CN102408439A - Cefmenoxime hydrochloride compound used for injection - Google Patents
Cefmenoxime hydrochloride compound used for injection Download PDFInfo
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- CN102408439A CN102408439A CN 201110320076 CN201110320076A CN102408439A CN 102408439 A CN102408439 A CN 102408439A CN 201110320076 CN201110320076 CN 201110320076 CN 201110320076 A CN201110320076 A CN 201110320076A CN 102408439 A CN102408439 A CN 102408439A
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Abstract
The invention relates to a cefmenoxime hydrochloride compound used for injection which is a crystal. X-ray powder obtained through Cu-K alpha ray measurement is diffracted at a 2 theta of 6.0 degree, 7.4 degree, 11.0 degree, 12.2 degree, 17.5 degree, 19.8 degree, 21.6 degree, 24.8 degree and 27.7 degree with characteristic peaks shown. The main granularity of the cefmenoxime hydrochloride crystal is 30-45 Mum and the distribution width of the cefmenoxime hydrochloride crystal is 25-75 Mum. Injections prepared through the cefmenoxime hydrochloride compound not only are rapid to dissolve and applicable to clinical application, but also have excellent stability, and are safe and reliable.
Description
Technical field
The present invention relates to a kind of cefmenoxime hydrochloride in compound, specifically, relate to a kind of new crystal of water-soluble, all good Cefmenoxime Hemihydrochloride of stability.
Background technology
Cefmenoxime Hemihydrochloride (cefmenoxime hydrochloride) is semisynthetic cephalosporins, and the cell walls through suppressing bacterium synthetic reaches germicidal action.Most of Gram-positives and negative bacterium are had the germicidal action of wide spectrum, and bacteriogenic β-Nei Xiananmei is stablized, can be widely used in the treatment of the various inflammation that cause because of infectation of bacteria.
But because Cefmenoxime Hemihydrochloride water-soluble very poor, slightly soluble only in water is given in the practical application and has been brought a lot of difficulties.At present, people have done a lot of researchs to the preparation of Cefmenoxime Hemihydrochloride.Document " synthesizing of Cefmenoxime Hemihydrochloride " discloses a kind of compound method of Cefmenoxime Hemihydrochloride in (fine chemistry industry, in January, 2009), wherein; Adopted cefmenoxime is dissolved in the soda ash light, through decolouring, filtration, washing, with salt acid for adjusting pH value to 1.5; Stirred growing the grain 2 hours; Filter washing, vacuum drying crystalline powder to Cefmenoxime Hemihydrochloride.
Document " preparation of Cefmenoxime Hemihydrochloride " discloses a kind of compound method of Cefmenoxime Hemihydrochloride in (2008 the 8th phases of Heilungkiang scientific and technical information); Wherein, with adding sodium hydrogencarbonate in the cefmenoxime acid, add hydrochloric acid and ethanol then to dissolving; 5 ℃ of stirred crystallization 2 hours; Filter, filtrate water and ethanol wash respectively, and vacuum-drying obtains crystalline powder.
The crystalline particle of the Cefmenoxime Hemihydrochloride of above prepared is thicker; Because the poorly water-soluble of Cefmenoxime Hemihydrochloride itself; So the Cefmenoxime Hemihydrochloride that adopts method for preparing is after being prepared into injection, dissolution time is very long; At least need 5～15 minutes ability fully to dissolve, clinical application is very inconvenient.
The applicant discloses a kind of preparation technology of quick-dissolving Cefmenoxime Hemihydrochloride in the patent ZL200910114629.8 " preparation technology of instantly-dissolving cefmenoxime hydrochloride " that declared in 2009, the Cefmenoxime Hemihydrochloride bullion is added water be mixed with suspension-s, adds yellow soda ash; Obtain clear liquor; It is 0.8～1.2 that the salt acid for adjusting pH value is used in decolouring, filtration, washing back, collects and filtrates, and using the weakly alkaline dissolving to regulate the pH value again is 1.3～1.75; Stirred crystallization obtains a kind of Cefmenoxime Hemihydrochloride of instant type.The preparation of the Cefmenoxime Hemihydrochloride that this method prepares can dissolve about 30 seconds, and its effect still remains to be improved.
