Pharmaceutical phase, concepts

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

MLC enables to analyse drugs and active phamiaceutical substances without using special column and lai ge quantity of organic solvents. So, from the point of view of pharmaceutical analysis ecology and green chemistry conception, assay with MLC using will be better than conventional reversed-phase chromatography. 

Note that our primary focus is on reversed-phase HPLC (RPLC) since it is the predominant mode for pharmaceutical analysis. Many of these concepts, however, are applicable to other modes of HPLC such as ion-exchange, adsorption, and gel-permeation chromatography. 

This chapter provides an overview of essential concepts in HPLC including retention, selectivity, efficiency, and resolution as well as their relationships with key column and mobile phase parameters such as particle size, column length and diameter, mobile phase strength, pH, and flow rate. The significance of several concepts important in pharmaceutical analysis such as peak capacity, gradient time, void volume, and limit of quantitation are discussed. 

Fig. 1. The Pharmaceutical Pipeline. The different phases of drug development are outlined, starting with a lead compound and moving forward through preclinical and clinical testing towards market approval. (CS candidate selection IND investigational new drug application POC proof of concept NDA new drug application FTIH first time in human).

It is intereshng that 12 of the previous 15 chapter authors in this book have menhoned the E factor, which shows how embedded the concept has become in the pharmaceutical industry. Eurthermore, in 2007 GlaxoSmithKline (GSK) became the first company to set E factor goals (or its equivalent, mass productivity ) across its phase-three development compounds and to pubhsh those goals on... 

The legal games that are played over patents and pharmaceuticals are dizzying, and the impact of patents is present throughout all phases of a drug s development. At the outset of this chapter were mentioned the ideas of cocrystals and polymorphs. These concepts... 

Many companies use the same cleaning procedure for all products (i.e., a generic cleaning procedure). This one size fits all concept may work well for men s socks, but it does not work well for the cleaning of pharmaceutical products, some of which may require considerable effort to effectively and adequately clean. The development of cleaning procedures should be product-specific and ought to receive the same consideration during the development phase as the formulation for the new product. 

Many pharmaceutical preparations contain multiple components with a wide array of physico-chemical properties. Although CZE is a very effective means of separation for ionic species, an additional selectivity factor is required to discriminate neutral analytes in CE. Terabe first introduced the concept of micellar electrokinetic capillary chromatography (MEKC) in which ionic surfactants were included in the running buffer at a concentration above the critical micelle concentration (CMC) [17], Micelles, which have hydrophobic interiors and anionic exteriors, serve as a pseudostation-ary phase, which is pumped electrophoretically. Separations are based on the differential association of analytes with the micelle. Interactions between the analyte and micelles may be due to any one or a combination of the following electrostatic interactions, hydrogen bonding, and/or hydro-phobic interactions. The applicability of MEKC is limited in some cases to small molecules and peptides due to the physical size of macromolecules... 

Thermodynamics is a branch of physical chemistry that deals quantitatively with the inter-exchange of heat and work evolved in physical and chemical processes. This subject is widely utilized to explain equilibrium systems in physical pharmacy. For example, a pharmaceutical scientist may use equilibrium thermodynamics to study isotonic solutions, solubility of drugs, distributions of drugs in different phases, or ionization of weak acids and weak bases. Even though the gas laws are not usually directly related to pharmaceutical science (with some exceptions such as aerosols), these concepts must be introduced when dealing with simple thermodynamic systems of gases and the universal gas constant, R. 

The changes in retention and selectivity can also be exploited in the thermally tuned tandem column concept by Mao and Carr [25], in which the temperatures of two sequentially linked columns containing different stationary phases can be altered to provide the optimum separation. The technique was applied to the separation of barbiturates, phenylthiohydantoin amino acids [26], and selected basic pharmaceuticals, such as antihistamines (Figure 18-1) [27]. 

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