ES2332168A1 - Nicardipine hydrochloride dihydrate and chloroformate - Google Patents
Nicardipine hydrochloride dihydrate and chloroformate Download PDFInfo
- Publication number
- ES2332168A1 ES2332168A1 ES200801269A ES200801269A ES2332168A1 ES 2332168 A1 ES2332168 A1 ES 2332168A1 ES 200801269 A ES200801269 A ES 200801269A ES 200801269 A ES200801269 A ES 200801269A ES 2332168 A1 ES2332168 A1 ES 2332168A1
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- nicardipine hydrochloride
- water
- solvent
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960002289 nicardipine hydrochloride Drugs 0.000 title claims abstract description 66
- AIKVCUNQWYTVTO-UHFFFAOYSA-N nicardipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 AIKVCUNQWYTVTO-UHFFFAOYSA-N 0.000 title claims abstract description 65
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 title description 7
- 239000012453 solvate Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 230000001631 hypertensive effect Effects 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000012530 fluid Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012296 anti-solvent Substances 0.000 claims description 10
- 239000001569 carbon dioxide Substances 0.000 claims description 10
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 10
- SJWFXCIHNDVPSH-UHFFFAOYSA-N octan-2-ol Chemical compound CCCCCCC(C)O SJWFXCIHNDVPSH-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 230000008018 melting Effects 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 6
- -1 (±) -2- (Benzylmethylamino) ethyl methyl Chemical group 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- GNHQSAUHXKRQMC-UHFFFAOYSA-N benzene;chlorine Chemical compound [Cl].C1=CC=CC=C1 GNHQSAUHXKRQMC-UHFFFAOYSA-N 0.000 claims description 3
- 229940043232 butyl acetate Drugs 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 6
- 150000004683 dihydrates Chemical group 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 208000019553 vascular disease Diseases 0.000 abstract description 3
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 21
- 229960001783 nicardipine Drugs 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000001757 thermogravimetry curve Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020802 Hypertensive crisis Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- IGWCIHCQFSETGG-UHFFFAOYSA-N carbonochloridic acid;hydron;chloride Chemical compound Cl.OC(Cl)=O IGWCIHCQFSETGG-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000010437 gem Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000010983 kinetics study Methods 0.000 description 1
- 208000020442 loss of weight Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Forma pseudopolimórfica de hidrocloruro de nicardipina, procedimiento para su preparación y formulación que la contiene.Pseudopolymorphic form of hydrochloride of nicardipine, procedure for its preparation and formulation that the contains
La presente invención se refiere a una nueva forma pseudopolimórfica de hidrocloruro de nicardipina. En particular, la invención se refiere a la forma hidrocloruro de nicardipina di hidratado, denominada de aquí en adelante Forma Dh.The present invention relates to a new pseudopolymorphic form of nicardipine hydrochloride. In In particular, the invention relates to the hydrochloride form of hydrated nicardipine, referred to hereinafter Form Dh.
La presente invención también se refiere a un procedimiento para la preparación de dicha nueva Forma Dh, al procedimiento para la obtención de un solvato de hidrocloruro de nicardipina, útil para la preparación de dicha nueva forma pseudopolimórfica, y a la utilización de esta Forma Dh como medicamento.The present invention also relates to a procedure for the preparation of said new Form Dh, at procedure for obtaining a hydrochloride solvate of nicardipine, useful for the preparation of said new form pseudopolymorphic, and to the use of this Dh Form as medicine.
La nueva forma pseudopolimórfica Dh de hidrocloruro de nicardipina es útil para la preparación de formulaciones farmacéuticas de liberación rápida de emergencia para el tratamiento de enfermedades vasculares, como las crisis hipertensivas.The new pseudopolymorphic form Dh of Nicardipine hydrochloride is useful for the preparation of Emergency rapid release pharmaceutical formulations for the treatment of vascular diseases, such as crises hypertensive
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El hidrocloruro de nicardipina es una sal orgánica derivada de una 1,4-dihidropiridina cuya nomenclatura química según la IUPAC es: hidrocloruro de (\pm)-2-(Bencilmetilamino)etil metil 1,4-dihidro-2,6-dimetil-4-(m-nitrofenil)piridino-3,5-dicarboxilato [Índice Merk, Ed.12, página 6580]. Se trata de una molécula con dos centros quirales, marcados como 1 y 2 en la fórmula química del hidrocloruro de nicardipina que se incluye a continuación.Nicardipine hydrochloride is an organic salt derived from a 1,4-dihydropyridine whose chemical nomenclature according to IUPAC is: (±) -2- (Benzylmethylamino) ethyl methyl 1,4-dihydro-2,6-dimethyl- hydrochloride 4- (m-nitrophenyl) pyridino-3,5-dicarboxylate [ Merk Index, Ed.12, page 6580 ]. It is a molecule with two chiral centers, marked 1 and 2 in the chemical formula of nicardipine hydrochloride, which is included below.
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El hidrocloruro de nicardipina fue sintetizado por primera vez en los laboratorios japoneses Yamanouchi Pharma Co. Ltd. [M. Murakami et al. Belg. Patent 811324; 1974; idem US pat. 3985758; 1976; Iwanami et al., Chem. Pharm. Bull. 1979, 27, 1426] en forma de mezcla racémica donde le fueron identificadas propiedades terapéuticas como agente vasodilatador. Desde entonces hasta la actualidad se han hallado aplicaciones para el tratamiento de diversos trastornos y enfermedades como las que se referencían a continuación:Nicardipine hydrochloride was first synthesized in Japanese laboratories Yamanouchi Pharma Co. Ltd. [ M. Murakami et al . Belg. Patent 811324 ; 1974 ; idem US pat. 3985758 ; 1976 ; Iwanami et al., Chem. Pharm. Bull . 1979 , 27, 1426 ] in the form of a racemic mixture where therapeutic properties were identified as vasodilator agent. From then until now, applications have been found for the treatment of various disorders and diseases such as those referred to below:
- Tratamiento de la hipertensión arterial, crisis hipertensivas, angina estable de pecho, isquemia (muerte celular) por infarto cerebral [US2007249689-A1; WO2007121483-A2; L. E. Muñoz Almeda et al. Rev. Esp. Anestesiol. Reanim; 2001, 48, 71; J. Varon et al. Chest, 2000, 118, 221].- Treatment of hypertension, hypertensive crisis, stable angina pectoris, ischemia (cell death) due to cerebral infarction [ US2007249689-A1; WO2007121483-A2; LE Muñoz Almeda et al. Rev. Esp. Anesthesiol. Reanim ; 2001 , 48, 71; J. Varon et al. Chest , 2000 , 118, 221 ].
