Identification of the ‘wrong’ active pharmaceutical ingredient in a counterfeit Halfan™ drug product using accurate mass electrospray ionisation mass spectrometry, accurate mass tandem mass spectrometry and liquid chromatography/mass spectrometry

Abstract

Methodology is presented for identifying an unknown active (pharmaceutical) ingredient (AI) in a counterfeit drug product. A range of mass spectrometric techniques, i.e., accurate mass mass spectrometry, tandem mass spectrometry (MS/MS) and liquid chromatography/mass spectrometry (LC/MS), has been employed to determine the AI in a counterfeit Halfan suspension, an antimalarial drug. In particular, use of LockSpray accurate mass MS/MS allowed identification of parts of the molecule from fragments, hence limiting the number of possible elemental compositions for the nominal mass of 278 found for the AI in the counterfeit product. The analysis of the isotope pattern observed for the protonated molecule further reduced the number of possible elemental compositions. A literature search for readily commercially available compounds of molecular formula C(12)H(14)N(4)O(2)S suggested that the AI was either sulfamethazine or sulfisomidine. An LC/MS separation of those two compounds and reference MS/MS spectra obtained for sulfamethazine and sulfisomidine led to the conclusion that the AI in the counterfeit Halfan suspension is sulfamethazine, which is an antibacterial agent.

Characterization of Counterfeit Artesunate Antimalarial Tablets From Southeast Asia

“…26 However, chloroquine has very low antimalarial efficacy throughout mainland southeast Asia and has been abandoned as therapy for P. falciparum malaria. 10 Recent examples of unexpected ingredients in counterfeit antiinfective drugs include a sulfonamide drug (sulfamethazine or sulfisomidine) in counterfeit halofantrine syrup from west Africa 30 and chloramphenicol, metronidazole, pyrimethaminesulfadoxine, and metamizole in types of counterfeit artesunate not examined in this study. 29 These potentially dangerous pharmaceuticals, with no or minimal antimalarial action, are probably leftover ingredients available to the counterfeiters in a poor quality production process.…”

Mass spectrometry for small molecule pharmaceutical product development: A review

“…A recent review by Olsen and Kiehl (2006) summarizes a variety of methodologies used to address this issue. An example of the identification of the ''wrong'' API in a counterfeit sample of an antimalarial drug, Halfan TM was discussed by Wolff, Thomson, and Eckers (2003). A range of mass spectrometric techniques, including accurate mass LC/MS and MS/MS, were employed to successfully identify the unknown API in the counterfeit drug product as the antibacterial agent, sulfamethazine, instead of antimalarial drug Halfan TM .…”

Substandard/Counterfeit Antimicrobial Drugs

“…An excessive dose of the active ingredient in low-quality antimicrobials may be toxic to humans, especially in children or with antimicrobials with a narrow therapeutic range, such as quinine (7,46,211,212). Counterfeit antimicrobials such as antimalarials (168,213,214) may have dangerous components or infectious contaminants, which can cause side effects. For example, injectable counterfeit antibiotics may contain methanol, a potentially lethal product for humans which may be responsible for pancreatitis, blindness, coma, cardio-circulatory failure, and death (17).…”