CN104119323A - Amorphous substance of canagliflozin and preparation method of amorphous substance - Google Patents
Amorphous substance of canagliflozin and preparation method of amorphous substance Download PDFInfo
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- CN104119323A CN104119323A CN201310152699.9A CN201310152699A CN104119323A CN 104119323 A CN104119323 A CN 104119323A CN 201310152699 A CN201310152699 A CN 201310152699A CN 104119323 A CN104119323 A CN 104119323A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention discloses an amorphous substance of canagliflozin and a preparation method of the amorphous substance. Through DSC (Differential Scanning Calorimetry) scanning, the amorphous substance is found to have an endothermic peak within the temperature range of 53-63 DEG C and has characteristic absorption peaks at the wavelengths of about 832cm<-1> and 809cm<-1> in an infrared spectrogram. The invention also discloses an application of the amorphous substance to preparation of drugs for treating type-2 diabetes.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to clean amorphous article of a kind of Ka Gelie and preparation method thereof, and the application of this amorphous article aspect medicine.
Background technology
Ka Gelie clean (Canagliflozin), chemistry is by name: 1-(-D-glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienyl methyl) benzene, structure is suc as formula shown in I, and it can disclose method preparation by CN101801371.
A kind of selectivity 2 type sodium glucose cotransporter (SGLT2) inhibitor of Johnson & Johnson company of Ka Gelie Jing Shi U.S. research and development, are mainly used in the treatment of the II type glycosuria patient by moving or keep on a diet invalid.
Ka Gelie belongs to slightly water-soluble compound only, in preparation, generally uses with solid form, therefore the research tool of its crystal formation is of great significance.
Patent CN101573368 discloses the clean semihydrate crystal formation of a kind of Ka Gelie, and it has the 2 θ value tag diffraction peaks such as 4.36o, 13.54 o, 16.00o, 19.32o and 20.80o in the X-ray powder diffraction in CuK α source; This crystal formation by solidifying and obtain in ethyl acetate/diethyl ether/water or acetone/water system.
Patent CN101801371 discloses another kind of crystal formation, and it has the 2 θ value tag diffraction peaks such as 10.9o, 15.5 o, 17.3o, 18.8o and 20.3o in the X-ray powder diffraction in CuK α source; This crystal formation obtains by crystallization in ethyl acetate/normal heptane/aqueous systems.
Because Ka Gelie contains one-D-glucopyranosyl only, make crystallization curing ratio more difficult, current disclosed most methods are all curing for adding a large amount of crystal seeds to induce.
The inventor, in the process of the clean crystal formation of research Ka Gelie, prepares the clean amorphous article of a kind of Ka Gelie, and this amorphous article is the controlled pressed powder of particle diameter, easily preserves, and is conducive to make various preparations.General be unformedly prepared as that spraying is dry, melting and solidification or rapid evaporation solvent solidify etc., these method industrialization costs are higher, and acquire a certain degree of difficulty, bad control.And the unformed preparation method of the present invention is simple, can also play the effect of purifying, and the amorphous article of preparing is different from the amorphous article prepared of appeal general method, more advantage is that this preparation method is applicable to suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the clean amorphous article of a kind of Ka Gelie, this amorphous article preparation technology is easy, chemical stability is good, is suitable for use in several formulations, is more suitable for suitability for industrialized production.
In one embodiment, Ka Gelie of the present invention is only unformed, and its X-ray powder diffraction has feature as shown in Figure 1.
In the above-described embodiment, Ka Gelie of the present invention is only unformed, and its DSC scanning has an endotherm(ic)peak between 53～63 DEG C, particularly reaches peak value (endotherm(ic)peak) at approximately 58 DEG C, wherein " approximately " representative
+0.1 error.
In the above-described embodiment, Ka Gelie of the present invention is only unformed, and its infrared absorption is about 832cm
-1and 809cm
-1there is charateristic avsorption band.
In a preferred embodiment, Ka Gelie of the present invention is only unformed, and its X-ray powder diffraction has feature as shown in Figure 1, and its DSC scanning reaches peak value at 57.9 DEG C, and its infrared absorption is about 832cm
-1and 809cm
-1there is charateristic avsorption band.
The X-ray powder diffraction analysis of the clean amorphous article of Ka Gelie of the present invention is under envrionment temperature and ambient moisture, has measured through the CuK α source (α=1.5406) of Japanese Shimadzu XRD-6000 type x-ray diffractometer." envrionment temperature " is generally 0～40 DEG C; " ambient moisture " is generally 30%～80% relative humidity.
