Process for preparing aggregated crystalline medium-chain sodium fatty acid salts

Abstract

The process of the present invention is used to prepare agglomerated crystalline particles of a medium chain fatty acid sodium salt, such as sodium caprate. The process includes: (a) dissolving a medium chain fatty acid in a first solvent, where the first solvent comprises an aprotic polar solvent, to produce a first solution; (b) adding a solution comprising (i) a second solvent, where the second solvent comprises a medium chain aliphatic hydrocarbon solvent, and (ii) a sodium salt of a short chain alcohol, to the first solution to produce a resulting slurry; and (c) isolating the agglomerated crystals from the resulting slurry. The first solvent can comprise acetonitrile, and the second solvent can comprise heptane. Additionally, products produced by the process, such as sodium caprylate products, having excellent flowability and compressibility properties, are also provided.

Description

[Background technology]

[0001] Sodium salts of medium-chain saturated organic acids are surprisingly difficult to crystallize. These molecules have a strong tendency to gel, resulting in unstable batch conditions in most solvent systems. The natural crystalline forms of these compounds are long fibers / needles that readily entrain solvents, making isolation difficult with standard instrumentation, and they possess undesirable powder properties for formulation. Most commercially available materials of this type are very expensive and retain suboptimal fibrous forms, either isolated by spray drying or formed from dense, unagitable slurries.

[0002] Sodium caprate (or sodium decanoate) is the sodium salt of capric acid, a saturated fatty acid with 10 carbon atoms, and can form micelles and liquid crystal phases in aqueous solutions. Sodium caprate can assist in the transport of biologically active molecules and can play a role in enhancing the bioavailability of APIs as an FDA-approved food additive and a component of finished pharmaceuticals. Furthermore, sodium caprate is a known intestinal permeation enhancer. There are known methods for preparing sodium caprate, including the synthetic method described in "B. Zacharie, et al., Organic Process Research & Development 2009, 13, 581-583", but in these preparation methods, unlike the present invention, the sodium caprate material gels regardless of which of many solvent systems are used. Gelation makes it difficult to use sodium caprate (powder) in large-scale manufacturing and is not practical. However, in the few solvent systems where gelation can be suppressed, sodium caprate crystallizes into small, thin needles or fibers, resulting in a non-stirrable slurry. As a result, these slurries pose their own problems as they are difficult to transfer from one equipment train to another (e.g., from a crystallization tank to a filter / dryer or centrifuge). Furthermore, these particles have poor filterability and a significant amount of interstitial liquid is incorporated, resulting in excessive aggregation during drying. Considerable energy input is required to crush the formed cake, resulting in the formation of hard chunks that are widely dispersed and affect the blendability of the material. These particles are also prone to cracking or breaking. Overall, it is very difficult to isolate sodium caprate on an industrial scale. As a potential result of these formulation challenges, the GMP supply of sodium caprate is limited.

[0003] Therefore, there are regulatory and technical barriers to the industrial use of caprates as excipients in pharmaceutical formulations.

Prior Art Documents

Non-Patent Documents

[0004] [Non-Patent Document 1] B. Zacharie, et al., Organic Process Research & Development 2009, 13, 581-583 [Overview of the project] [Problems that the invention aims to solve]

[0005] This disclosure provides a process for producing a solid, aggregate with adjustable particle size that has superior powder flow properties and compressible behavior compared to commercially available alternatives. The process is cost-effective and produces a material with excellent flow and compressible properties, making it suitable for use in manufacturing processes and as an excipient in final pharmaceutical products. The process is also scalable, as it can produce large quantities of solid material. In various embodiments, the process encompasses a method for producing medium-chain sodium fatty acid salts, such as sodium caprate.

[0006] Furthermore, the products generated by the process are also provided herein. These products are solid crystalline powders that can function as excipients in drug formulations and have superior flow and compressibility properties compared to commercially available medium-chain sodium fatty acid salts. These products are substantially free of gelation or dispersion of fibrous or needle-like crystals. [Means for solving the problem]

[0007] The present invention (a) Dissolving a medium-chain fatty acid in a first solvent (where the first solvent includes an aprotic polar solvent) to produce a first solution; (b) A step of preparing a slurry by adding (i) a second solvent (wherein the second solvent is a medium-chain aliphatic hydrocarbon solvent) and (ii) a solution containing the sodium salt of a short-chain alcohol to the first solution; and (c) A step of isolating aggregated crystals from the slurry obtained above; This relates to a process for preparing aggregated crystals of sodium salts of medium-chain fatty acids, including [specific component].

[0008] In various embodiments, the first solvent includes or is an aprotic polar solvent. While not wishing to be bound by theory, aprotic polar solvents are particularly suitable for dissolving medium-chain fatty acids (e.g., capric acid) while avoiding excessive solubilization of crystalline products (e.g., sodium caprate). In some embodiments, the first solvent includes an aprotic polar solvent selected from acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMAC), and n-methyl-2-pyrrolidone (NMP). In some embodiments, the second solvent includes a medium-chain aliphatic hydrocarbon solvent selected from heptane, hexane, and octane. In some embodiments, the second solvent includes a solvent selected from heptane and hexane. Thus, in some embodiments, the process is (a) Dissolving medium-chain fatty acids in an aprotic polar solvent selected from acetonitrile, DMF, DMAC, and NMP to produce a first solution; (b) Adding approximately 1 molar equivalent of a solution containing an aliphatic hydrocarbon solvent selected from heptane and hexane, and a sodium salt of a short-chain alcohol, to the first solution to prepare the resulting slurry; and (c) The step of isolating aggregated crystals from the obtained slurry; Includes.

[0009] In some embodiments, the process is (a) A step of dissolving medium-chain fatty acids in acetonitrile to produce a first solution; (b) Adding approximately 1 molar equivalent of a solution containing heptane and a sodium salt of a short-chain alcohol to the first solution to prepare the resulting slurry; and (c) The step of isolating aggregated crystals from the obtained slurry; Includes.

[0010] In some embodiments, the sodium salt of the short-chain alcohol is sodium methoxide. In some embodiments, the solution containing the sodium salt of the short-chain alcohol contains methanol or ethanol. In certain embodiments, the solution contains methanol. In certain embodiments, the solution containing the sodium salt of the short-chain alcohol contains methanol and sodium methoxide.

[0011] In various embodiments, a solution containing a second solvent and a sodium salt of a short-chain alcohol is added separately to the first solution. This is referred to in this disclosure as addition via “separate supply lines”.

[0012] In various embodiments, the aggregated crystals in the resulting slurry contain sodium caprate. This aggregated crystalline product may be referred to herein as "Product A".

