title: An experimental and theoretical investigation of loperamide hydrochloride-glutaric acid cocrystals.
abstract: Cocrystallization is a powerful method to improve the physicochemical properties of drugs. Loperamide hydrochloride is a topical analgesic for the gastrointestinal tract showing low and pH-dependent solubility; for this reason, an enhancement of its solubility or dissolution rate, particularly at the pH of the intestinal tract, could improve its local efficacy. Here we prepared cocrystals of this active principle with glutaric acid and so obtained a new crystalline solid representing a viable alternative to improve the physicochemical properties and thus the pharmaceutical behavior of the drug. Differential scanning calorimetry, X-ray powder diffraction, Fourier infrared spectroscopy, solid-state NMR, and scanning electron microscopy coupled to the energy-dispersive X-ray spectrometry were used to investigate the new solid-phase formation. DFT calculations at B3LYP/6-31G(d) level of theory, in the gas phase, including frequencies computation, provided a rationale for the interaction between loperamide hydrochloride and glutaric acid. The cocrystals showed improved water solubility in comparison with loperamide HCl, and the pharmaceutical formulation proposed was able to release the drug more rapidly in comparison with three reference commercial products when tested at neutral pH values.
authors.affiliation: C.S.G.I. - Department of Chemistry, Physical-Chemistry Section, University of Pavia, Viale Taramelli 16, 27100 Pavia, Italy. giovanna.bruni@unipv.it
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bruni
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Maietta
authors.forename: Lauretta
authors.initials: L
authors.lastname: Maggi
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Mustarelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrara
authors.forename: Vittorio
authors.initials: V
authors.lastname: Berbenni
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.forename: Federico
authors.initials: F
authors.lastname: Scotti
authors.forename: Chiara
authors.initials: C
authors.lastname: Milanese
authors.forename: Alessandro
authors.initials: A
authors.lastname: Girella
authors.forename: Amedeo
authors.initials: A
authors.lastname: Marini
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D005977:Glutarates / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008139:Loperamide / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D005977:Glutarates; D008139:Loperamide; C035736:glutaric acid