ZA200502691B - Pharmaceutical composition comprising crystalline sibutramine methanesulfonate hemihydrate. - Google Patents
Pharmaceutical composition comprising crystalline sibutramine methanesulfonate hemihydrate. Download PDFInfo
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- ZA200502691B ZA200502691B ZA200502691A ZA200502691A ZA200502691B ZA 200502691 B ZA200502691 B ZA 200502691B ZA 200502691 A ZA200502691 A ZA 200502691A ZA 200502691 A ZA200502691 A ZA 200502691A ZA 200502691 B ZA200502691 B ZA 200502691B
- Authority
- ZA
- South Africa
- Prior art keywords
- sibutramine
- formula
- ether
- group
- crystalline
- Prior art date
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- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 title claims description 140
- 229960004425 sibutramine Drugs 0.000 title claims description 133
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims description 130
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 68
- 238000000034 method Methods 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000013078 crystal Substances 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 17
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 12
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 claims description 7
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 27
- KFNNPQDSPLWLCX-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-n,n,3-trimethylbutan-1-amine;hydron;chloride;hydrate Chemical compound O.Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 KFNNPQDSPLWLCX-UHFFFAOYSA-N 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 24
- 239000004480 active ingredient Substances 0.000 description 20
- 229960005303 sibutramine hydrochloride monohydrate Drugs 0.000 description 19
- UNAANXDKBXWMLN-MRXNPFEDSA-N (1r)-1-[1-(4-chlorophenyl)cyclobutyl]-n,n,3-trimethylbutan-1-amine Chemical compound C=1C=C(Cl)C=CC=1C1([C@H](N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-MRXNPFEDSA-N 0.000 description 15
- UNAANXDKBXWMLN-INIZCTEOSA-N (1s)-1-[1-(4-chlorophenyl)cyclobutyl]-n,n,3-trimethylbutan-1-amine Chemical compound C=1C=C(Cl)C=CC=1C1([C@@H](N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-INIZCTEOSA-N 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- MVODTGURFNTEKX-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)-n-(thiophen-2-ylmethyl)ethanamine;hydrobromide Chemical class Br.BrCCN(CCBr)CC1=CC=CS1 MVODTGURFNTEKX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 229960003466 sibutramine hydrochloride Drugs 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 206010033307 Overweight Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940045623 meridia Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- CSJCEQXZVMIHRX-UHFFFAOYSA-N 2,3-dibenzyl-2,3-dihydroxybutanedioic acid Chemical compound C=1C=CC=CC=1CC(O)(C(O)=O)C(O)(C(=O)O)CC1=CC=CC=C1 CSJCEQXZVMIHRX-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000003981 vehicle 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Description
SPECIFICATION
PHARMACEUTICAL COMPOSITION COMPRISING
CRYSTALLINE HEMIHYDRATE OF SIBUTRAMINE
METHANESULFONATE
Fig. 1 shows powder X-ray diffraction spectra of the crystalline sibutramine methanesulfonate hemihydrate according to the present invention.
Fig. 2 shows powder X-ray diffraction spectra of the anhydrous sibutramine methanesulfonate according to the present invention.
Fig. 3 shows powder X-ray diffraction spectra of the sibutramine hydrochloride monohydrate according to the present invention.
Fig. 4 shows differential scanning calorimeter thermograms of the crystalline sibutramine methanesulfonate hemihydrate according to the present invention.
Fig. 5 shows differential scanning calorimeter thermograms of the anhydrous sibutramine methanesulfonate according to the present invention.
Fig. 6 shows preparation procedure of (+)-sibutamine methanesulfonate hemihydrate or (-)-sibutramine methanesulfonate hemihydrate from racemic sibutramine.
The present invention relates to a pharmaceutical composition for treating or preventing obesity, and specifically, relates to a pharmaceutical composition comprising crystalline hemihydrate of sibutramine acid-addition salt.
Sibutramine, N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3- methylbutylamine of formula (II); may be used for preventing or treating depression, Parkinson’s disease and obesity (see GB Patent No. 2,098,602, Korean Patent Publication No. 90-00274,
International Publication No. WO 88/06444, and Korean Patent Publication
No0.99-164435). Further, sibutramine may be used for reducing the resistance to insulin or enhancing the resistance to sugar, and for preventing or treating such diseases as gout, hyperuricemia, hyperlipemia, osteoarthritis, anxiety disorder, somnipathy, sexual dysfunction, chronic fatigue syndrome and cholelithiasis (see US Patent Nos. 6,174,925, 5,459,164, 6,187,820, 6,162,831, 6,232,347, 6,355,685, 6,365,631, 6,376,554, 6,376,551 and 6,376,552).
However, since sibutramine is oil, which is hard to use in a pharmaceutical application, it is needed to convert to an acid-addition salt in the pharmaceutical application.
GB Patent No. 2,098,602 and Korean Patent Publication No. 90-00274 disclose methods for preparing oil type sibutramine and an anhydrous hydrochloride form thereof as a pharmaceutically acceptable acid-addition salt.