[0013] Other embodiments, aspects, and features of the present invention will be further described in or become apparent in the following description, examples, and appended claims. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 shows powder X-ray diffraction data for product A using the present invention, compared with a commercially available substitute for sodium caprate. [Figure 2] Figure 2 shows a differential scanning calorimeter (DSC) scan of product A. [Figure 3] Figure 3 shows the thermogravimetric analysis of product A. [Figure 4] Figure 4 shows the particle size analysis of product A. [Figure 5] Figure 5 shows a scanning electron microscope (SEM) image of product A. [Figure 6] Figure 6 is a graph showing the compressibility of a solid dosage form of an aggregated material (product A) containing one or more compression aids, compared to the corresponding commercially available form of crystalline sodium caprate. [Figure 7]Figure 7 shows SEM images comparing the commercial form of sodium caprate crystals with product A. [Figure 8] Figure 8 is a SEM image of sodium pelargonate crystals formed in acetonitrile and heptane. [Figure 9] Figure 9 is a SEM image of sodium laurate crystals formed in acetonitrile and heptane. [Figure 10] Figure 10 shows optical microscope images demonstrating the formation of sodium caprate aggregates using different aprotic polar organic solvents (NMP and DMAC) and heptane. [Figure 11] Figure 11 shows SEM images of sodium caprate crystals formed in acetonitrile and hexane. [Figure 12] Figure 12 shows SEM images of sodium caprate crystals formed in acetonitrile and heptane using 1 L / kg (1V) and 2 L / kg (2V) of acetonitrile. [Figure 13] Figure 13 shows a photograph taken during the implementation of an exemplary process used to produce approximately 1.0 kg of aggregated sodium caprate crystal product. This product is shown in the lower rectangular glass dish.

Mode for Carrying Out the Invention

[0015] The present invention provides (a) dissolving a medium-chain fatty acid in a first solvent (where the first solvent includes an aprotic polar solvent selected from acetonitrile, DMF, DMAC, and NMP) to produce a first solution; (b) adding a solution containing (i) a second solvent (where the second solvent includes a medium-chain aliphatic hydrocarbon solvent selected from heptane, hexane, and octane), and (ii) a sodium salt of a short-chain alcohol, to the first solution to produce the resulting slurry; and (c) isolating the aggregated crystals from the resulting slurry. This relates to a process for preparing aggregated crystals of sodium salts of medium-chain fatty acids, including [specific component].

[0016] In the first embodiment, the first solvent in the process contains acetonitrile, and the second solvent contains heptane. Therefore, in this embodiment, the present invention is (a) A step of dissolving medium-chain fatty acids in acetonitrile to produce a first solution; (b) Adding a solution containing heptane and a sodium salt of a short-chain alcohol to the first solution to prepare the resulting slurry; and (c) The step of isolating aggregated crystals from the obtained slurry; This relates to a process for preparing aggregated crystals of sodium salts of medium-chain fatty acids, including [specific component].

[0017] In various embodiments, the medium-chain fatty acid comprises capric acid, and the first solvent comprises acetonitrile.

[0018] In a further embodiment of the first embodiment, in step (b), a solution containing heptane and a sodium salt of a short-chain alcohol (e.g., sodium methoxide in methanol) is added to the first solution to induce liquid-liquid phase separation and create the resulting slurry. In some embodiments, the solution containing the sodium salt of the short-chain alcohol contains 15% to 40% by weight of sodium methoxide (e.g., in methanol). In certain embodiments, about 1 molar equivalent of the solution containing 15% to 40% by weight of sodium methoxide is added in step (b).

[0019] In a further embodiment of the first embodiment, in step (b), a solution containing heptane and a sodium salt of a short-chain alcohol is added to the first solution at a temperature below about 40°C. In some embodiments, the heptane is added at a controlled rate over about 3.5 to about 4.5 hours with constant stirring.

[0020] In a second embodiment, the present invention is (a) Dissolving capric acid in a first solvent (where the first solvent includes acetonitrile) to produce a first solution; (b) Adding a solution containing a second solvent (wherein the second solvent is heptane) and sodium methoxide to the first solution to prepare the resulting slurry; and (c) The step of isolating aggregated crystals of sodium caprate (product A) from the obtained slurry; This study focuses on the process of preparing aggregated crystals of sodium caprate (product A), which includes [specific component].

[0021] In a further embodiment of the second embodiment, the aggregated crystal is sodium caprate. As such, a process is provided for preparing aggregated crystals of sodium caprate (product A), wherein the process is: (a) The step of dissolving capric acid in acetonitrile to produce a first solution; (b) Adding about 1 mole (e.g., about 0.9 to about 1.5 moles) equivalent of a solution containing heptane and sodium methoxide to the first solution to prepare the resulting slurry; and (c) The step of isolating aggregated crystals of sodium caprate (product A) from the obtained slurry; Includes.

[0022] In the second embodiment, the addition of heptane in step (b) induces liquid-phase separation. In some embodiments, liquid-phase separation is induced by adding heptane and sodium methoxide at a temperature below about 40°C. In some embodiments, about 1.7 L / kg to 2.1 L / kg of heptane is added at this stage. In some embodiments, the heptane is added over about 3.5 to about 4.5 hours.

[0023] In further embodiments of the first or second embodiment, after step (b), the obtained slurry is stirred for at least 1 hour. In some embodiments, the obtained slurry is stirred for 1 to 30 hours, 5 to 25 hours, 5 to 15 hours, 10 to 25 hours, 10 to 15 hours, 15 to 25 hours, 20 to 25 hours, 25 to 30 hours, 20 to 30 hours, 20 to 24 hours, or 21 to 24 hours. In some embodiments, the obtained slurry is stirred for about 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 25 hours. In some embodiments, the obtained slurry is stirred for 15 to 25 hours. In particular, the slurry is stirred for 20 to 24 hours.

[0024] In the third embodiment, the process for preparing aggregated crystals of sodium caprate (product A) is as follows: (a) Dissolving capric acid in 1 L / kg to 50 L / kg of acetonitrile to produce a first solution; (b) Adding approximately 0.94 to 1.2 molar equivalents of a solution containing 1.5 L / kg to 5 L / kg of heptane and approximately 20% to 40% by weight of sodium methoxide to the first solution to prepare the resulting slurry; (c) The step of stirring the obtained slurry for at least 1 hour; and, (d) The step of filtering the obtained slurry to obtain aggregated sodium caprate crystals (product A); Includes.

[0025] In some embodiments of the above embodiments, the addition in step (b) is carried out at a temperature of 60°C or lower. In some embodiments of the above embodiments, the addition in step (b) is carried out at a temperature of 50°C or lower, 45°C or lower, 40°C or lower, or 35°C or lower. In some embodiments of the above embodiments, the addition in step (b) is carried out at a temperature of approximately 40°C or lower. In some embodiments, the addition in step (b) is carried out at approximately 40°C. In some embodiments, the addition in step (b) is carried out at approximately 35°C. In some embodiments, the addition in step (b) is carried out at room temperature. In some embodiments, the addition in step (b) is carried out at approximately 22°C to approximately 35°C. In some embodiments, the addition in step (b) is carried out at approximately 22°C, 23°C, 24°C, 25°C, 27.5°C, 30°C, 32.5°C, 35°C, 37.5°C or 40°C.

[0026] In some sub-embodiments, the process for preparing aggregated sodium caprate crystals is as follows: (a) Dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution; (b) Adding a 0.75 to 1.5 molar equivalent solution containing 1.5 L / kg to 5 L / kg of heptane and about 20 to about 40% by weight of sodium methoxide to the first solution at a temperature below about 40°C to induce liquid-liquid phase separation and prepare the resulting slurry; (c) The step of stirring the obtained slurry for at least 1 hour; and, (d) The step of filtering the obtained slurry to obtain aggregated sodium caprate crystals; Includes.

