CN112472668A - Method for preparing amiodarone hydrochloride injection - Google Patents
Method for preparing amiodarone hydrochloride injection Download PDFInfo
- Publication number
- CN112472668A CN112472668A CN202011207802.1A CN202011207802A CN112472668A CN 112472668 A CN112472668 A CN 112472668A CN 202011207802 A CN202011207802 A CN 202011207802A CN 112472668 A CN112472668 A CN 112472668A
- Authority
- CN
- China
- Prior art keywords
- injection
- amiodarone hydrochloride
- water
- polysorbate
- liquid medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960003234 amiodarone hydrochloride Drugs 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002347 injection Methods 0.000 title claims abstract description 21
- 239000007924 injection Substances 0.000 title claims abstract description 21
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 41
- 239000007788 liquid Substances 0.000 claims abstract description 40
- 239000008215 water for injection Substances 0.000 claims abstract description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000243 solution Substances 0.000 claims abstract description 33
- 229920000136 polysorbate Polymers 0.000 claims abstract description 23
- 229950008882 polysorbate Drugs 0.000 claims abstract description 23
- 238000011049 filling Methods 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims abstract description 11
- 238000005303 weighing Methods 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 230000001954 sterilising effect Effects 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000004382 potting Methods 0.000 claims abstract description 6
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 5
- 229960004217 benzyl alcohol Drugs 0.000 claims abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 18
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 14
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 14
- 229920000053 polysorbate 80 Polymers 0.000 description 14
- 229940068968 polysorbate 80 Drugs 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 9
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- 239000005388 borosilicate glass Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960005260 amiodarone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010003662 Atrial flutter Diseases 0.000 description 1
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 208000008376 Pre-Excitation Syndromes Diseases 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004031 devitrification Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 208000008510 paroxysmal tachycardia Diseases 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There is provided a method for preparing amiodarone hydrochloride injection, which comprises the steps of: weighing: weighing the prescribed amount of polysorbate, amiodarone hydrochloride, benzyl alcohol and water for injection; liquid preparation: adding polysorbate to obtain a polysorbate solution and amiodarone hydrochloride to obtain an amiodarone hydrochloride solution while controlling a part of the water for injection to be at a temperature in a range of 60-75 ℃ and charging nitrogen, then cooling the amiodarone hydrochloride solution to room temperature and adding benzyl alcohol, and making up the remaining part of the water for injection to obtain a liquid medicine; and (3) filtering: sterilizing and filtering the liquid medicine; and a potting step: filling the filtered liquid medicine into a container while filling nitrogen, wherein the method does not adopt a sterilization step. The method can prepare amiodarone hydrochloride injection with low impurity content with high production efficiency.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for preparing amiodarone hydrochloride injection.
Background
Amiodarone hydrochloride injection is one of the commonly used drugs for arrhythmia and angina pectoris in clinic. The amiodarone hydrochloride injection can selectively expand the blood flow of coronary artery, simultaneously reduce the oxygen consumption of myocardium, slow down heart rate, reduce the atrioventricular conduction speed, has the effect similar to that of a beta-receptor blocker, and has excellent treatment effects on supraventricular and ventricular tachycardia, paroxysmal atrial flutter and fibrillation, pre-excitation syndrome, refractory paroxysmal tachycardia, chronic coronary insufficiency, angina pectoris and the like.
The existing preparation process of amiodarone hydrochloride injection has higher production cost and higher impurity content, thereby generating hidden danger to medication safety.
Therefore, it is necessary to develop an amiodarone hydrochloride injection with low impurity content to ensure the safety of medication.
Disclosure of Invention
In view of the problems of the prior art, the present inventors have conducted intensive studies and found that the production efficiency problem caused by indissolvability of amiodarone hydrochloride can be solved and the problem of high impurity content of the injection produced by the existing method can be solved by controlling the temperature of the solution preparation and the charging sequence during the solution preparation process, thereby completing the present invention.
Accordingly, it is an object of the present invention to provide a method for preparing amiodarone hydrochloride injection which can prepare amiodarone hydrochloride injection having a low impurity content with high productivity.
