FR2503710A1 - PROCESS FOR THE PRODUCTION OF SODIUM SALT OF AMOXICILLIN - Google Patents

Abstract

THE INVENTION IS CONCERNED WITH THE PRODUCTION OF THE SODIUM SALT OF AMOXICILLIN. THE PROCESS OF THE INVENTION CONSISTS OF SPRAY-DRYING A SODIUM SALT SOLUTION OF AMOXICILLIN IN AQUEOUS TERTIOBUTANOL. AMOXICILLIN IS A KNOWN SUBSTANCE WITH ANTIBACTERIAL ACTIVITY.

Description

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  The present invention relates to the production of solid amoxicillin sodium salt by the drying process.

  by spraying a solution of the sodium salt of the amoxic acid

  cillin in a mixture of water and tert-butanol.

  The solid sodium salt of amoxicillin was prepared by precipitation (as described in British Patent Nos. 1,241,844 and 1,286,199) but, from the point of view of

  In commercial terms, it is considered that the product is unsatisfactory

  due to contamination from residues of reagents such as triethylamine or sodium 2-ethylhexanoate or excessive amounts of residual solvent. The solid sodium salt of ampicillin was also prepared by lyophilization (as described in British Patent Nos. 1,527,557 and 1,543,317), but the production of the amount required for commercial purposes requires extremely expensive equipment; in addition, the extremely low temperatures that are required have the effect that the process requires very long periods, which reduces the

  yield of any given part of the apparatus.

  In carrying out the process of this

  invention, a spray drying device is used.

  operating in a closed circuit; The main components of this unit are the drying chamber, the cyclone-to-product, the exhaust fan, a condenser / purifier (glycol-cooled contact plate), a nitrogen fan, a heat exchanger (Dowtherm) and a feed pump. The apparatus is set to operate in conjunction with the discharge of the cyclone product. The plant is first purged with nitrogen to reduce the oxygen level to a safe level, so that the solvent mixture can be loaded into the condenser (allowing rapid drying conditions in steady state). The device is

  then adjusted to the desired parameters such as temperature

  nitrogen intake rate, gas flow, condenser temperature, etc. The feed (sodium salt of amoxicillin in aqueous tertiobutanol) is then pumped through a spray nozzle to the portion

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  2. Upper of the drying chamber. The dry product and the gas are discharged from the base for separation into a cyclone.

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  3. Test conditions and results obtained in the case of the use of aqueous tertiobutanol Test Dissolution Amoxicillin trihydrate, kg NaOH (molar ratio) Approximate temperature, OC Time, minutes Final pH Load volume, 1 Drying operation Type Nozzle pressure A 6.0 1.02 9, 2 pressure B, 0 1.02 9.31 pressure C 6.0 1.02 9.15 Rotary Manometric pressure (MPa) or rotational speed l1.12

000 20,000

  rpm rpm Temperatures, C Nitrogen input Nitrogen output Condenser Charge flow (l / h) Total drying time (minutes) Product characteristics

H20,%

  (Karl Fischer) Bulk density (g / cm3) Chemical strength Biological titre (as is) Iodine absorbing substances (1) pH (3% in water) Tertiobutanol,% Klett (10%, blue filter), 2 32 , 3 o 38.5 1-2

1.8, 1.4 2.5, 2.7 1.5, 1.4 1.2, 1.3

  0.43 6.9 8.7 0.8 0.53 9.7 8.7 0.8 0.26 4.2 8.7 0.9 0.26 4.4 8.7 0.9

72 59

D, 0 1.02 9.2 Rotative

80

  e3 71n 4. (1) Determined on an anhydrous basis without solvent, using the method described in the British Pharmacopoeia for measuring contamination with penicilloic acid or its

  dimers or similar substances. -

  The purity and physical properties of the four resulting batches of spray-dried amoxicillin sodium salt are suitable for commercial use after

  sterilization for example by ethylene oxide.

