AU2007203451B2 - Pharmaceutical composition containing a crystalline form of perindopril tert-butylamine salt - Google Patents
Pharmaceutical composition containing a crystalline form of perindopril tert-butylamine salt Download PDFInfo
- Publication number
- AU2007203451B2 AU2007203451B2 AU2007203451A AU2007203451A AU2007203451B2 AU 2007203451 B2 AU2007203451 B2 AU 2007203451B2 AU 2007203451 A AU2007203451 A AU 2007203451A AU 2007203451 A AU2007203451 A AU 2007203451A AU 2007203451 B2 AU2007203451 B2 AU 2007203451B2
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- AU
- Australia
- Prior art keywords
- crystalline form
- compound
- pharmaceutical composition
- formula
- intensity
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 30
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical class CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 title claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 11
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 238000010586 diagram Methods 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 239000002934 diuretic Substances 0.000 claims description 5
- 230000001882 diuretic effect Effects 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000006071 cream Substances 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 claims description 3
- 229960004569 indapamide Drugs 0.000 claims description 3
- 239000007937 lozenge Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000006190 sub-lingual tablet Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 229940125810 compound 20 Drugs 0.000 claims 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 7
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 5
- 229960002582 perindopril Drugs 0.000 description 5
- QNRXNRGSOJZINA-QMMMGPOBSA-N (2s)-2,3-dihydro-1h-indole-2-carboxylic acid Chemical compound C1=CC=C2N[C@H](C(=O)O)CC2=C1 QNRXNRGSOJZINA-QMMMGPOBSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- -1 benzyl ester Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- AUVAVXHAOCLQBF-YUMQZZPRSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxopentan-2-yl]azaniumyl]propanoate Chemical compound OC(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC AUVAVXHAOCLQBF-YUMQZZPRSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- CHAJBHNQIZAJJM-RGMNGODLSA-N ethyl (2s)-2-aminopentanoate;hydrochloride Chemical compound Cl.CCC[C@H](N)C(=O)OCC CHAJBHNQIZAJJM-RGMNGODLSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 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
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- DPBOUPADTRCCIH-LURJTMIESA-N ethyl (2s)-2-aminopentanoate Chemical compound CCC[C@H](N)C(=O)OCC DPBOUPADTRCCIH-LURJTMIESA-N 0.000 description 1
- QQXQAEWRSVZPJM-UHFFFAOYSA-N ethyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1 QQXQAEWRSVZPJM-UHFFFAOYSA-N 0.000 description 1
- KISPUTPAKVZNBI-UHFFFAOYSA-N ethyl 2,3-dihydro-1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)CC2=C1 KISPUTPAKVZNBI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Description
AUSTRALIA Patents Act 1990 Les Laboratoires Servier COMPLETE SPECIFICATION Invention Title: A crystalline form of perindopril tert-butylamine salt The invention is described in the following statement: 2 Technical Field The present invention relates to a new cx crystalline form of perindopril tert-butylamine salt of formula (I): H N C0 2 H .tBUNH 2 (> 0
CH
3 H C NH (s)
CO
2 Et 5 in a pharmaceutical composition. Background Art 10 Perindopril and its pharmaceutically acceptable salts, and more especially its tert-butylamine salt, have valuable pharmacological properties. The principal property of these compounds is that of inhibiting angiotensin I converting enzyme (or kininase II), which prevents, on the one hand, conversion of the decapeptide 15 angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, degradation of bradykinin (a vasodilator) to an inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular disease, more especially in arterial hypertension and heart failure. 20 In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, any crystalline form should be reproducible, easily 25 formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.
