Evaluation, Method Development, and Validation for Content Determination of Potential Genotoxic Impurities (PGIs) at the TTC Level in Telmisartan API

Abstract

Telmisartan is an angiotensin II receptor antagonist used in the cure of hypertension and other heart diseases. In the current research work, the synthetic route of Telmisartan, including those of starting materials, was evaluated to identify nine potential genotoxic impurities (PGIs) (impurities I−IX) by making use of the literature-, statistical-, and rule-based methods. To date, no suitable methods have been developed for the separation and quantification of these nine impurities in Telmisartan at the threshold of toxicological concern (TTC) level. Based on the identified impurities, four chromatographic methods were developed and validated as per the International Council on Harmonisation (ICH) guidelines. The developed methods are practical and efficient in the detection as well as quantification of PGIs and may be adopted to guarantee the safe use of Telmisartan.

A rapid and sensitive UPLC-MS/MS method for simultaneous determination of four potential mutagenic impurities at trace levels in ripretinib drug substance

“…In particular, the residual of starting materials and intermediates was the direct source. [9][10][11] Among the starting materials and intermediates employed in the industrial production of ripretinib, four impurities (Fig. 1) were found to contain the structural alerts of the primary aromatic amine and aldehyde groups by visual evaluation, triggering the concern of PMIs.…”

“…Additionally, impurities should not be assessed based solely on a visual structural alert. 7,17 (Quantitative) structure-activity relationships [(Q)SAR] technique is a highly recommended method to predict the Ames assay results according to the structural alerts, sequentially estimating and classifying the mutagenic risk of these compounds, 9,10,[17][18][19][20] since it is impractical to perform the toxicity experiment on each impurity. There is an expectation that structural alert assessment should be conducted using two complementary (Q)SAR systems, one expert rule-based and the other statistics-based, as proposed by ICH M7(R1).…”

Development and validation of sensitive high‐performance liquid chromatography‐photodiode array method for determination of three sulfonated esters and N‐methyl‐O‐phenyldiamine dihydrochloride as potential genotoxic impurities in Amlodipine and Telmisartan fixed‐dose combination

“…Various methods have already been developed [12,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] for the determinations of AMLO with various GTIs and have even achieved the detection level of 1 μg/ml and ∼20 ppb levels [24,25]. However, these reported analytical methods involved sophisticated LC-MS/MS techniques, which are normally not available in developing or upcoming pharmaceutical laboratories, Therefore, it was seeming essential to develop a sensitive, stability-indicating, accurate and robust HPLC-photodiode array (HPLC-PDA)based analytical method to quantify NMOPD, and selected alkyl benzene sulfonates in TELMI and AMLO that might be present in finished pharmaceutical preparations.…”

“…The N ‐methyl‐ O ‐phenylenediamine dihydrochloride (NMOPD; Figure 1B–I) is a non‐pharmacopeial potential genotoxic impurity of TELMI (TELMI; Figure 1B) which is an essential building block or key starting material of TELMI synthesis [12]. The predicted in silico toxicity report Protox [13] and Lazar [14] reflects that NMOPD is mutagenic and carcinogenic.…”