Chiral purity ingredients

Much of the knowledge needed for manufacturing a pharmaceutical is related to the last step in the process, including understanding the bulk active ingredient, its impurity profile, chiral purity, and crystal form. To cut down the entire scale-... 

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

PLATE I Determination of the enantiomeric purity of active pharmaceutical ingredient (main compound = MC, peak I is the enantiomeric impurity). Conditions lOOmM sodium phosphate buffer pH = 3.0, lOmM trimethyl -cyclodextrin, 60 cm fused silica capillary (effective length 50 cm) X 75 pm I.D., injection 10 s at 35 mbar, 25°C, 20 kV (positive polarity) resulting in a current of approximately lOOpA, detection UV 230 nm. The sample solution is dissolved in a mixture of 55% (v/v) ethanol in water. (A) Typical electropherogram of an API batch spiked with all chiral impurities, (B) overlay electropherograms showing the selectivity of method toward chiral and achiral impurities, a = blank, b = selectivity solution mixture containing all known chiral and achiral compounds, c = API batch, d = racemic mixture of the main compound and the enantiomeric impurity. 

A more detailed discussion of the stationary phase types and mechanism of interaction and separation theory in relation to chiral compounds is given in Chapter 22. A large number of chiral stationary phases are currently available to meet the needs of the pharmaceutical industry for determination of the enantiomeric purity of active pharmaceutical ingredients, raw materials, and metabolites. As a consequence, there are a multitude of options in terms of columns, separation mode, and separation conditions to explore in achieving an enantioseparation. 

The addition of a chiral crown ether [(+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid] to the background electrolyte allowed Blanco and Valverde [147] to separate the enantiomers of benser-azide and determine the enantiomeric purity of Dopa (3,4-dihydroxyphenyl-alanine). Levodopa is the main active ingredient in the pharmaceutical formulation Madopar , which is used to treat Parkinson s disease, while dextradopa causes unwanted side effects. The dextradopa impurity was clearly resolved from the main peak and determined to be 0.5%. 

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. 

Health authorities worldwide have fixed purity requirements for active pharmaceutical ingredients (APIs). When applied to chiral drugs, this implies that, if one enantiomer is chosen to be developed and marketed as an API, the counterpart isomer will be considered an impurity. The rule affects new chemical entities (NCEs) and chiral dmgs previously commercialized as a racemic mixture chiral switches). Therefore, techniques to perform the analytical control of the enantiomeric composition, at any of the drug development steps, together with processes to produce enantiomeric compounds with the desired enantiomeric purity, are essential in this domain. Liquid chromatography using chiral stationary phases (CSPs) is applied at two levels, analysis and production of enantiomerically pure compounds. At present, it can be considered the most universal technique for enantiomer separation. 

Following asymmetric synthesis or chiral separation, further chiral purification is often needed to increase the enantiomeric excess (ee). This occurs often in the pharmaceutical industry because of the requirement for high purity of active pharmaceutical ingredients (APIs). Enantioenrichment by crystallization is therefore an integral part of chiral separation. 

---