CN1951919A - Milrinone salt preparation method and its uses - Google Patents

Milrinone salt preparation method and its uses Download PDF

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Publication number
CN1951919A
CN1951919A CN 200610070061 CN200610070061A CN1951919A CN 1951919 A CN1951919 A CN 1951919A CN 200610070061 CN200610070061 CN 200610070061 CN 200610070061 A CN200610070061 A CN 200610070061A CN 1951919 A CN1951919 A CN 1951919A
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milrinone
preparation
salt
injection
water
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薛克亮
刘爱芹
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INSTITUTE OF MATERIA MEDICA SHANDONG ACADEMY OF MEDICAL SCIENCES
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INSTITUTE OF MATERIA MEDICA SHANDONG ACADEMY OF MEDICAL SCIENCES
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Abstract

The invention discloses a preparing method of Milinong salt and application in the lyophilized product, which is characterized by the following: adopting refined Milinong as raw material; reacting with alcaine, phosphoric acid, sulfuric acid, methanesulfonic acid, sodium hydroxide and potassium hydroxide to obtain the soluble product; blending soluble Milinong salt and auxiliary material to form injection lyophilized product.

Description

The preparation method of Milrinone salt and application thereof
1, technical field
The present invention relates to a kind of preparation method and application thereof of medicine, a kind of preparation method of salt of milrinone and application thereof specifically belongs to chemical industry and chemical field of medicaments.
2, background technology
Milrinone, English name Milrinone, chemical name 2-methyl-6-oxygen-1,6-dihydro-[3,4 ' two pyridines]-the 5-formonitrile HCN, being white solid, is the s-generation bipyridines cardiac tonic in U.S.'s listing in 1987, and this medicine is by cyclic monophosphate (C-AMP) in the phosphodiesterase iii in the selectivity inhibition myocardial cell, the increase cell, change the running of the inside and outside calcium of cell, thereby increase myocardial contraction, its cardiac activity are 20 times of the homologue amrinone, and untoward reaction is little.But because milrinone itself is water insoluble, being used for clinical milrinone injection formulation at present, is that milrinone is added water, adds lactic acid then, transfers pH3.2～4.0, makes the milrinone dissolving form the aqueous solution of milrinone lactate, makes injection formulation then.Because milrinone lactate is the aqueous injection injection liquid, therefore existing deficiency is in actual application: poor stability, be difficult for storing, and be inconvenient to transport.
3, summary of the invention
The purpose of this invention is to provide a kind of is raw material with the pure product of milrinone after refining, adopt mineral acid or alkali (example hydrochloric acid, phosphoric acid, sulfuric acid, methylsulfonic acid, sodium hydroxide, potassium hydroxide etc.) and milrinone reaction, the acetone that adds 5 times of amounts of liquor capacity then, cooling, separate out precipitation, promptly obtain can be as the salt of the milrinone of pharmaceutical raw material with oven dry after filtration.
The preparation method of Milrinone salt.
Milrinone and inorganic acid reaction formula are as follows:
C 12H 9N 3O+HX=C 12H 9N 3X is an inorganic acid radical in the OHX formula;
The reaction formula of milrinone and mineral alkali is as follows:
C 12H 9N 3O+ROH=C 12H 8N 3R is an atoms metal in the OR formula;
Structural formula:
Figure A20061007006100051
The concrete preparation process of milrinone inorganic base salts and milrinone hydrochlorate is as follows:
(1) preparation of milrinone sodium salt: get the 10g milrinone and place the 500ml beaker, drip 0.1N aqueous sodium hydroxide solution and stirring under the room temperature and make it to dissolve,, add the acetone of 5 times of amounts of liquor capacity to pH value of solution value 7～8,2～4 ℃ of frozen water coolings, separate out white precipitate, filtration under diminished pressure, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, the milrinone sodium salt, yield 92%;
Ultimate analysis: C 12H 8N 3ONa, calculated value C:61.74% H:3.43% N:18.01%Na:9.86%, experimental value C:61.70%H:3.38% N:17.94% Na:9.83%;
Infrared spectra (KBr, cm -1): 3,636 3,264 3,057 2,214 1,594 1,550 1,522 14,821,400 1,367 1,259 827 807 789 601;
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 333nm, 269nm;
Structural formula:
(2) preparation of hydrochloric acid milrinone:
