Browsing by Subject "Excipients"

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    Excipient phase behavior in the freeze-concentrate
    (2013-06) Burcusa, Michael R.
    Development of robust protein formulations is of paramount importance to the pharmaceutical industry. Traditionally, the development of such products has been an empirical exercise. Efforts should be taken to transition lyophilization R&D away from an empirical exercise and towards an evidence-based science. This thesis will (i) document the pH shift in frozen buffer (sodium phosphate) - sugar (sucrose or trehalose) systems at different buffer and sugar concentrations, (ii) evaluate solute crystallization in these frozen systems using synchrotron radiation, (iii) investigate the thermal behavior (glass transitions) by differential scanning calorimetry with the goal of identifying the two freeze concentrate populations and, (iv) use IR spectroscopy to characterize the two populations and specifically the complexation between trehalose and the buffer components in the two populations.
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    Physical Stability Of Pharmaceutical Salts And Cocrystals In Drug Product Environment
    (2018-04) Koranne, Sampada
    A developmental risk associated with pharmaceutical salt and cocrystal forms is their propensity to undergo unintended disproportionation, resulting in reversion to the corresponding free drug and counter-ion (as in a salt) or coformer (as in a cocrystal). This can negate the solubility, stability and bioavailability advantages conferred by salt (or cocrystal) formation. The central goal of this thesis work was to gain a comprehensive mechanistic understanding of the influence of formulation components (specifically excipients) and processing conditions (including storage) on solid-state stability of salts and cocrystals. Disproportionation of pioglitazone HCl in tablets and indomethacin sodium in lyophilized formulations were investigated. In tablets, the disproportionation reaction, mediated by water, was attributed to the microenvironmental acidity “experienced” by the salt. The nature and concentration of the formulation excipients influenced the microenvironmental acidity. The in situ tablet mapping experiments, by synchrotron X-ray diffractometry (SXRD), revealed that the disproportionation reaction was initiated at the tablet surface and progressed towards the tablet core. In lyophilized formulations, disproportionation of a soluble salt (indomethacin sodium) to an insoluble free acid occurred because of selective crystallization of a buffer component and the consequent pH shift during freeze-drying. A complex interplay of the indomethacin sodium and buffer concentrations dictated the salt stability in the final lyophile. The second part of the thesis focused on excipient-induced dissociation of theophylline cocrystals in tablet formulations. In prototype tablets of theophylline-glutaric acid cocrystal, water mediated dissociation reaction occurred rapidly and the theophylline concentration (the dissociation product), monitored by SXRD, was strongly influenced by the formulation composition. Investigation of binary compacts of theophylline-glutaric acid cocrystal with each excipient, revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, thereby providing mechanistic insights into the dissociation reaction. Finally, the role of coformer properties on solid-state stability of theophylline cocrystals highlighted the risk of excipient-induced dissociation in cocrystals comprising of acidic and basic coformers. Furthermore, relative solubilities of the cocrystal and its constituents were important determinants of solid-state cocrystal stability.