[0027] In the fourth embodiment, the process for preparing aggregated sodium caprate crystals is as follows: (a) Dissolving capric acid in 4 L / kg to 8 L / kg of acetonitrile to produce a first solution; (b) A step of preparing a slurry by adding a solution of approximately 0.96 to 1.05 molar equivalents containing approximately 1.5 L / kg to approximately 2.5 L / kg of heptane and approximately 25% to approximately 30% by weight of sodium methoxide to the first solution over a period of approximately 1.0 to approximately 10.0 hours at a temperature of approximately 22°C to approximately 35°C while maintaining constant stirring; (c) The step of stirring the obtained slurry for at least 1 hour, and optionally 20 to 24 hours; and, (d) The obtained slurry is filtered to separate the obtained solid, and the obtained solid is dried to obtain aggregated crystals of sodium caprate; Includes.

[0028] In the fifth embodiment, the preparation process is as follows: (a) Dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution; (b) Adding approximately 1 molar equivalent of a solution containing approximately 30% by weight of sodium methoxide to the first solution over approximately 4.5 to 5.5 hours at a temperature of approximately 20°C to 30°C while maintaining constant stirring; (c) Approximately 1 hour after adding the solution containing sodium methoxide in step (b), approximately 1.5 L / kg to approximately 4 L / kg of heptane is added to produce the resulting slurry; (d) A step of stirring the obtained slurry for 15 to 25 hours; and, (e) The obtained slurry is filtered to separate the obtained solid, and the obtained solid is dried to obtain aggregated crystals of sodium caprate; Includes.

[0029] In any embodiment, within step (d), after filtering the solids resulting from stirring the slurry, the obtained solids may be washed to remove residual chemicals (e.g., residual methoxide). In some embodiments, the solids are washed with a solution containing acetonitrile and methanol. As such, in the sixth embodiment, the process for preparing aggregated sodium caprate crystals is: (a) Dissolving capric acid in 4 L / kg to 8 L / kg of acetonitrile to produce a first solution; (b) A step of producing a slurry by adding a solution of approximately 0.96 to 1.05 molar equivalents containing approximately 1.5 L / kg to approximately 2.5 L / kg of heptane and approximately 25% to approximately 30% by weight of sodium methoxide to the first solution over a period of approximately 1.0 to approximately 10.0 hours at a temperature of approximately 22°C to approximately 35°C while maintaining constant stirring; (c) The obtained slurry is stirred for 20 to 24 hours; (d) A step of filtering the obtained slurry to separate the obtained solid matter; (e) Washing the obtained solid with a solution containing acetonitrile and methanol; and, (f) A step of drying the obtained solid to obtain aggregated crystals of sodium caprate; Includes.

[0030] For example, in step (e) of the sixth embodiment, the obtained solid can be washed with a solution containing 2 L / kg to 10 L / kg of acetonitrile and methanol. In some sub-embodiments, two washes of 2 L / kg each are performed. In some embodiments, the washing solution contains acetonitrile and methanol in a volume ratio of about 10:1, 9:1, or 8:1 parts. In certain embodiments, the washing solution contains 9 parts acetonitrile and 1 part methanol (v / v) (9:1). In some embodiments, this washing step is omitted.

[0031] In any of the embodiments described, in step (a), capric acid is dissolved in 1 L / kg to 50 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 3 L / kg to 30 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 7.5 L / kg to 25 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 10 L / kg to 25 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 10 L / kg to 20 L / kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in approximately 25 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 15, 20, 25, or 30 L / kg of acetonitrile. In some embodiments, 1, 2, or 3 L / kg of acetonitrile may be used. In some embodiments, about 3 L / kg of acetonitrile is used.

[0032] In any of the embodiments described, capric acid is dissolved in 6 L / kg to 8 L / kg of acetonitrile to produce the first solution (i.e., in step (a), 6 L / kg to 8 L / kg of acetonitrile is added). In some embodiments, about 6.0 L / kg of acetonitrile is used. About 7.0 L / kg or 8.0 L / kg of acetonitrile may be used.

[0033] In various embodiments, a solution containing a sodium salt of a short-chain alcohol (e.g., sodium methoxide) is added over a period of 1.0 to 10.0 hours at a temperature of 5°C to 40°C while maintaining constant stirring. In any embodiment, 0.5 to 1.5 molar equivalents of a solution containing sodium methoxide are added to the first solution. In any embodiment, about 0.75 to about 1.5 molar equivalents of a solution containing 15% to 40% by weight, 20% to 40% by weight, 15% to 35% by weight, about 15% to 30% by weight, or about 25% to 30% by weight of sodium methoxide are added. In some embodiments, about 0.9 to about 1.5, 0.9 to 1.00, about 0.96 to about 1.05, or about 0.93 to about 1.00 molar equivalents of a solution containing 15% to 40% by weight or 25% to 30% by weight of sodium methoxide are added. In certain embodiments, 0.97 molar equivalents of 25% to 30% by weight of sodium methoxide are added. In some embodiments, the solution containing the sodium salt of a short-chain alcohol (e.g., sodium methoxide) is added over at least 2.0 hours. In any of the embodiments, sodium methoxide is added over about 4 to 6 hours with constant stirring. In some embodiments, sodium methoxide is added over about 4 to 6 hours or about 5 to 5.5 hours at a temperature of about 20°C to 30°C. In some embodiments, sodium methoxide is added over 4.0 hours. In some embodiments, sodium methoxide is added over about 5 to 5.5 hours.

[0034] In any embodiment, the second solvent is added to the solution containing sodium methoxide in step (b) about 1 hour after the solution containing sodium methoxide is added. In some embodiments, step (b) includes adding the second solvent at a controlled rate with constant stirring about 1 hour after the sodium methoxide is added, where the second solvent contains heptane. Step (b) may include adding 1.5 L / kg to 5.0 L / kg of heptane at a controlled rate over 3 to 5 hours with constant stirring about 1 hour after the solution containing sodium methoxide is added. In any embodiment, about 1.5 L / kg to about 2.5 L / kg of heptane is added at a controlled rate over 3 to 5 hours with constant stirring about 1 hour after the sodium methoxide is added. In any embodiment, about 1.9 L / kg of heptane is added at a controlled rate over 3 to 5 hours about 1 hour after the sodium methoxide is added. In one of the embodiments, heptane is added at a controlled rate over 3 to 5 hours while maintaining constant stirring, at a rate of approximately 3.5 L / kg to approximately 4.0 L / kg.

[0035] In some embodiments, heptane is added at a controlled rate over approximately 1.5 to 5 hours while maintaining constant stirring, at a rate of 1.5 L / kg to 5.0 L / kg, 1.5 L / kg to 4 L / kg, 1.5 L / kg to 2.5 L / kg, 1.7 L / kg to 2.1 L / kg, or 3.5 L / kg to 4.0 L / kg. In some embodiments, heptane is added at a controlled rate over 3.5 to 4.5 hours, or over 4.5 to 5.5 hours, while maintaining constant stirring. In some embodiments, heptane is added at a rate of approximately 1.7 L / kg to approximately 2.1 L / kg over approximately 3.5 to 4.5 hours, over approximately 4.5 to 5 hours, or over approximately 4.5 to 5.5 hours. In some embodiments, heptane is added at a rate of approximately 3.7 L / kg over approximately 3.5 to 4.5 hours, or over approximately 4.5 to 5 hours. In some embodiments, heptane is added at a rate of approximately 1.9, 2.0, or 2.5 L / kg over approximately 4.5 to 5 hours.

[0036] In a further embodiment of the fourth embodiment, in step (c), heptane is added at a controlled rate over approximately 3.5 to 4.5 hours while maintaining constant stirring.

