title: Is the amorphous fraction of a dried nanosuspension caused by milling or by drying? A case study with Naproxen and Cinnarizine.
abstract: One of the benefits of nanocrystals is their positive effect on the solubility and dissolution rate without alterations to the solid state. Up to now, amorphization of nanocrystals after milling or drying has only rarely been described. The results we present in this article prove that amorphization occurs in some specific cases. This conclusion is based on careful investigation of two different drugs and one polymeric stabilizer. Milling is often mentioned as the prime suspect for solid-state alterations; however, milling proved to be an unlikely cause as the water present in the nanosuspensions acts as a plasticizer that triggers recrystallization. The cause of amorphization can instead be found in the interplay between drug and stabilizer after drying. If a drug is soluble in the stabilizer in the solid state, an amorphous solid dispersion is formed at the interface. Calculations show that the total amount of amorphous material is rather low, but even a small amount could have an influence on both chemical and physical stability or influence the bioavailability if uncontrolled crystallization occurs during storage. In general, those results prove that in depth testing and characterization of the solid state of a dried nanocrystal formulation remains very important.
authors.affiliation: Laboratory of Pharmacotechnology and Biopharmacy, Department of Pharmaceutical and Pharmacological Sciences, Ku Leuven, Leuven, Belgium.
authors.forename: Pieterjan
authors.initials: P
authors.lastname: Kayaert
authors.forename: Guy
authors.initials: G
authors.lastname: Van den Mooter
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D002936:Cinnarizine / Q000737:chemistry*; D003460:Crystallization; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D053758:Nanoparticles; D009288:Naproxen / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility; D013535:Suspensions
chemical_list: D005079:Excipients; D013535:Suspensions; D002936:Cinnarizine; D065347:Hypromellose Derivatives; D009288:Naproxen; D008747:Methylcellulose