Pharmaceutical granules containing water-soluble active pharmaceutical ingredients

Abstract

To provide pharmaceutical granulations containing granules with an active pharmaceutical ingredient featuring high water solubility.SOLUTION: A granulation comprises a plurality of granules, where, the granules comprise greater than 95 wt.% of an active pharmaceutical ingredient (API), where wt.% is based on the total weight of the granulation; and the active pharmaceutical ingredient has an aqueous solubility greater than 100 mg / mL.SELECTED DRAWING: Figure 10A

Description

[Technical Field]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 040,780, filed June 18, 2020, which is incorporated by reference in its entirety.

[0002] The present invention relates to a pharmaceutical granulation having granules with a high load of an active pharmaceutical ingredient characterized by high aqueous solubility, the granules having a narrow particle size distribution and a smooth outer surface. [Background technology]

[0003] Certain treatment methods require the administration of high doses of active pharmaceutical ingredients. In order to minimize the amount of pharmaceutical preparation administered to a patient in such treatments, it is desirable for the pharmaceutical composition to contain a high content of active pharmaceutical ingredients and minimize the amount of pharmaceutical excipients.

[0004] Oral controlled release dosage forms can contain granules coated with a coating that provides a desired release profile in the gastrointestinal tract. To facilitate achieving the desired oral controlled release profile, the oral dosage form can include a granulation that includes granules with a controlled release coating.

[0005] To improve the palatability of oral pharmaceutical suspensions, it is desirable that the size of the particles containing the active pharmaceutical ingredient be less than 500 μm.

[0006] Pharmaceutical granulations with high bulk density of active pharmaceutical ingredients (API), particle size less than 500 μm, and surfaces suitable for coating are desired. Summary of the Invention [Means for solving the problem]

[0007] According to the present invention, the granulation comprises a plurality of granules, the granules comprising greater than 95% by weight of an active pharmaceutical ingredient (API), where the weight % is based on the total weight of the granulation, and the active pharmaceutical ingredient has a water solubility greater than 100 mg / mL.

[0008] According to the present invention, the pharmaceutical composition comprises a granulation according to the present invention.

[0009] According to the present invention, a method for preparing a granulation according to the present invention includes mixing an active pharmaceutical ingredient, a binder, and an antistatic agent to form a dry mixture, wet granulating the dry mixture to obtain a wet granulation, wet massing the wet granulation to obtain a wet mass granulation, and drying the wet mass granulation to obtain a granulation. [Brief explanation of the drawings]

[0010] Those skilled in the art will understand that the drawings described herein are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0011] [Figure 1A] 1 shows particle size distributions for pharmaceutical granulations (1) prepared using different wet massing times. [Figure 1B] 1 shows SEM images of pharmaceutical granulation (1) at two different magnifications. [Figure 1C] 1 shows SEM images of pharmaceutical granulation (1) at two different magnifications. [Figure 2A] 1 shows particle size distributions for pharmaceutical granulations (2) prepared using different wet massing times. [Figure 2B] Shown are SEM images of pharmaceutical granulation (2) at two different magnifications. [Figure 2C] Shown are SEM images of pharmaceutical granulation (2) at two different magnifications. [Figure 3A] 1 shows particle size distributions for pharmaceutical granulations (3) prepared using different wet massing times. [Figure 3B] 1 shows SEM images of pharmaceutical granulation (3) at two different magnifications. [Figure 3C]1 shows SEM images of pharmaceutical granulation (3) at two different magnifications. [Figure 4A] 1 shows particle size distributions for pharmaceutical granulations (4) prepared using different wet massing times. [Figure 4B] 1 shows SEM images of pharmaceutical granulation (4) at two different magnifications. [Figure 4C] 1 shows SEM images of pharmaceutical granulation (4) at two different magnifications. [Figure 5A] 1 shows particle size distributions for pharmaceutical granulations (5) prepared using different wet massing times. [Figure 5B] 1 shows SEM images of pharmaceutical granulation (5) at two different magnifications. [Figure 5C] 1 shows SEM images of pharmaceutical granulation (5) at two different magnifications. [Figure 6A] 1 shows particle size distributions for pharmaceutical granulations (6) prepared using different wet massing times. [Figure 6B] 1 shows SEM images of pharmaceutical granulation (6) at two different magnifications. [Figure 6C] 1 shows SEM images of pharmaceutical granulation (6) at two different magnifications. [Figure 7A] 1 shows particle size distributions for pharmaceutical granulations (7) prepared using different wet massing times. [Figure 7B] 1 shows SEM images of pharmaceutical granulation (7) at two different magnifications. [Figure 7C] 1 shows SEM images of pharmaceutical granulation (7) at two different magnifications. [Figure 8A] 1 shows particle size distributions for pharmaceutical granulations (8) prepared using different wet massing times. [Figure 8B] 1 shows SEM images of pharmaceutical granulation (8) at two different magnifications. [Figure 8C] 1 shows SEM images of pharmaceutical granulation (8) at two different magnifications. [Figure 9A] 1 shows particle size distributions for pharmaceutical granulations (9) prepared using different wet massing times. [Figure 9B]1 shows SEM images of pharmaceutical granulation (9) at two different magnifications. [Figure 9C] 1 shows SEM images of pharmaceutical granulation (9) at two different magnifications. [Figure 9D] 1 shows SEM images of pharmaceutical granulation (9) at two different magnifications. [Figure 9E] 1 shows SEM images of pharmaceutical granulation (9) at two different magnifications. [Figure 9F] 1 shows the size distribution of the particles used to form pharmaceutical granulation (9). [Figure 10A] 1 shows particle size distribution of active pharmaceutical ingredients before and after jet milling. [Figure 10B] 1 shows particle size distribution of active pharmaceutical ingredients before and after jet milling. [Figure 11] 1 is a table summarizing the granulation and wet agglomeration conditions for Examples 1-9. [Figure 12] 1 is a table summarizing the properties of the granulated products of Examples 1 to 9. [Figure 13] 1 shows an SEM image of the as-crystallized active pharmaceutical ingredient of Example 13 at 700x magnification. [Figure 14] 1 shows an SEM image of the active pharmaceutical ingredient of Example 13 at 700x magnification after jet milling. [Figure 15] 1 shows the particle size distribution of the as-crystallized active pharmaceutical ingredient described in Example 13. [Figure 16] 1 shows the particle size distribution of the active pharmaceutical ingredient described in Example 13 after jet milling. [Figure 17] 1 shows an SEM image of granules prepared as described in Example 13 at 100x magnification. [Figure 18] 1 shows an SEM image of granules prepared as described in Example 13 at 240x magnification. DETAILED DESCRIPTION OF THE INVENTION

[0012] For purposes of the following detailed description, it should be understood that the embodiments provided by the present disclosure may assume various alternative variations 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.

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

[0014] 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.

[0015] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the active pharmaceutical 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 from may release more than 90%, more than 95%, or more than 98% of the active pharmaceutical 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 active pharmaceutical ingredients that are absorbed into the systemic circulation from the upper gastrointestinal tract.

[0016] "Controlled-release" pharmaceutical compositions include modified-release, delayed-release, sustained-release, and extended-release formulations. These formulations are intended to release an active pharmaceutical ingredient from a pharmaceutical composition at a desired rate and / or time and / or at a specific location or locations in the gastrointestinal tract after oral administration by a patient. 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. More specifically, modified-release (MR) solid oral dosage forms include extended-release (ER) and delayed-release (DR) products. Delayed-release products release the drug all at once rather than immediately after administration. Modified-release formulations may include delayed-release formulations using enteric coatings, site-specific or timed-release formulations, such as for colonic delivery, sustained release, including formulations capable of providing zero-order, first-order, or biphasic release profiles, and programmed release, such as pulsatile release and delayed-release.

[0017] "Alkoxy" refers to the radical -OR where R is alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups include, for example, C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 It may be alkoxy, ethoxy or methoxy.

[0018] "Alkyl" refers to a saturated, branched, or straight-chain monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent alkane. Alkyl groups include, for example, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, or C 1-3 The alkyl group can be methyl, ethyl, n-propyl, iso-propyl, or tert-butyl.

[0019] "Cycloalkyl" refers to a saturated cyclic alkyl radical. Cycloalkyl groups include, for example, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 5-6 Cycloalkyl may be cyclopropyl, cyclopentyl, or cyclohexyl. For example, cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] "Alkoxycarbonyl" refers to the radical -C(=O)-OR, where R is C 1-6 Alkyl, e.g., C 1-4 Alkyl, or C 1-3 For example, R may be selected from methyl, ethyl, n-propyl, iso-propyl, and tert-butyl.

[0021] "Cycloalkoxycarbonyl" refers to the radical -C(=O)-OR where R is C 3-8 Cycloalkyl, e.g., C 4-7 Cycloalkyl or C 4-6 For example, R may be selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] "Patient" refers to a mammal, for example, a human.

[0023] "Pharmaceutically acceptable" refers to that which is listed, approved, or approvable by a regulatory agency of the Federal or State government, or in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0024] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include inorganic acids as well as acid addition salts formed with one or more protonatable functional groups, such as primary, secondary, or tertiary amines, in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can also be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid. Salts may be formed with 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Salts may be formed when one or more acidic protons present in the parent compound are replaced by coordination with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a combination thereof, or an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts may be hydrochlorides. Pharmaceutically acceptable salts may be sodium salts. For compounds with two or more ionizable groups, a pharmaceutically acceptable salt can include one or more counterions, such as a disalt, e.g., a dihydrochloride salt.

[0025] The term "pharmaceutically acceptable salts" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is understood that the specific salt (e.g., hydrochloride salt) is an example of a salt, and that other salts can be formed using techniques known to those skilled in the art. In addition, using techniques generally known in the art, those skilled in the art will be able to convert a pharmaceutically acceptable salt into the corresponding compound, free base, and / or free acid.

[0026] A "prodrug" refers to a derivative of a drug molecule that requires transformation within 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 (defined herein) to the drug via a functional group.

[0027] Bulk density can be determined according to USP 616, Method 1.

[0028] Tapped bulk density can be determined according to USP 616.

[0029] The specific surface area can be determined by laser diffraction.

[0030] The Hausner ratio can be determined according to USP 1174.

[0031] The parameter D90 refers to the point in the size distribution of a sample that contains up to 90% of the total volume of material in the sample. For example, for a D90 of 400 μm, 90% of the sample volume has a size of 400 μm or less, and D50 is the size that contains less than 50% of the total volume of material in the sample. Similarly, D10 refers to the size that contains less than 10% of the total volume of material in the sample. The volume distribution of a sample can be determined by laser diffraction or sieve analysis.

[0032] Next, reference is made to pharmaceutical granules, compositions comprising the pharmaceutical granules, and methods for making the pharmaceutical granules. The disclosed pharmaceutical granules, compositions comprising the pharmaceutical granules, and methods for making the pharmaceutical granules are not intended to limit the scope of the claims. On the contrary, the claims are intended to encompass all alternatives, modifications, and equivalents.

[0033] The granules provided by the present disclosure include a plurality of granules, each granule comprising greater than 95 wt%, e.g., greater than 98 wt%, or greater than 99 wt%, of the active pharmaceutical ingredient, where the weight percent is based on the total weight of the granules, and the granules are characterized by a particle size distribution (D50, median diameter) of, e.g., 150 μm to 400 μm, 150 μm to 350 μm, or 150 to 300 μm. The granules are characterized by a D50 of, e.g., less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, or less than 200 μm.

[0034] The granules can contain a high load of active pharmaceutical ingredient or a combination of high loads of active pharmaceutical ingredients. For example, the granules can contain greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, or greater than 99% by weight of the active pharmaceutical ingredient, where the weight percentage is based on the total weight of the granule. The granules can contain, for example, 95% to 99.5% by weight of the active pharmaceutical ingredient, 96% to 99.5% by weight of the active pharmaceutical ingredient, 96% to 99% by weight, 97% to 99% by weight, or 98% to 99% by weight of the active pharmaceutical ingredient, where the weight percentage is based on the total weight of the granule.

[0035] The granules may contain active pharmaceutical ingredients that have high water solubility.

[0036] For example, the active pharmaceutical ingredient can have an aqueous solubility of greater than 100 mg / mL, greater than 150 mg / mL, greater than 200 mg / mL, greater than 250 mg / mL, greater than 300 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, greater than 500 mg / mL, or greater than 600 mg / mL. The active pharmaceutical ingredient can have an aqueous solubility of, for example, 100 mg / mL to 600 mg / mL, 200 mg / mL to 500 mg / mL, or 250 mg / mL to 450 mg / mL.

[0037] Water solubility is determined by high pressure liquid chromatography (HPLC).