[0037] In some embodiments, the second solvent (e.g., heptane) is added to the solution containing sodium methoxide less than one hour after the addition of the solution. In some embodiments, the second solvent (e.g., heptane) is added to the solution approximately 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 40 minutes, 50 minutes, or 55 minutes after the addition of the solution containing sodium methoxide. In some embodiments, the second solvent is added to the solution almost simultaneously with the solution containing sodium methoxide.

[0038] The process of the present invention makes it possible to directly crystallize aggregated crystalline particles of medium-chain sodium fatty acid salts, such as sodium caprate. This process avoids gel formation and other undesirable processing challenges typically seen in the production of sodium caprate. For crystallizing this type of compound, the present invention utilizes particle aggregation induced by liquid-liquid phase separation. The process can be used to produce aggregated particles of medium-chain sodium fatty acid salts, such as sodium caprate, on a production scale. For example, using the process, it is possible to produce amounts of sodium caprate in a single batch including about 0.5 kg (Example 1A), 1.0 kg (Example 1B), 50 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 340 kg, 350 kg, 360 kg, 375 kg, 390 kg, or 400 kg. Using this process, sodium caprate can be produced in batches of two or more quantities containing approximately 800 kg, 900 kg, 1000 kg, or 1100 kg (or 1.1 tons).

[0039] By identifying a solvent composition that suppresses gel formation and encapsulates solids within the second-phase dispersion droplets, a single-pot, low-energy crystallization process using inexpensive, commercially available starting materials has been achieved. The resulting aggregated sodium caprate crystals behave like conventional slurries and do not entrain the solvent, allowing for gentle stirring and easy isolation. The aggregates exhibit sufficient hardness to retain their shape during discharge and handling. Furthermore, the resulting aggregates have a substantially homogeneous morphology and / or a single-mode, normal size distribution. The aggregates also exhibit excellent powder flowability. In some embodiments, the aggregates exhibit a Carr's Index of less than 9.0%. In some embodiments, the aggregates exhibit a Hausner Ratio of less than 1.15. The indices of the Carr's Index and Hausner Ratio correspond to increased flowability. The Carr's Index and Hausner Ratio of any of the disclosed compositions can be calculated using any method known in the art, for example, by measuring the bulk density and tap density of the composition using a graduated cylinder and tap density device.

[0040] As such, in some embodiments, compositions comprising sodium caprate (e.g., crystalline powder compositions) are provided, wherein the composition exhibits a curl index of less than about 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9.5%, less than 9%, less than 8.75%, less than 8.5%, less than 8%, less than 7.5%, less than 7%, or less than 6%. In some embodiments, the composition exhibits a curl index of less than 9%. In some embodiments, the curl index is between 8% and 9%. In a particular embodiment, the composition exhibits a curl index of 8.7%.

[0041] In some embodiments, such compositions (e.g., crystalline powder compositions) are provided, wherein the composition exhibits a Hausner ratio of less than 1.25, less than 1.20, less than 1.15, less than 1.14, less than 1.13, less than 1.12, less than 1.11, less than 1.10, less than 1.9, less than 1.8, or less than 1.75. In some embodiments, the composition exhibits a Hausner ratio of about 1.1. In certain embodiments, the composition exhibits a Hausner ratio of 1.10.

[0042] Described herein are products produced by any of the disclosed processes. Specifically, compositions comprising a sodium salt of a medium-chain fatty acid (e.g., sodium caprate) produced using any of the disclosed processes are provided herein. In various embodiments, the product comprises any of the aggregated crystals provided, for example, aggregated sodium caprate crystals.

[0043] definition Certain technical and scientific terms are defined below. Unless otherwise specifically defined elsewhere in this Specified, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art in which this disclosure relates. That is, each term used herein has its own independent and ordinary meaning. Nevertheless, and unless otherwise indicated, the following definitions apply throughout this Specified and Claims Specified. Chemical names, common names and chemical structures can be used interchangeably to describe the same structure. If a compound is referred to by both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure shall prevail. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise indicated.

[0044] The examples following the terms "e.g." or "for example" are not intended to be exhaustive or restrictive.

[0045] Where used in this specification and throughout this disclosure, the following terms should be understood to have the meanings set forth below, unless otherwise indicated.

[0046] Where used herein, including in the attached claims, the singular forms of words such as "a," "an," and "the" encompass their corresponding plural forms unless the context clearly indicates otherwise.

[0047] Where used herein, the term “one or more” includes not only a single item selected from the list, but also a mixture of two or more items selected from the list.

[0048] Unless expressly indicated otherwise, all ranges referenced herein are inclusive; that is, they include not only the upper and lower limits of the range but also all values ​​between them. Furthermore, all ranges are intended to encompass all subranges, even if not explicitly stated. For example, temperature ranges, percentages, equivalent ranges, etc., described herein include the upper and lower limits of the range, as well as any values ​​on the continuum between them. The use of the numerical values ​​and term “about” provided herein may include variations of ±1%, ±2%, ±3%, ±4%, ±5%, and ±10%, as well as their numerical equivalents. When “about” is used to modify a numerically defined parameter (e.g., temperature or reaction time length described herein), it means that the parameter may vary by 10% below or above the numerical value described for that parameter; where appropriate, the described parameter may be rounded to the nearest integer. For example, a temperature of about 30°C may vary between 25°C and 35°C. Furthermore, the term "or" as used herein indicates options that can be combined where appropriate; that is, the term "or" includes each of the listed options individually.

[0049] Where used herein, “Product A” refers to the aggregated crystalline form of sodium caprate obtained from the process. In some embodiments, “Product A” is synonymous with “aggregates.”

[0050] As used herein, the term “medium-chain fatty acid” is intended to mean an aliphatic carbohydrate having a primary carboxylic acid group and 5 to 15 carbon atoms. Examples include capric acid, lauric acid, pelargonic acid, and undecylic acid. In embodiments of the present invention, the medium-chain fatty acid includes or is capric acid, pelargonic acid, or lauric acid. In further embodiments, the medium-chain fatty acid includes capric acid.

[0051] As used herein, the term “short-chain alcohol” is intended to mean a linear saturated hydrocarbon having 1 to 3 carbon atoms and a terminal hydroxyl functional group. Examples include methanol or ethanol. In one embodiment, the short-chain alcohol is methanol. In one embodiment, the sodium salt of the short-chain alcohol is sodium methoxide.

[0052] As used herein, the term “aprotic polar solvent” is intended to mean a compound or mixture of compounds used as a process solvent that lacks acidic protons, is polar, and has a chemical structure capable of functioning as a hydrogen bond acceptor. Examples include dimethylformamide, dimethylacetamide, tetrahydrofuran, or acetonitrile. In one embodiment of the present invention, the aprotic polar solvent includes acetonitrile. Any aprotic polar solvent described contains an aprotic polar substance, but may further contain additional substances. These additional substances are not necessarily aprotic or polar themselves.

