CN113081975A - Preparation method of clindamycin phosphate freeze-dried powder injection for injection - Google Patents
Preparation method of clindamycin phosphate freeze-dried powder injection for injection Download PDFInfo
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- CN113081975A CN113081975A CN202110392963.0A CN202110392963A CN113081975A CN 113081975 A CN113081975 A CN 113081975A CN 202110392963 A CN202110392963 A CN 202110392963A CN 113081975 A CN113081975 A CN 113081975A
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
- C07H15/16—Lincomycin; Derivatives thereof
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
Abstract
The invention provides a preparation method of a clindamycin phosphate freeze-dried powder injection for injection, belonging to the technical field of medicine preparation, wherein the preparation method comprises the steps of taking water for injection with the temperature of less than or equal to 25 ℃, adding clindamycin phosphate in batches, slowly dropwise adding an alkali solution at the same time, keeping the system temperature of less than or equal to 25 ℃, dropwise adding the alkali solution until the clindamycin phosphate is dissolved and the pH value of the system is 6.0-6.4, stopping dropwise adding, decoloring, sterilizing, filtering, and freeze-drying to obtain the clindamycin phosphate freeze-dried powder injection for injection. According to the method, the feeding mode, the dissolving temperature and the finally adjusted pH value of the clindamycin phosphate are adjusted, so that the hydrolysis reaction of the clindamycin phosphate is effectively reduced, the stability of the clindamycin phosphate is improved, the impurity content of a finished product is reduced, and the problem of high impurity content of the finished product is solved.
Description
Technical Field
The invention relates to preparation of a freeze-dried powder injection, in particular to a preparation method of a clindamycin phosphate freeze-dried powder injection for injection.
Background
Clindamycin phosphate (Clindamycin phosphate) is a chemically semi-synthesized Clindamycin derivative, has no antibacterial activity in vitro, can be rapidly hydrolyzed into Clindamycin in vivo to show the pharmacological activity of the Clindamycin, so that the antibacterial spectrum, the antibacterial activity and the treatment effect are the same as those of Clindamycin, but the lipid solubility and the permeability of the Clindamycin phosphate are obviously superior to those of Clindamycin. Meanwhile, the antibacterial action of the clindamycin phosphate is 4-8 times stronger than that of the lincomycin, and the adverse reaction is reduced, so the clindamycin phosphate is mainly adopted clinically to achieve the treatment effect. The clindamycin phosphate for injection is suitable for treating various infectious diseases caused by gram-positive bacteria, including tonsillitis, suppurative otitis media, nasosinusitis, acute bronchitis, acute episode of chronic bronchitis, pneumonia, lung abscess, bronchiectasis complicated with infection, skin and soft tissue infection, urinary system infection, osteomyelitis, septicemia, peritonitis, oral infection and the like.
In the process of preparing clindamycin phosphate for injection, impurities such as lincomycin and clindamycin are mainly generated, and although the impurities also have certain antibacterial activity, the medicinal effect of the impurities is obviously lower than that of the clindamycin phosphate. Meanwhile, the clindamycin phosphate is easy to decompose under heating, and is easy to hydrolyze to generate impurities particularly under heating in water; and the clindamycin phosphate is easier to hydrolyze in acid solution and alkaline solution to generate impurities.
The Chinese patent application with publication number CN112206212A discloses a preparation method of clindamycin phosphate for injection, which improves the preparation process of clindamycin phosphate, but a small amount of clindamycin phosphate is hydrolyzed in the preparation process; in the refining process, the temperature is raised to 55 ℃ for many times, and although experiments prove that under the temperature, the clindamycin phosphate cannot be hydrolyzed in a large amount at one time, the hydrolysis phenomenon of the clindamycin phosphate is increased due to the temperature rise. Therefore, the stability of clindamycin phosphate for injection is still to be studied.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a clindamycin phosphate freeze-dried powder injection for injection.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of a clindamycin phosphate freeze-dried powder injection for injection comprises the steps of taking water for injection with the temperature of less than or equal to 25 ℃, adding clindamycin phosphate in batches, meanwhile, slowly dropwise adding an alkali solution, keeping the temperature of a system to be less than or equal to 25 ℃, stopping dropwise adding until the clindamycin phosphate is dissolved and the pH value of the system is 6.0-6.4, decoloring, sterilizing, filtering, and freeze-drying to obtain the clindamycin phosphate freeze-dried powder injection for injection.
