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

Abstract

The method of the present invention is useful for preparing agglomerated crystalline particles of a medium chain sodium fatty acid salt, such as sodium caprate. The method comprises the steps of: a) dissolving a medium chain fatty acid in a first solvent to produce a first solution, wherein the first solvent comprises an aprotic polar solvent; b) adding to the first solution (i) a second solvent, wherein the second solvent comprises a medium chain aliphatic hydrocarbon solvent, and (ii) a solution comprising a sodium salt of a short chain alcohol to produce a resulting slurry; and c) separating agglomerated crystals from the resulting slurry. The first solvent may comprise acetonitrile and the second solvent may comprise heptane. Further provided are products produced by the process, including sodium caprate products having excellent flowability and compressive properties.

Description

Background of the Invention

[0002] The sodium salts of medium chain length (medium chain) saturated organic acids are surprisingly difficult to crystallize. These molecules have strong gelation and a tendency to cause unstirable batch conditions in most solvent systems. The natural crystallization form of these compounds is a long fiber / needle, which tends to carry solvents, is difficult to separate in a standard equipment chain, and has undesirable powder properties for formulation manufacturing. Most commercially available materials of this type are either very expensive and separated by spray drying, or keep the suboptimal fibrous form formed by an unstirable thick slurry.

[0003] Sodium caprate or sodium decanoate is the sodium salt of capric acid (a 10-carbon saturated fatty acid), which can form micelles and liquid crystal phases in aqueous solution. Sodium caprate may contribute to the transport of bioactive molecules, and as a component of FDA-approved food additives and finished drug products, it may be used to enhance the bioavailability of API. In addition, sodium caprate is a known intestinal permeation enhancer. Although there are known methods for preparing sodium caprate, including the synthesis described in B. Zacharie et al., Organic Process Research & Development 2009, 13, 581–583, these methods, unlike the present invention, use any of many solvent systems, resulting in gelation of sodium caprate materials. Gelation makes it difficult and impractical to use sodium caprate (powder) in large-scale manufacturing. However, in a few solvent systems where gelation can be suppressed, sodium caprate crystallizes into small fine needles or fibers, which results in the production of unstirrable slurries. Therefore, these slurries present their own challenges because it is difficult to transfer these slurries from one equipment chain to another, such as from a crystallization tank to a filter / dryer or centrifuge. In addition, these particles filter poorly and trap a significant amount of interstitial liquid, resulting in excessive agglomeration during the drying process. The filter cake formed requires a large amount of energy input to disintegrate and results in the formation of widely distributed material lumps, which affects the ability to formulate the material. These particles are also more prone to cracking or breaking. In short, sodium decanoate is very difficult to separate at an industrial scale. As a potential consequence of these formulation challenges, the GMP supply of sodium decanoate is limited.

[0004] Therefore, there are regulatory and technical barriers to the industrial use of decanoate as an excipient in the formulation of drug products. SUMMARY OF THE INVENTION

[0006] The disclosure provides the method for generating solid, and the solid is an agglomerate with adjustable particle size, powder flow properties and compression behavior that are superior to commercially available substitutes. The method is cost-effective, and generates materials with excellent flow and compaction properties, so that it is suitable for use as an excipient in manufacturing process and finished drug products. The method is also scalable, because it can generate a large amount of solid materials. In various embodiments, the method comprises producing medium chain fatty acid sodium salts, such as the method for sodium caprate.

[0007] The present invention further provides products generated by the present method. These products, which are solid crystalline powders that can serve as excipients in pharmaceutical preparations, have excellent flow properties and compaction properties relative to commercial medium-chain fatty acid sodium salts. These products can be substantially free of gelled or fibrous or needle-like crystal dispersions.

[0008] The present invention relates to a method for preparing agglomerated crystals of sodium salt of medium-chain fatty acid, which comprises the following steps:

[0009] a) dissolving a medium-chain fatty acid in a first solvent to produce a first solution, wherein the first solvent comprises an aprotic polar solvent;

[0010] b) adding (i) a second solvent, wherein 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

[0011] c) separating the agglomerated crystals from the resulting slurry.

[0012] 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 dissolution of crystalline products (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. Therefore, in some aspects, the method comprises the following steps:

[0013] a) dissolving a medium chain fatty acid in an aprotic polar solvent selected from acetonitrile, DMF, DMAC and NMP to produce a first solution;

[0014] b) adding an aliphatic hydrocarbon solvent selected from the group consisting of heptane and hexane, and about 1 molar equivalent of a solution comprising a sodium salt of a short chain alcohol to the first solution to produce a resulting slurry; and

[0015] c) separating the agglomerated crystals from the resulting slurry.

[0016] In some aspects, the method comprises the steps of:

[0017] a) dissolving a medium chain fatty acid in acetonitrile to produce a first solution;

[0018] b) adding heptane and about 1 molar equivalent of a solution comprising a sodium salt of a short chain alcohol to the first solution to produce a resulting slurry; and

[0019] c) separating the agglomerated crystals from the resulting slurry.

[0020] In some embodiments, the sodium salt of a short-chain alcohol is sodium methoxide. In some embodiments, the solution comprising the sodium salt of a short-chain alcohol comprises methanol or ethanol. In a specific embodiment, the solution contains methanol. In a specific embodiment, the solution comprising the sodium salt of a short-chain alcohol comprises methanol and sodium methoxide.

[0021] In various embodiments, the second solvent and the solution comprising the sodium salt of the short-chain alcohol are added separately to the first solution. This is referred to in the present disclosure as addition via "separate feed lines".

[0022] In various embodiments, the agglomerated crystals in the resulting slurry comprise sodium caprate. This agglomerated crystalline product may be referred to herein as "Product A".

[0023] Other embodiments, aspects and features of the present invention are further described or apparent in the ensuing description, examples and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Shown is X-ray powder diffraction data for Product A using the present invention compared to a commercially available sodium decanoate substitute.

[0026] Figure 2 is a differential scanning calorimeter (DSC) scan of Product A.

[0027] Figure 3 Thermogravimetric analysis of product A is depicted.

[0028] Figure 4 Particle size analysis of Product A is depicted.

[0029] Figure 5 A scanning electron microscope (SEM) image of Product A is shown.

[0030] Figure 6 is a graph depicting the compression performance of a solid formulation of an agglomerated material (Product A) with one or more compression aids compared to a corresponding commercially available form of crystalline sodium caprate.

[0031] Figure 7SEM images comparing commercially available forms of sodium decanoate crystals with Product A are depicted.

[0032] Figure 8 is a SEM image of sodium nonanoate crystals grown in acetonitrile and heptane.

[0033] Fig. 9 is a SEM image of sodium laurate crystals grown in acetonitrile and heptane.

