Functionalization of Polymeric Materials to Control the Kinetics of Pharmaceutical Crystallization
dc.contributor.author | Frank, Derek | |
dc.date.accessioned | 2020-01-27T16:22:32Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2020-01-27T16:22:32Z | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/153338 | |
dc.description.abstract | Crystallization is ubiquitous in the pharmaceutical industry and is employed in the design, development, and manufacturing of drugs. In particular, controlling the kinetics of crystallization can improve the efficiency of batch crystallization processes and ensure the physical stability of metastable drug products. Although the crystallization rate of a small-molecule pharmaceutical is often tuned by altering parameters such as pharmaceutical concentration, temperature, or solvent, there is a considerable demand for additives that can alter crystallization kinetics without changing the thermodynamic solubility of a pharmaceutical. However, the relationship between the molecular structure and impact of an additive on crystallization kinetics is still poorly understood. This dissertation presents structure-function relationships dictating how polymers can be engineered to most effectively increase or decrease the crystallization rate of small-molecule pharmaceuticals in solution and in the amorphous phase. Insoluble, crosslinked polymers are demonstrated to accelerate acetaminophen nucleation in solution. Maximizing interaction strength between polymer and acetaminophen while minimizing interaction strength between polymer and water leads to polymers best able to induce crystallization. These insoluble crystallization accelerators are leveraged to discover water-soluble polymers to inhibit crystallization. Functionalities that rapidly accelerate crystallization when tethered to soluble polymers are shown to be strong inhibitors of crystallization when attached to water-soluble polymers. This methodology of screening functionalities on insoluble polymers to determine their interaction strength with a target pharmaceutical streamlines the discovery of polymers to inhibit crystallization. The relationship between polymers designed to inhibit crystallization in solution and in the solid-state is also explored. Using a common set of polymeric materials, it is shown that increasing polymer hydrophobicity improves both the physical stability of supersaturated solutions and the physical stability of amorphous solid dispersions. Finally, the relationship between polymer functionality and physical stability is investigated for amorphous solid dispersions of the hydrophobic drug nabumetone. The solubility of polymer excipient in amorphous nabumetone is demonstrated to have a crucial effect in determining the ability of polymers to stabilize amorphous solid dispersions. Throughout all of these studies, postpolymerization functionalization is used to synthesize libraries of polymers containing a range of functional group chemistry without changing physical parameters of polymers such as number-average chain length or backbone chain chemistry to isolate the effects of polymer chemistry on the ability of a polymer to alter crystallization rates. Fundamental parameters, including interaction strength between polymer and drug, interaction strength between polymer and solvent, and cohesive polymer-polymer interactions, are shown to dictate the ability of a polymer to speed or slow crystallization, and the effect of polymers to either speed or slow crystallization is compared and contrasted for crystallizations in solution and in the amorphous phase. | |
dc.language.iso | en_US | |
dc.subject | crystallization kinetics | |
dc.subject | polymeric materials | |
dc.subject | pharmaceuticals | |
dc.title | Functionalization of Polymeric Materials to Control the Kinetics of Pharmaceutical Crystallization | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Macromolecular Science & Engineering | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Matzger, Adam J | |
dc.contributor.committeemember | Kuroda, Kenichi | |
dc.contributor.committeemember | McNeil, Anne Jennifer | |
dc.contributor.committeemember | Tuteja, Anish | |
dc.subject.hlbsecondlevel | Materials Science and Engineering | |
dc.subject.hlbsecondlevel | Chemistry | |
dc.subject.hlbtoplevel | Engineering | |
dc.subject.hlbtoplevel | Science | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/153338/1/dsfrank_1.pdf | |
dc.identifier.orcid | 0000-0002-0564-074X | |
dc.identifier.name-orcid | Frank, Derek; 0000-0002-0564-074X | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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