To this end, the present invention provides a method for preparing amiodarone hydrochloride injection, comprising the steps of: weighing: weighing the prescribed amount of polysorbate, amiodarone hydrochloride, benzyl alcohol and water for injection; liquid preparation: adding polysorbate to obtain a polysorbate solution and amiodarone hydrochloride to obtain an amiodarone hydrochloride solution while controlling a part of the water for injection to be at a temperature in a range of 60-75 ℃ and charging nitrogen, then cooling the amiodarone hydrochloride solution to room temperature and adding benzyl alcohol, and making up the remaining part of the water for injection to obtain a liquid medicine; and (3) filtering: sterilizing and filtering the liquid medicine; and a potting step: filling the filtered liquid medicine into a container while filling nitrogen, wherein the method does not adopt a sterilization step.
The method according to the present invention further comprises a step of holding at 70-75 ℃ for more than 1 hour after the potting step.
According to the method of the present invention, further, the part of the water for injection accounts for 60 to 80 vol% of the total amount of the water for injection.
Further, according to the method of the present invention, each 3mL of the injection solution contains 150mg of amiodarone hydrochloride, 60mg of benzyl alcohol and 300mg of polysorbate.
Advantageous effects
The method according to the present invention can prepare amiodarone hydrochloride injection having a low impurity content with high production efficiency. In addition, the method can further eliminate the crystallization phenomenon of the amiodarone hydrochloride injection.
Detailed Description
The method according to the invention comprises the following steps: weighing: weighing the prescribed amount of polysorbate, amiodarone hydrochloride, benzyl alcohol and water for injection; liquid preparation: adding polysorbate to obtain a polysorbate solution and amiodarone hydrochloride to obtain an amiodarone hydrochloride solution while controlling a part of the water for injection to be at a temperature in a range of 60-75 ℃ and charging nitrogen, then cooling the amiodarone hydrochloride solution to room temperature and adding benzyl alcohol, and making up the remaining part of the water for injection to obtain a liquid medicine; and (3) filtering: sterilizing and filtering the liquid medicine; and a potting step: filling the filtered liquid medicine into a container while filling nitrogen, wherein the method does not adopt a sterilization step.
The method according to the invention uses an aseptic production process, since the sterilization process will lead to a significant growth of the substances involved.
In one or more embodiments, each 3mL injection may contain 150mg of amiodarone hydrochloride, 60mg of benzyl alcohol, and 300mg of polysorbate.
According to the present invention, the liquid preparation step is very critical for controlling the amount of the relevant substances. The order of addition and temperature should be controlled during the compounding step. When amiodarone hydrochloride is first added to water for injection, amiodarone hydrochloride is poorly soluble in water and dissolves slowly, especially at a dissolution temperature below 60 ℃. When the polysorbate is added firstly and then the amiodarone hydrochloride is added, the polysorbate can greatly promote the dissolution speed of the amiodarone hydrochloride. Therefore, the polysorbate should be added to the water prior to amiodarone hydrochloride. Benzyl alcohol should be added last. When benzyl alcohol is added first, turbidity of the solution is caused, and thus it is not preferable. Therefore, the charging sequence of the invention is determined to be polysorbate-amiodarone hydrochloride-benzyl alcohol. On the basis, when preparing the polysorbate solution and the amiodarone hydrochloride solution, the temperature of the preparation solution should be 60-75 ℃. Incomplete dissolution may occur when the temperature is below 60 ℃; and when the temperature is higher than 75 ℃, the related substances can be remarkably increased. When benzyl alcohol was added, the amiodarone hydrochloride solution was cooled to room temperature to further reduce the amount of related substances. In addition, according to the invention, nitrogen is filled in the liquid preparation process, so that the quantity of related substances can be further reduced.
According to the invention, the filtration step can be carried out using syringe filters of PVDF and PTFE. According to the present invention, the filtered chemical liquid is filled into the container, and nitrogen gas is introduced during the filling process in order to further reduce the amount of the relevant substances.
According to the invention, the method can also comprise a step of keeping the temperature at 70-75 ℃ for more than 1 hour after the encapsulating step so as to eliminate the crystallization phenomenon. The holding time should be more than 1 hour, and crystallization cannot be eliminated when the holding time is less than 1 hour. The holding temperature should be 70-75 ℃. When the temperature is lower than 70 ℃, the crystallization cannot be eliminated, and when the temperature is higher than 75 ℃, the amount of the substance related to the liquid medicine is remarkably increased, which is not preferable.
Examples
Preliminary test-influence of temperature of liquid preparation and sequence of addition of material to dissolution of drug substance
Taking two parts of experimental injection water at 50 ℃, 60 ℃, 70 ℃ and 80 ℃, respectively, and adding the amiodarone hydrochloride raw material medicine into one part of the experimental injection water for dissolving; adding polysorbate 80(II) into the other part, and adding the raw materials after completely dissolving. The dissolution and stability results are shown in table 1 below.
TABLE 1
Taking two parts of experimental water for injection respectively, wherein one part is added with benzyl alcohol, and then sequentially added with polysorbate 80(II) and amiodarone hydrochloride; and adding polysorbate 80(II) into the other part, and then sequentially adding amiodarone hydrochloride and benzyl alcohol. The dissolution and stability results are shown in Table 2 below.
TABLE 2
According to the results shown in tables 1 and 2, the order of addition was determined to be polysorbate 80(II) -amiodarone hydrochloride-benzyl alcohol, and the temperature of the solution preparation was initially set to 60-80 ℃.
Example 1
150g of amiodarone hydrochloride, 60g of benzyl alcohol, 300g of polysorbate 80(II) and 3L of water for injection were weighed. Taking 80 volume percent of water for injection, controlling the temperature of the water for injection at 70 ℃, charging nitrogen, controlling the dissolved oxygen amount to be less than 2mg/L, adding polysorbate 80(II) into the water for injection until the polysorbate is completely dissolved, adding amiodarone hydrochloride until the amiodarone hydrochloride is completely dissolved, cooling the liquid medicine to room temperature, adding benzyl alcohol until the amiodarone hydrochloride is completely dissolved, and fixing the volume to the total amount of the liquid medicine.
The drug solution was filtered using a 0.2 μm pVDF millipore filter. Filling the liquid medicine into a 5ml colorless medium borosilicate glass ampoule bottle with the filling amount of 3.2ml while filling nitrogen, and controlling the dissolved oxygen to be less than 2mg/L and the residual oxygen to be less than 3 percent; the sample was placed in an oven at 70 ℃ and held for 1 h.
Example 2
150g of amiodarone hydrochloride, 60g of benzyl alcohol, 300g of polysorbate 80(II) and 3L of water for injection were weighed. Taking 80 volume percent of water for injection, controlling the temperature of the water for injection at 70 ℃, charging nitrogen, controlling the dissolved oxygen amount to be less than 2mg/L, adding polysorbate 80(II) into the water for injection until the polysorbate is completely dissolved, adding amiodarone hydrochloride until the amiodarone hydrochloride is completely dissolved, cooling the liquid medicine to room temperature, adding benzyl alcohol until the amiodarone hydrochloride is completely dissolved, and fixing the volume to the total amount of the liquid medicine.
The drug solution was filtered using a 0.2 μm pVDF millipore filter. Filling the liquid medicine into a 5ml colorless medium borosilicate glass ampoule bottle with the filling amount of 3.2ml while filling nitrogen, and controlling the dissolved oxygen to be less than 2mg/L and the residual oxygen to be less than 3 percent; the sample was placed in a sterilizer at 70 ℃ for 0.5 h.
Example 3
150g of amiodarone hydrochloride, 60g of benzyl alcohol, 300g of polysorbate 80(II) and 3L of water for injection were weighed. Taking 80 volume percent of water for injection, controlling the temperature of the water for injection at 60 ℃, charging nitrogen, controlling the dissolved oxygen amount to be less than 2mg/L, adding polysorbate 80(II) into the water for injection until the polysorbate is completely dissolved, adding amiodarone hydrochloride until the amiodarone hydrochloride is completely dissolved, cooling the liquid medicine to room temperature, adding benzyl alcohol until the amiodarone hydrochloride is completely dissolved, and fixing the volume to the total amount of the liquid medicine.
The drug solution was filtered using a 0.2 μm pVDF millipore filter. Filling the liquid medicine into a 5ml colorless medium borosilicate glass ampoule bottle with the filling amount of 3.2ml while filling nitrogen, and controlling the dissolved oxygen to be less than 2mg/L and the residual oxygen to be less than 3 percent; the sample was placed in an oven at 70 ℃ and held for 1 h.
Comparative example 1
150g of amiodarone hydrochloride, 60g of benzyl alcohol, 300g of polysorbate 80(II) and 3L of water for injection were weighed. Taking 80 volume percent of water for injection, controlling the temperature of the water for injection at 80 ℃, charging nitrogen, controlling the dissolved oxygen amount to be less than 2mg/L, adding polysorbate 80(II) into the water for injection until the polysorbate is completely dissolved, adding amiodarone hydrochloride until the amiodarone hydrochloride is completely dissolved, cooling the liquid medicine to room temperature, adding benzyl alcohol until the amiodarone hydrochloride is completely dissolved, and fixing the volume to the total amount of the liquid medicine.
The drug solution was filtered using a 0.2 μm pVDF millipore filter. Filling the liquid medicine into a 5ml colorless medium borosilicate glass ampoule bottle with the filling amount of 3.2ml while filling nitrogen, and controlling the dissolved oxygen to be less than 2mg/L and the residual oxygen to be less than 3 percent; the sample was placed in an oven at 70 ℃ and held for 1 h.
Comparative example 2
150g of amiodarone hydrochloride, 60g of benzyl alcohol, 300g of polysorbate 80(II) and 3L of water for injection were weighed. Taking 80 volume percent of water for injection, controlling the temperature of the water for injection at 60 ℃, adding polysorbate 80(II) into the water for injection until the dissolution is complete, adding amiodarone hydrochloride until the dissolution is complete, cooling the liquid medicine to room temperature, adding benzyl alcohol until the dissolution is complete, and metering the volume to the total amount of the liquid medicine.
The drug solution was filtered using a 0.2 μm pVDF millipore filter. Encapsulating the liquid medicine in a 5ml colorless medium borosilicate glass ampoule bottle with the filling amount of 3.2 ml; the sample was placed in an oven at 70 ℃ and held for 1 h.
Method for measuring substance concerned
(1) Instruments and appliances: analytical balance, high performance liquid chromatograph (ultraviolet detector), acidimeter, solvent filter, 0.45 μm organic microporous filter membrane (matched with solvent filter), ultrasonic instrument, beaker, and C18(4.6 × 250mm, 5 μm) chromatographic column.
(2) Reagent and test solution: purified water, methanol (chromatographic purity), acetonitrile (chromatographic purity), glacial acetic acid, ammonia water, amiodarone hydrochloride reference, impurity A reference, impurity B reference, impurity C reference, impurity D reference, impurity E reference, impurity F reference and impurity G reference.
(3) Operation of
Mobile phase: using buffer solution (taking glacial acetic acid 3.0ml, adding water 800ml, adjusting pH value to 4.9 with ammonia test solution, adding water to dilute to 1000ml) -methanol-acetonitrile (30: 40)
Detection wavelength: 240nm
Column temperature: 30 deg.C
Sample introduction volume: 20 μ l
Operating time: 60min
Blank solvent: water-methanol-acetonitrile (20: 30: 50)
Test solution: precisely measuring 1ml of the product, placing the product in a 100ml measuring flask, adding a solvent to dilute the product to a scale, and shaking up.
Control solution: respectively weighing appropriate amount of amiodarone hydrochloride, impurity A, impurity B, impurity C, impurity D, impurity E, impurity F and impurity G as reference substances, precisely weighing, adding solvent to dissolve and dilute to obtain a solution containing about 8 μ G of impurity D, 1 μ G of amiodarone hydrochloride and other known impurities per 1 ml.
Precisely measuring 20 mu l of reference solution, injecting into a liquid chromatograph, recording a chromatogram, and sequentially eluting impurities A, D, E, B, C, G, F and amiodarone, wherein the separation degree between peaks of each chromatogram is in accordance with the requirement. The determination method comprises the following steps: precisely measuring the above solutions each 20 μ l, injecting into liquid chromatograph, and recording chromatogram.
The substances related to the drug solution were measured by the above-described measurement method and the crystallization of the drug solution sample was observed. The results are shown in Table 3.
TABLE 3
As shown in table 3, by comparing example 1 with comparative example 1, it can be seen that the amount of the drug solution-related substance significantly increased when the temperature of the water for injection was increased from 70 ℃ to 80 ℃; by comparing example 3 with comparative example 2, it can be seen that the amount of the substance related to the chemical solution is significantly reduced in the case where nitrogen gas is introduced during the liquid preparation and potting processes. As can be seen from example 2, when the incubation time was 0.5h, the devitrification phenomenon could not be eliminated.
The above-described embodiments are merely illustrative of the present invention and are not intended to limit the present invention. It will be appreciated by those skilled in the art that modifications and variations to the embodiments of the present invention are within the scope of the present invention without departing from the spirit and scope of the invention.
Claims (4)
1. A process for preparing amiodarone hydrochloride injection, which process comprises:
weighing: weighing the prescribed amount of polysorbate, amiodarone hydrochloride, benzyl alcohol and water for injection;
liquid preparation: adding polysorbate to obtain a polysorbate solution and amiodarone hydrochloride to obtain an amiodarone hydrochloride solution while controlling a part of the water for injection to be at a temperature in a range of 60-75 ℃ and charging nitrogen, then cooling the amiodarone hydrochloride solution to room temperature and adding benzyl alcohol, and making up the remaining part of the water for injection to obtain a liquid medicine;
and (3) filtering: sterilizing and filtering the liquid medicine; and
encapsulating: filling the filtered liquid medicine into a container while filling nitrogen,
wherein the method does not employ a sterilization step.
2. The method of claim 1, further comprising the step of incubating at 70-75 ℃ for more than 1 hour after the potting step.
3. The method according to claim 1 or 2, wherein the portion of water for injection is 60-80 vol.% of the total amount of water for injection.
4. The method according to claim 1 or 2, wherein 150mg amiodarone hydrochloride, 60mg benzyl alcohol and 300mg polysorbate are contained per 3mL injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011207802.1A CN112472668B (en) | 2020-10-29 | 2020-10-29 | Method for preparing amiodarone hydrochloride injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011207802.1A CN112472668B (en) | 2020-10-29 | 2020-10-29 | Method for preparing amiodarone hydrochloride injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112472668A true CN112472668A (en) | 2021-03-12 |
| CN112472668B CN112472668B (en) | 2023-02-28 |
Family
ID=74926349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011207802.1A Active CN112472668B (en) | 2020-10-29 | 2020-10-29 | Method for preparing amiodarone hydrochloride injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112472668B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114917187A (en) * | 2022-06-10 | 2022-08-19 | 苏州弘森药业股份有限公司 | Preparation method of amiodarone hydrochloride injection |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3248401A (en) * | 1966-04-26 | Diethylaminoe hoxybenzoyl benzofurans | ||
| FR2735978A1 (en) * | 1995-06-30 | 1997-01-03 | Sanofi Sa | PHARMACEUTICAL COMPOSITION OF AMIODARONE FOR PARENTERAL ADMINISTRATION |
| WO1998040067A1 (en) * | 1997-03-10 | 1998-09-17 | Sanofi | Use of benzofuran derivatives for reducing death rate after myocardial infarction |
| RU2192855C1 (en) * | 2001-12-10 | 2002-11-20 | Сыров Кирилл Константинович | Method of amiodarone-base injection medicinal agent preparing |
| US20030139468A1 (en) * | 2002-01-22 | 2003-07-24 | American Home Products Corporation | Amiodarone solutions suitable for intravenous administration |
| CN1531427A (en) * | 2001-03-29 | 2004-09-22 | ���ع��ʹ�˾ | Premixed amiodarone parenteral solution and method for making the same |
| CN103800910A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating clouding phenomenon of Tween surfactants |
| CN104414970A (en) * | 2013-09-10 | 2015-03-18 | 成都力思特制药股份有限公司 | Amiodarone hydrochloride injection and preparation method thereof |
| TW201521786A (en) * | 2013-03-13 | 2015-06-16 | Armetheon Inc | BUDIODARONE formulations |
| CN107753439A (en) * | 2016-08-22 | 2018-03-06 | 黑龙江迪龙制药有限公司 | A kind of hydrochloride for injection amiodarone and preparation method thereof |
-
2020
- 2020-10-29 CN CN202011207802.1A patent/CN112472668B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3248401A (en) * | 1966-04-26 | Diethylaminoe hoxybenzoyl benzofurans | ||
| FR2735978A1 (en) * | 1995-06-30 | 1997-01-03 | Sanofi Sa | PHARMACEUTICAL COMPOSITION OF AMIODARONE FOR PARENTERAL ADMINISTRATION |
