CN101804061A - New methylprednisolone tablets and crystal form and preparation method thereof - Google Patents
New methylprednisolone tablets and crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention relates to new methylprednisolone tablets and a crystal form and preparation method thereof. The tablets contains methylprednisolone in crystal form 1 as the active ingredient and one or more of pharmaceutical auxiliary materials used for tablets, wherein the X-ray powder diffraction diagram of methylprednisolone in crystal form 1 has characteristic peaks where diffraction angle 2 theta is 7.9 degrees, 13.1 degrees, 14.6 degrees, 17.2 degrees, 20.3 and 21.5.
Description
Invention field:
The invention belongs to and relate to a kind of steroidal compounds, particularly new methylprednisolone crystal formation and preparation method thereof and the application in preparation.
Background technology:
Methylprednisolone (CAS:83-43-2) its chemical structural formula is shown below for Methylprednisolone, MP:
Methylprednisolone is a kind of middle glucocorticoid medicine of imitating by the exploitation of U.S. Upjohn company, has pharmacological actions such as antiinflammatory, immunosuppressant, antiallergic, shock.The antiinflammatory action of this medicine is stronger, is equivalent to 5 times of hydrocortisone, is 1.4 times of prednisone.In numerous glucocorticoids, the affinity of methylprednisolone and glucocorticoid receptor (GR) is the strongest, is 12 times of hydrocortisone, 23 times of prednisone.And mineralocorticoid sample effect (as water, sodium retention) is faint, is about 1/200 of deoxycorticosterone, and significantly less than prednisone, to the inhibitory action of hypothalamus one hypophysis one hypothalamic pituitary adrenal axis a little less than.U.S. Pat 3053832 and US2897218 disclose the synthetic method of methylprednisolone, but in the prior art and the crystal formation of unexposed methylprednisolone, the peroral dosage form of methylprednisolone, it mainly is tablet, commercially available methylprednisolone tablets has the methylprednisolone tablets (Pfizer production, 4mg/ sheet) of trade name " Medrol " at present.Tianjin Tianyao Pharmaceutical Co., Ltd. (applicant's subsidiary) is imitated successful methylprednisolone crude drug in 1999, and the imitated immediately home-made methylprednisolone tablets (trade name: Eugene of having produced, Tianjin Tianyao Pharmaceutical Co., Ltd. produces, the 4mg/ sheet), (the bioequivalence Journal of Sex Research of homemade methylprednisolone tablets such as Zhu Zhu, Chinese Pharmaceutical Journal the 36th the 4th phase of volume of April calendar year 2001,261-264) think that above-mentioned homemade methylprednisolone tablets and import tablet have bioequivalence, yet in tablet formulation is produced, we find, because the methylprednisolone crude drug of producing all is unbodied at present, when being used for tablet manufacturing, exist and be unfavorable for many drawbacks of producing, because unbodied methylprednisolone raw material flowability is bad, when mixing, need stir for a long time and just can reach the uniformity of dosage units requirement with adjuvant, seriously reduce the efficient of producing, improved the energy, the consumption of equipment.And because the use of unbodied raw material, the less stable of the feasible methylprednisolone tablets that is worth, in the tabletting process, because the mobile official post of methylprednisolone raw material problems such as sticking, pitted skin, fracture occur when getting tabletting easily, the yield rate that makes tablet is lower
Summary of the invention:
The crystal formation research work of medicine has become more and more important at present, the crystallization polymorphic that Chinese patent ZL200580026414.0 discloses certain drug usually is difficulty or ease, stability, dissolubility, the storage stability of medication preparation, a pharmacological important factor of judgment in preparation difficulty or ease and the body.
Surprisingly, we are in carrying out methylprednisolone crystal formation research process, we have found a kind of brand-new methylprednisolone crystal formation, at present, investigate through stability test, this brand-new methylprednisolone crystal formation is compared with existing amorphous methylprednisolone crude drug and is shown better stability, and be convenient to more pulverize, the flowability of the micropowder that pulverizing obtains is better, and stability is better, easier and auxiliary materials and mixing.Therefore this brand-new methylprednisolone crystal formation can become the new selection of methylprednisolone preparation product.
