NP-647, a novel TRH analogue: Investigating physicochemical parameters critical for its oral and parenteral delivery

NP-647 (l-pGlu-(2-propyl)-l-His-l-ProNH2) 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. pKa 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 D7.4 (−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.

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