The 10g milrinone is placed the 500ml beaker, drip 0.1N hydrochloric acid soln and stirring and make it to dissolve, make pH value of solution value 4～4.5, add the acetone of 5 times of amounts of liquor capacity, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, Milrinone salt hydrochlorate 12g, yield 93%.
Infrared spectra (KBr, cm -1): 3,223 3,026 2,987 2,784 2,627 2,235 1,873 16,541,626 1,570 1,511 1,478 1,371 1,336 1,182 1,031 830 687 583
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 331nm, 265nm.
Ultimate analysis: C 12H 9N 3OHCl.Calculated value C:58.11% H:4.07% N:16.56%Cl:14.31%, experimental value C:58.11% H:4.07% N:16.56% Cl:13.98%
Structural formula:
Figure A20061007006100061
In the method for the invention, generate and at the mineral alkali of the salt of pharmaceutical industry widespread usage NaOH, KOH to be arranged with milrinone reaction.
In the preparation method of Milrinone salt of the present invention, can give birth to salifiable acid with the milrinone reaction has: hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid.
Positively effect of the present invention is: milrinone is converted into salt soluble in water, is prepared into the freeze-dried preparation of Milrinone salt, promptly solved solvability and stability problem, and be more convenient for storing and transportation.
4, embodiment
Use by the salt preparation of following specific embodiment explanation milrinone with at the preparation freeze-drying preparation for injection.
Embodiment 1: the preparation of milrinone sodium salt
The 10g milrinone is placed the 500ml beaker, drip 0.1N aqueous sodium hydroxide solution and stirring and make it to dissolve,, add the acetone of 5 times of amounts of liquor capacity to pH value 7～8, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, milrinone sodium salt 10.16g, yield 92%.
Ultimate analysis: C 12H 8N 3ONa, calculated value C:61.74% H:3.43% N:18.01% Na:9.86%, experimental value C:61.70% H:3.38% N:17.94% Na:9.83%;
Infrared spectra (KBr, cm -1): 3,636 3,264 3,057 2,214 1,594 1,550 1,522 14,821,400 1,367 1,259 827 807 789 601
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 333nm, 269nm.
The preparation of embodiment 2. milrinone sylvite
The 10g milrinone is placed the 500ml beaker, drip 0.1N potassium hydroxide solution and stirring and make it to dissolve, to pH value of solution value 7～8, the acetone that adds 5 times of amounts of liquor capacity, white precipitate is separated out in cooling, filters, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, milrinone sylvite 5.0g, mother liquor reclaim 4.5g, yield 80.5%.
Ultimate analysis: C 12H 8N 3OK, calculated value C:57.78% H:3.21% N:16.85% K:15.64%, experimental value C:57.63% H:3.23% N:16.80% K:15.60%
Infrared spectra (KBr, cm -1): 3,335 3,032 2,213 1,596 1,549 1,525 1,480 13,981,367 1,270 1,226 830 790 597
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 334nm, 266nm.
The preparation of embodiment 3. Milrinone salt hydrochlorates
The 10g milrinone is placed the 500ml beaker, drip 0.1N hydrochloric acid soln and stirring and make it to dissolve, make pH value of solution value 4～4.5, add the acetone of 5 times of amounts of liquor capacity, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, Milrinone salt hydrochlorate 12g, yield 93%.
Ultimate analysis; C 12H 9N 3OHCl, calculated value C:58.11% H:4.07% N:16.56%Cl:14.31%, experimental value C:58.11% H:4.07% N:16.56% Cl:13.98%
Infrared spectra (KBr, cm -1): 3,223 3,026 2,987 2,784 2,627 2,235 1,873 16,541,626 1,570 1,511 1,478 1,371 1,336 1,182 1,031 830 687 583
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 331nm, 265nm.
The phosphatic preparation of embodiment 4. milrinones
The 10g milrinone is placed the 500ml beaker, drip 0.1N phosphoric acid solution and stirring and make it to dissolve, make pH value of solution value 4～4.5, add the acetone of 5 times of amounts of liquor capacity, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, milrinone phosphoric acid salt 14g, yield 95%.
Ultimate analysis: C 12H 9N 3OH3PO4 calculated value C:46.70% H:3.90% N:13.50%P:10.02%, experimental value C:46.70% H:3.90% N:13.30% P:9.76%
Infrared spectra (KBr, cm -1): 3,216 3,070 2,990 2,823 2,766 2,234 1,657 16,261,607 1,559 1,508 1,475 1,378 1,330 1,179 1,103 1,030 906 827 688584
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 334nm, 264nm.
The preparation of embodiment 5. milrinone vitriol
The 10g milrinone is placed the 500ml beaker, drip 0.1N sulphuric acid soln and stirring and make it to dissolve, make pH value of solution value 4～5, add the acetone of 5 times of amounts of liquor capacity, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, milrinone vitriol 14.3g, yield 97%.Elemental analysis molecular formula: [C 12H 9N 3O] 2H 2SO 4H 2O
Ultimate analysis: calculated value C:53.49% H:4.09% N:15.60% S:5.94%, experimental value C:53.64% H:4.10% N:15.21% S:5.92%
Infrared spectra (KBr, cm -1): 3,455 3,216 2,990 2,824 2,766 2,234 1,800 16,581,627 1,607 1,569 1,508 1,475 1,379 1,330 1,281 1,119 1,000 828 688,619 584
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 332nm, 264nm.
The preparation of embodiment 6. milrinone mesylates
The 10g milrinone is placed the 500ml beaker, drip 0.1N methanesulfonic acid solution and stirring and make it to dissolve, make pH value of solution value 4～5, add the acetone of 5 times of amounts of liquor capacity, cooling, separate out white precipitate, filter, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, milrinone mesylate 14.0g, yield 96.2%.
Ultimate analysis: C 12H 9N 3OCH 3SO 3H, calculated value C:50.69% H:4.21% N:13.66%S:10.27%, experimental value C:50.69% H:4.21% N:13.20% S:10.27%
Infrared spectra (KBr, cm -1): 3,447 3,071 2,988 2,787 2,227 1,660 1,628 15,701,508 1,477 1,421 1,381 1,332 1,224 1,149 1,038 1,005 909 834 772,683 555
Ultra-violet absorption spectrum: measure maximum λ in the aqueous solution MaxBe 332nm, 264nm.
Embodiment 7
The preparation of the freeze-dried preparation of injection Milrinone salt:
Prescription:
Milrinone salt hydrochlorate 11.72g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
Preparation process is as follows:
(1) pharmacy liquid: take by weighing the N.F,USP MANNITOL of recipe quantity, add the water for injection stirring and make dissolving, add the Milrinone salt hydrochlorate of recipe quantity again, add the injection water to 2000ml.
(2) depyrogenation: in water for injection, add 0.1% (g/ml) pin carbon 2g, heated and boiled 5 minutes, whip attachment 20 minutes, decarburization is filtered.
(3) degerming: the soup of step (2) is carried out Sterile Filtration with 0.22 μ m millipore filtration.Carry out pH value, clarity and half-finished content inspection then.
(4) can:
The processing of cillin bottle: ultrasonic cleaning, wash down the inside and outside wall of bottle with tap water, it is qualified to wash to wash-down water clarity with deionized water and filterable water for injection successively again, dries 1 hour for 250 ℃, removes pyrogen, and it is standby to move to sterilisable chamber after reducing to 60 ℃.Carry out sterile filling at 100 grades of clean areas, the false add plug.
(5) freeze-drying:
In special-purpose freeze drying box, be cooled to-45 ℃, pre-freeze 4 hours: vacuumize, distillation after removing 90% moisture, is warming up to 35 ℃ more gradually naturally, and freeze-drying finishes, and automatically jumps a queue in the freeze drying box.
(6) seal:
Take out cillin bottle, the jewelling lid is finished product in batches.
Embodiment 8
Preparation injection milrinone phosphoric acid salt
Prescription:
Milrinone phosphoric acid salt 14.64g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 9
Preparation injection milrinone vitriol
Prescription:
Milrinone vitriol 14.64g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 10
Preparation injection milrinone mesylate
Prescription:
Milrinone mesylate 14.56g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 11
Preparation injection milrinone sodium salt
Milrinone sodium salt 11.04g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 12
Preparation injection milrinone sylvite
Milrinone sylvite 11.79g
N.F,USP MANNITOL 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 13
Preparation injection milrinone phosphoric acid salt
Prescription:
Milrinone phosphoric acid salt 14.64g
Lactose 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 14
Preparation injection milrinone vitriol
Prescription:
Milrinone vitriol 14.64g
Dextran-40 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 15
Preparation injection milrinone mesylate
Prescription:
Milrinone mesylate 14.56g
Dextran-70 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 16
Preparation injection milrinone sodium salt
Milrinone sodium salt 11.04g
Sorbyl alcohol 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Embodiment 17
Preparation injection milrinone sylvite
Milrinone sylvite 11.79g
Dextran-40 160g
Water for injection 2000ml
Make 1000 of dried frozen aquatic productses altogether, every contains milrinone 10mg.
The preparation method is with example 1.
Quality control standards (QCS):
Product is by " checking that every index is all up to specification under Chinese pharmacopoeia version appendix in 2005 the IB injection item.

Claims (5)

1, the preparation method of Milrinone salt is characterized in that milrinone and inorganic acid reaction formula are as follows:
C 12H 9N 3O+HX=C 12H 9N 3X is an inorganic acid radical in the OHX formula;
The reaction formula of milrinone and mineral alkali is as follows:
C 12H 9N 3O+ROH=C 12H 8N 3R is an atoms metal in the OR formula;
Figure A2006100700610002C2
The concrete preparation process of milrinone inorganic base salts and hydrochlorate is as follows:
(1) preparation of milrinone sodium salt: get the 10g milrinone and place the 500ml beaker, drip the 0.1N aqueous sodium hydroxide solution under the room temperature and stir and make it dissolving, to pH value of solution value 7～8, add the acetone of 5 times of amounts of liquor capacity, 2～4 ℃ of frozen water coolings, separate out white precipitate, filtration under diminished pressure, filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, the milrinone sodium salt;
Structural formula:
Figure A2006100700610002C3
(2) preparation of hydrochloric acid milrinone:
The 10g milrinone is placed the 500ml beaker, drip 0.1N hydrochloric acid soln and stirring and make it to dissolve, make pH value of solution value 4～4.5, add the acetone of 5 times of amounts of liquor capacity, white precipitate is separated out in cooling, filters, and filter cake is washed 2 times with acetone, airing, 105 ℃ of dryings are 2 hours then, the Milrinone salt hydrochlorate;
Structural formula:
Figure A2006100700610003C1
2, the preparation method of Milrinone salt according to claim 1 is characterized in that giving birth to salifiable mineral alkali with the milrinone reaction has NaOH, KOH.
3, the preparation method of Milrinone salt according to claim 1 is characterized in that giving birth to salifiable mineral acid with the milrinone reaction has: hydrochloric acid, sulfuric acid and phosphoric acid, methylsulfonic acid.
4, Milrinone salt the preparation freeze-drying preparation for injection application:
Prescription:
Milrinone salt 5-30g
Auxiliary material 160g
Water for injection 2000ml
Preparation process is as follows:
(1) pharmacy liquid: take by weighing the N.F,USP MANNITOL of recipe quantity, add the water for injection stirring and make dissolving, add the Milrinone salt hydrochlorate of recipe quantity again, add the injection water to 2000ml.
(2) depyrogenation: in water for injection, add 0.1% (g/ml) pin carbon 2g, heated and boiled 5 minutes, whip attachment 20 minutes, decarburization is filtered.
(3) degerming: the soup of step (2) is carried out Sterile Filtration with 0.22 μ m millipore filtration.Carry out pH value, clarity and half-finished content inspection then.
(4) can: the processing of cillin bottle: ultrasonic cleaning, wash down the inside and outside wall of bottle with tap water, it is qualified to wash to wash-down water clarity with deionized water and filterable water for injection successively again, dries 1 hour for 250 ℃, remove pyrogen, it is standby to move to sterilisable chamber after reducing to 60 ℃.Carry out sterile filling at 100 grades of clean areas, the false add plug.
(5) freeze-drying: in special-purpose freeze drying box, be cooled to-45 ℃, pre-freeze 4 hours; Vacuumize, distillation after removing 90% moisture, is warming up to 35 ℃ more gradually naturally, and freeze-drying finishes, and automatically jumps a queue in the freeze drying box.
(6) seal: take out cillin bottle, the jewelling lid is finished product in batches.
5, Milrinone salt according to claim 4 is characterized in that in the application of preparation freeze-drying preparation for injection, and used auxiliary material is wherein a kind of of N.F,USP MANNITOL, lactose, dextran-40, dextran-70, sorbyl alcohol.
CN 200610070061 2006-11-10 2006-11-10 Milrinone salt preparation method and its uses Pending CN1951919A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664773A (en) * 2013-12-18 2014-03-26 南京易亨制药有限公司 Preparing method and refining method for milrinone
CN115057814A (en) * 2021-12-07 2022-09-16 山东新时代药业有限公司 Milrinone malate crystal
CN115073368A (en) * 2021-12-07 2022-09-20 山东新时代药业有限公司 Milrinone-5-sulfosalicylic acid crystal form

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664773A (en) * 2013-12-18 2014-03-26 南京易亨制药有限公司 Preparing method and refining method for milrinone
CN115057814A (en) * 2021-12-07 2022-09-16 山东新时代药业有限公司 Milrinone malate crystal
CN115073368A (en) * 2021-12-07 2022-09-20 山东新时代药业有限公司 Milrinone-5-sulfosalicylic acid crystal form
CN115073368B (en) * 2021-12-07 2022-12-27 山东新时代药业有限公司 Milrinone-5-sulfosalicylic acid crystal form

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