Chiral excipients

Oral liquids Solubility, polymorphic conversions, chirality, excipient interactions, chemical stability, photostability, pH effects, and container interactions (e.g., type III glass). 

Similar to the solid dosage forms containing chiral excipients, biological membranes may provide chiral environments (see Chapter 3). Most drugs cross the gastrointestinal membrane through simple passive diffusion thus, no stereoselectivity in the process is expected. It appears. 

Many pharmaceutical excipients consist of chiral molecules. The common chiral excipients are listed in Table 3 [54]. When a chiral excipient is used in a formulation, the dissolution rate of the opposite enantiomers may differ, because the interactions between the excipient and each enantiomer are diastereomeric and may therefore differ. In the field of chromatography, the different strengths of the diastereomeric interactions form the basis of enantiomeric separation on a chiral column. Because the opposite enantiomer may exhibit different pharmacological, toxicological, or pharmacokinetic properties, it is of practical value to compare the release rate of the opposite enantiomers from a formulation containing a chiral excipient. 

Table 3 List of Common Chiral Excipients and Their Applications in Pharmaceutics... 

Maggi, L. Massolini, G. De Lorenzi, E. Conte, U. Caccialanza, G. Evaluation of stereoselective dissolution of verapamil hydrochloride from matrix tablets press-coated with chiral excipients. Int. J. Pharm. 19%, 136,43-52. 

Janjikhel, R.K. Adeyeye, C.M. Dissolution of ibuprofen enantiomers from coprecipitates and suspensions containing chiral excipients. Pharm. Dev. Tech. 1999, 4, 9 17. 

Use of Chiral Excipients in Formulations Containing Chiral Drugs... 

Chiral excipients have been widely used in pharmaceutical dosage forms. A selected list of commonly used excipients along with their major applications is shown in Table 1. The interactions of chiral excipients with drugs and their influence on the therapeutic outcomes have not been thoroughly investigated. This may be due to the misconception that excipients are... 

Table 1 Selected Chiral Excipients and Their Pharmaceutical Applications...

In light of the current trend and rationale for the development of optically pure enantiomeric drugs, one can also make a case for the development of single isomers for chiral excipients when one stereoform of an excipient confers superior attributes to the dosage form over its antipode, which may be translated as unique benefits for the drug product. As an example, only the l-l isomer of aspartame (A-aspartylalanine methyl ester) is marketed as artificial sweetener or sugar substitute with potential... 

Optical Activity. Optical activity is the most characteristic index of optical purity in cases where the chiral excipients are suspected to be enantiomerically impure. Chiral excipients with no observable optical activity are assumed to be in a 1 1 ratio of enantiomers (racemates). However, the measurement may be accidental due to the storage conditions (such as temperature and medium) in which the determination was done, which could lead to changes in optical activity [15]. In such cases, the sample is not considered racemic but is said to be cryptochiral [16]. 

Attempts have been made to determine enantiospecific differences between enantiomers and racemates in solution using microcalorimetry [29]. The microcalorimetric method can be used to understand the magnitude of stereoselective interactions that could result from the mixing of solutions of enantiomers of a chiral excipient. The heat evolved or heat of solution (A/T ° ) is measured for the racemate as well as the enantiomers and could be indicative of enantioselective discrimination. However, Horeau and Guette [30] reported that enantioselective interaction in an aqueous medium measured using microcalorimetry may be inconsistent and flawed because of the insufficient purity of the optically active samples used and the insensitivity of the measurement relative to small differences in magnitude of the observed effects. 

Chromatography. Chromatography (HPLC, GC, and TLC) is commonly used in characterization of chiral drugs and has consequently been used in the evaluation of chiral excipient-drug interactions. Many authors have used HPLC to study stereoselectivity between chiral excipients and drugs [3,8,9,40-42]. The columns used in these studies range form octa-desylsilane to chiral selectors such as Chiral AG and molecularly imprinted stationary phases. 

STEREOSELECTIVE INTERACTIONS OF CHIRAL EXCIPIENTS WITH STEREOISOMERIC DRUGS... 

Understanding of the stereochemistry of chiral excipients and its implications on product performance can be beneficial in developing formulations of chiral drugs, and it may answer some of the questions raised in previous sections. A relevant discussion on selected chiral excipients and examples of stereoselective interactions between the excipients and chiral drugs is presented here. 

Dipeptides and Polymeric Di- and Tripeptides. Aspartame is a polymeric dipeptide with a specific rotation of -1-14.5° to -1-16.5° [68]. Stereoselective differences in organoleptic properties of aspartame have been documented. Methyl esters of some dipeptides such as alanylalanine and tryptophylalanine have been reported to interact stereoslectively with p-CD. Since these peptides can serve both as active ingredients and as excipients, possible chiral excipient irug or exdpient xdpient interaction should be investigated. 

In the future, the choice between developing the racemate of a chiral drug versus single enantiomers will largely depend on a critical evaluation of their chiral characteristics with respect to their pharmacodynamic, pharmacokinetic, and toxicological effects. The potential for stereoselectivity in skin permeation due to stereochemical interactions between chiral drug, chiral excipients, and the biomembranes has generally been overlooked. Nevertheless, extrapolation of enantioselectivity in the permeation of enantiomers from in vitro data to in vivo behavior (permeation, disposition, and efficacy) is important and should be carried out carefully. 

Because many of the pharmaceutical excipients used in the formulation of racemic drugs are chiral and optically pure, there is a potential for the stereoselective interaction of the enantiomers with the chiral matrix included in the formulation. For example, enantioselective pH-dependent release of tiaprofenic acid enantiomers from a sustained release formulation containing microcrystalline cellulose has been reported [260]. The differential release of tiaprofenic acid enantiomers, however, did not alter the pharmacokinetics of the individual enantiomers in rats. The possible effects of chiral excipients on the stereoselective release of racemates are discussed in a separate chapter in this book. 

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