title: Crystal form control and particle size control of RG3487, a nicotinic α7 receptor partial agonist.
abstract: This paper describes solid form control and particle size control of RG3487, a nicotinic receptor partial agonist. Four crystal forms were identified by polymorph screen under ∼100 varying conditions. Form A and Form B are anhydrates, while Forms C and D are solvates. Forms A, which is enantiotropically related to Form B, is the more thermodynamically stable form under ambient conditions and the desired form selected for clinical development. The crystal form control of Form A was achieved by crystallization solvent selection which consistently produced the desired form. Several process parameters impacting particle size of Form A in the final crystallization step were identified and investigated through both online and offline particle size measurement. The investigation results were utilized to control crystallization processes which successfully produced Form A with different particle size in 500g scale.
authors.affiliation: Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA. Electronic address: shanming.kuang@gmail.com.
authors.forename: Shanming
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Cambrex Charles City Inc., 12051 11(th) Street, Charles City, IA 50616, USA.
authors.forename: Eric Z
authors.initials: EZ
authors.lastname: Dong
authors.affiliation: Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA.
authors.forename: Geremia
authors.initials: G
authors.lastname: Jennings
authors.affiliation: Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA.
authors.forename: Baoshu
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pierce
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D054333:Drug Partial Agonism; D007191:Indazoles / Q000737:chemistry*; D015394:Molecular Structure; D010316:Particle Size; D013816:Thermodynamics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: D001643:Bridged Bicyclo Compounds; D007191:Indazoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C554954:N-((3S)-1-azabicyclo(2.2.2)oct-3-yl)-1H-indazole-3-carboxamide hydrochloride
keywords: Crystal form control; Crystallization; Form stability; Particle size control; Polymorph screen; RG3487