title: Isolation and Physical Property Optimization of an Amorphous Drug Substance Utilizing a High Surface Area Magnesium Aluminometasilicate (Neusilin(®) US2).
abstract: Control and optimization of the physical properties of a drug substance (DS) are critical to the development of robust drug product manufacturing processes and performance. A lack of isolatable, for example, crystalline, DS solid forms can present challenges to achieving this control. In this study, an isolation scheme for an amorphous DS was developed and integrated into the synthetic route producing DS with optimized properties. An inert absorbent excipient (Neusilin® US2) was used to isolate the DS via a novel antisolvent scheme as the final step of the route. Isolation was executed at kilogram scale utilizing conventional equipment. The resulting 50 wt% DS:Neusilin complex had improved physical stability and exceptional micromeritic and tableting properties. Improved dissolution was observed and attributed to enhanced dispersion and increased surface area. Characterization data suggest a high degree of penetration of the DS into the Neusilin, with DS occupying 70% of mesopore and 12% of macropore volume. This approach has application in the isolation and particle engineering of difficult to isolate DS without additional unit operation, such as spray drying, and has the potential for a high degree of optimization and control of physical properties over the course of DS development.
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225. Electronic address: m_allgeier@lilly.com.
authors: Matthew C
authors: MC
authors: Allgeier
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: Jared L
authors: JL
authors: Piper
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: Jeremy
authors: J
authors: Hinds
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: Matthew H
authors: MH
authors: Yates
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: Kevin J
authors: KJ
authors: Kolodsick
authors: Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, Pennsylvania 17605.
authors: Richard
authors: R
authors: Meury
authors: Process Research & Development, AbbVie, Chicago, Illinois 60064.
authors: Bruce
authors: B
authors: Shaw
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: Mehuli R
authors: MR
authors: Kulkarni
authors: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46225.
authors: David M
authors: DM
authors: Remick
mesh_terms: D017607:Aluminum Compounds / Q000737:chemistry* / Q000302:isolation & purification*; D000538:Aluminum Silicates / Q000737:chemistry / Q000302:isolation & purification; D019245:Compressive Strength; D008274:Magnesium / Q000737:chemistry / Q000302:isolation & purification; D017616:Magnesium Compounds / Q000737:chemistry* / Q000302:isolation & purification*; D010316:Particle Size; D017640:Silicates / Q000737:chemistry* / Q000302:isolation & purification*; D013499:Surface Properties; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D017607:Aluminum Compounds; D000538:Aluminum Silicates; D017616:Magnesium Compounds; D017640:Silicates; C033065:aluminum magnesium silicate; D008274:Magnesium
keywords: Micromeritics; amorphous; crystal engineering; deliquescence; formulation; physical characterization; physical stability; powder technology; processing