| WO1998040067A1 (en) * | 1997-03-10 | 1998-09-17 | Sanofi | Use of benzofuran derivatives for reducing death rate after myocardial infarction |
| CN1531427A (en) * | 2001-03-29 | 2004-09-22 | ���ع��ʹ�˾ | Premixed amiodarone parenteral solution and method for making the same |
| RU2192855C1 (en) * | 2001-12-10 | 2002-11-20 | Сыров Кирилл Константинович | Method of amiodarone-base injection medicinal agent preparing |
| US20030139468A1 (en) * | 2002-01-22 | 2003-07-24 | American Home Products Corporation | Amiodarone solutions suitable for intravenous administration |
| CN103800910A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating clouding phenomenon of Tween surfactants |
| TW201521786A (en) * | 2013-03-13 | 2015-06-16 | Armetheon Inc | BUDIODARONE formulations |
| CN104414970A (en) * | 2013-09-10 | 2015-03-18 | 成都力思特制药股份有限公司 | Amiodarone hydrochloride injection and preparation method thereof |
| CN107753439A (en) * | 2016-08-22 | 2018-03-06 | 黑龙江迪龙制药有限公司 | A kind of hydrochloride for injection amiodarone and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 唐芳等: "盐酸胺碘酮注射液的处方工艺因素研究", 《2013年中国药学大会暨第十三届中国药师周论文集》 * |
| 姚松林: "吐温(TWeen)在中草药制剂中的应用及其应注意的问题", 《江西中医药》 * |
| 钱传训: "在含吐温80的注射液中苯甲醇的影响", 《国际药学研究杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114917187A (en) * | 2022-06-10 | 2022-08-19 | 苏州弘森药业股份有限公司 | Preparation method of amiodarone hydrochloride injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112472668B (en) | 2023-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104887673B (en) | A kind of pharmaceutical composition containing Esomeprazole sodium and preparation method thereof | |
| CN112472668B (en) | Method for preparing amiodarone hydrochloride injection | |
| CN101987094A (en) | Ornithine aspartate injection and preparation method thereof | |
| CN105439925B (en) | A kind of preparation of lipoic acid polymeric impurities and its detection method | |
| CN106432276A (en) | Cefazolin sodium compound prepared according to novel intelligent crystallization technology and preparation of cefazolin sodium compound | |
| CN111499553B (en) | Preparation method of paricalcitol and injection thereof | |
| CN105301127A (en) | Ribavirin medicinal composition and related substance detection method for same | |
| CN113101273A (en) | Omeprazole sodium for injection | |
| CN104614468A (en) | Method for separating imidafenacin and related substances thereof by using high performance liquid chromatography | |
| CN105079015B (en) | Troxerutin freeze-dried powder injection and preparation method thereof | |
| CN106176585A (en) | A kind of preparation method of ornidazole injection | |
| CN103304597B (en) | Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition | |
| CN104922080A (en) | Pharmaceutical ilaprazole sodium freeze-dried powder injection composition for treating digestive system diseases | |
| CN101199514B (en) | Ketoralac ammonia butanetriol injection and preparing method thereof | |
| CN105640873A (en) | Sodium valproate injection, preparation method and applications thereof | |
| CN112250591B (en) | Preparation method of lysine-amino-profen | |
| CN110960488A (en) | Preparation method for improving stability of oxytocin injection | |
| CN112569184A (en) | Tirofiban hydrochloride injection and preparation method thereof | |
| CN111265474B (en) | Parthenocinolate injection and preparation method thereof | |
| CN113398065A (en) | Preparation method of phloroglucinol injection | |
| CN112156069B (en) | Production process of deslanoside injection | |
| CN106943342B (en) | Argatroban-containing pharmaceutical composition | |
| CN110862319A (en) | Preparation method of ozagrel impurity | |
| CN108929269B (en) | Benzisoquinoline non-depolarizing muscle relaxant and preparation method and application thereof | |
| CN106432149A (en) | Method for preparing medicine ranitidine hydrochloride compound for treating stomach illness |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Method for preparing amiodarone hydrochloride injection Effective date of registration: 20231113 Granted publication date: 20230228 Pledgee: Harbin Enterprise Credit Financing Guarantee Group Co.,Ltd. Pledgor: Taiyangsheng (Bozhou) Biomedical Technology Co.,Ltd. Registration number: Y2023990000555 |