[0038] Examples of active pharmaceutical ingredients with aqueous solubilities greater than 100 mg / mL include acetohydroxamic acid, aliskiren, amifostine, aminocaproic acid, aminolevulinic acid, aminophylline, ascorbic acid, benzethonium, benzphetamine, betasol, bretylium, bromotheophylline, brompheniramine, bronopol, bupropion hydrochloride, folinic acid, captopril, carbamoylcholine, chloral hydrate, cidofovir, citrulline, clavulanic acid, clindamycin, and codeine phosphate. , cycloserine, cysteamine, cytarabine, d-glucose, dinoprost tromethamine, d-serine, dyphylline, edetic acid, emtricitabine, esketamine hydrochloride, arketamine hydrochloride, ethambutol hydrochloride, ferrous bisglycinate, flurazepam, fomepizole, framycetin, gabapentin, gamma-aminobutyric acid, gemifloxacin, gentamicin, gluconic acid, gluconolactone, glucosamine, glutathione, ibandronate, ibutilide, isoniazid, ketorolac, lactitol, Lactose, lactulose, levamisole hydrochloride, levetiracetam, levocarnitine, lisdexamfetamine, mannitol, metformin hydrochloride, methenamine, methimazole, methyl aminolevulinate, migalastat hydrochloride, miglustat, nalmefene hydrochloride, naltrexone hydrochloride, neostigmine bromide, netilmicin, nicotinamide, nicotine, nitrofural, norfloxacin, ornithine, oxycodone, penicillamine, pentoxyverine, phenformin, phenylephrine, furunculosis phenylpropanolamine, pidolic acid, piperazine, piracetam, pregabalin, procarbazine hydrochloride, promethazine hydrochloride, pyridoxine, pyruvic acid, ranitidine hydrochloride, rolitetracycline, ropinirole, scopolamine, selenomethionine, sodium ascorbate, sodium oxybate, terbutaline, thiamine hydrochloride, tobramycin, tranexamic acid, tromethamine salts, valacyclovir, and venlafaxine hydrochloride, or a pharmaceutically acceptable salt of any of the foregoing.

[0039] Active pharmaceutical ingredients with a water solubility greater than 100 mg / mL include salt forms, hydrates, and / or solvates with a water solubility greater than 100 mg / mL, where the parent active pharmaceutical ingredient has a water solubility less than 100 mg / mL.

[0040] The active pharmaceutical ingredient can include gamma-hydroxybutyric acid or a derivative of gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid has the structure of formula (1): [ka]

[0041] Prodrug derivatives of gamma-hydroxybutyric acid have the structure of formula (2): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen and C 1-6 alkyl, R 2 and R 3 each independently represents hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-8 cycloalkoxycarbonyl.

[0042] In the compound of formula (2), R 1 is hydrogen and C 1-3 It may be selected from alkyl.

[0043] In the compound of formula (2), R 1 may be selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl.

[0044] In the compound of formula (2), R 1 can be iso-propyl.

[0045] In the compound of formula (2), R 2 and R3 At least one of 1-3 It may be selected from alkyl.

[0046] In the compound of formula (2), R 2 and R 3 each independently represents hydrogen and C 1-3 It may be selected from alkyl.

[0047] In the compound of formula (2), R 2 and R 3 Each of may be hydrogen.

[0048] In the compound of formula (2), R 1 is hydrogen and C 1-3 alkyl, and R 2 is C 1-6 Alkoxycarbonyl and C 5-6 cycloalkoxycarbonyl.

[0049] In the compound of formula (2), R 2 and R 3 Each of R can be hydrogen; 1 is hydrogen and C 1-3 It may be selected from alkyl.

[0050] In the compound of formula (2), R 2 and R 3 Each of R can be hydrogen; 1 may be selected from methyl, ethyl, n-propyl, and iso-propyl.

[0051] In the compound of formula (2), R 2 and R 3 Each of R can be hydrogen; 1 can be iso-propyl.

[0052] In the compound of formula (2), R 1 The carbon atom to which is attached may be in the (R)-configuration.

[0053] In the compound of formula (2), R 1 The carbon atom to which is attached may be in the (S)-configuration.

[0054] The compound of formula (2) 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, a pharmaceutically acceptable salt of any of the foregoing, and It may be selected from any combination of the foregoing.

[0055] The compound of formula (2) can be 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof: [ka]

[0056] The compound of formula (2) can be 4-(glycyloxy)butanoic acid (2b) or a pharmaceutically acceptable salt thereof: [ka]

[0057] The compound of formula (2) can be 4-((L-alanyl)oxy)butanoic acid (2c) or a pharmaceutically acceptable salt thereof: [ka]

[0058] The compounds of formulas (2) to (2c) are prodrugs of gamma-hydroxybutyric acid, and upon oral administration, gamma-hydroxybutyric acid is obtained in the blood of a patient. The compounds of formulas (2) to (2c) exhibit a relative oral bioavailability of gamma-hydroxybutyric acid in a patient of greater than 10%F, greater than 20%F, greater than 30%F, greater than 40%F, greater than 50%F, or greater than 60%F.

[0059] Prior to incorporation into the granules, the active pharmaceutical ingredient may have a high bulk density.

[0060] The active pharmaceutical ingredient can have a bulk density of, for example, less than 0.20 g / mL, less than 0.30 g / mL, less than 0.40 g / mL, or less than 0.50 g / mL.

[0061] The active pharmaceutical ingredient can have a bulk density of, for example, 0.15 g / mL to 0.33 g / mL, 0.16 g / mL to 0.32 g / mL, 0.17 g / mL to 0.31 g / mL, 0.18 g / mL to 0.30 g / mL, 0.19 g / mL to 0.29 g / mL, or 0.20 g / mL to 0.28 g / mL.

[0062] The active pharmaceutical ingredient can have a tapped bulk density of, for example, 0.15 g / mL to 0.50 g / mL, 0.20 g / mL to 0.45 g / mL, 0.25 g / mL to 0.40 g / mL, or 0.30 g / mL to 0.40 g / mL.

[0063] The active pharmaceutical ingredient may have a particle size distribution characterized, for example, by a D10 of 1 μm to 3 μm, a D50 of 6.5 μm to 8.5 μm, and a D90 of 15 μm to 17 μm.

[0064] The active pharmaceutical ingredient can, for example, have a particle size distribution substantially as shown in Figure 9F.

[0065] The active pharmaceutical ingredient can be jet milled to reduce particle size.

[0066] The active pharmaceutical ingredient can have a bulk density of, for example, 0.10 g / mL to 0.30 g / mL, 0.12 g / mL to 0.28 g / mL, 0.14 g / mL to 0.26 g / mL, 0.16 g / mL to 0.24 g / mL, or 0.18 g / mL to 0.22 g / mL.

[0067] The active pharmaceutical ingredient can have a tapped bulk density of, for example, 0.15 g / mL to 1 g / mL, 0.15 g / mL to 0.8 g / mL, 0.15 g / mL to 6 g / mL, 0.25 g / mL to 0.50 g / mL, 0.27 g / mL to 0.48 g / mL, 0.29 g / mL to 0.46 g / mL, 0.31 g / mL to 0.44 g / mL, or 0.33 g / mL to 0.42 g / mL.

[0068] The active pharmaceutical ingredient is e.g., 200m 2 / kg~1200m 2 / kg, e.g., 400m 2 / kg~1000m 2 / kg, or 400m 2 / kg~800m 2 / kg, the specific surface area being determined using laser diffraction. 2 / kg over 400m 2 / kg over 600m 2 / kg over 800m 2 / kg over 1,000m 2 / kg or more.

[0069] The active pharmaceutical ingredient may have a particle size distribution characterized, for example, by a D10 of 10 μm to 14 μm, a D50 of 32 μm to 36 μm, and a D90 of 65 μm to 80 μm.

[0070] The active pharmaceutical ingredient may, for example, have a particle size distribution substantially as shown in FIG.

[0071] The jet-milled active pharmaceutical ingredient can have, for example, a tapped bulk density of less than 0.20 g / mL, less than 0.30 g / mL, less than 0.40 g / mL, or less than 0.50 g / mL.

[0072] The jet-milled active pharmaceutical ingredient can have a tapped bulk density of, for example, 0.10 g / mL to 0.30 g / mL, 0.12 g / mL to 0.28 g / mL, 0.14 g / mL to 0.26 g / mL, 0.16 g / mL to 0.24 g / mL, or 0.18 g / mL to 0.22 g / mL.

[0073] The jet-milled active pharmaceutical ingredient may have a particle size distribution characterized, for example, by a D10 of 6 μm to 10 μm, a D50 of 14 μm to 18 μm, and a D90 of 24 μm to 32 μm.

[0074] The jet-milled active pharmaceutical ingredient can have, for example, a particle size distribution substantially as shown in FIG.

[0075] Pharmaceutical compositions provided by the present disclosure can include an active pharmaceutical ingredient, a binder, and an antistatic agent.

[0076] The granules can include a binder or a combination of binders. The granules can include, for example, less than 1 wt. %, less than 0.8 wt. %, less than 0.6 wt. %, less than 0.4 wt. %, or less than 0.2 wt. % binder, where the weight percentage is based on the total weight of the granule. The granules can include, for example, 0.1 wt. % to 1.0 wt. %, 0.2 wt. % to 0.9 wt. %, 0.2 wt. % to 0.8 wt. %, 0.25 wt. % to 0.75 wt. %, or 0.3 wt. % to 0.7 wt. % binder, where the weight percentage is based on the total weight of the granule.

[0077] The granules can, for example, contain less than 1.5 wt. % binder, less than 1.2 wt. %, less than 1.0 wt. %, less than 0.8 wt. %, or less than 0.6 wt. % binder, where the wt. % is based on the total weight of the granule.

[0078] The granules may contain a suitable binder, examples of which include natural binders such as starch, pregelatinized starch, sodium alginate, and gelatin, synthetic binders such as polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polymethacrylate, sodium carboxymethylcellulose, and polyethylene glycol, and sugars such as modified cellulose, hydroxypropylcellulose, sorbitol, xylitol, and mannitol.

[0079] Examples of other suitable binders include acacia, copovidone, carbomer, corn starch, pregelatinized starch, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellosum calcium, carboxymethylcellulose sodium, carmellose sodium, ceratonia, chitosan hydrochloride, dextrates, dextrin, ethylcellulose, liquid glucose, guar galatomannan, guar gum, hydroxyethylcellulose, microcrystalline cellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropyl starch, hypromellose / hydroxypropylmethylcellulose, Methocel®, inulin, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene glycol, polyethylene oxide, povidone, sodium alginate, starch, pregelatinized starch, sucrose, compressible sugar, zein, gelatin, polymethacrylate, sorbitol, glucose, and sodium alginate.

[0080] The granules may include an antistatic agent or a combination of antistatic agents.

[0081] The granules can contain, for example, less than 2 wt. % of the antistatic agent, less than 1.25 wt. % of the antistatic agent, less than 1 wt. % of the antistatic agent, less than 0.75 wt. % of the antistatic agent, less than 0.5 wt. % of the antistatic agent, or less than 0.25 wt. % of the antistatic agent, where the weight percentage is based on the total weight of the granules. The granules can contain, for example, 0.1 wt. % to 2.0 wt. % of the antistatic agent, 0.2 wt. % to 1.8 wt. % of the antistatic agent, 0.5 wt. % to 1.50 wt. % of the antistatic agent, or 0.75 wt. % to 1.25 wt. % of the antistatic agent, where the weight percentage is based on the total weight of the granules.

[0082] The granules may include a suitable antistatic agent.

[0083] Examples of suitable antistatic agents include silica, talc, magnesium stearate, sodium stearyl fumarate, and combinations of any of the foregoing.

[0084] The antistatic agent can include silica, such as hydrophilic silica, such as hydrophilic fumed silica.

[0085] The antistatic agent can include, for example, hydrophilic fumed silica such as Aerosil® fumed silica from Evonik Industries, Cab-o-sil® fumed silica from Cabot Corporation, or HDK® fumed silica from Brenntag Solutions Group.

[0086] Antistatic agents may include Aerosil® 200 available from Evonik Industries.

[0087] Hydrophilic fumed silica is 100m 2 / g~300m 2 / g, e.g., 175m 2 / g~225m 2 / g specific surface area (BET), pH value of 3.7-4.5 in a 4% aqueous dispersion, loss on drying for 2 hours at 105°C of 1.5% or less, tap density of about 40g / L to 60g / L, and SiO2 content of more than 99.8% based on pyrotechnic material.

[0088] In certain granulations, the antistatic agent comprises talc. Pharmaceutical grade talc is available, for example, from Imerys Talc and Elementis PLC. In certain granulations, the antistatic agent does not comprise talc.

[0089] The granules or granules may contain, for example, 95.0% to 99.5% by weight of the active pharmaceutical ingredient, 0.1% to 1.0% by weight of a binder, and 0.1% to 2.0% by weight of an antistatic agent, the weight percentages being based on the total weight of the granules or granules.