Further, the clindamycin phosphate is prepared by the following refining method: adding a clindamycin phosphate crude product into a methanol water solution, dropwise adding an aqueous alkali till the clindamycin phosphate crude product is dissolved and the pH value of the methanol water solution is 6.0-6.4, stopping dropwise adding, decoloring, slowly dropwise adding ethanol for crystallization, filtering, and vacuum-drying at 20-30 ℃ for 3-6 hours to obtain the clindamycin phosphate.
Further, the content of methanol in the methanol aqueous solution is 50-80 vol%.
Furthermore, after refining the clindamycin phosphate and before preparing the freeze-dried powder injection, a supercritical extraction method is also needed to remove residual solvent.
Further, the supercritical extraction comprises the following steps which are carried out in sequence: taking the vacuum-dried clindamycin phosphate, performing static extraction and dynamic extraction by adopting carbon dioxide, controlling the extraction temperature to be 30-35 ℃ and the pressure to be 7.2-15 MPa, and collecting substances in extraction equipment after the extraction is finished, namely the clindamycin phosphate after the residual solvent is removed;
the static extraction time is 0.5-1 h;
the dynamic extraction time is 1-3 h;
in the dynamic extraction process, the amount of the supercritical carbon dioxide introduced per hour is 3-5 times of the weight of the vacuum-dried clindamycin phosphate.
Further, the weight volume ratio of the clindamycin phosphate crude product to the methanol water solution is 1 kg: 4-7L.
Further, the crystallization is carried out by firstly cooling to 10-15 ℃ for first crystallization for 0.5-1 h, then cooling to 4-6 ℃ for second crystallization for 0.5-1 h, and finally cooling to-5-0 ℃ for third crystallization for 3-6 h.
Further, in the purification method, the temperature of the methanol aqueous solution is always 25 ℃ or lower.
Further, the freeze drying comprises the following steps which are carried out in sequence:
pre-freezing: pre-freezing for 2-3.5 h under the conditions that the pressure is 10-15 MPa and the temperature is-40 to-35 ℃;
sublimation drying: keeping the pressure at 10-15 MPa, heating to-30-25 ℃ at 3-5 ℃/h, and carrying out primary sublimation drying for 0.5-1 h;
keeping the pressure at 10-15 MPa, heating to-20-15 ℃ at 3-5 ℃/h, and carrying out secondary sublimation drying for 0.5-1 h;
keeping the pressure at 10-15 MPa, heating to-10 to-5 ℃ at the speed of 3-5 ℃/h, and carrying out sublimation drying for the third time for 0.5-1.5 h;
keeping the pressure at 10-15 MPa, heating to 0-5 ℃ at a speed of 3-5 ℃/h, and carrying out resolution drying for 1-2 h for the fourth time;
and (3) resolving and drying: keeping the pressure at 10-15 MPa, heating to 10-15 ℃ at the speed of 3-5 ℃/h, and carrying out primary analysis and drying for 0.5-1.5 h;
keeping the pressure at 10-15 MPa, heating to 20-25 ℃ at 3-5 ℃/h, and carrying out secondary analysis and drying for 2-3 h.
Further, after the sterilization filtration and before the freeze drying, the mixture is subpackaged according to specifications;
the alkali solution is sodium hydroxide solution;
the dropping speed of the alkali solution is 0.5-1L/h.
The preparation method of the clindamycin phosphate freeze-dried powder injection for injection has the beneficial effects that:
according to the invention, the feeding mode, the dissolving temperature and the pH value of the clindamycin phosphate are adjusted, so that the hydrolysis of the clindamycin phosphate is effectively reduced, the stability of the clindamycin phosphate is increased, and the impurity content of a finished product is reduced;
according to the method, a proper dissolving system is selected, the ratio of methanol to water is adjusted, and the occurrence of the hydrolysis reaction of the clindamycin phosphate is reduced on the premise that the clindamycin phosphate can be completely dissolved; the proper pH value is selected, so that the clindamycin phosphate is fully dissolved, and the occurrence of hydrolysis reaction can be reduced;
removing a small amount of residual solvent, namely methanol, from the crystallized clindamycin phosphate in a supercritical extraction mode; the supercritical extraction has mild operation conditions, safety, no toxicity and simple process, and the extraction and separation are completed at one time, thereby avoiding the decomposition of the clindamycin phosphate at high temperature and simultaneously avoiding the introduction of new solvent to cause secondary pollution; by selecting proper temperature and pressure, the residual solvent is fully dissolved into the supercritical carbon dioxide when the supercritical carbon dioxide is contacted with the clindamycin phosphate, and the clindamycin phosphate is not dissolved into the supercritical carbon dioxide, so that the effect of thoroughly removing the residual solvent is achieved;
the crystallization is carried out in a gradient cooling mode, so that the separation of impurities caused by sudden cooling is avoided, the separation of different crystal forms of clindamycin phosphate is reduced, and the purity and the yield of the clindamycin phosphate are improved;
according to the invention, through adjusting the technological parameters in the sublimation drying process and the desorption drying process, the clindamycin phosphate can be fully and uniformly dried when being under the eutectic point in the drying process by adopting a slow heating and sectional drying mode, so that the water residue and solute migration in the liquid medicine of the clindamycin phosphate in the desorption drying process are prevented, the consistency of the upper structure and the lower structure of the clindamycin phosphate in the desorption process is maintained, the plumpness and the looseness of a finished product are effectively ensured, the surface of the obtained finished product is smoother, the appearance is good, and the re-dissolubility is excellent;
aiming at the fact that the clindamycin phosphate is likely to be decomposed to generate impurities in the heating process, the method effectively reduces the decomposition of the clindamycin phosphate in the heating process and further increases the stability of the finished product through slow heating and sectional drying; meanwhile, aiming at the fact that the clindamycin phosphate can form different crystal forms when rapidly heated in the crystallization process, the crystal form of the finished product is ensured to be single through slow heating and sectional drying, and further the better curative effect is ensured.
Detailed Description
The technical solutions in the embodiments of the present invention are 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.
Example 1 preparation method of clindamycin phosphate freeze-dried powder injection for injection
The embodiment is a preparation method of a clindamycin phosphate freeze-dried powder injection for injection, and the specific preparation process comprises the following steps in sequence:
1) purification of clindamycin phosphate
Taking 5L of methanol aqueous solution with the temperature of 20 ℃ and the methanol content of 71.5 vol%, adding 1kg of clindamycin phosphate crude product (the purity is 98.10%), according to Chinese pharmacopoeia (2015 edition of general rules of four parts 0512), measuring by adopting high performance liquid chromatography, stirring and fully dispersing in the methanol aqueous solution, slowly dripping 20 wt% of sodium hydroxide aqueous solution at the dripping speed of 0.5L/h, always maintaining the system temperature at 20 ℃ in the dripping process, stirring and fully dissolving the clindamycin phosphate crude product, then dripping the sodium hydroxide aqueous solution until the clindamycin phosphate crude product is fully dissolved and the pH value of the system is 6.2, adding 25g of medicinal active carbon, maintaining the decoloring at 20 ℃ for 30min (recorded as first decoloring), slowly dripping ethanol until a small amount of crystals are separated out, stopping adding (the dripping speed is generally controlled at about 0.5L/h), firstly cooling to 10 ℃ for first crystallization for 1h, cooling to 5 ℃ for secondary crystallization for 1h, finally cooling to 0 ℃ for third crystallization for 4h, keeping low temperature for filtration after crystallization is finished, washing for 3 times by using 20mL of ethanol, and vacuum drying for 4h at 25 ℃ to obtain 0.9813kg of clindamycin phosphate with the purity of 99.82%.
And (2) completely filling the clindamycin phosphate into an extraction device, filling carbon dioxide, setting the temperature to be 31.26 ℃, the pressure to be 7.2MPa, statically extracting for 0.5h, maintaining the same temperature and pressure, keeping the flow of supercritical carbon dioxide at 4kg/hr, dynamically extracting for 3h, and collecting a sample in the extraction device after extraction is finished, namely the clindamycin phosphate (pure product), wherein the weight of the sample is 0.9796kg, the total recovery rate is 97.96%, and the purity is 99.99%.
