CN103275102B - 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)-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:
For oral third generation cephalosporin, has a broad antifungal spectrum, be hydrolyzed to Cefpodoxime performance anti-microbial effect through nonspecific esterase after entering in body, gram-positive microorganism and Gram-negative bacteria are had to the antimicrobial spectrum of wide scope, stable to β-lactamase.Be applicable to clinically responsive microbial upper respiratory tract infection, lower respiratory infection, pure urinary tract infection, pure skin and skin soft-tissue infection, acute simplex gonococcal urethritis and trachelitis, the anal inflammation being caused by Neisseria gonorrheae etc.
Cefpodoxime Proxetil (cefpodoxime proxetil) be beginning of the nineties listing the 3rd generation oral semi-synthetic cynnematin, all more stable to the β-lactamase of plasmid, Chromosome-encoded, thereby solved preferably bacterial resistance problem.Cefpodoxime is extensive pedigree antibiotic, and common gram-positive, negative bacterium are all had to reasonable antibacterial effect.After oral, what the non-specific lipase on gastrointestinal wall can play anti-microbial effect is Cefpodoxime.Cefpodoxime Proxetil is more extensive in the application of respiratory tract, urinary tract, gynecological infection disease in recent years, is obtaining good curative effect aspect treatment children with acute tympanitis, 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, without fixing fusing point, in water, do not dissolve.Destructive test shows, Cefpodoxime Proxetil is poor at light, heat, wet condition stability inferior, be easily degraded and produce degradation production, and powder flowbility is poor.
In recent years, along with the development of crystal engineering, increasing pharmacy worker has turned one's attention to the research of drug crystal forms, for some because of physico-chemical property medicine not fully up to expectations, the crystal formation that changes medicine can improve to a certain extent its solubleness, reduces fusing point, improve the effects such as stability, is then used for improving its bioavailability 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
The first object of the present invention is to provide a kind of Cefpodoxime ester cpds.
The second object of the present invention is the preparation method of the Cefpodoxime ester cpds that provides described.
The 3rd object of the present invention is to provide a kind of pharmaceutical composition, and this pharmaceutical composition contains above-mentioned Cefpodoxime ester cpds.
For realizing the first object 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 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 the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for Cefpodoxime ester cpds, wherein, described preparation method comprises the steps:
1) Cefpodoxime Proxetil bulk drug is added by methyl alcohol and the formulated mixed solvent of dimethyl formamide, be stirred to dissolve, add activated carbon decolorizing, filter filtrate for later use;
2) under room temperature, under the condition stirring, the filtrate of step 1) gained is added to the water, after filtrate adds, is cooled to 0～5 ℃, obtain continuing to stir after crystal; Filter, filter cake methanol wash, drying under reduced pressure, obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.
The first optimal technical scheme of the preparation method of Cefpodoxime Proxetil of the present invention is: the mass volume ratio of the bulk drug of Cefpodoxime Proxetil described in step 1) and described mixed solvent is 0.15～0.25:1g/mL, preferably 0.2:1g/mL; In described mixed solvent, the volume ratio of methyl alcohol and dimethyl formamide is 3～7:1.
The second optimal technical scheme of the preparation method of Cefpodoxime Proxetil of the present invention is: step 2) described in the speed that stirs be 800～1000r/min, the time of continuing to stir is 8～12min, preferably 10min.
The preparation method's of Cefpodoxime Proxetil of the present invention the 3rd optimal technical scheme is: mixed solvent and the step 2 described in step 1)) described in the volume ratio of water be 1:15～25, preferably 1:20.
The present invention also provides a kind of pharmaceutical composition, contains Cefpodoxime ester cpds of the present invention and pharmaceutical excipient in described pharmaceutical composition.
As a kind of preferred version of 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, the present invention is preferably prepared into the oral dosage forms such as tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
The present invention also further provides the preparation method of described pharmaceutical composition, and the method comprises the steps:
1) Cefpodoxime Proxetil bulk drug is added by methyl alcohol and the formulated mixed solvent of dimethyl formamide, be stirred to dissolve, add activated carbon decolorizing, filter filtrate for later use;
2) under room temperature, under the condition stirring, the filtrate of step 1) gained is added to the water, after filtrate adds, is cooled to 0～5 ℃, obtain continuing to stir after crystal; Filter, filter cake methanol wash, drying under reduced pressure, obtains light yellow crystalline powder, is Cefpodoxime ester cpds;
3) the Cefpodoxime ester cpds of gained is mixed with pharmaceutical excipient and obtain described pharmaceutical composition.
As the preparation method's of aforementioned pharmaceutical compositions preferred version, described preparation method also comprises further and described pharmaceutical composition is prepared into oral dosage form, preferred tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
Below the present invention is further described:
The present invention, by changing the crystallization condition of Cefpodoxime Proxetil, has prepared a kind of Cefpodoxime ester cpds that is different from prior art, and its X-ray powder diffraction figure as shown in Figure 1.
Prior art shows that Cefpodoxime Proxetil belongs to unformed powder, poor at light, heat, wet condition stability inferior, is easily degraded and produces degradation production.The present invention, by changing the crystallization condition of Cefpodoxime Proxetil, has prepared a kind of Cefpodoxime ester cpds with certain crystallographic structure that is different from prior art.And show by stability test, Cefpodoxime ester cpds of the present invention is obviously better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The stability of temperature and illumination is also better than to the Cefpodoxime Proxetil of prior art.Product purity is apparently higher than the Cefpodoxime Proxetil of prior art.In addition, the inventor finds also pleasantly surprisedly, and Cefpodoxime ester cpds provided by the present invention has extraordinary mobility, is easy to packing.
The preparation method of Cefpodoxime ester cpds of the present invention comprises the steps:
1) Cefpodoxime Proxetil bulk drug is added by methyl alcohol and the formulated mixed solvent of dimethyl formamide, be stirred to dissolve, add activated carbon decolorizing, filter filtrate for later use;
2) under room temperature, under the condition stirring, the filtrate of step 1) gained is added to the water, after filtrate adds, is cooled to 0～5 ℃, obtain continuing to stir after crystal; Filter, filter cake methanol wash, drying under reduced pressure, obtains light yellow crystalline powder, is described Cefpodoxime ester cpds.
The first optimal technical scheme of the preparation method of Cefpodoxime Proxetil of the present invention is: the mass volume ratio of the bulk drug of Cefpodoxime Proxetil described in step 1) and described mixed solvent is 0.15～0.25:1g/mL, preferably 0.2:1g/mL; In described mixed solvent, the volume ratio of methyl alcohol and dimethyl formamide is 3～7:1.
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 that nucleus forms and crystal is grown.Under higher degree of supersaturation condition, nucleation rate is greater than crystal growth rate, is conducive to short grained formation.But, along with the continuous increase of drug solution mass concentration, in mixing process, generating rapidly a large amount of drug particles, drug particles quantity sharply increases, thereby causes particle adhesion, reunion, and then generates larger particle, makes grain diameter become large.Therefore, in preparation process, to avoid as far as possible or reduce the generation of aggregating state.For this reason, the present invention, by room temperature, controls the size-grade distribution of having investigated different pharmaceutical concentration of polymer solution products obtained therefrom when churning time is 10min, the results are shown in Figure shown in 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, preferably 0.2:1g/mL.
The second optimal technical scheme of the preparation method of Cefpodoxime Proxetil of the present invention is: step 2) described in the speed that stirs be 800～1000r/min, the time of continuing to stir is 8～12min, preferably 10min.
Pattern and the granularity of churning time on Cefpodoxime Proxetil particle all has obvious impact.The inventor is that 25 ℃ of room temperatures, mixing speed are 800～1000r/min by controlling temperature of reaction, the mass volume ratio of Cefpodoxime Proxetil bulk drug and mixed solvent is 0.2:1g/mL, investigate the impact of churning time on products obtained therefrom granularity, show in the time that churning time is 30s and 5min, dry powder pattern irregularity, particle size is larger, and size-grade distribution is wide, and agglomeration is serious; Extend churning time, be conducive to larger-size medicine crystal particle to be smashed, form the little and uniform particle of granularity, in the time that churning time is 10min, can make comparatively loose product dry powder, its granule-morphology is comparatively regular, individual particle particle diameter is little, and narrow particle size distribution; Continue to extend churning time to 12min or shorten churning time to 8min, dry powder particle pattern and change of size are little, and therefore, it is 8～12min that the present invention selects suitable churning time, preferably 10min.
The preparation method's of Cefpodoxime Proxetil of the present invention the 3rd optimal technical scheme is: mixed solvent and the step 2 described in step 1)) described in the volume ratio of water be 1:15～25, preferably 1:20.
The anti-solvent volume of solvent is than being also the important factor that affects crystal growth.The present invention has investigated the impact of the anti-solvent ratio of different solvents on products obtained therefrom grain graininess, and result as shown in Figure 3.In the time that 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, continue raising ratio to 1:30, because whole crystallizing system drug level diminishes, the nucleation rate that has reduced crystal, drug precipitation is less, and yield is less, and granular size is inhomogeneous, broad particle distribution.Therefore, mixed solvent and step 2 described in step 1) of the present invention) described in the volume ratio of water be 1:15～25, preferably 1:20.
In preparation method of the present invention, by the meticulous control to crystallization condition, obtain a kind of new Cefpodoxime ester cpds that is different from prior art.The present invention adopts antisolvent crystallisation liquid-phase precipitation method to prepare a kind of new Cefpodoxime ester cpds that is different from prior art, be dissolved in the larger mixed solvent of its solubleness by Cefpodoxime Proxetil, then under the condition stirring, it is in anti-solvent to its poorly soluble solvent that this drug solution is joined to another kind, medicine reach supersaturation and from the mixing solutions of three kinds of solvents crystallization, by the terms and conditions of crystallization control process, can prepare the Cefpodoxime ester cpds of even particle size distribution, favorable dispersity.
Find through stability test, Cefpodoxime ester cpds of the present invention is obviously better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The stability of temperature and illumination is also better than to the Cefpodoxime Proxetil of prior art.Product purity is apparently higher than the Cefpodoxime Proxetil of prior art.
The present invention further by fluidity test pleasantly surprised find, Cefpodoxime ester cpds of the present invention has very excellent mobility, is conducive to improve the accuracy of packing, and is easy to mix while mixing with other composition.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the Cefpodoxime ester cpds prepared of the embodiment of the present invention 1;
Fig. 2 is the particle size distribution figure of the 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 the Cefpodoxime ester cpds of the volume ratio gained of different methyl alcohol/dimethyl formamide mixed solvent and water.
Embodiment
With embodiment, technical scheme of the present invention is further described below; by the advantage contributing 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 methyl alcohol and the formulated mixed solvent 10L(of dimethyl formamide wherein the volume ratio of methyl alcohol and dimethyl formamide be 3:1) in, be stirred to dissolve to obtain liquid, add the activated carbon decolorizing of liquid cumulative volume 0.1%g/ml, filter filtrate for later use;
2) under room temperature, under the condition that low whipping speed is 900r/min, the filtrate of step 1) gained is joined in 200L water, after filtrate adds, be cooled to 3 ℃, obtain continuing to stir 10min after crystal; Filter, 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.
Be below embodiment 2-8, operation steps is with embodiment 1, and concrete technology parameter is in table 1:
Table 1, embodiment 2-8
The X-ray powder diffraction spectrogram that uses Cu-K alpha-ray to measure to the prepared Cefpodoxime ester cpds of embodiment 2-8 is consistent with embodiment 1.
[FORMULATION EXAMPLE 1] Cefpodoxime Proxetil tablet
This embodiment uses Cefpodoxime ester cpds that the embodiment of the present invention 1 makes to prepare the pharmaceutical composition of tablet form.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 |
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).By mixture by the pulverizer mill of 1.0mm sieve is housed, and with at a high speed collision forward.Lactose and hydroxypropylcellulose pass through 600 μ m object sieves, and mix with the mixture grinding in the mixing tank (octagon mixing tank) without shearing.Gained mixture is dried granulating by extruding.Sieve by extrudate by 710 μ m orders (B.S.screens (BBS) 25) is to obtain particle.To sieve big or small particle and Magnesium Stearate (by B.S.screens (BBS) 44; 355 μ m object sieves) mix, be then pressed into tablet.
[FORMULATION EXAMPLE 2] Cefpodoxime proxetil suspension
Prescription:
Preparation method: get sucrose and cross 100 mesh sieves, 120 mesh sieves are for subsequent use excessively respectively to get hypromellose, xanthan gum; Get the Cefpodoxime Proxetil 50g of embodiment 2 and the sucrose 660g of pulverizing mixes, add 95% ethanol 200g softwood processed, then 40 mesh sieves are granulated, the wet granular making 45～50 ℃ dry 30 minutes, cross the whole grain of 40 mesh sieves; Mix with the hypromellose 71g of pulverizing and the xanthan gum 71g of pulverizing making dry particle, to obtain final product.
[FORMULATION EXAMPLE 3] Cefpodoxime proxetil suspension
Preparation method: with 80 mesh sieves screenings Glyceryl Behenates, get the Cefpodoxime Proxetil that the embodiment 3 of recipe quantity makes and mix with the Glyceryl Behenate of screening.Mixture is placed in to 80-85 ℃ of constant temperature oven and heats 10-15 minute, Cefpodoxime Proxetil and Glyceryl Behenate are melted jointly.Then the mixture of gained melting is cooled to room temperature, then pulverizes, cross 60 mesh sieves and divide.In the fine powder of screening gained, add sucrose, N.F,USP MANNITOL, Xylo-Mucine, xanthan gum, aspartame, Mint Essence, micropowder silica gel.After said mixture is mixed with 40 mesh sieves, point packing, every bag packing 2.535g.
[FORMULATION EXAMPLE 4] Cefpodoxime Proxetil dispersible tablet
Prescription:
Preparation method: all auxiliary materials are crossed respectively to 100 mesh sieves.Take Cefpodoxime Proxetil, sodium starch glycolate, Microcrystalline Cellulose, hydroxypropylcellulose, polyvinylpolypyrrolidone, aspartame, the sodium lauryl sulphate that the embodiment 4 of recipe quantity makes and fully mix, cross 60 mesh sieve 1 time.The micropowder silica gel and the flavoring orange essence that add recipe quantity, fully mix, and measures content, calculates sheet heavy rear with the stamping of Ф 10.0mm scrobicula, obtains Cefpodoxime Proxetil dispersible tablet (hardness 5～6kgf).
[FORMULATION EXAMPLE 5] Cefpodoxime Proxetil capsule
Prescription:
Preparation method:
1) respectively by dry to sodium starch glycolate and Microcrystalline Cellulose, pulverizing, cross 80 mesh sieves, obtain respectively sodium starch glycolate powder and Microcrystalline Cellulose powder;
2) sodium starch glycolate powder and the Microcrystalline Cellulose powder of getting recipe quantity mix, and repeatedly cross 80 mesh sieves, obtain auxiliary material mixture;
3) to the Cefpodoxime Proxetil powder that adds the embodiment 5 of recipe quantity to make in above-mentioned auxiliary material mixture, mixture is even, then adds 5%PVP K30 aqueous solution softwood processed in right amount, crosses 20 order nylon mesh and granulates, and obtains Cefpodoxime Proxetil wet granular;
4) above-mentioned Cefpodoxime Proxetil wet granular is dried to moisture 2.0% under 60 ℃ of conditions, obtains Cefpodoxime proxetil particle;
5) above-mentioned Cefpodoxime proxetil particle is crossed to the whole grain of 20 order nylon mesh, then added Magnesium Stearate, mix, after quality inspection is qualified, dress capsule, obtains Cefpodoxime Proxetil capsule.
[FORMULATION EXAMPLE 6] Cefpodoxime Proxetil chewable tablet
Prescription:
Preparation technology:
Take Cefpodoxime Proxetil that embodiment 6 makes and by N.F,USP MANNITOL, Star Dri 5, sucrose, aspartame, mentha camphor and the sweet orange powdered flavor of 80 mesh sieves; put in a step tablets press and mix; spraying into the appropriate 5%PVP K30 aqueous solution granulates; after dry, weigh; take 1% Magnesium Stearate; add in dry-mixed machine and mix with dried particles, the qualified rear compressing tablet of work in-process content, to obtain final product.
Test example 1
At room temperature, control churning time is 10min to this test example, 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 Figure shown in 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, preferably 0.2:1g/mL.
Test example 2
The anti-solvent volume of solvent is than being also the important factor that affects crystal growth.The impact of the different volumes comparison products obtained therefrom grain graininess 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, result as shown in Figure 3.In the time that 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, continue raising ratio to 1:30, because whole crystallizing system drug level diminishes, the nucleation rate that has reduced crystal, drug precipitation is less, and yield is less, and granular size is inhomogeneous, broad particle distribution.Therefore, the volume ratio of solvent in the present invention---mixed solvent of methyl alcohol and dimethyl formamide and anti-solvent---water is 1:15～25, preferably 1:20.
Test example 3
It is as follows that Cefpodoxime ester cpds of the present invention passes through temperature, humidity, light durability is investigated result:
Control sample: according to " preparation of Cefpodoxime Proxetil " [Zhang Yanlong, normal in. the preparation [J] of Cefpodoxime Proxetil. applied science, 2002,29(8)] Cefpodoxime Proxetil that makes;
Test sample: the Cefpodoxime ester cpds that the embodiment of the present invention 1 is prepared.
1, humid test:
Condition: 75% relative humidity, 40 ℃ of dew are put ten days.
Content result:
| ? | Before placement (%) | After ten days (%) | Content decline (%) |
| Control sample | 90.3 | 88.0 | 2.3 |
| Test sample | 99.6 | 99.3 | 0.3 |
Note: with HPLC method mensuration content.
2, humid test:
Condition: 60 ℃ of glass are airtight, two weeks.
Content result:
| ? | Before placement (%) | After two weeks (%) | Content decline (%) |
| Control sample | 90.3 | 88.1 | 2.2 |
| Test sample | 99.6 | 99.4 | 0.2 |
Note: with HPLC method mensuration content.
3, exposure experiments to light:
Condition: 2000nX, one week
Content result:
| ? | Before placement (%) | Illumination is after one week (%) | Content decline (%) |
| Control sample | 90.3 | 87.5 | 2.8 |
| Test sample | 99.6 | 97.8 | 1.8 |
Note: with HPLC method mensuration content.
4, product purity contrast:
| ? | Content (%) | Impurity spot |
| Control sample | ＜95.0 | Have |
| Test sample | ＞99.5 | Nothing |
Note: content assaying method: HPLC, impurity determination method: TLC
Show by above-mentioned test-results: Cefpodoxime ester cpds of the present invention is obviously better than the Cefpodoxime Proxetil of prior art to the stability of humidity; The stability of temperature and illumination is also better than to the Cefpodoxime Proxetil of 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 the mobility of the Cefpodoxime Proxetil of investigating Cefpodoxime ester cpds of the present invention and prior art.
According to 6 batches of the method continuous productions of the embodiment of the present invention 1 (batch being respectively test 1, test 2, test 3, test 4, test 5 and test 6) Cefpodoxime ester cpds, from 6 batches, its mobility is investigated in sampling in accordance with the following methods respectively.
Method: adopt fixed funnel method, funnel is placed in to the suitable height on graph paper, make Cefpodoxime ester cpds from flare opening Free-flow, until the cone top forming contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of Cefpodoxime Proxetil accumulation horizon.
Result: in 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. the preparation [J] of Cefpodoxime Proxetil. applied science, 2002,6 batches of method continuous productions 29(8)] (batch be respectively contrast 1, contrast 2, contrast 3, contrast 4, contrast 5 and contrast 6) Cefpodoxime Proxetil, from 6 batches, its mobility is investigated in sampling according to the method described above 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 |
Can find out from the test-results of table 3 and table 4, compare compared with the Cefpodoxime Proxetil of prior art, the mobility of Cefpodoxime ester cpds of the present invention is fine, is conducive to improve the accuracy of packing, and is easy to mix while mixing with other composition.The prepared Cefpodoxime ester cpds of other embodiments of the invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Claims (13)
1. a Cefpodoxime ester cpds, is characterized in that, described Cefpodoxime ester cpds has the chemical structural formula shown in 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. a preparation method for Cefpodoxime ester cpds claimed in claim 1, is characterized in that, described preparation method comprises the steps:
1) Cefpodoxime Proxetil bulk drug is added by methyl alcohol and the formulated mixed solvent of dimethyl formamide, be stirred to dissolve, add activated carbon decolorizing, filter filtrate for later use;
2) under room temperature, under the condition stirring by step 1) filtrate of gained is added to the water, and after filtrate adds, is cooled to 0～5 ℃, obtain continuing to stir after crystal; Filter, 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 step 1) described in the mass volume ratio of the former medicine of Cefpodoxime Proxetil and described mixed solvent be 0.15～0.25:1g/mL; In described mixed solvent, the volume ratio of methyl alcohol and dimethyl formamide is 3～7:1.
4. preparation method according to claim 3, is characterized in that step 1) described in the mass volume ratio of the former medicine of Cefpodoxime Proxetil and described mixed solvent be 0.2:1g/mL.
5. preparation method according to claim 2, is characterized in that step 2) described in stir speed be 800～1000r/min, continue stir time be 8～12min.
6. preparation method according to claim 5, is characterized in that step 2) in continue stir time be 10min.
7. preparation method according to claim 2, is characterized in that step 1) described in mixed solvent and step 2) described in the volume ratio of water be 1:15～25.
8. preparation method according to claim 7, is characterized in that step 1) described in mixed solvent and step 2) described in the volume ratio of water be 1:20.
9. a pharmaceutical composition, is characterized in that, contains Cefpodoxime ester cpds claimed in claim 1 and pharmaceutical excipient in described pharmaceutical composition.
10. pharmaceutical composition according to claim 9, is characterized in that, described pharmaceutical composition is oral dosage form.
11. pharmaceutical compositions according to claim 10, is characterized in that, described oral dosage form is tablet, capsule, dry suspensoid, dispersible tablet or chewable tablet.
The preparation method of 12. 1 kinds of pharmaceutical compositions claimed in claim 9, is characterized in that, described preparation method comprises the steps:
1) Cefpodoxime Proxetil bulk drug is added by methyl alcohol and the formulated mixed solvent of dimethyl formamide, be stirred to dissolve, add activated carbon decolorizing, filter filtrate for later use;
2) under room temperature, under the condition stirring by step 1) filtrate of gained is added to the water, and after filtrate adds, is cooled to 0～5 ℃, obtain continuing to stir after crystal; Filter, filter cake methanol wash, drying under reduced pressure, obtains light yellow crystalline powder, is Cefpodoxime ester cpds;
3) the Cefpodoxime ester cpds of gained is mixed with pharmaceutical excipient and obtain described pharmaceutical composition.
The preparation method of 13. pharmaceutical compositions according to claim 12, is characterized in that, described preparation method also comprises further described pharmaceutical composition is prepared into oral dosage form.
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| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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