Low‐level Determination of Residual Methyl Methane Sulfonate and Ethyl Methane Sulfonate in Pharmaceuticals by Gas Chromatography with Mass Spectrometry

Sarat, M; Ramakrishna, M.; Suresh, Y.; Harikrishna, S.; Rambabu, C.; Kishore, K.; Reddy, K. Nagabhushana

doi:10.1155/2010/460185

Cited by 2 publications

(4 citation statements)

References 4 publications

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“…The rationale for assay development is always based on speculation or assertion regarding the actual or potential presence of alkyl sulfonates in sulfonic acid salt drug substances, with no supporting evidence. For example, Sarat et al, 2010, state the following:Recently the potential health hazards of trace amounts of mesylate esters, including methylmethanesulfonate (MMS) and ethylmethanesulfonate (EMS), in pharmaceuticals have attracted the attention of regulatory authorities. These mesylate esters are known to be potent mutagenic, carcinogenic, and teratogenic compounds 1–4.…”

Section: Analytical Aspectsmentioning

confidence: 99%

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Elusive Impurities—Evidence versus Hypothesis. Technical and Regulatory Update on Alkyl Sulfonates in Sulfonic Acid Salts

Snodin¹

2019

Org. Process Res. Dev.

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There is a widespread and long-standing perception that drug substances presented as sulfonic acid salts pose an inherent risk to patients, owing to the potential presence of mutagenic alkyl sulfonate impurities. Extensive and indisputable kinetic, mechanistic, and experimental evidence indicates that this is not a sustainable position. Sulfonic acid salt formation normally involves addition of a sulfonic acid to an equimolar amount of the base form of a drug substance dissolved in a suitable solvent (most frequently ethanol or other protic solvent). In such systems, no alkyl sulfonate impurities are generated via an ester-forming side reaction, owing to essentially instantaneous base protonation and neutralization of the acidic component. Carryover of impurities in sulfonic acids is considered highly unlikely, given the use of pharma-grade reagents and the significant in-built purge factors based on dilution and the high solubility of alkyl sulfonates in alcohol solvents. Efforts to create a dialogue with the main drug regulatory agencies with a view to reversing current approaches based on disproved hypotheses have been largely unproductive. One exception is the European Medicines Agency (EMA), which undertook an internal evaluation, resulting in the conclusion that the formation of alkyl sulfonate impurities is unlikely but could not be totally excluded. Requests to EMA to provide evidence supporting this position were all unsuccessful. Although both EMA and the European Pharmacopoeia have proposed "risk assessment" as an alternative to analytical testing, to date there has been no progress on defining appropriate parameters.

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Section: Analytical Aspectsmentioning

confidence: 99%

“…1 The rationale for assay development is always based on speculation or assertion regarding the actual or potential presence of alkyl sulfonates in sulfonic acid salt drug substances, with no supporting evidence. For example, Sarat et al, 2010, 42 state the following:…”

Section: ■ Analytical Aspectsmentioning

confidence: 99%

Elusive Impurities—Evidence versus Hypothesis. Technical and Regulatory Update on Alkyl Sulfonates in Sulfonic Acid Salts

Snodin¹

2019

Org. Process Res. Dev.

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“…1) is an antimuscarinic. The IUPAC name was 4-[ethyl- [1-(4-methoxyphenyl) propan-2-yl] amino] butyl 3,4-dimethoxybenzoate; hydrochloride with molecular formula C 25 H 36 ClNO 5 . It belongs to a group of compounds called musculotropic antispasmodics.…”

Section: Introductionmentioning

confidence: 99%

“…An approach based on GC-MS is feasible within limits of time, ease of application, sensitivity, and cost. Despite the importance of the issue, no method is so far reported for the simultaneous determination of these impurities in API of mebeverine HCl [5,6].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Determination of 2-Chloro Methyl Propionate, 1,4-Di-Bromo Butane and Para Anisic Aldehyde in Mebeverine Hydrochloride Api by Gas Chromatography-Mass Spectrometric With Selected-Ion-Monitoring Mode

Babu

Surendrababu²,

K³

2016

Asian J Pharm Clin Res

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Objective: To develop an accurate, precise and linear gas chromatography-mass spectrometric (GC-MS) selected-ion-monitoring (SIM) method for quantitative estimation of 2-chloro methyl propionate (2-CMP), 1,4-dibromo butane and para anisic aldehyde (PAA) as an genotoxic impurities in mebeverine HCl API (MEB) at ppm level and validated as per International Council of Harmonization (ICH) guidelines. Methods:This method used in SIM mode mass selective detection was developed and validated for the trace level analysis of three impurities. All these three impurities are simultaneously determined by a GC-MS method using VF-624 Capillary column (60 m×0.32 mm×1.80 µm) with Helium as carrier gas and a flow rate of 2.0 mL/minutes. Chromatographic separation of 2-CMP, 1,4-DBB, and PAA was achieved in 7.91, 13.69, 18.45 minutes and m/z values were 63, 55, 135 on SIM mode. Results:The method was linear for 2-CMP, 1,4-DBB and PAA in mebeverine HCl 1.90 µg/ml to 7.5 µg/ml, respectively. The coefficient of correlation (r 2 ) for the 2-CMP, 1,4-DBB and PAA was better than 0.999. The limit of detection obtained was 0.28, 0.35, 0.22 µg/ml and the limit of quantification (LOQ) obtained was 0.85, 1.06, 0.66 µg/ml. The method was fully validated, complying Food and Drug Administration, ICH and European Medicines Agency guidelines. Furthermore, verified precision, accuracy, LOQ precision, LOQ accuracy, ruggedness, and robustness. Conclusion:The proposed method is specific, accurate, precise, linear, rugged and robust for the determination of the three genotoxic impurities in API of mebeverine HCl, and hence, is of wide applicability in pharmaceutical industries.

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Low‐level Determination of Residual Methyl Methane Sulfonate and Ethyl Methane Sulfonate in Pharmaceuticals by Gas Chromatography with Mass Spectrometry

Cited by 2 publications

References 4 publications

Elusive Impurities—Evidence versus Hypothesis. Technical and Regulatory Update on Alkyl Sulfonates in Sulfonic Acid Salts

Elusive Impurities—Evidence versus Hypothesis. Technical and Regulatory Update on Alkyl Sulfonates in Sulfonic Acid Salts

Simultaneous Determination of 2-Chloro Methyl Propionate, 1,4-Di-Bromo Butane and Para Anisic Aldehyde in Mebeverine Hydrochloride Api by Gas Chromatography-Mass Spectrometric With Selected-Ion-Monitoring Mode

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