[0034] Fig.10 Optical microscopy images depicting the formation of sodium decanoate agglomerates using different aprotic polar organic solvents (NMP and DMAC) and heptane are shown.

[0035] Fig.11 SEM images showing sodium decanoate crystals formed in acetonitrile and hexane.

[0036] Fig.12 Shown are SEM images of sodium decanoate crystals generated in acetonitrile and heptane using 1 L / kg (1V) and 2 L / kg (2V) of acetonitrile.

[0037] Fig.13 Depicted are photographs taken during the performance of an exemplary process for producing approximately 1.0 kg of sodium caprate agglomerated crystals product. This product is shown in a rectangular glass dish at the bottom. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention relates to a method for preparing agglomerated crystals of sodium salt of medium-chain fatty acid, which comprises the following steps:

[0040] a) dissolving a medium-chain fatty acid in a first solvent to produce a first solution, wherein the first solvent comprises an aprotic polar solvent selected from the group consisting of acetonitrile, DMF, DMAC, and NMP to produce a first solution;

[0041] b) adding (i) a second solvent, wherein the second solvent comprises a medium chain aliphatic hydrocarbon solvent selected from the group consisting of 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

[0042] c) separating the agglomerated crystals from the resulting slurry.

[0043] In a first embodiment, the first solvent of the present method comprises acetonitrile and the second solvent comprises heptane. Therefore, in this embodiment, the present invention relates to a method for preparing agglomerated crystals of sodium salts of medium-chain fatty acids, comprising the following steps:

[0044] a) dissolving a medium chain fatty acid in acetonitrile to produce a first solution;

[0045] b) adding heptane and a solution comprising a sodium salt of a short chain alcohol to the first solution to produce a resulting slurry; and

[0046] c) separating the agglomerated crystals from the resulting slurry.

[0047] In various aspects, the medium chain fatty acid comprises capric acid and the first solvent comprises acetonitrile.

[0048] In another aspect of the first embodiment, in step b, heptane and a solution comprising a sodium salt of a short-chain alcohol (e.g., sodium methoxide in methanol) are added to the first solution to induce liquid-liquid phase separation and produce a resulting slurry. In some aspects, the solution comprising a sodium salt of a short-chain alcohol comprises 15 to 40 weight % sodium methoxide (e.g., in methanol). In particular aspects, approximately 1 molar equivalent of a solution comprising 15 to 40 weight % sodium methoxide is added in step b.

[0049] In another aspect of the first embodiment, in step b, heptane and the solution comprising the sodium salt of the short chain alcohol are added to the first solution at a temperature below about 40° C. In some aspects, heptane is added at a controlled rate over about 3.5 to about 4.5 hours with constant stirring.

[0050] In a second embodiment, the present invention is directed to a process for preparing agglomerated crystals of sodium caprate (Product A), comprising the steps of:

[0051] a) dissolving capric acid in a first solvent to produce a first solution, wherein the first solvent comprises acetonitrile;

[0052] b) adding a second solvent and a solution comprising sodium methoxide to the first solution to produce a resulting slurry, wherein the second solvent comprises heptane; and

[0053] c) separating agglomerated crystals of sodium caprate from the resulting slurry (Product A).

[0054] In another aspect of the second embodiment, the agglomerated crystals are sodium caprate. Therefore, a method for preparing agglomerated crystals of sodium caprate (product A) is provided, which comprises the following steps:

[0055] a) dissolving capric acid in acetonitrile to produce a first solution;

[0056] b) adding heptane and about 1 molar (e.g., about 0.9 to about 1.5 molar) equivalent of a solution comprising sodium methoxide to the first solution to produce a resulting slurry; and

[0057] c) separating agglomerated crystals of sodium caprate from the resulting slurry (Product A).

[0058] In a second embodiment, the addition of heptane in step b initiates liquid-phase separation. In some aspects, the addition of heptane and sodium methoxide initiates liquid-liquid phase separation at a temperature below about 40° C. 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.

[0059] In another 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 to 30 hours, 5 to 25 hours, 5 to 15 hours, 10 to 25 hours, 10 to 15 hours, 15 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 specific aspects, the slurry is stirred for 20 hours to 24 hours.

[0060] In a third embodiment, a method for preparing agglomerated crystals of sodium caprate (Product A) comprises the following steps:

[0061] a) dissolving capric acid in 1 L / kg to 50 L / kg of acetonitrile to produce a first solution;

[0062] b) adding 1.5 L / kg to 5 L / kg of heptane and about 0.94 to 1.2 molar equivalents of a solution comprising about 20 wt % to about 40 wt % sodium methoxide to the first solution to produce a resulting slurry,

[0063] c) stirring the resulting slurry for at least 1 hour; and

[0064] d) filtering the resulting slurry to provide agglomerated sodium caprate crystals (Product A).

[0065] In some aspects of the above embodiments, the addition in step b is carried out at a temperature equal to or lower than 60°C. In some aspects of the above embodiments, the addition in step b is carried out at a temperature equal to or lower than 50°C, equal to or lower than 45°C, equal to or lower than 40°C, or equal to or lower than 35°C. In some aspects of the above embodiments, the addition in step b is carried out at a temperature equal to or lower than about 40°C. In some aspects, the addition in step b is carried out at about 40°C. In some aspects, the addition in step b is carried out at about 35°C. In some aspects, the addition in step b is carried out at room temperature. In some aspects, the addition in step b is carried out at about 22°C to about 35°C. In some aspects, the addition 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.

[0066] In some sub-embodiments, the method of preparing agglomerated sodium caprate crystals comprises the following steps:

[0067] a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution;

[0068] b) adding 1.5 L / kg to 5 L / kg of heptane and 0.75 to 1.5 molar equivalents of a solution comprising 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 and produce a resulting slurry;

[0069] c) stirring the resulting slurry for at least 1 hour; and

[0070] d) filtering the resulting slurry to provide agglomerated sodium caprate crystals.

[0071] In a fourth embodiment, a method for preparing agglomerated sodium caprate crystals comprises the following steps:

[0072] a) dissolving capric acid in 4 L / kg to 8 L / kg of acetonitrile to produce a first solution;

[0073] 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 comprising about 25 wt % to about 30 wt % sodium methoxide to the first solution at a temperature of about 22° C. to about 35° C. over about 1.0 to about 10.0 hours with constant stirring to produce a resulting slurry;

[0074] c) stirring the resulting slurry for at least 1 hour, optionally 20 hours to 24 hours; and

[0075] d) filtering the resulting slurry to separate the resulting solid and drying the resulting solid to provide agglomerated crystals of sodium caprate.

