CN113061110A - Purification method of ciprofloxacin hydrochloride, ciprofloxacin hydrochloride freeze-dried powder for injection and preparation method thereof - Google Patents
Purification method of ciprofloxacin hydrochloride, ciprofloxacin hydrochloride freeze-dried powder for injection and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention belongs to the technical field of medicament purification, and particularly relates to a ciprofloxacin hydrochloride purification method, ciprofloxacin hydrochloride freeze-dried powder for injection and a preparation method thereof. The purification method of ciprofloxacin hydrochloride comprises the following steps: heating and dissolving the ciprofloxacin hydrochloride crude product in ethanol with the volume fraction of 68-72%, decoloring by using activated carbon, adjusting the pH to 3.0-4.5, crystallizing, and drying to obtain the purified ciprofloxacin hydrochloride. According to the method, ethanol with a specific volume fraction of 68-72% is used as a purification solvent, and the steps of activated carbon decolorization and pH adjustment are combined, so that the ciprofloxacin hydrochloride injection prepared from the purified ciprofloxacin hydrochloride is high in purity and low in impurity content; the purification method is suitable for any one of the conventional ciprofloxacin hydrochloride preparation methods to prepare the crude ciprofloxacin hydrochloride.
Description
Technical Field
The invention belongs to the technical field of medicament purification, and particularly relates to a ciprofloxacin hydrochloride purification method, ciprofloxacin hydrochloride freeze-dried powder for injection and a preparation method thereof.
Background
Ciprofloxacin hydrochloride is the hydrochloride of ciprofloxacin which is a third-generation fluoroquinolone antibacterial drug, and is used for urogenital system infection caused by sensitive bacteria, including simple and complex urinary tract infection, bacterial prostatitis, Neisseria gonorrhoeae urethritis or cervicitis (including those caused by enzyme-producing strains). Respiratory infections, including acute episodes of bronchial infections and pulmonary infections caused by susceptible gram-negative bacilli. Gastrointestinal infections are caused by Shigella, Salmonella, enterotoxigenic Escherichia coli, Aeromonas hydrophila, Vibrio parahaemolyticus, and the like. In addition, it can be used for treating cold injury, joint infection, skin soft tissue infection, and septicemia.
The ciprofloxacin hydrochloride used clinically at present comprises an oral preparation and an injection. The specifications of marketed ciprofloxacin hydrochloride tablets and capsules indicate that: "crystallization of urine can occur in large doses or at urine pH above 7; in order to avoid the occurrence of crystallized urine, more water is needed, and the urine output is kept above 1200mL for 24h, so the use of alkalizer is avoided. The daily water inflow is sufficient so as to keep the daily urine volume above 1200-1500 mL. Because ciprofloxacin hydrochloride is easy to separate out under the alkaline condition and is absorbed by the gastrointestinal tract, partial ciprofloxacin hydrochloride can be separated out and crystallized in the alkaline small intestine environment and cannot be absorbed by the human body, the drug effect is influenced, and meanwhile calculus of the urinary system is easy to form. In addition, the difference of the pH value of the gastrointestinal tract of different patients is large, so that the problem of difference of in vivo absorption is easily caused when the medicine is taken by different patients with alkaline gastrointestinal tract, and the medicine effect exerted by the patients with the same disease condition after the medicine is taken is inconsistent.
In view of the above-mentioned disadvantages of oral preparations, parenteral ciprofloxacin hydrochloride injection formulations are more widely used, but research shows that the existing ciprofloxacin hydrochloride injection has high impurity content of related substances.
Disclosure of Invention
Aiming at the problems, the invention provides a ciprofloxacin hydrochloride purification method, ciprofloxacin hydrochloride freeze-dried powder for injection and a preparation method thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for purifying ciprofloxacin hydrochloride comprises the following steps:
heating and dissolving the ciprofloxacin hydrochloride crude product in ethanol with the volume fraction of 68-72%, decoloring by using activated carbon, adjusting the pH to 3.0-4.5, crystallizing, and drying to obtain the purified ciprofloxacin hydrochloride.