- Retrasa la aparición del deterioro cognitivo en la demencia vascular y en el Alzheimer [S. López, Ensayo Clínico experimental doble ciego, aleatorizado, 5 controlado con placebo, del efecto del nicardipina en la función cognitiva en pacientes afectos de demencia vascular, II Conferencia Nacional del Alzheimer, Noviembre 1999, Bilbao; España].- Delays the onset of cognitive impairment in vascular dementia and Alzheimer's [S. López, Randomized , double-blind, placebo-controlled experimental clinical trial of the effect of nicardipine on cognitive function in patients with vascular dementia , II National Alzheimer's Conference, November 1999, Bilbao; Spain].
- La formulación oral del hidrocloruro de nicardipina conjunta con anti- cancerígenos y anti-neoplásicos incrementa la biodisponibilidad (cantidad en sangre) de estos [WO9715269-A; ES2109899-T3].- The oral formulation of hydrochloride joint nicardipine with anticancer drugs and anti-neoplastic increases bioavailability (amount in blood) of these [WO9715269-A; ES2109899-T3].
Durante las etapas de síntesis del hidrocloruro de nicardipina fue posible aislar dicho fármaco en dos formas cristalinas, que fueron denominadas fases alfa (\alpha) y fase beta (\beta), cuyos puntos de fusión son 189-190 y 169-170ºC, respectivamente. Posteriormente, las fases fueron caracterizadas mediante las técnicas de infrarrojo, rayos X en polvo, y se estudiaron las cinéticas de solubilización a PH=7 en agua destilada de cada una de las fases. Los estudios de cinética de solubilización mostraron que la fase \beta se solubiliza de una forma ligeramente más rápida que la fase \alpha. Sin o embargo, después de 30 min. la concentración de saturación en agua es de 0,96 mg/L para la fase \alpha y 0,98 mg/L para la fase \beta, siendo estas dos concentraciones prácticamente idénticas [J. Yan, P. Giundechi; Boll. Chim. Pharm. 1990, 129, 276]. La fase \beta, debido a su menor punto de fusión (169ºC) y a su ligera mayor velocidad de disolución, es metaestable respecto a la fase \alpha. Su mayor velocidad de disolución hace que sea esta fase \beta, la que se haya comercializado mayoritariamente en forma de polvo sólido del racemato.During the synthesis stages of nicardipine hydrochloride it was possible to isolate said drug in two crystalline forms, which were called alpha (?) And beta (?) Phases, whose melting points are 189-190 and 169-170 ° C, respectively . Subsequently, the phases were characterized by infrared techniques, X-ray powder, and the solubilization kinetics at PH = 7 in distilled water of each phase were studied. The solubilization kinetics studies showed that the β phase is solubilized slightly faster than the α phase. However, after 30 min. the saturation concentration in water is 0.96 mg / L for the α phase and 0.98 mg / L for the β phase, these two concentrations being practically identical [J. Yan, P. Giundechi; Boll Chim. Pharm 1990, 129, 276 ]. The β phase, due to its lower melting point (169 ° C) and its slightly higher dissolution rate, is metastable with respect to the α phase. Its higher dissolution rate makes this β-phase the most commercially available as solid racemate powder.
Por otra parte, ambas formas cristalinas son sensibles a la luz, presentando la fase \beta una cinética de degradación por incidencia de la luz más rápida que la fase a y la molturación de ambas causa su amorfización [R. Teraoka, M. Otsuka, Y. Matsuda, Int. J. Pharm. 2004, 286, 1].On the other hand, both crystalline forms are sensitive to light, the β phase presenting a degradation kinetics due to the incidence of light faster than the a phase and the grinding of both causes their amorphization [R. Teraoka, M. Otsuka, Y. Matsuda, Int. J. Pharm . 2004, 286, 1].
Existen hasta la fecha formulaciones que contienen el hidrocloruro de nicardipina aptas para ser administradas por vía oral, transdermal e intravenosa. El hidrocloruro de nicardipina, administrado oralmente, en la forma cristalina \beta, y en la forma racémica (el hidrocloruro de nicardipina se comercializa y administra en forma de mezcla racémica), posee una biodisponibilidad de entre un 10-40%, siendo sólo activo el enantiómero (S), en dosis de 20 ó 30 mg del fármaco. El resto es degradado por el hígado antes de poder ejercer su acción terapéutica por el denominado metabolismo de primer paso [el medicamento es metabolizado (reacciones químicas de degradación) con gran eficacia por el hígado a partir de la circulación portal (vena porta), lo que supone la necesidad de administrar dosis mucho mayores cuando se administra por vía oral respecto de cualquier otra vía]. Además, al presentar muy alta permeabilidad a los tejidos corporales, se producen incrementos rápidos de la concentración de fármaco en cortos espacios de tiempo en el corriente sanguíneo, hecho que produce efectos secundarios.There are to date formulations containing nicardipine hydrochloride suitable for oral, transdermal and intravenous administration. Nicardipine hydrochloride, administered orally, in the β crystalline form, and in the racemic form (nicardipine hydrochloride is marketed and administered as a racemic mixture), has a bioavailability of between 10-40%, being only active the enantiomer (S), in doses of 20 or 30 mg of the drug. The rest is degraded by the liver before it can exert its therapeutic action by the so-called first-pass metabolism [the drug is metabolized (chemical degradation reactions) with great efficiency by the liver from the portal circulation (portal vein), what which implies the need to administer much higher doses when administered orally with respect to any other route]. In addition, by presenting very high permeability to body tissues, rapid increases in drug concentration occur in short periods of time in the bloodstream, which produces side effects.
Para liberaciones rápidas de emergencia, el hidrocloruro de nicardipina se formula para ser administrado de forma inmediata por vía intravenosa disuelto. Se describen formulaciones estables durante un año, ya preparadas en recipientes protegidos de la luz que norequieren dilución para ser administradas en caso de emergencia médica [WO2007123984].For emergency quick releases, the Nicardipine hydrochloride is formulated to be administered from immediately dissolved intravenously. They describe stable formulations for one year, already prepared in containers protected from light that do not require dilution to be administered in case of medical emergency [WO2007123984].
Sin embargo, dichas formulaciones orales de liberación rápida de emergencia poseen baja biodisponibilidad por el denominado metabolismo de primer paso, lo que supone la necesidad de administrar dosis mucho mayores cuando se administra por vía oral respecto de cualquier otra vía.However, these oral emergency quick-release formulations have low bioavailability due to the so-called first-pass metabolism , which implies the need to administer much higher doses when administered orally with respect to any other route.
La presente invención proporciona una nueva
forma pseudopolimórfica del hidrocloruro de
(\pm)-2-(bencilmetila-
mino)etil
metil
1,4-dihidro-2,6-dimetil-4-(m-nitrofenil)piridino-3,5-dicarboxilato
(hidrocloruro de nicardipina), que posee solubilidad y cinética de
solubilización mejoradas con respecto a las formas polimórficas
\alpha y \beta conocidas en el estado de la técnica, con una
farmacocinética modificada respecto de ambas formas polimórficas
\alpha y \beta, y con una biodisponibilidad superior respecto a
las formas polimórficas \alpha y \beta conocidas.The present invention provides a new pseudopolymorphic form of the hydrochloride of (±) -2- (benzylmethyl-
mino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4- (m-nitrophenyl) pyridino-3,5-dicarboxylate (nicardipine hydrochloride), which has improved solubility and kinetics of solubilization with respect to polymorphic forms α and β known in the state of the art, with a modified pharmacokinetics with respect to both α and β polymorphic forms, and with a higher bioavailability with respect to the known α and β polymorphic forms.
