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Thermal stability implication of positional isomerism of novel biphenyl derivatives

Thermal stability implication of positional isomerism of novel biphenyl derivatives

Owusu-Ware, Samuel K., Masud, Mohammed, Baltus, Christine, Spencer, John and Antonijevic, Milan (2011) Thermal stability implication of positional isomerism of novel biphenyl derivatives. In: 2011 AAPS Annual Meeting and Exposition, 23-27 Oct 2011, Washington Convention Center, Washington, D.C., USA. (Unpublished)

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Abstract

Purpose
Understanding the thermodynamic and kinetics parameters associated with solid-state reactions is of great importance. The information gleaned provides a means of predicting possible stability problems during the development of an active pharmaceutical ingredient (API). It is a general practice in the pre-development stage to modify the molecular structure around the pharmacophore of an API to improve its pharmacological profile. However, such modifications could result in significant changes to the physical and chemical stability of the API and therefore impact its developmentability. This foregoing study will investigate how positional isomers influence the thermal stability of novel biphenyl derivatives (Figure 1).

Figure 1: Structures of biphenyl positional isomers with either meta (a) or para (b) substitution patterns

Methods
Thermal gravimetric analysis (TGA 2950, TA instrument) and differential scanning calorimetry (METTLER TOLEDO DSC 1) studies were performed using a 2 mg sample in a 40 µL aluminium crucibles with pinhole pans under a nitrogen atmosphere.

Results
The initial results show that both samples under investigation undergo a single melt followed by evaporation on the 1st heating from ambient to 500°C. TGA results show that there are no significant differences in the evaporation process for the positional isomers. However, DSC results show significant differences in the melting temperature (149 ± 1°C and 224 ± 1°C for meta- and para-isomers respectively). Heat-cool-heat experiments on the DSC have also been performed which have shown that the two isomers exhibit different solid-state polymorphic transitions.

Conclusion
TGA and DSC studies have so far demonstrated that positional isomerism has a significant impact on the thermal stability of a drug-like molecule. A para-substituted biphenyl derivative exhibits greater physical stability over its meta-analogue, based on the melting temperature on the 1st heating. The reason for such differences can only be attributed to the differences in the packing order in the crystal lattice. Further work is underway to explore the kinetics associated with the melting and evaporation transitions and the solid-state polymorphic behaviour of the two isomers.

Item Type: Conference or Conference Paper (Paper)
Additional Information: [1] Paper Reference No: W5363.
Uncontrolled Keywords: biphenyls, stability, polymorphs, thermal analysis
Subjects: Q Science > QD Chemistry
Faculty / Department / Research Group: Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
Related URLs:
Last Modified: 07 Dec 2016 14:17
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
URI: http://gala.gre.ac.uk/id/eprint/7192

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