Optionally, the mass-to-volume ratio of the ciprofloxacin hydrochloride crude product to 68-72% ethanol is 1g (3.7-4.3) mL.
Optionally, the mass ratio of the ciprofloxacin hydrochloride crude product to the activated carbon is 100 (0.4-0.5).
Optionally, the heating and dissolving temperature is 58-62 ℃;
in the step of decoloring the active carbon, adding the active carbon, continuously heating at 58-62 ℃ for 24-26 min, and then filtering while the solution is hot.
Optionally, drying the solid obtained in the crystallization step at 60-65 ℃ under reduced pressure for 3.5-4.5 h.
The invention also provides ciprofloxacin hydrochloride freeze-dried powder for injection, which contains ciprofloxacin hydrochloride and mannitol obtained by purifying the ciprofloxacin hydrochloride purification method.
Optionally, the mass ratio of the ciprofloxacin hydrochloride to the mannitol is 1 (0.4-0.6).
The invention also provides a preparation method of the ciprofloxacin hydrochloride freeze-dried powder for injection, which comprises the following steps:
heating and dissolving ciprofloxacin hydrochloride and mannitol in water for injection, adding medicinal activated carbon, stirring and filtering, then adding water for injection into the filtrate, adjusting the pH value to 3.0-4.5, and filtering again to obtain a semi-finished product; and (5) after the semi-finished product is detected to be qualified, freezing and drying to obtain the product.
Optionally, the ratio of the total volume of ciprofloxacin hydrochloride, mannitol and water for injection to the mass of the medicinal activated carbon in the semi-finished product preparation step is 100mL (0.08-0.12) g.
Optionally, in the step of freeze drying, pre-freezing for 1.5-2.5h at-50 to-40 ℃, and then raising the temperature to 35-40 ℃ at a temperature rise rate of 2 ℃/h and keeping for 3-4h under the condition of a vacuum degree of 15 Pa.
Optionally, the second filtration is performed by sterile filtration with a 0.22 μm microporous membrane.
Optionally, the semi-finished product detection comprises detecting the color, content and the like of the solution of the semi-finished product.
The invention has the beneficial effects that:
1. the inventor finds that the content of impurity components such as fluoroquinolinic acid, ciprofloxacin impurity B, ciprofloxacin impurity C, ciprofloxacin impurity D, ciprofloxacin impurity E and ciprofloxacin impurity I in the purified ciprofloxacin hydrochloride is remarkably reduced by adopting ethanol with a specific volume fraction of 68-72% as a purification solvent; the ethanol with the volume fraction of 68-72% is adopted, the optimal concentration of heating dissolution and cooling crystallization can be considered, if the concentration of the ethanol is too low, the solubility of ciprofloxacin hydrochloride is increased, less solid is precipitated during crystallization, and the yield is reduced; if the concentration of ethanol is too high, ciprofloxacin hydrochloride cannot be completely dissolved in ethanol, and the yield is reduced. Ethanol with a specific concentration is selected as a purification solvent, so that the purity of the ciprofloxacin hydrochloride can be improved, the impurity content is reduced, and the yield of the ciprofloxacin hydrochloride can be improved.
According to the method, ethanol with a specific volume fraction of 68-72% is used as a purification solvent, and the active carbon decolorization and pH adjustment steps are combined, so that the content of impurity A (fluoroquinolinic acid) in ciprofloxacin hydrochloride freeze-dried powder for injection prepared from purified ciprofloxacin hydrochloride can be controlled to be 0.02%; the sum of ciprofloxacin impurity B, ciprofloxacin impurity C, ciprofloxacin impurity D and ciprofloxacin impurity E can be controlled to be less than 0.15%; the content of other single impurities can be controlled below 0.02%, and the sum of total impurities can be controlled below 0.15%; the purification method is suitable for any one of the conventional ciprofloxacin hydrochloride preparation methods to prepare the crude ciprofloxacin hydrochloride.
2. According to the purification method of ciprofloxacin hydrochloride, provided by the invention, the mass-volume ratio of the crude ciprofloxacin hydrochloride to ethanol with a specific volume fraction is further limited, and the steps of activated carbon decolorization and pH adjustment are combined, so that the impurity content of the purified ciprofloxacin hydrochloride can be further reduced, and the purification yield is improved.
