Year: 2022
Type: dissertation
Abstract: For many oral drugs, the rate-limiting step in intestinal absorption is dictated by the kinetics of release of the active pharmaceutical ingredient (API) from the solid form. The rate of release is a function of several factors, foremost being the aqueous solubility of the API. A more recently developed formulation strategy to increase absorption is based on using cocrystals, most notably for BCS II or IV drug substances. Despite significant efforts in cocrystal prediction and formation, the role of coformer properties and cocrystal stoichiometry (molar ratio of drug to coformer) remains largely empirical and understudied. To advance cocrystals as a novel strategy for improving poor drug solubility, we investigate cocrystals of Theophylline (THY, a BCS Class I drug) with different coformers: 3-nitrobenzoic acid (3NBA, a higher solubility coformer) & 4-nitrobenzoic acid (4NBA, a lower solubility coformer) and in distinct stoichiometries: 1:1 and 1:2 with 3NBA to test whether, i) solubility of a cocrystal is dependent on coformer properties, & ii) solubility improvement at 1:1 stoichiometry could be improved further by increasing the relative coformer number. To further understand how the above conditions apply to poorly water-soluble drugs (BCS Class II drugs), we investigate Theobromine (THE), a structurally similar, BCS Class II drug, and its cocrystals with the same coformers, and see how the rules change and how can we make the coformer selection and stoichiometry decision process more rationale. To answer these questions, equal moles of THY and 3NBA or 4NBA were used for cocrystal formation through liquid assisted grinding (LAG) method, and slurry methods. Confirmed by PXRD and DSC, the LAG and slurry processes yielded two new materials with 3NBA, with 1:1 and 1:2 stoichiometries and one new material with 4NBA by LAG process, with a 1:1 stoichiometry, confirmed by XRD and 1H NMR studies. Solubility studies revealed that, while 1:1 cocrystal with 3NBA displayed a modest 1.5-fold increase in solubility, the higher 1:2 stoichiometry cocrystal displayed substantial, a near 5-fold, increase in solubility. On the other hand, cocrystal with 4NBA display a 0.25-fold decrease in solubility. Phase solubility and triangular phase diagram results were utilized in establishing theoretical models for solubility prediction, which displayed a decent comparison with our experimental studies. For THE we also observed a higher stoichiometry (1:2) cocrystal with 3NBA, same as THY. However, since THE had limited solubility, although a similar order of solubility improvement as THY was seen, a lower overall solubility (relative to theophylline) was observed. Our phase solubility studies provided insight of why theobromine exhibited this behavior. This was further confirmed by the mathematical complexation model that best fit our solubility data. With this work, we introduce the mathematical model equations for 1:2 stoichiometry cocrystals. This model can be functionally applied to capture the solubility increase for any 1:2 (or even higher stoichiometry with few alterations in the equations) cocrystals with any new drug-coformer system. We plan to further develop the model by adding more drug coformers to the test systems. Based on these findings, for a BCS class I drug and coformer, due to higher solubility of the components, more drug molecules get into solution, therefore, a higher possibility of higher stoichiometries becomes available, in order to maximize the interactions, and thus the molecules form higher complexes. Therefore, going forward, this work suggests that for BCS Class I drugs, selecting a coformer functional group complementarity should be utilized as a principle for designing higher stoichiometry cocrystal, and selecting a coformer of similar order solubility could prove beneficial to improve their solubility further with higher stoichiometry. For BCS class II drugs however, since there is intrinsic solubility limitation, selecting a coformer with higher solubility could produce greater magnitude of higher order complexes (more so for higher stoichiometry). Thus, in order to elevate the solubility of such drugs, such coformers could prove beneficial. Therefore, selection of coformers could be streamlined based on these principles observed. Such methodology could make cocrystals (particularly higher stoichiometries) more viable an option for mainstream and commercial drug design.
DOI: 10.17077/etd.006368
Language: English
Subfield: Materials Chemistry
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4290994296