Photoreactivity of biologically active compounds. XIX: Excited states and free radicals from the antimalarial drug primaquine

The formation and reactivity of excited states and free radicals from primaquine was studied in order to evaluate the primary photochemical reaction mechanisms. The excited primaquine triplet was not detected, but is likely to be formed with a short lifetime (< 50 ns) and with a triplet energy < 250 kJ/mol as the drug is an efficient quencher of the fenbufen triplet and the biphenyl triplet, and forms 1O2 by laser flash photolysis (PQΦΔ = 0.025). Primaquine photoionises by a biphotonic process and also forms the monoprotonated cation radical (PQH2+•) by one electron oxidation by OH• (kq = 6.6•109 M-1s-1) and Br2•- (kq = 4.7•109 M-1s-1) at physiological pH, detected as a long-lived transient decaying essentially by a second order process (k2 = 7.4•108 M-1s-1). PQH2+• is scavenged by O2, although at a limited rate (kq = 1.0•106 M-1s-1). The reduction potential (E°) of PQH2+• / PQH+ is < +1015 mV. Primaquine also forms PQH2+• at pH 2.4, by one electron oxidation by Br2•- and proton loss (kq = 2.7•109 M-1s-1). The non-protonated cation radical (PQ+•) is formed during one electron oxidation with Br2•- at alkaline conditions (kq = 4.2•109 M-1s-1 at pH 10.8). The estimated pKa-value of PQH2+•/ PQ+• is pKa ~ 7-8. Primaquine is not a scavenger of O2•- at physiological pH. Thus self-sensitization by O2•- is eliminated as a degradation pathway in the photochemical reactions. Impurities in the raw material and photochemical degradation products initiate photosensitized degradation of primaquine in deuterium oxide, prevented by addition of the 1O2 quencher sodium azide. Photosensitized degradation by formation of 1O2 is thus important for the initial photochemical decomposition of primaquine, which also proceeds by free radical reactions. Formation of PQH2+• is expected to play an essential part in the photochemical degradation process in a neutral, aqueous medium

Photosensitive drugs: a review on their photoprotection by liposomes and cyclodextrins.

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the development of methods aimed to protect molecular integrity and therapeutic activity of drugs from effects of light. The photostability characterization is ruled by ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details throughout basic protocols of stability tests to be performed on new medicinal products for human use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufacturing and for human healthy as well, since light exposure may affect either drugs or drug formulations giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping the molecules in a hollow of their structure by weak noncovalent interactions and protecting them from light. The best known supramolecular matrices belong to the 'auto-assembled' structures, of which liposomes are the most representative, and the 'host-guest' systems, of which cyclodextrins represent the most common 'host' counterpart. A relevant number of papers concerning the use of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over the last 20 years, demonstrating that this topic captures interest in an increasing number of researchers