However, since anhydrous sibutramine hydrochloride is too hygroscopic, it is hard to maintain the content of an active ingredient constantly, and may have an effect on the quality of the product by inducing hydrolysis and chemical decomposition of an active ingredient. Accordingly, it is difficult to use anhydrous sibutramine hydrochloride as an active ingredient of a pharmaceutical composition.
In order to solve the above problem, non-hygroscopic sibutramine hydrochloride monohydrate of formula (IV) was developed (see GB Patent No. 2,184,122 and Korean Patent Publication No. 94-08913), and therefore, sibutramine can be used in medication. Sibutramine hydrochloride monohydrate is being used as an active ingredient of medication for treating obesity such as Meridia and Reductil. * HCls H,0 (IV)
However, it is obvious that an active ingredient used in a pharmaceutical composition has to be non-hygroscopic and stable at high temperature, and have higher solubility for water or aqueous solution having broad pH range, because the solubility of an active ingredient for aqueous solution have an effect on release rate of composition, and further have an effect on bioavailability of a drug. Generally, solubility of more than 1 mg/ml is desire in the range from pH 1 to pH 7. In case of solubility of less than 3 mg/ml, absorption after in vivo administration can be limited in considering of disintegrating rate.
Sibutramine hydrochloride monohydrate as an active ingredient of
Meridia and Reductil, which is marketed for treating obesity, has a problem of relatively low solubility in water as an active ingredient of a pharmaceutical composition. For example, solubility of sibutramine hydrochloride monohydrate is 2.9 mg/ml at pH 5.2, which does not meet the lowest limit of the solubility needed for an active ingredient of a pharmaceutical composition (see Merck Index, 13™ Ed, p1522). Accordingly, there has been a need to develop a novel salt or hydrate of crystalline sibutramine, which is suitable for use in a pharmaceutical composition in stability for high temperature and humidity, non-hygroscopicity, and solubility for water.
The present inventors hereby have endeavored to develop sibutramine
: CL : : methanesulfonate hemihydrate, which is non-hygroscopic and being stable under a high temperature/humidity condition, and has a high solubility in water.
It is an object of the present invention to provide a pharmaceutical composition for treating or preventing obesity or diseases related therewith, comprising an acid-addition salt of sibutramine which has a high solubility in water and are stable under a high humidity/temperature condition as an active ingredient.
It is another object of the present invention to provide an acid-addition salt of sibutramine and a method for the preparation thereof.
In accordance with one aspect of the present invention, the present invention provides a pharmaceutical composition comprising the novel crystalline sibutramine methanesulfonate hemihydrate of formula (I), which has a high solubility in water and a high stability under a high humidity/temperature condition. or ¢ CH3SO3Hs 1/2H,0 0)
In accordance with another aspect of the present invention, the present invention provides crystalline sibutramine methanesulfonate hemihydrate of formula (I) and a method for the preparation thereof.
Herein, the term “sibutramine” refers to racemic sibutramine, unless otherwise indicated.
The present invention is described in detail as follows.
The crystalline sibutramine methanesulfonate hemihydrate of formula (I) according to the present invention has a eminently high solubility in water, and is stable under a high humidity/temperature condition and non-hygroscopic, which is needed for an active ingredient of a pharmaceutical composition.
Specifically, the 20 values of peaks observed in X-ray diffraction spectrum of the crystalline sibutramine methanesulfonate hemihydrate of formula (I), when I/I0 =200, are 8.2+0.2, 10.8+0.2, 11.7+0.2, 12.0+0.2, 12.3+0.2, 15.8+0.2, 16.4+0.2, 17.4+0.2, 17.4+0.2, 17.8+0.2, 19.0+0.2, 21.2+0.2, 21.9+0.2, 22.2+0.2, 22.8+0.2, 23.3+0.2, 24.4+0.2, 24.9+0.2, 25.3+0.2, 25.6x0.2 and 26.8+0.2.
There are two methods for preparing the crystalline sibutramine methanesulfonate hemihydrate of formula (I) as follows.
First, the crystalline sibutramine methanesulfonate hemihydrate of formula (I) may be prepared by reacting sibutramine of formula (II) with methanesulfonic acid in a mixture of an organic solvent and water (hereinafter, “the 1* method”).
Foes (I)
In the 1* method, methanesulfonic acid may be employed in an amount ranging from 1 to 2 mole equivalents, preferably from 1.1 to 1.2 mole equivalents, based on 1 mole equivalent of sibutramine of formula (I).
Generally, methanesulfonic acid is dropwisely added to the substrate, which may be neat sibutramine or a solution thereof dissolved in an organic solvent.
In the 1% method, water may be employed in an amount ranging from 0.5 to 5 mole equivalents based on 1 mole equivalent of sibutramine of formula 11).
In the 1 method, an organic solvent may be employed in an amount ranging from 3 to 20 ml, preferably from 5 to 15 ml, based on 1 g of sibutramine of formula (II).
The organic solvent used in the 1* method may be more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; or a mixture of more than one ketone from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone and more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether.
When a mixture of a ketone and ether is used, the ketone to ether ratio is preferably in ranging of 1:0.5 to 1:1.5, more preferably 1:2 to 1:3.
In this method, the reaction is performed at a reaction temperature ranging from OC to the boiling point of the solvent, preferably from 15 to 35°C, for 0.5 to 5hrs after adding methanesulfonic acid.
Second, the crystalline sibutramine methanesulfonate hemihydrate of formula (I) may be prepared by (i) reacting sibutramine of formula (II) with methanesulfonic acid in an anhydrous organic solvent to obtain anhydrous sibutramine methanesulfonate of formula (IIT); and (ii) bringing the sibutramine methanesulfonate of formula (III) into contact with water in an organic solvent to obtain crystals, and filtering the produced crystal (hereinafter, “the 2" method”). + CH;SO3H (I)
In the 2™ method, methanesulfonic acid may be employed in an amount ranging from 1 to 2 mole equivalents, preferably from 1.1 to 1.2 mole equivalents, based on 1 mole equivalent of the sibutramine of formula (1D).
Generally, methanesulfonic acid is dropwisely added to neat sibutramine of formula (II) or a solution thereof dissolved in an organic solvent.
In the 2™ method, water may be employed in an amount ranging from 0.5 to 5 mole equivalents, based on 1 mole equivalent of sibutramine methanesulfonate hemihydrate of formula (III).
In the step 1) and 11) of the 2™ method, an organic solvent may be employed in an amount ranging from 3 to 20 ml, preferably from 5 to 15 ml, based on 1 g of each sibutramine of formula (II) and anhydrous sibutramine of formula (III).
The anhydrous organic solvent of the step i) of the 2° method may be more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ketone from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone; more than one ether from the group consisting of ethyl ether, isopropyl ether and t-butyl methyl ether; toluene; or a mixture thereof.
The organic solvent of the step ii) of the 2° method may be more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; or a mixture of more than one ketone from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone, and more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether.
When the organic solvent is a mixture of a ketone and ether, the ketone to ether ratio is preferably in the range of from 1:0.5 to 1:1.5, more preferably from 1:2 to 1:3.
In the 2" method, the reaction is performed at a temperature ranging from 0 C to the boiling point of the solvent, preferably from 15 to 35 C, for 0.5 to Shrs after adding methanesulfonic acid in the step i). It is preferred that anhydrous sibutramine methanesulfonate of formula (III) is brought into contact with water for 2 hrs to 5 days in the step 11).
Crystalline sibutramine methanesulfonate hemihydrate of formula (I) prepared according to the said two methods has an enhanced solubility in water, and is non-hygroscopic and highly stable under a high humidity/temperature condition similarly in comparison with sibutramine hydrochloride monohydrate of formula (IV) used as a conventional acid-addition salt.
Since this enhanced solubility in water of crystalline sibutramine methanesulfonate hemihydrate of formula (I), the said crystalline sibutramine methanesulfonate hemihydrate has a favorable release rate from the composition comprising thereof, and has a good bioavailability.
Meanwhile, one embodiment of the present invention examined whether crystalline sibutramine methanesuifonate hemihydrate of the present invention can be prepared from either of the (+)- and (-)-enantiomers of sibutramine (see
Fig. 6). It was checked through the following comparative test that crystalline sibutramine methanesulfonate hemihydrate of the present invention failed to form from (+)- and (-)-enantiomers of sibutramine. And it can be one example to prove the uniqueness and creativity of crystalline sibutramine methanesulfonate and a method for the preparation thereof.
Specifically, examined was whether crystalline sibutramine methanesulfonate hemihydrate of the present invention can be prepared from each of (+)- and (-)-enantiomers separated from racemic sibutramine.
Racemic sibutramine was optically resolved to obtain (+)- and (-)-sibutramine, according to the method disclosed in US Patent Publication US No. 2002/0006963, US 2002/0006964 or International Patent publication No. WO 00/10551. Then, the (+)- and (-)-sibutramine were each treated according to the method of the present invention and similar method to see whether crystalline (+)- or (-)-methanesulfonate hemihydrate can be prepared therefrom.
Specifically, racemic sibutramine is reacted with L-DBTA (dibenzyl tartaric acid) in ethyl acetate and filtered, and the produced crystals is collected and extracted with ethyl acetate and isopropyl alcohol to obtain more than 99.3 % ee (enantiomers excess) of L-DBTA salt of pure (-)-sibutramine. And the filtrate obtained by filtration after reacting with L-DBTA is neutralized with sodium hydroxide, and then extracted with chloroform to obtain (+)-sibutramine, which is nearly pure (+)-isomer. D-DBTA is added thereto to obtain crystals and the crystals can be recrystallized to obtain more than 99.3 % ee of D-DBTA salt of (+)-sibutramine. The obtained L-DBTA salt of (-)-sibutramine and D-
DBTA salt of (+)-sibutramine are neutralized and extracted to obtain (-)- sibutramine and (+)-sibutramine free bases. However, each of the (-)- or (+)- sibutramine free base failed to give crystalline methanesulfonate hemihydrate when the method according to the present invention is employed.
Accordingly, it is conceivable that the crystalline sibutramine methanesulfonate hemihydrate of the present invention has Intrinsic physicochemical characteristics in crystalloid, which can not be easily prepared by conventional methods.
