TWI471307B - 培哚普利（ＰＥＲＩＮＤＯＰＲＩＬ）之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物 - Google Patents

培哚普利（ＰＥＲＩＮＤＯＰＲＩＬ）之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物 Download PDF

Info

Publication number
TWI471307B
TWI471307B TW101150658A TW101150658A TWI471307B TW I471307 B TWI471307 B TW I471307B TW 101150658 A TW101150658 A TW 101150658A TW 101150658 A TW101150658 A TW 101150658A TW I471307 B TWI471307 B TW I471307B
Authority
TW
Taiwan
Prior art keywords
perindopril
dimethyl hydrazine
mixture
acetonitrile
pharmaceutical composition
Prior art date
Application number
TW101150658A
Other languages
English (en)
Other versions
TW201331178A (zh
Inventor
Julie Linol
Arnaud Grenier
Original Assignee
Servier Lab
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=47427277&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TWI471307(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Servier Lab filed Critical Servier Lab
Publication of TW201331178A publication Critical patent/TW201331178A/zh
Application granted granted Critical
Publication of TWI471307B publication Critical patent/TWI471307B/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B43/00—Forming, feeding, opening or setting-up containers or receptacles in association with packaging
    • B65B43/42—Feeding or positioning bags, boxes, or cartons in the distended, opened, or set-up state; Feeding preformed rigid containers, e.g. tins, capsules, glass tubes, glasses, to the packaging position; Locating containers or receptacles at the filling position; Supporting containers or receptacles during the filling operation
    • B65B43/46—Feeding or positioning bags, boxes, or cartons in the distended, opened, or set-up state; Feeding preformed rigid containers, e.g. tins, capsules, glass tubes, glasses, to the packaging position; Locating containers or receptacles at the filling position; Supporting containers or receptacles during the filling operation using grippers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G47/00—Article or material-handling devices associated with conveyors; Methods employing such devices
    • B65G47/74—Feeding, transfer, or discharging devices of particular kinds or types
    • B65G47/90—Devices for picking-up and depositing articles or materials
    • B65G47/91—Devices for picking-up and depositing articles or materials incorporating pneumatic, e.g. suction, grippers
    • B65G47/912—Devices for picking-up and depositing articles or materials incorporating pneumatic, e.g. suction, grippers provided with drive systems with rectilinear movements only
    • 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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G2201/00—Indexing codes relating to handling devices, e.g. conveyors, characterised by the type of product or load being conveyed or handled
    • B65G2201/02—Articles
    • B65G2201/0235—Containers

Description

培哚普利(PERINDOPRIL)之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物
本發明係關於式(I)之培哚普利(perindopril)L-精胺酸鹽之δ結晶型式、 其製備方法及含有其之醫藥組合物。
培哚普利及其醫藥上可接受之鹽、且更特定而言其精胺酸鹽具有有價值之藥理學特性。
其主要特性為抑制血管收縮素I轉化酶(或激肽酶II)，此使得一方面可防止十肽血管收縮素I轉化成八肽血管收縮素II(一種血管收縮劑)，且另一方面可防止緩激肽(一種血管舒張劑)降解成無活性肽。
該兩種作用有助於培哚普利在心血管疾病、更特定而言在高動脈壓、心臟衰竭及穩定性冠狀動脈疾病中之有益效應。
培哚普利、其製備及其在治療中之用途已闡述於歐洲專利說明書EP 0 049 658中。
培哚普利之精胺酸鹽首次闡述於歐洲專利說明書EP 1 354 873中。
培哚普利之精胺酸鹽之α及β結晶型式已闡述於歐洲專利說明書EP 1 989 182及EP 2 016 051中。
培哚普利之精胺酸鹽之γ結晶型式已闡述於專利申請案WO 2009/157018中。
獲得培哚普利精胺酸之方法已闡述於專利說明書SI 23001中。
鑒於培哚普利精胺酸之醫藥價值，以極佳穩定性獲得其尤為重要。
更特定而言，本發明係關於式(I)之化合物之δ結晶型式。
本發明培哚普利精胺酸之δ結晶型式之特徵可在於其X-射線繞射圖(圖1)及/或在於其固體NMR光譜(圖3)。
在賦形劑及雜質不存在下，本發明培哚普利精胺酸之δ結晶型式之特徵可在於以下X-射線粉末繞射圖，其係使用具有銅對陰極之繞射計來量測，且以平面間距d、布拉格角度(Bragg's angle)2θ及相對強度(表示為相對於最強譜線之百分比)來表示：
認為每一譜線之2θ精確度為±0.2°。
相對強度係出於資訊目的而給出。
X-射線粉末繞射光譜係在以下測試條件下來量測：˙Panalytical X'Pert Pro繞射計˙X'Celerator檢測器˙銅對陰極，電壓40 kV，電流30 mA；˙照射(Transmission)安裝；固定試樣；˙溫度：環境；˙量測範圍：3°至40°；˙每一量測之間之增量：0.017°；˙量測時間/步：49 s； ˙無內標準；˙用X'Pert Highscore軟體(2.2a版)來處理測試數據
在雜質或賦形劑存在下，尤其在乳糖存在下，可遮蔽本發明δ型培哚普利精胺酸之某些X-射線繞射峰。
端視賦形劑或雜質之性質而定，則本發明培哚普利精胺酸之δ結晶型式之特徵可在於以下X-射線粉末繞射峰，其係使用具有銅對陰極之繞射計來量測，且以如下角度2-θ(°)來表示：4.3、11.0、11.1、13.2、14.6、16.0及21.9；或4.3、11.0、11.1、11.9、13.2、14.6、19.2、21.9及22.6；或4.3、11.0、11.1、11.9、12.5、13.2、14.6、16.0、19.2、19.4、21.9、22.2及22.6。
培哚普利之精胺酸鹽之δ結晶型式之特徵亦在於固態NMR光譜。
固態13 C NMR光譜係在環境溫度下使用具有4 mmCP/MAS SB VTN型探針之Bruker SB Avance光譜儀在以下條件下來記錄：- 頻率：125.76 MHz，- 光譜寬度：40 kHz，- 試樣之魔角(Magic Angle)自旋速率：10 kHz，- 利用SPINAL64去耦合(去耦合功率為80 kHz)之CP(交叉極化)脈衝序列，- 重複延遲：10 s，- 採集時間：47 ms，- 接觸時間：4 ms - 掃描次數：4096。
在傅立葉轉換(Fourier Transformation)之前將譜線加寬5 Hz。
由此獲得之光譜係相對於金剛烷試樣(將金剛烷之高頻率峰設置為38.48 ppm)來參考。
已將所觀察之峰於下表中理序(以ppm±0.2 ppm表示)：
本發明亦係關於製備培哚普利之精胺酸鹽之δ結晶型式之方法，其係在高於20℃之溫度下，使培哚普利精胺酸鹽自乙腈、乙酸乙酯或甲基第三丁基醚與二甲基亞碸之二元混合物或乙腈、二甲基亞碸與甲苯之三元混合物中結晶或再結晶。
在結晶方法之情形下，可自另一種培哚普利鹽(例如第三丁基胺鹽)開始來獲得培哚普利之精胺酸鹽，使該另一種培哚普利鹽與酸反應，獲得呈游離酸型式之培哚普利，藉由存於乙腈、乙酸乙酯或甲基第三丁基醚與二甲基亞碸之二元混合物或乙腈、二甲基亞碸與甲苯之三元混合物中 之精胺酸將該呈游離酸型式之培哚普利轉化為鹽。
在再結晶方法之情形下，用作起始材料之培哚普利精胺酸鹽可呈無水或水合型式、呈非晶形型式或呈任一結晶型式。
當使用乙腈、乙酸乙酯或甲基第三丁基醚與二甲基亞碸之二元混合物時，乙腈/二甲基亞碸、乙酸乙酯/二甲基亞碸或甲基第三丁基醚/二甲基亞碸之比率較佳係介於90/10 w/w與10/90 w/w之間，包括其限值。
在結晶或再結晶期間，介質之溫度較佳係介於25℃與80℃之間且包括25℃及80℃，更佳介於60℃與80℃之間且包括60℃及80℃。
有利地，可在冷卻步驟期間在混合物中添加晶種(「加晶種」模式)。
當不在混合物中添加晶種時(「不加晶種」模式)，與溶劑混合物接觸之時間較佳大於6小時。
本發明亦係關於醫藥組合物，其包含作為活性成份的式(I)之化合物之δ結晶型式，及一或多種適當且無毒之惰性賦形劑。在本發明醫藥組合物中，更尤其可提及彼等適於經口、非經腸(靜脈內或經皮下)或經鼻投與者，即錠劑或糖衣丸、舌下錠劑、膠囊、菱形錠劑、栓劑、乳膏、軟膏、皮膚凝膠、可注射之製劑及可飲用之懸浮液。
呈錠劑形式之醫藥組合物較佳係藉由直接壓縮來製備。
有用劑量可根據病症之性質及嚴重程度、投與途徑亦及患者之年齡及體重而變。有用劑量係每天一或多次投與1 mg至20 mg不等，較佳每天一次投與2.5 mg至10 mg不等。
本發明醫藥組合物亦可包含一或多種選自利尿劑(例如吲達帕胺(indapamide))、鈣拮抗劑(例如胺氯地平(amlodipine))及If電流抑制劑(例如依伐佈雷定(ivabradine))之其他活性成份。
當本發明醫藥組合物亦包含吲達帕胺時，吲達帕胺之量較佳係介於0.625 mg與2.5 mg之間，包括限值。
當本發明醫藥組合物亦包含胺氯地平時，胺氯地平之量較佳係介於5 mg與10 mg之間，包括限值。
當本發明醫藥組合物亦包含依伐佈雷定時，依伐佈雷定之量較佳係介於5 mg與30 mg之間，包括限值。
以下實例闡釋本發明。
在下文之實例1至4中，用作起始材料之培哚普利精胺酸鹽之水含量為約3%至4%。
縮寫：
實例1：培哚普利之精胺酸鹽之δ結晶型式(乙腈/二甲基亞碸25/75 w/w之二元混合物，「不加晶種」模式)
將55.32 g培哚普利精胺酸鹽、297.50 g二甲基亞碸及94.49 g乙腈引入至反應器中。
在70℃及攪拌下將混合物加熱7小時，且然後以1℃/min 冷卻至40℃。在40℃下30分鐘之後，經玻璃料過濾混合物。用乙酸乙酯洗滌濾餅，並在風扇循環烘箱中於50℃下乾燥過夜，從而以54%之產率得到培哚普利精胺酸之δ結晶型式。
實例2：培哚普利之精胺酸鹽之δ結晶型式(乙腈/二甲基亞碸25/75 w/w之二元混合物，「加晶種」模式)
將52.2 g培哚普利精胺酸鹽、216 g二甲基亞碸及76 g乙腈引入至反應器中。
在攪拌下將混合物加熱至70℃。在70℃下，添加0.52 g δ型培哚普利精胺酸以引發結晶。
在70℃下將混合物加熱5小時(直至濁度曲線穩定為止)，且然後以0.5℃/min冷卻至40℃。在40℃下30分鐘之後，在1L不銹鋼單元中藉助過濾介質(直徑=5 cm，過濾臨限值=20微米)來過濾混合物。
用乙酸乙酯洗滌濾餅，並在風扇循環烘箱中於50℃下乾燥過夜。
以72%之產率(減去晶種)獲得培哚普利精胺酸之δ結晶型式。
實例3：培哚普利之精胺酸鹽之δ結晶型式(乙腈/二甲基亞碸10/90 w/w之二元混合物，「加晶種」模式)
將280 g培哚普利精胺酸鹽、950 g二甲基亞碸及97 g乙腈引入至2L反應器中。
將懸浮液加熱至80℃且觀察到其逐漸變為溶液。混合物維持在80℃下5分鐘，然後以0.5℃/min之速率冷卻至 70℃。一旦混合物之溫度到達70℃後，即添加乙腈(197 g，傾倒時間=20分鐘)。在添加結束時，混合物依然透明。在溶液中添加6 g δ型培哚普利精胺酸作為晶種。70℃階段為45分鐘。
以0.5℃/min之速率將懸浮液冷卻至25℃。在25℃下之接觸時間為4小時，之後使用2 L單元過濾。用乙酸乙酯洗滌濾餅，並在風扇循環烘箱中於50℃下乾燥過夜。以91%之產率(減去晶種)獲得培哚普利精胺酸之δ結晶型式。
實例4：培哚普利之精胺酸鹽之δ結晶型式(乙腈/二甲基亞碸10/90 w/w之二元混合物，「25℃下」模式)
在機械攪拌下將25 g培哚普利精胺酸鹽及90 g乙腈/二甲基亞碸10/90(w/w)之二元混合物引入至反應器中。在25℃及攪拌下接觸72小時之後，完全轉變成δ型。
然後，過濾反應混合物，從而單離出79%產率之培哚普利精胺酸之δ結晶型式。
實例5：自培哚普利(游離酸)開始，在乙腈/DMSO 25/75之二元混合物中得到培哚普利之精胺酸鹽之δ結晶型式
將培哚普利(12.5 g，1當量)及L-精胺酸(5.32 g-0.9當量)懸浮於乙腈(20 g,d=0.787)與DMSO(61 g,d=1.100)之混合物中。在50℃下將反應混合物加熱過夜。然後，經過玻璃料過濾來分離產物。洗滌並乾燥濾餅。
相對於培哚普利，以79%之產率獲得培哚普利精胺酸之δ結晶型式。
實例6：培哚普利之精胺酸鹽之δ結晶型式(乙酸乙酯/二甲基亞碸70/30 w/w之二元混合物，「加晶種」模式)
將15 g培哚普利精胺酸及43.6 g DMSO引入至0.5 L反應器中。培哚普利精胺酸於混合物中之濃度為25.6%(重量%)。將混合物加熱至約70℃，且然後經20分鐘添加102 g乙酸乙酯(乙酸乙酯/DMSO之比率：70/30 w/w)。
在70℃下在混合物中添加0.3 g δ結晶型式作為晶種。在加晶種之後，在70℃及攪拌下將混合物維持2小時。以0.2℃/min之速率冷卻至20℃，隨後接觸16小時時間。
在單元中經過濾介質(孔隙度0.41 μm)實施產物之分離。用乙酸乙酯/DMSO之混合物將固體洗滌一次且用乙酸乙酯洗滌兩次，並在烘箱中於真空中及50℃下乾燥。
以93%之產率(減去晶種)獲得培哚普利精胺酸之δ結晶型式。
實例7：醫藥組合物
製備1000個各自含有5 mg活性成份之錠劑之配方：δ型培哚普利精胺酸............................................5 g羥丙基纖維素....................................................2 g小麥澱粉.........................................................10 g乳糖..............................................................100 g硬脂酸鎂...........................................................3 g滑石粉..............................................................3 g
實例8：醫藥組合物
含有10 mg培哚普利精胺酸之錠劑，終重量為100 mg：δ型培哚普利精胺酸.......................................10 mg乳糖一水合物.............................................64.2 mg微晶纖維素..................................................25 mg硬脂酸鎂.....................................................0.5 mg無水膠質二氧化矽.......................................0.3 mg
實例9：熱穩定性
比較δ型與先前技術型式在開口燒瓶中在110℃下之熱穩定性。
結果如下：
該等結果展示，培哚普利精胺酸鹽之δ結晶型式與其他已知形式相比具有改良之熱穩定性。
圖1：δ型培哚普利精胺酸之繞射圖。
圖2：δ型培哚普利精胺酸於乙腈/二甲基亞碸之二元混 合物中之相圖。
圖3：δ型培哚普利精胺酸之固體之NMR光譜。

