Physico-chemical and structural cocrystallization study of potential API molecular patterns

  • Anaëlle Tilborg

Student thesis: Doc typesDoctor of Sciences

Abstract

Cocrystallization is a well-known method, which appears in specialized literacy since more than a hundred
years but is highlighted since the last ten years to improve physico-chemical properties of target pharmaceutical
compounds during development process.
Despite the semantic lack of consensus about the real definition of what a cocrystal truly is, several
categories of assemblies – ionic or zwitterionic, as studied in this work - could emerge from the nature itself of
the cocrystallizing agent, or partners engaged in the cocrystal (also called coformers).
The main goal of this work is to in-depth analyze several cocrystals implying amino acids, and more
specifically Proline. This particular amino acid has been chosen for different reasons. First, its rigid structure,
due to the presence of a 5-membered cycle, is an important advantage. This latter could also be considered as
an elementary pattern in pharmaceutical compounds. On another hand, Proline possesses the highest water
solubility among classical amino acids.
With this aim in mind, several formation techniques are employed, the principal being mechanochemistry
or (Liquid-Assisted) grinding. X-ray diffraction allows to analyze in details cocrystal structure, and to observe
common organization patterns, or supramolecular synthons. Calorimetry techniques, and more particularly
differential scanning calorimetry or thermogravimetric analysis, permit to characterize the thermal or the
solubilizing behavior of the compounds formed via establishment of binary melting or ternary phase diagrams.
A panel of other spectroscopic methods (also NMR, elementary analysis, HPLC) allows collecting information
on the compounds, to eventually obtain the quantitative solubility of the cocrystals of API formed.
Proline cocrystals, classified as ionic with MnCl2, zwitterionic with fumaric acid - a classical coformer in
cocrystallization - or with naproxen, a marketed API from profen family, are characterized along this work. A
solubility study of naproxen cocrystal finally come out, proving once more the advantages of tuning via
cocrystallization poorly soluble compounds which do not possess an ionizable center.
Original compounds derived from prolinamide are also highlighted and analyzed in this work, arising from
aerial carbamatation of this proline derivative. Several theoretical studies, based on different aspects of the
simulation of experimentally obtained cocrystals complete the study, opening the way to potential predicting
aspects.
Date of Award26 Sep 2013
Original languageEnglish
Awarding Institution
  • University of Namur
SupervisorJohan Wouters (Supervisor), STEVE LANNERS (President), Laurence LEHERTE (Jury), Luc Quéré (Jury), Gérard Coquerel (Jury) & Tom Leyssens (Jury)

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