• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    This invention provides an improvement in the large scale processing of vancomycin which comprises the quiescent precipitation of vancomycin base from an aqueous solution at a pH of at least about 7.8.
    公开号:SU1760970A3
    申请号:SU884613142
    申请日:1988-12-22
    公开日:1992-09-07
    发明作者:Рэймонд Кэтт Гарольд；Бернард Хэйс Гарольд
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    J
    14.
    The invention relates to the production of antibiotics, in particular, to the method of deposition of vancomycin.
    Owing to the interest and importance shown to vancomycin, a continuous search for more efficient methods for isolating the antibiotic from its fermentation mixtures is conducted.
    Vancomycin is a fermentation product. Usually, the fermentation broth is filtered, the filtrate is acidified and passed through one or more layers of chromatographic resin in order to cause separation of the fractions with antibiotic activity. When the base is added with stirring, the pH of the eluate containing the purified antibiotic is adjusted to 8-8.2. The deposition of zancomycins (bases), as a rule, begins at a pH of 7.2-7.5, i.e. before reaching the required pH. Suspension
    the crystals are mixed with continuous adjustment of the pH to the desired value until complete precipitation. In this way, irreproducible yields are achieved, unpredictable precipitation occurs and the formation of an unevenly difficult filter cake (1).
    The difficulties encountered in filtering vancomycin suspensions (bases) are punching in the industrial production of vancomycin, which has existed for about twenty years.
    The aim of the invention is to improve the quality of the sediment.
    It was found that if the precipitation of vancomycin (s) was delayed until the pH of the solution was set to at least 7.8 and the precipitation was completed without stirring, in this case the product was continuously formed as well-formed large plastic.
    CJ
    nok. Such plates can be easily filtered on a Buchner funnel using a centrifuge or filter press. In addition, the product yield increases and the improved filterability of the product allows processing of solutions with a higher concentration of vancomycin, which also increases the vancomycin yield for loading and improves the efficiency of the process.
    The described method of the present invention consists in quickly combining an aqueous solution of vancomycin with an aqueous solution of a base to obtain a solution with a pH value before precipitating at least 7.8 and then continuing the precipitation without moving. The expression pH value of at least 7.8 means the minimum pH value at which the use of static deposition technology results in well-formed, easily filtered vancomycin plates (bases). At high concentrations of vancomycin, it is possible to obtain such a precipitate at such low pH values as 7.5, if the solution is not stirred. However, under these conditions, precipitation is not complete and the yield decreases. Increasing the pH to 9 affects the stability of vancomycin, and the yield decreases and valuable products form in a bleach. The best results are achieved when precipitation begins at a pH of 7.8-8.24. It is recommended to set the pH to 7.8-8.24 and stop stirring before sedimentation begins.
    In one embodiment of the invention, the pH value of the eluted vancomycin concentrate is adjusted to 6.5-7 by adding a base, i.e. compounds forming hydroxyl ions in an aqueous solution, such as sodium hydroxide, potassium hydroxide, and the like. An aliquot is taken, which is titrated to determine the amount of base to be added before the pH is raised to at least 7.8. The calculated amount of base is rapidly and with stirring added with the eluted concentrate to a pH of at least 7.8 before precipitation begins. The stirring is stopped immediately after the addition of the base and the solution is allowed to settle. It is recommended that the base be added at a rate such that pH is set at 8-8.24, and stirring is stopped. As a result, large, well-formed and easily filterable product plates are obtained.
    In another embodiment of the invention, p H of the eluted concentrate is set to
    limits of 6.5-7. The solution is quickly added, with stirring, to a solution of the base of the appropriate concentration to obtain a final pH value of
    at least 7.8. The base solution may be buffered. Stirring is stopped immediately after addition of the eluted concentrate. Again, it is again recommended that the eluate be added in full and that the final pH is in the range of 8-8.24. And in this case, large, well-formed and easily filterable product plates are obtained.
    5 The precipitation rate is affected by the temperature of the solution. It is recommended that the temperature of the solution be 10-30 ° C. When the temperature of the solution is above 30 ° C, precipitation often begins before the pH reaches a value of 7.8, and the resulting vancomycin (base) is difficult to filter. On the contrary, at a temperature below 10 ° C, precipitation occurs slowly and in two hours is completed less than half. Thus, crystallization is recommended to be carried out at a temperature of 10-30 ° C, most preferably at 20-25 ° C, to obtain an easily filterable precipitate for a suitable time from an industrial point of view.
    The precipitation rate is also influenced by the concentration of vancomycin in the eluate. It is recommended that the eluted concentrate contains 75-200 mg / ml of vancomycin, most preferably 85-160 mg / ml. In general, the higher the concentration, the faster the precipitation proceeds and the more complete it is. At higher concentrations may
    There is a need to adjust the pH at 20 ° C or lower in order to avoid premature precipitation of vancomycin (base). The temperature can then be raised to 25 ° C in order to complete 5 precipitation. Deposition of vancomycin (base) from solutions with a concentration of less than 75 mg / ml occurs more slowly and leads to a product that filters more slowly compared to more concentration.
    0 trirovanny solutions. PRI me R 1.
    Aliquots of the eluted concentrate — 440 ml each, containing 75 mg / ml vancomycin, are adjusted to pH 7 by adding at
    Stirring 3N sodium hydroxide solution. Then the pH is raised from 7 to 8.24 by adding, over 75 seconds, an Sr solution of sodium hydroxide. Stirring is stopped immediately after the addition of sodium hydroxide. After 1.5 minutes begins to precipitate
    vancomycin (base). The temperature of the solution is maintained at 25 ° C. The degree of crystallization is controlled by ultraviolet analysis. After about 6 hours, the suspension is filtered on a Büchner funnel with a diameter of 1.25 inches (3.2 cm) equipped with a glass column under a pressure of 0.984 at. The filter cake is washed with 105 ml of 50% aqueous methanol and then 105 ml of methanol. The initial washing time is 7.5 minutes, the first washing takes 11 minutes, the second washing is 9 minutes. The output of vancomycin (base) 90%.
    Example 2-5.
    The procedure of Example 1c was reproduced using an eluted concentrate containing 90, 120 and 160 mg / ml of vancomycin. Deposition from a solution with 160 mg / ml of vancomycin was carried out twice. During the first experiment at a controlled temperature of 25 ° C, precipitation begins at pH 7.9. Stirring is stopped after adding the entire aliquot amount of sodium hydroxide (pH 8.24). In the second experiment, the temperature of the eluate is 10 ° C, the temperature of the sodium hydroxide solution is 15 ° C, the crystallization temperature as a result reaches 210 ° C. Stirring is stopped immediately after adding sodium hydroxide solution, pI 8.23. Deposition starts after 35-40 seconds. The results obtained in examples 1-5 are summarized in table 1.
    Examples 6-9.
    Reproduced the method of example 1 using eluted concentrate containing 83.7 mg / ml vancomycin and temperature change. The results obtained are summarized in Table 2. In Example 9, at 30 ° C, precipitation began before all the sodium hydroxide solution was added.
    PRI me R 10.
    To an aliquot of 200 ml of eluted concentrate containing 74 mg / ml of vancomycin, urea (14.8 g) is added. The pH is adjusted to 6.5 with the addition of 33 ml of 3N sodium hydroxide solution. With stirring, the resulting solution is added to 30 ml of 3N sodium hydroxide solution containing 2.5 g of sodium acetate with stirring, and stirring is immediately stopped. The resulting solution has a pH of 8. The temperature of the solution is maintained at 25 ° C. Deposition of vancomycin begins immediately. After 30 minutes, the slurry is filtered on a 9 cm diameter Buchner funnel. The filter cake is washed with 100 ml of 50% aqueous methanol, followed by repeated washing with 100 ml of methanol. The filtration time is 1.9 minutes, the first washing takes 2.6 minutes, the second washing takes 2.6 minutes. Yield 95%. Examples 11-14.
    The procedure of Example 10 was reproduced using different amounts of urea and sodium acetate. In some cases, methanol is used for the second wash and acetone is used for the third wash.
    For comparison, 200 ml of a suspension of crystals obtained by a known method from an eluate containing 73 mg / ml of vancomycin is filtered on a Büchner funnel 9 cm in diameter.
    The results of examples 10-14 are summarized in E table 3.
    PRI me R 15,
    By adding sodium hydroxide (19 ° C) to 750 l of eluted concentrate (15 ° C) containing 35 mg / ml of vancomycin, the pH is adjusted to 7. The aliquot amount is adjusted to pH 8.2 and the amount of 3N sodium hydroxide necessary to establish pH 8.2 in the eluate. The calculated amount (56 l) of the vessel under pressure is blown into the tank for 2.5 minutes into the tank and the stirring is stopped. The precipitation begins before the entire amount of sodium hydroxide is added. The temperature of the solution is stabilized at 25 ° C. After 4.5 hours, the slurry is filtered using a filter press. The filter cake is washed with water to lower the conductivity below 3000 µm ohm (about 1300 L), and then re-washed with acetone (950 L). Filtration time - 10 min. the first washing takes 15 minutes, the second washing takes 7 minutes, yield 92%.
    PRI me R s 16, 17.
    The procedure of Example 15 is reproduced, except that sodium hydroxide is added in 1.5 minutes and precipitation begins 15 seconds after completion of the addition.
    The results of examples 15 and 16 are compared with the average filtration time for three experiments carried out according to a known method using a zljuat containing 75115 mg / ml vancomycin.
    The results of the examples are summarized in table 4.
    权利要求:
    Claims (2)
    [1]
    1. A method for precipitating vancomycin (base), which involves reacting a solution containing vancomycin with a sodium hydroxide solution, characterized in that, in order to improve the quality of the precipitate by increasing its filtration ability, a solution of vancomycin is used with a concentration of 60-100 mg / ml and reacting the reactants when one of them is added to the other with stirring during the precipitation of vancomycin
     Deposition starts at pH 7.9.
    Results of Vancomycin Deposition
    from 10 seconds to 2.5 minutes until the pH in the mixture reaches 7.8-8.24, after which the stirring is stopped and the mixture is settled.
    [2]
    2. A method according to claim 1, characterized in that the process is carried out at 10-30 ° C.
    Table 1
    table 2
    Filtration results of precipitated vancomycin
    Filtration results of precipitated vancomycins
    Table 3
    Table 4
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1760970A3|1992-09-07|Method of vancomycin | settling
    KR100293172B1|2001-06-15|Streptomyces sp. Novel method for isolating clavulanic acid and its pharmaceutically acceptable salts from fermentation broth of P6621 FERM P2804
    CH645341A5|1984-09-28|METHOD FOR PRODUCING DIPEPTIDES.
    CN105368910B|2019-01-11|A kind of method of enzymatic clarification Cefprozil
    HU212578B|1996-08-29|Process for producing high purity potassium salt of clavulanic acid with purification of unrefined clavulanic acid using n,n'-substituted ethylendiammonium-diclavulanate and process for producing ethylen diammonium-diclavulanats
    CN110423241B|2020-11-27|Process for preparing cephalosporin C sodium salt and 7-aminocephalosporanic acid
    EP0705280B1|1999-04-14|Cyclodextrin refining process
    US6100393A|2000-08-08|Process for purifying 7-substituted aminodeacetoxy-cephalosporins through the use of filtration membranes
    DE69826852T2|2005-11-17|IMPROVED METHOD FOR THE FERMENTATIVE MANUFACTURE OF PENICILINATE
    US5037652A|1991-08-06|Vancomycin precipitation process
    US3467654A|1969-09-16|Process for the recovery and purification of cephalosporin c
    US3817831A|1974-06-18|Process for production of alkali metal salt of heparin
    CA2178369C|2001-10-16|Process for the purification and crystallisation of iopamidol
    EP0126887B1|1986-06-04|Process for obtaining pure l-leucine
    BG63086B1|2001-03-30|Method for isolation of clavulanic acid from fermentation nutrient by means of ultrafiltration
    US4219641A|1980-08-26|Process for preparing erythromycin succinate
    US4203903A|1980-05-20|Process for the recovery of spectinomycin
    US4588818A|1986-05-13|Method for recovery of optically active tryptophane
    CN108239056B|2020-06-23|Method for recovering mevastatin from mevastatin crystallization mother liquor
    US4458018A|1984-07-03|Process for purifying elastase
    CN107074742A|2017-08-18|The salt of phenyl glycine methyl ester
    CN111196795A|2020-05-26|Method for recovering mevastatin from mevastatin crystallization mother liquor
    WO1995009243A1|1995-04-06|METHOD OF PRODUCING α,α-TREHALOSE
    EP0126886A2|1984-12-05|Process for the separation of L-leucine and L-isoleucine
    DE2046596C3|1974-04-25|Process for the preparation of high activity protease powders suitable for incorporation into detergents
    同族专利:
    公开号 | 公开日
    EP0323150B1|1993-04-07|
    IL88781A|1993-06-10|
    DK719788A|1989-06-29|
    DK719788D0|1988-12-23|
    AU606772B2|1991-02-14|
    NZ227433A|1990-11-27|
    CA1320312C|1993-07-13|
    MX168814B|1993-06-09|
    AR244237A1|1993-10-29|
    CN1021228C|1993-06-16|
    PH25591A|1991-08-08|
    PT89305A|1989-12-29|
    CN1033997A|1989-07-19|
    ZA889541B|1990-08-29|
    PT89305B|1995-01-31|
    DE3880119T2|1993-08-05|
    DE3880119D1|1993-05-13|
    JPH01224388A|1989-09-07|
    ES2045154T3|1994-01-16|
    IL88781D0|1989-07-31|
    EP0323150A2|1989-07-05|
    EP0323150A3|1990-07-25|
    HUT49150A|1989-08-28|
    KR890010210A|1989-08-07|
    AU2751988A|1989-06-29|
    AT87940T|1993-04-15|
    GR3007584T3|1993-08-31|
    IE883850L|1989-06-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3067099A|1955-09-16|1962-12-04|Lilly Co Eli|Vancomycin and method for its preparation|
    JPH0689038B2|1983-12-12|1994-11-09|イーライ・リリー・アンド・カンパニー|Vancomycin improved purification method and its product|US5149784A|1990-07-10|1992-09-22|Abbott Laboratories|Process for making vancomycin|
    US5258495A|1990-07-10|1993-11-02|Abbott Laboratories|Process for making vancomycin HC1|
    US5574135A|1990-07-10|1996-11-12|Abbott Laboratories|Process for making vancomycin|
    US5235037A|1991-08-15|1993-08-10|American Cyanamid Company|Vancomycin precipitation process|
    CA2133644C|1992-04-20|2008-09-09|Alexander H. T. Chu|Process for making vancomycin|
    CN101440127B|2007-11-19|2012-10-17|浙江医药股份有限公司新昌制药厂|Preparation of high-purity vancomycin hydrochloride|
    CN101456903B|2007-12-14|2013-06-05|浙江医药股份有限公司新昌制药厂|Separation and purification method of vancocin|
    CN101613396B|2008-06-26|2016-08-17|浙江医药股份有限公司新昌制药厂|Non-crystalline form Lyphocinand its production and use and its pharmaceutical composition|
    CN103408638B|2013-06-24|2016-03-30|江苏海阔生物医药有限公司|A kind of preparation technology of vancomycin crystallization|
    CN106518983A|2015-09-15|2017-03-22|江苏海阔生物医药有限公司|Method for preparing vancomycin by hydrochloric acid|
    CN106518984A|2015-09-15|2017-03-22|江苏海阔生物医药有限公司|Preparation method for preparing vancomycin from 2-methylpyridine|
    CN105524146B|2016-01-23|2018-10-09|雅赛利制药有限公司|A kind of vancomycin crystallization processes|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US13873587A| true| 1987-12-28|1987-12-28|
    [返回顶部]