PENICILLIN GLYCOLATE

Abstract: New solvates of penicillin, in particular amoxycillin glycolate has been provided for together with a simple one-step process to prepare the same.

Description: PENICILLIN GLYCOLATE This invention relates to a glycolate form of a penicillin antibiotic as for instance amoxycillin or ampicillin. In par¬ ticular this invention relates to a glycolate form of 6- . D-3- amino-p-hydroxyphenylacetamido) -penicillanic acid (amoxycillin) which is substantially free of water, and to a process for the preparation thereof. The solvates of for instance amoxycillin or ampicillin may also be converted into non-toxic, pharmaceuti¬ cally acceptable salts by a method known per se . Amoxycillin is known to exist in two forms, namely the crystalline trihydrate form and the mono hydrated amorphous form. The amoxycillin antibiotic is active against Gram-positive and Gram-negative bacteria and is useful as a therapeutic and prophylactic agent against bacterial infections in man including animals . British patent No. 1286199 describes a process whereby amoxycillin containing a minimum water content of 3-5% can be prepared by drying an alkanolate of amoxycillin trihydrate. However, it has been described that the intermediate alkanolate form is not stable and is subjected to a potency loss after a few days . European patent No. 0262207 discloses a process for the preparation of crystalline amoxycillin mono-methanolate from amoxycillin trihydrate. A water-free solution of amoxycillin has been prepared by adding molecular sieves 4 A into a clear sol¬ ution of amoxycillin trihydrate, obtained by adding triethylamine into a suspension of amoxycillin trihydrate in a mixture of dichloromethane and methanol . Thereafter, the result¬ ing mixture has been treated with acetic acid and, subsequently, by seeding with crystals of amoxycillin methanolate crystalline amoxycillin mono-methanolate has been provided. However, this solvate itself is not unsuspicious for use as medicament. Now, it has been found that a new glycolate of penicillin antibiotic, especially amoxycillin can surprisingly easily be prepared in good quality from amoxycillin trihydrate and glycol- e. The new amoxycillin glycolate contains less than 3% of water and is stable, in any case at room temperature. The present invention provides new penicillin glycolates, in particular amoxycillin glycolate, preferably with a water content of less than 3%. The present invention also provides a process for the preparation of the same by the reaction of penicillin, in particular amoxycillin or ampicillin, and glycol in an organic solvent . Preferably, amoxycillin 1, 2-propanediola- te has been provided for. In a preferred embodiment a suspension of amoxycillin has been stirred in a mixture of dichloromethane and 1, 2-propanediol for some time and then, after isolating the suspension through filtration, subsequently, thoroughly washed with dichloromethane and dried. Formation of a gelatinous type of product has not been observed. The amoxycillin 1, 2-propanediolate may contain about 0.5 mol of 1, 2-propanediol . The present invention also provides a pharmaceutical compo¬ sition which comprises penicillin, in particular amoxycillin glycolate or ampicillin glycolate and a pharmaceutically accept¬ able carrier. The compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of infections in mammals including humans . The penicillin, in particular amoxycillin glycolate or ampicillin glycolate may be the sole therapeutic agent in the composition of the invention or a combination with other anti¬ biotics or with a /3-lactamase inhibitor as for instance clavula- nic acid preferably in its potassium clavulanate form, or sulb- actam, may be employed. The following example illustrates the process according to the invention without, however, being considered to be restricted thereto. EXAMPLE Preparation of amoxycillin 1,2-propanediolate Dichloromethane (63 ml; methanol-free) was added to amoxy- cillin trihydrate (3.5 g; purity by HPLC 86%; water 12.9%) with stirring at room temperature and, then, followed by the addition of 1, 2-propanediol (22 ml) . The reaction mixture was further stirred for about 20 min at the same temperature. The product was filtered and, then, washed on the filter with dichlorome- thane (100 ml) . Thereafter, the product was suspended in dichlo¬ romethane (80 ml) and stirred for about 20 min at room tempera¬ ture. The resulting suspension was filtered, washed on the filter with dichloromethane (100 ml) and, then, dried under vacuum overnight . Results of the analysis: HPLC: 88.5% of amoxycillin, as calculated as free acid Water (KF) : 2.1% NMR: Molecular ratio: amoxycillin/l, 2-propanediol = ca. 65/35, indicating the presence of about 1/2 mole of 1,2- propanediol compared to amoxycillin 1 mole IR (in nujol mul) : 1773 (beta-lactam)

Claims: Claims 1. Penicillin glycolate and a pharmaceutically acceptable salt thereof. 2. Penicillin glycolate according to claim 1 where the penicillin glycolate is amoxycillin glycolate. 3. Amoxycillin glycolate according to claim 2 with a water content of less than 3%. 4. Amoxycillin glycolate according to claim 2 or 3 , con¬ sisting essentially of glycolate and amoxycillin in a ratio of 1:2. 5. Amoxycillin glycolate according to any one of the claims 1-4, wherein the glycolate is 1, 2-propanediolate. 6. A process for the preparation of penicillin glycolate as defined in any one of the claims 1-5, characterized by the reaction of penicillin hydrate and glycol in an organic solvent and optional conversion into a pharmaceutically acceptable salt. 7. A process for the preparation of amoxycillin glycolate as defined in any one of the claim 2-5, characterized by the reaction of amoxycillin trihydrate and glycol in an organic solvent and optional conversion into a pharmaceutically accept¬ able salt . 8. A process according to claim 6 or 7, characterized in that the organic solvent used is dichloromethane. 9. A pharmaceutical composition comprising an effective amount of penicillin glycolate as defined in any one of the claims 1-5. 10. A pharmaceutical composition according to claim 9 com¬ prising an effective amount of penicillin glycolate and clavula- nate or sulbactam. 11. A pharmaceutical composition according to claim 9 comprising an effective amount of amoxycillin glycolate and clavulanate . 12. A pharmaceutical composition according to claim 9 comprising an effective amount of ampicillin glycolate and sulbactam.

Inventors: KAPUR JAGDISH CHANDER, KAPUR, JAGDISH, CHANDER
Applicants: GIST BROCADES BV, KAPUR JAGDISH CHANDER, GIST-BROCADES B.V., KAPUR, JAGDISH, CHANDER
Application year: 1996
Main classification: C07D499
IPC codes: A61K31, A61P31, C07D499