3. According to the purification method of ciprofloxacin hydrochloride provided by the invention, the impurity content in the purified ciprofloxacin hydrochloride can be further reduced and the purification yield is improved by further limiting the mass ratio of the crude ciprofloxacin hydrochloride to the active carbon.
4. According to the purification method of ciprofloxacin hydrochloride, provided by the invention, ethanol with a specific concentration is used as a purification solvent, and the steps of decoloring by using activated carbon, adjusting the pH value, crystallizing, drying and parameters in the steps are combined, so that the purified ciprofloxacin hydrochloride is high in content, and the content of impurities in related substances is low.
5. Compared with the existing ciprofloxacin hydrochloride injection (including ciprofloxacin hydrochloride freeze-dried powder for injection), the ciprofloxacin hydrochloride freeze-dried powder for injection prepared by using the ciprofloxacin hydrochloride purified by the ciprofloxacin hydrochloride purification method provided by the invention can obviously reduce the impurity content therein.
6. According to the preparation method of the ciprofloxacin hydrochloride freeze-dried powder for injection, active carbon is firstly used for decoloring, and then the pH value is adjusted, so that the condition that the pH value of a final product exceeds the standard due to the fact that the active carbon is firstly adjusted and then decolored can be effectively prevented; the semi-finished product is checked for color and content of the solution and then is freeze-dried, so that the qualification rate of the product can be improved. Compared with the existing ciprofloxacin hydrochloride freeze-dried powder for injection, the ciprofloxacin hydrochloride freeze-dried powder for injection prepared by using the ciprofloxacin hydrochloride purified by the purification method for ciprofloxacin hydrochloride provided by the invention has the advantage that the content of each impurity in related substances is reduced.
Detailed Description
The technical solution of the present invention is clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
The purification method of ciprofloxacin hydrochloride provided by the invention is suitable for any one of the existing ciprofloxacin hydrochloride preparation methods to prepare crude ciprofloxacin hydrochloride. However, for comparison, the crude ciprofloxacin hydrochloride used in the following examples and comparative examples was prepared as follows:
30kg of cyclopropanecarboxylic acid (106.5mol), 50kg of piperazine (580.5mol) and 150L of 2-pyrrolidone were put in a 250L clean three-necked flask. Stirring uniformly, heating to 70-80 ℃, timing and preserving heat for about 3 hours. The sampling liquid phase is monitored, and the carboxylic acid residue is controlled below 1.5 percent. After the heat preservation reaction is finished, cooling to 28 +/-2 ℃; after the temperature reduction is finished, standing for 3h, carrying out suction filtration, putting a filter cake into 150L of water, stirring and heating to 85 ℃, dropwise adding 30% by mass of hydrochloric acid until the reaction solution is clear, then stirring and dropwise adding 30% by mass of hydrochloric acid until the pH value is 3.0, slowly cooling to 35 ℃, stirring and crystallizing, carrying out suction filtration, rinsing for 2 times by using 20L of 95% ethanol, paving and naturally standing for 0.5h to obtain 50kg of ciprofloxacin hydrochloride crude product. The determination is carried out according to the content determination method of ciprofloxacin hydrochloride in the 2020 edition Chinese pharmacopoeia, and the content of ciprofloxacin hydrochloride in the crude product is 84.5 percent.
Example 1
The embodiment provides a method for purifying ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.0L of 70% ethanol solution by volume fraction, heating to 60 ℃, stirring for dissolving, then adding 7.0g of activated carbon, keeping the temperature at 60 ℃, heating for 25min, filtering while hot, adjusting the pH of filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 1.30kg of ciprofloxacin hydrochloride as white crystalline powder.
Example 2
The embodiment provides a method for purifying ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 5.5L of ethanol solution with the volume fraction of 68%, heating to 62 ℃, stirring for dissolving, then adding 7.5g of activated carbon, keeping the temperature at 58 ℃, heating for 26min, filtering while hot, adjusting the pH of filtrate to 3.0 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum filtration to obtain white crystals, and drying the white crystals at 60 ℃ for 4.5h under reduced pressure to obtain 1.25kg of ciprofloxacin hydrochloride as white crystalline powder.