Claims (16)

  1. 一種式(I)之培哚普利(perindopril)L-精胺酸鹽之δ結晶型式， 其特徵在於以下X-射線粉末繞射峰，該等X-射線粉末繞射峰係使用具有銅對陰極之繞射計來量測，且以布拉格角度(Bragg’s angle)2θ(°)來表示：4.3、11.0、11.1、13.2、14.6、16.0及21.9。
  2. 如請求項1之式(I)之化合物之δ結晶型式，其中以下X-射線粉末繞射峰係使用具有銅對陰極之繞射計來量測，且以布拉格角度2θ來表示：4.3、11.0、11.1、11.9、12.5、13.2、14.6、16.0、19.2、19.4、20.0、21.9、22.2及22.6。
  3. 如請求項1之式(I)之化合物之δ結晶型式，其中以下X-射線粉末繞射圖係使用具有銅對陰極之繞射計來量測，且以平面間距d、布拉格角度2θ及以相對於最強譜線之百分比表示之相對強度來表示：
  4. 如請求項1之式(I)之化合物之δ結晶型式，其中固態13 C CPMAS NMR光譜具有以下以ppm表示之峰：
  5. 一種製備如請求項1至4中任一項之式(I)之化合物之δ結 晶型式之方法，其係在高於20℃之溫度下，自乙腈、乙酸乙酯或甲基第三丁基醚與二甲基亞碸之二元混合物中或自乙腈、二甲基亞碸與甲苯之三元混合物中結晶或再結晶。
  6. 如請求項5之方法，其中乙腈、乙酸乙酯或甲基第三丁基醚與二甲基亞碸之該二元混合物中乙腈/二甲基亞碸、乙酸乙酯/二甲基亞碸或甲基第三丁基醚/二甲基亞碸之比率係在90/10 w/w至10/90 w/w範圍內。
  7. 如請求項5或6中任一項之方法，其中介質之溫度係介於25℃與80℃之間且包括25℃及80℃。
  8. 如請求項7之方法，其中將該混合物加熱至60℃至80℃之溫度。
  9. 如請求項5之方法，其中該混合物係添加該δ結晶型式作為晶種。
  10. 一種醫藥組合物，其包含作為活性成份的如請求項1至4中任一項之化合物以及一或多種惰性無毒且醫藥上可接受之載劑。
  11. 如請求項10之醫藥組合物，其中其亦包含利尿劑、鈣拮抗劑或If電流抑制劑。
  12. 如請求項11之醫藥組合物，其中該利尿劑係吲達帕胺(indapamide)。
  13. 如請求項11之醫藥組合物，其中該鈣拮抗劑係胺氯地平(amlodipine)。
  14. 如請求項11之醫藥組合物，其中該If電流抑制劑係依伐 佈雷定(ivabradine)。
  15. 如請求項1至4中任一項之化合物，其用於治療心血管疾病。
  16. 如請求項1至4中任一項之化合物，其用於治療高動脈壓、心臟衰竭或穩定性冠狀動脈疾病。
TW101150658A 2012-01-05 2012-12-27 培哚普利（ＰＥＲＩＮＤＯＰＲＩＬ）之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物 TWI471307B (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR1200033A FR2985511B1 (fr) 2012-01-05 2012-01-05 Forme cristalline delta du sel d'arginine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent

Publications (2)

Publication Number Publication Date
TW201331178A TW201331178A (zh) 2013-08-01
TWI471307B true TWI471307B (zh) 2015-02-01

Family

ID=47427277

Family Applications (1)

Application Number Title Priority Date Filing Date
TW101150658A TWI471307B (zh) 2012-01-05 2012-12-27 培哚普利（ＰＥＲＩＮＤＯＰＲＩＬ）之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物

Country Status (44)

Country Link
US (1) US8835652B2 (zh)
EP (1) EP2612850B1 (zh)
JP (1) JP5722923B2 (zh)
KR (1) KR101502945B1 (zh)
CN (1) CN103193864B (zh)
AP (1) AP2013006657A0 (zh)
AR (1) AR089631A1 (zh)
AU (1) AU2012268815B2 (zh)
BR (1) BR102013000161B1 (zh)
CA (1) CA2800946C (zh)
CL (1) CL2013000021A1 (zh)
CO (1) CO6700139A1 (zh)
CR (1) CR20120655A (zh)
CU (1) CU20130001A7 (zh)
CY (1) CY1114704T1 (zh)
DK (1) DK2612850T3 (zh)
EA (1) EA022574B1 (zh)
EC (1) ECSP13012365A (zh)
ES (1) ES2439871T3 (zh)
FR (1) FR2985511B1 (zh)
GE (1) GEP20146182B (zh)
GT (1) GT201300003A (zh)
HK (1) HK1187061A1 (zh)
HR (1) HRP20131164T1 (zh)
IL (1) IL223752A (zh)
JO (1) JO3084B1 (zh)
MA (1) MA35002B1 (zh)
MD (1) MD4350C1 (zh)
MX (1) MX2013000013A (zh)
MY (1) MY176877A (zh)
NI (1) NI201200194A (zh)
PE (1) PE20131327A1 (zh)
PH (1) PH12012000393A1 (zh)
PL (1) PL2612850T3 (zh)
PT (1) PT2612850E (zh)
RS (1) RS53001B (zh)
SA (1) SA113340173B1 (zh)
SG (1) SG192336A1 (zh)
SI (1) SI2612850T1 (zh)
TN (1) TN2012000619A1 (zh)
TW (1) TWI471307B (zh)
UA (1) UA111334C2 (zh)
UY (1) UY34552A (zh)
WO (1) WO2013102741A1 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3050380B1 (fr) 2016-04-20 2020-07-10 Les Laboratoires Servier Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains.
CN110283104B (zh) * 2018-08-22 2022-06-14 南京济群医药科技股份有限公司 一种精氨酸培哚普利的制备方法
EP3842035A1 (en) 2019-12-23 2021-06-30 KRKA, d.d., Novo mesto Composition for the preparation of perindopril arginine granules, a method for their preparation and pharmaceutical composition comprising the granules
SI26268A (sl) 2021-11-18 2023-05-31 Zupet Rok Postopek za pripravo hidratirane oblike perindopril l-arginina
CN114149357A (zh) * 2021-12-29 2022-03-08 江苏嘉逸医药有限公司 一种γ晶型培哚普利精氨酸盐的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090186934A1 (en) * 2006-02-28 2009-07-23 Les Laboratoires Servier Beta Crystalline form of the Arginine Salt of Perindopril, a Process for its Preparation and Pharmaceutical Compositions Containing it.
US20090203758A1 (en) * 2006-02-28 2009-08-13 Les Laboratoires Servier Alpha Crystalline form of the Arginine salt of Perindopril, a Process for its Preparation and Pharmceutical Compositions Containing it.
US20100056802A1 (en) * 2008-09-03 2010-03-04 Apotex Pharmachem Inc. Amorphous form of an l-arginine salt of perindopril and processes for preparation thereof
US20110301357A1 (en) * 2008-06-24 2011-12-08 Matrix Laboratories Ltd Novel polymorphic forms of perindopril (l)-arginine and process for the preparation thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2503155A2 (fr) * 1980-10-02 1982-10-08 Science Union & Cie Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme
FR2620703B1 (fr) * 1987-09-17 1991-10-04 Adir Procede de synthese industrielle de l'acide perhydroindole carboxylique - 2(2s, 3as, 7as). application a la synthese de carboxyalkyl dipeptides
JPH04352788A (ja) * 1990-08-30 1992-12-07 Kanebo Ltd 新規キノリンカルボン酸誘導体、該化合物を有効成分とする抗菌剤および該化合物の製造方法
ZA977103B (en) * 1996-08-09 1999-02-08 Eisai Co Ltd Benzopiperidine derivatives
FR2838648B1 (fr) * 2002-04-18 2004-05-21 Servier Lab Nouveau sel de perindopril et les compositions pharmaceutiques qui le contiennent
JP4402361B2 (ja) * 2003-03-31 2010-01-20 大日本印刷株式会社 塩酸エピナスチンの結晶多形
US20090099370A1 (en) * 2005-08-12 2009-04-16 Sandoz Ag Crystalline Form of Perindopril Erbumine
EP1864973A1 (en) * 2006-06-09 2007-12-12 Sochinaz SA Process for the preparation of perindopril and salts thereof
AU2009231130B2 (en) * 2008-04-01 2013-02-28 Biolotus Biotechnology Ag Highly pure pentamycin
SI23001A (sl) * 2009-03-20 2010-09-30 Diagen@d@o@o Nove soli perindoprila nov postopek za njihovo pripravo in njihova uporaba za zdravljenje kardiovaskularnih bolezni
CN102114017A (zh) * 2011-01-05 2011-07-06 王定豪 包含氨氯地平和培哚普利的药物组合物及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090186934A1 (en) * 2006-02-28 2009-07-23 Les Laboratoires Servier Beta Crystalline form of the Arginine Salt of Perindopril, a Process for its Preparation and Pharmaceutical Compositions Containing it.
US20090203758A1 (en) * 2006-02-28 2009-08-13 Les Laboratoires Servier Alpha Crystalline form of the Arginine salt of Perindopril, a Process for its Preparation and Pharmceutical Compositions Containing it.
US20110301357A1 (en) * 2008-06-24 2011-12-08 Matrix Laboratories Ltd Novel polymorphic forms of perindopril (l)-arginine and process for the preparation thereof
US20100056802A1 (en) * 2008-09-03 2010-03-04 Apotex Pharmachem Inc. Amorphous form of an l-arginine salt of perindopril and processes for preparation thereof

