Process for preparing agglomerated crystalline medium chain fatty acid sodium 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 and are prone to unstable batch conditions in most solvent systems. The natural crystalline forms of these compounds are long fibers / needles that tend to entrain solvent, are difficult to isolate on standard equipment lines, and have powder characteristics that are undesirable for formulation manufacturing. Most commercially available materials of this type retain a suboptimal fiber-like morphology that is very expensive and isolated by spray drying or formed from thick, unstirrable slurries.

[0002] Sodium caprate (or sodium decanoate) is the sodium salt of caproic acid, a saturated fatty acid containing 10 carbon atoms, and can form micellar and liquid crystalline phases in aqueous solutions. Sodium caprate can aid in the transport of biologically active molecules and can serve to enhance the bioavailability of APIs as an ingredient in FDA-approved food additives and finished pharmaceutical products. In addition, 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 unlike the present invention, these preparations result in the gelation of the sodium caprate material in any of a number of solvent systems. Gelling makes it difficult and impractical to use sodium caprate (powder) in large-scale manufacturing. However, in the few solvent systems that can suppress gelation, sodium caprate crystallizes into small, thin needles or fibers, resulting in an unstirrable slurry. As a result, these slurries pose unique challenges as they are difficult to transfer from one equipment line to another (e.g., from crystallizer to filter / dryer or centrifuge). Furthermore, these particles have poor filterability and are contaminated with significant amounts of interstitial liquid, resulting in excessive agglomeration during drying. Crushing the formed cake requires significant energy input, resulting in the formation of widely dispersed hard agglomerates that affect material compoundability. These particles are also prone to cracking or breaking. Overall, sodium caprate is very difficult to isolate on an industrial scale. As a potential result of these formulation challenges, GMP supplies of sodium caprate are limited.

[0003] As a result, there are regulatory and technical barriers to the industrial use of caprate as an excipient in pharmaceutical formulations. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] B. Zacharie, et al., Organic Process Research & Development 2009, 13, 581-583 Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides a process for producing tunable size aggregate solids with superior powder flow properties and compaction behavior over commercially available alternatives. The process is cost-effective and produces a material with superior flow and compaction properties, making it suitable for use as an excipient in manufacturing processes and final pharmaceutical products. The process is also scalable, as it can produce large quantities of solid material. In various embodiments, the process includes a method for producing a medium chain fatty acid sodium salt, such as sodium caprate.

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

[0007] The present invention relates to (a) dissolving a medium chain fatty acid in a first solvent (wherein the first solvent comprises an aprotic polar solvent) to form a first solution; (b) adding (i) a second solvent, where the second solvent comprises a medium chain aliphatic hydrocarbon solvent, and (ii) a solution comprising 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 present invention relates to a process for preparing agglomerated crystals of sodium salts of medium chain fatty acids, comprising:

[0008] In various aspects, the first solvent comprises or is an aprotic polar solvent. Without 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 the crystalline product (e.g., sodium caprate). In some aspects, the first solvent comprises an aprotic polar solvent selected from acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMAC) and n-methyl-2-pyrrolidone (NMP). In some aspects, the second solvent comprises a medium chain aliphatic hydrocarbon solvent selected from heptane, hexane and octane. In some embodiments, the second solvent comprises a solvent selected from heptane and hexane. Thus, in some aspects, the process comprises: (a) dissolving a medium chain fatty acid in an aprotic polar solvent selected from acetonitrile, DMF, DMAC, and NMP to form a first solution; (b) adding an aliphatic hydrocarbon solvent selected from heptane and hexane and about one molar equivalent of a solution comprising a sodium salt of a short chain alcohol to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals from the resulting slurry; Includes.

[0009] In some embodiments, the process comprises: (a) dissolving a medium chain fatty acid in acetonitrile to form a first solution; (b) adding about one molar equivalent of a solution comprising heptane and a sodium salt of a short chain alcohol to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals from the resulting slurry; Includes.

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

[0011] In various embodiments, the solution containing the second solvent and the sodium salt of the short chain alcohol is added separately to the first solution, which is referred to in this disclosure as "separate feed line" addition.

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

[0013] Other embodiments, aspects and features of the present invention are further described in or will be apparent from the ensuing description, examples and appended claims. [Brief description of the drawings]

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

[0015] The present invention relates to (a) dissolving a medium chain fatty acid in a first solvent, where the first solvent comprises an aprotic polar solvent selected from acetonitrile, DMF, DMAC, and NMP, to form a first solution; (b) adding (i) a second solvent, wherein the second solvent comprises a medium chain aliphatic hydrocarbon solvent selected from heptane, hexane, and octane, and (ii) a solution comprising 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 present invention relates to a process for preparing agglomerated crystals of sodium salts of medium chain fatty acids, comprising:

[0016] In a first embodiment, the first solvent of the process comprises acetonitrile and the second solvent comprises heptane. Thus, in this embodiment, the present invention provides a process for the preparation of a process comprising: (a) dissolving a medium chain fatty acid in acetonitrile to form a first solution; (b) adding a solution containing heptane and a sodium salt of a short chain alcohol to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals from the resulting slurry; The present invention relates to a process for preparing agglomerated crystals of sodium salts of medium chain fatty acids, comprising:

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

[0018] In a further aspect of the first embodiment, in step (b), a solution comprising 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 a resulting slurry. In some aspects, the solution comprising a sodium salt of a short chain alcohol comprises 15% to 40% by weight sodium methoxide (e.g., in methanol). In certain aspects, about 1 molar equivalent of a solution comprising 15% to 40% by weight sodium methoxide is added in step (b).

