CN101398254B - Peptide-containing antibiotic finished product drying method - Google Patents
Peptide-containing antibiotic finished product drying method Download PDFInfo
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- CN101398254B CN101398254B CN2007101641258A CN200710164125A CN101398254B CN 101398254 B CN101398254 B CN 101398254B CN 2007101641258 A CN2007101641258 A CN 2007101641258A CN 200710164125 A CN200710164125 A CN 200710164125A CN 101398254 B CN101398254 B CN 101398254B
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Abstract
The invention relates to a novel drying method of a peptide containing antibiotics finished-product. The drying method comprises the following steps: (1) Wet materiel is positioned in a hopper which is provided with a filter plate or a silk screen, a filter is on the hopper, nitrogen is added into a dry close system and isolated from air to boil the material; (2) When the oxygen content of the system is less than 10 percent, a blower and a condenser are turned on synchronously to supply a little nitrogen so as to condense and collect the material between 5 DEG C and 35 DEG C and wind amount between 5 m<3>/min/kg and 100 m<3>/min/kg; (3) When the majority of solution is completely collected, the blower is closed, nitrogen and nitrogen circulation is stopped, and air is added simultaneously and the blower is opened for the operation. The blower is operated for an hour more after the temperature difference between an inlet and outlet of the boiling device is less than or equal to 1 DEG C, and a half-finished product is obtained; and (4) The half-finished product is dried in vacuum, and finally the finished product is prepared. The method can ensure that the residual solvent of the product meets the requirements of ICH on related residual solution of raw material drug.
Description
Technical field
The present invention relates to a kind of new drying method, more particularly, relate to a kind of new drying method of peptide-containing antibiotic finished product, so that the product residue solvent reaches the requirement of ICH about the relevant residual solvent of bulk drug.
Background technology
It is generally all soluble in water to contain peptide antibiotic example hydrochloric acid vancomycin (Vancomycin Hydrochloride), teicoplanin (Teicoplanin), Daptomycin (Daptomycin), Dalbavancin (dalbavancin), oritavancin (oritavancin); Its solid and water molecules are tight; Simultaneously because this type antibiotic has thermal instability mostly; Can not be dry down at high temperature (more than 50 ℃), so it is moisture is not easy removal, same; The alcohols of some low-carbon (LC)s, ketone or ether organic solvent combine closely with vancomycin hydrochloride equally, and general drying means is difficult to reach the requirement of ICH to bulk drug.
The bed process that the present invention includes with a kind of improvement removes and the contained residual solvent that reduces the bulk drug that contains peptide antibiotic significantly; Under high vacuum, lower temperature, the qualified further drying of bulk drug intermediate of above-mentioned residual solvent is reached the purpose of removing most of moisture with a kind of, finally make residual solvent and moisture all meet the relevant residual solvent of current edition EP, USP and the relevant requirements of moisture.
Vancomycin hydrochloride is that a kind of glycopeptide antibiotics with resisting gram-positive bacteria that separation obtains in the zymotic fluid that does not have branch acid (Amycolatopsis Oriertalis) is intended in the east that from Indonesia's soil, screened in 1956; Be developed to product by the U.S. Li Lai company same period, and obtained FDA by 1958 and ratify listing.Though vancomycin hydrochloride came out in 1956, because its poor stability is difficult for refining and crystallization, its chemical constitution just added their confirmation up to nineteen eighty-two.The vancomycin molecule is made up of two basic structures, i.e. glycosyl part α-o-vancosamine-β-o-glucosyl and peptide base section center seven peptides nuclear.The vancomycin that uses clinically is its hydrochloride.
The vancomycin hydrochloride zymotic fluid filters under alkali condition, and filtrating is through macroporous absorbent resin, with the aqueous hydrochloric acid solution wash-out that contains ethanol; Add activated carbon decolorizing; The filtrating that filtration obtains concentrating obtains the vancomycin hydrochloride aqueous solution, precipitates, and obtains the vancomycin bullion after the separation.Bullion dissolves the back and filters in the aqueous solution, chromatographic purifying obtains the effective chromatographic solution of vancomycin B content more than 93%.Effectively obtain the vancomycin hydrochloride concentrate after the ultrafiltration of chromatographic solution process, the nanofiltration.Carry out vancomycin hydrochloride elaboration deposition then, the vancomycin hydrochloride filter cake carries out first time top with 90% ethanol water earlier to be washed, and carries out second time top with absolute ethyl alcohol again and washes, and pushes up promptly to get vancomycin hydrochloride after washing and precipitate the article of wetting.Also can use in concentrate, directly to add solvent crystallization, which kind of method for crystallising that don't work all contains a large amount of solvents and moisture, these solvents such as ethanol, acetone, methyl alcohol, butanols etc. in the wet article.
Teicoplanin is a new efficient glycopeptide antibiotics, and chemical constitution is similar with vancomycin, the antibiotic complex of being made up of 5 quite similar compounds of chemical constitution.It can suppress Gram-positive aerobic bacteria and anaerobic bacteria.Have bactericidal action, its mechanism of action is the biosynthesis that suppresses bacteria cell wall through the polymerization of disturbing peptide glycan.Teicoplanin produces bacterium Actinoplanes teichomyceticu by teicoplanin and under carbon source, nitrogenous source and other nutritional labeling, produces through fermentation; Zymotic fluid obtains destainer through filtration, resin adsorption, decolouring; Destainer carries out the sedimentation and filtration oven dry with solvent and obtains teicoplanin crude product after nanofiltration concentrates, dissolving crude product filters through chromatography, collects effective chromatographic solution; Again through decolouring and nanofiltration; Precipitate with acetone at last, obtain wet article teicoplanin, include a large amount of acetone and small amount of moisture.
Daptomycin (DAPTOMYCIN; CUBICIN) be in streptomycete (S.reseosporus) zymotic fluid, to extract a cyclic ester peptide matters that obtains; It not only has novel chemical constitution; And its binding mode is also with arbitrary to have got permission antibiotic different: these article can destroy the bacterial cell membrane function in many aspects, kill gram positive bacteria thus rapidly.The decapacitation of these article acts on outside most of clinical relevant gram positive bacterias, the more important thing is external still to have a strong active to being drug resistance isolated strains such as methicillin (Methicillin), vancomycin and Linezolid.Vancomycin derivatives oritavancin (oritavancin) has the activity of anti-VRE, penicillin resistant streptococcus pneumonia, MRSA and VISA bacterial strain.Dalbavancin (dalbavancin) is the teicoplanin analog, and these antibiotic have all improved character such as absorption, distribution, metabolism and secretion.They can run into similar problem mostly in production technology, all use alcohols, ketone or the ether organic solvent of some low-carbon (LC)s at refining stage.
Patent USP 5,853, mention in 720 and use spray-drying or use the vacuum Rotary drying to prepare vancomycin hydrochloride; The former temperature is 115 ℃～130 ℃ of inlet temperatures, and outlet temperature is 85 ± 5 ℃, and latter's temperature is 45 ℃～50 ℃; And vancomycin hydrochloride has thermal instability, and color can deepen under higher high-temperature, and impurity can increase; And under 45 ℃～50 ℃, carrying out vacuum drying, residual solvent is difficult to reach the requirement of ICH, thereby above stoving process is difficult to realize industrialization.At present the drying process great majority of this series products are taked cryodesiccated method, the advantage of this method is the stability that has guaranteed product preferably, but shortcoming is an equipment has high input, energy consumption high, batch output is little, thereby production cost is higher.
Summary of the invention
In order to overcome above-mentioned defective, the invention provides a kind of new drying method, at normal temperature or be lower than and carry out drying under the normal temperature, so that the product residue solvent reaches the requirement of ICH about the relevant residual solvent of bulk drug.
According to the present invention, a kind of peptide-containing antibiotic finished product drying method said method comprising the steps of:
(1) wet material being placed in the hopper that filter or silk screen are housed, is filter above the hopper, in dry closed system, adds nitrogen and secluding air, so that material " boiling ";
(2) when the oxygen content of this system less than 10% the time, open blower fan and condenser simultaneously, replenish small amount of nitrogen, be 5～35 ℃ at EAT; Air quantity is 5～100M
3/ minute/the wet article of KG carry out also collection of condensation down;
(3) when most of solvent has been collected, Blowing stopper stops the adding and the circulation of nitrogen, adds air simultaneously, opens fan operation again; Move to boiling equipment out temperature poor≤1 ℃ the time, reruned 1 hour, obtain semi-finished product;
(4) semi-finished product that obtain more than the general; Put into vacuum drying oven or double-cone vacuum drier (requiring the preparation high-vacuum pump), the control temperature is 25 ℃～35 ℃, controls final vacuum 15Pa～150Pa; Drying time is about 6～24 hours, can obtain high density vancomycin hydrochloride finished product.
Wherein, nitrogen gets in the boiling equipment through clean the processing from the bottom in the step (1).Said clean the processing is included in primarily efficient filter in the air cleaning apparatus, medium air filtration and high efficiency filter.
According to the present invention, said filter or silk screen aperture are 100～800 orders, and the filter pore size is 10～200 μ m.
According to the present invention, said condenser is equipped with chilled brine.
Have, the present invention adopts vacuum drying oven or double-cone vacuum drier to carry out vacuum drying again.Wherein, said vacuum drying baking temperature is 25～35 ℃.Said vacuum drying vacuum is 15～150Pa.Said vacuum drying drying time is 6～24 hours.
In addition; According to the present invention; Said drying means also is applicable to the drying of peptide-containing antibiotic finished product, such as vancomycin (Vancomycin), vancomycin hydrochloride (VancomycinHydrochloride), teicoplanin (Teicoplanin), Daptomycin (Daptomycin), Dalbavancin (dalbavancin), oritavancin peptide-containing antibiotics such as (oritavancin).
Experiment shows, the ICH through the resultant product of drying means of the present invention requires all to be less than or equal to 0.5%.
Description of drawings
Fig. 1 representes the flow chart of drying process of the present invention.
The specific embodiment
Referring to flow chart 1 further explain.As shown in Figure 1, wet material places in the hopper that filter or silk screen are housed, and is filter above the hopper, the dry incipient stage; Unlatching nitrogen, with air displacement in the system, gas gets in the boiling equipment, with the material in the hopper " boiling " from the bottom through clean processing the (just effect, middle effect and high efficiency filter); Solvent gets into to be condensed in the condensing plant with gas and is collected in the recycling can, replenishes small amount of nitrogen in the process, when most of solvent has been collected, and Blowing stopper; Close nitrogen valve 3 and circulating valve 4 simultaneously, open air and get into valve 2 and atmospheric valve 1, start blower fan once more; Move to boiling equipment out temperature poor≤1 ℃ the time, reruned 1 hour, finish.Wherein, process control parameter: hopper filter or silk screen aperture 100～800 orders, boiling tower internal filter aperture 1～200 μ m, 5～35 ℃ of intake air temperature; Air quantity 5～100M
3/ minute/the wet article of Kg.
With the above semi-finished product that obtain; Put into vacuum drying oven or double-cone vacuum drier (requiring the preparation high-vacuum pump), the control baking temperature is 25 ℃～35 ℃, the vacuum 15Pa～150Pa of control drier; Drying time is about 6～24 hours, can obtain the vancomycin hydrochloride finished product.Experiment shows that the ICH of resultant product requires all to be less than or equal to 0.5%.
Filter or silk screen aperture can be selected according to the characteristic of material, and scope is 100～800 orders, and the pore size of air cleaner can confirm that general range is 1～200 μ m according to dry powder particle diameter distribution situation.
The present invention illustrates as follows, but is not limited to the process parameters range in following several example.
Embodiment 1
In hopper, put into the vancomycin hydrochloride wet-milling 100Kg that contains 30% ethanol approximately, dry closed system is opened atmospheric valve 1; Open nitrogen valve 3 and circulating valve 4, close air and advance valve 2, when oxygen determination electrode in this system records oxygen content less than 10% the time; Close atmospheric valve 1, open blower fan, simultaneously open cold condenser chilled brine; Replenish small amount of nitrogen in the process, regulate fan frequency converter and make air quantity remain on 3000～4000 M
3/ minute, regulate temperature control valve, the control intake air temperature is at 20 ℃～25 ℃, move about 2 hours after, collecting tank internal solvent volume reaches 35L.Blowing stopper closes nitrogen valve 3 and circulating valve 4, opens atmospheric valve 1 and advances valve 2 with air; Open blower fan, after reruning 3 hours, outlet temperature and intake air temperature difference reach below 1 ℃; Reruned 1 hour, sampling test sample article residual ethanol is 0.01% (it is smaller or equal to 0.5% that ICH requires).
In hopper, put into the vancomycin hydrochloride wet-milling 80Kg that contains 30% ethanol approximately, dry closed system is opened atmospheric valve 1; Open nitrogen valve 3 and circulating valve 4, close air and advance valve 2, when oxygen determination electrode in this system records oxygen content less than 10% the time; Close atmospheric valve 1, open blower fan, simultaneously open cold condenser chilled brine; Replenish small amount of nitrogen in the process, regulate fan frequency converter and make air quantity remain on 400～2400 M
3/ minute, regulate temperature control valve, the control intake air temperature is at 31 ℃～35 ℃, move about 3 hours after, collecting tank internal solvent volume reaches 31L.Blowing stopper closes nitrogen valve 3 and circulating valve 4, opens atmospheric valve 1 and advances valve 2 with air; Open blower fan, after reruning 3 hours, outlet temperature and intake air temperature difference reach below 1 ℃; Reruned 1 hour, sampling test sample article residual ethanol is 0.05% (it is smaller or equal to 0.5% that ICH requires).
In hopper, put into the vancomycin hydrochloride wet-milling 90Kg that contains 30% ethanol approximately, dry closed system is opened atmospheric valve 1; Open nitrogen valve 3 and circulating valve 4, close air and advance valve 2, when oxygen determination electrode in this system records oxygen content less than 10% the time; Close atmospheric valve 1, open blower fan, simultaneously open cold condenser chilled brine; Replenish small amount of nitrogen in the process, regulate fan frequency converter and make air quantity remain on 5400～9000 M
3/ minute, regulate temperature control valve, the control intake air temperature is at 5 ℃～19 ℃, move about 3 hours after, collecting tank internal solvent volume reaches 30L.Blowing stopper closes nitrogen valve 3 and circulating valve 4, opens atmospheric valve 1 and advances valve 2 with air; Open blower fan, after reruning 3 hours, outlet temperature and intake air temperature difference reach below 1 ℃; Reruned 1 hour, sampling test sample article residual ethanol is 0.02% (it is smaller or equal to 0.5% that ICH requires).
Embodiment 4
In hopper, put into the teicoplanin wet-milling 5Kg that contains 40% acetone approximately, dry closed system is opened atmospheric valve 1; Open nitrogen valve 3 and circulating valve 4, close air and advance valve 2, when oxygen determination electrode in this system records oxygen content less than 10% the time; Close atmospheric valve 1, open blower fan, simultaneously open cold condenser chilled brine; Replenish small amount of nitrogen in the process, regulate fan frequency converter and make air quantity remain on 200-300 M
3/ minute, regulate temperature control valve, the control intake air temperature is at 26 ℃～30 ℃, move about 1.5 hours after, collecting tank internal solvent volume reaches 2L.Blowing stopper closes nitrogen valve 3 and circulating valve 4, opens atmospheric valve 1 and advances valve 2 with air; Open blower fan, after reruning 2.5 hours, outlet temperature and intake air temperature difference reach below 1 ℃; Reruned 1 hour, sampling test sample article residual acetone is 0.06% (it is smaller or equal to 0.5% that ICH requires).
Embodiment 5
In hopper, put into the Daptomycin wet-milling 4.5Kg that contains 35% methyl alcohol approximately, dry closed system is opened atmospheric valve 1; Open nitrogen valve 3 and circulating valve 4, close air and advance valve 2, when oxygen determination electrode in this system records oxygen content less than 10% the time; Close atmospheric valve 1, open blower fan, simultaneously open cold condenser chilled brine; Replenish small amount of nitrogen in the process, regulate fan frequency converter and make air quantity remain on 200～300 M
3/ minute, regulate temperature control valve, the control intake air temperature is at 30 ℃～35 ℃, move about 1.5 hours after, collecting tank internal solvent volume reaches 1.5L.Blowing stopper closes nitrogen valve 3 and circulating valve 4, opens atmospheric valve 1 and advances valve 2 with air; Open blower fan, after reruning 2.5 hours, outlet temperature and intake air temperature difference reach below 1 ℃; Reruned 1 hour, sampling test sample article residual methanol is 0.09% (it is smaller or equal to 0.5% that ICH requires).
Embodiment 6
With the vancomycin hydrochloride semi-finished product that obtain among the embodiment 1, detecting moisture is 18.6%, and it is put into the baking oven that is equipped with the high vacuum unit; Control heat medium temperature is 25～35 ℃; Vacuum constantly descends in the baking oven, and when drying time reaches 6 hours, vacuum reaches 150Pa in this moment baking oven; Detecting moisture content of finished products is 4.4% (criterion of acceptability of EP and USP regulation vancomycin hydrochloride bulk drug moisture is smaller or equal to 5%), and residual ethanol is 0.01%.
Embodiment 7
With the vancomycin hydrochloride semi-finished product that obtain among the embodiment 1, detecting moisture is 18.6%, and it is put into the baking oven that is equipped with the high vacuum unit; Control heat medium temperature is 25～35 ℃; Vacuum constantly descends in the baking oven, and when drying time reaches 24 hours, vacuum reaches 15Pa in this moment baking oven; Detecting moisture content of finished products is 2.1% (criterion of acceptability of EP and USP regulation vancomycin hydrochloride bulk drug moisture is smaller or equal to 5%), and residual ethanol is 0.01%.
The present invention is illustrated through top embodiment, still, should be appreciated that the present invention is not limited to described particular example and embodiment here.The purpose that comprises these particular example and embodiment here is to help those of skill in the art to put into practice the present invention.Any those of skill in the art are easy to further improving without departing from the spirit and scope of the present invention and perfect; Therefore the present invention only receives the restriction of the content and the scope of claim of the present invention, and its intention contains all and is included in alternative and equivalent in the spirit and scope of the invention that is limited accompanying claims.
Claims (10)
1. peptide-containing antibiotic finished product drying method said method comprising the steps of:
(1) wet material is placed in the hopper that filter or silk screen are housed of dry closed system boiling equipment; Said boiling equipment comprises filter and filter or the silk screen above the hopper; In said dry closed system, add nitrogen and secluding air, so that the material boiling;
(2) when the oxygen content of this drying closed system less than 10% the time, open blower fan and condenser simultaneously, replenish small amount of nitrogen, be 5～35 ℃ at EAT, air quantity is the wet article 5～100M of every Kg
3/ minute under solvent is carried out condensation and collects;
(3) when most of solvent has been collected, close blower fan, stop the adding and the circulation of nitrogen, add air simultaneously, open fan operation again; Move to said boiling equipment out temperature poor≤1 ℃ the time, reruned 1 hour, obtain semi-finished product;
(4) above-mentioned semi-finished product are carried out vacuum drying, obtain finished product.
2. drying means as claimed in claim 1, wherein, nitrogen gets in the said boiling equipment from the bottom through clean the processing in the step (1).
3. drying means as claimed in claim 2, wherein, said clean the processing is included in primarily efficient filter in the air cleaning apparatus, medium air filtration and high efficiency filter.
4. drying means as claimed in claim 1, wherein, said filter or silk screen aperture are 100～800 orders, the filter pore size is 1～200 μ m.
5. drying means as claimed in claim 1, wherein, said condenser is equipped with chilled brine.
6. drying means as claimed in claim 1 wherein, adopts the baking oven that is equipped with the high vacuum unit to carry out vacuum drying.
7. drying means as claimed in claim 6, wherein, said vacuum drying baking temperature is 25～35 ℃.
8. drying means as claimed in claim 6, wherein, said vacuum drying vacuum is 15～150Pa.
9. drying means as claimed in claim 6, wherein, said vacuum drying drying time is 6～24 hours.
10. like the arbitrary described drying means of claim 1～9; Wherein, Said drying means is applicable to the drying of peptide-containing antibiotic finished product, and said peptide-containing antibiotic finished product comprises vancomycin hydrochloride, teicoplanin, Daptomycin, Dalbavancin or oritavancin.
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| CN106546067B (en) * | 2015-09-18 | 2022-08-19 | 海南椰国食品有限公司 | Low-temperature integrated drying method for replacing bacterial cellulose gel film |
| CN110548130A (en) * | 2018-06-04 | 2019-12-10 | 浙江医药股份有限公司新昌制药厂 | daptomycin-containing spray dry powder and industrial preparation method thereof |
| CN111578627A (en) * | 2020-05-21 | 2020-08-25 | 上海上药第一生化药业有限公司 | Drying process of protein medicine |
| CN112197514B (en) * | 2020-10-26 | 2022-02-01 | 湖南精诚制药机械有限公司 | Vacuum drying oven that likepowder medicament is dry with drying efficiency height |
| CN113074519B (en) * | 2021-06-07 | 2021-10-29 | 美药星（南京）制药有限公司 | Method for efficiently removing residual organic solvent in insulin aspart |
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| CN1565697A (en) * | 2003-07-07 | 2005-01-19 | 珠海经济特区新科应用研究所 | Novel non-oxygen low temperature-extraction concentration spraying and desiccating production line |
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| CN1565697A (en) * | 2003-07-07 | 2005-01-19 | 珠海经济特区新科应用研究所 | Novel non-oxygen low temperature-extraction concentration spraying and desiccating production line |
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