CN114149357B - Preparation method of gamma-crystal form perindopril arginine salt - Google Patents
Preparation method of gamma-crystal form perindopril arginine salt Download PDFInfo
- Publication number
- CN114149357B CN114149357B CN202111630897.2A CN202111630897A CN114149357B CN 114149357 B CN114149357 B CN 114149357B CN 202111630897 A CN202111630897 A CN 202111630897A CN 114149357 B CN114149357 B CN 114149357B
- Authority
- CN
- China
- Prior art keywords
- perindopril
- gamma
- arginine
- crystal form
- filter cake
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- RYCSJJXKEWBUTI-YDYAIEMNSA-N perindopril arginine Chemical class OC(=O)[C@@H](N)CCCNC(N)=N.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 RYCSJJXKEWBUTI-YDYAIEMNSA-N 0.000 title claims abstract description 15
- 229960002582 perindopril Drugs 0.000 claims abstract description 33
- 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 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012065 filter cake Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 12
- 229930064664 L-arginine Natural products 0.000 claims abstract description 12
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 238000002386 leaching Methods 0.000 claims abstract description 3
- 238000005086 pumping Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 6
- 238000010438 heat treatment Methods 0.000 abstract description 4
- 238000004108 freeze drying Methods 0.000 abstract description 3
- 238000010992 reflux Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000004475 Arginine Substances 0.000 description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 11
- 235000009697 arginine Nutrition 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 7
- -1 arginine perindopril salts Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical group C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 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
- 206010019280 Heart failures Diseases 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010067484 Adverse reaction Diseases 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
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- 206010020772 Hypertension 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
- 241000233805 Phoenix Species 0.000 description 1
- 230000006838 adverse reaction Effects 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
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002457 bidirectional effect 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
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 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 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012353 t test 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
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a preparation method of gamma-crystal form perindopril arginine salt, which comprises the steps of adding perindopril and L-arginine into water, stirring and clearing, filtering, mixing filtrate with an organic solvent in a dropwise manner, cooling to room temperature after dropwise addition, stirring and crystallizing for 1-2 hours, filtering to obtain a filter cake, leaching the filter cake, pumping, and drying the filter cake to obtain the gamma-crystal form perindopril arginine salt. The method has the advantages of no need of low temperature, no special requirements on equipment by freeze-drying and other operations, no need of reflux or heating operation, wide crystallization temperature application range, good filtration, easy separation and high quality level of the obtained product.
Description
Technical Field
The invention relates to a synthesis method of arginine perindopril, in particular to a preparation method of gamma-crystal form perindopril arginine salt, belonging to the technical field of pharmaceutical chemicals.
Background
Perindopril is a third generation angiotensin converting enzyme inhibitor, which is commonly used clinically for treating hypertension and heart failure, and has pharmacological properties of mainly inhibiting angiotensin I converting enzyme (or kininase II), so that on one hand, the conversion of decapeptide angiotensin I into octapeptide angiotensin II (an vasoconstrictor) can be prevented, and on the other hand, the degradation of bradykinin (an vasodilator) into inactive peptide can be prevented, and the two effects enable perindopril to have beneficial effects on cardiovascular diseases, especially arterial hypertension and heart failure. The perindopril is marketed in the form of tert-butylamine salt at the earliest, has the advantages of small dosage, wide treatment range, rapid and durable curative effect, small adverse reaction and the like, but the perindopril tert-butylamine salt is sensitive to heat and humidity and is easy to degrade, and the perindopril arginine salt has better stability and moisture resistance than the tert-butylamine salt, and is more suitable for drug production and popularization and application.
The preparation and use of arginine perindopril salts have been described in the specification of European patent EP 1354873. Later, a certain research was also carried out in the prior art concerning the preparation of different crystal forms of arginine perindopril salt: for example, the invention patent with patent publication number CN101389603B describes an alpha crystal form and a method for preparing the same, the invention patent with patent publication number CN101389604B describes a beta crystal form and a method for preparing the same, the invention patent with patent publication number CN103193863a describes a delta crystal form and a method for preparing the same, the international invention patent with patent publication number WO 2009157018A 2 and the invention patent with patent publication number CN103172696a describes a gamma crystal form and a method for preparing the same, and the US invention with patent publication number US2010056802 A1 describes an amorphous form and a method for preparing the same; etc. The gamma crystal form is considered to be a stable medicinal crystal form which is easier to obtain, but the existing preparation method of the gamma crystal form still has more defects.
