CN105218434A - Carbinoxamine maleate crystal formation and preparation method thereof - Google Patents
Carbinoxamine maleate crystal formation and preparation method thereof Download PDFInfo
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- CN105218434A CN105218434A CN201510715622.7A CN201510715622A CN105218434A CN 105218434 A CN105218434 A CN 105218434A CN 201510715622 A CN201510715622 A CN 201510715622A CN 105218434 A CN105218434 A CN 105218434A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to pharmacy field, be specifically related to a kind of carbinoxamine maleate new crystal and preparation method thereof.The X-ray powder diffraction of described carbinoxamine maleate crystal formation has characteristic peak in following d value: 9.005,5.768,5.265,4.657,4.401,4.292,4.063,3.920,3.817,3.508,3.343,3.202,2.940,2.831,2.490, above d value limit of error ± 0.2.Described preparation method comprises the following steps: be dissolved in by carbinoxamine maleate in organic solvent, carries out crystallization, obtains described crystal formation.Described new crystal good stability, its preparation method controllability is good, favorable reproducibility, is suitable for mass-producing pharmaceutical manufacturing.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to a kind of carbinoxamine maleate new crystal and preparation method thereof.
Background technology
Carbinoxamine maleate (carbinoxaminemaleate), also known as toxilic acid Rotoxamine, it is a kind of gentle calm Loratadine, its chemistry N-[2-[(4-chloro-phenyl-) (2-pyridyl) methoxyl group] ethyl]-N, N-dimethyl amine maleate by name.Carbinoxamine is the chiral molecules with a chiral carbon atom, is divided into R and S configuration thus, pharmaceutically the main maleate with its mix-configuration, and clinical being mainly used in alleviates symptoms of allergic, flu, cough.
The existing medicine of carbinoxamine maleate remains barely satisfactory in steady stability in storage, bioavailability etc., to be improved.And up to the present, do not have the crystal formation of carbinoxamine maleate to report yet.
Summary of the invention
The invention provides a kind of carbinoxamine maleate new crystal and preparation method thereof, described new crystal good stability, its preparation method controllability is good, favorable reproducibility, is suitable for mass-producing pharmaceutical manufacturing.
For solving the problem, the present invention by the following technical solutions:
Design a kind of carbinoxamine maleate crystal formation, the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 9.005,5.768,5.265,4.657,4.401,4.292,4.063,3.920,3.817,3.508,3.343,3.202,2.940,2.831,2.490, above d value limit of error ± 0.2.
Preferably, the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 5.132,4.593,3.433,3.284,3.136,2.742, above d value limit of error ± 0.2.
Preferred, the X-ray powder diffraction of described crystal formation as shown in Figure 1.
Preferred, the differential thermal/thermogravimetric analysis collection of illustrative plates of described crystal formation as shown in Figure 2.
The present invention also designs a kind of preparation method of above-mentioned carbinoxamine maleate crystal formation: be dissolved in by carbinoxamine maleate in organic solvent, carry out crystallization, to obtain final product.
Described organic solvent is at least one in Virahol, ethyl acetate, acetone, be preferably the mixed solvent of ethyl acetate and Virahol, and more have choosing, in described mixed solvent, the two volume ratio is 3:1, and consumption is 10 times of carbinoxamine maleate weight.
Preferred concrete steps are as follows: join in container by carbinoxamine maleate and organic solvent, are heated to 50 DEG C, then after stirring 30min, naturally cool to 25 DEG C, crystallization, filter, and with organic solvent washing twice, collect filter cake, 50 DEG C of forced air drying 6h and get final product.
positive beneficial effect of the present invention:
The different crystal forms of same medicine may have remarkable difference in outward appearance, solubleness, fusing point, dissolution rate, biological effectiveness etc., thus has influence on stability, the bioavailability of compound, and this kind of phenomenon clearly.Polymorph in pharmaceuticals phenomenon is one of important factor affecting drug quality and clinical efficacy.The steady stability in storage of carbinoxamine maleate crystal formation of the present invention is good, and active good, bioavailability is high, and its preparation method controllability is good, and favorable reproducibility is suitable for large-scale production.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) collection of illustrative plates of carbinoxamine maleate crystal formation of the present invention.
Fig. 2 is differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates of carbinoxamine maleate crystal formation of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in more detail.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Carbinoxamine maleate raw material used in following examples of the present invention, also prepares gained by method described in US Patent No. 19572800485 by commercial.
embodiment 1
A kind of preparation method of carbinoxamine maleate crystal formation, comprise the following steps: carbinoxamine maleate 20g is dissolved in 200g ethyl acetate/Virahol=3/1 mixed solvent, be heated to 50 DEG C, stir 30min, naturally cool to 25 DEG C, crystallization, filter, wash twice with ethyl acetate/Virahol=3/1 mixed solvent, collect filter cake, 50 DEG C of forced air drying 6h, obtain white powder crystal 12g, its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 1 (concrete data see under), its differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates as shown in Figure 2, DSC/TG analyzes and shows that sample is in 116.8 ~ 121.1oC heat absorption melting.
No.Pos.[°2Th.]d-spacing[?]Rel.Int.[%]FWHM[°2Th.]MatchedbyArea[cts*°2Th.]Backgr.[cts]Height[cts]
19.82249.005032.520.1171208.871076.581808.29
215.36215.767982.640.1338250.09828.001894.49
316.83865.265391.010.2342167.65814.00725.70
417.27965.131990.890.8029507.37810.93640.57
519.05914.656654.390.1004311.18794.003142.95
619.32614.592904.890.1338462.54791.003503.82
720.17954.40055100.000.217515372.71783.0071661.85
820.69744.291619.450.16731118.06779.006775.56
921.87854.0625213.750.15061463.56767.009854.84
1022.68383.920096.600.1506702.69760.004731.53
1123.30233.817427.240.1673856.34754.655189.49
1225.39143.507895.660.1840735.97735.004054.61
1325.95553.432912.060.1673243.38730.001474.88
1426.66643.342986.370.2175978.76722.764562.64
1527.15343.284122.280.1673269.16718.111631.13
1627.85983.202437.500.1506798.57712.005377.17
1728.46093.136151.460.1673172.35706.001044.46
1830.40802.939636.820.23421128.25688.004883.82
1931.60162.831275.290.1673625.80676.463792.42
2032.65462.742331.010.1673119.97667.00727.01
2136.06902.490191.160.2676218.72746.00828.41。
embodiment 2
A kind of preparation method of carbinoxamine maleate crystal formation, comprise the following steps: carbinoxamine maleate 20g is dissolved in 100g Virahol, be heated to 50 DEG C, stir 30min, naturally cool to 25 DEG C, crystallization, filter, by washed with isopropyl alcohol twice, collect filter cake, 50 DEG C of forced air drying 6h obtain white powder crystal 10g, its X-ray powder diffraction (XRPD) collection of illustrative plates and differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates identical with embodiment 1.
embodiment 3
A kind of preparation method of carbinoxamine maleate crystal formation, comprise the following steps: carbinoxamine maleate 20g is dissolved in 300g ethyl acetate, be heated to 50 DEG C, stir 30min, naturally cool to 25 DEG C, crystallization, filter, ethyl acetate washes twice, and collects filter cake, 50 DEG C of forced air drying 6h obtain white powder crystal 13g, its X-ray powder diffraction (XRPD) collection of illustrative plates and differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates identical with embodiment 1.
embodiment 4
A kind of preparation method of carbinoxamine maleate crystal formation, comprise the following steps: carbinoxamine maleate 20g is dissolved in 100g acetone, be heated to 50 DEG C, stir 30min, naturally cool to 25 DEG C, crystallization, filter, washing with acetone twice, collect filter cake, 50 DEG C of forced air drying 6h obtain white powder crystal 11g, its X-ray powder diffraction (XRPD) collection of illustrative plates and differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates identical with embodiment 1.
embodiment 5
Carry out to the carbinoxamine maleate sample with these crystal formation data of above preparation the test that keeps sample for a long time for 3,6 months, the sampling that expires detects by quality standard, detects data as following table:
The Detection of Stability data of table 1 crystal form samples of the present invention
。
The X-ray powder diffraction data of 3 months samples of keeping sample for a long time is as follows:
No.Pos.[°2Th.]d-spacing[?]Rel.Int.[%]FWHM[°2Th.]MatchedbyArea[cts*°2Th.]Backgr.[cts]Height[cts]
19.96938.872683.620.1338253.271044.941918.57
212.98626.817420.660.8029277.90878.48350.86
315.49445.719023.850.1338269.27794.002039.73
416.87125.255281.680.2342205.33786.00888.81
517.71775.006063.270.1506257.38782.001733.06
619.18994.625216.750.1338471.88773.003574.59
719.46484.560497.230.1171442.18771.003828.09
820.30524.37360100.000.18409613.03766.0052960.07
920.81804.2670114.140.16731235.81763.007489.18
1022.00324.0397819.680.15061547.74756.0010421.64
1122.81933.897119.830.1506773.33751.005207.17
1223.41933.7986110.940.1673955.97747.005793.28
1325.52353.490028.770.1506689.74734.004644.34
1426.08713.415893.150.1673274.97731.001666.35
1526.80123.326478.710.1506684.69726.004610.36
1627.28343.268773.700.1673323.30723.471959.24
1728.00523.1861410.690.1506840.96719.005662.56
1830.53772.927446.280.1840604.03704.003327.74
1931.73412.819756.560.1338458.32696.003471.82
2032.78362.731841.420.1673124.51691.00754.53
2136.20962.480841.810.2676253.16818.00958.87。
The X-ray powder diffraction data of 6 months samples of keeping sample for a long time is as follows:
No.Pos.[°2Th.]d-spacing[?]Rel.Int.[%]FWHM[°2Th.]MatchedbyArea[cts*°2Th.]Backgr.[cts]Height[cts]
19.94508.894309.200.1004279.361019.372821.56
212.66186.991321.850.5353299.57870.56567.32
315.48145.723807.960.1338322.00790.002439.21
416.96855.225354.450.2342315.04780.001363.68
517.73235.001968.800.1338356.27775.002698.83
619.44614.5648320.320.1338822.45764.006230.17
720.29644.37548100.000.13384047.22758.0030658.31
820.80824.2690031.770.15061446.72755.009741.44
921.99674.0409523.870.1338966.22747.007319.27
1022.81013.8986720.580.1506937.02741.006309.38
1123.41123.7999120.600.16731042.02737.006314.78
1225.51563.4910922.680.16731147.58723.006954.44
1326.07323.417679.050.1840503.56719.002774.19
1426.80243.326339.290.1171329.02714.002848.45
1527.27633.269606.490.1338262.59710.881989.19
1627.97603.1893913.340.1506607.38706.004089.80
1728.57243.124165.090.1673257.73702.001561.90
1830.54972.926316.450.1338260.87689.001976.15
1931.71362.821537.330.1338296.71680.872247.65
2032.76362.733463.210.2007194.61675.00982.82
2136.39162.468851.980.8029480.66692.00606.84。
More than test shows, the carbinoxamine maleate stability of crystal form of preparation of the present invention is better, and along with the prolongation of time, its quality measurements still meets quality standard, and without considerable change, steady quality, is beneficial to preservation; In X-diffraction data, main diffraction peak is without considerable change, stable crystal form.This crystal formation stable is beneficial to preservation, is applicable to medicinal.
The present invention is not limited to above-mentioned embodiment, and those skilled in the art also can make multiple change accordingly, but to be anyly equal to the present invention or similar change all should be encompassed in the scope of the claims in the present invention.
Claims (10)
1. a carbinoxamine maleate crystal formation, it is characterized in that: the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 9.005,5.768,5.265,4.657,4.401,4.292,4.063,3.920,3.817,3.508,3.343,3.202,2.940,2.831,2.490, above d value limit of error ± 0.2.
2. carbinoxamine maleate crystal formation according to claim 1, it is characterized in that: the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 5.132,4.593,3.433,3.284,3.136,2.742, above d value limit of error ± 0.2.
3. carbinoxamine maleate crystal formation according to claim 2, is characterized in that: the X-ray powder diffraction of described crystal formation as shown in Figure 1.
4. carbinoxamine maleate crystal formation according to claim 1, is characterized in that: the differential thermal/thermogravimetric analysis collection of illustrative plates of described crystal formation as shown in Figure 2.
5. a preparation method for carbinoxamine maleate crystal formation described in claim 1, is characterized in that: be dissolved in by carbinoxamine maleate in organic solvent, carries out crystallization, to obtain final product.
6. preparation method according to claim 5, is characterized in that: described organic solvent is at least one in Virahol, ethyl acetate, acetone.
7. preparation method according to claim 6, is characterized in that: described organic solvent is the mixed solvent of ethyl acetate and Virahol.
8. preparation method according to claim 7, is characterized in that: in described mixed solvent, the volume ratio of ethyl acetate and Virahol is 3:1.
9. preparation method according to claim 8, is characterized in that: described mixed solvent consumption is 10 times of carbinoxamine maleate weight.
10. preparation method according to claim 5, it is characterized in that: carbinoxamine maleate and organic solvent are joined in container, be heated to 50 DEG C, after stirring 30min again, naturally cool to 25 DEG C, crystallization, filter, with organic solvent washing twice, collect filter cake, 50 DEG C of forced air drying 6h and get final product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108420791A (en) * | 2018-05-14 | 2018-08-21 | 山东达因海洋生物制药股份有限公司 | A kind of carbinoxamine maleate oral sustained release suspension and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH583197A5 (en) * | 1973-05-17 | 1976-12-31 | Medimac Sa | |
| US6881744B2 (en) * | 2001-12-14 | 2005-04-19 | Jame Fine Chemicals, Inc. | Carbinoxamine tannate |
| CN104774174A (en) * | 2015-03-31 | 2015-07-15 | 淮海工学院 | Asymmetric synthesis method of S-carbinoxamine |
-
2015
- 2015-10-29 CN CN201510715622.7A patent/CN105218434A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH583197A5 (en) * | 1973-05-17 | 1976-12-31 | Medimac Sa | |
| US6881744B2 (en) * | 2001-12-14 | 2005-04-19 | Jame Fine Chemicals, Inc. | Carbinoxamine tannate |
| CN104774174A (en) * | 2015-03-31 | 2015-07-15 | 淮海工学院 | Asymmetric synthesis method of S-carbinoxamine |
Non-Patent Citations (1)
| Title |
|---|
| V. BERTOLAS, ET AL: "Crystallographic and Conformational Studies on Histamine H1 Receptor Antagonists. I. Structure of Carbinoxamine Maleate", 《ACTA CRYST.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108420791A (en) * | 2018-05-14 | 2018-08-21 | 山东达因海洋生物制药股份有限公司 | A kind of carbinoxamine maleate oral sustained release suspension and preparation method thereof |
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Application publication date: 20160106 |