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

[0020] In a second embodiment, the present invention provides a method for producing a cellular membrane comprising: (a) dissolving capric acid in a first solvent, where the first solvent comprises acetonitrile, to form a first solution; (b) adding a solution comprising a second solvent, where the second solvent comprises heptane, and sodium methoxide to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals of sodium caprate (Product A) from the resulting slurry; The present invention relates to a process for preparing agglomerated crystals of sodium caprate (Product A), comprising:

[0021] In a further aspect of the second embodiment, the agglomerated crystals are sodium caprate. As such, there is provided a process for preparing agglomerated crystals of sodium caprate (Product A), the process comprising: (a) dissolving capric acid in acetonitrile to form a first solution; (b) adding about 1 molar (e.g., about 0.9 to about 1.5 molar) equivalent of a solution containing heptane and sodium methoxide to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals of sodium caprate (Product A) from the resulting slurry; Includes.

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

[0023] In a further aspect of the first or second embodiment, after step (b), the resulting slurry is stirred for at least 1 hour. In some aspects, the resulting slurry is stirred for 1 hour to 30 hours, 5 hours to 25 hours, 5 hours to 15 hours, 10 hours to 25 hours, 10 hours to 15 hours, 15 hours to 25 hours, 20 hours to 25 hours, 25 hours to 30 hours, 20 hours to 30 hours, 20 hours to 24 hours, or 21 hours to 24 hours. In some aspects, the resulting 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 aspects, the resulting slurry is stirred for 15 hours to 25 hours. In particular, the slurry is stirred for 20 hours to 24 hours.

[0024] In a third embodiment, the process for preparing agglomerated crystals of sodium caprate (Product A) comprises: (a) dissolving capric acid in 1 L / kg to 50 L / kg of acetonitrile to form a first solution; (b) adding about 0.94 to about 1.2 molar equivalents of a 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 to form a resultant slurry; (c) stirring the resulting slurry for at least 1 hour; and (d) filtering the resulting slurry to obtain flocculated sodium caprate crystals (Product A); Includes.

[0025] In some aspects of the above embodiments, the adding in step (b) is carried out at a temperature of 60° C. or less. In some aspects of the above embodiments, the adding in step (b) is carried out at a temperature of 50° C. or less, 45° C. or less, 40° C. or less, or 35° C. or less. In some aspects of the above embodiments, the adding in step (b) is carried out at a temperature of about 40° C. or less. In some aspects, the adding in step (b) is carried out at about 40° C. In some aspects, the adding in step (b) is carried out at about 35° C. In some aspects, the adding in step (b) is carried out at room temperature. In some aspects, the adding in step (b) is carried out at about 22° C. to about 35° C. In some aspects, the adding in step (b) is carried out at about 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 subembodiments, the process for preparing agglomerated sodium caprate crystals comprises: (a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to form a first solution; (b) adding 1.5 L / kg to 5 L / kg of heptane and 0.75 to 1.5 molar equivalents of a solution containing about 20 to about 40 wt. % sodium methoxide to the first solution at a temperature below about 40° C. to induce liquid-liquid phase separation to form a resultant slurry; (c) stirring the resulting slurry for at least 1 hour; and (d) filtering the resulting slurry to obtain flocculated sodium caprate crystals; Includes.

[0027] In a fourth embodiment, the process for preparing agglomerated sodium caprate crystals comprises: (a) dissolving capric acid in 4 L / kg to 8 L / kg of acetonitrile to form a first solution; (b) adding about 1.5 L / kg to about 2.5 L / kg of heptane and about 0.96 to 1.05 molar equivalents of a solution containing about 25% to about 30% by weight of sodium methoxide to the first solution over a period of about 1.0 to about 10.0 hours at a temperature of about 22° C. to about 35° C. with constant agitation to form a resultant slurry; (c) stirring the resulting slurry for at least 1 hour, optionally for 20 hours to 24 hours; and (d) filtering the resulting slurry to separate the resulting solids and drying the resulting solids to obtain agglomerated crystals of sodium caprate; Includes.

[0028] In a fifth embodiment, the preparation process comprises: (a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to form a first solution; (b) adding about 1 molar equivalent of a solution containing about 30% by weight sodium methoxide to the first solution over a period of about 4.5 to about 5.5 hours at a temperature of about 20° C. to about 30° C. with constant stirring; (c) about 1 hour after adding the sodium methoxide containing solution in step (b), adding about 1.5 L / kg to about 4 L / kg of heptane to form a resultant slurry; (d) stirring the resulting slurry for 15 to 25 hours; and (e) filtering the resulting slurry to separate the resulting solids and drying the resulting solids to obtain agglomerated crystals of sodium caprate; Includes.

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

[0030] For example, in step (e) of the sixth embodiment, the resulting solid can be washed with a solution comprising 2 L / kg to 10 L / kg of acetonitrile and methanol. In some subembodiments, two washes of 2 L / kg each are performed. In some embodiments, the wash solution comprises about 10:1 parts acetonitrile and methanol by volume. In certain embodiments, the wash solution comprises 9 parts acetonitrile and 1 part methanol (v / v) (9:1). In some embodiments, this wash step is omitted.

[0031] In any of the described embodiments, in step (a), capric acid is dissolved in 1 L / kg to 50 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 3 L / kg to 30 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 6 L / kg to 30 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 7.5 L / kg to 25 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 10 L / kg to 25 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 10 L / kg to 20 L / kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in about 25 L / kg of acetonitrile to produce the first solution. In some embodiments, 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 described embodiments, capric acid is dissolved in 6 L / kg to 8 L / kg of acetonitrile to produce a first solution (i.e., in step (a), acetonitrile is added in an amount of 6 L / kg to 8 L / kg). In some aspects, 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 between 5° C. and 40° C. with constant stirring. In any of the embodiments, 0.5 to 1.5 molar equivalents of a solution containing sodium methoxide are added to the first solution. In any of the embodiments, 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 sodium methoxide are added. In some embodiments, a solution containing a sodium salt of a short chain alcohol (e.g., sodium methoxide) is added over at least 2.0 hours. In any of the embodiments, the sodium methoxide is added over about 4 to about 6 hours with constant stirring. In some embodiments, the sodium methoxide is added over about 4 to about 6 hours, or about 5 to about 5.5 hours, at a temperature of about 20° C. to about 30° C. In some embodiments, the sodium methoxide is added over 4.0 hours. In some embodiments, the sodium methoxide is added over about 5 to 5.5 hours.

[0034] In any of the embodiments, the second solvent is added to the solution about 1 hour after the solution comprising sodium methoxide is added in step (b). In some embodiments, step (b) comprises adding a second solvent at a controlled rate with constant agitation about 1 hour after the sodium methoxide is added, where the second solvent comprises heptane. Step (b) may comprise adding 1.5 L / kg to 5.0 L / kg of heptane at a controlled rate with constant agitation for 3 to 5 hours about 1 hour after the solution comprising sodium methoxide is added. In any of the embodiments, about 1.5 L / kg to about 2.5 L / kg of heptane is added at a controlled rate with constant agitation for 3 to 5 hours about 1 hour after the sodium methoxide is added. In any of the embodiments, about 1.9 L / kg of heptane is added at a controlled rate for 3 to 5 hours about 1 hour after the sodium methoxide is added. In any of the embodiments, about 3.5 L / kg to about 4.0 L / kg of heptane is added at a controlled rate over a period of 3 to 5 hours with constant stirring.

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

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

[0037] In some embodiments, the second solvent (e.g., heptane) is added to the solution less than 1 hour after adding the solution containing sodium methoxide. In some embodiments, the second solvent (e.g., heptane) is added to the solution about 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 40 minutes, 50 minutes, or 55 minutes after adding the solution containing sodium methoxide. In some embodiments, the second solvent is added to the solution at about the same time as the solution containing sodium methoxide.

[0038] The process of the present invention allows for the direct crystallization of agglomerated crystalline particles of medium chain fatty acid sodium salts such as sodium caprate. This process avoids the formation of gels and other undesirable processing issues typically encountered in the manufacture of sodium caprate. The present invention for crystallizing this type of compound utilizes particle aggregation induced by liquid-liquid phase separation. The process can be used to produce agglomerated particles of medium chain fatty acid sodium salts such as sodium caprate on a production scale. For example, the process can be used to produce sodium caprate in amounts 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 in a single batch. The process can be used to produce two or more batches of sodium caprate in amounts including about 800 kg, 900 kg, 1000 kg, or 1100 kg (or 1.1 tonnes).

[0039] By identifying a solvent composition that suppresses gel formation and traps solids within dispersed droplets of the second phase, a single-pot, low-energy crystallization process using inexpensive, commercially available starting materials has been achieved. The provided agglomerated sodium caprate crystals behave like a conventional slurry and do not entrain solvent, allowing for gentle stirring and easy isolation. The agglomerates exhibit sufficient hardness to retain their morphology upon discharge and handling. Additionally, the provided agglomerates have a substantially homogenous morphology and / or a unimodal normal size distribution. The agglomerates further have excellent powder flowability. In some embodiments, the agglomerates exhibit a Carr's Index of less than 9.0%. In some embodiments, the agglomerates exhibit a Hausner Ratio of less than 1.15. The Carr Index and Hausner Ratio indices correspond to increased flowability. The Carr 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 tapped density of the composition using a graduated cylinder and a tapped density device.

[0040] As such, in some embodiments, compositions (e.g., crystalline powder compositions) comprising sodium caprate are provided, wherein the compositions exhibit 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 compositions exhibit a curl index of less than 9%. In some embodiments, the curl index is between 8% and 9%. In certain embodiments, the compositions exhibit a curl index of 8.7%.

[0041] As such, in some embodiments, compositions (e.g., crystalline powder compositions) comprising sodium caprate are provided, wherein the compositions exhibit a Hausner ratio of less than about 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 compositions exhibit a Hausner ratio of about 1.1. In certain embodiments, the compositions exhibit a Hausner ratio of 1.10.