[0053] As used herein, the term “medium-chain aliphatic hydrocarbon solvent” is intended to mean a compound or mixture of compounds used as a process solvent having a chemical structure consisting of 5 to 9 carbon atoms linked together to form a non-aromatic chain, bonded only to each other and to hydrogen atoms. Examples include heptane, 2-methylhexane, hexane, octane, and cyclohexane. As used herein, “heptane” may include straight-chain heptane, branched-chain heptane, n-heptane, or a blend of heptane isomers (e.g., commercially available heptane blends such as “Heptanes, mixture of isomers” sold by Thermo Scientific Chemicals). As used herein, “hexane” may include straight-chain hexane, branched-chain hexane, n-hexane, or a blend of hexane isomers. In one embodiment of the present invention, the medium-chain aliphatic hydrocarbon solvent comprises n-heptane (which is simply referred to as “heptane” in the examples). In another embodiment of the present invention, the medium-chain aliphatic hydrocarbon solvent is n-hexane. The medium-chain aliphatic hydrocarbon solvents described all contain medium-chain aliphatic hydrocarbons, but may also contain additional substances. These additional substances do not necessarily have to be medium-chain aliphatic hydrocarbons themselves.

[0054] Where used herein, the expression “controlled rate” is intended to mean the addition of a solution using a flow rate planned before batch initiation, typically delivered using a pump or flow controller and administered according to a program or schedule.

[0055] Where used herein, the expression “constant stirring” is intended to mean stirring of a solution substantially without interruption. This expression encompasses the occurrence of one or more interruptions to stirring, which, collectively, have a substantial effect on the formation of the intended slurry (e.g., several interruptions of 1 to 3 seconds each). Constant stirring can be performed mechanically (e.g., by a magnetic stirring rod) or manually.

[0056] The process may or may include one or more steps of stirring the solution. Examples of stirring techniques include, but are not limited to, overhead stirring, magnetic stirring, and shaker plate mixing.

[0057] Liquid-liquid phase separation (LLPS) occurs when a mixture of two solutions contains an immiscible solvent and is caused by the thermodynamically suboptimal solution behavior of the solvents involved. Gibbs free energy is the thermodynamic potential that is minimized when the system reaches equilibrium. If the solvent mixture behaves ideally, the Gibbs free energy has one local minimum, and no phase separation occurs. If the behavior of the solvent mixture is suboptimal, there exists a range of temperatures and pressures where the Gibbs free energy has two local minimums, and two thermodynamically stable liquid phases with different overall compositions may be formed. For example, methanol and acetonitrile are perfectly miscible solvents, but heptane has a miscibility gap with both methanol and acetonitrile. In disolvent systems consisting of or containing methanol and heptane, and in disolvent systems consisting of acetonitrile and heptane, respectively, there exists a set of compositions in which the solvents do not mix and two immiscible liquid phases are formed. A miscibility gap also exists in the case of ternary solvent systems consisting of or containing methanol, acetonitrile, and heptane. In other words, there exists a set of compositions in which three types of solvents do not mix, resulting in the formation of two immiscible liquid phases. The formation of two immiscible liquid phases by the addition of solvents is referred to herein as liquid-liquid separation (LLPS).

[0058] This invention utilizes known filtration techniques (which include centrifugal separation, vacuum filtration, pressure filtration, etc.).

[0059] Methods for preparing aggregated crystals of sodium salts of medium-chain fatty acids, particularly crystals of sodium caprate, are illustrated in the following scheme and examples. Starting materials are prepared according to procedures known in the art or according to the procedures illustrated herein. The following abbreviations are used herein: [Table 1]

[0060] In some cases, the order in which the reaction scheme is carried out can be altered to facilitate the reaction or to avoid undesirable reaction products. The following examples are provided to better understand the present invention. These examples are merely illustrative and should not be construed as limiting the invention. [Examples]

[0061] Examples Example 1A [ka]

[0062] Capric acid (1) (25 g, 145 mmol) and acetonitrile (630 mL) were combined in a suitable container equipped with a suitable stirrer. The batch was stirred at room temperature until completely dissolved. Sodium methoxide (2) (8.23 g, 152 mmol) was added over 5 hours with vigorous stirring as a 25 wt% solution in methanol (32.92 g) to form a slurry. After the first hour following the addition of (2), heptane (93-103 mL) was added simultaneously over 4 hours using a separate supply line. The resulting slurry was stirred for a further hour. The solid was filtered, washed with acetonitrile (100 mL, twice), and then dried under reduced pressure with nitrogen sweep at 35-40°C to obtain crystalline sodium caprate (3, product A) (27.79 g, yield 99%).

[0063] Example 1B [ka]

[0064] Capric acid (1) (1.00 kg, 5.81 mol) and acetonitrile (6.0 L) were combined in a suitable container equipped with a suitable stirrer. The batch was stirred at room temperature until completely dissolved. Sodium methoxide (2) (0.304 g, 5.63 mol) was added over 5.5 hours with vigorous stirring as a 30 wt% solution in methanol (1.01 kg). Simultaneously with the addition of (2), heptane (1.9 L) was added over 5 hours using a separate feed line. The resulting slurry was stirred for a further 24 hours. The solid was filtered and washed twice with 2 L of acetonitrile:methanol (9:1 volume ratio) solution, and then dried under reduced pressure with nitrogen sweep at 35-40°C to obtain crystalline sodium caprate (3, product A) (1.09 kg, yield 97%). Photographs of the slurry and isolated sodium caprate crystals produced using this procedure are shown in Figure 13. A 1.0 kg scale product was generated.

[0065] Example 1C [ka]

[0066] Capric acid (1) (5.02 g, 29.1 mmol) and acetonitrile (30 mL) were combined in a suitable container with a suitable stirrer to produce a homogeneous solution. Sodium methoxide (2) (28.3 mmol) was added as a 30 wt% solution in methanol over 5 hours with vigorous stirring to form a slurry. Simultaneously with the addition of (2), hexane (10.54 mL) was added over 5 hours using a separate supply line. The resulting slurry was stirred for a further 17 hours. The solid was then filtered and washed twice with 15 mL of acetonitrile:methanol (9:1 volume ratio) solution, and then dried under reduced pressure with nitrogen overhead sweep at 40°C to obtain crystalline sodium caprate (3, product A) (5.24 g, yield 93%). Figure 11 shows the substance produced using this procedure.

[0067] Example 1D [ka]

[0068] Capric acid (1) (5 g, 29 mmol) and acetonitrile (10 mL) were combined in a suitable container equipped with a suitable stirrer. The batch was stirred at 35°C until completely dissolved. Sodium methoxide (2) (1.55 g, 29 mmol) was added over 5.5 hours with vigorous stirring as a 30 wt% solution in methanol (5.18 g) to form a slurry. Simultaneously with the addition of (2), heptane (7.4 mL) was added over 5 hours using a separate supply line. The resulting slurry was stirred for a further 15 hours. After maturation, an additional 1 mL of heptane was added, and the batch was heated to 40°C. The slurry was further matured for 3 hours. The solid was filtered, washed with acetonitrile (10 mL, twice), and dried under reduced pressure with nitrogen sweep at 35-40°C to obtain crystalline sodium caprate (3, product A) (4.1 g, yield 74%). Figure 12 shows the substance prepared using this procedure.

[0069] Example 1E [ka]

[0070] Capric acid (1) (10 g, 58.5 mmol) and acetonitrile (10 mL) were combined in a suitable container equipped with a suitable stirrer. The batch was stirred at 40°C until completely dissolved. Sodium methoxide (2) (3.17 g, 58.5 mmol) was added over 5.5 hours with vigorous stirring as a 30 wt% solution in methanol (10.57 g) to form a slurry. Simultaneously with the addition of (2), heptane (15.15 mL) was added over 5 hours using a separate supply line. The resulting slurry was stirred for a further 24 hours. The solid was filtered and washed twice with 20 mL of acetonitrile:methanol (9:1 volume ratio) solution, and then dried under reduced pressure with nitrogen sweep at 35–40°C to obtain crystalline sodium caprate (3, product A) (9.48 g, yield 83%). Figure 12 shows the substance prepared using this procedure.

