CN103073542A - Preparation method and application of tropisetron citrate crystal form II - Google Patents
Preparation method and application of tropisetron citrate crystal form II Download PDFInfo
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- CN103073542A CN103073542A CN2013100292594A CN201310029259A CN103073542A CN 103073542 A CN103073542 A CN 103073542A CN 2013100292594 A CN2013100292594 A CN 2013100292594A CN 201310029259 A CN201310029259 A CN 201310029259A CN 103073542 A CN103073542 A CN 103073542A
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- tropisetron
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Abstract
The invention discloses a preparation method and an application of a tropisetron citrate crystal form II. The tropisetron citrate crystal form II is obtained through selecting from different crystal solvents and temperatures. The tropisetron citrate crystal form is simple in preparation technology, and has good stability; a sample prepared with the method can effectively reduce residual quantity of introduced solvents, such as methylbenzene, trichloromethane and pyridine in a synthesis process; product purity is better; and industrial production is facilitated.
Description
Technical field
The invention belongs to medicine and biological field, relate to novel antiemetic tropisetron citrate crystal form II preparation method and the application in drug development thereof of the nausea and vomiting that a kind of prevention and treatment cancer chemotherapy cause.
Background technology
Tropisetron hydrochloride (Tropisetron hydrochloride, external trade(brand)name: Navoban), developed by Switzerland Novartis Co.,Ltd, it is a kind of efficient, selectivity 5-HT3 receptor antagonist, its hydrochloride preparation is mainly used in preventing and treating the nausea and vomiting that tumour patient is caused by chemotherapy, radiotherapy or postoperative in Holland's listing in 1992.This medicine oral absorption is complete rapidly, and tolerance is good, without the extrapyramidal system untoward reaction, can be used as the choice drug of cancer Radiotherapy chemotherapy patient emesis.Along with the end of protection period, domesticly begin imitated research,
Fuzhou Pharmaceutical Co., Ltd., Tongyinbi GroupIndependent research has obtained the patent of tropisetron citrate, and raw material and preparation are the whole nation and produce without competition.The tropisetron citrate curative effect is equal to Tropisetron hydrochloride, compares hydrochloride, has better stability, and its injection liquid can adopt excessive method sterilization, and the related substance of product obviously reduces, and aseptic guarantee is also higher, has more reliably quality.Chemistry is by name: 8-methyl-8-azabicyclo [3,2,1]-3 α-octane-1H-Indole-3-Carboxylic Acid ester citrate, and its molecular structural formula is as follows:
The present patent application people is disclosed in Chinese patent 200910114940 namely
Fuzhou Pharmaceutical Co., Ltd., Tongyinbi GroupA kind of synthesis technique of tropisetron citrate, but unformed for crystal formation, and existing document all crystal formation and the preparation method of unexposed tropisetron citrate, the spectral response curve of more not mentioned relevant crystal formation.We find that tropisetron citrate has multiple crystal formation now, i.e. crystalline form I and crystal form II.
Drug crystal forms is directly connected to drug effect and drug safety, and is no matter for the still research of imitated medicine of original new drug, all significant.The different crystal forms of same medicine often has different physico-chemical properties such as stability and solubleness etc., and the research of drug crystal forms is significant to guaranteeing stability and the safety and effectiveness in the clinical use in the pharmaceutical production storage process.Which kind of crystallographic system the crystal formation of medicine belongs to, which kind of lattice structure is relevant with drug molecular structure, and cooling when the used solvent species of crystallisation process, strength of solution, crystallization, velocity of evaporation, drying means etc. all have relation during simultaneously also with preparation.
Summary of the invention
Have not yet to see tropisetron citrate crystal form II preparation method's bibliographical information.The purpose of this invention is to provide the tropisetron citrate crystal formation method that preparation is simple, yield is high, purity is high, and the application of this crystal formation in drug development.
One of technical solution of the present invention: a kind of tropisetron citrate crystal form II, it uses the Cu-Ka radiation, with angle of diffraction 2 θ (°), interplanar distance d() and relative abundance I/I
oThe X-ray powder diffraction of expression has following characteristic peak:
The infrared spectra that this crystal formation is characterized in that measuring with pressing potassium bromide troche is at 3268cm
-1, 3124 cm
-1, 2965 cm
-1, 2889 cm
-1, 2729 cm
-1, 1737 cm
-1, 1666 cm
-1, 1539 cm
-1, 1530 cm
-1, 1500 cm
-1, 1477 cm
-1, 1437 cm
-1, 1392 cm
-1, 1362 cm
-1, 1314 cm
-1, 1251 cm
-1, 1210 cm
-1, 1189 cm
-1, 1170cm
-1, 1128cm
-1, 1105cm
-1, 1079cm
-1, 1063cm
-1, 1037cm
-1, 1024cm
-1, 972cm
-1, 916cm
-1, 808cm
-1, 781cm
-1, 754cm
-1, 716cm
-1, 663cm
-1, 631cm
-1, 592cm
-1, 553cm
-1, 493cm
-1, 466cm
-1, 429cm
-1There is charateristic avsorption band at the place;
This crystal formation differs from formula scanning calorimetric analysis, from 203.2
OCBegin to have a sharp-pointed endotherm(ic)peak, peak temperature is 209.5
oC.
Two of technical solution of the present invention: the preparation method of described a kind of tropisetron citrate crystal form II, described method comprises the steps:
(1) tropisetron citrate is dissolved in about 20 ~ 80
oIn the water that contains acetone 10 ~ 70% of C;
(2) crystallization or stirring and crystallizing are placed in cooling, or directly 20 ~ 60
oGet crystal after the C solvent evaporated under reduced pressure;
(3) the crystalliferous solution filter of step (2) gained is 40 ~ 105
oC dry 1 ~ 4 hour, gets the dry product of tropisetron citrate.
Preferably: recrystallization temperature is controlled at 0 ~ 20 in the described step (2)
OC
Described step (3) is carried out drying and is obtained the tropisetron citrate crystallisate under following condition: 40 ~ 105
oC dry 1 ~ 4 hour, gets the dry product of tropisetron citrate.
Solvent in the described step (1) is to contain acetone to surpass 10% the aqueous solution, and the used suitable temperature of dissolution sample is 40 ~ 70
oC.
Three of technical solution of the present invention: a kind of pharmaceutical composition, it contains described tropisetron citrate crystal form II and one or more pharmaceutical excipients.
Described pharmaceutical composition is oral solid preparation and liquid infusion agent.
Described oral solid preparation comprises tablet, capsule and granule, wherein contains tropisetron citrate crystal form II 8.38mg in the per unit preparation, is equivalent to tropisetron 5mg; The injection liquid specification is that 5ml contains tropisetron citrate crystal form II 8.38mg, is equivalent to tropisetron 5mg.
The preparation method of above-mentioned tropisetron citrate crystal form II provided by the invention, technique is simple, and yield is high, and cost is low, and is environmentally friendly, is more suitable in suitability for industrialized production, and products obtained therefrom purity reaches more than 98.5%, and dissolvent residual meets the Chinese Pharmacopoeia requirement.
The crystal form II related substance of high-performance liquid chromatogram determination aforesaid method preparation, impurity has no obvious increase, the gas Chromatographic Determination dissolvent residual, do not detect trichloromethane, pyridine, tetrahydrofuran (THF), methylene dichloride, dioxane and toluene level are lower than 0.01%, and methyl alcohol, ethanol, acetone content are lower than 0.1%.
The tropisetron citrate crystal form II that the present invention makes all has satisfactory stability, and it is more effective than the synthetic middle dissolvent residual that uses of alone water recrystallization removal that use contains the alcoholic solvent recrystallization.The present invention has a good application prospect in preparation Antiemetics tropisetron citrate.
The present invention also provides the application of above-mentioned tropisetron citrate crystal form II in pharmaceutical preparation.Tropisetron citrate crystal form II and pharmaceutical excipient are made pharmaceutical preparation, be oral solid preparation or injection liquid, such as tablet, capsule, granule or injection liquid etc., medicinal tax material is one or more in following: lactose, Microcrystalline Cellulose, hydroxypropylcellulose, carboxymethyl cellulose, N.F,USP MANNITOL, Magnesium Stearate, sodium-chlor, water etc. wherein contain tropisetron citrate crystal form II 8.38mg in the per unit preparation.
The preparation of tropisetron citrate crystal form II of the present invention, used recrystallisation solvent is mainly the aqueous solution that contains acetone, cost is lower, technique is simple, the solvent for use security is good, and effectively reduces the residual quantities in finished product such as the larger tetrahydrofuran (THF) of the synthetic middle toxicity of using, toluene, trichloromethane.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrogram of a kind of tropisetron citrate crystal form II of the present invention.
Fig. 2 is the infrared absorpting light spectra of a kind of tropisetron citrate crystal form II of the present invention.
Fig. 3 is the poor formula scanning amount thermogram of a kind of tropisetron citrate crystal form II of the present invention.
Embodiment
Below with the implementation example technical scheme of the present invention is described, but protection scope of the present invention is not limited to this.
The preparation of embodiment 1 tropisetron citrate crystal form II
Get tropisetron citrate raw material 1.0g, add 20% acetone water, 20 ~ 50ml, bath temperature is not higher than 60
OCStirring and dissolving, cooling keeps 10
OCFollowing crystallization, crystallization time are no less than 2 hours, and after crystallization finished, suction filtration separated, and gets the tropisetron citrate solid, in 60
oC ~ 80
OC, dried by the fire first 0.5 ~ 1 hour, again 90
OC~ 105
OCDry 1-2 hour and get final product.Gained tropisetron citrate crystal form II X-diffracting spectrum, infrared spectrogram and poor formula scanning amount thermal map and accompanying drawing 1, accompanying drawing 2, accompanying drawing 3 are consistent.
Tablet and the preparation thereof of embodiment 2 tropisetron citrate crystal form IIs
Prescription: tropisetron citrate crystal form II 8.38g, lactose 70g, Microcrystalline Cellulose 40g, hydroxypropylcellulose 10 g, carboxymethylstach sodium 6 g, Magnesium Stearate 9 g, polyethylene glycol 6000 6 g, the 5% polyvidone aqueous solution is an amount of.
Method for making: above raw material is taken by weighing by above amount behind 80 mesh sieves respectively excessively, then tropisetron citrate, lactose, hydroxypropylcellulose, polyethylene glycol 6000 and the 20g Microcrystalline Cellulose with recipe quantity mixes, with 5% polyvidone aqueous solution softwood processed, crossing 20 mesh sieves granulates, again oven dry, whole grain, then carboxymethylstach sodium, the Magnesium Stearate with 20g Microcrystalline Cellulose, recipe quantity mixes, be pressed into 1000, namely get the tablet of tropisetron citrate crystal form II, every contains tropisetron citrate 8.38mg, counts 5mg with tropisetron.
Embodiment 3 contains capsule and the preparation thereof of tropisetron citrate crystal form II
Prescription: tropisetron citrate crystal form II 8.38g, lactose 50g, Microcrystalline Cellulose 60g, sodium starch glycolate 30g, Magnesium Stearate 1g.
Method for making: the lactose in above-mentioned, Microcrystalline Cellulose, sodium starch glycolate were pulverized respectively 100 mesh sieves, in 100
oC is dry more than 10 hours, be chilled to room temperature, mix with tropisetron citrate, dry granulation adds Magnesium Stearate, mixing, be filled in 1000 Capsuleses, both got the capsule of tropisetron citrate crystal form II, every capsules contains tropisetron citrate crystal form II 8.38mg, counts 5mg with tropisetron.
Embodiment 4 contains tropisetron citrate crystal form II injection and preparation thereof
Prescription: tropisetron citrate crystal form II 8.38g, activated carbon 1.5g, water for injection adds to 1000ml.
Method for making: take by weighing tropisetron citrate crystal form II 8.38g, join 70
oC ~ 80
oAmong C water for injection 500 ml, after stirring makes dissolving, add gac 1.5 g, stir evenly, be heated to 100
oC is incubated 15 min, and filtering decarbonization is added water for injection to 1000 ml, after stirring evenly, transfers in right amount pH value to 4.5 with 10% citric acid soln, stirs evenly, smart filter, embedding in 5 ml ampoules, 115
oC pressure sterilizing 30 min after the visible foreign matters passed examination, pack and get final product.
More than implement only to be used for further explaining the present invention, be not used in the restriction that also should not be understood to claim among the present invention.
Claims (8)
1. tropisetron citrate crystal form II, it uses the Cu-Ka radiation, with angle of diffraction 2 θ (°), interplanar distance d() and relative abundance I/I
oThe X-ray powder diffraction of expression has following characteristic peak:
The infrared spectra that this crystal formation is characterized in that measuring with pressing potassium bromide troche is at 3268cm
-1, 3124 cm
-1, 2965 cm
-1, 2889 cm
-1, 2729 cm
-1, 1737 cm
-1, 1666 cm
-1, 1539 cm
-1, 1530 cm
-1, 1500 cm
-1, 1477 cm
-1, 1437 cm
-1, 1392 cm
-1, 1362 cm
-1, 1314 cm
-1, 1251 cm
-1, 1210 cm
-1, 1189 cm
-1, 1170cm
-1, 1128cm
-1, 1105cm
-1, 1079cm
-1, 1063cm
-1, 1037cm
-1, 1024cm
-1, 972cm
-1, 916cm
-1, 808cm
-1, 781cm
-1, 754cm
-1, 716cm
-1, 663cm
-1, 631cm
-1, 592cm
-1, 553cm
-1, 493cm
-1, 466cm
-1, 429cm
-1There is charateristic avsorption band at the place;
This crystal formation differs from formula scanning calorimetric analysis, from 203.2
OCBegin to have a sharp-pointed endotherm(ic)peak, peak temperature is 209.5
oC.
2. a preparation method who prepares a kind of tropisetron citrate crystal form II as claimed in claim 1 is characterized in that described method comprises the steps:
(1) tropisetron citrate is dissolved in about 20 ~ 80
oIn the water that contains acetone 10 ~ 70% of C;
(2) crystallization or stirring and crystallizing are placed in cooling, or directly 20 ~ 60
oGet crystal after the C solvent evaporated under reduced pressure;
(3) the crystalliferous solution filter of step (2) gained is 40 ~ 105
oC dry 1 ~ 4 hour, gets the dry product of tropisetron citrate.
3. the preparation method of a kind of tropisetron citrate crystal form II as claimed in claim 2 is characterized in that recrystallization temperature is controlled at 0 ~ 20 in the described step (2)
OC
4. the preparation method of a kind of tropisetron citrate crystal form II as claimed in claim 2 is characterized in that described step (3) carries out drying and obtain the tropisetron citrate crystallisate under following condition: 40 ~ 105
oC dry 1 ~ 4 hour, gets the dry product of tropisetron citrate.
5. the preparation method of a kind of tropisetron citrate crystal form II as claimed in claim 2 is characterized in that the solvent in the described step (1) is to contain acetone to surpass 10% the aqueous solution, and the used suitable temperature of dissolution sample is 40 ~ 70
oC.
6. pharmaceutical composition, it contains tropisetron citrate crystal form II claimed in claim 1 and one or more pharmaceutical excipients.
7. pharmaceutical composition as claimed in claim 6 is characterized in that described pharmaceutical composition is oral solid preparation and liquid infusion agent.
8. pharmaceutical composition as claimed in claim 7 is characterized in that described oral solid preparation comprises tablet, capsule and granule, wherein contains tropisetron citrate crystal form II 8.38mg in the per unit preparation, is equivalent to tropisetron 5mg; The injection liquid specification is that 5ml contains tropisetron citrate crystal form II 8.38mg, is equivalent to tropisetron 5mg.
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| CN201310029259.4A CN103073542B (en) | 2013-01-25 | 2013-01-25 | Preparation method and application of tropisetron citrate crystal form II |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408543A (en) * | 2013-08-12 | 2013-11-27 | 回音必集团抚州制药有限公司 | High purity citric acid and navoban compound |
| CN104971050A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection |
| CN105055334A (en) * | 2015-09-18 | 2015-11-18 | 青岛华之草医药科技有限公司 | Postoperative antiemetic tropisetron hydrochloride composition granule |
| CN105078916A (en) * | 2015-09-15 | 2015-11-25 | 青岛华之草医药科技有限公司 | Vomit-stopping drug tropisetron hydrochloride composition tablet |
| CN105168212A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine tropisetron hydrochloride composition for treating nausea and emesis |
| CN105193737A (en) * | 2015-09-21 | 2015-12-30 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition dry suspension for treating nausea and emesis |
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| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN102351857A (en) * | 2011-08-23 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
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2013
- 2013-01-25 CN CN201310029259.4A patent/CN103073542B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN102351857A (en) * | 2011-08-23 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408543A (en) * | 2013-08-12 | 2013-11-27 | 回音必集团抚州制药有限公司 | High purity citric acid and navoban compound |
| CN103408543B (en) * | 2013-08-12 | 2014-02-12 | 回音必集团抚州制药有限公司 | High purity citric acid and navoban compound |
| CN104971050A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection |
| CN105168212A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine tropisetron hydrochloride composition for treating nausea and emesis |
| CN105078916A (en) * | 2015-09-15 | 2015-11-25 | 青岛华之草医药科技有限公司 | Vomit-stopping drug tropisetron hydrochloride composition tablet |
| CN105055334A (en) * | 2015-09-18 | 2015-11-18 | 青岛华之草医药科技有限公司 | Postoperative antiemetic tropisetron hydrochloride composition granule |
| CN105193737A (en) * | 2015-09-21 | 2015-12-30 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition dry suspension for treating nausea and emesis |
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