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 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.

Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions.

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the "amorphous solubility", and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.

Representative Scale-Down Lyophilization Cycle Development Using a Seven-Vial Freeze-Dryer (MicroFD).

We have implemented the use of a small-scale, 7-vial Micro Freeze Dryer (MicroFD; Millrock Technology, Inc.) that has the capability to accurately control heat transfer during lyophilization. We demonstrate the ability to fine-tune the MicroFD vial heat transfer coefficient (K) to match the K of vials in a LyoStar III laboratory-scale unit.

Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy.

Liquid crystalline (LC) materials and their nonmedical applications have been known for decades, especially in the production of displays; however, the pharmaceutical implications of the LC state are inadequately appreciated, and the misunderstanding of experimental data is leading to possible errors, especially in relation to the physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems, taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous but a vitrified smectic (vSm) phase with a glass transition temperature of 59.

Phase Behavior of Drug-Hydroxypropyl Methylcellulose Amorphous Solid Dispersions Produced from Various Solvent Systems: Mechanistic Understanding of the Role of Polymer using Experimental and Theoretical Methods.

The vast majority of studies evaluating amorphous solid dispersions (ASDs) utilize solvent evaporation techniques as the preparation method. However, the impact of the solvent/cosolvent system properties on the polymer conformation and the phase behavior of the resultant drug/polymer blends is poorly understood. Herein, we investigate the influence of solvent properties on the phase behavior of ASDs containing itraconazole (ITZ) and hydroxypropylmethyl cellulose (HPMC) prepared using spin coating from binary/ternary cosolvent systems containing alkyl alcohols, dichloromethane (DCM), and water.

In situ monitoring of nanoparticle formation: Antisolvent precipitation of azole anti-fungal drugs.

In this work we report the effect of stabilizer choice and concentration on nanoparticle (NP) stability over time. Three different BCS class II active pharmaceutical ingredient (APIs): itraconazole (ITR), ketoconazole (KETO) and posaconazole (POS) were chosen due to their poor aqueous solubility and closely related chemical structures. Polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether (DMPEG) with a molecular weight of 2000 Da were included as stabilisers.

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating.

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals.

Insights into Water-Induced Phase Separation in Itraconazole-Hydroxypropylmethyl Cellulose Spin Coated and Spray Dried Dispersions.

For amorphous solid dispersions, understanding the phase behavior of a given drug-polymer blend and factors that influence miscibility is crucial to designing an optimally performing formulation. However, it can be challenging to fully map the phase behavior of some systems, especially those produced using a cosolvent system. In this study, a comprehensive investigation of phase separation in itraconazole-hydroxypropylmethylcellulose (ITZ-HPMC) blends fabricated using solvent evaporation processes, including spin coating and spray drying, has been carried out.

A Comparative Study on the Performance of Inert and Functionalized Spheres Coated with Solid Dispersions Made of Two Structurally Related Antifungal Drugs.

Fluid bed coating offers potential advantages as a formulation platform for amorphous solid dispersions (ASDs) of poorly soluble drugs, being a one-step manufacturing process which could reduce the risk of phase separation associated with multiple step manufacturing approaches. However, the impact of the physicochemical nature of nonpareil carriers on the properties and drug release from the ASDs has not been studied in detail. In this work, tartaric acid (TAP) and microcrystalline cellulose (CEL) spheres were chosen as examples of functional and inert beads, respectively.

Crystal Habits of Itraconazole Microcrystals: Unusual Isomorphic Intergrowths Induced via Tuning Recrystallization Conditions.

The external appearance of a crystal of active pharmaceutical ingredient (API), usually referred to as a crystal habit, has a substantial impact on the API's physicochemical and physiochemical properties and, subsequently, its pharmaceutical performance. In this work, we investigate the role of different parameters of antisolvent crystallization impacting on the itraconazole (ITR) crystal habit and how this crystal habit manipulation, including crystal intergrowth, can affect crystal interactions with water molecules. Three distinct isomorphic crystal habits of ITR, a twinned blade-shaped (CHtw), a plate-shaped (CHpl), and a flat sheet-shaped with dendritic ends (CHsh), were obtained by controlling crystallization conditions.

Mesophase and size manipulation of itraconazole liquid crystalline nanoparticles produced via quasi nanoemulsion precipitation.

The fabrication of drug nanoparticles (NPs) with process-mediated tunable properties and performances continues to grow rapidly during the last decades. This study investigates the synthesis and phase tuning of nanoparticulate itraconazole (ITR) mesophases using quasi nanoemulsion precipitation from acetone/water systems to seek out an alternative pathway to the nucleation-based NP formation. ITR liquid crystalline (LC) phases were formed and nematic-smectic mesomorphism was achieved via controlling solvent:antisolvent temperature difference (ΔTS:AS).

Heat induced evaporative antisolvent nanoprecipitation (HIEAN) of itraconazole.

Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug's apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below 250 nm, using heat induced evaporative antisolvent nanoprecipitation (HIEAN) from acetone was developed.