The Technology for Preparation of Generic (Monoenantiomeric) Antimalarial Drug Primaquine by Using Supercritical Fluid Chromatography. Separation of Primaquine from Quinocide: Simultaneous Resolution of the Enantiomers of Primaquine and Their Separation from Quinocide in One Run

Abstract

Malaria is one of the most harmful diseases on the globe. According to the World Health Organization (WHO), several million people die every year from malaria, and most of them are children. Hundreds of millions of fresh cases of malaria are registered by the WHO every year, and more than one-third of the earth's population lives in malaria-endemic areas. Primaquine is an important antimalarial drug because it has gametocytocidal properties and prevents relapse in most cases. However, primaquine is a highly toxic substance, especially to the Negroid race (in Africa, Australia and North, Latin and South America) and some others. Negroid male children are most vulnerable to the toxic effects of primaquine. The toxicity of primaquine can be enhanced in mixtures with other antimalarial drugs. In the present study, unprocessed primaquine and primaquine tablets highly contaminated with quinocide (I. Brondz, Historical Overview of Chromatography and Related Techniques in Analysis of Antimalarial Drug Primaquine (Editor I. Brondz), Nova Science Publishers, Inc. (2011) ISSN 978-1-61761-944-1) are discussed versus monoenantiomeric primaquine as a drug. The contamination of primaquine with quinocide enhances the toxicity of primaquine by additive or synergistic action. The use of contaminated primaquine can be harmful. Development of a useful antimalarial vaccine can take a decade or longer. This paper describes the possibility of preparing antimalarial generic monoenantiomeric primaquine, free of both quinocide contamination and the ineffective enantiomer of primaquine, using fractionation by supercritical fluid chromatography equipped with a new experimental High Resolution Isomer Column (HRIC). By this approach, it is possible to produce a significant amount of pharmacologically active enantiomer of primaquine at relatively low cost for a broad range of patients sensitive to contaminated primaquine. Leading pharmacopoeias should no longer deny the presence of the toxic contaminant quinocide in relatively high concentrations in unprocessed primaquine and in primaquine tablets. New standards for antimalarial primaquine diphosphate tablets must be adopted in pharmacopoeias and by the pharmaceutical industry.

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“…It is not possible by these reactions and UV spectroscopic measurements to differentiate the constitutional isomers or to quantify them correctly. Chromatographic or capillary electrophoretic methods must be used [3] [7] [8] [17]- [26]. In publication [28], the authors were well aware of the presence of isomers in their analytical procedure, because they previously published papers [2] [27].…”

“…Before presentation [3] and the following series of papers [7] [8] [17]- [26], the publication of papers such as [30]- [35] were partly excusable because of the absence of information about contamination with quinocide. After presentation of [3] [7] [8] [17]- [26], it is not acceptable for serious scientists to publish such data as [28]. The isomers undergo the same derivatization and give the similar UV spectra.…”

“…The biological consequences of primaquine contamination with quinocide were presented in 2011 [26]. All this information was presented over a significant period of time at international meetings, and in technical and scientific international journals and could not be missed by any serious scientist.…”

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“…The structure of primaquine is shown on Figure 4. Some of batches of primaquine are heavily contaminated with quinocide [1], [7]- [22]. Quinocide is more toxic than primaquine [1] the structure of quinocide is shown on Figure 5.…”

“…The main disadvantage of primaquine and all 8-aminoquinolines is that the drugs cause methemoglo- binemia, however the other toxic effects of primaquine and 8-aminoquinolines should not been overseen [1]. It should be mentioned that pure primaquine as pro analyses grade never was biologically tested out, the substance always was contaminated with quinocide [1] [7]- [22].…”