LV13556B - Pharmaceutical composition comprising a salt of mirtazapine - Google Patents
Pharmaceutical composition comprising a salt of mirtazapine Download PDFInfo
- Publication number
- LV13556B LV13556B LVP-06-130A LV060130A LV13556B LV 13556 B LV13556 B LV 13556B LV 060130 A LV060130 A LV 060130A LV 13556 B LV13556 B LV 13556B
- Authority
- LV
- Latvia
- Prior art keywords
- mirtazapine
- salt
- acid
- maleic acid
- enantiomer
- Prior art date
Links
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 150000003839 salts Chemical class 0.000 title claims abstract description 42
- 229960001785 mirtazapine Drugs 0.000 title claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 33
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 25
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 25
- 239000011976 maleic acid Substances 0.000 claims abstract description 25
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 17
- RONZAEMNMFQXRA-INIZCTEOSA-N LSM-5894 Chemical compound C1C2=CC=CN=C2N2CCN(C)C[C@H]2C2=CC=CC=C21 RONZAEMNMFQXRA-INIZCTEOSA-N 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000001530 fumaric acid Substances 0.000 claims abstract description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000859 sublimation Methods 0.000 claims description 20
- 230000008022 sublimation Effects 0.000 claims description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- RONZAEMNMFQXRA-MRXNPFEDSA-N esmirtazapine Chemical class C1C2=CC=CN=C2N2CCN(C)C[C@@H]2C2=CC=CC=C21 RONZAEMNMFQXRA-MRXNPFEDSA-N 0.000 description 67
- 239000003826 tablet Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000009472 formulation Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- -1 castle Substances 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- 239000002585 base Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 239000007857 degradation product Substances 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 229940088679 drug related substance Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 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 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 150000002689 maleic acids Chemical class 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000008429 bread Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- MYXKPFMQWULLOH-UHFFFAOYSA-M tetramethylazanium;hydroxide;pentahydrate Chemical compound O.O.O.O.O.[OH-].C[N+](C)(C)C MYXKPFMQWULLOH-UHFFFAOYSA-M 0.000 description 2
- NWXITVQAKIFZLZ-UHFFFAOYSA-N 191546-96-0 Chemical compound C1C2=CC=CN=C2N2CCN(C)C(=O)C2C2=CC=CC=C21 NWXITVQAKIFZLZ-UHFFFAOYSA-N 0.000 description 1
- RZDFSDWHGNDESU-UHFFFAOYSA-N 191546-97-1 Chemical compound O=C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RZDFSDWHGNDESU-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 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
- GAFCUVMEBFTFQJ-UHFFFAOYSA-N Mirtazapine-N-oxide Chemical compound C1C2=CC=CN=C2N2CCN(C)(=O)CC2C2=CC=CC=C21 GAFCUVMEBFTFQJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
1. Farmaceitiska kompozīcija, kas satur mirtazapīna enantiomēru, raksturīga ar to, ka mirtazapīns ir farmaceitiski pieņemama cieta mirtazapīna sāls formā, kas nesublimējas.
2. Farmaceitiska kompozīcija saskaņā ar 1. punktu, kas raksturīga ar to, ka sāls ir izvēlēts no kopas, kas sastāv no maleīnskābes, bromūdeņražskābes, fumārskābes un metānsulfoskābes sāls.
3. Farmaceitiska kompozīcija saskaņā ar 2. punktu, kas raksturīga ar to, ka sāls ir maleīnskābes vai metānsulfoskābes sāls.
4. Farmaceitiska kompozīcija saskaņā ar jebkuru punktu no 1. līdz 3. punktam, kas raksturīga ar to, ka mirtazapīna enantiomērs ir Senantiomērs.
5. Paņēmiens mirtazapīna sublimācijas novēršanai no farmaceitiskas kompozīcijas, kas satur mirtazapīna enantiomēru cietā formā, raksturīgs ar to, ka farmaceitiskās kompozīcijas ražošanas laikā tiek izvēlēts farmaceitiski pieņemams S- vai R-mirtazapīna sāls, kas nesublimējas.
1/1
PHARMACEUTICAL ČOMPOSITION COMPRISING A SALT OF MIRTAZAPINE
The invention relates to pharmaceutical formulations comprising a pure enantiomer of mirtazapine.
Mirtazapine is a widely used drug with several therapeutic uses. The form of the drug vvhich is available in pharmaceutical compositions for prescribing to patients is the base of the compound as racemic mixture. In vievv of nevv uses of the drug and the different pharmacological properties of the enantiomers it is needed to make the separate single Sand R-enantiomers available for pharmaceutical compositions. Pharmaceutical compositions for oral use of enantiomers vvere implied to be available according to the publication of Fink and Irvvin (Psychopharmacology, Vol 78, pp. 44-48, 1982) who describe the administration of the S-enantiomer and the R-enantiomer of mirtazapine to human voiunteers for research purposes. The compounds vvere given in the form ofthe free base of an S- or R- enantiomer of mirtazapine.
It vvas found that such formulations suffer from problems caused by subiimation of the mirtazapine. It vvas found that the pure bases of S- and R-mirtazapine are slowly sublimating compounds at ambient temperature and that some, but not all salts of S- and R-mirtazapine do not have this disadvantage. Thus, the usefulness of such a pharmaceutical čomposition comprising an enantiomer of mirtazapine in solid form can be improved, according to this invention, by seiecting a pharmaceutically suitable nonsublimating and solid salt of an enantiomer of mirtazapine for use as the form of mirtazapine in the čomposition. The invention aiso provides for a method for the manufacture of a pharmaceutical formulation comprising a pure enantiomer of mirtazapine in a solid form, whereby the solid form is a pharmaceutically suitable non-sublimating salt of S- or R-mirtazapine.
Other desirable properties for a pharmaceutical ingredient, such as ease in preparation or purification or Chemical or physical stability in capsules and/or tablets can also be obtained by use of a salt according to this invention. Improved physical stability can be due to reduced migration of compound out of the formulation and improved Chemical stability can be due to reduced degradation of mirtazapine. Non-sublimating and solid salts of S-mirtazapine as vvell as R-mirtazapine are found to be a.o. the maleic acid, the hydrochloric acid, the hydrobromic acid, the fumaric acid and the methanesulfonic acid salts of mirtazapine. The maleic acid salt is particularly advantageous, because it has a high melting point, readily forms crystals, for vvhich there form no other polymorphs and it is not hygroscopic. Also, methanesulfonic acid salt is a very useful salt for an enantiomer of mirtazapine, in vievv of non-sublimation and non-hygroscopicity. A trifluoroacetic acid salt of S- or R-mirtazapine is an example ofa salt vvhich showed sublimation. Moreover, the latter salt is not a pharmaceutically suitable salt.
The property of sublimation can be observed and quantified vvith knovvn methods to measure sublimation. For example, sublimation can be measured in an apparatus vvith a chamber in vvhich the tēst compound is placed in its solid state and maintained in that state by controlled temperature. The gas phase in the chamber, optionally under low pressure, can be analyzed for content of tēst compound. It is also possible to continuousiy clear the tēst compound in the gas phase from the chamber either by a continuous renevval stream of a gas or by creating a sink for the tēst compound out of the gas phase, for example by a cold surface. The amount of material collected from sublimation or escaped from the sample by sublimation can be analyzed. The degree of sublimation is expressed as the fraction (as percentage) of the initial sample size.
The term 'non-sublimatīng salt' is defined to be a salt of S- or R-mirtazapine, from vvhich less than 1 % ofthe mirtazapine is subiimating from the sample, calculated on the basis of the amount of the base, vvhen a sample of approximately 10 mg (for example an amount betvveen 8-12 mg) is placed for the duration of 72 hours under Standard conditions of 150 mBar pressure and 60 °C temperature.
Pharmaceutica!ly suitable acids approved for use to provide for the anion in a salt of a medicinally active compound are hydrochioric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, methylsuifonic acid, acetic acid, and other acids mentioned in the article of Philip L. Gould (International Journal of Pharmaceutics, Vol. 33, (1986), pp. 201207. This publication provides for the limiting and defined list of acids, vvhich can be tested according to prescribed procedures in this description to obtain a salt according to the invention.
The term 'solid' in this description means that the amorphic or crystailine compound remains in a solid state at room temperature.
The term mirtazapine refers to the compound 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine as active ingredient for a pharmaceutical formulation. The term is used here to refer to the free base as separate compound or to the base component in a mirtazapine salt.
Reference to a formulation comprising an enantiomer of mirtazapine refers to a formulation in vvhich an enantiomerically purified form of mirtazapine vvas used in the preparation, contrary to a formulation for vvhich the racemic form of mirtazapine vvas used. Purification in this paragraph is meant to implicate one or more steps in the preparation of mirtazapine, vvhich are aimed at obtaining some degree of separation ofthe tvvo enantiomers. Preferably a pure enantiomer of 90%, or preferably better up to 95%, 98%, 99%, 99.5% or 99.8% purity over the other enantiomer is used
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3c][2]benzazepine, can be prepared by knovvn methods. Synthesis of racemic mirtazapine is described, for example, in US4062848 vvherein a four stage synthetic scheme is disclosed starting from a 2-substituted nicotfnitrile. Further modifications to various stages of this route have subsequently been described in WO 00/62782, WO 01/23345 and US 6,376,668.
The preparation of enantiomerically pure mirtazapine has been addressed in US 4062848, WO 00/62782 and Seldifz et. al., 1998 (J. Chromatography, 1998, vol 803, pp 169-177). By the method disclosed in US 4062848, enantiomerically pure mirtazapine is obtained by fractional crystallisation of the diastereoisomeric salts formed by reaction of racemic mirtazapine vvith enantiomerically pure dibenzoyltartaric acid in ethanol follovved by regeneration of the free base by treatment vvith aqueous ammonia. Other methods of forming pure mirtazapine by recrystallisation of crude mirtazapine are disclosed in WO 00/62782. Seiditz ef. al. describe a chromatographic method to separate the enantiomers.
Pharmaceutical compositions are made vvith an active ingredient, vvhich is a salt of S- or R-mirtazapine in this context, to vvhich carriers and other excipients are added.
The characteristics ofthe salts according to the invention make them most suitable for manufacture and use in various pharmaceutical formulations for dosaged administration to a subject. Such forms are adapted to use for particular routes of administration, such as oral, rectal or transdermal.
For making dosage forms, such as pilis, tablets, suppositories, (micro-)capsules, povvders, emulsions, creams, ointments, implants, a patch, a gel, or any other preparation for sustained release, sprays, injection preparations in the form ofa suspension, suitable auxiliaries such as fillers, binders, lubricants, dispersants, emulsifiers, stabilisers, surfactants, penetration enhancers, anti-oxidants, colorants, preservatives and the like can be used e.g. as described in the Standard reference, Gennaro et al., Remington; The
Science and Practice of Pharmacy; 20th ed., Publisher: Lippincott VVilliams & Wilkīns; Baltimore; USA in Part 5) and the Handbook of Pharmaceutical Excipients (3nd edition edited by Arthur H. Kibbe; Published by the American Pharmaceutical Association, VVashington D.C. and The Pharmaceutical Press, London in 2000). In general any pharmaceutically acceptable auxiliary which does not interfere vvith the function of the active compound is suitable and can be used. The amount of S- or R-mirtazapine salt in the dosage form can be adapted to the particular circumstances. Generaliy, a dosage unit vvill contain betvveen 0.05 and 90 mg of S- or R-mirtazapine salt, expressed on the basis of the amount of base.
Suitable fillers or carriers vvith vvhich the compositions can be administered include agar, alcohol, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrroiidone, silica, steriie saline and the like, or mixtures thereof, used in suitable amounts.
Binders are aģents used to impart cohesive properties to a pharmaceutical composition resulting in minimal loss from the pharmaceutical composition during production and handling. Binders are for example cellulose, starches, polyvinylpyrrolidone, and the like.
A suitable lubricant vvith vvhich the active aģent ofthe invention can be administered is, for example, magnesium stearate.
Surfactants are aģents facilitating the contact and migration of compounds in different physical environments such as hydrophilic and hydrophobic environments. Many surfactants are knovvn in the art of making pharmaceutical compositions as for example described in chapter 21 of Gennaro ef al, Remington; The Science and Practice of Pharmacy; 20th ed., Publisher: Lippincott VVilliams SVVilkins; Baltimore; USA).
Surfactants that can be used during the process of preparing the pharmaceutical formulation are, for example, polyethylene glycol (PEG), and the like.
The salts according to the invention can be made vvith methods well-known in the art. The base is dissolved in a suitable solvent, such as methanol, ethanol, ethylacetate or acetone and acid is added either purely or dissolved in, for example ethanol, ethylacetate or acetone. The salt can be collected from the solvens by precipitation or crysta!lisation, vvhich is, if needed, provoked by cooling the solution or evaporating the solventia.
Figurē: Schematic presentation ofthe sublimation tēst equipment. A sample is placed on the bottom of a vessel, vvhich is closed at the top by a vessel-shaped stopper into vvhich cooling liguid (CL) is circulating and vvhich vessel has an outlet connected to a vacuum pump (Vac). The vessel is placed in a closed chamber under constant temperature control (TC). A sublimate (SubI) can accumulate against the surface of the stopper vvithin the vessel.
Examples
In the examples S-mirtazapine is used. In view of the symmetry these can be directly copied to apply to R-mirtazapine as vvell, except for the example 8, in vvhich case (-)-0,0dibenzoyl-L-tartaric acid must be used for R-mirtazapine.
1. Crvstallization of S-mirtazapine hvdrochloric acid salt
To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol vvas added at room temperature a solution of 939 pl of hydrochloric acid in 20 ml of ethyl acetate. Part ofthe solvent vvas evaporated and an oil was formed in the solution. Then the solution was cooled to 0 °C. A seed crystal vvas added vvhereupon crystallisation started. The vvhite crysta!s vvere collected by filtration and vvere dried in a vacuum oven at 40 °C. This gavē 1.96 g of vvhite crystals of S-mirtazapine.hydrochloric acid salt (57%).
Endotbermic peak (DSC): 275 °C; XRPD and ss-NMR: crystaliine material of one polymorhic form, no amorphous material. The compound starts to sublimē above 170 °C. Dynamic vapor sorption measurement demonstrated that the salt is very hygroscopic.
2. Crvstallization of S-mirtazapine maleic acid salt
To a solution of 3.01 g of S-mirtazapine in 10 ml of ethanol vvas added at room temperature a solution of 1.32 g of maleic acid in 10 ml of ethanol. After stirring for several minūtes crystallization started. After stirring for several hours at room temperature the vvhite crystals vvere collected by filtration and vvere dried in a vacuum oven at 40 °C. This gavē 3.98 g of vvhite crystals of S-mirtazapine maleic acid salt (92%).
Endothermic peak (DSC): 206 °C; XRPD and ss-NMR: crystalline material; ratio mirtazapine/maleic acid; 1:1; one polymorphic form, no amorphous material. Dynamic vapor sorption measurement demonstrated that the salt is not hygroscopic.
3. Crvstallization of S-mirtazapine fumaric acid salt
To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol vvas added at room temperature 1.31 g of fumaric acid resulting in a quick precipitation. An additional of 5 ml of methanol and 20 ml of ethyI acetate vvere added to the suspension to redissolve the solid. Part of the solvent vvas evaporated to start the crystallization from a clear solution. After stirring for several hours, the vvhite crystals vvere collected by filtration and vvere dried in a vacuum oven at 40 °C. This gavē 3.76 g of vvhite crystals of S-mirtazapine fumaric acid salt (87%). Endothermic peak (DSC): 178 °C; XRPD and ss-NMR: probabiy a mixture of three poiymorphic forms and some amorphous material. The fumaric acid salt attracts vvater from environmental air to form a hydrate, vvhich can loose its vvater content upon drying.
4. Crvstallization of S-mirtazapine hvdrobromic acid salt
To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol was added at room temperature a solution of 1290 μϊ of hydrobromic acid in 20 ml of ethyl acetate. Part of the solvent vvas evaporated, vvhich resulted in the formation of an oil. The mixture vvas cooled to 0 °C vvhereupon crystailization started. The vvhite crystals vvere collected by filtration and vvere dried in a vacuum oven at 40 °C. This gavē 3.74 g vvhite crystals of Smirtazapine hydrobromide salt (95%). Endothermic peak (DSC): 253 °C; XRPD and ssNMR: mainly one polymorphic form and some amorphous material. The HBr salt has a clear affinity for vvater and forms a monohydrate under ambient conditions. A vvater free drug substance sample attracts vvater vvhen it comes in contact vvith environmental air, vvhile it may loose vvater upon drying.
5. Crvstallization of S-mirtazapine methanesulfonic acid salt
To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol vvas added at room temperature a solution of 743 μϊ of methanesulfonic acid in 20 ml of ethyl acetate. After partly evaporation of the solvent, the crystailization started. The vvhite crystals vvere collected by filtration and vvere dried in a vacuum oven at 40 °C. This gavē 2.09 g vvhite crystals of S-mirtazapine methanesulfonic salt (51%). Endothermic peak (DSC): 208 °C; XRPD and ss-NMR: crystalline material mainly one polymorph.
6. Crvstallization of S-mirtazapine trifiuoroacetic acid salt
To a solution of 0.50 g of S-mirtazapine in ethyi acetate vvas added a solution of 142 μϊ of trifluoroacetic acid in ethyl acetate. As crystallization did not stari spontaneously the ' solvent vvas evaporated slowly. During evaporation of the solvent the salt started to crystallize. This yielded 0.65 g of S-mirtazapine trifiuoroacetic acid salt. Endothermic peak: 185 °C. In experiments according to exampie 10, it vvas found that this salt vvas not a non-sublimating salt according to the definition of a non-sublimating salt in this description.
7. Solidification of S-mirtazapine formic acid salt, S-mirtazapine acetic acid salt, Smirtazapine propionic acid salt and S-mirtazapine phosphoric acid salt did not succeed.
Example 8.
This is to demonstrate the first step in a manner of preparation of enantiomerically pure mirtazapine. The salt of this example is not approved for pharmaceutical use. Crvstallization of S-mirtazapine (+)-O.O-Dibenzoyl-D-Tartaric acid salt 23.33 g mirtazapine (Org 3770) vvas dissolved in 94 ml of ethanol at a temperature of 52 °C. A filtered solution of 33.06 g (+)-O,O-dibenzoyl-D-Tartaric acid hydrate in 132 ml of ethanol (100%) vvas added to the vvarm solution. Then the reaction mixture vvas cooled dovvn to room temperature. A seed crystal vvas added to the reaction mixture to initiate crystallization. After stirring for 19 hours, the crystals vvere collected by filtration. The yield ofthe vvet crysta!s vvas 25.7 g and the e.e. vvas 88.04%. The crystals vvere suspended in 880 ml of ethanol and dissolved at reflux temperature. The reaction mixture vvas cooled dovvn and crystallisation started. After 16 hours the crystals vvere collected by filtration. The yield ofthe vvet crystals vvas 20.4 g and the e.e. vvas 98.9%. The remaining mother liquor can be used to obtain R-mirtazapine by combining vvith (-)-0,0-Dibenzoyl-L-Tartaric acid
9. Assav for S-mirtazapine and degradation products bv HPLC
| Column | Hypersil ODS, 250 x 4.6 mm I.D., 5 pm or equivaient column |
| Column temperature | 40 °C |
| Solution A | Methanol + acetonitrile + tetrahydrofuran, 36.2+42.5 + 21.3, V+V+V. |
| Mobile phase | Solution A + tetramethylammonium hydroxide pentahydrate solution 0.1 M (pH=7.4), 35 + 65, V+V |
| Flovv rāte | 1.5 mUmin |
| Detection | S-mirtazapine: UV 290 nm Degr prod A: UV 240 nm Degr prod B: UV 240 nm Degr prod C: UV 240 nm Degr prod D: UV 240 nm |
| Iniection volume | 10 pL |
| Run time | 27 minūtes |
| Approximate retention times * S-mirtazapine Degr prod A Degr prod B | 14.5 <tR< 17.5 minūtes 23.1 minūtes 3.0 minūtes |
| Degr prod C | 5.6 minūtes |
| Degr prod D | 3.7 minūtes |
* If the retention time ofthe S-mirtazapine peak is not conform the system suitability criteria prior to analysis, the mobile phase should be adjusted by adding some solution A or tetramethylammonium hydroxide pentahydrate solution 0.1 M.
The detection limit of S-mirtazapine as free base or as active entity in its corresponding salt is below 0.02 mg.
Names:
Degr prod A: 2,3,4,4a-Tetrahydro-3-methylpyrazino[2,1-a]pyrido[2,3-cj[2]benzazepine9(1H)-one
Degr prod B: 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3c][2]benzazepine-2-oxide dihydrate
Degr prod C: 3,4,10,14b-Tetrahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepin1(2H)-one
Degr prod D: N-t2-(5l10-dihydro-10-oxo-11H-pyrido[2,3-c][2]benzazepin-11-yl)ethyl]-Nmethyl-formamide
10. Sublimation tests
A sample (approximately 10 mg) vvas placed in a sample chamber of sublimation tēst equipment as illustrated in Figurē 1. The temperature in the sample chamber is controllable. The sample holder has a reduced pressure, vvhich vvas 150 mBar by default The sample chamber also consists of a section vvith reduced temperature (the “cold finger”), vvhere the temperature is approximately 5°C. The majority of material that sublimates in the tēst sample vvith high temperature vvill precipitate on the cold finger. The amount of material on the cold finger after a tēst period of 72 hrs has been quantified using HPLC analysis. The degree of sublimation is expressed as the fraction materialon the cold finger (as percentage) ofthe initial sample size. Additional]y, the sublimation of active compound from tablets “drug product” has been tested.
