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Enantiopure medicine: Chiral synthesis, separation & development

Valliappan Kannappan, Selvakumar Kanthiah
Wednesday, January 3, 2018, 08:00 Hrs  [IST]

Over the last decades 'drug chirality' has become an area of considerable interest since the enantiomers often exhibit stereoselective pharmacokinetic, pharmacodynamic and toxicological profile in a chiral environment (human body). In addition, drug regulatory agencies from USA, European Union, Canada, China and Japan insist on the development of enantiopure medicines. Hence, the enantiomerically pure drugs have been gathering ever-increasing attention in the drug discovery and development process.

The production of enantiopure drugs has potential value from the point of view of drug therapy and efficacy. There are basically three viable options for the production of enantiopure drugs viz., De novo development of enantiopure drug; Enantioselective release from chiral matrix and Chiral switching.

De novo development of enantiopure drug
In De novo synthesis of enantiopure chiral drugs basically three approaches are employed viz., (a) to start from a pure enantiomer of a natural product (chiral pool), (b) to employ a stereoselective synthesis (including enzymatic and biological procedures), and (c) to separate a race mate obtained from non-stereoselective synthetic protocol (chiral resolution) are considered.

In chiral pool synthesis, natural enantiopure compounds viz., amino acids, carboxylic acids and monosaccharides are included in the structure of the final product. This strategy is helpful if the desired molecule bears a great resemblance to enantiopure natural products. A stereoselective synthesis in which one set of stereoisomer is formed predominantly than the other. Stereoselective synthesis is traditionally known as asymmetric synthesis. It is classified into diastereoselective or enantioselective depends upon diastereomer or an enantiomer that is being produced. In stereoselective reactions, either chiral auxiliary or chiral reagent or chiral catalyst is included as a source of chirality.

Chiral auxiliaries are enantiomerically pure compounds and attached to substrate and influence the course of stereoselective reaction. A chiral auxiliary is a stereogenic group that is temporarily incorporated into an organic substance to control stereochemical outcome of the synthesis and also to control the absolute configuration of stereogenic centres. A chiral auxiliary aided stereoselective transformation involves three steps: initially, the auxiliary is covalently bonded to the substrate, then the resulting compound undergoes one or more diastereoselective transformations and finally the auxiliary is removed under conditions that do not cause racemization of the desired products. A stereoselective transformation with chiral auxiliaries allows most time-efficient access to enantiomerically pure products. A chiral reagent either includes all the necessary stereocentres or is used to control the introduction of new stereocentres. In some cases, chiral reagents are preferable over chiral auxiliaries as they function independent of the substrate’s chirality. A chiral catalyst directs the formation of one particular stereoisomer. Since the chiral catalyst is not consumed in reaction process it may be used in a sub-stoichiometric quantity - potentially improving efficiency and avoiding waste. The chemical correlation methods viz., X-ray crystallography, nuclear magnetic resonance (NMR) techniques and vibrational circular dichroism (VCD) are used in de novo development process to assess absolute configuration of chiral drugs.

Chiral resolution is a process of separation of racemic compounds into their component enantiomers. The enantioselective chromatographic techniques are the most commonly adopted techniques to separate racemate obtained by a non-stereoselective synthetic protocol. Liquid chromatographic techniques including high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), gas chromatography (GC), super fluid chromatography (SFC), and capillary electrophoresis (CE) are considered as the most useful tool in chiral separation. In last two decades, HPLC has become one of the mostly applied modality in the chiral resolution of different racemates. Several chiral stationary phases (CSPs) have been developed and used for the chiral resolution of a variety of racemates. The popular CSPs include pirkle types, cellulose or amylose polysaccharides, cyclodextrins and its derivatives, protein phases, chiral crown ethers and macrocyclic antibiotics. Among these, polysaccharides based CSPs are very important as they have achieved a great reputation in the ?eld of chiral separation.

The technique relying on HPLC coupled with CSPs offer certain advantages like no need to chemically manipulate the compound, method can be readily scaled to commercial production, and permits structure identification when coupling with MS or NMR. In addition, enantioselective chromatographic method has become the most time- and cost effective approach at the drug discovery stage.

Enantioselective release
Enantioselectively controlled release (ESR) of the desired enantiomer (eutomer) from a racemate by retarding the other isomer is another approach toward chiral drug development process. In this context, two major strategies viz., (i) start using chiral matrix (chiral excipients) and (ii) molecularly imprinted polymer (MIP) techniques, have been employed in the development of ESR. Excipients are traditionally used in many pharmaceutical dosage forms. A majority of the excipients employed in pharmaceutical dosage forms including the derivatives of cellulose, amylose, starch, sugars, and cyclodextrins etc. are optically pure form. These excipients found to play key role in the development of ESR. One of the to-be- released enantiomers favourably undergoes interaction with the chiral excipient resulting in the preferential diffusion of it. Currently, various synthetic polymers like biodegradable polymers, amino acid derived polymers, artificial chiral helical polymers, and chiral mesoporous silica have become much interest towards the development of novel chiral materials for ESR.

The second approach rely on molecular imprinting technique (MIP) involves create an enantiospecific cavity by excluding the chiral template, through which ESR could be achieved. MIPs provide specific recognition sites, especially in polymeric matrix. In most chiral MIPs, a single enantiomer is chosen as printing template. Functional monomers are arranged around the chiral template by non-covalent interactions, like hydrogen bonding, and ionic or hydrophobic interactions, to form a complex. The complex then undergoes copolymerization with a cross-linking monomer. After copolymerization and removing the template, recognition sites are generated towards the template for selective administration of the preferred enantiomer. The deliberate enantiospecific retardation/acceleration in the release of the enantiomers could be exploited for the design of enantioselective dosage forms.
 
Chiral switching
A chiral switching is the process of developing a single enantiomer from a previously marketed racemate with respect to desired and undesired pharmacological effects. As a result of advancement in chiral technology, number of racemic drugs has been re-developed into single enantiopure medicines (chiral switch). Recently, Indian companies actively engaged in the development of enantiopure medicines.

The development of unichiral drugs aided in possibly halving the racemic dose, less metabolic load, prevention of accumulation of inactive or less active enantiomer (distomer), lesser side effects, safer than the racemate and lesser potential for drug-drug interactions. In the development of enantiopure medicine, combination of de novo methods such as chiral pool, chiral resolution and stereoselective synthesis proved to supply broad variety of enantiopure compounds. The development of chiral delivery systems could be an alternate approach to enantiopure chiral drugs without the need for chiral synthesis or separation. Thus, these chiral development strategies will enable the production of enantiopure medicines that could improve the therapeutic efficacy and safety of chiral pharmaceuticals.  

(Valliappan Kannappan is professor of Quality Assurance (Retired), Dept. of Pharmacy, Annamalai University, Tamil Nadu 608 002 and Selvakumar Kanthiah is assistant professor, Acharya & BM Reddy College of Pharmacy, Bangalore 560 107)

 

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