title: Co-crystal formation based on structural matching.
abstract: A co-crystal is defined as a single crystalline structure composed of two or more components with no proton transfer which are solid at room temperature. Our group has come up with the following rationale selection of co-formers for initial co-crystal screening: 1) selection of co-formers with the highest potential for hydrogen bonding with the API and 2) selection of co-formers with diversity of secondary structural characteristics. We demonstrate the feasibility of this technique with a Novartis drug candidate A. In the first tier, 20 co-formers were screened and two hits were identified. By examining the two co-formers, which worked from the first round, a second round of screening was undertaken with more focused chemical matter. Nineteen co-crystal formers closely related to the two hits in the first screen were screened in the second tier. From this screen five hits were identified. All the hits were compared for their physical and chemical stability and dissolution profile. Based on the comparison 4-aminobenzoic co-crystal was chosen for in-vivo comparison with the free form. The co-crystal had 12 times higher exposure than the free form thus overcoming the solubility limited exposure.
authors.affiliation: Ipsen Bioscience, 650 E. Kendall Street, Cambridge, MA 02142, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Chemical and Pharmaceutical Profiling, Technical Research and Development, Novartis Pharmaceuticals, Cambridge, MA 02139, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dodd
authors.affiliation: Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Capacci-Daniel
authors.affiliation: Chemical and Pharmaceutical Profiling, Technical Research and Development, Novartis Pharmaceuticals, Cambridge, MA 02139, United States.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Garad
authors.affiliation: WuXi App Tech, Suite 1100, 222 Third Street, Cambridge, MA 02142, United States.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Panicucci
authors.affiliation: Chemical and Pharmaceutical Profiling, Technical Research and Development, Novartis Pharmaceuticals, Emeryville, CA 94608, United States.
authors.forename: Vijay
authors.initials: V
authors.lastname: Sethuraman
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002616:Chemical Engineering / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004304:Dosage Forms; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry*; D012995:Solubility; D014227:Triazines / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D004304:Dosage Forms; D010069:Oxadiazoles; D014227:Triazines; D010129:4-Aminobenzoic Acid
keywords: 4-Aminobenzoic acid; Co-crystal; Dissolution; Form; Hydrogen bond; Salt; Solid state; Solubility