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

[0043] definition Certain technical and scientific terms are specifically defined below. Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this disclosure pertains. That is, the terms used herein have their ordinary meanings, independent of each occurrence. Nevertheless, and unless otherwise indicated, the following definitions apply throughout this specification and claims. Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If a compound is referred to using 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 regardless of whether the term is used alone or in combination with other terms, unless otherwise indicated.

[0044] Examples following the term "eg" or "for example" are not intended to be exhaustive or limiting.

[0045] As used throughout this specification and disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0046] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural forms unless the context clearly dictates otherwise.

[0047] As used herein, the term "one or more" items encompasses not only a single item selected from the list, but also mixtures of two or more items selected from the list.

[0048] Unless expressly indicated otherwise, all ranges cited herein are inclusive; that is, the range includes the upper and lower limits of the range as well as all values ​​therebetween. Also, all ranges are intended to encompass all subranges included, even if not necessarily explicitly stated. By way of example, temperature ranges, percentages, equivalent ranges, and the like described herein include the upper and lower limits of the range, as well as any values ​​in the continuum therebetween. Numerical values ​​provided herein and the use of the term "about" may encompass 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., a temperature or length of reaction time 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, as used herein, the term "or" refers to combinable options where appropriate; that is, the term "or" includes each listed option individually.

[0049] As 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 "agglomerate."

[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, undecylic acid, and the like. In an embodiment of the invention, the medium chain fatty acid comprises or is capric acid, pelargonic acid, or lauric acid. In a further embodiment, the medium chain fatty acid comprises capric acid.

[0051] As used herein, the term "short chain alcohol" is intended to mean a straight chain saturated hydrocarbon having 1-3 carbon atoms and a terminal hydroxide functionality. Examples include methanol or ethanol. In one embodiment of the invention, 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 an acidic proton, is polar, and has a chemical structure that can function as a hydrogen bond acceptor. Examples include dimethylformamide, dimethylacetamide, tetrahydrofuran, or acetonitrile. In one embodiment of the present invention, the aprotic polar solvent comprises acetonitrile. Any of the aprotic polar solvents described include aprotic polar materials, but may further comprise additional materials. These additional materials may not necessarily be 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 composed of 5-9 carbon atoms linked together to form a non-aromatic chain and bonded to each other and only to hydrogen atoms. Examples include heptane, 2-methylhexane, hexane, octane, and cyclohexane. As used herein, "heptane" can include straight chain heptane, branched chain heptane, n-heptane, or a blend of heptane isomers (e.g., a commercially available heptane blend such as "Heptanes, mixture of isomers" sold by Thermo Scientific Chemicals). As used herein, "hexane" can 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 referred to simply 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 a medium chain aliphatic hydrocarbon, but may further contain additional materials, which are not necessarily medium chain aliphatic hydrocarbons themselves.

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

[0055] As used herein, the expression "constant stirring" is intended to mean substantially uninterrupted stirring of the solution. This expression encompasses the occurrence of one or more interruptions to the stirring, which collectively have no substantial effect on the production of the intended slurry (e.g., several interruptions of 1-3 seconds each). Constant stirring can be performed mechanically (e.g., by a magnetic stir bar) or manually.

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

[0057] "Liquid-liquid phase separation" (LLPS) occurs when a mixture of two solutions contains immiscible solvents and is caused by the thermodynamically non-ideal solution behavior of the solvents involved. The Gibbs free energy is the thermodynamic potential that is minimized when a system reaches equilibrium. If the solvent mixture behaves ideally, the Gibbs free energy has one local minimum and no phase separation occurs. If the solvent mixture behaves non-ideally, there exists a range of temperatures and pressures where the Gibbs free energy has two local minima, and two thermodynamically stable liquid phases with different overall compositions can form. For example, methanol and acetonitrile are completely miscible solvents, but heptane has a miscibility gap with both methanol and acetonitrile. In the bisolvent systems consisting of or including methanol and heptane and acetonitrile and heptane, respectively, there exists a set of compositions where the solvents do not mix and two immiscible liquid phases form. Miscibility gaps also exist in the case of ternary solvent systems consisting of or including methanol, acetonitrile, and heptane. That is, there exists a set of compositions in which the three solvents do not mix, resulting in the formation of two immiscible liquid phases. The formation of two immiscible liquid phases upon the addition of a solvent is referred to herein as liquid-liquid separation (LLPS).

[0058] The present invention employs known filtration techniques, which include centrifugation, vacuum filtration, pressure filtration, and the like.

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

[0060] In some cases, the order of carrying out the above reaction schemes can be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided to provide a more complete understanding of the present invention. These examples are merely illustrative and should not be construed as limiting the present invention in any way. EXAMPLES

[0061] Working Example Example 1A [ka]

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

[0063] Example 1B [ka]

[0064] Capric acid (1) (1.00 kg, 5.81 mol) and acetonitrile (6.0 L) were combined in a suitable vessel 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 as a 30 wt% solution in methanol (1.01 kg) over 5.5 hours with vigorous stirring. Beginning simultaneously with the addition of (2), heptane (1.9 L) was added simultaneously over 5 hours using a separate feed line. The resulting slurry was stirred for an additional 24 hours. The solid was filtered, washed twice with 2 L of a solution of acetonitrile:methanol (9:1 by volume), and then dried under reduced pressure with a nitrogen sweep at 35-40°C to give crystalline sodium caprate (3, product A) (1.09 kg, 97% yield). Photographs of the slurry and isolated sodium caprate crystalline produced using this procedure are shown in Figure 13. A 1.0 kg scale product was produced.

