Bosentan monohydrate and sildenafil base as two companions in enabling formulations.

HYPOTHESIS: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs. EXPERIMENTS: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs. FINDINGS: It was shown that binary formulations in which bosentan was molecularly dispered in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.

High energy ball milling vs. nano spray drying in the development of supersaturated systems loaded with bosentan.

In this study, high energy ball milling and nano spray drying were used to prepare amorphous solid dispersions of bosentan in copovidone for the first time. In particular, the impact of this polymer on the bosentan amorphization kinetics was investigated. Copovidone was shown to facilitate the amorphization of bosentan upon ball milling. As a result, bosentan was dispersed in copovidone at the molecular level, forming amorphous solid dispersions, regardless of the ratio of the compounds. The similarity between the values of the adjustment parameter that describes the goodness of fit of the Gordon-Taylor equation to the experimental data (K = 1.16) and that theoretically calculated for an ideal mixture (K = 1.13) supported these findings. The kind of coprocessing method determined the powder microstructure and the release rate. The opportunity to prepare submicrometer-sized spherical particles using nano spray drying was an important advantage of this technology. Both coprocessing methods allowed the formation of long-lasting supersaturated bosentan solutions in the gastric environment with maximum concentrations reached ranging from four (11.20 µg/mL) to more than ten times higher (31.17 µg/mL) than those recorded when the drug was vitrified alone (2.76 µg/mL). Moreover, this supersaturation lasted for a period of time at least twice as long as that of the amorphous bosentan processed without copovidone (15 min vs. 30-60 min). Finally, these binary amorphous solid dispersions were XRD-amorphous for a year of storage under ambient conditions.

Spray drying and nano spray drying as manufacturing methods of drug-loaded polymeric particles.

In this review, benefits and drawbacks of the process of spray drying and nano spray drying with regard to the manufacturing of polymeric particles for pharmaceutical applications are discussed. Spray drying has been used for many years in the food, chemical and pharmaceutical industries for converting liquids into solids, in order to form products of uniform appearance. The construction of spray dryer enables to atomize the liquid into small droplets, which ensures a large surface area for heat and mass transfer, and significantly shortens the processing. Each droplet dries to an individual solid microparticle of characteristic features that can be tailored by optimizing formulation variables and critical process parameters. Since spray drying technology is easy to scale up and can be used for drying almost any drug in a solution or suspension, there are numerous examples of products in clinical use, in which this process has been successfully applied to improve drug stability, enhance bioavailability or control its release rate. In recent years, nano spray drying technology has been proposed as a method for lab-scale manufacturing of nanoparticles. Such an approach is of particular interest at early stages of drug development, when a small amount of new chemical entities is available. Here, the nebulization technique is used for feed atomization, while laminar gas flow in the drying chamber ensures gentle drying conditions. Moreover, electrostatic collectors have gradually replaced cyclone separators, ensuring high effectiveness in producing solid nanoparticles, even if a small volume of the sample is processed.

Kollidon® VA 64 and Soluplus® as modern polymeric carriers for amorphous solid dispersions.

As the number of new drug candidates that are poorly soluble in water grows, new technologies that enable the enhancement of their solubility are needed. This is the case with amorphous solid dispersions (ASDs) that, nowadays, not only ensure the solubility, but can also be used to control the release rate of poorly soluble drugs. However, this dosage form must overcome the major disadvantage of ASDs, which is limited stability upon storage. Thus, a thorough knowledge on polymeric carriers that can enhance drug solubility while ensuring stability in the amorphous form is necessary. In this review, the state of the art in the application of Kollidon® VA 64 (copovidone) and Soluplus® (graft copolymer of polyvinyl caprolactam-polyvinyl acetate and poly(ethylene glycol) (PEG)) in the manufacturing of ASDs over the last 20 years is presented. Apart from the classical methods, namely solvent evaporation or melting, more advanced technologies such as pulse combustion drying, high-speed electrospinning and single-step 3D printing are described. It has been shown that both the dissolution rate (in vitro) and enhancement in bioavailability (in vivo) regarding poorly soluble active ingredients of natural or synthetic origin are possible using these matrix-forming polymers.