Evaluating the utility of ion mobility separation in combination with high‐pressure liquid chromatography/mass spectrometry to facilitate detection of trace impurities in formulated drug products

Abstract

Many formulated products contain complex polymeric excipients such as polyethylene glycols (PEGs). Such excipients can be readily ionized by electrospray and may be present at very high concentrations, thus making it very difficult to identify trace level impurities such as degradants in samples, even if hyphenated techniques such as liquid chromatography/mass spectrometry (LC/MS) are used. Ion mobility (IM) spectrometry is a very rapid gas-phase separation technique and offers additional separation capability within the LC timeframe. This work investigates the use of an IM separator in combination with high-pressure liquid chromatography (HPLC) and MS, to improve the separation of drug-related materials from excipients, thus aiding the identification of trace-level impurities in an anti-HIV medication, Combivir. Copyright # 2007 John Wiley & Sons, Ltd.Organic impurities in pharmaceutical formulations may arise from a number of sources including process-and drug-related impurities (together with degradants), excipient-related impurities, and products of the interaction of the active pharmaceutical ingredient (API), excipients and packaging in the formulated drug products. The levels of such impurities in the API and formulated products come under regulatory control (e.g. the International Conference on Harmonisation guidelines 1 ) and in order to understand how these impurities can arise, be monitored and ultimately controlled they first have to be identified. There are many analytical techniques which are used for this purpose; high-pressure liquid chromatography (HPLC) combined with diode-array detection (DAD) or with mass spectrometry (MS) are amongst the most common.A particular analytical challenge when dealing with formulated products is that high concentrations of excipients may be present which can mask the responses of the impurities of interest, possibly preventing detection and subsequent identification. Whilst conventional analytical approaches, or combinations thereof, can go a long way towards alleviating the problem, these can often be time and resource consuming and in some cases may compromise sample integrity. A less conventional approach, which may be of benefit, is the combination of ion mobility spectrometry (IMS) with LC/MS, providing an additional rapid, orthogonal separation capability.IMS offers an alternative means of separation to LC or MS and is based on differing ion mobilities in a gas as opposed to hydrophobicity or mass-to-charge ratio alone. Mobility separation is normally achieved by propelling a packet of ions through a background gas using a relatively weak electric field. The time taken for an ion species to traverse the gas-filled region will be dependent on its mobility, which in turn is dependent on factors such as the mass of the ion, and its charge, size and shape. 2 In general IMS does not afford a highly efficient separation mechanism with mass resolutions reported in the tens to low hundreds range. However, it is extremely rapid and therefore in combination with mass ...

Computational fluid dynamics-Monte Carlo method for calculation of the ion trajectories and applications in ion mobility spectrometry

“…IMS is a well-known method to analyze chemical substance using gas-phase mobility in a weak electric field [14][15][16], and is more and more used in the detection of explosives, drugs, chemical warfare agents, biological and medical samples [17][18][19][20][21][22][23][24][25]. Unlike the mass spectrometry [26,27], which operates in vacuum, IMS detects chemical compounds at atmospheric pressure.…”

Dopant-Assisted Negative Photoionization Ion Mobility Spectrometry for Sensitive Detection of Explosives

“…1−7 In addition, it also can provide sensitive and selective detection after separation of gas chromatography 8−11 or high-performance liquid chromatography. 12 Ionization source is one of the most important components of an IMS instrument. The widely used ionization source in commercial IMS is 63 Ni source due to its simplicity, stability, long lifetime, and no need for an extra power supply.…”

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

“…Often samples contain unwanted additives such as salts, plasticizers or interfering analytes that hinder the detection of the compounds of interest. Even though ion suppression may still occur in the electrospray process, IM-MS can reveal specific analyte ions which are present in the spectra but difficult to discern, by separating them from interfering background ions based on their charge and shape/size [30,31]. Such filtering can also be performed post-acquisition, provided that the data were recorded in ion mobility mode [32].…”