CS254944B1

CS254944B1 - A method of treating triethylene glycol for injectable solutions

Info

Publication number: CS254944B1
Application number: CS863615A
Authority: CS
Inventors: Jan Cvengros; Peter Slivko; Livia Magulova
Original assignee: Jan Cvengros; Peter Slivko; Livia Magulova
Priority date: 1986-05-19
Filing date: 1986-05-19
Publication date: 1988-02-15
Also published as: CS361586A1

Abstract

Riešenie sa týká oboru farmacie a rieši úpravu trietylénglykolu pre injekčné roztoky s cieíom zvýšiť jeho oxidačnú stabilitu. Postupuje sa tým sposobom, že trietylénglykol sa zmieša s antioxidantom 2,6-diterc.butyl-4-metylfenolom v množstve 0,02 až 0,06 pere. hmot. a táto zmes sa podrobí molekulovej destilácii na krátkocestnej odparke so stieraným filmom. Pri teplote 70 až 80 CC a tlaku 1 až 20 Pa sa z nástreku odpaří najprv predná frakcia v množstve 3 až 15 % z nástreku a potom pri teplote 80 až 95 °C a tlaku 1 až 20 Pa sa oddestiluje hlavná destilátová frakcia v množstve 70 až 90 % z nástreku. Postupom sa získá destilát trietylénglykolu s obsahom použitého antioxidantu na zabezpečenie oxidačnej stability. Postup může byť využitý vo farmaceutických výrobách pri príprave injekčných roztokov, obsahujúcich trietylénglykol.The solution relates to the field of pharmacy and solves the treatment of triethylene glycol for injection solutions with the aim of increasing its oxidative stability. The method is that triethylene glycol is mixed with the antioxidant 2,6-ditert.butyl-4-methylphenol in an amount of 0.02 to 0.06 per. wt. and this mixture is subjected to molecular distillation on a short-path evaporator with a wiped film. At a temperature of 70 to 80 °C and a pressure of 1 to 20 Pa, the front fraction is first evaporated from the feed in an amount of 3 to 15% of the feed and then at a temperature of 80 to 95 °C and a pressure of 1 to 20 Pa, the main distillate fraction is distilled off in an amount of 70 to 90% of the feed. The process yields a distillate of triethylene glycol containing the antioxidant used to ensure oxidative stability. The process can be used in pharmaceutical production for the preparation of injection solutions containing triethylene glycol.

Description

Vynález sa týká sposobu úpravy trietylénglykolu pre injekčné roztoky š cielom zvýšit' jebo oxidačnú stabilitu.The present invention relates to a process for treating triethylene glycol for injectable solutions with the aim of increasing or oxidizing stability.

Podlá doteraz známých postupov sa trietylénglykol pře injekčné roztoky dočisťuje vákuovou rektifikáciou. Nevýhodou tohto sposobu úpravy je, že prebieha pri relativné vysokých teplotách 120—140 °C počas poměrně dlhej doby vystavenia destilovanej látky účinku zvýšených teplot desiatky až stovky minút pri vyšších tlakoch 10²až 103 p_a ρ_Γ] značnom parciálnom tlaku kyslíka. Všetky tieto faktory znamenajú zvýšené nebezpečenstvo termickej oxidácie trietylénglykolu. Trietylénglykol je látka značné náchylná na oxidáciu, a to i pri běžných laboratórnych teplotách, v prvom stádiu za tvorby peroxldických zlúčenín, z ktorých potom vznikajú karbonylové a karboxylové zlúčeniny. Produkty oxidácie trietylénglykolu potom katalyzujú rozkladné reakcie vlastného medikamentu, čím sa znižuje jeho koncentrácia a účinnost', připadne produkty rozkladu samy možu byť toxické a fyziologicky neúnosné. Na zamedzenie oxidácie sa k trietylénglykolu pridávajú vhodné antioxidanty, ich účinok može však byť značné znížený a obmedzený, ak sa nepřidají! včas, ešte před vytvořením zvýšenej hladiny peroxidických zlúčenín. Produkty z počiatočnej fázy oxidácie ostávajú však aj potom v sústave přítomné a spósobujú nestabilitu injekčného roztoku.According to the prior art, triethylene glycol is purified by means of vacuum rectification before injection solutions. A disadvantage of this treatment method is that it takes place at relatively high temperatures of 120-140 ° C for a relatively long period of exposure of the distilled substance to elevated temperatures of tens to hundreds of minutes at higher pressures of 10 ² to 103 p _and ρ _Γ ] considerable partial oxygen pressure. All these factors present an increased risk of thermal oxidation of triethylene glycol. Triethylene glycol is a substance susceptible to oxidation, even at normal room temperatures, in the first stage to form peroxidic compounds, which then form carbonyl and carboxyl compounds. The oxidation products of triethylene glycol then catalyze the degradation reactions of the drug itself, thereby reducing its concentration and efficiency, and the degradation products themselves may be toxic and physiologically intolerable. Suitable antioxidants are added to triethylene glycol to prevent oxidation, but their effect may be greatly reduced and limited if they are not added! in time, before the formation of elevated levels of peroxidic compounds. However, products from the initial oxidation phase remain present in the system and cause instability of the injectable solution.

Tieto nevýhody sú odstránené pri sposobe úpravy trietylénglykolu pre injekčné roztoky podta vynálezu, ktorého podstatou je, že trietylénglykol s obsahom peroxidických látok do 200 mmol l¹, redukujúcich látok do 2 mmol l'^: as aciditou do 0,40 mmol T¹sa zmieša s 2,6-diterc.butyl-4-metylfenolom v množstve 0,02—0,06 % hniot. a z tejto zmesi sa v tenkom stieranom filme s hrúbkou 0,03—0,15 mm pri teplote 70—80 °C a tlaku 1—20 Pa oddestiluje predná frakcia v množstve 3—15 % z nástreku a pri teplote 80—95 °C a tlaku 1—20 Pa sa oddesti'uje hlavná destilátová frakcia v množstve 70—90 % z nástreku.These disadvantages are eliminated in a method of treatment of triethylene glycol for the injectable solution according to the invention, which is characterized in that the triethylene glycol content of peroxide compounds in the 200 mM L ^1, the reducing agents 2 mmol l ^'and acidity to 0.40 mmol T ¹ is mixed with 2,6-di-tert-butyl-4-methylphenol in an amount of 0.02-0.06% of rot. and from this mixture, a front fraction of 3-15% of the feed at 80-95 ° C is distilled off in a thin wiped film having a thickness of 0.03-0.15 mm at a temperature of 70-80 ° C and a pressure of 1-20 Pa. at a pressure of 1-20 Pa, the main distillate fraction is distilled off at 70-90% of the feed.

Sposob úpravy trietylénglykolu pre injekčné roztoky podta vynálezu má nekoíko výhod. Využitie šetrnej destilačnej metody molekulovej destilácie so stleraným filmom v krátkocestnej odparke podstatné eliminuje možnosti oxidačného narušenta trietylénglykolu na minimum. Súvisí to jednak s výrazným znížením pracovnej teploty v dósledku rapídneho zníženia tlaku neskondenzovaných plynov v odparke na úroveň 10° až 10¹ Pa, jednak s krátkou dobou expozície destilovanej kvapaliny účinku zvýšených teplot na 5—50 s pri jej distribúcii do tenkého stieraného filmu na odparnom válci odparky. Krátkocestné usporiadanie destilačného priestoru so vzdialenosťou odparovač — kondenzátor 10—50 mm umožňuje destiláciu bez významných tlakových gradientov v zariadení, čo znamená ďalšie zníženie pracovnej teploty vo filme destilované] kvapaliny. S hlbokým znížením tlaku neskondenzovatetných plynov súvisí aj příslušné zníženie parciálneho tlaku kyslíka, čo je rovnako významným faktorom, obmedzujúcim rozvinutie oxidačných pochodov. H'av,nou výhodou však je skutečnost, že postupom podfa vynálezu je možné zabezpečit ochranu trietylénglykolu pomocou antioxidantu počas celého destilačného procesu, a to v kvapalnej fáze destilovanej kvapaliny na odparnej ploché, v parnej fáze v destilačnom priestore a tiež v kondenzovanej kvapalnej fáze na chladiacej ploché odparky. Je to umožněné tým, že pri daných teplotných a tlakových pomerocb destilácie majú použitý antioxidant 2,6-di-terc.butyl-4-metylfenol i trietylénglykol blízké rýchlosti odparovania a destiluji! spoločné. Takto získaný trietylénglykol vykazuje nízký obsah peroxidických i redukujúcich látok a nízku aciditu, pričom nízké hodnoty uvedených parametrov sa udržujú dlhodobo. V případe, že východiskový trietylénglykol nedosahuje predpísaná parametre, može sa s výhodou postupovat tak, že trietylénglykol pre přípravu zmesi s antioxidantom sa před zmiešaním spracuje šetrnou destiláciou na molekulovej odparke so stieraným filmom, pričom sa na ďalšie spracovaníe použije středná frakcia. Takáto výhodná kombinácia dvoch destilácií na molekulovej odparke zabezpečí přípravu trietylénglyko lu s vysokou oxidačnou stabilitou. Na zamedzenie oxidácie potom stačí minimálně množstvo antioxidantu. Na úpravu trietylénglykolu podfa vynálezu je možné výhodné použiť kontinuálnu molekulovú odparku so stieraným filmom jednostupňovú podfa čs. AO 204 444, alebo viacstupňovú podfa čs. AO 181 054.The process for treating triethylene glycol for injection solutions of the invention has several advantages. The use of a gentle distillation method of sclerified film distillation in a short path evaporator substantially eliminates the possibility of oxidizing triethylene glycol disturbance to a minimum. This is related both to a significant decrease in working temperature due to the rapid reduction of non-condensable gases in the evaporator to 10 ° to 10 ¹ Pa, and also to a short exposure time of distilled liquid to elevated temperatures of 5 to 50 seconds. evaporator cylinders. The short-path arrangement of the distillation space with an evaporator-condenser distance of 10-50 mm allows distillation without significant pressure gradients in the plant, which further reduces the working temperature in the distilled liquid film. The low pressure reduction of non-condensable gases is also associated with a corresponding reduction in the partial pressure of oxygen, which is also an important factor limiting the development of oxidation processes. However, the advantage of the process of the present invention is to provide protection of triethylene glycol with an antioxidant throughout the distillation process, in the liquid phase of the distilled liquid on a vaporizing flat, in the vapor phase in the distillation space and also in the condensed liquid phase. Cooling flat evaporators. This is made possible by the fact that the antioxidant 2,6-di-tert-butyl-4-methylphenol and triethylene glycol used at the given distillation temperatures and pressures have near evaporation rates and distillation! common. The triethylene glycol thus obtained shows a low content of peroxide and reducing substances and a low acidity, while the low values of said parameters are maintained for a long time. If the initial triethylene glycol does not meet the prescribed parameters, it may be advantageous to treat the triethylene glycol to prepare a mixture with the antioxidant by gentle distillation on a wiped-film molecular evaporator prior to mixing, using the middle fraction for further processing. Such a preferred combination of two distillations on a molecular evaporator will ensure the preparation of triethylene glycol with high oxidation stability. A minimum amount of antioxidant is then sufficient to prevent oxidation. For the treatment of the triethylene glycol according to the invention, it is advantageous to use a continuous wiped-film molecular evaporator according to the one-stage process. AO 204 444, or multistage according to MS. AO 181 054