3 Although there are industrial synthesis processes for perindopril, conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner have been difficult to achieve. 5 The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, reproducible crystalline form that especially exhibits valuable characteristics of filtration, drying, stability and ease of formulation. Disclosure of Invention 10 In a first aspect, the present invention provides an a crystalline form of the compound of formula (I): H N CO 2 H .tBu (2 0
CH
3 H C 3 (S) NH (S) CO2Et the a crystalline form characterised by the following powder X-ray diffraction diagram, 15 measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray): Angle 2 theta Inter-planar . Relative intensity (0) distance d (A) Inensity /) 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 4 Angle 2 theta Inter-planar Relative intensity (0) distance d (A) Intensity 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7 In a second aspect, the present invention provides a process for preparation of the ax crystalline form of the compound of formula (I) according to the first aspect of the present invention, comprising heating a solution of perindopril tert-butylamine salt in ethyl acetate at reflux and 5 gradually cooling the solution until crystallisation is complete, wherein the solution at reflux is first cooled to a temperature of from 55 to 65*C at a rate of from 5 to 10*C/hour, and then cooled to ambient temperature. In a preferred form, the concentration of the perindopril tert-butylamine salt in the ethyl acetate 10 is from 70 to 90 g/litre. In a preferred form, the solution of perindopril tert-butylamine salt in ethyl acetate is seeded during the cooling step at a temperature of from 76 to 65*C. 15 In a preferred form, the solution of the perindopril tert-butylamine salt in ethyl acetate at reflux is first cooled to a temperature of from 55 to 65C at a rate of from 6 to 8 0 C/hour, and then to ambient temperature. Preferably, the a crystalline form of the perindopril tert-butylamine salt is obtained in the form 20 of filterable individual needles. In a third aspect, the present invention provides a pharmaceutical composition comprising as active ingredient the c crystalline form of the compound according to the first aspect of the 5 present invention, in combination with one or more pharmaceutically acceptable, inert, non toxic canrers. The a crystalline form of the compound of formula (I) is preferably isolated in the form of 5 individual needles which can be further processed before formulation into the pharmaceutical composition. Examples of such processing are well known to the art and include crushing or grinding the needle crystals to a fine powder. Preferably, the pharmaceutical composition typically is in the form of tablets or drag6es, 10 sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, or drinkable suspensions. More preferably, the pharmaceutical composition is in the form of a tablet. 15 The pharmaceutical composition typically comprises from 1 to 500 mg of the a crystalline form of the compound of formula (I). In a preferred form, the pharmaceutical composition comprises from 1 to 100 mg of the a crystalline form of the compound. In another preferred form, the pharmaceutical composition comprises from 4 to 50 mg of the a crystalline form of the compound. In another preferred form, the pharmaceutical composition comprises from 2 to 20 8 mg of the a crystalline form of the compound. More preferably, the pharmaceutical composition comprises 4 mg of the a crystalline form of the compound of formula (I). The pharmaceutical composition may further comprising a diuretic. Preferably, the diuretic is indapamide. 25 In a fourth aspect, the present invention provides use of the pharmaceutical composition according to the third aspect of the present invention as an inhibitor of angiotensin I converting enzyme. 30 Preferably, the use is for treatment of cardiovascular disease. In a fifth aspect, the present invention provides a method of treatment of cardiovascular disease comprising administering to a patient in need of such treatment an efficacious amount of the a crystalline form of compound of formula (I) according to the first aspect of the present 35 invention.
