title: Viscosity-Reducing Bulky-Salt Excipients Prevent Gelation of Protein, but Not Carbohydrate, Solutions.
abstract: The problem of gelation of concentrated protein solutions, which poses challenges for both downstream protein processing and liquid formulations of pharmaceutical proteins, is addressed herein by employing previously discovered viscosity-lowering bulky salts. Procainamide-HCl and the salt of camphor-10-sulfonic acid with L-arginine (CSA-Arg) greatly retard gelation upon heating and subsequent cooling of the model proteins gelatin and casein in water: Whereas in the absence of additives the proteins form aqueous gels within several hours at room temperature, procainamide-HCl for both proteins and also CSA-Arg for casein prevent gel formation for months under the same conditions. The inhibition of gelation by CSA-Arg stems exclusively from the CSA moiety: CSA-Na was as effective as CSA-Arg, while Arg-HCl was marginally or not effective. The tested bulky salts did not inhibit (and indeed accelerated) temperature-induced gel formation in aqueous solutions of all examined carbohydrates-starch, agarose, alginate, gellan gum, and carrageenan.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Awanish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. klibanov@mit.edu.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Klibanov
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D002164:Camphor / Q000031:analogs & derivatives / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D002364:Caseins / Q000737:chemistry*; D002417:Cattle; D005079:Excipients / Q000737:chemistry* / Q000494:pharmacology*; D005780:Gelatin / Q000737:chemistry*; D005782:Gels; D011342:Procainamide / Q000494:pharmacology; D012492:Salts / Q000737:chemistry* / Q000494:pharmacology*; D012996:Solutions; D013450:Sulfones / Q000494:pharmacology; D013696:Temperature; D014783:Viscosity
chemical_list: D002241:Carbohydrates; D002364:Caseins; D005079:Excipients; D005782:Gels; D012492:Salts; D012996:Solutions; D013450:Sulfones; C085561:camphor-10-sulfonyl chloride; D002164:Camphor; D005780:Gelatin; D001120:Arginine; D011342:Procainamide
keywords: Carbohydrates; Downstream processing of biologics; Gel formation; Hydrophobic salts; Intermolecular interactions in solution; Proteins