CN103130858B - A kind of preparation method of methylprednisolone crystallization - Google Patents
A kind of preparation method of methylprednisolone crystallization Download PDFInfo
- Publication number
- CN103130858B CN103130858B CN201110392057.7A CN201110392057A CN103130858B CN 103130858 B CN103130858 B CN 103130858B CN 201110392057 A CN201110392057 A CN 201110392057A CN 103130858 B CN103130858 B CN 103130858B
- Authority
- CN
- China
- Prior art keywords
- methylprednisolone
- crystal formation
- preparation
- oxolane
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Steroid Compounds (AREA)
Abstract
A kind of preparation method of methylprednisolone crystallization, the interplanar distance 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, for methylprednisolone is dissolved in the mixed solvent of C1～C4 low-grade monobasic alcohol and oxolane, utilize evaporative crystallization to obtain methylprednisolone II crystal formation.
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 is developed by Upjohn company of the U.S., is in one, to imitate glucocorticoid medicine, has anti-inflammatory, immune pressing downThe pharmacological actions such as system, antiallergy, anti-shock. The antiinflammatory action of this medicine is stronger, is equivalent to 5 times of hydrocortisone, is strongPine 1.4 times. In numerous glucocorticoids, the affinity of methylprednisolone and GCR is the strongest, is that hydrogenation canLoose 12 times, 23 times of prednisone, and mineralocorticoid sample effect (as water, sodium retention) is faint, is about deoxidation cortex1/200 of ketone, and be significantly less than prednisone, to the inhibitory action of HPAA 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 " ICrystal formation ") and methylprednisolone II crystal formation (hereinafter to be referred as " II crystal formation "). Document J.Pharm.Sci., Vol52, reports in No.2The interplanar distance data of X-ray powder diffraction of two kinds of crystal formations, the interplanar distance that I crystal formation is corresponding be 9.87nm, 8.42nm,7.08nm, 5.50nm, absworption peak (as Fig. 1) has been located in 2 θ=9.0 °, 9.7 °, 15.0 °, 16.3 °, 18.0 °. II crystal formationCorresponding interplanar distance is 12.10nm, 7.37nm, 6.32nm, 6.06nm, 5.09nm, 3.88nm, corresponding X rayPowder diffraction in 2 θ=7.3 °, 11.9 °, 12.1 °, 14.0 °, 14.6 °, 17.4 °, 22.9 ° located absworption peak (as Fig. 2).The difficult soluble substance of methylprednisolone, but according to the document, the solubility in water of II crystal formation is 1.8 times of I crystal formation, soII crystal formation has higher bioavilability than I crystal formation.
Chinese patent application CN201010137069.0 also discloses a kind of methylprednisolone crystal formation 1, and its X-ray powder diffraction is spreading outCharacteristic peak has been located in firing angle 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °. As shown in Figure 3, this crystal formationPreparation method for methylprednisolone is dissolved in organic solvent 1 entirely, reduction vaporization, to starting to occur crystallization, slowly adds hydro carbons moltenMatchmaker, and below slow cooling to 0 DEG C, insulation, stirs 1-3h, filters, and obtains. In the document, unexposed this crystal formation first is sprinkled Buddhist nunThe dissolubility data of dragon.
We,, in exploitation methylprednisolone bulk drug, conduct in-depth research the preparation method of its II crystal formation, about firstPrednisolone II crystal formation preparation method's bibliographical information is little. Higuchi, the people such as W.I are at J.Pharm.Sci., Vol52, No.2(1963) in, reported, adopted the methylprednisolone that distils at 190 DEG C to prepare the method for II crystal formation. But this method is easily madeBecome methylprednisolone at high temperature to decompose or carbonization, success rate is low, and sublimed method is not suitable in industrial middle utilization. Higuchi,The people such as W.I are at J.Pharm.Sci., Vol56, and No.2 reported in (1967), recrystallization preparation II crystal formation in the tert-butyl alcoholMethod, but we find, the dissolubility extreme difference of methylprednisolone in the tert-butyl alcohol, all can not be complete in the tert-butyl alcohol of 50 times of volumesCL, so low dissolubility is not suitable for suitability for industrialized production. And we adopt method in this report recrystallization, through X-Ray powder diffraction proves (as Fig. 1), and the crystallization obtaining is methylprednisolone I crystal formation, the described method poor repeatability of visible report.
Summary of the invention:
The present invention proposes a kind of preparation method of methylprednisolone II crystal formation. The X-of methylprednisolone II crystal formation obtained by this methodThe interplanar distance of ray powder diffraction is 12.2nm, 7.4nm, 6.3nm, 6.1nm, 5.1nm, 3.9nm, with bibliographical informationThe interplanar distance data consistent of II crystal formation, the relative diffracted intensity of II crystal formation is respectively in fact its detailed spectrogram (Fig. 1) instituteShow. Described term " in fact ", the diffracted intensity that should be understood to characteristic peak along with crystal preparing technology, sample installation method andThe difference of measuring instrument can change to some extent, also should be within the scope of the invention. In addition, the difference of instrument and other factors canThe interplanar distance value of above-mentioned II crystal formation can affect interplanar distance value, so can change in existing value ± 0.2nm.
We are dissolved in methylprednisolone in the mixed solvent of C1～C4 low-grade monobasic alcohol and oxolane, utilize evaporative crystallization to obtainMethylprednisolone 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 oxolaneIt 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 oxolaneIt 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, normal propyl alcohol orIsopropyl alcohol.
The preparation method of described methylprednisolone II crystal formation, is characterized in that: methylprednisolone is dissolved in to isopropyl alcohol and oxolane mixedIn bonding solvent, utilize evaporative crystallization to obtain, the volume ratio of isopropyl alcohol and oxolane is 3: 7～7: 3.
The preparation method of described methylprednisolone II crystal formation, is characterized in that: methylprednisolone is dissolved in to normal propyl alcohol and oxolane mixedIn bonding solvent, utilize evaporative crystallization to obtain, the volume ratio of normal propyl alcohol and oxolane 1: 3～3: 2.
The preparation method of described methylprednisolone II crystal formation, is characterized in that: will contain the mixed solvent of methylprednisolone, heat up rapidlyTo the boiling of 50 DEG C～solvent, keep evaporating temperature fluctuation range can not exceed 3 DEG C, under normal pressure or reduced pressure, evaporate.
The preparation method of described methylprednisolone II crystal formation, is characterized in that: preferably reduction vaporization.
Methylprednisolone solubility in oxolane is better, just can be molten clear less than 10 times (w/vs) under heating condition,In mixed solvent, add oxolane, the mixed solvent of 10～30 times (w/vs) 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 when evaporation, the ratio of THF is too low, and what obtain isI crystal formation product, so it is very important to control the ratio of oxolane and alcohol.
The preparation method of the methylprednisolone II crystal formation that the present invention proposes, the quantity of solvent needing is few, reproducible, can realize II crystalline substanceThe industrialized production of type.
Methylprednisolone crystallization provided by the invention is analyzed with X-ray powder diffraction.
Brief description of the 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 prepared of embodiment 1
Fig. 3 is the X-ray powder diffraction spectrogram of the disclosed crystal formation of Chinese patent application CN201010137069.0
Detailed description of the invention:
Below will by embodiment, the invention will be further described, these descriptions are not that content of the present invention is done furtherLimit. The technical staff who understands crystallization knowledge should be understood that the replacement that is equal to that technical characterictic of the present invention is done, or changes accordinglyEnter, 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 αRay (λ=1.5405), graphite monochromator, sweep speed 1s/step.
Embodiment 1
Get in the mixed solvent that 5g methylprednisolone is dissolved in 21mL isopropyl alcohol and 49mL oxolane, be heated to molten clear, thenAt 60 DEG C of reduction vaporizations, occur lowering the temperature, filter, being dried after crystal, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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 absorptionPeak, angle of diffraction 2 θ and relatively diffracted intensity are as shown in Figure 2
Embodiment 2
Get in the mixed solvent that 40g methylprednisolone is dissolved in 900mL isopropyl alcohol and 100mL oxolane, be heated to solution and boilRise, after crystal, lowering the temperature, filter, being dried, appear in reduction vaporization, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 3
Get in the mixed solvent that 6g methylprednisolone is dissolved in 140mL isopropyl alcohol and 60mL oxolane, be heated to molten clear, soAfter at 50 DEG C of reduction vaporizations, there is cooling after crystal, filter, dry, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 4
Get in the mixed solvent that 16g methylprednisolone is dissolved in 150mL normal propyl alcohol and 150mL oxolane, be heated to molten clear,Then at 70 DEG C of reduction vaporizations, occur lowering the temperature, filter, being dried after crystal, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 5
Get in the mixed solvent that 15g methylprednisolone is dissolved in 180mL normal propyl alcohol and 120mL oxolane, be heated to molten clear,Then at 80 DEG C of reduction vaporizations, occur lowering the temperature, filter, being dried after crystal, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 6
Get in the mixed solvent that 5g methylprednisolone is dissolved in 15mL methyl alcohol and 45mL oxolane, be heated to molten clear, then 65After crystal, lowering the temperature, filter, being dried, appear in atmospheric evaporation at DEG C, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 7
Get in the mixed solvent that 3.5g methylprednisolone is dissolved in 90mL n-butanol and 10mL oxolane, be heated to molten clear, soAfter crystal, lowering the temperature, filter, being dried, appear in rear 90 DEG C of reduction vaporizations, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak embodiment 8
Get in the mixed solvent that 10g methylprednisolone is dissolved in 80mL ethanol and 80mL oxolane, be heated to molten clear, thenAfter crystal, lowering the temperature, filter, being dried, appear in atmospheric evaporation, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 9
Get in the mixed solvent that 10g methylprednisolone is dissolved in 200mL normal propyl alcohol and 70mL oxolane, be heated to molten clear, soAfter at 50 DEG C of reduction vaporizations, there is cooling after crystal, filter, dry, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak
Embodiment 10
Get in the mixed solvent that 8g methylprednisolone is dissolved in 350mL isobutanol and 70mL oxolane, be heated to molten clear, soAfter crystal, lowering the temperature, filter, being dried, appear in rear atmospheric evaporation, obtain methylprednisolone crystal.
To axonometry X-ray powder diffraction after dry, record interplanar distance and be 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° locate absworption peak.
Claims (9)
1. a preparation method for methylprednisolone II crystal formation, is characterized in that: methylprednisolone is dissolved in the mixed solvent of C1 ~ C4 low-grade monobasic alcohol and oxolane, utilizes evaporative crystallization to obtain, the volume ratio of C1 ~ C4 low-grade monobasic alcohol and oxolane is 1:3 ~ 9:1.
2. the preparation method of methylprednisolone II crystal formation as claimed in claim 1, is characterized in that: the volume ratio of C1 ~ C4 low-grade monobasic alcohol and oxolane is 1:3 ~ 5:1.
3. the preparation method of the methylprednisolone II crystal formation as described in as arbitrary in claim 1 ~ 2, is characterized in that: C1 ~ C4 low-grade monobasic alcohol preferred alcohol, normal propyl alcohol or isopropyl alcohol.
4. the preparation method of methylprednisolone II crystal formation as claimed in claim 3, is characterized in that: methylprednisolone is dissolved in isopropyl alcohol and oxolane mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio of isopropyl alcohol and oxolane is 3:7 ~ 7:3.
5. the preparation method of methylprednisolone II crystal formation as claimed in claim 3, is characterized in that: methylprednisolone is dissolved in normal propyl alcohol and oxolane mixed solvent, utilizes evaporative crystallization to obtain, the volume ratio 1:3 ~ 3:2 of normal propyl alcohol and oxolane.
6. the preparation method of methylprednisolone II crystal formation as claimed in claim 3, it is characterized in that: will contain the mixed solvent of methylprednisolone, be warming up to rapidly 50 DEG C ~ solvent boiling temperature, keep evaporating temperature fluctuation range can not exceed 3 DEG C, under normal pressure or reduced pressure, evaporate.
7. the preparation method of the methylprednisolone II crystal formation as described in as arbitrary in claim 4 ~ 5, it is characterized in that: will contain the mixed solvent of methylprednisolone, be warming up to rapidly 50 DEG C ~ solvent boiling temperature, keep evaporating temperature fluctuation range can not exceed 3 DEG C, under normal pressure or reduced pressure, evaporate.
