Influence of the solid form of siramesine hydrochloride on its behavior in aqueous environments.
OBJECTIVE
To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments.


METHODS
The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate-hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy.


RESULTS
At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate-hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled.


CONCLUSIONS
During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.
Zimmermann
Anne
A
Faculty of Pharmaceutical Sciences, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark. anz@farma.ku.dk
Tian
Fang
F
Lopez de Diego
Heidi
H
Ringkjøbing Elema
Michiel
M
Rantanen
Jukka
J
Müllertz
Anette
A
Hovgaard
Lars
L
D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004304:Dosage Forms; D000431:Ethanol / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D008853:Microscopy; D044367:Phase Transition; D033362:Powder Diffraction; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013141:Spiro Compounds / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry*
D004304:Dosage Forms; D007211:Indoles; C109644:Lu 28-179; D012997:Solvents; D013141:Spiro Compounds; D014867:Water; D000431:Ethanol