NL8201467A - PROCESS FOR PREPARING SOLID SODIUM OXICILLIN. - Google Patents

Description

* -> * 9 VO 3131

Process for preparing solid sodium amoxicillin.

The invention relates to the preparation of solid sodium amoxicillin by spray drying a solution of sodium amoxicillin in a mixture of water and tert-butanol.

Solid sodium amoxicillin has been prepared by precipitation (see 5 British Patents 1,241,844 and 1,286,199) but on a technical scale the product has been found to be unsatisfactory due to contamination caused by residues of reagents such as triethylamine or sodium 2-ethylhexanoate or excessive amounts of residual solvent .

Solid sodium ampicillin has also been prepared by lyophilization (see British Pat. Nos. 1,527,557 and 1,543,317), but this requires extraordinarily expensive equipment to produce the amount needed for technical application; moreover, the extraordinarily necessary low temperatures make the procedure require very long periods of time, thereby reducing the production of any given piece of equipment.

In the practice of the method of the present invention, use was made of a closed-circuit spray dryer, the main components of this equipment are a drying chamber, a product cyclone, a discharge fan, a condenser / scrubber (shock-cooled plate, cooled by glycol), a nitrogen fan, a heat exchanger (Dowtherm) and a feed pump. The equipment was installed for simultaneous operation with a cyclone product discharge. The unit was first cleaned with nitrogen to lower the oxygen content to a safe level so that the solvent mixture could be introduced into the condenser 25 (this allowed stable drying conditions to be achieved quickly). The unit was then equilibrated to the desired inlet temperature, gas flow rate, condenser temperature, etc. Then the feed (sodium amoxicillin in aqueous tert-butanol) was pumped through a spray nozzle at the top of the drying chamber. Dry product and gas were drained through the bottom to separate into a cyclone.

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Test conditions and results using aqueous tert-butanol.

Test _A__C__D_ solution step 5 amoxicillin trihydrate (kg) 6.0 5.0 6) 0 5.0

NaOS (mol ratio) 1.02 1.02 1.02 1.02 temperature (° C) +25 +25 +25 +25 duration (min) 10 11 9 5 10 final pH 9.2 9.31 9.15 9.2 feed volume (&) 32 27 33 26 drying step nozzle type pressure pressure rotary rotating 15 ^ 11 bar * 12 bar 20,000 20,000 rpm / min temperatures (° C) inlet N2 200 180 180 180 outlet 117 116 117 125 condenser 2 3 0 1-2 20 feed rate (Fire) 40.2 32.3 38.5 28 total drying time (min) 56 46 56 48 .. -. _. -....... - ~ - _ - _ ^ • f 25 product data% H20 (KF) 1 »8? 1.4 2.5; 2.7 1.5; 1.4 1.2; 1.3 bulk density (g / cm ^) 0.43 0 , 53 0.26 0.26

Chemical strength 830 786 894 858 bioanalysis ("as is") 768 732 844 816 30 I_ absorbents (1) 6.9 9.7 4.2 4.4 pH (3% in H 2 O) 8.7 8.7 8.7 8.7% t-butanol 0.8 0.8 0.9 0.9

Klett (10% with blue filter) 72 59 65 80 1 8201467 1) Determined on an anhydric solvent-free base using the British Pharmacopeia procedure to measure contamination by penicilloic acid or dimers and the like.

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The purity and physical properties of the obtained four batches of solid, spray-dried sodium amoxicillin, after sterilization by, for example, ethylene oxide, were suitable for technical application.

In the preparation of food for the dryer (solution step above), microscopically powdered amoxicillin trihydrate (strength 845 mcg / mgm) was suspended in aqueous tert-butanol using 2.4 l of water and 1.5 l of t-butanol per kg of amoxicillin trihydrate and kept at 25 ° C. To this suspension was continuously added 1.97 N aqueous sodium hydroxide using about 2% excess (1.23 L / kg).

__________Test_E_F_G_H___ • y.

solution step 15 amoxicillin trihydrate (kg) 6.0 6.0 6.0 6.0 drying step nozzle type pressure pressure pressure pressure pressure (bar) 58.6 100.4 / 103.4 131.0 103.4 20 temperatures (° C) inlet N2 183/184 181/183 190/191 180 outlet N2 82/115 115/117 115 115 product data 25 bulk density (g / cm ^) 0.299 0.271 0.257 0.274 maximum particle size 90% 65.8 43.8 39.1 45.3 (VM) '50% 28.1 20.5 18.0 42.7 10% 7.67 6.73 6.27 34.7

Klett (10% with 30 blue filter) 74 68 62 62% H20 (KF) 2.9 2.5 2.4 1.9% t-butanol 1.2 + 1.4 1.0 1.2 1.2

Chem. strength 817 839 831 846 "axis is"

Chem. strength 35 (anhyd.) 865 869 862 873 8201 467 -4-

Continuation.

bioanalysis ("as is") 784 824 829 824 bioanalysis (anhyd.) 830 854 860 850 I- absorbent ...

5 substances "as is" - I2 absorbents (anhyd.) - Determined on an anhydric solvent-free base using the British Pharmacopeia procedure to measure contamination by penicilloic acid or dimers and the like.

Test_I_J_K_L_ solution step amoxicillin 15 trihydrate (kg) 6.0 6.0 6.0 6.0 drying step nozzle type pressure pressure pressure pressure pressure (bar) 103.4 103.4 103.4 110.3 20 temperatures (° C) inlet N2 180 180 '180 201 outlet N2 115 115 115 128 product data 25 bulk density (g / cm3) 0.287 0.273 N / A 0.221 maximum particle size (ym) 90% 34.7 44.8 39.5 50% 17.4 20.7 21.5 10% 6.27 6.92 7.4

Klett (10% with blue filter) 64 68 62 63 30% H 2 O (KF) 2.0 1.7 1.6 1.4% t-butanol 1.3 1.3 1.4 1.3 chemical strength " as is "815 817 818 836 chemical strength (anhyd.) 843 842 843 861 35 bioanalysis (" as is ") 800 795 787 832 8201467

. V - C

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Continuation.

bioanalysis (anhyd.) 827 820 811 855 I absorbent. 1.

2 substances "as is" 1 6.8 7.5 7.6 5.4 I "absorbent 5 (anhyd.) 7.0 7.7 7.8 5.5 ^ Determined on an anhydric solvent-free base using of the British Pharmacopeia procedure to measure contamination by penicilloic acid or dimers and the like.

In the spray drying step, the pressure is varied to obtain the desired particle size.

Conducting the spray drying process under sterile conditions, using the pressure nozzle, results in sterile solid sodium amoxicillin which can be filled into bottles directly under sterile conditions.

The antibacterial properties and clinical application methods of axnoxicillin are well known in the medical literature for the oral use of the trihydrate. For parenteral administration, it is often preferable to inject an aqueous solution, which involves conversion of the insoluble trihydrate into the highly soluble sodium salt as required in the method 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 amoxycillin: dose dependence after 25 intravenous, oral and intramuscular administration; Antimicrobial Agents and Chemotherapy, il_, 132 (1977) and by S.A. Hill et al., Pharmacokinetics of parenterally administered amoxycillin, Journal of Infection 2, 320-332 (1980).

8201467

Claims (3)

Process for preparing solid sodium amoxicillin, characterized in that a solution of sodium amoxicillin in aqueous tert-butanol is spray dried. Method according to claim 1, characterized in that the inlet temperature is about 180 ° C and the outlet temperature is about 120 ° C. Process according to claim 1, characterized in that the solution to be spray-dried contains about 1.5 l of t-butanol for every 3.6 l of water. 8201467