Amonafide salts

Abstract

The monohydrochloride and the monomethanesulfonate of amonafide are described. The salts have good pharmaceutical properties besides their antitumor action.

Description

DESCRIPTION

The present invention relates to novel salts of amonafide.

Amonafide (Eur. J. Med. Chem. Chim. Ther. 16, 209 (1981)) is a substance which has antitumor action. It exists in the form of very fine needle-like yellow crystals which are reminiscent of asbestos and are very difficult to process to oral forms or injection solutions.

Attempts to react amonafide with acids such as hydrochloric acid or methanesulfonic acid result in salts which, because of their strongly acidic properties, are unsuitable for the preparation of pharmaceutical forms. The reason for this is that the salts elicit irritant effects because of their strongly acidic nature. An additional factor is that they are incompatible with many pharmaceutical auxiliaries required for preparing capsules.

It has now been found that although certain salts of amonafide do not have the abovementioned adverse properties, they do not differ from amonafide in terms of the antitumor action.

The invention relates to salts of amonafide of the formula ##STR1## in which X.sup.- is a Cl.sup.- or CH.sub.3 --SO.sub.3 -- ion. stable in the dark, and in solid form they can easily be metered, are free-flowing, readily compressible and only moderately hygroscopic and easy to dry. They have the further advantage that they are compatible with gelatin so that they can easily be processed to soft and hard gelatin capsules. The latter particularly applies to the monohydrochloride.

The salts are prepared by reacting amonafide with the calculated amount of acid. The salt formation preferably takes place in alcoholic solution.

Examples 1 and 2 show the preparation of the novel salts:

3 g of amonafide were dissolved under reflux in 60 ml of virtually anhydrous ethanol. Subsequently 1 ml of 35% strength hydrochloric acid was added dropwise while shaking vigorously. After cooling, the resulting crystals were filtered off and washed with 10 ml of anhydrous ethanol. 3.1 g (93%) of amonafide monohydrochloride were obtained (C.sub.16 H.sub.18 ClN.sub.3 O.sub.2), melting point=290.degree. C.

Example 2

3.4 g (85%) of amonafide monomethanesulfonate, melting point=255.degree. C., are obtained in analogy to Example 1 by reaction with 0.8 ml of methanesulfonic acid.

The following examples show the good pharmaceutical processability of the novel salts:

Example A

Preparation of amonafide tablets ______________________________________Amonafide.HCl 288.4 mgD-mannitol 40.6 mgPolyvinylpyrroldone [sic] 13.0 mgMicrocrystalline cellulose 20.0 mgSodium carboxymethylstarch 10.0 mgHighly disperse silica 2.0 mgTalc 4.0 mgMagnesium stearate 2.0 mg 380.0 mg______________________________________

Granules were obtained by granulation of active substance and mannitol with the aid of polyvinylpyrrolidone and, after mixing with the other substances mentioned, were readily converted into tablets in conventional tablet presses. Used as tableting tool were 11 mm round punches. The tablet disintegration time was 9 min.

The polyvinylpyrrolidone used had the viscosity of 20 mPa.sec in a 20% strength aqueous solution at 25.degree. C.

Example B

Preparation of film-coated tablets

Tablets from Example A were coated with a coating of the following composition until the weight gain per tablet core was found to be about 20-30 mg:

______________________________________Hydroxypropylmethylcellulose 0.064 kgPolyethylene glycol with the 0.040 kgaverage molecular weight 8000Talc 0.080 kgTitanium dioxide 0.020 kgSodium lauryl sulfate 0.002 kgEthanol 0.794 kg______________________________________

Example C

Preparation of enteric tablets

Tablets from Example A were coated with a coating of the following composition until the weight gain per tablet core was found to be about 40-50 mg.

______________________________________Hydroxypropylmethylcellulose 0.1620 kgphthalateDibutyl phthalate 0.0324 kgAcetone 0.8826 kgIsopropanol 0.8826 kgColoring pigment 0.0404 kg______________________________________

Example D

Preparation of an injection solution as concentrate ______________________________________Amonafide.HCl 564.3 mgWater for injection ad 10 ml______________________________________

The solution was sterilized by filtration, dispensed into 10 ml brown glass ampoules and autoclaved.

Example E

Preparation of amonafide injection concentrate as lyophilisate ______________________________________Amonafide.2HCl 2.992 kgNaOH, 5 m 1.998 kgWater for injection ad 20.000 kg______________________________________

The solution was sterilized by filtration and subsequently dispensed in 2 ml portions into vials of glass type I (brown glass) and freeze-dried. The pH of the reconstituted solution was 5.5.+-.0.5, the osmolarity was about 1,000 mosmol/kg and the residual moisture was about 1%.

The amonafide was in the form of the monohydrochloride in the concentrate.

Example F

Preparation of soft gelatin capsules ______________________________________Amonafide.HCl 28.2 gSilicone oil ad 100.0 g______________________________________

The homogeneous suspended composition was dispensed into soft gelatin capsules of size 16 minims.

Claims

1. A salt of amonafide of the formula ##STR2## in which X.sup.- is a Cl.sup.- or CH.sub.3 --SO.sub.3.sup.- ion.

2. Amonafide monohydrochloride.

3. An antitumor composition which comprises an antitumor effective amount of the monohydrochloride salt of amonafide and a pharmaceutical auxiliary and/or carrier.

4. An antitumor composition which comprises an antitumor effective amount of the monomethanesulfonate salt of amonafide and a pharmaceutical auxiliary and/or carrier.