Por lo tanto, el primer aspecto de la presente invención es proporcionar la forma pseudopolimórfica de hidrocloruro de nicardipina di D hidratado, denominada de aquí en adelante Forma (pseudopolimórfica) Dh.Therefore, the first aspect of the present invention is to provide the pseudopolymorphic form of hydrated nicardipine di D hydrochloride, referred to herein as Forward Form (pseudopolymorphic) Dh.
Un segundo aspecto de la invención es proporcionar un procedimiento para la preparación de dicha Forma pseudopolimórfica Dh a partir de un solvato de hidrocloruro de nicardipina.A second aspect of the invention is provide a procedure for the preparation of said Form pseudopolymorphic Dh from a hydrochloride solvate of Nicardipine
Un tercer aspecto de la invención es proporcionar un procedimiento para la obtención de dicho solvato de hidrocloruro de nicardipina, útil para la preparación de la Forma pseudopolimórfica Dh.A third aspect of the invention is provide a procedure for obtaining said solvate from Nicardipine hydrochloride, useful for the preparation of the Form pseudopolymorphic Dh.
Un cuarto aspecto de la invención es proporcionar un procedimiento alternativo para la obtención de dicho solvato de hidrocloruro de nicardipina, útil para la preparación de la Forma pseudopolimórfica Dh.A fourth aspect of the invention is provide an alternative procedure for obtaining said nicardipine hydrochloride solvate, useful for Preparation of the pseudopolymorphic form Dh.
Un quinto aspecto de la invención es la Forma pseudopolimórfica Dh como medicamento.A fifth aspect of the invention is the Form pseudopolymorphic Dh as medicine.
Un sexto aspecto de la invención es la utilización de dicha Forma pseudopolimórfica Dh para la preparación de un medicamento destinado al tratamiento de enfermedades vasculares.A sixth aspect of the invention is the use of said pseudopolymorphic form Dh for the preparation of a medicine for the treatment of diseases vascular
Un séptimo aspecto de la invención es una formulación farmacéutica que comprende dicha Forma pseudopolimórfica Dh juntamente con excipientes farmacéuticamente aceptables.A seventh aspect of the invention is a pharmaceutical formulation comprising said Form pseudopolymorphic Dh together with pharmaceutically excipients acceptable.
Ventajosamente, dicha formulación farmacéutica posee biodisponibilidad superior a la de las formas polimórficas \alpha y \beta y, por lo tanto, son necesarias dosis menores del fármaco.Advantageously, said pharmaceutical formulation it has bioavailability superior to that of polymorphic forms α and β and, therefore, lower doses are necessary of the drug.
La Figura 1.1 muestra el difractograma de rayos X de la Forma Dh de hidrocloruro de nicardipina (eje vertical: altura (Cuentas); eje horizontal: ángulo º2\theta).Figure 1.1 shows the ray diffractogram X of the Dh Form of nicardipine hydrochloride (vertical axis: height (beads); horizontal axis: angle º2 \ theta).
La Figura 1.2 comparativa muestra el difractograma de rayos X de la Forma Dh comparado con el de las Formas \alpha y \beta.Comparative Figure 1.2 shows the X-ray diffractogram of Form Dh compared to that of Forms α and β.
La Figura 2.1 muestra el espectro de infrarrojo (IR) de la Forma Dh de hidrocloruro de nicardipina y de las Formas \alpha y \beta en el intervalo de números de onda 400-4.000 cm^{-1}.Figure 2.1 shows the infrared spectrum (IR) of Form Dh of nicardipine hydrochloride and of Forms α and β in the range of wave numbers 400-4,000 cm -1.
La Figura 2.2 muestra el espectro de infrarrojo (IR) de la Forma Dh y de las Formas \alpha y \beta ampliado en el intervalo de números de onda 1.400-1.750 cm^{-1}.Figure 2.2 shows the infrared spectrum (IR) of the Form Dh and of the Forms α and β extended in the range of wave numbers 1,400-1,750 cm -1.
La Figura 3 muestra el análisis por calorimetría diferencial de barrido (DSC) del hidrocloruro de nicardipina di hidratado, Forma Dh, y de las Formas \alpha y \beta.Figure 3 shows the calorimetry analysis Scan Differential (DSC) of Nicardipine Di Hydrochloride hydrated, Form Dh, and of the α and β forms.
La Figura 4.1 muestra el perfil del termograma (TGA) correspondiente a la nueva fase cuando es calentada a 1ºC/min.Figure 4.1 shows the profile of the thermogram (TGA) corresponding to the new phase when heated to 1ºC / min.
La Figura 4.2 muestra el análisis por
espectrometría de masas por impacto electrónico de los gases
desprendidos durante el proceso de calentamiento de la nueva fase
(Forma Dh) en la caracterización por análisis termogravimé-
trico.Figure 4.2 shows the mass spectrometry analysis by electronic impact of the gases released during the heating process of the new phase (Form Dh) in the characterization by thermogravimetric analysis.
trico.
La Figura 5 muestra la estructura cristalina del hidrocloruro de nicardipina di hidratado, Forma Dh. En la Figura 5 se ha representado la perspectiva de una celda unidad constituida por 4 moléculas de hidrocloruro de nicardipinio y 8 moléculas de agua desde el eje cristalográfico b.Figure 5 shows the crystalline structure of hydrated nicardipine hydrochloride, Form Dh. Figure 5 shows the perspective of a unit cell consisting of 4 molecules of nicardipinium hydrochloride and 8 molecules of water from the crystallographic axis b .
La Figura 6 muestra la estructura molecular que presenta el hidrocloruro de nicardipina di hidratado en la Forma Dh.Figure 6 shows the molecular structure that Introduces Hydrated Nicardipine Hydrochloride in the Form Dh.
La Figura 7 muestra de forma esquemática un equipo para llevar a cabo la obtención de un solvato de hidrocloruro de nicardipina, útil como material de partida para la preparación de la nueva Forma Dh.Figure 7 schematically shows a equipment to carry out obtaining a solvate of nicardipine hydrochloride, useful as a starting material for Preparation of the new Form Dh.
De acuerdo con el primer aspecto de la invención, se proporciona una Forma pseudopolimórfica de hidrocloruro de nicardipina (Forma Dh) caracterizada por tener unos picos en el difractograma de rayos X de polvo que se muestran en la Tabla 1 que sigue. La Figura 1 muestra dicho difractograma.According to the first aspect of the invention, a pseudopolymorphic form of nicardipine hydrochloride (Form Dh) characterized by having spikes on the powder X-ray diffractogram shown in the Table 1 below. Figure 1 shows said diffractogram.
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Para registrar los difractogramas de rayos X en polvo se ha utilizado un difractrómetro Bruker AXS D8 | : | equipado con un detector Lynxeye sensible a la posición.To register X-ray diffractograms in powder a Bruker AXS D8 diffractrometer has been used | : | equipped with a position sensitive Lynxeye detector.
Los polvos se trituraron en un mortero de ágata y, posteriormente, se depositaron cuidadosamente en el hueco de un soporte para muestras equipado con un monocristal de cuarzo (suministrado por The Gem Dugout, Swarthmore, PA). Regulación del generador: 40 kV, 40 mA.The powders were crushed in an agate mortar and subsequently carefully deposited in the hollow of a sample holder equipped with a quartz monocrystal (supplied by The Gem Dugout , Swarthmore, PA). Generator regulation: 40 kV, 40 mA.
Por otro lado, la Forma Dh del hidrocloruro de nicardipina también está caracterizada por un espectro de infrarrojo (IR) con los picos, en unidades de cm^{-1}, que se muestran en las Figuras 2.1 y 2.2.On the other hand, the Dh Form of the hydrochloride of Nicardipine is also characterized by a spectrum of infrared (IR) with the peaks, in units of cm -1, which are shown in Figures 2.1 and 2.2.
Y, finalmente, la Forma Dh del hidrocloruro de nicardipina también está caracterizada por poseer un punto de fusión de 135-150ºC, tal y como se muestra en la Fig 3.And finally, the Dh Form of the hydrochloride of Nicardipine is also characterized by having a point of melting of 135-150 ° C, as shown in the Fig 3.
Es también objeto de la presente invención proporcionar un procedimiento para la preparación de la Forma Dh del hidrocloruro de nicardipina.It is also object of the present invention provide a procedure for the preparation of Form Dh of nicardipine hydrochloride.
El procedimiento de preparación de la forma
pseudopolimórfica Dh se caracteriza porque comprende suspender el
hidrocloruro de nicardipina o un solvato de éste en un
no-disolvente y agua, a una temperatura comprendida
entre -20ºC y 60ºC, o bien suspender el hidrocloruro de nicardipina
o un solvato de éste en agua pura, a una temperatura com-
prendida entre 1-99ºC, en ambos casos a presión
atmosférica, para así proporcionar la Forma pseudopolimórfica
Dh.The process for preparing the pseudopolymorphic form Dh is characterized in that it comprises suspending nicardipine hydrochloride or a solvate thereof in a non-solvent and water, at a temperature between -20 ° C and 60 ° C, or suspending nicardipine hydrochloride or a solvate of the latter in pure water, at a comparative temperature
lit between 1-99 ° C, in both cases at atmospheric pressure, in order to provide the pseudopolymorphic form Dh.
El no-disolvente puede saturarse, sobresaturarse o bien mezclarse con agua a una relación disolvente orgánico:agua de 100:1 a 1:100 (v/v), preferiblemente de 1:1 (v/v).The non-solvent can saturate, supersaturate or mix with water at a ratio organic solvent: water from 100: 1 to 1: 100 (v / v), preferably of 1: 1 (v / v).
En la presente invención por el término "no-disolvente", también denominado "mal disolvente" o "disolvente pobre", se entiende un disolvente en el que el hidrocloruro de nicardipina o un solvato de éste es insoluble o parcialmente soluble.In the present invention for the term "non-solvent", also called "bad solvent "or" poor solvent "means a solvent in which nicardipine hydrochloride or a solvate thereof is insoluble or partially soluble.
Preferiblemente, dicho no-disolvente se selecciona entre éter etílico, éter metílico, éter propílico, éter butílico, tetrahidrofurano, agua, etilenglicol, acetonitrilo, isopropanol, 2-octanol, acetona, metietilcetona, o mezclas de los mismos, siendo preferible el éter etílico.Preferably said non-solvent is selected from ethyl ether, methyl ether, propyl ether, butyl ether, tetrahydrofuran, water, ethylene glycol, acetonitrile, isopropanol, 2-octanol, acetone, methyl ketone, or mixtures of the same, with ethyl ether being preferable.
A partir de una muestra poli cristalina de hidrocloruro de nicardipina di hidratado, Forma Dh, obtenida de esta manera, se ha realizado un estudio de la estructura cristalina del hidrocloruro de nicardipina di hidratado a partir del perfil de difracción de rayos-X en polvo. La nueva fase dihidratada (Dh) cristaliza en el sistema monoclínico y el grupo espacial P2_{1}/c. Los parámetros de celda correspondientes son: a = 11,3214; b = 10,69677; c = 24,01993; \alpha = 90; \beta = 99,11943; \gamma = 90; V_{celda} = 2872,1Ä^{3}. Véase Figura 5 estructura cristalina y Figura 6 estructura molecular.From a poly crystalline sample of Hydrated nicardipine hydrochloride, Form Dh, obtained from In this way, a study of the crystalline structure has been carried out of nicardipine di hydrochloride hydrated from the profile of X-ray powder diffraction. The new phase dihydrate (Dh) crystallizes in the monoclinic system and the group spatial P2_ {1} / c. The corresponding cell parameters are: a = 11.3214; b = 10.69677; c = 24,01993; α = 90; ? = 99,11943; γ = 90; V_ {cell} = 2872,1Ä3. See Figure 5 Crystal structure and Figure 6 molecular structure.
A continuación, se incluye la Tabla 2 donde se muestran las coordenadas atómicas de la estructura cristalina del hidrocloruro de nicardipina di hidratado.Next, Table 2 is included where show the atomic coordinates of the crystalline structure of the hydrated nicardipine hydrochloride.
En un tercer aspecto de la invención, se proporciona un procedimiento para la obtención de un solvato de hidrocloruro de nicardipina, útil para la preparación de la Forma pseudopolimórfica Dh, que comprende:In a third aspect of the invention, provides a procedure for obtaining a solvate of Nicardipine hydrochloride, useful for the preparation of the Form pseudopolymorphic Dh, comprising:
- la disolución de hidrocloruro de nicardipina (NiH) (forma \alpha, forma \beta, cualquier mezcla de éstas o un solvato)en un disolvente orgánico a una concentración comprendida entre 10^{-4} y 1 g NiH/ml;- the solution of nicardipine hydrochloride (NiH) (form α, form β, any mixture of these or a solvate) in an organic solvent at a concentration between 10-4 and 1 g NiH / ml;
- adición lenta de un anti-solvente a una temperatura comprendida entre -20ºC y 40ºC, que provoca la precipitación del solvato de hidrocloruro de nicardipina.- slow addition of a anti-solvent at a temperature between -20ºC and 40ºC, which causes the solvate precipitation of nicardipine hydrochloride.
En la presente invención por el término "disolvente orgánico", se entiende un disolvente iónico; neutro polar o neutro apolar. El disolvente puede contener C, H, O, F, CI, I, Br, N, S, Se, P, B en su estructura química.In the present invention for the term "organic solvent" means an ionic solvent; Neutral polar or neutral apolar. The solvent may contain C, H, O, F, CI, I, Br, N, S, Se, P, B in its chemical structure.
Preferiblemente, dicho disolvente orgánico se selecciona entre cloroformo, acetona, ácido acético, acetona, anisol, 1-butanol, 2-butanol, butilacetato, tert-butil metil éter, cloro benceno, cumeno, acetato de etilo, di metil sulfóxido, etanol, etil éter, formiato de etilo, ácido fórmico, heptano, isobutil acetato, isopropil acetato, acetato de metilo, 3-metil-1-butanol, metiletilcetona, metil isobutilcetona, 2-metil-1-propanol, pentano, 1-pentanol, 1-propanol, 2-propanol, nitrometano, nitrobenceno, benzonitrilo, N-metilpirrolidona, tolueno, xileno, acetonitrilo, dimetilformamida, 2-octanol, 1-octanol, formamida, piridina, dietilformamida, 2-metoxietanol, 1,1,2-tricloroeteno, diclorometano, 1,4-dioxano, agua, sulfolano, metanol, etilenglicol, polietilenglicol, o mezclas de estos en cualquier proporción, preferiblemente (1:1) (v/v).Preferably, said organic solvent is select from chloroform, acetone, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, tert-butyl methyl ether, chlorine benzene, cumene, ethyl acetate, di-methyl sulfoxide, ethanol, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, nitromethane, nitrobenzene, benzonitrile, N-methylpyrrolidone, toluene, xylene, acetonitrile, dimethylformamide, 2-octanol, 1-octanol, formamide, pyridine, diethylformamide, 2-methoxyethanol, 1,1,2-trichloroethene, dichloromethane, 1,4-dioxane, water, sulfolane, methanol, ethylene glycol, polyethylene glycol, or mixtures of these in any proportion, preferably (1: 1) (v / v).
En la presente invención por el término "anti-solvente", se entiende un disolvente que induce la precipitación de un soluto que se encuentra en disolución.In the present invention for the term "anti-solvent" means a solvent that induces the precipitation of a solute found in dissolution.
Preferiblemente, dicho anti-solvente se selecciona entre hexano, éter etílico, pentano, éter metílico, agua, acetona, metil etilcetona, acetato de etilo, 2-propanol, 1-propanol, acetonitrilo, 1,4-dioxano, tolueno, ciclohexano, benzeno, o mezclas de estos en cualquier proporción, preferiblemente (1:1) (v/v).Preferably said anti-solvent is selected from hexane, ether ethyl, pentane, methyl ether, water, acetone, methyl ethyl ketone, ethyl acetate, 2-propanol, 1-propanol, acetonitrile, 1,4-dioxane, toluene, cyclohexane, benzene, or mixtures of these in any proportion, preferably (1: 1) (v / v).
Todavía más preferiblemente, dicho disolvente orgánico es cloroformo y dicho anti-solvente se selecciona entre hexano y éter etílico. En una realización preferida se obtiene el cloroformato de hidrocloruro de nicardipina (1:1).Even more preferably, said solvent organic is chloroform and said anti-solvent is Select between hexane and ethyl ether. In one embodiment preferred is obtained nicardipine hydrochloride chloroformate (1: 1).
En un cuarto aspecto de la invención, se proporciona un procedimiento alternativo para la obtención de un solvato de hidrocloruro de nicardipina que comprende:In a fourth aspect of the invention, provides an alternative procedure for obtaining a nicardipine hydrochloride solvate comprising:
- disolución de hidrocloruro de nicardipina (forma a, forma R, cualquier mezcla de éstas, cualquier solvato o la forma Dh) en un disolvente orgánico a una concentración comprendida entre 10^{4} y 1 g NiH/ml,- nicardipine hydrochloride solution (form a, form R, any mixture thereof, any solvate or Dh form) in an organic solvent at a concentration between 10 4 and 1 g NiH / ml,
- termostatización de dicha disolución a una temperatura comprendida entre -50ºC y 50ºC,- thermostatization of said solution at a temperature between -50ºC and 50ºC,
- adición de un fluido comprimido, que es soluble con el disolvente orgánico y que actúa como anti-solvente sobre el hidrocloruro de nicardipina, hasta alcanzar una presión de trabajo comprendida entre 1 y 200 bares, lo que provoca la precipitación del solvato en forma sólida; y- addition of a compressed fluid, which is soluble with the organic solvent and acting as anti-solvent on nicardipine hydrochloride, until reaching a working pressure between 1 and 200 bars, which causes solvate precipitation in solid form; Y
- separación del sólido precipitado resultante a la presión de trabajo.- separation of the resulting precipitated solid a working pressure
Dicho fluido comprimido se selecciona entre dióxido de carbono (CO_{2}), Freones como el Freón R-124 (F_{2}HC-CHF_{2}), etano (CH_{3}-CH_{3}), monóxido de carbono (CO), hidrógeno (H_{2}). Dicho disolvente orgánico y dicho solvato es tal y como se han definido más arriba.Said compressed fluid is selected from carbon dioxide (CO2), Freons like Freon R-124 (F 2 HC-CHF 2), ethane (CH 3 -CH 3), carbon monoxide (CO), hydrogen (H2). Said organic solvent and said solvate is as defined above.
Ventajosamente, se lleva a cabo una etapa de agitación en el reactor para favorecer el contacto entre el fluido comprimido, la disolución que comprende el hidrocloruro de nicardipina y el disolvente orgánico.Advantageously, a stage of stirring in the reactor to favor contact between the fluid tablet, the solution comprising the hydrochloride of Nicardipine and organic solvent.
