CN107162969A - Montelukast sodium crystal and preparation method thereof and pharmaceutical composition - Google Patents
Montelukast sodium crystal and preparation method thereof and pharmaceutical composition Download PDFInfo
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- CN107162969A CN107162969A CN201710540527.7A CN201710540527A CN107162969A CN 107162969 A CN107162969 A CN 107162969A CN 201710540527 A CN201710540527 A CN 201710540527A CN 107162969 A CN107162969 A CN 107162969A
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- montelukast sodium
- sodium crystal
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- menglusitena
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- 0 CC(C)(c1c(CCC(c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(C*)CC2)cccc1)O Chemical compound CC(C)(c1c(CCC(c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(C*)CC2)cccc1)O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention belongs to chemical medicine, and in particular to montelukast sodium crystal and its production and use.The technical problem to be solved in the present invention is that unformed Menglusitena purity is relatively low, draws moist high, low to temperature stability.The scheme that the present invention solves above-mentioned technical problem is to provide the montelukast sodium crystal that a kind of prior art has no report.Present invention also offers the preparation method and its usage of above-mentioned montelukast sodium crystal.The montelukast sodium crystal that the present invention is provided has higher purity, moist, high to the stability of temperature without drawing.
Description
Technical field
The invention belongs to chemical medicine, and in particular to montelukast sodium crystal and its production and use.
Background technology
Menglusitena (Montelukast sodium), entitled [R- (E)] -1- [[[1- [3- [2- (the chloro- 2- of 7- of chemistry
Quinoline) vinyl] phenyl] -3- [2- (1- hydroxyl -1- Methylethyls) phenyl] propyl group] sulphur] methyl] cyclopropaneacetic acid sodium, it is tied
Structure is as shown in Equation 1：
Menglusitena is a kind of oral selective LTRA, can specific half Guang suppressed in air flue
Aminoacyl leukotriene (CysLT1) acceptor, so as to improve airway inflammation, effective Control of asthma symptom.At present, several not isomorphous
The Menglusitena of type has been observed that, such as：International Patent Publication application WO2011033470A1 discloses montelukast sodium crystal
D1, and the preparation method of this crystal is disclosed, using the mixed solvent of dichloromethane and n-hexane to unformed Meng Lusi
Special sodium, which is handled, can obtain Menglusitena crystal D1；And for example：United States Patent (USP) US7560559B2 discloses Menglusitena
Crystal A and B, and preparation method is disclosed, Menglusitena solid is handled using acetonitrile, can be divided under different conditions
Montelukast sodium crystal A or B are not prepared；For another example：United States Patent (USP) US7544805B2 discloses a kind of unformed montelukast
Sodium, and disclose this unformed Menglusitena preparation method, Menglusitena is dissolved in the water, using freeze-drying or
The method of person's spray drying can obtain unformed Menglusitena；For another example：United States Patent (USP) US8450491B2 discloses a kind of without fixed
Type Menglusitena, and this unformed Menglusitena preparation method is disclosed, by montelukast acid and sodium hydroxide in first
Reacted in alcohol, the processing of gained solid n-hexane can obtain unformed Menglusitena.
The content of the invention
The invention provides a kind of new montelukast sodium crystal different from all prior arts, this montelukast
Sodium crystal on the X-ray powder diffraction spectrogram represented with 2 θ, 11.96 ± 0.20 °, 13.43 ± 0.20 °, 15.15 ±
0.20°、16.71±0.20°、17.14±0.20°、17.60±0.20°、18.45±0.20°、19.46±0.20°、19.99
±0.20°、20.58±0.20°、21.84±0.20°、23.60±0.20°、24.68±0.20°、25.61±0.20°、
29.20±0.20°、33.46±0.20°、35.44±0.20°、37.58±0.20°、39.37±0.20°、41.80±0.20°
With characteristic diffraction peak；On differential thermal analysis collection of illustrative plates, there is extrapolated melting point at 161.2 ± 0.5 DEG C.
Present invention also offers the preparation method of above-mentioned montelukast sodium crystal, this method comprises the following steps：
A, Menglusitena solid is added in alcohols solvent, it is complete to be heated to 50~70 DEG C of dissolvings, adds carboxylate
Class solvent；
B, cool to 0 DEG C or so, separate out crystal；
C, crystal is filtered out, dry, obtain the montelukast sodium crystal.
Wherein, in above-mentioned preparation method, alcohols solvent described in step a is times in methanol, ethanol, normal propyl alcohol, isopropanol
What is a kind of.
Wherein, in above-mentioned preparation method, the envelope-bulk to weight ratio of alcohols solvent described in step a and Menglusitena solid is 5
~15: 1.
Wherein, in above-mentioned preparation method, carboxylic acid esters solvent is described in step a：Methyl acetate, ethyl acetate, acetic acid fourth
Any one of ester.
Wherein, in above-mentioned preparation method, the volume ratio of carboxylic acid esters solvent and alcohols solvent described in step a is 2~5:
1。
Present invention also offers the pharmaceutical composition of the montelukast sodium crystal prepared by the above method, said composition is by Meng
Montelukast sodium crystal is constituted with one or more pharmaceutically acceptable auxiliary materials, and concrete composition composition is：The milli of montelukast sodium crystal 5
Gram, 65 milligrams of sodium carboxymethylcellulose, 0.5 milligram of magnesium stearate, 270 milligrams of lactose, 12 milligrams of microcrystalline cellulose, tartaric acid 2
Milligram, 1.5 milligrams of Aspartame and appropriate flavouring.
Present invention also offers the chewable tablet that a kind of aforementioned pharmaceutical compositions are made.
The beneficial effects of the present invention are：The invention provides the montelukast sodium crystal that a kind of prior art has no report
And preparation method thereof, this crystal not only have higher purity, and low in hygroscopicity, to temperature stabilization, be easy to long term storage,
Extend the term of validity of medicine.
Brief description of the drawings
Fig. 1：The X-ray diffracting spectrum of montelukast sodium crystal prepared by the embodiment of the present invention 1.
Fig. 2：The X-ray diffracting spectrum of montelukast sodium crystal prepared by the embodiment of the present invention 2.
Fig. 3：The X-ray diffracting spectrum of montelukast sodium crystal prepared by the embodiment of the present invention 3.
Fig. 4：The X-ray diffracting spectrum of montelukast sodium crystal prepared by the embodiment of the present invention 4.
Fig. 5：The differential thermal analysis collection of illustrative plates of montelukast sodium crystal prepared by the embodiment of the present invention 1.
Fig. 6：The differential thermal analysis collection of illustrative plates of montelukast sodium crystal prepared by the embodiment of the present invention 2.
Fig. 7：The differential thermal analysis collection of illustrative plates of montelukast sodium crystal prepared by the embodiment of the present invention 3.
Fig. 8：The differential thermal analysis collection of illustrative plates of montelukast sodium crystal prepared by the embodiment of the present invention 4.
Embodiment
The invention provides a kind of montelukast sodium crystal and preparation method thereof, while containing the Meng Lusi there is provided a kind of
The pharmaceutical composition of special sodium crystal and the chewable tablet being made up of said composition.Below, by embodiment and accompanying drawing to the present invention
Content be further described.
The preparation of comparative example Menglusitena crude product
With reference to the embodiment 4 in United States Patent (USP) US8450491B2, Menglusitena crude product is prepared for：By 720 grams of hydroxides
Sodium is dissolved in 50 liters of methanol, is cooled under -5 DEG C, stirring and 10 kilograms of montelukast acids are added portionwise, and phase equality of temperature is kept after adding
Stirring reaction 30 minutes are spent, 30 DEG C is then raised temperature to and stirs 30 minutes, 250 grams of activated carbons are added, stirring is removed by filtration after 1 hour
Activated carbon, filtrate is depressurized below 40 DEG C and evaporates methanol, and 80 liters of n-hexanes are added into residue, and 30 DEG C are stirred 1.5 hours,
Filtered under nitrogen atmosphere, solid is washed with 20 liters of n-hexanes, is dried under reduced pressure at 40 DEG C to constant weight, obtains white solid 9.83 thousand
Gram, as Menglusitena crude product.
The preparation of the montelukast sodium crystal of embodiment 1
5 grams of Menglusitena crude product prepared by comparative example is added in 25 ml methanols under agitation, is heated to
50 DEG C, solid all dissolvings are treated, 50 DEG C of 50 milliliters of methyl acetates of dropwise addition is kept, after adding, reduces the temperature to 0 DEG C, be filtered under diminished pressure,
Washed with the methanol/methyl acetate mixed solvent for being cooled to 0 DEG C on a small quantity, solid is placed in depressurize in vacuum drying chamber at room temperature and done
It is dry to arrive constant weight, 3.42 grams of white crystalline powder, as montelukast sodium crystal are obtained, the crystal has following characteristics：With 2
On the X-ray powder diffraction spectrogram that θ is represented, 11.96 °, 13.43 °, 15.15 °, 16.71 °, 17.14 °, 17.60 °,
18.45°、19.46°、19.99°、20.58°、21.84°、23.60°、24.68°、25.61°、29.20°、33.46°、35.44°、
37.58 °, 39.37 °, 41.80 ° have characteristic diffraction peak；On differential thermal analysis collection of illustrative plates, there is extrapolated melting point at 161.2 DEG C.
The preparation of the montelukast sodium crystal of embodiment 2
5 grams of Menglusitena crude product prepared by comparative example is added in 50 milliliters of ethanol under agitation, is heated to
60 DEG C, solid all dissolvings are treated, 60 DEG C of 150 milliliters of ethyl acetates of dropwise addition is kept, after adding, reduces the temperature to 0 DEG C, depressurized
Filter, is washed, solid is placed in vacuum drying chamber at room temperature to be subtracted with the ethanol/ethyl acetate mixed solvent for being cooled to 0 DEG C on a small quantity
Pressure is dried to constant weight, obtains 4.26 grams of white crystalline powder, as montelukast sodium crystal, the crystal has following characteristics：
On the X-ray powder diffraction spectrogram represented with 2 θ, 11.91 °, 13.45 °, 15.11 °, 16.77 °, 17.11 °, 17.62 °,
18.43°、19.47°、19.96°、20.61°、21.89°、23.67°、24.70°、25.68°、29.13°、33.48°、35.47°、
37.52 °, 39.31 °, 41.85 ° have characteristic diffraction peak；On differential thermal analysis collection of illustrative plates, there is extrapolated melting point at 161.1 DEG C.
The preparation of the montelukast sodium crystal of embodiment 3
5 grams of Menglusitena crude product prepared by comparative example is added in 75 milliliters of normal propyl alcohols under agitation, heating
To 70 DEG C, solid all dissolvings are treated, 70 DEG C of 300 milliliters of butyl acetates of dropwise addition is kept, after adding, reduces the temperature to 0 DEG C, depressurized
Filter, is washed, solid is placed in vacuum drying chamber at room temperature with the normal propyl alcohol/butyl acetate mixed solvent for being cooled to 0 DEG C on a small quantity
Constant weight is dried under reduced pressure, 4.55 grams of white crystalline powder, as montelukast sodium crystal is obtained, the crystal has following spy
Levy：On the X-ray powder diffraction spectrogram represented with 2 θ, 11.97 °, 13.47 °, 15.12 °, 16.77 °, 17.14 °,
17.65°、18.48°、19.41°、19.92°、20.53°、21.88°、23.58°、24.62°、25.63°、29.27°、33.48°、
35.44 °, 37.55 °, 39.33 °, 41.85 ° have characteristic diffraction peak；On differential thermal analysis collection of illustrative plates, there is extrapolation at 161.5 DEG C
Fusing point.
The preparation of the montelukast sodium crystal of embodiment 4
5 grams of Menglusitena crude product prepared by comparative example is added in 75 milliliters of isopropanols under agitation, heating
To 70 DEG C, solid all dissolvings are treated, 70 DEG C of 375 milliliters of butyl acetates of dropwise addition is kept, after adding, reduces the temperature to 0 DEG C, depressurized
Filter, is washed, solid is placed in vacuum drying chamber at room temperature with the isopropanol/butyl acetate mixed solvent for being cooled to 0 DEG C on a small quantity
Constant weight is dried under reduced pressure, 4.62 grams of white crystalline powder, as montelukast sodium crystal is obtained, the crystal has following spy
Levy：On the X-ray powder diffraction spectrogram represented with 2 θ, 11.88 °, 13.48 °, 15.11 °, 16.71 °, 17.10 °,
17.60°、18.46°、19.60°、20.01°、20.50°、21.81°、23.61°、24.66°、25.66°、29.28°、33.44°、
35.45 °, 37.52 °, 39.36 °, 41.87 ° have characteristic diffraction peak；On differential thermal analysis collection of illustrative plates, there is extrapolation at 161.0 DEG C
Fusing point.
The preparation of the montelukast sodium crystal of embodiment 5
5000 grams of Menglusitena crude product prepared by comparative example is added in 75 liters of isopropanols under agitation, heating
To 70 DEG C, solid all dissolvings are treated, 70 DEG C of 375 liters of butyl acetates of dropwise addition is kept, after adding, reduces the temperature to 0 DEG C, depressurized
Filter, is washed, solid is placed in vacuum drying chamber at room temperature with the isopropanol/butyl acetate mixed solvent for being cooled to 0 DEG C on a small quantity
Constant weight is dried under reduced pressure, 4708 grams of white crystalline powder, as montelukast sodium crystal is obtained.
The montelukast sodium crystal X-ray diffraction of embodiment 6 is tested
Using the montelukast sodium crystal obtained by embodiment 1~4 as sample, spread out using X ' Pert Pro MRD X-rays
Penetrate instrument (PANalytical, Netherland) to be tested, Cu K α 1 radiate (0.154056nm), graphite monochromator, tube voltage
40kV, tube current 40mA, 20 ° of θ scanning ranges~60 °, 0.01 °/s of sweep speed, 0.01 ° of step-length.Menglusitena is obtained
Crystal X-ray diffracting spectrum (accompanying drawing：Fig. 1~Fig. 4), from Fig. 1~Fig. 4：Montelukast sodium crystal prepared by embodiment
On the X-ray powder diffraction spectrogram represented with 2 θ, 11.96 ± 0.20 °, 13.43 ± 0.20 °, 15.15 ± 0.20 °,
16.71±0.20°、17.14±0.20°、17.60±0.20°、18.45±0.20°、19.46±0.20°、19.99±
0.20°、20.58±0.20°、21.84±0.20°、23.60±0.20°、24.68±0.20°、25.61±0.20°、29.20
± 0.20 °, 33.46 ± 0.20 °, 35.44 ± 0.20 °, 37.58 ± 0.20 °, 39.37 ± 0.20 °, 41.80 ± 0.20 ° has
Characteristic diffraction peak, is differed with the X-ray diffracting spectrum of all montelukast sodium crystals disclosed in prior art.
The montelukast sodium crystal differential thermal analysis of embodiment 7 is tested
Using the montelukast sodium crystal obtained by embodiment 1~4 as sample, using EXSTAR6000 thermomechanical analyzers
(NSK) is tested, and programming rate is 10 DEG C/min, and temperature elevating range is 20 to 290 DEG C.Menglusitena is obtained brilliant
Differential thermal analysis collection of illustrative plates (the accompanying drawing of body：Fig. 5~Fig. 8), from Fig. 5~Fig. 8：Montelukast sodium crystal prepared by embodiment exists
161.2 ± 0.5 DEG C have extrapolated melting point, are differed with the fusing point of all montelukast sodium crystals disclosed in prior art.
The montelukast sodium crystal of embodiment 8 draws moist investigation
The Menglusitena crude product prepared with the montelukast sodium crystal obtained by embodiment 1~4 and comparative examples
For sample, in 25 DEG C of temperature, relative humidity to be placed 24 hours in 80% insulating box, measure draws moist, and measurement result is shown in Table
1, it is seen that montelukast sodium crystal obtained by embodiment 1~4 rate of body weight gain after moist investigation is drawn is respectively less than 0.2%, form without
Change, it is moist without drawing；Menglusitena crude product rate of body weight gain is 18.83%, and outward appearance conglomeration, humidity draw moist very strong.
The montelukast sodium crystal of table 1 draws moist data
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Crude product | |
| Weight (milligram) before experiment | 12525 | 13526 | 11962 | 14164 | 12948 |
| Weight (milligram) after experiment | 12541 | 13548 | 11984 | 14184 | 15386 |
| Rate of body weight gain | 0.13% | 0.16% | 0.18% | 0.14% | 18.83% |
| Outward appearance before experiment | White powder | White powder | White powder | White powder | White powder |
| Outward appearance after experiment | White powder | White powder | White powder | White powder | Conglomeration, humidity |
The Menglusitena crystal temperature effect study on the stability of embodiment 9
The Menglusitena crude product prepared with the montelukast sodium crystal obtained by embodiment 1~4 and comparative examples
For sample, it is positioned in the insulating box of 40 DEG C of temperature and places respectively at the 0th, determines HPLC chromatogram purity within 5,10,30,60 days, survey
Surely 2 be the results are shown in Table, it is seen that the montelukast sodium crystal obtained by embodiment 1~4 is small in the front and rear chromatographic purity change of investigation, greatly
In 99%, illustrate that sample is stablized relatively to temperature；Chromatographic purity of the Menglusitena crude product before and after investigation is declined by 98.06%
To 96.86%, illustrate that sample chromatogram purity is not high, and stability is affected by temperature greatly.
The Menglusitena crystal temperature effect stability data (HPLC normalization methods) of table 2
Pharmaceutical composition of the embodiment 10 containing montelukast sodium crystal and its chewable tablet of preparation
Pharmaceutical composition prescription：
50 grams of montelukast sodium crystal, 650 grams of sodium carboxymethylcellulose, 5 grams of magnesium stearate, the lactose of the preparation of embodiment 5
2700 grams, 120 grams of microcrystalline cellulose, 20 grams of tartaric acid, 15 grams of Aspartame and appropriate flavouring.
Preparation method：
(1) the montelukast sodium crystal and auxiliary material of recipe quantity are added and stirred in preparing tank, that is, obtain medicine group
Compound；
(2) aforementioned pharmaceutical compositions are subjected to tabletting, piece is adjusted to 0.356 gram again, you can obtain 10000 every and contain
The chewable tablet that 5 milligrams of montelukast sodium crystal.
Claims (10)
1. a kind of montelukast sodium crystal, it is characterised in that：The montelukast sodium crystal is in the X-ray powder represented with 2 θ
On diffraction spectrogram, 11.96 ± 0.20 °, 13.43 ± 0.20 °, 15.15 ± 0.20 °, 16.71 ± 0.20 °, 17.14 ±
0.20°、17.60±0.20°、18.45±0.20°、19.46±0.20°、19.99±0.20°、20.58±0.20°、21.84
±0.20°、23.60±0.20°、24.68±0.20°、25.61±0.20°、29.20±0.20°、33.46±0.20°、
35.44 ± 0.20 °, 37.58 ± 0.20 °, 39.37 ± 0.20 °, 41.80 ± 0.20 ° have characteristic diffraction peak.
2. montelukast sodium crystal according to claim 1, it is characterised in that：On differential thermal analysis collection of illustrative plates, 161.2 ±
0.5 DEG C has extrapolated melting point.
3. a kind of preparation method of the montelukast sodium crystal any one of claim 1 to 2, this method includes following step
Suddenly：
A, Menglusitena solid is added in alcohols solvent, it is complete to be heated to 50~70 DEG C of dissolvings, adds carboxylic acid esters molten
Agent；
B, cool to 0 DEG C or so, separate out crystal；
C, crystal is filtered out, dry, obtain the montelukast sodium crystal.
4. the preparation method of montelukast sodium crystal according to claim 3, it is characterised in that：Alcohols described in step a is molten
Agent is any one of methanol, ethanol, normal propyl alcohol, isopropanol.
5. the preparation method of montelukast sodium crystal according to claim 3, it is characterised in that：Alcohols described in step a is molten
The envelope-bulk to weight ratio of agent and Menglusitena solid is 5~15: 1.
6. the preparation method of montelukast sodium crystal according to claim 3, it is characterised in that：Carboxylate described in step a
Class solvent is：Any one of methyl acetate, ethyl acetate, butyl acetate.
7. the preparation method of montelukast sodium crystal according to claim 3, it is characterised in that：Carboxylic acid described in step a
The volume ratio of esters solvent and alcohols solvent is 2~5: 1.
8. a kind of pharmaceutical composition containing montelukast sodium crystal any one of claim 1 to 2, it is characterised in that：
Said composition is as montelukast sodium crystal any one of claim 1 to 2 and one or more pharmaceutically acceptable auxiliary materials
Composition.
9. pharmaceutical composition according to claim 8, it is characterised in that：The constituent of the pharmaceutical composition is：Meng Lu
Special 5 milligrams of the sodium crystal of department, 65 milligrams of sodium carboxymethylcellulose, 0.5 milligram of magnesium stearate, 270 milligrams of lactose, microcrystalline cellulose 12
Milligram, 2 milligrams of tartaric acid, 1.5 milligrams of Aspartame and appropriate flavouring.
10. the chewable tablet that a kind of pharmaceutical composition as described in claim 9 is made.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005075427A2 (en) * | 2004-01-30 | 2005-08-18 | Teva Pharmaceutical Industries Ltd. | Montelukast sodium polymorphs |
| CN1852713A (en) * | 2003-04-15 | 2006-10-25 | 麦克公司 | Polymorphic form of montelukast sodium |
| US7544805B2 (en) * | 2004-02-03 | 2009-06-09 | Chemagis Ltd. | Stable amorphous forms of montelukast sodium |
| KR20100067897A (en) * | 2008-12-12 | 2010-06-22 | 한미약품 주식회사 | Crystalline form of montelukast sodium and method for the preparation thereof |
| WO2011033470A1 (en) * | 2009-09-16 | 2011-03-24 | Ranbaxy Laboratories Limited | Crystalline form of montelukast sodium |
| US8450491B2 (en) * | 2003-06-06 | 2013-05-28 | Morepen Laboratories Limited | Method for the preparation of montelukast acid and sodium salt thereof in amorphous form |
| CN107778228A (en) * | 2016-08-25 | 2018-03-09 | 天津汉瑞药业有限公司 | A kind of exquisite method of Menglusitena |
-
2017
- 2017-07-05 CN CN201710540527.7A patent/CN107162969A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1852713A (en) * | 2003-04-15 | 2006-10-25 | 麦克公司 | Polymorphic form of montelukast sodium |
| US8450491B2 (en) * | 2003-06-06 | 2013-05-28 | Morepen Laboratories Limited | Method for the preparation of montelukast acid and sodium salt thereof in amorphous form |
| WO2005075427A2 (en) * | 2004-01-30 | 2005-08-18 | Teva Pharmaceutical Industries Ltd. | Montelukast sodium polymorphs |
| US7544805B2 (en) * | 2004-02-03 | 2009-06-09 | Chemagis Ltd. | Stable amorphous forms of montelukast sodium |
| KR20100067897A (en) * | 2008-12-12 | 2010-06-22 | 한미약품 주식회사 | Crystalline form of montelukast sodium and method for the preparation thereof |
| WO2011033470A1 (en) * | 2009-09-16 | 2011-03-24 | Ranbaxy Laboratories Limited | Crystalline form of montelukast sodium |
| CN107778228A (en) * | 2016-08-25 | 2018-03-09 | 天津汉瑞药业有限公司 | A kind of exquisite method of Menglusitena |
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