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Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
Published on: April 27, 2017
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Cilengitide--exceptional pseudopolymorphism of a cyclic pentapeptide
Summary
Cilengitide anhydrate (A1) is surprisingly more stable than its tetrahydrate form in water. Higher solubility pseudo-polymorphs (S1, S2) can be obtained from methanol/ethanol mixtures, avoiding low-solubility A1.
Area of Science:
- Pharmaceutical Sciences
- Solid-State Chemistry
- Crystallography
Background:
- Cilengitide (Cil), a cyclic pentapeptide (cyclo-(Arg-Gly-Asp-D-Phe-N-MeVal)), exists as an anhydrate (A1) and a tetrahydrate (Cil1(H2O)4).
- Understanding the thermodynamic stability and solubility of different crystalline forms is crucial for drug formulation and development.
Purpose of the Study:
- To investigate the thermodynamic stability and solubility of Cilengitide anhydrate (A1) and tetrahydrate (Cil1(H2O)4) forms.
- To explore the formation and properties of non-stoichiometric water-alcohol solvates (S1, S2) of Cilengitide.
- To identify optimal crystallization strategies for obtaining more soluble Cilengitide forms.
Main Methods:
- Competitive slurry experiments to assess thermodynamic stability.
- Thermodynamic solubility measurements.
- Crystallization studies using aqueous and mixed solvent systems (methanol, ethanol).
Main Results:
- The anhydrate form (A1) demonstrated greater thermodynamic stability in aqueous environments compared to the tetrahydrate form (Cil1(H2O)4).
- Lower solubility of A1 is attributed to specific hydrogen bonding motifs in its crystal structure.
- Non-stoichiometric solvates (S1, S2) incorporating methanol or ethanol exhibit higher solubility than A1 but rapidly convert to A1 in aqueous media.
- S1 and S2 can be obtained via crystallization from methanol/ethanol mixtures, circumventing A1 formation.
Conclusions:
- Cilengitide anhydrate (A1) is the most thermodynamically stable form in aqueous environments.
- While non-stoichiometric solvates (S1, S2) offer enhanced solubility, their instability in water limits their direct use.
- Crystallization from solvent mixtures containing methanol and ethanol is a viable strategy to produce highly soluble pseudo-polymorphs of Cilengitide.
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