DOWN STREAMING PROCESS FOR THE PRODUCTION OF POLYUNSATURATED FATTY ACID SALTS

Abstract

The invention provides an improved down streaming process for production of polyunsaturated fatty acid salts suitable for tableting by direct compression.

Claims

1. A process for granulating a polyunsaturated fatty acid salt, comprising: i. providing a starting composition comprising at least one polyunsaturated omega-3 or omega-6 fatty acid component; ii. providing a counter ion composition; iii. admixing an aqueous, aqueous-alcoholic or alcoholic solution comprising the starting composition and the counter ion composition to form an admixture; and iv. subjecting the admixture to granulation in a fluidized bed, thereby forming a solid product composition comprising at least one salt of a cation derived from the counter ion with an anion derived from a polyunsaturated omega-3 or omega-6 fatty acid, wherein a ratio of an amount of carboxylic acid functions in the starting composition to an amount of counter ions provided is in a range of 1:0.5 to 1:2 (carboxylic acid functions:counter ions) on molar basis.

2. The process of claim 1, wherein the granulation is performed at an average bed temperature (T) of 50° C. to 90° C., at an average atomization pressure (A) of 0.5 to 10 bar, and with a process factor of greater than 1.6 to 10.0, wherein the process factor (PF) is defined as: $\mathrm{PF}=\frac{\left(3\sqrt{S}÷T\right)\times 100}{3\sqrt{A}}$ wherein S is a batch size in kg, T is the average bed temperature in ° C., and A is the average atomization pressure in bar.

3. The process of claim 1, wherein the granulation is selected from the group consisting of spray granulation, dry granulation, slugging, planetary mixing granulation, high shear granulation, melt granulation, and top spray granulation, the granulation being batch granulation, continuous granulation, or modified forms thereof.

4. The process of claim 1, wherein the counter ion is a basic amine selected from the group consisting of lysine, arginine, ornithine, and choline, or a metal ion selected from magnesium (Mg.sup.2+), potassium (K.sup.+), and mixtures thereof.

5. The process of claim 1, wherein the counter ion is L-lysine or a mixture of L-lysine and L-arginine having a ratio of L-lysine to L-arginine of 10:1 to 1:1.

6. The process of claim 1, wherein the omega-3 or omega-6 fatty acid is derived from a fatty acid source which is at least one selected from the group consisting of: fish oil, squid oil, krill oil, linseed oil, borage seed oil, algal oil, hemp seed oil, rapeseed oil, flaxseed oil, canola oil, and soybean oil.

7. Particles formed by the process of claim 1.

8. Particles comprising one or more salts of cations derived from a counter ion with anions derived from one or more polyunsaturated omega-3 or omega-6 fatty acids, the particles obtainable by a granulation process with and having a particle size distribution curve exhibiting at least two of the following properties: A. D90 is between 350 μm and 1500 μm, B. In multimodal curves, a tallest peak has a peak intensity in the range of 200 μm to 1500 μm, wherein the peak intensity (as measured on Y axis) of a second tallest peak is not more than 50% of the tallest peak; C. In multimodal curves, an intensity difference (as measured using Y axis value) between the tallest and the second tallest peak is equal to or less than 30%, and the second tallest peak has the highest peak intensity in the range of 400 μm to 1500 μm, wherein a trough intensity on Y scale between above two peaks is more that 25% of the tallest peak; and D. A base of the tallest peak in the PSD curve (as measured by difference in microns between the two lowest points of the peak on Y axis) is at least 400 μm wide by absolute value.

9. The particles of claim 8, wherein the counter ion is a basic amine, selected from the group consisting of lysine, arginine, ornithine, and choline, or a metal ion selected from magnesium (Mg.sup.2+), potassium (K.sup.+), and mixtures thereof.

10. The particles of claim 8, wherein a ratio of an amount of carboxylic acid functions to an amount of counter ions is in a range of 1:0.5 to 1:2 (carboxylic acid functions:counter ions) on molar basis.

11. The particles of claim 8, wherein the granulation is selected from the group consisting of spray granulation, dry granulation, slugging, planetary mixing granulation, high shear granulation, melt granulation, and top spray granulation, the granulation being batch granulation, continuous granulation, or modified forms thereof.

12. The particles of claim 8, wherein the granulation is carried out in the presence of one or more excipients selected from the group consisting of diluents, binders, flow promoters, lubricants, and plasticizers.