[0065] Example 1C [ka]

[0066] Capric acid (1) (5.02 g, 29.1 mmol) and acetonitrile (30 mL) were combined in a suitable vessel equipped with a suitable stirrer to produce a homogenous solution. Sodium methoxide (2) (28.3 mmol) was charged as a 30 wt% solution in methanol over 5 hours with vigorous stirring to form a slurry. Starting simultaneously with the addition of (2), hexane (10.54 mL) was added simultaneously over 5 hours using a separate feed line. The resulting slurry was stirred for an additional 17 hours. The solid was then filtered, washed twice with 15 mL of a solution of acetonitrile:methanol (9:1 by volume), and then dried under reduced pressure at 40° C. with a nitrogen overhead sweep to give crystalline sodium caprate (3, product A) (5.24 g, 93% yield). Figure 11 shows the material 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 vessel equipped with a suitable stirrer. The batch was stirred at 35° C. until complete dissolution. Sodium methoxide (2) (1.55 g, 29 mmol) was added as a 30 wt % solution in methanol (5.18 g) over 5.5 hours with vigorous stirring to form a slurry. Concurrent with the addition of (2), heptane (7.4 mL) was added simultaneously over 5 hours using a separate feed line. The resulting slurry was stirred for an additional 15 hours. After aging, an additional 1 mL of heptane was added and the batch was heated to 40° C. The slurry was aged for an additional 3 hours. The solid was filtered, washed with acetonitrile (10 mL, 2 times), and dried under reduced pressure with a nitrogen sweep at 35-40° C. to give crystalline sodium caprate (3, product A) (4.1 g, 74% yield). Figure 12 shows the material produced 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 vessel equipped with a suitable stirrer. The batch was stirred at 40° C. until complete dissolution. Sodium methoxide (2) (3.17 g, 58.5 mmol) was added as a 30 wt % solution in methanol (10.57 g) over 5.5 hours with vigorous stirring to form a slurry. Concurrent with the addition of (2), heptane (15.15 mL) was added simultaneously over 5 hours using a separate feed line. The resulting slurry was stirred for an additional 24 hours. The solid was filtered, washed twice with 20 mL of a solution of acetonitrile:methanol (9:1 volume ratio), and then dried under reduced pressure with a nitrogen sweep at 35-40° C. to give crystalline sodium caprate (3, product A) (9,48 g, 83% yield). Figure 12 shows the material produced using this procedure.

[0071] X-ray Powder Diffraction (XRPD) X-ray powder diffraction (XRPD) data were acquired on a Panalaytical X-Pert configured in Bragg-Brentano configuration and equipped with a Cu radiation source monochromated to Kα using a nickel filter, as seen in Figure 1. Fixed slit optics were employed to acquire the data. Data was acquired from 2 to 40° 2θ. Samples were prepared by gently pressing the sample into a zero-background silicon holder. All samples shown in Figure 1 were obtained in this manner and are included to compare the material made by the process with commercially available materials.

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

[0073] Differential Scanning Calorimetry (DSC) A TA Instruments Discovery Differential Scanning Calorimeter (DSC) was used to monitor the thermal events as a function of increasing temperature. Samples of product A (2-5 mg) in sealed non-hermetic aluminum pans with two pinholes were cycled twice from 10 to 300 °C at a heating rate of 10 °C / min.

[0074] The images in Figure 2 show two heating cycles and one cooling cycle performed on a sodium caprate material from room temperature to 300 °C. The downward peaks are endotherms, indicating 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 are upward peaks (exotherms, heat is released). These are reversals of the physical phenomenon that occurred during heating. The presence of hysteresis between the onset and reversal temperatures is typically due to differences in the kinetic barriers between the forward and reverse processes. The width of the hysteresis usually depends on the rate at which the temperature changes during the DSC scan. In Figure 2, there are two overlaying heating curves (y-axis below zero). The overlap of the two lines indicates that the changes that product A experienced during the experiment were reversible and that product A was not destroyed during the scan. The change in width of the first downward peak between the two heating curves is related to the presence of water absorbed in the first scan. The DSC pattern can be used as a characterization technique since the peak locations and areas and the overall shape of the scan are characteristic of sodium caprate.

[0075] Residual Solvents by Gas Chromatography (GC) Preparation of standards: Prepare 0.01% v / v standards in n-heptane, methanol, and acetonitrile by serial dilution for quantitation and 0.001% v / v limit of quantitation (LOQ) for limit reporting.

[0076] Sample preparation: Dissolve sample in diluent at approximately 20 mg / mL. Vortex and sonicate as necessary to dissolve sample.

[0077] Equipment Requirements: [Table 2]

[0078] result: [Table 3]

[0079] thermogravimetric analysis Thermogravimetric analysis (TGA) of product A was performed on 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 nitrogen at 200 mL / min. As seen in Figure 3, the top curve in Figure 3 monitors the change in mass of product A as it is heated under nitrogen atmosphere. The initial slow mass loss (0.8 wt%) at 250 °C is in good agreement with the expected absorbed surface water in the material. Above 250 °C, a drop begins, indicating the onset of decomposition or evaporation. The bottom curve of the graph corresponds to the derivative of the mass change and captures the rate of change of the top curve.

