GB2096599A - Production of sodium amoxicillin by spray-drying - Google Patents
Production of sodium amoxicillin by spray-drying Download PDFInfo
- Publication number
- GB2096599A GB2096599A GB8206075A GB8206075A GB2096599A GB 2096599 A GB2096599 A GB 2096599A GB 8206075 A GB8206075 A GB 8206075A GB 8206075 A GB8206075 A GB 8206075A GB 2096599 A GB2096599 A GB 2096599A
- Authority
- GB
- United Kingdom
- Prior art keywords
- drying
- spray
- amoxicillin
- production
- sodium amoxicillin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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
SPECIFICATION
Production of sodium amoxicillin by spray-drying
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 U.K. 1,241,844 and U.K.
1,286,1 but 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 freezedrying (as in U.K. 1,527,557 and U.K. 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.
The solution to be spray-dried preferably contains 1.56 l of t-buttanol for each 3.6 l 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 (Dow therm) 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 N2 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-butaon
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 20,000 rpm 20,000 rpm
Temperatures ("C.) Inlet N2 200 180 180 180
Outlet N2 11 7 11 6 11 7 1 25 Condenser 2 3 0 1-2
Feed Rate (lah) 40.2 32.3 38.5 28
Total Drying
Time (min) 56 46 56 48
Run E F G H
Dissolution
Amoxicillin
Trihydrate, kg. 6.0 6.0 6.0 6.0
Drying Step
Nozzle Type Pressure Pressure Pressure Pressure
Pressure (psig) 850 1456/15001900 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 74 68 62 62
blue filter) %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 i2 Absorbing
Substances as is (" - - 12 Absorbing
Substances (Anhyd.) - - - ( 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
Dissolution
Amoxicillin
Trihydrate, kg. 6.0 6.0 6.0 6.0
Drying Step
Nozzle Type Pressure Pressure Pressure Pressure
Pressure (psig) 1 500 1 500 1 500 1600
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
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 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 12 Absorbing
Substances as is (1) 6.8 7.5 7.6 5.4 12 Absorbing
Substances (Anhyd.) 7.0 7.7 7.8 5.5
(') Determined on an anhydrous solent 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 1.5; 1.4 1.2; 1.3
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 i2 Absorbing
Substances (') 6.9 9.7 4.2 4.4 pH (3% in H20) 8.7 8.7 8.7 8.7 % t-BuOH 0.8 0.9 0.9
Klett (10% with 72 59 65 80
blue filter) (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.
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 I. water and 1.5 I. 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 I./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.
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,
11, 1 32 (1977) and by S. A. Hill et al., Pharmacokinetics of parenterally administered amoxycillin, Journal of Infection 2, 320-332 (1980).
Claims (4)
1. A process for the production of solid sodium amoxicillin which comprises spray-drying a solution of sodium amoxicillin in aqueous t-butanol.
2. A process as claimed in Clam 1 in which the inlet temperature 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 I. t-butanoi for each 3.6 1. water.
4. A process for the production of solid sodium amoxicillin substantially as hereinbefore described in the Example.
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 |
|---|---|
| GB2096599A true GB2096599A (en) | 1982-10-20 |
| GB2096599B GB2096599B (en) | 1985-01-23 |
Family
ID=9257255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8206075A Expired GB2096599B (en) | 1981-04-10 | 1982-03-02 | 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) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0131147A1 (en) * | 1983-06-10 | 1985-01-16 | Beecham Group Plc | Crystalline amoxycillin salt |
| EP0596262A1 (en) * | 1992-10-05 | 1994-05-11 | ISTITUTO BIOCHIMICO ITALIANO GIOVANNI LORENZINI S.p.A. | Process for the preparation of sterile beta-lactam 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 |
| CN105055169A (en) * | 2015-07-11 | 2015-11-18 | 山东新时代药业有限公司 | Preparation method of imipenem-cilastatin sodium sterile powder |
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 |
| EP0012496B1 (en) * | 1978-12-08 | 1983-07-20 | 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 KR KR8201511A patent/KR880001410B1/en active
- 1982-04-06 NO NO821174A patent/NO821174L/en unknown
- 1982-04-06 DK DK157382A patent/DK157382A/en not_active IP Right Cessation
- 1982-04-06 NL NL8201467A patent/NL8201467A/en not_active Application Discontinuation
- 1982-04-07 FI FI821247A patent/FI821247L/en not_active Application Discontinuation
- 1982-04-07 ES ES511295A patent/ES511295A0/en active Granted
- 1982-04-07 IT IT48188/82A patent/IT1148165B/en active
- 1982-04-07 ZA ZA822400A patent/ZA822400B/en unknown
- 1982-04-08 CH CH2211/82A patent/CH651836A5/en not_active IP Right Cessation
- 1982-04-08 DE DE19823213308 patent/DE3213308A1/en not_active Withdrawn
- 1982-04-08 JP JP57057416A patent/JPS57179191A/en active Granted
- 1982-04-08 NZ NZ200281A patent/NZ200281A/en unknown
- 1982-04-08 IE IE844/82A patent/IE52939B1/en not_active IP Right Cessation
- 1982-04-08 SE SE8202269A patent/SE8202269L/en not_active Application Discontinuation
- 1982-04-08 PT PT74727A patent/PT74727B/en unknown
- 1982-04-08 CA CA000400753A patent/CA1182108A/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0131147A1 (en) * | 1983-06-10 | 1985-01-16 | Beecham Group Plc | Crystalline amoxycillin salt |
| EP0596262A1 (en) * | 1992-10-05 | 1994-05-11 | ISTITUTO BIOCHIMICO ITALIANO GIOVANNI LORENZINI S.p.A. | Process for the preparation of sterile beta-lactam 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 |
| US7807196B2 (en) | 2000-05-30 | 2010-10-05 | Sandoz Gmbh | Process for drying amoxicillin |
| CN105055169A (en) * | 2015-07-11 | 2015-11-18 | 山东新时代药业有限公司 | Preparation method of imipenem-cilastatin sodium sterile powder |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CH651836A5 (en) | 1985-10-15 |
| KR830010116A (en) | 1983-12-26 |
| KR880001410B1 (en) | 1988-08-01 |
| NZ200281A (en) | 1984-12-14 |
| ES8304138A1 (en) | 1983-02-16 |
| PT74727B (en) | 1985-01-08 |
| GB2096599B (en) | 1985-01-23 |
| AU8045582A (en) | 1982-10-14 |
| DK157382A (en) | 1982-10-11 |
| YU43282A (en) | 1985-06-30 |
| PT74727A (en) | 1982-05-01 |
| AU559766B2 (en) | 1987-03-19 |
| BE892451A (en) | 1982-09-10 |
| IT8248188A0 (en) | 1982-04-07 |
| YU43132B (en) | 1989-04-30 |
| IT1148165B (en) | 1986-11-26 |
| ZA822400B (en) | 1983-02-23 |
| JPS57179191A (en) | 1982-11-04 |
| DE3213308A1 (en) | 1982-11-11 |
| SE8202269L (en) | 1982-10-11 |
| NO821174L (en) | 1982-10-11 |
| GR76106B (en) | 1984-08-03 |
| FR2503710B1 (en) | 1985-07-05 |
| ES511295A0 (en) | 1983-02-16 |
| FR2503710A1 (en) | 1982-10-15 |
| JPH0219119B2 (en) | 1990-04-27 |
| IE52939B1 (en) | 1988-04-13 |
| FI821247A0 (en) | 1982-04-07 |
| IE820844L (en) | 1983-10-10 |
| CA1182108A (en) | 1985-02-05 |
| LU84007A1 (en) | 1983-02-22 |
| NL8201467A (en) | 1982-11-01 |
| FI821247L (en) | 1982-10-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20020301 |