2) Preparation of clindamycin phosphate freeze-dried powder injection for injection
The prescription of the clindamycin phosphate freeze-dried powder injection for injection in the embodiment is as follows:
table 1 recipe (Specification 0.3g)
| Clindamycin phosphate | 300g |
| 20% by weight of sodium hydroxide | Proper amount of |
| Water for injection | Adding to 2000mL |
| Is made into | 1000 bottle |
Table 2 recipe (Specification 0.6g)
Boiling water for injection, and cooling;
adding 300g of clindamycin phosphate (the purified pure product can be generally added in three to five batches in the embodiment) into 2000mL of boiled injection water at 15 ℃, slowly adding 20 wt% of sodium hydroxide water at a dropping speed of 0.5L/h, keeping the temperature of the system at 15 ℃ all the time in the feeding process, stirring and dissolving the clindamycin phosphate, then adding the sodium hydroxide water until the clindamycin phosphate is completely dissolved and the pH value of the system is 6.2, stopping dropping, adding 10g of needle activated carbon, stirring and decoloring at 15 ℃ for 30min (marked as second decoloring), performing circulating decarburization filtration by using a3 mu m filter stick, detecting the obtained filtered filtrate, filtering by using a 0.22 mu m primary sterilization filter after passing the detection, and performing secondary terminal sterilization filtration by using a 0.22 mu m filter to obtain a standby liquid medicine;
subpackaging the liquid medicine according to the required specification, half plugging, transferring into a freeze dryer for vacuum freeze drying, wherein the vacuum freeze drying comprises prefreezing, sublimation drying and analysis drying;
pre-freezing: firstly, cooling a product in a freeze-drying machine to-40 ℃, keeping the pressure in the freeze-drying machine to be 10MPa, and pre-freezing at the temperature of-40 ℃ (0.3g of specification is pre-frozen for 2.5h, and 0.6g of specification is pre-frozen for 3.5 h);
sublimation drying: keeping the pressure in the box at 10MPa, heating to-30 ℃ at the speed of 5 ℃/h, and carrying out first sublimation drying (0.3g specification is dried for 0.5h, 0.6g specification is dried for 1 h);
keeping the pressure in the box at 10MPa, heating to-20 ℃ at the speed of 5 ℃/h, and carrying out secondary sublimation drying (0.3g specification is dried for 0.5h, 0.6g specification is dried for 1 h);
keeping the pressure in the box at 10MPa, heating to-10 deg.C at 5 deg.C/h, and performing sublimation drying for the third time (0.3g for 0.5h, 0.6g for 1.5 h);
keeping the pressure in the box at 10MPa, heating to 0 ℃ at the speed of 5 ℃/h, and carrying out sublimation drying for the fourth time (0.3g specification is dried for 1h, 0.6g specification is dried for 2 h);
and (3) resolving and drying: heating to 10 deg.C at 5 deg.C/h, maintaining the pressure in the oven at 10MPa, and performing first analysis and drying (0.3g for 0.5h, 0.6g for 1.5 h);
the temperature is raised to 20 ℃ at the speed of 5 ℃/h, the pressure in the oven is kept at 10MPa, and the second analysis drying is carried out (0.3g specification drying for 0.5h, 0.6g specification drying for 1.5 h).
And after drying, pressing the whole plug under a vacuum condition, and taking out of the box to obtain the clindamycin phosphate freeze-dried powder injection for injection.
Example 2-6 preparation method of clindamycin phosphate freeze-dried powder injection for injection
Examples 2 to 6 are methods for preparing clindamycin phosphate freeze-dried powder injection for injection, the steps of which are basically the same as those in example 1, and the differences are only in the amount of raw materials and process parameters, and the details are shown in table 3:
TABLE 3 summary of the process parameters of examples 2 to 6
The contents of the other portions of examples 2 to 6 are the same as those of example 1.
The clindamycin phosphate freeze-dried powder injection for injection prepared in the embodiment 1-6 has good stability and clarity, high main drug content, less impurities, smooth surface of a finished product, good appearance and excellent re-solubility.