Example 3
The embodiment provides a method for purifying ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.4L of 72% ethanol solution by volume fraction, heating to 58 ℃, stirring for dissolving, then adding 6g of activated carbon, keeping the temperature of 62 ℃, heating for 24min, filtering while hot, adjusting the pH of filtrate to 4.0 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum filtration to obtain white crystals, and drying the white crystals at 62 ℃ for 4.5h under reduced pressure to obtain 1.20kg of ciprofloxacin hydrochloride as white crystalline powder.
Example 4
The embodiment provides a method for purifying ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 5.0L of 70% ethanol solution by volume fraction, heating to 60 ℃, stirring for dissolving, then adding 7.0g of activated carbon, keeping the temperature at 60 ℃, heating for 25min, filtering while hot, adjusting the pH of filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 1.28kg of ciprofloxacin hydrochloride as white crystalline powder.
Example 5
The embodiment provides a method for purifying ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.0L of 70% ethanol solution by volume fraction, heating to 60 ℃, stirring for dissolving, then adding 5.5g of activated carbon, keeping the temperature at 60 ℃, heating for 25min, filtering while hot, adjusting the pH of filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum suction filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 1.18kg of ciprofloxacin hydrochloride as white crystalline powder.
Example 6
The embodiment provides ciprofloxacin hydrochloride freeze-dried powder for injection, which is prepared by the following steps:
50g of ciprofloxacin hydrochloride purified in example 1 and 25g of mannitol are mixed with 800mL of water for injection, heated to 60 ℃ and stirred to be dissolved; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Example 7
The embodiment provides ciprofloxacin hydrochloride freeze-dried powder for injection, which is prepared by the following steps:
50g of ciprofloxacin hydrochloride purified in example 2 and 20g of mannitol are mixed with 800mL of water for injection, heated to 55 ℃, and stirred to be dissolved; then adding 1.2g of medicinal activated carbon, continuously keeping the temperature of 55 ℃ and stirring for 10min, filtering to remove the medicinal activated carbon while the mixture is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 3.0 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2.5h at-50 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 40 ℃, desorbing and drying until the temperature of the product reaches more than 40 ℃, balancing for 3h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Example 8
The embodiment provides ciprofloxacin hydrochloride freeze-dried powder for injection, which is prepared by the following steps:
50g of ciprofloxacin hydrochloride obtained by purification in example 3 and 30g of mannitol are mixed with 800mL of water for injection, heated to 50 ℃ and stirred to be dissolved; then adding 1.0g of medicinal activated carbon, continuously keeping the temperature of 50 ℃ and stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.0 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 1.5h at-45 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 35 ℃, desorbing and drying until the temperature of the product reaches more than 35 ℃, balancing for 4h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Example 9
The embodiment provides ciprofloxacin hydrochloride freeze-dried powder for injection, which is prepared by the following steps:
50g of ciprofloxacin hydrochloride purified in example 4 and 25g of mannitol are mixed with 800mL of water for injection, heated to 60 ℃ and stirred to be dissolved; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Example 10
The embodiment provides ciprofloxacin hydrochloride freeze-dried powder for injection, which is prepared by the following steps:
50g of ciprofloxacin hydrochloride purified in example 5 and 25g of mannitol are mixed with 800mL of water for injection, heated to 60 ℃ and stirred to be dissolved; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Comparative example 1
The comparative example provides a purification method of ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.0L of water, stirring for dissolving, then adding 7.0g of activated carbon, heating to 60 ℃, keeping for 25min, filtering while hot, adjusting the pH of the filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum suction filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 0.9kg of yellow crystalline powder ciprofloxacin hydrochloride.
Comparative example 2
The comparative example provides a purification method of ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.0L of 65% ethanol solution by volume fraction, heating to 60 ℃, stirring for dissolving, then adding 7.0g of activated carbon, keeping the temperature at 60 ℃, heating for 25min, filtering while hot, adjusting the pH of filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum suction filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 1.01kg of yellowish crystalline powder ciprofloxacin hydrochloride.
