Crystalline 4-((L-valyl)oxy)butanoic acid

Abstract

Crystalline 4-((L-valyl)oxy)butanoic acid, methods for preparing crystalline 4-((L-valyl)oxy)butanoic acid, pharmaceutical compositions of crystalline 4-((L-valyl)oxy)butanoic acid, and methods of treatment using crystalline 4-((L-valyl)oxy)butanoic acid are disclosed.

Description

[Technical Field]

[0001] The present invention relates to crystalline 4-((L-valyl)oxy)butanoic acid, methods for preparing crystalline 4-((L-valyl)oxy)butanoic acid, pharmaceutical compositions containing crystalline 4-((L-valyl)oxy)butanoic acid, and methods of treatment using crystalline 4-((L-valyl)oxy)butanoic acid. [Background technology]

[0002] 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid (GHB), which is useful in treating 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, the compound is crystalline 4-((L-valyl)oxy)butanoic acid. [ka]

[0004] According to the present invention, the pharmaceutical composition comprises a compound according to the present invention.

[0005] According to the present invention, an oral dosage form comprises a compound according to the present invention or a pharmaceutical composition according to the present invention.

[0006] 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.

[0007] According to the present invention, a method for treating a disease in a patient 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, wherein the disease can be treated with gamma-hydroxybutyric acid.

[0008] The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure. [Brief explanation of the drawings]

[0009] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline 4-((L-valyl)oxy)butanoic acid. [Figure 2] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of crystalline 4-((L-valyl)oxy)butanoic acid. DETAILED DESCRIPTION OF THE INVENTION

[0010] For purposes of the following detailed description, it should be understood that the embodiments provided by the present disclosure may assume various alternative modifications and step sequences, unless expressly indicated to the contrary. Furthermore, other than as examples of any operations, or where otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims, for example, should be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques.

[0011] 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. However, any numerical value inherently contains certain errors necessarily resulting from the standard variation found in their respective testing measurements.

[0012] It should also be understood that any numerical range recited 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 including) the recited minimum of 1 and the recited maximum of 10, i.e., minimums of 1 or greater and maximums of 10 or less.

[0013] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the pharmacologically active ingredient into a patient's gastrointestinal tract within less than one 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 more than 90%, more than 95%, or more than 98% of the pharmacologically active ingredient in the pharmaceutical composition into the gastrointestinal tract within less than one hour, 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. An immediate release pharmaceutical composition may be suitable for administering a pharmacologically active ingredient that is absorbed into the systemic circulation from the upper gastrointestinal tract.

[0014] "Modified-release" pharmaceutical compositions include controlled-release, delayed-release, sustained-release, extended-release, timed-release, pulsatile-release, and pH-dependent release formulations. These formulations are intended to release a pharmacologically active ingredient from a pharmaceutical composition at a desired rate and / or at a desired time after oral administration by a patient, and / or at a specific location or locations in the gastrointestinal tract, and / or at a specific pH in the gastrointestinal tract. The United States Pharmacopeia defines a modified-release system as one in which the time course or location of drug release, or both, is selected to achieve a therapeutic efficacy or convenience objective not met by immediate-release dosage forms. Modified-release oral dosage forms can include sustained-release and delayed-release components. Delayed-release dosage forms release the drug all at once rather than immediately after administration. Modified-release formulations can include delayed release using enteric coatings, site-specific or timed release, such as for colonic delivery, sustained release formulations, including formulations capable of providing zero-order, first-order, or biphasic release profiles, and programmed release, such as pulsatile release and delayed-release.

[0015] "Sustained release" pharmaceutical compositions and coatings provide a dissolution rate over an extended period of time after oral administration. A granulation comprising granules with a sustained release coating can be referred to as a sustained release granulation. A pharmaceutical composition comprising a sustained release granulation can be referred to as a sustained release pharmaceutical composition.

[0016] "pH-release" pharmaceutical compositions and coatings provide an increased dissolution rate at a designated pH.

[0017] "Pulsatile release" pharmaceutical compositions and coatings exhibit increased dissolution rates at intervals, where the release intervals can be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsatile 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.

[0018] "Timed-release" pharmaceutical compositions and coatings have a dissolution rate that is a function of time. Timed-release pharmaceutical compositions or coatings include, for example, delayed-release, sustained-release, and extended-release pharmaceutical compositions and coatings.

[0019] "Delayed release" pharmaceutical compositions and coatings provide an increased dissolution rate at a designated time after administration.

[0020] "Patient" refers to a mammal, for example, a human.

[0021] "Pharmaceutically acceptable" refers to that approved or approvable by a regulatory agency of the Federal or State government, or as set forth in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0022] "Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or a combination of any of the foregoing, with which a compound provided by the present disclosure may be administered to a patient, which does not destroy its pharmacological activity, and which is non-toxic when administered in a dosage sufficient to provide a therapeutically effective amount of the compound.

[0023] "Pharmaceutical composition" refers to 4-((L-valyl)oxy)butanoic acid and at least one pharmaceutically acceptable vehicle with which the 4-((L-valyl)oxy)butanoic acid is administered to a patient. Pharmaceutically acceptable vehicles are known in the art.

[0024] "Disease" refers to any of the diseases, disorders, conditions or symptoms mentioned above.

[0025] "Preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., preventing at least one of the clinical symptoms of the disease from developing in a patient who may be exposed to or susceptible to the disease, but who has not yet experienced or displayed symptoms of the disease). In some embodiments, "preventing" or "prevention" refers to reducing the symptoms of the disease by administering a compound provided by the present disclosure in a prophylactic manner. The application of a therapeutic agent to prevent or for the prevention of a disorder is known as "prophylaxis." The compounds provided by the present disclosure can provide superior prevention due to their low long-term side effects.

[0026] A "prodrug" refers to a derivative of a drug molecule that requires transformation in the body to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs can typically be obtained by attaching a promoiety to a drug via a functional group. For example, with reference to 4-((L-valyl)oxy)butanoic acid, the NH2-CH(-CH3)2)-promoiety is attached to gamma-hydroxybutyric acid. 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid that can be metabolized in the patient's body to release gamma-hydroxybutyric acid.

[0027] A "promoiety" refers to a group attached to a drug, typically a functional group of a drug, via a bond(s) that is / are cleavable under specific conditions of use. The bond(s) between the drug and the promoiety may be cleaved by enzymatic or non-enzymatic means. Under conditions of use, for example, after administration to a patient, the bond(s) between the drug and the promoiety may be cleaved, releasing the parent drug. Cleavage of the promoiety may proceed spontaneously, such as by hydrolysis, or may be catalyzed or induced by another agent, such as an enzyme, by light, by acid, or by changes in or exposure to physical or environmental parameters, such as changes in temperature or pH. The drug may be endogenous to the conditions of use, such as enzymes present in the systemic circulation of the patient to whom the prodrug is administered or the acidic conditions of the stomach, or it may be exogenously supplied. The compounds provided by the present disclosure are prodrugs of gamma-hydroxybutyric acid. The structure of the promoiety of 4-((L-valyl)oxy)butanoic acid is as follows: [ka]

[0028] The promoiety is cleaved in vivo to gamma-hydroxybutyric acid in the patient's systemic circulation.

[0029] "Curing" a disease refers to eliminating the disease or disorder or eliminating the symptoms of the disease or disorder.

[0030] "Sealed storage stability" refers to the stability of a compound when the compound is sealed in two sealed polyethylene bags with a desiccant sandwiched between them, and the two sealed polyethylene bags are then sealed in a sealed single-layer aluminum bag.

[0031] "Treating" or "treatment" of a disease or disorder refers to inhibiting a disease or disorder or one or more clinical symptoms of a disease or disorder, preventing the onset of a disease or disorder or one or more clinical symptoms of a disease or disorder, alleviating a disease or disorder or one or more clinical symptoms of a disease or disorder, causing regression of a disease or disorder or one or more clinical symptoms of a disease or disorder, reducing the severity of one or more clinical symptoms of a disease or disorder, delaying the onset of one or more clinical symptoms of a disease or disorder, alleviating one or more clinical symptoms of a disease or disorder, and / or stabilizing a disease or disorder or one or more clinical symptoms of a disease or disorder. "Treating" or "treatment" of a disease or disorder includes producing a clinically beneficial effect without curing the underlying disease or disorder.

[0032] A "therapeutically effective amount" refers to the amount of a compound, such as a pharmacologically active ingredient, that, when administered to a patient for treating a disease or at least one of the clinical symptoms of the disease, is sufficient to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" can vary depending, for example, on the compound, the disease and / or symptoms of the disease, the severity of the disease, and / or symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. The therapeutically effective amount in any given case can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0033] A "therapeutically effective amount" refers to a dose that provides effective treatment of a disease or disorder in a patient. Therapeutically effective amounts may vary from compound to compound and from patient to patient, and may depend on factors such as the condition of the patient and the route of delivery. Therapeutically effective amounts can be determined according to routine pharmacological procedures known to those skilled in the art.

[0034] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. The vehicle can be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0035] Bulk density can be determined according to USP 616, Method 1.

[0036] Tapped bulk density can be determined in accordance with USP616.

[0037] The specific surface area can be determined by laser diffraction.

[0038] The Hausner ratio can be determined according to USP1174.

[0039] The parameter D90 refers to the size in a sample's size distribution such that 90% of the total volume of material in the sample is equal to or less than that size. For example, for a D90 of 400 μm, 90% of the sample volume has a size of 400 μm or less. D50 refers to the size such that 50% of the total volume of material in the sample is less than that size. Similarly, D10 refers to the size such that 10% of the total volume of material in the sample is less than that size. The volume distribution of a sample can be determined by laser diffraction or sieve analysis.

[0040] An equivalent of gamma-hydroxybutyric acid, such as gram equivalent of gamma-hydroxybutyric acid, refers to the number of grams of gamma-hydroxybutyric acid in a quantity of crystalline 4-((L-valyl)oxy)butanoic acid. The gram equivalent of gamma-hydroxybutyric acid can be determined by multiplying the gm equivalent of crystalline 4-((L-valyl)oxy)butanoic acid by 0.512. For example, 10 grams of 4-((L-valyl)oxy)butanoic acid corresponds to 5.12 gram equivalents of gamma-hydroxybutyric acid.

[0041] Reference is now made to crystalline 4-((L-valyl)oxy)butanoic acid, methods for making crystalline 4-((L-valyl)oxy)butanoic acid, pharmaceutical compositions containing crystalline 4-((L-valyl)oxy)butanoic acid, and uses of crystalline 4-((L-valyl)oxy)butanoic acid. The disclosed crystalline 4-((L-valyl)oxy)butanoic acid, pharmaceutical compositions, methods, and uses are not intended to limit the scope of the claims. To the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

[0042] Crystalline 4-((L-valyl)oxy)butanoic acid is a stable crystalline form of 4-((L-valyl)oxy)butanoic acid. The structure of crystalline 4-((L-valyl)oxy)butanoic acid is as follows: [ka]

[0043] 4-((L-valyl)oxy)butanoic acid is also known as (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid.

[0044] Methods for synthesizing 4-((L-valyl)oxy)butanoic acid and the properties of 4-((L-valyl)oxy)butanoic 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.

[0045] Crystalline 4-((L-valyl)oxy)butanoic acid can be prepared as described in Example 1.

[0046] 4-((L-valyl)oxy)butanoic acid can be characterized by an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at least at 8.28°±0.20°, 16.75°±0.20°, and 25.33±0.20°, expressed in 2θ angles, determined using Cu-Kα radiation.

[0047] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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°, determined using Cu-Kα radiation and expressed in 2θ angles.

[0048] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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 determined using Cu-Kα radiation and expressed in 2θ angles.

[0049] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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 determined using Cu-Kα radiation and expressed in 2θ angles.

[0050] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing characteristic diffraction peaks at at least 8.28°±0.10°, 16.75°±0.10°, and 25.33±0.10°, expressed in 2θ angles, determined using Cu-Kα radiation.

[0051] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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°, determined using Cu-Kα radiation and expressed in 2θ angles.

[0052] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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 determined using Cu-Kα radiation and expressed in 2θ angles.

[0053] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing 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 determined using Cu-Kα radiation and expressed in 2θ angles.

[0054] Crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by the XRPD pattern shown in FIG.

[0055] The crystalline 4-((L-valyl)oxy)butanoic acid may have an onset melting temperature of, for example, 135°C to 141°C, such as 136°C to 140°C or 137°C to 139°C, as determined by differential scanning calorimetry.

[0056] The crystalline 4-((L-valyl)oxy)butanoic acid can have an onset melting 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, as determined by differential scanning calorimetry.

[0057] The crystalline 4-((L-valyl)oxy)butanoic acid can have an enthalpy of fusion 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, as determined by differential scanning calorimetry.

[0058] The crystalline 4-((L-valyl)oxy)butanoic acid may have an enthalpy of fusion 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, where the enthalpy of fusion is determined by differential scanning calorimetry.

[0059] The crystalline 4-((L-valyl)oxy)butanoic acid may 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, the melting peak temperature being determined by differential scanning calorimetry.

[0060] The crystalline 4-((L-valyl)oxy)butanoic acid may have a melting peak temperature of 139.9°C ± 2.0°C, for example, 139.9°C ± 1.0°C, or 139.9°C ± 0.5°C, where the melting peak temperature is determined by differential scanning calorimetry.

[0061] Crystalline 4-((L-valyl)oxy)butanoic acid can exhibit a differential scanning calorimetry curve as shown in FIG.

[0062] The crystalline 4-((L-valyl)oxy)butanoic acid may have a weight loss of 0.16% to 0.36% at temperatures between 20°C and 70°C, e.g., 0.18% to 0.34% at temperatures between 20°C and 70°C, 0.20% to 0.32% at temperatures between 20°C and 70°C, or 0.22% to 0.30% at temperatures between 20°C and 70°C, as determined by thermogravimetric analysis at a scan rate of 2°C / min.

[0063] Crystalline 4-((L-valyl)oxy)butanoic acid can have a weight loss of 0.26% ± 0.20%, for example, 0.26% ± 0.10%, or 0.26% ± 0.05%, at temperatures between 20 °C and 70 °C, as determined by thermogravimetric analysis at a scan rate of 2 °C / min.

[0064] The crystalline 4-((L-valyl)oxy)butanoic acid provided by the present disclosure can exhibit a differential thermal calorimetry curve substantially as shown in FIG.

[0065] The crystalline 4-((L-valyl)oxy)butanoic acid can have a water content of 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 mol %, or 6.2 mol %, where mol % is based on the total number of moles of 4-((L-valyl)oxy)butanoic acid and water in the crystalline 4-((L-valyl)oxy)butanoic acid.

[0066] The crystalline 4-((L-valyl)oxy)butanoic 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 %, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid and water in the crystalline 4-((L-valyl)oxy)butanoic acid.

[0067] The water content of crystalline 4-((L-valyl)oxy)butanoic acid can be determined using Karl Fischer analysis.

[0068] Crystalline 4-((L-valyl)oxy)butanoic acid is substantially stable under sealed storage conditions.

[0069] For example, after sealed storage at 25° C. / 60% RH for 1 month, 3 months, and / or 6 months, the crystalline 4-((L-valyl)oxy)butanoic 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 %, where the weight % is based on the total weight of 4-((L-valyl)oxy)butanoic acid and water in the crystalline 4-((L-valyl)oxy)butanoic acid, and the water content is determined using Karl Fischer analysis.

[0070] For example, the moisture content after 36 months of sealed storage at 25°C / 65% RH can be less than 2.5 wt% or less than 2.0 wt%, where the wt% is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butanoic acid. It has been determined that crystalline 4-((L-valyl)oxy)butanoic acid does not form hydrates.

[0071] The crystalline 4-((L-valyl)oxy)butanoic acid can have a purity of, for example, greater than 95 wt%, greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, greater than 99 wt%, greater than 99.2 wt%, greater than 99.4 wt%, greater than 99.6 wt%, or greater than 99.8 wt%, where the weight percent is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butanoic acid and the purity is determined using high pressure liquid chromatography.

[0072] The crystalline 4-((L-valyl)oxy)butanoic acid has 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%, where the wt% is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butanoic acid, and the purity is determined using high pressure liquid chromatography.

[0073] After storage at 25° C. / 60% RH for 1 month, 3 months, and / or 6 months, the crystalline 4-((L-valyl)oxy)butanoic 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 %, where the wt % is based on the total weight of the sample of crystalline 4-((L-valyl)oxy)butanoic acid, and the purity is determined using high pressure liquid chromatography.

[0074] The impurity content of crystalline 4-((L-valyl)oxy)butanoic acid is determined using high pressure liquid chromatography.

[0075] The crystalline 4-((L-valyl)oxy)butanoic 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%, where the percent (%) is based on the total moles of crystalline 4-((L-valyl)oxy)butanoic acid and the chiral purity is determined using high pressure liquid chromatography.

[0076] The unmilled crystalline 4-((L-valyl)oxy)butanoic acid can 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, as determined by sieve analysis or laser diffraction.

[0077] The unmilled crystalline 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized by a D10 of 9 μm to 15 μm, a D50 of 31 μm to 37 μm, and a D90 of 69 μm to 73 μm, the particle sizes being determined by sieve analysis or laser diffraction.

[0078] The unmilled crystalline 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized by a D10 of 7 μm to 17 μm, a D50 of 29 μm to 39 μm, and a D90 of 67 μm to 75 μm, the particle sizes being determined by sieve analysis or laser diffraction.

[0079] The unmilled crystalline 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized by D[4,3] being 35 μm to 41 μm, such as 36 μm to 40 μm or 37 μm to 39 μm, where the particle size is determined by sieve analysis or laser diffraction.

[0080] Unmilled crystalline 4-((L-valyl)oxy)butanoic acid can have a uniformity of 0.45 to 0.65, such as 0.50 to 0.60, where the uniformity is determined using laser diffraction.

[0081] Unground crystalline 4-((L-valyl)oxy)butanoic acid was 280m 2 / kg~300m 2 / kg, etc., 270m 2 / kg~310m 2 / kg, where the surface area is determined using laser diffraction.

[0082] The unmilled crystalline 4-((L-valyl)oxy)butanoic acid can have a bulk density of, for example, 0.15 g / mL to 0.25 g / mL, such as 0.18 g / mL to 0.22 g / mL, where the bulk density is determined according to USP 616, Method 1.

[0083] Unmilled crystalline 4-((L-valyl)oxy)butanoic 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, where the Hausner ratio is determined in accordance with USP 1174.

[0084] The milled crystalline 4-((L-valyl)oxy)butanoic acid can 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, where the particle sizes are determined by sieve analysis or laser diffraction.

[0085] The milled crystalline 4-((L-valyl)oxy)butanoic acid can have 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, the particle sizes being determined by sieve analysis or laser diffraction.

[0086] The milled crystalline 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized by D[4,3] being 12 μm to 22 μm, such as 14 μm to 20 μm or 16 μm to 18 μm, where the particle size is determined by sieve analysis or laser diffraction.

[0087] The milled crystalline 4-((L-valyl)oxy)butanoic acid can have a uniformity of 0.2 to 0.6, such as 0.3 to 0.5, where the uniformity is determined by laser diffraction.

[0088] Milled crystalline 4-((L-valyl)oxy)butanoic acid was used in 450 ml 2 / kg~610m 2 / kg or 470m 2 / kg~490m 2 / kg, etc., 430m 2 / kg~630m 2 / kg, where the surface area is determined using laser diffraction.

[0089] The milled crystalline 4-((L-valyl)oxy)butanoic acid can have a bulk density of 0.10 g / mL to 0.14 g / mL, such as 0.11 g / mL to 0.13 g / mL, where the bulk density is determined according to USP 616, Method 1.

[0090] The milled crystalline 4-((L-valyl)oxy)butanoic acid can have a Hausner ratio of, for example, 1.6 to 1.8 or 1.65 to 1.75, the Hausner ratio being determined in accordance with USP 1174.

[0091] Methods for synthesizing 4-((L-valyl)oxy)butanoic acid and the properties of 4-((L-valyl)oxy)butanoic 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.

[0092] Methods for the synthesis of 4-((L-valyl)oxy)butanoic acid and the properties of 4-((L-valyl)oxy)butanoic acid are also disclosed in Examples 1 and 2.

[0093] For example, 4-((L-valyl)oxy)butanoic acid can be prepared by (a) contacting benzyl bromide with butyrolactone to provide benzyl 4-hydroxybutanoate (2a), (b) contacting benzyl 4-hydroxybutanoate (2a) with carbobenzyloxy-L-valine to provide 4-(benzoyloxy)-4-oxobutyl((benzoyloxy)carbonyl)-L-valinate (2b), and (c) deprotecting 4-(benzoyloxy)-4-oxobutyl((benzoyloxy)carbonyl)-L-valinate (2b).

[0094] Alternatively, 4-((L-valyl)oxy)butanoic acid can be prepared according to the method shown in Scheme 1. [ka]

[0095] Boc-L-valine may be coupled to butane-1,4-diol to provide (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a) 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-methylmorpholinium chloride (DMTMM), HATU, HBTU, TBTU, PyAOP, PyBOP, 1,1'-thiocarbonyldiimidazole (TCDI), or 1,1'-carbonyldiimidazole (CDI). To suppress racemization, 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) can be included.

[0096] (S)-4-Hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a) can be treated with an oxidizing agent to give (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b). Examples of suitable oxidizing agents include Jones's reagent, potassium permanganate, ruthenium tetroxide, pyridinium dichromate in dimethylformamide (DMF), tetrapropylammonium perruthenate, or a catalytic amount of tetrapropylammonium perruthenate used with a stoichiometric amount of N-methylmorpholine N-oxide. The alcohol is oxidized to an aldehyde using, for example, Dess-Martin periodinane, and then to a carboxylic acid using, for example, sodium chlorite.

[0097] (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b) can be treated with an acid to provide the salt form of compound (1b). Examples of suitable acids include HCl, HCl in ethyl acetate, aqueous HCl, HCl in 1,4-dioxane, trifluoroacetic acid, and the like. 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 scavenger include propylene oxide, an organic base, an amine base, an inorganic base, a carbonate salt, or a hydroxide salt.

[0098] 4-((L-valyl)oxy)butanoic acid can alternatively be prepared according to the methods outlined in Scheme 2. [ka]

[0099] Benzyl 4-hydroxybutanoate (2a) can be prepared by ring-opening hydrolysis of γ-butyrolactone followed by benzylation. Alternatively, benzyl 4-hydroxybutanoate (2a) can be purchased commercially.

[0100] CBz-L-valine can be coupled to benzyl 4-hydroxybutanoate (2a) using peptide coupling reagents 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-valinate (2b). To suppress racemization, 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) can be included in the reaction.

[0101] 4-(Benzyloxy)-4-oxobutyl(benzyloxy)carbonyl)-L-valinate (2b) can be hydrogenated in the presence of hydrogen gas and a catalyst derived from a metal such as palladium, platinum, ruthenium, nickel, rhodium, or iridium to provide 4-((L-valyl)oxy)butanoic acid.

[0102] Crystalline 4-((L-valyl)oxy)butanoic acid can be prepared by (i) dissolving 4-((L-valyl)oxy)butanoic acid in a first solvent to obtain a solution, and (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butanoic acid.

[0103] The first solvent can include, for example, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, isobutanol, isopropyl acetate, acetonitrile, 2-butanone, toluene, water, tert-butyl methyl ether, n-propanol, isopentanol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, ethyl ether, or a combination of any of the foregoing.

[0104] 4-((L-valyl)oxy)butanoic acid can be dissolved in the solvent at a temperature of, for example, 60°C to 90°C, 65°C to 85°C, or 70°C to 80°C.

[0105] After dissolving 4-((L-valyl)oxy)butanoic acid in a first solvent, a second solvent can be added to the solution. For example, the second solvent can include acetonitrile, tetrahydrofuran, isopropanol, acetone, ethyl acetate, tert-butyl methyl ether, 1,4-dioxane, or any combination thereof.

[0106] Crystallizing 4-((L-valyl)oxy)butanoic acid can 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 this temperature for, for example, 0.5 hours to 2 hours.

[0107] Crystallization can further include cooling the heated solution to a temperature of, for example, 20°C to 25°C.

[0108] The crystallized 4-((L-valyl)oxy)butanoic acid can be filtered and washed to provide crystalline 4-((L-valyl)oxy)butanoic acid. [1] Recrystallization of crystalline 4-((L-valyl)oxy)butanoic acid can be performed, for example, by warming a solvent, adding crystalline 4-((L-valyl)oxy)butanoic acid to the solvent, and dissolving the crystalline 4-((L-valyl)oxy)butanoic acid in the solvent. The solvent can be, for example, ethanol, 50:1 ethanol / water, water, methanol, or isopropanol. Additional solvents can be added, and / or a suitable 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 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 obtain crystalline 4-((L-valyl)oxy)butanoic acid as a solid precipitate.

[0109] Crystalline 4-((L-valyl)oxy)butanoic acid can be incorporated into pharmaceutical compositions that are administered to a patient by any suitable route of administration, including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical. The pharmaceutical compositions provided by the present disclosure can be injectable formulations. The pharmaceutical compositions provided by the present disclosure can be injectable intravenous formulations. The pharmaceutical compositions provided by the present disclosure can be oral formulations. The oral formulations can be oral dosage forms.