A continuación, se incluye una realización preferida de la invención para la obtención de un solvato de hidrocloruro de nicardipina, en particular el cloroformato de hidrocloruro de nicardipina, haciéndose referencia a la Figura 7, sin que la misma sea limitativa del alcance de protección de la presente invención y entendiendo que un conocedor en la materia pueda realizar modificaciones sin que ello varíe la esencia de la presente invención.Next, an embodiment is included of the invention for obtaining a solvate of nicardipine hydrochloride, in particular chloroformate of nicardipine hydrochloride, referring to Figure 7, without limiting the scope of protection of the present invention and understanding that a person skilled in the art can make modifications without changing the essence of the present invention
En una realización preferida, el procedimiento para la obtención del cloroformato de hidrocloruro de nicardipina, se lleva a cabo en un equipo representado esquemáticamente en la Figura 7.In a preferred embodiment, the process for obtaining nicardipine hydrochloride chloroformate, it is carried out in a team schematically represented in the Figure 7
En particular, el Equipo presenta un recipiente (12) que contiene una disolución de hidrocloruro de nicardipina (fase \alpha, fase \beta, fase amorfa, solvato de hidrocloruro de nicardipina, fase Dh) en cloroformo a una concentración comprendida entre 10^{-4} y 1 g NiH/mL (disolución A). Este recipiente (12) está conectado, mediante una tubería, a una bomba (10), gracias a la cual puede suministrarse la disolución a la vasija de precipitación (6), siempre que la válvula (11) está abierta. Asimismo, el recipiente que contiene el fluido comprimido que actúa como antisolvente (1) se encuentra también conectado a una bomba (3), mediante la cual se introduce dicho fluido comprimido a dicha vasija (6), siempre que las válvulas (2) y (4) estén abiertas. Se termostatiza el reactor (6) entre -50 y 50ºC, y se introduce un volumen conocido de Disolución A en el reactor (6) a través de la boquilla (5). El fluido comprimido se introduce en el reactor (6) una vez abierta la válvula (4), hasta alcanzar la presión final deseada (1 a 200 bars), y una concentración deseada del fluido comprimido en el cloroformo expandido (X_{FC} = 0,01-0,99). El precipitado formado como consecuencia del efecto antisolvente del fluido comprimido sobre la Disolución A se deposita sobre el filtro (7), el cual separa el material particulado en función de la luz del mismo filtro. En una realización preferida, puede utilizarse un sistema de agitación (14) para favorecer el alcance del equilibrio del sistema durante esta etapa. La separación del material particulado ha de realizarse a la misma presión trabajo, en las que se ha dado la precipitación. Por lo tanto, al abrir la válvula (8) para iniciar la filtración, es necesario el suministro de nitrógeno gas (13) al reactor (6), el cual actúa como émbolo y mantiene la presión constante dentro del reactor (6). Alternativamente, el filtro puede ser externo respecto al reactor (6), siempre y cuando esté a las mismas condiciones de presión (P) que el reactor (6). Una vez finalizada la separación del sólido, se procede a la despresurización de la unidad de filtración, para poder recoger el sólido precipitado. Preferiblemente, antes de la despresurización y después del filtrado, puede realizarse una etapa de secado del material particulado. El secado puede realizarse mediante, por ejemplo, una corriente del fluido comprimido.In particular, the Team presents a container (12) containing a solution of nicardipine hydrochloride (α phase, β phase, amorphous phase, hydrochloride solvate of nicardipine, phase Dh) in chloroform at a concentration between 10-4 and 1 g NiH / mL (solution A). This vessel (12) is connected, via a pipe, to a pump (10), thanks to which the solution can be supplied to the precipitation vessel (6), provided that the valve (11) is open Also, the container containing the compressed fluid which acts as an anti-solvent (1) is also connected to a pump (3), through which said fluid is introduced compressed to said vessel (6), provided that the valves (2) and (4) are open The reactor (6) is thermostatized between -50 and 50 ° C, and a known volume of Solution A is introduced into the reactor (6) through the nozzle (5). The compressed fluid is introduced into the reactor (6) once the valve (4) is opened, until reaching the desired final pressure (1 to 200 bars), and a desired concentration of the compressed fluid in the expanded chloroform (X_ {FC} = 0.01-0.99). The precipitate formed as a consequence of the anti-solvent effect of the compressed fluid on Solution A it is deposited on the filter (7), which separates the material particulate depending on the light of the same filter. In a preferred embodiment, a stirring system can be used (14) to favor the reach of the system equilibrium during this stage. Particulate material must be separated at the same work pressure, in which the precipitation has occurred. Therefore, when opening the valve (8) to start the filtration, It is necessary to supply nitrogen gas (13) to the reactor (6), the which acts as a plunger and maintains constant pressure within the reactor (6). Alternatively, the filter may be external with respect to to the reactor (6), as long as it is at the same conditions of pressure (P) than the reactor (6). Once the separation is finished of the solid, depressurization of the unit of filtration, to collect the precipitated solid. Preferably, before depressurization and after filtered, a drying stage of the material can be performed particulate Drying can be done by, for example, a compressed fluid stream.
En la Figura 1.1 y Figura 1.2 comparativa se encuentran representados los perfiles de difracción de la fase dihidratada (Dh), la fase \beta y la fase \alpha. Tal y como puede observarse, el perfil de difracción de la fase dihidratada (Dh) posee picos en diferentes posiciones 2\theta e intensidades relativas diferentes que las fases \alpha y \beta.In Figure 1.1 and Comparative Figure 1.2, the diffraction profiles of the phase are represented dihydrate (Dh), the β phase and the α phase. Just like the diffraction profile of the dihydrated phase can be observed (Dh) has peaks in different positions 2 \ theta and intensities relative different than the α and β phases.
Los espectros de infrarrojo de la fase cristalina dihidratada, y de las fases \alpha y \beta, entre 400-4000 cm^{-1} se encuentran representados en la Figura 2.1. En la figura puede observarse que el perfil de las bandas situadas entre 2.250-2.700 cm^{-1} es diferente para las tres fases. Esta banda ancha, múltiple y de intensidad media probablemente puede ser asignada a la vibración de tensión del grupo NH^{+} de la amina cuaternaria. Si se amplía el espectro en el rango de números de onda entre 1.400-1.750 cm^{-1}, (Figura 2.2) se observan diferencias en las posiciones relativas de las bandas centradas alrededor de 1.700, 1.650 y 1.605 cm^{-1} para las tres fases. Estas bandas pueden ser asignadas a las vibraciones de tensión uC=O de los grupos esteres, uC=C del sistema conjugado de la 1,4-dihidropiridina y a la vibración de tensión uC=C del grupo benceno enlazado al anillo de dihidropiridina, respectivamente.The infrared spectra of the phase crystalline dihydrate, and of the? and? phases, between 400-4000 cm -1 are represented in the Figure 2.1. In the figure it can be seen that the profile of the bands located between 2,250-2,700 cm -1 is Different for all three phases. This broadband, multiple and medium intensity can probably be assigned to the vibration of tension of the NH + group of the quaternary amine. If the spectrum in the range of wave numbers between 1,400-1,750 cm -1, (Figure 2.2) are observed differences in the relative positions of the centered bands around 1,700, 1,650 and 1,605 cm -1 for all three phases. These bands can be assigned to voltage vibrations uC = O of the esters groups, uC = C of the conjugate system of the 1,4-dihydropyridine and at voltage vibration uC = C from the benzene group linked to the dihydropyridine ring, respectively.
Los análisis por DSC (Figura 3) realizados utilizando una rampa de calentamiento de 5ºC/min, revelan que esta fase cristalina (fase Dh) producida a partir del cloroformato funde entre 135-150°C, punto de fusión que es diferente del las fases \alpha y beta \beta, cuyos puntos de fusión son 189-190 y 169-170ºC, respectivamente.The DSC analyzes (Figure 3) performed using a heating ramp of 5ºC / min, they reveal that this crystalline phase (Dh phase) produced from the melt chloroformate between 135-150 ° C, melting point that is different of the? and beta? phases, whose melting points are 189-190 and 169-170 ° C, respectively.
La nueva fase fue caracterizada mediante un analizador termogravimétrico acoplado a un espectrómetro de masas, por impacto electrónico, que detecta los gases desprendidos por la muestra durante el proceso de calentamiento. El perfil de TGA, obtenido al someter una muestra de fase Dh a una rampa de calentamiento lenta de 1ºC/min, se representa en la Figura 4.1. En la Figura 4.2 se representa la variación de la intensidad de los picos del espectro de masas de los gases desprendidos durante el experimento de análisis termogravimétrico, donde se observan los picos moleculares m/z = 17 y m/z = 18 que son característicos del agua.The new phase was characterized by a thermogravimetric analyzer coupled to a mass spectrometer, by electronic impact, which detects the gases emitted by the Sample during the heating process. TGA's profile, obtained by submitting a sample of phase Dh to a ramp of Slow heating of 1 ° C / min, is shown in Figure 4.1. In Figure 4.2 shows the variation of the intensity of the peaks of the mass spectrum of gases released during the thermogravimetric analysis experiment, where the molecular peaks m / z = 17 and m / z = 18 that are characteristic of Water.
Tal y como puede observarse a partir del perfil obtenido mediante análisis termogravimétrico (TGA) y de la evolución del espectro de masas, se produce una perdida de peso del 6,5%, entre 110-150ºC, la cual corresponde a una pérdida de agua de la muestra. Este resultado indica que la relación molar entre el hidrocloruro de nicardipina y el agua es de 1:2. Por otro lado, esta perdida de agua coincide con el punto de fusión de la muestra observado por DSC (véase Figura 3).As can be seen from the profile obtained by thermogravimetric analysis (TGA) and of the evolution of the mass spectrum, there is a loss of weight of the 6.5%, between 110-150ºC, which corresponds to a Sample water loss. This result indicates that the molar ratio between nicardipine hydrochloride and water is of 1: 2 On the other hand, this water loss coincides with the point of sample fusion observed by DSC (see Figure 3).
Los análisis de solubilidad realizados, muestran que la nueva Forma pseudopolimórfica Dh posee un valor de solubilidad superior a las fases polimórficas ya conocidas, probablemente debido a que las interacciones intermoleculares en el sólido son de menor intensidad, tal y como queda reflejado en su menor temperatura de fusión. Además, la presencia de agua en la nueva Forma Dh favorece que sea más hidrófila y que presente menor tensión superficial entre el sólido y el agua. Inesperadamente, la presencia de agua en la estructura química de la nicardipina ha demostrado modificar la farmacocinética de la misma que unida a un menor punto de fusión conlleva que se trate de una fase cristalina termodinámicamente menos estable que las fases conocidas y se solubiliza de una forma más rápida que las fases anhidras conocidas.The solubility analyzes performed show that the new pseudopolymorphic form Dh has a value of higher solubility than known polymorphic phases, probably because intermolecular interactions in the solid are of less intensity, as reflected in their lower melting temperature In addition, the presence of water in the new Dh Form favors it being more hydrophilic and presenting less surface tension between solid and water. Unexpectedly, the presence of water in the chemical structure of nicardipine has demonstrated to modify the pharmacokinetics of the same as linked to a lower melting point means that it is a crystalline phase thermodynamically less stable than known phases and it solubilizes faster than the anhydrous phases known.
Estos resultados hacen de la nueva Forma pseudopolimórfica Dh un buen candidato como medicamento. Además, dicha Forma Dh es especialmente útil para los tratamientos de emergencia de enfermedades vasculares, como las crisis hipertensivas.These results make the new Form pseudopolymorphic Dh a good candidate as a medicine. Further, Said Dh Form is especially useful for the treatments of emergence of vascular diseases, such as crises hypertensive
Por lo tanto, la invención también se refiere a una formulación farmacéutica que comprende dicha Forma pseudopolimórfica Dh juntamente con excipientes farmacéuticamente aceptables. Y es especialmente ventajosa una formulación farmacéutica del hidrocloruro de nicardipina di hidratado en suspensión, solución y en disoluciones sólidas de liberación rápida de emergencia.Therefore, the invention also relates to a pharmaceutical formulation comprising said Form pseudopolymorphic Dh together with pharmaceutically excipients acceptable. And a formulation is especially advantageous Nicardipine Di Hydrochloride Pharmaceutical Hydrate in suspension, solution and in fast-release solid solutions of emergency.
Se suspenden 100 mg de un cloroformato de hidrocloruro de nicardipina (1:1) en 20 mL de éter etílico saturado de agua (aprox. 10 mg de agua/20 mL eter). Se deja unas horas a T = 8ºC y se obtiene la nueva Forma Dh, con un 100% de rendimiento.100 mg of a chloroformate of nicardipine hydrochloride (1: 1) in 20 mL of saturated ethyl ether of water (approx. 10 mg of water / 20 mL ether). Leave a few hours at T = 8 ° C and the new Dh Form is obtained, with a 100% yield.
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Se suspenden 100 mg del cloroformato de hidrocloruro de nicardipina (1:1) en 20 mL de éter etílico sobresaturado en agua (100 mg de agua/20 mL eter). Se deja unas horas a T = 8ºC y se obtiene la nueva Forma Dh. Con un 100% de rendimiento.100 mg of chloroformate are suspended nicardipine hydrochloride (1: 1) in 20 mL of ethyl ether supersaturated in water (100 mg of water / 20 mL ether). It leaves some hours at T = 8 ° C and the new Form Dh is obtained. With 100% of performance.
Se suspenden 300 mg del cloroformato de hidrocloruro de nicardipina (1:1) en una mezcla 1:1 (v/v) de agua y éter etílico (volumen total, V = 40 mL) a T = 8ºC. Una porción de sólido no solubilizada queda suspendida en agua. Al cabo de poco tiempo se forma la nueva Forma Dh, con un rendimiento cuantitativo.300 mg of chloroformate are suspended nicardipine hydrochloride (1: 1) in a 1: 1 (v / v) mixture of water and ethyl ether (total volume, V = 40 mL) at T = 8 ° C. A portion of Unsolubilized solid is suspended in water. After a while time the new Dh Form is formed, with a performance quantitative.
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Se suspenden 300 mg del cloroformato de hidrocloruro de nicardipina (1:1) en 20 mL de agua a T = 8ºC. Una porción de sólido no solubilizada queda suspendida en agua. Al cabo de poco tiempo se forma la nueva Forma Dh, con un rendimiento cuantitativo.300 mg of chloroformate are suspended Nicardipine hydrochloride (1: 1) in 20 mL of water at T = 8 ° C. A portion of unsolubilized solid is suspended in water. After in a short time the new Dh Form is formed, with a performance quantitative.
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Se prepara una disolución de hidrocloruro de nicardipina, fase \beta en cloroformo con una concentración C = 0,08 g NiH/mL de cloroformo. Se añaden 7 mL de esta disolución en un tubo de ensayo. Se adicionan alrededor de 20 mL de n-hexano. Al cabo de 72 horas se observa la aparición de cristales del cloroformato de hidrocloruro de nicardipina (p.f = 115ºC).A solution of nicardipine hydrochloride, β phase in chloroform with a concentration C = 0.08 g NiH / mL of chloroform is prepared. 7 mL of this solution is added in a test tube. About 20 mL of n-hexane are added . After 72 hours, the appearance of crystals of nicardipine hydrochloride chloroformate (mp = 115 ° C) is observed.
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Se prepara una disolución de hidrocloruro de nicardipina, fase \beta en cloroformo con una concentración C = 0,08 g NiH/mL de cloroformo. Se añaden 7 mL de esta disolución en un tubo de ensayo. Se adicionan alrededor de 20 mL de éter etílico. Al cabo de 72 horas se observa la aparición de cristales de un cloroformato de hidrocloruro de nicardipina (p.f = 115ºC).A solution of nicardipine hydrochloride, β phase in chloroform with a concentration C = 0.08 g NiH / mL of chloroform is prepared. 7 mL of this solution is added in a test tube. About 20 mL of ethyl ether are added . After 72 hours, the appearance of crystals of a nicardipine hydrochloride chloroformate (mp = 115 ° C) is observed.
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Se prepara una disolución de hidrocloruro de nicardipina, fase \beta en cloroformo con una concentración C = 0,12 g NiH/mL de cloroformo (Disolución A). Se introducen 115 mL de esta disolución en un reactor a alta presión de 275 mL. Se adiciona lentamente a un caudal de 5 ml/min CO_{2} líquido y se agita el sistema a una velocidad aproximada de 500 rpm (revoluciones por minuto). La presurización del sistema por adición de CO_{2} se lleva a cabo hasta que la presión final del sistema es de P = 10 MPa, y la fracción molar de CO_{2} en el cloroformo expandido de X_{CO2}=0,7. Como consecuencia del efecto anti-solvente del CO_{2} sobre la disolución A, se obtiene un precipitado, el cual se filtra a la presión de 10 MPa, mediante la utilización de N_{2} gas. Una vez finalizada la filtración, el sistema se despresuriza hasta 4 MPa. En todo el proceso la temperatura del sistema se mantiene a 35ºC. Se lleva a cabo un corto secado con CO_{2} puro trabajando en continuo a P=4 MPa. Una vez terminada la etapa de secado, se efectúa la despresurización del sistema hasta presión atmosférica, y se accede a la unidad filtrante para recoger el sólido. El sólido obtenido en este experimento corresponde al cloroformato de hidrocloruro de nicardipina (p.f = 115ºC), y el rendimiento es cuantitativo 99%.A hydrochloride solution of nicardipine, β phase in chloroform with a concentration C = 0.12 g NiH / mL chloroform (Solution A). 115 mL of this solution in a 275 mL high pressure reactor. Is added slowly at a flow rate of 5 ml / min liquid CO2 and stir the system at an approximate speed of 500 rpm (revolutions per minute). The pressurization of the system by the addition of CO2 is carried out until the final system pressure is P = 10 MPa, and the molar fraction of CO2 in the expanded chloroform of X_ {CO2} = 0.7. As a consequence of the effect CO2 solvent on solution A, se obtains a precipitate, which is filtered at a pressure of 10 MPa, by using N2 gas. Once the filtration, the system depressurizes up to 4 MPa. In all the process the system temperature is maintained at 35 ° C. It takes make a short drying with pure CO2 working continuously at P = 4 MPa. Once the drying stage is finished, the depressurization of the system to atmospheric pressure, and access to the filter unit to collect the solid. The solid obtained in This experiment corresponds to the hydrochloride chloroformate of Nicardipine (p.f = 115 ° C), and the yield is quantitative 99%.
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JPH09263537A (en) * | 1996-03-29 | 1997-10-07 | Taiyo Yakuhin Kogyo Kk | Sustained release nicardipine hydrochloride pharmaceutical preparation |
EP1413294A1 (en) * | 2001-07-27 | 2004-04-28 | Yamanouchi Pharmaceutical Co. Ltd. | COMPOSITIONS CONTAINING SUSTAINED−RELEASE FINE GRAINS FOR TABLETS QUICKLY DISINTEGRABLE IN THE ORAL CAVITY AND PROCESS FOR PRODUCING THE SAME |
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GB1455502A (en) * | 1973-02-20 | 1976-11-10 | Yamanouchi Pharma Co Ltd | 1,4-dihydropyridine derivatives |
IT1097538B (en) * | 1978-07-17 | 1985-08-31 | Medea Res Srl | PROCESS FOR THE PREPARATION OF 2,6-DIMETHYL-4-3 (3-NITROFENIL) -3-METOXYCARBONYL-1,4-DIDROPYRIDIN-5-CARBOXYLATE OF 2 (N-BENZYL-N-METHYLAMINE) |
ES491466A0 (en) * | 1980-05-14 | 1981-05-16 | Prodes Sa | A PROCEDURE FOR THE PREPARATION OF W- (N-BENCIL-N-AL-QUILAMINO) ALKYL ACID 2,6-DIMETHYL-4- (3-NITROPHENYL) -3-ALCOXYCARBONYL-1,4-DIHYDROPYRIDIN-5-CARBOXYLIC |
DK8602336A (en) * | 1985-05-21 | 1986-11-22 | ||
SI8810082A8 (en) * | 1988-01-18 | 1995-12-31 | Lek Tovarna Farmacevtskih | Process for preparing new inclusion complex of nicardipine or its hydrochloride with beta-cyclodextrine |
-
2008
- 2008-04-30 ES ES200801269A patent/ES2332168B1/en not_active Expired - Fee Related
-
2009
- 2009-04-30 WO PCT/EP2009/055286 patent/WO2009133180A1/en active Application Filing
Patent Citations (2)
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JPH09263537A (en) * | 1996-03-29 | 1997-10-07 | Taiyo Yakuhin Kogyo Kk | Sustained release nicardipine hydrochloride pharmaceutical preparation |
EP1413294A1 (en) * | 2001-07-27 | 2004-04-28 | Yamanouchi Pharmaceutical Co. Ltd. | COMPOSITIONS CONTAINING SUSTAINED−RELEASE FINE GRAINS FOR TABLETS QUICKLY DISINTEGRABLE IN THE ORAL CAVITY AND PROCESS FOR PRODUCING THE SAME |
Non-Patent Citations (2)
Title |
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J YAN et al., Boll. Chim. Farmaceutico 1990, vol. 129, págs. 276-278. "{}Characterization of alfa and beta crystalline forms of nicardipine hydrochloride"{}, todo el documento. * |
J YAN et al., Boll. Chim. Farmaceutico 1990, vol. 129, págs. 276-278. "Characterization of alfa and beta crystalline forms of nicardipine hydrochloride", todo el documento. * |
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ES2332168B1 (en) | 2010-10-27 |
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