KR880001410B1 - Process for preparing sodium amoxicillin - Google Patents
Process for preparing sodium amoxicillin Download PDFInfo
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- KR880001410B1 KR880001410B1 KR8201511A KR820001511A KR880001410B1 KR 880001410 B1 KR880001410 B1 KR 880001410B1 KR 8201511 A KR8201511 A KR 8201511A KR 820001511 A KR820001511 A KR 820001511A KR 880001410 B1 KR880001410 B1 KR 880001410B1
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- amoxacillin
- amx
- water
- sodium
- butanol
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- 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
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- 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
Description
본 발명은 향상된 소디움 아목사실린 및 그것의 제조방법에 관한 것이다. 더욱 상세하게, 본 발명은 t-부타놀 혼합액에서 소디움 아목사실린 용액을 분무 건조시켜 고형의 소디움 아목사실린을 제조하는 방법에 관한 것이다.The present invention relates to an improved sodium amoxacillin and a method for preparing the same. More specifically, the present invention relates to a method for preparing solid sodium amoxacillin by spray drying a sodium amoxacillin solution in a t-butanol mixture.
영국특허 제1,241,844호 및 제1,286,199호에서는 고형의 소디움 아목사실린을 침전시켜 제조하는 방법을 기술하고 있으나 결과의 생설물은 트리에틸아민 또는 소디움 2-에틸헥사노에이트 등과 같은 잔존시약 또는 과잉양의 용매에 의한 불순물을 10%까지 함유하고 있다. 이러한 양의 불순물은 인체 및 가축에 독성은 없지만, 그래도 저장에 있어서의 안정성 및 고순도를 가진 아목사실린의 제조방법이 요망되어 왔다.British Patent Nos. 1,241,844 and 1,286,199 describe a process for the precipitation of solid sodium amoxacillin, but the resulting raw material is a residual reagent or an excess amount such as triethylamine or sodium 2-ethylhexanoate. Contains up to 10% impurities by solvent. Although these amounts of impurities are not toxic to humans and livestock, there is still a need for a method for producing amoxacillin with stability and high purity in storage.
영국특허 제1,527,557호 및 제1,543,317호에서는 고형의 소디움 앰피실린을 동결 건조시켜 제조하는 방법을 기술하고 있으나, 이러한 제조방법은 상업적 수요에 필요한 양의 아목사실린을 제조하기 위해서는 비용이 엄청나게 들뿐만 아니라, 처리 기간중 장시간 동안 매우 낮은 온도로 반응물을 유지시켜야 하므로, 이로 말미암아 주어진 단위장치로 부터의 생산량을 감소시킨다.British Patent Nos. 1,527,557 and 1,543,317 describe methods for the freeze-drying of solid sodium ampicillin, but these methods are costly to produce the amount of amoxacillin required for commercial demand. Therefore, it is necessary to keep the reactants at very low temperatures for a long time during the treatment period, thereby reducing the output from a given unit.
이러한 문제점을 해결하고자, 본 발명에서는 폐쇄회로 분무 건조기를 사용하여 아목사실린을 분무 건조하는 방법을 기술하고 있다. 본 발명의 방법은 수행하는 폐쇄회로 분무 건조기는 주로 건조실, 생성물 사이클론, 패기팬(fan), 응축기/스크루우버(충돌판, 냉각되는 글리콜), 질소팬, 열 교환기(Dowtherm) 및 공급펌푸로 구성되어 있다. 상기장치에서 처리되는 공급물과 사이클론 생성물의 배출은 병류로 조작된다. 이러한 단위 장치는 먼저 질소로 정화되어 안전한 양으로 산소의 양을 감소시킴으로서 용매 혼합물이 응축기에 충전될 수 있도록 한다(이로인해 안정한 상태의 건조조건으로 신속히 돌아온다). 그다음, 단위 장치는 바람직한 입구온도, 가스유속, 응축기 온도 등과 평형한 후, 공급물(수용성 t-부타놀내의 소디움 아목사실린)은 건조실의 탑부에서 분무 노즐을 통해 펌푸질된다. 건조 생성물 및 가스는 사이클론 내에서 분리되도록 기부에서 배출된다.To solve this problem, the present invention describes a method of spray drying amoxacillin using a closed-loop spray dryer. The closed-circuit spray dryer to carry out the process of the present invention mainly consists of drying chamber, product cyclone, fan, condenser / screw (cold plate, cooled glycol), nitrogen fan, heat exchanger (Dowtherm) and feed pump It is. The discharge of the feed and cyclone products processed in the apparatus is operated in co-current. This unit is first purged with nitrogen to reduce the amount of oxygen in a safe amount so that the solvent mixture can be charged to the condenser (this quickly returns to a stable dry condition). The unit is then equilibrated with the desired inlet temperature, gas flow rate, condenser temperature and the like, and then the feed (sodium amoxacillin in water-soluble t-butanol) is pumped through the spray nozzle at the top of the drying chamber. Dry product and gas exit the base to be separated in the cyclone.
고형의 소디움 아목사실린의 제조방법은 하기표에 나타난 바와같이 용해 단계 및 건조단계로 구성되어 있다.The method for producing solid sodium amoxacillin consists of a dissolution step and a drying step as shown in the following table.
본 발명은 25℃에서 적어도 5부피%가 수용성인 2차 또는 3차 카르비놀 및 물을 함유한 용매내에서 소디움 아목사실린의 용액을 분무 건조하여 고형의 소디움 아목사실린을 제조하는 것이다. 적합한 2차 또는 3차 카르비놀은 sec-부타놀, t-부타놀, 2-펜타놀 및 2-메틸부탄-2-올 등이 있는데, 이중에서도 t-부타놀은 처리 및 조작의 용이함, 고순도 및 생성물의 독물학적 허용도 등의 장점때문에 특히 양호하게 사용된다. 사용되는 아목사실린은 아목사실린 트리하이드레이트가 양호하며, 염기로는 수산화나트륨이 양호하다.The present invention provides a solid sodium amoxacillin by spray drying a solution of sodium amoxacillin in a solvent containing secondary or tertiary carbinol and water at least 5% by volume at 25 ° C. Suitable secondary or tertiary carbinols include sec-butanol, t-butanol, 2-pentanol and 2-methylbutan-2-ol, among which t-butanol is easy to process and manipulate, and has high purity. And toxicological tolerances of the product. The amoxacillin used is preferably amoxacillin trihydrate, and sodium hydroxide is preferred as a base.
분무건조기 전에, 미세 분말화된 아목사실린 트리하이드레이트(화학적 역가 845mcg/mgm)는 아목사실린 트리하이드레이트 kg당 2.4의 물과 1.5의 t-부타놀을 함유한 수용성 t-부타놀내에서 슬러리화 된다. 그다음, 상기 슬러리에 1.97N의 수용성 수산화나트륨 약 2%의 과잉량(1.23l/kg)이 연속적으로 첨가된다. 보편적으로, 수산화나트륨 염기는 투명한 용액이 얻어질때까지, 서서히 가하는데, 이때, 너무 많은 양이 첨가되지 않도록 주의해야 한다. 염기의 첨가가 시작될때 용액의 온도는 분해를 최소화 하기 위하여 25℃로 유지시킨다.Prior to the spray dryer, the finely powdered amoxacillin trihydrate (chemical titer 845 mcg / mgm) is slurried in an aqueous t-butanol containing 2.4 water and 1.5 t-butanol per kg amoxacillin trihydrate. . Next, an excess (1.23 l / kg) of 1.97 N of water-soluble sodium hydroxide of about 2% is continuously added to the slurry. Generally, sodium hydroxide base is added slowly until a clear solution is obtained, with care being taken not to add too much. When the addition of base begins, the temperature of the solution is kept at 25 ° C. to minimize degradation.
분무 건조단계에서는 압력을 변화시켜 원하는 입자크기를 얻을 수 있다. 이때, 건조기로 유입되는 공급물 및 건조기에서 제조되어 배출되는 생성물의 사이클 조작을 원활히 수행하기 위하여 건조기의 입구 및 출구는 질소로 정화되며, 입구에서의 질소온도는 약 180℃이고 출구에서의 질소온도는 약 120℃정도가 적당하다. 멸균 조건하에 압력 노즐을 사용하여 분무 건조하는 방법에 의해 바이알(vial)로 직접 채워질 수 있는 멸균된 고형의 소디움 아목사실린을 산출할 수도 있다. 상기 단계에서의 노즐 형태, 압력, 온도, 공급속도, 및 건조시간은 12개의 배치(batch)를 사용하여 본 발명의 방법을 수행한 하기의 표에 기술되어 있다. 또한, 그 결과의 생성물인 고형의 소디움 아목사실린의 분석치도 하기의 표에 기술되어 있다.In the spray drying step, the desired particle size can be obtained by varying the pressure. At this time, inlet and outlet of the dryer are purged with nitrogen in order to smoothly perform the cycle operation of the feed flowing into the dryer and the product manufactured and discharged from the dryer, the nitrogen temperature at the inlet is about 180 ℃ and nitrogen temperature at the outlet About 120 ℃ is suitable. Spray drying using a pressure nozzle under sterile conditions may also yield a sterile solid sodium amoxacillin that can be filled directly into a vial. The nozzle type, pressure, temperature, feed rate, and drying time at this stage are described in the following table in which the method of the present invention was carried out using 12 batches. In addition, the analytical values of the solid sodium amoxacillin as a resultant product are also described in the table below.
[표][table]
수용성 t-부타놀을 사용한 시험 조건 및 결과Test Conditions and Results with Water Soluble t-Butanol
용해단계Dissolution step
건조단계Drying stage
생성물 데이타Product data
용해단계Dissolution step
건조단계Drying stage
생성물 데이타Product data
용해단계Dissolution step
건조단계Drying stage
생성물 데이타Product data
(1)페니실로산 혹은 이합체 등에 의한 오염도를 측정키위해 영국약전의 처리방법으로 무수물 용매에서 유리염기를 측정한다.(1) To measure the degree of contamination by penicillic acid or dimers, measure free base in anhydrous solvents using the methods of British Pharmacopoeia.
상기 각 배치에서 생성된 고형의 분무 건조된 소디움 아목사실린은 에틸렌옥사이드를 사용하여 멸균시킨 후, 상업상 제품으로서 사용하기에 적합하다.The solid spray dried sodium amoxacillin produced in each batch is sterilized using ethylene oxide and then suitable for use as a commercial product.
아목사실린의 트리하이드레이트 형태로서의 경구용 투여에 대한 아목사실린의 향균성과 임상사용방법은 의학서적에 잘 소개되어 있다.The antibacterial and clinical use of amoxacillin for oral administration of amoxacillin as a trihydrate form is well described in the medical literature.
비 경구투여로는 본 발명의 방법에서와 같이, 불용성 트리하이드레이트를 고용해성 나트륨염으로 전환하는 수용액을 주입하는 것이 양호하다. 수용성 소디움 아목사실린의 비경구투여의 결과는 D.A.Spyker외 다수의 pharmacokinetics of amoxycillin : dose dependence after intravenous, oral and intramuscular administration ; Antimicrobial Agents and Chemotherapy, 11,132(1977), 그리고 S.A.Hill외 다수의 Pharmacokinetics of parenterally administered amoxycillin, Journal of Infection 2,320-332(1980)에 기술되어 있다.For oral administration, as in the method of the present invention, it is preferred to inject an aqueous solution which converts insoluble trihydrate to a high dissolved sodium salt. The results of parenteral administration of water-soluble sodium amoxacillin have been described in D.A.Spyker et al. In pharmacokinetics of amoxycillin: dose dependence after intravenous, oral and intramuscular administration; Antimicrobial Agents and Chemotherapy, 11,132 (1977), and in S.A. Hill et al., Pharmacokinetics of parenterally administered amoxycillin, Journal of Infection 2,320-332 (1980).
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8107247A FR2503710B1 (en) | 1981-04-10 | 1981-04-10 | PROCESS FOR PRODUCING SODIUM SALT OF AMOXICILLIN |
| FR81-07247 | 1981-04-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR830010116A KR830010116A (en) | 1983-12-26 |
| KR880001410B1 true KR880001410B1 (en) | 1988-08-01 |
Family
ID=9257255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR8201511A KR880001410B1 (en) | 1981-04-10 | 1982-04-06 | Process for preparing sodium amoxicillin |
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) | ES8304138A1 (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 KR KR8201511A patent/KR880001410B1/en active
- 1982-04-06 NL NL8201467A patent/NL8201467A/en not_active Application Discontinuation
- 1982-04-06 NO NO821174A patent/NO821174L/en unknown
- 1982-04-06 DK DK157382A patent/DK157382A/en not_active IP Right Cessation
- 1982-04-07 ES ES511295A patent/ES8304138A1/en not_active Expired
- 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
- 1982-04-08 PT PT74727A patent/PT74727B/en unknown
- 1982-04-08 CH CH2211/82A patent/CH651836A5/en not_active IP Right Cessation
- 1982-04-08 NZ NZ200281A patent/NZ200281A/en unknown
- 1982-04-08 SE SE8202269A patent/SE8202269L/en not_active Application Discontinuation
- 1982-04-08 JP JP57057416A patent/JPS57179191A/en active Granted
- 1982-04-08 IE IE844/82A patent/IE52939B1/en not_active IP Right Cessation
- 1982-04-08 CA CA000400753A patent/CA1182108A/en not_active Expired
- 1982-04-08 DE DE19823213308 patent/DE3213308A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2503710A1 (en) | 1982-10-15 |
| AU559766B2 (en) | 1987-03-19 |
| IE52939B1 (en) | 1988-04-13 |
| JPH0219119B2 (en) | 1990-04-27 |
| ZA822400B (en) | 1983-02-23 |
| CA1182108A (en) | 1985-02-05 |
| JPS57179191A (en) | 1982-11-04 |
| CH651836A5 (en) | 1985-10-15 |
| DK157382A (en) | 1982-10-11 |
| GB2096599B (en) | 1985-01-23 |
| IT8248188A0 (en) | 1982-04-07 |
| ES511295A0 (en) | 1983-02-16 |
| GR76106B (en) | 1984-08-03 |
| YU43132B (en) | 1989-04-30 |
| FR2503710B1 (en) | 1985-07-05 |
| PT74727B (en) | 1985-01-08 |
| IE820844L (en) | 1983-10-10 |
| YU43282A (en) | 1985-06-30 |
| FI821247L (en) | 1982-10-11 |
| LU84007A1 (en) | 1983-02-22 |
| NL8201467A (en) | 1982-11-01 |
| KR830010116A (en) | 1983-12-26 |
| NO821174L (en) | 1982-10-11 |
| NZ200281A (en) | 1984-12-14 |
| ES8304138A1 (en) | 1983-02-16 |
| DE3213308A1 (en) | 1982-11-11 |
| PT74727A (en) | 1982-05-01 |
| AU8045582A (en) | 1982-10-14 |
| IT1148165B (en) | 1986-11-26 |
| GB2096599A (en) | 1982-10-20 |
| SE8202269L (en) | 1982-10-11 |
| BE892451A (en) | 1982-09-10 |
| FI821247A0 (en) | 1982-04-07 |
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