title: Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG 517 in HPMC-AS Using DSC, Solid-State NMR, and Solution Calorimetry.
abstract: Intimate phase mixing between the drug and the polymer is considered a prerequisite to achieve good physical stability for amorphous solid dispersions. In this article, spray dried amorphous dispersions (ASDs) of AMG 517 and HPMC-as were studied by differential scanning calorimetry (DSC), solid-state NMR (SSNMR), and solution calorimetry. DSC analysis showed a weakly asymmetric (ΔTg ≈ 13.5) system with a single glass transition for blends of different compositions indicating phase mixing. The Tg-composition data was modeled using the BKCV equation to accommodate the observed negative deviation from ideality. Proton spin-lattice relaxation times in the laboratory and rotating frames ((1)H T1 and T1ρ), as measured by SSNMR, were consistent with the observation that the components of the dispersion were in intimate contact over a 10-20 nm length scale. Based on the heat of mixing calculated from solution calorimetry and the entropy of mixing calculated from the Flory-Huggins theory, the free energy of mixing was calculated. The free energy of mixing was found to be positive for all ASDs, indicating that the drug and polymer are thermodynamically predisposed to phase separation at 25 °C. This suggests that miscibility measured by DSC and SSNMR is achieved kinetically as the result of intimate mixing between drug and polymer during the spray drying process. This kinetic phase mixing is responsible for the physical stability of the ASD.
authors.affiliation: Oral Delivery Product and Process Development, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , 789 South Limestone Street, Lexington, Kentucky 40536, United States.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Calahan
authors.affiliation: Oral Delivery Product and Process Development, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Azali
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , 789 South Limestone Street, Lexington, Kentucky 40536, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Munson
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech Inc. , 465 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning / Q000379:methods*; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D044367:Phase Transition; D011108:Polymers / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D052160:Benzothiazoles; D005079:Excipients; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011108:Polymers; D011743:Pyrimidines; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose
keywords: Flory−Huggins; amorphous solid dispersion; phase mixing; physical stability; solution calorimetry