CN103130858A - Preparing method for methylprednisolone crystal - Google Patents
Preparing method for methylprednisolone crystal Download PDFInfo
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- CN103130858A CN103130858A CN2011103920577A CN201110392057A CN103130858A CN 103130858 A CN103130858 A CN 103130858A CN 2011103920577 A CN2011103920577 A CN 2011103920577A CN 201110392057 A CN201110392057 A CN 201110392057A CN 103130858 A CN103130858 A CN 103130858A
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Abstract
Disclosed is a preparing method for a methylprednisolone crystal. The interplanar crystal spacing diffracted by X-ray powder of a methylprednisolone II crystal form produced by the method is 12.2 nm, 7.4 nm, 6.3 nm, 6.1 nm, 5.1 nm and 3.9 nm. Methylprednisolone is dissolved in a C1-C4 low-level mixed solvent of monohydric alcohol and tetrahydrofuran, and the methylprednisolone II crystal form is obtained through evaporative crystallization.
Description
Technical field:
The invention belongs to and relate to a kind of steroidal compounds polymorphic, the particularly preparation method of methylprednisolone II crystal formation.
Background technology:
Its chemical structural formula of methylprednisolone (Methylprednisolone, CAS:83-43-2) is as follows:
Methylprednisolone by the exploitation of U.S. Up john company, is a kind of middle effect glucocorticoid medicine, has the pharmacological actions such as anti-inflammatory, immunosuppression, antianaphylaxis, antishock.The anti-inflammatory action of this medicine is stronger, is equivalent to 5 times of hydrocortisone, is 1.4 times of prednisone.In numerous glucocorticosteroids, the avidity of methylprednisolone and glucocorticoid receptor is the strongest, 12 times of hydrocortisone, 23 times of prednisone, and mineralocorticoid sample effect (as water, sodium retention) is faint, be about 1/200 of Doca, and significantly less than prednisone, to the restraining effect of hypothalmus-pituitary-adrenal axis a little less than.
In existing bibliographical information, two kinds of methylprednisolone crystal formations are disclosed, be respectively methylprednisolone I crystal formation (hereinafter to be referred as " I crystal formation ") and methylprednisolone II crystal formation (hereinafter to be referred as " II crystal formation ").Document J.Pharm.Sci., Vol 52, the spacing data of the X-ray powder diffraction of two kinds of crystal formations have been reported in No.2, the spacing that the I crystal formation is corresponding is 9.87nm, 8.42nm, 7.08nm, 5.50nm, and absorption peak (as Fig. 1) has been located in 2 θ=9.0 °, 9.7 °, 15.0 °, 16.3 °, 18.0 °.The spacing that the II crystal formation is corresponding is 12.10nm, 7.37nm, 6.32nm, 6.06nm, 5.09nm, 3.88nm, corresponding X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak (as Fig. 2).The difficult soluble substance of methylprednisolone, but according to the document, the solubleness in water of II crystal formation is 1.8 times of I crystal formation, so the II crystal formation has higher bioavailability than I crystal formation.
Chinese patent application CN201010137069.0 also discloses a kind of methylprednisolone crystal formation 1, and its X-ray powder diffraction has been located characteristic peak diffraction angle 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °.As shown in Figure 3, the preparation method of this crystal formation is for entirely to be dissolved in methylprednisolone in organic solvent 1, and reduction vaporization slowly adds the hydro carbons solvent to beginning to occur crystallization, and below slow cooling to 0 ℃, 1-3h is stirred in insulation, filters, and obtains.The dissolubility data of unexposed this crystal formation methylprednisolone in the document.
We conduct in-depth research the preparation method of its II crystal formation in exploitation methylprednisolone bulk drug, about methylprednisolone II crystal formation preparation method's bibliographical information seldom.Higuchi, the people such as W.I are at J.Pharm.Sci., and Vol 52, and No.2 has reported in (1963), adopts the methylprednisolone that distils under 190 ℃ to prepare the method for II crystal formation.Yet this method easily causes methylprednisolone at high temperature to decompose or carbonization, and success ratio is low, and subliming method is not suitable in industrial middle utilization.Higuchi, the people such as W.I are at J.Pharm.Sci., Vol 56, No.2 has reported in (1967), recrystallization prepares the method for II crystal formation in the trimethyl carbinol, but we find, the solvability extreme difference of methylprednisolone in the trimethyl carbinol, all can not dissolve fully in the trimethyl carbinol of 50 times of volumes, so low solvability is not suitable for suitability for industrialized production.And we adopt the method recrystallization in this report, prove (as Fig. 1) through the X-ray powder diffraction, and the crystallization that obtains is methylprednisolone I crystal formation, as seen reports described method poor repeatability.
Summary of the invention:
The present invention proposes a kind of preparation method of methylprednisolone II crystal formation.The spacing of the X-ray powder diffraction of methylprednisolone II crystal formation obtained by this method is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm, with the spacing data consistent of the II crystal formation of bibliographical information, the relative diffracted intensity of II crystal formation is respectively in fact shown in its detailed spectrogram (Fig. 1).Described term " in fact ", the diffracted intensity that should be understood to characteristic peak also should be within the scope of the invention along with the difference of crystal preparing technology, sample installation method and surveying instrument can change to some extent.In addition, the difference of instrument and other factors may affect the spacing value, so the spacing value of above-mentioned II crystal formation can change in existing value ± 0.2nm.
We are dissolved in methylprednisolone in the mixed solvent of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF), utilize evaporative crystallization to obtain methylprednisolone II crystal formation.
The preparation method of described methylprednisolone II crystal formation is characterized in that: the volume ratio of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF) is 1: 3～9: 1.
The preparation method of described methylprednisolone II crystal formation is characterized in that: the volume ratio of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF) is 1: 3～5: 1.
The preparation method of described methylprednisolone II crystal formation is characterized in that: C1～C4 low-grade monobasic alcohol preferred alcohol, n-propyl alcohol or Virahol.
The preparation method of described methylprednisolone II crystal formation is characterized in that: methylprednisolone is dissolved in Virahol and tetrahydrofuran (THF) mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio of Virahol and tetrahydrofuran (THF) is 3: 7～7: 3.
The preparation method of described methylprednisolone II crystal formation is characterized in that: methylprednisolone is dissolved in n-propyl alcohol and tetrahydrofuran (THF) mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio of n-propyl alcohol and tetrahydrofuran (THF) 1: 3～3: 2.
The preparation method of described methylprednisolone II crystal formation is characterized in that: will contain the mixed solvent of methylprednisolone, and be warming up to rapidly the boiling of 50 ℃～solvent, and keep the vaporization temperature fluctuation range not surpass 3 ℃, and evaporate under normal pressure or reduced pressure.
The preparation method of described methylprednisolone II crystal formation is characterized in that: preferred reduction vaporization.
Methylprednisolone solubleness in tetrahydrofuran (THF) is better, just can be molten clear less than 10 times (weightmeasurement ratios) under heating condition, add tetrahydrofuran (THF) in mixed solvent, the mixed solvent of 10～30 times (weightmeasurement ratios) just can be realized the recrystallization of methylprednisolone.If but the ratio of in experimenting, we find out that THF is too high, easy bumping during evaporation, the ratio of THF is too low, and what obtain is I crystal formation product, so it is very important to control the ratio of tetrahydrofuran (THF) and alcohol.
The preparation method of the methylprednisolone II crystal formation that the present invention proposes, the quantity of solvent that needs is few, and good reproducibility can be realized the industrialized production of II crystal formation.
Methylprednisolone crystallization provided by the invention is analyzed with the X-ray powder diffraction.
Description of drawings:
Fig. 1 is the X-ray powder diffraction spectrogram of methylprednisolone I crystal formation
Fig. 2 is the X-ray powder diffraction spectrogram of the methylprednisolone crystallization of embodiment 1 preparation
Fig. 3 is the X-ray powder diffraction spectrogram of the disclosed crystal formation of Chinese patent application CN201010137069.0
Embodiment:
The below will the invention will be further described by embodiment, and these descriptions are not that content of the present invention is done further to limit.The technician who understands crystallization knowledge should be understood that and is equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, within still belonging to protection scope of the present invention.
The crystal formation determining instrument that embodiment is used: Rigaku (Rigaku) D/max-2500 type monochromatic x-rays diffractometer, CuK alpha-ray (λ=1.5405), graphite monochromator, scanning speed 1s/step.
Embodiment 1
Get in the mixed solvent that the 5g methylprednisolone is dissolved in 21mL Virahol and 49mL tetrahydrofuran (THF), be heated to molten clearly, then at 60 ℃ of reduction vaporizations, cooling after crystal, filtration, drying occur, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.
X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak, angle of diffraction 2 θ and relative diffracted intensity are as shown in Figure 2
Embodiment 2
Get in the mixed solvent that the 40g methylprednisolone is dissolved in 900mL Virahol and 100mL tetrahydrofuran (THF), be heated to the solution boiling, cooling after crystal, filtration, drying appear in reduction vaporization, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Embodiment 3
Get in the mixed solvent that the 6g methylprednisolone is dissolved in 140mL Virahol and 60mL tetrahydrofuran (THF), be heated to molten clearly, then at 50 ℃ of reduction vaporizations, cooling after crystal, filtration, drying occur, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Embodiment 4
Get in the mixed solvent that the 16g methylprednisolone is dissolved in 150mL n-propyl alcohol and 150mL tetrahydrofuran (THF), be heated to molten clearly, then at 70 ℃ of reduction vaporizations, cooling after crystal, filtration, drying occur, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Get in the mixed solvent that the 15g methylprednisolone is dissolved in 180mL n-propyl alcohol and 120mL tetrahydrofuran (THF), be heated to molten clearly, then at 80 ℃ of reduction vaporizations, cooling after crystal, filtration, drying occur, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.2nm, 7.3nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Embodiment 6
Get in the mixed solvent that the 5g methylprednisolone is dissolved in 15mL methyl alcohol and 45mL tetrahydrofuran (THF), be heated to molten clearly, cooling after crystal, filtration, drying appear in 65 ℃ of lower atmospheric evaporations then, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.1nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Embodiment 7
Get in the mixed solvent that the 3.5g methylprednisolone is dissolved in 90mL propyl carbinol and 10mL tetrahydrofuran (THF), be heated to molten clearly, cooling after crystal, filtration, drying appear in 90 ℃ of reduction vaporizations then, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.1nm, 7.3nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak embodiment 8
Get in the mixed solvent that the 10g methylprednisolone is dissolved in 80mL ethanol and 80mL tetrahydrofuran (THF), be heated to molten clearly, cooling after crystal, filtration, drying appear in atmospheric evaporation then, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.1nm, 7.3nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Embodiment 9
Get in the mixed solvent that the 10g methylprednisolone is dissolved in 200mL n-propyl alcohol and 70mL tetrahydrofuran (THF), be heated to molten clearly, then at 50 ℃ of reduction vaporizations, cooling after crystal, filtration, drying occur, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.1nm, 7.3nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak
Get in the mixed solvent that the 8g methylprednisolone is dissolved in 350mL isopropylcarbinol and 70mL tetrahydrofuran (THF), be heated to molten clearly, cooling after crystal, filtration, drying appear in atmospheric evaporation then, obtain the methylprednisolone crystal.
To axonometry X-ray powder diffraction after drying, recording spacing is 12.1nm, 7.3nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm.X-ray powder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absorption peak.
Claims (8)
1. the preparation method of a methylprednisolone II crystal formation, is characterized in that: methylprednisolone is dissolved in the mixed solvent of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF), utilizes evaporative crystallization to obtain.
2. the preparation method of methylprednisolone II crystal formation as claimed in claim 1, it is characterized in that: the volume ratio of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF) is 1: 3～9: 1.
3. the preparation method of methylprednisolone II crystal formation as claimed in claim 2, it is characterized in that: the volume ratio of C1～C4 low-grade monobasic alcohol and tetrahydrofuran (THF) is 1: 3～5: 1.
4. the preparation method of described methylprednisolone II crystal formation as arbitrary in claim 1～3, is characterized in that: C1～C4 low-grade monobasic alcohol preferred alcohol, n-propyl alcohol or Virahol.
5. the preparation method of methylprednisolone II crystal formation as claimed in claim 4, it is characterized in that: methylprednisolone is dissolved in Virahol and tetrahydrofuran (THF) mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio of Virahol and tetrahydrofuran (THF) is 3: 7～7: 3.
6. the preparation method of methylprednisolone II crystal formation as claimed in claim 4, is characterized in that: methylprednisolone is dissolved in n-propyl alcohol and tetrahydrofuran (THF) mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio of n-propyl alcohol and tetrahydrofuran (THF) 1: 3～3: 2.
7. the preparation method of described methylprednisolone II crystal formation as arbitrary in claim 4-6, it is characterized in that: the mixed solvent that will contain methylprednisolone, be warming up to rapidly the boiling of 50 ℃～solvent, keep the vaporization temperature fluctuation range not surpass 3 ℃, evaporate under normal pressure or reduced pressure.
8. the preparation method of methylprednisolone II crystal formation as claimed in claim 7, is characterized in that: preferred reduction vaporization.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101804061A (en) * | 2010-04-01 | 2010-08-18 | 天津金耀集团有限公司 | New methylprednisolone tablets and crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101804061A (en) * | 2010-04-01 | 2010-08-18 | 天津金耀集团有限公司 | New methylprednisolone tablets and crystal form and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| W. I. HIGUCHI ET AL: "Polymorphism and Drug Availability II", 《JOURNAL OF PHARMACEUTICAL SCIENCES》, vol. 56, no. 2, 28 February 1967 (1967-02-28), pages 200 - 207 * |
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