X-ray Crystallography

The three dimensional structure of fluoxetine has been determined by X-ray crystallography. In the solid state the planes defined by the two aromatic rings are skewed preventing the possibility of intramolecular interactions between the rings.The methylene units of the methylpropanamine part adopt the expected conformational relationships thus minimising torsional strain.The C1-C2-C3-O4 dihedral angle is 60.6. From this it can be concluded that the propanamine side chain folds towards the phenoxy part as opposed to adopting a fully extended configuration. This folded three dimensional relationship is thought to be essential for a high affinity interaction with the serotonin uptake carrier to take place. The various substituents on the phenoxy part of fluoxetione are also very important in determining its potency and selectivity.

Although th folded propylamine part of fluoxetine plays in acrucial role in its pharmacological properties, the 3-phenyl group is also a critical aspect of its structure. It is thought that the enhancement of potency attributed to this group can be explained in terms of its interaction with a hydrophobic pocket on the serotonin uptake carrier. Evidence in support of this hypothesis is the similar potency of both enantiomers of fluoxetine. This would be expected if the afore-mentioned hydrophobic interaction is important.

Fluoxetine hydrochloride crystallised from water as colourless needles in the orthorhombic space group known as Pcab. Each unit cell contains eight molecules and the molecules are arranged in bilayers with the hydrophobic(trifluoromethyl) phenoxy and hydrophilic amine hydrochloride parts juxtaposed to the corresponding regions of a second fluoxetine molecule.

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