Investigating the Potential of Ethyl Cellulose and a Porosity-Increasing Agent as a Carrier System for the Formulation of Amorphous Solid Dispersions.

In the present work, an insoluble polymer, i.e., ethyl cellulose (EC), was combined with the water-soluble polyvinylpyrrolidone (PVP) as a carrier system for the formulation of amorphous solid dispersions. The rationale was that by conjoining these two different types of carriers a more gradual drug release could be created with less risk for precipitation. Our initial hypothesis was that upon contact with the dissolution medium, PVP would be released, creating a porous EC matrix through which the model drug indomethacin could diffuse. On the basis of observations of EC as a coating material, the effect of the molecular weight of PVP, and the ratio of EC/PVP on the miscibility of the polymer blend, the solid state of the solid dispersion and the drug release from these solid dispersions were investigated. X-ray powder diffraction, modulated differential scanning calorimetry, and solid-state nuclear magnetic resonance were used to unravel the miscibility and solid-state properties of these blends and solid dispersions. Solid-state nuclear magnetic resonance appeared to be a crucial technique for this aspect as modulated differential scanning calorimetry was not sufficient to grasp the complex phase behavior of these systems. Both EC/PVP K12 and EC/PVP K25 blends were miscible over the entire composition range, and addition of indomethacin did not alter this. Concerning the drug release, it was initially thought that more PVP would lead to faster drug release with a higher probability that all of the drug molecules would be able to diffuse out of the EC network as more pores would be created. However, this view on the release mechanism appeared to be too simplistic as an optimum was observed for both blends. On the basis of this work, it could be concluded that drug release from this complex ternary system was affected not only by the ratio of EC/PVP and the molecular weight of PVP but also by interactions between the three components, the wettability of the formulations, and the viscosity layer that was created around the particles.

Unravelling the Miscibility of Poly(2-oxazoline)s: A Novel Polymer Class for the Formulation of Amorphous Solid Dispersions.

Water-soluble polymers are still the most popular carrier for the preparation of amorphous solid dispersions (ASDs). The advantage of this type of carrier is the fast drug release upon dissolution of the water-soluble polymer and thus the initial high degree of supersaturation of the poorly soluble drug. Nevertheless, the risk for precipitation due to fast drug release is a phenomenon that is frequently observed. In this work, we present an alternative carrier system for ASDs where a water-soluble and water-insoluble carrier are combined to delay the drug release and thus prevent this onset of precipitation. Poly(2-alkyl-2-oxazoline)s were selected as a polymer platform since the solution properties of this polymer class depend on the length of the alkyl sidechain. Poly(2-ethyl-2-oxazoline) (PEtOx) behaves as a water-soluble polymer at body temperature, while poly(2-n-propyl-2-oxazoline) (PPrOx) and poly(2-sec-butyl-2-oxazoline) (PsecBuOx) are insoluble at body temperature. Since little was known about the polymer's miscibility behaviour and especially on how the presence of a poorly-water soluble drug impacted their miscibility, a preformulation study was performed. Formulations were investigated with X-ray powder diffraction, differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance spectroscopy. PEtOx/PPrOx appeared to form an immiscible blend based on DSC and this was even more pronounced after heating. The six drugs that were tested in this work did not show any preference for one of the two phases. PEtOx/PsecBuOx on the other hand appeared to be miscible forming a homogeneous blend between the two polymers and the drugs.

Complex amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate): Study of drug release from a hydrophilic insoluble polymeric carrier in the presence and absence of a porosity increasing agent.

Amorphous solid dispersions are nowadays typically made up of a drug compound and a water-soluble polymer. However, recently it has been demonstrated that amorphous solid dispersions based on insoluble polymers have a different and more delayed drug release profile, resulting in a prolonged duration of supersaturation. In this paper, binary and ternary amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate) were prepared through spray drying to further investigate the potential of this type of carrier. As drug release from this matrix system was expected to be dictated by a diffusion-driven process, porosity of the formulation was adjusted by the inclusion of a water-soluble polymer. The solid state of the formulations was characterized with modulated differential scanning calorimetry, X-ray powder diffraction and thermogravimetric analysis. The release of drug and of the porosity increasing agent was measured in acidic and neutral conditions. In addition, the release performance of the spray dried product was compared with the drug release from poly(2-hydroxyethyl methacrylate) beads, which had already been reported in literature. It appeared that in the case of the spray dried poly(2-hydroxyethyl methacrylate), drug and porosity increasing agent could only be released to a certain extent due to entrapment of both compounds in the poly(2-hydroxyethyl methacrylate) network. While the chemical crosslinks of poly(2-hydroxyethyl methacrylate) beads ensured a more rigid structure with sufficient free space for drug diffusion, the spray dried product was susceptible to intense physical crosslinking upon contact with the dissolution medium.