title: Discovery of a stable molecular complex of an API with HCl: a long journey to a conventional salt.
abstract: We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 140 degrees C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development.
authors.affiliation: Merck & Co, Inc, Pharmaceutical R&D, PO Box 2000, Rahway, New Jersey 07065, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Peresypkin
authors.forename: Narayan
authors.initials: N
authors.lastname: Variankaval
authors.forename: Russell
authors.initials: R
authors.lastname: Ferlita
authors.forename: Robert
authors.initials: R
authors.lastname: Wenslow
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Smitrovich
authors.forename: Karen
authors.initials: K
authors.lastname: Thompson
authors.forename: Jerry
authors.initials: J
authors.lastname: Murry
authors.forename: Louis
authors.initials: L
authors.lastname: Crocker
authors.forename: David
authors.initials: D
authors.lastname: Mathre
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Harmon
authors.forename: Martha
authors.initials: M
authors.lastname: Ellison
authors.forename: Sherry
authors.initials: S
authors.lastname: Song
authors.forename: Alexey
authors.initials: A
authors.lastname: Makarov
authors.forename: Roy
authors.initials: R
authors.lastname: Helmy
mesh_terms: D003460:Crystallization; D006851:Hydrochloric Acid / Q000737:chemistry*; D006860:Hydrogen Bonding; D015394:Molecular Structure; D009010:Monte Carlo Method; D004364:Pharmaceutical Preparations; D012492:Salts / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D004364:Pharmaceutical Preparations; D012492:Salts; D006851:Hydrochloric Acid