Disclose a kind of cefmenoxime hydrochloride composition powder injection among the ZL200910303437.1, this powder pin has adopted Cefmenoxime Hemihydrochloride has been utilized acetone recrystallization, is ground to 400～600 orders again, is prepared into the powder pin then.This patent adopts acetone as solvent Cefmenoxime Hemihydrochloride to be carried out recrystallization; And a spot of dissolvent residual is arranged all in the recrystallization that generally makes; So this recrystallization has certain potential safety hazard, in addition, adopted first recrystallization abrasive method again in this patent; Process step is comparatively complicated, mobile, less stable.
For this reason, the present invention proposes a kind of new compound that is suitable for preparing the Cefmenoxime Hemihydrochloride of preparation.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of new compound of Cefmenoxime Hemihydrochloride.
In order to accomplish the object of the invention, the technical scheme of employing is:
The present invention relates to a kind of cefmenoxime hydrochloride in compound; Described cefmenoxime hydrochloride compound is a crystal, and the X-ray powder diffraction that uses the Cu-K alpha-ray to measure is 6.0 °, 7.4 °, 11.0 °, 12.2 °, 17.5 °, 19.8 °, 21.6 °, 24.8 ° and 27.7 ° at 2 θ and shows characteristic peak.
First optimal technical scheme of the present invention is: the crystal master granularity of Cefmenoxime Hemihydrochloride is 20～45 μ m, and distribution density is 20～150 μ m; Preferred main granularity is 25～45 μ m, and distribution density is 25～100 μ m; More preferably main granularity is 30～45 μ m, and distribution density is 25～75 μ m.
Second optimal technical scheme of the present invention is that the preparation method may further comprise the steps:
(1) get the Cefmenoxime Hemihydrochloride solid and add water and stir and to process suspension-s, under 5～15 ℃ of conditions, add soda ash light, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.01～0.1% activated carbon decolorizing, stirs the filtrating of 0.5～1.5 hour after-filtration; The mass percent that adds gac is preferably 0.01～0.05%;
(3) filtrating that step (2) is obtained is under 5～15 ℃ of conditions; In frequency is that 15～30KHz, output rating are under the sound field of 20～60W; Add hydrochloric acid and organic solvent while stirring simultaneously, regulating the pH value is 1.4～1.6, and described organic solvent is the mixing solutions of methyl alcohol and isopropylcarbinol; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 1～3 hour, obtain the crystal after-filtration, washing, vacuum-drying 2～6 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The 3rd optimal technical scheme of the present invention is: the frequency of described sound field is 18～30KHz, preferred 18～25KHz; Output rating is 25～50W, preferred 30～45W.
The 4th optimal technical scheme of the present invention is: the volume of organic solvent that is added be in the step (2) preparation obtain 0.25～1 times of filtrate volume, preferred 0.25～0.5 times.
The 5th optimal technical scheme of the present invention by: in adding methyl alcohol and the isopropylcarbinol mixing solutions volume ratio of methyl alcohol and isopropylcarbinol be 1: 0.5～1.5, preferred 1: 0.75～1.25, more preferably 1: 0.75～1.
The 6th optimal technical scheme of the present invention by: the stirring velocity when adding hydrochloric acid and organic solvent be 15～60 rev/mins, preferred 30～60 rev/mins.
The 7th optimal technical scheme of the present invention by: the speed of adding organic solvent be 10～25ml/min, preferred 15～25ml/min.
