Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble Mesylate Salt

Haloperidol, an antipsychotic drug,
was screened for new solid
crystalline phases using high throughput crystallization in pursuit
of solubility improvement. Due to the highly basic nature of the API,
all the solid forms with acids were obtained in the form of salts.
Eleven crystalline salts in the form of oxalate (1:1), benzoate (1:1),
salicylate (1:1 and 1:2), 4-hydroxybenzoate (1:1), 4-hydroxybenzoate
ethyl acetate solvate (1:1:1), 3,4-dihydroxybenzoate (1:1), 3,5-dihydroxybenzoate
(1:1), mesylate (1:1), besylate (1:1), and tosylate (1:1) salt were
achieved. There is an insertion of carboxylate or sulfonate anion
into the hydrogen bonding pattern of haloperidol. The salts with the
aliphatic carboxylic acids were found to be more prone to form salt
hydrates compared with aromatic carboxylate salts. All the salts were
subjected to solubility measurement in water at neutral pH. There
was no direct correlation observed between the solubility of the salt
and its coformer. All the salts are stable at room temperature as
well as after 24 h slurry experiment except the oxalate salt, which
showed an unusual phase transformation from its hydrated form to the
anhydrous form. A structure–property relationship was examined
to analyze the solubility behavior of the solid forms.