Understanding the Solution Phase Chemistry and Solid State Thermodynamic Behavior of Pharmaceutical Cocrystals.
dc.contributor.author | Maheshwari, Chinmay | en_US |
dc.date.accessioned | 2013-02-04T18:05:53Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2013-02-04T18:05:53Z | |
dc.date.issued | 2012 | en_US |
dc.date.submitted | 2012 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/96113 | |
dc.description.abstract | This dissertation focuses on the thermodynamic stability and solubility of pharmaceutical cocrystals. Specifically, the objectives are to; (i) investigate the influence of coformer properties such as solubility and ionization characteristics on cocrystal solubility and stability as a function of pH, (ii) measure the thermodynamic solubility of metastable cocrystals, and study the solubility differences measured by kinetic and equilibrium methods, (iii) investigate the role of surfactants on the solubility and synthesis of cocrystals, (iv) investigate the solid state phase transformation of reactants to cocrystals and the factors that influence the reaction kinetics and, (v) provide models that enable the prediction of cocrystal formation by calculating the free energy of formation for a solid to solid transformation of reactants to cocrystals. It was found that melting point is not a good indicator of cocrystal solubility as solute-solvent interactions quantified by the activity coefficient play a huge role in the observed solubility. Similar to salts, cocrystals also exhibit pHmax, however the salts and cocrystals have different dependencies on the parameters that govern the value of pHmax. It is also shown that cocrystals could provide solubility advantage over salts as lamotrigine-nicotinamide cocrystal hydrate has about 6 fold higher solubility relative to lamotrigine-saccharin salt. In the case of mixtures of solid reactants, it was observed that cocrystals can form spontaneously when the reactants are in physical contact and that temperature, relative humidity, and disorder in the reactants caused by mechanical stress such as milling can enhance the reaction rates. Prediction of spontaneous cocrystal formation was investigated by developing models to calculate the Gibbs free energy of formation. Thermal behavior of cocrystal reactants was investigated by calorimetry and the interaction between the reactants is explained by investigating the heats of mixing in the melt. These principles are applied on cocrystals that are divided into two categories; (i) Where the cocrystal melting point is between that of its reactants and, (ii) where the cocrystal melting point is below that of its components. Generalized equations were developed that enable the calculation of Gibbs free energy of formation from fusion temperatures, enthalpy and entropy of fusion. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Cocrystal Solubility | en_US |
dc.subject | Solid State Thermodynamic Behavior of Pharmaceutical Cocrystals | en_US |
dc.subject | Cocrystal Solution Phase Chemistry | en_US |
dc.subject | PH Solubility Dependence of Cocrystals | en_US |
dc.subject | Gabapentin Lactam, Lamotrigine Cocrystals | en_US |
dc.subject | Cocrystal PHmax, Thermodyamic Cycles, Differential Scanning Calorimetry | en_US |
dc.title | Understanding the Solution Phase Chemistry and Solid State Thermodynamic Behavior of Pharmaceutical Cocrystals. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutical Sciences | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Rodriguez-Hornedo, Nair | en_US |
dc.contributor.committeemember | Van Der Ven, Anton | en_US |
dc.contributor.committeemember | Amidon, Gordon L. | en_US |
dc.contributor.committeemember | Amidon, Gregory E. | en_US |
dc.subject.hlbsecondlevel | Chemical Engineering | en_US |
dc.subject.hlbsecondlevel | Engineering (General) | en_US |
dc.subject.hlbsecondlevel | Materials Science and Engineering | en_US |
dc.subject.hlbsecondlevel | Pharmacy and Pharmacology | en_US |
dc.subject.hlbsecondlevel | Chemistry | en_US |
dc.subject.hlbsecondlevel | Science (General) | en_US |
dc.subject.hlbtoplevel | Engineering | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/96113/1/mchinmay_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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