[0090] The granules or granules may contain, for example, 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, the weight percentages being based on the total weight of the granules or granules.

[0091] The granules or granules may contain, for example, 98.25% to 98.75% by weight of the active pharmaceutical ingredient, 0.33% to 0.65% by weight of the binder, and 0.74% to 1.25% by weight of the antistatic agent, the weight percentages being based on the total weight of the granules or granules.

[0092] In addition to the active pharmaceutical ingredient, binder, and antistatic agent, the granules can include one or more excipients such as, for example, flow control agents, lubricants, disintegrants, fillers, compression aids, surfactants, diluents, colorants, buffers, glidants, and combinations of any of the foregoing.

[0093] The granules can contain, for example, less than 3 wt % of one or more excipients, less than 2 wt %, less than 1 wt %, or less than 0.5 wt % of one or more excipients, where the weight percentages are based on the total weight of the granules. The granules can contain, for example, 0 wt % to 3 wt % of one or more excipients, 0.1 wt % to 3 wt %, 0.5 wt % to 2 wt %, or 1 wt % to 2 wt % of one or more excipients, where the weight percentages are based on the total weight of the granules.

[0094] Examples of suitable flow control agents or glidants include magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, and combinations of any of the foregoing.

[0095] Examples of suitable lubricants include magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, zinc stearate, and combinations of any of the foregoing.

[0096] Examples of suitable disintegrants include croscarmellose sodium citrate, colloidal silicone dioxide, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and combinations of any of the foregoing.

[0097] The surfactant may be an ionic surfactant or a non-ionic surfactant. Examples of suitable ionic surfactants include docusate sodium (dioctyl sulfosuccinate sodium salt), sodium lauryl sulfate, and any combination thereof. Examples of suitable non-ionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamers, polysorbates, sorbitan esters, glyceryl monooleate, and any combination thereof.

[0098] Examples of suitable fillers and compression aids include lactose, calcium carbonate, calcium sulfate, compression sugar, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, sucrose, and combinations of any of the foregoing.

[0099] The granules or granules may comprise an active pharmaceutical ingredient, a binder, and an antistatic agent. In addition to the active pharmaceutical ingredient, the granules may comprise a binder comprising hydroxypropyl cellulose and / or an antistatic agent comprising hydrophilic fumed silica. The granules or granules may comprise an active pharmaceutical ingredient selected from the compounds of formula (2), a binder comprising hydroxypropyl cellulose, and an antistatic agent comprising hydrophilic fumed silica. The granules may contain trace amounts of water. In certain granules, the active pharmaceutical ingredient does not comprise 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof, the binder does not comprise hydroxypropylmethylcellulose, and / or the antistatic agent does not comprise talc.

[0100] Granules provided by the present disclosure can be characterized by a sphericity of 0.90 to 1, such as 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. 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. 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.

[0101] The granules provided by the present disclosure are solid and characterized by a substantially homogeneous composition throughout the granule.

[0102] For high doses of active pharmaceutical ingredients, particularly when reconstituted in a suspension before administration, it may be useful for the granules to have a small average diameter to improve palatability.

[0103] The granulated product provided by the present disclosure can be characterized, for example, by a particle size distribution D50 of 150 μm to 500 μm, 150 μm to 450 μm, 150 μm to 400 μm, 225 μm to 400 μm, 150 μm to 350 μm, e.g., 175 μm to 325 μm, 200 μm to 300 μm, or 225 μm to 275 μm. The granulated product can be characterized, for example, by a particle size distribution D50 of less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, or less than 200 μm.

[0104] The granules can be characterized by a particle size distribution D10 of, for example, 50 μm to 150 μm, 60 μm to 140 μm, 70 μm to 120 μm, or 80 μm to 110 μm. The granules can be characterized by a particle size distribution D10 of, for example, less than 200 μm, less than 180 μm, less than 160 μm, or less than 140 μm.

[0105] The granules can be characterized by a particle size distribution D90 of, for example, 450 μm to 750 μm, 475 μm to 725 μm, 500 μm to 700 μm, 525 μm to 675 μm, or 550 μm to 650 μm. The granules can be characterized by a particle size distribution of, for example, less than 800 μm, less than 700 μm, less than 600 μm, or less than 500 μm.

[0106] The granules can be characterized, for example, by a particle size distribution D10 of 50 μm to 150 μm, a particle size distribution D50 of 220 μm to 320 μm, and a particle size distribution D90 of 480 μm to 560 μm.

[0107] The granules can be characterized, for example, by a particle size distribution D10 of 60 μm to 140 μm, a particle size distribution D50 of 230 μm to 310 μm, and a particle size distribution D90 of 490 μm to 550 μm.

[0108] The granules can be characterized, for example, by a particle size distribution D10 of 70 μm to 130 μm, a particle size distribution D50 of 240 μm to 300 μm, and a particle size distribution D90 of 500 μm to 540 μm.

[0109] The granules can be characterized, for example, by a particle size distribution D10 of 70 μm to 230 μm and a particle size distribution D90 of 400 μm to 750 μm.

[0110] The granules can be characterized, for example, by a particle size distribution D10 of 80 μm to 120 μm and a particle size distribution D90 of 510 μm to 650 μm.

[0111] An example of a particle size distribution for a granulation provided by the present disclosure is shown in FIG. 9A.

[0112] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0113] The 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.

[0114] The granulated product 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 granulated product 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.

[0115] Bulk density can be determined using a bulk density cylinder.

[0116] Scanning electron micrograph (SEM) images of example granules provided by the present disclosure are shown in Figures 9B-9C at magnifications of 110x, 220x, 1,000x, and 2,000x, respectively. The granules shown in Figures 9B-9E are characterized by substantially smooth surfaces.

[0117] 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 higher 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.

[0118] The granules provided by the present disclosure, when dried, can be characterized 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, when dried, can be characterized 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.

[0119] The LOD is determined by thermogravimetric analysis.

[0120] The granules provided by the present disclosure can be characterized by a friability value of 0 wt% to 2 wt%, such as 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 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.

[0121] Granulations provided by the present disclosure can, for example, have a friability of less than 1.02%, where friability is determined using sonic sieving.

[0122] The granulations provided by the present disclosure can be prepared by blending an active pharmaceutical ingredient and one or more excipients to form a dry mixture, wet-granulating the dry mixture to obtain a wet granulation, and wet-massing the wet granulation to obtain a granulation. The wet-granulation and wet-massing steps can be repeated one or more times, for example, 1 to 6 times, for example, 1, 2, 3, 4, 5, 6, or more times.

[0123] The dry mix can include, for example, an active pharmaceutical ingredient, a binder, and an antistatic agent.

[0124] The dry mix can include an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients. The dry mix can include greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, or greater than 99% by weight of the active pharmaceutical ingredient, where the weight percentage is based on the total weight of the dry mix. The dry mix can include, for example, 95% to 99.5% by weight, 96% to 99% by weight, 97% to 99% by weight, or 98% to 99% by weight of the active pharmaceutical ingredient, where the weight percentage is based on the total weight of the dry mix.

[0125] The dry mix can include a binder or combination of binders. The dry mix can include, for example, less than 3 wt%, less than 2.5 wt%, less than 2 wt%, less than 1.5 wt%, less than 1 wt%, less than 0.8 wt%, less than 0.6 wt%, less than 0.4 wt%, or less than 0.2 wt%, where the weight percentages are based on the total weight of the dry mix. The dry mix can include, for example, 0.1 wt% to 3.0 wt%, 0.1 wt% to 2.0 wt%, 0.1 wt% to 1.5 wt%, 0.2 wt% to 0.9 wt%, 0.2 wt% to 0.8 wt%, 0.25 wt% to 0.75 wt%, or 0.3 wt% to 0.7 wt%, where the weight percentages are based on the total weight of the dry mix.

[0126] The dry mixture can include, for example, less than 3 wt. % of the antistatic agent, less than 2 wt. % of the antistatic agent, less than 1.25 wt. % of the antistatic agent, less than 1 wt. % of the antistatic agent, less than 0.75 wt. % of the antistatic agent, less than 0.5 wt. % of the antistatic agent, or less than 0.25 wt. % of the antistatic agent, where the weight percentages are based on the total weight of the dry mixture. The dry mixture can include, for example, 0.1 wt. % to 2.0 wt. % of the antistatic agent, 0.2 wt. % to 1.75 wt. % of the antistatic agent, 0.5 wt. % to 1.50 wt. % of the antistatic agent, or 0.75 wt. % to 1.25 wt. % of the antistatic agent, where the weight percentages are based on the total weight of the dry mixture.

[0127] The dry mixture can contain, for example, 95.0% to 99.5% by weight of the active pharmaceutical ingredient, 0.1% to 1.0% by weight of the binder, and 0.1% to 2.0% by weight of the antistatic agent, the weight percentages being based on the total weight of the dry mixture.

[0128] The dry mix can include, for example, 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of the binder, and 0.5% to 1.5% by weight of the antistatic agent, the weight percentages being based on the total weight of the dry mix.

[0129] The dry blend can include, for example, 98.25% to 98.75% by weight of the active pharmaceutical ingredient, 0.33% to 0.65% by weight of the binder, and 0.74% to 1.25% by weight of the antistatic agent, the weight percentages being based on the total weight of the dry blend.

[0130] The active pharmaceutical ingredient can be screened, de-lumped, co-milled, Fitz milled, pin-milled, or jet milled before being added to the dry blend.

[0131] The active pharmaceutical ingredient can have a size distribution characterized by a D90 of, for example, 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 by a D90 of, for example, 10 μm to 30 μm, 11 μm to 25 μm, or 10 μm to 20 μm. The as-crystallized active pharmaceutical ingredient can be jet milled to obtain a suitable particle size distribution.

[0132] The dry mix can be mixed in a bowl for, for example, 0.5 to 5 minutes to obtain a homogenous dry mix.

[0133] 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.

[0134] Granulating the dry mixture can include, for example, granulating at a mixer speed of 700 rpm to 1000 rpm, e.g., 800 rpm to 900 rpm, and a chopper speed of, e.g., 3,000 rpm to 4200 rpm, e.g., 3,200 rpm to 4,000 rpm, or 3,400 rpm to 3,800 rpm, for a period of, e.g., 5 minutes to 20 minutes, e.g., 5 minutes to 15 minutes, or 5 minutes to 10 minutes.

[0135] The dry granulation product obtained in step (a) can be wet granulated.

[0136] During wet granulation, water can be added to the dry granulation at a rate of, for example, 0.0025 wt% / min to 0.0075 wt% / min, where wt% is based on the total weight of the dry granulation. The wet granulation can be granulated for, for example, 5 to 20 minutes, for example, 5 to 15 minutes, or 5 to 10 minutes. During wet granulation, the mixer speed can be, for example, 700 rpm to 1000 rpm, for example, 800 rpm to 900 rpm, and the chopper speed can be, for example, 3,000 rpm to 4,200 rpm, for example, 3,200 rpm to 4,000 rpm, or 3,400 rpm to 3,800 rpm.

[0137] At the end of the process, the wet granulation can contain, for example, 3% to 7% water by weight, e.g., 3.5% to 6.5% by weight, or 4% to 6% water by weight, where the weight percentages are based on the total weight of the wet granulation.

[0138] The amount of water added is determined by weighing the amount of water incorporated / consumed into the granulation.

[0139] During the wet granulation, the temperature of the wet granulated product can be maintained at, for example, 20°C to 25°C.

[0140] The wet granulation can then be wet massed to form smooth, dense granules.

[0141] Wet massing can be carried out for 20 to 100 minutes, e.g., 30 to 90 minutes, 30 to 80 minutes, or 30 to 60 minutes, with a mixer speed of, for example, 400 rpm to 700 rpm, e.g., 500 rpm to 600 rpm, and a chopper speed of, for example, 1300 rpm to 2300 rpm, e.g., 1500 rpm to 2100 rpm.

[0142] During wet massing, the temperature of the wet granulation can be maintained, for example, at a temperature of from 20° C. to 25° C., such as from 22° C. to 25° C. The temperature of the wet granulation can be maintained, for example, by immersing the mixing bowl containing the granulation in a temperature-controlled bath.

[0143] Wet massing can be carried out, for example, using a granulator bowl at a temperature of 22°C to 24°C, a mixer speed of 525 rpm to 575 rpm, and a chopper speed of 1700 rpm to 1900 rpm for 20 minutes to 80 minutes, e.g., 25 minutes to 70 minutes, 30 minutes to 60 minutes, or 35 minutes to 55 minutes.

[0144] During wet massing, the wet granulation can contain, for example, 0.01 wt. % to 0.1 wt. % water, 0.02 wt. % to 0.085 wt. %, 0.025 wt. % to 0.075 wt. %, or 0.035 wt. % to 0.065 wt. % water, the water being based on the total weight of the wet granulation.

[0145] After wet massing, the granulation can be dried.

[0146] The granulation can be dried in an oven or fluid bed dryer until the loss on drying is less than 1.0 wt%.

[0147] The granules prepared by the methods provided by the present disclosure can be characterized by a 55% to 70% by weight yield in the particle size range of 100 μm to 425 μm, a 63% by weight yield in the particle size range of 100 μm to 425 μm, a 30% to 40% by weight yield in the particle size range of 200 μm to 350 μm, and a 36% by weight yield in the particle size range of 200 μm to 350 μm, where the particle size ranges are determined by sieve analysis and the weight percentages are based on the total weight of the granules.

[0148] In certain methods for preparing a granulation provided by the present disclosure, the active pharmaceutical ingredient can have a particle size distribution D50 of, for example, less than 30 μm, less than 25 μm, or less than 20 μm. The active pharmaceutical ingredient can have a specific gravity of, for example, 200 m / kg to 1200 m / kg.

[0149] During one or more granulation steps, the temperature of the granulation can be maintained at, for example, 20°C to 25°C. It may be desirable to add water to the granulation at the slowest possible rate, such as less than 2 g / min. Slow addition of water can minimize agglomeration. During one or more granulation steps, about 5% to 25% by weight, e.g., 10% to 20% by weight, of total water can be added, where the weight percentage is based on the total weight of the active pharmaceutical ingredient. During each of the one or more granulation steps, it may be useful to maintain a mixer speed as fast as possible, such as greater than 600 rpm, greater than 700 rpm, greater than 800 rpm, or greater than 1000 rpm.

[0150] During the one or more wet massing steps, the temperature of the granulation can be maintained at a temperature in the form of, for example, 15° C. to 25° C. During each of the one or more wet massing steps, it can be useful to maintain a mixer speed as high as possible, such as greater than 600 rpm, greater than 700 rpm, greater than 800 rpm, or greater than 1000 rpm.

[0151] The granulation and wet massing steps are repeated until the granulation exhibits the desired bulk density and / or until the bulk density of the granulation does not increase significantly. For example, if the bulk density of the granulation increases by less than 10% or less than 5% after the last wet massing step, the granulation can be considered complete. The granulation and wet massing steps can be repeated until the bed height does not decrease significantly after the last wet massing step.

[0152] The granules provided by the present disclosure can include one or more coatings.

[0153] The coating can have an average thickness of, for example, less than 300 μm, less than 200 μm, less than 150 μm, less than 100 μm, less than 50 μm, or less than 25 μm.

[0154] The coated granules can contain, for example, less than 50% by weight coating, less than 40% by weight, less than 30% by weight, less than 20% by weight, or less than 10% by weight coating, where the weight percent is based on the total weight of the coated granules. Dosage forms containing highly water-soluble active pharmaceutical ingredients require thick coatings to reduce the release rate of the active pharmaceutical ingredient.

[0155] The coating may include a pharmaceutically acceptable polymer, a plasticizer, an anti-tack agent, a colorant or pigment, a glidant, and a viscosity modifier.

[0156] For example, the coating can include an immediate-release coating or a controlled-release coating. Controlled-release coatings can include, for example, delayed-release coatings, pH-release coatings, sustained-release coatings, or modified-release coatings. Delayed-release drug delivery systems are designed to deliver a drug at a specific time or over a period of time after administration.

[0157] The coating may include a water-soluble coating and may include polymers such as polyvinyl alcohol, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, and combinations of any of the foregoing.

[0158] The coating may comprise a water-insoluble or water-resistant coating to protect the dosage form from absorbing water during storage. Examples of suitable water-insoluble or water-resistant coatings may include polymers such as ethyl cellulose, polyacrylates, polymethacrylates, and combinations of any of the foregoing.

[0159] The coating can provide, for example, time-dependent release, pH-dependent release, or sustained release.

[0160] The 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 coating onto the granules in a fluidized bed apparatus.

[0161] Pharmaceutical compositions provided by the present disclosure can include granulations provided by the present disclosure.

[0162] The pharmaceutical composition can comprise any suitable dosage form for oral administration.

[0163] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, and suspensions.

[0164] Oral dosage forms can contain, for example, 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 active pharmaceutical ingredient. 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, or more than 8 grams of active pharmaceutical ingredient.

[0165] Oral formulations provided by the present disclosure can include oral tablet formulations.

[0166] Oral formulations provided by the present disclosure can include oral suspensions.

[0167] Aspects of the present invention The present invention is further defined by the following aspects.

[0168] Aspect 1. A granulation comprising a plurality of granules, wherein the granules are characterized by greater than 95% by weight of an active pharmaceutical ingredient (API), and wherein the granulation is characterized by a particle size distribution (PSD) (D50) of 150 μm to 300 μm, wherein the weight percent is based on the total weight of the granulation.

[0169] Aspect 2. The granule of Aspect 1, wherein the granule comprises 98% to 99% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the granule.

[0170] Aspect 3. The granule according to aspect 1 or 2, wherein the granule has a PSD (D50) of 225 μm to 275 μm.

[0171] Embodiment 4. A granulation according to any one of embodiments 1 to 3, wherein the granulation is characterized by a friability of less than 2 wt.%, the wt.% being based on the total weight of the granulation.

[0172] Aspect 5. A granulation according to any one of aspects 1 to 4, wherein the granulation is characterized by a PSD (D10) of 50 μm to 150 μm, and a PSD (D90) of 450 μm to 750 μm, the PSD being determined by sieve analysis.

[0173] Aspect 6. A granulation according to any one of aspects 1 to 4, wherein the granulation is characterized by a PSD (D10) of 80 μm to 120 μm, and a PSD (D90) of 510 μm to 650 μm, the PSD being determined by sieve analysis.

[0174] Aspect 7. A granulation according to any one of aspects 1 to 4, wherein the granulation is characterized by a PSD (D10) of 106 μm, a PSD (D50) of 267 μm, and a PSD (D90) of 533 μm, the PSD being determined by sieve analysis.

[0175] Aspect 8. The granulation of any one of aspects 1 to 7, wherein the granulation has an active pharmaceutical ingredient bulk density of 0.150 g / mL to 0.320 g / mL, the bulk density being determined using USP 616, Method I.

[0176] Aspect 9. The granulation of aspect 1 or 2, wherein the granulation has an active pharmaceutical ingredient bulk density of 0.250 g / mL to 0.280 g / mL, the bulk density being determined using USP 616, Method I.

[0177] Aspect 10. A granulation according to any one of aspects 1 to 7, wherein the granulation has a bulk density of 0.70 g / mL to 1.70 g / mL, the bulk density being determined using USP 616, Method I.

[0178] Embodiment 11. A granulation according to any one of embodiments 1 to 10, wherein the granulation is characterized by a loss on drying (LOD) of 0% to 1.5% by weight, wherein the weight % is based on the weight of the granulation after drying.

[0179] Embodiment 12. The granule of any one of embodiments 1 to 10, wherein the granule is characterized by a loss on drying (LOD) of 0.2 wt% to 1.2 wt%, the weight % being based on the weight of the granule after drying.

[0180] Aspect 13. A granulation according to any one of aspects 1 to 12, wherein the granulation is characterized by a friability of 0.95% to 1.10%, wherein the friability is determined using a sieve shaker as described in the Examples.

[0181] Embodiment 14. The granulation of any one of embodiments 1 to 12, wherein the granulation is characterized by a friability of 1.02%, wherein the friability is determined using a sieve shaker as described in the Examples.

[0182] Aspect 15. A granulation according to any one of aspects 1 to 14, wherein the granules are characterized by a sphericity of 0.90 to 1.00, the sphericity being determined by dynamic image analysis.

[0183] Embodiment 16. A granulation according to any one of embodiments 1 to 14, wherein the granules are characterized by a surface roughness substantially as shown in Figures 9B to 9E.

[0184] Aspect 17. The granulation of any one of aspects 1 to 15, wherein the active pharmaceutical ingredient has a water solubility of greater than 100 mg / mL.

[0185] Aspect 18. A granulation according to any one of Aspects 1 to 15, wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL.

[0186] Aspect 19. A granulation according to any one of Aspects 1 to 18, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

[0187] Aspect 20. The granulation of any one of Aspects 1 to 18, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid, a derivative of gamma-hydroxybutyric acid, or a pharmaceutically acceptable salt of any of the foregoing.

[0188] Aspect 21. The active pharmaceutical ingredient is a compound of formula (2): [ka] or a pharmaceutically acceptable salt thereof, R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 19. The granule according to any one of aspects 1 to 18, wherein the cycloalkoxycarbonyl is independently selected from the group consisting of cycloalkoxycarbonyl.

[0189] Aspect 22. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, a pharmaceutically acceptable salt of any of the foregoing, and 22. The granulation of aspect 21, selected from any combination of the foregoing.

[0190] Aspect 23. The granulation of aspect 21, wherein the active pharmaceutical ingredient is 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof: [ka]

[0191] Aspect 24. A granulation according to any one of aspects 1 to 23, wherein the granulation further comprises a binder and an antistatic agent.

[0192] Aspect 25. The granule of Aspect 24, wherein the granule comprises 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, the weight percentages being based on the total weight of the granule.

[0193] Aspect 26. The granulation of aspect 24, wherein the granulation comprises 98.5 wt.% of the active pharmaceutical ingredient, 0.5 wt.% of the binder, and 1.0 wt.% of the antistatic agent, the weight percentages being based on the total weight of the granulation.

[0194] Aspect 27. A granulation according to any one of aspects 24 to 26, wherein the binder comprises hydroxypropyl cellulose.

[0195] Aspect 28. A granulation according to any one of aspects 24 to 27, wherein the antistatic agent comprises hydrophilic fumed silica.

[0196] Aspect 29. A granulation according to any one of aspects 1 to 28, wherein the granules comprise a coating.

[0197] Embodiment 30. The granule of embodiment 29, wherein the granule comprises less than 2 wt. % of the coating, the weight % being based on the total weight of the granule.

[0198] Aspect 31. The granulation of aspect 29 or 30, wherein the coated granules comprise more than 95% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the granules.

[0199] Embodiment 32. A granulation according to any one of embodiments 29 to 31, wherein the coating comprises a controlled release coating.

[0200] Aspect 33. A pharmaceutical composition comprising the granule according to any one of aspects 1 to 32.

[0201] Aspect 34. The pharmaceutical composition of aspect 33, wherein the pharmaceutical composition comprises an oral formulation.

[0202] Aspect 35. The pharmaceutical composition according to aspect 33 or 34, wherein the pharmaceutical composition comprises an immediate release formulation.

[0203] Aspect 36. The pharmaceutical composition according to aspect 33 or 34, wherein the pharmaceutical composition comprises a controlled release formulation.

[0204] Aspect 37. A method for preparing a granulation according to any one of Aspects 1 to 32, comprising: mixing an active pharmaceutical ingredient, a binder, and an antistatic agent to form a dry mixture; wet granulating the dry mixture for 5 minutes to 10 minutes to obtain a wet granulation; wet massing the wet granulation for 30 minutes to 60 minutes to obtain a wet granulation; and drying the wet granulation to obtain a granulation.

[0205] Embodiment 38. The method of embodiment 37, wherein the wet granulating comprises granulating the dry mixture for 5 to 15 minutes at a mixer speed of 800 rpm to 900 rpm and a chopper speed of 3200 rpm to 4000 rpm; adding water at a rate of 0.0025 wt% / min to 0.0075 wt% / min, wherein the wt% is based on the total weight of the dry mixture; and maintaining the temperature of the wet granulation at a temperature of 20°C to 25°C during the wet granulation.

[0206] Embodiment 39. The method of embodiment 37, wherein wet granulating comprises granulating for 5 minutes to 60 minutes at a mixer speed of 850 rpm and a chopper speed of 3600 rpm; adding water at a rate of 0.005 wt% / min, wherein the wt% is based on the total weight of the mixture; and maintaining the temperature of the wet granulation at 22°C to 24°C.

[0207] Embodiment 40. The method of any one of embodiments 37-39, wherein wet massing comprises wet massing for 30 to 60 minutes at a mixer speed of 550 rpm, and a chopper speed of 1,500 rpm to 2,100 rpm, and maintaining the temperature of the wet granulation at a temperature of 20°C to 25°C.

[0208] Embodiment 41. The method of any one of embodiments 37-39, wherein wet massing comprises wet massing for 30 to 60 minutes at a mixer speed of 500 rpm to 600 rpm, and a chopper speed of 1800 rpm, and maintaining the temperature of the wet granulation at 22°C to 24°C.

[0209] Embodiment 42. The method of any one of embodiments 37 to 41, wherein the mixture comprises 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of the binder, and 0.5% to 1.5% by weight of the antistatic agent, the weight percentages being based on the total weight of the mixture.

