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Disappearing and reappearing polymorphs. The benzocaine:picric acid system
J O Henck1, J Bernstein, A Ellern
1Institut für Pharmakognosie der Universität Innsbruck Innrain 52, Josef-Moeller-Haus, 6020 Innsbruck, Austria.
Journal of the American Chemical Society
|July 18, 2001
Summary
Investigating the benzocaine (BC) and picric acid (PA) system revealed methods to crystallize elusive polymorphic forms. Understanding thermal behavior is key to obtaining metastable crystal structures.
Area of Science:
- Crystallography
- Materials Science
- Chemical Engineering
Background:
- The benzocaine:picric acid (BC:PA) 1:1 complex previously exhibited a
- disappearing polymorph
- a metastable form that is difficult to isolate.
- Polymorphism in pharmaceutical cocrystals is critical for drug stability and bioavailability.
Purpose of the Study:
- To reinvestigate the benzocaine:picric acid (BC:PA) system.
- To develop robust crystallization procedures for various BC:PA phases.
- To understand the conditions for crystallizing metastable polymorphic forms.
Main Methods:
- Thermomicroscopy and differential scanning calorimetry (DSC) for thermal analysis.
- Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy.
- X-ray crystallography for structural determination.
- Graph set analysis for hydrogen-bonding characterization.
Main Results:
- The phase diagram of the BC:PA system was established.
- Four distinct crystalline phases were identified and characterized: two 1:1 complexes, a 1:1 hydrate, and a 2:1 complex.
- Structural analysis revealed specific hydrogen-bonding patterns in each phase.
- Strategies for crystallizing metastable forms were developed based on thermal behavior.
Conclusions:
- Thorough thermal analysis combined with calorimetric methods enables the crystallization of difficult-to-obtain metastable polymorphic forms.
- Understanding phase behavior is crucial for controlling the crystallization of cocrystal systems.
- This study provides a framework for accessing metastable polymorphs in other chemical systems.
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