Recent Pharmaceutical Applications

The present chapter will review instrumental aspects for successful coupling of CE with MS, regarding interfaces, ionization sources, and analyzers. Practical considerations concerning different CE modes such as CZE, NACE, MEKC, and CEC coupled with MS will also be discussed and illustrated with a focus on recent pharmaceutical applications. Additionally, quantitative CE-MS will be presented and various methodologies used to achieve sensitive and repeatable analysis will be discussed. Finally, the final section of this chapter will give an overview on new devices (i.e., microchips), hyphenated to MS, in terms of fabrication methods, microchip designs, MS interfacing, and applications. 

There has been a surge of research activity in the physical chemistry of membranes, bilayers, and vesicles. In addition to the fundamental interest in cell membranes and phospholipid bilayers, there is tremendous motivation for the design of supported membrane biosensors for medical and pharmaceutical applications (see the recent review by Sackmann [64]). This subject, in particular its biochemical aspects, is too vast for full development here we will only briefly discuss some of the more physical aspects of these systems. The reader is referred to the general references and some additional reviews [65-69]. 

Applications Pressurised fluid extraction (ASE , ESE ) is still in its early stage of development, both for polymeric and other samples. At present, most applications are found in the environmental, food, pharmaceutical and nutraceutical areas. Few reports describe the application of PEE to the extraction of monomers, oligomers and additives from polymers and most work is very recent. An application note [488] has provided some guiding principles for ASE applied to additives in polymers, namely as follows ... 

Poly-j3-malate is readily degraded completely to L-malic acid under both acid and base conditions [108], and it can also be hydrolyzed by enzymes within the cell [105,106]. Recently, several bacteria were isolated which were able to utilize poly-/i-malate as sole carbon source for growth [109]. Because the polymer is biodegradable and bioadsorbable, it is of considerable interest for pharmaceutical applications, especially in controlled-release drug delivery systems [97,98]. Chemical routes to poly-/ -malate are expected to provide materials with various properties [110]. 

Recently, many studies have focused on self-assembled biodegradable nanoparticles for biomedical and pharmaceutical applications. Nanoparticles fabricated by the self-assembly of amphiphilic block copolymers or hydrophobically modified polymers have been explored as drug carrier systems. In general, these amphiphilic copolymers consisting of hydrophilic and hydrophobic segments are capable of forming polymeric structures in aqueous solutions via hydrophobic interactions. These self-assembled nanoparticles are composed of an inner core of hydrophobic moieties and an outer shell of hydrophilic groups [35, 36]. 

Similarly to the phospholipid polymers, the MPC polymers show excellent biocompatibility and blood compatibility [43—48]. These properties are based on the bioinert character of the MPC polymers, i.e., inhibition of specific interaction with biomolecules [49, 50]. Recently, the MPC polymers have been applied to various medical and pharmaceutical applications [44-47, 51-55]. The crosslinked MPC polymers provide good hydrogels and they have been used in the manufacture of soft contact lenses. We have applied the MPC polymer hydrogel as a cell-encapsulation matrix due to its excellent cytocompatibility. At the same time, to prepare a spontaneously forming reversible hydrogel, we focused on the reversible covalent bonding formed between phenylboronic acid and polyol in an aqueous system. 

Raman spectroscopy is emerging as a powerful analytical tool in the pharmaceutical industry, both in PAT and in qualitative and quantitative analyses of pharmaceuticals. Reviews of analyses of pharmaceuticals by Raman spectroscopy have been published.158 159 Applications include identification of raw materials, quantification of APIs in different formulations, polymorphic screening, and support of chemical development process scale-up. Recently published applications of Raman spectroscopy in high-throughput pharmaceutical analyses include determination of APIs in pharmaceutical liquids,160,161 suspensions,162 163 ointments,164 gel and patch formulations,165 and tablets and capsules.166-172... 

An HPLC detector is often a modified spectrophotometer equipped with a small flow cell, which monitors the concentration (or mass) of eluting analytes.Common detectors in the pharmaceutical laboratory are listed in Table 2 with their respective attributes and sensitivity levels. A recent survey found that 85% of pharmaceutical applications use absorbance detectors such as UVA/ is or photodiode array detectors (PDA). These two detectors are covered in more detail in this section. 

Coming from a collaboration between Pfizer and OSI Pharmaceutical, CP-609754 has recently entered phase II, but the structure of this molecule has not been disclosed [182]. Moreover, in recent patent applications [183] Pfizer claimed several compounds bearing a striking resemblance to Johnson Johnson s tipifarnib. One enantiomer (Fig. 4) was emphasized but no data were presented. 

Polyelectrolytes have recently found application in the development of pH sensitive liposomal controlled release systems. This application arises from the fact that polyelectrolytes may be used both to stabilize liposomes, and to disrupt liposomes in a pH dependent manner. Although the use of liposomes in oral pharmaceutical compositions has been discussed [424], liposomes generally suffer from poor stability and are therefore prone to leakage of the entrapped active agents. To overcome this problem, several authors have stabilized the liposomes using polyelectrolytes. For example, Tirrell and coworkers have employed ionene [425], and polyethylene imine) [426] to stabilize liposomes. Similarly, Sato and coworkers have studied maleic acid copolymers [427], and Sumamoto and coworkers have studied liposomes [428] coated with polysaccharides. In related work, Kondo and coworkers have emphasized the use of carboxymethyl chitin to produce artificial red blood cells [429-435]. 

Modern infrared (IR) spectroscopy is a versatile tool applied to the qualitative and quantitative determination of molecular species of all types. Its applications fall into three categories based on the spectral regions considered. Mid-IR (MIR) is by far the most widely used, with absorption, reflection, and emission spectra being employed for both qualitative and quantitative analysis. The NIR region is particularly used for routine quantitative determinations in complex samples, which is of interest in agriculture, food and feed, and, more recently, pharmaceutical industries. Determinations are usually based on diffuse reflectance measurements of untreated solid or liquid samples or, in some cases, on transmittance studies. Far-IR (FIR) is used primarily for absorption measurements of inorganic and metal-organic samples. 

Florence (1983) provide a comprehensive reference for the use of surfactants in drug formulation development. The treatment by Florence (1981) of drug solubilization in surfactant systems is more focused on the question at hand and provides a clear description of surfactant behavior and solubilization in conventional hydrocarbon-based surfactants, especially nonionic surfactants. This chapter will discuss the conventional surfactant micelles in general as well as update the reader on recent practical/commercial solubilization applications utilizing surfactants. Other uses of surfactants as wetting agents, emulsiLers, and surface modiLers, and for other pharmaceutical applications are nc emphasized. Readers can refer to other chapters in this book for details on these uses of surfactant Polymeric surfactant micelles will be discussed in Chapter 13, Micellization and Drug Solubility Enhancement Part II Polymeric Micelles. 

One indication of the developing interest in PATs in the pharmaceutical area is the number of book chapters and review articles in this field that have appeared in the last few years. Several chapters in The Handbook of Vibrational Spectroscopy3 are related to the use of various optical spectroscopies in pharmaceutical development and manufacturing. Warman and Hammond also cover spectroscopic techniques extensively in their chapter titled Process Analysis in the Pharmaceutical Industry in the text Pharmaceutical Analysis.4 Pharmaceutical applications are included in an exhaustive review of near-infrared (NIR) and mid-infrared (mid-IR) by Workman,5 as well as the periodic applications reviews of Process Analytical Chemistry and Pharmaceutical Science in the journal Analytical Chemistry. The Encyclopedia of Pharmaceutical Technology has several chapters on spectroscopic methods of analysis, with the chapters on Diffuse Reflectance and Near-Infrared Spectrometry particularly highlighting on-line applications. There are an ever-expanding number of recent reviews on pharmaceutical applications, and a few examples are cited for Raman,7 8 NIR,9-11 and mid-IR.12... 

Biocatalytic processes increasingly penetrate the chemical industry. In a recent study, 134 industrial-scale biotransformations, on a scale of > 100 kg with whole cells or enzymes starting from a precursor other than a C-source, were analyzed. Hydrolases (44%), followed by oxido-reductases (30%), dominate industrial biocatalytic applications. Average performance data for fine chemicals (not pharmaceuticals) applications are 78% yield, a final product concentration of 108 g I.1, and a volumetric productivity of 372 g (L d) 1. 

Slevin, C.J., Unwin, P.R. and Zhang, J. (2001) Hydrodynamic techniques for investigating reaction kinetics at liquid-liquid interfaces historical overview and recent developments. In A.G. Volkov (Ed.) Liquid Interfaces in Chemical, Biological and Pharmaceutical Applications. Dekker, New York, Chapter 13. 

The first uses of microtechnology for screening applications were presented recently. For instance, Watts and Haswell [2] presented first work on microfluidic combinatorial organic chemistry. Most of the examples described apply to glass, polymer or silicon reactors, which restricts their usage to low-pressure operation similar to pharmaceutical applications. They concluded that micro reactors could be a tool for rapid reaction development and process optimization. 

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