Method development overview

Professor Bartlett brought the CC method, developed earlier by others, into the mainstream of electronic structure theory. For a nice overview of his work on the CC method see ... 

The identification of unknown chemical compounds isolated in inert gas matrices is nowadays facilitated by comparison of the measured IR spectra with those computed at reliable levels of ab initio or density functional theory (DFT). Furthermore, the observed reactivity of matrix isolated species can in some instances be explained with the help of computed reaction energies and barriers for intramolecular rearrangements. Hence, electronic structure methods developed into a useful tool for the matrix isolation community. In this chapter, we will give an overview of the various theoretical methods and their limitations when employed in carbene chemistry. For a more detailed qualitative description of the merits and drawbacks of commonly used electronic structure methods, especially for open-shell systems, the reader is referred to the introductory guide of Bally and Borden.29... 

In supercritical fluid chromatography, fluids above their critical point are used as mobile phases. This chapter discusses the principles of operation, mobile phase considerations, parameters that can be adjusted in method development as well as an overview of instrumentation required and a few pertinent examples from current literature. Not everything can be illustrated, but the advantages of this diverse technology will be highlighted. 

It is important to keep in mind that safety assessment is only one of many components involved in the discovery and development of new pharmaceuticals. The entire process has become enormously expensive, and completing the transit of a new drug from discovery to market has to be as efficient and expeditious a process as possible. Even the narrow part of this process (safety assessment) is dependent on many separate efforts. Compounds must be made, analytical and bioanalytical methods developed, and dosage formulations developed, to name a few. One needs only to refer to Beyer (1978), Hamner (1982), Matoren (1984), Sneader (1986) (a good short overview), Zbinden, (1992) or Spilker (1994) for more details on this entire process and all of its components. 

In this way, we aim to give an overview of what can be used as a separation technique and which conditions will most likely give an (beginning of) enantiomer separation after a first screening. Chiral method development starter kits are also available and evaluated in some papers [2], but we will not focus on this kind of applications. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

FIGURE I Schematic overview of an advanced method development process. Method development is a continuous process in which all stakeholders collaborate intensively to design the final method. Reprinted with permission from reference I. 

In this chapter I will provide a brief historic perspective, outline the manufacturing drivers for process analysis, provide a high-level overview of process analytical instrumentation, describe the PA method development life cycle prior to implementation and highlight the common pitfalls and challenges within the PA field. I have taken a pragmatic approach herein as the many benefits of PA are realized when a suitable process instrument and method is successfully implemented within a routine manufacturing environment, which is most often a multifaceted endeavor. 

In this chapter, we give an overview on how the API techniques work and which factors have an important influence on the performance. Examples are presented mostly from published work to demonstrate how LC-MS, LC-MS-MS, collision-induced dissociations (CIDs), accurate mass measurements and hydro-gen/deuterium exchange have been systematically and successfully applied in the structural elucidation of impurities, degradation products and metabolites. In addition, these also illustrate how mass spectrometry has offered a third dimension to chromatographic method development and validation. 

The approach taken is loosely based on the input-process-output meta-model utilized to transform a problem statement into a functional process. The section Scope definition discusses the intended purpose and potential constraints of the isolation effort, followed by an overview of the Toolbox available to the practitioner (input). The section Method development scouting and scale-up reviews platform-based, highly automated approaches to selectivity scouting, development of the isolation as well as options for scaling up the chromatographic separation depending on purpose and constraints (process). The final section. Performing the task, explores a work breakdown structure approach to the preparative isolation of impurities as a unit operation in the development process (output). 

P.J.Schoenmakers and M.Mulholland, An Overview of Contemporary Method Development in Liquid Chromatography, Chromatographia, 25(8) (1988) 737-748. 

Efficient methods of selection of admixed configurations in this approach are described in [12]. The computer code for generating the reduced configuration state list is presented in [13]. A special diagonalisation method is developed to reduce the orders of matrices to be diagonalised [14]. A more detailed overview of the methods considered may be found in [15]. All these improvements considerably speed up the calculations and widen the domains of applicability of the methods developed. 

In the following sections, different methods of establishing functional DNA-protein conjugates are discussed, following a short historic overview of IPCR method development. As IPCR offers additional advantages in addition to the obvious enhancement of sensitivity, the unique potential for multiplex detection and an increased linear quantification range of the method is introduced. We show how various ELISA types suitable for... 

This chapter is intended to be a practical overview of the liquid chromatography sorbents, instrumentation, and the various method development approaches used in pharmaceutical laboratories for both relatively small molecules and biomolecules. 

Usually, those who develop chromatographic methods rely on knowledge, experience and skill. This makes the field an especially hard one for newcomers to enter. The overview in this section provides an organized approach to method development, which is intended to introduce (relative) newcomers to the remainder of the book. Therefore, this section will contain many references to subsequent chapters and sections. 

Abstract This contribution focuses upon the application of evolutionary algorithms to the non-deterministic polynomial hard problem of global cluster geometry optimization. The first years of method development in this area are sketched briefly followed by a characterization of the current state of the art by an overview of recent application work. Strengths and weaknesses of this approach are highlighted by comparison with alternative methods. Last but not least, current method development trends and desirable future development directions are summarized. 

The remainder of this review is outlined as follows. The historical method development of EA use for global cluster geometry optimization is briefly recalled in Sect. 2. An overview of typical application work in recent years is provided in Sect. 3. In Sect. 4, we take a side glance at other methods to tackle the same and related problems, and briefly discuss advantages and disadvantages of some the prominent alternatives to EAs. Finally, in Sect. 5 recent method development work is summarized, and we try to give some (personal, biased) opinions on which open questions such developments should address in the future. 

We are not going into details of the above groups of procedures and shall limit ourselves to an overview of the main results of ordinary Rayleigh-Schroedinger perturbation theory for long range interactions first, and then of the methods developed in [40,41] to deal with short range interactions. 

---