C. over 2 hours and stirred at this temperature for 2 hours. The product was recovered by filtration, washed with IPA (16.7 g) and dried at 35° C. under an air flow of 30 mbar-50 mbar for 17 hours. 16.87 g of product was recovered (yield 83.96%). The crystallization process was very smooth. The product was a white crystalline powder. No 2-CP was detected.

[0094] Two more batches were prepared using the same protocol. In both batches, the 2-CP levels of the products were less than 1 ppm.

[0095] The foregoing is illustrative of the present invention and should not be construed as limiting thereof. The present invention is defined by the following claims, with equivalents of the claims to be included therein. All publications, patent applications, patents, patent disclosures, and any other references cited herein are incorporated by reference in their entirety for the purposes of the teachings relevant to the sentence and / or paragraph in which the reference is presented.

[0096] This application can be implemented by:

[0097] Item 1. A solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride, characterized in that Figure 1 Form B has substantially the same powder X-ray diffraction pattern as shown and / or a powder X-ray diffraction pattern having peaks at approximately 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 2-theta.

[0098] Item 2. A solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 1, further characterized in that, according to differential scanning calorimetry, it has a broad endotherm starting at 69.1°C and having a peak at 71.7°C, and a sharp endotherm starting at 182.5°C and having a peak at 183.6°C.

[0099] Item 3. The solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 1 or 2, wherein the solvate form is a hemihydrate.

[0100] Item 4. A solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to any one of Items 1-3, further characterized in that it is prepared by slurrying (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v).

[0101] Item 5. A method for preparing a solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein the method for preparing the solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride includes: a slurrying step of slurrying (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v); and a step of collecting the solvate by vacuum filtration.

[0102] Item 6. A method for preparing a solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 5, wherein the slurrying step is carried out at room temperature.

[0103] Item 7. A method for preparing a solvate form of (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 5 or 6, wherein the slurrying step is carried out for at least about 20 hours.

[0104] Item 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 form of a solvate according to any one of Items 1-4.

[0105] Item 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 form of a solvate according to any one of items 1-4.

[0106] Item 10. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 8 or 9, wherein the composition is in a dosage form.

[0107] Item 11. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 10, wherein the composition is an immediate-release oral dosage form.

[0108] Item 12. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 11, wherein the composition is a tablet or a capsule.

[0109] Item 13. A method, comprising the step of administering to a subject the composition of any one of Items 8-11, wherein the method is used 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 in a subject in need of the method, or to promote smoking cessation in a subject in need of the method.

[0110] Item 14. The method according to Item 13, wherein the tablet is administered once daily.

[0111] Item 15. The method according to Item 13, wherein the tablet is administered more than once a day.

[0112] Item 16. A method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein the preparation method minimizes the pollution caused by 2-chloropropane, and the preparation method comprises: crystallizing (R)-2-amino-3-phenylpropylcarbamate hydrochloride in an aqueous HCl solution to produce (R)-2-amino-3-phenylpropylcarbamate hydrochloride crystals.

[0113] Item 17. The method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 16, wherein the crystallization is carried out at a temperature of about 25°C to about 35°C.

[0114] Item 18. The method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to Item 16 or 17, further comprising the step of drying the crystals of (R)-2-amino-3-phenylpropylcarbamate hydrochloride at a temperature below about 35°C.

[0115] Item 19. The method for preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to any one of Items 16-18, wherein the 2-chloropropane content of (R)-2-amino-3-phenylpropylcarbamate hydrochloride is less than about 5 ppm.

[0116] 20. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein the (R)-2-amino-3-phenylpropylcarbamate hydrochloride composition comprises less than about 5 ppm of 2-chloropropane.

[0117] 21. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to item 20, wherein the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is prepared by the method according to any one of items 16 to 19.

[0118] 22. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to item 20 or 21, wherein the composition is in a dosage form.

[0119] 23. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to item 22, wherein the composition is an immediate-release oral dosage form.

[0120] 24. The composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride according to item 23, wherein the composition is a tablet or a capsule.

[0121] 25. A method comprising administering to a subject the composition of any one of items 20 to 24, wherein the method is for 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 of the method, or for promoting smoking cessation in a subject in need of the method.

[0122] 26. The method according to item 25, wherein the tablet is administered once daily.

[0123] 27. The method according to item 25, wherein the tablet is administered more than once a day.

Claims

1. A crystal in the form of a solvate of (R)-2-amino-3-phenylpropylcarbamate hydrochloride, characterized in that: a powder X-ray diffraction pattern substantially the same as Form B shown in Figure 1 and / or a powder X-ray diffraction pattern having peaks at approximately 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, Wherein, the solvate form is a hemihydrate.

2. The crystal according to claim 1, further characterized by having a broad endotherm starting at 69.1°C and having a peak at 71.7°C, and a sharp endotherm starting at 182.5°C and having a peak at 183.6°C according to differential scanning calorimetry.

3. The crystal according to claim 1, further characterized in that it is prepared by slurrying (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v).

4. A method for preparing the crystal according to any one of claims 1 to 3, comprising: Slurry (R)-2-amino-3-phenylpropylcarbamate hydrochloride in acetonitrile / water (95% / 5% v / v); collect the solvate by vacuum filtration; and dry the solvate at a relative humidity of 50% or greater.

5. The method according to claim 4, wherein The slurrying is performed at about room temperature.

6. The method according to claim 4 or 5, wherein: The slurrying is performed for at least about 20 hours.

7. A composition comprising (R)-2-amino-3-phenylpropylcarbamate hydrochloride, wherein At least 30% of the (R)-2-amino-3-phenylpropylcarbamate hydrochloride is in the form of crystals according to any one of claims 1 to 3.

8. The composition according to claim 7, wherein The composition is a dosage form.

9. The composition according to claim 8, wherein The composition is an immediate release oral dosage form.

10. The composition according to claim 9, wherein The composition is a tablet or a capsule.

11. Use of the composition according to any one of claims 7 to 10 in the preparation of a medicament for treating a condition selected from the group consisting of 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 for promoting smoking cessation in a subject in need thereof.

12. The use according to claim 11, wherein the disorder is excessive daytime sleepiness.

13. The use according to claim 11, wherein The composition is administered once daily.

14. The use according to claim 11, wherein The composition is administered more than once daily.

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