Analisi per la valutazione della stabilità dei farmaci

La continua evoluzione della terapia, intesa come scoperta e immissione sul mercato di sempre nuovi farmaci d’incrementata attività ed efficacia, ha esaltato l’importanza che hanno lo studio e la formulazione dei preparati farmaceutici con particolare attenzione alle problematiche connesse alla loro stabilità e possibile stabilizzazione. Un confronto tra le Farmacopee: italiana, britannica, statunitense e danese, mostra che i criteri adottati nel trattare il problema della stabilità sono spesso sostanzialmente divergenti tanto nelle indicazioni che nelle prescrizioni e limitazioni temporali. Riguardo a tali problematiche negli anni recenti sono state intraprese molte importanti iniziative, sia in ambito legislativo che industriale, allo scopo di promuovere l’armonizzazione a livello internazionale dei dati di stabilità richiesti per la registrazione dei prodotti farmaceutici.
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The purpose of the present work is to illustrate the application of a new methodology for analysing drug’s stability. The procedure allows a considerable saving in terms of time, substances and reactives comparing to the classic isotherm conditions.
The sympathomimetic molecule of (-)adrenalin has been adopted as a model, since it was shown that the eudismic ratio between the two enantiomeric forms can reach values of 40 and more regarding to pharmacological activity. The drug can easily undergo to racemisation and this process is strongly dependent on the temperature, as well as on the hydrogen ion concentration.
The procedure consists of the application of a new mathematic algoritm to data obtained from a single experiment performed at variable temperature by means of which it is possible to obtain the values of k (kinetic constant of the reaction) as a continuous curve in the range of temperatures considered and to extrapolate to values outside of that range.
It is possible besides to calculate the termodynamic changes related to the achieving of the activate-state of the reaction (enthropy, enthalpy and free-energy).
In this work the racemisation of adrenaline is investigated as a function of temperature, by following the change in optical rotation by means of an “optical nulle” polarimeter.
All experiments have been carried out in strong acid solution (pH 0) of adrenalin (conc. 1%) in hydrocloridric acid. Previous papers have shown that in so acid a medium no oxidation can actually occur, so that we can merely consider the phenomenon of pure racemisation, which takes place according to the laws for a monomolecular process.
Kinetics measurements have been performed at the temperatures of 323, 333, 343 K and the values of k, DH#, DS# and DG# obtained by means of the Eyring equation have been compared to those obtained by a single experiment performed between 313 and 343 K (rate of increasing temperature: 1.663 mK/s). Data obtained in the latter conditions were in perfect agreement with those achieved by the classical methodology confirming the reliability of the new tecnique.
Experiments have been successfully repeated by varying temperatures’ range, in order to test robustness.