Also Published As

Publication number Publication date
HK1187061A1 (zh) 2014-03-28
GT201300003A (es) 2014-03-14
EA201201668A1 (ru) 2013-10-30
MA35002B1 (fr) 2014-04-03
JP2013139444A (ja) 2013-07-18
IL223752A0 (en) 2013-07-31
FR2985511B1 (fr) 2014-01-03
AU2012268815A1 (en) 2013-07-18
PE20131327A1 (es) 2013-11-15
EP2612850A1 (fr) 2013-07-10
EA022574B1 (ru) 2016-01-29
CU20130001A7 (es) 2014-08-28
FR2985511A1 (fr) 2013-07-12
PH12012000393B1 (en) 2014-07-28
MY176877A (en) 2020-08-25
HRP20131164T1 (hr) 2014-01-03
CA2800946C (fr) 2014-07-15
JO3084B1 (ar) 2017-03-15
ES2439871T3 (es) 2014-01-27
PH12012000393A1 (en) 2014-07-28
WO2013102741A1 (fr) 2013-07-11
UY34552A (es) 2013-07-31
ECSP13012365A (es) 2013-04-30
NI201200194A (es) 2013-05-13
SG192336A1 (en) 2013-08-30
GEP20146182B (en) 2014-10-27
MD4350C1 (ro) 2015-12-31
MD4350B1 (ro) 2015-05-31
BR102013000161A2 (pt) 2015-05-12
DK2612850T3 (da) 2013-12-16
KR20130080814A (ko) 2013-07-15
AP2013006657A0 (en) 2013-01-31
BR102013000161B1 (pt) 2021-11-09
CN103193864A (zh) 2013-07-10
CN103193864B (zh) 2014-09-17
CR20120655A (es) 2013-03-05
PL2612850T3 (pl) 2014-01-31
AU2012268815B2 (en) 2014-02-13
SI2612850T1 (sl) 2014-01-31
CA2800946A1 (fr) 2013-07-05
CO6700139A1 (es) 2013-06-28
EP2612850B1 (fr) 2013-09-18
JP5722923B2 (ja) 2015-05-27
UA111334C2 (uk) 2016-04-25
CY1114704T1 (el) 2016-10-05
KR101502945B1 (ko) 2015-03-16
TW201331178A (zh) 2013-08-01
MX2013000013A (es) 2013-07-15
RS53001B (en) 2014-04-30
US20130178464A1 (en) 2013-07-11
TN2012000619A1 (fr) 2014-04-01
AR089631A1 (es) 2014-09-03
SA113340173B1 (ar) 2015-07-09
CL2013000021A1 (es) 2014-07-18
IL223752A (en) 2016-08-31
PT2612850E (pt) 2013-11-21
NZ605264A (en) 2013-12-20
US8835652B2 (en) 2014-09-16
MD20120130A2 (en) 2013-07-31

Similar Documents

Publication Publication Date Title
JP3602826B2 (ja) ペリンドプリルｔｅｒｔ−ブチルアミン塩のα結晶形
JP5611524B2 (ja) ペリンドプリルのアルギニン塩のβ結晶形態、その製造法、およびそれを含有する薬学的組成物
JP3592296B2 (ja) ペリンドプリルｔｅｒｔ−ブチルアミン塩の新しいγ結晶形、その製造方法及びこれを含む医薬組成物
JP3592297B2 (ja) ペリンドプリルｔｅｒｔ−ブチルアミン塩の新しいβ結晶形、その製造方法及びこれを含む医薬組成物
TWI471307B (zh) 培哚普利（ＰＥＲＩＮＤＯＰＲＩＬ）之精胺酸鹽之δ結晶型式、其製備方法及含有其之醫藥組合物
JP5255454B2 (ja) ペリンドプリルのアルギニン塩のα結晶形態、その製造法、およびそれを含有する薬学的組成物
HU230483B1 (hu) Erlotinib sók
NZ605264B (en) Delta crystalline form of the arginine salt of perindopril, a process for its preparation, and pharmaceutical compositions containing it
US20030203965A1 (en) Polymorphic forms of fasidotril, their methods of preparation and pharmaceutical compositions comprising them
MX2008010266A (en) αcrystalline form of the arginine salt of perindopril, process for preparing it, and pharmaceutical compositions comprising it
OA16425A (fr) Forme cristalline delta du sel d'arginine du périndopril, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent.