DESC:PROCESS FOR PREPARATION OF DIRECTLY COMPRESSIBLE DRY POWDER FORMULATION OF ASTAXANTHIN
Related Application
This application is related to and takes priority from Provisional Application 201921001506 filed on 13th January 2019 and is incorporated herein in its entirety.

Field of the invention
The present invention relates to a manufacturing process for producing directly compressible stable dry powder formulation of Astaxanthin by granulation for manufacturing of pharmaceutical and nutraceutical preparations.

Background of the Invention
Astaxanthin is a xanthophyll carotenoid which is found in various microorganisms and marine aquatics. It is a red fat-soluble pigment having pharmaceutical and nutraceutical values. The Haematococcuspluvialis is a green microalga, which accumulates high astaxanthin content under stress conditions such as high salinity, nitrogen deficiency, high temperature and light. Astaxanthin produced from H. pluvialis is a main source for human consumption for dietary supplement. The use of astaxanthin as a nutritional supplement has been rapidly growing in foods, feeds, nutraceuticals and pharmaceuticals.
Indian patent 264507 has provided a process for the preparation of water dispersible astaxanthin composition. This is primarily to impart red color to the aqueous medium due to presence of carotenoid in astaxanthin.
US5976575 provides a dry powder of carotenoids produced by grinding a mixture of carotenoids and oil and emulsifying the mixture with an encapsulating mixture and drying the emulsification.
US6296877 has proposed a process for preparing a stable aqueous dispersion of xanthophylls which achieved good coloring action and bioavailability.
Furthermore, US5968251 claims a process for the production of carotenoid preparations in the form of coldwater-dispersible powders.
Natural Astaxanthin obtained from green microalgae is extracted, stored and available in oil form. Use of oily actives during manufacturing of solid dosage forms limits its use; by being oily for an active ingredient, there are handling issues and respective losses, oil leaching in the formulation, surface mottling particularly in tablet dosage forms due to presence of oil, poor flow properties of blends (pre-compression tablet blend or finished blend of capsules), poor hardness to tablets, capping during compression, weight variation, content uniformity and so on.
Astaxanthin being obtained from natural sources is lipophilic in nature, photosensitive and susceptible for oxidation which may lead to loss of its activity. To overcome these problems, the present invention provides a process to convert oily active (Astaxanthin) into directly compressible dry stable powder formulation using granulation technology.

Brief Description of Invention
The invention relates to a manufacturing process for producing stable dry powder formulation of Astaxanthin for manufacturing of pharmaceutical and nutraceutical formulations by direct compression technology. Additionally formulation of present invention is used for conventional tablet manufacturing and capsule manufacturing as well.