The TG-DSC analysis condition of the clean amorphous article of Ka Gelie of the present invention is under envrionment temperature and ambient moisture, completes through Switzerland Mettler 1100LF type instrument test.Purge with the flow velocity of 50ml/min with high-purity Ar gas, carry out temperature programming with the speed of 10 DEG C/min, intensification scope is that room temperature to 400 DEG C is tested." envrionment temperature " is generally 0～40 DEG C; " ambient moisture " is generally 30%～80% relative humidity.
The IR spectroscopic analysis that lattice of the present invention are listed as clean amorphous article is that the Fourier transformation infrared spectrometer (Nicolet Atavar FT-IR330) through Nicolet company of the U.S. is generally less than 80% in relative humidity, and temperature is generally test at 15～30 DEG C.When test, carry out compressing tablet with KBr, spectrophotometer is proofreaied and correct (wavelength) with polystyrene.
Lattice provided by the invention are listed as the representational IR spectrum atlas of clean amorphous article and list in accompanying drawing 3." representational IR spectrum atlas " refers to that the IR spectrum atlas feature of this crystal formation meets the overall pattern that this collection of illustrative plates shows, be understandable that in test process, due to be subject to many factors (as grind granular size, compressing tablet degree and airborne relative humidity etc.) impact, measured IR spectrum atlas go out peak position or peak intensity has certain difference.Can be ± 2 cm of the experimental error of the characteristic absorbance peak value in IR spectrum atlas
-1." approximately " in above-mentioned infrared data is error ± 2 cm
-1.
Object of the present invention also provides the clean unformed preparation method of a kind of Ka Gelie, and the method comprises solidifies out it by joining containing the clean solution of Ka Gelie in anti-solvent.
In one embodiment, the clean unformed preparation method of Ka Gelie, comprises the following steps:
1) Ka Gelie clean (comprising dry product or wet product) is dissolved with suitable good solvent, obtain the clean solution of Ka Gelie, wherein, solvent temperature is 0～100 DEG C, preferably 20～60 DEG C;
2) by joining in clean Ka Gelie solution in suitable anti-solvent, it is solidified out, solidification value is-20～50 DEG C, preferably 0～40 DEG C;
3) solid of separating out is filtered or centrifugation;
4) optional, the solid that separation is obtained is dried, and drying temperature is generally 20～60 DEG C, and preferably 30～50 DEG C, can constant pressure and dry, also can drying under reduced pressure, when decompression, vacuum tightness is generally 300～760mmHg, preferably 600～760mmHg.
In the above-described embodiment, method of the present invention, in step 1), said suitable good solvent comprises ethyl acetate, toluene, ethanol, methyl alcohol, acetone, methylene dichloride, tetrahydrofuran (THF) etc. or their mixture, ethyl acetate, toluene or their mixture; Step 2) in said suitable anti-solvent comprise normal hexane, hexanaphthene, normal heptane, sherwood oil, methyl tertiary butyl ether, isopropyl ether or their mixture, preferably normal hexane, hexanaphthene or their mixture.
In the above-described embodiment, method of the present invention, solidifying that Ka Gelie is clean is generally to complete under agitation condition.
General obtain unformed method and have that spraying is dry, melting and solidification and rapid evaporation solvent solidify, wherein spraying is dry to equipment requirements harshness, industrialization cost is high; Melting and solidification condition is violent, larger to the quality influence of product; Rapid evaporation solvent solidifies comparatively difficulty of control of industrialization; And amorphous article preparation technology of the present invention is easy, adopt common equipment and mild conditions just can complete, be suitable for suitability for industrialized production.
For the prepared unformed difference to some extent of the clean amorphous article of Ka Gelie of the present invention and above-mentioned general unformed preparation method is described, the inventor has chosen and has compared by the curing prepared amorphous article of above comparatively practical rapid evaporation solvent, and comparative result is as follows:
Above-mentioned test-results shows, the clean unformed stability of Ka Gelie of the present invention is obviously better than quick solvent flashing and solidifies prepared unformed.
Another object of the present invention is to provide the purposes of the clean unformed treatment diabetes of Ka Gelie, i.e. the clean unformed application manufacturing in preparation treatment type ii diabetes or type i diabetes medicine of Ka Gelie.
