title: Mannitol/l-Arginine-Based Formulation Systems for Freeze Drying of Protein Pharmaceuticals: Effect of the l-Arginine Counter Ion and Formulation Composition on the Formulation Properties and the Physical State of Mannitol.
abstract: Previous studies have shown that protein storage stability in freeze-dried l-arginine-based systems improved in the presence of chloride ions. However, chloride ions reduced the glass transition temperature of the freeze concentrate (Tg') and made freeze drying more challenging. In this study, l-arginine was freeze dried with mannitol to obtain partially crystalline solids that can be freeze dried in a fast process and result in elegant cakes. We characterized the effect of different l-arginine counter ions on physicochemical properties of mannitol compared with mannitol/sucrose systems. Thermal properties of formulations with different compositions were correlated to thermal history during freeze drying and to physicochemical properties (cake appearance, residual moisture, reconstitution time, crystallinity). Partially crystalline solids were obtained even at the highest l-arginine level (mannitol:l-arginine of 2:1) used in this study. All l-arginine-containing formulations yielded elegant cakes. Only cakes containing l-arginine chloride and succinate showed a surface "crust" formed by phase separation. X-ray powder diffraction showed that inhibition of mannitol crystallization was stronger for l-arginine compared with sucrose and varied with the type of l-arginine counter ion. The counter ion affected mannitol polymorphism and higher levels of mannitol hemi-hydrate were obtained at high levels of l-arginine chloride.
authors: GILYOS GmbH, Wuerzburg 97076, Germany.
authors: Peter
authors: P
authors: Stärtzel
authors: GILYOS GmbH, Wuerzburg 97076, Germany.
authors: Henning
authors: H
authors: Gieseler
authors: GILYOS GmbH, Wuerzburg 97076, Germany.
authors: Margit
authors: M
authors: Gieseler
authors: F. Hoffmann-La Roche Ltd., Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, Basel 4070, Switzerland.
authors: Ahmad M
authors: AM
authors: Abdul-Fattah
authors: F. Hoffmann-La Roche Ltd., Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, Basel 4070, Switzerland.
authors: Michael
authors: M
authors: Adler
authors: F. Hoffmann-La Roche Ltd., Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, Basel 4070, Switzerland; Lonza AG, Drug Product Services, Basel 4052, Switzerland.
authors: Hanns-Christian
authors: HC
authors: Mahler
authors: F. Hoffmann-La Roche Ltd., Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, Basel 4070, Switzerland. Electronic address: pierre.goldbach@roche.com.
authors: Pierre
authors: P
authors: Goldbach
mesh_terms: D001120:Arginine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods*; D005612:Freeze Drying / Q000379:methods; D007477:Ions; D008353:Mannitol / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D007477:Ions; D008353:Mannitol; D001120:Arginine
keywords: X-ray powder diffraction; crystallinity; differential scanning calorimetry; freeze drying/lyophilization; l-arginine counter ions; mannitol polymorphism