[0080] Particle Size Analysis with Microtrac FlowSync Make and model of device : Microtrac, M5001-3L Sync + FlowSync methodApproximately 50 mg of powder sample was transferred into a 20 mL scintillation vial and 5 mL of IsoparG / 0.25% w / v lecithin solution was added to the vial followed by gentle shaking to disperse the particles. 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 of 3 mL) and all rinses were poured into the FlowSync. 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%. Particle size distribution was calculated as the average of three 30 second scans. Results are reported as volume distribution. Samples were analyzed without sonication, and with 25% powder sonicated for 30, 60 and 90 seconds.

[0081] Sonication is a standard laboratory technique in which vibrational energy is applied to powders to disperse agglomerates within the material and ensure that particle size measurements capture the true particle size of the product particles. Agglomerates are commonly observed in dry solids due to natural adhesion and can skew measurements and overestimate the particle size of powder particles, therefore sufficient sonication is important for analytical accuracy. Figure 4 shows representative volume-weighted particle size distribution results for a batch of Product A produced by the process described in Example 1. The curve shows the probability density that a particle of the product has a radius of the size specified on the x-axis. The curve also shows the effect of sonication on the measured particle size. The reduction and normalization of particle size with increasing sonication is typical behavior indicative of deagglomeration of the dry solid 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 sonication, indicating that samples of this material require at least 60 seconds for proper measurement.

[0082] Figure 4 also shows how the process produced primary particles with a unimodal particle size distribution, which is desirable for manufacturing processes. A unimodal distribution is desirable because it indicates particle uniformity with minimal fines or large agglomerates that lead to uneven flow, filtration and compaction behavior. A unimodal distribution also indicates proper control during the crystallization and aggregation process, as it provides evidence that undesirable particle generating phenomena such as attrition are not occurring and that the overall particle size and morphology are set by the control variables manipulated during batch design.

[0083] Scanning Electron Microscope (SEM) A sodium caprate powder sample was mounted on a SEM stub (32 mm) using carbon sticky. The sample was 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 at 2 kV and the spot intensity was set at 30 (unity). Images were acquired at multiple magnifications.

[0084] The images in Figure 5 showed that the morphology of Product A exists as well-defined aggregated plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more desirable than elongated plates or needles. The demonstrated morphology reflects the superior compression performance of the manufacturing procedure and dosage forms using Product A as an excipient.

[0085] Compression Performance (i) Samples of sodium caprate powder produced by the process and (ii) samples of the formulation containing sodium caprate sample were compressed into cylindrical compacts using a single station compression simulator. The samples were compressed using a 9.525 mm circular flat face tablet press die using compression pressures ranging from 10 to 400 megapascals (MPa). The compression simulation of the formulation was carried out under force control. The composite punch speed was in the range of 50 to 100 mm / s. The weight (W), thickness (h), diameter (D) and hardness (B) of the resulting compacts were measured. Hardness is defined as the peak force required to break the cylindrical compact. The weight of the compacts was controlled in the range of 225 to 375 mg. The obtained values ​​for thickness and hardness were used to calculate the tensile strength (T) of the tablets using the formula X. The obtained tablet tensile strength and compression pressure are combined into a tabletting curve.

number

[0086] Table 1 shows the compositions of the example formulated tablet products containing sodium caprate obtained from various commercial sources. The formulations included: disintegrant, glidant, lubricant, and two compression aids (i.e., diluents or binders): lactose and microcrystalline cellulose. Four of the formulations contained commercial sodium caprate lots, and one used the agglomerated material product A produced by 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 results of the compression profile of the five formulations. These results show that Product A (solid circle) demonstrated superior compression performance compared to all commercial materials tested. Figure 6 reflects the tensile strength of tablets formulated with sodium caprate sources (including Product A). The image shows that the material produced with Product A (depicted by the solid circle) resulted in the toughest material within the relevant processing range of compression pressures. The in-die powder bulk density of these five formulations was estimated using the pre-compression compact mass and the filled die volume. The in-die bulk density of the formulation containing commercial material 2 was the lowest of all materials tested, nominally 0.39 g / mL. The in-die bulk densities of the remaining four formulations ranged from 0.44 to 0.47 g / mL. All observed in-die bulk densities indicate acceptable values ​​for tableting these blends.

[0089] liquidity Bulk and tapped density measurements were used to compare the flow characteristics of Product A with sodium caprate materials obtained from various commercial sources. Bulk and tapped density indicate the density at which a powder packs onto itself. A low density is an indication of a material that has poor flow and packability. Carr Index and Hausner Ratio are indices that are calculated using bulk and tapped density measurements. A low value for both indices indicates that the material has improved flow properties. Bulk density was measured using a 100 mL graduated cylinder and at least 50 mL of powdered material. The powdered material was dispensed into the graduated cylinder and both the mass and volume of the material were recorded. The ratio of mass to volume was calculated to obtain the bulk density of the powder. The graduated cylinder was then filled into a USP <661> The resulting volume of the material was then used to calculate the tap density value.

[0090] Table 2 lists the bulk and tapped densities of the materials and provides the calculated Curr Index and Hausner Ratio results. As shown in Table 2, Product A exhibited a Curr Index of 8.7% and a Hausner Ratio of 1.10. Both of these values ​​are significantly lower than those of commercial materials 1-4, indicating that Product A exhibits excellent powder flowability. The agglomerated sodium caprate crystals produced in the present invention (Product A) exhibit excellent flowability despite their low density, which is reflected in both the low Curr Index and Hausner Ratio.

[0091] [Table 5]

[0092] FIG. 7 shows SEM images of sodium caprate from commercial materials 1-4, providing a comparison of their respective morphologies. The method of preparation of the compound has a significant impact on the structure and physical appearance of the material. Commercial material 1 (sodium caprate from BSI) was a smooth sphere produced by spray drying. Commercial material 3 (sodium caprate from TCI Chemical) and commercial product 4 (sodium caprate from Jost) were elongated large thin plates. Product A constituted an agglomerated solid, with a rough surface and no extension in any axial direction. The process allowed for this unique morphology of Product A, which is easy to manufacture and handle on standard equipment and has desirable properties for formulation manufacturing.

[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. The vial was charged with n-heptane (0.3 mL) to form a slurry of flocculated particles. An optical microscope image depicting these particles is shown in the top 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, which was then charged with n-heptane (0.2 mL) to form a slurry of flocculated 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. The vial was charged with n-heptane (0.2 mL) to form a slurry of agglomerated particles. An optical microscope image depicting these particles is shown in the lower panel of FIG. 10.

[0097] DMAc, DMF and NMP are each polar aprotic solvents. As highlighted by the image shown in Figure 10, combining sodium caprate with heptane and a polar aprotic solvent results in an aggregated crystalline sodium caprate product. As such, any of a number of polar aprotic solvents may be used in the disclosed process for making sodium caprate aggregates.

[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 vessel equipped with a suitable stirrer to give a homogeneous solution. Sodium methoxide (2) (15.9 mmol) was charged to the solution as a 25 wt% solution in methanol over 5 hours with vigorous stirring to form a slurry. After the first hour of addition of (2), heptane (9.3 mL) was added simultaneously to the solution over 4 hours. The slurry was stirred for an additional hour. The solid was filtered, washed with acetonitrile (2×15 mL), and then dried under reduced pressure with a nitrogen sweep at 35-40° C. to give sodium pelargonate (5) (2.68 g, 94% yield).

[0100] Scanning Electron Microscope (SEM) Sodium pelargonate powder samples were mounted on SEM stubs (32 mm) using carbon sticky. The samples were sputter coated with platinum. The samples were loaded into a Hitachi TM3030 Tabletop Scanning Electron Microscope. The samples were imaged in high vacuum mode and images were acquired using a secondary electron (SE) detector. The voltage was set at 2 kV and the spot intensity was set at 30 (unity). Images were acquired at multiple magnifications. The image in Figure 8 showed that the morphology of the sodium pelargonate aggregated crystals exists as well-defined plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more desirable than elongated plates or needles, as such morphologies tend to exhibit superior compression performance in the manufacturing procedure.

[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 vessel 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 charged to the solution as a 25 wt % solution in methanol over 5 hours with vigorous stirring to form a slurry. After the first hour of addition of (2), heptane (9.3 mL) was added simultaneously to the solution over 4 hours. The slurry was stirred for an additional hour. The solid was filtered, washed with acetonitrile (2×15 mL), and then dried under reduced pressure with a nitrogen sweep at 35-40° C. to give sodium laurate (7) (2.7 g, 97% yield).

[0103] Scanning Electron Microscope (SEM) Sodium laurate powder samples were mounted on SEM stubs (32 mm) using carbon sticky. The samples were sputter coated with platinum. The samples were loaded into a Hitachi SU5000 Scanning Electron Microscope. The samples were imaged in high vacuum mode and images were acquired using a secondary electron (SE) detector. The voltage was set at 2 kV and the spot intensity was set at 30 (unity). Images were acquired at multiple magnifications. The image in FIG. 9 showed that the morphology of the sodium laurate aggregated crystals exists as well-defined plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more desirable than elongated plates or needles, as such a morphology tends to exhibit superior compression performance in manufacturing procedures and dosage forms.

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

[0105] Equivalent Although several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily envision various other means for performing the functions described herein and / or obtaining the results described herein and / or obtaining one or more of the advantages described herein. Each such variation and / or modification is deemed to be within the scope of the embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials and / or configurations will depend on the particular application in which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. Thus, it should be understood that the foregoing embodiments are presented by way of example only, and that within the scope of the appended claims and their equivalents, the embodiments may be practiced otherwise than as specifically described and claimed. The embodiments of the present disclosure are directed to the individual features, materials and / or methods described herein. Furthermore, any combination of two or more such features, materials and / or methods is encompassed within the scope of the present disclosure, provided that such features, materials and / or methods are not mutually inconsistent.

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

[0107] The indefinite articles "a" and "an," as used in the specification and claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

[0108] The term "and / or" as used herein and in the claims should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether or not related to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in combination with open-ended language such as "comprising," may, for example, refer to only A in one embodiment (which may optionally include elements other than B); in another embodiment, refer to only B (which may optionally include elements other than A); in yet another embodiment, refer to both A and B (which may optionally include other elements); and so forth.

[0109] As 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 being inclusive, i.e., including not only at least one of a number or list of elements, but also two or more, and possibly including additional items not in the list. Only terms clearly indicating the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," indicate the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein should be interpreted as indicating exclusive alternatives (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] Whenever a composition is disclosed or claimed as "comprising" one or more features, it is understood that embodiments in which such composition "consists of" and "consists essentially of" those one or more features are also disclosed or claimed. The transitional phrase "consisting essentially of" is to have its ordinary 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," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. In contrast, 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 expressly indicated to the contrary, it should be understood that in any method claimed herein that includes two or more steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are described.

Claims

1. 1. A process for preparing agglomerated crystals of a sodium salt of a medium chain fatty acid, comprising: (a) dissolving a medium chain fatty acid in a first solvent, where the first solvent comprises an aprotic polar solvent, to form a first solution; (b) adding (i) a second solvent, where the second solvent comprises a medium chain aliphatic hydrocarbon solvent, and (ii) a solution comprising 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 process comprising:

2. 2. The process of claim 1, wherein the first solvent is selected from acetonitrile, DMF, DMAC, and NMP.

3. 3. The process of claim 1 or 2, wherein the second solvent is selected from heptane and hexane.

4. 4. The process of claim 1, wherein the medium chain fatty acid comprises capric acid and the first solvent comprises acetonitrile.

5. 1. A process for preparing agglomerated crystals of a sodium salt of a medium chain fatty acid, comprising: (a) dissolving a medium chain fatty acid in acetonitrile to form a first solution; (b) adding about one molar equivalent of a solution comprising heptane and a sodium salt of a short chain alcohol to the first solution to form a resulting slurry; and (c) isolating the agglomerated crystals from the resulting slurry; The process comprising:

6. 6. The process of claim 5, wherein in step (b), the solution comprising heptane and the sodium salt of the short chain alcohol is added to the first solution at a temperature of less than about 40°C.

7. 7. The process of claim 5 or 6, wherein in step (b), heptane is added at a controlled rate with constant agitation over a period of about 3.5 to about 4.5 hours.

8. The process of any one of claims 5 to 7, wherein after step (b), the resulting slurry is stirred for at least 1 hour.

9. The process of any one of claims 5 to 8, wherein after step (b), the resulting slurry is stirred for 15 to 25 hours.

10. 1. A process for preparing agglomerated crystals of sodium caprate, comprising the steps of: (a) dissolving capric acid in acetonitrile to form a first solution; (b) adding about one molar equivalent of a solution containing heptane and sodium methoxide to the first solution to form a slurry; and (c) isolating the agglomerated crystals of sodium caprate from the resulting slurry; The process comprising:

11. 11. The process of claim 10, wherein in step (b), the solution comprising heptane and sodium methoxide is added to the first solution at a temperature less than about 40° C. to induce liquid-liquid phase separation.

12. 12. The process of claim 10 or 11, wherein after step (b), the resulting slurry is stirred for at least 1 hour.

13. 13. The process of any one of claims 5 to 12, wherein in step (a) 6 L / kg to 8 L / kg of acetonitrile is added.

14. 14. The process of any one of claims 5 to 13, wherein in step (b) 1.7 L / kg to 2.1 L / kg of heptane is added.

15. 15. The process of any one of claims 5 to 14, wherein in step (b), heptane is added over a period of about 3.5 to about 4.5 hours.

16. (a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to form a first solution; (b) adding 1.5 L / kg to 5 L / kg heptane and 0.75 to 1.5 molar equivalents of a solution containing about 20 to about 40 wt. % sodium methoxide to the first solution at a temperature below about 40° C. to induce liquid-liquid phase separation to form a resultant slurry; (c) stirring the resulting slurry for at least 1 hour; and (d) filtering the resulting slurry to obtain flocculated sodium caprate crystals; The process according to any one of claims 10 to 12, comprising:

17. (a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to form a first solution; (b) adding about 1 molar equivalent of a solution containing about 30% by weight sodium methoxide to the first solution over a period of about 4.5 to about 5.5 hours at a temperature of about 20° C. to about 30° C. with constant agitation; (c) about 1 hour after adding the sodium methoxide containing solution in step (b), adding about 1.5 L / kg to about 4 L / kg of heptane to form a resulting slurry; (d) stirring the resulting slurry for 15 to 25 hours; and (e) filtering the resulting slurry to separate the resulting solids and drying the resulting solids to obtain agglomerated crystals of sodium caprate; The process according to any one of claims 10 to 12, comprising:

18. 18. The process of claim 17, wherein in step (c), heptane is added at a controlled rate with constant agitation over a period of about 3.5 to about 4.5 hours.

19. 19. A composition comprising a sodium salt of a medium chain fatty acid produced using the process of any one of claims 1 to 18.

20. A composition comprising sodium caprate exhibiting a curl index of less than 9.0%.

21. A composition comprising sodium caprate, the composition exhibiting a Hausner ratio of less than 1.15.

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