A further object of the present invention has been to provide a kind of pharmaceutical composition, contains the clean unformed and pharmaceutical excipient of Ka Gelie.
Specifically, pharmaceutical composition of the present invention, is generally unformedly to make pharmaceutical composition or preparation with one or more pharmaceutical excipients by clean the Ka Gelie for the treatment of significant quantity, and the mode that this pharmaceutical composition or preparation can pharmacy field be known is prepared.
Said preparation comprises: tablet, capsule, drageeing, granule, Sublingual tablet, injectable formulation, drinkable suspensoid and disintegratable paste etc. are suitable for formulation oral, that enteron aisle outer (intravenously or subcutaneous) uses.Described composition or the dosage of preparation are adjusted according to the character of disease and seriousness, route of administration and patient's age, body weight etc., change, in single or divided doses in every day between 10mg to 1g.
When being solid orally ingestible, the pharmaceutical composition of the invention described above can contain conventional vehicle, such as weighting agent, glidant, lubricant, tackiness agent etc., can carry out if desired different dressings, described weighting agent generally comprises Microcrystalline Cellulose, pregelatinized Starch, lactose, Icing Sugar, N.F,USP MANNITOL, secondary calcium phosphate, calcium sulfate etc.They can use separately also can mix use, wherein preferably microcrystalline cellulose, pregelatinized Starch, lactose, described glidant agent generally comprises micropowder silica gel, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Xylo-Mucine, agar, calcium carbonate and sodium bicarbonate etc., they can use separately also can mix use, wherein be preferably micropowder silica gel, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, described lubricant generally comprises talcum powder, stearic acid, Magnesium Stearate, calcium stearate, palmitinic acid, pure aluminium silicate, stearylamide, talcum powder, solid ethylene glycol, silicon-dioxide.They can use separately also can mix use, wherein preferably talc powder, stearic acid, Magnesium Stearate, magnesium calcium stearate, described tackiness agent generally comprises the ethanolic soln of polyvidone, Microcrystalline Cellulose, hydroxypropylcellulose, starch slurry, Vltra tears, polyvinyl alcohol, water, various concentration, and they can use separately also can mix use.Wherein preferred polyvidone, Microcrystalline Cellulose, Vltra tears.If necessary, can also in pharmaceutical composition of the present invention, add other auxiliary materials, as sweeting agent, tinting material, odor mask, stablizer.
The pharmaceutical composition of the invention described above can be prepared according to preparing any ordinary method that oral solid formulation adopts, as: encapsulated after wet granule compression tablet, direct powder compression, granulation.Use conventional coating device, can, by this pharmaceutical composition coating, make film coated tablet or sugar coated tablet.Coated substrate comprises cellulose family, crylic acid resin, carbohydrate, as Vltra tears, EudragAt L, sucrose.In this coated substrate, also can add softening agent, antisticking agent, opalizer.Solid composite medicament of the present invention can be by carrying out granulation step, encapsulation step or film-making step and coating steps (if necessary) obtains with routine dose form successively, is generally tablet, powder, the granule of tablet or surface coatings, granule or the capsule dosage form of surface coatings.
The pharmaceutical composition of the invention described above can be prepared by pharmaceutics routine techniques.As capsule can adopt powder directly encapsulated encapsulated with wet granulation.
The experiment proved that, in the clean unformed preparation at preparation of Ka Gelie of the present invention and storage, keep satisfactory stability and pharmaceutical activity.
The pharmaceutical composition of the invention described above or preparation are mainly used in treatment but are not limited to by moving or keep on a diet invalid type ii diabetes.
Ka Gelie of the present invention is clean, and unformed to have preparation method easy, and the advantages such as satisfactory stability and preparation adaptability, have industrialization practicality.
Because Ka Gelie belongs to insoluble drug only, control size and contribute to improve dissolution rate, the Ka Gelie preparing according to method of the present invention is clean, its epigranular, volume average particle size, between 10-100um, has larger meaning to dissolution rate and the bioavailability of improving its preparation.
Brief description of the drawings
Fig. 1 is the x-ray diffraction pattern of the clean amorphous article of Ka Gelie of the present invention.
Fig. 2 is the TG-DSC figure of the clean amorphous article of Ka Gelie of the present invention.
Fig. 3 is the clean amorphous article infrared spectrogram of Ka Gelie of the present invention.
Fig. 4 is the particle size distribution figure of the clean amorphous article of Ka Gelie of the present invention.
