CN103275102A - Cefpodoxime proxetil compound as well as preparation method and medicinal composition thereof - Google Patents
Cefpodoxime proxetil compound as well as preparation method and medicinal composition thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a cefpodoxime proxetil compound as well as a preparation method and a medicinal composition thereof. The cefpodoxime proxetil compound has a chemical structural formula shown in a formula (I); and the cefpodoxime proxetil compound adopts an X-ray powder diffraction pattern which is obtained by Cu-Kalpha ray measurement and shown in a figure 1. The stability test shows that the humidity stability of the cefpodoxime proxetil compound is obviously superior to that of cefpodoxime proxetil in the prior art, the temperature and illumination stability of the cefpodoxime proxetil compound is also superior to that of cefpodoxime proxetil in the prior art, and the purity of the cefpodoxime proxetil compound is obviously higher than that of cefpodoxime proxetil in the prior art; and in addition, surprisingly, the cefpodoxime proxetil compound provided by the invention has good fluidity and is easy to subpackage.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of Cefpodoxime ester cpds, its preparation method and pharmaceutical composition thereof.
Background technology
Cefpodoxime Proxetil, its chemical name is: (6R, 7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-the 2-(methoxyimino)-kharophen]-3-methoxyl methyl-8-oxo-5-thia-1-azabicyclo-[4.2.0] oct-2-ene-2-carboxylic acid isopropyl oxygen carbonyl oxygen ethyl ester, molecular formula: C
21H
27N
5O
9S
2, molecular weight: 557.61, structural formula is:
Be oral third generation cephalosporin, has a broad antifungal spectrum enters in the body and is hydrolyzed to Cefpodoxime performance anti-microbial effect by nonspecific esterase, and gram-positive microorganism and Gram-negative bacteria are had the antimicrobial spectrum of wide scope, and is stable to β-Nei Xiananmei.Be applicable to responsive microbial upper respiratory tract infection, lower respiratory infection, simple property urinary tract infection, simple property skin and skin soft-tissue infection, acute simplex gonococcal urethritis and trachelitis clinically, the anal inflammation that is caused by Neisseria gonorrheae etc.
Cefpodoxime Proxetil (cefpodoxime proxetil) is the oral semi-synthetic cynnematin of the 3rd generation of listing at the beginning of the nineties, and is all more stable to the β-Nei Xiananmei of plasmid, karyomit(e) mediation, thereby solved the bacterial resistance problem preferably.Cefpodoxime is extensive pedigree antibiotic, and common gram-positive, negative bacterium are all had reasonable antibacterial effect.After oral, the non-specific lipase on the gastrointestinal wall can play the Cefpodoxime that is of anti-microbial effect.The Cefpodoxime Proxetil application in respiratory tract, urinary tract, gynecological infection disease in recent years is more extensive, is obtaining curative effect preferably aspect treatment children with acute tympanitis, the pharyngitis simultaneously.
Prior art is as " preparation of Cefpodoxime Proxetil dispersible tablet and dissolution determination " [Wang Jiansong, king antelope Li. the preparation of Cefpodoxime Proxetil dispersible tablet and dissolution determination [J], Central-South pharmacy, 2009,7(11): 813-816] show that Cefpodoxime Proxetil belongs to amorphous powder, do not have fixing fusing point, in water, do not dissolve.Destructive test shows, Cefpodoxime Proxetil is less stable under light, heat, wet condition, be degraded easily and produce degradation production, and powder flowbility is poor.
In recent years, development along with crystal engineering, increasing pharmacy worker has turned one's attention to the research of medicine crystal formation, for some because of physico-chemical property medicine not fully up to expectations, the crystal formation that changes medicine can improve effects such as its solubleness, reduction fusing point, raising stability to a certain extent, is used for improving its bioavailability then and improves preparation process.Whether can improve its stability by the crystalline structure that changes Cefpodoxime Proxetil, in view of this, special proposition the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of Cefpodoxime ester cpds.
Second purpose of the present invention is to provide the preparation method of described Cefpodoxime ester cpds.
The 3rd purpose of the present invention is to provide a kind of pharmaceutical composition, and this pharmaceutical composition contains above-mentioned Cefpodoxime ester cpds.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of Cefpodoxime ester cpds, wherein, described Cefpodoxime ester cpds has the chemical structural formula shown in the formula (I):
Formula (I);
The X-ray powder diffraction spectrogram that described Cefpodoxime ester cpds use Cu-K alpha-ray measures as shown in Figure 1.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of Cefpodoxime ester cpds, wherein, described preparation method comprises the steps:
1) the Cefpodoxime Proxetil bulk drug is added by in the formulated mixed solvent of methyl alcohol and dimethyl formamide, stir and make dissolving, add activated carbon decolorizing, filtration, filtrate for later use;
2) under the room temperature, the filtrate with the step 1) gained under stirring condition is added to the water, and is cooled to 0～5 ℃ after filtrate adds, and obtains continuing to stir behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.
First optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the mass volume ratio of the bulk drug of Cefpodoxime Proxetil described in the step 1) and described mixed solvent is 0.15～0.25:1g/mL, preferred 0.2:1g/mL; The volume ratio of methyl alcohol and dimethyl formamide is 3～7:1 in the described mixed solvent.
Second optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the speed that stirs step 2) is 800～1000r/min, and the time of continuing to stir is 8～12min, preferred 10min.
The 3rd optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the volume ratio of the water mixed solvent and the step 2 described in the step 1)) is 1:15～25, preferred 1:20.
The present invention also provides a kind of pharmaceutical composition, contains Cefpodoxime ester cpds of the present invention and pharmaceutical excipient in the described pharmaceutical composition.
A kind of preferred version as pharmaceutical composition of the present invention, pharmaceutical composition of the present invention can be prepared into pharmaceutically acceptable formulation, as oral dosage form, as more preferably scheme of the present invention, preferred preparation of the present invention becomes oral dosage forms such as tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
The present invention also further provides described preparation of drug combination method, and this method comprises the steps:
1) the Cefpodoxime Proxetil bulk drug is added by in the formulated mixed solvent of methyl alcohol and dimethyl formamide, stir and make dissolving, add activated carbon decolorizing, filtration, filtrate for later use;
2) under the room temperature, the filtrate with the step 1) gained under stirring condition is added to the water, and is cooled to 0～5 ℃ after filtrate adds, and obtains continuing to stir behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is the Cefpodoxime ester cpds;
3) the Cefpodoxime ester cpds of gained and pharmaceutical excipient are mixed obtain described pharmaceutical composition.
As the preparation method's of aforementioned pharmaceutical compositions preferred version, described preparation method also comprises further and described preparation of pharmaceutical compositions is become oral dosage form, preferred tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
Below the present invention is done further explanation:
The present invention has prepared a kind of Cefpodoxime ester cpds that is different from prior art by changing the crystallization condition of Cefpodoxime Proxetil, and its X-ray powder diffraction figure as shown in Figure 1.
Prior art shows that Cefpodoxime Proxetil belongs to unformed powder, and less stable under light, heat, wet condition is degraded easily and produces degradation production.The present invention has prepared a kind of Cefpodoxime ester cpds with certain crystallographic structure that is different from prior art by changing the crystallization condition of Cefpodoxime Proxetil.And show that by stability test Cefpodoxime ester cpds of the present invention obviously is better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The Cefpodoxime Proxetil that the stability of temperature and illumination also is better than prior art.Product purity is apparently higher than the Cefpodoxime Proxetil of prior art.In addition, the inventor finds that also pleasantly surprisedly Cefpodoxime ester cpds provided by the present invention has extraordinary flowability, is easy to packing.
The preparation method of Cefpodoxime ester cpds of the present invention comprises the steps:
1) the Cefpodoxime Proxetil bulk drug is added by in the formulated mixed solvent of methyl alcohol and dimethyl formamide, stir and make dissolving, add activated carbon decolorizing, filtration, filtrate for later use;
2) under the room temperature, the filtrate with the step 1) gained under stirring condition is added to the water, and is cooled to 0～5 ℃ after filtrate adds, and obtains continuing to stir behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.
First optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the mass volume ratio of the bulk drug of Cefpodoxime Proxetil described in the step 1) and described mixed solvent is 0.15～0.25:1g/mL, preferred 0.2:1g/mL; The volume ratio of methyl alcohol and dimethyl formamide is 3～7:1 in the described mixed solvent.
Medicine is directly relevant with the mass concentration of drug solution with the mass volume ratio of solution.The mass concentration that increases drug solution can improve the degree of supersaturation of system, and degree of supersaturation is the impellent of recrystallization process, and its size directly affects the speed of nucleus formation and crystal growth.Under higher degree of supersaturation condition, nucleation rate is conducive to short grained formation greater than crystal growth rate.But, along with the continuous increase of drug solution mass concentration, generating a large amount of drug particles in the mixing process rapidly, drug particles quantity sharply increases, thereby causes particle adhesion, reunion, and then generates bigger particle, makes grain diameter become big.Therefore, in preparation process, to avoid as far as possible or reduce the generation of aggregating state.For this reason, the present invention has investigated the size-grade distribution of different pharmaceutical solution quality concentration products obtained therefrom by at room temperature when controlling churning time for 10min, the results are shown in shown in Figure 2.By test, it is 0.15～0.25:1g/mL that the present invention selects the mass volume ratio of Cefpodoxime Proxetil bulk drug and mixed solvent, preferred 0.2:1g/mL.
Second optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the speed that stirs step 2) is 800～1000r/min, and the time of continuing to stir is 8～12min, preferred 10min.
Churning time all has more significantly influence to pattern and the granularity of Cefpodoxime Proxetil particle.The inventor is that 25 ℃ of room temperatures, mixing speed are 800～1000r/min by the control temperature of reaction, the mass volume ratio of Cefpodoxime Proxetil bulk drug and mixed solvent is 0.2:1g/mL, investigated the influence of churning time to the products obtained therefrom granularity, show when churning time is 30s and 5min, dry powder pattern irregularity, particle size is bigger, and size-grade distribution is wide, and agglomeration is serious; Prolong churning time, be conducive to larger-size medicine crystal particle is smashed, form the little and uniform particle of granularity, when churning time is 10min, can make comparatively loose product dry powder, its granule-morphology is comparatively regular, the individual particle particle diameter is little, and narrow particle size distribution; Continue to prolong churning time to 12min or shorten churning time to 8min, dry powder particle pattern and change of size are little, and therefore, the churning time that the present invention selects to suit is 8～12min, preferred 10min.
The 3rd optimal technical scheme of Preparation of Cefpodoxime Proxetil method of the present invention is: the volume ratio of the water mixed solvent and the step 2 described in the step 1)) is 1:15～25, preferred 1:20.
The anti-solvent volume of solvent is the important factor that influences crystal growth than also.The present invention has investigated the influence of the anti-solvent ratio of different solvents to the products obtained therefrom grain graininess, and the result as shown in Figure 3.When the anti-solvent ratio of solvent is increased to 1:25 by 1:15, the saturation solubility of medicine in mixed solution reduces, thereby degree of supersaturation increases, and finally causes reducing of grain diameter, continues the raising ratio to 1:30, because whole crystallizing system drug level diminishes, reduced the nucleation rate of crystal, drug precipitation is less, and yield is less, and granular size is inhomogeneous, broad particle distribution.Therefore, the described mixed solvent of step 1) of the present invention and step 2) described in the volume ratio of water be 1:15～25, preferred 1:20.
Among the preparation method of the present invention, by the meticulous control to crystallization condition, obtained a kind of new Cefpodoxime ester cpds that is different from prior art.The present invention adopts the antisolvent crystallisation liquid-phase precipitation method to prepare a kind of new Cefpodoxime ester cpds that is different from prior art, being about to Cefpodoxime Proxetil is dissolved in the bigger mixed solvent of its solubleness, then under stirring condition, joining this drug solution another kind of is in the anti-solvent to its poorly soluble solvent, then medicine reach supersaturation and from the mixing solutions of three kinds of solvents crystallization separate out, by the terms and conditions of crystallization control process, can prepare the Cefpodoxime ester cpds of even particle size distribution, favorable dispersity.
Find that through stability test Cefpodoxime ester cpds of the present invention obviously is better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The Cefpodoxime Proxetil that the stability of temperature and illumination also is better than prior art.Product purity is apparently higher than the Cefpodoxime Proxetil of prior art.
The present invention finds pleasantly surprisedly by fluidity test that further Cefpodoxime ester cpds of the present invention has very excellent flowability, is conducive to improve the accuracy of packing, and is easy to mix when mixing with other composition.
Description of drawings
Fig. 1 is the X-ray powder diffraction of the Cefpodoxime ester cpds of the embodiment of the invention 1 preparation;
Fig. 2 is the particle size distribution figure of Cefpodoxime ester cpds of the mass volume ratio gained of different Cefpodoxime Proxetil bulk drug and mixed solvent;
Fig. 3 is the particle size distribution figure of Cefpodoxime ester cpds of the volume ratio gained of different methyl alcohol/dimethyl formamide mixed solvent and water.
Embodiment
Below with embodiment technical scheme of the present invention is further described; to help the advantage to technical scheme of the present invention; effect has further to be understood, and embodiment does not limit protection scope of the present invention, and protection scope of the present invention is decided by claim.
The preparation of [embodiment 1] Cefpodoxime ester cpds
1) 2.1kg Cefpodoxime Proxetil bulk drug is added by the formulated mixed solvent 10L(of methyl alcohol and dimethyl formamide wherein the volume ratio of methyl alcohol and dimethyl formamide be 3:1) in, stirring make dissolve soup, the activated carbon decolorizing that adds soup cumulative volume 0.1%g/ml, filter filtrate for later use;
2) under the room temperature, low whipping speed is under the condition of 900r/min the filtrate of step 1) gained to be joined in the 200L water, is cooled to 3 ℃ after filtrate adds, and obtains continuing to stir 10min behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.IR(VBr) cm
-11780(beta-lactam C=O), 1680(acid amides C=O),
1HNMR1.31(6H, d, CH(CH
3)
2), 1.56(3H, d, CHCH
3) 3.30(3H, S, OCH
3) 3.52(2H, brS, 2-CH
2), 4.00(3H, S, NOCH
3), 4.32(2H, S, 3 '-CH
2) 4.5-5.2(1H, m, CH (CH
3)
2), 5.06 (1H, d, 6-CH), 6.02(1H, dd, 7-CH), 6.72(1H, S, thiazole ring 5-CH), 7.88 and 7.96(1H, q * 2, CHCH
3), 8.06 and 8.10(1H, d * 2,7-NHCO).
The X-ray powder diffraction spectrogram that prepared Cefpodoxime ester cpds use Cu-K alpha-ray measures as shown in Figure 1.
Below be embodiment 2-8, operation steps is with embodiment 1, and concrete processing parameter sees Table 1:
Table 1, embodiment 2-8
Consistent with embodiment 1 to the X-ray powder diffraction spectrogram that the prepared Cefpodoxime ester cpds of embodiment 2-8 uses the Cu-K alpha-ray to measure.
[FORMULATION EXAMPLE 1] Cefpodoxime Proxetil tablet
This embodiment uses the pharmaceutical composition of the Cefpodoxime Proxetil compound tablet form that the embodiment of the invention 1 makes.Adopt dry granulating to prepare the oral preparations of tablet form as processing technology.This pharmaceutical composition is listed in table 2.
Table 2
| Composition | %w/w |
| Cefpodoxime Proxetil | 49.79 |
| Xylo-Mucine | 42.07 |
| Hydroxypropylcellulose | 1.64 |
| Sodium lauryl sulphate | 2.05 |
| Magnesium Stearate | 0.82 |
The preparation method: the Cefpodoxime Proxetil of embodiment 1 is mixed with Xylo-Mucine and sodium lauryl sulphate, and by sieve (B.S.screens (BBS) 25; 600 μ m).With mixture by the pulverizer mill of 1.0mm sieve is housed, and with collision forward at a high speed.Lactose and hydroxypropylcellulose pass through 600 μ m purpose sieves, and mix with the mixture that ground in not having the mixing tank of shearing (octagon mixing tank).The gained mixture is by the dry granulating of extruding.With the sieve of extrudate by 710 μ m orders (B.S.screens (BBS) 25) to obtain particle.To sieve big or small particle and Magnesium Stearate (by B.S.screens (BBS) 44; 355 μ m purpose sieves) mix, be pressed into tablet then.
[FORMULATION EXAMPLE 2] Cefpodoxime proxetil suspension
Prescription:
The preparation method: get sucrose and cross 100 mesh sieves, 120 mesh sieves are standby excessively respectively to get hypromellose, xanthan gum; Get the Cefpodoxime Proxetil 50g of embodiment 2 and the sucrose 660g of pulverizing and mix, add 95% ethanol 200g softwood processed, 40 mesh sieves are granulated then, and the wet granular that makes is crossed the whole grain of 40 mesh sieves 45～50 ℃ of dryings 30 minutes; Mix with the hypromellose 71g of pulverizing and the xanthan gum 71g of pulverizing making dried particle, namely.
[FORMULATION EXAMPLE 3] Cefpodoxime proxetil suspension
Preparation method: with 80 mesh sieves screenings Glyceryl Behenate, get Cefpodoxime Proxetil that the embodiment 3 of recipe quantity makes and the Glyceryl Behenate of screening and mix.Mixture is placed 80-85 ℃ of constant temperature oven heating 10-15 minute, Cefpodoxime Proxetil and Glyceryl Behenate are melted jointly.Mixture with the gained fusion is cooled to room temperature then, then pulverizes, and crosses 60 mesh sieve branches.In the fine powder of screening gained, add sucrose, N.F,USP MANNITOL, Xylo-Mucine, xanthan gum, aspartame, peppermint essence, micropowder silica gel.After said mixture mixed with 40 mesh sieves, divide packing, every bag packing 2.535g.
[FORMULATION EXAMPLE 4] Cefpodoxime Proxetil dispersible tablet
Prescription:
Preparation method: all auxiliary materials are crossed 100 mesh sieves respectively.Take by weighing the abundant mixing of Cefpodoxime Proxetil, sodium starch glycolate, Microcrystalline Cellulose, hydroxypropylcellulose, polyvinylpolypyrrolidone, aspartame, sodium lauryl sulphate that the embodiment 4 of recipe quantity makes, cross 60 mesh sieves 1 time.Add micropowder silica gel and the flavoring orange essence of recipe quantity, fully mix, measure content, calculate the heavy back of sheet with the stamping of Ф 10.0mm scrobicula, namely get Cefpodoxime Proxetil dispersible tablet (hardness 5～6kgf).
[FORMULATION EXAMPLE 5] Cefpodoxime Proxetil capsule
Prescription:
The preparation method:
1) respectively with sodium starch glycolate and Microcrystalline Cellulose drying, pulverizing, crosses 80 mesh sieves, obtain sodium starch glycolate powder and Microcrystalline Cellulose powder respectively;
2) get sodium starch glycolate powder and the Microcrystalline Cellulose powder mixing of recipe quantity, cross 80 mesh sieves repeatedly, obtain the auxiliary material mixture;
3) add the Cefpodoxime Proxetil powder that the embodiment 5 of recipe quantity makes in the above-mentioned auxiliary material mixture, mixture is even, adds 5%PVP K30 aqueous solution softwood processed in right amount then, crosses 20 order nylon mesh and granulates, and obtains the Cefpodoxime Proxetil wet granular;
4) above-mentioned Cefpodoxime Proxetil wet granular is dried to moisture 2.0% under 60 ℃ of conditions, obtains the Cefpodoxime proxetil particle;
5) above-mentioned Cefpodoxime proxetil particle is crossed the whole grain of 20 order nylon mesh, added Magnesium Stearate then, mix, after quality inspection was qualified, the dress capsule namely got the Cefpodoxime Proxetil capsule.
[FORMULATION EXAMPLE 6] Cefpodoxime Proxetil chewable tablet
Prescription:
Preparation technology:
Take by weighing Cefpodoxime Proxetil that embodiment 6 makes and N.F,USP MANNITOL, Star Dri 5, sucrose, aspartame, mentha camphor and sweet orange powdered flavor by 80 mesh sieves; put in the step tablets press and mix; spraying into an amount of 5%PVP K30 aqueous solution granulates; weigh after the drying; take by weighing 1% Magnesium Stearate; mix with dried particles in the adding dry-mixed machine, the qualified back of work in-process content compressing tablet, namely.
Test example 1
This test example at room temperature, the control churning time is 10min, has investigated the size-grade distribution of the mass volume ratio products obtained therefrom of different Cefpodoxime Proxetil bulk drugs and mixed solvent under the identical condition of other condition, the results are shown in shown in Figure 2.By test, it is 0.15～0.25:1g/mL that the present invention selects the mass volume ratio of Cefpodoxime Proxetil bulk drug and mixed solvent, preferred 0.2:1g/mL.
Test example 2
The anti-solvent volume of solvent is the important factor that influences crystal growth than also.The different volumes of this test example has been investigated solvent under the identical condition of other conditions---mixed solvent of methyl alcohol and dimethyl formamide and anti-solvent---water is compared the influence of products obtained therefrom grain graininess, and the result as shown in Figure 3.When the anti-solvent ratio of solvent is increased to 1:25 by 1:15, the saturation solubility of medicine in mixed solution reduces, thereby degree of supersaturation increases, and finally causes reducing of grain diameter, continues the raising ratio to 1:30, because whole crystallizing system drug level diminishes, reduced the nucleation rate of crystal, drug precipitation is less, and yield is less, and granular size is inhomogeneous, broad particle distribution.Therefore, the volume ratio of solvent among the present invention---mixed solvent of methyl alcohol and dimethyl formamide and anti-solvent---water is 1:15～25, preferred 1:20.
Test example 3
The result is as follows through temperature, humidity, light durability investigation for Cefpodoxime ester cpds of the present invention:
Control sample: according to " Preparation of Cefpodoxime Proxetil " [Zhang Yanlong, normal in. Preparation of Cefpodoxime Proxetil [J]. applied science, 2002,29(8)] Cefpodoxime Proxetil that makes;
Test sample: the Cefpodoxime ester cpds that the embodiment of the invention 1 is prepared.
1, humid test:
Condition: 75% relative humidity, 40 ℃ of dew were put ten days.
Content result:
| ? | Before placing (%) | After ten days (%) | Content decline (%) |
| Control sample | 90.3 | 88.0 | 2.3 |
| Test sample | 99.6 | 99.3 | 0.3 |
Annotate: measure content with the HPLC method.
2, humid test:
Condition: 60 ℃ of glass are airtight, two weeks.
Content result:
| ? | Before placing (%) | Two week backs (%) | Content decline (%) |
| Control sample | 90.3 | 88.1 | 2.2 |
| Test sample | 99.6 | 99.4 | 0.2 |
Annotate: measure content with the HPLC method.
3, exposure experiments to light:
Condition: 2000nX, a week
Content result:
| ? | Before placing (%) | Illumination one week back (%) | Content decline (%) |
| Control sample | 90.3 | 87.5 | 2.8 |
| Test sample | 99.6 | 97.8 | 1.8 |
Annotate: measure content with the HPLC method.
4, product purity contrast:
| ? | Content (%) | The impurity spot |
| Control sample | ＜95.0 | Have |
| Test sample | ＞99.5 | Do not have |
Annotate: content assaying method: HPLC, impurity determination method: TLC
Show by above-mentioned test-results: Cefpodoxime ester cpds of the present invention obviously is better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The Cefpodoxime Proxetil that the stability of temperature and illumination also is better than prior art.Product purity is apparently higher than the Cefpodoxime Proxetil of prior art.
The Cefpodoxime ester cpds prepared to other embodiment of the present invention also carried out above-mentioned test, and the result of its acquisition is similar.
Test example 4
This test example is to investigate the flowability of the Cefpodoxime Proxetil of Cefpodoxime ester cpds of the present invention and prior art.
According to the method for the embodiment of the invention 16 batches of preparations continuously (batch be respectively test 1, test 2, test 3, test 4, test 5 and test 6) Cefpodoxime ester cpds, its flowability is investigated in sampling in accordance with the following methods from 6 batches respectively.
Method: adopt the fixed funnel method, funnel is placed suitable height on the graph paper, the Cefpodoxime ester cpds is freely flowed down from flare opening, contact with flare opening up to the cone top that forms, measure hypotenuse and the horizontal angle (slope of repose θ) of Cefpodoxime Proxetil accumulation horizon.
Result: see Table 3.
The fluidity test result of table 3, Cefpodoxime ester cpds of the present invention
| Batch | Test 1 | Test 2 | Test 3 | Test 4 | |
Test 6 | Mean value |
| θ（°） | 34 | 35 | 35 | 33 | 32 | 33 | 33.7 |
Equally, according to " Preparation of Cefpodoxime Proxetil " [Zhang Yanlong, in normal. Preparation of Cefpodoxime Proxetil [J]. applied science, 2002, continuously 6 batches of preparations of method 29(8)] (batch be respectively contrast 1, contrast 2, contrast 3, contrast 4, contrast 5 and contrast 6) Cefpodoxime Proxetil, its flowability is investigated in sampling according to the method described above from 6 batches respectively.The results are shown in Table 4.
The fluidity test result of the Cefpodoxime Proxetil of table 4, prior art
| Batch | Contrast 1 | Contrast 2 | Contrast 3 | Contrast 4 | |
Contrast 6 | Mean value |
| θ（°） | 43 | 42 | 43 | 42 | 44 | 45 | 43.2 |
From the test-results of table 3 and table 4 as can be seen, compare than the Cefpodoxime Proxetil of prior art, Cefpodoxime ester cpds of the present invention mobile fine is conducive to improve the accuracy of packing, and is easy to mix when mixing with other composition.The prepared Cefpodoxime ester cpds of other embodiments of the invention has also been carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a Cefpodoxime ester cpds is characterized in that, described Cefpodoxime ester cpds has the chemical structural formula shown in the formula (I):
Formula (I);
The X-ray powder diffraction spectrogram that described Cefpodoxime ester cpds use Cu-K alpha-ray measures as shown in Figure 1.
2. the preparation method of the described Cefpodoxime ester cpds of claim 1 is characterized in that, described preparation method comprises the steps:
1) the Cefpodoxime Proxetil bulk drug is added by in the formulated mixed solvent of methyl alcohol and dimethyl formamide, stir and make dissolving, add activated carbon decolorizing, filtration, filtrate for later use;
2) under the room temperature, the filtrate with the step 1) gained under stirring condition is added to the water, and is cooled to 0～5 ℃ after filtrate adds, and obtains continuing to stir behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.
3. preparation method according to claim 2 is characterized in that, the mass volume ratio of the former medicine of Cefpodoxime Proxetil described in the step 1) and described mixed solvent is 0.15～0.25:1g/mL, preferred 0.2:1g/mL; The volume ratio of methyl alcohol and dimethyl formamide is 3～7:1 in the described mixed solvent.
4. preparation method according to claim 2 is characterized in that step 2) described in the speed that stirs be 800～1000r/min, the time of continuing to stir is 8～12min, preferred 10min.
5. preparation method according to claim 2 is characterized in that, mixed solvent and the step 2 described in the step 1)) described in the volume ratio of water be 1:15～25, preferred 1:20.
6. a pharmaceutical composition is characterized in that, contains the described Cefpodoxime ester cpds of claim 1 and pharmaceutical excipient in the described pharmaceutical composition.
7. pharmaceutical composition according to claim 6 is characterized in that, described pharmaceutical composition is oral dosage form.
8. pharmaceutical composition according to claim 7 is characterized in that, described oral dosage form is tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
9. the described preparation of drug combination method of claim 6 is characterized in that described preparation method comprises the steps:
1) the Cefpodoxime Proxetil bulk drug is added by in the formulated mixed solvent of methyl alcohol and dimethyl formamide, stir and make dissolving, add activated carbon decolorizing, filtration, filtrate for later use;
2) under the room temperature, the filtrate with the step 1) gained under stirring condition is added to the water, and is cooled to 0～5 ℃ after filtrate adds, and obtains continuing to stir behind the crystal; Filter, the filter cake methanol wash, drying under reduced pressure obtains light yellow crystalline powder, is the Cefpodoxime ester cpds;
3) the Cefpodoxime ester cpds of gained and pharmaceutical excipient are mixed obtain described pharmaceutical composition.
10. preparation of drug combination method according to claim 9 is characterized in that, described preparation method also comprises further described preparation of pharmaceutical compositions is become oral dosage form.
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Cited By (2)
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| CN103479589A (en) * | 2013-09-22 | 2014-01-01 | 海南葫芦娃制药有限公司 | Cefpodoxime proxetil dispersible tablet and preparation method thereof |
| CN108530468A (en) * | 2018-03-21 | 2018-09-14 | 山东睿鹰先锋制药有限公司 | A kind of Cefpodoxime Proxetil impurity and its preparation method and application |
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| WO2002068429A1 (en) * | 2001-02-27 | 2002-09-06 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime proxetil |
| CN1640879A (en) * | 2004-01-08 | 2005-07-20 | 上海三维制药有限公司 | One-step method for preparing high-purity cefpoxime proxetil |
| CN101278914A (en) * | 2008-01-02 | 2008-10-08 | 海南三叶药业有限公司 | Cefpodoxime proxetil suspension composition and preparation thereof |
| EP2520578A1 (en) * | 2011-05-06 | 2012-11-07 | Lupin Limited | Process for purification of cephalosporins |
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Patent Citations (4)
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| WO2002068429A1 (en) * | 2001-02-27 | 2002-09-06 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime proxetil |
| CN1640879A (en) * | 2004-01-08 | 2005-07-20 | 上海三维制药有限公司 | One-step method for preparing high-purity cefpoxime proxetil |
| CN101278914A (en) * | 2008-01-02 | 2008-10-08 | 海南三叶药业有限公司 | Cefpodoxime proxetil suspension composition and preparation thereof |
| EP2520578A1 (en) * | 2011-05-06 | 2012-11-07 | Lupin Limited | Process for purification of cephalosporins |
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| CN103479589A (en) * | 2013-09-22 | 2014-01-01 | 海南葫芦娃制药有限公司 | Cefpodoxime proxetil dispersible tablet and preparation method thereof |
| CN103479589B (en) * | 2013-09-22 | 2016-04-13 | 海南葫芦娃制药有限公司 | cefpodoxime proxetil dispersible tablet and preparation method thereof |
| CN108530468A (en) * | 2018-03-21 | 2018-09-14 | 山东睿鹰先锋制药有限公司 | A kind of Cefpodoxime Proxetil impurity and its preparation method and application |
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