Do further to explain and explanation in the face of technical scheme of the present invention down:
The present invention relates to a kind of cefmenoxime hydrochloride in compound; Described cefmenoxime hydrochloride compound is a crystal; The X-ray powder diffraction that uses the Cu-K alpha-ray to measure is 6.0 °, 7.4 °, 11.0 °, 12.2 °, 17.5 °, 19.8 °, 21.6 °, 24.8 ° and 27.7 ° at 2 θ and shows characteristic peak; Measuring its fusing point is 169～172 ℃, and proterties is yellowish crystalline powder, measures through sem observation and particle size analyzer; The crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.The crystal of the present invention's preparation, its granularity is less, and good dispersibility, and the water-soluble of its preparation is greatly improved.
Cefmenoxime hydrochloride compound crystalline preparation method of the present invention may further comprise the steps:
(1) get the Cefmenoxime Hemihydrochloride solid and add water and stir and to process suspension-s, under 5～15 ℃ of conditions, add soda ash light, stirring and dissolving obtains clear liquor; Wherein, temperature is preferred 10～15 ℃;
(2) clear liquor being added mass percent is 0.01～0.1% activated carbon decolorizing, stirs the filtrating of 0.5～1.5 hour after-filtration; The mass percent that adds gac is preferably 0.01～0.05%, and most preferably 0.03%;
(3) filtrating that step (2) is obtained is that 15～30KHz, output rating are under the sound field of 20～60W in frequency under 5～15 ℃ of conditions, adds hydrochloric acid and organic solvent while stirring simultaneously, and regulating the pH value is 1.4～1.6, and the concentration of hydrochloric acid is 2～6mol/L; The volume of organic solvent that is added be in the step (2) preparation obtain 0.25～1 times of filtrate volume, preferred 0.25～0.5 times; Stirring velocity is 15～60 rev/mins, preferred 30～60 rev/mins; Described organic solvent is the mixing solutions of methyl alcohol and isopropylcarbinol, and the volume ratio of methyl alcohol and isopropylcarbinol is 1: 0.5～1.5, preferred 1: 0.75～1.25, more preferably 1: 0.75～1; The speed that adds organic solvent is 10～25ml/min, preferred 15～25ml/min; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 1～3 hour, obtain the crystal after-filtration, washing, vacuum-drying 2～6 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The present invention has prepared a kind of new Cefmenoxime Hemihydrochloride crystal through the condition of crystallization control, and the present invention is through to the control of temperature, pH value, sound field, flow acceleration, stirring velocity, thus the crystallisation process of strict control solution more.
The present invention has adopted under certain sound field Cefmenoxime Hemihydrochloride has been carried out crystallization, and additional sound field can produce cavitation bubble in supersaturated solution, and the pressure that produces when the non-linear vibration of bubble and bubble-break changes the energy of system each point.The fluctuation of energy of system is very big, and Intermolecular Forces is weakened, and soltion viscosity descends; Increase the collision opportunity between solute molecule and be easy to nucleation; And except that the pressure that produces, it is vaporific to produce bubble cloud during bubble-break, and this helps to reduce interfacial energy; Make the nucleus particle with fresh surface become comparatively stable, being able to continues to grow up is nucleus.The present invention through the control to the sound field output rating, makes the sound field among the present invention promote nucleus to generate through repeatedly experiment, and does not influence crystalline and generate.
In Cefmenoxime Hemihydrochloride crystalline crystallisation process, adopted three kinds of mixed solvents that solvent forms, thereby made solution form the system of Cefmenoxime Hemihydrochloride crystal-methyl alcohol-isopropylcarbinol-water; This system has the long steady district of crystallization Jie; The adding of organic solvent slowly descends the saturation solubility of Cefmenoxime Hemihydrochloride, thereby the system degree of supersaturation of making slowly rises, through the adding of a large amount of organic solvents; The degree of supersaturation of solution increases, thereby makes the crystalline particle size reduction.
The present invention also controls the crystalline temperature, and the temperature of employing is 5～15 ℃, through experiment repeatedly, under this temperature, is fit to the growth of Cefmenoxime Hemihydrochloride crystalline in sound field more.
Through above-mentioned condition crystalline is controlled, thereby obtained that crystal size is more evenly distributed, granularity is moderate, thereby make the Cefmenoxime Hemihydrochloride crystal of acquisition have good flowability.
