CN102816145B - Methanesulfonic acid imatinib polymorphic substance and medical combination thereof - Google Patents
Methanesulfonic acid imatinib polymorphic substance and medical combination thereof Download PDFInfo
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Abstract
The invention discloses methanesulfonic acid imatinib polymorphic substance III. In addition, the invention further discloses a preparation and medical combination of the methanesulfonic acid imatinib polymorphic substance III.
Description
Technical field
The present invention relates to the polymorphic form of medical compounds, more particularly, relate to a kind of polymorphic form of novel imatinib mesylate, in addition, the invention still further relates to preparation method and the pharmaceutical composition thereof of this polymorphic form.
Background technology
Imatinib mesylate, is a kind of tyrosinase inhibitor, is used for the treatment of patients with gastrointestinal stromal tumors (GISTs).Its chemical name is that 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-benzamide mesylate, chemical structure is as follows:
Chinese patent application-application number 98807303.X (hereinafter to be referred as No. 303, patent application) discloses two kinds of polymorphic form α and the β of imatinib mesylate; Wherein, the feature of alpha-crystal form is to have water absorbability, the needle crystal that mobility is bad, and its typical XRPD collection of illustrative plates shows that α type is 4.9,10.5,14.9,16.5,17.7,18.1,18,6,19.1,21.3,21.6, there is peak at 22.7,23.2,23.8,24.9,27.4,28.0 and 28.6 ± 0.1 degree 2 θ places.
The beta crystal feature that this patent documentation is recorded is:, good fluidity little at Thermodynamically stable 140 ℃ below, water absorbability, be easy to the non-needle crystal of storing and processing.These features are all to the preparation of preparation and store useful; 9.7,13.9, there is peak at 14.7,17.5,18.2,20.0,20.6,21.1,22.1,22.7,23.8,29.8 and 30.8 ± 0.1 degree 2 θ places; And provide the preparation method of its polycrystalline thing.The preparation method who provides in this document is as follows:
Alpha crystalline form: free 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine of 98.6g (0.2mol)-2-is amino] phenyl]-benzamide (preparation is referring to EP-A-0564409) joins in 1.4 liters of ethanol.In this cream-coloured suspension, with 20 minutes dropping 19.2g (0.2mol) methylsulfonic acids.By this vlil 20 minutes, and then filtering at 65 ℃.Filtrate is evaporated to 50%, and residue filters (strainer material A) at 25 ℃.Mother liquid evaporation is extremely dry.Residue and strainer material A are suspended in 2.2 liters of ethanol and add 30ml water backflow dissolving.Cool overnight to 25 ℃, filters and is dried until constant weight at 65 ℃.4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-that obtains oldlace is amino] phenyl]-benzamide mesylate crystallization.
Beta-crystalline form:
Method 1: the 4-of 11% (w/w) α-crystalline form (4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-benzamide mesylate suspension in methyl alcohol approximately 25 ℃ of dippings 2 days.Filtering separation crystallization on G4 glass filter, at room temperature dried overnight on filter paper.
Method 2: 50.0g (101mmol) 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-benzamide mesylate is suspended in methyl alcohol (480ml).Add 9.71g (101mmol) methylsulfonic acid and methyl alcohol (20ml), be heated to 50 ℃, add gac (5.0), this mixture is seethed with excitement 30 minutes under refluxing, filter and evaporation concentration.Resistates is dissolved in methyl alcohol (150ml), and inoculation 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-benzamide mesylate (β variant, several milligrams), cause product crystallization.Dry at 50 person of outstanding talent bar and 60 ℃, obtain 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino of β variant] phenyl]-benzamide mesylate.
Method 3: 670g (1136mmol) 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-benzamide mesylate (α-variant) heats in methyl alcohol (1680ml).At 60 ℃, in this solution, inoculate 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl]-benzamide mesylate (β variant, 55 milligrams), now product starts crystallization.Dry at 50 person of outstanding talent bar and 100 ℃, obtain 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino of β variant] phenyl]-benzamide mesylate.
In addition, at patent WO2006/024863, WO2005/077933, CN200680030515.X, 200680044007.7 disclose the crystallized form of the imatinib mesylate of stable α, α 2, δ, ε, F, G, H, I and K type.
Disclosed crystallization method is all that imatinib is suspended in to the crystallized form directly obtaining with methylsulfonic acid salify in organic solvent above; Or imatinib mesylate is suspended in solvent and under certain temperature, adds or do not add crystal seed to turn brilliant acquisition.It is loaded down with trivial details that existing these methods exist technique, and circulation ratio is unstable, and technical scheme cannot guarantee effectively to remove mechanical impurity, and technical scheme can cause the residual genetoxic impurity risk that exists in product, is not suitable for the poor serial shortcoming of suitability for industrialized production and product purity.
For the polymorphic of medicine, different polymorphics can have different chemistry and physical property, comprises fusing point, chemical stability, apparent solubility, dissolution rate, optics and mechanical properties, vapour pressure and density.These character can directly affect processing or the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of preparation.Therefore, the polymorphic of medicine has great importance for quality, security and the validity of pharmaceutical preparation.
For imatinib mesylate, this area exists such demand: be suitable for commercial scale production, the purity of product is high, absolutely not containing genetoxic impurity, physicochemical property excellence, can effectively apply to the novel polymorphic medicine that medicine preparation and list marketing are used.
Summary of the invention
Contriver is through a large amount of research, be surprisingly found out that a kind of new imatinib mesylate polymorph, successfully solved the deficiency that prior art exists, and polymorphic form of the present invention possesses simultaneously: the purity of product is high, absolutely not containing genetoxic impurity, physico-chemical property is excellent, good stability, is more suitable for industrially scalable preparation, can effectively apply to the advantages such as novel polymorphic medicine that medicine preparation and list marketing are used.
The object of this invention is to provide the novel imatinib mesylate polymorph III with above-mentioned technological merit.
Another object of the present invention is to provide the preparation method of the novel polymorphic thing III with above-mentioned technological merit.
The 3rd object of the present invention is to provide the medicinal compositions with containing of above-mentioned technological merit above-mentioned novel polymorphic thing III.
Specifically, the invention provides a kind of imatinib mesylate polymorph III that does not basically contain solvent (organic solvent or water).
The polymorphic form III of imatinib mesylate provided by the present invention, use Cu-Ka radiation, the typical x-ray diffraction pattern that it is multiple batches of, 2 θ that represent with degree are 5.9 ± 0.2, 17.1 ± 0.2 and 24.2 ± 0.2 have diffraction peak, particularly 5.9 ± 0.2, 9.5 ± 0.2, 12.8 ± 0.2, 14.0 ± 0.2, 15.1 ± 0.2, 15.5 ± 0.2, 15.8 ± 0.2, 17.1 ± 0.2, 18.0 ± 0.2, 18.6 ± 0.2, 19.1 ± 0.2, 19.7 ± 0.2, 20.8 ± 0.2, 23.2 ± 0.2, 23.7 ± 0.2, 24.2 ± 0.2, 25.1 ± 0.2, there is diffraction peak at 28.3 ± 0.2 places, see Fig. 1.The polymorphic form III of imatinib mesylate provided by the present invention, use Cu-Ka radiation, the typical x-ray diffraction pattern that it is multiple batches of, 2 θ that represent with degree have diffraction peak at 5.9 ± 0.2,9.5 ± 0.2,12.8 ± 0.2,14.0 ± 0.2,15.1 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.7 ± 0.2,20.8 ± 0.2,23.2 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,25.1 ± 0.2,28.3 ± 0.2 places, and the relative intensity of these diffraction peaks (I/IO) is greater than 20.