Comparative example 3
The comparative example provides a purification method of ciprofloxacin hydrochloride, which specifically comprises the following steps:
putting 1.5kg of ciprofloxacin hydrochloride crude product into a 10L flask, adding 6.0L of 75% ethanol solution by volume fraction, heating to 60 ℃, stirring for dissolving, then adding 7.0g of activated carbon, keeping the temperature at 60 ℃, heating for 25min, filtering while hot, adjusting the pH of filtrate to 4.5 by using 30% hydrochloric acid solution, then cooling to room temperature, crystallizing, carrying out vacuum suction filtration to obtain white crystals, and drying the white crystals at 65 ℃ for 4h under reduced pressure to obtain 1.02kg of yellowish crystalline powder ciprofloxacin hydrochloride.
Comparative example 4
The comparative example provides ciprofloxacin hydrochloride freeze-dried powder for injection, and the preparation method comprises the following steps:
mixing 50g of ciprofloxacin hydrochloride purified in comparative example 1 and 25g of mannitol with 800mL of water for injection, heating to 60 ℃, and stirring to dissolve; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Comparative example 5
The comparative example provides ciprofloxacin hydrochloride freeze-dried powder for injection, and the preparation method comprises the following steps:
mixing 50g of ciprofloxacin hydrochloride purified in the comparative example 2 and 25g of mannitol with 800mL of water for injection, heating to 60 ℃, and stirring to dissolve; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Comparative example 6
The comparative example provides ciprofloxacin hydrochloride freeze-dried powder for injection, and the preparation method comprises the following steps:
mixing 50g of ciprofloxacin hydrochloride purified in comparative example 3 and 25g of mannitol with 800mL of water for injection, heating to 60 ℃, and stirring to dissolve; then adding 0.8g of medicinal activated carbon, continuously keeping the temperature of 60 ℃, stirring for 10min, filtering to remove the medicinal activated carbon while the solution is hot, supplementing the water for injection to 1000mL, adjusting the pH value to 4.5 by using 30% hydrochloric acid, and performing aseptic filtration by using a 0.22 mu m microporous filter membrane to obtain a semi-finished product;
1mL of the semi-finished product is diluted by 5 times of water, the obtained solution is clear, and the color of the solution is lighter compared with yellow or yellow-green No. 4 standard colorimetric solution in a color inspection method of a solution of four parts 0901 in the 2020 edition of Chinese pharmacopoeia. Taking 1mL of semi-finished product, diluting the semi-finished product by 500 times with 0.025mol/L phosphoric acid solution-acetonitrile (87:13) (adjusting the pH value to 3.0 by triethylamine), then determining ciprofloxacin hydrochloride according to a determination method under the item of content determination of ciprofloxacin hydrochloride for injection of national drug standard WS1- (X-012) -2012Z, filling the semi-finished product in a controlled injection bottle according to the amount of 0.2g of ciprofloxacin in each bottle, and semi-tamponading;
transferring the semi-tamponade product into a freeze dryer, pre-freezing for 2h at-40 ℃, vacuumizing until the vacuum degree reaches 15Pa, heating at 2 ℃/h for sublimation until the temperature of the product reaches more than 1 ℃, setting the temperature of a partition plate to be 38 ℃, desorbing and drying until the temperature of the product reaches more than 38 ℃, balancing for 3.5h, fully tamponade, and taking out of the box;
and (5) rolling and sealing the product after the product is taken out of the box by using an aluminum plastic cover to obtain the product.
Experimental example 1
The ciprofloxacin hydrochloride obtained by purifying the ciprofloxacin hydrochloride obtained in the embodiments 1-5 and the comparative examples 1-3 is respectively detected according to content determination, related substances, clarity, color, acidity (pH), identification and other detection methods of the ciprofloxacin hydrochloride in China pharmacopoeia 2020 edition.
Wherein, the identification and the clarity and the color of the solution all accord with the pharmacopoeia standard, and the specific other detection results are shown in the following table.