To the preparation the Cefmenoxime Hemihydrochloride crystal through efficient liquid phase chromatographic analysis, purity reaches 99.9%, its structure is proved conclusively through proton nmr spectra.
Cefmenoxime Hemihydrochloride crystal of the present invention application clinically is generally to be prepared into injection, and it consists of: Cefmenoxime Hemihydrochloride crystal 10 weight parts, soda ash light 1.5～2.5 weight parts; Preferred Cefmenoxime Hemihydrochloride crystal 10 weight parts, soda ash light 1.75～1.8 weight parts, Cefmenoxime Hemihydrochloride crystal 10 weight parts most preferably, soda ash light 1.75 weight parts.
The preparation method of this injection is:
(1) takes by weighing Cefmenoxime Hemihydrochloride crystal and soda ash light, thorough mixing in proportion;
(2) divide in the cillin bottle be filled to after the sterilization and jump a queue.
Preparing method of the present invention can adopt this area other preparing method's preparations commonly used, and can its condition be optimized through the experiment of limited number of time.
The injection preparation method of cefmenoxime hydrochloride in compound of the present invention is simple, need not confirm that through dissolution experiment injection of the present invention dissolution time at normal temperatures was 3～10 seconds through processing such as grindings, and dissolution rate is very fast.And the consumption of soda ash light is little, and the clarity of the injection after the dissolving, insoluble particle etc. are conformance with standard all.Because crystal of the present invention is the particle that spontaneous nucleation forms, size is even, rule of surface, and good fluidity is easy to mix and packing.Cefmenoxime Hemihydrochloride behind the available technology adopting polishing, its surface-area is big, and surface irregularity, irregular; Mobile poor, cause certain difficulty for the packing meeting of preparation, and because the Cefmenoxime Hemihydrochloride after the grinding; Its big or small heterogeneity can cause dissolution time inconsistent, and the small-particle dissolving is fast; The dissolving of big particle is slow, in use, visual inspection can occur and all dissolve and just be used for the patient's vein instillation; But the wherein also not consoluet dissolving of some macrobead, thus cause the particulate matter of preparation defective, bring potential safety hazard.The Cefmenoxime Hemihydrochloride crystal of the present invention's preparation, its even particle size unanimity, its dissolution rate in dissolution process is consistent, and dissolving is rapid, stable, synchronous; And the Cefmenoxime Hemihydrochloride that grinds preparation is because its surface irregularity, and surface-area is big, thereby is more prone to the moisture absorption, and deliquescence takes place, thereby also can influence its stability.
The Cefmenoxime Hemihydrochloride preparation that the present invention prepares not only dissolves rapidly, be applicable to clinically to use, and have good stability, safe and reliable.
Description of drawings
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystalline Cu-K alpha-ray that Fig. 1 prepares for embodiment 1 measures.
Embodiment of the present invention only limits to content of the present invention is done further explanation and explanation, content of the present invention is not constituted restriction.All adopt the commercial reagent among the present invention.
Embodiment
The preparation of embodiment 1 Cefmenoxime Hemihydrochloride crystalline
(1) get Cefmenoxime Hemihydrochloride solid 0.5Kg and add water 10L and stir and to process suspension-s, under 15 ℃ of conditions, add soda ash light 90g, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.01% activated carbon decolorizing, stirs the filtrating of 0.5 hour after-filtration;
(3) filtrating that step (2) is obtained is under 10 ℃ of conditions; In frequency is that 30KHz, output rating are under the sound field of 50W, adds 2mol/L hydrochloric acid and organic solvent while stirring simultaneously, and regulating the pH value is 1.4; The volume of organic solvent that is added is 2.5L, and stirring velocity is 60 rev/mins; Organic solvent is that volume ratio is 1: 0.75 the methyl alcohol and the mixing solutions of isopropylcarbinol; The speed that adds organic solvent is 25ml/min, stops after hydrochloric acid and mixing solutions add stirring, and continues in sound field, to leave standstill growing the grain 1 hour, obtains the crystal after-filtration, washing, and vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal for preparing uses the Cu-K alpha-ray to measure is as shown in Figure 1, and measuring its fusing point is 169～172 ℃, and proterties is yellowish crystalline powder.Measure through sem observation and particle size analyzer, the crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.Its purity of high-performance liquid chromatogram determination is 99.99%.
Embodiment 2
(1) get Cefmenoxime Hemihydrochloride solid 0.5Kg and add water 10L and stir and to process suspension-s, under 15 ℃ of conditions, add soda ash light 90g, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.02% activated carbon decolorizing, stirs the filtrating of 1 hour after-filtration;
(3) filtrating that step (2) is obtained is under 10 ℃ of conditions; In frequency is that 25KHz, output rating are under the sound field of 45W, adds 4mol/L hydrochloric acid and organic solvent while stirring simultaneously, regulates pH value to 1.6; The volume of organic solvent that is added is 5L, and stirring velocity is 45 rev/mins; Described organic solvent is that volume ratio is 1: 1 the methyl alcohol and the mixing solutions of isopropylcarbinol; Speed when adding organic solvent is 20ml/min; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 2 hours, obtain the crystal after-filtration, washing, vacuum-drying 3 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The Cefmenoxime Hemihydrochloride crystal for preparing is identical with the characteristic peak of the X-ray diffraction in crystals collection of illustrative plates of embodiment 1 preparation, and fusing point is identical.Measure through sem observation and particle size analyzer, the crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.Its purity of high-performance liquid chromatogram determination is 99.99%.
Embodiment 3
(1) get Cefmenoxime Hemihydrochloride solid 0.5Kg and add water 10L and stir and to process suspension-s, under 15 ℃ of conditions, add yellow soda ash 90g, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.05% activated carbon decolorizing, stirs the filtrating of 1.5 hours after-filtration;
(3) filtrating that step (2) is obtained is under 10 ℃ of conditions; In frequency is that 30KHz, output rating are under the sound field of 40W; The hydrochloric acid and the organic solvent that add 2mol/L while stirring simultaneously, regulating the pH value is 1.5, the volume of organic solvent that is added is 10L; Stirring velocity is 45 rev/mins, and organic solvent is that volume ratio is 1: 0.5 the methyl alcohol and the mixing solutions of isopropylcarbinol; The speed that adds organic solvent is 25ml/min; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 1 hour, obtain the crystal after-filtration, washing, vacuum-drying 6 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The Cefmenoxime Hemihydrochloride crystal for preparing is identical with the characteristic peak of the X-ray diffraction in crystals collection of illustrative plates of embodiment 1 preparation, and fusing point is identical.Measure through sem observation and particle size analyzer, the crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.Its purity of high-performance liquid chromatogram determination is 99.99%.
Embodiment 4
(1) get Cefmenoxime Hemihydrochloride solid 0.5Kg and add water 10L and stir and to process suspension-s, under 15 ℃ of conditions, add yellow soda ash 90g, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.04% activated carbon decolorizing, stirs the filtrating of 1 hour after-filtration;
(3) filtrating that step (2) is obtained is under 5～15 ℃ of conditions; In frequency is that 20KHz, output rating are under the sound field of 30W, adds 2mol/L hydrochloric acid and organic solvent while stirring simultaneously, and regulating the pH value is 1.5; Volume of organic solvent is 4L, and stirring velocity is 60 rev/mins; Organic solvent is that volume ratio is 1: 1.25 the methyl alcohol and the mixing solutions of isopropylcarbinol; The speed that adds organic solvent is 15ml/min; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 2 hours, obtain the crystal after-filtration, washing, vacuum-drying 5 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The Cefmenoxime Hemihydrochloride crystal for preparing is identical with the characteristic peak of the X-ray diffraction in crystals collection of illustrative plates of embodiment 1 preparation, and fusing point is identical.Measure through sem observation and particle size analyzer, the crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.Its purity of high-performance liquid chromatogram determination is 99.99%.
Embodiment 5
(1) get Cefmenoxime Hemihydrochloride solid 0.5Kg and add water 10L and stir and to process suspension-s, under 15 ℃ of conditions, add yellow soda ash 90g, stirring and dissolving obtains clear liquor;
(2) clear liquor being added mass percent is 0.03% activated carbon decolorizing, stirs the filtrating of 1 hour after-filtration;
(3) filtrating that step (2) is obtained is under 8 ℃ of conditions; In frequency is that 20KHz, output rating are under the sound field of 25W, adds 2mol/L hydrochloric acid and organic solvent while stirring simultaneously, and regulating the pH value is 1.6; The volume of organic solvent that is added is 4.5L, and stirring velocity is 45 rev/mins; Organic solvent is that volume ratio is 1: 0.8 the methyl alcohol and the mixing solutions of isopropylcarbinol; Speed when adding organic solvent is 22.5ml/min; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 1.5 hours, obtain the crystal after-filtration, washing, vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The Cefmenoxime Hemihydrochloride crystal for preparing is identical with the characteristic peak of the X-ray diffraction in crystals collection of illustrative plates of embodiment 1 preparation, and fusing point is identical.Measure through sem observation and particle size analyzer, the crystal master granularity of this Cefmenoxime Hemihydrochloride is 30～45 μ m, and distribution density is 25～75 μ m.Its purity of high-performance liquid chromatogram determination is 99.99%.
The preparation of the injection of embodiment 6 cefmenoxime hydrochloride compounds
Consisting of of this injection: Cefmenoxime Hemihydrochloride crystal 10 weight parts of the embodiment of the invention 1～5 preparation, soda ash light 1.75 weight parts.
The preparation method is:
(1) takes by weighing Cefmenoxime Hemihydrochloride and soda ash light, thorough mixing in proportion;
(2) divide in the cillin bottle be filled to after the sterilization and jump a queue.
Experimental example 1 solubility experiment
Adopt the Cefmenoxime Hemihydrochloride crystal of embodiment 1～5 preparation, be prepared into preparation, under identical condition, experimentize according to the method for embodiment 6.
Comparative Examples 1 preparation method: adopt the preparation of common commercially available Cefmenoxime Hemihydrochloride raw material according to the method preparation of embodiment 6;
Comparative Examples 2 preparing methods: adopt common commercially available Cefmenoxime Hemihydrochloride raw material to cross 500 orders, according to the preparation of the method for embodiment 6 preparation;
Comparative Examples 3 preparing methods: according to ZL200910114629.8 embodiment 4 preparation the Cefmenoxime Hemihydrochloride powder, according to the preparation of the method preparation of embodiment 6;
Get the injection 1g of each formulation preparation, add the water for injection of 10ml, according to the jolting of obtain solution general method, under identical experiment condition, its dissolving situation is measured, experimental result is seen table 1;
Table 1:
Can know according to dissolution experiment; The Cefmenoxime Hemihydrochloride crystalline preparation of the present invention's preparation, under normal temperature condition, dissolution rate is rapid; Be higher than far away and adopt common Cefmenoxime Hemihydrochloride prepared preparation, with similar through the dissolution rate of the Cefmenoxime Hemihydrochloride after grinding.Under lower temperature, the crystal of the present invention's preparation still can dissolve rapidly, and the dissolution rate at low temperatures of the preparation in the Comparative Examples is slowed down.
Experimental example 2 stability tests
Adopt the Cefmenoxime Hemihydrochloride crystal of embodiment 1～5 preparation, be prepared into preparation (preparation 1, preparation 2, preparation 3, preparation 4, preparation 5) according to the method for embodiment 6, the preparation method of Comparative formulation 1,2,3 carries out stability test with experimental example 1:
1. high temperature test
Get preparation 1,2,3,4,5, Comparative formulation 1,2,3, simulation listing packing in 60 ℃ of temperature held 10 days, was taken a sample with the 10th day in the 5th day, detected by stable high spot reviews project.
2. high humidity test
Get preparation 1,2,3,4,5, Comparative formulation 1,2,3, simulation listing packing is put in the constant humidity encloses container, the condition held of 25 ℃ of relative humidity 90% ± 5% 10 days, takes a sample with the 10th day in the 5th day, detects by stable high spot reviews project.
3. strong illumination test
Get preparation 1,2,3,4,5, Comparative formulation 1,2,3, simulation listing packing is put in the sealing clean container, and placing illumination is the condition held 10 days of 4500lx ± 500lx, takes a sample with the 10th day in the 5th day, detects by stable high spot reviews project.
The influence factor test-results sees the following form 2.
Table 2: Cefmenoxime Hemihydrochloride crystal influence factor test-results (batch: 0101)
The result shows: these article are under the condition of simulation listing packing, and high temperature, high humidity, illumination condition held 10 days, removing related substance slightly increased, and outside content slightly reduced, other each item indexs did not have considerable change.And the underproof situation of insoluble particle has all appearred in drugs compared 1 and 2, and under the condition of high temperature and high humidity, its related substances occurred and increased, the situation that medicament contg reduces.
Experimental example 3 stable accelerated tests
Adopt the Cefmenoxime Hemihydrochloride crystal of embodiment 1～5 preparation; Method according to embodiment 6 is prepared into preparation (preparation 1, preparation 2, preparation 3, preparation 4, preparation 5); The preparation method of Comparative formulation 1,2,3 carries out stable accelerated test with experimental example 1: the difference sample thief, in 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition held 6 months; At duration of test once, each stable high spot reviews project is tested respectively at the 1st, 3,6 sampling at the end of month.Test-results is seen table 3.
Table 3:
The result shows: these article are being simulated under the condition of packing of going on the market, acceleration environment held 6 months, and removing related substance slightly increases, and outside content slightly reduced, other each item indexs did not have considerable change.And the content of the related substance in the drugs compared 1,2,3 obviously raises; The underproof situation of insoluble particle has all appearred in the drugs compared 1 and 2; The preparation that proves crystal preparation of the present invention not only has good stability; Indexs such as the clarity of its preparation, insoluble particle are all up to specification, are superior to the medicine of prior art.
Experimental example 4 stability tests
Adopt the Cefmenoxime Hemihydrochloride crystal of embodiment 1～5 preparation; Method according to embodiment 6 is prepared into preparation (preparation 1, preparation 2, preparation 3, preparation 4, preparation 5); The preparation method of Comparative formulation 1,2,3 carries out stable accelerated test with experimental example 1: the difference sample thief, put in the sealing clean container; In 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% condition held 24 months, each stable high spot reviews project is tested.Test-results is seen table 4.
Table 4:
The result shows: these article are under the condition of simulation listing packing, and normal temperature condition held 24 months, removing related substance slightly increased, and outside content slightly reduced, other each item indexs did not have considerable change.And the content of the related substance in the drugs compared 1,2 raises to some extent; The underproof situation of insoluble particle has all appearred in the drugs compared 1 and 2; The preparation that proves crystal preparation of the present invention not only has good stability; Indexs such as the clarity of its preparation, insoluble particle are all up to specification, are superior to the medicine of prior art.
Can know according to experiment, Cefmenoxime Hemihydrochloride crystalline preparation of the present invention, its stability amount is high, and the proterties of solution and clarity all are better than prior art formulations.
Claims (8)
1. cefmenoxime hydrochloride in compound; It is characterized in that; Described cefmenoxime hydrochloride compound is a crystal, and the X-ray powder diffraction that uses the Cu-K alpha-ray to measure is 6.0 °, 7.4 °, 11.0 °, 12.2 °, 17.5 °, 19.8 °, 21.6 °, 24.8 ° and 27.7 ° at 2 θ and shows characteristic peak.
