Characterization of Pharmaceutical Materials by Thermal and Analytical Methods

Morphological and thermodynamic transitions in drugs as well as their amorphous and crystalline content in the solid state have been distinguished by Thermal Analytical techniques, which include dielectric analysis (DEA), differential scanning calorimetry (DSC), and macro-photo-micrography. These techniques were used to establish a structure vs. property relationship with the United States Pharmacopeia (USP) standard set of active pharmaceutical ingredients (API). DEA measures and differentiates the crystalline solid (low; 10¿¿¿¿¿ pS/cm) and amorphous liquid (high; 10¿¿¿ pS/cm) API electrical ionic conductivity. DEA ionic conductivity cycle establishes the quantitative amorphous/ crystalline content in the solid state at frequencies of 0.1 - 1.00 Hz and to greater than 30 ¿¿C below the melting transition as the peak melting temperature. This describes the “activation energy method”. An Arrhenius plot, log ionic conductivity vs. reciprocal temperature (1/K), of the pre-melt DEA transition yields frequency dependent activation energy (Ea, J/mol) for the complex charging in the solid state. The amorphous content is inversely proportional to the Ea. Where, Ea for the crystalline form is higher and lower for the amorphous form with a standard deviation of ¿¿ 2%. An alternate technique has been established for the drugs of interest based on an obvious amorphous and crystalline state identified by macro-photomicrography and compared to the conductivity variations. This second “empirical method” correlates well with the “activation energy” method. A comparison of overall average amorphous content by the empirical method had a linear relationship with the activation energy method with a correlation coefficient of R¿¿ = 0.925. Additionally, new test protocols have been developed which describe the temperature and material characterization calibration of thermal analyzers with pharmaceuticals. These test protocols can be blended into a universal standard protocol for DSC, DEA and thermomechanical analysis (TMA). While calibrating DSC, a thermodynamic transition i.e. a change in heat flow, is marked by absorption (or release) of energy by the calibrants; for DEA, at the melt transition temperature, an abrupt change in DEA permittivity is observed; for TMA, at the transition temperature of the test specimen, there is a change in dimensional stability and a measured change in the coefficient of thermal expansion or contraction/softening is recorded. These test protocols were accomplished based on “The ASTM standard test methods for temperature calibration of thermal analytical methods”. The R¿¿ correlation value of the calibrants for known standard literature transition temperatures vs. DSC melting peak temperatures, DEA Permittivity melting temperatures and TMA extrapolated onset-melting temperatures was 0.999.Next, drug salts were investigated by DEA in order to evaluate ionic conductivity in pharmaceuticals. The ionic conductivity varied by several orders of magnitude in the amorphous form of the drug salt. The drug salts have an enhanced DEA ionic conductivity due to their ionic mobility of the salt component in the liquid phase. The primary aim of this study is to investigate the thermal and electrical behavior of pharmaceutical hydrochlorides using DEA and DSC techniques. From these analyses we can predict the quality, stability and behavior of a drug salt. This study also provides a comprehensive characterization of ionic conductivity and molecular mobility (related to tan delta in DEA) properties in pharmaceutical salts through the measurement of the characteristic activation energies Ea (k) and Ea (¿¿) as well as polarization times (¿¿). The typical ionic conductivity of a melted drug, i.e. the amorphous phase, is 10¿¿¿ pS/cm and for the salt it is higher than 10¿¿¿ pS/cm. It is our opinion that a quality and a stable drug salt form will have a high ionic conductivity of >10¿¿¿ pS/cm. The DEA properties described here can be further developed to estimate the storage stability or shelf life of the drug salts by activation energies and polarization times. Salts with advantageous properties are typically patentable as new chemical entities. Electro synthesis is suggested for future drug development with the high ionic conductivity of the salts, >10¿¿¿ pS/cm to aid reaction kinetics to form new complexes or modified salts.The dielectric science developed to understand the crystalline and amorphous components in pharmaceuticals would be validated by calorimetry, X-ray diffraction and scanning electron microscopy. It has been established that the crystalline and amorphous content measured by the DEA activation energy method is related to the DSC melting, glass-transition profile as well as the crystal structure by X-ray diffraction and scanning electron microscopic images.