CN103588695B - Oxiracetam compound of a kind of crystallized form and preparation method thereof - Google Patents
Oxiracetam compound of a kind of crystallized form and preparation method thereof Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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Abstract
The present invention relates to oxiracetam compound of a kind of crystallized form and preparation method thereof, belong to medical art.The X-ray powder diffraction of the oxiracetam compound of described crystallized form is 5.2 ± 0.2 ° at 2 θ, 11.5 ± 0.2 °, 13.6 ± 0.2 °, 15.8 ± 0.2 °, and 17.5 ± 0.2 °, 19.1 ± 0.2 °, there is characteristic peak at 20.8 ± 0.2 ° of places.It is high that the oxiracetam compound of this crystallized form has bioavailability, good stability, and being placed with related substance does not for a long time increase, the good characteristic that clarity does not decline, and is more suitable for as bulk drug for the production of pharmaceutical preparation and storage.
Description
Technical field
The present invention relates to a kind of compound and preparation method thereof, particularly relate to oxiracetam compound of a kind of crystallized form and preparation method thereof, belong to medical art.
Background technology
Oxiracetam, English name Oxiracetam, chemical name is Esomeprazole, structural formula as shown in Equation 1:
Oxiracetam is a kind of nootropics, memory and the learning functionality of senile dementia and memory disorder patient can be improved, result of study shows, oxiracetam can promote Phosphorylcholine and phosphatidyl ethanolamine synthesis, improve the ratio of ATP/ADP in brain, the synthesis of protein and nucleic acid in brain is increased.Be widely used at present the treatment of memory that the diseases such as light moderate vascular dementia, senile dementia and cerebral trauma cause and disturbance of intelligence clinically, determined curative effect, security is good.
Polymorphism is the critical nature of compound, for most chemicals, generally all there is polymorphism, and the different crystal formation of same drug has important impact for the stability of medicine, homogeneity, bioavailability and preparation production etc.Therefore, when a kind of medicine exists polytropism, be necessary to further investigate its crystal formation.About Oxiracetam crystal form and preparation method thereof, prior art is existing following open:
Chinese patent CN102558014 discloses crystal formation containing a hypocrystalline water oxiracetam compound and preparation method, recrystallisation solvent is the methyl alcohol of 70-99.9%, and the X-ray powder diffraction of its crystal formation is that 6.96 °, 11.48 °, 15.36 °, 16.02 °, 16.92 °, 17.96 °, 19.84 °, 20.90 °, 22.16 °, 22.78 °, 23.58 °, 24.92 °, 25.30 °, 25.74 °, 28.36 ° places show characteristic peak at 2 θ.
Chinese patent CN102351770 discloses the oxiracetam with two crystal water, and its X-ray powder diffraction pattern is that 17.3 °, 19.1 °, 21.6 °, 23.2 °, 27.0 °, 28.4 °, 30.0 °, 31.0 °, 31.7 °, 33.2 °, 36.9 °, 39.3 °, 40.2 °, 45.7 °, 51.2 ° places show characteristic peak at 2 θ.This compound crystal system is DMF/ethylene glycol mixed solvent and isopropyl ether.
Chinese patent CN103342673 discloses a kind of not containing the Oxiracetam crystal form of crystal water, its X-ray powder diffraction is 15.6 ± 0.2 ° at 2 θ, 17.7 ± 0.2 °, 19.9 ± 0.2 °, 21.5 ± 0.2 °, there is characteristic peak at 24.9 ± 0.2 ° of places, and the Relative Peak being 21.5 ± 0.2 ° of places at reflection angle 2 θ is by force 100%, this stable crystal form, mobility are excellent, are prepared by solvent with water.
As can be seen here, be the focus of current New drug discovery research to the research of drug crystal forms, the new crystalline forms of the existing medicine of research and development, to improve its preparation, to play its clinical advantage, is one of current pharmaceutical industry road walking autonomous innovation.
Summary of the invention
The depth & wideth that the applicant is devoted for years in oxiracetam bulk drug is studied, to developing the oxiracetam bulk drug of various ways for pharmaceutical preparation, and applied for patent of invention CN201110200730.2 in 2011, which disclose a kind of oxiracetam compound containing 0.25 crystal water, but do not disclose the existence form of this compound.And in fact, the above-mentioned oxiracetam compound containing 0.25 crystal water is a kind of crystalline form, use Cu-K α radiation, its X-ray powder diffraction pattern is 4.79 ° at reflection angle 2 θ, 6.71 °, 11.66 °, 13.48 °, 15.67 °, 17.54 °, there is characteristic peak at 25.22 ° of places, see accompanying drawing 3.
In follow-up study process, the applicant surprisingly finds the preparation method adopting other, the oxiracetam compound containing 0.25 crystal water of another crystallized form can be obtained, the i.e. new crystal of oxiracetam four/monohydrate, and this crystal formation has excellent characteristic: good stability, being placed with related substance does not for a long time increase, and clarity does not decline, especially bioavailability significantly improves, and is more suitable for as bulk drug for the production of pharmaceutical preparation and storage.
Given this, first object of the present invention is to provide a kind of oxiracetam compound of crystallized form.
Second object of the present invention is to provide the method for the oxiracetam compound preparing above-mentioned crystallized form.
Object of the present invention is achieved through the following technical solutions.
An oxiracetam compound for crystallized form, use Cu-K α radiation, its X-ray powder diffraction is 5.2 ± 0.2 ° at reflection angle 2 θ, 11.5 ± 0.2 °, 13.6 ± 0.2 °, 15.8 ± 0.2 °, 17.5 ± 0.2 °, 19.1 ± 0.2 °, there is characteristic peak at 20.8 ± 0.2 ° of places.
Further, the oxiracetam compound of crystallized form of the present invention, uses Cu-K α radiation, its X-ray powder diffraction is also 6.9 ± 0.2 ° at reflection angle 2 θ, 21.5 ± 0.2 °, 23.9 ± 0.2 °, 24.4 ± 0.2 °, 25.4 ± 0.2 °, there is characteristic peak at 31.8 ± 0.2 ° of places.
Further, the oxiracetam compound of crystallized form of the present invention, uses Cu-K α radiation, and its X-ray powder diffraction is also 7.5 ± 0.2 ° at reflection angle 2 θ, 8.3 ± 0.2 °, 10.8 ± 0.2 °, 16.5 ± 0.2 °, 19.8 ± 0.2 °, 29.0 ± 0.2 °, 29.7 ± 0.2 °, 31.5 ± 0.2 °, there is characteristic peak at 32.4 ± 0.2 ° of places.
Karl_Fischer method is the classical way of moisture content in universally acknowledged mensuration material, is also, the most accurately chemistry in detecting the most single-minded to water, is particularly useful for the mensuration of water content in organic compound.
Be 2.75-2.90% by the moisture content that Ka Er-Fei Xiushi method measures in the oxiracetam compound of crystallized form of the present invention, in oxiracetam 1/4 hydrate, the theoretical content of water is 2.76%, shows that the oxiracetam compound of crystallized form of the present invention contains 0.25 crystal water.
Thermal gravimetric analysis results TGA collection of illustrative plates shows, the oxiracetam compound of crystallized form of the present invention loses planar water at about 60-100 DEG C, crystal water is lost at about 120-150 DEG C, crystal water weightlessness is 2.74%, consistent with the mass percent 2.76% that 0.25 crystal water accounts in oxiracetam molecule, show in the oxiracetam compound of crystallized form of the present invention containing 0.25 crystal water.
To the research that oxiracetam is work with perseverance, it is consistent, the long-term target of the applicant, for obtaining the oxiracetam raw material still ensuring the quality of products stable through long-term placement, applicant has carried out accelerated stability test research to the oxiracetam compound of crystallized form of the present invention.Result shows, the oxiracetam compound of crystallized form of the present invention is placed after 6 months under temperature 40 DEG C ± 2 DEG C, relative humidity are 75% ± 5% condition, and its clarity of solution does not decline; Related substance does not have considerable change yet, does not almost increase compared with 0 month, illustrates that the oxiracetam compound of crystallized form of the present invention has extraordinary stability, is suitable as very much bulk drug for the production of pharmaceutical preparation and standing storage.
For investigating the oxiracetam compound absorbing state in vivo of crystallized form of the present invention, the applicant has carried out pharmacokinetic to the oxiracetam compound of crystallized form of the present invention, amazingly be, result of study shows every pharmacokinetic parameter AUC0-t of the oxiracetam compound of crystallized form of the present invention, Cmax, oxiracetam compound disclosed in the CN201110200730.2 that Tmax applies for before being obviously better than the applicant, the oxiracetam compound showing crystallized form of the present invention degree of absorption in vivo and uptake rate aspect have significant advantage, bioavailability obtains and greatly improves.
The method of the oxiracetam compound of preparation provided by the invention crystallized form of the present invention, comprises the steps:
A) get oxiracetam crude product, be added to the water, be warming up to 80 DEG C of stirring and dissolving to limpid;
B) slow cooling to 25 ~ 30 DEG C, insulation growing the grain 8 hours;
C) slow cooling to 0 ~ 5 DEG C are continued, insulation growing the grain 8 hours;
D) filter, by filter cake in 30 ~ 45 DEG C of dryings, obtain crystallized form oxiracetam finished product.
Wherein,
Described step a) in the weight (g) of oxiracetam crude product and water: volume (ml) is than being 1:1 ~ 5, preferred 1:2;
Described step b) in slow cooling be control to be cooled to 25 ~ 30 DEG C in 3 hours;
Described step c) in slow cooling be control to be cooled to 0 ~ 5 DEG C in 3 hours;
Described step b) and c) in cooling, insulation growing the grain while stir, mixing speed is adjusted to 20 ~ 30 revs/min, preferably 25 revs/min;
Described steps d) in time of drying be 7 ~ 10 hours, preferably 8 hours, drying temperature preferably 40 DEG C.
Oxiracetam crude product of the present invention, can conventionally in arbitrary preparation method obtain.
In the oxiracetam compound preparation process of crystallized form of the present invention, only used water and make solvent, do not introduce other any organic solvents, environmental protection, simple to operate, be conducive to reducing costs, product organic solvent-free remains, security is good, is particularly suitable for suitability for industrialized production.
Crystallized form of the present invention oxiracetam compound can pharmaceutically acceptable carrier or vehicle be prepared into useful clinically dosage form with one or more, comprise the capsule of pro ore, tablet, soft capsule, oral liquid, granule, syrup, dripping pill and sustained-release preparation etc., also comprise the liquid drugs injection injection liquid of injection, freeze-dried powder, aseptic powder injection and infusion solutions etc., most preferably formulation is capsule and lyophilized injectable powder, can be used for all disease occasions being suitable for oxiracetam clinically.
Accompanying drawing explanation
The XRPD figure of the oxiracetam compound of Fig. 1 crystallized form of the present invention.
The TGA figure of the oxiracetam compound of Fig. 2 crystallized form of the present invention.
The XRPD figure of oxiracetam compound disclosed in Fig. 3 CN201110200730.2.
Embodiment
Below by embodiment, the present invention is described in further detail, but these embodiments do not form any restriction to the present invention.
The preparation of the oxiracetam compound of embodiment 1 crystallized form of the present invention
Get oxiracetam crude product 50g, add in 100ml water, be warming up to 80 DEG C of stirring and dissolving to limpid, mixing speed be adjusted to 25 revs/min, slow cooling, controls to be cooled to 25 ~ 30 DEG C in 3 hours, insulation growing the grain 8 hours, continue slow cooling, control to be cooled to 0 ~ 5 DEG C in 3 hours, insulation growing the grain 8 hours; Filter, by filter cake in 40 DEG C of dryings 8 hours, obtain the oxiracetam compound 46.2g of crystallized form, yield 92.4%.Measure 3 times through Karl_Fischer method, computation of mean values, in the oxiracetam compound of this crystallized form, moisture content is 2.75%(theoretical value: 2.76%).
Results of elemental analyses: measured value (calculated value)
C：44.38（44.30），H：6.42（6.46），N：17.20（17.21），O：31.91（32.00）。
Adopt D/Max-2500, 9161 type x-ray diffractometers measure the X-ray powder diffraction figure of the oxiracetam compound of this crystallized form, condition determination is: Cu Ka target, tube voltage 40kV, tube current 150Ma, sweep limit 0-60 °, in the X-ray powder diffraction figure of the oxiracetam compound of this crystallized form, it is 5.233 ° at reflection angle 2 θ, 6.942 °, 11.486 °, 13.589 °, 15.910 °, 17.574 °, 19.085 °, 20.850 °, 21.552 °, 23.834 °, 24.512 °, 25.477 °, 31.800 there is diffraction peak at a ° place, XPRD collection of illustrative plates as shown in Figure 1.
Thermogravimetric analysis TGA collection of illustrative plates as shown in Figure 2, the oxiracetam compound of this crystallized form loses planar water at about 60-100 DEG C, crystal water is lost at about 120-150 DEG C, crystal water weightlessness is 2.74%, consistent with the mass percent 2.76% that 0.25 crystal water accounts in oxiracetam molecule, show in the oxiracetam compound of crystallized form of the present invention containing 0.25 crystal water.
The preparation of the oxiracetam compound of embodiment 2 crystallized form of the present invention
Get oxiracetam crude product 50g, add in 250ml water, be warming up to 80 DEG C of stirring and dissolving to limpid, mixing speed be adjusted to 30 revs/min, slow cooling, controls to be cooled to 25 ~ 30 DEG C in 3 hours, insulation growing the grain 8 hours, continue slow cooling, control to be cooled to 0 ~ 5 DEG C in 3 hours, insulation growing the grain 8 hours; Filter, by filter cake in 45 DEG C of dryings 10 hours, obtain the oxiracetam compound 45.0g of crystallized form, yield 90.0%.Measure 3 times through Karl_Fischer method, computation of mean values, in the oxiracetam compound of this crystallized form, moisture content is 2.83%(theoretical value: 2.76%).
Results of elemental analyses: measured value (calculated value)
C：44.35（44.30），H：6.52（6.46），N：17.30（17.21），O：31.96（32.00）。
Measuring through X-ray powder diffraction, in the X-ray powder diffraction figure of the oxiracetam compound of this crystallized form, is 5.296 ° at reflection angle 2 θ, 6.944 °, 11.503 °, 13.620 °, 15.799 °, 17.469 °, 19.170 °, 20.788 °, 21.458 °, 23.992 °, 24.408 °, 25.460 °, there is diffraction peak at 31.838 ° of places, and the peak type of XPRD collection of illustrative plates, peak position and accompanying drawing 1 are basically identical.
The TGA collection of illustrative plates of the oxiracetam compound of this crystallized form is substantially the same manner as Example 1.
The preparation of the oxiracetam compound of embodiment 3 crystallized form of the present invention
Get oxiracetam crude product 50g, add in 50ml water, be warming up to 80 DEG C of stirring and dissolving to limpid, mixing speed be adjusted to 20 revs/min, slow cooling, controls to be cooled to 25 ~ 30 DEG C in 3 hours, insulation growing the grain 8 hours, continue slow cooling, control to be cooled to 0 ~ 5 DEG C in 3 hours, insulation growing the grain 8 hours; Filter, by filter cake in 30 DEG C of dryings 8 hours, obtain crystallized form oxiracetam compound 44.7g, yield 89.4%.Measure 3 times through Karl_Fischer method, computation of mean values, in the oxiracetam compound of this crystallized form, moisture content is 2.90%(theoretical value: 2.76%).
Results of elemental analyses: measured value (calculated value)
C：44.31（44.30），H：6.50（6.46），N：17.17（17.21），O：32.05（32.00）。
Measuring through X-ray powder diffraction, in the X-ray powder diffraction figure of the oxiracetam compound of this crystallized form, is 5.197 ° at reflection angle 2 θ, 6.860 °, 11.597 °, 13.699 °, 15.899 °, 17.483 °, 19.105 °, 20.878 °, 21.518 °, 23.937 °, 24.442 °, 25.384 °, there is diffraction peak at 31.958 ° of places, and the peak type of XPRD collection of illustrative plates, peak position and accompanying drawing 1 are basically identical.
The TGA collection of illustrative plates of the oxiracetam compound of this crystallized form is substantially the same manner as Example 1.
The stability test of the oxiracetam compound of test example 1 crystallized form of the present invention
According to (Chinese Pharmacopoeia version in 2010 two annex XIX C) relevant regulations, accelerated test is carried out to the oxiracetam compound of crystallized form of the present invention.Place 6 months under temperature 40 DEG C ± 2 DEG C, relative humidity are 75% ± 5% condition, sample respectively respectively at the 0th, 1,2,3,6 the end of month, investigate the changing conditions of clarity of solution, related substance, the results are shown in following table 1:
Table 1 embodiment 1-3 stability test result
Above result shows, the oxiracetam compound of crystallized form of the present invention is placed after 6 months under temperature 40 DEG C ± 2 DEG C, relative humidity are 75% ± 5% condition, clarity does not decline, related substance does not have considerable change, substantially do not increase, illustrate that the oxiracetam compound of crystallized form of the present invention has extraordinary stability.
Bioavailability study in the body of the oxiracetam compound of test example 2 crystallized form of the present invention
Test objective: the bioavailability being investigated the oxiracetam compound of crystallized form of the present invention by pharmacokinetic.
Trial drug:
Capsule preparations prepared by the oxiracetam compound of test group--crystallized form of the present invention.
The capsule preparations that disclosed in control group-patent of invention CN201110200730.2 prepared by oxiracetam compound.
Above-mentioned two groups of medicines all adopt prescription and preparation method's preparation of embodiment 4 in CN201110200730.2.
Experimental animal: Wistar rat, body weight 150-200g, male and female are also used.
Dosage and mode: Rat Fast spends the night, oral administration gavage administration 100mg/kg.
Blood sampling time: before administration and after administration 0.25,0.50,1.00,1.50,2.00,3.00,4.00,6.00,12.00h.
Test method: after blood specimen collection, is collected in vitro, goes out serum through centrifugation, and-12 degree ice chests save backup, and get serum sample 0.5ml respectively and measure serum drug level with HPLC method, calculate main pharmacokinetic parameter.
Test-results: in table 3
Table 3 pharmacokinetic trial result
Conclusion: AUC0-t, Cmax of the oxiracetam compound of crystallized form of the present invention are apparently higher than control group oxiracetam compound, and Tmax is also obvious fast than control group, the oxiracetam compound showing crystallized form of the present invention degree of absorption in vivo and uptake rate are better than control group, and bioavailability is significantly improved.
The explanation of above embodiment just understands the present invention for helping, not in order to limit the present invention, within the spirit and principles in the present invention all, and any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (2)
1. the oxiracetam compound of a crystallized form, it is characterized in that, its X-ray powder diffraction using Cu-K α radiation to obtain is 5.2 ± 0.2 ° at reflection angle 2 θ, 6.9 ± 0.2 °, 7.5 ± 0.2 °, 8.3 ± 0.2 °, 10.8 ± 0.2 °, 11.5 ± 0.2 °, 13.6 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 17.5 ± 0.2 °, 19.1 ± 0.2 °, 19.8 ± 0.2 °, 20.8 ± 0.2 ° 21.5 ± 0.2 °, 23.9 ± 0.2 °, 24.4 ± 0.2 °, 25.4 ± 0.2 °, 29.0 ± 0.2 °, 29.7 ± 0.2 °, 31.5 ± 0.2 °, 31.8 ± 0.2 °, there is characteristic peak at 32.4 ± 0.2 ° of places, its thermogravimetric analysis collection of illustrative plates shows, and lose planar water at about 60-100 DEG C, lose crystal water at about 120-150 DEG C, crystal water weightlessness is 2.74%.
2. prepare a method for the oxiracetam compound of crystallized form as claimed in claim 1, it is characterized in that, comprise the steps:
A) get oxiracetam crude product, be added to the water, be warming up to 80 DEG C of stirring and dissolving to limpid, the weight of described oxiracetam crude product and water: volume ratio is 1:1 ~ 5;
B) slow cooling to 25 ~ 30 DEG C, insulation growing the grain 8 hours, stir, mixing speed is adjusted to 20 ~ 30 revs/min simultaneously, and described slow cooling is, controls to be cooled to 25 ~ 30 DEG C in 3 hours;
C) continue slow cooling to 0 ~ 5 DEG C, insulation growing the grain 8 hours, stir, mixing speed is adjusted to 20 ~ 30 revs/min simultaneously, and described slow cooling is, controls to be cooled to 0 ~ 5 DEG C in 3 hours;
D) filter, by filter cake in 30 ~ 45 DEG C of dryings, time of drying is 7 ~ 10 hours, and drying temperature is 40 DEG C, obtains the oxiracetam compound of crystallized form.
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