6 In a sixth aspect, the present invention provides a method of treatment of cardiovascular disease comprising administering to a patient in need of such treatment an efficacious amount of a pharmaceutical composition according to the third aspect of the present invention. 5 In a seventh aspect, the present invention provides use of the a crystalline form of the compound of formula (I) according to the first aspect of the present invention for the manufacture of a medicament for treatment of cardiovascular disease. 10 In a preferred form, the a crystalline form of the compound of formula (I) is further characterized by being in the form of individual needles. Preferably, the individual needles are about 0.2 mm long. The individual needles allow rapid and efficient filtration and drying. Throughout this specification, unless the context requires otherwise, the word "comprise", or 15 variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Any discussion of documents, acts, materials, devices, articles or the like which has been 20 included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia prior to development of the present invention. 25 In order that the present invention may be more clearly understood, preferred embodiments will be described with reference to the following examples. Mode(s) for Carrying Out the Invention 30 The present invention relates to the a crystalline form of the compound of formula (I), the crystalline form being characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray): 7 Angle 2 theta Inter-planar Relative intensity (0) distance d (A) Intensity 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7 In a preferred form, the a crystalline form of the compound of formula (I) is further characterized by being in the form of individual needles. Preferably, the individual needles are about 0.2 mm long. The individual needles allow rapid and efficient filtration and drying. 5 The invention relates also to a process for the preparation of the a crystalline form of the compound of formula (I), which process is characterised in that a solution of perindopril tert butylamine salt in ethyl acetate is heated at reflux and is cooled gradually until crystallisation is complete. 10 In the crystallisation process according to the invention it is possible to use the compound of formula (I) obtained by any suitable process. For example, the compound of formula (I) can be obtained by the preparation process described in patent specification US 4914214 (corresponding to EP 0308341). The compound of formula (1) then undergoes the 8 crystallisation process according to the present invention to produce the a crystalline form of the compound. The concentration of the compound of formula (I) in the ethyl acetate is preferably from 70 to 5 90 g/litre. Preferably, the solution of the compound of formula (I) in ethyl acetate at reflux is first cooled to a temperature of from 55 to 65'C at a rate of from 5 to 10*C/hour, preferably from 6 to 8 0 C/hour, and then to ambient temperature. 10 The solution can advantageously be seeded during the cooling step at a temperature of from 76 to 65 0 C. The a crystalline form of perindopril tert-butylamine salt that is thereby obtained is in the form 15 of individual needles about 0.2 mm long. That homogeneous crystal distribution has the advantage of allowing especially rapid and efficient filtration and drying, as well as allowing the preparation of pharmaceutical formulations having a uniform and reproducible composition, which is especially advantageous when those formulations are intended for oral administration. 20 The a crystalline form of the compound of formula (I) thereby obtained is sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level. 25 The invention relates also to pharmaceutical compositions comprising as active ingredient the a crystalline form of the compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there. may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or drag6es, sublingual tablets, gelatin 30 capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc. The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. It varies from I to 500 mg per day 35 in one or more administrations. In tablet form, 4 mg is preferred.
9 The pharmaceutical compositions according to the invention may also comprise a diuretic such as indapamide. 5 The following Examples illustrate the invention but do not limit it in any way. EXAMPLE 1: Synthesis-of perindopril tert-butylamine salt Industrial Synthesis of the tert-Butylamine Salt of (2S,3aS,7aS)- 1- {2-[ 1 -(ethoxycarbonyl)-(S) 10 butylamino] -(S)-propionyl } -octahydroindole-2-carboxylic acid Stage I. (2S, 3aS, 7aS)-2-Carboxyoctahydroindole Stage 1a: 2-Ethoxycarbonylindole 15 Heat 5 kg of 2-carboxyindole suspended in ethanol in the presence of sulfuric acid to boiling for 8 hours. Evaporate. Evaporate off the ethyl acetate, take up the crystalline mass with hexane. After filtering off 20 and drying, 5.3 kg of crystals are obtained. Melting point: 1230 to 125 0 C. Microanalysis: Calculated: C % 69.83; H % 5.86; N % 7.40; Found: C % 69.56; H % 5.74; N 25 %7.30. Spectrometry in the infrared: 2150 cm- 1 (NH); 1680 cm- 1 (carboxylic acid). Stage IB: (R,S)-2-Ethoxycarbonylindoline 30 Suspend, in a reactor, 10 kg of 2-ethoxycarbonylindoline obtained previously in 110 liters of hydrochloric ethanol. Next, add 20 kg of granulated tin. Keep stirring for approximately 2 days at ambient temperature.