Results
Table 1 līsts the sublimation results ofthe S-mirtazapine, S-mirtazapine.HBr, Smirtazapine.maleic acid, S-mirtazapine.fumaric acid and tablets containing some of these compounds under several tēst conditions.
| Table 1: Sublimation results | Sublimate3 | |
| Temperature: 40°C | Drug substance | |
| Pressure: 150 mbar | S-mirtazapine Batch E | 0.75% |
| Tēst period: 72 hrs | S-mirtazapine Batch J | 0.88% |
| Temperature: 60°C | Drug substance | |
| Pressure: 150 mbar | S-mirtazapine Batch E | 5.32%, 2.22% |
| Tēst period: 72 hrs | S-mirtazapine Batch J | 4.29% |
| S-mirtazapine.HBr | <DL | |
| S-mirtazapine.maleic acid | <DL | |
| S-mirtazapine.fumaric acid | <DL | |
| S-miriazapine.HCI | 0.2% | |
| 0.2% | ||
| S-mirtazapine.methanesulfonic acid | 0.1%, 0.0% | |
| Drug product (tablets)1 S-mirtazapine tablets2 | 7.21% | |
| S-mirtazapine.HBr tablets | <DL | |
| S-mirtazapine.maleic acid tablets1 | <DL |
<DL = Below Ievel of detection “ If tvvo values are mentioned these are results of replication experiments.
1 The composition of the tablets used for the sublimation tēst detailed in table 3.
2 Formulation C as in tabie 3.
Table 2:Stability results
| Drug substance | Formuiation 1 | Content (% of initial content) | |||||
| T = 1 month | |||||||
| 5°e/A | 25°C/ 60%RH | 30°C/ 60%RH | 40°C/A | 4o°cr 75%RH | 60°C/A | ||
| S-mirtazapine | Formuiation A | 100.7 | 94.1 | ||||
| S-mirtazapine | Formuiation B | 100.5 | 94.8 | ||||
| S-mirtazapine | Formuiation C | 100.2 | 06.4 | ||||
| S-mirtazapine | Formuiation D | 95.8 | 91.0 | ||||
| S-mirtazapine. Maleic acid 2 | Formuiation F | 99.8 | 98.8 | 99.0 | 99.5 | 100.2 | 99.3 |
| S-mirtazapine. Maleic acid2 | Formuiation G | 98.9 | 99.3 | 99.1 | 99.9 | 99.9 | 100.0 |
Table 2 continued
| Drug substance | Formuiation 1 | Content (% of initial content) | |||||
| T=3 months | |||||||
| 5°C/A | 25°C 60%RH | 30°C/ 60%RH | 40°C/A | 40°C/ 75%RH | 60°C/A | ||
| S-mirtazapine | Formuiation A | 100.6 | 101.0 | 96.3 | 90.5 | 18.0 | |
| S-mirtazapine | Formuiation B | 100.6 | 99.6 | 96.8 | 91.8 | 25.5 | |
| S-mirtazapine | Formuiation C | 101.1 | 98.5 | 95.3 | 91.3 | 43.0 | |
| S-mirtazapine | Formuiation D | 95.4 | 96.9 | 93.3 | 90.9 | 33.6 | |
| S-mirtazapine. Maleic acid2 | Formuiation F | 103.3 | 102.4 | 102.9 | 103.2 | 104.8 | 103.4 |
| S-mirtazapine. Maleic acid 2 | Formuiation G | 101.2 | 102.4 | 100.0 | 100.3 | 102.6 | 101.5 |
A = ambient humidity
RH = relative humidity 1 Ali tablets, except some ofthe S-mirtazapine.maleic acid salt tablets, contain about 1 mg S-mirtazapine calculated on basis ofthe amount ofthe base. Hovvever, due to losses during the manufacturing process, the content may be lovver. The formulations are shovvn in table 3.
2 The first row shovvs the results from the 1 mg/65 mg tablets (formuiation F; see table 3), The second row shovvs the results from the 10 mg/160 mg tablets (formuiation G; see table 3).
Table 3: Composition of the tablets
| Component | Quantity per tablet [mg] | |||
| Formulation A | Formulation B | Form. C | Form. D | |
| S-mirtazapine1 | 1.0 | 1.0 | 1.0 | 1.0 |
| S-mirtazapine.HBr1 | ||||
| S-mirtazapine. maleic acid 1 | '' | |||
| Magnesium stearate | 0.325 | 0.325 | 0.325 | 0.325 |
| Sodium starch glycolate | 1.95 | 1.95 | ||
| Maize starch | 6.5 | |||
| Potato starch | 5.1 | |||
| Dicalcium phosphate | 26.0 | |||
| Hydroxypropylcellulose | 1.3 | |||
| Aerosil | 0.975 | |||
| Povidone | 15.4 | |||
| Lactose monohydrate | To 65 | To 65 | 43.5 | |
| Microcrystalline cellulose | To 65 | |||
| Total tablet welght | 65 | 65 | 65 | 65 |
Table 3 continued
| Component | Quantity per tablet [mg] | ||
| Formulation E | Formulation F | Formulation G | |
| S-mirtazapine1 | |||
| S-mirtazapine.HBr1 | 1.305 2 | ||
| S-mirtazapine.maleic acid 1 | 1.4372 | 14.37 3 | |
| Magnesium stearate | 0.325 | 0.325 - 0.49 | 1.2 |
| Sodium starch glycolate | 1.95 | 1.95 | 4.8 |
| Maize starch | |||
| Potato starch | |||
| Dicalcium phosphate | |||
| Hydroxypropylcellulose | |||
| Aerosil | |||
| Povidone | |||
| Lactose monohydrate | To 65 | To 65 | To 160 |
| Microcrystalline cellulose | |||
| Total tablet vveight | 65 | 65 | 160 |
Notēs to Table 3 1 Due to losses or other problems during the manufacturing process, the content may be lovver or higher.
2 Corresponds to 1 mg S-mirtazapine as base.
3 Corresponds to 10 mg S-mirtazapine as base.
The results of the sublimation tēst shovv that the free base S-mirtazapine sublimates at the conditions used. The S-mirtazapine hydrobromic acid salt, S-mirtazapine maleic acid salt, and S-mirtazapine fumaric acid salt do not subiimate, This difference is also seen in tablets containing S-mirtazapine, S-mirtazapine.HBr, orS-mirtazapine.maleic acid.
The stability of tablets containing S-mirtazapine and S-mirtazapine.maleic acid vvas also maesured (tables 2 and 4). It is ciear that the S-mirtazapine content decreases in the tablets containing the free base S-mirtazapine. The decrease is probabiy caused by sublimation. In the tablets containing S-mirtazapine.maleic acid no decrease in the content vvas observed.
The Chemical stability of the drug products vvas further analysed by determination of Chemical degradation products. The assay values after storage are shovvn in table 4.
Table 4: Stability results assay and degradation products
| Drug substance | Formulation 1 | T=3 months | |||||
| 5°C/A | 25°C | 30°C/ | 40°C/A | 40C/ | 60°C/A | ||
| 60%RH | 60%RH | 75%RH | |||||
| S-mirtazapine | Formulation A | 100.6 | 101.0 | 96.3 | 90.5 | 18.0 | |
| Degradation products | |||||||
| Degr prod A | <0.1% | <0.1% | <0.1% | <0.1% | 0.53% | ||
| Degr prod B | <0.1% | <0.1% | <0.1% | 0.16% | 3.70% | ||
| Degr prod C | <0.1% | <0.1% | <0.1% | 0.14% | 1.06% | ||
| Deqr prod D | <0.1% | 0.11% | 0.14% | 0.35% | 5.57% | ||
| S-mirtazapine.maleic acid | Formulation F | 103.3 | 102.4 | 102.9 | 103.2 | 104.8 | 103.4 |
| Degradation products | n.d. | n.d. | |||||
| Degr prod A | <0.1% | <0.1% | <0.1% | <0.1% | |||
| Degr prod B | <0.1% | <0.1% | <0.1% | 0.18% | |||
| Degr prod C | <0.1% | <0.1% | <0.1% | <0.1% | |||
| Degr prod D | <0.1% | <0.1% | <0.1% | 0.11% |
Notēs to Table 4 1 Ali tablets contain about 1 mg active entity (S-mirtazapine). Hovvever, due to losses during the manufacturing process, the active entity content may be lovver. The formulations are shovvn in table 3.
n.d. = not determined
A = ambient humidity
Note that in the tablets containing S-mirtazapine.maleic acid no decrease in the content vvas observed. Degradation products found in tablets containing S-mirtazapine or Smirtazapine. maleic acid are provided in Table 4. The formulation of the tablets is similar (table 3). In tablets containing S-mirtazapine.maleic acid stored for 3 months at 40°/75%RH the concentration of the degradation products vvas lovver than in tablets containing the free base S-mirtazapine that vvere stored during the same period. Losses under conditions of 60 °C at ambient temperature vvere not much more for the maleic acid salt, vvhereas for the formulation vvith the free base the degradation products already amount to about 11 %.
Claims (5)
- Claims1. A pharmaceutical formulation comprising an enantiomer of mirtazapine, characterised in that the mirtazapine is present as a pharmaceutically suitable nonsublimating and solid salt of mirtazapine.
- 2. The pharmaceutical formulation according to claim 1, characterised in that the salt is selected from the līst consisting ofthe salt of maleic acid, hydrobromic acid, fumaric acid and methanesulfonic acid.
- 3. The pharmaceutical formulation according to claim 2, characterised in that the salt is of maleic acid or of methanesulfonic acid.
- 4. The pharmaceutical formulation according to any one of claim 1-3, characterised in that the enantiomer of mirtazapine is the S-enantiomer.
- 5. A method to prevent sublimation of mirtazapine from a pharmaceutical formulation comprising an enantiomer of mirtazapine in a soiid form, characterised by selecting a pharmaceutically suitable non-sublimating salt of S- or R-mirtazapine during manufacturing the pharmaceutical formulation.
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| EP1792618A1 (en) * | 2005-11-30 | 2007-06-06 | Rainer Freynhagen | R-mirtazapine for the treatment of pain |
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| PT3261645T (pt) | 2015-02-27 | 2021-06-17 | Dechra Ltd | Estimulação do apetite, gestão da perda de peso, e tratamento da anorexia em cães e gatos |
| CN111053735A (zh) * | 2020-02-25 | 2020-04-24 | 上海阶平医院管理有限公司 | 一种治疗失眠的冷敷凝胶 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL189199C (nl) * | 1975-04-05 | 1993-02-01 | Akzo Nv | Werkwijze ter bereiding van farmaceutische preparaten met werking op het centraal zenuwstelsel op basis van benz(aryl)azepinederivaten, de verkregen gevormde farmaceutische preparaten, alsmede werkwijze ter bereiding van de toe te passen benz(aryl)azepinederivaten. |
| US4193828A (en) * | 1976-07-27 | 1980-03-18 | Fiber Materials, Inc. | Method of forming carbon composites |
| US4515792A (en) * | 1982-09-30 | 1985-05-07 | Ciba-Geigy Corporation | Tetracyclic heterocycles and antidepressant compositions thereof |
| IL121076A (en) * | 1996-06-19 | 2000-10-31 | Akzo Nobel Nv | Pharmaceutical combinations comprising mirtazapine and one or more selective serotonin reuptake inhibitors |
| EP0813873B1 (en) * | 1996-06-19 | 2002-02-13 | Akzo Nobel N.V. | Pharmaceutical composition comprising mirtazapine and one or more selective serotonin reuptake inhibitors |
| WO1999051237A1 (en) * | 1998-04-02 | 1999-10-14 | Akzo Nobel N.V. | Oral liquid antidepressant solution |
| AU5764900A (en) * | 1999-06-25 | 2001-01-31 | University Of South Florida | Mirtazapine for weight gain in wasting diseases |
| US6281207B1 (en) * | 1999-09-15 | 2001-08-28 | Reed Richter | Treatment of movement disorders by administration of mirtazapine |
| WO2001042239A1 (fr) * | 1999-12-13 | 2001-06-14 | Sumika Fine Chemicals Co., Ltd. | Procede de preparation d'un compose pyridinemethanol |
| PT1242092E (pt) * | 2000-04-05 | 2003-11-28 | Akzo Nobel Nv | Combinacao de farmacos para o tratamento da dor de cabeca que compreende mirtazapina e paracetamol ou um farmaco nao esteroide anti-inflamatorio |
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- 2005-04-19 CN CN201010174000A patent/CN101824035A/zh active Pending
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