13. A method of manufacturing food products comprising polyunsaturated omega-3 or omega-6 fatty acids, wherein the polyunsaturated omega-3 or omega-6 fatty acids are present as the particles of claim 8.

14. A method of manufacturing nutritional products comprising polyunsaturated omega-3 or omega-6 fatty acids, wherein the polyunsaturated omega-3 or omega-6 fatty acids are present as the particles of claim 8.

15. A method of manufacturing pharmaceutical products comprising polyunsaturated omega-3 or omega-6 fatty acids, wherein the polyunsaturated omega-3 or omega-6 fatty acids are present as the particles of claim 8.

16. A solid oral dosage form comprising the particles of claim 8, wherein the solid oral dosage form is selected from tablets, granules or capsules.

Description

EXAMPLES

Comparative Examples 1-3

Spray Drying Process

[0077] Process details for spray drying (C1-C3): PUFA lysine salts hydroethanolic solutions were prepared and spray dried using below mentioned process parameters (table 1).

TABLE-US-00001 TABLE 1 Spray drying process parameters Process parameters C-1 C-2 C-3 Batch size (g) 2243 2752 100  Gas inlet temperature (° C.) 170 170 52-57 Aver. atomization air pressure (bar) 6 6 10

TABLE-US-00002 TABLE 2 Spray drying process - granules characterization Example C-1 C-2 C-3 Bulk Density (g/cc) — — 0.294 Tapped density (g/cc) — — 0.408 Compressibility index (%) — — 27.94 Angle of repose — — 42.55 PSD data Avg D90 (μm) 82.332 95.813 60.64 Type of PSD curve Monomodal Monomodal Multimodal Mean tallest peak intensity 7.96, 7.45 7.99, 7.78 ~2.32 in the PSD curve (Y-axis) Tallest peak point in the PSD ~40 40-50 ~35-40 curve (X-axis, μm) 2.sup.nd tallest peak — — 0.86 in the PSD curve (Y-axis) 2.sup.nd tallest peak — — 15 point in the PSD curve (X-axis, μm) Intensity difference — — 62.93 (Y-axis) of 2.sup.nd tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between — —  0.15-0.17 the tallest and 2.sup.nd tallest peak Trough intensity wrt to — — 6.90 tallest peak (limit more than 25%) Base width of the ~110 ~120 282.2 tallest peak (μm)

[0078] The products could not be processed on a tableting machine, due to bad flow properties. The characterization of the granules is summarized in table 2. The criteria A to D as defined above were not met.

Comparative Examples 4-6

Spray Granulation with Recirculation of Fines

[0079] Process details for spray granulation (C4-C5): PUFA lysine salts hydroethanolic solutions were prepared and spray granulated using below mentioned process parameters (table 3). For comparative example C-6, PUFA lysine salt was granulated with a Rapid mixer granulator (CPM RMG-10, Chamunda Pharma Machinary Pvt. Ltd.).

TABLE-US-00003 TABLE 3 Process parameters for comparative examples C-4 to C-6 Process parameters C-4 C-5 C-6 Batch size (g) 1000 1500 500 Inlet air temperature (° C.) 115 115 40 Average bed temperature (° C.) 68 72 — Atomization air pressure (bar) 1 1 — Process factor 1.47 1.59 —

TABLE-US-00004 TABLE 4 Spray granulation process - granules characterization Example C-4 C-5 C-6 Bulk Density (g/cc) 0.403 0.417 0.403 Tapped density (g/cc) 0.521 0.545 0.521 Compressibility index (%) 22.581 23.577 22.581 Avg D90 (μm) 602.30 309.83 400-595 Type of PSD curve Multimodal Multimodal Monomodal Mean tallest peak intensity ~1.6 ~1.3 in the PSD curve (Y-axis) Tallest peak point in the 45-50 40-60 PSD curve (X-axis, μm) 2nd tallest peak in ~0.87 ~1.16 the PSD curve (Y-axis) 2nd tallest peak point in 500-800 100-200 the PSD curve (X-axis, μm) Intensity difference (Y-axis) 45.63 10.77 of 2nd tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between 0.2-0.3 0.825-0.925 the tallest and 2nd tallest peak Trough intensity wrt 15.63 67.31 to tallest peak (limit more than 25%) Base width of the 200 70 ~800 tallest peak (μm)

[0080] The products could not be processed on a tableting machine, due to bad flow properties or issues related to sticking of tablets on tooling or both. The characterization of the granules is summarized in table 4. The criteria A to D as defined above were not met for C4 and C5.

Examples 1-5

Spray Granulation with Recirculation of Fines (Inventive)

[0081] Process details for spray granulation: PUFA lysine salts hydroethanolic solutions were prepared and spray granulated using below mentioned process parameters (see table 5).

TABLE-US-00005 TABLE 5 Spray granulation process parameters Process parameters 1 2 3 4 5 Batch size (g) 1000 1000 1000 750 1500 Average bed 61 64 59 58 60 temperature (° C.) Aver. atomization 1 0.6 0.6 0.6 0.6 pressure (bar) Process factor (P.F.) 1.64 1.85 2.01 1.86 2.26

TABLE-US-00006 TABLE 6 Spray granulation process - granules characterization Example 1 2 3 4 5 Bulk Density (g/cc) 0.452 0.421 0.455 0.419 0.439 Tapped density (g/cc) 0.556 0.484 0.560 0.543 0.512 Compressibility index (%) 18.669 12.919 18.770 22.900 14.327 PSD data Avg D90 (μm) 891.75 612.89 1005.00 918.36 1103.08 Type of PSD curve Multimodal Multimodal Multimodal Multimodal Multimodal Mean tallest peak intensity in the 1.2 1.67 1.73 1.39 1.74 PSD curve (Y-axis) Tallest peak point in the PSD 50-60 300-400 800-900 700-900 700-800 curve (X-axis, μm) 2.sup.nd tallest peak in the PSD curve ~0.711 0.33 0.79 1.03 0.433 (Y-axis) 2.sup.nd tallest peak point in the PSD 800-900 44-60 46-52 50-58 50 curve (X-axis, μm) Intensity difference (Y-axis) of 2.sup.nd 40.75 80.23 54.34 25.90 75.11 tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between the tallest 0.125-0.275 0.2 0.15  0.2-0.225 0.09-0.1  and 2.sup.nd tallest peak Trough intensity wrt to tallest peak 16.67 11.98 8.67 15.29 5.46 (limit more than 25%) Base width of the tallest peak 300 ~1400 ~1300 ~1300 ~1300 (μm) Workability (flow) on tableting No Yes Yes Yes Yes machine Remarks (acceptance Passed Passed Passed Passed Passed criteria) A, B A, D A, D A, B, D A, D

[0082] The characterization of the granules is shown in table 6. The acceptance criteria A to D as defined above were analyzed: according to the present invention, the particle size distribution curve shall exhibit at least two of the following properties: [0083] A. D90 is between 400 μm and 1500 μm; [0084] B. In multimodal curves, the tallest peak has a peak intensity in the range of 200 μm to 1500 μm, wherein the intensity (as measured on Y axis) of second tallest peak is not more than 50% of the tallest peak; [0085] C. In multimodal curves, the intensity difference (as measured using Y axis value) between the tallest and the second tallest peak is equal to or less than 30%, and the second tallest peak has the highest intensity in the range of 400 μm to 1500 μm, wherein the trough intensity on Y scale between above two peaks is more that 25% of the tallest peak; [0086] D. Base of the tallest peak in the PSD curve (as measured by difference in microns between the two lowest points of the peak on Y axis) is at least 400 μm wide by absolute value.

[0087] In all the examples, particles were produced, which fulfilled at least two of the listed acceptance criteria A to D and workability on the tableting machine was possible.

Example 6

Granulation Using Top Spray Granulation (Inventive)

[0088] PUFA lysine salt was granulated with water using top spray granulator using below mentioned process parameters (table 7).

[0089] For the experiments using planetary mixer 500 g of lysine-salt of omega-3 fatty acid was granulated for 2 mins with 22-25 g of purified water. The wet granules were dried to a LOD of <2.5% and sized to obtained desired particle size.

TABLE-US-00007 TABLE 7 Spray granulation process parameters Process parameters 6 Granulation technique Top spray granulation Batch size (g) 800 Residual moisture (%) 0.5 Inlet air temperature (° C.) 50-65 Average bed temperature (° C.) 35-45 Aver. atomization pressure (bar) 1 Process factor (P.F.) 2.32

TABLE-US-00008 TABLE 8 Spray granulation process - granules characterization Example 6 Bulk Density (g/cc) 0.401 Tapped density (g/cc) 0.457 Compressibility index (%) 12.297 PSD data Avg D90 (μm) 585.69 Type of PSD curve Monomodal Mean tallest peak intensity in the 1.52 PSD curve (Y-axis) Tallest peak point in the PSD 200-300 curve (X-axis, μm) 2nd tallest peak in the PSD curve — (Y-axis) 2nd tallest peak point in the PSD — curve (X-axis, μm) Intensity difference (Y-axis) of 2nd — tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between the tallest — and 2nd tallest peak Trough intensity wrt to tallest peak — (limit more than 25%) Base width of the tallest peak ~1500 (μm) Workability on tableting machine Yes Remarks (acceptance criteria) Passed A, D

[0090] The characterization of the granules is shown in table 8. The acceptance criteria A to D as defined above were analyzed.

[0091] In all the examples, particles were produced, which fulfilled at least two of the listed acceptance criteria A to D and workability on the tableting machine was possible.

Examples 7-9

Spray Granulation with Top Granulation Technique (Inventive)

[0092] PUFA lysine salt was granulated with water using top spray granulator using below mentioned process parameters (table 9).

TABLE-US-00009 TABLE 9 Top spray granulation process parameters Process parameters 7 8 9 Batch size (g) 4500 4500 10500 Average bed temperature (° C.) 62 68 68 Aver. atomization air pressure (bar) 1.3-1.8 2.5 2.5 Process factor (P.F.) 2.33 1.79 2.37

TABLE-US-00010 TABLE 10 Spray granulation process - granules characterization Example 7 8 9 Bulk Density (g/cc) 0.489 0.459 0.454 Tapped density (g/cc) 0.588 0.565 0.557 Compressibility index (%) 16.560 18.587 18.523 PSD data Avg D90 (μm) 648.41 423.24 504.507 Type of PSD curve Multimodal Monomodal Multimodal Mean tallest peak ~1.075 ~0.99 ~1.01 intensity in the PSD curve (Y-axis) Tallest peak point 40-50 70 70 in the PSD curve (X-axis, μm) 2nd tallest peak in 0.635 — 0.342 the PSD curve (Y-axis) 2nd tallest peak point ~700-890  — ~1500 in the PSD curve (X-axis, μm) Intensity difference 40.93 — 66.14 (Y-axis) of 2nd tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between 0.25-0.30 — 0.175-0.325 the tallest and 2nd tallest peak Trough intensity wrt 25.58 — 24.75 to tallest peak (limit more than 25%) Base width of the 240 ~1500 850 tallest peak (μm) Workability on Yes Yes Yes tableting machine Remarks Passed A, C Passed A, D Passed A, D

[0093] The characterization of the granules is shown in table 10. The acceptance criteria A to D as defined above were analyzed.

[0094] In all the examples, particles were produced, which fulfilled at least two of the listed acceptance criteria A to D and workability on the tableting machine was possible.

Example 10

Tableting Trials

[0095] PUFA salts were prepared using spray granulation with recirculation of fines (as described above for comparative example C-4) and using spray granulation according to the inventive example 2 and formulated as shown in table 11 with tableting excipients for tableting trials.

TABLE-US-00011 TABLE 11 Compositions for tableting trials Component (mg) Use C-4 (comparative) 2 PUFA lysine salts 400.00 400.00 Prosolv Easy tab Nutra Filler 356.00 356.00 Aerosil 200 P Glidant 8.00 8.00 Croscarmellose sodium Disintegrant 16.00 16.00 Magnesium stearate Lubricant 20.00 20.00

TABLE-US-00012 TABLE 12 Characterization of tablets C4 (comparative) 2 Target tablet weight (mg) 800.00 800.00 Tablet weight (mg) 799-810 799-805 Tablet thickness (mm) 5.77-5.80 5.62-5.65 Hardness (N) 73-77 83-88 Friability (%) 0.2133 0.246 Workability (flow) on tableting machine No Yes

[0096] The results of the tableting trials are summarized in table 12. Workability on tableting machine was only possible with granules produced according to the present invention.

Examples 11-13

Spray Granulation Using Different PUFA Salts (Inventive)

[0097] For the inventive examples 11 and 12, the PUFA potassium salts/PUFA ornithine salts solution (50% w/w) in 50% hydroethanolic and spray granulated using below mentioned process parameters. For the inventive example 13, PUFA lysine salts solution (50% w/w) were prepared in a hydroethanolic solution and spray granulated using below mentioned process parameter in a continuous fluidized bed granulator with a sieve-grinding cycle (see table 13).

TABLE-US-00013 TABLE 13 Spray granulation process parameters Process parameters 11 12 13 Batch size (g) 1300 1300 16600 Average bed temperature (° C.) 55 53 60 Aver. atomization pressure (bar) 1.2 1.2 2.0 Process factor (P.F.) 1.87 1.94 3.37

TABLE-US-00014 TABLE 14 Spray granulation process - granules characterization Example 11 12 13 Bulk Density (g/cc) 0.439 0.402 0.39 Tapped density (g/cc) 0.491 0.494 0.43 Compressibility index (%) 10.59 18.62 8.11 PSD data Avg D90 (μm) 892.3 873.7 805.9 Type of PSD curve Monomodal Monomodal Monomodal Mean tallest peak — — — intensity in the PSD curve (Y-axis) Tallest peak point 541.9 594.9 594.9 in the PSD curve (X-axis, μm) 2nd tallest peak — — — in the PSD curve (Y-axis) 2nd tallest peak — — — point in the PSD curve (X-axis, μm) Intensity difference — — — (Y-axis) of 2nd tallest peak as compared to tallest peak (limit NMT 50%) Lowest trough between — — — the tallest and 2nd tallest peak Trough intensity wrt — — — to tallest peak (limit more than 25%) Base width of the 1436 1179 1051 tallest peak (μm) Workability on Yes Yes Yes tableting machine Remarks Passed A, D Passed A, D Passed A, D

Tableting Trials:

[0098] PUFA salts were prepared as described above for inventive example 11-13 and were formulated as shown below. The tableting composition is summarized in table 15 and the results of the tableting trials are summarized in table 16.

TABLE-US-00015 TABLE 15 Compositions for tableting trials Component (mg) 11 12 13 PUFA potassium salt 243 — — PUFA ornithine salt — 243 — PUFA lysine salt — — 243 Microcrystalline cellulose 550.8 550.8 550.8 (Avicel 200) Croscarmellose sdium (Ac-di-sol) 16.2 16.2 16.2 Total (tablet weight) 810 810 810

TABLE-US-00016 TABLE 16 Characterization of tablets 11 12 13 Target tablet weight (mg) 810 810 810 Actual tablet weight (mg) 793-820 798-814 804-814 Tablet thickness (mm) 5.91-6.03 6.67-6.72 6.92-6.98 Hardness (N) 47-55 71-77 63-76 Friability (%) 0.06 0.33 0.59 Workability (flow) on tableting Yes Yes Yes machine

Scanning Electron Microcopy (SEM) Studies:

[0099] PUFA salts prepared as described in inventive example 13 (PUFA lysine salts, prepared by continuous granulation) and comparative example C6 (PUFA lysine salts, prepared by rapid mixer granulation) were evaluated using SEM to understand particle surface characteristics (internal structure). The results are shown in FIG. 3 and FIG. 4.

[0100] As shown in FIG. 3, the internal structure of spray granulated PUFA salt prepared according to inventive example I-13 has a highly porous nature. In contrast to this, for RMG granulated PUFA salt prepared according to comparative example C-6, such porous structure was not seen (FIG. 4). Instead it was more rigid, thus less preferred for tableting operations.

Exposure to High Humidity on the PUFA Salt Granules Prepared Using Different Methods:

[0101] PUFA salts from inventive example 13 (PUFA lysine salts, prepared by continuous granulation) and comparative example C6 (PUFA lysine salts, prepared by rapid mixer granulation) were exposed to 40° C./75% relative humidity (RH) conditions for 1 hour and observed under microscope in order to understand the sensitivity of these materials while handling during tableting operations.

[0102] After exposure of the samples to 40° C./75% relative humidity (RH) conditions for 1 hour, the surface of continuous spray granulated PUFA lysine salt showed no appreciable changes due to high temperature and humidity exposure. In contrast to this, the surface of rapid mixer granulated PUFA lysine salt turned sticky and oily on exposure difficult to process further for tableting.