10 Evaporate off the ethanol, take up the residue with water and add 110 liters of toluene. Stir for approximately 20 minutes. Alkalify with aqueous ammonia. Separate off the aqueous phase and extract once again with 150 liters of toluene. 5 Combine the toluene phases and wash them with water. Separate off the toluene phases, filter. Remove the water by distilling the water-toluene azeotrope. Cool and pass through a stream of anhydrous HCI gas. Cool. Evaporate down and wash with pure toluene. 10 Weight obtained: 10.11 kg. Yield: 84%. 15 Thin layer chromatography: Solvent: toluene: 10; ethyl acetate: 5; Support: Merck silica 60 F 254; Developer: UV; Rf: 0.55. Stage JC: (R,S)-2-Carboxyindoline 20 2.15 kg of (R,S)-2-ethoxycarbonylindoline dissolved in ethanol are saponified with 12.5 liters of N sodium hydroxide with stirring for 24 hours. After washing the alkaline solution, neutralize with concentrated hydrochloric acid. After filtering off, washing and drying, 1.57 kg of white crystals of the expected product are obtained. 25 Yield: 86%. Melting point: 1880 to 189 0 C. Spectrometry in the infrared: NH 2 +: 2500-2000 cm~' ; COO~: 1620 cm-'. 30 Stage ID: (S)-2-Carboxyindoline 6.05 kg of (R,S)-2-carboxyindoline are added to a solution of 4.49 kg of (+)-a methylbenzylamine in anhydrous ethanol. A white precipitated product is obtained which, l1 after filtering off, is digested in refluxing isopropanol. After cooling, the solid is filtered off and washed with a little isopropanol; the white crystals obtained are dried: 3.68 kg. Rotatory power: [a] 21 =-5.3 (c=l% ethanol). 5 (S)-2-Carboxyindoline is prepared in a quantitative yield by dissolving 1 kg of the above salt in 5 liters of water and neutralizing with an aqueous hydrochloric acid solution. This precipitate is filtered off, washed with water and dried. 10 Stage JE: (2S, 3aS, 7aS)-2-Carboxyoctahydroindole Place 25 kg of (S)-2-carboxyindoline, obtained previously, in 110 liters of methanol in a vessel. Keep stirred. Charge the rhodium (5% dry) catalyst into a mixer. 15 Start up the stirring in a hydrogenator, charge the methanolic suspension of (S)-2 carboxyindoline by passing it through the mixer and rinse the assembly with water. Heat to 60'C and pressurize with hydrogen (30 bar). Filter off the catalyst on a single-plate filter. Collect the hydroalcoholic liquors in a reactor 20 and evaporate the methanol off under vacuum. After concentrating, charge approximately 300 kg of dioxane. Heat to boiling and add water until a solution is obtained. Allow to cool. Filter off and dry. 22.3 kg of crystals are obtained. 25 Yield: 86.1%. Stage 2. N-[(S)-J-Carbethoxybutyl]-(S)-alanine Stage 2A: Ethyl L-norvalinate hydrochloride 30 Place 35 kg of L-norvaline in approximately 300 kg of denatured ethanol in a reactor. Introduce approximately 60 kg of thionyl chloride, slowly and gradually. After stirring for a quarter of an hour, heat to reflux for 3 hours and then evaporate off the 35 ethanol under vacuum.
12 Take up the residue with 300 liters of cyclohexane and heat to boiling. Allow to cool, filter, wash with cyclohexane and dry. 52.9 kg of ethyl L-norvalinate hydrochloride are obtained, that is a 97.6% yield. 5 The product thus obtained is employed as such in the next stage. Stage 2B: N-[(S)-J-carbethoxybutyl]-(S)-alanine 10 Place 45 kg of ethyl N-norvalinate hydrochloride obtained in the preceding stage and approximately 110 liters of water in a vessel equipped with a stirrer. Alkalify, then pour 23 kg of pyruvic acid very gradually into the solution obtained previously and stir the reaction mixture for 30 minutes. 15 Place an aqueous suspension of charcoal containing 5% palladium and the alkaline solution of ethyl L-norvalinate obtained previously in a hydrogenation apparatus. Hydrogenate under pressure (30 bar) at ambient temperature for approximately one day. 20 Filter under vacuum and evaporate the filtrate under reduced pressure, filter off and dry. Treat the residue obtained with ethanol; remove the insoluble material, consisting of sodium chloride, by filtration and rinse it with ethanol. Combine the ethanolic solutions; evaporate off the ethanol under reduced pressure and crystallize the residue from acetonitrile. 25 34.3 kg of N-[(S)-1-carbethoxybutyl]-(S)-alanine are obtained, that is a 63.9% yield. Stage 3: tert-Butylamine salt of (2S,3aS, 7aS)-I-{2-[1-ethoxycarbonyl)-(S)-butylamino]-(S) propionyl)octahydroindole-2-carboxylic acid 30 Stage 3A: para-Toluenesulfonate of the benzyl ester of (2S,3aS, 7aS)-2-carboxyoctahydroindole In a 30-liter reactor, reflux 12.5 kg of (2S,3aS,7aS)-2-carboxyperhydroindole, 50 kg of para toluenesulfonic acid and 14.2 kg of benzyl alcohol and 38.4 kg of toluene, removing the water 13 formed with the aid of a continuous separator. When no more water separates out, cool, filter off the precipitate formed, and dry. Yield: 91.3%. 