TR201611771A2 - Pure oxideropium bromide production process - Google Patents
Pure oxideropium bromide production process Download PDFInfo
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- TR201611771A2 TR201611771A2 TR2016/11771A TR201611771A TR201611771A2 TR 201611771 A2 TR201611771 A2 TR 201611771A2 TR 2016/11771 A TR2016/11771 A TR 2016/11771A TR 201611771 A TR201611771 A TR 201611771A TR 201611771 A2 TR201611771 A2 TR 201611771A2
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- bromide
- norscopolamine
- dimethylformamide
- solvent
- dimethyl
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title abstract description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 26
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 229960000797 oxitropium Drugs 0.000 claims abstract description 12
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical compound CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 claims abstract description 11
- 229940102396 methyl bromide Drugs 0.000 claims abstract description 9
- 239000013543 active substance Substances 0.000 claims abstract description 8
- 239000012535 impurity Substances 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 229960001609 oxitropium bromide Drugs 0.000 claims description 24
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 239000007858 starting material Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 23
- 239000000126 substance Substances 0.000 description 21
- 239000002994 raw material Substances 0.000 description 10
- 238000001308 synthesis method Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- MOYZEMOPQDTDHA-UHFFFAOYSA-N norscopolamine Natural products C1C(C2OC22)NC2CC1OC(=O)C(CO)C1=CC=CC=C1 MOYZEMOPQDTDHA-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- MOYZEMOPQDTDHA-YQYZCKNZSA-N norhyoscine Chemical compound C1([C@H](C(=O)OC2C[C@@H]3N[C@@H]([C@H]4O[C@H]43)C2)CO)=CC=CC=C1 MOYZEMOPQDTDHA-YQYZCKNZSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 2
- LCELQERNWLBPSY-YAYGZGPXSA-M oxivent Chemical compound [Br-].C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-YAYGZGPXSA-M 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound 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 1
- NVOYVOBDTVTBDX-AGUVMIOSSA-N 8g15t83e6i Chemical compound C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 NVOYVOBDTVTBDX-AGUVMIOSSA-N 0.000 description 1
- WNAABYNIWFSPED-UHFFFAOYSA-N C(Cl)Cl.C(C)#N.C(C)OCC Chemical compound C(Cl)Cl.C(C)#N.C(C)OCC WNAABYNIWFSPED-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- MVGLBXWFOSHCCP-UHFFFAOYSA-N chloroform;tetrachloromethane Chemical compound ClC(Cl)Cl.ClC(Cl)(Cl)Cl MVGLBXWFOSHCCP-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- -1 norscopolamine compound Chemical class 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Bu buluş, yeni bir oksitropiyum bromür üretim prosesi ile ilgili olup, söz konusu proses (-)-N-etilnorskopolamin başlangıç maddesinin metil bromür ile N,N-dimetilformamid ortamında gerçekleşen reaksiyonu sonucu farmasötik açıdan daha saf oksitropiyum bromür etkin maddesinin sentezini kapsamaktadır.The present invention relates to a process for the production of a novel oxytropium bromide, the process comprising the synthesis of the pharmaceutically pure oxytropium bromide active substance by the reaction of the starting material (-) - N-ethylnorscopolamine with methyl bromide in the presence of N, N-dimethylformamide.
Description
TARIFNAME SAF OKSITROPIYUM BROMÜR ÜRETIM PROSESI Bu bulus, yeni bir oksitropiyum bromür üretim prosesiyle ilgili olup, söz konusu proses sonUCu elde edilen oksitropiyum bromür farmasötik açidan yüksek safliktadir. DESCRIPTION PURE OXYTROPIUM BROMIDE PRODUCTION PROCESS This invention relates to a new oxitropium bromide production process, the result of which is The obtained oxitropium bromide is of high pharmaceutical purity.
Teknigin Arka_ Plani Oksitropiyum bromürün kimyasal adi (8R)-6ß,7ß-epoksi-8-etil-3a-hidroksi-ldHßaH-tropaniyum bromid(-)-tropat'tir ve asagidaki yapiya sahiptir: olup, bronkodilatör etkileri nedeniyle solunum _sistemi hastaliklarinda kullanilmaktadir. Background of the Technique Chemical name of oxytropium bromide (8R)-6ß,7ß-epoxy-8-ethyl-3a-hydroxy-ldHßaH-tropanium is bromide(-)-tropate and has the following structure: It is used in respiratory system diseases due to its bronchodilator effects.
Oksitropiyum bromür, özellikle astim veya kronik obstruktif akciger hastaliginin (KOAH) tedavisinde terapötik yarar saglamaktadir. Oksitropiyum bromürün uygulamasi inhalatif yollar yedi-dokuz saat kadar devam eder. Oxytropium bromide, especially for asthma or chronic obstructive pulmonary disease (COPD) provides therapeutic benefit in the treatment. Administration of oxitropium bromide by inhalative routes lasts for seven to nine hours.
Oksitropiyum ilk olarak Avrupa'da 1982 tarihinde onaylanmis olup, Boehringer lngelheim tarafindan Oxivent ve Tersigan ticari isimleriyle ölçülü doz inhaleri (ODI) ve nebul dozaj formlariyla piyasaya sunulmustur. Oxytropium was first approved in Europe in 1982 by Boehringer Ingelheim. in metered dose inhaler (ODI) and nebule dosage forms under the trade names Oxivent and Tersigan. has been put on the market.
Oksitropiyum bromür üretim prosesi .ilk kez 3,472,861 sayili ABD patentinde açiklanmistir. prosesi asagidakileri basamaklari kapsamaktadir; a) Bir norskopolamin bilesigin'in etil bromür ile asetonitril içinde, baz olarak sodyum karbonat içeren bir alkilasyon reaksiyonu sonucunda N-etiI-norskopolamin ara ürüinü elde b) N-etiI-norskopolamin. ara ürününün metil bromür ile asetonitril içindeki bir kuarternizasyon reaksiyonu ' sonucunda N-metil-N-etiI-norskopolamin bromür (oksitropiyum bromür) elde edilir. The production process of oxytropium bromide was first described in US patent 3,472,861. The process includes the following steps; a) A norscopolamine compound in acetonitrile with ethyl bromide, sodium as the base N-ethyl-norscopolamine intermediate is obtained as a result of an alkylation reaction containing carbonate. b) N-ethyl-norscopolamine. of the intermediate with methyl bromide in acetonitrile. N-methyl-N-ethyl-norscopolamine bromide as a result of the quaternization reaction (oxitropium bromide).
Bu basamaklar sonucu elde edilen oksitropiyum bromür asetonitril kullanilarak rekristalizasy'on ile saflastirilmistir. Bahsi geçen reaksiyonda adi geçen N-etiI-norskopolamin (Il). ve norskopolamin (III) madderinin kimyasal yapi formülleri asagida verilmektedir. 3,472,861 sayili ABD patentinde açiklanan sentez metoduna uygun olarak asetonitril içinde gerçeklesen reaksiyon sonucu elde edilen oksitropiyum bromür, safsizlik olarak bir yan reaksiyon ürünü olan IN,N-dimetil-norskopolamin bromür (IV) bilesigini yüksek miktarda içermektedir. The oxitropium bromide obtained as a result of these steps is recrystallized using acetonitrile. has been purified. N-ethyl-norscopolamine (II) mentioned in said reaction. and norscopolamine (III) The chemical structure formulas of the substances are given below. in acetonitrile according to the synthesis method described in US Patent 3,472,861 Oxitropium bromide, obtained as a result of the reaction taking place, is a side reaction as an impurity. It contains high amount of IN,N-dimethyl-norscopolamine bromide (IV) compound.
Tanimlanmis bir safsizlik olan, N,N-dimetil-norskopolamin bromür safsizliginin kimyasal yapisi ise asagida verilmektedir. The chemical structure of the N,N-dimethyl-norscopolamine bromide impurity, which is a defined impurity, is are given below.
Bu bulus, bilinen bir oksitropiyum bromür üretim prosesine alternatif olup, söz konusu proses (-)- N-etil-norskdpoiamin baslangiç maddesinin metil bromür ile N,N-dimetilf0rmamid ortaminda gerçeklesen reaksiyonu sonucu farmasötik açidan daha saf oksitropiyum bromür etkin maddesinin sentezini açiga çikarmaktadir. - Bulusun Özeti . 3,472,861 sayili ABD patentinde oksitropiyum bromür ürününün saflastirilmasi için asetonitril kullanilarak yapilan rekristalizasyon islemi neticesinde elde edilen N,N-dimetil-n0rskop0lamin safsizlik ürününün miktari, kabul edilebilir tanimlanmis spesifikasyon degerinin üzerinde ortaya çikmaktadir. Ayrica, saflastirma islemininbirkaç defa tekrarlanmasina ragmen N,N-dimetil- norskopolamin safsizlik ürününün miktari için kabui edilebilir spesifikasyon degerine ulasabilmenin mümkün olmadigi gözlemlenmistir. This invention is an alternative to a known oxitropium bromide production process, the process in question being (-)- N-ethyl-norskdpoiamine starting material with methyl bromide in the presence of N,N-dimethylformamide of the pharmaceutically pure oxitropium bromide active ingredient reveals its synthesis. - Summary of the Invention . Acetonitrile for purification of oxitropium bromide product in US patent 3,472,861 N,N-dimethyl-n0rskop0lamine obtained as a result of the recrystallization process using The amount of impurity product occurs above the acceptable defined specification value. is coming out. In addition, although the purification process was repeated several times, N,N-dimethyl- the acceptable specification value for the amount of norscopolamine impurity product. It has been observed that it is not possible to reach it.
Bu bulus, yeni bir oksitropiyum bromür üretim prosesi ile ilgili olup, söz konusu proses (-)-N-eti|- norskopolamin baslangiç maddesinin metil bromür ile . N,N-dimetilformamid ortaminda gerçeklesen reaksiyonu sonucu farmasötik açidan daha saf oksitropiyum bromür etkin maddesinin sentezini kapsamaktadir. Bu yeni sentez metodu' ile, oksitropiyum bromür etkin maddesinde potansiyel safsizliklardan biri olarak tanimlanan N,N-dimetiI-norskopolamin bromür bilesigi Avrupa Farmakopesi versiyon 8.0'a göre kabul edilebilir limit olan %0.1'in altindaki oranlarda elde edilebilmistir. This invention relates to a new oxitropium bromide production process, which is (-)-N-ethyl|- with methyl bromide as the starting substance of norscopolamine. in the presence of N,N-dimethylformamide of the pharmaceutically pure oxitropium bromide active ingredient includes synthesis. With this new synthesis method, oxitropium bromide in the active ingredient compound N,N-dimethyl-norscopolamine bromide identified as one of the potential impurities Obtained at rates below 0.1%, which is the acceptable limit according to the European Pharmacopoeia version 8.0. can be achieved.
Ilaç endüstrisinde en. temel hedeflerden-biri, ilaçlarin mümkün olan en yüksek saflikta hazirlanmasidir. Bu amaçla, mevcut ilaç üretim proseslerinde, baslangiç maddeleri ve ilaç maddelerinin test edilmesi, belirlenen sabit üretim islemlerinin kullanilmasi, ara ürün. ve bitmis ürünlerin safsizliklarinin test edilmesi ve bu baglamda yapilan testler sonucunda baslangiç maddeleri ve etkin maddelerin, üreticinin belirttigi ve farmakope ya da resmi otoriteler tarafindan belirlenen kilavuzlarda tanimli özelliklerde olmasi gerekmektedir. best in the pharmaceutical industry. One of the main goals is to ensure that drugs are of the highest possible purity. is the preparation. For this purpose, starting materials and drugs are used in existing drug production processes. testing substances, using established fixed production processes, intermediate product. and finished As a result of testing the impurities of the products and the tests carried out in this context, the initial substances and active substances specified by the manufacturer and approved by the pharmacopoeia or official authorities. must have the features defined in the specified guides.
Terapötik kullanima yönelik bilesikler seklinde tanimlanan ilaç hammaddelerinin yüksek potensleri nedeniyle, etkin sentez yöntemleri ile olasi en saf formda bulundurulmalari gerekmektedir. Ancak ilaç `hammaddeleri beraberlerinde s'afsiziik olarak tanimlanan terapötik etki göstermeyen ve istenmeyen diger maddeleri de içerebilmektedirler. Safsizliklar siklikla aktif bilesenin sentezlenmesi esnasinda yan -ürün olarak. ortaya çikmakta, kilavuzlar ve farmakopeler çerçevesinde izlenmektedir. Bu baglamda, etkin maddenin safsizlik profilinin saptanmasi ve Istenmeyen bu kimyasal maddelerin küçük miktardaki varligi bile, farmasötik ürünlerin etkinligini ' ve güvenligini etkileyebilmektedir. Ilacin kalite Ve güvenligini garanti altina almak için s-afsizliklari'n ' izlenmesi ve kontrol altina alinmasi gerekmektedir. High potencies of pharmaceutical raw materials defined as compounds for therapeutic use Therefore, they should be kept in the purest possible form with efficient synthesis methods. However medicine whose raw materials do not show any therapeutic effect defined as pure and They may also contain other undesirable substances. Impurities are often present in the active ingredient. as a by-product during its synthesis. emerging, guidelines and pharmacopoeias framework is monitored. In this context, determination of the impurity profile of the active substance and Even the presence of small amounts of these undesirable chemicals can affect the effectiveness of pharmaceutical products. and may affect safety. In order to guarantee the quality and safety of the drug, naivety's ' must be monitored and controlled.
Bitmis ilaç ürününde safsizlik varligi iki sekilde degerlendirilebilir: 1) Ilaç hammaddesinin (baslangiç maddesi ve içerdigi safsizliklar, üretim islemi ve bu süreçte kullanilan yöntem ve kimyasallar, vb.) imalat islemiyle ilgili bilgiye bagli olarak, her hammadde için spesifikasyonlar/teknik veriler yoluyla veya 2) Ilaç hammaddeleri ve eger gerekli ise bitmis üründeki (üretim süreci boyunca ve sonrasinda potansiyel olarak ortaya çikan maddeler, bozunma ürünleri gibi) olasi safsizliklarin fizikokimyasal ' analizi yoluyla degerlendirilebilir. The presence of impurities in the finished drug product can be evaluated in two ways: 1) Pharmaceutical raw material (starting substance and its impurities, production process and in this process) methods and chemicals used, etc.) for each raw material, depending on the knowledge of the manufacturing process through specifications/technical data or 2) Pharmaceutical raw materials and, if necessary, in the finished product (during and after the production process physicochemical analysis of possible impurities (such as potentially occurring substances, decomposition products) can be evaluated through analysis.
Ilaç hammaddelerinin organik sentez reaksiyonlari neticesinde %100 verimle %100 saflikta tek bir ürün halinde hazirlanmasi oldukça nadir bir durumdur. Sentez reaksiyonlari sonucunda istenilen ürün ile birlikte yan reaksiyonlar sonucu istenmeyen yan ürünlerin de olusma olasiligi bulunmaktadir. Bu sebeple, organik sentez reaksiyonlari sonucunda elde edilen ilaç hammaddeleri çözücüler, saflastirma basamaklari ve hatta saklama kosullari etkin. madde safsizlik profilini dogrudan etkilemektedir. As a result of organic synthesis reactions of pharmaceutical raw materials, a single product of 100% purity with 100% yield. It is a very rare case that it is prepared as a product. As a result of the synthesis reactions, the desired Possibility of formation of unwanted by-products as a result of side reactions with the product are available. For this reason, pharmaceutical raw materials obtained as a result of organic synthesis reactions solvents, purification steps and even storage conditions are active. substance impurity profile directly affects.
Terapötik kullanima yönelik ilaç hammaddeleri tarafindan karsilanmasi gereken yüksek saflik gereksinimi, muhtemel yan reaksiyon ürünlerininde miktarinin en düsük seviyede olmasini gerektirir. High purity to be met by pharmaceutical raw materials for therapeutic use The requirement is that the amount of possible by-reaction products is at the lowest level. requires.
Safsizlik içeren ilaç aktif maddelerinin saflastirilmasi için birçok farkli saflastirma yöntemi uygulanabilmekle birlikte, yaygin olarak uygun çözücü veya çözücü karisimlari kullanilmak suretiyle kristallendirilerek yapilir. Lakin ana ürünlerden yapisal olarak sadece biraz farkli olan yan ürünlerin mevcudiyeti durumunda nihai ürünün saflastirilmasi genellikle daha zordur. Many different purification methods for the purification of APIs containing impurities. Although it can be applied, it is commonly used to use suitable solvents or solvent mixtures. It is made by crystallization. However, the side products that are only slightly different from the main products in terms of structure. Purification of the final product is often more difficult in the presence of products.
Ilaç hammaddeleri ve bitmis ilaç ürünü içinde olasi tanimlanmis safsizliklar için safsizlik profilleri genellikle lCi-l (Uluslararasi Harmonizasyon Konferansi) kilavuzlari ve farmakopeler çerçevesinde' izlenmektedir. Çesitli farmakopelerde, örnegin Avrupa farmakopesi (Ph. Eur), Amerikan farmakopesi (USP), Japon farmakopesi (JP) gibi, ilaç hammaddeleri ve bitmis ilaç ürünleri içinde mevcut olan safsizliklar için kabul edilebilir konsantrasyon limitleri verilmektedir. Impurity profiles for possible identified impurities in pharmaceutical raw materials and finished drug product usually within the framework of ICi-1 (International Conference on Harmonization) guidelines and pharmacopeias' is monitored. In various pharmacopoeias, eg European pharmacopoeia (Ph. Eur), American in pharmaceutical raw materials and finished pharmaceutical products, such as pharmacopoeia (USP), Japanese pharmacopoeia (JP) Acceptable concentration limits are given for the impurities present.
Oksitropiyum bromür yüksek tedavi etkinligi nedeniyle, çok düsük dozlarda dahi kullanilabilen bir ilaç aktif maddesidir. Bu nedenle, ürünün yüksek verim ile üretilme hedefinin_ yani sira yüksek saflikta üretilmesi de önemli bir gereklilik olup, buna yönelik bir sentez yöntemi gelistirilmesi gerekmektedir. _ ' 3,472,861 sayili ABD patentinde örnek 11'de açiklandigi üzere N-etiI-norskopolamin ara ürününün metil bromür ile asetonitril içindeki kuarternizaSyon reaksiyonu neticesinde Oksitropiyum bromür ürünü elde edilmektedir. Bahsi geçen sentez reaksiyonu uygulandiginda yari ürün olarak N,N- bromür içerisinde safsizlik olarak yer alan N,N-dimetiI-norskopolamin bromür safsizliginin ayriimasinda ise kromatografik ayirma tekniklerin kullanimi mümkün degildir. Oxytropium bromide is a drug that can be used even at very low doses, due to its high therapeutic efficacy. is the active ingredient of the drug. Therefore, the goal of producing the product with high yield_ as well as high Purity production is also an important requirement, and a synthesis method should be developed for this. required. _ ' As described in example 11 of US Patent No. 3,472,861, the intermediate of N-ethyl-norscopolamine Oxytropium bromide as a result of quaternization reaction with methyl bromide in acetonitrile product is obtained. When the aforementioned synthesis reaction is applied, N,N- as a semi-product N,N-dimethyl-norscopolamine bromide impurity, which is an impurity in bromide, In the separation, it is not possible to use chromatographic separation techniques.
Bu sebeple, N,N-dimetil-norskopolamin bromür safsizliginin oksitropiyum bromür sentezi sirasinda daha düsük miktarlarda olusmasinayönelik, ticari açidan avantaj saglayacak yeni bir sentez metodunun gelistirilmesine ihtiyaç bulunmaktadir. Therefore, oxitropium bromide synthesis of N,N-dimethyl-norscopolamine bromide impurity It is a new product that will provide a commercial advantage for the formation of lower quantities during The synthesis method needs to be developed.
Sorunun çözümü . ' . Solution of the problem. ' .
Mevcut bulusun amaci farmasötik açidan kabul edilebilir safsizlik profiline sahip oksitropiyum- bromürün (I) yüksek saflikta elde edildigi yeni bir. sentez metodu gelistirmektir. The object of the present invention is oxitropium- A novel method in which bromide (I) is obtained in high purity. to develop a synthesis method.
Bu bulusta, reaksiyon Ortaminda kullanilacak çözücü sisteminin oksitropiyum' bromür etkin. maddesinin safsizlik profiline etkisi incelenmistir. In this invention, oxitropium' bromide of the solvent system to be used in the reaction Medium is active. The effect of the substance on the impurity profile was investigated.
Mevcut bulusta, kabul edilebilir safsiziik profiline sahip oksitropiyum bromür elde etmek için en uygun çözücü olarak N,N-dimetilformamid seçilmistir. In the present invention, it is best to obtain oxitropium bromide with an acceptable impurity profile. N,N-dimethylformamide was chosen as the suitable solvent.
Bu yeni sentez metodu ile reaksiyon ortaminda çözücü olarak N,N-dimetilformamid kullanildiginda Formül (IV) ile ifade edilen N,N-dimetiI-n0rsk0poiamin olusumuna sebebiyet veren yanreaksiyon engellenmektedir. When N,N-dimethylformamide is used as a solvent in the reaction medium with this new synthesis method. Side-reaction leading to the formation of N,N-dimethyl-nOrsk0poiamine expressed by formula (IV) is blocked.
Mevcut bulus sayesinde, bu yan reaksiyonun olasi ürünü olan Formül (IV) ile ifade edilen N,N- dimetiI-norskopolamin bromür kabul edilebilir limit olan %0.1 degerinin altindaki oranlarda elde edilmektedir. Owing to the present invention, N,N-, expressed by Formula (IV), which is the possible product of this side reaction Dimethyl-norscopolamine bromide is obtained at rates below the acceptable limit of 0.1%. is being done.
Bu bulusta, oksitropiyum bromür etkin madde üretimine yönelik yeni bir sentez yolu kesfedilerek, yüksek saflikta ve ticari boyutlarda üretim yapmak mümkün olmustur. Bu sayede hastalarin daha ekonomik bir biçimde tedavisi de mümkün kilinmistir. In this invention, a new synthesis route for the production of oxitropium bromide active substance was discovered, It has been possible to produce in high purity and commercial sizes. In this way, patients Economic treatment is also possible.
Uygulamalarin Açiklamasi - Bu bulus ile farmasötik açidan uygun safsizlik profiline sahip, yüksek saflikta oksitropiyum bromür bromür etkin maddesi disinda kalan maddelerdir. Söz konusu safsizlik, özellikle N,N-dimetil norskopolamin maddesidir. çözücü kalintilarinin belirlenmesi, kalitatif ve kantitatif tayinini hedefleyen bir analitik aktiviteler grubunun genel bir ismi olarak ifade edilir. Description of Applications - With this invention, high purity oxitropium bromide with a pharmaceutically favorable impurity profile are substances other than bromide active ingredient. The impurity in question, especially N,N-dimethyl norscopolamine substance. An analytical activities aimed at the determination, qualitative and quantitative determination of solvent residues. expressed as a general name of the group.
”Yüksek saflikta oksitropiyum bromrür'f terimi ile kastedilen, bulus konusu olan üretim metodu ile' elde edilen oksitropiyum bromür etkinmaddesi için saflik degerinin 9697'den yüksek bir degere sahip olmasi ve Avrupa farmakopesinde tanimlanmis tüm kriterlere uygun olmasidir. 'The term 'high purity oxitropium bromide' means by the method of production which is the subject of the invention' For the oxitropium bromide active substance obtained, the purity value must be higher than 9697. and it complies with all the criteria defined in the European pharmacopoeia.
Gerek etkin maddeve gerek ise bitmis üründe istenilen özelliklerin saglanip saglanmadiginin anlasilmasi için çesitli analitik ve s-pektral yöntemlere basvurulmaktadir. Oksitropiyum bromür ilaç aktif maddesi `içinde' safsizlik olarak bulunan N,N-dimetil~norskopolamin HPLC analizi ile belirlenebilir've spektral veriler ile tanimlanabilir. Whether the desired properties are provided in both the active substance and the finished product. Various analytical and s-pectral methods are used for understanding. Oxytropium bromide drug by HPLC analysis of N,N-dimethyl~norscopolamine, whose active ingredient is as an impurity 'in' can be determined and described by spectral data.
Sentezlenen oksitro'piyum bromür ürününde N,N-dimetiI-norskopolamin maddesinin 've miktarinin' tespiti için HPLC analiz metodu tercih edilmistir. The 'and amount' of N,N-dimethyl-norscopolamine in the synthesized oxytro'pyrium bromide product HPLC analysis method was preferred for determination.
N,N-dimetiI-norskopolamin maddesinin olusumunu tetikleyen birçok faktör olabilir. Reaksiyon sicakligi, reaksiyon süresi, reaksiyonun gerçeklestigi çözücünün tipi ve çözelti derisimi bunlarin arasinda sayilabilir. There may be many factors that trigger the formation of N,N-dimethyl-norscopolamine. Reaction temperature, reaction time, type of solvent in which the reaction takes place, and solution concentration. can be counted among
(-)-N-etiI-norskopolamin ve metil .bromür arasinda gerçeklesen reaksiyonlar için reaksiyon sicaklik I araligi 0 °C ile 40 "C degerleri arasinda olup, tercih edilen sicaklik araligi 20 °C ile 30 °C degerleri arasindadir. Reaction temperature I for the reactions between (-)-N-ethyl-norscopolamine and methyl bromide The range is between 0 °C and 40 "C, and the preferred temperature range is between 20 °C and 30 °C. are in between.
Bulus sahipleri, bulus konusu olan sentez metodunda N,N-dimetil-norskopolamin maddesinin olusumunu etkileyen faktörlerden en etkili olaninin reaksiyonun gerçeklestigi çözücünün tipi oldugunu gözlemlemislerdir. Bulus sahipleri reaksiyona çözücü tipi etkisini arastirmak amaciyla farkli çözücüler ile denemeler yapmislardir. The inventors, in the synthesis method, which is the subject of the invention, use N,N-dimethyl-norscopolamine substance. The most effective factor affecting its formation is the type of solvent in which the reaction takes place. they have observed. In order to investigate the effect of solvent type on the reaction, the inventors They experimented with different solvents.
Söz konusu uygun inert organik-çözücüler asetonitrii, eter, tetrahidrofuran, benzeri, toluen, diklorometan, kloroformr karbon tetraklorür, aseton ve bunlarin karisimlarindan olusan bir gruptan seçilebilir. Suitable inert organic solvents are acetonitrile, ether, tetrahydrofuran, the like, toluene, dichloromethane, chloroform carbon tetrachloride, acetone and their mixtures. can be selected from the group.
(-)-N-etil-norskopolamin ve metil bromür arasinda gerçeklesen çözücü tipi etkisinin incelendigi reaksiyon Formül (V) ile ifade edilmistir. The effect of solvent type between (-)-N-ethyl-norscopolamine and methyl bromide was investigated. The reaction is expressed by Formula (V).
H * çözücü - H V l-I-N-EtlI-norskopolamin I Dksitropiyum bromür CasHzgNO4 , CisHasBrNOq Oksitropiy'um bromür sentezinde kullanilan farkli çözücüler ve elde edilen sonuçlar Tablo 1'de özetlenmistir. Çözücü ' Rea ktif Reaksiyon Analiz (HPLC)* verimi Etil- N,N-Dimetil- Oksitropiyum ' A5et0nitril+ Dietileter Asetonitril Diklorometan I I Dietileter miktari %0.07 olarak tespit edilmekte olup Avrupa farmakopesi versiyon 8.0'da yer alan oksitropiyum bromür monografina göre %0.1 olan limit degerinden daha düsük bir degerdedir. H * solvent - H V 1-I-N-EthIII-norscopolamine I Dxitropium bromide CasHzgNO4 , CisHasBrNOq The different solvents used in the synthesis of oxitropyum bromide and the results obtained are given in Table 1. is summarized. Solvent ' Reactive Reaction Analysis (HPLC)* yield Ethyl- N,N-Dimethyl- Oxitropium ' A5et0nitrile+ diethylether acetonitrile Dichloromethane I I diethylether The amount is determined as 0.07% and it is listed in the European Pharmacopoeia version 8.0. It is lower than the 0.1% limit value according to the oxitropium bromide monograph.
Mevcut bulusta önerilen sentez metoduna uygun olarak üretilen oksitropiyum bromür, içerdigi N,N-dimetiI-norskop0lamin safsizligi bakimindan, Avrupa farmakopesi 8.0'a göre safsizlik B olarak tanimli N,N-dimetiI-norskopolamin maddesi için verilen limit degerinin altinda olarak Avrupa farmakopesi metotlari ve spesifikasyonlari dogrultusunda analizlenerek uygun bulunmustur. Oxitropium bromide, produced in accordance with the synthesis method proposed in the present invention, contains In terms of N,N-dimethyl-norscolamine impurity, as impurity B according to European pharmacopoeia 8.0 Europe below the limit value given for the defined N,N-dimethyl-norscopolamine substance It was found suitable by analyzing in accordance with the pharmacopoeia methods and specifications.
Mevcut bulus konusu olan yeni oksitropiyum- bromürüretim metodu,N,N-dimetiI-norskopolamin safsizliginin reaksiyon esnasinda olusumunun engellenmesi' için gerekli olup, uygun olmayan ürünün saflastirilmasi için gerekli; fakat ürün veriminin düsmesine neden olacak tekrar tekrar yapilan saflastirma asamalarini içermemesi sebebiyle ekonomik açidan da avantaj saglamaktadir. The new oxitropium-bromide production method, which is the subject of the present invention, N,N-dimethyl-norscopolamine necessary to prevent the formation of impurities during the reaction, necessary for purification of the product; but again and again, which will cause a decrease in crop yield. It also provides an advantage in terms of economy as it does not include the purification steps.
Bu baglamda sunulan prosesin avantajlari söyle siralanmaktadir: Sentez endüstriyelölçekte gerçeklestirilebilir olup parti büyüklügünün örneklerde tarif edilen etkilememektedir. In this context, the advantages of the presented process are listed as follows: The synthesis can be performed on an industrial scale and the batch size is not as described in the examples. does not affect it.
Bu bulus, diger bir yönü ile yüksek saflikta oksitropiyum bromür eldesi ile daha yüksek saflikta bir bitmis ürünü de mümkün kilmistir. Zira inhaler ürünlerde büyük miktarda safsizlik içeren bir etkin madde kullanilmasindan kaynaklanarak, aerosol bilesiminin de kimyasal bozunmaya ugramasi ve yüksek safsizlik içermesi nedeniyle ürün raf ömürlerinde stabilite sikintilari yasanabilmektedir. Another aspect of this invention is to obtain high purity oxitropium bromide with a higher purity made the finished product possible. Because it is an active ingredient containing a large amount of impurities in inhaler products. chemical degradation of the aerosol composition resulting from the use of the substance and Due to the high impurity content, stability problems may be experienced during the shelf life of the product.
Ancak mevcut bulus sahipleri sentez iyilestirmesi ile etkin' madde üretiminden gelen safsizliklari büyük oranda azaltarak daha üstün özellikli bir bitmis ürün eldesini saglamislardir. However, the present inventors have eliminated the impurities from the production of active substance by synthesis improvement. they have provided a superior finished product by greatly reducing it.
Asagidaki örnek mevcut bulusu açiklamak için verilmis olup bulusun kapsamini sinirlandirmamalidir. The following example is given to illustrate the present invention and does not cover the scope of the invention. should not be annoying.
Metil bromür maddesi oda sicakliginda N,N-dimetilformamid çözücüsü içinde bulunan(-)-N-etil- .bromür reaksiyon çözeltisi oda sicakliginda yaklasik 5-7 gün arasinda bir süre karistirilir. Olusan oksitropiyum bromür maddesi beyaz renkli kristal toz halinde reaksiyon çözeltisinden filtre edilerek ayrilir. (141.6 g, 85%). The methyl bromide substance is (-)-N-ethyl-containing in N,N-dimethylformamide solvent at room temperature. The .bromide reaction solution is stirred at room temperature for about 5-7 days. Formed oxitropium bromide substance as white crystalline powder filtered through the reaction solution is separated. (141.6 g, 85%).
Claims (9)
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