Abstract
Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl5, BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N-dealkylation reaction. The thermal stability kinetics of the N-dealkylation process leading to MnTE-2-PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t90%) of MnTE-2-PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2-N-alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.
Highlights
Water-soluble, cationic Mn(III) porphyrins derived from the 2-N-pyridylporphyrin scaffold were originally developed as potent superoxide dismutase (SOD) mimics, peroxynitrite scavengers, and later proven to be efficient redox-active therapeutics [1,2,3,4,5,6]
In our previous studies on the thermal stability of MnTE-2PyPCl5 [28], we established that the thermogravimetric events of this Mn-porphyrin under dynamic air were associated with three major processes: (i) dehydration, (ii) Ndealkylation, and (iii) organic matter degradation to yield Mn oxide as the final residue at 900 or 950°C
The loss of ethyl chloride (EtCl) was characterized by gas chromatography-mass spectrometry (GC-MS) of the evolved gas (EtCl) and by characterization of the residue at 279°C, which was consistent with MnT-2-PyPCl by spectroscopic and chromatographic analyses [28]
Summary
Water-soluble, cationic Mn(III) porphyrins derived from the 2-N-pyridylporphyrin scaffold were originally developed as potent superoxide dismutase (SOD) mimics, peroxynitrite scavengers, and later proven to be efficient redox-active therapeutics [1,2,3,4,5,6]. Despite the large number of studies dedicated to unravelling the biological and clinical aspects of MnTE-2PyPCl5 both in vitro and in vivo [1, 16,17,18, 22], studies on the stability of this class of compounds are still somewhat limited [28,29,30] It is worth noting, that information on MnTE-2-PyPCl5 stability may shed light on the stability of other MnP analogues [28] and likely support protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds [31,32,33,34]
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