Further, the present invention provides a pharmaceutical composition for treating obesity and diseases related therewith, which comprises the crystalline sibutramine methanesulfonate hemihydrate of formula (I) as an active ingredient, and a pharmaceutically acceptable carrier, diluent and excipient.
Preferably, the pharmaceutical composition of the present invention is administrated as an oral formulation in the form of a tablet or capsule.
Tablets may be prepared by mixing the active ingredient with a carrier, diluent or excipient. Examples of the carrier, excipient and diluent employed in the pharmaceutical composition of the present invention are a disintegrator such as starch, sugar and mannitol; a filler and extender such as calcium phosphate and silicate derivatives; a binder such as carboxymethyl cellulose and derivatives thereof, gelatin, and polyvinyl pyrrolidone); and a lubricant such as talc, calcium stearate and magnesium stearate, and solid polyethylene glycol.
And hard or soft capsules containing the active ingredient may be prepared without or with an additive such as a carrier, diluent and excipient, according to a conventional method.
Preferably, the effective amount of the crystalline sibutramine methanesulfonate hemihydrate of formula (I) in the inventive pharmaceutical composition ranges from 1 to 50 weight part, based on 250 weight part of the composition.
For example, 250 mg of the pharmaceutical composition of the present invention may be prepared to contain 10mg of crystalline sibutramine methanesulfonate hemihydrate of formula (I), 115mg of fine crystalline cellulose, 115mg of lactose, Smg of silicon dioxide and 5Smg of magnesium stearate. However. the above composition ratio dose should not be intended to limit the scope of the invention in any way.
Hereinafter, the following Examples are intended to further illustrate crystalline sibutramine methanesulfonate hemihydrate of formula (I) of the present invention and a method for the preparation thereof without limiting its scope.
Preparation Example 1: Preparation of sibutramine hydrochloride monohydrate (compound of formula (IV))
Anhydrous sibutramine hydrochloride was prepared according to the method disclosed in GB Patent No. 2,098,602 or Korean Patent Publication No. 90-00274. And 10g of the prepared anhydrous sibutramine hydrochloride was dissolved in a boiling mixture of acetone (110ml) and water (1.2ml), and the mixture was hot-filtered and distillated 80 ml of solvent to concentrate the filtrate according to the method disclosed in GB Patent No. 2,184,122 or
Korean Patent Publication No. 94-08913. The concentrate was cooled and filtered to obtain crystals, and the crystals were dried under a vacuum to obtain 9.2g of the compound of formula (IV) having a melting point 195 CT (Yield: 87%).
Example 1: Preparation of sibutramine methanesulfonate hemihydrate (compound of formula (I) by the 1*! method 1-1) Preparation of sibutramine methanesulfonate hemihydrate 1
30.0g of sibutramine of formula (II) was dissolved in 120ml of isopropyl acetate, 1.94ml of water was added, and then 10.9g of methanesulfonic acid was dropwisely added thereto. The reaction mixture was stirred for lhr, cooled to 0 °C, again stirred for about 2hrs, and then filtered to obtain crystals. The crystals were sequentially washed with 30ml of isopropyl acetate and 30ml of isopropyl ether, and then dried at 50 “C to obtain 38.46g of the title compound as a white solid (Yield: 92.5%).
Melting point; 164~165 C (shrunk at about 130 Ty,
Water content: 2.35% (Theoretical value: 2.34%); and 'H-NMR (5, DMSO-d6): 8.5(1H, br. s), 7.7~7.2(4H, dd), 3.7(1H, 1), 2.8(3H, d), 2.5(2H, d), 2.4(3H, s), 2.3(2H, d), 2.1(3H, d), 1.9(1H, m), 1.7~1.6(2H, m), 1.3(2H, t), 1.0(6H, t). 1-2) Preparation of sibutramine methanesulfonate hemihydrate 2 10.0g of sibutramine of formula (II) was dissolved in a mixture of 40ml of ethyl acetate and 40ml of t-butyl methyl ether, 0.97ml of water was added, and then 3.8g of methanesulfonic acid was dropwisely added thereto. The reaction mixture was stirred for 1hr, cooled to 0 C again stirred for about 2hrs, and then filtered to obtain crystals. The crystals were sequentially washed with a mixture of 30ml of isopropyl acetate and 30ml of isopropyl ether, and then dried at 50 C to obtain 12.1g of the title compound as a white solid (Yield: 88%). The water content of the title compound was 2.38% (Theoretical value: 2.34%), and the melting point and the "H-NMR data thereof were the same as those observed in 1-1). 1-3) Preparation of sibutramine methanesulfonate hemihydrate 3 11.7g of the title compound (Yield: 85%) was prepared by repeating the procedure of the above 1-2), except for employing 30m! of acetone and 60ml of t-butyl methyl ether, instead of 40ml of ethyl acetate and 40ml of t-butyl methyl ether. The water content of the title compound was 2.27% (Theoretical value: 2.34%), and the melting point and the "H-NMR data thereof were the same as those observed in 1-1).
Example 2: Preparation of sibutramine methanesulfonate hemihydrate (compound of formula (I)) by 2°! method 2-1) Preparation of anhydrous sibutramine methanesulfonate (compound of formula (III) (step 1 of the 2™ method)
Anhydrous sibutramine methanesulfonate was prepared from the sibutramine in following 2-1-1) to 2-1-3) respectively, as a step 1 of the 2 method to prepare sibutramine methanesulfonate hemihydrate. 2-1-1) Preparation of anhydrous sibutramine methanesulfonate 1 10.0g of sibutramine of formula (II) was dissolved in 70m] of acetone, and then 3.75g of methanesulfonic acid was dropwisely added at room temperature. The reaction suspension was stirred for 1hr, cooled to 0 C, again stirred for about 2hrs, and then filtered to obtain crystals. The crystals were washed with 30ml of ether, and then dried at 50 C to obtain 11.7g of the title compound as a white solid (Yield: 87%).
Melting point: 164~165 TC;
Water content: 0.2%; and "H-NMR (8, DMSO-d6): 8.5(1H, br. s), 7.5(4H, dd), 3.7(1H, t), 2.8(3H, d), 2.5(2H, d), 2.4(3H, s), 2.3(2H, d), 2.1(3H, d), 1.9(1H, m), 1.7~1.6(2H, m), 1.4(2H, t), 1.0(6H, 1). 2-1-2) Preparation of anhydrous sibutramine methanesulfonate 2 10.0g of sibutramine of formula (IT) was dissolved in 80ml of toluene, and then 3.75g of methanesulfonic acid was dropwisely added at room temperature. The reaction suspension was stirred for 2hrs, cooled to 0C, stirred for about 2hrs, and then filtered to obtain crystals. The crystals were washed with 20ml of ether and then dried at SOC to obtain 12.82 of the title compound as a white solid (Yield: 95%). The water content of the title compound was 0.1%, and the melting point and the 'H-NMR data thereof were the same as those observed in 2-1-1). 2-1-3) Preparation of anhydrous sibutramine methanesulfonate 3 12.5g of the title compound as a white solid was prepared by repeating the procedure of the above 2-1-2) (Yield: 93%), except for using isopropyl acetate instead of toluene. The water content of the product was 0.1%, and the melting point and the "H-NMR data thereof were the same as those observed in 2-1-1). 2-2) Preparation of sibutramine methanesulfonate hemihydrate (compound of formula (II)) (step 2 of the 2"! method)
In following 2-2-1) and 2-2-2), sibutramine methanesulfonate hemihydrates were prepared from the anhydrous sibutramine methanesulfonate prepared in 2-1-1) to 2-1-3) respectively. 2-2-1) Preparation of sibutramine methanesulfonate hemihydrate 1 5.0g of anhydrous sibutramine methanesulfonate of formula (III) prepared in any one of 2-1-1) to 2-1-3) was dissolved in a mixture of 50ml of ether and 25ml of acetone, and then 0.72ml of water was added thereto. The reaction mixture was stirred for 18hrs at room temperature, and then filtered to obtain crystals. The crystals were washed with 10ml of a mixture of ether and acetone (2:1 v/v), dried at 50 TC to obtain 3.89g of the title compound as a white solid (Yield: 76%). The water content of the obtained compound was 2.30% (Theoretical value: 2.34%), and the melting point and the "H-NMR data thereof was the same as those observed in 1-1). 2-2-2) Preparation of sibutramine methanesulfonate hemihydrate 2
. 10.0g of anhydrous sibutramine methanesulfonate of formula (III) prepared in any one of 2-1-1) to 2-1-3) was dissolved in a mixture of 100ml of ether and 40ml of methyl isobutyl ketone, and then 1.44ml of water was added thereto. The reaction mixture was stirred for 24hrs at room temperature and then filtered to obtain crystals. The crystals were washed with 30ml of a mixture of ether and methyl ethyl ketone (2:1 v/v), dried under warm wind to obtain 7.5g of the title compound as a white solid (Yield: 73%). The water content of the obtained compound was 2.32% (Theoretical value: 2.34%), and the melting point and the "H-NMR data thereof were the same as those observed in 1-1).
Example 3: Qualitative analysis of the structure of crystalline sibutramine methanesulfonate hemihydrate of formula (I)
Powder X-ray diffraction data and a differential scanning calorimeter thermogram of sibutramine methanesulfonate hemihydrate of formula (I) prepared in Example 1 and 2, anhydrous sibutramine hemihydrate of formula (IIT), and sibutramine hydrochloride monohydrate of formula (IV) prepared in
Preparation example 1 showed that crystal shape of sibutramine methanesulfonate hemihydrate of the present invention was different from either conventional sibutramine hydrochloride monohydrate or anhydrous sibutramine methanesulfonate (see Figs. 1 to 5).
The powder X-ray diffraction spectrum of sibutramine methanesulfonate hemihydrate of formula (I) showed characteristic peaks (Fig. 1), which are represented in Table 1. In table 1, “26”, “d” and “I/I,” mean the diffraction angel, the distance between crystal facets, and the relative peak intensity, i respectively.
Table 1 26(x0.2) d Ul, 26(£0.2) d 1, 8.2 10.8 868 21.2 4.19 785 10.8 8.17 218 21.9 4.06 646 11.7 7.53 210 22.2 4.00 315 12.0 7.36 276 22.8 3.90 286 12.3 7.19 661 23.3 3.81 456 15.8 5.61 716 24.4 3.65 537 16.4 5.39 725 24.9 3.58 596 17.4 5.10 792 25.3 3.52 322 17.8 4.97 498 25.6 3.47 351 19.0 4.68 556 26.8 3.33 1000
Experimental Example 1: Measurement of solubility in water
The solubility in water was compared between sibutramine methanesulfonate hemihydrate of formula (I) prepared in Example 1 and 2, and sibutramine hydrochloride monohydrate of formula (IV) have been used as an active ingredient of pharmaceutical composition of sibutramine.
Sibutramine methanesulfonate hemihydrate of formula (I) and sibutramine hydrochloride monohydrate were each dissolved to the saturation point at pH 5.2, and then subjected to high performance liquid chromatography (HPLC) to determine the dissolved amount (based on free base of sibutramine).
The results are shown in Table 2.
Table 2
Solubility in water
Salt (mg/ml, pH5.2)
Sibutramine hydrochloride monohydrate 29 (compound of formula (IV)) )
Sibutramine methanesulfonate hemihydrate 2.500 (compound of formula (I)) ’
As can be seen in Table 2, sibutramine methanesulfonate hemihydrate had a markedly higher solubility in water than that of conventional sibutramine hydrochloride monohydrate. Therefore, it is expected that the bioavailability of crystalline sibutramine methanesulfonate hemihydrate is better than that of sibutramine hydrochloride monohydrate.
Experimental Example 2: Test of stability under a high humidity/temperature condition
Since the thermal stability of an active ingredient used in pharmaceutical composition is very important fact in a preparation of tablets or capsules, and a long-term storage, the stability of crystalline methanesulfonate hemihydrate under high temperature was compared with that of the sibutramine hydrochloride monohydrate of formula (IV) in accordance with time lapse.
Specifically, the residual rates of each compounds based on the initial value of an active ingredient at 60°C after 1, 2, 3 and 6 months are compared by HPLC, and the results were shown in Table 3.
Table 3
Sibutramine hydrochloride monohydrate 1.000 1.000 0.999 0.999 0.992 (Compound of formula (IV))
Sibutramine methanesulfonate hemihydrate 1.000 1.001 0.999 0.999 1.000 (Compound of formula (I))
As can be seen in Table 3, sibutramine hydrochloride monohydrate of formula (IV) showed a little reduction of an amount of an active ingredient after 6 months, but sibutramine methanesulfonate hemihydrate of formula (I) showed no degradation after 6 months, and existed stably in an absolute amount as much as initial amount. Crystalline sibutramine hemihydrate is as stable as, or more stable than sibutramine hydrochloride monohydrate.
Experimental Example 3: Non-hygroscopic test
Crystalline sibutramine methanesulfonate hemihydrate of formula (I)
prepared in Example 1 and 2, and conventional sibutramine hydrochloride monohydrate were each exposed to a high temperature/humidity condition of 40C and 75% relative humidity for 1, 2, and 5 days, and the water content thereof was measured by employing Kaal-Fisher moisture analyzer. The results are shown in Table 4. In table 4, the measurement figures showed content of water (weight %) contained in an active ingredient.
A similar series of experiments were conducted at 40C and 10% relative humidity by measuring degree of dissociation of water of crystallization, in order to examine whether the respective compounds are stable hydrate not releasing water of crystallization.
In addition to, hygroscopic property of anhydrous sibutramine methanesulfonate prepared by the conventional preparation method of pharmaceutically acceptable salt was measured to show that sibutramine methanesulfonate hemihydrate is stable in water.
Table 4 elative methanesulfonate humidity (TC) (day) (formula (I) monohydrate methanesulfonate (formula (IV)) (formula (IT)) 2.30 5.48 2.25 5 2.26 5.36 0.70
As can be seen in Table 4, crystalline sibutramine methanesulfonate hemihydrate of formula (I) is non-hygroscopic as same as conventional hydrochloride monohydrate under a high humidity condition, and it is a stable hydrate, which is not release the water of crystallization under a dry condition.
Therefore, crystalline sibutramine methanesulfonate hemihydrate of formula (I) having a high solubility in water, and enhanced stability under a high humidity/temperature condition is useful as an active ingredient of pharmaceutical composition.
Experimental Example 4: Conformation of weight loss effect of crystalline sibutramine methanesulfonate hemihydrate
The following test was conducted to examine the effect of treating or preventing obesity of crystalline sibutramine methanesulfonate hemihydrate of formula (I) prepared in Example 1 and 2. 16 each of overweight Zuker rats (fa/fa) and thin Zuker rats (Fa/Fa) (from Charles River Japan, BioGenomics) were divided into drug- administrating and control groups (8 rats per group), and the weight of each rat was measured prior to the test. A 3mg/kg dose of crystalline sibutramine methanesulfonate hemihydrate was administrated to each rat of the drug- administrating groups, whiling the vehicle was administrated to those of the control groups, everyday for 21days. During the period, rats were allowed free access to high-fat food, and the average weights of the drug administrating and control groups were determined in order to calculate the weight gain and loss.
The results were shown in Table 5.
Table 5
Overweight Zuker rats Thin Zuker rats
The drug The The drug The administrating | control | administratin | control group group g group group
The average weigh before test (g: A) 245.0
The average weight after test (g: B) 455.6 486.2 303.4 323.6
Weight gain (g: B-A) 123.4 153.0
Weight loss effect (g: (Gain in weight of the control 29.6 20.4 group)-(Gain in weight of the drug administrating group))
As can be shown in Table 5, the group administrated with crystalline methanesulfonate hemihydrate of formula (I) showed a remarkable weight loss effect, as compared with the control group. Accordingly, it was demonstrated that crystalline methanesulfonate hemihydrate of formula (I) is available for treating or preventing obesity.
Comparative Example: Preparation of (+)- and (-)-isomer of sibutramine methanesulfonate hemihydrate
The following test was conducted to examine whether a corresponding sibutramine methanesulfonate hemihydrate can be prepared from an optical isomer of sibutramine. (1) Optical resolution of sibutramine [(+)- and (-)-isomer of compound of formula (II)] 12.3g of racemic sibutramine was dissolved in 85ml of ethyl acetate, L-
DBTA dissolved in 85ml of ethyl acetate was added thereto. The reaction mixture was heated under reflux, cooled to room temperature and then filtered to obtain crystals (ee: about 85%). And then, the crystals were suspended in 220ml of ethyl acetate, and heated under reflux for 30 min to obtain solids.
The solids were recrystallized from 450ml of isopropyl alcohol to obtain L-
DBTA salt of (-)-sibutramine (ee: >99.3%). The L-DBTA salt of (-)- sibutramine was neutralized to pH 8.5 with saturated sodium bicarbonate, and then extracted with chloroform to obtain (-)-sibutramine free base.
The filtrate obtained by filtration after reacting with L-DBTA was neutralized to pH 8.5 with sodium hydroxide, and then extracted with chloroform to obtain (+)-sibutramine, which was nearly pure (+)-isomer. D-
DBTA was added thereto to obtain crystals and the crystals were recrystallized from 450ml of isopropyl alcohol to obtain D-DBTA salt of (+)-sibutramine (ee: >99.3%). The D-DBTA salt of (+)-sibutramine was neutralized to pH 8.5 with saturated sodium bicarbonate, and then extracted with chloroform to obtain (+)- sibutramine free base. (2) Preparation of (+) and (-)-isomer of sibutramine methanesulfonate (+)- and (-)-isomer free bases of sibutramine prepared in above (1) were treated according to the same method as that described in 2-1-2) of Example 2 to prepare the respective anhydrous methanesulfonate: (+)-sibutramine methanesulfonate: m.p. 156.5~157.5 TC, water-content 0.30%; (-)-sibutramine methanesulfonate: m.p. 156.5~157.5 C, water-content 0.05%. (3) Attempt to prepare (+)- and (-)-isomer of sibutramine methanesulfonate hemihydrate
Anhydrous (+)- and (-)-isomer of sibutramine methanesulfonate prepared in (2) were each treated according to the same method as that described in 2-2) of Example 2. However, no crystal formation was observed.
Accordingly, the solvent of (+)- or (-)-sibutramine methanesulfonate was replaced with toluene to induce crystal formulation. However, the crystals obtained had the same melting points/water-contents as those of anhydrous (+)- and (-)-sibutramine methanesulfonate prepared in above (2), respectively.
Further, anhydrous (+)- and (-)-sibutramine methanesulfonate were each placed for 1 day at room temperature under 75% relative humidity. Each melted within 2 hours, and became a transparent liquid in 1 day.
The above results which a corresponding sibutramine methanesulfonate cannot be prepared from respective optical isomer of sibutramine showed that sibutramine methanesulfonate hemihydrate of the present invention cannot be easily prepared by a conventional method.
The inventive crystalline sibutramine methanesulfonate hemihydrate, a methanesulfonic acid-additional salt of sibutramine, has an enhanced solubility in water, and identical or improved stability and non-hygroscopicity, as compared with the control group. Therefore, a pharmaceutical composition comprising the compound in an effective amount for treating or preventing can be prepared, and used to treat or prevent obesity or its related disease.