[0110] Pharmaceutical compositions provided by the present disclosure can include a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butanoic acid, together with a suitable amount of one or more pharmaceutically acceptable vehicles to provide the composition for proper administration to a patient. Suitable pharmaceutical vehicles and methods for preparing pharmaceutical compositions are described in the art.

[0111] The pharmaceutical compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the patient's systemic circulation following administration to the patient, for example, following oral administration to the patient.

[0112] Thus, it is within the ability of one of ordinary skill in the art to assay and use crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof for therapeutic purposes.

[0113] The crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof can be used in an amount effective to achieve the intended purpose. For example, the crystalline 4-((L-valyl)oxy)butanoic acid or pharmaceutical composition thereof can be administered to a patient in a therapeutically effective amount to treat a disease or symptom of a disease, such as a sleep disorder.

[0114] The amount of crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof that will be 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 can optionally be employed to help identify optimal dosage ranges. The appropriate dosage of crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof can depend on the patient being treated, the patient's weight, the severity of the disease, the method of administration, and the judgment of the prescribing physician, among other factors.

[0115] Crystalline 4-((L-valyl)oxy)butanoic acid can be assayed in vitro and in vivo for the desired therapeutic activity prior to use in humans. Crystalline 4-((L-valyl)oxy)butanoic acid may also be demonstrated to be effective and safe using animal model systems.

[0116] In certain embodiments, a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof can provide therapeutic benefit without causing substantial toxicity. The toxicity of crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof can be determined using standard pharmaceutical procedures and ascertained by one of ordinary skill in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index. The crystalline 4-((L-valyl)oxy)butanoic acid compound and / or pharmaceutical compositions thereof can exhibit a high therapeutic index in the treatment of diseases and disorders. The dose of crystalline 4-((L-valyl)oxy)butanoic acid and / or pharmaceutical compositions thereof can be within a range of circulating concentrations that includes an effective dose with minimal toxicity.

[0117] The pharmaceutical compositions provided by the present disclosure may further comprise one or more pharmaceutically active compounds in addition to crystalline 4-((L-valyl)oxy)butanoic acid. Such compounds may be provided to treat the disease being treated with the compound of formula, or to treat a disease, disorder, or condition other than the disease being treated with crystalline 4-((L-valyl)oxy)butanoic acid.

[0118] Crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof can be used in combination with at least one other therapeutic agent. Crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof may be administered to a patient along with other compounds to treat the patient's disease, such as a sleep disorder. Crystalline 4-((L-valyl)oxy)butanoic acid and the at least one other therapeutic agent can act additively or synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle containing crystalline 4-((L-valyl)oxy)butanoic acid, or can be included in a separate pharmaceutical composition or vehicle. Thus, the methods provided by the present disclosure further include, in addition to administering crystalline 4-((L-valyl)oxy)butanoic acid, administering one or more therapeutic agents effective to treat a different disease, disorder, or condition other than the disease treated with gamma-hydroxybutyric acid. The methods provided by the present disclosure include the administration of crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof and one or more other therapeutic agents, provided that the combined administration does not interfere with the therapeutic effect of the crystalline 4-((L-valyl)oxy)butanoic acid and / or gamma-hydroxybutyric acid and / or does not result in adverse combined effects.

[0119] A pharmaceutical composition comprising crystalline 4-((L-valyl)oxy)butanoic acid may be administered simultaneously with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as or a different pharmaceutical composition from the pharmaceutical composition comprising crystalline 4-((L-valyl)oxy)butanoic acid. The crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof may be administered before or after the administration of the other therapeutic agent. In certain embodiments of combination therapy, the combination therapy may involve alternating between the administration of crystalline 4-((L-valyl)oxy)butanoic acid and a pharmaceutical composition comprising another therapeutic agent, such as to minimize adverse drug effects associated with a particular drug. When crystalline 4-((L-valyl)oxy)butanoic acid is administered simultaneously with another therapeutic agent that could potentially produce adverse drug effects, including, for example, toxicity, the other therapeutic agent may be administered at a dose below the threshold at which an adverse drug reaction is elicited.

[0120] Pharmaceutical compositions containing crystalline 4-((L-valyl)oxy)butanoic acid may be administered with one or more substances to enhance, regulate, and / or control, for example, the release, bioavailability, therapeutic effect, therapeutic efficacy, and / or stability of crystalline 4-((L-valyl)oxy)butanoic acid. For example, to enhance the therapeutic effect, crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition containing crystalline 4-((L-valyl)oxy)butanoic acid may be co-administered with one or more active agents to increase absorption or diffusion and / or transport of the compound of formula from the gastrointestinal tract to the systemic circulation, or to inhibit the degradation of crystalline 4-((L-valyl)oxy)butanoic acid in the patient's blood. Pharmaceutical compositions containing crystalline 4-((L-valyl)oxy)butanoic acid may also be co-administered with active agents that have pharmacological effects that enhance the therapeutic efficacy of the compound of formula or the therapeutic effect of gamma-hydroxybutyric acid.

[0121] For oral therapeutic administration, the crystalline 4-((L-valyl)oxy)butanoic acid can be incorporated with excipients and used in the form of, for example, tablets, buccal tablets or tabs, troches, capsules, elixirs, suspensions, syrups, or wafers, mixed with an aqueous medium. The dosage forms can contain a therapeutically effective amount of crystalline 4-((L-valyl)oxy)butanoic acid, or a sub-therapeutically effective amount of crystalline 4-((L-valyl)oxy)butanoic acid.

[0122] An oral formulation, such as an oral dosage form, can contain, for example, 1 gram to 18 grams of crystalline 4-((L-valyl)oxy)butanoic acid.

[0123] An oral formulation, such as an oral dosage form, can contain, for example, 0.5 gram equivalents to 9 gram equivalents of gamma-hydroxybutyric acid.

[0124] Oral dosage forms such as granules, tablets, troches, pills, capsules, and suspensions may also contain natural binders such as tragacanth gum, acacia, cornstarch, and gelatin, or synthetic binders such as polyvinyl acetate, excipients such as dicalcium phosphate, disintegrating agents such as cornstarch, potato starch, and alginic acid, lubricants such as magnesium stearate, sweeteners such as lactose and saccharin, or natural or synthetic flavors. If the dosage form is a capsule for mixing with a certain amount of aqueous medium, the dosage form may include a liquid carrier. Various other materials may be present as coatings or may otherwise modify the physical form of the dosage unit. For example, tablets, pills, and capsules may be coated with sugar, natural polymers, synthetic polymers, or any combination of the foregoing.

[0125] The oral dosage form can include a granulation, which includes granules comprising crystalline 4-((L-valyl)oxy)butanoic acid. The granulation can include immediate-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid, modified-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid, or a combination thereof.

[0126] The granules can include a core comprising crystalline 4-((L-valyl)oxy)butanoic acid and, optionally, a coating surrounding the core. The coating can be, for example, a seal coating or a modified release coating. Granules that include an uncoated core are referred to as uncoated granules.

[0127] The uncoated granules of crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an average particle size of, for example, 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, where the average particle size is determined by sieve analysis or laser diffraction.

[0128] The uncoated granules can contain a large amount of crystalline 4-((L-valyl)oxy)butanoic acid. For example, the uncoated granules can contain more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, or more than 99 wt% crystalline 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules. The uncoated granules can contain, for example, 80 wt% to 99.5 wt% crystalline 4-((L-valyl)oxy)butanoic acid, 85 wt% to 95 wt%, 87 wt% to 93 wt%, or 88 wt% to 92 wt% crystalline 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules. The uncoated granules may contain, for example, 85% to 95% by weight of crystalline 4-((L-valyl)oxy)butanoic acid, 86% to 94% by weight, 87% to 93% by weight, or 88% to 92% by weight of crystalline 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules.

[0129] The uncoated granules or granules may contain, for example, 80% to 99% by weight of crystalline 4-((L-valyl)oxy)butanoic 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 hydroxypropyl methylcellulose, where the weight percentages are based on the total weight of the granules or granules. The uncoated granules or granules may contain, for example, 85% to 95% by weight of crystalline 4-((L-valyl)oxy)butanoic 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 hydroxypropyl methylcellulose, where the weight percentages are based on the total weight of the granules or granules. The uncoated granules or granules provided by the present disclosure can contain, for example, 87% to 93% by weight of crystalline 4-((L-valyl)oxy)butanoic acid, 3% to 7% by weight of an antistatic agent such as hydrated magnesium silicate (talc), and 3% to 7% by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, the weight percentages being based on the total weight of the granules or granules.

[0130] The uncoated granules or granules can be characterized by an average sphericity of 0.90 to 1, such as 0.91 to 0.99, or 0.92 to 0.98, determined using a wet dispersion particle shape method or using dynamic image analysis. The uncoated granules or granules can be characterized by an average sphericity of, 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.

[0131] Uncoated granules are solid and characterized by a substantially homogeneous composition throughout the granule.

[0132] The uncoated granules provided by the present disclosure can be characterized by a sphericity of 0.90 to 1, for example, 0.91 to 0.99, or 0.92 to 0.98, where the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The granules provided by the present disclosure can be characterized by an average sphericity of, 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 granules provided by the present disclosure can include a plurality of granules characterized by an average sphericity of, 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.

[0133] The uncoated granules provided by the present disclosure are solid and characterized by a substantially homogeneous composition throughout the granule.

[0134] 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.

[0135] The uncoated granules can have a bulk density of, for example, 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. The granules can have a bulk density of, for example, 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.

[0136] Bulk density can be determined using a bulk density cylinder.

[0137] The uncoated granules provided by the present disclosure have a smooth surface. A smooth granule surface facilitates the ability to coat the granules with a thin, continuous coating having a substantially uniform thickness. The quality of the coating can be important for controlled-release formulations. For example, a rough and / or porous surface tends to require a significantly greater amount of coating to achieve a release profile comparable to that of a smooth surface. In addition, coating a rough and / or porous surface can result in different dissolution or release profiles.

[0138] The uncoated granules provided by the present disclosure can be characterized, upon drying, by a loss on drying (LOD) of, for example, 0.05% to 1.5%, 0.1% to 1.4%, 0.2% to 1.2%, 0.2% to 1.3%, 0.3% to 1.2%, 0.7% to 1.1%, 0.92% to 0.98%, 0.93% to 0.97%, or 0.94% to 0.96% by weight, where the weight percentage is based on the total weight of the granule. The granules provided by the present disclosure can be characterized, upon drying, by a loss on drying (LOD) of, for example, less than 1.5%, less than 1.3%, less than 1.1%, less than 0.9%, less than 0.7%, less than 0.5%, or less than 0.1% by weight, where the weight percentage is based on the total weight of the granule. LOD represents the removal of water incorporated into the granules during preparation and after drying of the granulation.

[0139] The LOD is determined by thermogravimetric analysis.

[0140] The uncoated granules provided by the present disclosure can be characterized by a friability value of 0 wt% to 2 wt%, e.g., less than 2 wt%, less than 1.5 wt%, less than 1 wt%, or less than 0.5 wt%, where the weight percentage is based on the total weight of the granules. The granules provided by the present disclosure can be characterized by a friability value of, e.g., 0.1 wt% to 2 wt%, 0.2 wt% to 1.8 wt%, 0.2 wt% to 1.6 wt%, 0.4 wt% to 1.2 wt%, or 0.6 wt% to 1.2 wt%, where the weight percentage is based on the total weight of the granules. Granules with low friability are easier to coat than granules with high friability. Friability is defined as the amount (wt%) of granules having a diameter less than 75 μm produced by subjecting the granules to a sonic sieve operated at an amplitude of 8, corresponding to 3,600 sonic energy pulses per minute, for at least 2 minutes.

[0141] The uncoated granulation provided by the present disclosure can have, for example, a friability of less than 1.02%, where friability is determined using sonic sieving.

[0142] Uncoated granules containing crystalline 4-((L-valyl)oxy)butanoic acid can be prepared using MicroPX® micropelletization technology (Glatt GmbH).

[0143] Uncoated granules containing crystalline 4-((L-valyl)oxy)butanoic acid can be prepared by a combination of dry and wet granulation.

[0144] The crystalline 4-((L-valyl)oxy)butanoic acid can be screened, de-lumped, co-milled, Fitz milled, pin-milled, or jet milled before being added to the dry mixture.

[0145] The crystalline 4-((L-valyl)oxy)butanoic acid can have a size distribution characterized, for example, by a D90 of less than 30 μm, less than 25 μm, less than 20 μm, or less than 15 μm. The active pharmaceutical ingredient can have a size distribution characterized, for example, by a D90 of 10 μm to 30 μm, 11 μm to 25 μm, or 10 μm to 20 μm. The as-crystallized active pharmaceutical ingredient can be jet milled to obtain a suitable particle size distribution.

[0146] The dry mix can be mixed in a bowl for, for example, 0.5 to 5 minutes to obtain a homogenous dry mix.

[0147] Granulating can include (a) granulating the dry mixture to obtain a dry granulation, and (b) adding water to the dry granulation and granulating to obtain a wet granulation.

[0148] The granulation may comprise an immediate release granulation.

[0149] The immediate release granulation can include a plurality of uncoated granules or a plurality of granules that include a seal coating.

[0150] The seal coating can include a water soluble polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any of the water soluble polymers disclosed herein.

[0151] The seal coating may include an antistatic agent such as talc, magnesium stearate, or a combination thereof.

[0152] The seal coating can include, for example, 65% to 95% by weight of water soluble polymer, such as 70% to 90% or 75% to 85% by weight of water soluble polymer, and 5% to 35% by weight of antistatic agent, such as 10% to 30% or 15% to 25% by weight of antistatic agent, the weight percentages being based on the total weight of the seal coating.

[0153] The seal coating can have an average 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.

[0154] An immediate-release granulation comprising a plurality of uncoated or seal-coated granules can comprise, for example, greater than 80% by weight, such as 85% to 95% by weight, of crystalline 4-((L-valyl)oxy)butanoic acid. The immediate-release granulation comprising uncoated or seal-coated granules can completely dissolve in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes, or less than 4 minutes when tested in a USP Type 2 dissolution apparatus at a pH 4.5 aqueous buffer solution, a temperature of 37° C., and a paddle speed of 100 rpm.

[0155] The immediate-release granules can comprise a plurality of coated granules or seal-coated granules having an immediate-release functional coating. The immediate-release granules comprising a plurality of coated granules can comprise more than 80% by weight of crystalline 4-((L-valyl)oxy)butanoic acid. The immediate-release granules comprising coated granules can completely dissolve in, for example, 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 pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 100 rpm. The immediate-release granules comprising coated granules can release more than 80% of the crystalline 4-((L-valyl)oxy)butanoic acid in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes when tested in a USP Type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 100 rpm. Coated immediate release granules can include a coating comprising a water soluble polymer such as, for example, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. Coated immediate release granules can include a coating comprising an antistatic agent such as talc, magnesium stearate, or silicon dioxide.

[0156] The modified release granules can include a plurality of granules coated with a functional coating. The functional coating can 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 can be configured, for example, to release the crystalline 4-((L-valyl)oxy)butanoic acid from the coated granules over a intended period of time after ingestion and / or within an intended region of the gastrointestinal tract.

[0157] The modified release granules can include uncoated granules containing crystalline 4-((L-valyl)oxy)butanoic acid with one or more functional coatings surrounding the uncoated granules.

[0158] Each of the one or more functional coatings can independently have an average thickness of, for example, 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 an average thickness of, for example, 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.

[0159] The coated granules or coated granulate can contain, for example, more than 50 wt. % crystalline 4-((L-valyl)oxy)butanoic acid, more than 55 wt. %, more than 60 wt. %, more than 70 wt. %, more than 70 wt. %, more than 80 wt. %, or more than 85 wt. % crystalline 4-((L-valyl)oxy)butanoic acid, where the weight percent is based on the total weight of the coated granules or coated granulate.

[0160] The coated granule, or coated granulation comprising a plurality of coated granules, can comprise, for example, 50% to 90% by weight of crystalline 4-((L-valyl)oxy)butanoic 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)butanoic acid, where the weight percentages are based on the total weight of the coated granule or coated granulation.

[0161] The coated granules or coated granules can contain, for example, less than 50 wt. % of the functional coating, less than 40 wt. % of the functional coating, less than 30 wt. % of the functional coating, less than 20 wt. % of the functional coating, or less than 10 wt. % of the functional coating, where the weight % is based on the total weight of the coated granules or coated granules. The coated granules or coated granules can contain, for example, 10 wt. % to 50 wt. % of the functional coating, 10 wt. % to 45 wt. % of the functional coating, or 15 wt. % to 40 wt. % of the functional coating, or 15 wt. % to 35 wt. % of the functional coating, where the weight % is based on the total weight of the coated granules. The coated granules containing crystalline 4-((L-valyl)oxy)butanoic acid can have a thick coating, which reduces the release rate of the crystalline 4-((L-valyl)oxy)butanoic acid and / or increases the storage stability of the crystalline 4-((L-valyl)oxy)butanoic acid by minimizing or preventing moisture ingress.

[0162] The functional coating can include a time-release coating that releases the crystalline 4-((L-valyl)oxy)butanoic acid over time in an aqueous environment. The release of the crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by a zero-order release profile.

[0163] The functional coating can include a matrix polymer, or a combination of matrix polymers. The matrix polymer and / or pore-forming polymer combination can be selected to provide a desired release profile of the crystalline 4-((L-valyl)oxy)butanoic acid in the gastrointestinal tract.

[0164] The functional coating can include, for example, 55% to 95% by weight of matrix polymer, 60% to 90% by weight, 65% to 90% by weight, 70% to 85% by weight, or 75% to 85% by weight of matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0165] The functional coating can include a matrix polymer, or a combination of matrix polymers, which can be selected to provide a desired release profile of 4-((L-valyl)oxy)butanoic acid in the gastrointestinal tract.

[0166] The functional coating can include, for example, 55% to 95% by weight of matrix polymer, 60% to 90% by weight, 65% to 90% by weight, 70% to 85% by weight, or 75% to 85% by weight of matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0167] The functional coating can include, for example, less than 95 wt. % 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. % matrix polymer, where the wt. % is based on the total weight of the functional coating.

[0168] The functional coating can include, for example, greater than 50% matrix polymer, greater than 55% by weight, greater than 60% by weight, greater than 65% by weight, greater than 70% by weight, greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, or greater than 90% by weight matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0169] The matrix polymer can include a water insoluble polymer or a combination of water insoluble polymers.

[0170] Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl acetate, polyacrylates, and polymethacrylates.

[0171] The water-insoluble polymer, such as ethyl cellulose, can have an average molecular weight of, for example, 25,000 daltons to 300,000 daltons, eg, 50,000 daltons to 200,000 daltons, 50,000 daltons to 150,000 daltons, or 50,000 daltons to 100,000 daltons.

[0172] A water-insoluble polymer such as ethyl cellulose can have a viscosity of 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, for example, an 80:20 mixture of toluene / ethanol.

[0173] Examples of suitable ethylcellulose polymers include Aqualon® T10 Pharm, N7 Pharm, N10 Pharm, N14 Pharm, N22 Pharm, N50 Pharm, and N100 Pharm polymers available from Ashland. Other examples of suitable ethylcellulose polymers include Ethocel® Standard 7, Standard 10, Standard 14, and Standard 20 polymers available from DuPont.

[0174] The matrix polymer can comprise, for example, 90% to 100% by weight of the water-insoluble polymer, 91% to 99% by weight, 82% to 98% by weight, or 93% to 97% by weight, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can comprise, for example, more than 90% by weight of the water-insoluble polymer, more than 92% by weight, more than 94% by weight, more than 96% by weight, or more than 98% by weight, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can comprise, for example, less than 100% by weight of the water-insoluble polymer, less than 98% by weight, less than 96% by weight, less than 94% by weight, or less than 92% by weight, where the weight percentages are based on the total weight of the matrix polymer.

[0175] The matrix polymer can include a pore-forming polymer. Examples of pore-forming polymers include water-soluble polymers, swelling or expanding polymers such as carbomers, and polymers soluble in gastric juice, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methacrylic acid-methyl methacrylate copolymer, and polyvinyl acetate phthalate. The pore-forming polymer can increase the permeability of the functional coating under intended conditions.

[0176] The matrix polymer can include a water-soluble polymer or a combination of water-soluble polymers.

[0177] Examples of suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, copovidone, and poloxamer.

[0178] Water-soluble polymers such as hydroxypropyl cellulose 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.

[0179] Water-soluble polymers such as hydroxypropyl cellulose can have a viscosity 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, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0180] Examples of suitable hydroxypropyl cellulose polymers include Klucel® HF Pharm, MF Pharm, GF Pharm JF Pharm, LF Pharm, EF Pharm, and ELF Pharm polymers available from Ashland.

[0181] Examples of suitable hydroxypropyl methylcellulose polymers include Pharmacoat® 603, 645, 606, and 615 polymers available from Shin-Etsu Chemical Co.

[0182] The matrix polymer can include, for example, 0% to 15% by weight of a water-soluble polymer such as ethyl cellulose, 0% to 10% by weight, 1% to 8% by weight, or 2% to 6% by weight of a water-soluble polymer, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can include, for example, greater than 0% by weight of a water-soluble polymer such as hydroxypropyl cellulose, or greater than 2% by weight, 4% by weight, 6% by weight, or greater than 8% by weight of a water-soluble polymer, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can include, for example, less than 10% by weight of a water-soluble polymer, less than 8% by weight, less than 6% by weight, less than 4% by weight, or less than 2% by weight of a water-soluble polymer, where the weight percentages are based on the total weight of the matrix polymer.

[0183] The matrix polymer can contain, for example, 90% to 100% by weight of a water-insoluble polymer such as ethyl cellulose and 0% to 10% by weight of a water-soluble polymer such as hydroxypropyl cellulose, 92% to 98% by weight of a water-insoluble polymer and 2% to 8% by weight of a water-soluble polymer, or 94% to 96% by weight of a water-insoluble polymer and 4% to 6% by weight of a water-soluble polymer, where the weight percentages are based on the total weight of the matrix polymer.

[0184] The functional coating can be applied to the granules provided by the present disclosure by any suitable method, such as spraying a solution, suspension, or dispersion of the functional coating onto the granules in a fluidized bed apparatus.

[0185] In addition to the matrix polymer, or combination of matrix polymers, the functional coating can include, for example, a plasticizer, an antistatic agent, an antiblocking agent, a colorant or pigment, a flow promoter, a viscosity modifier, or a combination of any of the foregoing.

[0186] The functional coating can include an antistatic agent or a combination of antistatic agents.

[0187] Antistatic agents are useful to minimize or prevent granule agglomeration during application of the functional coating.

[0188] Examples of suitable antistatic agents include talc (hydrated magnesium silicate), magnesium stearate, and silicon dioxide.

[0189] The functional coating can include, for example, 5 wt % to 25 wt % of the antistatic agent, e.g., 8 wt % to 22 wt %, or 10 wt % to 20 wt % of the antistatic agent, where the weight percent is based on the total weight of the functional coating. The functional coating can include, for example, less than 25 wt % of the antistatic agent, less than 23 wt %, less than 18 wt %, or less than 15 wt % of the antistatic agent, where the weight percent is based on the total weight of the functional coating. The functional coating can include, for example, more than 5 wt % of the antistatic agent, more than 8 wt %, more than 12 wt %, more than 16 wt %, or more than 20 wt % of the antistatic agent, where the weight percent is based on the total weight of the functional coating.

[0190] The functional coatings provided by the present disclosure are free of plasticizers such as dibutyl sebacate, polyethylene glycol, triacetin, triethyl citrate, and the like.

[0191] The functional coating provided by the present disclosure can include, for example, 70% to 95% by weight of a matrix polymer and 5% to 30% by weight of an antistatic agent, where the weight percentages are based on the total weight of the functional coating.

[0192] The functional coating provided by the present disclosure can include, for example, 70% to 90% by weight of a matrix polymer and 10% to 25% by weight of an antistatic agent, the weight percentages being based on the total weight of the functional coating.

[0193] The functional coating provided by the present disclosure can include, for example, 80% to 90% by weight of a matrix polymer and 10% to 12% by weight of an antistatic agent, the weight percentages being based on the total weight of the functional coating.

[0194] In the functional coatings provided by the present disclosure, the matrix polymer can include ethyl cellulose and hydroxypropyl cellulose, and the antistatic agent can include magnesium stearate, or hydrated magnesium silicate, or a combination thereof.

[0195] A functional coating, such as a modified release coating of the present disclosure, 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 methyl cellulose, and 11% to 22% by weight of an antistatic agent, such as magnesium stearate or hydrated magnesium silicate, where the weight percentages are based on the total weight of the functional coating. A functional coating, such as a modified release coating of the present disclosure, 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 methyl cellulose, and 13% to 20% by weight of an antistatic agent, such as magnesium stearate or hydrated magnesium silicate, where the weight percentages are based on the total weight of the functional coating. A functional coating, such as a modified release coating of the present disclosure, can include, for example, 76% to 88% by weight of a water-insoluble polymer, such as ethyl cellulose, 1% to 3.0% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose, and 14% to 18% by weight of an antistatic agent, such as magnesium stearate or hydrated magnesium silicate, where the weight percentages are based on the total weight of the functional coating.

[0196] The modified-release granules or granules provided by the present disclosure can include, for example, a core and a modified-release coating surrounding the core. The core can include, for example, 85% to 95% by weight of crystalline 4-((L-valyl)oxy)butanoic acid, 1% to 9%, such as 3% to 7%, by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, and 1% to 9%, such as 3% to 7%, by weight of an antistatic agent such as magnesium stearate or magnesium silicate hydrate, where the weight percentages are based on the total weight of the core. The modified-release coating surrounding the core can 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 hydroxypropylcellulose, and 11% to 21%, such as 14% to 18%, by weight of an antistatic agent such as magnesium stearate or magnesium silicate hydrate, where the weight percentages are based on the total weight of the modified-release coating.

[0197] The modified release granulations provided by the present disclosure can be configured to provide a single nighttime dose, a once-daily dose (QD), a twice-daily dose (BID), a three-times-daily dose (TID), or a four-times-daily dose (QID). For example, the modified release granulations can release substantially 100% of the 4-((L-valyl)oxy)butanoic acid over a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0198] The coated granules provided by the present disclosure can have a moisture 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.%, where the weight percent is based on the total weight of the coated granule.

[0199] The coated granules provided by the present disclosure can have a moisture content of, for example, 0.1 wt % to 2 wt %, 0.1 wt % to 1 wt %, or 0.2 wt % to 0.6 wt %, where the weight percentage is based on the total weight of the coated granule.

[0200] The coated pharmaceutical granulation 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.

[0201] The coated pharmaceutical granules can 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.

[0202] Bulk density can be determined using a bulk density cylinder.

[0203] The functional coating provided by the present disclosure can be coated onto the granulation using any suitable equipment and process. Examples of suitable coating methods include the Wurster fluidized bed film coating process, the compression coating process, and the phase inversion process.

[0204] The functional coating can be applied to uncoated granulation or to granulation that includes a seal coating provided by the present disclosure.

[0205] Examples of coating compositions are provided in the Experimental Examples. Coating composition refers to a composition that is applied to uncoated or seal-coated granulation to provide a coated granulation.

[0206] The functional coating composition can comprise more than 70 wt%, more than 75 wt%, more than 80 wt%, more than 85 wt%, or more than 90 wt% of a non-aqueous solvent, such as ethanol or acetone, where the weight percent is based on the total weight of the functional coating solution / suspension composition used to coat the granules.

[0207] The functional coating composition can include, for example, less than 20 wt. % water, less than 15 wt. % water, less than 10 wt. % water, or less than 5 wt. % water, where the wt. % is based on the functional coating solution / suspension composition used to coat the granules.

[0208] For highly water-soluble and hygroscopic pharmacologically active ingredients, such as 4-((L-valyl)oxy)butanoic acid, it may be useful to minimize the amount of water in the functional coating composition. Reducing the level of water in the functional coating solution / suspension composition can generate static electricity, which can cause problems in the coating process.

[0209] The functional coating solution / suspension composition can include, 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%, where the weight percentage is based on the functional coating solution / suspension composition.

[0210] The functional coating composition can include, 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 %, where the wt % is based on the functional coating composition.

[0211] Examples of coating process conditions using a Wurster column inserted into a fluidized bed coating apparatus are provided in the Experimental Examples.

[0212] The pharmaceutical composition provided by the present disclosure can include a combination of immediate-release granules and modified-release granules. For example, the pharmaceutical composition can include 4-((L-valyl)oxy)butanoic acid as the immediate-release granules and 4-((L-valyl)oxy)butanoic acid as the modified-release granules in a weight percent ratio of 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:2 to 1:3.

[0213] The pharmaceutical compositions provided by the present disclosure may comprise 17% to 37% by weight of immediate release granules, 20% to 35% by weight, 23% to 32% by weight, or 25% to 29% by weight of an immediate release composition, where the weight percentages are based on the total weight of the immediate release granules and the modified release granules.The pharmaceutical compositions provided by the present disclosure may comprise 63% to 83% by weight of modified release granules, 65% to 81% by weight, 68% to 78% by weight, or 71% to 75% by weight of a modified release composition, where the weight percentages are based on the total weight of the immediate release granules and the modified release granules.

[0214] In the pharmaceutical compositions provided by the present disclosure, 21% to 41% by weight of the 4-((L-valyl)oxy)butanoic acid may be present in the immediate release component, which may be 24% to 38%, 27% to 35%, or 29% to 32% by weight, where wt% is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition. In the pharmaceutical compositions provided by the present disclosure, 59% to 79% by weight of the 4-((L-valyl)oxy)butanoic acid may be present in the modified release component, which may be 62% to 76%, 65% to 73%, or 68% to 62% by weight, where wt% is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0215] The pharmaceutical compositions provided by the present disclosure can include the coated granules provided by the present disclosure.

[0216] The pharmaceutical composition can comprise any suitable dosage form for oral administration.

[0217] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions, and suspensions.

[0218] Oral dosage forms provided by the present disclosure can contain, for example, 0.1 grams to 20 grams of 4-((L-valyl)oxy)butanoic acid, 0.1 grams to 15 grams, 0.1 grams to 12 grams, 0.1 grams to 10 grams, 0.2 grams to 8 grams, 0.5 grams to 5 grams, 1 gram to 4.5 grams, or 1.5 grams to 4 grams of 4-((L-valyl)oxy)butanoic acid. Oral dosage forms can contain, for example, more than 0.5 grams, more than 1 gram, more than 2 grams, more than 3 grams, more than 4 grams, more than 6 grams, more than 8 grams, more than 10 grams, more than 14 grams, or more than 18 grams of 4-((L-valyl)oxy)butanoic acid.

[0219] Oral compositions provided by the present disclosure can include oral suspensions of coated granules having a modified release functional coating provided by the present disclosure. Oral compositions can include modified release granules and immediate release granules provided by the present disclosure.

[0220] Oral compositions can include a combination of immediate release and modified release granulations provided by the present disclosure.

[0221] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a period of time.

[0222] For example, oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a 3 hour, 6 hour, 8 hour, or 10 hour period.

[0223] Oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a period of 4 to 12 hours, 4 to 10 hours, or 4 to 8 hours.

[0224] Oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid for a period of 1 hour to 12 hours after oral administration, 2 hours to 10 hours after oral administration, or 4 hours to 8 hours after oral administration.

[0225] The oral compositions provided by the present disclosure can be once-nightly compositions, in which a patient is administered a dose of 4-((L-valyl)oxy)butanoic acid before bed and allowed to sleep through the night, such as for 6 or 8 hours, without receiving a second dose during the night.

[0226] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient.

[0227] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral composition.

[0228] The oral compositions provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid of 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.

[0229] The oral compositions provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid 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.

[0230] The oral compositions provided by the present disclosure may provide a therapeutically effective amount of C of gamma-hydroxybutyrate in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral composition. 最大 Against C 最小 The ratio can be provided from less than 3 or less than 2.

[0231] Oral compositions provided by the present disclosure can include a gamma-hydroxybutyric acid derivative of formula (2), 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-hydroxybutyric acid.

[0232] The pharmaceutical compositions provided by the present disclosure 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 an immediate-release component and a modified-release component suitable for administration to a patient, as well as instructions for administering the pharmaceutical composition to a patient. The kit can be used, for example, to treat sleep disorders. The kit can 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.

[0233] Oral compositions provided by the present disclosure can be provided, for example, as sachets containing the coated granules provided by the present disclosure. The sachets can be provided with different doses of 4-((L-valyl)oxy)butanoic acid, for example, 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 of 4-((L-valyl)oxy)butanoic acid. The coated granules can be combined, for example, with water, to provide an orally ingestible dosage form.

[0234] Oral dosage forms containing crystalline 4-((L-valyl)oxy)butanoic acid can include an immediate release component and a modified release component.

[0235] For example, the immediate release component can comprise a solution containing 4-((L-valyl)oxy)butanoic acid or immediate release granules containing 4-((L-valyl)oxy)butanoic acid.

[0236] For example, the modified release component can include modified release granules that include crystalline 4-((L-valyl)oxy)butanoic acid.

[0237] The combined release oral dosage form can include modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid suspended in a solution comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0238] The oral dosage form can comprise granules. For example, the oral dosage form can comprise immediate-release granules and modified-release granules. For example, the oral dosage form can include a suspension comprising crystalline 4-((L-valyl)oxy)butanoic acid. The oral dosage form can comprise a suspension of immediate-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid and modified-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid. The oral dosage form can comprise crystalline 4-((L-valyl)oxy)butanoic acid dissolved in a solution, such as an aqueous solution, and modified-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid suspended in the solution.

[0239] Pharmaceutical compositions and dosage forms provided by the present disclosure can include any suitable excipients, salts, acids, pH adjusting, adjusting or buffering compounds or agents, flavorings, solutions, solvents, dispersions, glycerol, glycols, oils, antibacterial and antifungal agents, antibiotics and antihistamines, binders, disintegrants, lubricants, sweeteners, or any other suitable additives or ingredients.

[0240] Examples of suitable oral formulations and oral dosage forms are disclosed in U.S. Patent Application Publication No. 2021 / 0393537, U.S. Patent No. 11,304,906, U.S. Patent Application Publication No. 2022 / 0023247, U.S. Patent No. 11,395,801, and U.S. Patent No. 11,510,892, each of which is incorporated by reference in its entirety.

[0241] The oral formulation may include a combination of immediate release granulations and modified release granulations.

[0242] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient over a period of time, for example, 3 hours, 6 hours, 8 hours, or 10 hours.

[0243] Oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid over a period of 4 to 12 hours, 4 to 10 hours, or 4 to 8 hours.

[0244] Oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid over a period of, for example, 1 hour to 12 hours after oral administration, 2 hours to 10 hours, or 4 hours to 8 hours after oral administration.

[0245] The oral formulations provided by the present disclosure can be once-a-nightly formulations, in which a patient is administered a dose of crystalline 4-((L-valyl)oxy)butanoic acid and / or gamma-hydroxybutyric acid as a prodrug provided by the present disclosure before going to bed and is allowed to sleep through the night, such as for 6 or 8 hours, without administering a second dose during the night.

[0246] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient. The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral formulation.

[0247] The oral formulations provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid of, for example, 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.

[0248] The oral formulations provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid of, for example, 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.

[0249] The oral formulations provided by the present disclosure may provide a therapeutically effective amount of C of gamma-hydroxybutyrate in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral formulation. 最大 Against C 最小 The ratio can be provided from, for example, less than 3 or less than 2.

[0250] Oral formulations provided by the present disclosure can contain crystalline 4-((L-valyl)oxy)butanoic acid, for example, 0.5 g equivalents of gamma-hydroxybutyric acid, 1 g equivalents, 2 g equivalents, 3 g equivalents, 4 g equivalents, 5 g equivalents, 6 g equivalents, 7 g equivalents, 8 g equivalents, 9 g equivalents, 10 g equivalents, 11 g equivalents, or 12 g equivalents of gamma-hydroxybutyric acid. Oral formulations provided by the present disclosure can contain crystalline 4-((L-valyl)oxy)butanoic acid, for example, 0.5 g equivalents to 12 g equivalents of gamma-hydroxybutyric acid, 1 g equivalents to 12 g equivalents, 2 g equivalents to 12 g equivalents, 3 g equivalents to 11 g equivalents, 4 g equivalents to 10 g equivalents, or 5 g equivalents to 9 g equivalents of gamma-hydroxybutyric acid. Oral formulations provided by the present disclosure can include, for example, more than 0.5 g equivalents of gamma-hydroxybutyric acid, more than 1 g equivalents, more than 3 g equivalents, more than 5 g equivalents, more than 7 g equivalents, more than 9 g equivalents, or more than 11 g equivalents of gamma-hydroxybutyric acid.

[0251] The oral formulations provided by the present disclosure can include suspensions, such as aqueous suspensions, of immediate-release and controlled-release granules containing crystalline 4-((L-valyl)oxy)butanoic acid. The core of the granules can contain more than 90% by weight, such as more than 94% by weight, or more than 96% by weight, of crystalline 4-((L-valyl)oxy)butanoic acid, where the weight percent is based on the total weight of the core of the granule.

[0252] Oral formulations provided by the present disclosure can be provided as sachets or packages that include an immediate release component, such as immediate release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid, and a modified release component, such as modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid. The sachets or packages can be provided in different dose equivalents of gamma-hydroxybutyric acid, for example, 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 equivalents of gamma-hydroxybutyric acid.

[0253] Oral dosage forms such as coated granules, including immediate release granules and modified release granules, can be combined with, for example, water to provide an orally ingestible dosage form.

[0254] Crystalline 4-((L-valyl)oxy)butanoic 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 comprising crystalline 4-((L-valyl)oxy)butanoic 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 a sleep disorder. The kit can include crystalline 4-((L-valyl)oxy)butanoic acid, a pharmaceutically acceptable vehicle for administering the crystalline 4-((L-valyl)oxy)butanoic acid, and instructions for administering the crystalline 4-((L-valyl)oxy)butanoic acid to a patient.

[0255] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0256] The instructions supplied with the kit may be printed and / or supplied as, for example, an electronically readable medium, video cassette, audio tape, flash memory device, or may be accessible on an internet website or distributed as an electronic communication to the patient and / or healthcare provider.

[0257] Crystalline 4-((L-valyl)oxy)butanoic acid can be metabolized in the patient's systemic circulation to provide gamma-hydroxybutyric acid.

[0258] Methods provided by the present disclosure include providing a therapeutically effective amount of gamma-hydroxybutyric acid into the systemic circulation of a patient to treat a disease or disorder or a symptom of a disease or disorder in the patient, comprising administering crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof to the patient.

[0259] A suitable dosage of crystalline 4-((L-valyl)oxy)butanoic acid can provide, for example, a dosage of 1 gram equivalent to 12 gram equivalents of gamma-hydroxybutyric acid, e.g., 1 gram equivalent to 10 gram equivalents, 2 gram equivalents to 9 gram equivalents, 3 gram equivalents to 8 gram equivalents, or 4 gram equivalents to 7 gram equivalents of gamma-hydroxybutyric acid.

[0260] However, it will be understood that the specific dosage level and frequency of administration for a particular patient will vary and will depend upon a variety of factors including metabolic stability and duration of action, age, body weight, general health, sex, diet, method and time of administration, rate of excretion, drug combination, severity of the particular condition, the host being treated, etc.

[0261] When initiating treatment with crystalline 4-((L-valyl)oxy)butanoic acid, titration to the appropriate plasma concentration can facilitate successful outcomes and avoid adverse effects. For example, the dose can be divided into two 2.25 g doses, one at bedtime and the other 2.5 to 4 hours later, equivalent to 4.5 g of gamma-hydroxybutyrate. The starting dose can be decreased by 1.5 g / day (0.75 g per dose) to 3.0 g / day or increased by 1.5 g / day (0.75 g per dose) to 9.0 g / day. Although a single dose can provide a sufficient 8 hours of sleep, very little gamma-hydroxybutyrate remains in the patient's plasma after 8 hours.

[0262] Pharmaceutical compositions provided by the present disclosure can be configured to provide single nighttime dosing, once-daily dosing (QD), twice-daily dosing (BID), three-times-daily dosing (TID), or four-times-daily dosing (QID). For example, a pharmaceutical composition including a modified-release granulation can release substantially 100% of the crystalline 4-((L-valyl)oxy)butanoic acid over a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0263] Crystalline 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid.

[0264] Crystalline 4-((L-valyl)oxy)butanoic acid can be used to treat any disease or disorder known to be treated by gamma-hydroxybutyric acid or determined to be treated by gamma-hydroxybutyric acid.

[0265] For example, crystalline 4-((L-valyl)oxy)butanoic 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.

[0266] Crystalline 4-((L-valyl)oxy)butanoic acid can be used to treat REM sleep behavior disorder, convulsive dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, symptoms of Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety.

[0267] Crystalline 4-((L-valyl)oxy)butanoic 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.

[0268] Crystalline 4-((L-valyl)oxy)butanoic acid and pharmaceutical compositions thereof can be used to treat sleep disorders such as apnea, sleep time disorders, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucinations, sleep arousals, insomnia, and nocturnal myoclonus.

[0269] Crystalline 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof can be used to treat a disease selected from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, symptoms of Parkinson's disease, neurodegenerative diseases, sleep disturbance syndromes, fatigue, improvement of nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal / 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 hemiplegic alternation syndrome, sedative abuse, and binge eating disorder.

[0270] For a particular treatment method, the effectiveness of the treatment can be measured by one or more of the following criteria: an increase in mean sleep latency as determined by the Maintenance of Wakefulness Test (MWT); an improvement in the Clinical Global Impression (CGI) rating of sleepiness; a reduction in the number of cataplexy attacks (NCA) as determined from the cataplexy frequency item on a sleep and symptom diary; a reduction in nocturnal sleep disturbances (DNS), nocturnal disruptive events, or adverse respiratory events as determined by polysomnographic (PSG) measurements of sleep fragmentation; a reduction in excessive daytime sleepiness (EDS) as measured by patient self-report on the Epworth Sleepiness Scale (ESS); a reduction in daytime sleepiness assessed by the Maintenance of Wakefulness Test (MWT) based on electroencephalographic (EEG) measurements of wakefulness; a reduction in PSG transitions from N / 2 to N / 3 and from REM sleep to wakefulness and N1 sleep as determined as described in the AASM Manual of Assessment of Sleep and Concomitant Events; A reduction in the number of awakenings or arousals as determined from PSG, as defined by the American Academy of Neurology (AASM); an improvement in sleep quality as determined using (i) a sleep and symptom diary, (ii) a visual analog scale (VAS) for sleep quality, and / or (iii) a VAS for quality sleep; and a reduction in hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsy patients as measured by a sleep and symptom diary.

[0271] 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 without cataplexy. A diagnosis of narcolepsy (with or without cataplexy) may be confirmed by one or a combination of the following: (i) Overnight polysomnography (PSG) and multiple sleep latency test (MSLT) performed within the past two years. (ii) Complete documentation supporting the diagnosis by PSG and MSLT from a sleep laboratory must be available. (iii) Current symptoms of narcolepsy: current complaints of EDS (Epworth Sleepiness Scale (ESS) >10) within the past three months. (iv) Mean maintenance of wakefulness test (MWT) of less than eight minutes. (v) A mean occurrence of eight cataplexy events per week at baseline in the sleep / cataplexy diary. and / or (vi) cataplexy attacks occurring in the past 3 months with 28 weekly occurrences during the screening period.

[0272] Aspects of the present invention The present invention is further defined by the following aspects.

[0273] Aspect 1. A compound, crystalline 4-((L-valyl)oxy)butanoic acid. [ka]

[0274] Aspect 2. The compound of aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at 8.28°±0.20°, 16.75°±0.20°, and 25.33±0.20°, as determined using Cu-Kα radiation and expressed in terms of 2θ angles.

[0275] Aspect 3. The compound of aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu-Kα radiation: 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°.

[0276] Aspect 4. The compound of aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks, determined using Cu-Kα radiation and expressed in 2θ angles, at least at the following angles: 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°.

[0277] Embodiment 5. The compound of embodiment 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks, determined using Cu-Kα radiation and expressed in 2θ angles, at least at the following angles: 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°.

[0278] Aspect 6. The compound of aspect 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at 8.28°±0.10°, 16.75°±0.10°, and 25.33±0.10°, as determined using Cu-Kα radiation and expressed in terms of 2θ angles.

[0279] Embodiment 7. The compound of embodiment 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu-Kα radiation: 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°.

[0280] Embodiment 8: The compound of embodiment 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu-Kα radiation: 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°.

[0281] Embodiment 9. The compound of embodiment 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks, determined using Cu-Kα radiation and expressed in 2θ angles, at least at the following angles: 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°.

[0282] Embodiment 10 The compound of embodiment 1, wherein said compound is characterized by an XRPD pattern as shown in FIG.

[0283] Aspect 11 The compound of any one of Aspects 1 to 10, wherein the compound has an onset melting temperature of 135° C. to 141° C., and the onset melting temperature is determined by differential scanning calorimetry.

[0284] Aspect 12 The compound of any one of aspects 1 to 10, wherein said compound has an onset melting temperature of 137.7° C.±1.0° C., said onset melting temperature being determined by differential scanning calorimetry.

[0285] Aspect 13 The compound of any one of aspects 1 to 12, wherein said compound has an enthalpy of fusion of 197 J / g to 207 J / g, said enthalpy of fusion being determined by differential scanning calorimetry.

[0286] Aspect 14. The compound of any one of aspects 1 to 12, wherein said compound has an enthalpy of fusion of 202.2 J / g±1.0 J / g, said enthalpy of fusion being determined by differential scanning calorimetry.

[0287] Aspect 15 The compound of any one of aspects 1 to 14, wherein the compound has a melting peak temperature of 138.0° C. to 142.0° C., wherein said melting peak temperature is determined by differential scanning calorimetry.

[0288] Aspect 16. The compound of any one of aspects 1 to 14, wherein said compound has a peak melting temperature of 139.9° C.±2.0° C., wherein said peak melting temperature is determined by differential scanning calorimetry.

[0289] Embodiment 17 The compound of any one of embodiments 1 to 16, wherein the compound exhibits a differential scanning calorimetry curve as shown in FIG.

[0290] Aspect 18. The compound of any one of aspects 1 to 17, wherein the compound has a weight loss of 0.16% to 0.36% by weight 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.

[0291] Aspect 19. The compound of any one of aspects 1 to 17, wherein the compound has a weight loss of 0.26% by weight ±0.20% by weight 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. / minute.

[0292] Aspect 20. The compound of any one of aspects 1 to 19, wherein said compound exhibits a differential calorimetry curve substantially as shown in FIG.

[0293] Aspect 21. The compound of any one of aspects 1 to 20, wherein the compound has a water content of 5.8 mol % to 6.6 mol %, where mol % is based on the total number of moles of 4-((L-valyl)oxy)butanoic acid and water in the crystalline 4-((L-valyl)oxy)butanoic acid, and the water content is determined using Karl Fischer analysis.

[0294] Aspect 22. The compound of any one of aspects 1 to 21, wherein the compound has a water content of less than 5 wt. %, where wt. % is based on the total weight of 4-((L-valyl)oxy)butanoic acid and water in the crystalline 4-((L-valyl)oxy)butanoic acid, and said water content is determined using Karl Fischer analysis.

[0295] Aspect 23. The compound of any one of aspects 1 to 22, wherein the compound absorbs less than 2% by weight of water under conditions of 25° C. / 60% RH for 36 months.

[0296] Aspect 24. The compound of any one of aspects 1 to 23, wherein the compound has an impurity content of less than 1% by weight under conditions of 25° C. / 60% RH for 36 months.

[0297] 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, where wt. % is based on the total weight of the compound, water, and impurities, and the water content is determined using Karl Fischer analysis and the impurity content is determined using high pressure liquid chromatography.

[0298] Aspect 26. The compound of any one of aspects 1 to 25, wherein the unmilled compound has a particle size distribution characterized by a D10 of 7 μm to 17 μm, a D50 of 29 μm to 39 μm, and a D90 of 67 μm to 75 μm, wherein the particle sizes are determined by sieve analysis or laser diffraction.

[0299] Aspect 27. The compound of any one of aspects 1 to 26, wherein the unmilled compound has a particle size distribution characterized by D[4,3] being from 35 μm to 41 μm, such as from 36 μm to 40 μm or from 37 μm to 39 μm, and the particle size being determined by sieve analysis or laser diffraction.

[0300] Aspect 28. The compound of any one of aspects 1 to 27, wherein the unmilled compound has a uniformity of 0.45 to 0.65, such as 0.50 to 0.60, wherein the uniformity is determined using laser diffraction.

[0301] Aspect 29: The unground compound is 280 ml 2 / kg~300m 2 / kg, etc., 270m 2 / kg~310m 2 29. The compound of any one of embodiments 1 to 28, wherein the compound has a surface area of ​​1 / kg / kg, the surface area being determined using laser diffraction.

[0302] Aspect 30. The compound of any one of aspects 1 to 29, wherein the unmilled compound has a bulk density of from 0.15 g / mL to 0.25 g / mL, e.g., from 0.18 g / mL to 0.22 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

[0303] Aspect 31. The compound of any one of aspects 1 to 30, wherein the unmilled compound has a Hausner ratio, e.g., of 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.

[0304] Aspect 32. The compound of any one of aspects 1 to 31, wherein the milled compound has a particle size distribution characterized by a D10 of from 1 μm to 5 μm, a D50 of from 4 μm to 8 μm, and a D90 of from 10 μm to 14 μm, wherein the particle sizes are determined by sieve analysis or laser diffraction.

[0305] Aspect 33. The compound of any one of aspects 1 to 32, wherein the milled compound has a particle size distribution characterized by D[4,3] being from 12 μm to 22 μm, such as from 14 μm to 20 μm or from 16 μm to 18 μm, and the particle size is determined by sieve analysis or laser diffraction.

[0306] Aspect 34. The compound of any one of aspects 1 to 33, wherein the milled compound has a uniformity of 0.2 to 0.6, such as 0.30 to 0.50, wherein the uniformity is determined by laser diffraction.

[0307] Aspect 35: The milled compound is 450 ml 2 / kg~610m 2 / kg or 470m 2 / kg~490m 2 / kg, etc., 430m 2 / kg~630m 2 35. The compound of any one of embodiments 1 to 34, wherein the compound has a surface area of ​​1 / kg / kg, the surface area being determined using laser diffraction.

[0308] Aspect 36. The compound of any one of aspects 1 to 35, wherein the milled compound has a bulk density of from 0.10 g / mL to 0.14 g / mL, e.g., from 0.11 g / mL to 0.13 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

[0309] Aspect 37. The compound of any one of aspects 1 to 36, wherein the milled compound has a Hausner ratio, e.g., of 1.6 to 1.8 or 1.65 to 1.75, wherein the Hausner ratio is determined according to USP 1174.

[0310] Aspect 38. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 37.

[0311] Aspect 39: The pharmaceutical composition of claim 43, wherein said pharmaceutical composition comprises a therapeutically effective amount of said compound to treat a disorder in a patient, said disorder being selected from narcolepsy, cataplexy, cataplexy associated with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative disorders, sleep disturbance syndromes, fatigue, improvement of nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, and chronic fatigue syndrome.

[0312] Aspect 40. The pharmaceutical composition of any one of aspects 38 to 39, wherein the pharmaceutical composition comprises an oral formulation.

[0313] Aspect 41 The pharmaceutical composition of any one of aspects 38 to 40, wherein the pharmaceutical composition comprises between 1 gram equivalent and 10 gram equivalents of gamma-hydroxybutyric acid.

[0314] Aspect 42 The pharmaceutical composition of any one of aspects 38 to 41, wherein the pharmaceutical composition comprises between 1 gram and 20 grams of crystalline 4-((L-valyl)oxy)butanoic acid.

[0315] Aspect 43. The pharmaceutical composition of any one of aspects 38 to 42, wherein the pharmaceutical composition comprises an immediate release component and a modified release component.

[0316] Aspect 44. The pharmaceutical composition of aspect 43, wherein the immediate release component comprises a solution comprising 4-((L-valyl)oxy)butanoic acid.

[0317] Aspect 45. The pharmaceutical composition of aspect 43, wherein said immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0318] Aspect 46. The pharmaceutical composition of any one of aspects 43 to 45, wherein the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0319] 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.

[0320] Aspect 48. The oral dosage form of aspect 47, wherein the oral dosage form comprises between 1 gram equivalent and 10 gram equivalents of gamma-hydroxybutyric acid.

[0321] Aspect 49. The oral dosage form of aspect 47 or 48, wherein said oral dosage form comprises between 1 gram and 20 grams of crystalline 4-((L-valyl)oxy)butanoic acid.

[0322] Embodiment 50. The oral dosage form of any one of embodiments 47 to 48, wherein the oral dosage form comprises an immediate release component and a modified release component.

[0323] Aspect 51. The oral dosage form of aspect 50, wherein the immediate release component comprises a solution comprising 4-((L-valyl)oxy)butanoic acid.

[0324] Aspect 52. The oral dosage form of aspect 50, wherein the immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0325] Aspect 53. The oral dosage form of any one of aspects 50 to 52, wherein the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0326] Aspect 54. The oral dosage form of any one of aspects 50 to 52, wherein the oral dosage form comprises modified-release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid suspended in a solution comprising 4-((L-valyl)oxy)butanoic acid.

[0327] 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.

[0328] Embodiment 56 The kit of embodiment 55, wherein said kit comprises an immediate release component comprising crystalline 4-((L-valyl)oxy)butanoic acid and a modified release component comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0329] Aspect 57. The kit of any one of aspects 55 to 56, wherein the immediate release component comprises immediate release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid, and the modified release component comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid.

[0330] Aspect 58. The kit according to any one of aspects 55 to 57, wherein the kit comprises the pharmaceutical composition retained in a sachet.

[0331] Embodiment 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 of any one of embodiments 1 to 37, a pharmaceutical composition of any one of embodiments 38 to 46, or an oral dosage form of any one of embodiments 47 to 54, wherein the disease is treated with gamma-hydroxybutyric acid.

[0332] Embodiment 60. A method of treating a disorder 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 embodiments 1 to 37, or a pharmaceutical composition according to any one of embodiments 38 to 46, or an oral dosage form according to any one of embodiments 47 to 54, wherein the disorder is selected from narcolepsy, cataplexy, cataplexy associated with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, symptoms of Parkinson's disease, neurodegenerative diseases, sleep disturbance syndromes, fatigue, improvement of nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, chronic fatigue syndrome, essential tremor, hemiplegia in patients with infantile hemiplegic alternations, sedative abuse, and binge eating disorder.

[0333] Embodiment 61 A method for 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 embodiments 1 to 37, a pharmaceutical composition according to any one of embodiments 38 to 46, or an oral dosage form according to any one of embodiments 47 to 54.

[0334] Embodiment 62 A method for 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 embodiments 1 to 37, a pharmaceutical composition according to any one of embodiments 38 to 46, or an oral dosage form according to any one of embodiments 47 to 54.

[0335] Embodiment 63 The method of embodiment 62, wherein said disease is cataplexy associated with narcolepsy.

[0336] Embodiment 64: The method of embodiment 62, wherein said disorder is excessive daytime sleepiness associated with narcolepsy.

[0337] Aspect 65. The method of aspect 62, wherein the disorder is excessive daytime sleepiness in Parkinson's disease patients.

[0338] Aspect 66. The method of aspect 62, wherein the disease is chronic fatigue in Parkinson's disease patients.

[0339] Embodiment 67 A method of treating a symptom 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, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of embodiments 1 to 37, a pharmaceutical composition according to any one of embodiments 38 to 46, or an oral dosage form according to any one of embodiments 47 to 54.

[0340] Embodiment 68. A method for treating REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, symptoms of Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of embodiments 1 to 37, a pharmaceutical composition according to any one of embodiments 38 to 46, or an oral dosage form according to any one of embodiments 47 to 54.

[0341] Aspect 69. A method for treating symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety, 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.

[0342] Embodiment 70. The method of any one of embodiments 59 to 69, wherein the administering comprises oral administration.

[0343] Embodiment 71 The method of any one of embodiments 59 to 70, wherein administering comprises administering QD.

[0344] Embodiment 72. The method of any one of embodiments 59 to 70, wherein administering comprises administering BID.

[0345] Aspect 73: A method for preparing a compound according to any one of aspects 1 to 37, comprising the steps of: (i) dissolving 4-((L-valyl)oxy)butanoic acid in a first solvent to obtain a solution; (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butanoic acid.

[0346] Aspect 74. The method of 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, isopentanol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, ethyl ether, or a combination of any of the foregoing.

[0347] Embodiment 75 The method of any one of embodiments 73 to 74, wherein dissolving comprises dissolving in the first solvent at a temperature between 60°C and 90°C.

[0348] Embodiment 76 The method of any one of embodiments 73 to 75, comprising adding a second solvent to the solution after dissolving to form the solution.

[0349] Aspect 77 The method of 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.

[0350] Embodiment 78 The method of any one of embodiments 73 to 77, wherein crystallizing comprises heating the solution to a temperature of 60° C. to 90° C. for 0.5 hours to 2 hours.

[0351] Embodiment 79. The method of any one of embodiments 73 to 78, wherein crystallizing comprises cooling the solution to a temperature of 20°C to 25°C.

[0352] Embodiment 80 The method of any one of embodiments 73 to 79, comprising, after crystallizing, recrystallizing the crystalline 4-((L-valyl)oxy)butanoic acid. [Example]

[0353] The following examples describe in detail the methods for preparing, properties of, and methods of using crystalline 4-((L-valyl)oxy)butanoic acid provided by the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the invention.

[0354] Example 1 Synthesis of (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid Step 1: Preparation of (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a). [ka]

[0355] (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 butane-1,4-diol (829 mg, 9.21 mmol) in dichloromethane (DCM) (20 mL). The reaction was stirred at 25 °C for 16 h. The reaction mixture was diluted with saturated aqueous NHCl (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous NaSO, and evaporated. The residue was purified by silica gel flash column chromatography using hexane / ethyl acetate (Hex / EA) = 5:1 to obtain compound (1a) (700 mg, 53%) as a colorless oil. 1 H NMR was performed at 400 MHz using CDC13 as the solvent: δ = 5.07 (d, J = 8.8 Hz, 1 H), 4.16 - 4.11 (m, 3 H), 3.62 (t, J = 6.2 Hz, 2 H), 2.32 (br. s., 1 H), 2.12 - 2.04 (m, 1 H), 1.75 - 1.68 (m, 2 H), 1.62 - 1.56 (m, 2 H), 1.40 (s, 9 H), 0.92 (d, J = 7.2 Hz, 3 H), 0.85 (d, J = 7.2 Hz, 3 H).

[0356] Step 2: Preparation of (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b). [ka]

[0357] To a stirred mixture of (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (1a) (500 mg, 1.73 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) was added Jones reagent in portions at 0 °C. The reaction proceeded at 0 °C for over 1 h, and the progress of the reaction was monitored using thin-layer chromatography (TLC). After completion of the reaction, the reaction was quenched by the dropwise addition of isopropanol, diluted with ethyl acetate (EA) (10 mL), and filtered. The filter cake was washed with EA (5 mL), and the combined filtrate was washed with saturated brine (2 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified on a silica gel flash column with Hex / EA = 10:1-5:1 to give compound (1b) (170 mg, 32%) as a white solid. 1 H NMR was performed at 400 MHz using CDCl3 as the solvent: δ = 5.03 (d, J = 9.2 Hz, 1H), 4.30-4.24 (m, 1H), 4.22-4.13 (m, 2H), 2.46 (t, J = 7.4 Hz, 2H), 2.16-2.08 (m, 1H), 2.06-1.96 (m, 2H), 1.45 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H).

[0358] Step 3: Preparation of (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid. [ka]

[0359] A solution of (S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (1b) (104 mg, 0.34 mmol) in HCl / EA (up to 2 M, 1.5 mL) was stirred at 25° C. for 24 h. The reaction mixture was filtered, and the precipitate was collected, washed with EtO (0.5 mL), and dried in vacuo to give the title compound (50 mg, 71%) as a white solid in the form of the HCl salt. 1 H NMR was performed at 400 MHz using CD3OD as the solvent: δ = 4.33-4.26 (m, 2H), 3.92 (d, J = 4.8 Hz, 1H), 2.42 (t, J = 7.2 Hz, 2H), 2.34-2.25 (m, 11), 2.05-1.94 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H).

[0360] A suspension of the HCl salt (800 mg, 3.3 mmol) in ethanol (4 mL) was stirred at 80° C. for 30 minutes to give 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 the suspension was filtered. The white solid was collected, washed with cold ethanol, and dried in vacuo to give the compound (510 mg, 75%) as the free base. 1 H NMR was performed at 400 MHz using d6-DMSO as the solvent: δ = 4.10-3.99 (m, 2H), 3.11 (d, J = 5.2 Hz, 1H), 2.29 (t, J = 7.4 Hz, 2H), 1.90-1.74 (m, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H).

[0361] Example 2 Alternative synthesis of (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid Step 1: Preparation of benzyl 4-hydroxybutanoate (2a) [ka]

[0362] Sodium hydroxide (1.0 equiv.) was dissolved in methanol (5 volumes) and stirred while maintaining the temperature below 40°C. The reaction mixture was cooled to room temperature, and butyrolactone (1.0 equiv.) was added while maintaining the temperature below 30°C. The reaction mixture was stirred for 5-6 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 equiv.) 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 organics were washed with water and concentrated in vacuo while coevaporating with dichloromethane to give benzyl 4-hydroxybutanoate (2a) in 69.5% yield.

[0363] Step 2: Preparation of 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valinate (2b) [ka]

[0364] Benzyl 4-hydroxybutanoate (2a) (0.95 equiv.) was dissolved in dichloromethane (2.5 vol.). CBz-L-valine (1.00 equiv.) and 4-dimethylaminopyridine (DMAP) (0.20 equiv.) were added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.20 equiv.) while maintaining the reaction mixture 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 in silica gel (50% wt.). The silica plug was washed with dichloromethane and the combined organics were concentrated in vacuo while coevaporating with methanol to give 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valinate (2b) in 76.7% yield.

[0365] Step 3: Preparation of 4-((L-valyl)oxy)butanoic acid [ka]

[0366] 4-(Benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valinate (2b) (1.0 equiv.) was dissolved in methanol (5 volumes) and Pd / C (10% Pd, 15% wt) was added under a nitrogen atmosphere. The nitrogen atmosphere was replaced with a continuous stream of H2, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite (50% wt), activated carbon (25% wt) was added, and the mixture was stirred for 18 hours. The reaction mixture was filtered through Celite (50% wt), and the filter cake was rinsed with methanol. The reaction mixture was concentrated in vacuo while coevaporating with methanol. The residue was redissolved in tert-butyl methyl ether and stirred at room temperature for 30 minutes. An additional tert-butyl methyl ether (3 volumes) was added dropwise within 2 hours. The reaction mixture was stirred for 4 hours and then filtered. The filter cake was dried in vacuo to give 4-((L-valyl)oxy)butanoic acid in 49.6% yield.