[0210] Embodiment 43. The method of any one of embodiments 37 to 41, wherein the mixture comprises 98.5 wt.% of the active pharmaceutical ingredient, 0.5 wt.% of the binder, and 1.0 wt.% of the antistatic agent, the weight percentages being based on the total weight of the mixture.

[0211] Embodiment 44. The method of any one of embodiments 37 to 43, wherein the granulation is characterized by a 55% to 70% by weight yield in a particle size range of 100 μm to 425 μm, the particle size range being determined by laser diffraction, and the weight percentage being based on the total weight of the granulation.

[0212] Embodiment 45. The method of any one of embodiments 37 to 44, wherein the granulation is characterized by a 63 wt% yield in the particle size range of 100 μm to 425 μm, the particle size range being determined by laser diffraction, and the wt% being based on the total weight of the granulation.

[0213] Aspect 46. The method of any one of aspects 37 to 45, wherein the granulation is characterized by a 30% to 40% by weight yield in the particle size range of 200 μm to 350 μm, the particle size range being determined by laser diffraction, and the weight percentage being based on the total weight of the granulation.

[0214] Embodiment 47. The method of any one of embodiments 37 to 46, wherein the granulation is characterized by a 36 wt% yield in the particle size range of 200 μm to 350 μm, the particle size range being determined by laser diffraction, and the wt% being based on the total weight of the granulation.

[0215] Embodiment 48. The method of any one of embodiments 37 to 47, wherein the wet granulation comprises 0.025% to 0.075% by weight of water, the weight percentage being based on the total weight of the wet granulation.

[0216] Embodiment 49. The method of any one of embodiments 37 to 47, wherein the wet granulation comprises 0.05% by weight of water, the weight percentage being based on the total weight of the wet granulation.

[0217] Aspect 1A. A granulation comprising a plurality of granules, the granules comprising greater than 95% by weight of an active pharmaceutical ingredient (API), the weight % being based on the total weight of the granulation, and the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL.

[0218] Aspect 2A. The granulation of Aspect 1A, wherein the active pharmaceutical ingredient is characterized by a particle size distribution characterized by a D90 of less than 30 μm.

[0219] Aspect 3A. The active pharmaceutical ingredient is 200 ml 2 / kg~1200m 2 1B. The granule of any one of claims 1A to 2A, characterized by a specific surface area of ​​0.1g / kg, wherein the specific surface area is determined using laser diffraction.

[0220] Aspect 4A. The granulation of any one of Aspects 1A-3A, wherein the active pharmaceutical ingredient is characterized by a bulk density of 0.1 g / mL to 0.4 g / mL, wherein the bulk density is determined according to USP 616, Method 1.

[0221] Aspect 5A. The granulation of any one of Aspects 1A-4A, wherein the active pharmaceutical ingredient has a bulk density of 0.15 g / mL to 0.35 g / mL, wherein the bulk density is determined using USP 616, Method I.

[0222] Aspect 6A. A granulation according to any one of Aspects 1A to 5A, wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL.

[0223] Aspect 7A. A granulation according to any one of Aspects 1A-6A, wherein the granules comprise 96% to 99.5% by weight of the active pharmaceutical ingredient, the weight percentages being based on the total weight of the granules.

[0224] Aspect 8A. A granulation according to any one of Aspects 1A to 7A, wherein the granulation is characterized by a particle size distribution (PSD) characterized by a D50 of 150 μm to 500 μm, the particle size distribution being determined by laser diffraction or sieve analysis.

[0225] Aspect 9A. The granulation of any one of Aspects 1A-7A, wherein the granulation is characterized by a particle size distribution D50 of 200 μm to 400 μm, the particle size distribution being determined by laser diffraction or sieve analysis.

[0226] Aspect 10A. A granulation according to any one of Aspects 1A to 7A, wherein the granulation is characterized by a particle size distribution D10 of 50 μm to 250 μm, and a particle size distribution D90 of 400 μm to 750 μm, wherein the particle size distribution is determined by laser diffraction or sieve analysis.

[0227] Aspect 11A. A granulation according to any one of Aspects 1A to 7A, wherein the granulation is characterized by a particle size distribution D10 of 80 μm to 120 μm, and a particle size distribution D90 of 510 μm to 650 μm, wherein the particle size distribution is determined by laser diffraction or sieve analysis.

[0228] Aspect 12A. A granulation of any one of Aspects 1A-11A, wherein the granulation has a bulk density of 0.50 g / mL to 1.20 g / mL, the bulk density being determined according to USP 616, Method I.

[0229] Aspect 13A. A granulation of any one of Aspects 1A-12A, wherein the granulation has a bulk density of 0.40 g / mL to 0.80 g / mL, the bulk density being determined according to USP 616, Method I.

[0230] Embodiment 14A. The granulation of any one of Embodiments 1A-13A, wherein the granulation is characterized by a loss on drying (LOD) of 0.05% to 1.5% by weight, wherein the weight % is based on the weight of the granulation after drying.

[0231] Embodiment 15A. The granulation of any one of Embodiments 1A-13A, wherein the granulation is characterized by a loss on drying (LOD) of 0.2 wt% to 1.2 wt%, wherein the wt% is based on the weight of the granulation after drying.

[0232] Embodiment 16A. A granulation of any one of embodiments 1A-15A, wherein the granulation is characterized by a friability of less than 2 wt.%, where wt.% is based on the total weight of the granulation and the friability is determined using a sieve shaker according to the method described in the Examples.

[0233] Embodiment 17A. A granulation of any one of embodiments 1A-15A, wherein the granulation is characterized by a friability of less than 1.10 wt.%, where wt.% is based on the total weight of the granulation and the friability is determined using a sieve shaker according to the method described in the Examples.

[0234] Embodiment 18A. A granulation of any one of embodiments 1A-15A, wherein the granulation is characterized by a friability of less than 1.02 wt.%, where wt.% is based on the total weight of the granulation and the friability is determined using a sieve shaker according to the method described in the Examples.

[0235] Aspect 19A. A granulation according to any one of Aspects 1A to 18A, wherein the granules are characterized by a sphericity of 0.90 to 1.00, the sphericity being determined by dynamic image analysis.

[0236] Embodiment 20A. A granulation according to any one of embodiments 1A-19A, wherein the granules are characterized by a surface roughness substantially as shown in Figures 9B-9E.

[0237] Embodiment 21A. A granulation according to any one of embodiments 1A-19A, wherein the granules are characterized by a surface roughness substantially as shown in Figures 19-20.

[0238] Aspect 22A. A granulation according to any one of Aspects 1A to 21A, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

[0239] Aspect 23A. A granulation according to any one of Aspects 1A to 21A, wherein the active pharmaceutical ingredient comprises a derivative of gamma-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

[0240] Aspect 24A. The active pharmaceutical ingredient is a compound of formula (2): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3 Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 The granule of any one of Aspects 1A to 21A, wherein the cycloalkoxycarbonyl is independently selected from the group consisting of:

[0241] Aspect 25A. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, a pharmaceutically acceptable salt of any of the foregoing, and A granulation product according to any one of Aspects 1A to 21A, selected from any combination of the foregoing.

[0242] Aspect 26A. The granulation of any one of Aspects 1A-21A, wherein the active pharmaceutical ingredient is 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof: [ka]

[0243] Aspect 27A. A granulation according to any one of Aspects 1A to 26A, wherein the granules further comprise a binder and an antistatic agent.

[0244] Embodiment 28A. The granulation of embodiment 27A, wherein the granules comprise 2 wt.% or less of a binder, the wt.% being based on the total weight of the granules.

[0245] Aspect 29A. The granulation of Aspect 27A or 28A, wherein the granules comprise 1.5 wt. % or less of an antistatic agent, the wt. % being based on the total weight of the granule.

[0246] Aspect 30A. A granulation according to any one of Aspects 27A to 29A, wherein the granules comprise 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, the weight percentages being based on the total weight of the granule.

[0247] Aspect 31A. A granulation according to any one of Aspects 27A-29A, wherein the granules comprise greater than 98.5 wt.% of the active pharmaceutical ingredient, 0.5 wt.% or less of a binder, and 1.0 wt.% or less of an antistatic agent, the weight percentages being based on the total weight of the granules.

[0248] Embodiment 32A. A granulation of any one of embodiments 27A-31A, wherein the binder comprises hydroxypropyl cellulose.

[0249] Aspect 33A. The granulation of Aspect 32A, wherein the hydroxypropyl cellulose comprises a size distribution characterized by a D10 of 10 μm to 35 μm, a D50 of 45 μm to 90 μm, and a D90 of 100 μm to 300 μm.

[0250] Aspect 34A. The granulation of Aspect 32A or 33A, wherein the hydroxypropyl cellulose has a weight average molecular weight of 50,000 daltons to 110,000 daltons.

[0251] Aspect 35A. A granulation of any one of Aspects 32A to 34A, wherein the hydroxypropyl cellulose comprises a viscosity of 300 mPa×sec to 600 mPa×sec, as determined using a Brookfield viscometer at 25°C.

[0252] Aspect 36A. A granulation according to any one of Aspects 30A to 35A, wherein the antistatic agent comprises hydrophilic fumed silica.

[0253] Embodiment 37A. The granulation of embodiment 36A, wherein the hydrophilic fumed silica has a SiO2 content of greater than 99.8% based on pyrotechnic material.

[0254] Aspect 38A. Hydrophilic fumed silica is 175 m 2 / g~225m 2 The granule of any one of embodiments 36A and 37A, having a specific surface area (BET) of 1 / g.

[0255] Aspect 39A. The granulation of Aspect 36A or 37A, wherein the hydrophilic fumed silica has a pH value of 3.7 to 4.5 in a 4% aqueous dispersion.

[0256] Aspect 40A. The granulation of aspect 36A or 37A, wherein the hydrophilic fumed silica has an LOD of less than 1.5 wt.%.

[0257] Aspect 41A. The granulation of Aspect 36A or 37A, wherein the hydrophilic fumed silica has a tap density of 30 g / L to 70 g / L.

[0258] Embodiment 42A. A granulation according to any one of embodiments 1A-41A, wherein the granules comprise a coating.

[0259] Embodiment 43A. The granulation of embodiment 42A, wherein the granules comprise 1% to 10% by weight of the coating, wherein the weight percentage is based on the total weight of the granule.

[0260] Aspect 44A. The granulation of Aspect 42A or 43A, wherein the coating comprises a seal coating, a controlled-release coating, or a combination thereof.

[0261] Aspect 45A. A pharmaceutical composition comprising a granulation according to any one of Aspects 1A-44A.

[0262] Aspect 46A. The pharmaceutical composition of Aspect 45A, wherein the pharmaceutical composition comprises an oral formulation.

[0263] Aspect 47A. The pharmaceutical composition of Aspect 45A or 46A, wherein the oral formulation comprises an oral suspension.

[0264] Aspect 48A. The pharmaceutical composition of any one of Aspects 45A-47A, wherein the pharmaceutical composition comprises an immediate release formulation.

[0265] Aspect 49A. The pharmaceutical composition of any one of Aspects 45A-48A, wherein the pharmaceutical composition comprises a controlled release formulation.

[0266] Aspect 50A. A method of preparing a granulation of any one of Aspects 1A-44A, comprising: combining an active pharmaceutical ingredient, a binder, and an antistatic agent to form a dry mixture; wet-granulating the dry mixture to obtain a wet granulation; wet-massing the wet granulation to obtain a wet-mass granulation; and drying the wet-mass granulation to obtain a granulation.

[0267] Embodiment 51A. The method of embodiment 50A, wherein wet granulating the dry mixture comprises wet granulating for 5 to 10 minutes.

[0268] Aspect 52A. The method of Aspect 50A or 51A, wherein the wet granulating comprises adding 5% to 20% total water by weight, wherein the weight percentage is based on the total weight of the active pharmaceutical ingredients.

[0269] Embodiment 53A. The method of any one of Embodiments 50A-52A, wherein the temperature of the wet granulation is between 20°C and 25°C during wet granulation.

[0270] Embodiment 54A. The method of any one of Embodiments 50A-53A, wherein wet massing the wet granulation comprises wet massing for between 30 minutes and 60 minutes.

[0271] Embodiment 55A. The method of any one of Embodiments 50A-54A, wherein the method comprises repeating the wet granulating and wet massing steps one or more times before the drying step.

[0272] Embodiment 56A. The method of any one of Embodiments 50A-55A, wherein the method comprises repeating the wet granulating and wet massing steps one or more times, prior to the drying step, until the specific gravity of the granulation no longer increases significantly.

[0273] Embodiment 57A. The method of any one of Embodiments 50A-56A, wherein the wet granulating comprises granulating the dry mixture for 5 to 15 minutes at a mixer speed of 800 rpm to 900 rpm and a chopper speed of 3200 rpm to 4000 rpm; adding water at a rate of 0.0025 wt% / min to 0.0075 wt% / min, wherein the wt% is based on the total weight of the dry mixture; and maintaining the temperature of the wet granulation at a temperature of 20°C to 25°C during the wet granulation.

[0274] Embodiment 58A. The method of any one of Embodiments 50A-57A, wherein wet granulating comprises granulating for 5 minutes to 60 minutes at a mixer speed of 850 rpm and a chopper speed of 3600 rpm; adding water at a rate of 0.005 wt% / min, wherein the wt% is based on the total weight of the mixture; and maintaining the temperature of the wet granulation at 20°C to 25°C.

[0275] Embodiment 59A. The method of any one of Embodiments 50A-58A, wherein wet massing comprises wet massing for 30 to 60 minutes at a mixer speed of 550 rpm and a chopper speed of 1,500 rpm to 2,100 rpm, and maintaining the temperature of the wet granulation at a temperature of 15°C to 25°C.

[0276] Embodiment 60A. The method of any one of Embodiments 50A-58A, wherein wet massing comprises wet massing for 30 to 60 minutes at a mixer speed of 500 rpm to 600 rpm, and a chopper speed of 1800 rpm, and maintaining the temperature of the wet granulation at 20°C to 25°C.

[0277] Embodiment 61A. The method of any one of embodiments 50A-58A, wherein the binder comprises hydroxypropyl cellulose.

[0278] Embodiment 62A. The method of any one of embodiments 50A-58A, wherein the antistatic agent comprises hydrophilic fumed silica.

[0279] Aspect 63A. The method of any one of aspects 50A-58A, wherein the mixture comprises greater than 95 wt.% of the active pharmaceutical ingredient, greater than 0.25 wt.% of the binder, and greater than 0.5 wt.% of the antistatic agent, wherein the wt.% are based on the total weight of the mixture.

[0280] Embodiment 64A. The method of any one of embodiments 50A to 58A, wherein the mixture comprises 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of the binder, and 0.5% to 1.5% by weight of the antistatic agent, wherein the weight percentages are based on the total weight of the mixture.

[0281] Aspect 65A. The method of any one of aspects 50A to 58A, wherein the mixture comprises 98.2 wt% to 98.8 wt% of the active pharmaceutical ingredient, 0.3 wt% to 0.7 wt% of the binder, and 0.8 wt% to 1.2 wt% of the antistatic agent, the weight percentages being based on the total weight of the mixture.

[0282] Embodiment 66A. The method of any one of embodiments 50A-65A, wherein after drying, the wet granulation comprises between 0.025% and 0.075% by weight of water, wherein the weight percentage is based on the total weight of the wet granulation.

[0283] Embodiment 67A. The method of any one of Embodiments 50A-66A, wherein after drying, the wet granulation comprises 0.05% water by weight, the weight percentage being based on the total weight of the wet granulation. [Example]

[0284]

[0013] Embodiments provided by the present disclosure are further illustrated by reference to the following examples, which describe methods of making granulations, granules, oral dosage formulations, and granulations 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 present disclosure.

[0285] The following materials were used in the examples: The active pharmaceutical ingredient was a compound of formula (2a), 4-((L-valyl)oxy)butanoic acid. The binder was Pharmacoat® 606 HPMC (hydroxypropyl methylcellulose) (Shin-Etsu Chemical Company, Ltd.) (Example 1) or Klucel® EXF HPC (hydroxypropyl cellulose) (Ashland) (Examples 2-9). The antistatic agent was Aerosil® 200 (hydrophilic fumed silica, BWT SA200m 2 / g) (Evonik Industries). Milling was performed using Comil® (Quadro Engineering).

[0286] The dry mix ingredients for each of the examples are shown in Table 1. [Table 1]

[0287] The process conditions for each of Examples 1-9 are summarized in FIG. 11 and the granulation properties are summarized in FIG.

[0288] Example 1 Pharmaceutical granules (1) The components of the dry mix in weight percent are given in Table 1.

[0289] A total of 3.76 wt% of water was added during wet granulation, with the wt% being based on the total weight of the dry mixture. Water was added until the bed height was reduced by approximately two times, which meant a substantial increase in bulk density. The wet granulation was carried out for 7 minutes at a mixer speed of 800 rpm and a chopper speed of 2,000 rpm, and the average temperature of the wet granulation was 25.2°C.

[0290] The wet granulation was wet massed for 30 minutes.

[0291] Specific characteristics of pharmaceutical granulation (1) are shown in FIG.

[0292] The size distribution of the granules during wet massing is shown in Figure 1A, and SEM images of the resulting granules are shown in Figures 1B and 1C at 34x and 100x magnification, respectively.

[0293] Example 2 Pharmaceutical granules (2) The components of the dry mix in weight percent are given in Table 1.

[0294] A total of 3.69 wt% water was added during the wet granulation, with the wt% based on the total weight of the dry mixture. The wet granulation was carried out for 6 minutes at a mixer speed of 800 rpm and a chopper speed of 2,000 rpm, with an average wet granulation temperature of 25.4°C.

[0295] The wet granulation was wet massed for 45 minutes with a mixer speed of 1,200 rpm and a chopper speed of 2,000 rpm while maintaining the wet granulation temperature at an average temperature of 32.1°C.

[0296] Specific properties of pharmaceutical granulation (2) are shown in FIG.

[0297] The size distribution of the granules during wet massing is shown in Figure 2A, and SEM images of the resulting granules are shown in Figures 2B and 2C at 34x and 100x magnification, respectively.

[0298] Example 3 Pharmaceutical granules (3) The components of the dry mix in weight percent are given in Table 1.

[0299] A total of 3.75 wt% water was added during the wet granulation, with the wt% based on the total weight of the dry mixture. The wet granulation was carried out for 6 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm, with an average wet granulation temperature of 32°C.

[0300] After the initial granulation, the sub-batches were mixed in a jacketed bowl for wet massing. After 20 minutes of wet massing, there was no visible change in the granulation.

[0301] Wet granulation was continued for an additional 24 minutes at a mixer speed of 850 RPM and a chopper speed of 3,600 rpm. An additional amount of water of 8.0 wt % was added during the wet granulation, where the wt % is based on the total weight of the dry mixture.

[0302] The wet granulation was wet massed for 36 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm while the temperature of the wet granulation was between 16° C. and 33° C. Wet granulation was continued for an additional 24 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm. An additional amount of water of 8.0 wt % was added during the wet granulation, with the wt % being based on the total weight of the dry mixture.

[0303] Specific properties of pharmaceutical granulation (3) are shown in FIG.

[0304] The size distribution of the granules during wet massing is shown in Figure 3A, and SEM images of the resulting granules are shown in Figures 3B and 3C at 40x and 220x magnification, respectively.

[0305] Example 4 Pharmaceutical granules (4) The components of the dry blend in weight percent are shown in Table 1. The active pharmaceutical ingredient was passed through a Comil® fitted with a 0.045 inch screen before being added to the dry blend. The active pharmaceutical ingredient was not jet milled.

[0306] A total of 5.0 wt.% water was added during the wet granulation, with the wt.% being based on the total weight of the dry mixture. The water was added using a syringe and a two-fluid spray nozzle with the atomizing air set at 4 psi. The wet granulation was granulated for 10 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0307] A jacketed 4 L bowl was used throughout the process. An attached cooler was used during wet massing to prevent overheating of the product. After the initial granulation, sub-batches were mixed in the jacketed bowl for further granulation, followed by wet massing.

[0308] Wet granulation was continued for an additional 14 minutes. During this second stage of granulation, an additional 5.1 wt % water was added, the wt % being based on the total weight of the dry mix.

[0309] The wet granulation was wet massed for 50 minutes with a mixer speed of 850 rpm and a chopper speed of 3,600 rpm while maintaining the temperature of the wet granulation between 22.9°C and 25.4°C.

[0310] Specific properties of pharmaceutical granulation (4) are shown in FIG.

[0311] The size distribution of the granules before and after 20 minutes of wet massing is shown in Figure 4A, and SEM images of the resulting granules are shown in Figures 4B and 4C at magnifications of 110x and 340x, respectively.

[0312] Example 5 Pharmaceutical granules(5) The components of the dry blend in weight percent are shown in Table 1. The active pharmaceutical ingredient was passed through a Comil® fitted with a 0.045 inch screen before being added to the dry blend. The active pharmaceutical ingredient was not jet milled.

[0313] A total of 5.0 wt.% water was added during the wet granulation, with the wt.% being based on the total weight of the dry mixture. The water was added using a syringe and a two-fluid spray nozzle with the atomizing air set at 4 psi. The wet granulation was granulated for 10 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0314] After the initial granulation, the sub-batches were mixed in a jacketed bowl for the first wet massing. The initial granulation was wet massed for 20 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm. During wet massing, the temperature was maintained at 21°C to 22°C using a water chiller attached to the jacketed 4 L bowl.

[0315] After wet massing, a second wet granulation was carried out during which an additional amount of 6.5 wt % water was added at a mixer speed of 547 rpm and a chopper speed of 1800 rpm.

[0316] After the second wet granulation, a second wet massing was performed. The second wet granulation was wet massed for an additional 40 minutes with a mixer speed of 547 rpm and a chopper speed of 3600 rpm. The bowl temperature was maintained between 24°C and 31°C.

[0317] Specific properties of pharmaceutical granulation (5) are shown in FIG.

[0318] The size distribution of the granules during wet massing is shown in Figure 5A, and SEM images of the resulting granules are shown in Figures 5B and 5C at magnifications of 110x and 340x, respectively.

[0319] Example 6 Pharmaceutical granules(6) The components of the dry blend in weight percent are shown in Table 1. The active pharmaceutical ingredient was passed through a Comil® fitted with a 0.045 inch screen before being added to the dry blend. The active pharmaceutical ingredient was not jet milled.

[0320] A total of 5.0 wt.% water was added during the wet granulation, with the wt.% being based on the total weight of the dry mixture. The water was added using a syringe and a two-fluid spray nozzle with the atomizing air set at 4 psi. The wet granulation was granulated for 10 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0321] After the initial granulation, the two sub-batches were mixed in a jacketed bowl for the first wet massing. The initial granulation was wet massed for 20 minutes at a mixer speed of 547 rpm and a chopper speed of 1,800 rpm. During wet massing, the temperature was maintained at 21°C to 22°C using a water chiller attached to the jacketed 4 L bowl.

[0322] After wet massing, a second wet granulation was carried out during which an additional amount of 3.0 wt % water was added at a mixer speed of 850 rpm and a chopper speed of 3600 rpm.

[0323] After the second wet granulation, a second wet massing was performed. The second wet granulation was wet massed for an additional 30 minutes with a mixer speed of 547 rpm and a chopper speed of 3600 rpm. During the second wet massing, the bowl temperature was maintained at 18°C ​​to 21°C.

[0324] Specific properties of pharmaceutical granulation (6) are shown in FIG.

[0325] The size distribution of the granules during wet massing is shown in Figure 6A, and SEM images of the resulting granules are shown in Figures 6B and 6C at magnifications of 110x and 340x, respectively.

[0326] Example 7 Pharmaceutical granules(7) The components of the dry blend in weight percent are shown in Table 1. A different lot of active pharmaceutical ingredient was used in this granulation. The active pharmaceutical ingredient had less agglomeration than the active pharmaceutical ingredient used in Examples 1-6. The active pharmaceutical ingredient was passed through a Comil® equipped with a 0.045 inch screen before being added to the dry blend. The active pharmaceutical ingredient was not wet milled.

[0327] A total of 5.0 wt.% water was added during the wet granulation, with the wt.% being based on the total weight of the dry mixture. The water was added using a syringe and a two-fluid spray nozzle with the atomizing air set at 4 psi. The wet granulation was carried out for 9.7 minutes with a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0328] The wet granulation was wet massed for a maximum of 20 minutes with a mixer speed of 547 rpm and a chopper speed of 1,800 rpm while maintaining a temperature of 21°C.

[0329] Specific properties of pharmaceutical granulation (7) are shown in FIG.

[0330] The size distribution of the granules during wet massing is shown in Figure 7A, and SEM images of the resulting granules are shown in Figures 7B and 7C at magnifications of 110x and 340x, respectively.

[0331] Example 8 Pharmaceutical granules(8) The components of the dry blend in weight percent are shown in Table 1. The active pharmaceutical ingredient used in Example 8 was the same as that used in Examples 7 and 9.

[0332] A total of 4.8 wt% water was added during the wet granulation, with the wt% based on the total weight of the dry mixture. The water was added using a syringe and a two-fluid spray nozzle with the atomizing air set at 4 psi. The wet granulation was carried out for 11.5 minutes with a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0333] The wet granulation was wet massed for up to 60 minutes at a mixer speed of 547 rpm and a chopper speed of 1,800 rpm while the temperature of the wet granulation was maintained between 21°C and 23.5°C.

