NZ200281A

NZ200281A - Production of solid sodium amoxicillin

Info

Publication number: NZ200281A
Application number: NZ200281A
Authority: NZ
Inventors: J H Grossman; D L Warner
Original assignee: Bristol Myers Co
Priority date: 1981-04-10
Filing date: 1982-04-08
Publication date: 1984-12-14
Also published as: IT8248188A0; IE52939B1; KR830010116A; DE3213308A1; PT74727A; ES8304138A1; NO821174L; GB2096599B; ES511295A0; LU84007A1; NL8201467A; GB2096599A; CH651836A5; CA1182108A; FI821247L; FR2503710B1; GR76106B; FI821247A0; JPH0219119B2; IT1148165B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £00281 2002 SI Priority Dc: i Ccrr:;:!;:o Specification Filed:..$.'..tf.:.3e?... liDKML.. i5.!^-. Journal, No. 1565 p? n ft * (Pi ?A umv \M M r#J Patents Form No.5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "PRODUCTION OF SODIUM AMOXICILLIN" -I-jWE BRISTOL-MYERS COMPANY, a corporation organised and existing under the laws of the State of Delaware, U.S.A. of 345 Park Avenue,.New York, N.Y. 10022, U.S.A. hereby declare the invention, for which -i/we pray that a patent may be granted to me/us,-and the method by which it is to be performed, to be particularly described in and by the following-statement -1- -q\ to \ 2 00281 _ p _ The present invention concerns the production sodium amoxicillin by the process of spray-solution of sodium amoxicillin in a mixture and t-butanol. Solid sodium amoxicillin has been prepared by precipitation (as in U.K. 1,241,8^ and U.K. 1,286,199) but on a commercial scale the product is found to be unsatisfactory because of contamination caused by residual reagents such as triethylamine or sodium 2-ethylhexanoate or excessive amounts of residual solvent. Solid sodium ampicillin has also been prepared by freeze-drying (as in U.K. 1,527,557 and U.K. 1,5^5*317) "but this requires extremely expensive equipment to produce the quantity needed for commercial use; in addition the extremely necessary low temperatures make the procedure require very long periods of time which reduces the output from any given piece of equipment. In conducting the process of the present invention use was made of a closed cycle spray dryer; major components of this apparatus are drying chamber, product cyclone, exhaust fan, condenser/scrubber (impingement plate, glycol cooled), nitrogen fan, heat exchanger (Dowtherm) and feed pump. The apparatus was set up for concurrent operation with cyclone prod\ict discharge. The unit was first purged with nitrogen to reduce the level of oxygen to a safe level so that the solvent mixture could be charged to the condenser (this allowed steady state drying conditions to be reached quickly). The unit was then equilibrated to the desired inlet temperature, gas flowrate, condenser temperature, etc. The feed (sodium amoxicillin in aqueous t-butanol) was then pumped through a spray nozzle at the top of the drying chairber. Dry product and gas were discharged through the bottom to be separated in a cyclone. of solid drying a of water 2 0 0 2 3 T -3- Test Conditions and Results Using Aqueous t-butaonl Run A B C D Dissolution Amoxicillin Trihydrate, kg. NaOH (mol ratio) Approx. Temp. °C. Time (min.) Final pH Feed volume, 1. 6.0 1. 02 25 10 9-2 32 5-0 1.02 25 11 9-31 27 6.0 1.02 25 9 9.15 33 5.0 1. 02 25 5 9-2 26 Drying Step Nozzle Type Pressure Pressure Rotary Rotary Pressure (psig) ~l6o 175 20,000 rpm 20,000 rpm Temperatures (°C. ) • Inlet 200 180 180 180 Outlet N2 117 116 117 125 Condenser 2 3 0 1-2 Feed Rate (lph) '10.2 32.3 38.5 28 Total Drying Time (min) 56 U6 56 HQ 2 002 81 -4- Product Data io H20 (KF) 1.8; 1.4 2.5; 2.7 1.5; 1.1-2; 1-5 Bulk density (g/cnr) 0.43 0.53 0.26 0.26 Chem. potency 830 786 894 858 Bioassay (as is) 768 732 844 8l6 1^ Absorbing Substances ^ . 6.9 9.7 4.2 4.^ pH (3$ in H20) 8.7 8.7 8.7 8.7 $ t-BuOH 0.8 0.8 0.9 0.9 Klett (10# with . 72 59 65 80 blue filter) Determined on an anhydrous solvent free basis using the procedure of the British Pharmacopeia to measure contamination by penicilloic acid or dimers or the like. The purity and physical properties of the resulting four batches of solid., spray-dried sodium amoxicillin were suitable for commercial use after sterilization as by ethylene oxide. In the preparation of the feed to the dryer (Dissolution step above) micropulverized amoxicillin trihydrate (potency 845 mcg/mgm) was slurried in aqueous t-butanol using 2.4 1. water and 1.5 1- t-butanol per kg. of amoxicillin trihydrate and kept at 25°C. To this slurry 1.97 N aqueous sodium hydroxide was added continuously using about 2$ excess (1.23 l.Ag). /—\ 2 002 81 Run E_ F G_ II Dissolu l.ion Amoxi cillin Trihydrate, kg. 6.0 6.0 0.0 6.0 Drying Step Nozzle Type Pressure (psig) Temperatures (°C.) Inlet N2 Outlet N^ Pressure Pressure Pressure Pressure 850 l'l 56/1500 1900 1500 . 183/1814 181/183 190/191 180 82/115 115/117 115 115 Product Data Maximum Particle Size in microns "X Bulk density (g/cnr) 90% 50% 10% Klett (10# with blue filter) $ HgO (KF) io t-BuOH Chem. Potency, as is Chem. Potency (Anhyd.) Bioassay (as is) Bioassay (Anhyd.) I2 Absorbing • 299 65.8 28.1 7.67 74 2.9 1.2 + 1.4 817 865 784 830 (1) Substances (Anhyd.) Substances as is I2 Absorbing .271 .257 .274 43.8 39.1 ^5.3 20.5 18.0 42.7 6.73 6.27 3^-7 68 62 6.2 2.5 2.4 1-9 1.0 1.2 1.2 839 831 846 869 862 873 821) 829 824 8511 860 850 Determined on an anhydrous solvent free basis using the procedure of the British Pharmacopeia to measure contamination by penicilloic acid or dimers or the like. ' * -6- 2 002 8 1 • Run I_ J K L Dissolution Amoxicillin Trihydrate, kg. 6.0 6.0 6.0 6.0 Drying Step Nozzle Type Pressure Pressure Pressure Pressure Pressure (psig) 1500 1500 1500 1600 Temperatures (°C.) Inlet N2 180 180 180 201 Outlet Ng 115 115 115 128 Product Data Bulk density (g/cnr) ro 00 .273 N/A .221 Maximum Particle 90# J>b.7 44 .8 39-5 Size in' microns r~nt 17. '1 20.7 21.5 . 10# 6.27 6.92 7.4 Klett (10# with 64 68 62 63 blue filter) # H2O (KF) 2.0 1.7 1.6 1.4 # t-BuOH 1.3 1.3 1.4 1.3 Chem. Potency, as is 815 817 818 836 Chem. Potency (Anhyd.) 843 842 843 861 Bioassay (as is) 800 795 787 832 Bioassay (Anhyd.) 827 820 811 855 I0 Absorbing £1 / -1 \ (1) Substances as xs v ' 6.8 7.5 7.6 5-4 Ig Absorbing Substances (Anhyd.) 7-0 7.7 7.8 5-5 Determined on an anhydrous solvent free basis using the procedure of the British Pharmacopeia to measureocontamination by penicilloic acid or dimers or the like. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 7 - 2 002 81 In the step of spray-drying the pressure is varied to obtain the desired particle size. Operation of the spray-drying process under sterile conditions using the pressure nozzle produces sterile solid sodium amoxicillin which can be filled directly into vials under sterile conditions. The antibacterial properties and clinical methods of use of amoxicillin are well-known in the medical literature with regard to the oral use of its trihydrate. For parenteral administration it is often preferred to inject an aqueous solution which requires conversion of the insoluble trihydrate to the highly soluble sodium salt as in the process of the present invention. The results of parenteral administration of aqueous sodium amoxicillin have been described, for example, by D.A. Spyker et al., Pharmacokinetics of amoxicillin: dose dependence after intravenous, oral and intramuscular administratioi Antimicrobial Agents and Chemotherapy, _1]_, 132 (19 77) and by S.A. Hill et al., Pharmacokinetics of parenterally administered amoxicillin Journal of Infection 2, 320-332 (1980) The inlet temperature is preferably between about 170°C to 210°C the outlet temperature is preferably between the boiling point of the t-butanol/water mixture and about 130°C. The amount of t-butanol that is present in the mixture with water can vary within wide limits but will generally be less than 50% by volume of the total volume of the water/butanol mixture more preferably between about 25% and 40% by volume of the total volume. - 8 - - 200281 WHAT WE CLAIM IS

1. A process for the production of solid sodium amoxicillin characterized by spray-drying a solution of sodium amoxicillin in aqueous t-butanol.

2. The process of Claim 1 in which the inlet temperature is between oboufe- 170°C and about 210°C and the outlet temperature is between the boiling point of the aqueous t-butanol mixture and about 130°C.

3. The process of Claim 1 or Claim 2 in which the solution to be spray-dried contains less than 50% by volume of t-butanol.

4. A process as claimed in any one of Claims 1 to 3 wherein sodium amoxicillin is prepared by converting a slurry of amoxicillin trihydrate in aqueous t-butanol into sodium amoxicillin using sodium hydroxide.

5. A process as claimed in Claim 4 wherein an excess of sodium hydroxide is employed.

6. A process as claimed in any one of Claims 1 to 5 wherein the solution to be spray dried contains between 25 to 40% by volume of t-butanol.

7. A process as claimed in Claim 6 wherein the amount of t-butanol is 1.5 -1. for each 2.4 1. of water.

8. A process as claimed in any one of claims 1 to 7 wherein the pressure is controlled to provide a desired particle size.

9. A process as claimed in Claim 1 substantially as described herein in any one of Runs A to L. r

10. Solid sodium amoxicillin when obtained by the;./-. process of any one of Claims 1 to 9. ,/v? */v - 9 - 2

11. An injectable conposition prepared from solid sodium amoxicillin as claimed in Claim 10. "^orney's'fo'b'the applicants </div>