V trietylénglykole s obsahom peroxidických látok do 200 mmol I¹, redukujúcich látok do 2 mmol 1~^! a s aciditou do 0,40 mmol l¹ sa rozpustí 2,6-diterc.butyl-4-metylfenol v množstve 0,02—0,06 % hniot. Zmes sa kontinuálně dávkuje na krátkocestnú odparku so stieraným filmom, pričom rýchlosť nástreku a poměry stieranía sa volia vhodné tak, aby hrúbka filmu sa pohybovaia medzi 0,03—0,15 mm a priemerná doba pobytu na odparnej ploché bola 5 až 50 s. Při teplote 70—80 °C a tlaku 1—20 Pa sa odoberie predná frakcia v množstve 3—15 % z nástreku. Pri teplote 80—95 °C a tlaku 1—20 Pa sa potom získá hlavná destilátová frakcia v množstve 70—90 % z nástreku, ktorú tvoří čistý trietylénglykol s obsahom peroxidických látok do 25 mmol l^-1, redukujúcich látok do 0,30 mmol l¹ a s aciditou do 0,20 mmol l^-1, pričom acidita pri teste oxidačnej stability uzavretej vzorky pri 37 °C po 70 dňoch sa nezvýši nad 0,5 mmol l^-1. Přítomnost antioxidantu v hlavnej destilátovej frakcii je možné dokázat metodou EPR spektroskopie tak, že antioxi5The glycol content of peroxide compounds and 200 I, ¹ mmol, of reducing agents to 2 mmol of 1 ^~! and an acidity of 0.40 mmol l ¹ was dissolved 2,6-di-tertbutyl-4-methyl phenol in an amount of from 0.02 to 0.06% hniot. The mixture is fed continuously to a short-path wiped film evaporator, the feed rate and wiping ratios being selected so that the film thickness is between 0.03-0.15 mm and the average residence time on the evaporating flat is 5 to 50 s. At a temperature of 70-80 ° C and a pressure of 1-20 Pa, the front fraction is collected in an amount of 3-15% of the feed. At 80-95 ° C and 1-20 mbar was obtained main fraction of distillate in an amount of 70-90% of the feed with a distinct triethylene peroxide-containing compounds to 25 mmol L ^-1, reducing agents and 0.30 mmol l ¹ and the acidity to 0.20 mmol l ^-1, the acidity of the test the oxidative stability of the sample sealed at 37 after 70 days is not increased above 0.5 mmol l ^-1. The presence of the antioxidant in the main distillate fraction can be detected by EPR spectroscopy such that

234944 dant sa pomocou PbOz prevedie na svoj stabilný radikál. Z plochy EPR signálu sa stanoví obsah antioxidantu v hlavnej destilátovej frakcii relativné voči analogickému signálu stabilného radikálu antioxidantu v nástreku. Hlavná deštilátová frakcia obsahuje asi polovičně množstvo antioxidantu vzhladom k množstvu antioxidantu v nástreku. Ak východiskový trietylénglykol nemá požadovaná kvalitu a nedosahuje predpísané parametre, musí sa predbežne destilačne upravil, s výhodou molekulovou destiláciou 11a. krátkocestnej odparke so stieraným fii· mom dvojstupňovo. V prvom stupni pri tep lote 70—80 °C a tlaku 1—20 Pa sa odoberie predná frakcia v množstve 3—15 % z nástreku a v druhom stupni druhá destilátová frakcia v množstve 70—90 % z nástreku pri teplote 80—95 °C a tlaku 1—20 Pa.234944 dant is converted to its stable radical by PbOz. From the area of the EPR signal, the content of antioxidant in the main distillate fraction relative to the analogous stable radical signal of the antioxidant in the feed is determined. The main distillate fraction contains about half the amount of antioxidant relative to the amount of antioxidant in the feed. If the starting triethylene glycol does not have the desired quality and does not meet the prescribed parameters, it must be pre-distilled, preferably by molecular distillation 11a. short-path evaporator with wiped film two-stage. In the first stage at 70-80 ° C and 1-20 Pa the front fraction is collected at 3-15% from the feed and in the second stage the second distillate fraction at 70-90% from the feed at 80-95 ° C. and a pressure of 1-20 Pa.

Příklad 1Example 1

Trietylénglykol s obsahom peroxidických látok 60,2 mmol l^-1, stanovených spektrofotometricky s N,N-dimetyl-p-fenyléndiamíniumdichloridom pri 550 nm, s obsahom redukujúcich látok 0,50 mmol 1^_1, stanovených spektrofotometricky s tetrazolovou modrou pri 525 nm, a s aciditou 0,16 mmo’ l'¹, stanovenou potenciometrickou titráciou s NaOH, sa zmiešal s 2,6-diíerc.butyl-4-metylfenolom v množstve 0,05 % hmot. a po rozpuštění sa dávkoval 11a krátkocestnú odparku so stieraným filmom so vzdialenos tou odparovač — kondensátor 20 mm s priemernou hrubkou filmu. 0,10 mm s priemernou dobou pobytu na odparnej ploché 11 s. Pri teplote 75 °C a tlaku 10 Pa sa získala predná frakcia v množstve 9 % z nástreku. Pri teplote 88 °C a tlaku 8 Pa sa získala hlavná destilátová frakcia v množstve % z nástreku, v ktorej sa po vyhodnotení EPR spektra stanovilo 0,022 % hmot. antioxidantu. Obsah peroxidických látok bolTriethylene glycol containing peroxide compounds 60.2 mmol L ^-1, determined spectrophotometrically with N, N-dimethyl-p-fenyléndiamíniumdichloridom at 550 nm, with a reducing substance, 0.50 mmol 1 ^_1, tetrazole determined spectrophotometrically at A 525 nm, and an acidity of 0.16 mmol l ^-1, determined by potentiometric titration with NaOH, was mixed with 2,6-diíerc.butyl-4-methyl phenol in an amount of 0.05% by weight. and after dissolution 11a short-path wiped film evaporator was metered at a distance of 20 mm evaporator-condenser with an average film thickness. 0.10 mm with an average residence time on the evaporative flat 11 s. At a temperature of 75 ° C and a pressure of 10 Pa a front fraction of 9% of the feed was obtained. At a temperature of 88 ° C and a pressure of 8 Pa, the main distillate fraction was obtained in an amount of% feed from which, after evaluation of the EPR spectrum, 0.022 wt% was determined. antioxidant. The peroxide content was

20,7 mmol 1^_1, obsah redukujúcich látok 0,29 mmol l·¹ a acidita 0,14 mmol 1^_1. Po teste oxidačnej stability uzavretej vzorky pri 37 °C po 70 dňoch sa acidita zvýšila na 0,28 mmol 1 ¹ zatlal' čo u východiskového nedestilovaného trietylénglykolu bez antioxidantu z póvodných 0,16 mmol l”¹ sa zvýšila na 7,29 mmol l¹ a u východiskového nedestilovaného trietylénglykolu s 0,05 % hmot. antioxidantu sa zvýšila na 0,82 mmol i-¹.20.7 mmol ^_1 1, the content of reducing substances, 0.29 mmol · L ^1, and acidity of 0.14 mmol 1 ^_1. After the test the oxidative stability of the closed sample at 37 ° C for 70 days, the acidity is increased to 0.28 mmol of 1 Zatl ¹ 'as the starting triethylene glycol without antioxidant was not distilled from the original 0.16 mmol l ^"1 increased to 7.29 mmol l ¹ and in the starting undistilled triethylene glycol with 0.05 wt. of the antioxidant was increased to 0.82 mmol i- ¹ .

Příklad 2Example 2

Trietylénglykol s obsahom peroxidických látok 60,2 mmol 1 \ redukujúcich látok 0,50 mmol l^-1 a s aciditou 0,16 mmol i^-1 sa v krátkocestnej odparke so stieraným filmom so vzdialenosfou odparovač — kondenzátor 20 mm s priemernou hrubkou filmu 0,10 mm s priemernou dobou pobytu na odparnej ploché 11 s vyhrial na teplotu 75 °C pri tlaku 12 Pa, pričom sa získala predná frakcia v množstve 6 % z nástreku. Pri teplote 90 stupňov Celzia a tlaku 8 Pa sa potom získala druhá destilátová frakcia v množstve ®/o z nástreku s nasledujúcimi parametrami: obsah peroxidických látok 36,4 mmol Γ¹, obsah redukujúcich látok 0,29 mmol l¹, acidita 0,10 mmol l“¹, acidita vzorky po teste oxidačnej stability v uzavretej nádobě pri 37 °C po 70 dňoch 2,72 mmol 1^_1, zatial čo acidita povodnej nedestilovanej vzorky pri podobnom teste bola 7,29 mmol l^-1.Triethylene glycol with a content of peroxides of 60.2 mmol 1% of reducing substances 0.50 mmol l ^-1 and an acidity of 0.16 mmol i ^-1 in a short-path evaporator-capacitor with a film thickness of 20 mm with an average film thickness of 0.10 mm, with an average residence time of 11 [deg.] C., heated to 75 [deg.] C. at a pressure of 12 Pa, giving a front fraction of 6% of the feed. At a temperature of 90 degrees Celsius and a pressure of 8 Pa, a second distillate fraction was then obtained in an amount of / / oz feed with the following parameters: peroxide content 36.4 mmol Γ ¹ , reducing substances content 0.29 mmol l ¹ , acidity 0.10 mmol l ^'1, acidity of the sample after the test the oxidative stability of the closed vessel at 37 ° C for 70 days, 2.72 mmol 1 ^_1 while the acidity of the original sample-distilled in a similar assay was 7.29 mmol l ^-1.

Claims

254944 dant takes PbOz to his stable radical. From the area of the EPR signal, the content of anlioxidant in the main distillate fraction relative to the analogous signal of the stable antioxidant radical in the spray is determined. The main dehydrate fraction contains about half the amount of antioxidant to the amount of antioxidant in the feed. If the initial triethylene glycol does not require the desired quality and does not meet the prescribed parameters, it must be pre-distilled, preferably by molecular distillation, in a short-path evaporator with a wiping stage. In the first stage at a temperature of 70-80 ° C and a pressure of 1 - 20 Pa, a forward fraction of 3-15% is withdrawn from the coating and in the second stage a second distillate fraction of 70-90% is removed from the 80-95 batch. ° C and a pressure of 1 - 20 Pa. EXAMPLE 1 Triethylene glycol containing peroxidic compounds 60.2 mmol / l, determined spectrophotometrically with N, N-dimethyl-p-phenylenediaquinoline dichloride at 550 nm, with a reactant content of 0.50 mmol / l determined spectrophotometrically with a tetrazole modifier at 525 nm, and with an acidity of 0.16 mmol / l, determined by potentiometric titration of NaOH, was mixed with 2,6-di-tert-butyl-4-methylphenol in an amount of 0.05% by weight. and discharging was fed on a short-path wiped-film park with a vaporizer-condenser spacing of 20 mm with an average film thickness of 0.10 mm with an average residence time on the evaporation flat of 11 s. 9% of the impregnation front fraction. At a temperature of 88 ° C and a pressure of 8 Pa, the main distillate fraction was obtained in an amount of 81% of the feed, in which 0.022 wt. an antioxidant. The peroxide content was 20.7 mmol / l, the reducing agent content was 0.29 mmol / l and the acidity was 0.14 mmol / l. The increase in oxidation stability of the sealed sample at 37 ° C for 70 days resulted in an acidity of 0.28 mmol of 1 L, while 0.16 mmol of 1 "1 was increased to 7.29 mmol 1 of the initial distilled triethylene glycol without flood." Example 1 Triethylene glycol with a peroxide content of 60.2 mmol of a reducing agent of 0.50 mmol / l and an acidity of 0.16 mmol of i-1 and 1% in the starting triethylene glycol with 0.05% antioxidant. 1, at a short-distance wiped-film evaporator with a distance of 20 mm with an average film thickness of 0.10 mm with an average residence time on the evaporation surface of 11 s, heated to 75 ° C at a pressure of 12 Pa, giving a front fraction of 6% of the feed. At a temperature of 90 degrees Celsius and a pressure of 8 Pa, a second distillate fraction of 82% was obtained from the feed with the following parameters: peroxide content 36.4 mmol -1, reducing content 1 flux 0.29 mmol / l, acidity 0.10 mmol / l, acidity of the sample after the oxidation stability test in a sealed vessel at 37 ° C after 70 days 2.72 mmol / l, while the coacidity of the flooded non-distilled sample was 7.29 mmol l-1. P R E D Μ E T

A process for the preparation of triethylene glycol for injectable solutions, characterized in that triethylene glycol with a peroxide content of up to 200 mmol / l, reducing substances up to 2 mM and acidity up to 0.40 mmol / l of carbon black with 2% by weight. , 6-di-tert-butyl-4-methylphenol in an amount of 0.02-0.06% by weight, and more particularly in a scraped film having a thickness of 0.03-1.15 mm at a temperature of 70-80 ° C and a pressure of 1 ° C 2020 Pa distilled off the front fraction in a quantity of 3-15% of the feed, and at 80-95 ° C and a pressure of 1 - 20 Pa, the main decomposition fraction of 70-90% of the feed was distilled off.

2. Process according to claim 1, characterized in that a triethylene glycol obtained by distillation from a thin wiping film on a short path as a second distillate fraction in an amount of about 1% is used to prepare a mixture of triethylene glycol and 2,6-di-tert-butyl-4-methylphenol. 70-90% of the feed at a temperature of 80-95 degrees Celsius and a pressure of 1-20 Pa after a pre-fraction of 3-15% of the coating at a temperature of 70-80 ° C and a pressure of 1-20Pa.