title: Effect of cyclophosphamide on the solid form of mannitol during lyophilization.
abstract: Mannitol is a commonly used bulking agent in lyophilized formulations. It can crystallize into multiple solid forms during lyophilization thereby exhibiting phase heterogeneity and variability in product performance. In this manuscript, we studied the effect of cyclophosphamide (CPA), an anticancer drug, on the solid form of mannitol during lyophilization from aqueous solutions. Freeze-concentration studies were performed in the DSC while lyophilization was performed in a lab scale freeze dryer. DSC experiments revealed two-stage crystallization of mannitol (1.5% w/v) during freeze-concentration, evident as two distinct exothermic events (at -18.2°C and -30°C) in the cooling curve. This was complemented by two eutectic melting endotherms in the subsequent heating curve. Addition of CPA (4.0% w/v) completely inhibited the exotherm at -18.2°C, but enhanced the enthalpy of exotherm at -30°C by five folds. Likewise, only one eutectic melting endotherm was observed in the subsequent heating curve. Lyophilization of the solution containing only mannitol, yielded a mixture of β- (major) and δ- (minor) polymorphs of mannitol. However, in the presence of CPA, only δ-polymorph was observed in the lyophilized sample. This selective favoring of the metastable δ-polymorph over the stable β-polymorph, was explained by altered freezing kinetics of the solution in presence of CPA. The study provides mechanistic insights into solute crystallization behaviour during lyophilization of multi-component systems.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India.
authors.forename: Krupaliben
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India.
authors.forename: Bhushan
authors.initials: B
authors.lastname: Munjal
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India. Electronic address: akbansal@niper.ac.in.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Bansal
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D003520:Cyclophosphamide / Q000737:chemistry*; D005612:Freeze Drying / Q000379:methods; D005615:Freezing; D006361:Heating; D007700:Kinetics; D008353:Mannitol / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry
chemical_list: D012996:Solutions; D008353:Mannitol; D003520:Cyclophosphamide
keywords: Differential scanning calorimetry; Freeze-concentration; Mannitol; Moisture-induced transformation; Polymorphic form; X-ray diffractometry