5 Stage 3B: Benzyl ester of (2S,3aS, 7aS)-J-{2-[-(ethoxycarbonyl)-(S)-butylamino]-(S) propionyl}octahydroindole-2-carboxylic acid Add approximately 3.5 kg of triethylamine to a suspension of approximately 5 kg of para 10 toluenesulfonate of the benzyl ester of (2S,3aS,7aS)-2-carboxyoctahydroindole in approximately 60 kg of ethyl acetate, followed by approximately 6 kg of 1 hydroxybenzotriazole, approximately 7.5 kg of the N-[(S)- 1 -carbethoxybutyl]-(S)-alanine obtained in stage 2 and approximately 7.0 kg of dicyclohexylcarbodiimide. 15 Stir, cooling slightly for approximately 3 hours, then filter off the dicyclohexylurea formed by filtration and wash the organic phase with water. The dried organic phase is evaporated to dryness. Yield: 92.3%. 20 Stage 3C: (2S,3aS, 7aS)-J-(2-[-(Ethoxycarbonyl)-(S)-butylamino]-(S) propionyl}octahydroindole-2-carboxylic acid Dissolve, in a hydrogenator, 14 kg of benzyl ester of the (2S,3aS,7aS)-1-{2-[1 25 (ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}octahydroindole-2-carboxylic acid obtained in the preceding stage in cyclohexane. Add the charcoal containing 5% palladium and approximately 50 liters of water. Hydrogenate at ordinary temperature and pressure until the theoretical volume of hydrogen has been 30 absorbed. Filter, wash the insoluble material with cyclohexane, separate off the organic phase and wash the aqueous phase again with cyclohexane. Isolate the product from the aqueous phase by freeze-drying. Stage 3D: tert-Butylamine salt of (2S,3aS, 7aS)-1-{2-[J-(ethoxycarbonyl)-(S)-butylamino]-(S) 35 propionyl}octahydroindole-2-carboxylic acid 14 Place in a reactor approximately 140 liters of ethyl acetate and 10 kg of (2S,3aS,7aS)-1-{2-[1 ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl} octahyd roindole-2-carboxylic acid obtained previously. Add gradually approximately 2.20 kg of tert-butylamine, heat to reflux until all 5 has dissolved; filter. Cool, filter off and dry. Yield: 95%. EXAMPLE 2: a crystalline form of perindopril tert-butylamine salt 10 125 g of perindopril tert-butylamine salt obtained according to the process described in Example I above is dissolved in 1.68 litres of ethyl acetate heated at reflux. The temperature of the solution is then brought to 60'C in the course of 2 hours 30 minutes and is then cooled to ambient temperature. 15 The solid obtained is collected by filtration. The resulting compound is an a crystalline form of the compound of formula (I). The powder X-ray diffraction spectrum of the a crystalline compound was measured under the following experimental conditions: 20 - Siemens D5005 diffractometer, scintillation detector, - copper anticathode (X=1.5405 A), voltage 40 kV, intensity mA, - mounting 9-9, - measurement range: 5' to 300, - increment between each measurement: 0.020, 25 - measurement time per step: 2 s, - variable slits: v6, - filter Kp (Ni), - no internal reference, - zeroing procedure using the Siemens slits, 30 - experimental data processed using EVA software (version 5.0). Analysis was carried out under ambient conditions. Powder X-ray diffraction diagram.: 35 15 The powder X-ray diffraction profile (diffraction angles) of the a form of perindopril tert butylamine salt is given by the significant rays collated in the following table together with the intensity and relative intensity (expressed as a percentage of the most intense ray): Angle 2 theta Inter-planar . Relative intensity (0) distance d (A) intensity 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 . 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7 5 The a crystalline form of the compound of formula (I) was obtained via filtration in the form of individual needles about 0.2 mm long. EXAMPLE 3: Pharmaceutical composition 10 Preparation formula for 1000 tablets each containing 4 mg of active ingredient: C om pound of E xam ple 2 ................................................................................................... 4 g H ydroxyp ropylcellulose .................................................................................................... 2 g W h e at starc h ..................................................................................................................... 10 g 16 L a c to se ........................................................................................................................... 10 0 g M agnesium stearate ...................................................................................................... . 3 g T a lc .................................................................................................................................... 3 g 5 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. 10
