Crystalline 4-((l-valyl) oxy) butyric acid

Abstract

Disclosed are crystalline 4-((L-valyl) oxy) butyric acid, methods of making crystalline 4-((L-valyl) oxy) butyric acid, pharmaceutical compositions of crystalline 4-((L-valyl) oxy) butyric acid, and methods of treatment using crystalline 4-((L-valyl) oxy) butyric acid.

Description

Technical Field

[0001] The present invention relates to crystalline 4-((L-valyl)oxy)butyric acid, a method for preparing the crystalline 4-((L-valyl)oxy)butyric acid, a pharmaceutical composition containing the crystalline 4-((L-valyl)oxy)butyric acid, and a method of treatment using the crystalline 4-((L-valyl)oxy)butyric acid. Background Art

[0002] 4-((L-valyl)oxy)butyric acid is a prodrug of gamma-hydroxybutyric acid (GHB). GHB can be used to treat sleep disorders, such as excessive daytime sleepiness associated with narcolepsy and cataplexy associated with narcolepsy. Summary of the invention

[0003] According to the present invention, one compound is crystalline 4-((L-valyl)oxy)butyric acid:

[0004]

[0005] According to the invention, the pharmaceutical composition comprises a compound according to the invention.

[0006] According to the invention, the oral dosage form comprises a compound according to the invention or a pharmaceutical composition according to the invention.

[0007] According to the present invention, the kit comprises a compound according to the present invention, a pharmaceutical composition according to the present invention or an oral dosage form according to the present invention.

[0008] According to the present invention, a method for treating a disease in a patient, wherein the disease can be treated with gamma-hydroxybutyrate, comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the present invention, a pharmaceutical composition according to the present invention or an oral dosage form according to the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The drawings described herein are for illustration purposes only. The drawings are not intended to limit the scope of the present disclosure.

[0010] Figure 1 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 4-((L-valyl)oxy)butyric acid.

[0011] Figure 2 Shown are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of crystalline 4-((L-valyl)oxy)butyric acid. DETAILED DESCRIPTION

[0012] For the purpose of the following detailed description, it should be understood that, unless explicitly indicated to the contrary, the embodiments provided by the present disclosure may take various alternative variations and step sequences. In addition, except in any operating examples or when otherwise indicated, all numerals expressing the quantity of the components used in the present specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and the attached claims are approximate values ​​that can vary according to the desired properties to be obtained by the present invention. At least, and not attempting to limit the application of the principle of equivalents to the scope of the claims, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying common rounding techniques.

[0013] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0014] Furthermore, it should be understood that any numerical range described herein is intended to include all subranges subsumed therein. For example, a range of "1 to 10" is intended to include all subranges between (and ratios of) the recited minimum value of 1 and the recited maximum value of 10, i.e., having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10.

[0015] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the pharmaceutically active ingredients into the gastrointestinal tract of a patient within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, an immediate release dosage form can release greater than 90%, greater than 95%, or greater than 98% of the pharmaceutically active ingredients in the pharmaceutical composition into the gastrointestinal tract within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes. Immediate release pharmaceutical compositions can be suitable for administering pharmaceutically active ingredients that are absorbed into the systemic circulation from the upper portion of the gastrointestinal tract.

[0016] "Modified release" pharmaceutical compositions include controlled release formulations, delayed release formulations, extended release formulations, sustained release formulations, timed release formulations, pulsed release formulations, and pH-dependent release formulations. These formulations are intended to release pharmaceutically active ingredients from pharmaceutical compositions at a desired rate and / or at a desired time and / or at a certain position or positions in the gastrointestinal tract and / or at a certain pH in the gastrointestinal tract after oral administration to a patient. The American Medical Code (USP) defines a modified release system as a system in which the time course or position of drug release or both are selected to achieve the purpose of therapeutic effectiveness or convenience that cannot be achieved with an immediate release dosage form. Modified release oral dosage forms may include extended release and delayed release components. Delayed release dosage forms are dosage forms that release all of the drug at a certain time after administration rather than immediately. Modified release formulations may include delayed release using enteric coatings; site-specific or timed release such as for colon delivery; extended release formulations including, for example, formulations that can provide a zero-order, first-order, or biphasic release profile; and program release such as pulsed and delayed extended release.

[0017] "Sustained release" pharmaceutical compositions and coatings provide a dissolution rate over an extended period of time after oral administration. Granules comprising granules with a sustained release coating may be referred to as sustained release granulations. Pharmaceutical compositions comprising sustained release granulations may be referred to as sustained release pharmaceutical compositions.

[0018] "pH-release" pharmaceutical compositions and coatings provide an increased dissolution rate at a predetermined pH.

[0019] "Pulsate release" pharmaceutical compositions and coatings exhibit an increased dissolution rate at intervals, where the release intervals can be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsate release systems include capsule systems, osmotic systems, systems with erodible membranes, and systems with rupturable coatings. Examples of stimuli include temperature, chemicals, electrical stimuli, and magnetic stimuli.

[0020] "Timed release" pharmaceutical compositions and coatings have a dissolution rate that varies over time. Timed release pharmaceutical compositions or coatings include, for example, delayed release, sustained release, and extended release pharmaceutical compositions and coatings.

[0021] "Delayed release" pharmaceutical compositions and coatings provide an increased rate of dissolution at a predetermined time after administration.

[0022] "Patient" refers to a mammal, such as a human.

[0023] "Pharmaceutically acceptable" means approved or acceptable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0024] "Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, or any combination of the foregoing, which can be administered to a patient together with the compounds provided by the present disclosure, and when administered in a dose sufficient to provide a therapeutically effective amount of the compound, does not destroy its pharmacological activity and is non-toxic.

[0025] A "pharmaceutical composition" refers to 4-((L-valyl)oxy)butyric acid and at least one pharmaceutically acceptable carrier, wherein the 4-((L-valyl)oxy)butyric acid is administered to a patient. Pharmaceutically acceptable vehicles are known in the art.

[0026] "Disease" refers to any of the foregoing diseases, disorders, conditions or symptoms.

[0027] "Preventing" or "prevention" refers to reducing the risk of developing a disease or condition (i.e., preventing the clinical symptoms of at least one disease from developing in a patient who may be exposed to or susceptible to the disease but has not yet experienced or exhibited symptoms of the disease). In some embodiments, "preventing" or "prevention" refers to alleviating the symptoms of a disease by administering the compounds provided by the present disclosure in a preventive manner. The use of therapeutic agents to prevent diseases is called "prophylaxis". The compounds provided by the present disclosure can provide excellent prevention due to low long-term side effects over a long period of time.

[0028] "Prodrug" refers to a derivative of a drug molecule that requires transformation in vivo to release the active drug. Prodrugs are usually (although not necessarily) pharmacologically inactive until converted to the parent drug. Prodrugs can be obtained by combining a promoiety with a drug, usually via a functional group. For example, for 4-((L-valyl)oxy)butanoic acid, NH 2 -CH(-CH 3 ) 2 )-promoter part is combined with gamma-hydroxybutyrate. 4-((L-valyl)oxy)butyric acid is a prodrug of gamma-hydroxybutyrate, which can be metabolized in the patient's body to release gamma-hydroxybutyrate.

[0029] "Probody part" refers to a group that is bound to a drug (usually a functional group of a drug) via one or more bonds that are cleavable under specified conditions of use. One or more bonds between a drug and a probody part can be cleaved by an enzymatic or non-enzymatic process. Under the conditions of use, for example, after being administered to a patient, one or more bonds between a drug and a probody part can be cleaved to release the parent drug. The cleavage of the probody part can be spontaneous, such as via a hydrolysis reaction, or it can be catalyzed or induced by another agent (such as by an enzyme, by light, by an acid, or by a change in a physical or environmental parameter (such as a change in temperature or pH) or by exposure to a physical or environmental parameter (such as a change in temperature or pH)). The agent can be endogenous to the conditions of use, such as an enzyme present in the systemic circulation of a patient to whom the prodrug is administered, or the agent can be an exogenous supply. The compound provided in the present disclosure is a prodrug of γ-hydroxybutyric acid. The probody part of 4-((L-valyl)oxy)butyric acid has the following structure:

[0030]

[0031] This promoiety is cleaved in vivo in the patient's systemic circulation to gamma-hydroxybutyrate.

[0032] To "cure" a disease means to eliminate the disease or condition, or to eliminate the symptoms of the disease or condition.

[0033] "Sealed storage stability" refers to the stability of a compound packaged in two sealed polyethylene bags with a desiccant material placed between the two polyethylene bags and the two sealed polyethylene bags were sealed in a sealed single layer aluminum bag.

[0034] "Treating" or "treatment" of a disease or condition refers to inhibiting the disease or condition, or one or more clinical symptoms of a disease or condition; arresting the development of the disease or condition, or one or more clinical symptoms of a disease or condition; alleviating the disease or condition, or one or more clinical symptoms of a disease or condition; causing regression of the disease or condition, or one or more clinical symptoms of a disease or condition; reducing the severity of the disease or condition, or one or more clinical symptoms of a disease or condition; delaying the onset of one or more clinical symptoms of a disease or condition; alleviating one or more clinical symptoms of a disease or condition; and / or stabilizing the disease or condition, or one or more clinical symptoms of a disease or condition. "Treating" or "treatment" of a disease or condition includes producing a clinically beneficial effect without curing the underlying disease or condition.

[0035] A "therapeutically effective amount" refers to an amount of a compound, such as a pharmaceutically active ingredient, sufficient to affect such treatment of a disease or its symptoms when administered to a patient for the treatment of a disease or at least one clinical symptom of a disease. A "therapeutically effective amount" may vary depending on, for example, the compound, the disease and / or symptoms of the disease, the severity of the disease and / or symptoms of the disease or condition, the age, weight and / or health of the patient to be treated, and the judgment of the prescribing physician. The therapeutically effective amount in any given case may be determined by those skilled in the art or may be determined by routine experimentation.

[0036] A "therapeutically effective dose" refers to a dose that provides effective treatment for a disease or condition in a patient. A therapeutically effective dose may vary from compound to compound and from patient to patient, and may depend on factors such as the patient's condition and the route of delivery. A therapeutically effective dose may be determined according to conventional pharmacological procedures known to those skilled in the art.

[0037] "Vehicle" refers to a diluent, excipient or carrier with which a compound is administered to a patient. The vehicle may be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0038] Bulk density can be determined according to USP 616, Method 1.

[0039] The tapped bulk density can be determined according to USP 616.

[0040] The specific surface area can be determined by laser diffraction.

[0041] The Hausner ratio can be determined according to USP 1174.

[0042] The parameter D90 refers to the point in the size distribution of a sample up to and including which contains 90% of the total volume of material in the sample. For example, for a D90 of 400 μm, 90% of the sample volume is 400 μm or smaller in size. D50 is the size below which 50% of the total volume of material in the sample is contained. Similarly, D10 is the size below which 10% of the total volume of material in the sample is contained. The volume distribution of a sample can be determined by laser diffraction or by sieve analysis.

[0043] The equivalent of γ-hydroxybutyrate (such as, gm-equivalent of γ-hydroxybutyrate) refers to the grams of γ-hydroxybutyrate in the amount of crystalline 4-((L-valyl)oxy)butyrate. The amount of gm-equivalent of γ-hydroxybutyrate can be determined by multiplying the grams of crystalline 4-((L-valyl)oxy)butyrate by 0.512. For example, 10 grams of 4-((L-valyl)oxy)butyrate corresponds to 5.12 gm-equivalent of γ-hydroxybutyrate.

[0044] Reference is now made to crystalline 4-((L-valyl)oxy)butyric acid, methods of making crystalline 4-((L-valyl)oxy)butyric acid, pharmaceutical compositions comprising crystalline 4-((L-valyl)oxy)butyric acid, and uses of crystalline 4-((L-valyl)oxy)butyric acid. The disclosed crystalline 4-((L-valyl)oxy)butyric acid, pharmaceutical compositions, methods, and uses are not intended to limit the claims. On the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

[0045] Crystalline 4-((L-valyl)oxy)butyric acid is a stable crystalline form of 4-((L-valyl)oxy)butyric acid. Crystalline 4-((L-valyl)oxy)butyric acid has the structure:

[0046]

[0047] 4-((L-valyl)oxy)butyric acid is also known as (S)-4-(2-amino-3-methylbutyryloxy)butyric acid.

[0048] Methods for synthesizing 4-((L-valyl)oxy)butyric acid and properties of 4-((L-valyl)oxy)butyric acid are disclosed in U.S. Pat. No. 10,457,627 and U.S. Pat. No. 11,279,669, each of which is incorporated by reference in its entirety.

[0049] Crystalline 4-((L-valyl)oxy)butyric acid can be prepared as described in Example 1.

[0050] 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 16.75°±0.20°, and 25.33±0.20° expressed as 2θ angles determined using Cu-Kα radiation.

[0051] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.2°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 25.33±0.20°, and 26.08°±0.20° as expressed by 2θ angles determined using Cu-Kα radiation.

[0052] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 13.75°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 24.98°±0.20°, 25.33±0.20°, and 26.08°±0.20° as expressed by 2θ angles determined using Cu-Kα radiation.

[0053] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 11.63°±0.20°, 13.75°±0.02°, 16.75°±0.20°, 17.64°±0.20°, 19.93°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 22.22°±0.20°, 23.58°±0.20°, 24.98°±0.20°, 25.33±0.20°, and 26.08°±0.20° as expressed by 2θ angles determined using Cu-Kα radiation.

[0054] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, and 25.33±0.10° expressed as 2θ angles determined using Cu-Kα radiation.

[0055] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 25.33±0.10°, and 26.08°±0.10° as expressed by 2θ angles determined using Cu-Kα radiation.

[0056] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 9.58°±0.10°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 24.98°±0.10°, 25.33±0.10°, and 26.08°±0.10° as expressed by 2θ angles determined using Cu-Kα radiation.

[0057] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 9.58°±0.10°, 11.63°±0.10°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 19.93°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 22.22°±0.10°, 23.58°±0.10°, 24.98°±0.10°, 25.33±0.10°, and 26.08°±0.10° as expressed by 2θ angles determined using Cu-Kα radiation.

[0058] Crystalline 4-((L-valyl)oxy)butyric acid can be characterized by Figure 1 XRPD pattern shown.

[0059] The crystalline 4-((L-valyl)oxy)butyric acid may have, for example, a melting onset temperature of 135°C to 141°C, such as 136°C to 140°C or 137°C to 139°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

[0060] Crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a melting onset temperature of 137.7°C ± 1.0°C, such as 137.7°C ± 0.5°C, 137.7°C ± 0.2°C, or 137.7°C ± 0.1°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

[0061] Crystalline 4-((L-valyl)oxy)butyric acid can have a melting enthalpy of, for example, 197 J / g to 207 J / g, 199 J / g to 205 J / g, 200 J / g to 204 J / g, or 201 J / g to 203 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

[0062] Crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a melting enthalpy of 202.2 J / g ± 1.0 J / g, such as 202.2 J / g ± 0.5 J / g, 202.2 J / g ± 0.2 J / g, or 202.2 J / g ± 0.1 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

[0063] The crystalline 4-((L-valyl)oxy)butyric acid can have a melting peak temperature of, for example, 138.0°C to 142.0°C, 138.5°C to 141.5°C, 139.0°C to 141.0°C, or 139.5°C to 140.5°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

[0064] Crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a melting peak temperature of 139.9°C ± 2.0°C, such as 139.9°C ± 1.0°C or 139.9°C ± 0.5°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

[0065] Crystalline 4-((L-valyl)oxy)butyric acid can be shown as Figure 2 The differential scanning calorimetry curve shown in .

[0066] Crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a weight loss of 0.16% to 0.36% at a temperature of 20°C to 70°C, such as 0.18% to 0.34% at a temperature of 20°C to 70°C, 0.20% to 0.32% at a temperature of 20°C to 70°C, or 0.22% to 0.30% at a temperature of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scan rate of 2°C / min.

[0067] Crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a weight loss of 0.26%±0.20% (such as 0.26%±0.10% or 0.26%±0.05%) at a temperature of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scan rate of 2°C / min.

[0068] The crystalline 4-((L-valyl)oxy)butyric acid provided by the present disclosure may exhibit substantially Figure 2 Differential thermal calorimetry curve shown.

[0069] The crystalline 4-((L-valyl)oxy)butyric acid can have a water content of, for example, 5.8 mol % to 6.6 mol % (such as, 5.9 mol % to 6.5 mol %, 6.0 mol % to 6.4 mol %, 6.1 mol % to 6.3 wt % or 6.2 mol %), wherein the mol % is based on the total moles of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid.

[0070] The crystalline 4-((L-valyl)oxy)butyric acid can have a water content of, for example, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.8 wt%, less than 0.6 wt%, less than 0.4 wt%, less than 0.2 wt%, or less than 0.1 wt%, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid.

[0071] The water content of crystalline 4-((L-valyl)oxy)butyric acid can be determined using Karl Fischer analysis.

[0072] Crystalline 4-((L-valyl)oxy)butyric acid is substantially stable under sealed storage conditions.

[0073] For example, the crystalline 4-((L-valyl)oxy)butyric acid can have, for example, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.8 wt%, less than 0.6 wt%, less than less than 0.4 wt%, less than 0.2 wt%, or less than 0.1 wt% after sealed storage at 25°C / 60% RH for 1 month, 3 months, and / or 6 months, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid, and the water content is determined using Karl Fischer analysis.

[0074] For example, after sealed storage at 25°C / 65%RH for 36 months, the water content can be less than 2.5 wt% or less than 2.0 wt%, wherein the wt% is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butyric acid. Crystalline 4-((L-valyl)oxy)butyric acid was not observed to form a hydrate.

[0075] The crystalline 4-((L-valyl)oxy)butyric acid can have a purity of, for example, greater than 95 weight %, greater than 96 weight %, greater than 97 weight %, greater than 98 weight %, greater than 99 weight %, greater than 99.2 weight %, greater than 99.4 weight %, greater than 99.6 weight %, or greater than 99.8 weight %, wherein the weight % is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butyric acid and the purity is determined using high pressure liquid chromatography.

[0076] The crystalline 4-((L-valyl)oxy)butyric acid can have an impurity content of, for example, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.8 wt%, less than 0.6 wt%, less than 0.4 wt%, less than 0.2 wt%, or less than 0.1 wt%, wherein the wt% is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butyric acid and the purity is determined using high pressure liquid chromatography.

[0077] After storage at 25°C / 65%RH for 1 month, 3 months, and / or 6 months, the crystalline 4-((L-valyl)oxy)butyric acid can have an impurity content of, for example, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.8 wt%, less than 0.6 wt%, less than 0.4 wt%, less than 0.2 wt%, or less than 0.1 wt%, wherein the wt% is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butyric acid and the purity is determined using high pressure liquid chromatography.

[0078] The impurity content of crystalline 4-((L-valyl)oxy)butyric acid can be determined using high pressure liquid chromatography.

[0079] The crystalline 4-((L-valyl)oxy)butyric acid can have a chiral purity of, for example, greater than 98%, greater than 99%, greater than 99.2%, greater than 99.4%, greater than 99.6%, or greater than 99.8%, wherein the percentages (%) are based on the total moles of crystalline 4-((L-valyl)oxy)butyric acid and the chiral purity is determined using high pressure liquid chromatography.

[0080] Unmilled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by a D10 of 11.8 μm, a D50 of 34.0 μm, and a D90 of 72.3 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0081] Unmilled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by a D10 of 9 to 15 μm, a D50 of 31 to 37 μm, and a D90 of 69 to 73 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0082] Unmilled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by a D10 of 7 to 17 μm, a D50 of 29 to 39 μm, and a D90 of 67 to 75 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0083] Unmilled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by D[4,3] of 35 μm to 41 μm, such as 36 μm to 40 μm or 37 μm to 39 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0084] Unmilled crystalline 4-((L-valyl)oxy)butyric acid can have a homogeneity of 0.45 to 0.65, such as 0.50 to 0.60, wherein the homogeneity is determined using laser diffraction.

[0085] Unground crystalline 4-((L-valyl)oxy)butyric acid may have a m 2 / kg to 310m 2 / kg (such as 280m 2 / kg to 300m 2 / kg), where the surface area is determined using laser diffraction.

[0086] Unground crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a bulk density of 0.15 g / mL to 0.25 g / mL (such as 0.18 g / mL to 0.22 g / mL), wherein the bulk density is determined according to USP 616, Method 1.

[0087] Unground crystalline 4-((L-valyl)oxy)butyric acid can have a Hausner Ratio of, for example, 1.65 to 1.95, or 1.70 to 1.90, or 1.75 to 1.85, wherein the Hausner Ratio is determined according to USP 1174.

[0088] The ground crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by a D10 of 11.8 μm, a D50 of 5.6 μm, and a D90 of 10.6 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0089] The milled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by a D10 of 1 to 5 μm, a D50 of 4 to 8 μm, and a D90 of 10 to 14 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0090] The milled crystalline 4-((L-valyl)oxy)butyric acid may have a particle size distribution characterized by D[4,3] of 12 to 22 μm, such as 14 to 20 μm or 16 to 18 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0091] The ground crystalline 4-((L-valyl)oxy)butyric acid can have a homogeneity of 0.2 to 0.6 (such as 0.3 to 0.5), wherein the homogeneity is determined using laser diffraction.

[0092] The ground crystalline 4-((L-valyl)oxy)butyric acid may have a m 2 / kg to 630m 2 / kg (such as 450m 2 / kg to 610m 2 / kg or 470m 2 / kg to 490m 2 / kg), where the surface area is determined using laser diffraction.

[0093] The ground crystalline 4-((L-valyl)oxy)butyric acid can have a bulk density of, for example, 0.10 g / mL to 0.14 g / mL (such as 0.11 g / mL to 0.13 g / mL), wherein the bulk density is determined according to USP 616, Method 1.

[0094] The ground crystalline 4-((L-valyl)oxy)butyric acid can have, for example, a Hausner Ratio of 1.6 to 1.8 or 1.65 to 1.75, wherein the Hausner Ratio is determined according to USP 1174.

[0095] Methods for synthesizing 4-((L-valyl)oxy)butyric acid and the properties of 4-((L-valyl)oxy)butyric acid are disclosed, for example, in U.S. Pat. No. 10,457,627 and U.S. Pat. No. 11,279,669, each of which is incorporated by reference in its entirety.

[0096] Examples 1 and 2 also disclose a method for synthesizing 4-((L-valyl)oxy)butyric acid and the properties of 4-((L-valyl)oxy)butyric acid.

[0097] For example, 4-((L-valyl)oxy)butyric acid can be prepared by (a) contacting benzyl bromide with butyrolactone to provide benzyl 4-hydroxybutyrate (2a); (b) contacting benzyl 4-hydroxybutyrate (2a) with carbobenzyloxy-L-valine to provide 4-(benzoyloxy)-4-oxobutyl((benzoyloxy)carbonyl)-L-valine ester (2b); and (c) deprotecting 4-(benzoyloxy)-4-oxobutyl((benzoyloxy)carbonyl)-L-valine ester (2b) to provide 4-((L-valyl)oxy)butyric acid.

[0098] Alternatively, 4-((L-valyl)oxy)butyric acid can be prepared according to the method shown in Scheme 1:

[0099]

[0100] Boc-L-valine can be coupled with 1,4-butanediol using a peptide coupling reagent such as N,N'-dicyclohexylcarbodiimide (DCC), BOP, DEPBT, N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-chloromethylmorpholinium (DMTMM), HATU, HBTU, TBTU, PyAOP, PyBOP, 1,1'-thiocarbonyldiimidazole (TCDI), or 1,1'-carbonyldiimidazole (CDI) to provide (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a). 1-Hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) may be included to inhibit racemization.

[0101] (S)-4-Hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a) can be treated with an oxidizing agent to provide (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b). Examples of suitable oxidizing agents include Jones reagent, potassium permanganate, ruthenium tetroxide, pyridinium dichromate in dimethylformamide (DMF), tetrapropylammonium perruthenate, or catalytic tetrapropylammonium perruthenate with a stoichiometric amount of N-methylmorpholine N-oxide. The alcohol can be oxidized to the aldehyde (such as with Dess-Martin periodinane) and subsequently oxidized to the carboxylic acid (such as with sodium chlorite).

[0102] (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b) can be treated with an acid to provide a salt form of compound (1b). Examples of suitable acids include HCl, HCl in ethyl acetate, HCl in water, HCl in 1,4-dioxane, and trifluoroacetic acid. The salt form of compound (1b) can be neutralized with an acid scavenger to provide the free amine form of 4-((L-valyl)oxy)butanoic acid. Examples of suitable acid scavengers include propylene oxide, an organic base, an amine base, an inorganic base, a carbonate or hydroxide salt.

[0103] 4-((L-valyl)oxy)butyric acid can also be prepared according to the method summarized in Scheme 2:

[0104]

[0105] Benzyl 4-hydroxybutyrate (2a) can be prepared by ring-opening hydrolysis of γ-butyrolactone and subsequent benzylation. Alternatively, benzyl 4-hydroxybutyrate (2a) can be purchased commercially.

[0106] CBz-L-valine can be coupled with 4-hydroxybutyric acid benzyl ester (2a) using a peptide coupling reagent such as DCC, BOP, DEPBT, DIC, EDCI, DMTMM, HATU, HBTU, TBTU, PyAOP, PyBOP, TCDI or CDI to provide 4-(benzyloxy)-4-oxobutyl(benzyloxy)carbonyl)-L-valine (2b). 1-Hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) can be included in the reaction to inhibit racemization.

[0107] 4-(Benzyloxy)-4-oxobutyl(benzyloxy)carbonyl)-L-valine (2b) can be hydrogenated in the presence of hydrogen and a catalyst derived from a metal such as palladium, platinum, ruthenium, nickel, rhodium or iridium to provide 4-((L-valyl)oxy)butanoic acid.

[0108] Crystalline 4-((L-valyl)oxy)butyric acid can be prepared by the following method: (i) dissolving 4-((L-valyl)oxy)butyric acid in a first solvent to obtain a solution; and (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butyric acid.

[0109] The first solvent may include, for example, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, isobutanol, isopropyl acetate, acetonitrile, 2-butanone, toluene, water, tert-butyl methyl ether, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, diethyl ether, or a combination of any of the foregoing.

[0110] 4-((L-valyl)oxy)butyric acid can be dissolved in a solvent at a temperature of, for example, 60°C to 90°C, 65°C to 85°C, or 70°C to 80°C.

[0111] After dissolving 4-((L-valyl)oxy)butyric acid in the first solvent, a second solvent may be added to the solution. For example, the second solvent may include acetonitrile, tetrahydrofuran, isopropanol, acetone, ethyl acetate, tert-butyl methyl ether, 1,4-dioxane, or a combination of any of the foregoing.

[0112] Crystallizing 4-((L-valyl)oxy)butyric acid may include, for example, heating the solution to a temperature of 60°C to 90°C (such as 65°C to 85°C or 60°C to 80°C) and maintaining the solution at that temperature, for example, for 0.5 to 2 hours.

[0113] Crystallization may also include cooling the heated solution to a temperature of, for example, 20°C to 25°C.

[0114] The crystallized 4-((L-valyl)oxy)butyric acid can be filtered and washed to provide crystalline 4-((L-valyl)oxy)butyric acid.

[0115] Crystalline 4-((L-valyl)oxy)butyric acid can be recrystallized, for example, by warming the solvent, adding the crystalline 4-((L-valyl)oxy)butyric acid to the solvent and dissolving the crystalline 4-((L-valyl)oxy)butyric acid in the solvent. The solvent can be, for example, ethanol, 50:1 ethanol / water, water, methanol, or isopropanol. Additional solvent can be added and / or an appropriate amount of anti-solvent can be optionally added to the clear solution. Examples of suitable anti-solvents include acetone, ethyl acetate, and methyl tert-butyl ether. For example, the volume ratio of methanol to methyl tert-butyl ether can be about 1:3. After stirring the solution for about 30 minutes, the solution can be cooled to a temperature of 20° C. to 25° C. and filtered to provide crystalline 4-((L-valyl)oxy)butyric acid as a solid precipitate.

[0116] Crystalline 4-((L-valyl)oxy)butyric acid can be incorporated into a pharmaceutical composition for administration to a patient by any suitable route of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation or topical. The pharmaceutical composition provided by the present disclosure can be an injectable formulation. The pharmaceutical composition provided by the present disclosure can be an injectable intravenous formulation. The pharmaceutical composition provided by the present disclosure can be an oral formulation. The oral formulation can be an oral dosage form.

[0117] The pharmaceutical compositions provided by the present disclosure may include a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butyric acid and a suitable amount of one or more pharmaceutically acceptable vehicles to provide a composition for appropriate administration to a patient. Suitable pharmaceutical vehicles and methods for preparing pharmaceutical compositions are described in the art.

[0118] The pharmaceutical compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the systemic circulation of a patient after administration to the patient (such as, after oral administration to the patient).

[0119] Therefore, one skilled in the art is able to identify and use crystalline 4-((L-valyl)oxy)butyric acid and / or pharmaceutical compositions thereof for treatment.

[0120] Crystalline 4-((L-valyl)oxy)butyric acid and / or a pharmaceutical composition thereof can be used in an effective amount to achieve the intended purpose. For example, crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be administered to a patient in a therapeutically effective amount to treat a disease or disease symptom, such as a sleep disorder.

[0121] The amount of crystalline 4-((L-valyl)oxy)butyric acid or pharmaceutical composition thereof that is effective in treating a particular disorder will depend in part on the nature of the disorder or condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help determine optimal dosage ranges. The appropriate amount of crystalline 4-((L-valyl)oxy)butyric acid and / or pharmaceutical composition thereof to be administered will depend on, among other factors, the patient being treated, the patient's weight, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician.

[0122] The desired therapeutic activity of crystalline 4-((L-valyl)oxy)butyric acid can be determined in vitro and in vivo prior to use in humans. Crystalline 4-((L-valyl)oxy)butyric acid can also be demonstrated to be effective and safe using animal model systems.

[0123] In certain embodiments, a therapeutically effective dose of crystalline 4-((L-valyl)oxy)butyric acid and / or a pharmaceutical composition thereof can provide therapeutic benefit without causing significant toxicity. The toxicity of crystalline 4-((L-valyl)oxy)butyric acid and / or a pharmaceutical composition thereof can be determined using standard pharmaceutical procedures and can be determined by one skilled in the art. The dose ratio between toxicity and therapeutic effect is the therapeutic index. Compounds of crystalline 4-((L-valyl)oxy)butyric acid and / or a pharmaceutical composition thereof can exhibit a high therapeutic index in treating diseases and conditions. The dose of crystalline 4-((L-valyl)oxy)butyric acid and / or a pharmaceutical composition thereof can be within a circulating concentration range that includes an effective dose with minimal toxicity.

[0124] In addition to crystalline 4-((L-valyl)oxy)butyric acid, the pharmaceutical compositions provided by the present disclosure may further include one or more pharmaceutically active compounds. Such compounds may be provided to treat a disease that is treated with a compound of the formula, or to treat a disease, disorder, or condition other than a disease, disorder, or condition that is treated with crystalline 4-((L-valyl)oxy)butyric acid.

[0125] Crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be used in combination with at least one other therapeutic agent. Crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be administered to a patient together with another compound to treat a disease (such as a sleep disorder) in the patient. Crystalline 4-((L-valyl)oxy)butyric acid and at least one other therapeutic agent can act additively or synergistically. At least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle comprising crystalline 4-((L-valyl)oxy)butyric acid, or this can be in a separate pharmaceutical composition or vehicle. Thus, in addition to administering crystalline 4-((L-valyl)oxy)butyric acid, the methods provided by the present disclosure further comprise administering one or more therapeutic agents effective to treat a disease, disorder, or condition other than the disease treated with gamma-hydroxybutyric acid. The methods provided by the present disclosure comprise administering crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic efficacy of crystalline 4-((L-valyl)oxy)butyric acid and / or γ-hydroxybutyric acid and / or does not produce adverse combination effects.

[0126] A pharmaceutical composition comprising crystalline 4-((L-valyl)oxy)butyric acid may be administered simultaneously with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as that comprising crystalline 4-((L-valyl)oxy)butyric acid, or part of a different pharmaceutical composition than that comprising crystalline 4-((L-valyl)oxy)butyric acid. Crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof may be administered before or after administration of the other therapeutic agent. In certain embodiments of combination therapy, the combination therapy may include alternating between administration of crystalline 4-((L-valyl)oxy)butyric acid and a pharmaceutical composition comprising another therapeutic agent in order to minimize adverse drug effects associated with a particular drug. When crystalline 4-((L-valyl)oxy)butyric acid is administered simultaneously with another therapeutic agent that potentially can produce adverse drug effects (including, for example, toxicity), the other therapeutic agent may be administered at a dose that falls below the threshold for inducing an adverse drug reaction.

[0127] Pharmaceutical compositions comprising crystalline 4-((L-valyl)oxy)butyric acid can be administered with one or more substances, for example, to enhance, regulate and / or control the release, bioavailability, therapeutic efficacy, therapeutic effectiveness and / or stability of crystalline 4-((L-valyl)oxy)butyric acid. For example, to enhance the therapeutic efficacy of crystalline 4-((L-valyl)oxy)butyric acid, crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition comprising crystalline 4-((L-valyl)oxy)butyric acid can be co-administered with one or more active agents to increase the absorption or diffusion and / or transport of crystalline 4-((L-valyl)oxy)butyric acid from the gastrointestinal tract to the systemic circulation, or to inhibit the degradation of crystalline 4-((L-valyl)oxy)butyric acid in the patient's blood. Pharmaceutical compositions comprising crystalline 4-((L-valyl)oxy)butyric acid can be co-administered with an active agent having a pharmacological effect that enhances the therapeutic effect of the compound or the therapeutic effect of gamma-hydroxybutyric acid.

[0128] For oral therapeutic administration, crystalline 4-((L-valyl)oxy)butyric acid can be mixed with excipients and used in the form of, for example, tablets, lozenges or tablets, troches, capsules, elixirs, suspensions, syrups or wafers for mixing with an aqueous medium. The dosage form can include a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butyric acid or less than a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butyric acid.

[0129] An oral formulation, such as an oral dosage form, may contain, for example, 1 gram to 18 grams of crystalline 4-((L-valyl)oxy)butyric acid.

[0130] An oral formulation, such as an oral dosage form, may contain, for example, 0.5 gram equivalents to 9 gram equivalents of gamma-hydroxybutyrate.

[0131] Oral dosage forms (such as granules, tablets, lozenges, pills, capsules or suspensions) may also contain, for example, binders, natural (such as gum tragacanth, gum arabic, corn starch or gelatin) or synthetic (such as polyvinyl acetate); excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch or alginic acid; lubricants, such as magnesium stearate; sweeteners, such as lactose or saccharin, or natural or synthetic flavoring agents may be added. When the dosage form is a capsule for mixing with a specific volume of aqueous medium, the dosage form may contain a liquid carrier. Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with sugar, natural or synthetic polymers, or a combination of any of the foregoing.

[0132] The oral dosage form may include a granulation, wherein the granulation comprises granules containing crystalline 4-((L-valyl)oxy)butyric acid. The granulation may include immediate release granules containing crystalline 4-((L-valyl)oxy)butyric acid, modified release granules containing crystalline 4-((L-valyl)oxy)butyric acid, or a combination thereof.

[0133] The granulation may comprise a core comprising crystalline 4-((L-valyl)oxy)butyric acid and optionally a coating surrounding the core. The coating may be, for example, a seal coat or a modified release coat. Granules comprising an uncoated core are referred to as uncoated granulations.

[0134] The uncoated granules of crystalline 4-((L-valyl)oxy)butyric acid are characterized, for example, by an average particle size of 50 μm to 600 μm, 100 μm to 550 μm, 100 μm to 500 μm, 150 μm to 500 μm, 200 μm to 500 μm, 250 μm to 450 μm or 200 μm to 400 μm, wherein the average particle size is determined by sieve analysis or by laser diffraction.

[0135] Uncoated granules may comprise a high loading of crystalline 4-((L-valyl)oxy)butyric acid. For example, the uncoated granules may comprise greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt% of crystalline 4-((L-valyl)oxy)butyric acid, wherein the wt% are based on the total weight of the uncoated granules. The uncoated granules may comprise, for example, 80 wt% to 99.5 wt% of 4-((L-valyl)oxy)butyric acid, 85 wt% to 95 wt%, 87 wt% to 93 wt%, or 88 wt% to 92 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% are based on the total weight of the coated granules. Uncoated granules may contain, for example, 85 to 95% by weight of 4-((L-valyl)oxy)butyric acid, 86 to 94% by weight, 87 to 93% by weight, or 88 to 92% by weight of 4-((L-valyl)oxy)butyric acid, wherein the weight % is based on the total weight of the coated granules.

[0136] Uncoated granules or granulations may comprise, for example, 80% to 99% by weight of crystalline 4-((L-valyl)oxy)butyric acid, 1% to 10% by weight of an antistatic agent such as hydrated magnesium silicate (talc), and 1% to 10% by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, wherein the % by weight is based on the total weight of the granules or granulations. Uncoated granules or granulations may comprise, for example, 85% to 95% by weight of crystalline 4-((L-valyl)oxy)butyric acid, 2% to 8% by weight of an antistatic agent such as hydrated magnesium silicate (talc), and 2% to 8% by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, wherein the % by weight is based on the total weight of the granules or granulations. The uncoated granules or granulations provided by the present disclosure may contain, for example, 87 to 93 wt % of crystalline 4-((L-valyl)oxy)butyric acid, 3 to 7 wt % of an antistatic agent (such as hydrated magnesium silicate (talc)), and 3 to 7 wt % of a water-soluble polymer (such as hydroxypropylmethylcellulose), wherein the wt % is based on the total weight of the granules or granulations.

[0137] Uncoated granules or granulations may be characterized by an average sphericity, for example, from 0.90 to 1, such as from 0.91 to 0.99 or from 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. Uncoated granules or granulations may be characterized by an average sphericity, for example, greater than 0.90, greater than 0.91, greater than 0.92, greater than 0.93, greater than 0.94 or greater than 0.95.

[0138] Uncoated granules are solid and are characterized by having a substantially uniform composition throughout the granule.

[0139] The uncoated granules provided by the present disclosure may be characterized by sphericity, for example, 0.90 to 1, such as 0.91 to 0.99 or 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The granulation provided by the present disclosure may be characterized by average sphericity, for example, greater than 0.90, greater than 0.91, greater than 0.92, greater than 0.93, greater than 0.94 or greater than 0.95. The granulation provided by the present disclosure may include a plurality of granules, which are characterized by average sphericity, for example, greater than 0.94, greater than 0.95, greater than 0.96, greater than 0.97, greater than 0.98 or greater than 0.99.

[0140] The uncoated granules provided by the present disclosure are solid and are characterized by having a substantially uniform composition throughout the granule.

[0141] The uncoated granulation can have a bulk density of, for example, greater than 0.40 g / mL, greater than 0.50 g / mL, greater than 0.60 g / mL, greater than 0.90 g / mL, greater than 1.10 g / mL, greater than 1.30 g / mL, or greater than 1.50 g / mL.

[0142] Uncoated granules can have, for example, a bulk density of 0.40 g / mL to 1.60 g / mL, 0.40 g / mL to 1.20 g / mL, 0.40 g / mL to 0.80 g / mL, 0.50 g / mL to 1.60 g / mL, 0.50 g / mL to 1.40 g / mL, 0.50 g / mL to 1.20 g / mL, 0.60 g / mL to 1.60 g / mL, 0.70 g / mL to 1.50 g / mL, 0.80 g / mL to 1.40 g / mL, or 1.00 g / mL to 1.20 g / mL. Uncoated granules can have, for example, a bulk density of 0.5 g / mL to 0.8 g / mL, 0.55 g / mL to 0.75 g / mL, or 0.6 g / mL to 0.7 g / mL.

[0143] Bulk density can be determined using a bulk density cylinder.

[0144] Uncoated granules provided by the present invention have smooth surfaces. Smooth granule surfaces contribute to the ability to coat granules with a thin, continuous coating having substantially uniform thickness. The quality of the coating may be important for controlled release formulations. For example, rough and / or porous surfaces tend to require significantly higher amounts of coating to achieve a release profile comparable to a smooth surface. In addition, coatings on rough and / or porous surfaces may result in variable dissolution or release profiles.

[0145] The uncoated granulation provided by the present disclosure can be characterized by a loss on drying (LOD) of, for example, 0.05% to 1.5% by weight, 0.1% to 1.4% by weight, 0.2% to 1.2% by weight, 0.2% to 1.3% by weight, 0.3% to 1.2% by weight, 0.7% to 1.1% by weight, 0.92% to 0.98% by weight, 0.93% to 0.97% by weight, or 0.94% to 0.96% by weight when dried, wherein the wt% is based on the total weight of the granulation. The granulation provided by the present disclosure can be characterized by a loss on drying (LOD) of, for example, less than 1.5% by weight, less than 1.3% by weight, less than 1.1% by weight, less than 0.9% by weight, less than 0.7% by weight, less than 0.5% by weight, or less than 0.1% by weight when dried, wherein the wt% is based on the total weight of the granulation. LOD represents the amount of water removed from the granules during preparation of the granules and subsequently after drying.

[0146] LOD was determined by thermogravimetric analysis.

[0147] The uncoated granulation provided by the present disclosure may be characterized in that the friability is, for example, 0% to 2% by weight (such as, less than 2% by weight, less than 1.5% by weight, less than 1% by weight or less than 0.5% by weight), wherein the % by weight is based on the gross weight of the granulation. The granulation provided by the present disclosure may be characterized in that the friability is, for example, 0.1% to 2% by weight, 0.2% to 1.8% by weight, 0.2% to 1.6% by weight, 0.4% to 1.2% by weight or 0.6% to 1.2% by weight, wherein the % by weight is based on the gross weight of the granulation. Granules with low friability are easier to coat than granules with high friability. Friability is defined as the amount (% by weight) of particles with a diameter less than 75 μm produced by subjecting the granulation to a sonic sifter operating at a vibration amplitude of 8 corresponding to 3,600 acoustic energy pulses per minute for at least 2 minutes.

[0148] The uncoated granulations provided by the present disclosure can have, for example, a friability of less than 1.02%, wherein the friability is determined using a sonic sifter.

[0149] Uncoated granules containing crystalline 4-((L-valyl)oxy)butyric acid can be used Microgranulation technology (Glatt GmbH) was used for preparation.

[0150] Uncoated granules containing crystalline 4-((L-valyl)oxy)butyric acid can be prepared by a combination of dry granulation and wet granulation.

[0151] The crystalline 4-((L-valyl)oxy)butyric acid may be screened, delumped, co-milled, Fitz-milled, pin-milled or jet-milled prior to addition to the dry mixture.

[0152] The crystalline 4-((L-valyl)oxy)butyric acid may have a D90 size distribution characterized by, for example, less than 30 μm, less than 25 μm, less than 20 μm, or less than 15 μm. The active pharmaceutical ingredient may have a size distribution characterized by a D90 of, for example, 10 μm to 30 μm, 11 μm to 25 μm, or 10 μm to 20 μm. The as-crystallized active pharmaceutical ingredient may be jet milled to provide a suitable particle size distribution.

[0153] The dry mixture can be mixed in a bowl, for example, for 0.5 to 5 minutes to provide a homogenous dry mixture.

[0154] The granulation may include the steps of: (a) granulating the dry mixture to provide a dry granulation; and (b) adding water to the dry granulation and granulating to provide a wet granulation.

[0155] The granulations may include immediate release granulations.

[0156] The immediate release granulation may comprise a plurality of uncoated granules or a plurality of granules comprising a seal coat.

[0157] The seal coat may include a water soluble polymer such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or any of the water soluble polymers disclosed herein.

[0158] The seal coat may include an antistatic agent such as talc, magnesium stearate, or a combination thereof.

[0159] The seal coat can contain, for example, 65 to 95 wt % of a water-soluble polymer, such as 70 to 90 wt % or 75 to 85 wt % of a water-soluble polymer; and 5 to 35 wt % of an antistatic agent, such as 10 to 30 wt % or 15 to 25 wt % of an antistatic agent, wherein the wt % is based on the total weight of the seal coat.

[0160] The seal coat may have a thickness of, for example, 0.5 μm to 4 μm, 1 μm to 3.5 μm, 1 μm to 3 μm, or 1 μm to 2.5 μm.

[0161] The immediate release granulation comprising a plurality of uncoated or seal-coated granules may include, for example, greater than 80% by weight (such as, 85% to 95% by weight) of crystalline 4-((L-valyl)oxy)butyric acid. When tested in a USP Type 2 dissolution apparatus in an aqueous buffer solution at pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, the immediate release granulation comprising uncoated or seal-coated granules may be completely dissolved, for example, in less than 10 minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes, or less than 4 minutes.

[0162] The immediate release granulation can include multiple coated or sealed coated granules with an immediate release functional coating. The immediate release granulation comprising multiple coated granules can include greater than 80% by weight of crystalline 4-((L-valyl)oxy)butyric acid. When tested in a USP type 2 dissolution apparatus at a temperature of 37°C and a paddle speed of 100rpm in a buffer solution having a pH of 4.5, the immediate release granulation comprising the coated granules can be, for example, completely dissolved in less than 25 minutes, less than 20 minutes, less than 18 minutes, less than 16 minutes, less than 14 minutes, or less than 12 minutes. When tested in a USP type 2 dissolution apparatus at a temperature of 37°C and a paddle speed of 100rpm in a buffer solution having a pH of 4.5, the immediate release granulation comprising the coated granules can, for example, release greater than 80% of crystalline 4-((L-valyl)oxy)butyric acid in less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes. The coated immediate release granules may include a coating containing a water-soluble polymer such as, for example, hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone or polyethylene glycol. The coated immediate release granules may include a coating containing an antistatic agent such as talc, magnesium stearate or silicon dioxide.

[0163] The modified release granulation may include a plurality of granules coated with a functional coating. The functional coating may include, for example, a modified release coating, such as a controlled release coating, a sustained release coating, a pH release coating, a pulsatile release coating, a timed release coating, or a delayed release coating. The functional coating may be configured to release crystalline 4-((L-valyl)oxy)butyric acid from the coated granules, for example, within an expected time period after ingestion and / or in an expected region of the gastrointestinal tract.

[0164] Modified release granules may include uncoated granules comprising crystalline 4-((L-valyl)oxy)butyric acid with one or more functional coatings surrounding the uncoated granules.

[0165] Each of the one or more functional coatings can independently have, for example, an average thickness of less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. Each of the one or more functional coatings can independently have, for example, an average thickness of 5 μm to 50 μm, 5 μm to 40 μm, 5 μm to 30 μm, 5 μm to 20 μm, 5 μm to 15 μm, or 5 μm to 10 μm.

[0166] The coated granules or coated granules may contain, for example, greater than 50% by weight of crystalline 4-((L-valyl)oxy)butyric acid, greater than 55% by weight, greater than 60% by weight, greater than 70% by weight, greater than 70% by weight, greater than 80% by weight or greater than 85% by weight of crystalline 4-((L-valyl)oxy)butyric acid, wherein the weight % is based on the total weight of the coated granules or coated granules.

[0167] The coated granules or coated granules comprising a plurality of coated granules may contain, for example, 50 to 90% by weight of crystalline 4-((L-valyl)oxy)butyric acid, 60 to 90% by weight, 70 to 90% by weight, 75 to 85% by weight or 77 to 83% by weight of crystalline 4-((L-valyl)oxy)butyric acid, wherein the weight % is based on the total weight of the coated granules or coated granules.

[0168] Coated granules or coated granules can include, for example, a functional coating less than 50 % by weight, less than 40 % by weight, less than 30 % by weight, less than 20 % by weight or less than 10 % by weight, wherein % by weight is based on the gross weight of coated granules or coated granules. Coated granules or coated granules can include, for example, a functional coating less than 10 % by weight, less than 40 % by weight or less than 10 % by weight, wherein % by weight is based on the gross weight of coated granules or coated granules. Coated granules or coated granules can include, for example, a functional coating less than 10 % by weight, less than 45 % by weight, less than 40 % by weight or less than 15 % by weight, wherein % by weight is based on the gross weight of coated granules. The coated granules containing crystallization 4-((L-valyl) oxy) butyric acid can have a thick coating, to reduce the release rate of crystallization 4-((L-valyl) oxy) butyric acid and / or increase the storage stability of crystallization 4-((L-valyl) oxy) butyric acid by minimizing or preventing the entry of moisture.

[0169] The functional coating may include a time-release coating that releases crystalline 4-((L-valyl)oxy)butyric acid over time in an aqueous environment. The release of crystalline 4-((L-valyl)oxy)butyric acid may be characterized by a zero-order release profile.

[0170] The functional coating may include a matrix polymer or a combination of matrix polymers. The combination of matrix polymers and / or pore-forming polymers may be selected to provide a desired release profile for the crystalline 4-((L-valyl)oxy)butyric acid in the gastrointestinal tract.

[0171] The functional coating can contain, for example, 55 wt % to 95 wt % of the matrix polymer, 60 wt % to 90 wt %, 65 wt % to 90 wt %, 70 wt % to 85 wt % or 75 wt % to 85 wt % of the matrix polymer, wherein the wt % is based on the total weight of the functional coating.

[0172] The functional coating may include a matrix polymer or a combination of matrix polymers. The combination of matrix polymers may be selected to provide a desired release profile for the crystalline 4-((L-valyl)oxy)butyric acid in the gastrointestinal tract.

[0173] The functional coating can contain, for example, 55 wt % to 95 wt % of the matrix polymer, 60 wt % to 90 wt %, 65 wt % to 90 wt %, 70 wt % to 85 wt % or 75 wt % to 85 wt % of the matrix polymer, wherein the wt % is based on the total weight of the functional coating.

[0174] The functional coating may contain, for example, less than 95 wt % of the matrix polymer, less than 90 wt %, less than 85 wt %, less than 80 wt %, less than 75 wt %, less than 70 wt % or less than 60 wt % of the matrix polymer, wherein the wt % is based on the total weight of the functional coating.

[0175] The functional coating can contain, for example, greater than 50 wt % of the matrix polymer, greater than 55 wt %, greater than 60 wt %, greater than 65 wt %, greater than 70 wt %, greater than 75 wt %, greater than 80 wt %, greater than 85 wt % or greater than 90 wt % of the matrix polymer, wherein the wt % is based on the total weight of the functional coating.

[0176] The matrix polymer may include a water-insoluble polymer or a combination of water-insoluble polymers.

[0177] Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl acetate, polyacrylates, and polymethacrylates.

[0178] The water-insoluble polymer, such as ethylcellulose, can have an average molecular weight of, for example, 25,000 Daltons to 300,000 Daltons, such as 50,000 Daltons to 200,000 Daltons, 50,000 Daltons to 150,000 Daltons, or 50,000 Daltons to 100,000 Daltons.

[0179] The water-insoluble polymer (such as, ethylcellulose) can have a viscosity of, for example, less than 100 mPa×sec, less than 75 mPa×sec, less than 50 mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15 mPa×sec, as determined using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0180] Examples of suitable ethylcellulose polymers include ethylcellulose available from Ashland T10 Pharm, N7 Pharm, N10 Pharm, N14 Pharm, N22 Pharm, N50 Pharm, and N100 Pharm polymers. Other examples of suitable ethylcellulose polymers include those available from Dupont. Standard 7, Standard 10, Standard 14, Standard 20 polymers.

[0181] The matrix polymer can comprise the water-insoluble polymer of for example 90 % by weight to 100 % by weight, the water-insoluble polymer of 91 % by weight to 99 % by weight, 82 % by weight to 98 % by weight or 93 % by weight to 97 % by weight, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise the water-insoluble polymer of for example greater than 90 % by weight, greater than 92 % by weight, greater than 94 % by weight, greater than 96 % by weight or greater than 98 % by weight, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise the water-insoluble polymer of for example less than 100 % by weight, less than 98 % by weight, less than 96 % by weight, less than 94 % by weight or less than 92 % by weight, wherein % by weight is based on the gross weight of the matrix polymer.

[0182] The matrix polymer may include a pore-forming polymer. Examples of pore-forming polymers include water-soluble polymers, swellable or expanded polymers such as carbomers, and gastric fluid-soluble polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid-methyl methacrylate copolymers, and polyvinyl acetate phthalate. Pore-forming polymers can increase the permeability of the functional coating under expected conditions.

[0183] The matrix polymer may include a water-soluble polymer or a combination of water-soluble polymers.

[0184] Examples of suitable water-soluble polymers include hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, copovidone and poloxamer.

[0185] The water soluble polymer, such as hydroxypropylcellulose, can have an average molecular weight of, for example, less than 1,000,000 Daltons, less than 800,000 Daltons, less than 600,000 Daltons, less than 400,000 Daltons, less than 200,000 Daltons, less than 100,000 Daltons, or less than 50,0000 Daltons.

[0186] The water-soluble polymer, such as hydroxypropyl cellulose, can have a viscosity, for example, of less than 7,000 mPa×sec, less than 5,000 mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec, as determined using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0187] Examples of suitable hydroxypropylcellulose polymers include hydroxypropylcellulose available from Ashland HF Pharm, MFPharm, GF Pharm, JF Pharm, LF Pharm, EF Pharm and ELF Pharm polymers.

[0188] Examples of suitable hydroxypropyl methylcellulose polymers include those available from Shin-Etsu Chemical Co. 603, 645, 606 and 615 polymers.

[0189] Matrix polymer can comprise the water-soluble polymer (such as, ethyl cellulose) of for example 0 % by weight to 15 % by weight, the water-soluble polymer of 0 % by weight to 10 % by weight, 1 % by weight to 8 % by weight or 2 % by weight to 6 % by weight, wherein % by weight is based on the gross weight of matrix polymer.Matrix polymer can comprise the water-soluble polymer (such as, hydroxypropyl cellulose) of for example greater than 0 % by weight, greater than 2 % by weight, greater than 4 % by weight, greater than 6 % by weight or greater than 8 % by weight, wherein % by weight is based on the gross weight of matrix polymer.Matrix polymer can comprise the water-soluble polymer of for example less than less than 10 % by weight, less than 8 % by weight, less than 6 % by weight, less than 4 % by weight or less than 2 % by weight, wherein % by weight is based on the gross weight of matrix polymer.

[0190] The matrix polymer may include, for example, 90 to 100 wt % of a water-insoluble polymer (such as ethyl cellulose) and 0 to 10 wt % of a water-soluble polymer (such as hydroxypropyl cellulose), 92 to 98 wt % of a water-insoluble polymer and 2 to 8 wt % of a water-soluble polymer, or 94 to 96 wt % of a water-insoluble polymer and 4 to 6 wt % of a water-soluble polymer, wherein the wt % is based on the total weight of the matrix polymer.

[0191] The functional coating may be applied to the granules of the present disclosure by any suitable method, such as by spraying a solution, suspension or dispersion of the functional coating onto the granules in a fluidized bed apparatus.

[0192] In addition to the matrix polymer or combination of matrix polymers, the functional coating may include, for example, a plasticizer, an antistatic agent, an anti-adherent agent, a colorant or pigment, a glidant, a viscosity modifier, or a combination of any of the foregoing.

[0193] The functional coating may include an antistatic agent or a combination of antistatic agents.

[0194] Antistatic agents are used to minimize or prevent agglomeration of particles during application of the functional coating.

[0195] Examples of suitable antistatic agents include talc (hydrated magnesium silicate), magnesium stearate and silicon dioxide.

[0196] Functional coatings can include, for example, 5% to 25% by weight of antistatic agent, such as 8% to 22% by weight or 10% to 20% by weight of antistatic agent, wherein the weight % is based on the gross weight of the functional coating. Functional coatings can include, for example, less than 25% by weight of antistatic agent, less than 23% by weight, less than 18% by weight or less than 15% by weight of antistatic agent, wherein the weight % is based on the gross weight of the functional coating. Functional coatings can include, for example, greater than 5% by weight of antistatic agent, greater than 8% by weight, greater than 12% by weight, greater than 16% by weight or greater than 20% by weight of antistatic agent, wherein the weight % is based on the gross weight of the functional coating.

[0197] The functional coating provided by the present invention does not contain plasticizers such as dibutyl sebacate, polyethylene glycol, triacetin and triethyl citrate.

[0198] The functional coating provided by the present disclosure may contain, for example, 70 wt % to 95 wt % of a matrix polymer and 5 wt % to 30 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0199] The functional coating provided by the present disclosure may contain, for example, 75 to 90 wt % of a matrix polymer and 10 to 25 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0200] The functional coating provided by the present disclosure may comprise, for example, 80 to 90 wt % of a matrix polymer and 10 to 12 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0201] In the functional coating provided by the present disclosure, the matrix polymer may include ethyl cellulose and hydroxypropyl cellulose, and the antistatic agent may include magnesium stearate or hydrated magnesium silicate, or a combination thereof.

[0202] Functional coatings (such as modified release coatings) can include, for example, 72% to 92% by weight of a water-insoluble polymer (such as ethyl cellulose), 0.5% to 4% by weight of a water-soluble polymer (such as hydroxypropyl methylcellulose), and 11% to 22% by weight of an antistatic agent (such as magnesium stearate or hydrated magnesium silicate), wherein the weight % is based on the gross weight of the functional coating. Functional coatings (such as modified release coatings) can include, for example, 74% to 90% by weight of a water-insoluble polymer (such as ethyl cellulose), 1% to 3.5% by weight of a water-soluble polymer (such as hydroxypropyl methylcellulose), and 13% to 20% by weight of an antistatic agent (such as magnesium stearate or hydrated magnesium silicate), wherein the weight % is based on the gross weight of the functional coating. The functional coating (such as a modified release coating) can contain, for example, 76 wt % to 88 wt % of a water-insoluble polymer (such as ethyl cellulose), 1 wt % to 3.0 wt % of a water-soluble polymer (such as hydroxypropyl methylcellulose), and 14 wt % to 18 wt % of an antistatic agent (such as magnesium stearate or hydrated magnesium silicate), wherein the wt % is based on the total weight of the functional coating.

[0203] The modified release granules or granulation provided by the present disclosure may include, for example, a core and a modified release coating around the core. The core may include, for example, 85% to 95% by weight of 4-((L-valyl)oxy)butyric acid, 1% to 9% by weight (such as, 3% to 7% by weight) of a water-soluble polymer (such as, hydroxypropyl methylcellulose) and 1% to 9% by weight (such as, 3% to 7% by weight) of an antistatic agent (such as magnesium stearate or hydrated magnesium silicate), wherein % by weight is based on the gross weight of the core; and the modified release coating around the core may include, for example, 77% to 87% by weight of a water-insoluble polymer (such as, ethylcellulose), 0.1% to 5% by weight of a water-soluble polymer (such as, hydroxypropyl cellulose) and 11% to 21% by weight (such as, 14% to 18% by weight) of an antistatic agent (such as, magnesium stearate or hydrated magnesium silicate), wherein % by weight is based on the gross weight of the modified release coating.

[0204] The modified release granules provided by the present disclosure can be configured to provide for once-a-night dosing, once-a-day dosing (QD), twice-a-day dosing (BID), three times-a-day dosing (TID), or four times-a-day dosing (QID). For example, the modified release granules can release substantially 100% of 4-((L-valyl)oxy)butyric acid over a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0205] The coated granules provided by the present disclosure can have a water content of, for example, less than 2 wt%, less than 1.5 wt%, less than 1 wt%, less than 0.5 wt%, or less than 0.25 wt%, wherein the wt% is based on the total weight of the granules.

[0206] The coated granules provided by the present disclosure may have a water content of, for example, 0.1 wt % to 2 wt %, 0.1 wt % to 1 wt %, or 0.2 wt % to 0.6 wt %, wherein the wt % is based on the total weight of the granules.

[0207] The coated pharmaceutical granules can have a bulk density of, for example, greater than 0.55 g / mL, greater than 0.60 g / mL, greater than 0.65 g / mL, greater than 0.70 g / mL, or greater than 0.75 g / mL.

[0208] The coated pharmaceutical granules may have a bulk density of, for example, 0.55 g / mL to 0.80 g / mL, 0.60 g / mL to 75 g / mL, or 0.60 g / mL to 0.70 g / mL.

[0209] Bulk density can be determined using a bulk density cylinder.

[0210] The functional coating provided by the present disclosure can be coated onto the granulation using any suitable equipment and method. Examples of suitable coating methods include Worcester fluidized bed film coating method, compression coating process and phase inversion method.

[0211] The functional coating can be applied to uncoated granulations or to granulations comprising a seal coating as provided by the present invention.

[0212] Examples of coating compositions are provided in the Experimental Examples. The coating composition refers to a granulation that is applied to the uncoated granulation or seal coating to provide a coated granulation.

[0213] The functional coating composition may contain greater than 70 wt %, greater than 75 wt %, greater than 80 wt %, greater than 85 wt % or greater than 90 wt % of an alcohol solvent (such as ethanol or acetone), wherein the wt % is based on the total weight of the functional coating solution / suspension composition used to coat the granules.

[0214] The functional coating composition may contain, for example, less than 20 wt % water, less than 15 wt %, less than 10 wt % or less than 5 wt % water, wherein the wt % is based on the functional coating solution / suspension composition used to coat the granulation.

[0215] For highly water-soluble and hygroscopic pharmaceutically active ingredients (such as 4-((L-valyl)oxy)butyric acid), it may be useful to minimize the amount of water in the functional coating composition. Reducing the water content in the functional coating solution / suspension composition may lead to static electricity, which may make the coating process difficult.

[0216] The functional coating solution / suspension composition may comprise, for example, a solids content of less than 20 wt %, less than 18 wt %, less than 16 wt %, less than 14 wt %, less than 12 wt %, less than 10 wt %, less than 8 wt %, or less than 6 wt %, wherein the wt % is based on the functional coating solution / suspension composition.

[0217] The functional coating composition can contain, for example, a solids content of 2 wt % to 20 wt %, 4 wt % to 16 wt %, 4 wt % to 12 wt %, 6 wt % to 14 wt %, or 6 wt % to 10 wt %, wherein the wt % is based on the functional coating composition.

[0218] An example of coating process conditions using a Worcester column inserted into a fluidized bed coating apparatus is provided in the Experimental Examples.

[0219] The pharmaceutical composition provided by the present disclosure may include a combination of an immediate release granulation and a modified release granulation. The pharmaceutical composition may include a weight ratio of 4-((L-valyl)oxy)butyric acid as an immediate release granulation to 4-((L-valyl)oxy)butyric acid as a modified release granulation, for example, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:2 to 1:3.

[0220] The pharmaceutical composition provided by the present disclosure may include, for example, 17% to 37% by weight of the immediate release granulation, 20% to 35% by weight, 23% to 32% by weight, or 25% to 29% by weight of the immediate release granulation, wherein the weight % is based on the total weight of the immediate release granulation and the modified release granulation. The pharmaceutical composition provided by the present disclosure may include, for example, 63% to 83% by weight of the modified release granulation, 65% to 81% by weight, 68% to 78% by weight, or 71% to 75% by weight of the modified release granulation, wherein the weight % is based on the total weight of the immediate release granulation and the modified release granulation.

[0221] In the pharmaceutical compositions provided by the present disclosure, there is 21% to 41% by weight, 24% to 38% by weight, 27% to 35% by weight, or 29% to 32% by weight of 4-((L-valyl)oxy)butyric acid in the immediate release component, wherein the weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the pharmaceutical composition. In the pharmaceutical compositions provided by the present disclosure, there is 59% to 79% by weight, 62% to 76% by weight, 65% to 73% by weight, or 68% to 62% by weight of 4-((L-valyl)oxy)butyric acid in the modified release component, wherein the weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the pharmaceutical composition.

[0222] The pharmaceutical composition provided by the present disclosure may include the coated granules provided by the present disclosure.

[0223] The pharmaceutical composition may include any suitable dosage form for oral administration.

[0224] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions and suspensions.

[0225] The oral dosage forms provided by the present disclosure can include, for example, 0.1 to 20 grams of 4-((L-valyl)oxy)butyric acid, 0.1 to 15 grams, 0.1 to 12 grams, 0.1 to 10 grams, 0.2 to 8 grams, 0.5 to 5 grams, 1 to 4.5 grams, or 1.5 to 4 grams of 4-((L-valyl)oxy)butyric acid. The oral dosage forms can include, for example, greater than 0.5 grams, greater than 1 gram, greater than 2 grams, greater than 3 grams, greater than 4 grams, greater than 6 grams, or greater than 8 grams, greater than 10 grams, greater than 14 grams, or greater than 18 grams of 4-((L-valyl)oxy)butyric acid.

[0226] The oral composition provided by the present disclosure may include an oral suspension of coated granules having a modified release functional coating provided by the present disclosure. The oral composition may include a modified release granulation and an immediate release granulation provided by the present disclosure.

[0227] Oral compositions may include a combination of immediate release granulations and modified release granulations provided by the present disclosure.

[0228] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a certain period of time.

[0229] For example, the oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0230] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a period of 4 hours to 12 hours, 4 hours to 10 hours, or 4 hours to 8 hours.

[0231] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid for a duration of 1 hour to 12 hours after oral administration, 2 hours to 10 hours, or 4 hours to 8 hours after oral administration.

[0232] The oral composition provided by the present disclosure can be a once-a-night composition. For a once-a-night composition, a patient can take a dose of 4-((L-valyl)oxy)butyric acid before going to bed and sleep all night (such as for 6 or 8 hours) without having to take a second dose at night.

[0233] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma.

[0234] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma for a period of 4 hours, 6 hours, 8 hours, or 10 hours following oral administration of the modified release oral composition.

[0235] The oral compositions provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 10 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the modified release oral composition.

[0236] The oral compositions provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 15 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the modified release oral composition.

[0237] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of C in the patient's plasma after oral administration of the modified release oral composition. max With C min The gamma-hydroxybutyrate ratio is less than 3 or less than 2 for a duration of 4 hours, 6 hours, 8 hours, or 10 hours.

[0238] The oral composition provided by the present disclosure may include a γ-hydroxybutyric acid derivative of formula (2), and may include, for example, 0.5 g equivalent of γ-hydroxybutyric acid, 1 g equivalent, 2 g equivalent, 3 g equivalent, 4 g equivalent, 5 g equivalent, 6 g equivalent, 7 g equivalent, 8 g equivalent, 9 g equivalent, 10 g equivalent, 11 g equivalent or 12 g equivalent of γ-hydroxybutyric acid.

[0239] The pharmaceutical composition provided by the present disclosure may be included in a kit, which can be used to administer the compound to a patient for therapeutic purposes. The kit may include an immediate release component and a modified release component suitable for administration to a patient and instructions for administering the pharmaceutical composition to a patient. The kit may be used, for example, to treat sleep disorders. The kit may include an immediate release component and a modified release component, a pharmaceutically acceptable vehicle for administering the immediate release component and the modified release component, and instructions for administering the pharmaceutical composition to a patient.

[0240] The oral compositions provided by the present disclosure can be provided, for example, as medicine bags containing coated granules provided by the present disclosure. The medicine bags can be provided with different doses of 4-((L-valyl)oxy)butyric acid, such as 0.5g, 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 10g, 12g, 15g or 20g of 4-((L-valyl)oxy)butyric acid. The coated granules can be combined, for example, with water to provide an orally ingestible dosage form.

[0241] The oral dosage form comprising crystalline 4-((L-valyl)oxy)butyric acid may include an immediate release component and a modified release component.

[0242] For example, the immediate release component may include a solution containing 4-((L-valyl)oxy)butyric acid or an immediate release granule containing 4-((L-valyl)oxy)butyric acid.

[0243] For example, the modified release component can include modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

[0244] The combined release oral dosage form may include modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid suspended in a solution comprising crystalline 4-((L-valyl)oxy)butyric acid.

[0245] Oral dosage forms can include granules. For example, oral dosage forms can include immediate release granules and modified release granules. For example, oral dosage forms can include a suspension containing crystalline 4-((L-valyl)oxy)butyric acid. Oral dosage forms can include immediate release granules containing crystalline 4-((L-valyl)oxy)butyric acid and a suspension containing modified release granules of crystalline 4-((L-valyl)oxy)butyric acid. Oral dosage forms can include crystalline 4-((L-valyl)oxy)butyric acid dissolved in a solution (such as an aqueous solution) and modified release granules containing crystalline 4-((L-valyl)oxy)butyric acid suspended in the solution.

[0246] The pharmaceutical compositions and dosage forms provided by the present disclosure may include any suitable excipients, salts, acids, pH mediating, adjusting or buffering compounds or agents, flavoring agents, solutions, solvents, dispersions, glycerol, glycols, oils, antibacterial and antifungal agents, antibiotics and antihistamines, binders, disintegrants, lubricants, sweeteners, or any other suitable additive or ingredient.

[0247] Examples of suitable oral formulations and oral dosage forms are disclosed in U.S. Application Publication No. 2021 / 0393537, U.S. Patent No. 11,304,906, U.S. Application Publication No. 2022 / 0023247, U.S. Patent No. 11,395,801, and U.S. Patent No. 11,510,892, the entire contents of each of which are incorporated by reference.

[0248] Oral formulations may include a combination of immediate release granulations and modified release granulations provided by the present disclosure.

[0249] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma over a period of time. For example, the oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0250] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate over a period of 4 hours to 12 hours, 4 hours to 10 hours, or 4 hours to 8 hours.

[0251] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate over a period of time, such as 1 hour to 12 hours after oral administration, 2 hours to 10 hours, or 4 hours to 8 hours after oral administration.

[0252] The oral formulation provided by the present disclosure can be a once-a-night formulation. For a once-a-night formulation, a patient can take a dose of crystalline 4-((L-valyl)oxy)butyric acid and / or gamma-hydroxybutyric acid as a prodrug provided by the present disclosure before going to bed and sleep all night (such as for 6 or 8 hours) without having to take a second dose at night.

[0253] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma. The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral formulation.

[0254] The oral formulations provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 10 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the oral formulation.

[0255] The oral formulations provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 15 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the oral formulation.

[0256] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of C in the patient's plasma after oral administration of the modified release oral formulation. max With C min The gamma-hydroxybutyrate ratio is less than 3 or less than 2 for a duration of 4 hours, 6 hours, 8 hours, or 10 hours.

[0257] The oral formulations provided by the present disclosure may include crystalline 4-((L-valyl)oxy)butyric acid, and may include, for example, 0.5 g equivalent of gamma-hydroxybutyric acid, 1 g equivalent, 2 g equivalent, 3 g equivalent, 4 g equivalent, 5 g equivalent, 6 g equivalent, 7 g equivalent, 8 g equivalent, 9 g equivalent, 10 g equivalent, 11 g equivalent, or 12 g equivalent of gamma-hydroxy acid. The oral formulations provided by the present disclosure may include crystalline 4-((L-valyl)oxy)butyric acid, and may include, for example, 0.5 g equivalent to 12 g equivalent, 1 g equivalent to 12 g equivalent, 2 g equivalent to 12 g equivalent, 3 g equivalent to 11 g equivalent, 4 g equivalent to 10 g equivalent, or 5 g equivalent to 9 g equivalent of gamma-hydroxybutyric acid. The oral formulation provided by the present invention may contain, for example, greater than 0.5 g equivalent of γ-hydroxybutyric acid, greater than 1 g equivalent, greater than 3 g equivalent, greater than 5 g equivalent, greater than 7 g equivalent, greater than 9 g equivalent, or greater than 11 g equivalent of γ-hydroxybutyric acid.

[0258] The oral formulations provided herein can include suspensions, such as aqueous suspensions of immediate and controlled release granules containing crystalline 4-((L-valyl)oxy)butyric acid. The core of the granule can contain greater than 90% by weight (such as greater than 94% by weight) or greater than 96% by weight of crystalline 4-((L-valyl)oxy)butyric acid, wherein the weight % is based on the total weight of the granule core.

[0259] The oral formulations provided by the present disclosure can be provided, for example, in the form of a pouch or package containing an immediate release component (such as an immediate release granule containing crystalline 4-((L-valyl)oxy)butyric acid) and a modified release component (such as a modified release granule containing crystalline 4-((L-valyl)oxy)butyric acid). The pouch or package can be provided with different dose equivalents of gamma-hydroxybutyric acid (such as 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 10 g, 12 g, 15 g or 20 g equivalent of gamma-hydroxybutyric acid).

[0260] The oral dosage form (such as coated granulations containing immediate release granules and modified release granules) can be mixed with water to provide an oral dosage form.

[0261] Crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be included in a kit that can be used to administer the compound to a patient for therapeutic purposes. The kit can include a pharmaceutical composition containing crystalline 4-((L-valyl)oxy)butyric acid suitable for administration to a patient and instructions for administering the pharmaceutical composition to a patient. The kit can be used, for example, to treat sleep disorders. The kit can include crystalline 4-((L-valyl)oxy)butyric acid, a pharmaceutically acceptable vehicle for administering crystalline 4-((L-valyl)oxy)butyric acid, and instructions for administering crystalline 4-((L-valyl)oxy)butyric acid to a patient.

[0262] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0263] The instructions provided with the kit can be printed and / or supplied as, for example, an electronically readable medium, a videotape, an audiotape, a flash memory device, or can be accessed on an Internet website or distributed as electronic information to patients and / or healthcare providers.

[0264] Crystalline 4-((L-valyl)oxy)butyric acid can be metabolized in the patient's systemic circulation to provide gamma-hydroxybutyrate.

[0265] The present disclosure provides methods that include providing a therapeutically effective amount of gamma-hydroxybutyrate in the systemic circulation of a patient for treating a disease or condition in the patient or a symptom of a disease or condition in the patient, the method comprising administering crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof to the patient.

[0266] Suitable dosages of crystalline 4-((L-valyl)oxy)butyric acid can provide, for example, a dosage of 1 to 12 g equivalents of γ-hydroxybutyric acid, such as 1 to 10 g equivalents, 2 to 9 g equivalents, 3 to 8 g equivalents, or 4 to 7 g equivalents of γ-hydroxybutyric acid.

[0267] However, it should be understood that the specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including: metabolic stability and duration of action, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition and the host being treated.