[0334] Specific properties of pharmaceutical granulation (8) are shown in FIG.

[0335] The size distribution of the granules during wet massing is shown in Figure 8A, and SEM images of the resulting granules are shown in Figures 8B and 8C at magnifications of 34x and 110x, respectively.

[0336] Example 9 Pharmaceutical granules(9) The active pharmaceutical ingredient, having a bulk density of 0.263 g / mL, was passed through a Comil® equipped with a 0.056 inch screen. Prior to co-milling, the active pharmaceutical ingredient was stored in a dry environment.

[0337] The components of the dry mix in weight percent are given in Table 1.

[0338] Distilled water (4.7 wt%) was added to the dry mixture using a two-fluid spray nozzle with a pump and atomizing air set at 4 psi.

[0339] The granulation was held in a jacketed 4 liter bowel throughout processing.

[0340] The wet granulation was carried out for 9.7 minutes with a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0341] The wet granulation was wet massed for up to 60 minutes at a mixer speed of 547 rpm and a chopper speed of 1,800 rpm, while the temperature of the wet granulation was 23.1° C. to 23.6° C. A cooler was attached to the intestine to maintain a temperature below 25° C. during wet massing.

[0342] The conditions during wet massing are shown in Table 2. [Table 2]

[0343] The evolution of the PSD during wet agglomeration is shown in Figure 9A. The number of fine and large particles continued to decrease during wet agglomeration.

[0344] A more detailed PSD of the granulation after 60 minutes of wet massing as determined using laser diffraction is shown in Figure 9F.

[0345] SEM images of the granules are shown in Figures 9B-9E at magnifications of 110x, 220x, 1,000x, and 2,000x, respectively.

[0346] Example 10 Active Pharmaceutical Ingredient Characterization 10A and 10B show the particle size distributions of granules prepared from unmilled and milled active pharmaceutical ingredient, respectively. The active pharmaceutical ingredient was the same as that used in Examples 7-9 and had a purity of 99.3%.

[0347] The active pharmaceutical ingredient used in Examples 1 to 6 had a bulk density of 0.15 g / mL.

[0348] The active pharmaceutical ingredients used in Examples 12 and 13 generally had different morphologies characterized by larger crystal sizes (Figures 13-18). The as-crystallized active pharmaceutical ingredients were jet milled to reduce the crystal size to less than about 20 μm.

[0349] FIG. 13 shows an SEM image of the as-crystallized active pharmaceutical ingredient at 700x magnification.

[0350] FIG. 14 shows an SEM image of the jet-milled active pharmaceutical ingredient at 700x magnification.

[0351] 15 and 16 show the particle size distributions of the as-crystallized and jet-milled active pharmaceutical ingredient, respectively, as determined by laser diffraction. The PSD of the as-crystallized active pharmaceutical ingredient was characterized by a D10 of 11.8 μm, a D50 of 34.0 μm, and a D90 of 72.3 μm. The PSD of the jet-milled active pharmaceutical ingredient was characterized by a D10 of 7.8 μm, a D50 of 16.1 μm, and a D90 of 21.5 μm.

[0352] The specific surface area distribution of the as-crystallized and jet-milled active pharmaceutical ingredients was determined by laser diffraction. The as-crystallized active pharmaceutical ingredient had a specific surface area of ​​291 m 2 / kg, and the jet mill active pharmaceutical ingredient is 478m 2 In other samples, the jet milled active pharmaceutical ingredient had a specific surface area of ​​1174 m 2 It was characterized by a specific surface area of ​​1000 kJ / kg.

[0353] The specific properties of the active pharmaceutical ingredients used in Example 13 are shown in Table 3. [Table 3]

[0354] Example 11 Friability measurement Granules between 200 μm and 350 μm were separated using 45-mesh and 70-mesh screens. The screened granulation was placed on a 200-mesh screen in a sonic sieve and then exposed to a very high amplitude of 8, corresponding to 3,600 sonic energy pulses per minute, for 2 minutes. The granulation was weighed before and after exposure to sonic vibration. Approximately 1.02% by weight of the material passed through the 200-mesh screen. This material is considered to be fines resulting from attrition of the granules and is defined as friability.

[0355] Example 12 Pharmaceutical Granules(12) A granulation composition (800.0 g) was prepared by blending 98.5 wt% active pharmaceutical ingredient (394.0 g), 0.5 wt% binder (2.0 g), and 1.0 wt% antistatic agent (4.0 g), where the weight percentages were based on the total weight of the blend. The active pharmaceutical ingredient was the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, which was jet-milled. The binder was Klucel® EXF HPC (hydroxypropyl cellulose) (Ashland). The antistatic agent was Aerosil® 200 (hydrophilic fumed silica, BWT SA 200 m / g) (Evonik Industries). Milling was performed using Comil® (Quadro Engineering).

[0356] The active pharmaceutical ingredient was milled with a 32R screen, a square impeller, and a 0.175 inch spacer at 1349.8 rpm.

[0357] The composition was separated into two 400 g batches for granulation. Each sub-batch was granulated for approximately 6.75 minutes, and 12.1 g of water was added at a rate of approximately 1.8 g / min using 3.0 psi atomizing air pressure. The bed height was 4.0 cm. The mixer speed was 850 rpm, and the chopper speed was 3600 rpm.

[0358] Two sub-batches were mixed for wet massing.

[0359] The composition was wet massed for 10 minutes at a final temperature of 24.7°C with a bed height of 8.0 cm and a mixer speed of 547 rpm and a chopper speed of 1800 rpm.

[0360] After wet massing, the composition was wet milled using a 32R screen size, a square impeller, and a 0.175 inch spacer at a speed of 3000 rpm.

[0361] The wet-milled composition was then granulated for 22 minutes with the addition of 41 g (10.25 wt %) of water at a flow rate of 1.8 g / min and an atomizing air pressure of 3 psi. The bed height was 6.0 cm. The mixer speed was 850 rpm and the chopper speed was 3600 rpm.

[0362] The granulated composition was wet massed for 40 minutes at a temperature of 24.7°C to 30.9°C with a final bed height of 5.2 cm, a mixer speed of 547 rpm, and a chopper speed of 1800 rpm.

[0363] The granules were oven dried at 40°C for 20 hours.

[0364] The dried granules had a bulk density of 0.41 g / mL, a Hausner ratio of 1.38, and a viscosity of 1174 m 2 / kg surface area.

[0365] Example 13 Pharmaceutical Granules(13) A formulation (400.0 g) was prepared by mixing 98.5 wt. % active pharmaceutical ingredient (394.0 g), 0.5 wt. % binder (2.0 g), and 1.0 wt. % antistatic agent (4.0 g), where the wt. % was based on the total weight of the formulation. The active pharmaceutical ingredient was the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, which was jet-milled. The binder was Klucel® EXF HPC (hydroxypropyl cellulose) (Ashland). The antistatic agent was Aerosil® 200 (hydrophilic fumed silica, BWT SA200m 2 / g) (Evonik Industries). Milling was performed using Comil® (Quadro Engineering).

[0366] The formulation was granulated using a GMX Granumeist® high shear granulator (Freund-Vector Corporation) using a 4 L jacketed bowl equipped with an impeller and chopper.

[0367] The dry formulation was divided into two 400 g sub-batches for wet granulation.

[0368] In the first wet granulation step, a total of 9.0 wt. % (18.1 g) of water was added during the wet granulation, where wt. % is based on the total weight of the dry formulation sub-batch. Water was added dropwise into the mixing bowl at a rate of approximately 2.0 g / min. The wet granulation was carried out for approximately 9.3 minutes at an average wet granulation temperature of approximately 25°C, a mixer speed of 850 rpm, and a chopper speed of 3,600 rpm. The bed height was reduced by approximately 40% from 7.0 cm to 4.0 cm.

[0369] In the first wet massing step, the wet granulated sub-batches were mixed and wet massed for approximately 20 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at an average wet granulation temperature of 20.0° C. to 23.4° C. The bed height was reduced by approximately 30%, from 7.0 cm to 5.0 cm.

[0370] In the second granulation step, the product of the first wet massing step was granulated for 26.7 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at an average wet granulation temperature of 25.2° C. Water (53.6 g) was added by spraying at a distance of 4.19 cm from the granulation bed using an atomizing air pressure of 4.0 psi. The bed height was reduced from 5.0 cm to 4.0 cm.

[0371] In the second wet massing step, the second wet granulation was wet massed for 40 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at a wet granulation temperature of about 30° C. to 40° C. The bed height was reduced by about 12%, from 4.0 cm to 3.5 cm.

[0372] In the third granulation step, the product of the second wet massing step was granulated for 8.4 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at an average wet granulation temperature of 25.2° C. Water (17.3 g) was added by spraying at a distance of 5.69 cm from the granulation bed using an atomizing air pressure of 4.0 psi. The bed height remained the same at approximately 3.5 cm.

[0373] In the third wet massing step, the third wet granulation was wet massed for 20 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at a wet granulation temperature of about 30° C. to 40° C. The bed height was reduced by about 14%, from 3.5 cm to 3.0 cm.

[0374] In the fourth granulation step, the product of the third wet massing step was granulated for 8.3 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at an average wet granulation temperature of 25.2° C. Water (17.3 g) was added by spraying at a distance of 5.9 cm from the granulation bed using an atomizing air pressure of 4.0 psi. The bed height was reduced from 3.0 cm to 2.8 cm.

[0375] In the fourth wet massing step, the third wet granulation was wet massed for 20 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at a wet granulation temperature of about 19° C. to 20° C. The bed height remained approximately the same at 3.0 cm.

[0376] The product of the fourth wet massing step was then wet milled using a Comil® fitted with a 032R screen using a square impeller, 0.150 inch spacers, at a milling speed of 3005 rpm.

[0377] In the fifth wet massing step, the wet-milled granulation was wet massed for 20 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm at a wet granulation temperature of 15° C. to 25° C. The bed height was reduced from 3.0 cm to 2.4 cm.

[0378] The product of the fifth wet massing step was dried at 40°C for 19 hours.

[0379] A summary of the processing conditions used to prepare pharmaceutical granules (13) is shown in Table 4. [Table 4]

[0380] Approximately 35% of the granules had a particle size greater than 500 μm, 53% had a particle size between 210 μm and 500 μm, and 28% had a particle size less than 210 μm, particle sizes being determined by sieve analysis.

[0381] Specific properties of pharmaceutical granules (13) are shown in Table 5. [Table 5]

[0382] Figures 19 and 20 show photographs of the granules at 100x and 240x magnification, respectively.

[0383] It should be noted that there are alternative ways of implementing the embodiments disclosed herein. Accordingly, the present embodiments should be considered as illustrative and not restrictive. Moreover, the claims are not limited to the details given herein, but are entitled to their full scope and equivalents.