Claims (19)
- 7.680 11.50 390 8.8 8,144 10.85 230 5.2
- 9.037 9.78 4410 100
- 10.947 8.08 182 4.1 13,150 6.73 82 1.9
- 13.687 6.46 83 1.9
- 14.627 6.05 582 13.2
- 15.412 5.74 770 17.5
- 16.573 5.34 1115 25.3 17,357 5.10 340 7.7
- 18.109 4.89 193 4.4
- 19.922 4.45 306 6.9
- 20.609 4.31 375 8.5
- 21.412 4.15 226 5.1 21.832 4.07 217 4.9
- 22.158 4.01 483 11 22.588 3.93 386 8.8
- 23.323 3.81 107 2.4 24,200 3.67 448 10,2 18 Angle 2 theta (0) Inter-planar distance Intensity Relative intensity d (A) (%)
- 24.727 3.60 137 3.1
- 25.957 3.43 125 2.8
- 26.932 3.31 75 1.7
- 27.836 3.20 197 4.5
- 28.966 3.08 129 2.9 29,213 3.05 117 2.7 and further characterized by being in the form of individual needles. 2. The a crystalline form of the compound according to claim I wherein the individual 5 needles are about 0.2 mm long. 3. The a crystalline form of the compound according to claim 1 or 2, wherein the individual needles allow rapid and efficient filtration and drying. 10 4. A process for preparation of the a crystalline form of the compound of formula (I) according to any one of claims 1 to 3, comprising heating a solution of perindopril tert-butylamine salt in ethyl acetate at reflux and gradually cooling the solution until crystallisation is complete forming individual needles, wherein the solution at reflux is first cooled to a temperature of from 55 to 65 0 C at a rate of from 5 to I 0C/hour, and 15 then cooled to ambient temperature. 5. The process according to claim 4, wherein the concentration of the perindopril tert-butylamine salt in the ethyl acetate is from 70 to 90 g/litre. 20 6. The process according to claim 4 or 5, wherein the solution of perindopril tert butylamine salt in ethyl acetate is seeded during the cooling step at a temperature of from 76 to 65'C. 19 7. The process according to any one of claims 4 to 6, wherein the solution of the perindopril tert-butylamine salt in ethyl acetate at reflux is first cooled to a temperature of from 55 to 65*C at a rate of from 6 to 8*C/hour, and then to ambient temperature. 5 8. A pharmaceutical composition comprising as active ingredient a crystalline form of the compound of formula (I): H CO2H tBUN2 N 0 CH 3 H 3 C NH (s) CO 2 Et in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers; wherein the a crystalline form of the compound of formula (I) is characterised by 10 having the following powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray) Angle 2 theta (0) Inter-planar distance Intensity Relative intensity d (A) (%) 7.680 11.50 390 8.8 8,144 10,85 230 5,2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13,150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17,357 5.10 340 7.7 18.109 4.89 193 4.4 20 Angle 2 theta (*) Inter-planar distance Intensity Relative intensity d (A) (%) 19.922 4.45 306 69 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21,832 4.07 217 4.9 22,158 4.01 483 11 22.588 3.93 386 8.8 23,323 3.81 107 2.4 24.200 3.67 -448 10.2 24,727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9
- 29.213 3.05 117 2.7 and wherein the a crystalline form of compound of formula (I) has been isolated in the form of individual needles. 5 9. The pharmaceutical composition according to claim 8, wherein the individual needles are about 0.2 mm long. 10. The pharmaceutical composition according to claim 8 or 9, wherein the individual needles allow rapid and efficient filtration and drying. 10 11. The pharmaceutical composition according to any one of claims 8 to 10 in the form of tablets or drag6es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, or drinkable suspensions. 15 12. The pharmaceutical composition according to claim 11 in the form of a tablet. 21 13. The pharmaceutical composition according to any one of claims 8 to 12 comprising from I to 500 mg of the a crystalline form of the compound of formula (I). 14. The pharmaceutical composition according to claim 13 comprising 4 mg of the 5 a crystalline form of the compound of formula (I). 15. The pharmaceutical composition according to any one of claims 8 to 14, further comprising a diuretic. 10 16. The pharmaceutical composition according to claim 15, wherein the diuretic is indapamide. 17. Use of the pharmaceutical composition according to any one of claims 8 to 16 as an inhibitor of angiotensin I converting enzyme. 15 18. The use according to claim 17 for treatment of cardiovascular disease. 