Active pharmaceutical ingredients in dry powder inhaler (DPI) formulations need to have well-defined material properties. These can be influenced by the choice of processing parameters. The impact of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-pentanol and acetone on the crystallisation of beclomethasone dipropionate (BDP), an anti-inflammatory agent, was studied using infrared spectroscopy, X-ray powder diffraction, thermal analysis, gas chromatography with mass spectrometry, scanning electron microscopy and atomic force microscopy. Crystallisation from methanol, 1-butanol and 1-pentanol resulted in particulate BDP with a predominantly anhydrous character. In contrast, BDP solvates were formed using ethanol, 1-propanol, 2-propanol and acetone. The physical properties of the solvates were found to depending on the solvent used. Single crystal X-ray diffraction and solid state NMR confirmed the inclusion of ethanol, 1-propanol, 2-propanol and acetone within the crystalline BDP host. Based on NMR titration, DOSY, thermal analysis and XRD, the intermolecular interactions leading to the preferred formation of either solvated or anhydrous BDP from solution were analysed. The same combination of techniques can be potentially used to predict the formation of solvated compounds in general by assessing the forces acting between the host and guest molecules and analysing their impact on solvate formation and stability. The size, shape and surface characteristics of the crystalline particles were found to be influenced by the choice of solvent in a reproducible way. These properties were also found to translate to the anhydrous products prepared from the solvates through controlled desolvation. Thus, anhydrous BDP with defined surface properties were prepared. AFM was used to evaluate the adhesive and cohesive forces between lactose, a commonly used carrier material in DPI formulations, and anhydrous BDP prepared from the BDP ethanol, 1-propanol and 2-propanol solvates. The interparticulate forces in a DPI formulation depend to a large part on the surface roughness of the drug particles and the carrier material. It was demonstrated that the surface roughness of anhydrous BDP can be controlled through the manufacturing process. This is an important step towards the targeted preparation of well-defined formulations which have the potential to be tailored to specific patient needs.
|Publication status||Unpublished - 2018|
- CRYSTALLINE BECLOMETHASONE DIPROPIONATE, PHYSICOCHEMICAL PROPERTIES