Chiral compounds drugs

The quality of a drug substance is controlled by its specification. An internationally harmonized guideline on specifications and tests for chemical substances as active ingredients and in drug products makes reference to chiral compounds. This has recently been finalized and is discussed in Section 13.5.2. 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

Nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research has been used primarily in a classical, organic chemistry framework. Typical studies have included (1) the structure elucidation of compounds [1,2], (2) investigating chirality of drug substances [3,4], (3) the determination of cellular metabolism [5,6], and (4) protein studies [7-9], to name but a few. From the development perspective, NMR is traditionally used again for structure elucidation, but also for analytical applications [10]. In each case, solution-phase NMR has been utilized. It seems ironic that although —90% of the pharmaceutical products on the market exist in the solid form, solid state NMR is in its infancy as applied to pharmaceutical problem solving and methods development. 

The ideal solubility equation has significant value in chiral systems, where a single enantiomer is desired as the product [20]. The behaviour of chiral compounds is very important in biological systems and in drug development, where it is typical for just one enantiomer of an API to be biologically active. The undesired enantiomer may be inert, or possess more serious toxicity effects, as in the case of Thalidomide. Many enantiomeric systems form three discrete solid phases, depending on the solution concentration. Pure crystals of each enantiomer will form at high concentrations of their respective enantiomer. At... 

The resulting drug substances, called active pharmaceutical ingredients (APIs), are recovered and purified from solvents. More recent methods aim to isolate chiral compounds to improve drug-target interactions. 

Cyclic amines (including local anesthetic drugs) and amides were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], and ristocetin A [33] CSPs, under RPmode systems. Cyclic imides (including barbiturates, piperidine-2,6-diones, and mephenytoin) have been separated on a vancomycin CSP [157], under NP and RP mobile phase conditions. 

Lelievre and Gareil (31) studied chiral separations of nonsteroidal anti-inflammatory drugs (carprofen, flurbiprofen, indoprofen, ketoprofen, naproxen, propafenone, and suprofen) and determined the acidity and inclusion complex formation constants of these chiral compounds with different neutral CDs (/3-CD, HP-/3-CD, DM-/3-CD, TM-/3-CD, and HP-y-CD). In... 

Although about 40% of drugs are chiral compounds, only about 12% of drugs are administered as pure single enantiomers. This situation is gradually changing as a number of companies have now started to move towards producing enantiomerically... 

Wellbutrin and Zyban are marketed as a racemic mixture of bupropion as its hydrochloride salt. However, over the past 15 years there has been an increasing trend to develop new drugs as single enantiomers. Several publications have demonstrated that the enantiomers of many chiral compounds have distinct pharmacological profiles and the benefits in using a single enantiomer over the racemate... 

Separations of enantiomers can be achieved by chiral chromatography. Even, when the enantioselective synthesis of drugs and pharmaceuticals is possible, a major part of chiral compounds is still produced as a racemate and needs to be separated into the enantiomers by chiral high performance liquid chromatography. 

Drugs classified as either natural or semisynthetic in origin accounted for - 22% of the market share in 1991. Nearly 94% of the agents are chiral compounds and are sold as single enantiomers. Chiral synthetic... 

The last example reflects in a modest way the importance of the study of stereoisomerism. Biological conversions represent a glorious array of diastereomeric reactions and interactions a given chiral amino acid is metabolized but its enantiomer is not a certain complex drug (often a chiral molecule) alleviates pain but its enantiomer is inactive and subdc changes in structure alter a given chiral compound s action completely in the human body. 

User s Guide Separation of Chiral Drugs and Other Chiral Compounds on Chiral-AGP, Chiral-CBH and Chiral-HSA, Chrom Tech, Hagersten, Sweden (1994). 

A number of the new drugs under development are chiral. The two main reasons for this choice by pharmaceutical companies are the regulatory constraints to assess the properties of single enantiomers, even if the racemic mixture is developed, and the scientific evidence that enantiomers often have very different and, sometimes, opposite pharmacologic effects. Among the numerous techniques available today to industrial chemists, asymmetric synthesis has been used successfully to obtain chiral compounds. From an industrial point of view, asymmetric catalysis is becoming the preferred approach because of its low environmental impact and high potential productivity. 

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