19. A method of treatment of cardiovascular disease comprising administering to a patient in need of such treatment an efficacious amount of c crystalline form of the compound 20 of formula (I): H N CO 2 H tBuNH 2 0 CH( NH (S) CO 2 Et characterised by having the following powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar 22 distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray) Angle 2 theta (*) Inter-planar distance Intensity Relative intensity d (A) (%) 7.680 11.50 390 8.8 8,144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13,150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17,357 5.10 340 7.7 18.109 - 4.89 193 4.4 19,922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21,832 4.07 217 4.9 22,158 4.01 483 11 22.588 3.93 386 8.8 23,323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25,957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28,966 3.08 129 2.9 29.213 3.05 117 2.7 5 wherein the a crystalline form of the compound of formula (I) has been isolated in the form of individual needles. 20. The method of treatment according to claim 19 when the individual needles are about 0.2 mm long. 10 23 21. The method of treatment according to claim 19 or 20, wherein the individual needles allow rapid and efficient filtration and drying. 22. A method of treatment of cardiovascular disease comprising administering to a patient 5 in need of such treatment an efficacious amount of a pharmaceutical composition according to any one of claims 8 to 16. 23. Use of the a crystalline form of the compound of formula (I): H N CO2H tBuNH2 l 0 CH 3 H1 3 C (S NH (s) CO 2 Et 10 for the manufacture of a medicament for treatment of cardiovascular disease, wherein the a crystalline form of the compound of formula (I) is characterised by having the following powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with 15 respect to the most intense ray). Angle 2 theta (*) Inter-planar distance Intensity Relative intensity d (A) (%) 7.680 11.50 390 8.8 8,144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 24 Angle 2 theta (0) Inter-planar distance Intensity Relative intensity d (A) (%) 16.573 5.34 1115 25.3 17,357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21,832 4.07 217 4.9 22.158 4.01 483 11 22,588 3.93 386 8.8 23.323 3.81 107 2.4 24,200 3.67 448 10.2 24.727 3.60 137 3,1 25,957 3.43 125 2.8 26.932 3.31 75 1.7 27,836 3.20 197 4.5 28.966 3.08 129 2.9 29,213 3.05 117 2.7 and wherein the x crystalline form of the compound of formula (I) has been isolated in the form of individual needles. 5 24. The use according to claim 23 wherein the individual needles are about 0.2 mm long. 25. The use according to claim 23 or 24, wherein the individual needles allow rapid and efficient filtration and drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2007203451A AU2007203451B2 (en) | 2000-07-06 | 2007-07-25 | Pharmaceutical composition containing a crystalline form of perindopril tert-butylamine salt |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0008793A FR2811320B1 (en) | 2000-07-06 | 2000-07-06 | NOVEL ALPHA CRYSTALLINE FORM OF TERT-BUTYLAMINE SALT OF PERINDOPRIL, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR00/08793 | 2000-07-06 | ||
| AU2001276418A AU2001276418B2 (en) | 2000-07-06 | 2001-07-06 | A crystalline form of perindopril tert-butylamine salt |
| PCT/FR2001/002167 WO2001087835A1 (en) | 2000-07-06 | 2001-07-06 | Α crystalline form of perindopril tert-butylamine salt |
| AU2007203451A AU2007203451B2 (en) | 2000-07-06 | 2007-07-25 | Pharmaceutical composition containing a crystalline form of perindopril tert-butylamine salt |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001276418A Division AU2001276418B2 (en) | 2000-07-06 | 2001-07-06 | A crystalline form of perindopril tert-butylamine salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2007203451A1 AU2007203451A1 (en) | 2007-08-16 |
| AU2007203451B2 true AU2007203451B2 (en) | 2010-09-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2007203451A Ceased AU2007203451B2 (en) | 2000-07-06 | 2007-07-25 | Pharmaceutical composition containing a crystalline form of perindopril tert-butylamine salt |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2007203451B2 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0049658B1 (en) * | 1980-10-02 | 1984-06-13 | Adir | Substituted imino diacids, their preparation and pharmaceutical preparations containing them |
| EP0308341B1 (en) * | 1987-09-17 | 1990-12-12 | Adir Et Compagnie | Process for the industrial synthesis of perindopril and for its principal synthesis intermediates |
-
2007
- 2007-07-25 AU AU2007203451A patent/AU2007203451B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0049658B1 (en) * | 1980-10-02 | 1984-06-13 | Adir | Substituted imino diacids, their preparation and pharmaceutical preparations containing them |
| EP0308341B1 (en) * | 1987-09-17 | 1990-12-12 | Adir Et Compagnie | Process for the industrial synthesis of perindopril and for its principal synthesis intermediates |
Non-Patent Citations (1)
| Title |
|---|
| CAIRA, Topics in Current Chemistry (1998) 198: 163-208 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2007203451A1 (en) | 2007-08-16 |
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