Experimental example 1 influencing factors in Process for refining clindamycin phosphate
The same batch of crude clindamycin phosphate (purity 98.10%) was used, and comparative examples 1-10 were compared with the comparative test of the clindamycin phosphate refining process in example 1, except that:
in comparative example 1, water was used instead of the aqueous methanol solution, and the obtained clindamycin phosphate (pure product) had a total yield of 96.12% and a purity of 99.27%;
in comparative example 2, an aqueous methanol solution containing 40 vol% of methanol was used, and the total yield of the obtained clindamycin phosphate (pure product) was 97.11% and the purity was 99.04%;
in comparative example 3, an aqueous methanol solution containing 90 vol% of methanol was used, and the total yield of the obtained clindamycin phosphate (pure product) was 97.04% and the purity was 99.81%;
in comparative example 4, pure methanol was used instead of the aqueous methanol solution, and the obtained clindamycin phosphate (pure product) had an overall yield of 96.09% and a purity of 99.66%;
before crystallization in comparative example 5, the system temperature in the refining process was always maintained at 30 ℃, and the total yield of the obtained clindamycin phosphate (pure product) was 97.01%, and the purity was 99.81%;
in comparative example 6, the pH value was adjusted to 7.0, and the total yield of the obtained clindamycin phosphate (pure product) was 94.32% and the purity was 99.47%;
in comparative example 7, the pH value was adjusted to 5.5, and the total yield of the obtained clindamycin phosphate (pure product) was 95.11% and the purity was 99.68%;
in the comparative example 8, the temperature is directly reduced to 0 ℃ for crystallization for 6 hours during crystallization, and the total yield of the obtained clindamycin phosphate (pure product) is 97.83 percent, and the purity is 99.61 percent;
comparative example 9 the same batch of crude clindamycin phosphate was refined according to the refining method disclosed in example 2 of the chinese patent application publication No. CN107880083A, and the yield of the obtained clindamycin phosphate (pure product) was 96.74% and the purity was 98.97%;
comparative example 10 the same batch of crude clindamycin phosphate was refined according to the refining method disclosed in the specific embodiment of the chinese patent application publication No. CN112206212A, and the yield of the obtained clindamycin phosphate (pure product) was 97.65% and the purity was 98.79%;
as can be seen from the yield and purity of the clindamycin phosphate (pure product) obtained in the examples 1-6 and the comparative examples 1-10, the method can effectively inhibit the hydrolysis of the clindamycin phosphate by selecting a proper dissolving system, temperature and pH value, so as to improve the purity of the clindamycin phosphate;
by adjusting the crystallization mode, impurity precipitation caused by sudden cooling is avoided, precipitation of different crystal forms of clindamycin phosphate is reduced, and the purity of the clindamycin phosphate is improved;
after crystallization, a small amount of residual solvent, namely methanol, is thoroughly removed in a supercritical extraction mode, the purity of the clindamycin phosphate is further improved, and the harm of the residual solvent to human bodies is reduced.
Experimental example 2 Property measurement of clindamycin phosphate lyophilized powder for injection
Comparative examples 11 to 13 are comparative tests of the preparation process of the clindamycin phosphate freeze-dried powder injection (specification is 0.3g) for injection in example 1, and the differences are only that:
the pH was adjusted to 5.5 in comparative example 11;
in comparative example 12 the pH was adjusted to 7.0;
in comparative example 13, the temperature of the system was always maintained at 30 ℃ during the preparation of the drug solution;
comparative example 14 was prepared according to the preparation method disclosed in the examples of the chinese patent application publication No. CN112206212A, using clindamycin phosphate (pure product) prepared in example 1.
A1) Accelerated test
Taking clindamycin phosphate freeze-dried powder injections (specification 0.3g) for injection prepared in examples 1-6 and comparative examples 11-14, respectively placing the clindamycin phosphate freeze-dried powder injections for 12 months under the conditions of 40 +/-2 ℃ and RH75 +/-5%, respectively sampling at 1 st, 3 rd, 6 th, 9 th and 12 th months during the period, detecting according to stability check items, and comparing with day 0 data, wherein the specific determination method is as follows:
acidity: a proper amount of the product is taken, water is added to prepare a solution containing 10mg of clindamycin in each 1mL, and the pH value is measured according to the Chinese pharmacopoeia (2015 edition, general rules of the four parts of the world) 0631.
Clarity and color of the solution: adding water according to the marked amount to obtain a solution containing clindamycin 0.2g per 1mL, wherein the solution is clear and colorless; if the turbidity appears, the solution is not concentrated as compared with a turbidity standard solution No. 1 (Chinese pharmacopoeia (2015 edition four ministry general rule 0902 first method); if color development is observed, it should not be deeper than the yellow No. 2 standard colorimetric solution (Chinese pharmacopoeia 2015, first method 0901 in general rules in four departments).
Moisture content: the product is measured according to water determination method (Chinese pharmacopoeia (2015 edition four ministry general rule 0832 first method I)), and water content is not over 3.0%.
Related substances (mainly clindamycin and lincomycin): precisely weighing a proper amount of the product, adding a phosphate buffer solution (pH 3.9, the preparation method comprises the steps of taking 3.5mL of phosphoric acid, adding 1000mL of water and 2.5mL of concentrated ammonia water, adjusting the pH value to 3.9 +/-0.05 by using the concentrated ammonia water if necessary, adding 90 wt% of acetonitrile methanol solution, wherein the weight ratio of the phosphoric acid aqueous solution to the acetonitrile methanol solution is 80: 20), dissolving and quantitatively diluting, and determining according to the Chinese pharmacopoeia (2015 edition of the general rules of the four kingdoms 0512).
Content determination: according to Chinese pharmacopoeia (2015 edition four ministry of general regulation 0512), adopting high performance liquid chromatography to measure;
the specific test results are shown in the following table:
TABLE 4 summary of test results of accelerated test
As can be seen from Table 4, the stability of the clindamycin phosphate freeze-dried powder injections prepared in examples 1 to 6 is superior to that of the clindamycin phosphate freeze-dried powder injections prepared in comparative examples 11 to 14. And the content of related substances in the clindamycin phosphate freeze-dried powder injection for injection prepared in the embodiments 1 to 6 is lower, which shows that the impurities generated in the process of preparing the clindamycin phosphate freeze-dried powder injection for injection are less, and the process parameters of the invention are more beneficial to the preparation and storage of the clindamycin phosphate freeze-dried powder injection for injection.
A2) High temperature test
Taking the clindamycin phosphate freeze-dried powder injections (specification 0.3g) for injection prepared in the examples 1-6 and the comparative examples 10-13, respectively placing the clindamycin phosphate freeze-dried powder injections at 40 ℃ for 10 days, respectively sampling the samples on the 5 th and 10 th days in the period, detecting according to the stability key inspection items, and comparing with the data on the 0 th day, wherein the specific results are shown in the following table:
TABLE 5 summary of the test results of the high temperature test
As can be seen from Table 5, the clindamycin phosphate freeze-dried powder injection for injection prepared by the invention is very stable under high temperature condition, and all indexes have no obvious change.
A3) High humidity test
Taking the clindamycin phosphate freeze-dried powder injections (specification 0.3g) for injection prepared in the examples 1-6 and the comparative examples 10-13, respectively placing the clindamycin phosphate freeze-dried powder injections for 10 days under the conditions of 25 +/-2 ℃ and humidity of 90 +/-5%, respectively sampling the samples on the 5 th and 10 th days in the period, detecting according to the key stability inspection items, and comparing with the data on the 0 th day, wherein the specific results are shown in the following table:
table 6 summary of the test results of the high humidity test
As can be seen from Table 6, the clindamycin phosphate freeze-dried powder injection for injection prepared by the invention is very stable under high humidity conditions, and all indexes have no obvious change.
A4) Test by intense light irradiation
Taking the clindamycin phosphate freeze-dried powder injections (specification 0.3g) for injection prepared in the examples 1-6 and the comparative examples 10-13, respectively placing the clindamycin phosphate freeze-dried powder injections for 10 days under the condition of the illumination of 4500lx, respectively sampling the samples on the 5 th day and the 10 th day in the period, detecting according to the key stability inspection items, and comparing with the data of the 0 th day, wherein the specific results are shown in the following table:
table 7 table of test results of high illuminance test
As can be seen from Table 7, the clindamycin phosphate freeze-dried powder injection for injection prepared by the invention is very stable under the condition of strong light irradiation, and all indexes have no obvious change.
A5) Resolubility detection
Taking the clindamycin phosphate freeze-dried powder injection (specification is 0.3g) for injection prepared in the examples 1-6 and the comparative examples 10-13, adding 1.5mL of sterilized normal saline for dissolving, and observing the dissolving speed, wherein the test results are shown in the following table:
TABLE 8 summary of the results of the redissolution test
As can be seen from Table 8, the clindamycin phosphate freeze-dried powder injection for injection prepared by the invention has good re-solubility.
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. A preparation method of a clindamycin phosphate freeze-dried powder injection for injection is characterized by taking water for injection with the temperature of less than or equal to 25 ℃, adding clindamycin phosphate in batches, slowly dropwise adding an alkali solution at the same time, maintaining the system temperature of less than or equal to 25 ℃, stopping dropwise adding when the clindamycin phosphate is dissolved and the pH value of the system is 6.0-6.4, decoloring, sterilizing, filtering, and freeze-drying to obtain the clindamycin phosphate freeze-dried powder injection for injection.
2. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 1, wherein the clindamycin phosphate is prepared by the following refining method: and adding a clindamycin phosphate crude product into a methanol water solution, dropwise adding an aqueous alkali till the clindamycin phosphate crude product is dissolved and the pH value of the methanol water solution is 6.0-6.4, stopping dropwise adding, decoloring, slowly dropwise adding ethanol for crystallization, filtering, and drying in vacuum to obtain the clindamycin phosphate.
3. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 2, wherein the content of methanol in the methanol aqueous solution is 50-80 vol%.
4. The method for preparing the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 2 or 3, wherein a supercritical extraction method is used for removing residual solvent after the clindamycin phosphate is refined and before the clindamycin phosphate freeze-dried powder injection is prepared.
5. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 4, wherein the supercritical extraction comprises the following steps in sequence: and (3) taking the vacuum-dried clindamycin phosphate, performing static extraction and dynamic extraction by adopting carbon dioxide, controlling the extraction temperature to be 30-35 ℃ and the pressure to be 7.2-15 MPa, and collecting substances in extraction equipment after the extraction is finished, namely the clindamycin phosphate after the residual solvent is removed.
6. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 2, 3 or 5, wherein the weight volume ratio of the clindamycin phosphate crude product to the methanol water solution is 1 kg: 4-7L.
7. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 2, 3 or 5, wherein the crystallization is carried out by firstly cooling to 10-15 ℃ for the first crystallization for 0.5-1 h, then cooling to 4-6 ℃ for the second crystallization for 0.5-1 h, and finally cooling to-5-0 ℃ for the third crystallization for 3-6 h.
8. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in claim 2, 3 or 5, wherein in the refining method, the temperature of the methanol water solution is always below 25 ℃.
9. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in any one of claims 1 to 3 and 5, wherein the freeze-drying comprises the following steps which are carried out in sequence:
pre-freezing: pre-freezing for 2-3.5 h under the conditions that the pressure is 10-15 MPa and the temperature is-40 to-35 ℃;
sublimation drying: keeping the pressure at 10-15 MPa, heating to-30 to-25 ℃ at the speed of 3-5 ℃/h, and carrying out first sublimation drying for 0.5-1 h;
keeping the pressure at 10-15 MPa, heating to-20 to-15 ℃ at the speed of 3-5 ℃/h, and carrying out secondary sublimation drying for 0.5-1 h;
keeping the pressure at 10-15 MPa, heating to-10 to-5 ℃ at the speed of 3-5 ℃/h, and carrying out sublimation drying for the third time for 0.5-1.5 h;
keeping the pressure at 10-15 MPa, heating to 0-5 ℃ at a speed of 3-5 ℃/h, and carrying out resolution drying for 1-2 h for the fourth time;
and (3) resolving and drying: keeping the pressure at 10-15 MPa, heating to 10-15 ℃ at the speed of 3-5 ℃/h, and carrying out primary analysis and drying for 0.5-1.5 h;
keeping the pressure at 10-15 MPa, heating to 20-25 ℃ at 3-5 ℃/h, and carrying out secondary analysis and drying for 2-3 h.
10. The preparation method of the clindamycin phosphate freeze-dried powder injection for injection as claimed in any one of claims 1 to 3 and 5, wherein the preparation method is characterized in that the preparation method further comprises the step of subpackaging according to specifications after sterilization and filtration and before freeze drying.
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| CN115581675A (en) * | 2022-11-02 | 2023-01-10 | 海南锦瑞制药有限公司 | Preparation method of clindamycin phosphate for injection |
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Denomination of invention: Preparation method of clindamycin phosphate freeze-dried powder injection for injection Effective date of registration: 20230920 Granted publication date: 20221129 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |