Small Molecule Pharmaceutical Drugs

There are two distinct routes to the discovery of small molecule drugs (1) from natural products and (2) from rational design. 

Proponents of drugs from natural products argue that natural products provide a vast diversity of chemical compounds. These compounds with myriad chemical compositions and structures serve as reservoirs for many pharmacologically active lead compounds to be discovered. 

As described in Exhibit 3.2, there are now regulations enacted to protect the environment with respect to natural product collection. Bioprospecting from natural habitats has to take into account the 1993 Convention on Biologi- 

There are 34 fundamental phyla of life 17 occur on land and 32 in the sea (including some overlaps). More chemical diversity is found among marine hfe forms. Most of these are from invertebrate organisms— sponges, tunicates, and mollusks. Some of the compounds from marine life forms are extremely potent, given that these organisms have to defend themselves from attacks in vast volumes of water that dilute the compound. 

The range of climatic conditions, from tropical waters to cold arctic ocean, shallow continental shelves to great ocean depths with high pressure and low oxygen content, means that there is a potentially huge supply of life forms with extensive biodiversity. 

Hitherto, the normal source of collections has been from terrestrial habitats. However, marine bioprocessing represents a vast untapped area that is likely to be intensified. Exhibit 11.1 describes the diversity and life forms in this habitat. 

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There has been significant advancement in the applications of NMR to the development of small-molecule pharmaceutical products. For example, advances in NMR automation (e.g., flow-injection analysis) and directly coupled methods (e.g., LC-MS-NMR analysis) have made analysis and characterization of small-molecule drugs much easier.23 25 These improvements have helped chemists to develop and characterize small-molecule combinatorial libraries and to screen for active compounds.4 6 It is likely some of these techniques can also be used in biopharmaceutical product development. 

Though in competition with other analytical techniques, CE has proven its potential and necessity to be used for the characterization of small-molecule pharmaceuticals. Due to the versatility of the system, CE can be applied for the determination of physicochemical properties, identification, purity and stability analysis, and cleaning verification of the drug substance, its precursors, process chemicals, the drug product, and its excipients. 

A recent review on CE of small-molecule pharmaceuticals dedicates one part to the determination of drug-related impurities. ... 

While LIF monitoring is established in other manufacturing industries, it is relatively new within the pharmaceutical industry. The application of real-time intrinsic LIF for the manufacture of pharmaceuticals in general can be broken in to three areas (i) classic (small molecule) final drug product manufacturing (ii) biopharmaceutical prodnct manufacturing and (iii) factory operational applications. 

Drug manufacture. Enzymes are particularly useful when it comes to small-molecule pharmaceutical chemicals. This is because they are stereo-specific and are thus able to make... 

Purity determination is an essential component of the assessment of the quality of any drug. However, the purity determination of biopharmaceuticals is not as straightforward as for small-molecule pharmaceuticals because biopharmaceuticals are structurally complex and have a wide range of potential impurities. Approaches usually involve the judicious choice of a combination of methods that will enable the detection and quantitation of impurities from which an overall purity assessment can be made. CE-generated data now play a significant role in such purity assessments. 

Representative applications of small-molecule pharmaceuticals included in this section are antibiotics, barbiturates, flavonoids, vitamins, basic drugs, cold medicines, and corticosteroids. An MEKC method was validated according to... 

One straightforward approach for the introduction of stable-isotope-labeled peptides is to chemically synthesize them and add known quantities to the sample [299]. It extends to peptides with the well-established technique of stable isotope dilution, which is routinely used in pharmaceutical research for the quantification of small-molecule-based drugs. This approach is the most powerful and the most expensive available for absolute peptide... 

Enantiomericaiiy pure amines are commonly used as precursors for active pharmaceutical ingredients (APIs). In 2013, one in four of the top 200 selling drugs contained a chiral amine moiety [9]. In addition, chemical synthesis of these enantiomericaiiy pure amines is critical as 80% of small-molecule pharmaceutical dmgs approved by the FDA in 2006 contained chiral centers and 75% were single enantiomers [10]. Chiral amine compounds with high optical purities can be difficult to prepare by many types of traditional catalysts. 

One remarkable achievement of red biotechnology was that, although costs in drug development exploded, the costs for process development of manufacturing processes for proteins were reduced over time. This should also be the goal for small molecule pharmaceuticals, which represent the majority of active pharmaceutical ingredients (APIs). The sustainable production of affordable pharmaceuticals and health-care products should be a priority for biotechnology These objectives are... 

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