The international patent publication No. WO2009157018 A2 discloses various methods for preparing the gamma-crystalline form of arginine perindopril salt: the first preparation method is that perindopril is dissolved in water to form salt with L-arginine, insoluble matters are filtered, and clear filtrate is subjected to freeze drying or spray drying treatment to prepare gamma crystal forms, wherein a freeze dryer or spray drying equipment is needed; the second preparation method is that perindopril and L-arginine are dissolved in water, the first solvent is added, then the second solvent is added for crystallization and filtration, and the gamma crystal form is prepared, and the method uses more solvents, has complex process, poor crystallization state and difficult filtration; the third preparation method is that perindopril is dissolved in benign organic solvent, heated and dissolved, poor solvent is dripped for crystallization and filtration to prepare gamma crystal form, and the method needs to raise the system temperature and accelerates the degradation of perindopril; the fourth preparation method is that perindopril is dissolved in organic solvent, L-arginine water solution is dripped into salt, crystallization and filtration are carried out, and gamma crystal form is prepared, and the method has bad crystallization state and difficult filtration.
Another preparation method of the gamma-crystalline form of perindopril arginine salt is disclosed in the patent publication No. CN103172696a, wherein perindopril and L-arginine are dissolved in water, an organic solvent is added after stirring and clearing, water is separated by heating to reflux, and the mixture is cooled to room temperature and filtered by suction, and dried to obtain the gamma-crystalline form.
Disclosure of Invention
The invention aims to solve the problems of the existing preparation method of perindopril arginine salt, and provides a novel preparation method of gamma-crystal form perindopril arginine salt, which has the advantages of wide crystallization temperature application range, good filtration and easy separation of the obtained product, and high quality level.
The technical solution of the invention is as follows: a preparation method of gamma-crystal form perindopril arginine salt, which comprises the following steps: adding perindopril and L-arginine into water, stirring and dissolving, filtering, mixing filtrate with an organic solvent in a dropwise manner, cooling to room temperature after dropwise addition, stirring and crystallizing for 1-2 h, filtering to obtain a filter cake, leaching the filter cake, pumping to dry, and drying the filter cake to obtain the gamma-crystal form perindopril arginine salt.
Further, the ratio of the amount of perindopril to the amount of the substance added to L-arginine is 1:0.9 to 1.1.
Further, the organic solvent is one or more of dimethyl sulfoxide, acetone or toluene and is a non-alcohol solvent miscible with water, preferably a mixed solvent of dimethyl sulfoxide and water; the mass ratio of the filtrate to the organic solvent is 1:1-5, preferably, the filtrate is dropwise added into the organic solvent, and the dropwise heating temperature is controlled to be not more than 30 ℃, preferably not more than 20 ℃; the temperature of stirring crystallization is 20-30 ℃.
Further, the filter cake is rinsed with acetone, n-heptane or mixtures thereof.
The specific reaction chemical formula of the method is as follows:
。
Compared with the prior art, the invention has the advantages that:
1) The invention is simpler and more practical by selecting specific solvents or combined solvents, is easy to operate, does not need low temperature, freeze-drying and other operations to have special requirements on equipment, does not need reflux or heating operation, can realize mass production by matching with large-scale closed centrifuge and oven conjoined equipment commonly used by current manufacturers, has the advantage of easier centrifugal drying, can effectively reduce the occurrence of gel state in the crystallization process, fully ensures centrifugal desolventizing, reduces loss of effective components, further saves cost, and simultaneously improves the product quality;
2) The product obtained by the method has high purity and good stability, the purity of the final product reaches more than 99.5 percent, and the single degradation impurity is less than 0.3 percent (the degradation impurity is impurity B/F recorded in European pharmacopoeia). Under the high humidity condition (RH 90%), the gamma crystal form is not transformed, and is more stable than the alpha crystal form and the beta crystal form.
Drawings
Figure 1 is an XRD pattern for the gamma crystalline form produced by the water/dimethyl sulfoxide system of the examples.
Figure 2 is an XRD pattern for the gamma crystalline form produced in the water/acetone system of the examples.
FIG. 3 is a graph of mean blood concentration versus time for 10 healthy subjects in the example, single oral perindopril test and reference formulations, respectively.
FIG. 4 is a graph of mean blood concentration versus time for perindopril from 10 healthy subjects in the example, a single oral dose of perindopril in the test and reference formulations, respectively.
Detailed Description
The technical scheme of the invention is further described below according to a plurality of embodiments. In the description of the present specification, the contents of the various embodiments mean that specific technical features described in connection therewith are included in at least one embodiment of the present invention. In this specification, schematic representations of various embodiments do not necessarily refer to the same implementations or examples. Furthermore, the particular features described may be combined in any suitable manner in any one or more embodiments or examples.