The methylprednisolone chemical structural formula is as follows:
The present invention also provides a kind of crystal formation and the crystallization preparation method thereof of above-mentioned methylprednisolone.The preparation method of this methylprednisolone novel crystal forms is stable and can repeats easier industrialization.
The methylprednisolone of crystal formation 1 provided by the invention is measured with X-ray powder diffraction, its X-ray powder diffraction has been located characteristic peak the angle of diffraction 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °, and its relative diffracted intensity is respectively its detailed spectrogram in fact as shown in Figure 2.Described term " in fact " should be understood to the different to some extent trace variation of the diffracted intensity of characteristic peak along with crystal preparing technology, sample installation method and gauge, also should be within the scope of the invention.In addition, the difference of instrument and other factors may influence the angle of diffraction 2 θ values, so the above-mentioned angle of diffraction 2 θ values that characteristic peak arranged can be in variation in the existing value ± 0.2 °.
The present invention also provides a kind of preparation method of methylprednisolone of described crystal formation 1 as follows:
Methylprednisolone is dissolved in the organic solvent 1 entirely, and reduction vaporization slowly adds the hydro carbons solvent to beginning to occur crystallization, and slowly is cooled to below 0 ℃, and 1-3h is stirred in insulation, filters, and obtains methylprednisolone crystal formation 1.
Described organic solvent 1 is 5-10 with the envelope-bulk to weight ratio of methylprednisolone: 1
The envelope-bulk to weight ratio 10-20 of described hydro carbons solvent and methylprednisolone: 1
Described organic solvent 1 is selected from two or more in ether solvent, halogenated hydrocarbons, ketones solvent, the lower alcohol;
Preferred one or more lower alcohols with
The mixing organic solvent of one or more formations in ether solvent, halogenated hydrocarbons, the ketones solvent; The volume ratio of described lower alcohol and other organic solvents is 1: 1-10.
Described ether solvent is selected from ether, oxolane (THF), dioxane;
Described ketones solvent is selected from acetone, butanone;
Described lower alcohol is selected from methanol, ethanol;
Described halogenated hydrocarbons is selected from chloroform, dichloromethane.
Described organic solvent 1 is the mixed solvent that constitutes of methanol and dichloromethane most preferably, methanol: dichloromethane=1: 1-5 (volume ratio).
Described hydro carbons solvent is selected from benzene, cyclohexane extraction, the normal hexane one or more;
The application of methylprednisolone crystal formation 1 provided by the invention in the medicine of preparation treatment people or mammalian diseases.
The present invention also provides a kind of methylprednisolone tablets, and the methylprednisolone crystal formation 1 that contains as active component is applicable to the pharmaceutic adjuvant of tablet with one or more.
The preferred lactose monohydrate of described pharmaceutic adjuvant, starch, sucrose, dextrin, polyvinylpyrrolidone K30, Polyethylene Glycol, cross-linking sodium carboxymethyl cellulose, magnesium stearate.
The kind of the described pharmaceutic adjuvant that is applicable to tablet and consumption can be selected for use and add according to the adjuvant commonly used of disclosed tablet among " pharmaceutics " (Cui Fude, 2003 November the 5th edition).
From experimental example 2 as can be seen, the flowability of the micropowder that the methylprednisolone crystallization of embodiment of the invention preparation is made will be significantly better than embodiment 6 as can be seen, the tablet that adopts methylprednisolone crystal micropowder provided by the invention to make, compare with methylprednisolone tablets, has better stability, simultaneously as can be seen from embodiment 7, methylprednisolone crystal provided by the invention is under the same conditions pulverized than the easier quilt of methylprednisolone of the prior art, therefore when being used to prepare the micronized pharmaceutical preparation of various needs, has potential advantage.And show in experimental example 2, the flowability of methylprednisolone crystallization micropowder provided by the invention will be apparently higher than the methylprednisolone micropowder of commercially available same particle size, illustrate that to the invention provides the methylprednisolone crystallization mobile better after making micropowder, easier of the adjuvant mix homogeneously, thereby the raising quality of the pharmaceutical preparations reduces the preparation cost.The tablet formulation test of experimental example 3 shows, adopting invention that the methylprednisolone crystallization is provided is that the tablet content uniformity of raw material will be higher than that to adopt commercially available methylprednisolone be the tablet of raw material, the stability test of experimental example 4 also shows in addition, and adopting the tablet content stability that the invention provides methylprednisolone crystallization raw material to be higher than and adopting commercially available methylprednisolone is the tablet of raw material.Illustrate that methylprednisolone crystallization provided by the invention compares with existing methylprednisolone and have significant advantage when being used for preparation.
Used powder diffraction instrument is a Rigaku D/max-2500 powder diffractometer among the present invention, Japanese company of science product.
Description of drawings:
Fig. 1 is the X-ray powder diffraction spectrogram of the methylprednisolone that makes of embodiment 1
Fig. 2 is the X-ray powder diffraction spectrogram of commercially available methylprednisolone
The specific embodiment:
Commercially available methylprednisolone, content 98.7%, Tianjin Tianyao Pharmaceutical Co., Ltd. produces
Get commercially available methylprednisolone and carry out X-ray powder diffraction mensuration, no characteristic peak, as shown in Figure 2
Embodiment 1
Get the 1g methylprednisolone and be dissolved in 5mL methanol: in the mixed solvent of dichloromethane=1: 3 (volume ratio), reduction vaporization after crystal occurring, slowly is added dropwise to the 10ml cyclohexane extraction with 30min, and slowly cooling is cooled to 0 ℃ when dripping cyclohexane extraction.Keep 0 ℃ of insulated and stirred 1h, will separate out crystallization filtration, drying, carry out X-ray powder diffraction and measure.
X-ray powder diffraction is measured, and records characteristic peak positions and be 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 ° spectrograms such as Fig. 1 institute formula.
Embodiment 2
Get the 1g methylprednisolone and be dissolved in 7mL methanol: in the mixed solvent of dichloromethane=1: 1 (volume ratio), reduction vaporization after crystal occurring, slowly is added dropwise to the 15ml normal hexane with 45min, and slowly cooling is cooled to 0 ℃ when dripping cyclohexane extraction.Keep 0 ℃ of insulated and stirred 2h, will separate out crystallization filtration, drying, carry out X-ray powder diffraction and measure.
X-ray powder diffraction is measured, and records characteristic peak positions and be 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °
Embodiment 3
Get the 1g methylprednisolone and be dissolved in 8mL methanol: in the mixed solvent of dichloromethane=1: 2 (volume ratio), reduction vaporization after crystal occurring, slowly is added dropwise to 20ml benzene with 60min, and slowly cooling is cooled to 0 ℃ when dripping cyclohexane extraction.Keep 0 ℃ of insulated and stirred 3h, will separate out crystallization filtration, drying, carry out X-ray powder diffraction and measure.
X-ray powder diffraction is measured, and records characteristic peak positions and be 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 ° embodiment 4
Get the 1g methylprednisolone and be dissolved in 9mL methanol: in the mixed solvent of chloroform=1: 4 (volume ratio), reduction vaporization after crystal occurring, slowly is added dropwise to the 10ml cyclohexane extraction with 30min, and slowly cooling is cooled to 0 ℃ when dripping cyclohexane extraction.Keep 0 ℃ of insulated and stirred 1h, will separate out crystallization filtration, drying, carry out X-ray powder diffraction and measure.
X-ray powder diffraction is measured, and records characteristic peak positions and be 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °
Embodiment 5,
Get the 1g methylprednisolone and be dissolved in 10mL methanol: in the mixed solvent of chloroform=1: 5 (volume ratio), reduction vaporization after crystal occurring, slowly is added dropwise to the 20ml normal hexane with 30min, and slowly cooling is cooled to 0 ℃ when dripping cyclohexane extraction.Keep 0 ℃ of insulated and stirred 3h, will separate out crystallization filtration, drying, carry out X-ray powder diffraction and measure.
X-ray powder diffraction is measured, and records characteristic peak positions and be 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °
Embodiment 7 pulverizes experiment
Experimental facilities: WLFM-P-85 type jet mill Beijing Wei Ling Hu Xin Mechanical Equipment Co., Ltd produces
Grain diameter measurement instrument: Easysizer20 laser particle analyzer, Zhuhai OMEC Technology Co., Ltd.
The sample grouping: the A group is the made methylprednisolone crystal 5 of comparative examples 00g, is equally divided into ten pulverizing, feed size 80-100 order, the particle diameter D of ten pulverizing
90Carry out again average;
The B group is the made methylprednisolone crystal 5 00g of embodiment 2 methods, is equally divided into ten pulverizing, feed size 80-100 order, the particle diameter D of ten pulverizing
90Carry out again average.
Pulverization conditions: pulverize air-flow 1.0Mpa
Charging rate 0.5kg/h
Above-mentioned A group and B group sample are carried out comminution by gas stream according to above-mentioned pulverization conditions respectively, be, the average D of A group sample the product granularity that obtains
90=32.5 μ m, B group sample average D
90=23.1 μ m.
Experimental example 1 is pulverized experiment
Experimental facilities: WLFM-P-85 type jet mill Beijing Wei Ling Hu Xin Mechanical Equipment Co., Ltd produces
Grain diameter measurement instrument: Easysizer20 laser particle analyzer, Zhuhai OMEC Technology Co., Ltd.
The sample grouping: the A group is the made methylprednisolone crystal 5 of comparative examples method 00g, is equally divided into ten pulverizing, feed size 80-100 order, the particle diameter D of ten pulverizing
90Carry out again average;
The B group is commercially available methylprednisolone 500g, is equally divided into ten pulverizing, feed size 80-100 order, ten pulverizing
Particle diameter D
90Carry out again average.
Pulverization conditions: pulverize air-flow 1.0Mpa
Charging rate 0.5kg/h
Above-mentioned A group and B group sample are carried out comminution by gas stream according to above-mentioned pulverization conditions respectively, be, the average D of A group sample the product granularity that obtains
90=32.5 μ m, B group sample average D
90=23.1 μ m.
Mensuration and the bulk testing of 2 angle of reposes of experimental example
The preparation of test specimen: test specimen is divided into two groups of A, B, the A group is commercially available methylprednisolone, the B group is the methylprednisolone crystallization that makes according to embodiment of the invention method, content is 99.0%, adopt the jet mill in the experimental example 1 to pulverize respectively, A group D90=101.5 μ m, B group D90=102.6 μ m
Adopt fixedly conical bottom method.The chassis is the culture dish of diameter 7cm, and two glass funnels are overlapping up and down, is fixed on the iron stand, and following hopper outlet and chassis distance are 5.0cm.Slowly add from upper funnel, sample is deposited on the chassis gradually through the buffering of two funnels, form cone, till obtaining the highest cone.Measure the high H of cone, every kind of sample measured three times, averages, and is calculated as follows angle of repose:
α＝arctg(H/R)
Wherein, α is angle of repose, and R is the chassis radius
It is 35.6 ° that A organizes angle of repose, and it is 28.3 ° that B organizes angle of repose
Experimental example 3, tablet formulation embodiment feeds intake according to 10000
Mixing apparatus: WCH-10 trough type mixing machine
Prescription: methylprednisolone 40g,
Lactose monohydrate 545.0g
Starch 200.0g
Sucrose 200g
Dextrin 100g
Polyvinylpyrrolidone K30 50g
Macrogol 4000 10g
Cross-linking sodium carboxymethyl cellulose 50g
Magnesium stearate 5g
Feed intake to prepare 10000; remove polyvinylpyrrolidone; Polyethylene Glycol; the above-mentioned adjuvant pulverize separately of the recipe quantity that magnesium stearate is outer is crossed 100 mesh sieves; mix with the methylprednisolone micropowder that makes according to experimental example 2 methods; adopt the WCH-10 trough type mixing machine during mixing; rotating speed 12rpm; add fluidized bed pelletizer after mixing 10min; start fluid bed; polyvinylpyrrolidone with recipe quantity; the aqueous solution that Polyethylene Glycol is made into 20% (in the gross weight of above-mentioned two kinds of adjuvants) is spraying and carry out drying and granulating by the mode of heated fluidized bed continuously on fluid bed; magnesium stearate with recipe quantity when granulating end sucks fluidized bed pelletizer and abundant the mixing; the granule that obtains is carried out tabletting obtain 10000 of methylprednisolone sheets; sheet heavily is 120mg, methylprednisolone 4mg/ sheet
Adopt the commercially available methylprednisolone micropowder of A group in the experimental example 2 and the methylprednisolone crystallization micropowder that makes according to embodiment of the invention method of B group respectively to prepare 10000 methylprednisolone sheets respectively, be divided into tablet A (commercially available methylprednisolone) and tablet B (methylprednisolone crystallization) according to above-mentioned prescription and technology
Uniformity of dosage units detects
Content analysis method:
The methylprednisolone assay is analyzed with HPLC:
The chromatographic condition position of HPLC: chromatographic column octadecylsilane chemically bonded silica
Mobile phase methanol-water (95: 5)
Detect wavelength 243nm
The perfect damage of outward appearance from tablet A and tablet B respectively, smooth in appearance, each 10 in the uniform tablet of color and luster, according to the uniformity of dosage units inspection technique detection level uniformity in 2005 editions appendix 75-76 of Chinese Pharmacopoeia page or leaf,
Measuring every respectively is 100 relative amount X with labelled amount (4mg/ sheet), asks its meansigma methods
With standard deviation S, and the absolute value A of the difference of labelled amount and average,
The A+1.80S=13.5 of tablet A wherein, the A+1.80S=5.3 of tablet B all meets the pharmacopeia regulation, but the uniformity of dosage units of tablet B is better than tablet A, and under equal conditions preparation is described, methylprednisolone crystallization provided by the invention realizes uniformity of dosage units preferably easily because flowability is better.
Experimental example 4 tablet stability test data comparative examples
Content analysis method is with experimental example 3
The methylprednisolone assay is analyzed with HPLC:
The chromatographic condition position of HPLC: chromatographic column octadecylsilane chemically bonded silica
Mobile phase methanol-water (95: 5)
Detect wavelength 243nm
The tablet A and the tablet B that get preparation in the experimental example 3 respectively carry out the stable content property testing according to 178 pages of 2005 editions appendix of Chinese Pharmacopoeia " pharmaceutical preparation stability test guideline ", tablet A and tablet B are all adopted aluminium-plastic bubble plate packing, get 50 for every kind, carry out the accelerated stability test, experimental condition is 40 ℃ ± 2 ℃, and relative humidity 75% ± 5% is in test when initial and take a sample respectively the 1st, 2,3,6 the end of month and once measure content, 10 of each surveys
Record and the results are shown in following table: (
N=10)
The result shows that after off-test in 6 months, the content of the crystalline tablet B group of the methylprednisolone that adopts the embodiment of the invention to make is significantly higher than the tablet A group (P＜0.05) that adopts commercially available methylprednisolone.
Claims (10)
1. methylprednisolone tablets, the methylprednisolone crystal formation 1 that contains as active component is applicable to the pharmaceutic adjuvant of tablet with one or more, it is characterized in that the X-ray powder diffraction of described methylprednisolone crystal formation 1 has been located characteristic peak the angle of diffraction 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °.
2. tablet as claimed in claim 1, feature are the preferred lactose monohydrate of described pharmaceutic adjuvant, starch, sucrose, dextrin, polyvinylpyrrolidone K30, Polyethylene Glycol, cross-linking sodium carboxymethyl cellulose, magnesium stearate.
3. new methylprednisolone crystal formation 1, the X-ray powder diffraction of the described crystal formation 1 of its feature has been located characteristic peak the angle of diffraction 2 θ=7.9 °, 13.1 °, 14.6 °, 17.2 °, 20.3 °, 21.5 °.
4. the preparation method of a methylprednisolone crystal formation 3, it is characterized in that: methylprednisolone is dissolved in the organic solvent 1 entirely, and reduction vaporization is to beginning to occur crystallization, slowly add the hydro carbons solvent, and slowly be cooled to below 0 ℃, insulation, stir 1-3h, filter, obtain methylprednisolone crystal formation 1.
5. preparation method as claimed in claim 4 is characterized in that the described organic solvent 1 and the envelope-bulk to weight ratio of methylprednisolone are 5-10: 1, and the envelope-bulk to weight ratio 10-20 of described hydro carbons solvent and methylprednisolone: 1.
6. preparation method as claimed in claim 5 is characterized in that described organic solvent 1 is selected from two or more in ether solvent, halogenated hydrocarbons, ketones solvent, the lower alcohol.
7. preparation method as claimed in claim 6, it is characterized in that in described organic solvent 1 preferred one or more lower alcohols and ether solvent, halogenated hydrocarbons, the ketones solvent one or more formations mix organic solvent; The volume ratio of described lower alcohol and other organic solvents is 1: 1-10, and described ether solvent is selected from ether, oxolane (THF), dioxane; Described ketones solvent is selected from acetone, butanone;
Described lower alcohol is selected from methanol, ethanol;
Described halogenated hydrocarbons is selected from chloroform, dichloromethane.
8. preparation method as claimed in claim 7 is characterized in that the most preferably mixed solvent that constitutes of methanol and dichloromethane of described organic solvent 1, methanol: dichloromethane=1: 1-5 (volume ratio).
9. as the arbitrary described preparation method of claim 3-8, it is characterized in that described hydro carbons solvent is selected from one or more in benzene, cyclohexane extraction, the normal hexane.
10. the application of methylprednisolone crystal formation 1 as claimed in claim 3 in the medicine of preparation treatment people or mammalian diseases.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130858A (en) * | 2011-11-30 | 2013-06-05 | 天津金耀集团有限公司 | Preparing method for methylprednisolone crystal |
| CN104974208A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Preparation method of high-purity methylprednisolone aceponate |
| CN109925288A (en) * | 2017-12-18 | 2019-06-25 | 江苏开元药业有限公司 | A kind of glucocorticoid medicine tablet and preparation method thereof |
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| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101418029A (en) * | 2008-11-13 | 2009-04-29 | 湖南甾体化学品有限公司 | Method for synthesizing methylprednisolone |
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| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101418029A (en) * | 2008-11-13 | 2009-04-29 | 湖南甾体化学品有限公司 | Method for synthesizing methylprednisolone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130858A (en) * | 2011-11-30 | 2013-06-05 | 天津金耀集团有限公司 | Preparing method for methylprednisolone crystal |
| CN103130858B (en) * | 2011-11-30 | 2016-05-25 | 天津金耀集团有限公司 | A kind of preparation method of methylprednisolone crystallization |
| CN104974208A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Preparation method of high-purity methylprednisolone aceponate |
| CN104974208B (en) * | 2014-04-08 | 2018-01-19 | 天津金耀集团有限公司 | A kind of preparation method of high-purity Methylprednisolone Aceponate |
| CN109925288A (en) * | 2017-12-18 | 2019-06-25 | 江苏开元药业有限公司 | A kind of glucocorticoid medicine tablet and preparation method thereof |
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Application publication date: 20100818 Assignee: Tianjin Tianyao Pharmaceutical Co., Ltd. Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2017120000031 Denomination of invention: New methylprednisolone tablets and crystal form and preparation method thereof Granted publication date: 20120509 License type: Exclusive License Record date: 20170320 |
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