A new electrospray dual sprayer, LockSpray, was developed for accurate mass measurements on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (oa-Q-ToF). With the dual-sprayer ion source, both sprays are orthogonal to each other. A mechanism similar to the one employed on the multiplexed electrospray source (MUX) allows switching between reference and sample sprayer. The reference sprayer is optimized for low flow rates, whereas the sample sprayer is a conventional Z-spray type sprayer. Earlier work using a modified MUX ion source on an orthogonal acceleration time-of-flight instrument showed promising results. In this paper, examples obtained with the LockSpray, specifically designed for accurate mass measurements on an oa-Q-ToF, are presented. The examples include results obtained for the identification of impurities in drug substances such as cimetidine and rosiglitazone, using accurate mass tandem mass spectrometry in both positive and negative ion electrospray modes. Good mass accuracies, i.e., within 2 mDa of the theoretical value, were obtained in MS and MS/MS operation.

This paper describes the use of two separate electrosprays for introducing sample and reference for accurate mass liquid chromatography/mass spectrometry (LC/MS) on an orthogonal acceleration time-of-flight mass analyzer. This is carried out using an adaptation of the multiplexed electrospray ion source in which only two of the sprays are utilized. Results are shown for the positive ion detection of trace-level components in complex matrixes and good mass accuracies are obtained, even for very low level components. An example of accurate mass measurements obtained using negative ion LC/MS is also shown. To obtain additional structural information, an example of cone voltage fragmentation is included and shows that good mass accuracy can be obtained for both precursor and fragment ions.

This paper shows the use of a quadrupole time-of-flight mass spectrometer combined with a liquid chromatograph for the identification of trace impurities in a drug substance. LC/MS/MS data obtained on trace impurities using this instrument compare favourably with those previously obtained on triple quadrupole mass spectrometers and in addition the high resolution capabilities of the ToF analyser allow accurate mass measurement of the fragment ions to better than 5 ppm in most cases.

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 ...

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The use of liquid chromatography coupled to sector field inductively coupled plasma mass spectrometry (SF-ICP-MS) for the specific detection of sulfur-containing compounds is described. In the sulfur-containing drug substance cimetidine, structurally related impurities well below the 0.1% mass fraction level relative to the main drug substance could easily be detected. The structure of most of the impurities was confirmed by electrospray mass spectrometry (ESI-MS), and thus, the complementarity of the two techniques for drug analysis is shown. The limit of detection by SF-ICP-MS for cimetidine in solution was approximately 4-20 ng x g(-1), but it was blank-limited.

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.

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