  In the preparation of the feed introduced into the drying apparatus (dissolution step above), the

  amoxicillin trihydrate sprayed into microparticles

  Copies (potency 845 μg / mg) are suspended in aqueous tertiobutanol using 2.4 liters of water and 1.5 liters of tertiobutanol per kilogram of amoxicillin trihydrate and the suspension is maintained at 250 ° C. Sodium hydroxide in aqueous solution (1.97 N) was continuously added to this suspension using an excess of

about 2% (1.23 liter / kg).

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E F G

  H Dissolution Amoxicillin trihydrate, kg Drying step Nozzle type Manometric pressure, MPa Temperature, C Nitrogen input Nitrogen output Product characteristics Bulk density, g / cm3 Maximum particle diameter in micrometers%%% Klett (10 %, blue filter)

H O,%

  (Karl2 Fischer) Tertiobutanol,% Chemical power (as is) (anhydrous) Biological title (as is) (anhydrous) Iodine absorbing substances (as is) (1) (anhydrous)

6.0 6.0 6.0

to to

pressure pressure pressure

, 95 10.19 / 10.5

13.3

183/184 181/183 190/191

82/115 115/117 115

0.299, 8 28.1 7.67 2.9

1.2 + 1.4

  0.271 43.8, 6.73 2.5 1.0 0.257 39.1 18.0 6.27 2.4 1.2 Determined on an anhydrous basis without the method described in the British Pharmacopoeia for measurement contamination with penicilloic acid or dimers or

similar substances.

  6.0 at pressure, 5 0.274, 3 42.7 34.7 1.9 1.2 (1) solvent

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  6. Test Dissolution Amoxicillin trihydrate, kg Drying step Nozzle type Manometric pressure, MPa Temperature, C Nitrogen input Nitrogen output Product characteristics Bulk density, g / cm3 Maximum particle diameter in micrometers%

50%

% Klett (10%, blue filter)

H O,%

  (Kart Fischer) Tertiobutanol,% Chemical power (as is) (anhydrous) Biological titre (as is) (anhydrous) Iodine absorbing substances (as is) (1) (anhydrous)

I J,

  6.0 at pressure, 0.287 34.7 17.4 6.27 2.0 1.3 6.8 7.0 6.0 at pressure, 0.273 44.8, 7 6.92 1.7 1, 3 7.5 7.7 Determined on a basis according to the British method for the anhydrous solvent-free base described in the Pharmacopoeia measurement of contamination by penicilloic acid or dimers or

similar substances.

  K 6.0 at pressure, 5 N / AL 6.0 at pressure 11.2 0.221 39.5 21.5 7.4 1.4 1.3, 4, 5 1.6 1.4 7.6 7, 8 (1)

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  7. In the spray drying operation, the pressure is varied to obtain the desired particle diameter. If the spray drying operation is carried out under sterile conditions using the

  pressure nozzle, the solid sodium salt of amoxic acid is obtained

  sterile cillin that can be introduced directly into

  vials or ampoules under sterile conditions.

  The antibacterial properties and clinical methods of use of amoxicillin are well known in the medical literature with respect to the oral use of its trihydrate. For parenteral administration, it is often preferable to inject an aqueous solution which requires the 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 salt amoxicillin solution have been described for example by DA Spyker et al in "Pharmacokinetics of amoxycillin: dose dependence after intravenous, oral and intramuscular administration, Antimicrobial Agents and Chemotherapy", "Pharmacokinetics of Amoxicillin: Dose Dependence after Intravenous, Oral and Intramuscular Administration, Antimicrobial Agents and Chemotherapy" 11, 132 (1977) and by SA Hill et al., "Pharmacokinetics of parenterally administered amoxycillin" ( Pharmacokinetics of parenterally administered amoxicillin), Journal of

Infection 2, 320-332 (1980).

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8.

Claims (3)

  1. - Process for producing the solid sodium salt of amoxycillin, characterized in that it consists of spray drying a solution of sodium salt of amoxycillin in aqueous tert-butanol. 2. - Process according to claim 1, characterized in that the inlet temperature is about    C and the outlet temperature is about 120 C.   3. - Process according to claim 1, characterized in that the solution to be spray dried contains about 1.5 liters of tert-butanol for 3.6 liters of water.