Continuous preparation of 1:1 haloperidol-maleic acid salt by a novel solvent-free method using a twin screw melt extruder

Hung Lin Lee, Jaydip M. Vasoya, Marilia De Lima Cirqueira, Kuan Lin Yeh, Tu Lee, Abu T.M. Serajuddin

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


(Figure Presented) 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 (pHmax 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. 1H 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.

Original languageEnglish
Pages (from-to)1278-1291
Number of pages14
JournalMolecular Pharmaceutics
Issue number4
StatePublished - 3 Apr 2017


  • Cogrinding
  • Eutectic formation
  • Haloperidol
  • Haloperidol-maleic acid salt
  • Maleic acid
  • Melt crystallization
  • Pharmaceutical salt
  • Twin-screw melt extrusion


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