title: High-throughput 96-well solvent mediated sonic blending synthesis and on-plate solid/solution stability characterization of pharmaceutical cocrystals.
abstract: A 96-well high-throughput cocrystal screening workflow has been developed consisting of solvent-mediated sonic blending synthesis and on-plate solid/solution stability characterization by XRPD. A strategy of cocrystallization screening in selected blend solvents including water mixtures is proposed to not only manipulate solubility of the cocrystal components but also differentiate physical stability of the cocrystal products. Caffeine-oxalic acid and theophylline-oxalic acid cocrystals were prepared and evaluated in relation to saturation levels of the cocrystal components and stability of the cocrystal products in anhydrous and hydrous solvents. AMG 517 was screened with a number of coformers, and solid/solution stability of the resulting cocrystals on the 96-well plate was investigated. A stability trend was observed and confirmed that cocrystals comprised of lower aqueous solubility coformers tended to be more stable in water. Furthermore, cocrystals which could be isolated under hydrous solvent blending condition exhibited superior physical stability to those which could only be obtained under anhydrous condition. This integrated HTS workflow provides an efficient route in an API-sparing approach to screen and identify cocrystal candidates with proper solubility and solid/solution stability properties.
authors.affiliation: Pharmaceutical Research and Development, Small Molecule Process and Product Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Van
authors.initials: V
authors.lastname: Luu
authors.forename: Janan
authors.initials: J
authors.lastname: Jona
authors.forename: Mary K
authors.initials: MK
authors.lastname: Stanton
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: Henry G
authors.initials: HG
authors.lastname: Morrison
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
authors.forename: Helming
authors.initials: H
authors.lastname: Tan
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry*; D002110:Caffeine / Q000737:chemistry; D003460:Crystallization; D004355:Drug Stability; D057166:High-Throughput Screening Assays / Q000379:methods*; D019815:Oxalic Acid / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013806:Theophylline / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D012997:Solvents; D002110:Caffeine; D019815:Oxalic Acid; D013806:Theophylline