2 research outputs found
Intensified Crystallization Processes for 1:1 Drug–Drug Cocrystals of Sulfathiazole–Theophylline, and Sulfathiazole–Sulfanilamide
The
chemical synthesis and crystallization steps were integrated
successfully for directly producing a 1:1 cocrystal of sulfathiazole–theophylline
and a 1:1 cocrystal of sulfathiazole–sulfanilamide. The benefits
of this process intensification were the reduction of number of steps,
and the amount of energy consumption and solvent used. In addition,
the overall cocrystal yields by Intensified Method I were much higher
than the ones by the conventional method. Intensified Method I also
gave high-purity cocrystals of ≥99%. Sulfathiazole not forming
cocrystals with sulfanilamide by Intensified Method I was dissolved
in the mother liquor by taking advantage of the pH-dependent solubility
of sulfathiazole. Cocrystals of both sulfathiazole–theophylline
and sulfathiazole–sulfanilamide systems remained stable under
conditions of 40 °C and 75% relative humidity for a month
Continuous Preparation of 1:1 Haloperidol–Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder
Salts
are generally prepared by acid–base reaction in relatively
large volumes of organic solvents, followed by crystallization. In
this study, the potential for preparing a pharmaceutical salt between
haloperidol and maleic acid by a novel solvent-free method using a
twin-screw melt extruder was investigated. The pH–solubility
relationship between haloperidol and maleic acid in aqueous medium
was first determined, which demonstrated that 1:1 salt formation between
them was feasible (p<i>H</i><sub>max</sub> 4.8; salt solubility
4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid
at the extruder barrel temperature of 60 °C resulted in the formation
of a highly crystalline salt. The effects of operating temperature
and screw configuration on salt formation were also investigated,
and those two were identified as key processing parameters. Salts
were also prepared by solution crystallization from ethyl acetate,
liquid-assisted grinding, and heat-assisted grinding and compared
with those obtained by melt extrusion by using DSC, PXRD, TGA, and
optical microscopy. While similar salts were obtained by all methods,
both melt extrusion and solution crystallization yielded highly crystalline
materials with identical enthalpies of melting. During the pH-solubility
study, a salt hydrate form was also identified, which, upon heating,
converted to anhydrate similar to that obtained by other methods.
There were previous reports of the formation of cocrystals, but not
salts, by melt extrusion. <sup>1</sup>H NMR and single-crystal X-ray
diffraction confirmed that a salt was indeed formed in the present
study. The haloperidol–maleic acid salt obtained was nonhygroscopic
in the moisture sorption study and converted to the hydrate form only
upon mixing with water. Thus, we are reporting for the first time
a relatively simple and solvent-free twin-screw melt extrusion method
for the preparation of a pharmaceutical salt that provides material
comparable to that obtained by solution crystallization and is amenable
to continuous manufacturing and easy scale up