[0076] In a fifth embodiment, the method comprises:

[0077] a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution;

[0078] b) adding about 1 molar equivalent of a solution comprising about 30 wt % sodium methoxide to the first solution at a temperature of about 20° C. to about 30° C. over about 4.5 to about 5.5 hours with continuous stirring;

[0079] c) about 1 hour after adding the solution comprising sodium methoxide in step b, adding about 1.5 L / kg to about 4 L / kg of heptane to produce a resulting slurry;

[0080] d) stirring the resulting slurry for 15 to 25 hours; and

[0081] e) filtering the resulting slurry to separate the resulting solid and drying the resulting solid to provide agglomerated crystals of sodium caprate.

[0082] In any embodiment, in step d, after filtering the solid obtained by the stirring of the slurry, the resulting solid can be washed to remove any residual chemicals (e.g., residual methoxide). In some embodiments, the solid is washed with a solution comprising acetonitrile and methanol. Therefore, in a sixth embodiment, the method for preparing agglomerated sodium caprate crystals comprises the following steps:

[0083] a) dissolving capric acid in 4 L / kg to 8 L / kg of acetonitrile to produce a first solution;

[0084] 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 comprising about 25 wt % to about 30 wt % sodium methoxide to the first solution at a temperature of about 22° C. to about 35° C. over about 1.0 to about 10.0 hours with constant stirring to produce a resulting slurry;

[0085] c) stirring the obtained slurry for 20 to 24 hours;

[0086] d) filtering the resulting slurry to separate the resulting solids;

[0087] e) washing the obtained solid with a solution comprising acetonitrile and methanol; and

[0088] f) drying the resulting solid to provide agglomerated crystals of sodium caprate.

[0089] 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 sub-embodiments, two washes of 2 L / kg are performed each time. In some embodiments, the wash solution comprises approximately 10:1, 9:1 or 8:1 parts of acetonitrile:methanol by volume. In a specific embodiment, the wash solution comprises 9 parts of acetonitrile to 1 part of methanol (v / v) (9:1). In some embodiments, this wash step is omitted.

[0090] In any of the embodiments, in step a, capric acid is dissolved in 1 L / kg to 50 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in 3 L / kg to 30 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in 7.5 L / kg to 25 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in 10 L / kg to 25 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in 10 L / kg to 20 L / kg of acetonitrile to produce a first solution. In any embodiment, capric acid is dissolved in about 25 L / kg of acetonitrile to produce a first solution. In any embodiment, the 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 aspects, 1, 2, or 3 L / kg of acetonitrile can be used. In some aspects, about 3 L / kg of acetonitrile is used.

[0091] In any of the embodiments, the capric acid is dissolved in 6 L / kg to 8 L / kg of acetonitrile to produce a first solution (i.e., 6 L / kg to 8 L / kg of acetonitrile is added in step a). In some aspects, about 6.0 L / kg of acetonitrile is used. About 7.0 L / kg or 8.0 L / kg of acetonitrile can be used.

[0092] In various aspects, a solution containing a sodium salt of a short-chain alcohol (e.g., sodium methoxide) is added at a temperature of 5°C to 40°C over 1.0 to 10.0 hours with continuous stirring. In any embodiment, 0.5 to 1.5 molar equivalents of a solution containing sodium methoxide is 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 is added. In some embodiments, about 0.9 to about 1.5, 0.9 to 1.00, about 0.96 to 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 is added. In a specific embodiment, 0.97 molar equivalents of 25% to 30% by weight of sodium methoxide is added. In some embodiments, the solution comprising a sodium salt of a short chain alcohol (e.g., sodium methoxide) is added over at least 2.0 hours. In any embodiment, 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 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.

[0093] In any embodiment, in step b, the second solvent is added to the solution about 1 hour after adding the solution comprising sodium methoxide. In some embodiments, step b includes adding the second solvent at a controlled rate under continuous stirring about 1 hour after adding sodium methoxide, wherein the second solvent comprises 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 under continuous stirring about 1 hour after adding the solution comprising sodium methoxide. In any embodiment, add about 1.5 L / kg to about 2.5 L / kg of heptane at a controlled rate over 3 to 5 hours under continuous stirring about 1 hour after adding sodium methoxide. In any embodiment, add about 1.9 L / kg of heptane at a controlled rate over 3 to 5 hours after adding sodium methoxide. In any embodiment, add about 3.5 L / kg to about 4.0 L / kg of heptane at a controlled rate over 3 to 5 hours under continuous stirring.

[0094] In some embodiments, 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 of heptane is added at a controlled rate over about 1.5 to about 5 hours with continuous stirring. In some embodiments, 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, or 3.5 L / kg to 4.0 L / 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 continuous stirring. In some embodiments, about 1.7 L / kg to 2.1 L / kg of heptane is added over about 3.5 to about 4.5 hours, over about 4.5 to 5 hours, or over 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 over 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.

[0095] In another aspect of the fourth embodiment, in step c, heptane is added at a controlled rate over about 3.5 to about 4.5 hours with constant stirring.

[0096] In some embodiments, the second solvent (e.g., heptane) is added to the solution less than 1 hour after the addition of the solution comprising sodium methoxide. 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 comprising sodium methoxide. In some embodiments, the second solvent is added to the solution at approximately the same time as the solution comprising sodium methoxide.

[0097] The method of the present invention can directly crystallize the agglomerated crystalline particles of medium-chain fatty acid sodium salts, such as sodium caprate. This method avoids gel formation and other undesirable processing challenges common in the manufacture of sodium caprate. The present invention for the crystallization of this compound utilizes the particle agglomeration caused by liquid-liquid phase separation. The present method can be used to generate agglomerated particles of medium-chain fatty acid sodium salts, such as sodium caprate, in a production scale. For example, the present method can be used to generate a sodium caprate weight 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 present method can be used to generate a sodium caprate weight including about 800 kg, 900 kg, 1000 kg or 1100 kg (or 1.1 metric tons) in two or more batches.

[0098] By determining the solvent composition that inhibits gel formation and traps solids in the dispersed droplets of the second phase, a single pot low energy consumption crystallization method using cheap commercial starting materials is achieved. The agglomerated sodium decanoate crystals provided behave like traditional slurries and do not carry over solvents to enable gentle stirring and easy separation. The agglomerates exhibit sufficient hardness to maintain their morphology during discharge and operation. In addition, the agglomerates provided have a substantially uniform morphology and / or a unimodal normal size distribution. The agglomerates also 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's Index and Hausner Ratio indicators correspond to improved flowability. The Carr's Index and Hausner Ratio of any disclosed composition can be calculated using any method known in the art, such as by measuring the bulk density and tap density of the composition using a graduated cylinder and a tap density device.

[0099] Thus, in some aspects, provided herein are compositions (e.g., crystalline powder compositions) comprising sodium caprate, wherein the composition exhibits a Carr's Index of approximately less than 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 Carr's Index of less than 9%. In some embodiments, the Carr's Index is between 8% and 9%. In a specific embodiment, the composition exhibits a Carr's Index of 8.7%.

[0100] Thus, in some aspects, provided herein are compositions (e.g., crystalline powder compositions) comprising sodium caprate, wherein the composition exhibits a Hausner Ratio of approximately 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 approximately 1.1. In specific embodiments, the composition exhibits a Hausner Ratio of 1.10.

[0101] Products generated by any disclosed method are described herein. That is, compositions comprising sodium salts of medium-chain fatty acids (e.g., sodium caprate) generated using any disclosed method are provided herein. In various embodiments, the product comprises any provided agglomerated crystals, such as agglomerated sodium caprate crystals.

[0102] definition

[0103] Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this article, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure relates. That is, the terms used herein have their ordinary meanings, which are independent at each occurrence. Nevertheless and unless otherwise indicated, the following definitions apply to the entire specification and claims. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound and there is an ambiguity between the structure and the name, the structure shall prevail. Unless otherwise indicated, these definitions apply regardless of whether the term is used alone or in combination with other terms.

[0104] Any examples following the term "such as" are not intended to be exhaustive or limiting.

[0105] As used herein and throughout this disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0106] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0107] As used herein, the term "one or more" items each includes a single item selected from the list as well as a mixture of two or more items selected from the list.

[0108] Unless expressly provided to the contrary, all ranges cited herein are inclusive; that is, the range includes the values ​​of the upper and lower limits of the range and all values ​​therebetween. All ranges are also intended to include all subranges covered, although not necessarily explicitly stated. As an example, the temperature ranges, percentages, equivalent ranges, etc. described herein include the upper and lower limits of the range and any value in the continuum therebetween. The use of the numerical values ​​and term "approximately" provided herein may include changes of ±1%, ±2%, ±3%, ±4%, ±5% and ±10% and their numerical equivalents. When used to modify a numerically defined parameter (e.g., the temperature or time length of a reaction as described herein), "approximately" means that the parameter may vary up to 10% below or above the specified value of the parameter; where appropriate, the specified parameter may be rounded to the nearest integer. For example, a temperature of approximately 30°C may vary between 25°C and 35°C. In addition, the term "or" as used herein represents an alternative that can be combined where appropriate; that is, the term "or" includes each listed alternative separately.

[0109] As used herein, "Product A" refers to the agglomerated crystalline form of sodium caprate produced by the process of the present invention. In some embodiments, "Product A" is synonymous with "agglomerated material".

[0110] The term "medium chain fatty acid" as used herein is intended to mean an aliphatic carbohydrate having a primary carboxyl group and 5 to 15 carbon atoms. Examples include capric acid, lauric acid, nonanoic acid, undecanoic acid, etc. In one embodiment of the invention, the medium chain fatty acid comprises or is capric acid, nonanoic acid or lauric acid. In a further embodiment, the medium chain fatty acid comprises capric acid.

[0111] As used herein, the term "short-chain alcohol" is intended to mean a straight-chain saturated hydrocarbon having 1 to 3 carbon atoms and a terminal hydroxyl functional group. 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.

[0112] The term "aprotic polar solvent" as used herein is intended to mean a compound or mixture of compounds used as a process solvent, whose chemical structure lacks acidic protons, is polar, and can act as a hydrogen bond acceptor. Examples include dimethylformamide, dimethylacetamide, tetrahydrofuran, or acetonitrile. In one embodiment of the invention, the aprotic polar solvent comprises acetonitrile. Any of the aprotic polar solvents described herein comprises an aprotic polar substance, but may further include additional substances. These additional substances themselves may not necessarily be aprotic or polar.

[0113] The term "medium-chain aliphatic hydrocarbon solvent" as used herein is intended to mean a compound or mixture of compounds used as a process solvent, whose chemical structure consists of 5 to 9 carbon atoms that are linked to form a non-aromatic chain and are only bonded to each other and to hydrogen atoms. Examples include heptane, 2-methylhexane, hexane, octane and cyclohexane. As used herein, "heptane" may include a blend of linear heptane, branched heptane, n-heptane or heptane isomers (e.g., a commercially available heptane blend, such as "heptane, a mixture of isomers" sold by ThermoScientificChemicals). As used herein, "hexane" may include a blend of linear hexane, branched hexane, n-hexane or hexane isomers. In one embodiment of the invention, the medium-chain aliphatic hydrocarbon solvent includes n-heptane (which is referred to as "heptane" in the examples). In another embodiment of the invention, the medium-chain aliphatic hydrocarbon solvent is n-hexane. Any of the medium-chain aliphatic hydrocarbon solvents described herein includes medium-chain aliphatic hydrocarbons, but may further include additional substances. These additional substances themselves may not necessarily be medium chain aliphatic hydrocarbons.

[0114] As used herein, the phrase "controlled rate" is intended to mean the addition of a solution using a flow rate that is planned prior to the start of a batch, which is typically delivered using a pump or flow controller and metered according to a program or schedule.

[0115] As used herein, the phrase "continuous stirring" is intended to mean stirring the solution substantially uninterruptedly. This phrase includes one or more interruptions in stirring that collectively have no substantial effect on the production of the intended slurry (e.g., several interruptions of 1-3 seconds each). Continuous stirring can be performed mechanically (e.g., by a magnetic stirring bar) or manually.

[0116] The method of the present invention may use or include one or more solution stirring steps. Examples of stirring techniques include, but are not limited to, overhead stirring, magnetic stirring, shaker plate mixing, and the like.

[0117] When the liquid mixture of two solutions contains immiscible solvents, "liquid-liquid phase separation" (LLPS) occurs and is caused by the thermodynamic non-ideal 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 a local minimum and no phase separation occurs. If the behavior of the solvent mixture is non-ideal in turn, there may be a temperature and pressure range in which the Gibbs free energy has two local minima, which can lead to the formation of two thermodynamically stable liquid phases with different overall compositions. For example, methanol and acetonitrile are completely miscible solvents, while heptane has a miscibility gap with both methanol and acetonitrile. For two solvent systems composed of or comprising methanol and heptane and acetonitrile and heptane, respectively, there is a set of compositions in which the solvents do not mix to form two immiscible liquid phases. For a ternary solvent system consisting of or comprising methanol, acetonitrile and heptane, there is also a miscibility gap, i.e., there is a set of compositions where the three solvents do not mix so as to form two immiscible liquid phases. The formation of two immiscible liquid phases upon addition of solvents is referred to herein as liquid-liquid separation (LLPS).

[0118] The present invention uses known filtration techniques, including but not limited to centrifugation, vacuum filtration, filter press, etc.

[0119] The method of preparing agglomerated crystals of sodium salts of medium chain fatty acids, particularly sodium caprate crystals, is exemplified in the following schemes and examples. The starting materials are prepared according to procedures known in the art or as described herein. The following abbreviations are used herein:

[0120] DMAC dimethylacetamide

[0121] DMF dimethylformamide

[0122] DSC Differential Scanning Calorimeter

[0123] FID Flame Ionization Detector

[0124] GC gas chromatography

[0125] GMP Good Manufacturing Procedures

[0126] IPA Isopropyl Alcohol

[0127] LOQ limit of quantification

[0128] Me methyl

[0129] MeCNAcetonitrile

[0130] MeOHMethanol

[0131] NMP N-Methyl-2-pyrrolidone

[0132] RI refractive index

[0133] rt room temperature

[0134] TGA Thermogravimetric Analysis

[0135] v / vvol / vol;

[0136] XRPD X-ray powder diffraction

[0137] In some cases, the order of carrying out the aforementioned reaction scheme can be changed to promote reaction or avoid unwanted reaction products. The following examples are provided so that the present invention can be more fully understood. These embodiments are only exemplary and should not be construed as limiting the present invention in any way. Example

[0138] Example 1A

[0139]

[0140] Capric acid (1) (25 g, 145 mmol) and acetonitrile (630 ml) are combined in a suitable container with a suitable agitator. The batch is stirred at room temperature until complete dissolution is achieved. Under vigorous stirring, sodium methoxide (2) (8.23 g, 152 mmol) is added as a 25 wt % solution in methanol (32.92 g) over 5 hours to form a slurry. After the first hour of adding (2) has passed, a separate feed line is used to add heptane (93-103 ml) simultaneously over 4 hours. The resulting slurry is stirred for another 1 hour. The solid is filtered, washed with acetonitrile (100 ml twice), then dried under vacuum at 35-40 ° C under nitrogen purge to obtain crystallized sodium caprate (3, product A) (27.79 g, 99% yield).

[0141] Example 1B

[0142]

[0143] Capric acid (1) (1.00 kg, 5.81 mol) and acetonitrile (6.0 L) were combined in a suitable container with a suitable agitator. The batch was stirred at room temperature until complete dissolution was achieved. 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. Heptane (1.9 L) was added simultaneously over 5 hours using a separate feed line starting simultaneously with the addition of (2). The resulting slurry was stirred for an additional 24 hours. The solid was filtered, washed with a solution of acetonitrile:methanol (9:1 by volume), 2 L twice, and then dried under vacuum at 35-40°C under a nitrogen purge to give crystalline sodium decanoate (3, Product A) (1.09 kg, 97% yield). A photograph of the slurry generated using this procedure and the isolated sodium decanoate crystalline material is shown at Fig.13 The product was produced on a 1.0 kg scale.

[0144] Example 1C

[0145]

[0146] Capric acid (1) (5.02 g, 29.1 mmol) and acetonitrile (30 ml) were combined in a suitable container with a suitable agitator to produce a homogeneous solution. Sodium methoxide (2) (28.3 mmol) was charged as a 30 wt % solution in methanol over 5 hours under vigorous stirring to form a slurry. Hexane (10.54 ml) was added simultaneously over 5 hours using a separate feed line starting with the addition of (2). The resulting slurry was stirred for an additional 17 hours. The solid was then filtered, washed with a solution of acetonitrile: methanol (9: 1 by volume), 15 ml twice, and then dried under vacuum at 40 ° C under a nitrogen overhead purge to obtain crystalline sodium caprate (3, product A) (5.24 g, 93% yield). Fig.11 Depicts materials generated using this procedure.

[0147] Example 1D

[0148]

[0149] Combine capric acid (1) (5 g, 29 mmol) and acetonitrile (10 ml) in a suitable container with a suitable agitator. The batch is stirred at 35 ° C until complete dissolution is achieved. Under vigorous stirring, sodium methoxide (2) (1.55 g, 29 mmol) is added as a 30% by weight solution in methanol (5.18 g) over 5.5 hours to form a slurry. While adding (2), a separate feed line is used to simultaneously add heptane (7.4 ml) over 5 hours. The resulting slurry is stirred for another 15 hours. After aging, another 1 ml of heptane is added and the batch is heated to 40 ° C. The slurry is aged for another 3 hours. The solid is filtered, washed with acetonitrile (10 ml twice), then dried under vacuum at 35-40 ° C under nitrogen purge to obtain crystalline sodium caprate (3, product A) (4.1 g, 74% yield). Fig.12 Materials made using this procedure are depicted.

[0150] Example 1E

[0151]

[0152] Combine capric acid (1) (10 g, 58.5 mmol) and acetonitrile (10 ml) in a suitable container with a suitable agitator. The batch is stirred at 40 ° C until complete dissolution is achieved. Sodium methoxide (2) (3.17 g, 58.5 mmol) is added as a 30% by weight solution in methanol (10.57 g) under vigorous stirring over 5.5 hours to form a slurry. While adding (2), heptane (15.15 ml) is added simultaneously over 5 hours using a separate feed line. The resulting slurry is stirred for another 24 hours. The solid is filtered, washed with a solution of acetonitrile: methanol (9: 1 by volume), 20 ml twice, and then dried under vacuum at 35-40 ° C under nitrogen purge to obtain crystalline sodium caprate (3, product A) (9.48 g, 83% yield). Fig.12 Materials made using this procedure are depicted.

[0153] X-ray powder diffraction (XRPD)

[0154] The images were acquired on a Panalaytical X-Pert configured in a Bragg-Brentano configuration and equipped with a Cu radiation source monochromatized to Kα using a nickel filter. Figure 1 X-ray powder diffraction (XRPD) data as seen in . Data acquisition was performed using a fixed slit optical configuration. Data were acquired from 2 to 40° 2θ. The sample was prepared by gently pressing the sample onto a zero-background silicon holder. Figure 1 All samples presented in are used to compare materials made in the process of the present invention with commercial materials.

[0155] Figure 1 The XRPD pattern of Product A (material made by the process of the present invention) is depicted and shown in overlay comparison with the XPRD patterns of commercially available sodium decanoate substitutes (such as those available from Jost and BSI) made by different processes. Figure 1 Differences in reflection intensity are demonstrated, indicating that different preferred phases are produced, but the overall "fingerprint" of the crystal pattern is the same. The process of the present invention produces sodium decanoate crystals having a very different morphology than commercially available embodiments made by more expensive procedures.

[0156] Differential Scanning Calorimeter (DSC)

[0157] Thermal events were monitored as temperature increased using a TA Instruments Discovery differential scanning calorimeter (DSC).A sample of Product A (2-5 mg) in a closed non-hermetic aluminum pan with 2 pinholes was cycled twice from 10 to 300°C at a heating rate of 10°C / min.

[0158] Figure 2 The images show two thermal cycles and one cooling cycle performed on a sodium decanoate material from room temperature up to 300°C. The peak pointing downward is an endothermic peak indicating that the material is absorbing heat, which indicates a crystalline / solid state change or a phase transition (e.g., melting or boiling). The curve at the top is what happens to the same sample as it is cooled. During the cooling process, there are upward peaks (exothermic peaks where heat is released). These are the reversal of the physical phenomena that occurred during the heating process. The presence of a hysteresis between the onset temperature and the reversal temperature typically occurs due to the difference in the kinetic barriers between the forward and reverse processes. The width of the hysteresis typically depends on the rate at which the temperature changes during the DSC scan. Figure 2 There are two heating curves (below zero in the y-axis) overlapping in the DSC. The overlap of these two lines demonstrates that the changes that Product A undergoes during the experiment are reversible and that Product A is 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 some absorbed water in the initial scan. The DSC spectrum can be used as a characterization technique because the location and area of ​​the peaks and the overall shape of the scan are unique to sodium decanoate.

[0159] Residual solvents determined by gas chromatography (GC)

[0160] Standard preparation: 0.01% v / v standards in n-heptane, methanol and acetonitrile in diluent were prepared by serial dilution for quantification and 0.001% v / v limit of quantification (LOQ) for limit reporting.

[0161] Sample Preparation: Dissolve ~20 mg / mL sample in diluent. Vortex and sonicate as needed to dissolve sample.

[0162] Instrument conditions:

[0163]

[0164]

[0165] result:

[0166] Solvent n-Heptane Methanol Acetonitrile volume% Not detected 0.04 <LOQ

[0167] LOQ (Limit of Quantitation): 393 ppm for acetonitrile

[0168] Thermogravimetric analysis

[0169] Thermogravimetric analysis (TGA) of product A was performed on a TA Q 500 thermogravimetric analyzer (TA Instrument). The sample (5-15 mg) was heated from 25°C to 320°C at 10°C / min under a nitrogen purge of 200 mL / min. Figure 3 As seen in Figure 3 The top curve monitors the mass change of Product A as it is heated under a nitrogen atmosphere. The slight mass loss (0.8 wt %) at the first 250°C matches well with the expected absorbed surface water in the material. The beginning of the drop after 250°C indicates the onset of decomposition or evaporation. The curve at the bottom of the figure corresponds to the derivative of the mass change to capture the rate of change of the top curve.

[0170] Particle size analysis via Microtrac Flow Sync

[0171] Instrument make and model: Microtrac, M5001-3L Sync+FlowSync

[0172] Methods: Approximately 50 mg of powder sample was transferred to a 20 mL scintillation vial and 5 mL of IsoparG / 0.25% w / v lecithin fluid was added to the vial and gently shaken 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 fluid (3 mL total) and all rinses were poured into the FlowSync. Measurement parameters included volume distribution, geometric 8th root series between 0.0215 and 2000 μm, residuals disabled, standard filter enabled, particle RI = 1.51; irregular shape; fluid RI = 1.42, flow 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, 30 seconds, 60 seconds, and 90 seconds of sonication of 25% powder.

[0173] Sonication is a standard laboratory technique where vibrational energy is applied to a powder to help break up agglomerates within the material and ensure that particle size measurements capture the true size of the product particles. Agglomeration is often observed with dry solids due to natural adhesion and can bias measurements to overestimate the size of powder particles, so inducing adequate sonication can be important for analytical accuracy. Figure 4 The representative volume weighted particle size distribution results of a batch of product A made by the method described in Example 1 are shown. The probability density of the particles of these curves showing the product has the radius of the size specified in the x-axis. These curves also show the influence of supersound process on the particle size measured. Along with the increase of supersound process, the reduction and normalization of particle size are typical behaviors, which shows that the dry solids are deagglomerated towards the "real" distribution of primary particles, which is best captured by the curves marked as 60 s and 90 s. Figure 4 The particle size distribution is shown to be the same for 60 s and 90 s of sonication, indicating that samples of this material require at least 60 s for adequate measurement.

[0174] Figure 4 It is also demonstrated how the process of the present invention generates primary particles having a unimodal normal size distribution, which is ideal for a manufacturing process. Unimodal distributions are ideal because they indicate uniformity of the particles, with very few fines or large agglomerates that would result in uneven flow, filtration, and compression behavior. Uniform distributions are also an indication of proper control during crystallization and agglomeration, because they provide evidence that undesirable particle generation phenomena (such as attrition) are not occurring, and that the overall particle size and morphology are set by controlled variables manipulated during batch design.

[0175] Scanning electron microscopy (SEM)

[0176] Sodium decanoate powder sample was mounted on SEM stub (32 mm) using carbon sticky. Sample was coated with platinum sputtering. Sample was loaded into Hitachi TM3030 desktop scanning electron microscope. Sample was imaged in high vacuum mode and image was acquired using secondary electron (SE) detector. Voltage was set to 2 kV and spot intensity was set to 30 (units). Image was acquired at several magnifications.

[0177] Figure 5 The imaging in exemplifies that the morphology of Product A exists as clearly discernible agglomerated plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more ideal than elongated, plate-like or needle-like particles. The displayed morphology reflects the excellent compression properties in the manufacturing process and dosage form using Product A as an excipient.

[0178] Compression performance

[0179] A single-station compaction simulator is used to compress (i) sodium caprate powder generated by the method of the present invention and (ii) a sample of a preparation containing a sodium caprate sample into a cylindrical compact. Using a 9.525 mm round flat tablet press tool, the sample is compressed into a compact using a compression pressure range of 10 to 400 MPa (MPa). The compaction simulation of the preparation is carried out under force control. The combined punch speed is 50 to 100 mm / s. The weight (W), thickness (h), diameter (D) and hardness (B) of the obtained compact are measured. Hardness is defined as the peak force required to break the cylindrical compact. The compact weight is controlled to 225 mg to 375 mg. The obtained values ​​of thickness and hardness are used to calculate the tablet tensile strength (T) using equation X. The obtained tablet tensile strength and compression pressure are combined into a tabletability curve.

[0180]

[0181] Table 1 shows the composition (make-up) of the test example formulated tablet products containing sodium caprate from different commercial sources. These formulations contain a disintegrant, a glidant, a lubricant, and two compression aids (i.e., diluents or binders): lactose and microcrystalline cellulose. Four of these formulations contain commercially available sodium caprate batches, and one uses the agglomerated material product A produced by the process of the present invention. The formulation containing commercial material 1 uses sodium caprate from Pfaltz & Bauer, the formulation containing commercial material 2 uses sodium caprate from BSI, the formulation containing commercial material 3 uses sodium caprate from TCI Chemicals, and the formulation containing commercial material 4 uses sodium caprate from Jost.

[0182] Table 1. Composition of formulated products containing sodium caprate from different sources

[0183] Compound Function wt / wt% Sodium Decanoate Penetration enhancers 36.18 Microcrystalline cellulose Compression aids 29.65 lactose Compression aids 29.65 Croscarmellose Sodium Disintegrants 3.015 Silicon dioxide Glidants 1.005 Magnesium Stearate Lubricants 0.5025

[0184] Figure 6 The graph in shows the compaction curve results for five formulations. These results show that Product A (solid circles) exhibits superior compression properties when compared to all commercially available materials tested. Figure 6 The tensile strength of tablets prepared with sodium caprate (including product A) from different sources is reflected. The image shows that the material produced with product A (depicted as solid circles) obtains the toughest material within the relevant processing range of compression pressure. The in-mold powder bulk density of these five preparations is estimated using the mass of the pressed block and the volume of the filled mold before compression. The in-mold bulk density of the preparation containing commercial material 2 is the lowest among all test materials, nominally 0.39 g / mL. The in-mold bulk density of the remaining four preparations is 0.44 to 0.47 g / mL. All observed in-mold bulk densities show acceptable values ​​for these blends processed by tableting.

[0185] Liquidity

[0186] The flow properties of Product A and sodium caprate materials from different commercial sources were compared using bulk density and tap density measurements. Bulk density and tap density refer to the density of the powder on its own. Low density is a sign that the material will not flow or pack well. Carr's Index and Hausner Ratio are measurements calculated using the measurements of bulk density and tap density. Low values ​​for both of these measurements indicate that the material has improved flow properties. Bulk density is measured using a 100 mL graduated cylinder and no less than 50 mL of powdered material. Dispense the powdered material into the graduated cylinder and record the mass and volume of the material. Calculate the ratio of mass and volume to get the resulting bulk density of the powder. The tap density apparatus is then used to calculate the volume of the powder according to USP <661> The cylinder was tapped 1,250 times. The resulting volume of material was then used to calculate the resulting tap density value.

[0187] Table 2 reports the bulk density and tap density of the material and provides the results of the calculated Carr's Index and Hausner Ratio. As shown in Table 2, Product A exhibits a Carr's Index of 8.7% and a Hausner Ratio of 1.10. Both values ​​are significantly lower than those of commercial materials 1-4, indicating that Product A exhibits excellent powder flowability. Despite its low density, the agglomerated sodium caprate crystals (Product A) prepared by the present invention have excellent flow properties, which are reflected in the low Carr's Index and Hausner Ratio.

[0188] Table 2. Fluidity measurements of sodium decanoate from different sources

[0189]

[0190] Figure 7Show the SEM images of the sodium decanoate from commercial materials 1-4, provide the comparison of their respective morphologies.The preparation method of this compound has a significant impact on the structure and physical appearance of the material.Commercial material 1 (sodium decanoate from BSI) is a smooth sphere made by spray drying.Commercial material 3 (sodium decanoate from TCI Chemical) and commercial material 4 (sodium decanoate from Jost) are large elongated thin plates.Product A constitutes an agglomerated solid, has a rough surface area and does not have elongation on any axis.Method of the present invention can realize this unique morphology of product A, which is suitable for manufacturing and processing in standard equipment, and has a desirable property for formulation manufacturing.

[0191] Example 1F

[0192]

[0193] Sodium decanoate (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 added to the vial to form a slurry of agglomerated particles. An optical microscope image depicting these particles is shown in Fig.10 , in the picture above.

[0194]

[0195] Sodium decanoate (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 charged to the vial to form a slurry of agglomerated particles.

[0196]

[0197] Sodium decanoate (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 added to the vial to form a slurry of agglomerated particles. An optical microscope image depicting these particles is shown in Fig.10 , in the figure below.

[0198] DMAc, DMF and NMP are each polar aprotic solvents. Fig.10 As emphasized by the images shown in , the combination of sodium decanoate with heptane and a polar aprotic solvent produces an agglomerated crystalline sodium decanoate product. Thus, any of several polar aprotic solvents can be used in the disclosed method of making sodium decanoate agglomerates.

[0199] Example 2

[0200] Preparation of Sodium Nonanoate (C9)

[0201]

[0202] Nonanoic acid (4) (2.51 g, 15.9 mmol) and acetonitrile (63.5 ml) are combined in a suitable container with a suitable agitator to produce a homogeneous solution. Sodium methoxide (2) (15.9 mmol) as a 25 wt % solution in methanol is charged to the solution over 5 hours under vigorous stirring to form a slurry. After the first hour of addition of (2) has passed, heptane (9.3 ml) is simultaneously charged to the solution over 4 hours. The slurry is stirred for an additional hour. The solid is filtered, washed with acetonitrile (15 ml twice), and then dried under vacuum at 35-40° C. under a nitrogen purge to give sodium nonanoate (5) (2.68 g, 94% yield).

[0203] Scanning electron microscopy (SEM)

[0204] The sodium nonanoate powder sample was mounted on a SEM sample holder (32 mm) using carbon sticky. The sample was sputter coated with platinum. The sample was loaded into a Hitachi TM3030 desktop scanning electron microscope. The sample was imaged in high vacuum mode and the image was acquired using a secondary electron (SE) detector. The voltage was set to 2 kV and the spot intensity was set to 30 (units). Images were acquired at several magnifications. Figure 8 The imaging in exemplifies the morphology of the agglomerated crystals of sodium nonanoate as clearly discernible plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more desirable than elongated, plate-like or needle-like particles because they tend to exhibit superior compression properties during the manufacturing process.

[0205] Example 3

[0206] Preparation of Sodium Laurate (C12)

[0207]

[0208] Combine lauric acid (6) (2.5 g, 12.5 mmol) and acetonitrile (63.3 ml) in a suitable container with a suitable agitator. Stir the batch at 30 ° C until complete dissolution is achieved, then cool to room temperature. Under vigorous stirring, load sodium methoxide (2) (12.48 mmol) as a 25% by weight solution in methanol into the solution over 5 hours to form a slurry. After the first hour of adding (2) has passed, heptane (9.3 ml) is loaded into the solution simultaneously over 4 hours. The slurry is stirred for another 1 hour. Filter the solid, wash with acetonitrile (15 ml twice), then dry under vacuum at 35-40 ° C under nitrogen purge to obtain sodium laurate (7) (2.7 g, 97% yield).

[0209] Scanning electron microscopy (SEM)

[0210] The sodium laurate powder sample was mounted on a SEM sample holder (32 mm) using carbon sticky. 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 the image was acquired using a secondary electron (SE) detector. The voltage was set to 2 kV and the spot intensity was set to 30 (units). Images were acquired at several magnifications. Fig. 9 The imaging in exemplifies the morphology of the agglomerated crystals of sodium laurate as clearly discernible plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is more desirable than elongated, plate-like or needle-like particles because it tends to exhibit superior compression properties in manufacturing procedures and dosage forms.

[0211] While the present invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will appreciate that various adjustments, changes, modifications, substitutions, deletions or additions to procedures and arrangements may be made without departing from the spirit and scope of the present invention.

[0212] Equivalent

[0213] Although several embodiments of the present invention have been described and illustrated herein, it is easy for a person of ordinary skill in the art to think of various other means for performing the functions described herein and / or obtaining the results and / or one or more advantages described herein, and each such change and / or modification is considered to be within the scope of the embodiments described herein. More generally, it is easy for a person skilled in the art to recognize that all parameters, dimensions, materials and configurations described herein are intended to be exemplary, and the actual parameters, dimensions, materials and / or configurations depend on the specific application of the teachings of the present invention. Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments described herein using only conventional experimental methods. Therefore, it is to be understood that the aforementioned embodiments are given only as examples, and within the scope of the attached claims and their equivalents, the embodiments may not be practiced as specifically described and claimed. The embodiments of the present disclosure relate to each feature, material and / or method described herein. In addition, if these features, materials and / or methods are not contradictory, any combination of two or more such features, materials and / or methods is included within the scope of the present disclosure.

[0214] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0215] Unless explicitly indicated to the contrary, the indefinite articles "a" and "an" as used herein in the specification and claims should be understood to mean "at least one".

[0216] The phrase "and / or" as used herein in the specification and claims should be understood to refer to "either or both" of the elements so connected, i.e., elements that are present jointly in some cases and separately 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 connected. In addition to the elements specifically indicated by the "and / or" term, other elements may optionally be present, whether related or unrelated to those specifically indicated. Thus, as a non-limiting example, when used in conjunction with an open-ended term such as "comprising", a reference to "A and / or B" may refer to only A (optionally including elements other than B) in one embodiment; to only B (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0217] "Or" as used herein in the specification and claims 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, i.e., including at least one of a number or series of elements as well as including more than one, and optionally including additional unlisted items. Only terms that clearly indicate the contrary, such as "only one" or "exactly one", or when used in the claims, "consisting of..." means including exactly one element of a number or series of elements. Generally, the term "or" as used herein should be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") only when it is preceded by an exclusive term, such as "either", "one of", "only one" or "exactly one".

[0218] It is to be understood that whenever a composition is disclosed or claimed as "comprising" one or more features, embodiments in which such a composition "consists of" and "consists essentially of" these one or more features are also disclosed or claimed. The transition phrase "consists essentially of" shall have its ordinary meaning as used in the field of patent law. In the claims and the above description, all transition phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "having", "composed of", etc. shall be understood as open-ended, i.e., meaning including but not limited to. As described in MPEP 2111.03, the transition phrases "consists of" and "consists essentially of" shall be closed or semi-closed transition phrases, respectively.

[0219] It should also be understood that, unless explicitly indicated to the contrary, in any method claimed herein that includes more than one step or operation, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are listed.

Claims

1. A method for preparing agglomerated crystals of a sodium salt of a medium-chain fatty acid, comprising the following steps: a) dissolving a medium-chain fatty acid in a first solvent to produce a first solution, wherein the first solvent comprises an aprotic polar solvent; b) adding (i) a second solvent, wherein 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) separating the agglomerated crystals from the resulting slurry.

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

3. The method according to claim 1 or 2, wherein the second solvent is selected from heptane and hexane.

4. The method of any one of claims 1-3, wherein the medium-chain fatty acid comprises capric acid, and the first solvent comprises acetonitrile.

5. A method for preparing agglomerated crystals of sodium salts of medium-chain fatty acids, comprising the following steps: a) dissolving a medium chain fatty acid in acetonitrile to produce a first solution; b) adding heptane and about 1 molar equivalent of a solution comprising a sodium salt of a short chain alcohol to the first solution to produce a resulting slurry; and c) separating the agglomerated crystals from the resulting slurry.

6. The method of claim 5, wherein in step b, heptane and the solution comprising the sodium salt of the short chain alcohol are added to the first solution at a temperature below about 40°C.

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

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

9. The method according to any one of claims 5 to 8, wherein after step b, the obtained slurry is stirred for 15 to 25 hours.

10. A method for preparing agglomerated crystals of sodium caprate, comprising the following steps: a) dissolving capric acid in acetonitrile to produce a first solution; b) adding heptane and about 1 molar equivalent of a solution comprising sodium methoxide to the first solution to produce a resulting slurry; and c) separating agglomerated crystals of sodium caprate from the resulting slurry.

11. The method of claim 10, wherein in step b, heptane and a solution comprising sodium methoxide are added to the first solution at a temperature below about 40°C to induce liquid-liquid phase separation.

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

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

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

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

16. The method according to any one of claims 10 to 12, comprising the following steps: a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce 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 comprising 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 and produce a resulting slurry; c) stirring the resulting slurry for at least 1 hour; and d) filtering the resulting slurry to provide agglomerated sodium caprate crystals.

17. The method according to any one of claims 10 to 12, comprising the following steps: a) dissolving capric acid in 6 L / kg to 30 L / kg of acetonitrile to produce a first solution; b) adding about 1 molar equivalent of a solution comprising about 30 wt % sodium methoxide to the first solution at a temperature of about 20° C. to about 30° C. over about 4.5 to about 5.5 hours with continuous stirring; c) about 1 hour after adding the solution comprising sodium methoxide in step b, adding about 1.5 L / kg to about 4 L / kg of heptane to produce a resulting slurry; d) stirring the resulting slurry for 15 to 25 hours; and e) filtering the resulting slurry to separate the resulting solid and drying the resulting solid to provide agglomerated crystals of sodium caprate.

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

19. A composition comprising sodium salts of medium-chain fatty acids produced using the method of any one of claims 1-18.

20. A composition comprising sodium caprate, wherein the composition exhibits a Carr's Index of less than 9.0%.

21. A composition comprising sodium caprate, wherein the composition exhibits a Hausner Ratio of less than 1.15.

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