CN105837490B - A kind of crystal formation of Oxiracetam and preparation method thereof - Google Patents
A kind of crystal formation of Oxiracetam and preparation method thereof Download PDFInfo
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- CN105837490B CN105837490B CN201610268923.4A CN201610268923A CN105837490B CN 105837490 B CN105837490 B CN 105837490B CN 201610268923 A CN201610268923 A CN 201610268923A CN 105837490 B CN105837490 B CN 105837490B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to pharmaceutical technology field, specifically, is related to a kind of oxiracetam compound, the x-ray diffraction pattern of the compound is as shown in Figure 1.The invention further relates to a kind of preparation method of the oxiracetam compound, Oxiracetam crude product is dissolved in N at a certain temperature, in dinethylformamide/water, adjust after pH value is 4.5~5 and add activated carbon decolorizing filtering, after being concentrated under reduced pressure to give supersaturated solution, cooling vibration crystallization, obtains product.Oxiracetam novel crystal forms disclosed by the invention have good powder fluidity, are advantageous to pipeline transmission during pharmaceutical production, while have higher bioavilability.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically, is related to a kind of crystal formation of Oxiracetam and preparation method thereof.
Background technology
Oxiracetam (Oxiracetam) is a kind of pyrrolidones analog derivative, the entitled 4- hydroxyls -2- oxo pyrroles of chemistry
Alkane-N- acetamides, molecule are for C6H10N2O3, structural formula is as follows：
Researched and developed in 1974 successfully than Qie Mu company by Italian SmithKline and listed in 1987.The medicine have on the market it is more
Kind formulation, wherein parenteral solution administering mode are to be dissolved in physiological saline or other dilution iv drips, each 4g, daily one
It is secondary, increase and decrease dosage can be taken the circumstances into consideration.The usual course for the treatment of of treatment to neurological deficit is 2 weeks, and the treatment remembered with disturbance of intelligence is led to
The normal course for the treatment of is 3 weeks.
Oxiracetam is the derivative of Piracetam, and its main function mechanism includes the following aspects：1. promote phosphatide
Phatidylcholine and phosphatidyl ethanolamine synthesis, improve the ratio of ATP/ADP in brain, increase the synthesis of protein and nucleic acid in brain
Add；2. strengthening the Changes of Plasticity of brain, strengthen the mouldability of cynapse, improve the memory of senile dementia, memory disorder patient
And learning functionality；3. reducing cerebral vascular resistance, suppress platelet aggregation, improve microcirculation and increase cerebral tissue blood flow；4. promote
Enter the neurotoxic effect of damaged nerve cell excitatory amino acid.Suitable for brain damage and its caused neurological deficit,
Memory and the treatment of disturbance of intelligence, especially suitable for senile dementia, it may also be used for the brain diseases such as neurosis, encephalitis
Convalescence treatment etc..
The Chinese invention patent of Application No. 201410321549.0 discloses a kind of oxiracetam compound and its medicine
Composition.The X-ray powder diffraction that oxiracetam compound made from the invention is obtained using Cu-K alpha ray measurements is in 2 θ
Characteristic peak is shown at 12.2 °, 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 °.The compound
High-tension apparatus has been used in preparation process, and has used and the disagreeableness toluene of environment is crystallized as solvent, technics comparing
It is complicated.
The Chinese invention patent of Application No. 201310328754.5 discloses a kind of Oxiracetam crystal form and its preparation side
Method.Decrease temperature crystalline after the invention is dissolved and concentrated to Oxiracetam as solvent using the aqueous solution, avoid having used organic solvent.
But the invention has used the mode of stirring and crystallizing in crystallization process, due to influence of the blade to crystal nucleation in solution, can make
Into the defects of crystal grain is too small, structural instability.
In view of this, it is special to propose the present invention.
The content of the invention
It is an object of the invention to overcome existing technological deficiency, there is provided one kind is applied to technique productions, and drug effect is more excellent
Oxiracetam crystal formation.
To realize the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of crystal formation of Oxiracetam, the main diffraction peak of the x-ray diffraction pattern of the crystal formation are as follows：
The X-ray diffracting spectrum of above-mentioned Oxiracetam crystal form powder is a kind of new Aura substantially as shown in
Western smooth crystal formation.
Present invention also offers a kind of preparation method of the crystal formation of Oxiracetam, the preparation method comprises the following steps：
(1) Oxiracetam crude product is added in 40~60 DEG C of water and the solution of DMF and dissolved, wherein
The volume ratio of water and N,N-dimethylformamide is 1:3~6, the amount ratio of Oxiracetam crude product and solvent is 1g:10~15ml；
(2) after addition vinegar acid for adjusting pH is 4.5~5.0 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed in carrying out forward and reverse alternately shaking on shaking table,
0~10 DEG C is cooled to according to 2~5 DEG C/h of cooling rate simultaneously, isolates white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
In above-mentioned preparation method, pH value described in step (2) is 4.8.
The shaking frequency range of shaking table is 60~100 revs/min described in step (4).
The alternate run time of shaking table described in step (4) is 5~20 minutes, and the preferably alternate run time is 10 minutes.
Supersaturated solution is down to 5 DEG C with 3 DEG C/h of cooling rate described in step (4).
Solution temperature described in step (1) is 50 DEG C.
The volume ratio of water and N,N-dimethylformamide described in step (1) is 1:4, the use of Oxiracetam crude product and solvent
It is 1g to measure ratio:12mL.
The generation of nucleus has three kinds of forms：I.e. primary homogeneous nucleation, primary nonhomogen-ous nucleation and secondary nucleation.Satiated in height
Under degree, solution spontaneously generates the process of nucleus, referred to as primary homogeneous nucleation；Solution generates nucleus under the induction of exotic
Process, referred to as primary nonhomogen-ous nucleation；And the nucleation process in the solution containing solute crystals, referred to as secondary nucleation.Two
Secondary nucleation falls within nonhomogen-ous nucleation process, caused small crystalline substance when it is between crystal or crystal is collided with other solids
Occur under the induction of grain.
The present invention is being granted on the basis of Oxiracetam supersaturated solution decrease temperature crystalline using shaking table to the solution of sealing
Vibrations, it is surprised to find that the Oxiracetam of vibrations induction nucleation generates a kind of new crystalline structure in the process, and by
In the change of crystal structure, the solid that its crystallization forms is set to obtain excellent effect on powder fluidity, while analyzing
It is found that it has higher bioavilability during crystal formation absorbability in vivo.
Compared with prior art, the crystal formation of Oxiracetam of the invention has the biology of more preferable powder fluidity and Geng Gao
Availability.
Brief description of the drawings
Fig. 1 is the X-ray diffraction spectrogram of Oxiracetam crystal form prepared by the embodiment of the present invention 1.
Fig. 2 is that the blood concentration-time after Oral Administration in Rats is administered Oxiracetam crystal form prepared by comparative example 2 of the present invention is bent
Line.
Fig. 3 is that the blood concentration-time after Oral Administration in Rats is administered Oxiracetam crystal form prepared by the embodiment of the present invention 1 is bent
Line.
Embodiment
Below for the present invention embodiment, described embodiment be in order to further describe the present invention, rather than
The limitation present invention.
Embodiment 1
(1) Oxiracetam crude product 50g is added in 50 DEG C of water and the solution of DMF and dissolved, its reclaimed water
Volume ratio with N,N-dimethylformamide is 1:4, the amount ratio of Oxiracetam crude product and solvent is 1g:12ml；
(2) after addition vinegar acid for adjusting pH is 4.8 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed in carrying out just on the shaking table that frequency is 90 revs/min
Alternately being shaken to reverse, the alternate run time is 10 minutes, while is cooled to 5 DEG C according to 3 DEG C/h of cooling rate, point
Separate out white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
43.27g Oxiracetam powder is obtained through the above method, yield 86.54%, is 99.90% through HPLC detection purity,
X-ray diffracting spectrum is as shown in Figure 1.
Embodiment 2
(1) Oxiracetam crude product 50g is added in 40 DEG C of water and the solution of DMF and dissolved, its reclaimed water
Volume ratio with N,N-dimethylformamide is 1:3, the amount ratio of Oxiracetam crude product and solvent is 1g:15ml；
(2) after addition vinegar acid for adjusting pH is 4.5 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed in carrying out on the shaking table that frequency is 100 revs/min
Forward and reverse alternately shakes, and the alternate run time is 5 minutes, while is cooled to 10 DEG C according to 2 DEG C/h of cooling rate,
Isolate white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
41.73g Oxiracetam powder is obtained through the above method, yield 83.46%, is 99.87% through HPLC detection purity,
It is basically identical through the spectrogram that X-ray diffraction is drawn and embodiment 1.
Embodiment 3
(1) Oxiracetam crude product 50g is added in 60 DEG C of water and the solution of DMF and dissolved, its reclaimed water
Volume ratio with N,N-dimethylformamide is 1:6, the amount ratio of Oxiracetam crude product and solvent is 1g:10ml；
(2) after addition vinegar acid for adjusting pH is 5.0 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed in carrying out just on the shaking table that frequency is 60 revs/min
Alternately being shaken to reverse, the alternate run time is 20 minutes, while is cooled to 0 DEG C according to 5 DEG C/h of cooling rate, point
Separate out white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
42.15g Oxiracetam powder is obtained through the above method, yield 84.3%, is 99.82% through HPLC detection purity,
It is basically identical through the spectrogram that X-ray diffraction is drawn and embodiment 1.
Comparative example 1
Comparative example 1 is that step (1)~(3) in the preparation method recorded using this specification are obtained, with the phase of embodiment 1
Than difference is not use shaking table to shake saturated solution, but the mode for employing stirring carries out crystallization.
(1) Oxiracetam crude product 50g is added in 50 DEG C of water and the solution of DMF and dissolved, its reclaimed water
Volume ratio with N,N-dimethylformamide is 1:4, the amount ratio of Oxiracetam crude product and solvent is 1g:12ml；
(2) after addition vinegar acid for adjusting pH is 4.8 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) 90 revs/min of stirring is carried out to the supersaturated solution described in step (3), while according to 3 DEG C/h
Cooling rate is cooled to 5 DEG C, isolates white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
40.98g Oxiracetam powder is obtained through the above method, yield 81.96%, is 99.76% through HPLC detection purity.
Comparative example 2
Using commercially available Oxiracetam bulk drug, the emerging milky way chemical company in Hubei is originated from.
The powder fluidity test of the Oxiracetam of test example 1
The mobility of powder can not be expressed with single characteristic value, commonly use angle of repose and represent.Angle of repose refers in gravitational field
In, when being slided on the free inclined-plane of powder accumulation horizon, frictional force reaches balance and is in quiet particle between suffered gravity and particle
The maximum angular only measured under state.It can meet to give birth to it is generally acknowledged that good fluidity during angle of repose≤30 degree, during angle of repose≤40 degree
Need for liquidity during production.
Angle of repose is determined using injection method, powder is slowly added into above funnel, the material spilt from funnel bottom exists
The inclination angle of coniform accumulation body is formed on horizontal plane.
The solubility of Oxiracetam crystal form made from the embodiment of the present invention 1~3 and comparative example 1, comparative example 2 are compared
Compared with obtained experimental result is shown in Table 1.
The angle of repose test result of the Oxiracetam sample of table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| Angle of repose (°) | 36.7 | 37.4 | 37.2 | 41.5 | 45.2 |
As shown in Table 1, compared with the commercially available product Oxiracetam of comparative example 2, Oxiracetam crystal form provided by the invention and contrast
Example 1 has smaller angle of repose；And embodiment 1~3 is using the angle of repose for supersaturated solution shaking mode being made Oxiracetam
It is substantially better than in comparative example 1 and uses Oxiracetam made from stirring and crystallizing.It follows that to supersaturation in preparation method of the present invention
The vibrations of solution serve the effect of key in the crystal formation change of Oxiracetam, reduce angle of repose, make its acquisition excellent
Powder fluidity.
The bioavilability of test example 2 is tested
First, tested medicine：
The Oxiracetam crystal form as made from the embodiment of the present invention 1 and the three kinds of samples of commercially available product Oxiracetam bulk drug of comparative example 2
Product form.
2nd, zoopery：
The healthy male rat 20 for taking weight range to be 100~200g, is divided into 2 groups, every group of 1 group of embodiment and comparative example
10 only according to《Chemicals Non-clinical Pharmacokinetics investigative technique guideline (【H】GPT5-1)》Carry out experiment, before experiment
Water is can't help in fasting in 12 hours, is administered orally and is taken rat vein blood after the different time points in 12 hours, is placed in liquaemin processing
Centrifuge tube at a temperature of 4 DEG C with 4000r/min centrifuge 10min, take supernatant to be stored in -80 DEG C of refrigerators, afterwards with organic examination
Agent is extracted and detected using HPLC-MS, and acquired results are computed being shown in Table 2 after arranging.
The pharmacokinetic parameter of the oral Oxiracetam rat of table 2
| Pharmacokinetic parameter | 1 group of embodiment | 2 groups of comparative example |
| Cmax(mg/L) | 103.27±12.35 | 95.24±10.87 |
| Tmax(h) | 1.54±0.89 | 1.74±1.12 |
| AUC0-12h(mg·L-1·h-1) | 442.875±31.57 | 381.37±28.65 |
| Ke(h-1) | 0.28±0.12 | 0.40±0.08 |
| T1/2(h) | 2.48±1.06 | 1.72±0.26 |
As shown in Table 2, the relatively low (AUC of bioavilability of 2 groups of commercially available product Oxiracetams of Oral Administration in Rats comparative example0-12h=
378.37±28.65mg·L-1·h-1), 1 group of embodiment provided by the invention possesses more preferable bioavilability (AUC0-12h=
442.875±31.57mg·L-1·h-1)；And compared to 2 groups of the comparative example of commercially available product, 1 group of embodiment can be in the shorter time
Inside reach higher blood concentration (Cmax=103.27 ± 12.35mg/L, Tmax=1.54 ± 0.89h), also possess longer half
Decline the phase (T1/2=2.48 ± 1.06h).It follows that the vibrations in preparation method of the present invention to supersaturated solution are in Oxiracetam
Crystal formation form in serve the effect of key, substantially increase the oral administration biaavailability of Oxiracetam.
The data and result of summary test example, it is known that Oxiracetam crystal form of the invention is difficult to understand compared to existing commercially available product
La Xitan bulk drugs have more preferable powder fluidity, can preferably improve the bioavilability of Oxiracetam.The present invention's
Improvement of the vibrations to crystal formation in preparation method to supersaturated solution serves the effect of key.
Above-mentioned experiment is also carried out to the Oxiracetam crystal form prepared by other embodiments of the present invention, its result phase obtained
Seemingly.
The present invention is described in detail above, its object is to allow those skilled in the art to understand this
The content of invention is simultaneously carried out, and it is not intended to limit the scope of the present invention, all Spirit Essence institutes according to the present invention
The equivalent change or modification done, it should all cover within the scope of the present invention.
Claims (11)
1. a kind of crystal formation of Oxiracetam, it is characterised in that special when the angle of diffraction of the X-ray powder diffraction of the crystal formation is 2 θ
Sign peak includes：14.4 ± 0.1 °, 17.6 ± 0.1 °, 19.6 ± 0.1 °, 20.4 ± 0.1 °, 20.8 ± 0.1 °, 21.4 ± 0.1 °,
24.6 ± 0.1 °, 31.7 ± 0.1 °, 36.4 ± 0.1 °.
2. the crystal formation of Oxiracetam according to claim 1, it is characterised in that the x-ray diffraction pattern of the crystal formation spreads out
Penetrating peak includes：
3. the crystal formation of Oxiracetam according to claim 2, it is characterised in that the X-ray diffracting spectrum of the crystal formation is such as
Shown in Fig. 1.
4. the preparation method of the crystal formation of the Oxiracetam described in a kind of claims 1 to 3 any one, it is characterised in that described
Preparation method comprises the following steps：
(1) by Oxiracetam crude product add 40~60 DEG C water and DMF solution in dissolve, its reclaimed water with
The volume ratio of N,N-dimethylformamide is 1:3~6, the amount ratio of Oxiracetam crude product and solvent is 1g:10~15ml；
(2) after addition vinegar acid for adjusting pH is 4.5~5.0 in the solution of step (1), activated carbon decolorizing filtering is added；
(3) solution decompression after the filtering described in step (2) is concentrated, obtains supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed in carrying out forward and reverse alternately shaking on shaking table, simultaneously
0~10 DEG C is cooled to according to 2~5 DEG C/h of cooling rate, isolates white crystalline powder；
(5) by white crystalline powder is dried under reduced pressure described in step (4) and constant weight obtains product.
5. preparation method according to claim 4, it is characterised in that pH value described in step (2) is 4.8.
6. preparation method according to claim 4, it is characterised in that the shaking frequency range of shaking table described in step (4)
It is 60~100 revs/min.
7. preparation method according to claim 4, it is characterised in that the alternate run time of shaking table described in step (4)
For 5~20 minutes.
8. preparation method according to claim 7, it is characterised in that the alternate run time of shaking table described in step (4)
For 10 minutes.
9. preparation method according to claim 4, it is characterised in that supersaturated solution described in step (4) with 3 DEG C/
The cooling rate of hour is down to 5 DEG C.
10. preparation method according to claim 4, it is characterised in that the solution temperature described in step (1) is 50 DEG C.
11. preparation method according to claim 4, it is characterised in that water described in step (1) and N, N- dimethyl formyl
The volume ratio of amine is 1:4, the amount ratio of Oxiracetam crude product and solvent is 1g:12mL.
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