OPTICAL ROTATION

Carbon is the core element around which the chemistry of life- As the impact of chirality in the drug industry continues to grow, has evolved. Early chemists observed many instances of pairs of technologies to produce single enantiomer molecules are increas- organic compounds that have identical physical properties (exactly ingly important not only to the clinical success of the drug but also the same energy, solubility, boiling and melting points, NMR and IR to its commercial success as complex single enantiomer drugs are spectra, etc.). However, these pairs or compounds were considered often very expensive to manufacture. Specifications for the final as “optically active” since they were observed to rotate a beam of product need to assure identity, strength, quality and purity from the polarized light in equal amounts, but different directions. stereochemical perspective.

Organic molecules result from carbon bonding with four other mo- R. D. Laboratories, Inc. is ready to assist you in ensuring the quality ecules in a tetrahedral arrangement. Stereoisomers are molecules of your optically active pharmaceuticals and ingredients. We use that have the same molecular formula and the same connectivity polarimetery to evaluate the identity, purity and freedom from con- of atoms, but differ only in the three-dimensional arrangement of tamination by optical antipodes optically active materials. those atoms in space. A chiral molecule is non-superimposable on its mirror image, so that the mirror image is actually a different The magnitude of the optical rotation is affected by the concentra- molecule. tion of the solution, the length of the path of light, the wavelength of light and the temperature. The specific rotation [ ] is defined as Many biologically active molecules, including amino acids (the the observed angle of optical rotation when plane-polarized light is α building blocks of proteins), and sugars are chiral. In biological passed through a sample with a path length of 1 dm and a sample systems, most of these compounds are of the same chirality. All concentration of 1 g/mL. The specific rotation of a pure material naturally-occurring amino acids exist as only one of the two pos- is an intrinsic property of that material at a given wavelength and sible enantiomers, and so by extension, all proteins and enzymes temperature. are also chiral. R.D. Laboratories, Inc. utilizes a Rudolph Research Analytical Auto- The common way to refer to the chirality of a molecule is based on pol V with six wavelengths (325nm, 365nm, 405nm, 436nm, 546nm the direction that it rotates a plane of light. The clockwise direction and 589nm) and precise temperature control from 15°C to 30°C is termed dextorotary (d, or “+”) and the counterclockwise direction allows us to measure 99% of all optical rotation monographs found is levorotary (l or “-” ). The modern descriptors R and S or and do in the USP, EP, JP and BP. Non compendia determinations can be not define optical rotation but rather the orientation of bonding to a performed as well. α β chiral atom. Many “man made” compounds, including active phar- maceutical ingredients, have chiral centers and may be composed The Autopol V is one of the most accurate and precise of enantiomeric pairs or racemates often designated by ± or RS and digital polarimeters available with a resolution of have opposing rotation and no optical activity. 0.001º and reproducibility of 0.002º arc optical rotation. The polarimeter has been fully Drug regulatory authorities are paying particular attention to the validated (IQ/OQ/PQ) using NIST traceable potentially different pharmacological and toxicological profiles of calibration standards. enantiomers. The U.S. Food and Drug Administration (FDA) issued a policy regarding the development of new stereoisomeric drugs in 1992. Although the FDA leaves the decision to pursue a racemic or a single-enantiomer formulation of a new drug to its developers, it will likely be more difficult to obtain approval for racemates. The indus- try as a whole is interested in developing more potent, selective and specific drugs. In the last 10 years, approximately 80% of the small- molecule drugs approved by the FDA were chiral of which nearly 75% were approved as single enantiomer products.