Computational Support to Explore Ternary Solid Dispersions of Challenging Drugs Using Coformer and Hydroxypropyl Cellulose.

A majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e.

Phase homogeneity in ternary amorphous solid dispersions and its impact on solubility, dissolution and supersaturation - Influence of processing and hydroxypropyl cellulose grade.

As performance of ternary amorphous solid dispersions (ASDs) depends on the solid-state characteristics and polymer mixing, a comprehensive understanding of synergistic interactions between the polymers in regard of dissolution enhancement of poorly soluble drugs and subsequent supersaturation stabilization is necessary. By choosing hot-melt extrusion (HME) and vacuum compression molding (VCM) as preparation techniques, we manipulated the phase behavior of ternary efavirenz (EFV) ASDs, comprising of either hydroxypropyl cellulose (HPC)-SSL or HPC-UL in combination with Eudragit® L 100-55 (EL 100-55) (50:50 polymer ratio), leading to single-phased (HME) and heterogeneous ASDs (VCM). Due to higher kinetic solid-state solubility of EFV in HPC polymers compared to EL 100-55, we visualized higher drug distribution into HPC-rich phases of the phase-separated ternary VCM ASDs via confocal Raman microscopy.

Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose.

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) ntaining the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance.

Physiological Buffer Effects in Drug Supersaturation - A Mechanistic Study of Hydroxypropyl Cellulose as Precipitation Inhibitor.

Phosphate buffer is predominantly used instead of the more physiological bicarbonate buffer, as the latter requires a technical solution of adequate gas mixing. Recent pioneering work on how bicarbonate buffer affected drug supersaturation revealed interesting effects that call for more mechanistic understanding. Therefore, this study used hydroxypropyl cellulose as a model precipitation inhibitor and real-time desupersaturation testing was conducted with the drugs bifonazole, ezetimibe, tolfenamic acid and triclabendazole.

Boost of solubility and supersaturation of celecoxib via synergistic interactions of methacrylic acid-ethyl acrylate copolymer (1:1) and hydroxypropyl cellulose in ternary amorphous solid dispersions.

A current trend in the development of amorphous solid dispersions (ASDs) is the combination of two polymers for synergistic enhancement in supersaturation of poorly soluble drugs. We investigated the supersaturation potential of celecoxib (CXB) using combinations of methacrylic acid-ethyl acrylate copolymer (1:1) (EL 100-55) and hydroxypropyl cellulose (HPC) SSL. Initially, the supersaturation potential of single polymers and combinations in various ratios was assessed.

Hydroxypropyl Cellulose for Drug Precipitation Inhibition: From the Potential of Molecular Interactions to Performance Considering Microrheology.

There has been recent interest in using hydroxypropyl cellulose (HPC) for supersaturating drug formulations. This study investigated the potential for molecular HPC interactions with the model drug celecoxib by integrating novel approaches in the field of drug supersaturation analysis. Following an initial polymer characterization study, quantum-chemical calculations and molecular dynamics simulations were complemented with results of inverse gas chromatography and broadband diffusing wave spectroscopy.

and assessment of hydroxypropyl cellulose as functional additive for enabling formulations containing itraconazole.

Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays.

Phase behavior of ASDs based on hydroxypropyl cellulose.

Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies.

3D printed opioid medicines with alcohol-resistant and abuse-deterrent properties.

In the past decade, prescriptions for opioid medicines have been exponentially increasing, instigating opioid abuse as a global health crisis associated with high morbidity and mortality. In particular, diversion from the intended mode of opioid administration, such as injecting and snorting the opioid, is a major problem that contributes to this epidemic. In light of this, novel formulation strategies are needed to support efforts in reducing the prevalence and risks of opioid abuse.

Direct powder extrusion 3D printing: Fabrication of drug products using a novel single-step process.

Three-dimensional (3D) printing is revolutionising how we envision manufacturing in the pharmaceutical field. Here, we report for the first time the use of direct powder extrusion 3D printing: a novel single-step printing process for the production of printlets (3D printed tablets) directly from powdered materials. This new 3D printing technology was used to prepare amorphous solid dispersions of itraconazole using four different grades of hydroxypropylcellulose (HPC - UL, SSL, SL and L).

Powder bed 3D-printing of highly loaded drug delivery devices with hydroxypropyl cellulose as solid binder.

3D-printing is a promising tool to pave the way to the widespread adaption of individualized medicine. Several printing techniques have been investigated and introduced to pharmaceutical research. Until now, only one 3D-printed medicine is approved on the US market.

Competing for water: A new approach to understand disintegrant performance.

The understanding of tablet disintegration is still incomplete as not all involved factors and processes are known or accounted for. E.g.

Convenient replacement of the hydroxy by an amino group in 4 hydroxycoumarin and 4-hydroxy-6-methyl-2-pyrone under microwave irradiation.

The reaction of 4-hydroxycoumarin (1) with some primary amines 2a-h and morpholine (2i) under microwave irradiation occurred without opening of the lactone ring to give N-substituted 4-aminocoumarins 3a-i in excellent yields. Under the same experimental conditions, 4-hydroxy-6-methyl-2-pyrone (4) reacted with benzylamine (2e) or 2-phenyl- ethylamine (2f) to give the corresponding N,N'-disubstituted 4-amino-6-methyl-2-pyridones 5e,f. The main advantages of this procedure are dramatically shortened reaction times, higher amine utilization and considerably improved yields.

Pechmann reaction promoted by boron trifluoride dihydrate.

The Pechmann reaction of substituted phenols 1a-e with methyl acetoacetate (2) can be activated by boron trifluoride dihydrate (3) to give the corresponding 4-methyl- coumarin derivatives 4a-e in excellent yield (98-99 %).

Fries rearrangement of aryl formates: a mechanistic study by means of 1H, 2H, and 11B NMR spectroscopy and DFT calculations.

1H, 2H, and 11B NMR spectroscopy has been used to study the mechanism of the Fries rearrangement of aryl formates promoted by boron trichloride by monitoring both the substrate and the Lewis acid. DFT calculations were employed to investigate the energetics of several reaction paths and to calculate NMR chemical shifts of key intermediates and products. After the formation of a 1:1 substrate-Lewis acid adduct, the rearrangement proceeds in two steps, beginning with the cleavage of the ester bond and the release of formyl chloride in situ, which, in turn, acts as a formylating agent, introducing an aldehydic functionality into the aromatic ring.

Charge separation and efficient light energy conversion in sensitized mesoscopic solar cells based on binary ionic liquids.

A 7.4% power conversion efficiency at air mass (AM) 1.5 full sunlight was reached with a mesoscopic solar cell employing a new binary ionic liquid electrolyte composed of 1-propyl-3-methylimidazolium iodide and 1-ethyl-3-methylimidazolium tricyanomethanide in conjunction with the amphiphilic ruthenium complex NaRu(4-carboxylic acid-4'-carboxylate)(4,4'-dinonyl-2,2'-bipyridine)(NCS)(2), coded as Z-907Na.

Efficient liquid-phase synthesis of 2'-hydroxychalcones.

The condensation of 2'-hydroxyacetophenone (1) with aromatic aldehydes (2) in a well closed vessel using microwave irradiation or classical heating at 132 degrees C, provides a fast and simple method for the liquid-phase synthesis of 2'-hydroxychalcones without formation of by-products. Antiproliferative activity of these compounds were evaluated using MCF-7 cells.