Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior.

The use of amorphous solid dispersions (ASDs) in commercial drug products has increased in recent years due to the large number of poorly soluble drugs in the pharmaceutical pipeline. However, the release behavior of ASDs is complex and remains not well understood. Often, the drug release from ASDs is rapid and complete at lower drug loadings (DLs) but becomes slow and incomplete at higher DLs. The DL where release becomes hindered is termed the limit of congruency (LoC). Currently, there are no approaches to predict the LoC. However, recent findings show that one potential cause leading to the LoC is a change in phase morphology after water-induced phase separation at the ASD/solution interface. In this study, the phase behavior of ASDs in contact with aqueous solutions was described thermodynamically by constructing experimental and computational ternary phase diagrams, and these were used to predict morphology changes and ultimately the LoC. Experimental ternary phase diagrams were obtained by equilibrating ASD/water mixtures over time. Computational ternary phase diagrams were obtained by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). The morphology of the hydrophobic phase was studied with fluorescence confocal microscopy. It was demonstrated that critical point (plait point) composition approximately corresponded to the ASD DL, where the hydrophobic phase, formed during phase separation, became interconnected and hindered ASD release. This work provides mechanistic insights into the ASD release behavior and highlights the potential of in silico ASD design using phase diagrams.

Dissolution Mechanisms of Amorphous Solid Dispersions: A Close Look at the Dissolution Interface.

Despite the recent success of amorphous solid dispersions (ASDs) at enabling the delivery of poorly soluble small molecule drugs, ASD-based dosage forms are limited by low drug loading. This is partially due to a sharp decline in drug release from the ASD at drug loadings surpassing the 'limit of congruency' (LoC). In some cases, the LoC is as low as 5% drug loading, significantly increasing the risk of pill burden. Despite efforts to understand the mechanism responsible for the LoC, a clear picture of the molecular processes occurring at the ASD/solution interface remains elusive. In this study, the ASD/solution interface was studied for two model compounds formulated as ASDs with copovidone. The evolution of a gel layer and its phase behavior was captured in situ with fluorescence confocal microscopy, where fluorescent probes were added to label the hydrophobic and hydrophilic phases. Phase separation was detected in the gel layer for most of the ASDs. The morphology of the hydrophobic phase was found to correlate with the release behavior, where a discrete phase resulted in good release and a continuous phase formed a barrier leading to poor release. The continuous phase formed at a lower drug loading for the system with stronger drug-polymer interactions. This was due to incorporation of the polymer into the hydrophobic phase. The study highlights the complex molecular and phase behavior at the ASD/solution interface of copovidone-based ASDs and provides a thermodynamic argument for qualitatively predicting the release behavior based on drug-polymer interactions.

Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Drug Load and Molecular Interactions.

High drug load amorphous solid dispersions (ASDs) have been a challenge to formulate partially because drug release is inhibited at high drug loads. The maximum drug load prior to inhibition of release has been termed the limit of congruency (LoC) and has been most widely studied for copovidone (PVPVA)-based ASDs. The terminology was derived from the observation that below LoC, the polymer controlled the kinetics and the drug and the polymer released congruently, while above LoC, the release rates diverged and were impaired. Recent studies show a correlation between the LoC value and drug-polymer interaction strength, where a lower LoC was observed for systems with stronger interactions. The aim of this study was to investigate the causality between drug-PVPVA interaction strength and LoC. Four chemical analogues with diverse abilities to interact with PVPVA were used as model drugs. The distribution of the polymer between the dilute aqueous phase and the insoluble nanoparticles containing drug was studied with solution nuclear magnetic resonance spectroscopy and traditional separation techniques to understand the thermodynamics of the systems in a dilute environment. Polymer diffusion to and from ASD particles suspended in aqueous solution was monitored for drug loads above the LoC to investigate the thermodynamic driving force for polymer release. The surface composition of ASD compacts before and after exposure to buffer was studied with Fourier transform infrared spectroscopy to capture potential kinetic barriers to release. It was found that ASD compacts with drug loads above the LoC formed an insoluble barrier on the surface that was in pseudo-equilibrium with the aqueous phase and prevented further release of drugs and polymers during dissolution. The insoluble barrier contained a substantial amount of the polymer for the strongly interacting drug-polymer systems. In contrast, a negligible amount was found for the weakly interacting systems. This observation provides an explanation for the ability of strongly interacting systems to form an insoluble barrier at lower drug loads. The study highlights the importance of thermodynamic and kinetic factors on the dissolution behavior of ASDs and provides a potential framework for maximizing the drug load in ASDs.

Physicochemical Characterization and Prospecting Biological Activity of Some Authentic Transylvanian Essential Oils: Lavender, Sage and Basil.

Essential oils are a category of agro-based industrial products experiencing increasing demand. In this research, three essential oils obtained by steam distillation from lavender, sage and basil plants cultivated in temperate continental conditions of Transylvania were investigated for chemical composition, physical characteristics and biological activity (antimicrobial and cytotoxic effect on cancer cell lines). The number of identified compounds varied: 38 for lavender, 29 for sage essential oil and 41 for basil. The volatile profile was dominated by terpenes and terpenoids (>80%). Major components were beta-linalool and linalool acetate in lavender essential oil; thujones and camphor in sage essential oil; beta-linalool, thujone, camphor and eucalyptol in basil essential oil. Refractive index of the essential oils was lowest for lavender and highest for sage. Antibacterial activity was strongest for basil, moderate for lavender and weakest for sage essential oil. The most active on both colon adenocarcinoma (Caco-2) and ovary carcinoma (A2780) was sage essential oil.

Impact of Drug-Polymer Intermolecular Interactions on Dissolution Performance of Copovidone-Based Amorphous Solid Dispersions.

