Determination of volatiles in pharmaceutical certified reference materials

Abstract

Este trabalho compara os resultados obtidos na determinação de voláteis (água e solventes residuais) em novos materiais de referência certificados (MRC) ou candidatos a MRC dos ingredientes ativos farmacêuticos (API) captopril, metronidazol, diclofenaco sódico, diclofenaco potássico e furosemida, através do uso de diferentes técnicas: perda por dessecação (LOD), titulação coulométrica tipo Karl Fisher (KF), cromatografia gasosa (injeção por headspace estático) com detector por ionização em chama (sHS-GC-FID) e com espectrômetro de massas (sHS-GC-MS), análise termogravimétrica (TGA) e espectroscopia no infravermelho próximo (NIR) com análise estatística multivariada dos resultados. As três primeiras técnicas levaram a resultados complementares na determinação de voláteis, enquanto as outras duas mostraram pouca sensibilidade para a determinação de voláteis na faixa de concentração avaliada. A perda por dessecação foi considerada a técnica mais apropriada para determinação da fração mássica de voláteis a ser utilizada no cálculo do teor de API por balanço de massa.This work compares the results obtained for the determination of volatiles (water and residual solvents) in new certified reference materials (CRM) or candidate CRMs of the active pharmaceutical ingredients (API) captopril, metronidazole, sodium diclofenac, potassium diclofenac and furosemide, by means of different techniques: loss on drying (LOD), Karl Fischer (KF) coulometric titration, static headspace gas chromatography with flame ionization detection (sHS-GC-FID) and with mass spectrometry (sHS-GC-MS), thermogravimetric analysis (TGA) and near infrared spectroscopy (NIR) with multivariate chemometric analysis of results. The first three methods led to complementary results. The two other techniques were not sufficiently sensitive to determine volatiles in the concentration range evaluated. The loss on drying method was considered the most appropriate to determine the mass fraction of the volatiles to be used in the mass balance calculation of the API mass fraction in the pharmaceutical CRMs.Keywords: volatiles, water, residual solvents, active pharmaceutical ingredient (API), certified reference materials (CRM), analytical quality control IntroductionSeveral are the reasons for determining the mass fractions of water and residual solvents in pharmaceuticals, including their influence on the physicochemical 1-7 and microbiological stability of raw materials and finished products, their potential toxicity [1][2][3]8 and also economic aspects 9 since their presence results in analyte mass fractions smaller than 100%. Residual solvents may be introduced in active pharmaceutical ingredients (API) during their synthesis, especially if the final purification step is carried out by crystallization in different solvents, as well as during drug products formulation and manufacturing. 1,7,8 In the particular case of certified reference materials (CRM) of APIs, the determination of volatiles is essential both to demonstrate the compliance with Pharmacopeial acc...

Research design formation to determine quality indicators of potential api, 2. quality risks arising in the process of scaling the synthesis procedure

“…When developing the MQC under the section "Tests for purity" should be borne in mind that at all stages of scaling the synthesis technique there are risks due to the appearance of new impurities, which throughout the life of API should be tested for quality and especially quantity, as they can significantly affect safety of substances [13,24].…”

Об Аттестации Стандартных Образцов В Фармации: Метод Баланса Масс

“…Ñëåäóåò îòìåòèòü, ÷òî èìåþòñÿ ïóáëèêàöèè, â êîòîðûõ äëÿ îïðåäåëåíèÿ ñîäåðaeàíèÿ îñíîâíîãî âåùåñòâà è ïðèìåñåé (X RelSub ) â àòòåñòóåìûõ ñóáñòàíöèÿõ ïðèìåíÿþò ßÌÐ [18,22,27] èëè ÄÑÊ [19,21,23,25]. Ïðè ýòîì ìåòîä ÄÑÊ èñïîëüçóþò êàê ïðÿìîé ìåòîä îïðåäåëåíèÿ X RelSub , à ìåòîä ßÌÐ -êàê êîñâåííûé: èç 100 % âû÷èòàþò ñîäåðaeàíèå îñíîâíîãî âåùåñòâà, ðàññ÷èòàííîå ïî äàííûì ßÌÐ.…”

Study of the thermogravimetric analysis application to determine volatile impurities for the reference standards certification

“…При аттестации фармацевтических СО для определения летучих примесей используется метод ТГА [1]. В настоящее время сформулированы метрологические требования к аттестации фармацевтических СО, которые базируются на применении концепции неопределенности к фармацевтическому анализу и опираются на требования к надежности результатов анализа, для которого используется СО [11].…”

“…Определение летучих примесей с требуемой неопределенностью является актуальной задачей при аттестации стандартных образцов (СО), поскольку они могут вносить значимый вклад в аттестованное значение содержания СО. Одним из эффективных методов определения летучих примесей является термогравиметрический анализ (ТГА) [1]. Однако в научной литературе отсутствуют систематические исследования применимости данного метода к аттестации СО, опирающиеся на предназначение аттестуемого СО и вытекающие из этого требования к неопределенности аттестованного значения.…”