Fig. 5 is that rapid evaporation solvent obtains the clean unformed x-ray diffraction pattern of Ka Gelie.
Fig. 6 is that rapid evaporation solvent obtains the clean unformed TG-DSC figure of Ka Gelie.
Embodiment
Below in conjunction with embodiment, the invention will be further described, can make those skilled in the art more fully understand the present invention, but the scope not limiting the present invention in any way.
embodiment 1
The clean unformed preparation of Ka Gelie
Clean 50～60 DEG C of 20g Ka Gelie is dissolved in 80ml ethyl acetate, under room temperature, is added drop-wise in 160ml cyclohexane solution, and stir on dropping limit, limit, dropwises rear room temperature and continues to stir 1h, separates out solid, filters; Filter cake is the dry clean unformed 18g of get Ka Gelie at 30～40 DEG C, HPLC:99.5%.Test X-ray powder diffraction, result is as Fig. 1; Test TG-DSC, result is as Fig. 2; Test infrared spectra, result is as Fig. 3; Test granularity, result is as Fig. 4.
embodiment 2(comparative example)
The clean unformed preparation of Ka Gelie
Clean 30～40 DEG C of 10g Ka Gelie is dissolved in 100ml ethyl acetate, and 40～50 DEG C of explosive decompressions boil off solvent and obtain pressed powder; The clean amorphous article 9.9g of drying under reduced pressure get Ka Gelie at 40～50 DEG C, HPLC:99.5%.Test X-ray powder diffraction, result is as Fig. 5; Test TG-DSC, result is as Fig. 6.
?
embodiment 3
The clean unformed preparation of Ka Gelie
Clean 20～30 DEG C of 50g Ka Gelie is dissolved in 300ml toluene, under stirring, is added drop-wise to interior temperature and is in the 150ml hexane solution of 0～10 DEG C, and after dropwising, 0～10 DEG C is continued to stir 0.5h, separates out solid, filters; The clean amorphous article 43g of filter cake drying under reduced pressure get Ka Gelie at 40～50 DEG C, HPLC:99.7%.
The unformed feature with Fig. 1-3 of gained.
embodiment 4
The clean unformed preparation of Ka Gelie
In clean 30～40 DEG C of mixing solutionss that are dissolved in 200ml toluene and 100ml ethyl acetate of 50g Ka Gelie, under stirring, be added drop-wise to interior temperature and be in the mixing solutions of the 100ml normal hexane of 30～40 DEG C and 100ml hexanaphthene, dropwise rear room temperature and continue to stir 2h, separate out solid, filter; The clean amorphous article 40g of filter cake drying under reduced pressure get Ka Gelie at 40～50 DEG C, HPLC:99.8%.The unformed feature with Fig. 1-3 of gained.
embodiment 5
The clean capsule of Ka Gelie
Prepare the prescription of 1000 seed lac wafers, every dosage that contains 100mg:
The clean unformed 100g of Ka Gelie
Microcrystalline Cellulose 300g
Differential silica gel 17g
Talcum powder 15g
Preparation method:
Card taking lattice are listed as clean amorphous article and first carry out premix with Microcrystalline Cellulose, then micropowder silica gel, talcum powder are added in above-mentioned Preblend and are mixed, and cross 60 mesh sieves, remix, and weight is carried out capsule-filling in accordance with regulations.
Claims (10)
1. Yi Zhong Ka Gelie is only unformed, and base is characterised in that its X-ray powder diffraction has the feature as Fig. 1, and its DSC scanning has an endotherm(ic)peak between 53～63 DEG C, particularly.
2. as claimed in claim 1 unformed, its DSC scanning has endotherm(ic)peak at approximately 58 DEG C.
3. as claimed in claim 1 unformed, its infared spectrum is about 832cm
-1and 809cm
-1there is charateristic avsorption band.
4. prepare the clean unformed method of Ka Gelie, comprise the following steps:
1) Ka Gelie is dissolved only in suitable solvent, solvent temperature is 0～100 DEG C, obtains the clean solution of Ka Gelie;
2) clean Ka Gelie solution is joined in suitable anti-solvent, stir, separate out solid, solidification value is-20～50 DEG C;
3) solid of separating out is filtered or centrifugation;
4) optional, the solid that separation is obtained is dried, and drying temperature is 20～60 DEG C, preferably can constant pressure and dry, also can drying under reduced pressure, and when decompression, vacuum tightness is generally 300～760mmHg, preferably 600～760mmHg.
