Overview on Chirality and Applications of Stereo - selective Dissolution testing in the Formulation and Development Work

Introduction Chiral molecules exist in a pair of stereoisomers (enantiomers). If a plane of polarized light is passed through a sample of each enantiomer, one will rotate the light to the left (levorotatory or (-)-enantiomer or R-form),and the other will rotate the light to the right (dextrorotatory or (+)-enantiomer or Sform). Rotation of light will not be observed if the light is passed through an equimolar mixture (racemic mixture). Scientists have started using prefixes such as lev(e.g. levibuprofen),dex(e.g. dexmethylphenidate),ar(e.g. arbupivacaine) and es(e.g. esomeprazole) to describe enantiomerically pure active pharmaceutical ingredients (API). A glossary of the selective terms related to stereochemistry is given in Table 11. Rentsch2 reported that about 56% of the synthetic drugs currently in use are chiral compounds,and 88% of these chiral synthetic drugs are used therapeutically as racemates. However,the recent trend in industry is to market the drugs in a pure enantiomeric form to give new life to old drugs by patenting the pure enantiomer. Stephen3 reported that a worldwide sale of chiral drugs in single enantiomer was $133 billion in 2000. Forty percent of all dosage form drug sales in 2000 were of a single enantiomer. In 1999, the share was only one third. The advantages of marketing the drug in pure enantiomeric form are shown in Table 24. Racemic switch or chiral switch means that racemic mixtures are redeveloped as single enantiomers3. Abstract The importance of chirality is considered in various areas such as purchasing of active pharmaceutical ingredient,selection of adjuvants in dosage form development, in vitro dissolution studies,stability studies, in vitro/ in vivo correlation (IVIVC),dossier preparation for technology transfer,ANDA/NDA applications and in scale up and post approval changes (SUPAC). The use of chiral selective dissolution testing is recommended for certain drugs that exist in racemic form in order assess the performance of a product,both in vitro and in vivo. An extension of the Biopharmaceutics Classification System (BCS) is suggested for drugs that undergo chiral conversion after permeation through gastrointestinal wall, taking into account that the amount of active form of the drug reaching the receptor site is more important. It is suggested that the shelf life for chiral drugs shall be determined by considering the amount of degradation of the active form (R or S) of the drug. This paper also gives a brief overview of work done on chirality from the viewpoint of formulation of dosage forms. email correspondence to: [email protected]