The polymorphic form III of imatinib mesylate
| Peak numbering | 2θ | Flex width | D-value | Intensity | I/IO |
| 1 | 5.940 | 0.259 | 14.8665 | 3109 | 73 |
| 2 | 9.500 | 0.282 | 9.3020 | 1085 | 26 |
| 3 | 11.220 | 0.212 | 7.8796 | 530 | 13 |
| 4 | 11.960 | 0.259 | 7.3937 | 927 | 22 |
| 5 | 12.780 | 0.259 | 6.9210 | 1763 | 42 |
| 6 | 13.440 | 0.235 | 6.5826 | 874 | 21 |
| 7 | 13.980 | 0.282 | 6.3295 | 1973 | 47 |
| 8 | 15.120 | 0.235 | 5.8548 | 1659 | 39 |
| 9 | 15.520 | 0.212 | 5.7048 | 1471 | 35 |
| 10 | 15.840 | 0.235 | 5.5902 | 1592 | 38 |
| 11 | 17.060 | 0.282 | 5.1931 | 4011 | 94 |
| 12 | 18.020 | 0.259 | 4.9186 | 3448 | 81 |
| 13 | 18.620 | 0.235 | 4.7614 | 3299 | 78 |
| 14 | 19.080 | 0.329 | 4.6476 | 2521 | 59 |
| 15 | 19.700 | 0.282 | 4.5027 | 3503 | 82 |
| 16 | 20.840 | 0.282 | 4.2589 | 3807 | 89 |
| 17 | 22.080 | 0.376 | 4.0225 | 1640 | 39 |
| 18 | 22.660 | 0.212 | 3.9208 | 1526 | 36 |
| 19 | 23.200 | 0.329 | 3.8308 | 2072 | 49 |
| 20 | 23.720 | 0.259 | 3.7479 | 3223 | 76 |
| 21 | 24.160 | 0.282 | 3.6807 | 4282 | 100 |
| 22 | 25.120 | 0.282 | 3.5421 | 2518 | 59 |
| 23 | 25.900 | 0.282 | 3.4372 | 1201 | 29 |
| 24 | 28.280 | 0.306 | 3.1531 | 1665 | 39 |
| 25 | 28.840 | 0.235 | 3.0932 | 1153 | 27 |
| 26 | 29.060 | 0.235 | 3.0702 | 1248 | 30 |
| 27 | 30.320 | 0.471 | 2.9455 | 859 | 21 |
| 28 | 30.880 | 0.212 | 2.8933 | 799 | 19 |
Imatinib mesylate polymorph III provided by the present invention, detects through gas phase organic residue, and acetone and methyl ethyl ketone do not detect, and methyl tertiary butyl ether residual quantity is below 0.2%.The limit that organic residue meets ICH require (methyl tertiary butyl ether limit: 0.5%, acetone limit: 0.5%, methyl ethyl ketone limit: 0.5%); Through its moisture value of Ka Shi water content detection, be below 0.5%.The above results shows, imatinib mesylate polymorph III provided by the present invention is more suitable for medicinal requirement.
In embodiments of the invention, the invention provides the preparation method of imatinib mesylate polymorph III, the method comprises the step of following order:
(1) imatinib is added in methyl tertiary butyl ether and methylsulfonic acid, stir lower reaction, obtain imatinib mesylate; Here, preferably, the envelope-bulk to weight ratio of methyl tertiary butyl ether and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1; Preferably, under the arbitrary temp extremely refluxing in room temperature, insulated and stirred reaction is 1～10 hour, more preferably, and under reflux conditions insulated and stirred reaction 2 hours;
(2) stir borehole cooling crystallization 0.5 to 10 hour; Preferably, be cooled to room temperature; Preferably, the crystallization time is 1～5 hour;
(3) suction filtration;
(4) collect the filter cake obtaining, decompression is lower dry; Preferably, in room temperature～80 ℃, drying under reduced pressure, to constant weight, obtains imatinib mesylate polymorph III.
In the preparation method of above-mentioned imatinib mesylate polymorph III provided by the invention, wherein, the imatinib using in step (1) adopts EP-A-0564409 preparation, preferably prepares in the following way:
Imatinib mesylate crude product is added to the water, under agitation dissolves or be under agitation warming up to dissolving; Suction filtration, filtrate is down to room temperature, adds insoluble with imatinib or sl. sol. organic solvent under stirring; Then, add and imatinib mesylate crude product a kind of alkali of equimolar amount at least, make imatinib completely free; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake suitable quantity of water drip washing, takes out filtration cakes torrefaction and obtains imatinib.Here, described or sl. sol. organic solvent insoluble with imatinib is a kind of in acetone or methyl ethyl ketone, or their mixture; And the volume ratio of organic solvent and water is 1: 5-100; Described a kind of alkali is alkali-metal carbonate or supercarbonate, more preferably, is sodium carbonate or sodium bicarbonate, preferably preferably, is sodium bicarbonate.
In the preparation method of imatinib mesylate polymorph III of the present invention, described imatinib mesylate crude product can be prepared by existing method, for example, but be not limited to following patent CN98807303.X, WO2006/024863, WO2005/077933, CN200680030515.X, CN200680044007.7, obtains in CN201010286254.6, or the imatinib mesylate crude product of their α, α 2, δ, ε, F, G, H, I and K type.At this, these documents are introduced here as a reference with its full content.
As a kind of preferred embodiment, the invention provides the preparation method of a kind of imatinib mesylate polymorph III, comprise the steps:
(1) imatinib is added in methyl tertiary butyl ether and methylsulfonic acid, stir lower reaction, obtain imatinib mesylate; Here, preferably, the envelope-bulk to weight ratio of methyl tertiary butyl ether and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1; Preferably, under the arbitrary temp extremely refluxing in room temperature, insulated and stirred reaction is 1～10 hour, more preferably, and under reflux conditions insulated and stirred reaction 2 hours;
(2) stir borehole cooling crystallization 0.5 to 10 hour; Preferably, be cooled to room temperature; Preferably, the crystallization time is 1～5 hour;
(3) suction filtration;
(4) collect the filter cake obtaining, decompression is lower dry; Preferably, in room temperature～80 ℃, drying under reduced pressure, to constant weight, obtains imatinib mesylate polymorph III;
Here, the imatinib that described step (1) is used is prepared by following method: imatinib mesylate crude product is added to the water, under agitation dissolves or be under agitation warming up to dissolving; Suction filtration, filtrate is down to room temperature, adds insoluble with imatinib or sl. sol. organic solvent under stirring; Then, add and imatinib mesylate crude product a kind of alkali of equimolar amount at least, make imatinib completely free; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake suitable quantity of water drip washing, takes out filtration cakes torrefaction and obtains imatinib.Here, described or sl. sol. organic solvent insoluble with imatinib is a kind of in acetone or methyl ethyl ketone, or their mixture; And the volume ratio of organic solvent and water is greater than 1: 5; Described a kind of alkali is alkali-metal carbonate or supercarbonate, more preferably, is sodium carbonate or sodium bicarbonate, preferably preferably, is sodium bicarbonate.
As a kind of particularly preferred embodiment, the invention provides the preparation method of a kind of imatinib mesylate polymorph III, comprise the steps:
(1) imatinib is added in methyl tertiary butyl ether and methylsulfonic acid, under reflux conditions insulated and stirred reaction 1-10 hour, more preferably reacts 2 hours, thereby obtains imatinib mesylate; Here, the envelope-bulk to weight ratio of methyl tertiary butyl ether and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1;
(2) stir borehole cooling to room temperature, crystallization 1～5 hour;
(3) suction filtration;
(4) collect the filter cake obtaining, in room temperature～80 ℃, drying under reduced pressure, to constant weight, obtains imatinib mesylate polymorph III;
Here, the imatinib that described step (1) is used is prepared by following method: imatinib mesylate crude product is added to the water, under agitation dissolves or be under agitation warming up to dissolving; Suction filtration, filtrate is down to room temperature, adds acetone or methyl ethyl ketone or their mixture under stirring; Then, add and the imatinib mesylate crude product sodium bicarbonate of equimolar amount at least, make imatinib completely free; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake suitable quantity of water drip washing, takes out filtration cakes torrefaction and obtains imatinib.Here, the volume ratio of acetone or methyl ethyl ketone or their mixture and water is greater than 1: 5.
In the present invention, X-powdery diffractometry testing tool involved in the present invention and test condition are: anode turns target x-ray diffractometer D/max-2500/PC type (Rigaku); It is 3～40 ° of 0.3mm, 5 °/min of sweep velocity, sweep limits that copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, divergent slit and anti-scatter slit are 1 °, reception slit.Instrument is corrected through silicon-dioxide standard substance.
Imatinib mesylate content involved in the present invention and related substance testing conditions: according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), measure.
the condition of high performance liquid chromatography:
Chromatographic column: be weighting agent with the octadecylsilane chemically bonded silica of improvement.
Eluent (gradient): 0%b) in a), 20 minutes, 0% → 30%b then) in a), 10 minutes, 30%b then) in a), 5 minutes.
Eluent is a): 1% perfluoroetane sulfonic acid sodium solution (pH2.5): methyl alcohol (42: 58)
Eluent b): 1% perfluoroetane sulfonic acid sodium solution (pH2.5): methyl alcohol (4: 96)
Detect wavelength: 267nm
Flow velocity: 1.2ml/min
Column temperature: 25 ℃.
The characteristic of imatinib mesylate polymorph III
One, solubility experiment:
Method: it is appropriate that precision takes imatinib mesylate polymorph III, slowly adds a certain amount of dissolve medium, and every 5 minutes, powerful jolting was 30 seconds, observes the dissolving situation in 30 minutes, the results are shown in Table 1.
The solubility test of table 1 imatinib mesylate polymorph III
What the imatinib mesylate bulk drug having gone on the market adopted is beta crystal, has described the solvability of imatinib mesylate thereon: " imatinib mesylate is dissolved in the buffered soln of pH≤5.5 in city's specification sheets; Atomic molten to being insoluble to neutrality/alkaline water buffered soln; Be soluble in to being slightly soluble in methyl-sulphoxide, in methyl alcohol and ethanol; Be insoluble to n-Octanol, in acetone and acetonitrile ".Above-mentioned solubility experiment shows, imatinib mesylate polymorph III solvability in each solvent is obviously better than the crystal formation that goes on the market.
Two, stability
1, exposure experiments to light
Imatinib mesylate polymorph III is evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects, and contrast with the result of 0 day respectively at sampling in 5,10 days.The results are shown in Table 2.
Table 2 exposure experiments to light (4500 ± 500lx)
Note: range of temperature is 23～26 ℃; Relative humidity variations scope is 58%～63%
2, high temperature test
Imatinib mesylate polymorph III raw material is positioned in sealing clean vial, is placed in 60 ℃ of thermostatic drying chambers, respectively at sampling in 5,10 days, detect, and contrast with the result of 0 day.The results are shown in Table 3.
Table 3 high temperature test (60 ℃)
Note: relative humidity variations scope is 53%～61%
3, accelerated test
The raw material of imatinib mesylate polymorph III is packed with polyethylene film plastic bag sealing, be placed in 40 ± 2 ℃, in the fixed temperature and humidity incubator that relative humidity is 75 ± 5%, place six months, respectively at 1,2,3,6 samplings at the end of month detect, and contrast with the result of 0 month.The results are shown in Table 4.
Table 4 accelerated test (40 ℃, relative humidity 75%)
From the above results, the imatinib mesylate polymorph III that the present invention obtains, in exposure experiments to light and high temperature test (60 ℃), its outward appearance, related substance and content, all without obviously changing, illustrate that its physico-chemical property is relatively stable; This product, in long-term reserved sample observing test, is not observed crystal formation and is changed.
Above-mentioned experiment shows that the crystal habit of polymorphic form III of the present invention is relatively stable, is suitable for making medicine and preparation thereof.
In another embodiment of the invention, the invention provides the medicinal compositions that contains above-mentioned imatinib mesylate polymorph III and pharmaceutical excipient, preferably, it is 1-1000 milligram that this medicinal compositions unit formulation contains imatinib mesylate polymorph III, particularly preferably, contain approximately 50,100,200,400 milligrams of above-mentioned imatinib mesylate polymorph III.According to the instruction of state of the art, and the patent of quoting with reference to the present invention, medicinal compositions of the present invention can be made into various formulations, and selects suitable pharmaceutical excipient.For example, according to disease to be treated and object, medicinal compositions of the present invention, for example, by oral, parenteral (intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), suction spraying, nose, vagina, rectum, hypogloeeis or topical administration, preferably, for example, for parenteral (intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion) preparation, formulations such as freeze-dried preparation, injection.
The medicinal compositions that the present invention comprises imatinib mesylate polymorph III, optionally also can contain other therapeutic component.
Medicinal compositions of the present invention is once a day or repeatedly per daily dose and administration, and per daily dose is about 1-2500 mg/day, more preferably about 1-1000 mg/day.
The example that imatinib mesylate polymorph III of the present invention can be used for treating disease and symptom includes but not limited to: the diseases such as treatment myeloproliferative disease, Myelodysplastic syndromes, vasculogenesis, cancer, pain, macular degeneration, Myelodysplastic syndromes, asbestosis, anemia, nervous system disorders, dyssomnia, tetter, pulmonary hypertension, immune deficiency disorder, management of parasitic diseases, central nervous system injury.
Useful technique effect of the present invention is embodied in: although prior art-patent application discloses imatinib mesylate α and beta crystal thing and preparation method thereof for No. 303, the method for the polymorphic form of the preparation imatinib mesylate of No. 303 instructions of patent application is not suitable for the needs of mass-producing stably manufactured.
The preparation method that No. 303, patent application is at the temperature of 20 ℃～50 ℃, by the added methanesulfonic acid salify raw material Suspension of another kind of crystalline form or amorphous formula I compound in a kind of suitable polar solvent, or by the another kind of crystal formation of imatinib mesylate, under the suitable temp of backflow 6 temperature of 25 ℃～reaction mixture, be dissolved in a kind of polar solvent, then at 20 ℃～70 ℃, add β-crystalline form to cause crystallization as crystal seed.
1, the beta crystal providing in No. 303, patent application, although be better applicable to medicinally in physico-chemical property, preparation method is complicated, need to add crystal seed to cause, or has adopted and can cause prepared by the solvent of genetoxic impurity.
2, all technical schemes that patent application provides for No. 303 all can not effectively be removed impurity, and product purity is low.
In a word, in patent application 303 and prior art imatinib mesylate polymorph have such as: cannot avoid genetoxic impurity, poor stability, crystal formation poor fluidity etc. is unfavorable for medicinal shortcoming; Or complex process, complex operation, poor repeatability, the defective workmanship such as product purity is low, so existing imatinib mesylate polymorph or its preparation technology are all not ideal enough.
Yet, imatinib mesylate polymorph III provided by the invention, its preparation technology is simple, the purity of the product preparing is high, definitely avoid genetoxic impurity, physico-chemical property good stability, imatinib mesylate polymorph and the preparation method of applicable suitability for industrialized production, overcome the various defect problems that exist in prior art.
The polymorphic form of the present invention to imatinib mesylate, its crystallization condition fully takes into account existing methodical deficiency as above, has adopted more rationally and the preparation method of science:
1, preparation technology of the present invention is simple, simple to operate, quality controllable, and yield is high, and technique collimation and favorable reproducibility are applicable to technology and produce;
2, the prepared polymorphic form solvability of preparation technology of the present invention, stability, physico-chemical property excellence are suitable for medicinal;
3, polymorphous preparation method of the present invention can effectively remove mechanical impurity.
4, in polymorphous preparation method of the present invention, optionally use the non-alcohols of low toxicity and three kind solvents of ester class.Avoid generating alkyl sulfonates genetoxic impurity.This has played success or failure and conclusive effect to reality of the present invention is medicinal.
5, the preparation method of polymorphic form of the present invention optionally uses three kind solvents of low toxicity.Because this structural compounds textural property determines it, be easy to form solvate, the organic solvent that this present invention selects can effectively be avoided forming solvate with this structural compounds.Be more suitable in medicinal.
6, polymorphous preparation method of the present invention can effectively remove impurity, and particularly strong polar impurity, can obtain the high-purity imatinib mesylate up to 99.9%.
7, the tablet being prepared by polymorphic form of the present invention and capsule contrast crystal formation (β type) and have more excellent dissolution rate, are more suitable for medicinal.
Above advantage shows, the present invention is of value to the quality of product significantly improved and be more suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the typical XRPD figure of imatinib mesylate polymorph III of the present invention.
Fig. 2 is the color atlas of the imatinib mesylate polymorph III for preparing of the embodiment of the present invention 1.
| Peak # | Retention time | Area % |
| 1 | 2.930 | 0.009 |
| 2 | 4.866 | 0.023 |
| 3 | 10.783 | 0.055 |
| 4 | 14.093 | 99.867 |
| 5 | 23.216 | 0.010 |
| 6 | 29.365 | 0.036 |
Embodiment
The preparation of embodiment 1 imatinib mesylate crude product
By imatinib (2Kg), methylsulfonic acid (390g) and acetone (20L) add in reaction flask, are warming up to back flow reaction 2.5 hours under stirring.Be down to room temperature, stirring and crystallizing 3 hours.Suction filtration, the filter cake that collection obtains, in 70 ℃ of drying under reduced pressure to constant weight, obtains imatinib mesylate crude product 2.2Kg.Yield, 92.1%.
Purity: 98.7%.
The preparation of embodiment 2 polymorphic form III
Prepare imatinib free alkali
The imatinib mesylate crude product (1.5Kg) that embodiment 1 is obtained adds in water (15L), is warming up to 60 ℃, stirring and dissolving.Suction filtration removal of impurities.Filtrate is down to room temperature, adds acetone (4.5L) under stirring.Add sodium bicarbonate (214g), room temperature crystallization 3 hours.Suction filtration, is dried to constant weight after filter cake washing and obtains imatinib 1.17Kg.Yield: 92.9%.
Preparation imatinib mesylate
By imatinib obtained above (80g), methylsulfonic acid (15.6g) and methyl tertiary butyl ether (800ml) add in reaction flask, are warming up to back flow reaction 2 hours under stirring.Be down to room temperature, stirring and crystallizing 1 hour.Suction filtration, the filter cake that collection obtains, in 70 ℃ of drying under reduced pressure to constant weight, obtains imatinib mesylate polymorph III 87.6g, yield, 91.6%.
Purity: 99.87% (seeing Fig. 2).
Organic residue: acetone-not detecting (limit: 0.50%); Methyl tertiary butyl ether-0.15% (limit: 0.50%).
The preparation of embodiment 3 polymorphic form III
We are according to existing method, and the imatinib mesylate of the different crystal forms that the different process of take prepares is raw material, adopt embodiment 2 schemes to prepare the data list of polymorphic form III as follows:
From above-mentioned testing data, the imatinib mesylate crude product of crystal formation all can be converted into crystal formation of the present invention arbitrarily.Meanwhile, can effectively remove impurity, obtain the high-purity imatinib mesylate up to 99.9%.
The preparation of embodiment 4 polymorphic form III
Prepare imatinib free alkali
Imatinib mesylate crude product (100g) is added in water (1L), be warming up to 60 ℃, stirring and dissolving.Suction filtration removal of impurities.Filtrate is down to room temperature, adds methyl ethyl ketone (450ml) under stirring.Add sodium bicarbonate (14.2g), room temperature crystallization 2.5 hours.Suction filtration, is dried to constant weight after filter cake washing and obtains imatinib 75.6g.Yield: 90.3%.
Preparation imatinib mesylate
By imatinib obtained above (20g), methylsulfonic acid (3.9g) and methyl tertiary butyl ether (250mL) add in reaction flask, are warming up to back flow reaction 2 hours under stirring.Be down to room temperature, stirring and crystallizing 1 hour.Suction filtration, the filter cake that collection obtains, in 70 ℃ of drying under reduced pressure to constant weight, obtains imatinib mesylate polymorph III 21.6g, yield, 90.4%.
Purity: 99.89%.
Organic residue: acetone-not detecting (limit: 0.5%), methyl ethyl ketone-not detecting (limit: 0.5%), methyl tertiary butyl ether-0.12%.
The preparation of embodiment 5 polymorphic form III
We are according to existing method, and the imatinib mesylate of the different crystal forms that the different process of take prepares is raw material, adopt embodiment 4 schemes to prepare the data list of polymorphic form III as follows:
From above-mentioned testing data, the imatinib mesylate crude product of crystal formation all can be converted into crystal formation of the present invention arbitrarily.Meanwhile, can effectively remove impurity, obtain the high-purity imatinib mesylate up to 99.9%.
Prescription and the preparation technology of embodiment 6 methylsulfonic acid imatinib tablet agent:
With several vehicle, above-mentioned imatinib mesylate polymorph III is made to the tablet containing 100mg as follows.
| Imatinib mesylate (in imatinib) | 100g |
| Microcrystalline Cellulose | 40g |
| Hypromellose | 2g |
| Polyvinylpolypyrrolidone | 15g |
| Micropowder silica gel | 13g |
| Magnesium Stearate | 1.5g |
| Compacting | 1000 |
By prescription, take Microcrystalline Cellulose, hypromellose and polyvinylpolypyrrolidone, mix, obtain auxiliary material powder, standby.By prescription, take imatinib mesylate, mix with auxiliary material powder, obtain pastille mixed powder.To pastille mixed powder, add water appropriate, wet granular processed, dry rear whole grain, adds micropowder silica gel and Magnesium Stearate, mixes with dry particle, is pressed into tablet.
No. 303 beta crystal bulk drugs of patent application, by above-mentioned prescription and technique, are prepared into equally to tablet and measure dissolution rate.
Dissolution determination method: take 0.1mol/L hydrochloric acid soln as dissolution medium, measure according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia).
Dissolution data comparison:
| Dissolution time | Crystal form II I dissolution rate | The brilliant dissolution rate of No. 303 β of patent application |
| 10 minutes | 84％ | 73％ |
| 15 minutes | 92％ | 82％ |
Prescription and the preparation technology of embodiment 7 imatinib mesylate capsules:
With several vehicle, above-mentioned imatinib mesylate polymorph III is made to the capsule containing 100mg as follows.
| Imatinib mesylate (in imatinib) | 100g |
| Microcrystalline Cellulose | 40g |
| Polyvinylpolypyrrolidone | 15g |
| Micropowder silica gel | 15g |
| Magnesium Stearate | 1.5g |
| Fill | 1000 capsules |
By prescription, take Microcrystalline Cellulose, polyvinylpolypyrrolidone, micropowder silica gel and Magnesium Stearate, mix, obtain auxiliary material powder.By prescription, take imatinib mesylate, mix with auxiliary material powder, obtain pastille mixed powder.Pastille mixed powder is filled in No. 00 hard capsule and makes capsule.
No. 303 beta crystal bulk drugs of patent application, by above-mentioned prescription and technique, are prepared into equally to capsule and measure dissolution rate.
Dissolution determination method: take 0.1mol/L hydrochloric acid soln as dissolution medium, measure according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia).
Dissolution data comparison:
| Dissolution time | Crystal form II I capsule dissolubility | No. 303 beta crystal capsule dissolubilities of patent application |
| 10 minutes | 80％ | 73％ |
| 15 minutes | 89％ | 82％ |
| 20 minutes | 93％ | 85％ |
Although the dissolution rate with crystal formation capsule of the present invention of No. 303 beta crystal capsule dissolubilities of patent application all meets the requirements, from above-mentioned correlation data, crystal formation of the present invention is obviously better than beta crystal in medicinal properties, is more suitable in medicinal.
Claims (13)
1. the polymorphic form III of an imatinib mesylate, use Cu-Ka radiation, its x-ray diffraction pattern, has diffraction peak to spend 2 θ of expression at 5.9 ± 0.2,9.5 ± 0.2,12.8 ± 0.2,14.0 ± 0.2,15.1 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.7 ± 0.2,20.8 ± 0.2,23.2 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,25.1 ± 0.2,28.3 ± 0.2 places; And the relative intensity of described diffraction peak is greater than 20.
2. polymorphic form III according to claim 1, its x-ray diffraction pattern has following diffraction peak:
3. polymorphic form III according to claim 1, its x-ray diffraction pattern as shown in Figure 1.
4. one kind comprises in claims 1 to 3 the pharmaceutical composition of polymorphic form III described in arbitrary claim.
5. the preparation method of polymorphic form III described in arbitrary claim in claims 1 to 3, the method comprises the step of following order:
(1) imatinib is added in methyl tertiary butyl ether and methylsulfonic acid, stir lower reaction, obtain imatinib mesylate; Here, the mol ratio of methylsulfonic acid and imatinib is 1:1;
(2) stir borehole cooling crystallization 0.5 to 10 hour;
(3) suction filtration;
(4) collect the filter cake obtaining, under decompression, be drying to obtain imatinib mesylate polymorph III.
6. preparation method according to claim 5, wherein, in step (1), the envelope-bulk to weight ratio of methyl tertiary butyl ether and imatinib is 5～20:1.
7. preparation method according to claim 5, wherein, in step (1), the envelope-bulk to weight ratio of methyl tertiary butyl ether and imatinib is 10～15:1.
8. preparation method according to claim 5, wherein, in step (1) in room temperature to the arbitrary temp refluxing under insulated and stirred reaction 1～10 hour.
9. preparation method according to claim 5, wherein, in step (1), under reflux conditions insulated and stirred reaction is 2 hours.
10. preparation method according to claim 5, wherein, step (2) stirs borehole cooling to room temperature, and the crystallization time is 1～5 hour; Step (4) is in room temperature～80 ℃, and drying under reduced pressure is to constant weight.
11. according to the preparation method described in arbitrary claim in claim 5 to 10, and wherein, the imatinib using in step (1) is prepared in the following way:
Imatinib mesylate crude product is added to the water, under agitation dissolves or be under agitation warming up to dissolving; Suction filtration, filtrate is down to room temperature, adds insoluble with imatinib or sl. sol. organic solvent under stirring; Then, add and imatinib mesylate crude product a kind of alkali of equimolar amount at least, make imatinib completely free; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake suitable quantity of water drip washing, takes out filtration cakes torrefaction and obtains imatinib; Here, described or sl. sol. organic solvent insoluble with imatinib is a kind of in acetone or methyl ethyl ketone, or their mixture; And the volume ratio of organic solvent and water is 1:5-100; Described a kind of alkali is alkali-metal carbonate or supercarbonate.
12. preparation methods according to claim 11, wherein, described a kind of alkali is sodium carbonate or sodium bicarbonate.
13. preparation methods according to claim 12, wherein, described a kind of alkali is sodium bicarbonate.
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| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
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| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
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