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dc.contributor.authorMacEachern, Lauren
dc.date.accessioned2024-06-18T14:12:00Z
dc.date.available2024-06-18T14:12:00Z
dc.date.issued2024-06-11
dc.identifier.urihttp://hdl.handle.net/10222/84288
dc.description.abstractModern active pharmaceutical ingredients (APIs) often exhibit poor aqueous solubility, leading to poor bioavailability. Methods to improve dissolution include altering solid form (salts, polymorphs, cocrystals), creating amorphous dispersions, and particle size reduction. In this study, cocrystallization and particle size reduction of two nonionizable anthelmintic drugs, niclosamide (NCS) and praziquantel (PZQ), are investigated. The research aims to understanding parameters that influence cocrystal formation and particle size of materials prepared by spray drying and rapid expansion from supercritical solution (RESS). An NCS-urea cocrystal with mean particle size of 2 μm was prepared by spray drying with yield up to 73%. However, the process required large volumes of organic solvent. Feasibility of using CO2, a greener solvent, for preparation of the cocrystal was evaluated at different process conditions. Addition of between 2.7—3.5 % cosolvent significantly impacted cocrystal formation at 40 °C and 20 MPa. Adding 2-propanol increased cocrystal formation by 50—60% compared to neat scCO2, while cyclohexane reduced cocrystal formation by between 20—35%, and water hindered cocrystal formation. However, even with cosolvent, NCS was not sufficiently soluble to form a cocrystal using RESS. Furthermore, although a cocrystal was formed it did not exhibit improved solubility in biorelevant conditions. PZQ exhibited better solubility than NCS in scCO2 and was pursued to demonstrate the impact of solvent choice and processing parameters on cocrystal formation in scCO2. During the research a novel crystalline form of PZQ was discovered which was stable for up to 7.5 weeks and exhibited up to 20% improved solubility in biorelevant media. Adding cosolvent to scCO2 allowed for PZQ and coformer, malonic acid, to crystallized by RESS. While addition of acetone and tetrahydrofuran did not produce pure cocrystal, methanol and ethanol were successful. Investigation of RESS with MeOH cosolvent led to production of particles as small as 600 nm with yields above 65% and acceptable crystallinity and residual solvent. This work showed that with careful selection of process solvent(s) both spray drying and RESS are feasible processes for preparing phase pure co-crystals and simultaneously generating micron or sub-micron size particles which may be advantageous over mechanical particle size reduction methods.en_US
dc.language.isoenen_US
dc.subjectCocrystalen_US
dc.subjectpharmaceuticalen_US
dc.subjectsupercriticalen_US
dc.titleCocrystallization and Particle Size Reduction of Active Pharmaceutical Ingredients (APIs) Using Supercritical Carbon Dioxide Crystallization or Spray Dryingen_US
dc.date.defence2024-05-23
dc.contributor.departmentDepartment of Process Engineering and Applied Scienceen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerBlair Kathryn Brettmannen_US
dc.contributor.thesis-readerSu-Ling Brooksen_US
dc.contributor.thesis-readerSohrab Rohanien_US
dc.contributor.thesis-supervisorAzadeh Kermanshahi pouren_US
dc.contributor.thesis-supervisorSophia Heen_US
dc.contributor.ethics-approvalNot Applicableen_US
dc.contributor.manuscriptsYesen_US
dc.contributor.copyright-releaseYesen_US
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