[0367] Example 3 Crystallization of 4-((L-valyl)oxy)butanoic acid Approximately 25 mg of 4-((L-valyl)oxy)butanoic acid was weighed into an 8 mL glass vial, and an appropriate amount of water or methanol was added and the solid was dissolved with stirring. After complete dissolution, a certain amount of anti-solvent was slowly added over approximately 30 minutes.

[0368] The solvent is water or methanol, and suitable antisolvents are acetonitrile, isopropanol, acetone, ethyl acetate, methyl tert-butyl ether, 1,4-dioxane, and the like.

[0369] Approximately 50 mg or 100 mg of 4-((L-valyl)oxy)butanoic acid was weighed into a glass vial, and an appropriate amount (80 μL–300 μL) of solvent was added. The vial was then heated to a set temperature while stirring. After reaching the set temperature, the same solvent was slowly added to the suspension until the sample was completely dissolved, or an appropriate amount of anti-solvent was slowly added to the clear solution. The solution was stirred at the set temperature for approximately 30 minutes, after which the solution was slowly cooled to room temperature (20°C–25°C). The solid precipitate was collected by filtration. The solvents used were ethanol, 50:1 ethanol / water, water, methanol, and isopropanol. The anti-solvent, when used, was acetone, ethyl acetate, or methyl tert-butyl ether. The solvent could be methanol, and the anti-solvent could be methyl tert-butyl ether. The volume ratio of methanol to methyl tert-butyl ether was 1:3.

[0370] Example 4 X-ray powder diffraction (XPRD) of crystalline 4-((L-valyl)oxy)butanoic acid The X-ray powder diffraction (XRPD) pattern of crystalline 4-((L-valyl)oxy)butanoic acid was obtained using a Bruker D8 Advance X-ray powder diffractometer. The 2θ position was calibrated against a Panalytical Si standard disk. The X-ray wavelengths were Kα2 / Kα1 (1.540598 A / 1.544425 A), with an intensity ratio of 0.5. The X-ray tube output voltage was set to 40 kV and the current to 40 mA. A 1 / 8° fixed divergence slit was used to obtain a diffraction pattern from 3° to 40° (°2θ) in continuous scan mode with a step size of 0.02° (2θ) and a scan rate of 0.145° / min. The sample was transferred from the sample container to a zero-background XRPD holder and carefully polished to obtain a smooth surface.

[0371] A representative XPRD diffraction pattern of crystalline 4-((L-valyl)oxy)butanoic acid is shown in Figure 1, and the characteristic diffraction peaks are listed in Table 1.

[0372] [Table 1]

[0373] Example 5 Differential scanning calorimetry Differential scanning calorimetry was performed using a TA Instruments Q2000 DSC and calibrated with an indium reference standard. Samples were loaded into crimped aluminum pans. After equilibration at 25 °C, the samples were heated under a nitrogen (N2) atmosphere at a rate of 50 mL / min to a final temperature of 250 °C. The scan rate was 10 °C / min. The DSC curve is shown in Figure 2 and reflects an onset of melting at 137.73 °C and a peak melting temperature of 139.88 °C for crystalline 4-((L-valyl)oxy)butanoic acid.

[0374] Example 6 thermogravimetric analysis Thermogravimetric analysis was performed using a TA Instruments Q500 TGA calibrated with a nickel reference standard. Samples were placed in platinum or aluminum open pans, equilibrated at 35 °C, and then heated at 10 °C / min under a nitrogen (N2) atmosphere (flow rate 60 mL / min) to a final temperature of 200 °C. The TGA curve for the crystals shown in Figure 3 shows a 9.7% weight loss between 125 °C and 150 °C. The weight loss between 30 °C and 125 °C was 0.77%.

[0375] The TGA thermogram showed that the crystalline 4-((L-valyl)oxy)butanoic acid underwent no significant weight loss before melting, indicating that the crystalline form was anhydrous.

[0376] Example 7 Jet mill Crystalline 4-((L-valyl)oxy)butanoic acid was jet-milled to obtain a uniform particle size distribution centered at approximately 8.6 μm. An Alpine 50AS (PDS-PL-JM-01) jet mill (Hosokawa Alpine) was used to prepare the formulation. The injector gas pressure was 4.0 bar, and the milling gas pressure was 3.5 bar. Five grams of crystalline 4-((L-valyl)oxy)butanoic acid was gradually added to the jet mill, and the milled product was collected. The milled product was stored at 2°C to 8°C.

[0377] Example 8 Stability when stored in a sealed container Crystalline 4-((L-valyl)oxy)butanoic acid was packaged in a double low-density polyethylene (LDPE) zipper bag and sealed. The packaged sample was then placed in an outer aluminum foil bag (polyethylene, polyethylene terephthalate three-layer composite) and sealed. The fully packaged sample was placed in the stability testing room for the duration of the sealed storage stability test.

[0378] The sealed storage stability test was carried out under four conditions outside the packaged crystalline 4-((L-valyl)oxy)butanoic acid. 1. Acceleration conditions (40±2℃, 75±5%RH) 2.Mid-term storage conditions (30±2℃, 65±5%RH) 3.Long-term storage conditions (25±2℃, 60±5%RH). Conditions: 4.2-8°C.

[0379] The storage stability of crystalline 4-((L-valyl)oxy)butanoic acid (1) was tested in sealed containers in accordance with ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) document Q1A(R2) "Stability Testing of New Drug Substances and Products." Accordingly, samples were collected at 3 and 6 months. The assay percentage of crystalline 4-((L-valyl)oxy)butanoic acid was determined by electrochemical titration using acetic acid as the solvent and perchloric acid as the titrant. 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; column: Waters Atlantis T3, 4.6 × 150 mm, 3 μm). Samples were analyzed by XRPD analysis (XRPD instrument: Bruker D8 advance). The results of the sealed storage stability of crystalline 4-((L-valyl)oxy)butanoic acid stored under four storage conditions are summarized in Table 2.

[0380] [Table 2]

[0381] The results of sealed storage stability studies showed that crystalline 4-((L-valyl)oxy)butanoic acid was stable for up to 6 months under all sealed storage conditions. The crystalline samples were also chemically stable for up to 6 months under all sealed storage conditions.

[0382] Other testing demonstrated that crystalline 4-((L-valyl)oxy)butanoic acid is stable under sealed storage conditions for 36 months at 25±2°C and 60±5% RH. Stability is defined as samples of crystalline 4-((L-valyl)oxy)butanoic acid absorbing less than 2% water by weight and containing less than 2% absorbed impurities by weight for the specified period under the specified sealed storage conditions.

[0383] Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein, and therefore the present embodiments are illustrative and not limiting, and the claims are not to be limited to the details given herein, but may be modified within the scope and equivalents thereof.

Claims

1. The compound, crystalline 4-((L-valyl)oxy)butanoic acid. 【Chemical 1】

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

3. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu—Kα radiation: 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°.

4. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at at least the following angles 2θ, determined using Cu—Kα radiation: 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°.

5. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks, expressed in 2θ angles, at least at 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°, determined using Cu—Kα radiation.

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

7. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu—Kα radiation: 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°.

8. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu—Kα radiation: 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°.

9. 2. The compound of claim 1, wherein the compound is characterized by an XRPD pattern comprising characteristic diffraction peaks at least at the following angles 2θ, determined using Cu—Kα radiation: 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°.

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

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

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

13. 13. The compound of any one of claims 1 to 12, wherein the compound has an enthalpy of fusion of 197 J / g to 207 J / g, the enthalpy of fusion being determined by differential scanning calorimetry.

14. 13. The compound of any one of claims 1 to 12, wherein the compound has an enthalpy of fusion of 202.2 J / g±1.0 J / g, the enthalpy of fusion being determined by differential scanning calorimetry.

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

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

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

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

19. 18. 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, the weight loss being determined by thermogravimetric analysis at a scan rate of 2°C / min.

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

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

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

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

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

25. 25. The compound of any one of claims 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 at 25°C / 60% RH for 6 months, where wt. % is based on the total weight of the compound, water, and impurities, and the water content is determined using Karl Fischer analysis and the impurity content is determined using high pressure liquid chromatography.

26. 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 from 7 μm to 17 μm, a D50 of from 29 μm to 39 μm, and a D90 of from 67 μm to 75 μm, the particle sizes being determined by sieve analysis or laser diffraction.

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

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

29. The unground compound is 270 m ２ / kg ~ 310m ２ 30. The compound of any one of claims 1 to 28, having a surface area of ​​1 / kg, the surface area being determined using laser diffraction.

30. 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. 31. The compound of any one of claims 1 to 30, wherein the unmilled compound has a Hausner ratio of 1.65 to 1.95, the Hausner ratio being determined in accordance with USP 1174.

32. 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 from 1 μm to 5 μm, a D50 of from 4 μm to 8 μm, and a D90 of from 10 μm to 14 μm, the particle sizes being determined by sieve analysis or laser diffraction.

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

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

35. The crushed compound is 430 m ２ / kg ~ 630m ２ 35. The compound of any one of claims 1 to 34, having a surface area of ​​1 / kg, the surface area being determined by laser diffraction.

36. 36. The compound of any one of claims 1 to 35, wherein the ground 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. 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, the Hausner ratio being determined in accordance with USP 1174.

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

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

40. 40. A granule according to claim 38 or 39, wherein the granule comprises more than 80% by weight of the compound, the weight percentage being based on the total weight of the granule.

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

42. 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 a compound according to any one of claims 1 to 37 or a granulate according to any one of claims 38 to 42.

44. 44. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound to treat a disease in a patient, the disease being 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, improvement of nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal / dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, sleep onset and sleep maintenance disorders, and chronic fatigue syndrome.

45. 45. The pharmaceutical composition of claim 43 or 44, wherein the pharmaceutical composition comprises an oral formulation.

46. 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. 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)butanoic acid.

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

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

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

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

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

54. 54. The oral dosage form of claim 52 or 53, wherein the oral dosage form comprises 1 gram to 20 grams of crystalline 4-((L-valyl)oxy)butanoic acid.

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

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

58. 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)butanoic acid.

59. 57. The oral dosage form of claim 55 or 56, wherein the oral dosage form comprises modified release granules comprising crystalline 4-((L-valyl)oxy)butanoic acid suspended in a solution comprising 4-((L-valyl)oxy)butanoic acid.

60. 52. A kit 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.

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

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

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

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

65. 60. A method of treating a disease in a patient, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 37, a granulate of any one of claims 39 to 42, a pharmaceutical composition of any one of claims 43 to 51, or an oral dosage form of any one of claims 52 to 59 to a patient in need of such treatment, 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, improvement of nighttime sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal / 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 infantile hemiplegic alternation syndrome, sedative abuse, and binge eating disorder.

66. A method for 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 of any one of claims 1 to 37, a granulation of any one of claims 39 to 42, a pharmaceutical composition of any one of claims 43 to 51, or an oral dosage form of any one of claims 52 to 59.

67. 60. A method for 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 of any one of claims 1 to 37, a granulate of any one of claims 39 to 42, a pharmaceutical composition of any one of claims 43 to 51, or an oral dosage form of any one of claims 52 to 59.

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

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

70. 68. The method of claim 67, wherein the disorder is excessive daytime sleepiness in Parkinson's disease patients.

71. 68. The method of claim 67, wherein the disease is chronic fatigue in Parkinson's disease patients.

72. 60. A method for 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, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 37, a granulate of any one of claims 39 to 42, a pharmaceutical composition of any one of claims 43 to 51, or an oral dosage form of any one of claims 52 to 59.

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

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

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

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

77. 76. 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, comprising: (i) dissolving 4-((L-valyl)oxy)butanoic acid in a first solvent to obtain a solution; (ii) crystallizing the solution to obtain crystalline 4-((L-valyl)oxy)butanoic acid.

79. 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, isopentanol, butyl acetate, ethyl formate, methyl acetate, isobutyl acetate, n-heptane, dichloromethane, 1,4-dioxane, cyclohexane, xylene, 4-methyl-2-pentanone, ethyl ether, or any combination of the foregoing.

80. 80. The method of claim 78 or 79, wherein dissolving comprises dissolving in the first solvent at a temperature of from 60°C to 90°C.

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

82. 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 any combination of the foregoing.

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

84. 84. The method of any one of claims 78 to 83, comprising, after crystallizing, recrystallizing the crystalline 4-((L-valyl)oxy)butanoic acid.

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