[0268] When initiating treatment with crystalline 4-((L-valyl)oxy)butyric acid, titration to adequate plasma concentrations can help achieve positive results and avoid adverse effects. For example, the dose can be 4.5 g-equivalent gamma-hydroxybutyrate, divided into 2 equal doses of 2.25 g, the first taken at bedtime and the second taken 2.5 hours to 4 hours later. The starting dose can be reduced to 3.0 g / day, or increased in 1.5 g / day increments to 9.0 g / day (0.75 g per dose). The dose can provide eight hours of effective sleep, but at the end of the eight hours, very little gamma-hydroxybutyrate will remain in the patient's plasma.

[0269] The pharmaceutical compositions provided by the present disclosure can be configured to provide for once-a-night administration, once-a-day administration (QD), twice-a-day administration (BID), three-a-day administration (TID), or four-a-day administration (QID). For example, the pharmaceutical composition containing the modified release granules can release substantially 100% of the crystalline 4-((L-valyl)oxy)butyric acid within a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0270] Crystalline 4-((L-valyl)oxy)butyric acid is a prodrug of gamma-hydroxybutyric acid.

[0271] Crystalline 4-((L-valyl)oxy)butyric acid can be used to treat any disease or condition known to be treated by gamma-hydroxybutyric acid or determined to be treated by gamma-hydroxybutyric acid.

[0272] For example, crystalline 4-((L-valyl)oxy)butyric acid can be used to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and fibromyalgia.

[0273] Crystalline 4-((L-valyl)oxy)butyric acid can be used to treat REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headaches, symptoms of Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety disorders.

[0274] Crystalline 4-((L-valyl)oxy)butyric acid can be used to treat excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0275] Crystalline 4-((L-valyl)oxy)butyric acid and pharmaceutical compositions thereof can be used to treat sleep disorders (such as apnea, sleep time disorder, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucinations, sleep arousals, insomnia and nocturnal myoclonus).

[0276] Crystalline 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be used to treat a disease selected from narcolepsy, cataplexy, cataplexy associated with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, symptoms associated with Parkinson's disease, neurodegenerative diseases, sleep disorder syndromes, fatigue, improving nighttime sleep, hypnagogic hallucinations, sleep paralysis, segmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with childhood alternating hemiplegia, sedative abuse and binge eating disorder.

[0277] For certain treatment methods, the effectiveness of the treatment may be measured by one or more of the following criteria: an increase in mean sleep latency, such as measured by the Maintenance of Wakefulness Test (MWT); an improvement in the Clinical Global Impression (CGI) score for sleepiness; a reduction in the number of cataplexy attacks (NCA), such as determined by the cataplexy frequency item in a sleep and symptom daily diary; a reduction in disturbed nighttime sleep (DNS), disturbed nighttime activity, or adverse respiratory events (such as determined by polysomnography (PSG) of segmented sleep); a reduction in excessive daytime sleepiness (EDS), such as by patient report measurement via the Epworth Sleepiness Scale (ESS); a reduction in daytime sleepiness, such as by baseline sleepiness score; =As measured by the Maintenance of Wakefulness Test on EEG wakefulness measures; Reduced PSG transitions from N / 2 to N / 3 and REM sleep to wakefulness and N1 sleep, such as determined as described in the AASM Sleep and Related Events Scoring Manual; Reduced number of arousals or wakefulness, such as determined by PSG as defined by the American Academy of Sleep Medicine; Improved sleep quality, such as determined using (i) a sleep and symptom daily diary, (ii) a visual analog scale (VAS) for sleep quality and sleep diary, and / or (iii) a VAS for sleep refreshment quality; and, reduced symptoms of hypnagogic hallucinations (HH) or sleep paralysis (SP) in patients with NT1 narcolepsy (as measured by a sleep and symptom daily diary).

[0278] Narcolepsy type 1 (NT1) refers to narcolepsy characterized by excessive daytime sleepiness ("EDS") and cataplexy. Narcolepsy type 2 (NT2) refers to narcolepsy characterized by excessive daytime sleepiness but without cataplexy. The diagnosis of narcolepsy (with or without cataplexy) can be confirmed by one or a combination of the following: (i) overnight polysomnography (PSG) and multiple sleep latency test (MSLT) performed within the past 2 years; (ii) complete documentary evidence confirming the diagnosis of sleep laboratory PSG and MSLT must be provided; (iii) current symptoms of narcolepsy, including: current complaints of EDS (Epworth Sleepiness Scale (ESS) greater than 10) in the last 3 months; (iv) average maintenance of wakefulness test (MWT) less than 8 minutes; (v) average number of cataplexy events per week of 8 on the baseline sleep / cataplexy diary; and / or (vi) presence of cataplexy in the last 3 months and 28 events per week during the screening period.

[0279] Aspects of the Invention

[0280] The present invention is further defined by the following aspects.

[0281] Aspect 1 A compound, crystalline 4-((L-valyl)oxy)butyric acid:

[0282]

[0283] Aspect 2. The compound according to aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 16.75°±0.20° and 25.33±0.20° represented by 2θ angles determined using Cu-Kα radiation.

[0284] Aspect 3. A compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 25.33±0.20° and 26.08°±0.20° as represented by 2θ angles determined using Cu-Kα radiation.

[0285] Aspect 4. A compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 13.75°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 24.98°±0.20°, 25.33±0.20° and 26.08°±0.20° as represented by 2θ angles determined using Cu-Kα radiation.

[0286] Aspect 5. The compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 11.63°±0.20°, 13.75°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 19.93°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 22.22°±0.20°, 23.58°±0.20°, 24.98°±0.20°, 25.33±0.20° and 26.08°±0.20° as represented by 2θ angles determined using Cu-Kα radiation.

[0287] Aspect 6. The compound according to aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10° and 25.33±0.10° represented by 2θ angles determined using Cu-Kα radiation.

[0288] Aspect 7. A compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 25.33±0.10° and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

[0289] Aspect 8. A compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 24.98°±0.10°, 25.33±0.10° and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

[0290] Aspect 9. A compound according to aspect 1, wherein the compound is characterized by comprising an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 9.58°±0.10°, 11.63°±0.10°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 19.93°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 22.22°±0.10°, 23.58°±0.10°, 24.98°±0.10°, 25.33±0.10° and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

[0291] Aspect 10: The compound according to aspect 1, wherein the compound is characterized by Figure 1 XRPD pattern shown.

[0292] Aspect 11. A compound according to any one of aspects 1 to 10, wherein the compound has a melting onset temperature of 135°C to 141°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

[0293] Aspect 12. A compound according to any one of aspects 1 to 10, wherein the compound has a melting onset temperature of 137.7°C ± 1.0°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

[0294] Aspect 13. A compound according to any one of aspects 1 to 12, wherein the compound has a melting enthalpy of 197 J / g to 207 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

[0295] Aspect 14. A compound according to any one of aspects 1 to 12, wherein the compound has a melting enthalpy of 202.2 J / g ± 1.0 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

[0296] Aspect 15. A compound according to any one of aspects 1 to 14, wherein the compound has a melting peak temperature of 138.0°C to 142.0°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

[0297] Aspect 16. A compound according to any one of aspects 1 to 14, wherein the compound has a melting peak temperature of 139.9°C ± 2.0°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

[0298] Aspect 17 A compound according to any one of aspects 1 to 16, wherein the compound exhibits Figure 2 The differential scanning calorimetry curve shown in .

[0299] Aspect 18 A compound according to any one of Aspects 1 to 17, wherein the compound has a weight loss of 0.16 wt % to 0.36 wt % in the temperature range of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scan rate of 2°C / min.

[0300] Aspect 19. A compound according to any one of Aspects 1 to 17, wherein the compound has a weight loss of 0.26 wt%±0.20 wt% in the temperature range of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scanning rate of 2°C / min.

[0301] Aspect 20 A compound according to any one of aspects 1 to 19, wherein the compound exhibits Figure 2 The differential thermal calorimetry curve shown in .

[0302] Aspect 21. A compound according to any one of Aspects 1 to 20, wherein the compound has a water content of 5.8 mol% to 6.6 mol%, wherein the mol% is based on the total moles of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid, and the water content is determined using Karl Fischer analysis.

[0303] Aspect 22. A compound according to any one of Aspects 1 to 21, wherein the compound has a water content of less than 5 wt%, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid, and the water content is determined using Karl Fischer analysis.

[0304] Aspect 23. A compound according to any one of aspects 1 to 22, wherein the compound absorbs less than 2 wt% of water under conditions of 25°C / 60%RH for 36 months.

[0305] Aspect 24. A compound according to any one of aspects 1 to 23, wherein the compound has an impurity content of less than 1 wt% under conditions of 25°C / 60%RH for 36 months.

[0306] Aspect 25. The compound of any one of Aspects 1 to 24, wherein the compound has a water content of less than 5 wt.% and an impurity content of less than 5 wt.% after storage for 6 months at 25°C / 60% RH, wherein the wt.% is based on the total weight of the compound, water, and impurities; the water content is determined using Karl Fischer analysis, and the impurity content is determined using high pressure liquid chromatography.

[0307] Aspect 26. A compound according to any one of aspects 1 to 25, wherein the unmilled compound has a particle size distribution characterized by a D10 of 7 to 17 μm, a D50 of 29 to 39 μm, and a D90 of 67 to 75 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0308] Aspect 27 A compound according to any one of aspects 1 to 26, wherein the unmilled compound has a particle size distribution characterized by D[4,3] of 35 μm to 41 μm, such as 36 μm to 40 μm and 37 μm to 39 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0309] Aspect 28. A compound according to any one of aspects 1 to 27, wherein the unmilled compound has a homogeneity of 0.45 to 0.65, such as 0.50 to 0.60, wherein the homogeneity is determined using laser diffraction.

[0310] Aspect 29: A compound according to any one of aspects 1 to 28, wherein the unmilled compound has a mass of 270 m 2 / kg to 310m 2 / kg, such as 280m 2 / kg to 300m 2 / kg of surface area, where the surface area is determined using laser diffraction.

[0311] Aspect 30 A compound according to any one of aspects 1 to 29, wherein the unmilled compound has a bulk density of 0.15 g / mL to 0.25 g / mL, such as 0.18 g / mL to 0.22 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

[0312] Aspect 31. A compound according to any one of aspects 1 to 30, wherein the unmilled compound has a Hausner Ratio of, for example, 1.65 to 1.95, or 1.70 to 1.90, or 1.75 to 1.85, wherein the Hausner Ratio is determined according to USP 1174.

[0313] Aspect 32. A compound according to any one of aspects 1 to 31, wherein the milled compound has a particle size distribution characterized by a D10 of 1 μm to 5 μm, a D50 of 4 μm to 8 μm, and a D90 of 10 μm to 14 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0314] Aspect 33 A compound according to any one of aspects 1 to 32, wherein the milled compound has a particle size distribution characterized by D[4,3] of 12 μm to 22 μm, such as 14 μm to 20 μm and 16 μm to 18 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

[0315] Aspect 34. A compound according to any one of aspects 1 to 33, wherein the milled compound has a homogeneity of 0.2 to 0.6, such as 0.30 to 0.50, wherein the homogeneity is determined using laser diffraction.

[0316] Aspect 35: A compound according to any one of aspects 1 to 34, wherein the milled compound has 430 m 2 / kg to 630m 2 / kg, such as 450m 2 / kg to 610m 2 / kg or 470m 2 / kg to 490m 2 / kg of surface area, where the surface area is determined using laser diffraction.

[0317] Aspect 36. A compound according to any one of aspects 1 to 35, wherein the milled compound has a bulk density of, for example, 0.10 g / mL to 0.14 g / mL, such as 0.11 g / mL to 0.13 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

[0318] Aspect 37. The compound according to any one of aspects 1 to 36, wherein the milled compound has a Hausner Ratio of, for example, 1.6 to 1.8 or 1.65 to 1.75, wherein the Hausner Ratio is determined according to USP 1174.

[0319] Aspect 38 A pharmaceutical composition comprising a compound according to any one of aspects 1 to 37.

[0320] Aspect 39. The pharmaceutical composition according to aspect 38, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a patient, wherein the disease is selected from narcolepsy, cataplexy, cataplexy associated with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative diseases, sleep disorder syndromes, fatigue, improving nocturnal sleep, hypnagogic hallucinations, sleep paralysis, segmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, and chronic fatigue syndrome.

[0321] Aspect 40. The pharmaceutical composition according to any one of aspects 38 to 39, wherein the pharmaceutical composition comprises an oral formulation.

[0322] Aspect 41. The pharmaceutical composition of any one of aspects 38 to 40, wherein the pharmaceutical composition comprises 1 gram equivalent to 10 gram equivalents of gamma-hydroxybutyric acid.

[0323] Aspect 42. The pharmaceutical composition of any one of aspects 38 to 41, wherein the pharmaceutical composition comprises 1 gram to 20 grams of crystalline 4-((L-valyl)oxy)butyric acid.

[0324] Aspect 43. The pharmaceutical composition according to any one of aspects 38 to 42, wherein the pharmaceutical composition comprises an immediate release component and a modified release component.

[0325] Aspect 44. The pharmaceutical composition according to aspect 43, wherein the immediate release component comprises a solution containing 4-((L-valyl)oxy)butyric acid.

[0326] Aspect 45. The pharmaceutical composition according to aspect 43, wherein the immediate release component comprises immediate release granules containing crystalline 4-((L-valyl)oxy)butyric acid.

[0327] Aspect 46. The pharmaceutical composition of any one of aspects 43 to 45, wherein the modified release component comprises modified release granules containing crystalline 4-((L-valyl)oxy)butyric acid.

[0328] Aspect 47 An oral dosage form comprising a compound according to any one of aspects 1 to 37 or a pharmaceutical composition according to any one of aspects 38 to 46.

[0329] Aspect 48. The oral dosage form according to aspect 47, wherein the oral dosage form comprises 1 gram equivalent to 10 gram equivalents of gamma-hydroxybutyrate.

[0330] Aspect 49 The oral dosage form according to any one of aspects 47 to 48, wherein the oral dosage form comprises 1 gram to 20 grams of crystalline 4-((L-valyl)oxy)butyric acid.

[0331] Aspect 50 The oral dosage form according to any one of aspects 47 to 48, wherein the oral dosage form comprises an immediate release component and a modified release component.

[0332] Aspect 51. The oral dosage form according to aspect 50, wherein the immediate release component comprises a solution containing 4-((L-valyl)oxy)butyric acid.

[0333] Aspect 52. An oral dosage form according to aspect 50, wherein the immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

[0334] Aspect 53 An oral dosage form according to any one of aspects 50 to 52, wherein the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

[0335] Aspect 54 An oral dosage form according to any one of aspects 50 to 52, wherein the oral dosage form comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid suspended in a solution comprising 4-((L-valyl)oxy)butyric acid.

[0336] Aspect 55 A kit comprising a compound according to any one of aspects 1 to 37, a pharmaceutical composition according to any one of aspects 38 to 46, or an oral dosage form according to any one of aspects 47 to 54.

[0337] Aspect 56. The kit according to aspect 55, wherein the kit comprises an immediate release component containing crystalline 4-((L-valyl)oxy)butyric acid and a modified release component containing crystalline 4-((L-valyl)oxy)butyric acid.

[0338] Aspect 57 A kit according to any one of aspects 55 to 56, wherein the immediate release component comprises immediate release granules containing crystalline 4-((L-valyl)oxy)butyric acid and the modified release component comprises modified release granules containing crystalline 4-((L-valyl)oxy)butyric acid.

[0339] Aspect 58 The kit according to any one of aspects 55 to 57, wherein the pharmaceutical composition or oral dosage form is contained in a pouch.

[0340] Aspect 59 A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54, wherein the disease is treatable with gamma-hydroxybutyrate.

[0341] Aspect 60 A method of treating a disease in a patient, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54, wherein the disease is selected from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative diseases, sleep disturbance syndromes, fatigue, improving nighttime sleep, hypnagogic hallucinations, sleep paralysis, segmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with alternating hemiplegia of childhood, sedative abuse, and binge eating disorder.

[0342] Aspect 61 A method of treating fatigue or excessive daytime sleepiness associated with narcolepsy, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54.

[0343] Aspect 62 A method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54.

[0344] Aspect 63. A method according to aspect 62, wherein the disease is cataplexy associated with narcolepsy.

[0345] Aspect 64. The method according to Aspect 62, wherein the disorder is excessive daytime sleepiness associated with narcolepsy.

[0346] Aspect 65. The method according to Aspect 62, wherein the disease is excessive daytime sleepiness in a patient suffering from Parkinson's disease.

[0347] Aspect 66. The method according to Aspect 62, wherein the disease is chronic fatigue in a patient with Parkinson's disease.

[0348] Aspect 67 A method of treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54.

[0349] Aspect 68 A method of treating REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Claims 47 to 54.

[0350] Aspect 69 A method of treating symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of Aspects 1 to 37, a pharmaceutical composition according to any one of Aspects 38 to 46, or an oral dosage form according to any one of Aspects 47 to 54.

[0351] Aspect 70 The method according to any one of aspects 59 to 69, wherein administering comprises oral administration.

[0352] Aspect 71 The method according to any one of aspects 59 to 70, wherein administering comprises administering QDs.

[0353] Aspect 72 The method according to any one of aspects 59 to 70, wherein administering comprises administering BID.

[0354] Aspect 73 A method for preparing a compound according to any one of aspects 1 to 37, the method comprising: (i) dissolving 4-((L-valyl)oxy)butyric acid in a first solvent to obtain a solution; and

[0355] (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butyric acid.

[0356] Aspect 74 The method according to aspect 71, wherein the first solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, isobutanol, isopropyl acetate, acetonitrile, 2-butanone, toluene, water, tert-butyl methyl ether, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, diethyl ether or a combination of any of the foregoing.

[0357] Aspect 75 The method according to any one of aspects 73 to 74, wherein dissolving comprises dissolving in the first solvent at a temperature of 60°C to 90°C.

[0358] Aspect 76 A method according to any one of aspects 73 to 75, wherein the method comprises adding a second solvent to the solution after dissolving to form the solution.

[0359] Aspect 77. The method according to aspect 76, wherein the second solvent is selected from acetonitrile, tetrahydrofuran, isopropanol, acetone, ethyl acetate, tert-butyl methyl ether, 1,4-dioxane, or a combination of any of the foregoing.

[0360] Aspect 78 The method according to any one of aspects 73 to 77, wherein crystallization comprises heating the solution to a temperature of 60° C. to 90° C. for 0.5 to 2 hours.

[0361] Aspect 79. The method of any one of claims 73 to 78, wherein dissolving comprises dissolving in the first solvent at a temperature of 20°C to 25°C.

[0362] Aspect 80 The method according to any one of aspects 73 to 79, wherein the method comprises recrystallizing the crystalline 4-((L-valyl)oxy)butyric acid after crystallization.

[0363] Examples

[0364] The following examples describe in detail the methods for preparing crystalline 4-((L-valyl)oxy)butyric acid, the properties of crystalline 4-((L-valyl)oxy)butyric acid, and methods of using crystalline 4-((L-valyl)oxy)butyric acid provided by the present invention. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be made without departing from the scope of the present invention.

[0365] Example 1

[0366] Synthesis of (S)-4-(2-amino-3-methylbutyryloxy)butyric acid

[0367] Step 1: Preparation of (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a).

[0368]

[0369] (S)-2-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (1 g, 4.61 mmol), N,N'-dicyclohexylcarbodiimide (DCC) (1,044 mg, 5.07 mmol) and 4-dimethylaminopyridine (DMAP) (10 mg) were added to a stirred solution of 1,4-butanediol (829 mg, 9.21 mmol) in dichloromethane (DCM) (20 mL). The reaction was stirred at 25 °C for 16 hours. The reaction mixture was then washed with saturated NH 4 The mixture was diluted with aqueous Cl solution (10 mL) and stirred for 5 minutes. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (Hex / EA) = 5:1 to give Compound (1a) (700 mg, 53%) as a colorless oil.3 As solvent, it was performed at 400 MHz 1 H NMR: δ=5.07(d,J=8.8Hz,1H),4.16-4.11(m,3H),3.62(t,J=6.2Hz,2H),2.32(br.s.,1H),2.12-2.04(m ,1H),1.75-1.68(m,2H),1.62-1.56(m,2H),1.40(s,9H),0.92(d,J=7.2Hz,3H),0.85(d,J=7.2Hz,3H).

[0370] Step 2: Preparation of (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b).

[0371]

[0372] Jones reagent was added portionwise to (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a) (500 mg, 1.73 mmol) and (diatomaceous earth, 2g) in acetone (10mL) solution. The reaction was carried out at 0°C for more than 1 hour, and the progress of the reaction was monitored using thin layer chromatography (TLC). After completion, the reaction was quenched with isopropanol drops, diluted with ethyl acetate (EA) (10mL), and then filtered. The filter cake was washed with EA (5mL), and the combined filtrate was washed with saturated brine (2mL×2), and anhydrous Na 2 SO 4 Dried and concentrated. The residue was purified using a silica gel flash column with Hex / EA = 10:1-5:1 to give Compound (1b) (170 mg, 32%) as a white solid. CDCl 3 As solvent, it was performed at 400 MHz 1 H NMR: δ=5.03(d,J=9.2Hz,1H),4.30-4.24(m,1H),4.22-4.13(m,2H),2.46(t,J=7.4Hz,2H),2. 16-2.08(m,1H),2.06-1.96(m,2H),1.45(s,9H),0.96(d,J=6.8Hz,3H),0.89(d,J=6.4Hz,3H).

[0373] Step 3: Preparation of (S)-4-(2-amino-3-methylbutyryloxy)butyric acid.

[0374]

[0375] A solution of (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b) (104 mg, 0.34 mmol) in HCl / EA (-2M, 1.5 mL) was stirred at 25°C for 24 hours. The reaction mixture was then filtered and the precipitate was collected and washed with Et 2 O (0.5 mL) and dried in vacuo to give the title compound as a white solid in the form of an HCl salt (50 mg, 71%). 3 OD was used as solvent at 400 MHz 1 H NMR: δ=4.33-4.26(m,2H),3.92(d,J=4.8Hz,1H),2.42(t,J=7.2Hz,2H),2.34-2.25(m,1 11),2.05-1.94(m,2H),1.06(d,J=6.8Hz,6H).

[0376] A suspension of the HCl salt (800 mg, 3.3 mmol) in ethanol (4 mL) was stirred at 80 ° C for 30 minutes to provide a clear solution. The solution was gradually cooled to 25 ° C, and propylene oxide (580 mg, 10 mmol) was added dropwise. The reaction was stirred at 25 ° C for 16 hours, and then the suspension was filtered. The white solid was collected, washed with cold ethanol and dried in vacuo to give the compound as a free base (510 mg, 75%). With d 6 -DMSO as solvent at 400 MHz 1 HNMR: δ=4.10-3.99(m,2H),3.11(d,J=5.2Hz,1H),2.29(t,J=7.4Hz,2H),1.90-1.74(m,3H),0.87(d,J=6.8Hz,3H),0.82(d,J=6.4Hz,3H).

[0377] Example 2

[0378] Alternative Synthesis of (S)-4-(2-amino-3-methylbutyryloxy)butyric Acid

[0379] Step 1: Preparation of 4-hydroxybutyric acid benzyl ester (2a).

[0380]

[0381] Sodium hydroxide (1.0 equivalent) was dissolved in methanol (5 volumes) under stirring while keeping the temperature below 40°C. The reaction mixture was cooled to room temperature, and butyrolactone (1.0 equivalent) was added while keeping the temperature below 30°C, and the reaction mixture was stirred for 5 to 6 hours. The reaction mixture was concentrated in vacuo while coevaporating with tert-butyl methyl ether. The mixture was redissolved in dimethyl sulfoxide (DMSO) and benzyl bromide (0.95 equivalent) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, cooled to 15°C, and quenched with purified water. The aqueous phase was washed with tert-butyl methyl ether. The collected organic matter was washed with water and concentrated in vacuo while coevaporating with dichloromethane to provide 4-hydroxybutyric acid benzyl ester (2a) in a yield of 69.5%.

[0382] Step 2: Preparation of 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valine (2b).

[0383]

[0384] Benzyl 4-hydroxybutyrate (2a) (0.95 eq) was dissolved in dichloromethane (2.5 vol). CBz-L-valine (1.00 eq) and 4-dimethylaminopyridine (DMAP) (0.20 eq) were added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.20 eq) while the reaction mixture was maintained at 15°C. The reaction mixture was stirred at room temperature for 20 hours. 5% HCl (5 vol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The biphasic solution was separated and the aqueous layer was removed. The organic layer was washed with 5% sodium bicarbonate solution and purified water, concentrated in vacuo, and suspended with silica gel (50 wt%). The silica plug was washed with dichloromethane and the combined organics were concentrated in vacuo while coevaporating with methanol to provide 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valine ester (2b) in 76.7% yield.

[0385] Step 3: Preparation of 4-((L-valyl)oxy)butyric acid.

[0386]

[0387] 4-(Benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valine ester (2b) (1.0 equivalent) was dissolved in methanol (5 volumes) and Pd / C (10% Pd, 15 wt%) was added under nitrogen atmosphere. 2 The nitrogen atmosphere was replaced with a flow of 4% N 2 O and the reaction mixture was stirred at room temperature for 16 h. (50 wt%) was filtered and stirred with activated carbon (25 wt%) for 18 hours. The mixture was stirred for 30 minutes at room temperature under reduced pressure. The mixture was stirred for 4 hours under reduced pressure. The mixture was stirred for 30 minutes under reduced pressure. The mixture was stirred for 4 hours under reduced pressure. The mixture was stirred for 4 hours under reduced pressure. The mixture was stirred for 30 minutes under reduced pressure. The mixture was stirred for 4 hours under reduced pressure. The mixture was stirred for 40 minutes under reduced pressure. The mixture was stirred for 30 minutes ...

[0388] Example 3

[0389] Crystallization of 4-((L-valyl)oxy)butyric acid

[0390] About 25 mg of 4-((L-valyl)oxy)butyric acid was weighed and placed in an 8 mL glass bottle, and an appropriate amount of water or methanol was added under stirring to dissolve the solid. After complete dissolution, a set amount of anti-solvent was slowly added over a period of about 30 minutes.

[0391] The solvent is water or methanol, and suitable anti-solvents include acetonitrile, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, and 1,4-dioxane.

[0392] Weigh about 50 mg or 100 mg of 4-((L-valyl)oxy)butyric acid into a glass bottle, add an appropriate amount (80 μL to 300 μL) of solvent, and heat the vial to the set temperature under stirring. After reaching the set temperature, slowly add the same solvent to the suspension until the sample is completely dissolved, or slowly add an appropriate amount of anti-solvent to the clear solution. Stir the solution at the set temperature for about 30 minutes, and then slowly cool the solution to room temperature (20°C to 25°C). Collect the solid precipitate by filtration. The solvent is ethanol, 50:1 ethanol / water, water, methanol or isopropanol. If used, the anti-solvent is acetone, ethyl acetate or methyl tert-butyl ether. The solvent can be methanol and the anti-solvent can be methyl tert-butyl ether. The volume ratio of methanol to methyl tert-butyl ether can be about 1:3.

[0393] Example 4

[0394] X-ray powder diffraction (XPRD) of crystalline 4-((L-valyl)oxy)butyric acid

[0395] The X-ray powder diffraction (XRPD) pattern of crystalline 4-((L-valyl)oxy)butyric acid was obtained using a Bruker D8 Advance X-ray powder diffractometer. The 2θ position was calibrated based on a Panalytical Si standard disk. The X-ray wavelength was Kα2 / Kα1 The intensity ratio was 0.5. The X-ray tube was set to an output voltage of 40 kV and a current of 40 mA. A 1 / 8° fixed divergence slit was used, and a diffraction pattern from 3° to 40° (2θ) was obtained in a continuous scan mode using a step size of 0.02° (2θ) and a scan speed of 0.145° / min. The sample was transferred from the sample container to a zero background XRPD holder and gently ground to provide a smooth surface.

[0396] A representative XPRD diffraction pattern of crystalline 4-((L-valyl)oxy)butyric acid is shown at Figure 1 Its characteristic diffraction peaks are shown in Table 1.

[0397] Table 1. Characteristic peaks of XRPD patterns.

[0398]

[0399]

[0400] Example 5

[0401] Differential Scanning Calorimetry

[0402] Differential scanning calorimetry was performed using a TAInstruments Q2000 DSC and calibrated using an indium reference standard. The samples were loaded into corrugated aluminum pans. After equilibration at 25 °C, the samples were heated under nitrogen (N 2 ) atmosphere at a rate of 50 mL / min to a final temperature of 250°C. The scanning rate was 10°C / min. The DSC curve is shown in Figure 2 As shown and reflected, the onset melting temperature of crystalline 4-((L-valyl)oxy)butyric acid is 137.73°C and the peak melting temperature is 139.88°C.

[0403] Example 6

[0404] Thermogravimetric analysis

[0405] Thermogravimetric analysis was performed using a TAInstruments Q500 TGA calibrated with a nickel reference standard. The samples were placed in an open platinum or aluminum pan and, after equilibration at 35 °C, were heated under nitrogen (N 2 The sample was heated at a rate of 10°C / min to a final temperature of 200°C under a 2% CO atmosphere (60 mL / min flow rate). The TGA curve for crystallization as shown in FIG3 shows a weight loss of 9.7% between 125°C and 150°C. The weight loss from 30°C to 125°C is 0.77%.

[0406] The TGA thermogram showed that the crystalline 4-((L-valyl)oxy)butyric acid did not undergo any significant weight loss before melting, indicating that the crystalline form was anhydrous.

[0407] Example 7

[0408] Jet grinding

[0409] Crystalline 4-((L-valyl)oxy)butyric acid was jet milled to obtain a uniform particle size distribution centered at about 8.6 μm. An Alpine 50AS (PDS-PL-JM-01) jet mill (Hosokawa Alpine) was used to prepare the formulation. The ejector gas pressure was 4.0 bar and the milling gas pressure was 3.5 bar. Five (5) grams of crystalline 4-((L-valyl)oxy)butyric acid was gradually added to the jet mill and the milled product was collected. The milled product was stored at a temperature of 2°C to 8°C.

[0410] Example 8

[0411] Sealed storage stability

[0412] Crystalline 4-((L-valyl)oxy)butyric acid was packaged in double-layer low-density polyethylene (LDPE) zipper bags and sealed. The packaged samples were then placed in an aluminum foil outer bag (polyethylene, polyethylene terephthalate three-layer composite material) and sealed. The fully packaged samples were placed in a stability chamber during the sealed storage stability study.

[0413] Sealed storage stability studies were conducted under four sets of external conditions for packaged crystalline 4-((L-valyl)oxy)butyric acid:

[0414] 1. Accelerated conditions (40±2°C, 75±5%RH).

[0415] 2. Intermediate storage conditions (30±2°C, 65±5%RH).

[0416] 3. Long-term storage conditions (25±2°C, 60±5%RH).

[0417] 4.2-8℃ conditions.

[0418] The sealed storage stability of crystalline 4-((L-valyl)oxy)butyric acid (1) was tested according to the International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) document Q1A (R2) "Stability Testing of New Drug Substances and Products". Therefore, samples were taken at 3 and 6 months. The determination percentage of crystalline 4-((L-valyl)oxy)butyric acid was determined by electrochemical titration using acetic acid as solvent and perchloric acid as titrant. The water content was tested by Karl Fischer titration (Karl Fischer titrator: Mettler V30). Impurities were measured by HPLC (HPLC instrument: Waters Arc HPLC system with CAD; chromatographic column: Waters Atlantis T3, 4.6×150 mm, 3 μm). The samples were analyzed by XRPD analysis (XRPD instrument: Bruker D8 advance). The sealed storage stability results of crystalline 4-((L-valyl)oxy)butyric acid under four storage conditions are summarized in Table 2.

[0419] Table 2. Sealed storage stability of crystalline 4-((L-valyl)oxy)butyric acid.

[0420]

[0421] Note: D = Day, M = Month, C = Comply, N / A = Not Applicable.

[0422] The results of the sealed storage stability study showed that the crystalline 4-((L-valyl)oxy)butyric acid was stable for up to 6 months under all sealed storage conditions. Under all sealed storage conditions, the chemical stability of the crystalline sample was up to 6 months.

[0423] In other studies, crystalline 4-((L-valyl)oxy)butyric acid was shown to be stable for 36 months under sealed storage at 25±2°C and 60±5% RH. Stability was defined as a crystalline 4-((L-valyl)oxy)butyric acid sample absorbing less than 2 wt% water and less than 2 wt% impurity content over a period of time under specified sealed storage conditions.

[0424] Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein. Therefore, the present embodiments are to be considered as illustrative and not restrictive, and the claims are not to be limited to the details given herein, but may be modified within the scope and equivalents of the claims.

Claims

1. A compound, crystalline 4-((L-valyl)oxy)butyric acid:

2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 16.75°±0.20°, and 25.33±0.20° expressed by 2θ angles determined using Cu-Kα radiation.

3. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 25.33±0.20°, and 26.08°±0.20° represented by 2θ angles determined using Cu-Kα radiation.

4. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 13.75°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 24.98°±0.20°, 25.33±0.2°, and 26.08°±0.20° represented by 2θ angles determined using Cu-Kα radiation.

5. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 11.63°±0.20°, 13.75°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 19.93°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 22.22°±0.20°, 23.58°±0.20°, 24.98°±0.20°, 25.33±0.20°, and 26.08°±0.20° as represented by 2θ angles determined using Cu-Kα radiation.

6. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, and 25.33±0.10° expressed by 2θ angles determined using Cu-Kα radiation.

7. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 25.33±0.10°, and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

8. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.20°, 9.58°±0.20°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 24.98°±0.10°, 25.33±0.10°, and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

9. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least 8.28°±0.10°, 9.58°±0.10°, 11.63°±0.10°, 13.75°±0.10°, 16.75°±0.10°, 17.64°±0.10°, 19.93°±0.10°, 18.31°±0.10°, 19.42°±0.10°, 20.79°±0.10°, 22.22°±0.10°, 23.58°±0.10°, 24.98°±0.10°, 25.33±0.10°, and 26.08°±0.10° as represented by 2θ angles determined using Cu-Kα radiation.

10. The compound of claim 1, wherein the compound is characterized by the XRPD pattern as shown in Figure 1.

11. The compound according to any one of claims 1 to 10, wherein the compound has a melting onset temperature of 135°C to 141°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

12. The compound according to any one of claims 1 to 10, wherein the compound has a melting onset temperature of 137.7°C ± 1.0°C, wherein the melting onset temperature is determined by differential scanning calorimetry.

13. The compound according to any one of claims 1 to 12, wherein the compound has a melting enthalpy of 197 J / g to 207 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

14. The compound according to any one of claims 1 to 12, wherein the compound has a melting enthalpy of 202.2 J / g ± 1.0 J / g, wherein the melting enthalpy is determined by differential scanning calorimetry.

15. The compound of any one of claims 1 to 14, wherein the compound has a melting peak temperature of 138.0°C to 142.0°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

16. The compound of any one of claims 1 to 14, wherein the compound has a melting peak temperature of 139.9°C ± 2.0°C, wherein the melting peak temperature is determined by differential scanning calorimetry.

17. The compound according to any one of claims 1 to 16, wherein the compound exhibits a differential scanning calorimetry curve as shown in Figure 2.

18. The compound of any one of claims 1 to 17, wherein the compound has a weight loss of 0.16 wt% to 0.36 wt% over a temperature range of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scan rate of 2°C / min.

19. The compound of any one of claims 1 to 17, wherein the compound has a weight loss of 0.26 wt% ± 0.20 wt% over a temperature range of 20°C to 70°C, wherein the weight loss is determined by thermogravimetric analysis at a scan rate of 2°C / min.

20. The compound according to any one of claims 1 to 19, wherein the compound exhibits a differential thermal calorimetry curve as shown in Figure 2.

21. The compound of any one of claims 1 to 20, wherein the compound has a water content of 5.8 mol% to 6.6 mol%, wherein the mol% is based on the total moles of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid, and the water content is determined using Karl Fischer analysis.

22. The compound of any one of claims 1 to 21, wherein the compound has a water content of less than 5 wt%, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid and water in the crystalline 4-((L-valyl)oxy)butyric acid, and the water content is determined using Karl Fischer analysis.

23. The compound of any one of claims 1 to 22, wherein the compound absorbs less than 2 wt% water at 25°C / 60%RH for 36 months.

24. The compound according to any one of claims 1 to 23, wherein the compound has an impurity content of less than 1 wt% under conditions of 25°C / 60%RH for 36 months.

25. according to the compound described in any one of claims 1 to 24, wherein said compound has less than 5 wt % water content and less than 5 wt % impurity content after storage for 6 months at 25 ℃ / 60% RH, wherein wt % is based on the total weight of said compound, water and impurities; said water content is determined using Karl Fischer analysis, and said impurity content is determined using high pressure liquid chromatography.

26. The compound according to any one of claims 1 to 25, wherein the unmilled compound has a particle size distribution characterized by a D10 of 7 to 17 μm, a D50 of 29 to 39 μm and a D90 of 67 to 75 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

27. The compound according to any one of claims 1 to 26, wherein the unmilled compound has a particle size distribution characterized by D[4,3] of 35 to 41 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

28. The compound of any one of claims 1 to 27, wherein the unmilled compound has a homogeneity of 0.45 to 0.65, wherein the homogeneity is determined using laser diffraction.

29. A compound according to any one of claims 1 to 28, wherein the unground compound has a 2 / kg to 310m 2 / kg of surface area, where the surface area is determined using laser diffraction.

30. The compound of any one of claims 1 to 29, wherein the unmilled compound has a bulk density of 0.15 g / mL to 0.25 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

31. The compound according to any one of claims 1 to 30, wherein the unmilled compound has a Hausner Ratio of 1.65 to 1.95, wherein the Hausner Ratio is determined according to USP 1174.

32. The compound according to any one of claims 1 to 31, wherein the milled compound has a particle size distribution characterized by a D10 of 1 to 5 μm, a D50 of 4 to 8 μm and a D90 of 10 to 14 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

33. The compound according to any one of claims 1 to 32, wherein the milled compound has a particle size distribution characterized by D[4,3] of 12 to 22 μm, wherein the particle size is determined by sieve analysis or by laser diffraction.

34. The compound of any one of claims 1 to 33, wherein the milled compound has a homogeneity of 0.2 to 0.6, wherein the homogeneity is determined by laser diffraction.

35. A compound according to any one of claims 1 to 34, wherein the ground compound has a pH of 430. 2 / kg to 630m 2 / kg of surface area, where the surface area is determined by laser diffraction.

36. The compound of any one of claims 1 to 35, wherein the milled compound has a bulk density of 0.10 g / mL to 0.14 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

37. The compound of any one of claims 1 to 36, wherein the milled compound has a Hausner Ratio of 1.6 to 1.8, wherein the Hausner Ratio is determined according to USP 1174.

38. A granulation comprising a plurality of granules comprising a compound according to any one of claims 1 to 37.

39. The granulation according to claim 38, wherein the granules have an average particle size of 100 to 550 μm.

40. A granulation according to any one of claims 38 to 39, wherein the granules comprise greater than 80% by weight of the compound, wherein the % by weight is based on the total weight of the granules.

41. A granulation according to any one of claims 38 to 40, wherein the granule comprises a core and a modified release coating surrounding the core, the core comprising greater than 80% by weight of the compound.

42. A granulation according to any one of claims 38 to 41, wherein the granulation comprises immediate release granules and modified release granules.

43. A pharmaceutical composition comprising the compound according to any one of claims 1 to 37 or the granulated material according to any one of claims 38 to 42.

44. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a patient, wherein the disease is selected from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative diseases, sleep disturbance syndromes, fatigue, improving nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, and chronic fatigue syndrome.

45. The pharmaceutical composition of any one of claims 43 to 44, wherein the pharmaceutical composition comprises an oral formulation.

46. ​​The pharmaceutical composition of any one of claims 43 to 45, wherein the pharmaceutical composition comprises 1 gram equivalent to 10 gram equivalents of gamma-hydroxybutyric acid.

47. The pharmaceutical composition of any one of claims 43 to 46, wherein the pharmaceutical composition comprises 1 gram to 20 grams of crystalline 4-((L-valyl)oxy)butyric acid.

48. The pharmaceutical composition of any one of claims 43 to 47, wherein the pharmaceutical composition comprises an immediate release component and a modified release component.

49. The pharmaceutical composition of claim 48, wherein the immediate release component comprises a solution containing 4-((L-valyl)oxy)butyric acid.

50. The pharmaceutical composition of claim 48, wherein the immediate release component comprises immediate release granules containing crystalline 4-((L-valyl)oxy)butyric acid.

51. The pharmaceutical composition of any one of claims 48 to 50, wherein the modified release component comprises modified release granules containing crystalline 4-((L-valyl)oxy)butyric acid.

52. An oral dosage form comprising a compound according to any one of claims 1 to 38, a granulation according to any one of claims 39 to 42, or a pharmaceutical composition according to any one of claims 43 to 51.

53. The oral dosage form of claim 52, wherein the oral dosage form comprises 1 gram equivalent to 10 gram equivalents of gamma-hydroxybutyrate.

54. The oral dosage form of any one of claims 52 to 53, wherein the oral dosage form comprises 1 gram to 20 grams of crystalline 4-((L-valyl)oxy)butyric acid.

55. The oral dosage form of any one of claims 52 to 54, wherein the oral dosage form comprises an immediate release component and a modified release component.

56. The oral dosage form of claim 55, wherein the immediate release component comprises a solution comprising 4-((L-valyl)oxy)butyric acid.

57. The oral dosage form of claim 55, wherein the immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

58. The oral dosage form of any one of claims 55 to 57, wherein the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

59. The oral dosage form of any one of claims 55 to 56, wherein the oral dosage form comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid suspended in a solution comprising 4-((L-valyl)oxy)butyric acid. 60 . A kit comprising the compound according to claim 1 , the granulated material according to claim 39 , or the pharmaceutical composition according to claim 43 .

61. The kit of claim 60, wherein the kit comprises an immediate release component comprising crystalline 4-((L-valyl)oxy)butyric acid and a modified release component comprising crystalline 4-((L-valyl)oxy)butyric acid.

62. The kit of any one of claims 61, wherein the immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butyric acid and the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butyric acid.

63. The kit of any one of claims 60 to 62, wherein the pharmaceutical composition or oral dosage form is contained in a pouch.

64. A method of treating a disease in a patient, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59, wherein the disease is treatable with gamma-hydroxybutyrate.

65. A method of treating a disease in a patient, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59, wherein the disease is selected from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative diseases, sleep disorder syndromes, fatigue, improving nighttime sleep, hypnagogic hallucinations, sleep paralysis, segmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with alternating hemiplegia of childhood, sedative abuse, and binge eating disorder.

66. A method of treating fatigue or excessive daytime sleepiness associated with narcolepsy, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59.

67. A method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59.

68. The method of claim 67, wherein the disorder is cataplexy associated with narcolepsy.

69. The method of claim 67, wherein the disorder is excessive daytime sleepiness associated with narcolepsy.

70. The method of claim 67, wherein the disorder is excessive daytime sleepiness in a patient suffering from Parkinson's disease.

71. The method of claim 67, wherein the disease is chronic fatigue in a patient with Parkinson's disease.

72. A method of treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59.

73. A method of treating REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59.

74. A method of treating symptoms associated with REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 37, a granulation according to any one of claims 39 to 42, a pharmaceutical composition according to any one of claims 43 to 51, or an oral dosage form according to any one of claims 52 to 59.

75. The method of any one of claims 63 to 74, wherein administering comprises oral administration.

76. The method of any one of claims 63 to 75, wherein administering comprises administering QDs.

77. The method of any one of claims 63 to 75, wherein administering comprises administering BID.

78. A method for preparing a compound according to any one of aspects 1 to 37, the method include: (i) dissolving 4-((L-valyl)oxy)butyric acid in a first solvent to obtain a solution; as well as (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butyric acid.

79. The method of claim 78, wherein the first solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, isobutanol, isopropyl acetate, acetonitrile, 2-butanone, toluene, water, tert-butyl methyl ether, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, diethyl ether, or a combination of any of the foregoing.

80. The method of any one of claims 78 to 79, wherein dissolving comprises dissolving in the first solvent at a temperature of 60°C to 90°C.

81. The method of any one of claims 78 to 80, wherein the method comprises, after dissolving to form a solution, adding a second solvent to the solution.

82. The method of claim 81, wherein the second solvent is selected from acetonitrile, tetrahydrofuran, isopropanol, acetone, ethyl acetate, tert-butyl methyl ether, 1,4-dioxane, or a combination of any of the foregoing.

83. The method of any one of claims 78 to 82, wherein crystallization comprises heating the solution to a temperature of 60°C to 90°C for 0.5 to 2 hours.

84. The method of any one of claims 78 to 83, wherein the method comprises recrystallizing the crystalline 4-((L-valyl)oxy)butyric acid after crystallization.

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