Process for obtaining disodium tyrosine by spray drying

Abstract

The present invention relates to a process for obtaining disodium tyrosine in crystalline form, preferably the dihydrate, by spray drying technique.

Description

[Technical field]

[0001] The present invention relates to a method for obtaining disodium tyrosine in crystalline form, preferably the dihydrate, by spray drying technique. [Background technology]

[0002] Tyrosine disodium dihydrate is used as an ingredient in human food supplements and as an additive in cell culture media.

[0003] [ka]

[0004] Due to its significant solubility in water, it is difficult to obtain it by the common synthetic method of dissolving L-tyrosine in sodium hydroxide solution and precipitating it by adding an antisolvent.

[0005] In the authors' preliminary tests, it was necessary to add 12 kg of ethanol per kg of L-tyrosine to obtain precipitation of the product from an aqueous solution of L-tyrosine with sodium hydroxide (39.8% kg / kg solution). The main drawbacks of this method are the use of a significant amount of solvent and the insufficient yield (66.6%). Therefore, this method is not very sustainable from both an environmental and a production point of view.

[0006] Therefore, the present inventors have developed a method that uses spray drying technology to increase yields, significantly reduce process volumes, improve productivity, and avoid the use of organic solvents, thereby reducing costs and environmental impact.

[0007] US Patent No. 4,734,401 describes a spray drying process applied to the synthesis of amino acids in general, and to the amorphous (non-crystalline) form of tyrosine ammonium salt in particular. The technical problem to be solved in this patent was the need to obtain an amorphous product by a synthesis method that improves the process yield and reduces the amount of solvent used compared to conventional methods. The process described in US Patent No. 4,734,401 provides for the preparation of a solution of L-tyrosine (40.0 g / L solution) in 14% aqueous ammonia (pH 12-13) at 70°C. This solution is subjected to a spray drying process in an air or nitrogen stream, at an inlet temperature of 210-221°C and an outlet temperature of 106-132°C (preferably 100-125°C), while maintaining a solution feed rate of 100 g / min. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Pat. No. 4,734,401 Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention instead differs from that described in the prior art in that: - A crystalline product can be obtained instead of amorphous. the product is obtained as a disodium salt, preferably in the form of a dihydrate, and not as an ammonium salt; The inlet and outlet temperatures are preferably maintained at 130-180°C and 80-100°C, respectively, for processes carried out in a nitrogen stream, and at 165-180°C and 80-100°C, respectively, for processes carried out in an air stream (preferably 165°C and 95°C, respectively).

[0010] Summary of the Invention It is an object of the present invention to provide a method for producing disodium tyrosine, preferably dihydrate, by a spray drying process. [Means for solving the problem]

[0011] According to a first aspect, the present invention relates to a method for producing disodium tyrosine, preferably dihydrate, comprising the steps of: a) preparing an aqueous sodium hydroxide solution of L-tyrosine; b) subjecting the solution obtained to spray drying in an inert gas atmosphere, preferably in a nitrogen atmosphere, or in an air atmosphere.

[0012] In a preferred embodiment, the aqueous L-tyrosine solution of step a) is prepared in 28.5-32.5% by weight, preferably 30% by weight, of sodium hydroxide, more preferably at room temperature, according to the synthesis scheme reported below.

[0013] [ka]

[0014] Preferably, water is added to the sodium hydroxide solution to ensure complete dissolution of the disodium tyrosine prior to the spray drying step.

[0015] In a further preferred embodiment, the spray-drying step b) is carried out in a stream of inert gas, preferably in a stream of nitrogen.

[0016] In this embodiment, the inlet temperature is 130°C to 180°C, and the outlet temperature is 80°C to 100°C.

[0017] In a further alternative embodiment, the spray drying step b) is carried out in an air stream.

[0018] In this embodiment, the inlet temperature is 165°C to 180°C, preferably 165°C, and the outlet temperature is 80°C to 100°C, preferably 95°C. Effect of the Invention

[0019] Compared with classical methods for obtaining products, the method according to the invention can reduce the reaction volume, improve the productivity (as the yield is quantitative with minimal mechanical losses) and significantly reduce the amount of solvent wasted, which is undoubtedly advantageous in terms of environmental impact and cost. Moreover, the method according to the invention maintains the stability of products that are susceptible to oxidation. [Brief description of the drawings]

[0020] [Figure 1] 1 shows the XRPD (X-ray powder diffraction) spectrum of disodium tyrosine dihydrate obtained in Example 1 (the present invention). [Diagram 2] FIG. 2 is a comparison of the XRPD spectrum of disodium tyrosine dihydrate in FIG. 1 with the XRPD spectrum of crystalline disodium tyrosine dihydrate (reference) obtained by precipitation by addition of an antisolvent in the prior art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Unless otherwise defined, all technical terms, expressions, and other scientific terms used herein are intended to have the meaning commonly understood by those skilled in the art to which this disclosure belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference. Therefore, the inclusion of such definitions in this disclosure should not be interpreted as meaning a substantial difference from what is commonly understood in the art.

[0022] As used herein, the terms "approximately" and "about" refer to the range of experimental error inherent in performing experimental measurements.

[0023] The terms "comprising," "having," "including," and "containing" are intended to be open-ended terms (i.e., meaning "including, but not limited to") and are also considered to support terms such as "consist essentially of," "consisting essentially of," "consist of," or "consisting of."