[0384] [Claim 1] A granulated product containing a plurality of granules, the granules comprise greater than 95 wt. % of an active pharmaceutical ingredient (API), the wt. % being based on the total weight of the granulation; A granulation, wherein the active pharmaceutical ingredient has a water solubility of greater than 100 mg / mL. [Claim 2] 2. The granulation of claim 1, wherein the active pharmaceutical ingredient is characterized by a particle size distribution characterized by a D90 of less than 30 μm. [Claim 3] The active pharmaceutical ingredient is 200m 2 / kg~1200m 2 3. The granule according to claim 1 or 2, characterized by a specific surface area of ​​1000 kJ / kg, wherein the specific surface area is determined using laser diffraction. [Claim 4] 4. The granulation product according to claim 1, wherein the active pharmaceutical ingredient is characterized by a bulk density of 0.1 g / mL to 0.4 g / mL, the bulk density being determined according to USP 616, Method 1. [Claim 5] 5. The granulation product according to claim 1, wherein the active pharmaceutical ingredient has a bulk density of 0.15 g / mL to 0.35 g / mL, and the bulk density is determined using USP 616, Method I. [Claim 6] 6. The granule according to claim 1, wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL. [Claim 7] 7. The granule according to claim 1, wherein the granules contain 96% to 99.5% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the granules. [Claim 8] 8. The granule according to claim 1, wherein the granule is characterized by a particle size distribution (PSD) characterized by a D50 of 150 μm to 500 μm, the particle size distribution being determined by laser diffraction or sieve analysis. [Claim 9] 8. The granule according to claim 1, wherein the granule is characterized by a particle size distribution D50 of 200 μm to 400 μm, the particle size distribution being determined by laser diffraction or sieve analysis. [Claim 10] The granulated product is Particle size distribution D10 between 50 μm and 250 μm, and It features a particle size distribution D90 of 400 μm to 750 μm, 8. The granulated product according to claim 1, wherein the particle size distribution is determined by laser diffraction or sieve analysis. [Claim 11] The granulated product is Particle size distribution D10 between 80 μm and 120 μm, and It features a particle size distribution D90 of 510 μm to 650 μm, 8. The granulated product according to claim 1, wherein the particle size distribution is determined by laser diffraction or sieve analysis. [Claim 12] 12. The granule according to claim 1, wherein the granule has a bulk density of 0.50 g / mL to 1.20 g / mL, the bulk density being determined according to USP 616, Method I. [Claim 13] 13. The granule according to claim 1, wherein the granule has a bulk density of 0.40 g / mL to 0.80 g / mL, the bulk density being determined according to USP 616, Method I. [Claim 14] 14. The granule according to any one of claims 1 to 13, wherein the granule is characterized by a loss on drying (LOD) of 0.05 wt% to 1.5 wt%, the weight % being based on the weight of the granule after drying. [Claim 15] 14. A granulated product according to any one of claims 1 to 13, wherein the granulated product is characterized by a loss on drying (LOD) of 0.2 wt% to 1.2 wt%, the weight % being based on the weight of the granulated product after drying. [Claim 16] 16. The granule according to any one of claims 1 to 15, wherein the granule is characterized by a friability of less than 2 wt.%, where wt.% is based on the total weight of the granule, and the friability is determined using a sieve shaker according to the method described in the Examples. [Claim 17] 16. The granule according to any one of claims 1 to 15, wherein the granule is characterized by a friability of less than 1.10 wt.%, where wt.% is based on the total weight of the granule, and the friability is determined using a sieve shaker according to the method described in the Examples. [Claim 18] 16. The granule according to any one of claims 1 to 15, wherein the granule is characterized by a friability of less than 1.02 wt.%, where wt.% is based on the total weight of the granule, and the friability is determined using a sieve shaker according to the method described in the Examples. [Claim 19] 19. The granules according to claim 1, wherein the granules are characterized by a sphericity of 0.90 to 1.00, the sphericity being determined by dynamic image analysis. [Claim 20] 20. A granulated product according to any one of claims 1 to 19, wherein the granules are characterized by a surface roughness substantially as shown in Figures 9B to 9E. [Claim 21] 20. A granulated product according to claim 1, wherein the granules have a surface roughness substantially as shown in Figures 19-20. [Claim 22] 22. The granule according to claim 1, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharmaceutically acceptable salt thereof. [Claim 23] 22. The granule according to claim 1, wherein the active pharmaceutical ingredient comprises a derivative of gamma-hydroxybutyric acid or a pharmaceutically acceptable salt thereof. [Claim 24] The active pharmaceutical ingredient is a compound of formula (2): [C1] JPEG0007824387000015.jpg2791 or a pharmaceutically acceptable salt thereof, wherein: R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3 Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 22. The granule according to any one of claims 1 to 21, wherein the cycloalkoxycarbonyl is independently selected from cycloalkoxycarbonyls. [Claim 25] The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, a pharmaceutically acceptable salt of any of the foregoing, and 22. The granulated product according to claim 1, which is selected from any of the above combinations. [Claim 26] The granule according to any one of claims 1 to 21, wherein the active pharmaceutical ingredient is 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof. [Case 2] JPEG0007824387000016.jpg2891 [Claim 27] The granules are a binder; and 27. The granule according to claim 1, further comprising an antistatic agent. [Claim 28] 28. The granule of claim 27, wherein the granules comprise no more than 2% by weight of the binder, the weight percent being based on the total weight of the granules. [Claim 29] 29. A granule according to claim 27 or 28, wherein the granules comprise no more than 1.5 wt. % of the antistatic agent, the wt. % being based on the total weight of the granule. [Claim 30] The granules are 98% to 99% by weight of the active pharmaceutical ingredient; 0.25% to 0.75% by weight of the binder, and 0.5% by weight to 1.5% by weight of the antistatic agent, 30. The granule according to any one of claims 27 to 29, wherein the weight percentages are based on the total weight of the granules. [Claim 31] The granules are greater than 98.5% by weight of said active pharmaceutical ingredient; 0.5% by weight or less of said binder, and 1.0 wt. % or less of said antistatic agent; 30. The granule according to any one of claims 27 to 29, wherein the weight percentages are based on the total weight of the granules. [Claim 32] 32. The granule according to claim 27, wherein the binder comprises hydroxypropyl cellulose. [Claim 33] 33. The granulation of claim 32, wherein the hydroxypropyl cellulose comprises a size distribution characterized by a D10 of 10 μm to 35 μm, a D50 of 45 μm to 90 μm, and a D90 of 100 μm to 300 μm. [Claim 34] 34. The granule according to claim 32 or 33, wherein the hydroxypropyl cellulose has a weight average molecular weight of 50,000 to 110,000 daltons. [Claim 35] 35. The granule according to any one of claims 32 to 34, wherein the hydroxypropyl cellulose has a viscosity of 300 mPa x sec to 600 mPa x sec when determined using a Brookfield viscometer at 25°C. [Claim 36] 36. The granule according to claim 30, wherein the antistatic agent comprises hydrophilic fumed silica. [Claim 37] 37. The granulation of claim 36, wherein the hydrophilic fumed silica has an SiO content of more than 99.8% based on pyrotechnic material. [Claim 38] The hydrophilic fumed silica is 175 m 2 / g~225m 2The granule according to claim 36 or 37, having a specific surface area (BET) of 1000 sq. ft. / g. [Claim 39] 38. The granule according to claim 36 or 37, wherein the hydrophilic fumed silica has a pH value of 3.7 to 4.5 in a 4% aqueous dispersion. [Claim 40] 38. The granule of claim 36 or 37, wherein the hydrophilic fumed silica has an LOD of less than 1.5 wt.%. [Claim 41] 38. The granulated product according to claim 36 or 37, wherein the hydrophilic fumed silica has a tap density of 30 g / L to 70 g / L. [Claim 42] 42. The granule according to any one of claims 1 to 41, wherein the granules comprise a coating. [Claim 43] 43. The granule of claim 42, wherein the granule comprises 1% to 10% by weight of the coating, the weight percent being based on the total weight of the granule. [Claim 44] 44. The granulation of claim 42 or 43, wherein the coating comprises a seal coating, a controlled release coating, or a combination thereof. [Claim 45] A pharmaceutical composition comprising the granule according to any one of claims 1 to 44. [Claim 46] 46. ​​The pharmaceutical composition of claim 45, wherein the pharmaceutical composition comprises an oral formulation. [Claim 47] 47. The pharmaceutical composition of claim 45 or 46, wherein the oral formulation comprises an oral suspension. [Claim 48] 48. The pharmaceutical composition of any one of claims 45 to 47, wherein the pharmaceutical composition comprises an immediate release formulation. [Claim 49] 49. The pharmaceutical composition of any one of claims 45 to 48, wherein the pharmaceutical composition comprises a controlled release formulation. [Claim 50] A method for preparing the granules according to any one of claims 1 to 44, comprising: mixing the active pharmaceutical ingredient, a binder, and an antistatic agent to form a dry mix; wet granulating the dry mixture to obtain a wet granulation product; wet agglomerating the wet granulation to obtain a wet agglomerated product; drying said wet mass granulation to obtain said granulation. [Claim 51] 51. The method of claim 50, wherein wet granulating the dry mixture comprises wet granulating for 5 minutes to 10 minutes. [Claim 52] 52. The method of claim 50 or 51, wherein wet granulating comprises adding 5% to 20% by weight total water, wherein the weight percentage is based on the total weight of the active pharmaceutical ingredient. [Claim 53] 53. The method according to any one of claims 50 to 52, wherein the temperature of the wet granulate is between 20°C and 25°C during wet granulation. [Claim 54] 54. The method of any one of claims 50 to 53, wherein wet massing the wet granulation comprises wet massing for 30 minutes to 60 minutes. [Claim 55] 55. The method of any one of claims 50 to 54, wherein the method comprises repeating the wet granulating and wet massing steps one or more times before the drying step. [Claim 56] 56. The method of any one of claims 50 to 55, wherein the method comprises repeating the wet granulating and wet massing steps one or more times before the drying step until the specific gravity of the granulation does not increase significantly. [Claim 57] Wet granulation can granulating the dry mixture for 5 to 15 minutes at a mixer speed of 800 rpm to 900 rpm and a chopper speed of 3200 rpm to 4000 rpm; adding water at a rate of 0.0025 wt% / min to 0.0075 wt% / min, wherein the wt% is based on the total weight of the dry mix; 57. The method of any one of claims 50 to 56, comprising maintaining the temperature of the wet granulation at a temperature of 20°C to 25°C during wet granulation. [Claim 58] Wet granulation can Granulating for 5 to 60 minutes at a mixer speed of 850 rpm and a chopper speed of 3600 rpm; adding water at a rate of 0.005 wt% / min, wherein wt% is based on the total weight of the mixture; and maintaining the temperature of the wet granulation at 20°C to 25°C. [Claim 59] Wet agglomeration can be Wet massaging for 30 to 60 minutes at a mixer speed of 550 rpm and a chopper speed of 1,500 rpm to 2,100 rpm; and maintaining the temperature of the wet granulation at a temperature of from 15°C to 25°C. [Claim 60] Wet agglomeration can be Wet massaging for 30 to 60 minutes with a mixer speed of 500 rpm to 600 rpm and a chopper speed from 1800 rpm; and maintaining the temperature of the wet granulation at 20°C to 25°C. [Claim 61] 59. The method of any one of claims 50 to 58, wherein the binder comprises hydroxypropyl cellulose. [Claim 62] 59. The method of any one of claims 50 to 58, wherein the antistatic agent comprises hydrophilic fumed silica. [Claim 63] The mixture greater than 95% by weight of said active pharmaceutical ingredient; More than 0.25% by weight of a binder, and 59. The method of any one of claims 50 to 58, comprising more than 0.5 wt% of an antistatic agent, the wt% being based on the total weight of the mixture. [Claim 64] The mixture 98% to 99% by weight of the active pharmaceutical ingredient; 0.25% to 0.75% by weight of a binder, and 0.5% by weight to 1.5% by weight of an antistatic agent; 59. The method of any one of claims 50 to 58, wherein the weight percentages are based on the total weight of the mixture. [Claim 65] The mixture 98.2% to 98.8% by weight of the active pharmaceutical ingredient; 0.3% to 0.7% by weight of a binder, and 0.8% by weight to 1.2% by weight of an antistatic agent; 59. The method of any one of claims 50 to 58, wherein the weight percentages are based on the total weight of the mixture. [Claim 66] 66. The method of any one of claims 50 to 65, wherein after drying, the wet granulation comprises 0.025% to 0.075% by weight of water, the weight percentage being based on the total weight of the wet granulation. [Claim 67] 67. The method of any one of claims 50 to 66, wherein after drying, the wet granulation contains 0.05% by weight of water, the weight percentage being based on the total weight of the wet granulation.

Claims

1. A granulation for oral administration comprising a plurality of granules, the granules comprising more than 95% by weight of a compound of formula (2a), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; 0.1% to 3.0% by weight of hydroxypropyl cellulose; and 0.1 wt. % to 2.0 wt. % hydrophilic fumed silica; wherein the weight percentages are based on the total weight of the granules; The granules are characterized by: a particle size distribution (PSD) characterized by a D50 of 150 μm to 500 μm, said particle size distribution being determined by laser diffraction or sieve analysis; and the granules have a friability of less than 2% by weight, the friability being determined using sonic sieving; The granulated product.

2. The granules are More than 98.5% by weight of the compound of formula (2a), 0.5% by weight or less of said hydroxypropyl cellulose, and 1.0 wt. % or less of said hydrophilic fumed silica; The granulation of claim 1 , wherein the weight percentages are based on the total weight of the granules.

3. The granules are 98% to 99% by weight of the compound of formula (2a), 0.25% to 0.75% by weight of said hydroxypropyl cellulose, and 0.5% to 1.5% by weight of said hydrophilic fumed silica; The granulation of claim 1 , wherein the weight percentages are based on the total weight of the granules. The granulated product according to claim 1.

4. The granulated product is A particle size distribution D10 of 50 μm to 250 μm, and characterized by a particle size distribution D90 of 400 μm to 750 μm; The granulation of claim 1, wherein the particle size distribution is determined by laser diffraction or sieve analysis.

5. 10. The granulation of claim 1, wherein the granulation has a bulk density of 0.50 g / mL to 1.20 g / mL, wherein the bulk density is determined according to USP 616, Method I.

6. The granule of claim 1 , wherein the granule comprises a coating.

7. The granulation of claim 6 , wherein the coating comprises a controlled release coating.

8. A pharmaceutical composition comprising the granules according to claim 1.

9. 10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises an oral formulation.

10. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises immediate release granules.

11. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises controlled release granules.

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