Evaluation of the Formulation Parameter-Dependent Redispersibility of API Nanoparticles from Fluid Bed Granules.

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability.

Spray drying of API nanosuspensions: Importance of drying temperature, type and content of matrix former and particle size for successful formulation and process development.

Active pharmaceutical ingredient (API) nanosuspensions from naproxen (Nap) and itraconazole (Itra) stabilized with Kollidon®VA64 (KVA) and sodium dodecyl sulfate (SDS) were produced in two different size classes each by wet media milling. These API nanosuspensions were spray dried with lactose, trehalose and sucrose as matrix formers in different proportions and at different drying temperatures (T). T as well as the API content significantly influenced the redispersibility of the API nanoparticles.

Influence of Formulation Parameters on Redispersibility of Naproxen Nanoparticles from Granules Produced in a Fluidized Bed Process.

The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient's convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.

New Potent DOT1L Inhibitors for Evaluation in Mouse.

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane.

Purpose: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature.

Method: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane.

Trends in the precipitation and crystallization behavior of supersaturated aqueous solutions of poorly water-soluble drugs assessed using synchrotron radiation.

Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly soluble compounds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystallization tendency of six structural analogues belonging to the dihydropyridine class, in an aqueous environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy.

Classification of the crystallization behavior of amorphous active pharmaceutical ingredients in aqueous environments.

Purpose: To classify the crystallization behavior of amorphous active pharmaceutical ingredients (API) exposed to aqueous environments.

Methods: A set of approximately 50 chemically and physically diverse active pharmaceutical ingredients (APIs) was selected for this study. Two experimental setups were employed to characterize the crystallization behavior of the amorphous API in an aqueous environment.

Rapid insight into heating-induced phase transformations in the solid state of the calcium salt of atorvastatin using multivariate data analysis.

Purpose: To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.

Methods: Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases.

Results: By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice.

pH-Induced precipitation behavior of weakly basic compounds: determination of extent and duration of supersaturation using potentiometric titration and correlation to solid state properties.

Purpose: To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material.

Methods: Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined.

Nanoscale mid-infrared evaluation of the miscibility behavior of blends of dextran or maltodextrin with poly(vinylpyrrolidone).

Determining the extent of miscibility of amorphous components is of great importance for certain pharmaceutical systems, in particular for polymer-polymer and polymer-small molecule blends. In this study, the application of standard atomic force microscopy (AFM) measurements combined with nanoscale mid-infrared (mid-IR) spectroscopy was explored to evaluate miscibility in binary polymer blends. The miscibility characteristics of a set of 50/50 (w/w) polymer blends comprising of poly(vinylpyrrolidone) (PVP) with dextran or maltodextrin (DEX) of varying molecular weights (MWs) were investigated.

Nanoscale mid-infrared imaging of phase separation in a drug-polymer blend.

The applicability of nanoscale mid-infrared (mid-IR) spectroscopy for the study of the micro- and nanostructure of pharmaceutical drug-polymer systems was explored. Felodipine-poly(acrylic acid) (PAA) blends were used as model systems. Standard atomic force microscopy evaluation as a function of drug-polymer composition suggested limited miscibility, in line with previous findings.

Molecular weight effects on the miscibility behavior of dextran and maltodextrin with poly(vinylpyrrolidone).

Purpose: To characterize and interpret the miscibility of dextran and maltodextrin with poly(vinylpyrrolidone) (DEX-PVP) as a function of polymer molecular weights.

Methods: Blend miscibility was studied using 4 different molecular weight (MW) grades of DEX combined with 5 MW grades of PVP, over a broad compositional range. Miscibility was evaluated by inspection of glass transition events measured by differential scanning calorimetry (DSC).

Understanding the tendency of amorphous solid dispersions to undergo amorphous-amorphous phase separation in the presence of absorbed moisture.

Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API-polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous-amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity.

Influence of particle size on the ultraviolet spectrum of particulate-containing solutions: implications for in-situ concentration monitoring using UV/Vis fiber-optic probes.

Purpose: To critically evaluate the effect of submicron and micron-sized organic particulates on the ultraviolet (UV) absorption spectra of aqueous systems and assess the applicability of UV/Vis fiber-optic probes for in-situ concentration monitoring in the presence of particles of different sizes.

Methods: UV absorbance spectra were obtained for aqueous felodipine suspensions containing a range of particle sizes (300 nm-400 μm) and suspension concentrations and for methanolic solutions of different concentrations and amorphous films of different thicknesses. Select suspensions were further characterized using nuclear magnetic resonance (NMR) experiments.

Application of mid-IR spectroscopy for the characterization of pharmaceutical systems.