TABLE 1 test results
Note: the ciprofloxacin hydrochloride obtained after purification contains crystal water, wherein the content of the crystal water is 4.7-6.7%.
As can be seen from the data in the table above, the purity of the ciprofloxacin hydrochloride obtained by purifying the ciprofloxacin hydrochloride provided by the invention is better than that of the ciprofloxacin hydrochloride obtained by purifying by the purification method in the comparative example, and the content of each related substance in the ciprofloxacin hydrochloride obtained by purifying the invention is lower than that of the comparative example.
Experimental example 2
The ciprofloxacin hydrochloride freeze-dried powder for injection prepared in the examples 6 to 10 and the comparative examples 4 to 6 is prepared according to the national drug standard WS1The content determination, the clarity, the color, the acidity (pH), the identification and other detection methods of the ciprofloxacin hydrochloride for injection of (X-012) -2012Z are respectively detected. Wherein, the identification and the clarity and the color of the solution all accord with the pharmacopoeia standard, and the specific other detection results are shown in the following table.
TABLE 2 measurement results
As can be seen from the data in the table above, the content of impurities in each relevant substance in the ciprofloxacin hydrochloride freeze-dried powder for injection prepared by the invention is lower than that of the comparative example.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. The method for purifying ciprofloxacin hydrochloride is characterized by comprising the following steps:
heating and dissolving the ciprofloxacin hydrochloride crude product in ethanol with the volume fraction of 68-72%, decoloring by using activated carbon, adjusting the pH to 3.0-4.5, crystallizing, and drying to obtain the purified ciprofloxacin hydrochloride.
2. The method for purifying ciprofloxacin hydrochloride according to claim 1, wherein the mass-to-volume ratio of the crude ciprofloxacin hydrochloride to 68-72% by volume of ethanol is 1g (3.7-4.3) mL.
3. The method for purifying ciprofloxacin hydrochloride according to claim 1 or 2, wherein the mass ratio of the crude ciprofloxacin hydrochloride to the activated carbon is 100: 0.4-0.5.
4. A method for purifying ciprofloxacin hydrochloride according to any one of claims 1 to 3, wherein the temperature for heating and dissolving is 58 to 62 ℃;
in the step of decoloring the active carbon, adding the active carbon, continuously heating at 58-62 ℃ for 24-26 min, and then filtering while the solution is hot.
5. A method for purifying ciprofloxacin hydrochloride according to any one of claims 1 to 4, wherein the solid obtained in the crystallization step is dried at 60 to 65 ℃ under reduced pressure for 3.5 to 4.5 hours.
6. A freeze-dried powder of ciprofloxacin hydrochloride for injection, which comprises ciprofloxacin hydrochloride purified by the purification method of ciprofloxacin hydrochloride of any one of claims 1 to 5 and mannitol.
7. The ciprofloxacin hydrochloride freeze-dried powder for injection as claimed in claim 6, wherein the mass ratio of ciprofloxacin hydrochloride to mannitol is 1: 0.4-0.6.
8. A method for preparing ciprofloxacin hydrochloride freeze-dried powder for injection as claimed in claim 6 or 7, characterized by comprising the following steps:
heating and dissolving ciprofloxacin hydrochloride and mannitol in water for injection, adding medicinal activated carbon, stirring and filtering, then adding water for injection into the filtrate, adjusting the pH value to 3.0-4.5, and filtering again to obtain a semi-finished product; and (5) after the semi-finished product is detected to be qualified, freezing and drying to obtain the product.
9. The preparation method of ciprofloxacin hydrochloride freeze-dried powder for injection as claimed in claim 8, wherein the ratio of the total volume of ciprofloxacin hydrochloride, mannitol and water for injection to the mass of medicinal activated carbon in the semi-finished product preparation step is 100mL (0.08-0.12) g.
10. The preparation method of ciprofloxacin hydrochloride freeze-dried powder for injection as claimed in claim 8 or 9, wherein in the freeze-drying step, pre-freezing is carried out for 1.5-2.5h at-50 to-40 ℃, and then the temperature is raised to 35-40 ℃ at the temperature raising rate of 2 ℃/h and kept for 3-4h under the vacuum degree of 15 Pa.
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