title: From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor.
abstract: The solid-state development for the low dose drug molecule SAR114137, a selective and reversible inhibitor of cysteine cathepsin S/K, is reported. Six polymorphic forms as well as various solvate phases were discovered by an extensive polymorphism screening. The solid phase characterizations revealed that phase 1, from which a single crystal structure could be obtained, is the thermodynamically most stable form and therefore it was chosen for pharmaceutical development. The successful scale-up from development laboratory into pilot plant for the crystallization and drying processes is presented. Testing of different drying techniques, like agitated drying in conical or filter dryers as well as spray drying, proved them to be very promising alternatives to the conventional tray drying process and might be used during the industrialization phase of the project. The use of online analytical tools (e.g., Raman spectroscopy) for a better process understanding and as tools for process optimization is shown. Furthermore, wet milling by ultrasound was performed on laboratory scale and discussed as potential option to reach the desired particle size distribution necessary for a good content uniformity of the API in an oral formulation.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Chemical and Biotechnological Development Frankfurt Chemistry, Frankfurt, Germany. Martinphilipp.feth@sanofi.com
authors.forename: Martin Philipp
authors.initials: MP
authors.lastname: Feth
authors.forename: Winfried
authors.initials: W
authors.lastname: Heyse
authors.forename: Bruno
authors.initials: B
authors.lastname: Baumgartner
authors.forename: Norbert
authors.initials: N
authors.lastname: Nagel
authors.forename: Christoph
authors.initials: C
authors.lastname: Tappertzhofen
authors.forename: Thomas
authors.initials: T
authors.lastname: Olpp
authors.forename: Jörg
authors.initials: J
authors.lastname: Jurascheck
authors.forename: Joachim
authors.initials: J
authors.lastname: Ulrich
authors.forename: Lydia
authors.initials: L
authors.lastname: Helmdach
authors.forename: Christine
authors.initials: C
authors.lastname: Petzoldt
mesh_terms: D002152:Calorimetry, Differential Scanning; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D010316:Particle Size; D010865:Pilot Projects; D033362:Powder Diffraction; D013059:Spectrum Analysis, Raman; D013816:Thermodynamics; D013818:Thermogravimetry
chemical_list: D004791:Enzyme Inhibitors; D002403:Cathepsins; C028217:cathepsin S; D056657:Cathepsin K