In this article, the use of mid-IR in pharmaceutical settings is reviewed. An overview of mid-IR instrumentation and sampling techniques is provided. Subsequently, different pharmaceutical applications of the technique are described, including structure elucidation and identification, characterization of crystalline (polymorphs, hydrates, salts and co-crystals) and amorphous forms, as well as quantitative and remote sensing applications.

Solubility increases associated with crystalline drug nanoparticles: methodologies and significance.

In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies.

A classification system to assess the crystallization tendency of organic molecules from undercooled melts.

Assessing the viability of an amorphous formulation strategy is of great importance in an era of drug discovery where a large percentage of new molecules have solubility limited dissolution rates, and disruption of the crystal lattice is a potential strategy to improve this process. The objective of the current study was to evaluate the glass forming ability (GFA) of a large data set of organic molecules and also to evaluate potential links between GFA and glass stability (GS). The crystallization tendency from the undercooled melt was evaluated for a group of 51 organic molecules and separated into three separate classes [class (I), class (II), class (III)] based upon the presence/absence of observable crystallization during a heating/cooling/heating cycle, as measured using differential scanning calorimetry (DSC).

Small scale screening to determine the ability of different polymers to inhibit drug crystallization upon rapid solvent evaporation.

In this study, the ability of 7 chemically diverse polymers [Eudragit E100 (E100), poly(acrylic acid) (PAA), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), poly(styrene sulfonic acid) (PSSA), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS)] to inhibit the crystallization of 8 readily crystallizable model compounds [benzamide (BD), phenacetin (PH), flurbiprofen (FB), flufenamic acid (FFA), chlorpropamide (CP), chlorzoxazone (CZ), bifonazole (BI) and lidocaine (LI)] was investigated. Films of the different drug-polymer combinations were prepared by rapid evaporation from solution, using a spin coating method. A total of 7 different drug/polymer weight ratios [90/10, 75/25, 60/40, 50/50, 40/60, 25/75 and 10/90 (w/w)] were evaluated for each drug-polymer combination.

Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation--classification and comparison with crystallization tendency from undercooled melts.

In this study, the crystallization behavior of a variety of compounds was studied following rapid solvent evaporation using spin coating. Initial screening to determine model compound suitability was performed using a structurally diverse set of 51 compounds in three different solvent systems [dichloromethane (DCM), a 1:1 (w/w) dichloromethane/ethanol mixture (MIX), and ethanol (EtOH)]. Of this starting set of 153 drug-solvent combinations, 93 (40 compounds) were selected for further evaluation based on solubility, chemical solution stability, and processability criteria.

2-But-oxy-N-[2-(diethyl-amino)-eth-yl]quinoline-4-carboxamide (dibucaine).

The mol-ecular conformation of the title compound, C(20)H(29)N(3)O(2), is stabilized by an intra-molecular C-H⋯O hydrogen bond. The orientation of the amide group to the ring system is characterized by a C-C-C-O dihedral angle of 137.5 (3)°.

1-[(Biphenyl-4-yl)(phen-yl)meth-yl]-1H-imidazole (bifonazole).

In the title compound, C(22)H(18)N(2), the dihedral angles formed by the imidazole ring with the phenyl ring and the benzene ring of the biphenyl group are 87.02 (5) and 78.20 (4)°, respectively.

2-(Biphenyl-4-yl)acetic acid (felbinac).

The structure of the title compound, C(14)H(12)O(2), displays the expected inter-molecular hydrogen bonding of the carb-oxy-lic acid groups, forming dimers. The dihedral angle between the two aromatic rings is 27.01 (7)°.

Itraconazole/TPGS/Aerosil200 solid dispersions: characterization, physical stability and in vivo performance.

Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.

Downscaling drug nanosuspension production: processing aspects and physicochemical characterization.

In this study, scaling down nanosuspension production to 10 mg of drug compound and evaluation of the nanosuspensions to 1 mg of drug compound per test were investigated. Media milling of seven model drug compounds (cinnarizine-indomethacin-itraconazole-loviride-mebendazole-naproxen-phenytoin) was evaluated in a 96-well plate setup (10, 20, and 30 mg) and a glass-vial-based system in a planetary mill (10, 100, and 1,000 mg). Physicochemical properties evaluated on 1 mg of drug compound were drug content (high-performance liquid chromatography), size [dynamic light scattering (DLS)], morphology (scanning electron microscopy), thermal characteristics (differential scanning calorimetry), and X-ray powder diffraction (XRPD).

Magnetic field assisted nanoparticle dispersion.

Magnetohydrodynamic nanoparticle dispersion is an energy efficient method to deaggregate nanoparticles, combining hydrodynamic forces of turbulent flow with Lorentz forces generated by a magnetic field.