[0071] Powder X-ray diffraction (XRPD) As shown in Figure 1, X-ray powder diffraction (XRPD) data were acquired using a Panalaytical X-Pert with a Cu radiation source monochromatized to Kα using a nickel filter, configured in a Bragg-Brentano configuration. A fixed slit optical system was employed to acquire the data. Data were acquired at 2–40°2θ. Samples were prepared by lightly pressing them into a silicon holder with zero background. All samples shown in Figure 1 were obtained using this method and are intended for comparison between materials produced by this process and commercially available materials.

[0072] Figure 1 shows the XRPD pattern of "Product A," the material produced by this process, and a stack comparison with the XPRD patterns of commercially available sodium caprate substitutes (e.g., those from Jost and BSI) produced by different processes. Figure 1 shows differences in reflection intensity, indicating that although the preferred phases produced are different, the overall "fingerprint" of the crystal pattern is the same. This process produced sodium caprate crystals with a morphology significantly different from commercially available embodiments produced by more costly procedures.

[0073] Differential scanning calorimeter (DSC) Thermal events were monitored as a function of temperature rise using a TA Instruments Discovery differential scanning calorimeter (DSC). Samples of product A (2–5 mg) in a sealed, airtight aluminum pan with two pinholes were circulated twice from 10 to 300°C at a heating rate of 10°C / min.

[0074] The image in Figure 2 shows two heating cycles and one cooling cycle performed on a sodium caprate material from room temperature to 300°C. The downward peak indicates endothermic activity, showing that the material is absorbing heat. This suggests a change in crystalline / solid state or a phase change (e.g., melting or boiling). The upper curve shows what happens when the same sample is cooling. During cooling, there is an upward peak (exothermic activity, heat is released). These are reversals of the physical phenomena that occurred during heating. The presence of hysteresis between the onset temperature and the reversal temperature is typically due to differences in the motion barrier between the forward and backward processes. The width of the hysteresis usually depends on the rate at which the temperature changes during the DSC scan. Figure 2 shows two overlaid heating curves (y-axis less than or equal to zero). The overlap of these two lines indicates that the changes experienced by product A during the experiment were reversible and product A was not destroyed during the scan. The change in the width of the first downward peak between the two heating curves is related to the presence of water absorbed in the first scan. Since the peak position and area, as well as the overall scan shape, are specific to sodium caprate, the DSC pattern can be used as a characterization technique.

[0075] Residual solvent by gas chromatography (GC) Preparation of standard substances: 0.01% v / v standard solutions of n-heptane, methanol, and acetonitrile are prepared for quantitative analysis by serial dilution, and the 0.001% v / v limit of quantification (LOQ) is prepared for limit reporting.

[0076] Sample preparation: Dissolve approximately 20 mg / mL of the sample in the diluent. If necessary, vortex and sonication should be performed to dissolve the sample.

[0077] Equipment requirements: [Table 2]

[0078] result: [Table 3]

[0079] thermogravimetric analysis Thermogravimetric analysis (TGA) of product A was performed using a TA Q 500 Thermogravimetric Analyzer (TA Instrument). Samples (5–15 mg) were heated from 25°C to 320°C at 10°C / min while purging with 200 mL / min of nitrogen. As shown in Figure 3, the upper curve in Figure 3 monitors the change in mass of product A when heated under a nitrogen atmosphere. The initial gradual mass decrease (0.8 wt%) at 250°C was in good agreement with the expected absorbed surface water in the material. Above 250°C, a decrease began, indicating that decomposition or evaporation had started. The lower curve in the graph corresponds to the derivative of the mass change and captures the rate of change of the upper curve.

[0080] Particle size analysis using Microtrac FlowSync Equipment manufacturer and model : Microtrac, M5001-3L Sync + FlowSync methodApproximately 50 mg of the powder sample was transferred to a 20 mL scintillation vial. 5 mL of IsoparG / 0.25% w / v lecithin solution was added to the vial, and the particles were gently shaken to disperse them. After instrument initialization and background measurement (30 seconds), the suspension was poured into the flow cell unit. The vial was rinsed three times with 1 mL of IsoparG / 0.25% lecithin solution (total 3 mL), and all the rinse solution was poured into the FlowSync. The measurement parameters included: volume distribution, geometric 8-root progression from 0.0215 to 2000 μm, residuals disabled, standard filter enabled, particle RI = 1.51; irregular shape; fluid RI = 1.42; flow rate 60%. The particle size distribution was calculated as the average of three 30-second scans. The results are reported as volume distribution. Samples were analyzed with no sonication, and with 25% sonication for 30 seconds, 60 seconds, and 90 seconds.

[0081] Ultrasonic treatment is a standard experimental technique that applies vibrational energy to powders to disperse clumps within the material, ensuring that particle size measurements accurately capture the true particle size of the product particles. Clumps are commonly observed in dry solids due to natural adhesion and can distort measurements, potentially overestimating the particle size of powder particles; therefore, sufficient ultrasonic treatment is crucial for analytical accuracy. Figure 4 shows a typical volume-weighted particle size distribution result for a batch of product A produced using the process described in Example 1. The curve shows the probability density of product particles having a radius of a specified size on the x-axis. The curve also shows the effect of ultrasonic treatment on the measured particle size. The decrease and standardization of particle size with increasing ultrasonic treatment is typical behavior indicating deaggregation of dry solids relative to the "true" distribution of primary particles, which was best captured by the curves labeled 60 and 90 seconds. Figure 4 shows that the particle size distribution is the same for 60 and 90 seconds of ultrasonic treatment, indicating that a sample of this material requires at least 60 seconds for proper measurement.

[0082] Figure 4 further shows how the process generates primary particles with a desirable single-mode particle size distribution for the manufacturing process. A single-mode distribution is desirable because it indicates particle uniformity, minimizing the formation of fine particles or large aggregates that can lead to non-uniform flow, filtration, and compression behavior. A single-mode distribution also indicates proper control during the crystallization and aggregation processes, as it provides evidence that undesirable particle formation phenomena, such as grinding, are not occurring and that the overall particle size and morphology are set by control variables manipulated during batch design.

[0083] Scanning electron microscope (SEM) A sodium caprate powder sample was mounted on a 32mm SEM stub using carbon sticks. The sample was then sputter-coated with platinum. This sample was loaded into a Hitachi TM3030 Tabletop Scanning Electron Microscope. The sample was imaged in high vacuum mode, and images were acquired using a secondary electron (SE) detector. The voltage was set to 2kV, and the spot intensity was set to 30 (unity). Images were acquired at multiple magnifications.

[0084] The image in Figure 5 shows that the morphology of product A exists as distinctly aggregated, plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is preferable to elongated plate-like or needle-like forms. The demonstrated morphology reflects the excellent compressibility of the manufacturing procedure and dosage form in which product A is used as an excipient.

[0085] Compression performance (i) Samples of sodium caprate powder produced in the process and (ii) samples of formulations containing the sodium caprate sample were compressed into cylindrical molded bodies using a single-station compression simulator. The samples were compressed using a 9.525 mm circular flat-face tablet press die with compression pressures ranging from 10 to 400 megapascals (MPa). The compression simulation of the formulations was performed under force control. The combined punch speed was in the range of 50 to 100 mm / s. The weight (W), thickness (h), diameter (D), and hardness (B) of the obtained molded bodies were measured. Hardness is defined as the peak force required to break the cylindrical molded body. The weight of the molded bodies was controlled in the range of 225 to 375 mg. Using the obtained values ​​for thickness and hardness, the tensile strength (T) of the tablets was calculated using equation X. The obtained tensile strength and compression pressure of the tablets were combined with the tabletability curve.

number

[0086] Table 1 shows the composition of test examples of formulated tablet products containing sodium caprate obtained from various commercially available sources. These formulations include: a disintegrant, a flow enhancer, a lubricant, and two compression aids (i.e., diluents or binders): lactose and microcrystalline cellulose. Four of these formulations contained commercially available sodium caprate lots, and one used aggregated material product A produced in the process. The formulation containing commercial material 1 used sodium caprate from Pfaltz & Bauer, the formulation containing commercial material 2 used sodium caprate from BSI, the formulation containing commercial material 3 used sodium caprate from TCI Chemicals, and the formulation containing commercial material 4 used sodium caprate from Jost.

[0087] [Table 4]

[0088] The plot in Figure 6 shows the compression profile results for five different formulations. These results indicate that Product A (black circle) exhibited superior compressibility compared to all commercially available materials tested. Figure 6 reflects the tensile strength of tablets formulated using a sodium caprate source (including Product A). This image shows that the material produced using Product A (shown as a black circle) yielded the toughest material within the relevant processing range of compression pressures. The in-mold powder bulk density of these five formulations was estimated using the pre-compression mass of the molded body and the filling mold volume. The in-mold bulk density of the formulation containing commercial material 2 was the lowest of all materials tested, at a nominal 0.39 g / mL. The in-mold bulk densities of the remaining four formulations ranged from 0.44 to 0.47 g / mL. All observed in-mold bulk densities indicate acceptable values ​​for tableting these blends.

[0089] liquidity The flow properties of product A and sodium caprate materials obtained from various commercial sources were compared using measurements of bulk density and tap density. Bulk density and tap density indicate the density to which the powder fills itself. Low density is an indication of a material with poor flowability and packing ability. The Karl index and Hausner ratio are indices calculated using measurements of bulk density and tap density. Low values ​​for both indices indicate that the material has improved flowability. Bulk density was measured using a 100 mL graduated cylinder and more than 50 mL of powder material. The powder material was dispensed into the graduated cylinder, and both the mass and volume of the material were recorded. The bulk density of the powder was obtained by calculating the ratio of mass to volume. The graduated cylinder was then measured using a USP <661> The material was tapped 1,250 times using a tap density device according to the specified method. The tap density value was then calculated using the obtained volume of material.

[0090] Table 2 lists the bulk density and tap density of the materials and provides the calculated Karl index and Hausner ratio results. As shown in Table 2, Product A exhibited a Karl index of 8.7% and a Hausner ratio of 1.10. Both of these values ​​are significantly lower than those of commercially available materials 1-4, indicating that Product A exhibits excellent powder flowability. The aggregated sodium caprate crystals produced in this invention (Product A) exhibit excellent flowability despite their low density, which is reflected in the low Karl index and Hausner ratio.

[0091] [Table 5]

[0092] Figure 7 shows SEM images of commercially available sodium caprate from materials 1 to 4, providing a comparison of their respective morphologies. The method of preparing this compound significantly affects the structure and physical appearance of the material. Commercial material 1 (sodium caprate from BSI) was a smooth sphere produced by spray drying. Commercial materials 3 (sodium caprate from TCI Chemical) and 4 (sodium caprate from Jost) were elongated, large, thin plates. Product A constituted an aggregated solid with a rough surface and was not elongated in any axial direction. This process enabled this unique morphology of product A, which is easy to produce and handle with standard equipment and possesses desirable properties for formulation.

[0093] Example 1F [ka]

[0094] Sodium caprate (3) (77 mg, 0.40 mmol) and dimethylacetamide (DMAc) (1 mL) were combined in a 4 mL vial to form a slurry. n-heptane (0.3 mL) was then added to the vial to form a slurry of aggregated particles. Optical microscope images of these particles are shown in the upper panel of Figure 10. [ka]

[0095] Sodium caprate (3) (78 mg, 0.40 mmol) and dimethylformamide (DMF) (1 mL) were combined in a 4 mL vial to form a slurry. n-heptane (0.2 mL) was then added to the vial to form a slurry of aggregated particles. [ka]

[0096] Sodium caprate (3) (88 mg, 0.45 mmol) and n-methyl-2-pyrrolidone (NMP) (1 mL) were combined in a 4 mL vial to form a slurry. n-heptane (0.2 mL) was then added to the vial to form a slurry of aggregated particles. Optical microscope images of these particles are shown in the lower panel of Figure 10.

[0097] DMAc, DMF, and NMP are polar aprotic solvents, respectively. As highlighted by the image shown in Figure 10, agglomerated crystalline sodium caprate products can be obtained by combining sodium caprate with heptane and polar aprotic solvents. In the disclosed manufacturing process for sodium caprate aggregates, any of several polar aprotic solvents may be used.

[0098] Example 2 Preparation of sodium pelargonate (C9) [ka]

[0099] Pelargonic acid (4) (2.51 g, 15.9 mmol) and acetonitrile (63.5 mL) were combined in a suitable container equipped with a suitable stirrer to obtain a homogeneous solution. Sodium methoxide (2) (15.9 mmol) was added to this solution as a 25 wt% solution in methanol over 5 hours with vigorous stirring to form a slurry. After the first hour following the addition of (2), heptane (9.3 mL) was simultaneously added to the solution over 4 hours. The slurry was stirred for a further 1 hour. The solid was filtered, washed with acetonitrile (15 mL, twice), and then dried under reduced pressure with nitrogen sweep at 35-40°C to obtain sodium pelargonate (5) (2.68 g, yield 94%).

[0100] Scanning electron microscope (SEM) A sodium pelargonate powder sample was mounted on a 32mm SEM stub using carbon sticks. The sample was then sputter-coated with platinum. The sample was loaded into a Hitachi TM3030 Tabletop Scanning Electron Microscope. The sample was imaged in high vacuum mode, and images were acquired using a secondary electron (SE) detector. The voltage was set to 2kV, and the spot intensity was set to 30 (unity). Images were acquired at multiple magnifications. Figure 8 shows that the aggregated crystal morphology of sodium pelargonate exists as distinct plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is preferable to elongated plate-like or needle-like morphologies because such morphologies tend to exhibit superior compressibility during the manufacturing process.

[0101] Example 3 Preparation of sodium laurate (C12) [ka]

[0102] Lauric acid (6) (2.5 g, 12.5 mmol) and acetonitrile (63.3 mL) were combined in a suitable container equipped with a suitable stirrer. The batch was stirred at 30°C until completely dissolved, and then cooled to room temperature. Sodium methoxide (2) (12.48 mmol) was added to the solution as a 25 wt% solution in methanol over 5 hours with vigorous stirring to form a slurry. After the first hour following the addition of (2), heptane (9.3 mL) was simultaneously added to the solution over 4 hours. The slurry was stirred for a further hour. The solid was filtered, washed with acetonitrile (15 mL, twice), and then dried under reduced pressure with nitrogen sweep at 35-40°C to obtain sodium laurate (7) (2.7 g, 97% yield).

[0103] Scanning electron microscope (SEM) A sodium laurate powder sample was mounted on a 32mm SEM stub using carbon sticks. The sample was sputter-coated with platinum. The sample was loaded into a Hitachi SU5000 Scanning Electron Microscope. The sample was imaged in high vacuum mode, and images were acquired using a secondary electron (SE) detector. The voltage was set to 2kV, and the spot intensity was set to 30 (unity). Images were acquired at multiple magnifications. The image in Figure 9 shows that the aggregated crystal morphology of sodium laurate exists as distinct plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is preferable to elongated plate-like or needle-like morphologies because such morphologies tend to exhibit superior compressibility in manufacturing procedures and dosage forms.

[0104] While the present invention has been described and illustrated with reference to specific embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions to the procedures and protocols can be made without departing from the spirit and scope of the invention.

[0105] Equivalents While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily conceive of various other means to perform the functions described herein and / or to obtain the results described herein and / or to obtain one or more of the advantages described herein. Such variations and / or modifications will each be considered within the scope of the embodiments described herein. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials and configurations described herein are intended to be illustrative, and that actual parameters, dimensions, materials and / or configurations will depend on the specific application in which the teachings of the present invention are used. Those skilled in the art will be able to recognize or verify many equivalents to the specific embodiments described herein without doing anything more than routine experimentation. Accordingly, it should be understood that the embodiments described herein are presented only as examples, and that embodiments may be carried out in ways different from those specifically described and claimed, within the scope of the appended claims and their equivalents. Embodiments of this disclosure are directed toward the individual features, materials and / or methods described herein. Furthermore, any combination of two or more such features, materials, and / or methods is included within the scope of this disclosure, provided that such features, materials, and / or methods are not mutually inconsistent.

[0106] All definitions defined and used herein should be understood to take precedence over dictionary definitions, definitions in documents incorporated by reference, and / or the ordinary meanings of the terms defined.

[0107] The indefinite articles "a" and "an" used herein and in the claims should be understood to mean "at least one" unless explicitly indicated to mean the opposite.

[0108] As used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements thus combined, that is, elements that exist in some cases as a combination and in other cases as separate. Multiple elements listed with "and / or" should be interpreted in the same way, that is, "one or more" of the elements thus combined. Other elements may exist, in addition to the elements specifically identified by the "and / or" clause, whether or not they are related to the specifically identified elements. Thus, as a non-restrictive example, when a reference to "A and / or B" is used in combination with open-ended language such as "comprising," for example, in one embodiment it may refer to A only (which may include elements other than B); in another embodiment it may refer to B only (which may include elements other than A); in yet another embodiment it may refer to both A and B (which may include other elements); and so on.

[0109] Where used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including not only at least one of the elements or the list, but two or more, and, where applicable, additional items not on the list. Only terms that explicitly indicate the opposite, such as “only one of” or “exactly one of” or, as used in the claims, “consisting of,” indicate including exactly one of the elements or the list. In general, the term “or” as used herein should be interpreted as indicating an exclusive choice (i.e., “one or the other, but not both”) only when preceded by an exclusive term such as “either,” “one of,” “only one of” or “exactly one of.”

[0110] Where a composition is disclosed or claimed as "comprising" one or more features, it is understood that embodiments of such a composition "consisting of" and "consisting essentially of" these features are also disclosed or claimed. The transitional phrase "consisting essentially of" has its usual meaning as used in the field of patent law. In the claims and in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and "composed of" should be understood to be open-ended, meaning they include but are not limited to them. On the other hand, the transitional phrases "consisting of" and "consisting essentially of" are closed or semi-closed transitional phrases, respectively, as defined in MPEP 2111.03.

[0111] Furthermore, unless explicitly stated otherwise, it should be understood that in any method claimed herein that includes two or more steps or actions, the order of the steps or actions of that method is not necessarily limited to the order in which the steps or actions of that method are described.

Claims

1. A process for preparing aggregated crystals of sodium salts of medium-chain fatty acids, (a) A step of dissolving medium-chain fatty acids in acetonitrile to produce a first solution; (b) Adding a 1 molar equivalent solution containing heptane and a sodium salt of a short-chain alcohol to the first solution to prepare the resulting slurry; and, (c) The step of isolating aggregated crystals from the obtained slurry; Includes, Here, in step (b), heptane is added over a controlled rate for 3.5 to 4.5 hours while maintaining constant stirring. The aforementioned process.

2. The process according to claim 1, wherein in step (b), a solution containing heptane and a sodium salt of a short-chain alcohol is added to the first solution at a temperature below 40°C.

3. The process according to claim 1 or 2, wherein after step (b), the obtained slurry is stirred for at least one hour.

4. The process according to claim 1 or 2, wherein after step (b), the obtained slurry is stirred for 15 to 25 hours.

5. A process for preparing aggregated crystals of sodium caprate, (a) A step of dissolving capric acid in acetonitrile to produce a first solution; (b) A step of preparing a slurry by adding a 1 molar equivalent solution containing heptane and sodium methoxide to the first solution; and (c) The step of isolating aggregated crystals of sodium caprate from the obtained slurry; Includes, The process in which, in step (b), heptane is added at a controlled rate over 3.5 to 4.5 hours while maintaining constant stirring.

6. The process according to claim 5, wherein in step (b), the solution containing heptane and sodium methoxide is added to the first solution at a temperature below 40°C to induce liquid-liquid phase separation.

7. The process according to claim 5 or 6, wherein after step (b), the obtained slurry is stirred for at least one hour.

8. The process according to claim 1 or 5, wherein in step (a), 6 L / kg to 8 L / kg of acetonitrile is added.

9. The process according to claim 1 or 5, wherein in step (b), 1.7 L / kg to 2.1 L / kg of heptane is added.

10. The process according to claim 1 or 5, wherein in step (b), heptane is added over a period of 3.5 to 4.5 hours.

11. (a) Dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution; (b) Adding a 0.75 to 1.5 molar equivalent solution containing 1.5 L / kg to 5 L / kg of heptane and 20 to 40 wt% of sodium methoxide to the first solution at a temperature below 40°C to induce liquid-liquid phase separation and prepare the resulting slurry; (c) A step of stirring the obtained slurry for at least one hour; and, (d) The step of filtering the obtained slurry to obtain aggregated sodium caprate crystals; The process according to claim 5, including the process described in claim 5.

12. (a) Dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution; (b) Adding a 1 molar equivalent solution containing 30% by weight of sodium methoxide to the first solution over 4.5 to 5.5 hours at a temperature of 20°C to 30°C while maintaining constant stirring; (c) A step in which, one hour after adding the solution containing sodium methoxide in step (b), 1.5 L / kg to 4 L / kg of heptane is added to produce a slurry; (d) A step of stirring the obtained slurry for 15 to 25 hours; and, (e) A step of filtering the obtained slurry to separate the obtained solid, and drying the obtained solid to obtain aggregated crystals of sodium caprate; The process according to claim 5, including the process described in claim 5.

13. The process according to claim 12, wherein in step (c), heptane is added at a controlled rate over 3.5 to 4.5 hours while maintaining constant stirring.

14. The process according to claim 1, which yields sodium caprate exhibiting a curl index of less than 9.0%.

15. The process according to claim 1, wherein sodium caprate exhibiting a Hausner ratio of less than 1.15 is obtained.

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