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

Anna Krupa,Renata Jachowicz,Włodzimierz Mozgawa,Jakub Szlęk,Dorota Majda

doi:10.1208/s12249-016-0599-7

Anna Krupa, Renata Jachowicz + Show 3 more

Open Access

https://doi.org/10.1208/s12249-016-0599-7

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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.

Highlights

Throughout the last decade, scientists’ attention has focused on the development of new drug therapies for patients suffering from rare diseases
Sildenafil citrate is a derivative of benzenesulphonamides of the molecular weight of ca. 666.7 g/mol, which contains a pyrimidine ring (Fig. 1)
There is the third endotherm with the onset at about 250°C, which may correspond either to shifted melting endotherm of pure TD or to the interaction between BOS and SIL, as it was stated previously for their binary mixture. These results provide the evidence that there are no interactions between sildenafil citrate, tadalafil and monohydrate of bosentan either in binary or in ternary mixtures upon being heated together up to 200°C

Summary

Introduction

Throughout the last decade, scientists’ attention has focused on the development of new drug therapies for patients suffering from rare diseases. According to the European definition of a rare disease, it is a disorder or a disease that affects fewer than 1 person out of 2000 people. In the USA, a disease is rare if it affects fewer than 200,000 Americans at any given time. There are between 6000 and 8000 diseases classified as rare. They concern more than 30 million people in the E.U., among whom 50% are children. The origin of rare diseases is genetic in 80% of the cases. It is estimated that other factors, such as viral and bacterial infections, allergies, or environmental toxins, are responsible for 20% of them

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