Astaxanthin oil containing suitable preservative was emulsified in aqueous phase containing low molecular weight hydrophilic polymers. Emulsifying agent having HLB value more than 10 was used to favor emulsification process. Solvent/s or Organic solvent/s were not used for emulsification process. Second step is adsorbing prepared o/w emulsion on suitable solid carriers such as combination of cellulose derivative along with silica derivative to get dry solid stable powder formulation of oily active. Aqueous phase can be removed by means of drying. No direct drying of prepared o/w emulsion. Total oily active content of emulsion is 50% w/w. Ratio percentage mass of solid adsorbent carrier to oily component is 110%. Low viscosity polymer will help to build and maintain viscosity of o/w emulsion. Additionally it will also act as binder during wet granulation process.
The formulation, Astaxanthin powder, of the present invention is given below in Table 1.
Table 1. Formulation of Astaxanthin powder of the invention
Sr. No. Name of Ingredient Quantity (% w/w)
1 Astaxanthin oil 40 – 50
2 Oil adsorbent 25 – 30
3 Filler / Adsorbent 15 – 20
4 Antioxidant 1 0.5 – 1.5
5 Antioxidant 2 2 – 4
6 Preservative (Antioxidant 3) 0.2 – 2
7 Emulsifying agent 2 – 5
8 Thickening agent 1 – 3.5
9 Binder 3 – 9
10 Vehicle (purified water) q.s.
11 Purified water (extra water as additional binder q.s.
The above formulation provides 4% wt by wt astaxanthin powder.
The invention also provides a process of preparing directly compressible stable astaxanthin dry powder the details of which are given below:
1. Preparation of solution A
1.1: In clean glass beaker transfer quantity of purified water (10). Keep this beaker under overhead stirrer.
1.2: Transfer required quantity of emulsifying agent (7) to step 1.1 and stir on overhead stirrer till clear solution obtained.
1.3: To the step 1.2 slowly add required quantity of thickening agent (8) under continuous stirring till clear solution.
2. Preparation of solution B
2.1: In separate clean vessel transfer required quantity of Astaxanthin oil (1). Keep this beaker under separate overhead stirrer.
2.2: To the step 2.1 add preservative (6) and stir it well using overhead stirrer. Make sure homogenous solution is obtained.
3. Preparation of solution C
3.1: To the solution A slowly add solution of B with continuous stirring under overhead stirrer. Make sure formation of homogenous liquid phase.
4. Sifting
4.1: Co-sift Oil adsorbent (2), Filler/Adsorbent (3), Antioxidant 1 (4), Antioxidant 2 (5), Binder (9) through suitable mesh sieve. Suitable size of mesh sieve is 30# to 40#.
5. Dry mixing
5.1: Transfer sifted materials of stage 4.1 to the dry clean rapid mixer granulator (RMG). Dry mix this sifted materials for 1 min at impellor speed of 100 rpm.
6. Granulation
6.1: Granulate dry mixed blend of step 5.1 using solution C. Set impellor speed at 100 rpm and chopper speed at 3000 rpm. After complete addition of solution C allow RMG to run further for 2 min.
6.2: After 2 min stop RMG, open lid. Scrap material adhered (if any) to side walls and bowl surface near and surrounding impellor and chopper blade carefully. Manually mix scraped material with wet mass.
6.3: Start RMG and run for additional 3 min to get desired granule growth. If required add extra purified water (11) as binder aid.
7. Unloading
7.1: Unload wet granulated mass prepared in step 6.3 into a clean dry fluidized bed dryer bowl.
8. Drying in Fluidized bed dryer (FBD)
8.1: Set drying parameters as follows,
Inlet temperature : 70 OC ± 5 OC
Blower Speed : 2000 ± 200 rpm
Exhaust temperature : Not more than 60 OC ± 5 OC
Loss on drying limit : Not more than 2.2 %
9. Sifting of dried granules
9.1: Sift dried granules through suitable sieve (through 40# mesh size). Collect sifted and retained granules in separate containers.
10. Milling of coarse material
10.1: Mill coarse material retained in step 9.1 using suitable mill. Use suitable screen and milling speed to get desired size granules.
11. Sifting of milled granules
11.1: Sift milled granules obtained in step 10.1 through suitable sieve (through 40# mesh size) and collect in separate container.
12. Blending
12.1: Transfer sifted granules collected in step 9.1 and step 11.1 to the suitable blender. Blend for 2 min at speed of 10 rpm.
Collect material of stage 12.1 in separate container which is directly compressible astaxanthin powder of the invention.

Oil adsorbent in the present invention is selected from but not limited to silicon dioxide, colloidal silicon dioxide, modified silica, magnesium oxide, phosphate anhydrous salts, cross linked polymers etc. and combination thereof.
Filler / adsorbent is selected from but not limited to calcium carbonate, calcium phosphate, magnesium carbonate, microcrystalline cellulose, lactose monohydrate, modified starches, sugar alcohols and combination thereof.
Antioxidants are used in the present invention at multiple steps. These are specific and non- interchangeable as they are selected for the said step based on their lipophililc nature. Accordingly, antioxidant 1 is selected from the group consisting of sodium ascorbate, citric acid, tartaric acid and sodium citrate, antioxidant 2 is selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, lecithin, butylatedhydroxyanisole and butylatedhydroxytoluene; and preservative/antioxidant 3 is selected from the group consisting of D-alpha tocopherol and propyl gallate. Preferably, antioxidant 1 is sodium ascorbate; antioxidant 2 is ascorbyl palmitate and antioxidant 3 (preservative) is D-alpha tocopherol.

Emulsifying agent used in the present invention is selected from but not limited to Polyoxyethylenesorbitantristearate, Polyoxyethylenesorbitantrioleate, Polyoxyethylenesorbitanmonostearate, Polyoxyethylenesorbitanmonooleate, Polyoxyethylenesorbitanmonopalmitate and combinations thereof.
Thickening agent is a synthetic polymer used in the present invention which is selected from but not limited to hydroxy propyl methyl cellulose, hydroxy propyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and combinations thereof.
Binder used in the present invention can be selected from but not limited to, synthetic polymers, cellulose derivatives, sucrose and combinations thereof. Purified water was selected as aqueous vehicle in the present invention.

Applicants present the unique features of the present invention:
• Oily or lipophilic liquid active converted into dry form;
• Stable and dry powder formulation of oily active starting compound;
• Stable and Dry powder manufactured by granulation method;
• Organic solvents not used during processing;
• Stable formulation for direct compression functionality;
• Stable formulation for conventional tablet manufacturing and capsule manufacturing with no oil leaching out from formulation;
• Stable and dry powder formulation for solid oral dosage forms like tablets and capsules;
• Stable formulation for pharmaceutical and nutraceutical preparations.
,CLAIMS:Claims
I Claim:
1. A process of preparing astaxanthin powder formulation comprising producing directly compressible stable dry powder of Astaxanthin by granulation.
2. A process of preparing dry astaxanthin powder formulation wherein the said process comprises the following steps:
a) Mixing vehicle, emulsifying agent and thickening agent under continuous stirring until formation of clear solution;
b) Mixing astaxanthin oil and preservative/antioxidant 3under continuous stirring to obtain a homogenous solution;
c) Adding solution (b) to solution (a) slowly under continuous stirring to form a homogenous liquid phase;
d) Co-sifting oil adsorbent, filler/adsorbent, antioxidant 1, antioxidant 2 and binder ;
e) Transferring sifted excipients of (d) to dry clean rapid mixer granulator (RMG) and dry mixing for 1 minute at impellor speed of 100rpm to make it a dry mixed blend;
f) Granulating the dry mixed blend of (e) using solution of (c) in RMG to prepare a wet granulated mass;
g) unloading wet granulated mass of (f) and drying in fluidized bed dryer;
h) Sifting dried granules of (g) through sieve to collect sifted and coarse retained granules and milling coarse retained granules;
i) Blending sifted and milled granules of (h) and collecting the astaxanthin powder.
3. The process as claimed in claim 2 wherein the said oil adsorbent is selected from the group consisting of silicon dioxide, colloidal silicon dioxide, modified silica, magnesium oxide, phosphate anhydrous salts, cross linked polymers and a combination thereof.
4. The process as claimed in claim 2 wherein the said filler/adsorbent is selected from the group consisting of calcium carbonate, calcium phosphate, magnesium carbonate, microcrystalline cellulose, lactose monohydrate, modified starches, sugar alcohols and a combination thereof.
5. The process as claimed in claim 2 wherein the said emulsifying agent is selected from the group consisting of Polyoxyethylenesorbitantristearate, Polyoxyethylenesorbitantrioleate, Polyoxyethylenesorbitanmonostearate, Polyoxyethylenesorbitanmonooleate, Polyoxyethylenesorbitanmonopalmitate and a combination thereof.
6. The process as claimed in claim 2 wherein the said antioxidant 1 is selected from the group consisting of sodium ascorbate, citric acid, tartaric acid and sodium citrate, the antioxidant 2 is selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, lecithin, butylatedhydroxyanisole and butylatedhydroxytoluene; and the preservative/antioxidant 3 is selected from the group consisting of D-alpha tocopherol and propyl gallate.
7. The process as claimed in claim 2 wherein the said thickening agent is selected from the group consisting of hydroxy propyl methyl cellulose, hydroxy propyl cellulose, , polyvinyl pyrrolidone, polyvinyl alcohol and combinations thereof.
8. The process as claimed in claim 2 wherein the said binder is selected from the group consisting of, synthetic polymers, cellulose derivatives, sucrose and combinations thereof.
9. The process as claimed in claim 1 or 2 wherein the said directly compressible dry stable astaxanthin powder formulation is used for manufacturing of solid oral dosage forms selected from tablet or capsule.