title: Production of aprepitant nanocrystals by wet media milling and subsequent solidification.
abstract: The present study investigates the effects of formulation and process parameters on the production of aprepitant nanosuspensions applying wet media milling and subsequent solidification. Six stabilizers were used: two brands of hydroxylpropylmethyl cellulose (HPMC E-15LV and Pharmacoat 603), hydroxypropyl cellulose (HPC-SSL), polyvinylpyrollidone (PVP), D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS 1000), Poloxamer P188 and sodium dodecyl sulfate (SDS), while two diluents (mannitol and sucrose) were incorporated prior to solidification by two methods (spray- and freeze-drying). The polymorphic purity of the raw material, the particle size of nanocrystals, and the physicochemical properties of the final dried powders were assessed. Focus was placed on the energetic aspects of the crystal structure of aprepitant in order to rationalize particle breakage during wet milling. It was found that a combination of cellulosic polymers with SDS are suitable stabilizers for the production of aprepitant nanocrystals (∼300nm or smaller) by wet media milling. Regarding the solidification of the nanosuspensions, spray-drying is advantageous compared to freeze-drying, as it leads to the production of almost spherical individual micron-sized agglomerates of nanocrystals and few secondary agglomerates of them which are expected to exhibit improved handling behavior. Spray-dried nanocrystal agglomerates containing Pharmacoat 603 and mannitol exhibit reduced hygroscopity compared to those prepared with sucrose and HPC-SSL, making them the excipients of choice.
authors.affiliation: Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: F
authors.initials: F
authors.lastname: Toziopoulou
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: M
authors.initials: M
authors.lastname: Malamatari
authors.affiliation: Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: I
authors.initials: I
authors.lastname: Nikolakakis
authors.affiliation: Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Electronic address: kgk@pharm.auth.gr.
authors.forename: K
authors.initials: K
authors.lastname: Kachrimanis
mesh_terms: D000932:Antiemetics / Q000737:chemistry*; D000077608:Aprepitant; D004339:Drug Compounding / Q000379:methods; D005612:Freeze Drying; D009025:Morpholines / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000932:Antiemetics; D009025:Morpholines; D011108:Polymers; D013501:Surface-Active Agents; D000077608:Aprepitant; D012967:Sodium Dodecyl Sulfate
keywords: Aprepitant; Crystal polymorphism; Freeze-drying; Nanocrystals; Nanosuspensions; Spray-drying; Stabilizers; Wet media milling