Chirality is very important in the pharmaceutical field [1–3]. Chirality (sometimes called stereoisomerism, enantiomerism or dissymmetry) is a property of an object which renders it non-superimposable with its mirror image [2–8]. Chiral medicines are those medicines with a stereogenic center (often called an asymmetric carbon) and exhibit chiral properties [1–4]. Most pharmacological processes present a high degree of stereoselectivity which results in differences between the activities of the enantiomeric forms of chiral medicines [4, 7, 9, 10]. It is well known that a racemic mixture consists of an equimolar mixture of two enantiomers of the same chemical structure [9]. Enantiomers in some chiral medicines may exhibit marked differences in biological activities such as pharmacology, toxicology and pharmacokinetics [7, 9, 11, 12]. One enantiomer may be active while the other inactive, and may produce side-effects and/or exhibit toxicity [6, 9, 13, 14]. The use of racemic mixtures may present problems, such as adverse effects or toxicities particularly if they are associated with a less active, or inactive isomer [9, 15, 16].
There are many examples of chiral medicines whose enantiomers vary drastically in their properties. A well-known example of enantiomer related toxicity is the (R)- and (S)-enantiomers of thalidomide [1, 2, 4, 9]. The (R)-enantiomer of thalidomide is an effective sedative agent while, the (S)-enantiomer is known to cause teratogenic birth defects [1, 4, 9]. These defects included phocomelia, a severe shortening or lack of limb structures [9]. Ibuprofen, a painkiller has (S)-enantiomer with desired pharmacological activity while the (R)-enantiomer is totally inactive [1, 3, 17]. (R)-Naproxen is used for arthralgia pain while (S)- Naproxen is teratogenic [2]. Ofloxacin has a chiral mixture of levofloxacin [(S)-Ofloxacin] and dextrofloxacin [(R)-Ofloxacin], in which levofloxacin is 8-128 more active than dextrofloxacin [18]. So far, many chiral medicines are still used as racemates.
Worldwide, there is no mandatory regulatory requirement to enforce the development of new medicines exclusively as pure active single enantiomers [14, 19]. Some regulatory agencies leave the decision of a racemate or a single enantiomer formulation of a new medicine to the manufacturers [4, 14, 20]. However, the choice to make a racemic mixture versus a single enantiomer formulation must be justified based on quality, safety and efficacy together with the risk-benefit ratio between the two forms [4, 14, 20]. Due to the lack of regulatory requirements and increased technological developments, the number of new chiral entities as a pure active single enantiomers is increasing [5, 16]. This contribute to the availability of both single enantiomers and racemic mixtures circulating on the market particularly in developing countries such as Tanzania [5, 16]. Nonetheless, it has been reported that some manufacturers are marketing more single enantiomers of the old racemic drugs as a new drug; this is known as chiral switch, and has claims of greater activity, less toxicity or both [1, 5]. In addition, chiral switches have also contributed to a number of agents being commercially marketed as both single enantiomer and racemic mixture [4, 21].
Few studies conducted in some developed countries such as United States of America (USA) and Japan revealed that more single enantiomers are approved compared to racemates. [19, 22]. In the period between 2001 and 2011, the United States Food and Drugs Administration (USFDA) approved registration of 15 single enantiomeric medicines. These medicines showed improved therapeutic index through increased potency, selectivity and decreased side-effects [22].
A review of chiral medicines approved for use in Japan was conducted between 2001 and 2003 and the results indicated an increased trend towards development of single enantiomer medicines [19]. During that period, Japan approved 3 types of chiral medicines that were classified as single enantiomer (48%), racemic (13%) and achiral (39%). It is notable that single enantiomer medicines were produced three times more than racemic medicines [19].
In developing countries, little attention has been given on the importance of chiral medicines [23]. Some guidelines for submission of technical documents for medicines registration particularly in Africa have included the requirement for submission of evidence of the occurrence of isomers, chirality or polymorphorphism [24, 25, 26]. However, there is no requirement for the development of either single enantiomer medicines or racemic mixtures [6, 24, 25, 26]. The decision regarding the development of a single enantiomer or racemic mixture is left to the manufacturers [25]. Moreover, there is no need for manufacturers to give justification on to why they have decided to formulate single or racemate medicines [25, 26]. In addition, National Medicines Regulatory Agencies (NMRAs) in African countries have not set systems to conduct assessment of registered medicines to establish their chirality. Consequently, there is lack of information on the chirality status of registered medicines circulating on the market within the African region including Tanzania.
One of the functions of the Tanzania Medicines and Medical Devices Authority (TMDA) is to register quality, safe and effective medicines [27]. Since its establishment many human medicines have been approved of which some are chiral medicines [28]. However, their chirality status (single enantiomer or racemic mixtures) is not known. It is important to know the chirality status of medicines circulating on the market as such products may cause adverse effects to the users [1, 4, 9, 15, 16]. Therefore, this study aimed to establish the chirality status of registered human medicines in Tanzania. Additionally, it was considered valuable to know the pharmacological groups of registered chiral medicines and their availability in the essential medicine list. The findings can provide common understanding of the status of chiral medicines between manufacturers and regulatory authorities. This will facilitate improvement during development of chiral medicines and also the regulatory requirements.