8. the preparation method of methylprednisolone II crystal formation as claimed in claim 6, is characterized in that reduction vaporization.
9. the preparation method of methylprednisolone II crystal formation as claimed in claim 7, is characterized in that reduction vaporization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392057.7A CN103130858B (en) | 2011-11-30 | 2011-11-30 | A kind of preparation method of methylprednisolone crystallization |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392057.7A CN103130858B (en) | 2011-11-30 | 2011-11-30 | A kind of preparation method of methylprednisolone crystallization |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103130858A CN103130858A (en) | 2013-06-05 |
| CN103130858B true CN103130858B (en) | 2016-05-25 |
Family
ID=48491355
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110392057.7A Active CN103130858B (en) | 2011-11-30 | 2011-11-30 | A kind of preparation method of methylprednisolone crystallization |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103130858B (en) |
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 |
-
2011
- 2011-11-30 CN CN201110392057.7A patent/CN103130858B/en active Active
Patent 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 |
Non-Patent Citations (1)
| Title |
|---|
| Polymorphism and Drug Availability II;W. I. HIGUCHI et al;《Journal of Pharmaceutical Sciences》;19670228;第56卷(第2期);第200-207页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103130858A (en) | 2013-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Supercooling suppression and thermal behavior improvement of erythritol as phase change material for thermal energy storage | |
| CN101805591A (en) | Inorganic hydrated salt expanded graphite composite phase-changing heat storage material and preparation method thereof | |
| CN103880569B (en) | A kind of ADN surface modification method for coating | |
| CN104356072A (en) | 5-fluorouracil drug eutectic crystal and preparation method thereof | |
| CN107098921A (en) | The dysprosium complex constructed using 8 oxyquinoline acyl hydrazone derivatives as part and its synthetic method and application | |
| Dichi et al. | Reinvestigation of the paracetamol–caffeine, aspirin–caffeine, and paracetamol–aspirin phase equilibria diagrams | |
| Terada et al. | Polymorphic and pseudomorphic transformation behavior of acyclovir based on thermodynamics and crystallography | |
| Yang et al. | Preparation and characterization of solidified oleanolic acid–phospholipid complex aiming to improve the dissolution of oleanolic acid | |
| Kumar et al. | Experimental investigations on the performance of a single slope solar still with thermal energy storage | |
| CN103130858B (en) | A kind of preparation method of methylprednisolone crystallization | |
| CN106008438A (en) | Racemic dihydromyricetin anhydrous substance crystal | |
| CN101376101B (en) | Bitter earth nano-catalyst material capable of being used for high-energy solid propellant and synthetic method thereof | |
| US20170051002A1 (en) | Rebaudioside A Crystal And Its Preparation Method And Use | |
| CN105646195A (en) | Fenbufen pharmaceutical co-crystal and preparing method thereof | |
| CN103739639A (en) | Stevioside A glycoside crystal and preparation method and application thereof | |
| WO2008011791A1 (en) | Crystalline tetrabenzyl voglibose and their preparation | |
| CN105836732A (en) | Method for producing fullerene through macroscopic quantity separation of hydrocarbon system | |
| CN109651373A (en) | A kind of preparation method of Xi Gelieting phosphate monohydrate crystal form | |
| TW201336861A (en) | Crystalline compounds of androstane-3 β ,5 α ,6 β -triol and preparation method therefor | |
| RU2481427C1 (en) | METHODS OF PRODUCING COMPOUND CAESIUM HYDROSULPHATE PHOSPHATE HAVING COMPOSITION Cs5(HSO4)2(H2PO4)3 | |
| Murphy et al. | Thermodynamic stability considerations for isostructural dehydrates | |
| CN107056691A (en) | A kind of method for preparing Etoricoxib crystal formation V | |
| Guo et al. | Preparation, Characterization, and Chromatographic Evaluation of Nickel Oxide Deposited Silica Stationary Phase in Hydrophilic Interaction Liquid Chromatography | |
| Dichi et al. | Pharmaceutical phase diagram: aspirin-caffeine-paracetamol | |
| CN107827911A (en) | A kind of 7 phenylacetylamino cephalosporanic acid composite crystals and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |