L-(-)-Moprolol L-(+)-Tartrate

Abstract

L-(−)-moprolol L-(+)-tartrate salt (2:1), method for preparing it and pharmaceutical composition comprising it.

Description

EXAMPLE 1

Preparation of L-(−)-moprolol L-(+)-tartrate (2:1)

Step a)

2N sodium hydroxide solution was added dropwise to a solution of L-(−)-moprolol hydrochloride (10 g) in water (100 ml) with stirring, until no further precipitate was formed.

The precipitate was extracted with dichloromethane (100 ml). The organic phase was separated out and dried over sodium sulphate. Finally, the dichloromethane was removed by evaporation.

The solid residue thus obtained consisted of L-(−)-moprolol base (9.1 g).

Step b)

A solution of L-(+)-tartaric acid (1.57 g; 0.01 mol) in absolute ethanol (15 ml) was added to a solution of L-(−)-moprolol base (5.0 g; 0.02 mol) in hot absolute ethanol (30 ml).

After stirring the solution at 60° C. for 10 minutes, ethyl ether was added until precipitation was complete. The precipitate thus obtained (very hygroscopic) was separated out by decantation and crystallized from absolute ethanol (30 ml) to give the desired product (5.2 g).

m.p.=135° C. [α]=−1.1 (c=5 in H₂O)

Elemental Analysis

	For C30H48N2O12	C	H	N
	Calculated	57.31	7.70	4.46
	Found	57.16	7.79	4.38

Test 1

Ocular Tolerability

Two aqueous solutions were used.

The first contained 1% by weight of L-(−)-moprolol hydrochloride (corresponding to 0.87% by weight of L-(−)-moprolol). The second contained 1.14% by weight of L-(−)-moprolol L-(+)-tartrate (2:1) (corresponding to 0.87% by weight of L-(−)-moprolol).

12 male rabbits (New Zealand White) with an average weight of 2 kg and an average age of ten months were used, divided into two groups of six rabbits each. The first group was treated with 0.1 ml of the first test solution three times a day for fifteen days. The second group was treated with 0.1 ml of the second test solution three times a day for fifteen days.

The tolerability was evaluated according to J. Draize et al., Pharmacol. Exp. Ther., 83, 377-390 (1944). The results are shown in Table 1 below.

	TABLE 1
	Before the first	After the last
	application	application
	L-(−)-moprolol	L-(−)-moprolol
	hydrochloride	L-(+)-tartrate
Conjunctiva	Reddening	1	0
	Swelling	2	0
	Lachrymation	2	1
Iris		0	0
Cornea	Opacity	0	0
	Area of the cornea	0	0
	affected by opacity
	Total Score	5	1

Claims

1. L-(−)-moprolol L-(+)-tartrate salt (2:1).

2. Pharmaceutical composition for ophthalmic use, characterized in that it comprises L-(−)-moprolol L-(+)-tartrate (2:1) together with at least one pharmaceutically acceptable vehicle.

3. Pharmaceutical composition according to claim 2, characterized in that it is in the form of a gel, an ointment or eyedrops.

4. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of L-(−)-moprolol is between 0.01% and 20% by weight.

5. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of L-(−)-moprolol is between 1% and 8% by weight.

6. Process for preparing L-(−)-moprolol L-(+)-tartrate (2:1), characterized in that it includes the addition of L-(+)-tartaric acid, dissolved in a suitable organic solvent, to L-(−)-moprolol base, also dissolved in a suitable organic solvent, in a 2:1 molar ratio.

7. Process according to claim 6, characterized in that the salt thus formed is isolated via precipitation and filtration.

8. Process according to claim 6 or 7, characterized in that the abovementioned organic solvent is ethyl alcohol.

9. Process according to claim 8, characterized in that the salt is precipitated from the ethanolic solution via addition of ethyl ether.