The formation of colloidal drug aggregates of lipophilic drugs is thought to be of relevance for the oral delivery of poorly water-soluble drugs. In this study, the underlying basis for colloid formation from amorphous solid dispersions and the impact of additives on colloidal stability were evaluated. A relationship was found between the concentration at which colloidal droplets formed upon dissolution of an amorphous solid dispersion and the liquid-liquid phase separation (LLPS) transition concentration, whereby the latter is related to the theoretical amorphous "solubility" value. The composition of the dispersed phase in ritonavir-polymer-water solutions was confirmed to be a noncrystalline, ritonavir-rich droplet phase. Additives were found to impact the size, stability, and crystallization behavior of the colloidal phase. In general, charged additives reduced the kinetics of droplet coalescence, but had a variable effect on crystallization kinetics, either promoting or inhibiting crystallization. Through proper selection of formulation components, it thus appears possible to promote the formation of ∼ 250-350 nm colloidal droplets of ritonavir following dissolution of an amorphous solid dispersion, and to inhibit coalescence and crystallization from these two-phase supersaturated solutions.

Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much better solubility under acidic conditions due to amine protonation. The improved solubility in an acid environment is confounded by the poor chemical stability of clarithromycin that is quite labile toward acid-catalyzed degradation. This creates a complex system under gastrointestinal (GI) conditions: dissolution in the stomach, degradation, potential for precipitation in the small intestine, and interplay with the formulation components. We report herein a study of amorphous solid dispersion (ASD) of CLA with carboxyl-containing cellulose derivatives, which have recently been shown to be excellent ASD matrices for maximizing oral bioavailability. This approach was intended to improve CLA solubility in neutral media while minimizing release in an acid environment, and thereby increase its uptake from the small intestine. Amorphous polymer/CLA nanoparticles were also prepared by high-shear mixing in a multi-inlet vortex mixer (MIVM). Different extents of release were observed at low pH from the various formulations. Thus the solubility increase from nanosizing was deleterious to the concentration of intact CLA obtained upon reaching small intestine conditions; the high extent of release at gastric pH led to complete degradation of CLA. Using pH-switch experiments, it was possible to separate the effects of loss of CLA from solution by crystallization vs. that from chemical degradation. It was found that the hydrophobic cellulose derivative cellulose acetate adipate propionate (CAAdP) was effective at protecting CLA from dissolution in the stomach, and preventing CLA decomposition at low pH; 54% of CLA in CAADP ASD was released intact, vs. 0% and 6% from HPMCAS and CMCAB ASDs, respectively. We conclude that protection against degradation is central to enhancing overall release of intact CLA from ASD formulations; the formulations studied herein have great promise for simultaneous CLA solubility enhancement and protection from loss to chemical degradation, thereby reducing dose requirements and potentially decreasing colonic exposure to CLA (reduced colonic exposure is expected to minimize killing of beneficial colonic bacteria by CLA).

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Pine wood samples were used as model feedstock to study the properties of catalytic fast pyrolysis oils. The influence of two commercial zeolite catalysts (BASF and SudChem) and pretreatment of the pine wood with sodium hydroxide on pyrolysis products were investigated. The pyrolysis oils were first fractionated using column chromatography and characterized using GC-MS. Long chain aliphatic hydrocarbons, levoglucosan, aldehydes and ketones, guaiacols/syringols, and benzenediols were the major compounds identified in the pyrolysis oils. The catalytic pyrolysis increased the polycyclic hydrocarbons fraction. Significant decreases in phthalate derivatives using SudChem and long chain aliphatics using BASF catalyst were observed. Significant amounts of aromatic heterocyclic hydrocarbons and benzene derivatives were formed, respectively, using BASF and SudChem catalysts. Guaiacyl/syringyl and benzenediols derivatives were partly suppressed by the zeolite catalysts, while the sodium hydroxide treatment enriched phenolic derivatives. Zeolite catalyst and sodium hydroxide were employed together; they showed different results for each catalyst.

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