The Emergence of High-Resolution Ms As The Premier Analytical Tool in The Pharmaceutical Bioanalysis Arena
2012; Future Science Ltd; Volume: 4; Issue: 5 Linguagem: Inglês
10.4155/bio.12.16
ISSN1757-6199
AutoresRagu Ramanathan, Walter A. Korfmacher,
Tópico(s)Advanced Proteomics Techniques and Applications
ResumoBioanalysisVol. 4, No. 5 Special Focus: HRMS in DMPK - ForewordFree AccessThe emergence of high-resolution MS as the premier analytical tool in the pharmaceutical bioanalysis arenaRagu Ramanathan & Walter KorfmacherRagu Ramanathan* Author for correspondenceBristol-Myers Squibb, Department of Biotransformation, Princeton, NJ 08540, USA. & Walter KorfmacherConsultant for MS Imaging, Discovery BA & Discovery Drug Metabolism and PK, Westfield, NJ 07090, USAPublished Online:12 Mar 2012https://doi.org/10.4155/bio.12.16AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Today, high-resolution MS (HRMS) is used in many areas of science including the pharmaceutical industry. Looking back 100 years, a mass spectrometer with a mass resolving power of less than 20 was used by Sir Joseph John Thomson to discover electrons (1906 Nobel prize in physics). Thomson's student, Francis W Aston, designed and built several mass spectrometers before constructing one with a mass resolving power of approximately 2000. Aston indentified 212 of the 287 naturally occurring isotopes and characterized each of the isotopes by its mass defect (1922 Nobel prize in chemistry) [1]. In subsequent years leading up to the separation of uranium isotopes, significant improvements in resolving power, as well as ion source designs, were achieved by the work of Barber, Stevens, Mattauch, Herzog, Dempster, Jordan and Bainbridge. These scientists contributed to the identification of several other naturally occurring isotopes, as well as to further growth of the magnetic sector-based HRMS instrumentation, and achieved mass resolving power in the range of 10,000 [2]. In the 1940s Nier designed and constructed a simpler double-focusing sector-based HRMS instrument that helped to pave the way for the Manhattan Project and eventually contributed to ending World War II.During the period from 1950–1990s, scientists who needed high resolution and accurate mass measurement capabilities utilized magnetic sector-based mass analyzers. These types of instruments made distinct contributions in many areas of the sciences, including in the area of dioxin monitoring in the 1980s and 1990s. For magnetic sector-based mass analyzers to enjoy the stardom, parallel developments in ionization techniques, such as electron impact, chemical ionization, fast atom bombardment and computers were paramount. Within the pharmaceutical industry, sector-based mass analyzers were used to determine accurate mass information to confirm elemental composition of new chemical entities, metabolites and other drug compound-related materials. HRMS analyses during the sector era were conducted by highly specialized scientists and involved extensive sample clean-up and sample concentration steps. However, sector-based HRMS applications have steadily decreased over the last two decades due to incompatibilities with ionization sources that provide MS access to peptides, proteins, biological fluids and difficulties associated with coupling liquid chromatography-based separation systems.While instrumental developments in the sector-based mass analyzers were on-going, the concept of linear TOF was proposed in 1946 by William E Stephens of the University of Pennsylvania (PA, USA) and commercially made viable in the late 1950s through the work of Wiley and McLaren [3]. The concept was simple and involved ions being separated by differences in their velocities as they move in a straight path toward a collector in order of increasing m/z ratio. Until the introduction of time-lag focusing in the mid-1980s and the reflectron in the mid-1970s, TOFs were only capable of achieving resolution of several hundreds. Time-lag focusing improved mass resolution by simultaneously correcting for the initial spatial and kinetic energy distributions of the ions. The reflectron design, a common feature in today's TOF-based mass analyzers, corrects for the kinetic energy distribution of the ions. Collectively, implementation of time-lag focusing and the reflectron improved the resolution of TOFs from several hundreds to thousands [4,5].Two other Nobel prize winning mass analyzer designs that were being explored in the 1950s and 1960s by Wolfgang Paul and co-workers, included the quadrupole ion trap (QIT), which can trap and mass-analyze ions using a 3D quadrupolar radiofrequency electric field, and the quadrupole mass filter (QMF), which uses a combination of radiofrequency and direct current to separate ions. During the 1970s and 1980s, construction of the triple quadrupole mass spectrometer capable of performing MS/MS experiments [6,7] provided a huge advance for QMF technology, while incorporation of mass selective instability mode of operation and bath or damping gas (i.e., helium) improved resolution, peak shape, trapping efficiency and MS/MS time efficiency of the ion trap [8] and allowed QIT–MS technology to mature further. During the 1990s and 2000s, the ease of coupling to both atmospheric pressure ionization (API) techniques (ESI and APCI) and LC allowed QIT- and QMF-based mass analyzers to evolve into the MS techniques of choice for pharmaceutical qualitative and quantitative bioanalysis [9]. Linear ion trap (LIT), a variation of the QMF and QIT mass analyzer, was introduced in the 2000s to improve performance over the conventional QMF and QIT mass analyzers [10,11].In 1949, on a separate front, an ion cyclotron resonance (ICR) mass spectrometer was designed and demonstrated by Sommer, Thomas and Hipple [12]. The technique remained largely an academic tool until the application of fourier transform (FT) methods by Marshall and Comisarow in the early 1970s and developments in superconducting magnet technology [13]. Since frequencies can be measured more accurately than ion current or TOF, mass measurements with sub-parts per million (ppm) mass accuracies and >100,000 mass resolving power are routine with FTICR-MS. However, for routine metabolism studies, standalone FTICR-MS are not considered as mainstream mass analyzers due to practical limitations of this type of mass spectrometer resulting from operational pressure requirements in the range of 10-8 to 10-10 torr. In 2000, another mass analyzer that takes advantage of FT for simultaneous detection of a range of ions, the Orbitrap (OT), was introduced [14,15]. The OT utilizes electrical fields between sections of a roughly egg-shaped outer electrode and an inner electrode or a spindle, where the ions orbit and their oscillation is recorded as an image current on the spindle. Similar to FTICR, in OT, ions are measured using frequencies characteristic of the m/z values. In contrast to FTICR, where a combination of magnetic field and electrostatic potentials are used to trap and manipulate the ions within an ICR cell, ions in OT are manipulated using a combination of electrostatic potentials.Some of the desired qualities of the individual mass analyzer types and ion manipulation techniques have been combined into one instrument to configure various hybrid mass spectrometers. Hybrid mass spectrometers become very selective and specific when either TOF or FTMS-based HRMS is combined with either ITs or QMFs. For example, the ability of LITs and QMFs to operate in the vacuum pressure range of 10-5 to 10-6 torr makes these types of mass spectrometers ideally suited for coupling with LC separation and API techniques as well as with TOF- and FTMS-based mass analyzers, in tandem, for capitalizing on the high-resolution capabilities of the latter two mass analyzers.In this special focus issue, we focus on how HRMS has evolved during the last few years to meet the new and demanding role of MS in pharmaceutical bioanalysis, especially in the area of drug metabolism and pharmacokinetics (DMPK). What has changed in the recent past is that HRMS has now become a tool for quantitative, as well as qualitative, DMPK studies [16,17]. This technological advance will allow a paradigm shift in how MS is used for various DMPK assays in the future. At this writing, it appears that hybrid mass spectrometers, including orthogonal acceleration quadrupole-TOF, linear ion trap-OT (LIT-OT) and quadrupole-OT (Q-OT) will play a major role in the future of using HRMS in the pharmaceutical industry as part of the new drug discovery and development process. As evident in the special focus issue articles, along with HRMS techniques, UHPLC and column technologies have become important tools that are utilized in the discovery and development of efficacious, potent and safer small molecular weight-, middle molecular weight-, peptide- and protein-based drugs. Despite the recent widespread adoption and the benefits of using UHPLC–HRMS for drug metabolism, pharmacokinetics and metabonomic studies, challenges around automated user-friendly software tools, data file comparison techniques and ultimate quantitative sensitivity similar to triple quadrupole MS remain unconquered. While these challenges may slow the paradigm shift of using HRMS for both qualitative and quantitative DMPK applications, the articles in this special focus issue make it clear that the paradigm shift has already begun.Mass terminologyIn most of the seminal publications before the 1950s, 'R' was used for resolving power rather than resolution. Nowadays, additional confusion is generated between LC and MS resolving power. Therefore, it is always best to state 'mass resolving power' rather than 'resolving power'. For the benefit of the readers, mass resolving power, mass resolution and other selected terms are defined as the following [18–20]: ▪ Mass resolving power: in a mass spectrum, the observed mass divided by the difference between two masses that can be separated: m/Δm. The procedure by which Δm is obtained (i.e., 50% valley or full width at half maximum [FWHM]) must be given and the mass at which the measurement is made should be reported [20]. For consistency and to avoid confusion, the authors suggest MRP = m/Δm50 = m/ΔmFWHM. Mass resolving power is reported without any units;▪ Mass resolution: smallest mass difference Δm between two equal magnitude peaks so that the valley between them is a specified fraction of the peak height [20]. To calculate the resolution of a single peak, the formula m/Δm50 is still applicable, but Δm50 is the peak determined at FWHM. Resolution is reported without any units;▪ Mass unit: the mass unit is defined as 1/12 of the mass of carbon-12 [20]. The unified atomic mass unit (u) is the unit of mass that is accepted by most mass spectrometrists. The Dalton (Da) is also a widely accepted unit to describe biological molecules. The atomic mass unit (amu) is technically incorrect;▪ Exact mass: a calculated mass generated using the exact mass of a particular isotope (generally the most abundant) of each atom of a molecule;▪ Accurate mass: a measured mass that could be obtained using any type of mass analyzers. Mass accuracy improves with increasing resolution, but high resolution alone cannot provide accurate mass measurements, a well characterized stable mass–axis calibration is necessary during the mass analysis.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Bauer SH. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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