Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin
Daniel Komisarek1, Fulya Demirbas1, Takin Haj Hassani Sohi1
1Laboratory for Crystal Engineering, Department of Inorganic and Structural Chemistry 1, Heinrich-Heine-University Dueseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany.
Pharmaceutics
|September 28, 2023
Summary
This study examines crystal forms and multi-component compounds of gamma-amino butanoic acid (GABA) and gabapentin. It reveals how intermolecular forces and crystallization conditions influence phase formation, guiding future drug development.
Area of Science:
- Solid-state chemistry
- Crystallography
- Pharmaceutical science
Background:
- Polymorphism and multi-component crystal formation of gamma-amino butanoic acid (GABA) and gabapentin are not fully understood.
- GABA and gabapentin exhibit distinct phase behaviors, with specific polymorphs requiring special conditions or being prone to hydration.
Purpose of the Study:
- To structurally revisit known polymorphs of GABA and gabapentin, including gabapentin monohydrate.
- To clarify the accessibility and phase stability of different crystalline forms.
- To investigate the role of intermolecular interactions, molecular conformations, and crystallization environment in dictating phase formation.
Main Methods:
- Structural analysis of existing polymorphs and gabapentin monohydrate.
- Computational methods including lattice energy calculations, Atoms-in-Molecules (AIM) model, and Non-Covalent Interaction (NCI) plots.
- Synthesis and structural/computational analysis of six novel multi-component entities (salts and co-crystals) of GABA and gabapentin with fumaric and succinic acids.
Main Results:
- Lattice energy differences indicate similar stability between polymorphs.
- AIM and NCI analyses show comparable hydrogen bond strengths across polymorphs.
- Intermolecular interaction modes, combined with repulsion, dictate phase formation under varying crystallization conditions.
- Carboxyl/carboxylate interactions strongly direct the formation of multi-component phases, overriding other factors.
Conclusions:
- Crystallization behavior of zwitterionic GABA derivatives is governed by a complex interplay of intermolecular forces and environmental factors.
- Hydrogen bonds are key motif-directing forces in solid-phase GABA analogs.
- Understanding these commonalities is crucial for the rational design of future related pharmaceutical products.
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