AU2006235841A1 - Novel beta crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it - Google Patents
Novel beta crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it Download PDFInfo
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- AU2006235841A1 AU2006235841A1 AU2006235841A AU2006235841A AU2006235841A1 AU 2006235841 A1 AU2006235841 A1 AU 2006235841A1 AU 2006235841 A AU2006235841 A AU 2006235841A AU 2006235841 A AU2006235841 A AU 2006235841A AU 2006235841 A1 AU2006235841 A1 AU 2006235841A1
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- pharmaceutical composition
- crystalline form
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
- 238000000034 method Methods 0.000 title description 16
- 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 description 11
- 238000002360 preparation method Methods 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 238000010586 diagram Methods 0.000 claims description 3
- 239000002934 diuretic Substances 0.000 claims description 3
- 230000001882 diuretic effect Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 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 2
- 229960004569 indapamide Drugs 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 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 6
- 229960002582 perindopril Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 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
- 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
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 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
- 208000037849 arterial hypertension Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
P001 Section 29 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: Novel beta crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it The following statement is a full description of this invention, including the best method of performing it known to us:
IND-
NEW p CRYSTALLINE FORM OF PERINDOPRIL TERT-BUTYLAMINE SALT, A PROCESS FOR ITS PREPARATION Z AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT The present invention relates to a new p crystalline form of perindopril tert-butylamine salt of formula 00 (N H SN CO 2 H .tBuNH 2 HC 0 CH 3
NH
CO
2 Et to a process for its preparation and to pharmaceutical compositions containing it.
Perindopril and its pharmaceutically acceptable salts, and more especially its tertbutylamine salt, have valuable pharmacological properties.
Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase II), which prevents, on the one hand, conversion of the decapeptide 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 diseases, more especially in arterial hypertension and heart failure.
Perindopril, its preparation and its use in therapeutics have been described in European Patent specification EP 0 049 658.
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, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.
The patent specification EP 0 308 341 describes an industrial synthesis process for perindopril. However, that document does not specify the conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner.
The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics for formulation.
More specifically, the present invention relates to the P crystalline form of the compound of formula 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) Angle 2 theta Inter-planar Intensity Relative intensity distance d 5.169 17.08 523 16.5 8.379 10.54 1001 31.5 9.350 9.45 3175 100 14.746 6.00 236 7.4 15.411 5.74 753 23.7 15.931 5.56 279 8.8 16.711 5.30 113 3.6 18.161 4.88 122 3.8 20.564 4.32 1198 37.7 21.285 4.17 330 10.4 21.781 4.08 317 22.632 3.93 190 6 23.308 3.81 133 4.2 23.797 3.74 427 13.4 24.276 3.66 118 3.7 25.190 3.53 92 2.9 00 25.924 3.43 251 7.9 26.646 3.34 250 7.9 27.620 3.23 96 3 28.306 3.15 133 4.2 'The invention relates also to a process for the preparation of the P crystalline-form-of-the compound of formula which process is characterised in that: either, according to a first embodiment, a solution of perindopril tert-butylamine salt in dichloromethane is heated at reflux and is then rapidly cooled to 0°C and the solid obtained is collected by filtration, or, according to a second embodiment, a solution of perindopril tert-butylamine salt in ethyl acetate is heated at reflux and is then rapidly cooled to 5 0 C and the solid obtained is collected by filtration.
In the crystallisation process according to the invention it is possible to use the compound of formula obtained by any process. Advantageously, the compound of formula obtained by the preparation process described in patent specification EP 0 308 341 is used.
In the first embodiment of the process according to the invention, the concentration of the compound of formula in the dichloromethane is preferably from 100 to 200 g/litre.
In the second embodiment of the process according to the invention, the concentration of the compound of formula in the ethyl acetate is preferably from 70 to 90 g/litre.
The invention relates also to pharmaceutical compositions comprising as active ingredient the P crystalline form of the compound of formula 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 dragdes, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc..
IN -4- The useful dosage can be varied according to the nature and severity of the disorder, the Z administration route and the age and weight of the patient. It varies from 1 to 500 mg per day in one or more administrations.
The pharmaceutical compositions according to the invention may also comprise a diuretic 0 0 5 such as indapamide.
N The following Examples illustrate the invention but do not limit it in any way.
O
The powder X-ray diffraction spectrum was measured under the following experimental conditions Siemens D5005 diffractometer, scintillation detector, copper anticathode (X=1.5405 voltage 40 kV, intensity 40 mA, mounting -measurement range 50 to 300, increment between each measurement: 0.02°, measurement time per step 2 s, variable slits v6, filter K,6 (Ni), no internal reference, -zeroing procedure with the Siemens slits, experimental data processed using EVA software (version EXAMPLE 1: P crystalline form of perindopril tert-butylamine salt 135 g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP 0 308 341 are dissolved in 1100 ml of dichloromethane heated at reflux.
The solution is then cooled to 0°C and the solid obtained is collected by filtration.
Powder X-ray diffraction diagram The powder X-ray diffraction profile (diffraction angles) of the P form of perindopril tertbutylamine 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 In y Relative intensity distance d ensty 5.169 17.08 523 16.5 8.379 10.54 1001 31.5 9.350 9.45 3175 100 14.746 6.00 236 7.4 15.411 5.74 753 23.7 15.931 5.56 279 8.8 16.711 5.30 113 3.6 18.161 4.88 122 3.8 20.564 4.32 1198 37.7 21.285 4.17 330 10.4 21.781 4.08 317 22.632 3.93 190 6 23.308 3.81 133 4.2 23.797 3.74 427 13.4 24.276 3.66 118 3.7 25.190 3.53 92 2.9 25.924 3.43 251 7.9 26.646 3.34 250 7.9 27.620 3.23 96 3 28.306 3.15 133 4.2 EXAMPLE 2 P crystalline form of perindopril tert-butylamine salt 125 g of perindopril tert-butylamine salt obtained according to the process described in patent specification EP 0 308 341 are dissolved in 1.5 litres of ethyl acetate heated at reflux.
The solution is then cooled rapidly to 5°C and the solid obtained is collected by filtration.
6 IN EXAMPLE 3: Pharmaceutical composition 0 Z Preparation formula for 1000 tablets each containing 4 mg of active ingredient: SCompound of Example 1 4 g Hydroxypropylcellulose 2 g W heat starch 10 g Lactose 100 g Magnesium 3 g IN T alc 3 g Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (17)
1. p crystalline form of the compound of formula tBUNH2 M,) characterised by 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 Inter-planar Intensity Relative intensity distance d
5.169 17.08 523 16.5
8.379 10.54 1001 31.5
9.350 9.45 3175 100
14.746 6.00 236 7.4
15.411 5.74 753 23.7 15.931 5.56 279 8.8
16.711 5.30 113 3.6
18.161 4.88 122 3.8
20.564 4.32 1198 37.7
21.285 4.17 330 10.4 21.781 4.08 317
22.632 3.93 190 6
23.308 3.81 133 4.2 23.797 3.74 427 13.4
24.276 3.66 118 3.7
25.190 3.53 92 2.9 \0 z 00 0 Cc, 25.924 3.43 251 7.9
26.646 3.34 250 7.9
27.620 3.23 96 3
28.306 3.15 133 4.2 2. Pharmaceutical composition comprising as active ingredient the compound according to claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 3. Pharmaceutical composition according to claim 1 or claim 2 for use in the manufacture of medicaments for use as inhibitors of angiotensin I converting enzyme. 4. Pharmaceutical composition according to claim 3 for use in the manufacture of medicaments for use in the treatment of cardiovascular diseases. 5. Pharmaceutical composition according to any one of claims 2 to 4, characterised in that it also comprises a diuretic. 6. Pharmaceutical composition according to claim 5, characterised in that the diuretic is indapamide. 7. 3 crystalline form of the compound of formula substantially as hereinbefore described with reference to Examples 1 and 3. 8. Pharmaceutical composition comprising as active ingredient the 13 crystalline form of the compound of formula substantially as hereinbefore described with reference to Examples 1 and 3. DATED this day of 2006 LES LABORATOIRES SERVIER WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P22270AU01
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR00/08792 | 2000-07-06 | ||
| AU2001276419A AU2001276419B2 (en) | 2000-07-06 | 2001-07-06 | Novel beta crystalline form of perindopril tert- butylamine salt, preparation method and pharmaceutical compositions containing same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001276419A Division AU2001276419B2 (en) | 2000-07-06 | 2001-07-06 | Novel beta crystalline form of perindopril tert- butylamine salt, preparation method and pharmaceutical compositions containing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2006235841A1 true AU2006235841A1 (en) | 2006-11-23 |
Family
ID=37461050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2006235841A Abandoned AU2006235841A1 (en) | 2000-07-06 | 2006-11-03 | Novel beta crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2006235841A1 (en) |
-
2006
- 2006-11-03 AU AU2006235841A patent/AU2006235841A1/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application | ||
| NA | Applications received for extensions of time, section 223 |
Free format text: AN APPLICATION TO EXTEND THE TIME FROM 06 JUL 2007 TO 06 MAR 2008 IN WHICH TO PAY A CONTINUATION FEE HAS BEEN FILED . |
|
| NB | Applications allowed - extensions of time section 223(2) |
Free format text: THE TIME IN WHICH TO PAY A CONTINUATION FEE HAS BEEN EXTENDED TO 06 MAR 2008. |
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| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |