title: Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.
abstract: Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization. The integrated MiCoS approach has been demonstrated with a model compound, glybenclamide. Based on the solid state stability and kinetic solubility of the MBP, hydroxypropylmethylcellulose acetate succinate polymer with 40% or lower drug loading, and antisolvent (0.01 N HCl) to solvent (dimethylacetamide) ratio of 5:1 or higher were selected to make glybenclamide MBP. MiCoS can be applied to both early and late stage formulation processing. In early stage research programs, the system can be used to enable efficacy, pharmacokinetics or mini-toxicology studies for poorly water soluble molecules using minimal amount of drug substance (2-10mg). In late stage development programs, MiCoS can be used to optimize MBP formulation by expanding the experimental design space to include additional formulation variants.
authors.affiliation: pRED Formulation Research, Hoffmann-La Roche, Nutley, NJ, USA. qingyanhu@gmail.com
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Hu
authors.forename: Duk Soon
authors.initials: DS
authors.lastname: Choi
authors.forename: Hitesh
authors.initials: H
authors.lastname: Chokshi
authors.forename: Navnit
authors.initials: N
authors.lastname: Shah
authors.forename: Harpreet
authors.initials: H
authors.lastname: Sandhu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015736:Felodipine / Q000737:chemistry; D005905:Glyburide / Q000737:chemistry; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008904:Miniaturization; D009543:Nifedipine / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D011208:Powders; D012995:Solubility
chemical_list: D000180:Acrylic Resins; C446821:Eudragit L100-55; D011109:Polymethacrylic Acids; D011208:Powders; C038300:methylmethacrylate-methacrylic acid copolymer; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate; D009543:Nifedipine; D015736:Felodipine; D005905:Glyburide