TR2021016490A2 - USE OF REticULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACTS - Google Patents
USE OF REticULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACTSInfo
- Publication number
- TR2021016490A2 TR2021016490A2 TR2021/016490A TR2021016490A TR2021016490A2 TR 2021016490 A2 TR2021016490 A2 TR 2021016490A2 TR 2021/016490 A TR2021/016490 A TR 2021/016490A TR 2021016490 A TR2021016490 A TR 2021016490A TR 2021016490 A2 TR2021016490 A2 TR 2021016490A2
- Authority
- TR
- Turkey
- Prior art keywords
- morphine
- reticulin
- extracts
- determination
- impurity
- Prior art date
Links
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 117
- 229960005181 morphine Drugs 0.000 title claims abstract description 53
- 108010081750 Reticulin Proteins 0.000 title claims abstract description 33
- OFNXOACBUMGOPC-UHFFFAOYSA-N hydroxystreptomycin Natural products CNC1C(O)C(O)C(CO)OC1OC1C(C=O)(O)C(CO)OC1OC1C(N=C(N)N)C(O)C(N=C(N)N)C(O)C1O OFNXOACBUMGOPC-UHFFFAOYSA-N 0.000 title claims abstract description 33
- OKPOKMCPHKVCPP-UHFFFAOYSA-N isoorientaline Natural products C1=C(O)C(OC)=CC(CC2C3=CC(OC)=C(O)C=C3CCN2C)=C1 OKPOKMCPHKVCPP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- JTQHYPFKHZLTSH-UHFFFAOYSA-N reticulin Natural products COC1CC(OC2C(CO)OC(OC3C(O)CC(OC4C(C)OC(CC4OC)OC5CCC6(C)C7CCC8(C)C(CCC8(O)C7CC=C6C5)C(C)O)OC3C)C(O)C2OC)OC(C)C1O JTQHYPFKHZLTSH-UHFFFAOYSA-N 0.000 title claims abstract description 33
- OFNXOACBUMGOPC-HZYVHMACSA-N 5'-hydroxystreptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](CO)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O OFNXOACBUMGOPC-HZYVHMACSA-N 0.000 title claims abstract description 32
- 239000000284 extract Substances 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 title description 20
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 150000004677 hydrates Chemical class 0.000 claims abstract description 7
- 239000000543 intermediate Substances 0.000 claims abstract description 6
- 239000011265 semifinished product Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 238000013094 purity test Methods 0.000 claims description 2
- 238000013112 stability test Methods 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 238000011835 investigation Methods 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- 239000008896 Opium Substances 0.000 description 11
- 229960001027 opium Drugs 0.000 description 11
- 229930013930 alkaloid Natural products 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229960004126 codeine Drugs 0.000 description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 244000025254 Cannabis sativa Species 0.000 description 3
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 3
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- 239000004866 Hashish Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229960005195 morphine hydrochloride Drugs 0.000 description 2
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 2
- 229960004715 morphine sulfate Drugs 0.000 description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- -1 salts hydrates Chemical class 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- SVTKSKRNLMAUKF-HAIKCVHQSA-N (4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O SVTKSKRNLMAUKF-HAIKCVHQSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 244000037666 field crops Species 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960003066 morphine tartrate Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940124641 pain reliever Drugs 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000000829 suppository Chemical group 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Morfin, morfin tuzları, hidrat ve solvatları ile morfin ekstraktlarında, yarı mamullerinde ve ara ürünlerinde saflık, stabilite veya raf ömrü tayini için HPLC yöntemi ile retikulin miktarının belirlenmesi esasına dayanır.It is based on the determination of the amount of reticulin by HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, semi-finished products and intermediates.
Description
TARIFNAME MORFIN VE MORFIN EKSTRAKTLARI NDA RETIKULIN IMPÜRITESININ SAFLIK VE STABILITE SPESIFIKASYONU OLARAK KULLANILMASI Morfin çok etkili agri kesici ilaç etken maddesidir. Opioidlerin tipik aktif maddesidir ve bu grubun prototipidir. Ham afyonda % 10-12 oraninda mevcuttur. Morfin ilaç olarak DSÖ'nün Temel Ilaçlar Listesi'nde yer almaktadir. DESCRIPTION IMPURITY OF RETIKULIN IN MORPHINE AND MORPHINE EXTRACTS USING PURITY AND STABILITY SPECIFICATION Morphine is a very effective painkiller active ingredient. It is the typical active ingredient of opioids and this is the prototype of the group. It is present at the rate of 10-12% in raw opium. WHO's morphine drug It is on the Essential Medicines List.
Morfin, narkotik agri kesiciler grubunda yer alan çok güçlü bir ilaçtir. Cerrahi operasyonlar, kanser agrilari, kalp krizi, uzun süren kronik agrilarin tedavisinde kullanilir. Morphine is a very powerful drug in the group of narcotic pain relievers. surgical operations, It is used in the treatment of cancer pain, heart attack, and long-lasting chronic pain.
Afyon (Opium), hashas bitkisinin kapsüllerinden elde edilen bir drogdur. Kapsüldeki opium miktari %0.2-0.8 arasinda degismekle beraber yapilan islah çalismalari neticesinde bu oran % l”e ulastigi belirtilmektedir. Ülkemizde ve dünyada tibbi amaçla kullanilan afyonun üretimi hashas (Papaver somniferum L.) bitkisinden yapilmaktadir. Hashastan afyon üretimi; 1974 yilina kadar hashas kapsüllerinin çizimi ile yapilirken daha sonra bu üretim sekli yasaklanmis ve daha güvenli bir yöntem olan çizilmemis kuru hashas kapsüllerinden alkaloit üretimine geçilmistir. Ülkemizde morfin üretimi en güvenilir sekilde Afyoniun Bolvadin ilçesinde kurulan Alkaloit Fabrikasmda yapilmaktadir. (ARSLAN ve ark. “Afyon (Opium) Alkaloitleri ve Önemi” Tarla Bitkileri Merkez Arastirma Enstitüsü Dergisi, 2008, 17 (1-2] 1 Afyon bilesiminde takriben %10 mortinj %5 kodein, %6 narkotin bulunabilmektedir. Morfinin afyondan çözelti halinde elde edilmesi, buharlastirma ve kalsiyum klorür çözeltisi ile yeniden çözme islemlerini gerektirir. Bu çözeltinin ayrilmasindan sonra sivi kisim birkaç kez buharlastirilir ve geride kalan morfin ve kodein kristalleri toplanir. Bunlar amonyak yardimiyla çözüldükten sonra yeniden kristallestirilir. Böylece morfin çözeltide kalan kodeinden ayrilmis olur. Morfin bir molekül su ile ignemsi kristaller halinde kristallesir. biri fenolik, digeri alkol grubu olmak üzere 2 tane hidroksil grubuna sahiptir. Fenolik grup metillenerek kodein elde edilir. Morfin etkin madde olarak tipta hidroklorür, sülfat, asetat, tartarat tuzlari halinde kullanilir. Opium (Opium) is a drug obtained from the capsules of the hash plant. opium in capsule Although the amount varies between 0.2-0.8%, this rate is % as a result of the improvement studies. It is stated that it reaches l. Production of opium used for medical purposes in our country and in the world It is made from the hashish (Papaver somniferum L.) plant. Opium production from Hashastan; 1974 While it was made with the drawing of hashish capsules until the year of, later this form of production was prohibited. and alkaloid production from scratch-free dry hashish capsules, which is a safer method. has been passed. Morphine production in our country is most reliable in Afyoniun Bolvadin district. It is made in the established Alkaloid Factory. (ARSLAN et al. “Opium (Opium) Alkaloids and Its Importance” Journal of Field Crops Central Research Institute, 2008, 17 (1-2] 1 In the opium composition, approximately 10% mortality, 5% codeine and 6% narcotine can be found. Morphine extraction from opium in solution, evaporation and reconstitution with calcium chloride solution. requires solving operations. After separation of this solution, the liquid part is washed several times. evaporated and the remaining morphine and codeine crystals are collected. These are with the help of ammonia recrystallized after dissolution. Thus, morphine was separated from the remaining codeine in solution. It is possible. Morphine crystallizes as needle-like crystals with one molecule of water. It has 2 hydroxyl groups, one of which is phenolic and the other is alcohol. phenolic group It is methylated to produce codeine. Morphine is used as an active ingredient such as hydrochloride, sulfate, acetate, used as tartrate salts.
Formül 1 Tip ve eczacilikta kullanilan dozaj formlari olarak morfin hidroklorür veya sülfat enjeksiyon; mg morphin içeren Sivi formu ve 10 mg morfin içeren supozituar formu vardir. Formula 1 Morphine hydrochloride or sulfate injection as dosage forms used in medicine and pharmacy; There is a liquid form containing mg morphine and a suppository form containing 10 mg morphine.
Bulusun açiklanmasi EMA ve FDA kilavuzlarina göre kimyasal bilesiklerin kromatografik testlerinde görülen kritik olarak önemli olan piklerin tanimlanmasi ve karakterize edilmesi gerekmektedir. Mevcut basvuru Morfin, morfin tuzlari ve morfin ekstraktlarinda mevcut bir impürite olan Reticulin isimli bilesigin Morfin, morfin tuzlari ve morfin ekstraktlarinda safsizlik tayini, raf ömrü belirteci VE stabilite spesifîkasyonu olarak kullanilmasi için gelistirilmis bir metotla ilgilidir. Description of the invention Critical tests seen in chromatographic testing of chemical compounds according to EMA and FDA guidelines. It is necessary to define and characterize the peaks that are important. Available Reticulin, an impurity present in morphine, morphine salts, and morphine extracts Determination of impurity, shelf life of the compound named Morphine, morphine salts and morphine extracts It relates to an improved method for using the VE indicator as a stability specification.
Daha önce retikulin analizi ile safsizlik tayini, raf ömrü belirteci olarak morfin, morfin tuzlari ve morfin ekstraktlarinda stabilite izlenmemistir. Numunelerde retikulin agirlikça %0.001 ila %2 w/w arasinda Olabilir. Impurity determination by reticulin analysis before, morphine as shelf life indicator, morphine salts Stability was not observed in morphine and morphine extracts. 0.001% by weight of reticulin in samples May be between 2% w/w.
Retikulin, afyon alkoloidlerinden biridir (Formül 11). Dopaminerjik nöronlar üzerinde toksik etkisi olup, Guadeloupean Parkinsonism olarak bilinen atipik parkinsonizme neden olur. Reticulin is one of the opium alkaloids (Formula 11). Toxic on dopaminergic neurons effect, causing atypical parkinsonism known as Guadeloupean Parkinsonism.
Formül 11 Retikulin, fenantren halkasina sahip morfin ve diger bazi alkoloidlerin prekürsörüdür. Formula 11 Reticulin is a precursor of morphine and some other alkaloids with a phenanthrene ring.
Retikulinden morfin biyosentezi asagida gösterilmistir (Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March . Current HO = “I\ . xiiluliiridiiic A ». iliii iridinc O Q Mic q-nlhgm- I I ;4 mi. `mim û. Nm .\1i:() Md) .\îc() “co ului. iridinc xillllairixllliciVADPH 1 Troxidorcduclaw NADI H cniytiuc HO NMS.` .\.\IL' N.`lL' .”iunl- (i r-\ HU ili'imrlm'dnun s alin. iridinul morphiniiiie innrpliiiii` Bu basvuruda morfin teriminden; morfin, morfin tuzlari, hidrat ve solvatlari ile morfin ekstraktlari, morfin ara ürünleri ve yari mamullerinin kastedildigi anlasilmalidir. Morphine biosynthesis from reticulin is shown below (Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March . Current HO = “I\ . xiiluliiridiiic A ». iliii iridinc O Q Mic q-nlhgm-II ;4 ml. `m û. nm .\1i:() Md) .\îc() “co great iridinc xillairixllliciVADPH 1 Troxidorcduclaw NADI H cniytiuc HO NMS.` .\.\IL' N.`lL' .”iunl- (i r-\HU ili'imrlm'dnun take it. iridinul morphiniiiie innrpliiii' In this application, the term morphine; morphine, morphine salts, hydrates and solvates and morphine It should be understood that extracts, morphine intermediates and semi-finished products are meant.
Mevcut basvuru morfin, morfin tuzlari, hidrat ve solvatlari ile morfin ekstraktlarmda, morfin eldesi ara ürünleri ve yari mamullerinde saflik, stabilite veya raf` ömrü tayini için bir HPLC yöntemi olup, özelligi incelenen materyalde retikulin miktarinin belirlenmesini kapsar. Current reference is to use morphine, morphine salts, hydrates and solvates, and morphine extracts in morphine extracts. An HPLC for the determination of purity, stability, or shelf life of intermediates and semi-finished products. It is a method and includes the determination of the amount of reticulin in the material examined.
Mevcut basvuru morfin, morfin tuzlari, hidrat veya solvatlari Ile morfin ekstraktlarinda mevcut bir impürite olan Reticulin isimli bilesigin safsizlik tayini, raf ömrü belirteci ve stabilite spesifikasyonu olarak kullanilmasi için gelistirilmis bir yöntemle Ilgi | Idir. Available in morphine extracts with morphine, morphine salts, hydrates or solvates Impurity determination, shelf life indicator and stability of the compound named Reticulin, which is an impurity. Interested in an improved method for use as a specification | is.
Mevcut basvuru morfin ekstraktlarinda mevcut bir impürite olan Reticulin isimli bilesigin safsizlik tayini, raf ömrü tayini ve stabilite spesifikasyonu olarak kullanilmasi için gelistirilmis bir yöntemle ilgilidir. A compound called Reticulin, an impurity present in current reference morphine extracts. It was developed for use as an impurity determination, shelf life determination and stability specification. It's about a method.
Mevcut basvuru morfin yari-mamüllerinde mevcut bir impürite olan Reticulin isimli bilesigin safsizlik tayini, raf ömrü tayini ve stabilite spesifikasyonu olarak kullanilmasi için gelistirilmis bir yöntemle ilgilidir. A compound called Reticulin, an impurity present in current reference morphine semi-finished products It was developed for use as an impurity determination, shelf life determination and stability specification. It's about a method.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yöntemi incelenen materyalin raf ömrü tayini için uygulanir. The HPLC method, in which the amount of reticulin in the current application is determined, is the result of the examined material. used for shelf life determination.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yöntemi incelenen materyalin stabilite testi için uygulanir. The HPLC method, in which the amount of reticulin in the current application is determined, is the result of the examined material. used for stability testing.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yöntemi incelenen materyalin saflik testi için uygulanir. Böylece retükiiin impüritesi spesifikasyon olarak saflik, stabilite testlerinde ve raf ömrü belirlenmesinde kullanilabilir. The HPLC method, in which the amount of reticulin in the current application is determined, is the result of the examined material. used for purity testing. Thus, the impurity of reticuin as specification, purity, stability It can be used in tests and determination of shelf life.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yönteminde incelenen material olan morfin tuzlari morfin hidroklorür, morfîn sülfat, morfin tartrat, morfin Sitrat ve bu tuzlarin hidrat ve solvatlaridir. The material examined in the HPLC method, in which the amount of reticulin in the current application is determined morphine salts, morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate, and these salts hydrates and solvates.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yönteminde retikulin referans standardi R-retikulin, S-retikulin, rasemik retikulin veya R- ile S-retikulin karisimi olabilir. In the HPLC method, in which the amount of reticulin in the current application is determined, the reticulin reference standard may be R-reticulin, S-reticulin, racemic reticulin or a mixture of R- and S-reticulin.
Belirtilen retikulin referans standart en az %98 safliginda olmalidir. The specified reticulin reference standard must be at least 98% pure.
H P L C yöntemi asagidaki adimlari içerir: (:1) bir numune solüsyonu eldesi için bir morfin test materyalinin tartilan uygun bir miktari çözücü içinde çözülür; (ii) standart çözelti eldesi için Retikulin referans standardin tartilan uygun bir miktari çözücü içinde çözülür; (iiil numune ve standart çözeltiler bir HPLC kolonuna enjekte edilir; ve (iv) her çözeltinin ana pik alanlarinin belirlenir ve test materyalinde retikulin miktari hesaplanir. The HP P L C method includes the following steps: (:1) a suitable amount of a morphine test material weighed to obtain a sample solution dissolves in solvent; (ii) an appropriate amount of solvent, weighed, of the Reticulin reference standard for standard solution dissolves in it; (iii the sample and standard solutions are injected into an HPLC column; and (iv) the main peak areas of each solution are determined and the amount of reticulin in the test material is calculated.
Mevcut basvuru konusu retikulin miktarinin belirlendigi HPLC yönteminde sabit faz olarak kullanilir. As the stationary phase in the HPLC method, where the amount of reticulin is determined in the current application. used.
H PLC yönteminin islem parametreleri asagida belirtilmistir: ° Sabit faz: C18 kolon (2.1 x 100 mm, 1.8 mm) . Mobil Faz: acetonitrile (B) and 01% formic acid (FA) in water (Al. The processing parameters of the H PLC method are as follows: ° Stationary phase: C18 column (2.1 x 100 mm, 1.8 mm) . Mobile Phase: acetonitrile (B) and 01% formic acid (FA) in water (Al.
- Akis hizi: 0.4 mL/min ° Enjeksiyon hacmi: 8 pL. - Flow rate: 0.4 mL/min ° Injection volume: 8 pL.
° Kolon sicakligi: 45 0C. ° Column temperature: 45 0C.
° Gradient kosullari: Test yöntemi morfin, morfin tuzlari, hidrat ve solvatlari ile morfin ekstraktlarinda ve ara ürünleri ile yari mamullarinde uygulanacak olup, özelligi stabilitesi, safsizligi, raI` ömrü kriteri olarak retikulin kullanilmasidir. Bu metod ile retikulin miktarina göre morfin stabilitesi, safsizligi, raf ömrünün belirlenmesi büyük dogruluk ve hassasiyetle yapilabilecektir. ° Gradient conditions: The test method is used in morphine, morphine salts, hydrates and solvates, and morphine extracts and intermediates. It will be applied to products and semi-finished products, and its feature stability, impurity, shelf life criteria using reticulin. With this method, the stability of morphine according to the amount of reticulin, determination of its impurity and shelf life can be done with great accuracy and precision.
Yöntem konusundaki çalismalarda önce morfin hammaddesinde görülen en kritik pik arastirilmistir. Bu amaçla UPLC-QTOF-MS yöntemi uygulanmis, Sekil l”de görüldügü gibi sabit faz olarak Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 um) kolon, mobil faz olarak acetonitrile (B) ve suda 01% forrnic acid ile test edildiginde tutulma süresi 5.2 dakika olan pik önemli pik olarak belirlenmistir. Sivi kromatografisinden elüe olan siviyi dogrudan bir elektrospreye (Electrospray ionization = ESI) alinarak kütle spektrometrisinde analiz edilecek fraksiyonlar toplanmistir. Daha sonra Sekil 2 ve 3`te kütle spektrometrisinde görüldügü gibi bilinmeyen pikin 330.168 g/mol kütleye sahip retikulin bilesigine ait oldugu bulunmustur. In the studies on the method, first the most critical peak observed in the morphine raw material researched. For this purpose, the UPLC-QTOF-MS method was applied, as seen in Figure 1. Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 µm) column as stationary phase, mobile phase Peak retention time of 5.2 minutes when tested with acetonitrile (B) and 01% forrnic acid in water determined as the significant peak. A direct analysis of the liquid eluted from liquid chromatography will be electrosprayed (Electrospray ionization = ESI) and analyzed in mass spectrometry. fractions were collected. Then as seen in the mass spectrometry in Figures 2 and 3 The unknown peak was found to belong to the reticulin compound with a mass of 330.168 g/mol.
MS Parametreleri asagida belirtilmistir: - Mod: ESI Positive - Kurutma gazi akis hizi: 12 L/min - End plate ofiset: 500 V - Kapiler voltaj: +4500 V ° Kuru sicaklik: 200 0C - Funnel 1 RF and tunnel 2 RF: 200, 175 Vpp - CID enerjisi: 0 eV - Heksapol RF: 50 Vpp ° iyon enerjisi: 5 eV Kolüzyon hücre parametreleri asagidaki gibi ayarlanmistir. depolama 6 us. MS Parameters are given below: - Mode: ESI Positive - Drying gas flow rate: 12 L/min - End plate office: 500 V - Capillary voltage: +4500 V ° Dry temperature: 200 0C - Funnel 1 RF and tunnel 2 RF: 200, 175 Vpp - CID energy: 0 eV - Hexapol RF: 50 Vpp ° ion energy: 5 eV Collusion cell parameters are set as follows. storage 6 us.
. Veri analizi Sekillerin açiklamasi: Sekil 1. U PLC kromatograminda tutulma süresi 5.2 dakika olan impuritenin görünümü Metot: Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 um) column, Mobile Phase was acetonitrile (B) and 0.1% formic acid (FA) in water (Al Sekil 2. Bilinmeyen impuritenin kütle spektroskopisi (MS) Sekil 3. Bilinmeyen impuritenin prekürsör iyonu için MS/MS (mol agirligi = 330.168) Yöntemin avantajlari - Morfin HCLa Morfin Sülfat, Moriin diger formlari ve morfm ekstraktlari içerisinde mevcut reticulin (HPLC de, 19. dakikada gelen pik) analizi ile stabilitenin izlenmesi mümkündür. . Data analysis Description of figures: Figure 1. Appearance of impurity with retention time of 5.2 minutes in U PLC chromatogram Method: Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 µm) column, Mobile Phase was acetonitrile (B) and 0.1% formic acid (FA) in water (Al Figure 2. Mass spectroscopy (MS) of unknown impurity Figure 3. MS/MS for precursor ion of unknown impurity (mole weight = 330.168) Advantages of the method - Morphine HCLa Available in Morphine Sulphate, other forms of Moriin and morphine extracts It is possible to monitor stability by analysis of reticulin (peak at 19 minutes in HPLC).
- Dogal bir ürün olan morfin ve morfin ektraktiarinin analitik olarak izlenebilir bir impurite yoluyla miadinin uzatilabilmesi veya üretilmis serilerin reticulin impüritesi üzerinden birlestirilebilmesi mümkündür. - Analytical traceability of morphine and morphine extracts, a natural product can be extended by impurity or by reticulin impurity of produced batches possible to be combined.
- Retieulin impüritesinin morfin ve morfin ekstraktlarinin stabilite testlerinde, ürün bilgilerinde ve analiz sertifikalarinda Spesifikasyon olarak belirtilmesi mümkün olacaktir.- Stability tests of morphine and morphine extracts of retieulin impurity, product information and it will be possible to specify it as a Specification in the analysis certificates.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2021/016490A TR2021016490A2 (en) | 2021-10-22 | 2021-10-22 | USE OF REticULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACTS |
| PCT/TR2022/050286 WO2023069040A1 (en) | 2021-10-22 | 2022-04-01 | Use of reticulin impurity as purity and stability specification in morphine and morphine extracts |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2021/016490A TR2021016490A2 (en) | 2021-10-22 | 2021-10-22 | USE OF REticULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACTS |
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