CN103864869A - Method for preparing spherical zidovudine crystal - Google Patents
Method for preparing spherical zidovudine crystal Download PDFInfo
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- CN103864869A CN103864869A CN201210552902.7A CN201210552902A CN103864869A CN 103864869 A CN103864869 A CN 103864869A CN 201210552902 A CN201210552902 A CN 201210552902A CN 103864869 A CN103864869 A CN 103864869A
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Abstract
The invention discloses a method for preparing a spherical zidovudine crystal. The method comprises the following steps: a) adding a zidovudine raw material into water, and heating to be dissolved completely; b) cooling to 0-10 DEG C at a constant speed; c) carrying out heat preservation at the temperature of 0-10 DEG C, and carrying out stirring crystallization for 1-10 hours; and d) filtering, drying, and thus obtaining the spherical zidovudine crystal. The method for preparing the spherical zidovudine crystal can effectively solve the problems that a zidovudine crystal with a conventional shape has poor liquidity and poor dispersion so as to be not conducive to process operations of mixing, tabletting and the like in the preparing procedure, can achieve large-scale production, is conducive to production of a zidovudine preparation, provides the guarantee for quality stability of the zidovudine preparation, and has practical value.
Description
Technical field
The present invention relates to a kind of method of preparing spherical zidovudine crystal, belong to technical field of organic chemistry.
Background technology
Zidovudine is antiviral drug, the treatment of infecting for acquired immune deficiency syndrome (AIDS) or the syndromes patient relevant with acquired immune deficiency syndrome (AIDS) and immunodeficiency virus (HIV).On March 19th, 1987, FDA ratifies this medicine listing.Zidovudine is that first obtains the anti-AIDS medicine that U.S. FDA approval is produced in the world, because of its determined curative effect, becomes the most basic combined composition of therapeuticcocktail of anti-retrovirals.This medicine comprises that to reversal of viral human immunodeficiency virus (HIV) has high activity in vitro.In the cell being infected by the virus, turned to triphosphoric acid zidovudine by cell thymidine kinase phosphoric acid, the latter can selectivity suppress HIV Revertase, thereby causes the synthetic prevention HIV that stops of HIV chain to copy.Its chemical structure is as follows:
Current, in fact zidovudine becomes a standard drug, and whether the exploitation of any similar new product all will be take it as reference by academia and clinical approval.What known zidovudine crystal was reported in The Merck Index at present is shaped as needle-like, and at Acta Cryst. (1988) .C44, the monocrystalline of reporting in 767-769 is shaped as carefully bar-shaped.And those skilled in the art knows that the inevitable mobility of the crystal of these two kinds of shapes is bad, be unfavorable in preparation process the process operations such as batch mixing, compressing tablet, the production of many husbands customization agent that aligns has caused disadvantageous effect.
Summary of the invention
The problems referred to above that exist for prior art, the object of this invention is to provide a kind of method of preparing spherical zidovudine crystal, to solve poor fluidity that the zidovudine crystal of existing shape exists, dispersed bad, the difficult problem that is unfavorable for the process operations such as batch mixing, compressing tablet in preparation process, meet the production requirement of zidovudine preparation.
For achieving the above object, the technical solution used in the present invention is as follows:
A method of preparing spherical zidovudine crystal, is characterized in that, comprises the steps:
A) zidovudine raw material is added to the water, heating makes to dissolve completely;
B) to be at the uniform velocity cooled to 0～10 ℃;
C) insulation was 0～10 ℃ of stirring and crystallizing 1～10 hour;
D) filter, dry, obtain spherical zidovudine crystal.
Described zidovudine raw material can be unformed or the crystal formation of any known pattern.
As a kind of preferred version, HPLC purity >=95% of described zidovudine raw material.
As a kind of preferred version, described water is deionized water.
As a kind of preferred version, the mass ratio of zidovudine raw material and water is 1:1～1:15.
As further preferred version, the mass ratio of zidovudine raw material and water is 1:4～1:10.
As a kind of preferred version, the heating for dissolving temperature of step in a) is 60～95 ℃.
As a kind of preferred version, the rate of temperature fall of step in b) is 10～100 ℃/h.
As further preferred version, the rate of temperature fall of step in b) is 20～50 ℃/h.
As a kind of preferred version, step is c) that insulation was 3～8 ℃ of stirring and crystallizing 3～8 hours.
Compared with prior art, the present invention has following significance effect:
1. can make grain diameter by the inventive method is the spherical zidovudine crystal of 10 order～200 object, this pattern crystal must have better mobility than the zidovudine crystal of known needle-like or thin Rod-like shape, and has good dispersiveness through the prepared spherical zidovudine crystal of the visible the present invention of pattern photo;
2. the solvent that crystallization of the present invention adopts is water, adopts organic solvent to carry out crystallization more safe and reliable than known technology, does not exist dissolvent residual to affect the problem of the quality of the pharmaceutical preparations;
3. the inventive method is simple to operate, preparation cycle is short, yield is high, without specific installation and severe condition, be applicable to large-scale production;
Known in sum; the method of the spherical zidovudine crystal of preparation provided by the invention can effectively solve poor fluidity that the zidovudine crystal of existing shape exists, dispersed bad, the difficult problem that is unfavorable for the process operations such as batch mixing, compressing tablet in preparation process; can accomplish scale production; be conducive to the production of zidovudine preparation; for the steady quality of zidovudine preparation provides guarantee, there is practical value.
Accompanying drawing explanation
Fig. 1 is the XRD spectra of bar-shaped zidovudine raw material used in embodiment.
Fig. 2 is the displaing micro picture of bar-shaped zidovudine raw material used in embodiment.
Fig. 3 is the XRD spectra of the spherical zidovudine crystal that obtains of embodiment 1.
Fig. 4 is the displaing micro picture of the spherical zidovudine crystal that obtains of embodiment 1.
Embodiment
Below in conjunction with drawings and Examples, the present invention is described in more detail.
Bar-shaped zidovudine raw material used in embodiment can obtain HPLC purity >=95% with reference to the preparation of method described in ZL200710045286.5.
Embodiment 1
250kg zidovudine raw material is added in 1250L deionized water, stir and be warming up to 80 ℃, after raw material dissolves completely, be cooled to 5 ℃ and be incubated crystallization 3 hours with the rate of temperature fall of 20 ℃/h again, filter, dry, the spherical zidovudine crystal that obtains 225kg, mass yield is 90%; HPLC purity=99.8%.
What Fig. 1 showed is the XRD spectra of bar-shaped zidovudine raw material used, what Fig. 3 showed is the XRD spectra of the spherical zidovudine crystal of the present embodiment acquisition, visible in conjunction with Fig. 1 and Fig. 3: the zidovudine particle that the present embodiment obtains is still crystal, and has the X-ray powder diffraction feature identical with bar-shaped zidovudine raw material 2 θ values: 8.96,10.08,14.80,15.63,16.0,16.74,17.25,17.92,18.29,19.40,21.51,22.38,24.33,27.92 ± 0.2 °; But what both had that diverse shape characteristic: Fig. 2 shows is the displaing micro picture of bar-shaped zidovudine raw material used, Fig. 4 is the displaing micro picture of the spherical zidovudine crystal that obtains of the present embodiment.
100kg zidovudine raw material is added in 400L deionized water, stir and be warming up to 95 ℃, after raw material dissolves completely, be cooled to 8 ℃ and be incubated crystallization 4 hours with the rate of temperature fall of 30 ℃/h again, filter, dry, the spherical zidovudine crystal that obtains 93kg, mass yield is 93%; HPLC purity=99.9%.
Learn through X-ray powder diffraction analysis and microscopic inspection: the zidovudine crystal that the present embodiment obtains also has spherical pattern, and has XRD spectra feature as shown in Figure 3.
Embodiment 3
150kg zidovudine raw material is added in 1500L deionized water, stir and be warming up to 60 ℃, after raw material dissolves completely, be cooled to 4 ℃ and be incubated crystallization 5 hours with the rate of temperature fall of 15 ℃/h again, filter, dry, the spherical zidovudine crystal that obtains 134kg, mass yield is 89.3%; HPLC purity=99.8%.
Learn through X-ray powder diffraction analysis and microscopic inspection: the zidovudine crystal that the present embodiment obtains also has spherical pattern, and has XRD spectra feature as shown in Figure 3.
Visible in sum; the method of the spherical zidovudine crystal of preparation provided by the invention can effectively solve poor fluidity that the zidovudine crystal of existing shape exists, dispersed bad, the difficult problem that is unfavorable for the process operations such as batch mixing, compressing tablet in preparation process; can accomplish scale production; be conducive to the production of zidovudine preparation; for the steady quality of zidovudine preparation provides guarantee, there is practical value.
Finally be necessary to be pointed out that at this: above embodiment is only for being further described technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. a method of preparing spherical zidovudine crystal, is characterized in that, comprises the steps:
A) zidovudine raw material is added to the water, heating makes to dissolve completely;
B) to be at the uniform velocity cooled to 0～10 ℃;
C) insulation was 0～10 ℃ of stirring and crystallizing 1～10 hour;
D) filter, dry, obtain spherical zidovudine crystal.
2. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: described zidovudine raw material is unformed or the crystal formation of any known pattern.
3. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: HPLC purity >=95% of described zidovudine raw material.
4. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: described water is deionized water.
5. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: the mass ratio of zidovudine raw material and water is 1:1～1:15.
6. the method for the spherical zidovudine crystal of preparation according to claim 5, is characterized in that: the mass ratio of zidovudine raw material and water is 1:4～1:10.
7. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: the heating for dissolving temperature of step in a) is 60～95 ℃.
8. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: the rate of temperature fall of step in b) is 10～100 ℃/h.
9. the method for the spherical zidovudine crystal of preparation according to claim 8, is characterized in that: the rate of temperature fall of step in b) is 20～50 ℃/h.
10. the method for the spherical zidovudine crystal of preparation according to claim 1, is characterized in that: step is c) that insulation was 3～8 ℃ of stirring and crystallizing 3～8 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731600A (en) * | 2012-03-13 | 2012-10-17 | 绿洲生物技术（南通）有限公司 | Preparation method of zidovudine and its intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731600A (en) * | 2012-03-13 | 2012-10-17 | 绿洲生物技术（南通）有限公司 | Preparation method of zidovudine and its intermediate |
Non-Patent Citations (2)
| Title |
|---|
| SANJAY SINGH ET AL.: "Formulation and Evaluation of Solid Lipid Nanoparticles of a Water Soluble Drug: Zidovudine", 《CHEMICAL & PHARMACEUTICAL BULLETIN》, vol. 58, no. 5, 3 February 2010 (2010-02-03), pages 650 - 655 * |
| 张超等: "齐多夫定的合成新工艺", 《2006第六届中国药学会学术年会论文集》, 16 August 2007 (2007-08-16), pages 936 - 942 * |
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