IE52939B1 - Production of sodium amoxicillin by spray-drying - Google Patents
Production of sodium amoxicillin by spray-dryingInfo
- Publication number
- IE52939B1 IE52939B1 IE844/82A IE84482A IE52939B1 IE 52939 B1 IE52939 B1 IE 52939B1 IE 844/82 A IE844/82 A IE 844/82A IE 84482 A IE84482 A IE 84482A IE 52939 B1 IE52939 B1 IE 52939B1
- Authority
- IE
- Ireland
- Prior art keywords
- drying
- spray
- amoxicillin
- sodium amoxicillin
- production
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Abstract
A process for the production of solid sodium amoxicillin comprises spray-drying a solution of sodium amoxicillin in aqueous t-butanol.
Description
Price 90p
The present invention concerns the production of solid sodium amoxicillin by the process of spray-drying a solution of sodium amoxicillin in a mixture of water and t-butanol.
Solid sodium amoxicillin has been prepared by precipitation (as in 5 U.K. Patent Specification No. 1,241,844 and U.K. Patent Specification No.
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. Patent
Specification No. 1,527,557 and U.K. Patent Specification No. 1,543,317) 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 a preferred embodiment the inlet temperature of the drying chamber is
180°C and the outlet temperature is 120°C.
- 2 S2939
The solution to be spray-dried preferably contains 1.5 1 of t-butanol for each 3.6 1 of water.
The invention is illustrated by the following Example.
EXAMPLE
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 - Registered Trade Mark) and feed pump. The apparatus was set up for concurrent operation with cyclone product 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 Nz 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 chamber. Dry product and gas were discharged through the bottom to be separated in a cyclone.
Test Conditions and Results Using Aqueous t-butanol
Run_A_B C_D
Dissolution
Amoxicillin Trihydrate, kg. 6.0 5.0 6.0 5.0 NaOH (mol ratio) 1.02 1.02 1.02 1.02 Approx. Temp. °C. 25 25 25 25 Time (min.) 10 11 9 5 Final pH 9.2 9.31 9.15 9.2 Feed volume, 1. 32 27 33 26
Drying Step
Nozzle Type Pressure Pressure Rotary Rotary Pressure (psig) —-160 —175 20 .OOOrprn 20,000 rpm Temperatures (°C) Inlet Nz 200 180 180 180 Outlet N2 117 116 117 125 Condenser 2 3 0 1-2 Feed Rate (1 ph) 40.2 32.3 38.5 28 Total Drying Time (min) 56 46 56 48 Run E F G H Amoxicillin Trihydrate, kg. 6.0 6.0 6.0 6.0
Drying Step Nozzle Type Pressure Pressure . Pressure Pressure Pressure (psig) 850 1456/1500 1900 1500 Temperatures (°C) Inlet N2 183/184 181/183 190/191 180 Outlet N2 82/115 115/117 115 115
Product Data Bulk density (g/cm3) .299 .271 .257 .274 Maximum Particle 90% 65.8 43.8 39.1 45.3 Size in microns 50% 28.1 20.5 18.0 42.7 10% 7.67 6.73 6.27 34.7 Klett (10% with blue filter) 74 68 62 62 % H20 (KF) 2.9 2.5 2.4 1.9 % t-BuOH 1.2 + 1.4 1.0 1.2 1.2 Chem. Potency, as is 817 839 831 846 Chem. Potency (Anhyd.) 865 869 862 873 Bioassay (as is) 784 824 829 824 Bioassay (Anhyd.) 830 854 860 850
- 4 52939
I2Absorbing Substances as is I2 Absorbing
Substances (Anhyd.) - . 5 (1) 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.
Run I J K L 10 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 15 Temperatures (°C) Inlet N2 180 180 180 201 Outlet N2 115 115 115 128
Product Data Bulk density (g/cm3) .287 .273 N/A .221 20 Maximum Particle 90% 34.7 44.8 39.5 Size in microns 50% 17.4 20.7 21.5 10% 6.27 6.92 7.4 Klett (10% with blue filter) 64 68 62 63 % H20 (KF) 2.0 1.7 1.6 1.4 25 % 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 30 I2 Absorbing Substances as is 6.8 7.5 7.6 5.4 I2 Absorbing Substances (Anhyd.) 7.0 7.7 7.8 5.5
- 5 52939
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.
Product Data
% H20 (KF) 1.8; 1.4 2.5;2.7 1.50.4 1.20.3 Bulk density (g/cm3) 0.43 0.53 0.26 0.26 Chem. potency 830 786 894 858 Bioassay (as is) 768 732 844 816 10 I2 Absorbing Substances^ 6.9 9.7 4.2 4.4 pH (3% in HjO) 8.7 8.7 8.7 8.7 % t-BuOH 0.8 0.8 0.9 0.9 Klett (10% with blue filter) 72 59 65 80
(1) Determined on an anhydrous solvent free basis using the procedure 15 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 1./kg).
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.
- 6 52939
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 amoxycillin: dose dependence after intravenous, oral and intramuscular administration; Antimicrobial Agents and Chemotherapy, J_1_’ 132 (1977) and by S. A. Hill et al., Pharmacokinetics of parenterally administered amoxycillin, Journal of Infection 320-332 (1980).
Claims (5)
1. A process for the production of solid sodium amoxicillin which comprises spray-drying a solution of sodium amoxicillin in aqueous t-butanol. 15
2. A process as claimed in Claim 1 in which the inlet temprature is 180°C and the outlet temperature is 120°C.
3. A process as claimed in Claim 1 or Claim 2 in which the solution to be spray-dried contains 1.5 1. t-butanol for each 3.5 1. water.
4. A process for the production of solid sodium amoxicillin substantially 20 as hereinbefore described in the Example.
5. Solid sodium amoxicillin whenever prepared by a method as claimed in any one of the preceding claims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8107247A FR2503710B1 (en) | 1981-04-10 | 1981-04-10 | PROCESS FOR PRODUCING SODIUM SALT OF AMOXICILLIN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE820844L IE820844L (en) | 1983-10-10 |
| IE52939B1 true IE52939B1 (en) | 1988-04-13 |
Family
ID=9257255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE844/82A IE52939B1 (en) | 1981-04-10 | 1982-04-08 | Production of sodium amoxicillin by spray-drying |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS57179191A (en) |
| KR (1) | KR880001410B1 (en) |
| AU (1) | AU559766B2 (en) |
| BE (1) | BE892451A (en) |
| CA (1) | CA1182108A (en) |
| CH (1) | CH651836A5 (en) |
| DE (1) | DE3213308A1 (en) |
| DK (1) | DK157382A (en) |
| ES (1) | ES511295A0 (en) |
| FI (1) | FI821247L (en) |
| FR (1) | FR2503710B1 (en) |
| GB (1) | GB2096599B (en) |
| GR (1) | GR76106B (en) |
| IE (1) | IE52939B1 (en) |
| IT (1) | IT1148165B (en) |
| LU (1) | LU84007A1 (en) |
| NL (1) | NL8201467A (en) |
| NO (1) | NO821174L (en) |
| NZ (1) | NZ200281A (en) |
| PT (1) | PT74727B (en) |
| SE (1) | SE8202269L (en) |
| YU (1) | YU43132B (en) |
| ZA (1) | ZA822400B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3474023D1 (en) * | 1983-06-10 | 1988-10-20 | Beecham Group Plc | Crystalline amoxycillin salt |
| IT1255716B (en) * | 1992-10-05 | 1995-11-10 | PROCEDURE FOR THE PREPARATION OF STERILE BETA-LACTAMIC ANTIBIOTICS | |
| AT412213B (en) * | 2000-05-30 | 2004-11-25 | Sandoz Ag | METHOD FOR DRYING AMOXICILLIN OR AMOXICILLIN-CONTAINING, ORAL, SOLID PHARMACEUTICAL COMPOSITIONS USING A GAS WITH A DEFINED GAS HUMIDITY |
| CN105055169B (en) * | 2015-07-11 | 2019-01-22 | 鲁南制药集团股份有限公司 | A method of preparing Imipenem and Cilasatin Sodium aseptic powdery |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1471235A (en) * | 1974-09-18 | 1977-04-21 | Beecham Group Ltd | Amoxycillin derivatives |
| GB1527557A (en) * | 1976-07-07 | 1978-10-04 | Beecham Group Ltd | Process for preparing solid sodium amoxycillin |
| GB1576731A (en) * | 1976-08-10 | 1980-10-15 | Beecham Group Ltd | Process for the preparation of sodium amoxycillin |
| DE2965917D1 (en) * | 1978-12-08 | 1983-08-25 | Beecham Group Plc | A process for the preparation of a solid sodium amoxycillin and aqueous solutions thereof |
-
1981
- 1981-04-10 FR FR8107247A patent/FR2503710B1/en not_active Expired
-
1982
- 1982-02-12 AU AU80455/82A patent/AU559766B2/en not_active Expired
- 1982-02-16 GR GR67339A patent/GR76106B/el unknown
- 1982-02-26 YU YU432/82A patent/YU43132B/en unknown
- 1982-03-02 GB GB8206075A patent/GB2096599B/en not_active Expired
- 1982-03-10 BE BE0/207536A patent/BE892451A/en not_active IP Right Cessation
- 1982-03-12 LU LU84007A patent/LU84007A1/en unknown
- 1982-04-06 NL NL8201467A patent/NL8201467A/en not_active Application Discontinuation
- 1982-04-06 NO NO821174A patent/NO821174L/en unknown
- 1982-04-06 KR KR8201511A patent/KR880001410B1/en active
- 1982-04-06 DK DK157382A patent/DK157382A/en not_active IP Right Cessation
- 1982-04-07 IT IT48188/82A patent/IT1148165B/en active
- 1982-04-07 FI FI821247A patent/FI821247L/en not_active Application Discontinuation
- 1982-04-07 ZA ZA822400A patent/ZA822400B/en unknown
- 1982-04-07 ES ES511295A patent/ES511295A0/en active Granted
- 1982-04-08 JP JP57057416A patent/JPS57179191A/en active Granted
- 1982-04-08 CH CH2211/82A patent/CH651836A5/en not_active IP Right Cessation
- 1982-04-08 IE IE844/82A patent/IE52939B1/en not_active IP Right Cessation
- 1982-04-08 PT PT74727A patent/PT74727B/en unknown
- 1982-04-08 DE DE19823213308 patent/DE3213308A1/en not_active Withdrawn
- 1982-04-08 SE SE8202269A patent/SE8202269L/en not_active Application Discontinuation
- 1982-04-08 NZ NZ200281A patent/NZ200281A/en unknown
- 1982-04-08 CA CA000400753A patent/CA1182108A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GR76106B (en) | 1984-08-03 |
| NZ200281A (en) | 1984-12-14 |
| KR830010116A (en) | 1983-12-26 |
| ES8304138A1 (en) | 1983-02-16 |
| CA1182108A (en) | 1985-02-05 |
| ES511295A0 (en) | 1983-02-16 |
| ZA822400B (en) | 1983-02-23 |
| FI821247A0 (en) | 1982-04-07 |
| AU559766B2 (en) | 1987-03-19 |
| JPH0219119B2 (en) | 1990-04-27 |
| FR2503710B1 (en) | 1985-07-05 |
| FI821247L (en) | 1982-10-11 |
| GB2096599B (en) | 1985-01-23 |
| AU8045582A (en) | 1982-10-14 |
| GB2096599A (en) | 1982-10-20 |
| YU43282A (en) | 1985-06-30 |
| CH651836A5 (en) | 1985-10-15 |
| PT74727B (en) | 1985-01-08 |
| BE892451A (en) | 1982-09-10 |
| SE8202269L (en) | 1982-10-11 |
| IT1148165B (en) | 1986-11-26 |
| YU43132B (en) | 1989-04-30 |
| KR880001410B1 (en) | 1988-08-01 |
| DK157382A (en) | 1982-10-11 |
| LU84007A1 (en) | 1983-02-22 |
| NL8201467A (en) | 1982-11-01 |
| JPS57179191A (en) | 1982-11-04 |
| IE820844L (en) | 1983-10-10 |
| PT74727A (en) | 1982-05-01 |
| NO821174L (en) | 1982-10-11 |
| IT8248188A0 (en) | 1982-04-07 |
| FR2503710A1 (en) | 1982-10-15 |
| DE3213308A1 (en) | 1982-11-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |