HU198480B - Process for producing furaltadone-mesylate salt and pharmaceutical compositions comprising this salt - Google Patents

Abstract

5-(4-Morpholinomethyl)-3-[[(5-nitro-2-furanyl)methylene]amino]-2- oxazolidinone mesylate and the hydrates of this mesylate. A water-soluble compound is the citrate of this salt, the mesylate/citric acid ratio advantageously being from 1 to 4 by weight and preferably 2. The invention also comprises aqueous solutions of the salt in question and/or of its combinations.

Description

The present invention relates to a process for the preparation of furaltadone mesityl salt and hydrates thereof. More particularly, the invention is

FIELD OF THE INVENTION This invention relates to the preparation of a water-soluble mesylate salt of 5- (4-morpholinylmethyl) -3 - [[(5-nitro-2-furanyl) methylene] amino] -2-oxazolidinone (hereinafter "furaltadone") or a hydrate of the latter.

Furaltadone is a well-known antibacterial compound used primarily in veterinary medicine. It has only a limited solubility in water, i.e. about 75 mg at 100C (0.075%) at 25 ° C.

The acid addition salts of furaltadone with better solubility than furaltadone are known from Israeli Patent Nos. 16943 and 26665. For example, the hydrochloride salt gives a 4% solution. However, this degree of solubility does not allow the preparation of stable aqueous concentrates of these salts. By "aqueous concentrate" in the context of the present invention is meant an aqueous mixture containing a large amount of furaltadone derivative which is rapidly soluble in water to provide a concentration suitable for treating livestock and poultry.

It is well known that drinking water is most beneficial for the medicated treatment of sick pets and poultry. To date, furaltadone has been administered orally or a pharmaceutical composition containing this compound, such as a powder or tablet, has been dissolved in drinking water, which is a particularly cumbersome and unpleasant operation. However, transporting and storing a solution containing furaltadone in the final dose required for use is too costly and impractical.

It is therefore an object of the present invention to provide a pharmaceutically effective salt of furaltadone which is more soluble than the known salts, i.e., it is possible to obtain a high active ingredient concentrate which is readily soluble when mixed with the desired amount of drinking water.

It has been found that when furaltadone is reacted with methanesulfonic acid, furaltadone mesylate is formed which gives a 14% solution at room temperature and has a high dissolution rate.

It has further been found that, surprisingly, the solubility of furaltadone mesylate in water is significantly increased in the presence of citric acid.

This latter finding is surprising because the solubility of furaltadone citrate is rather low (2%) and the addition of citric acid to furaltadone hydrochloride does not significantly increase its water solubility.

Aqueous pharmaceutical compositions containing furaltadone mesylate and citric acid can be prepared in a manner known per se, as described below.

The following examples are intended to illustrate the invention.

EXAMPLE 1 Furaltadone (g) was suspended in ethanol (200 ml) and heated to reflux under vigorous stirring. It is then added in a single dose

5.83 g of methanesulfonic acid. The resulting volumetric suspension was heated to reflux with stirring for 15 minutes, cooled to room temperature and stirred for an additional 30 minutes. The resulting precipitate was filtered off and the separated crystals were washed with ethanol.

The crude crystals are resuspended in ethanol and the resulting suspension is brought to reflux with stirring. Water was added until the hemihydrate formed was completely dissolved, the hot solution was filtered and the filtrate was cooled in an ice bath. The resulting precipitate was filtered off, washed with ethanol and allowed to air-dry at room temperature. The yield was 97.4% of the one-mesylate salt of the furaldehyde melting at 258-260 ° C.

Analysis for C14H20N4O9S. Based on 1/2 H2O formula:

Calculated: C, 39.16; H, 4.98; N, 13.05; S, 7.46.

Found: C, 38.98; H, 4.76; N, 13.00

S, 7.38.

Mass spectrum (Cl, methane): M + 1325.3 (furaltadone) 96.9 (methanesulfonic acid)

IR: 3180, 3060, 1780, 1420, 1360, 1030,

970 and 745 cnr ¹

Water solubility at room temperature: 140 mg / ml (equivalent to 108 mg furaltadone / ml)

Water solubility at 37 'C: 250 mg / ml (corresponding to

192 mg furaltadone / ml) ³⁰

Example 2

2 g of furaltadone mesylate and 1 g of citric acid are mixed and 10 ml of water are added to the resulting mixture. While stirring, a rapid dissolution occurs to give a 20% aqueous solution of furaltadone mesylate (equivalent to a solution of 15.39% furaltadone). After standing for two months at room temperature, the solution retains its full effectiveness.

The following solutions may be prepared in the same way:

(a) A solution of 1 g of furaltadone mesylate and 1 g of citric acid in water is made up to 5 ml with 20% solution.

b) A solution of 2.5 g of furaltadone mesylate and 1.25 g of citric acid in water is added to 10 ml to give a 25% solution.

Example 3

1.3 g of furaltadone mesylate and 650 g are mixed and 5 ml of water are added. The resulting partial suspension is heated with stirring at 30 ° C, when complete dissolution occurs. The solution is then cooled to room temperature to give a 26% aqueous solution of furaltadone mesylate (corresponding to 20% furaltadone mesylate). After 1 month of storage at room temperature, the solution is subjected to biological analysis and found to retain its full effectiveness.

The following solutions can be prepared by the same method.

(a) A mixture of 1 g of furaltadone mesylate and 1 g of citric acid is made up to 5 ml with water to give a 20% solution.

(b) 20% odor in a mixture of 1 g of furaltadone mesylate and 0.125 g of citric acid in 5 ml of water

HU 198480 Β we get.

All solutions of Examples 2 and 3 are clear solutions.

Claims (5)

PATENT CLAIMS A process for the preparation of the mesylate salt of 5- (4-morpholinylmethyl) -3 - [[(5-nitro-2-furanyl) methylene] amino] -2-oxazolidione (furaltadone), and hydrates of the latter. characterized in that furaltadone is reacted with methanesulfonic acid, optionally in the presence of water. 10 A process for the preparation of aqueous solutions having antibacterial activity, wherein the furaltadone mesylate salt produced by the process of claim 1 or a hydrate thereof and optionally citric acid is dissolved in water. 3. A process according to claim 2, wherein the furaltadone mesylate salt or a hydrate thereof and the citric acid are used in a weight ratio of 1: 1 to 4: 1. 4. The process of claim 3, wherein the weight ratio is set to 2: 1. 5. The process according to any one of claims 1 to 3, wherein the concentration of the furaltadone mesylate salt is adjusted to 20-26%.