2. cefmenoxime hydrochloride in compound according to claim 1 is characterized in that, the crystal master granularity of described Cefmenoxime Hemihydrochloride is 20～45 μ m, and distribution density is 20～150 μ m; Preferred main granularity is 25～45 μ m, and distribution density is 25～100 μ m; More preferably main granularity is 30～45 μ m, and distribution density is 25～75 μ m.
3. cefmenoxime hydrochloride in compound according to claim 1 is characterized in that, described cefmenoxime hydrochloride compound crystalline preparation method may further comprise the steps:
(1) get the Cefmenoxime Hemihydrochloride solid and add water and stir and to process suspension-s, under 5～15 ℃ of conditions, add soda ash light, stirring and dissolving obtains clear liquor, preferred 10～15 ℃;
(2) clear liquor being added mass percent is 0.01～0.1% activated carbon decolorizing, stirs the filtrating of 0.5～1.5 hour after-filtration; The mass percent that adds gac is preferably 0.01～0.05%;
(3) filtrating that step (2) is obtained is under 5～15 ℃ of conditions; In frequency is that 15～30KHz, output rating are under the sound field of 20～60W; Add hydrochloric acid and organic solvent while stirring simultaneously, regulating the pH value is 1.4～1.6, and described organic solvent is the mixing solutions of methyl alcohol and isopropylcarbinol; Stop after hydrochloric acid and mixing solutions add stirring, continue in sound field, to leave standstill growing the grain 1～3 hour, obtain the crystal after-filtration, washing, vacuum-drying 2～6 hours obtains the Cefmenoxime Hemihydrochloride crystal.
4. cefmenoxime hydrochloride in compound according to claim 3 is characterized in that, the frequency of described sound field is 18～30KHz, preferred 18～25KHz; Output rating is 25～50W, preferred 30～45W.
5. cefmenoxime hydrochloride in compound according to claim 3 is characterized in that, the volume of organic solvent that is added be in the step (2) preparation obtain 0.25～1 times of filtrate volume, preferred 0.25～0.5 times.
6. cefmenoxime hydrochloride in compound according to claim 3 is characterized in that, add that the volume ratio of methyl alcohol and isopropylcarbinol is 1: 0.5～1.5 in methyl alcohol and the isopropylcarbinol mixing solutions, preferred 1: 0.75～1.25, more preferably 1: 0.75～1.
7. cefmenoxime hydrochloride in compound according to claim 3 is characterized in that, the stirring velocity when adding hydrochloric acid and organic solvent be 15～60 rev/mins, preferred 30～60 rev/mins.
8. cefmenoxime hydrochloride in compound according to claim 3 is characterized in that, add organic solvent speed be 10～25ml/min, preferred 15～25ml/min.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102816174A (en) * | 2012-09-10 | 2012-12-12 | 天津市嵩锐医药科技有限公司 | Amorphous cefmenoxime hydrochloride compound |
| CN103145735A (en) * | 2013-03-21 | 2013-06-12 | 四川省惠达药业有限公司 | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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| CN101735249A (en) * | 2009-12-12 | 2010-06-16 | 桂林澳林制药有限责任公司 | Process for preparing instantly-dissolving cefmenoxime hydrochloride |
| CN101798314A (en) * | 2010-03-24 | 2010-08-11 | 海南数尔药物研究有限公司 | High-purity cefmenoxime hydrochloride compound |
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| CN101735249A (en) * | 2009-12-12 | 2010-06-16 | 桂林澳林制药有限责任公司 | Process for preparing instantly-dissolving cefmenoxime hydrochloride |
| CN101798314A (en) * | 2010-03-24 | 2010-08-11 | 海南数尔药物研究有限公司 | High-purity cefmenoxime hydrochloride compound |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102816174A (en) * | 2012-09-10 | 2012-12-12 | 天津市嵩锐医药科技有限公司 | Amorphous cefmenoxime hydrochloride compound |
| CN103145735A (en) * | 2013-03-21 | 2013-06-12 | 四川省惠达药业有限公司 | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof |
| CN103145735B (en) * | 2013-03-21 | 2014-02-26 | 四川省惠达药业有限公司 | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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