5. method as claimed in claim 4, the solvent temperature in step 1) is 20～60 DEG C, step 2) in solidification value be 0～40 DEG C.
6. method as claimed in claim 4, the drying temperature in step 4) is 30～50 DEG C, vacuum tightness is 600～760mmHg.
7. the method as described in claim 3 or 4, described suitable good solvent is selected from ethyl acetate, toluene, ethanol, methyl alcohol, acetone, methylene dichloride, tetrahydrofuran (THF) and their mixture.
8. the method as described in claim 3 or 4, described suitable anti-solvent is selected from normal hexane, hexanaphthene, normal heptane, sherwood oil, methyl tertiary butyl ether, isopropyl ether and their mixture.
9. method as claimed in claim 7, described suitable good solvent is ethyl acetate, toluene or their mixture.
10. method as claimed in claim 7, described suitable anti-solvent is normal hexane, hexanaphthene or their mixture.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
| CN105541817A (en) * | 2016-02-20 | 2016-05-04 | 浙江华海药业股份有限公司 | Method for preparing amorphous canagliflozin through heat treatment |
| CN106317188A (en) * | 2015-06-18 | 2017-01-11 | 重庆医药工业研究院有限责任公司 | Method for preparing amorphous substance of carfilzomib |
| WO2017036389A1 (en) * | 2015-09-02 | 2017-03-09 | 常州方楠医药技术有限公司 | Composition of canagliflozin and pharmaceutical excipient, and preparation method therefor |
| WO2017084644A1 (en) | 2015-11-20 | 2017-05-26 | Zentiva, K.S. | A crystalline form of canagliflozin and a method of its preparation |
| WO2018149327A1 (en) | 2017-02-20 | 2018-08-23 | 浙江华海药业股份有限公司 | Method for preparing canagliflozin amorphous form |
| EP3262039A4 (en) * | 2015-02-27 | 2018-11-14 | MSN Laboratories Private Limited | Process for the preparation of amorphous (1s)-1,5-anhvdro-1-[3-[[5-(4 fluorophennyl)-2-thienyl]methvl]-4-methylphenyl]-d-glucitol and its polymorphs thereof |
| US11857559B2 (en) | 2018-09-10 | 2024-01-02 | Aurobindo Pharma Ltd. | Pharmaceutical composition comprising Canagliflozin, process of preparation and use thereof |
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2013
- 2013-04-28 CN CN201310152699.9A patent/CN104119323A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
| EP3262039A4 (en) * | 2015-02-27 | 2018-11-14 | MSN Laboratories Private Limited | Process for the preparation of amorphous (1s)-1,5-anhvdro-1-[3-[[5-(4 fluorophennyl)-2-thienyl]methvl]-4-methylphenyl]-d-glucitol and its polymorphs thereof |
| CN106317188A (en) * | 2015-06-18 | 2017-01-11 | 重庆医药工业研究院有限责任公司 | Method for preparing amorphous substance of carfilzomib |
| WO2017036389A1 (en) * | 2015-09-02 | 2017-03-09 | 常州方楠医药技术有限公司 | Composition of canagliflozin and pharmaceutical excipient, and preparation method therefor |
| WO2017084644A1 (en) | 2015-11-20 | 2017-05-26 | Zentiva, K.S. | A crystalline form of canagliflozin and a method of its preparation |
| CN105541817A (en) * | 2016-02-20 | 2016-05-04 | 浙江华海药业股份有限公司 | Method for preparing amorphous canagliflozin through heat treatment |
| WO2018149327A1 (en) | 2017-02-20 | 2018-08-23 | 浙江华海药业股份有限公司 | Method for preparing canagliflozin amorphous form |
| CN110431137A (en) * | 2017-02-20 | 2019-11-08 | 浙江华海药业股份有限公司 | A kind of unformed preparation method of canagliflozin |
| EP3584247A4 (en) * | 2017-02-20 | 2019-12-25 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing canagliflozin amorphous form |
| US11008357B2 (en) | 2017-02-20 | 2021-05-18 | Zhejiang Huahai Pharmaceutical Co., Ltd. (Cn) | Method for preparing canagliflozin amorphous form |
| US11857559B2 (en) | 2018-09-10 | 2024-01-02 | Aurobindo Pharma Ltd. | Pharmaceutical composition comprising Canagliflozin, process of preparation and use thereof |
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Application publication date: 20141029 |