Browsing by Subject "Physical stability"

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    Effects of additives on the molecular-level behavior of disordered pharamceuticals
    (2020-12) Amponsah-Efah, Kweku
    Amorphous solid dispersions (ASDs) can improve the oral bioavailability of poorly water-soluble drugs. However, the physical instability of the amorphous form, denoted by the propensity to recrystallize, is a major barrier to the use of ASDs. The overarching goal of this thesis was to understand the mechanisms by which two major classes of additives – antiplasticizers (various polymers) and plasticizers (mainly glycerol) – affect the physical stability of amorphous formulations, in the dry solid form, as well as in aqueous solution. In the first project, we investigated the impact of the strength of drug–polymer interactions, on the dissolution performance of ASDs. With ketoconazole and three polymers as model compounds, we observed that the interactions that stabilize amorphous drugs in the solid state, can also be relevant and important in sustaining the level of supersaturation in aqueous solution. The second project explored the use of analytical ultracentrifugation as a novel technique for characterizing drug–polymer interactions in aqueous buffers. It was possible to quantify the “free” versus “bound” fractions of drug in aqueous solution, and to semi-quantitatively assess the impact of interactions on the dissolution performance of ASDs. The third and fourth projects evaluated the effects of glycerol on the molecular mobility and physical stability of amorphous itraconazole (ITZ), in the “solid” state. It is well-known that small molecule plasticizers, such as water or glycerol, increase the molecular mobility and accelerate the crystallization of amorphous drugs. In the case of amorphized ITZ, however, glycerol at low concentrations did not cause physical instability. Rather, the smectic state (one of the intermediate liquid-crystalline phases of ITZ) was selectively stabilized. The mechanism by which glycerol stabilized the smectic state was investigated with high resolution techniques (synchrotron diffractometry, differential and adiabatic scanning calorimetry, and spectroscopy). The results revealed that additives with fast dynamics, can drive weak first-order (or second-order) intermediate liquid-crystalline phase transitions, to strong first-order transitions, by a possible coupling of the additive concentration to the order parameter. We also demonstrated that the stabilized smectic state can perform the dual role of maintaining good physical stability while achieving adequate dissolution performance.
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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.