[0024] The terms "consist essentially of" and "consisting essentially of" are intended as semi-closed terms and mean that no other components are included that affect the novel characteristics of the invention (and thus, optional excipients may be included).

[0025] The terms "consist of" and "consisting of" are intended as closed terms.

[0026] The term "room temperature" means a temperature between 15°C and 25°C, preferably between 20°C and 25°C.

[0027] Detailed Description of the Invention An object of the present invention is a process for preparing disodium tyrosine, preferably dihydrate, comprising the following steps: a) preparing an aqueous sodium hydroxide solution of L-tyrosine; b) subjecting the solution obtained to spray drying in an inert gas atmosphere, preferably in a nitrogen atmosphere, or in an air atmosphere.

[0028] The method according to the invention provides firstly the preparation of a basic aqueous solution of L-tyrosine, preferably obtained by adding 28.5-32.5% by weight, more preferably 30% by weight, of sodium hydroxide solution (e.g. 1.51 kg of 30% NaOH per kg of L-tyrosine) to L-tyrosine under stirring at room temperature, and even more preferably followed by the addition of water (e.g. 1 kg of water per kg of L-tyrosine). This solution is then subjected to a spray drying process carried out both under inert conditions and in a stream of air.

[0029] In a preferred embodiment, for a spray drying process carried out in a nitrogen stream, an inlet temperature of 130° C. to 180° C. and preferably an outlet temperature of 80° C. to 100° C. were preferably used. The end temperature difference (ranging from 40 to 80° C.) was adjusted by varying several parameters, such as the solution feed rate (varying between 26 and 56 Kg / h) and the type of nozzle used (pressure nozzle or two-fluid nozzle).

[0030] For the spray drying process carried out in an air stream, the inlet temperature is preferably between 165° C. and 180° C., and the outlet temperature is preferably between 80° C. and 100° C. An apparatus that can be used for the purposes of the present invention consists of a turbine atomizer with a rotation speed of 16,000 to 18,000 rpm.

[0031] The resulting product was subjected to the following analyses: ·Quality (potentiometric titration; optical rotation; APHA color) ·Solid state by X-ray; · Particle size (by sieving or laser diffraction analyzer).

[0032] The product tyrosine disodium salt dihydrate is preferably obtained by the process according to the invention: 1) has the desired quality as determined by potentiometric titration (98.0-102.0% w / w), color (APHA color, 1% aqueous solution, max. 200), and optical rotation (20°C, c=4g / 100mL, aqueous solution, -14.4° / 12.6° as free acid); 2) the moisture content, as determined by Karl Fischer (KF), is 12.0-16.0% w / w; 3) It is not amorphous, but a crystalline solid with a particle size distribution of 95% or more on a 100 mesh screen. EXAMPLES

[0033] Experimental Part Example 1: Synthesis of disodium tyrosine dihydrate by spray drying process in air stream according to the present invention 25 kg of L-tyrosine (137.98 mol) was added with stirring at room temperature to 37.75 kg of 30 wt% sodium hydroxide solution (283.13 mol, 2.05 eq.) 25 kg of water was added to the suspension and kept under stirring at room temperature for 2 hours until complete dissolution.

[0034] The resulting solution was subjected to a spray drying process in an air stream at an inlet temperature of 165° C. and an outlet temperature of 95° C. with a turbine speed of 16,000 rpm. The product obtained at the discharge was cooled to a temperature of 4-8° C. and then sieved. The process yield was quantitative (36.0 kg, 137.98 mol of L-tyrosine disodium dihydrate).

[0035] The product was analyzed to assess quality, solid state, and particle size and met the expected requirements as evidenced by the results presented below. Moisture content (Karl Fischer): 14.2% w / w APHA Color (Visual Test): <200 Potentiometric titration: 101.4%w / w Optical rotation [α] D 20 (20℃, c=4g / 100mL, free acid, aqueous solution): -14.2° Particle size (by 100 mesh sieve): 99.3% Determination of solid state by X-ray: crystalline solids.

Claims

1. A method for producing disodium tyrosine, comprising the following steps: a) the step of preparing an aqueous solution of L-tyrosine in a sodium hydroxide solution; and b) A step of subjecting the obtained solution to spray drying in an inert gas atmosphere or an air atmosphere.

2. The method according to claim 1, characterized in that the tyrosine disodium is tyrosine disodium dihydrate.

3. The method according to claim 1, characterized in that step a) is carried out at room temperature.

4. The method according to claim 1, characterized in that the sodium hydroxide solution is 28.5% by weight to 32.5% by weight.

5. The method according to claim 4, characterized in that the sodium hydroxide solution is 30% by weight.

6. The method according to claim 1, characterized in that a predetermined amount of water is added to the sodium hydroxide solution.

7. The method according to claim 6, characterized in that an amount of water equal to the initial amount of L-tyrosine is added to the sodium hydroxide solution.

8. The method according to any one of claims 1 to 7, characterized in that step b) is carried out in an inert gas atmosphere.

9. The method according to claim 8, characterized in that the inert gas is nitrogen.

10. The method according to claim 8, characterized in that the inlet temperature is 130°C to 180°C and the outlet temperature is 80°C to 100°C.

11. The method according to any one of claims 1 to 7, characterized in that step b) is carried out in an air atmosphere.

12. The method according to claim 11, characterized in that the inlet temperature is 165°C to 180°C and the outlet temperature is 80°C to 100°C.

13. The method according to claim 12, characterized in that the inlet temperature is 165°C.

14. The method according to claim 12, characterized in that the outlet temperature is 95°C.

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