Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases

Abstract

Abstract.The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra-and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.

The Effect of Particle Size and Surface Roughness of Spray-Dried Bosentan Microparticles on Aerodynamic Performance for Dry Powder Inhalation

“…The raw BST showed endotherm peak at 111.6 °C. The peak at 111.6 °C represents the melting point of BST, indicating that a high crystalline solid state is achieved [ 32 ] and the peak of the dehydration of the hydrated form was overlapped by melting peak. However, the solid state of SD formulations was extremely transformed by spray drying.…”

Tadalafil–Malonic Acid Cocrystal: Physicochemical Characterization, pH-Solubility, and Supersaturation Studies

“…The partition coefficient (Log P) of TDF is 1.54, which reflects poor drug solubility in water. 23 Many approaches have been tested and described in the literature to increase the dissolution rate and bioavailability of TDF. The approaches reported include the use of (1) inclusion complexes, 24 (2) solid dispersion, 25−27 (3) amorphous hot-melt extrudate, 28 (4) nanosuspension, 29 and (5) crystalline solvates forms.…”

“…TDF is a neutral drug with p K a of 15.17. The partition coefficient (Log P) of TDF is 1.54, which reflects poor drug solubility in water . Many approaches have been tested and described in the literature to increase the dissolution rate and bioavailability of TDF.…”

Dual Level Statistical Investigation of Equilibrium Solubility in Simulated Fasted and Fed Intestinal Fluid

“…This has the advantage of examining both fasted and fed states within the same experiment coupled with the ability to combine the data to provide an overall solubility assessment for both states. The equilibrium solubility of nine (for consistency and to aid the presented comparisons, drug classification is based on our original paper) BCS class II drugs was investigated: two acids (phenytoin and indomethacin), four bases (aprepitant (aprepitant with a reported p K a of 9.7 at the pH values in this study it will be predominantly un-ionized), tadalafil (tadalafil with a reported p K a value of 15 at the pH values in this study it will be predominantly un-ionized), zafirlukast (zafirlukast with a reported p K a value of 4 will in this system behave as an acidic drug), carvedilol), and three neutral drugs (felodipine, fenofibrate, probucol) and compared to the published fasted and fed DoE studies. The same samples of compounds were employed in the cited published DoE studies , thus eliminating any potential issues associated with the solid state during comparisons.…”