IMPROVED SYNTHESIS OF LYSINE ACETYLSALICYLATE GLYCINE PARTICLES

• US 20190322610A1
• Filed: 12/22/2017
• Published: 10/24/2019
• Est. Priority Date: 12/23/2016
• Status: Active Grant

• Current Assignee: AspiAir GmbH
• Original Assignee: Ventaleon GmbH
• Inventors: NOCKER, Karlheinz, ZUHSE, Ralf, OSTROVSKYI, Dmytro
• Granted Patent: US 10,882,811 B2
• Time in Patent Office: Days
• CPC Class Codes: C07C 227/18 by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• CPC Class Codes: C07C 227/42 Crystallisation
• CPC Class Codes: C07C 229/26 having more than one amino group bound to the carbon skeleton, e.g. lysine
• CPC Class Codes: C07C 51/00 Preparation of carboxylic acids or their salts, halides or anhydrides of acids by hydrolysis of oils, fats or waxes C11C
• CPC Class Codes: C07C 67/28 by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
• CPC Class Codes: C07C 67/52 by change in the physical state, e.g. crystallisation
• CPC Class Codes: C07C 69/157 containing six-membered aromatic rings

Abstract

The invention relates to a method for the production of acetylsalicylic acid lysinate, optionally lysine acetylsalicylate.glycine, comprising the following steps: a) providing a solution of acetylsalicylic acid in ethanol; b) providing an aqueous solution of lysine; c) combining the solutions of step a) and b) to form a mixture; d) optionally stirring the mixture; e) adding acetone to the mixture; f) incubating the mixture, to allow the formation of a acetylsalicylic acid lysinate product; g) isolating the acetylsalicylic acid lysinate product; wherein acetylsalicylic acid is used in excess compared to lysine and wherein no seed crystals are added to the mixture; and optionally the following further steps: h) providing a recrystallized glycine; wherein the glycine has been recrystallized with the following steps: h1) dissolving glycine in water; h2) adding acetone to the glycine solution; h3) stirring the mixture until a precipitate is obtained; i) combining the recrystallized glycine of step h) with the acetylsalicylic acid lysinate product of step g) to obtain lysine acetylsalicylate.glycine (LASAG) particles.

Claims

1. A method for the production of lysine acetylsalicylate.glycine comprising the steps:

a) providing a solution of acetylsalicylic acid in ethanol;

b) providing an aqueous solution of lysine;

c) combining the solutions of step a) and b) to form a mixture;

d) optionally stirring the mixture;

e) adding acetone to the mixture;

f) incubating the mixture, to allow the formation of a acetylsalicylic acid lysinate product;

g) isolating the acetylsalicylic acid lysinate product;

wherein acetylsalicylic acid is used in excess compared to lysine and

wherein no seed crystals are added to the mixture;

h) providing a recrystallized glycine;

wherein the glycine has been recrystallized with the following steps;

h1) dissolving glycine in water;

h2) adding acetone to the glycine solution;

h3) stirring the mixture until a precipitate is obtained;

i) combining the recrystallized glycine of step h) with the acetylsalicylic acid lysinate product of step g) to obtain lysine acetylsalicylate.glycine (LASAG) particles.

2. The method according to claim 1, wherein the particles obtained in step i) have a median particle size of less than 40 μ

m, and wherein at least 90% of the particles obtained in step i) have a particle size of less than 110 μ

m.

3. The method according to claim 1, wherein at least method steps c) to f) and/or h) and i) are performed at room temperature or below.

4. The method according to claim 1, wherein the incubation step f) is performed at 10°

C. or less.

5. The method according to claim 1, wherein the isolation in step g) is performed by filtration.

6. The method according to claim 1, wherein the isolation in step g) is performed by centrifugation.

7. The method according to claim 1, wherein the solution of acetylsalicylic acid provided in step a) comprises about 8 to 12% (w/v), preferably about 9 to 10% (w/v) acetylsalicylic acid.

8. The method according to claim 1, wherein the aqueous solution of lysine provided in step b) comprises about 30 to 35% (w/v) lysine.

9. The method according to claim 1, wherein the aqueous solution of lysine provided in step b) further comprises dissolved glycine, and wherein the concentration of the glycine in the solution is optionally from 2 to 20% (w/v).

10. The method according to claim 1, wherein the aqueous solution of lysine provided in step b) was prepared from lysine monohydrate.

11. The method according to claim 1, wherein acetylsalicylic acid and lysine are used at a molar ratio of 1 to 0.9, or at a ratio of 1 to 0.95.

12. The method according to claim 1, additionally comprising the step:

g1) washing the isolated product.

13. The method according to claim 12, wherein the washing step involves washing the product with acetone.

14. The method according to claim 1, wherein the method is performed under sterile conditions.

15. The method according to claim 1, wherein the method is performed under non-sterile conditions and comprises the additional step:

j) sterilizing the product by irradiation.

16. A lysine acetylsalicylate.glycine obtainable by a method according to claim 1.