# US 11,992,491 B2 · Crystalline salts of 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester

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- Number: US 11,992,491 B2
- Document ID: US11992491B2
- Status: Granted
- Kind: B2
- Application number: 17/258,014
- Filed: 2019-07-02
- Published: 2021-09-09
- Granted: 2024-05-28
- Earliest claimed: 2018-07-06
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Rudolf Moser; Viola Groehn; Ruth Boehni Stamm; Fritz Blatter; Martin Szelagiewicz
- Web page: https://patentgrep.com/patent/US11992491B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A23L 33/10: using additives (addition of substantially indigestible substances A23L33/21)
- A23L 33/40: {Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula}
- A61K 31/223: of alpha-aminoacids
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- C07C 229/08: the nitrogen atom of the amino group being further bound to hydrogen atoms
- C07D 475/04: with a nitrogen atom directly attached in position 2
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION

## Abstract

The present invention refers to a crystalline salt comprising 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester is from 1:0.3 to 1:3.0 (in mol/mol) and/or hydrates and/or solvates thereof as well as to a process of obtaining the same.

## Claims

### Claim 1

A crystalline salt comprising 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to L-valine ethyl ester is from 1:0.3 to 1:3.0 (in mol/mol), or a hydrate or solvate thereof.

### Claim 2 (depends on 1)

The crystalline salt of claim 1, wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to L-valine ethyl ester is from 1:0.5 to 1:2.5 (in mol/mol), or a hydrate or solvate thereof.

### Claim 3 (depends on 1)

The crystalline salt of claim 1, wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to L-valine ethyl ester is from 1:0.75 to 1:1.25 (in mol/mol), or a hydrate or solvate thereof.

### Claim 4 (depends on 1)

The crystalline salt of claim 1, wherein the ratio of 5-methyl-(6S)-tetrahydrofolic acid L-valine ethyl ester is approximately 1:1 (in mol/mol), or a hydrate or solvate thereof.

### Claim 5 (depends on 1)

The crystalline salt of claim 1, wherein the crystalline salt of 5-methyl-(6S)-tetrahydrofolic acid and L valine ethyl and has a powder x-ray diffraction (PXRD) pattern with characteristic peaks, which are expressed in 2θ±0.2° 20 with CuKα radiation, at 5.8, 6.9, 14.0, 19.0, 19.3, 22.2 and 25.9 (Form A).

### Claim 6 (depends on 1)

The crystalline salt of claim 1, wherein the crystalline salt of 5-methyl-(6S)-tetrahydrofolic acid L valine ethyl ester has a PXRD pattern with characteristic peaks, which are expressed in 2θ±0.2° 2θ with CuKα radiation, at 4.9, 7.4, 8.5, 14.1, 15.8, 16.3, 17.2, 18.6, 22.2 and 24.5 (Form B).

### Claim 7 (depends on 1)

The crystalline salt of claim 1 having at least 99 wt % or more chemical and/or stereoisomerical purity.

### Claim 8 (depends on 1)

A process for obtaining the crystalline salt comprising 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester according to claim 1 comprising the steps of: i) providing a mixture of 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester, optionally in a suitable solvent or a mixture of solvents ii) adding a base, optionally in a suitable solvent or a mixture of solvents, to dissolve the compounds; iii) heating the resultant composition to at least 60° C. and optionally carrying out a clear filtration; iv) crystallizing and cooling the mixture to a temperature between 1° C. and 30° C., optionally adding more solvent or mixture of solvents; and v) isolating the obtained solid material and optionally drying the product.

### Claim 9 (depends on 8)

The process of claim 8, wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester in step i) is in the range of from 1:1 to 1:3.

### Claim 10 (depends on 8)

The process of claim 8, wherein the solvent is water.

### Claim 11 (depends on 8)

The process of claim 8, wherein in step iii) and/or step iv) seed crystals are added.

### Claim 12 (depends on 8)

The process of claim 8, wherein L-valine ethyl ester is used as L-valine ethyl ester hydrochloride.

### Claim 13 (depends on 1)

A pharmaceutical composition, food additive or preparation comprising the crystalline salt comprising 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester, or, a hydrate or solvate thereof, according to claim 1 and optionally one or more acceptable excipients.

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13 wherein said composition is in the form of tablets, capsules, oral liquid preparations, powders, lyophilizates, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions, or suppositories.

### Claim 15 (depends on 13)

The pharmaceutical composition according to claim 13 further comprising at least one additional therapeutic agent.

### Claim 16 (depends on 13)

The pharmaceutical composition according to claim 13, wherein said composition is a pharmaceutical composition for oral, parenteral, intramuscular, intraspinal, intrathecal, periodontal, topical, or rectal administration.

### Claim 17 (depends on 1)

A method of producing a drug formulation or food additive formulation comprising; combining a drug or food additive with the crystalline salt comprising 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester, or a hydrate or solvate thereof, according to claim 1.