Example 1
5.0G of perindopril, 2.4g of L-arginine and 20ml of water are added into a reaction bottle, stirred at room temperature until the mixture is completely dissolved, filtered, 60ml of dimethyl sulfoxide is added into the filtrate in a dropwise manner, the temperature does not exceed 50 ℃ in the dropwise addition process, the temperature is reduced to 20-30 ℃ after the dropwise addition, stirring is continued for 1h, suction filtration is carried out, a filter cake is sequentially leached by 50ml of acetone and 50ml of n-heptane, and is dried, thus obtaining the gamma crystal form of the perindopril arginine salt. The XRD pattern of the gamma crystal form prepared by the water/dimethyl sulfoxide system is shown in figure 1.
Example 2
5.0G of perindopril, 2.4g of L-arginine and 20ml of water are added into a reaction bottle, stirred at room temperature until the mixture is completely dissolved, filtered, 100ml of acetone is dripped into the filtrate, the temperature does not need to be controlled in the dripping process, the temperature does not exceed 50 ℃, the temperature is reduced to 20-30 ℃ after the dripping is finished, the mixture is continuously stirred for 1h, suction filtration is carried out, a filter cake is leached by 50ml of n-heptane, suction drying is carried out, and the filter cake is dried, thus obtaining the gamma crystal form of the perindopril arginine salt. The XRD pattern of the gamma crystal form prepared by the water/acetone system is shown in figure 2.
Example 3
11.8Kg of perindopril, 5.5kg of L-arginine and 42.5kg of purified water were added to the reaction vessel, and the solution was stirred and filtered. 240kg of dimethyl sulfoxide aqueous solution cooled to below 10 ℃ is added, stirring is started, the solution is subjected to centrifugal filtration for 1h, the solution is washed by 118kg of acetone and is subjected to centrifugal filtration for 20min, then 70kg of n-heptane is used for washing and is subjected to centrifugal filtration for 20min, a filter cake is put into a baking tray, vacuum drying is carried out for 10 h at 45 ℃ and then vacuum drying is carried out for 30 h at 80 ℃ to obtain an industrial production finished product of arginine perindopril salt gamma crystal (purity: 99.62%, impurity B:0.081% and impurity F: 0.205%).
The preparation process of the arginine perindopril salt gamma crystal form pharmaceutical composition (10 mg/tablet) is specifically as follows:
prescription composition:
arginine perindopril 10mg
Lactose monohydrate 145mg
Magnesium stearate 0.9mg
Maltodextrin 18mg
Colloidal silica 0.54mg
Sodium carboxymethyl starch (type A) 5.4mg
Film coating 5mg
The technical process comprises the following steps: mixing arginine perindopril, lactose monohydrate and maltodextrin, adding water, granulating, drying, finishing, adding colloidal silicon dioxide, sodium carboxymethyl starch (A type) and magnesium stearate, mixing, tabletting, and coating to obtain arginine perindopril tablet product.
The bioequivalence test process of the arginine perindopril tablet is specifically as follows:
After 10 healthy subjects were respectively fasted with a cross-oral arginine perindopril tablet reference preparation 1 tablet (COVERSYL ® mg) or a test preparation 1 tablet (10 mg), the venous blood was collected from EDTA anticoagulant tubes at 0min, 10min, 20min, 30min, 45min, 1h, 1.25h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, and 48h, respectively, and plasma was collected to obtain average plasma concentration-time curves of perindopril and perindopril (metabolite of perindopril) plasma, as shown in fig. 3 and 4.
Pharmacokinetic data were statistically analyzed using Phoenix WinNonlin 6.0.0. After natural logarithmic conversion of parameters AUC 0-tau and Cmax of perindopril and perindopril obtained after single dose oral perindopril test preparation and reference preparation of a subject, bioequivalence evaluation is carried out by using variance analysis of double-cross test design and then bidirectional single-side t test, and whether bioequivalence is judged. The results of the Cmax and AUC0- τ equivalence test for perindopril and perindopril at a single administration are shown in the following table:
From the above table, when R is taken as a reference, the 90% confidence interval of the AUC0- τ geometric mean ratio of the test formulation T is in the range of 80% -125%, and the 90% confidence interval of the Cmax geometric mean ratio is in the range of 80% -125%, so that the test determination: the test formulation is bioequivalent to the reference formulation.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Claims (1)
1. A process for the preparation of perindopril arginine salt in the gamma-crystalline form, characterized in that it comprises in particular the following steps:
1) Adding perindopril and L-arginine into water, stirring, dissolving, and filtering to obtain filtrate;
2) Mixing the filtrate obtained in the step 1) with an organic solvent in a dropwise adding mode, cooling to room temperature after dropwise adding, stirring and crystallizing for 1-2 hours, and carrying out suction filtration to obtain a filter cake;
3) Leaching the filter cake obtained in the step 2), pumping and drying the filter cake to obtain gamma-crystal form perindopril arginine salt;
wherein the ratio of the amount of perindopril to the amount of the substance fed by L-arginine in the step 1) is 1:0.9-1.1;
The filtrate in the step 2) is mixed with the organic solvent in a dropwise manner, and the method specifically comprises the following steps: dropwise adding an organic solvent into the filtrate;
The organic solvent in the step 2) is dimethyl sulfoxide;
The mass ratio of the filtrate to the organic solvent in the step 2) is 1:1-5;
The temperature of dropwise adding and mixing in the step 2) is controlled to be not more than 30 ℃;
the temperature of stirring crystallization in the step 2) is 20-30 ℃;
The filter cake in the step 3) is sequentially rinsed by acetone and n-heptane.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111630897.2A CN114149357B (en) | 2021-12-29 | 2021-12-29 | Preparation method of gamma-crystal form perindopril arginine salt |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111630897.2A CN114149357B (en) | 2021-12-29 | 2021-12-29 | Preparation method of gamma-crystal form perindopril arginine salt |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114149357A CN114149357A (en) | 2022-03-08 |
CN114149357B true CN114149357B (en) | 2024-06-25 |
Family
ID=80449354
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111630897.2A Active CN114149357B (en) | 2021-12-29 | 2021-12-29 | Preparation method of gamma-crystal form perindopril arginine salt |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114149357B (en) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2897866B1 (en) * | 2006-02-28 | 2008-04-18 | Servier Lab | ALPHA CRYSTALLINE FORM OF PERINOPRIL ARGININE SALT, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
EP2318365B1 (en) * | 2008-06-24 | 2015-08-12 | Mylan Laboratories Limited | Novel polymorphic forms of perindopril (l)-arginine and process for the preparation thereof |
FR2985511B1 (en) * | 2012-01-05 | 2014-01-03 | Servier Lab | CRYSTALLINE DELTA FORM OF PERINOPRIL ARGININE SALT, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2985512B1 (en) * | 2012-01-05 | 2014-06-20 | Servier Lab | PROCESS FOR THE PREPARATION OF L-ARGININE SALT OF PERINDOPRIL |
CN103172696B (en) * | 2012-12-19 | 2014-12-17 | 宁波美诺华药业股份有限公司 | Preparation method of perindopril arginine salt of gamma-crystal form |
CN110283104B (en) * | 2018-08-22 | 2022-06-14 | 南京济群医药科技股份有限公司 | Preparation method of arginine perindopril |
CN112047999B (en) * | 2020-09-18 | 2022-12-02 | 天津力生制药股份有限公司 | Preparation method of gamma-crystal form arginine perindopril salt |
-
2021
- 2021-12-29 CN CN202111630897.2A patent/CN114149357B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN114149357A (en) | 2022-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018019300A1 (en) | Oral solid preparation and use thereof | |
TW201803853A (en) | Salts of 2,6-dimethylpyrimidone derivatives and uses thereof | |
CN114149357B (en) | Preparation method of gamma-crystal form perindopril arginine salt | |
CN103664882A (en) | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate | |
CN109438371B (en) | Methylpyrazine derivative arginine hydrate | |
WO2012126363A1 (en) | Amorphous asiatic tromethamine salt and preparation method thereof | |
CN112521385B (en) | Berberine hydrochloride eutectic crystal and preparation method thereof | |
CN111825547B (en) | Salt of aryl propionic acid compound and pharmaceutical application thereof | |
CN110354075A (en) | A kind of Loratadine nano suspension and preparation method thereof | |
CN104045615B (en) | (1S) crystal form A and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose | |
CN105055342A (en) | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer | |
CN112538123B (en) | Shugansu sodium crystal form M | |
CN107033163A (en) | A kind of Yi Dushaban is to benzene methanesulfonic acid salt novel crystal forms and its preparation method and application | |
WO2016078543A1 (en) | Revaprazan hydrochloride polymorphs and preparation method therefor | |
TW201900646A (en) | Methanesulfonate polycrystal of type 5 phosphodiesterase inhibitor, preparation method and application thereof | |
CN112654607B (en) | Crystalline forms of 6- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide | |
CN105412027A (en) | Preparation method of dronedarone hydrochloride tablets | |
KR100698595B1 (en) | Amorphous or semi-crystal modification of glimepiride, a preparation process and a phamrceutical composition thereof | |
CN102093234B (en) | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof | |
CN104784146A (en) | Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer | |
CN106279017A (en) | Bedaquinoline crystal form, composition and preparation method thereof | |
CN104045614B (en) | (1S) crystal C and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose | |
CN110314143A (en) | Injection dextrorotation Oxiracetam lyophilized preparation and preparation method thereof | |
CN113943271B (en) | Acetinib crystal form and preparation method thereof | |
CN115212171B (en) | Ticagrelor sustained-release pellet and pharmaceutical preparation containing same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant |