title: NP-647, a novel TRH analogue: investigating physicochemical parameters critical for its oral and parenteral delivery.
abstract: NP-647 (L-pGlu-(2-propyl)-L-His-L-ProNH(2)) is a novel thyrotropin releasing hormone (TRH) analogue, with potential antiepileptic activity. In the present study, the physicochemical parameters of NP-647, including its solid state properties, dissociation constant, partition coefficient, solubility (intrinsic solubility and pH-solubility profile) and stability (gastrointestinal enzymatic stability, pH-stability profile and temperature stability) were investigated for their criticality for oral and parenteral delivery. NP-647 was characterized as amorphous material having glass transition temperature of 66.73 °C at 50% RH. It was found very hygroscopic with deliquescent in nature. pK(a) of the compound, as determined using potentiometric titration, was found to be 7.2 ± 0.02 (basic). Intrinsic solubility and pH-solubility behavior were determined using dissolution titration template method. NP-647 has intrinsic solubility of 2.4 ± 0.01 mg mL(-1). Partition/distribution studies indicate that NP-647 has a low log P (-1.07 ± 0.06) and log D(7.4) (-1.20 ± 0.02), characteristic of hydrophilic molecule. It was found most stable in tartrate buffer of pH of 5.0. Arrhenius plot of NP-647 suggest its half life of ∼ 3.2 years and shelf life of ∼ 6 months. These studies conclude that amorphous nature of NP-647 with deliquescent property will be critical in its solid oral dosage formulation and need to be investigated further.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S Nagar, Mohali, Punjab, India.
authors.forename: Kailas
authors.initials: K
authors.lastname: Khomane
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.forename: Chhuttan Lal
authors.initials: CL
authors.lastname: Meena
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
authors.forename: Arvind
authors.initials: A
authors.lastname: Bansal
mesh_terms: D000284:Administration, Oral; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D005750:Gastric Juice / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007267:Injections; D007419:Intestinal Secretions / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D044367:Phase Transition; D012995:Solubility; D013818:Thermogravimetry; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000927:Anticonvulsants; C539979:pyroglutamyl-(2-propyl)histidyl-prolinamide; D013973:Thyrotropin-Releasing Hormone