For poorly soluble drugs formulated as amorphous solid dispersions (ASDs), fast and complete release with the generation of drug-rich colloidal particles is beneficial for optimizing drug absorption. However, this ideal dissolution profile can only be achieved when the drug releases at the same normalized rate as the polymer, also known as congruent release. This phenomenon only occurs when the drug loading (DL) is below a certain value. The maximal DL at which congruent release occurs is defined as the limit of congruency (LoC). The purpose of this study was to investigate the relationship between drug chemical structure and LoC for PVPVA-based ASDs. The compounds investigated shared a common scaffold substituted with different functional groups, capable of forming hydrogen bonds only, halogen bonds only, both hydrogen and halogen bonds, or nonspecific interactions only with the polymer. Intermolecular interactions were studied and confirmed by X-ray photoelectron spectroscopy and infrared spectroscopy. The release rates of ASDs with different DLs were investigated using surface area normalized dissolution. ASDs with hydrogen bond formation between the drug and polymer had lower LoCs, while compounds that were only able to form halogen bonds or nonspecific interactions with the polymer achieved considerably higher LoCs. This study highlights the impact of different types of drug-polymer interactions on ASD dissolution performance, providing insights into the role of drug and polymer chemical structures on the LoC and ASD performance in general.

Interaction of Polymers with Enzalutamide Nanodroplets-Impact on Droplet Properties and Induction Times.

Amorphous solid dispersions (ASDs), which consist of a drug dispersed in a polymeric matrix, are increasingly being applied to improve the in vivo performance of poorly water-soluble drugs delivered orally. The polymer is a critical component, playing several roles including facilitating drug release from the ASD, as well as delaying crystallization from the supersaturated solution generated upon dissolution. Certain ASD formulations dissolve to produce amorphous drug-rich nanodroplets. The interaction of the polymer with these nanodroplets is poorly understood but is thought to be important for inhibiting crystallization in these systems. In this study, the impact of ionic polymers on the crystallization kinetics of enzalutamide from supersaturated solutions containing different amounts of amorphous nanodroplets was evaluated by determination of nucleation induction times. The amount of the polymer associated with the drug nanodroplets was also determined. When comparing two polymers, hydroxypropylmethyl cellulose acetate succinate (HPMCAS) and Eudragit E PO, it was found that the crystallization tendency and physical properties of the drug nanodroplets varied in the presence of these two polymers. Both polymers distributed between the aqueous phase and the drug-rich nanodroplets. A greater amount of Eudragit E PO was associated with the drug-rich nanodroplets. Despite this, Eudragit E PO was a less-effective crystallization inhibitor than HPMCAS in systems containing nanodroplets. In conclusion, in supersaturated solutions containing amorphous nanodroplets, the extent of association of a polymer with the drug nanodroplet does not solely predict crystallization inhibition.

Combination of single-molecule magnet behaviour and luminescence properties in a new series of lanthanide complexes with tris(pyrazolyl)borate and oligo(ß-diketonate) ligands.

A series of tris(pyrazolyl)borate mono-, di- and trinuclear complexes, [Tp2Ln]nX (Ln = Eu, Tb, Gd, Dy, Xn- = various mono-, bis- and tris(ß-diketonates) has been prepared. The Tb3+ and Dy3+ complexes are luminescent single molecular magnets (SMM) and exhibit luminescence quantum efficiencies up to 73% for the Tb3+ and 4.4% for the Dy3+ compounds. Similar Eu3+ complexes display bright emission only at lower temperatures. The Dy3+ and Tb3+ complexes possess SMM behavior in a non-zero dc field at low temperatures, while the polynuclear Dy3+ complexes also show slow magnetic relaxation even in zero dc field up to 8 K. Ueff-values determined from dynamic magnetic measurements were up to 31 and 6 cm-1 for the Dy3+ and Tb3+ complexes, respectively. It was found that within a series of Dy3+ and Tb3+ compounds, Ueff and luminescence quantum yields decreased with increasing nuclearity of the compounds and a shortening of the intramolecular Ln-Ln distance. ΔOrbach-values estimated from low-temperature luminescence spectra were significantly higher than those obtained from ac magnetic data, which may be due to involvement of additional processes in the relaxation mechanism (quantum tunneling, Raman, direct) reducing the energy barrier. Some of the Tb3+-compounds also display metal-centred electroluminescence, giving them potential as emitting layers in LEDs.

Assessing Physical Stability of Colloidal Dispersions Using a Turbiscan Optical Analyzer.

The physical stability of aqueous colloidal dispersions containing highly concentrated droplets of poorly water-soluble drugs has recently been identified as one of the main considerations in developing amorphous solid dispersions (ASDs). The Turbiscan analyzer, an instrument based on multiple light scattering technology, was employed for the first time to assess colloidal dispersions with ritonavir as the model compound. The physical instability of ritonavir-rich droplets was monitored directly with and without the presence of candidate polymer additives at different drug concentrations and temperatures. The mechanism of the observed instability was confirmed to be coalescence of liquid droplets, based on the low glass transition temperature of water-saturated amorphous ritonavir determined using a newly developed experimental procedure. Temperature and solvent composition, within the range studied, have little influence on the kinetics of ritonavir coalescence. On the contrary, a higher concentration of drug, i.e., more droplets per unit volume, greatly accelerates the coalescence process. In addition, polymers with varying degrees of hydrophobicity resulted in different levels of effectiveness in stabilization, which is likely related to the strength of drug-polymer interactions and the corresponding differences in surface adsorption. This work demonstrates that the Turbiscan optical analyzer can be used as a rapid screening tool that provides a first-pass, high-throughput feasibility ranking of different excipients and additives to support the development of ASD formulations.