CN102367252A - Tropisetron hydrochloride compound - Google Patents
Tropisetron hydrochloride compound Download PDFInfo
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- CN102367252A CN102367252A CN 201110343022 CN201110343022A CN102367252A CN 102367252 A CN102367252 A CN 102367252A CN 201110343022 CN201110343022 CN 201110343022 CN 201110343022 A CN201110343022 A CN 201110343022A CN 102367252 A CN102367252 A CN 102367252A
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- tropisetron hydrochloride
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Abstract
Belonging to the field of medical technologies, the invention specifically relates to a tropisetron hydrochloride compound. The invention also relates to application of an injection containing the tropisetron hydrochloride compound in the crystal form of the invention in preparing medicaments for treating nausea and vomiting.
Description
Technical field
The invention belongs to medical technical field, be specifically related to crystal of Tropisetron hydrochloride and preparation method thereof, the invention still further relates to the medicine that uses this crystal manufacturing treatment nausea and vomiting.
Background technology
At present, chemotherapy and radiation remains antineoplastic main means, but because it can cause nausea, vomit, often causes patient's treatment effectively not carry out.The mechanism that chemotherapy and radiation causes nausea, vomits is to act on GI mucosal tissue because of radiotherapy, chemotherapy, makes gastrointestinal class pheochromocyte discharge Dopamine HCL and serotonin (5-HT), these neurotransmitters and 5-HT
3Receptors bind acts on vomiting center through neural reflex and causes nausea, vomits.So 5-HT is nauseant important chemical mediator, its substruction is indole ring.Research shows, tropisetron and 5-HT
3The avidity of acceptor is the strongest, can the utmost point competes the 5-HT of periphery and maincenter effectively
3Acceptor, thus the neural reflex of blocking-up vomiting has and can optionally block 5-HT
3The effect of acceptor.Single dose administration, lasting medicine does not have tolerance, and is reusable in each radiotherapy, chemotherapy treatment, do not have The extrapyramidal symptoms.Adopt recommended dose, can be used safely in old age, liver, renal insufficiency patient and children more than two years old.Tropisetron has injection and two kinds of formulations of capsule, oral almost completely absorption (> 95%), the blood medicine peaking time is 3 hours.Absolute bioavailability depends on dosage, when dosage is 5 mg, for about 6O%.It eliminates the transformation period oral is 8.6-41.9 hour, and quiet notes are 7.3-30.3 hour.Discharge through urine or bile, metabolite through the ratio of urine and excrement discharge be 5:1 therefore, administration every day 1 time can be kept curative effect for 24 hours.Chemotherapy the 1st day, half a hour before the chemotherapeutics infusion, vein 5 mg that slowly instil just can excellent control feel sick, vomiting.The few side effects of tropisetron only has one to cross headache or constipation, fatigue and gastrointestinal dysfunction individually, and these symptoms do not influence the continuation of medicine and use.
Tropisetron hydrochloride (tropisetron hydrochloride) is an antiemetic new drug, is the indolecarboxylic acid verivate, and structural formula is following:
The Tropisetron hydrochloride structural formula
Tropisetron hydrochloride is developed by Novartis Co.,Ltd, and commodity were called Navoban (trepisetron), were a kind of highly selective serotonin 3 (5 one HT in Holland's listing in 1992
3) receptor antagonist, be applicable to the nausea and vomiting that causes after prevention and treatment children and adult cancer chemotherapy, radiotherapy and the operation, at present in the national listing of global dozens of.With similar medicine relatively, it is little that these article have a determined curative effect, better tolerance, side reaction, and advantage such as easy to use.Tropisetron hydrochloride is used widely in big-and-middle-sized hospital.
Tropisetron hydrochloride has multiple preparation method, and because of preparation method especially process for purification is different, purity is also different.
In research process, repeat the method for document, the Tropisetron hydrochloride impurity number that obtains is more, and total impurities is higher, and the Tropisetron hydrochloride that makes moisture absorption weightening finish under high humidity is obvious.The advantage that the Tropisetron hydrochloride that the present invention obtains has: purity is high, and maximum contaminant is less than 1 ‰; Good stability is even the moisture absorption weightening finish is also not obvious under high humidity.
Summary of the invention
One object of the present invention discloses a kind of crystal of Tropisetron hydrochloride.
Another object of the present invention discloses Tropisetron hydrochloride crystalline preparation method.
Another purpose of the present invention discloses and has comprised Tropisetron hydrochloride crystalline pharmaceutical composition.
The invention also discloses the application of Tropisetron hydrochloride crystal in making treatment nausea and vomiting medicine.
Combine the object of the invention that content of the present invention is specifically described at present.
The invention provides a kind of Tropisetron hydrochloride (shown in the formula I) crystal,
This Tropisetron hydrochloride crystal adopts D/Max-2500.9161 type x-ray diffractometer to measure condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and the D value is as follows,
| The spectrum wire size | 2 θ (degree) | Spacing (d) | I/ |
| 1 | 19.140 | 4.6332 | 100 |
| 2 | 23.220 | 3.8275 | 2 |
| 3 | 28.120 | 3.1707 | 8 |
| 4 | 29.100 | 3.0661 | 11 |
| 5 | 32.200 | 2.7776 | 16 |
| 6 | 33.960 | 2.6376 | 79 |
| 7 | 38.720 | 2.3236 | 45 |
| 8 | 40.880 | 2.2057 | 1 |
| 9 | 47.400 | 1.9164 | 1 |
| 10 | 48.120 | 1.8894 | 2 |
| 11 | 48.860 | 1.8625 | 11 |
| 12 | 49.520 | 1.8392 | 1 |
See Fig. 1.
The mensuration of 2 θ values is used light source among the present invention, and precision is ± 0.2 °, therefore represents above-mentioned value of getting to allow certain reasonably limit of error, and its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two ones) appendix VI C first method, the fusing point that records is 280.1 ℃-281.1 ℃.
Another object of the present invention discloses Tropisetron hydrochloride crystalline preparation method, through with Tropisetron hydrochloride in the dissolving of acetone-heated in water solution, naturally cool to room temperature, be incubated for some time again to obtain.
It is characterized in that comprising the following steps: that Tropisetron hydrochloride adds in the mixed solution of 6-9 times of (weight or measurement (WM) ratio) acetone-water=9-6:1-4, be heated to 60 ℃-65 ℃, be incubated 30 minutes; Filtered while hot; Naturally cool to room temperature, be incubated 1-3 hour again, separate out crystallization; Filter, obtain the above-mentioned Tropisetron hydrochloride crystal of high purity through drying.
This method good reproducibility is amplified to pilot scale, and content and crystal formation all can fine reproductions.
Used Tropisetron hydrochloride, synthetic according to the method that document US 4789673 (1988) provides, the chemical structure of synthetic Tropisetron hydrochloride is correct through nuclear magnetic resonance spectrum, ultimate analysis proof chemical structure.
Another purpose of the present invention provides the compsn that comprises the Tropisetron hydrochloride that the pharmaceutically acceptable carrier of Tropisetron hydrochloride crystal and one or more forms.
Preparation of pharmaceutical compositions of the present invention is following: use standard and conventional technology; Make that acceptable liquid vehicle combines on crystal of the present invention and the technology of pharmaceutics, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Said composition is used to prepare injection.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (crystal of the present invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis; The amount of used compound or concentration are regulated in the scope of a broad, and the weight range of active compound is 1%～30% (weight) of compsn.
The present invention also provides the application of Tropisetron hydrochloride crystal in making treatment nausea and vomiting medicine.
Through mouse test, the crystal that Tropisetron hydrochloride crystal that the present invention obtains and document US 4789673 (1988) obtain (fusing point: 283 ℃-285 ℃) toxicity is suitable; Through the test of animal (pigeon) antiemetic, the crystal that Tropisetron hydrochloride crystal that the present invention obtains and document US 4789673 (1988) obtain (fusing point: 283 ℃-285 ℃) equivalence.
Stability test
The contriver studies the chemicalstability of crystal formation of the present invention, and the investigation condition is a high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance, content and related substance to high humidity to strong illumination.
The result: under high light, high temperature, super-humid conditions from 0-10 days, outward appearance, related substance, content do not change, and explains that chemicalstability is good, the manufacturing and the standing storage of suitable pharmaceutical prepn.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in the Tropisetron hydrochloride crystal that document US 4789673 (1988) obtains:
The result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the Tropisetron hydrochloride crystal that document US 4789673 (1988) obtains has the moisture absorption weightening finish.
Figure of description:
Fig. 1, Tropisetron hydrochloride X-ray diffraction in crystals figure;
Fig. 2, Tropisetron hydrochloride crystalline IR figure;
Embodiment:
Below in conjunction with embodiment the present invention is done further explanation, make this area professional and technical personnel better understand the present invention.It is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.
Tropisetron hydrochloride (tropisetron hydrochloride) used among the present invention is synthetic according to the method that document US 4789673 (1988) provides; Bullion is made with extra care 1 time with absolute ethyl alcohol or 95% ethanol; Get white crystals, fusing point: 283 ℃-285 ℃, purity 99.56% (HPLC normalization method); Make with extra care 1 time with absolute ethyl alcohol or 95% ethanol, get white crystals, though fusing point still is 283 ℃-285 ℃, purity is increased to 99.92% (HPLC normalization method).Its chemical structure is through nuclear magnetic resonance spectrum, ultimate analysis conclusive evidence.
Wherein results of elemental analyses is following:
Measured value (calculated value), C:63.64 (63.55), H:6.60 (6.63), N:8.73 (8.81),
Cl:11.05(11.11)；
The proof chemical structure is correct.
The moisture that uses the karl Fischer method to record is 0.28%.
In the 1000ml reaction flask of stirring, TM, condensing surface is housed, add acetone-water (8:2) mixed solution of 80 gram Tropisetron hydrochlorides (1 highly finished product) and 560ml, start stirring; Heat temperature raising to 60 ℃-65 ℃; Treat all to dissolve clearly, be incubated 30 minutes, filtered while hot.Filtrating naturally cools to room temperature, is incubated 2 hours again, separates out crystallization, filter, through being drying to obtain high-purity hydrochloric acid tropisetron crystal, fusing point: 280.1 ℃-281.1 ℃, purity 99.96% (HPLC normalization method), dissolvent residual detects and meets the requirements.
Results of elemental analyses:
Measured value (calculated value), C:63.64 (63.57), H:6.60 (6.62), N:8.73 (8.72),
Cl:11.05(11.01)；
This crystalline X-ray diffractogram is seen Fig. 1.Instrument model and condition determination: Japanese D/max 2500 type diffractometers of science; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
This crystalline infrared spectrogram is seen Fig. 2, uses the KBr compressing tablet during mensuration.
Embodiment 2
Use standard, routine techniques preparation contain Tropisetron hydrochloride crystalline injection liquid of the present invention, specification:
5mg/5ml/ props up.
Claims (6)
1. the Tropisetron hydrochloride compound that leads to formula I,
（Ⅰ）
It is characterized in that: in measuring as the characteristic X-ray powder with the CuKa ray, its collection of illustrative plates has following
2 θ diffraction angle, D value and relative intensity,
The error of 2 θ diffraction angle is 0.2.
2. the preparation method of the said Tropisetron hydrochloride compound of claim 1, through with Tropisetron hydrochloride in acetone-heated in water solution dissolving, naturally cool to room temperature, be incubated for some time again to obtain.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that Tropisetron hydrochloride adds in the mixed solution of 6-9 times of acetone-water=9-6:1-4, be heated to 60 ℃-65 ℃; Be incubated 30 minutes, filtered while hot naturally cools to room temperature; Be incubated 1-3 hour again; Separate out crystallization, filter, obtain through drying.
4. one kind contains the compsn that the pharmaceutically acceptable carrier of the said Tropisetron hydrochloride compound of claim 1 and one or more is formed.
5. right requires 4 described compsns, it is characterized in that said composition is used to prepare injection.
6. the application of the said Tropisetron hydrochloride of claim 1 in making treatment nausea and vomiting medicine.
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| CN 201110343022 CN102367252A (en) | 2011-11-03 | 2011-11-03 | Tropisetron hydrochloride compound |
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| CN 201110343022 CN102367252A (en) | 2011-11-03 | 2011-11-03 | Tropisetron hydrochloride compound |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073543A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form I |
| CN103073542A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form II |
| CN103360386A (en) * | 2013-07-18 | 2013-10-23 | 珠海金鸿药业股份有限公司 | Tropisetron hydrochloride compound, its preparation method, and pharmaceutical composition containing the same |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104945397A (en) * | 2015-07-30 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride medicine compound for treating nausea and vomit as well as preparation method thereof |
| CN105012302A (en) * | 2015-09-01 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride composition for vomit-stopping medicine |
| CN105055416A (en) * | 2015-08-10 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Postoperative antemetic tropisetron hydrochloride composition freeze-dried powder injection |
Citations (3)
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|---|---|---|---|---|
| CN101033225A (en) * | 2007-04-02 | 2007-09-12 | 北京成宇化工有限公司 | Process of preparing troipisetron |
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
| 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 |
-
2011
- 2011-11-03 CN CN 201110343022 patent/CN102367252A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101033225A (en) * | 2007-04-02 | 2007-09-12 | 北京成宇化工有限公司 | Process of preparing troipisetron |
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
| 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 |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073543A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form I |
| CN103073542A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form II |
| CN103360386A (en) * | 2013-07-18 | 2013-10-23 | 珠海金鸿药业股份有限公司 | Tropisetron hydrochloride compound, its preparation method, and pharmaceutical composition containing the same |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104945397A (en) * | 2015-07-30 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride medicine compound for treating nausea and vomit as well as preparation method thereof |
| CN105055416A (en) * | 2015-08-10 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Postoperative antemetic tropisetron hydrochloride composition freeze-dried powder injection |
| CN105012302A (en) * | 2015-09-01 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride composition for vomit-stopping medicine |
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Application publication date: 20120307 |