Claims (1)
- WHAT IS CLAIMED IS:1. A pharmaceutical composition for treating or preventing obesity, comprising the crystalline sibutramine methanesulfonate hemihydrate of formula (I). Fores ¢ CH3SO3He 172H,0 0)2. The pharmaceutical composition of claim 1, wherein the 20 values of the major peaks in the X-ray diffraction spectrum of the crystalline sibutramine methanesulfonate hemihydrate are:8.2+0.2, 10.8+0.2, 11.7+0.2, 12.0+0.2, 12.320.2, 15.820.2, 16.4+0.2,17.4+0.2, 17.420.2, 17.840.2, 19.0£0.2, 21.2+0.2, 21.920.2, 22.2+0.2, 22.8+0.2,23.320.2, 24.4+0.2, 24.9+0.2, 25.3+0.2, 25.6+0.2 and 26.8+0.2.3. The pharmaceutical composition of claim 1 or 2, further comprising a pharmaceutically acceptable carrier, diluent or excipient.4. The pharmaceutical composition of claim 1 or 2, wherein the crystalline sibutramine methanesulfonate hemihydrate is present in an amount ranging from 1 to 50mg.5. The crystalline sibutramine methanesulfonate hemihydrate of formula@. or ¢ CH3SO3He 1/2H;,0 06. The crystalline sibutramine methanesulfonate hemihydrate of formula (I) of claim 5, of which the 28 values of the major peaks in the X-ray diffraction spectrum are:8.2+0.2, 10.820.2, 11.7£0.2, 12.0+0.2, 12.320.2, 15.8+0.2, 16.4+0.2,17.4+0.2, 17.4+0.2, 17.8+0.2, 19.0+0.2, 21.2+0.2, 21.9+0.2, 22.2+0.2, 22.8+0.2,23.320.2, 24.4+0.2, 24.9+0.2, 25.3+0.2, 25.6=0.2 and 26.8+0.2.7. A method of preparing the crystalline sibutramine methanesulfonate hemihydrate according to claim 5 or 6, which comprises reacting sibutramine of formula (II) with methanesulfonic acid dissolved in a mixture of an organic solvent and water.8. The method of claim 7, wherein methanesulfonic acid is employed in an amount ranging from 1 to 2 mole equivalents, based on 1 mole of sibutramine of formula (II).9. The method of claim 7, wherein water is employed in an amount ranging from 0.5 to 5 mole equivalents, based on 1 mole of sibutramine of formula (II).10. The method of claim 7, wherein the organic solvent is more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ether, from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; or a mixture of more than one ketone, from the group consisting of acetone, methyl ethyl ketone, and methyl! isobutyl ketone, and more than one ether, from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether.11. A method of preparing the crystalline sibutramine methanesulfonate hemihydrate according to claim 5 or 6, which comprises (i) reacting sibutramine of formula (II) with methanesulfonic acid in an anhydrous organic solvent to obtain anhydrous sibutramine methanesulfonate of formula (III); and (i) bringing the sibutramine methanesulfonate of formula (III) into contact with water in an organic solvent to obtain crystals and filtering the crystals. oT of 0) N oer « CH,SO5H (1m)12. The method of claim 11, wherein methanesulfonic acid is employed in an amount ranging from 1 to 2 mole equivalents, based on 1 mole of sibutramine of formula (II).13. The method of claim 11, wherein water is employed in an amount ranging from 0.5 to 5 mole equivalents, based on 1 mole of anhydrous sibutramine methanesulfonate of formula (IIT).14. The method of claim 11, wherein the anhydrous organic solvent of step (1) is more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ketone solvent from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone; more than one ether from the group consisting of ethyl ether, isopropyl ether and t-butyl methyl ether; toluene; or a mixture thereof.15. The method of claim 11, wherein the organic solvent of step (ii) is more than one ester selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; or a mixture of more than one ketone from the group consisting of acetone, methyl ethyl ketone, and methyl isobutyl ketone, and more than one ether from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether.
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KR (1) | KR100536750B1 (en) |
CN (1) | CN100342851C (en) |
IL (1) | IL167659A (en) |
RS (1) | RS20050272A (en) |
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KR100618176B1 (en) * | 2004-12-02 | 2006-09-01 | 휴먼팜 주식회사 | Sibutramine tartrate, its preparation process and phamaceutical composition comprising it |
WO2006073292A1 (en) * | 2005-01-06 | 2006-07-13 | Cj Corporation | Inorganic acid salts of sibutramine |
KR100632470B1 (en) * | 2005-02-25 | 2006-10-12 | 민연식 | Crystalline Sibutramin Camsylate and Process for Preparing it |
KR100814384B1 (en) * | 2006-02-10 | 2008-03-18 | 대화제약 주식회사 | Pharmaceutical composition containing sibutramine salt, and manufacturing method thereof |
KR100800561B1 (en) * | 2006-03-29 | 2008-02-04 | 주식회사 삼오제약 | A method for preparation of Sibutramine sulfonate salt and a composition containing the same for treating and preventing obesity disease |
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ZA821577B (en) * | 1981-04-06 | 1983-03-30 | Boots Co Plc | Therapeutic agents |
IE52768B1 (en) * | 1981-04-06 | 1988-02-17 | Boots Co Ltd | 1-arylcyclobutylalkylamine compounds useful as therapeutic agents |
GB8531071D0 (en) * | 1985-12-17 | 1986-01-29 | Boots Co Plc | Therapeutic compound |
US6399826B1 (en) * | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
WO2002036540A2 (en) * | 2000-11-02 | 2002-05-10 | Torrent Pharmaceuticals Ltd | PROCESS FOR PREPARATION OF β-PHENETHYLAMINE DERIVATIVE |
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RS20050272A (en) | 2007-09-21 |
KR20040031574A (en) | 2004-04-13 |
KR100536750B1 (en) | 2005-12-16 |
CN100342851C (en) | 2007-10-17 |
UA76913C2 (en) | 2006-09-15 |
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