Abstract
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.
Highlights
Active pharmaceutical ingredients (APIs) with a poor aqueous solubility and low dissolution rate are a well-known and frequently encountered phenomenon
This effect has already been described by Katsumoto et al [29] for poly(2-isopropyl-2-oxazoline), which crystallized irreversibly when an aqueous solution was heated above the lower critical solution temperature, which was ascribed to a conformational change of the polymer backbone
In the second heating cycle, two distinct melting endotherms could be observed for the pure PPrOx, meaning that the polymer demonstrated semicrystalline behaviour
Summary
Active pharmaceutical ingredients (APIs) with a poor aqueous solubility and low dissolution rate are a well-known and frequently encountered phenomenon. A rapid drug release been associated with a higher risk for precipitation as this burst release effect will generate a high is often ensured as the water‐soluble polymer will dissolve almost instantaneously in the GI fluids, degree of supersaturation leading to either precipitation if the amorphous solubility is exceeded [7]. Associated with a higher risk for precipitation as this burst release effect will generate a high degree To delay this burst release, researchers started toifinvestigate insoluble carriers for the formulation of supersaturation leading to eitherhave precipitation the amorphous solubility is exceeded [7] or of ASDs. As the carrier will not dissolve, drug release is based on diffusion, creating a more steady precipitation of crystalline material due to the formation of nuclei, followed by crystal growth [8]. Droplets that are created via spray drying on the other hand, are generally larger compared to those obtained with electrospraying and a higher processing temperature will be required to ensure adequate evaporation of the solvent [25,26]
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