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Dissolution control of highly soluble active pharmaceutical ingredients via cocrystallisation
Author(s)
Nyamayaro, Kudzanai
Date Issued
2017
Type
Thesis
Publisher
Cape Peninsula University of Technology
Abstract
Crystal engineering involves the manipulation of intermolecular interactions to design
functionalised crystalline materials and has proved to be an effective tool for the modification
of physicochemical properties of active pharmaceutical ingredients (APIs). In the first section
of this study, the aim was to systematically influence the rate of dissolution of a highly soluble
active pharmaceutical ingredient using crystal engineering principles.
Salicylic acid (SA) was employed as a model API to form multicomponent crystals with a series
of selected cinchona alkaloids, namely quinine (QUIN), quinidine (QUID), cinchonine (CINC),
cinchonidine (CIND), N-benzylquininium chloride (NBQUIN), N-benzylcinchonidinium chloride
(NBCIND) and N-benzylcinchoninium chloride (NBCINC). The resulting novel crystalline forms
were found to be salts, and were characterised using single crystal X-ray diffraction, powder
X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The
dissolution profiles of the salicylate salts, measured from an aqueous media using high
performance liquid chromatography-mass spectroscopy, show a significant decrease in the
rate of dissolution of SA. Subsequently, Hirshfeld surface analysis was used as a tool for
quantitative and qualitative comparison of the crystal structures. This study indicates that the
rate of dissolution can be successfully influenced by methodically adding extra hydrophobic
groups onto the coformer.
In the second section, we applied the information obtained from the SA studies to
acetylsalicylic acid (aspirin, ASA). We sought to improve its thermal stability and dissolution
via the formation of new solid forms with the aforementioned cinchona alkaloids. We
successfully synthesized a novel drug-drug salt of an analgesic, non-steroidal antiinflammatory
and antipyretic drug (ASA), and an antimalarial and analgesic drug (QUIN). The
salt was formed both by using solution methods and liquid assisted grinding - a green
chemistry technique. The salt exhibited physicochemical properties different from the parent
drugs, and a reduced rate of dissolution.
functionalised crystalline materials and has proved to be an effective tool for the modification
of physicochemical properties of active pharmaceutical ingredients (APIs). In the first section
of this study, the aim was to systematically influence the rate of dissolution of a highly soluble
active pharmaceutical ingredient using crystal engineering principles.
Salicylic acid (SA) was employed as a model API to form multicomponent crystals with a series
of selected cinchona alkaloids, namely quinine (QUIN), quinidine (QUID), cinchonine (CINC),
cinchonidine (CIND), N-benzylquininium chloride (NBQUIN), N-benzylcinchonidinium chloride
(NBCIND) and N-benzylcinchoninium chloride (NBCINC). The resulting novel crystalline forms
were found to be salts, and were characterised using single crystal X-ray diffraction, powder
X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The
dissolution profiles of the salicylate salts, measured from an aqueous media using high
performance liquid chromatography-mass spectroscopy, show a significant decrease in the
rate of dissolution of SA. Subsequently, Hirshfeld surface analysis was used as a tool for
quantitative and qualitative comparison of the crystal structures. This study indicates that the
rate of dissolution can be successfully influenced by methodically adding extra hydrophobic
groups onto the coformer.
In the second section, we applied the information obtained from the SA studies to
acetylsalicylic acid (aspirin, ASA). We sought to improve its thermal stability and dissolution
via the formation of new solid forms with the aforementioned cinchona alkaloids. We
successfully synthesized a novel drug-drug salt of an analgesic, non-steroidal antiinflammatory
and antipyretic drug (ASA), and an antimalarial and analgesic drug (QUIN). The
salt was formed both by using solution methods and liquid assisted grinding - a green
chemistry technique. The salt exhibited physicochemical properties different from the parent
drugs, and a reduced rate of dissolution.
Additional information
Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017
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Name
212278282-Nyamayaro-Kudzanai-MGCHER-Chemistry-Appsc-2018.pdf
Description
Thesis
Size
11.51 MB
Format
Adobe PDF
Checksum
(MD5):b30659cf5e4810395a5ca3ffc782efa6
Sponsor(s)
National Research Foundation(NRF)