Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers.

In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

Mechanodegradation of Polymers: A Limiting Factor of Mechanochemical Activation in the Production of Amorphous Solid Dispersions by Cryomilling.

In this study, we report on the influence of mechanochemical activation on the chemical stability of amorphous solid dispersions made up of indomethacin and hydroxypropyl methyl cellulose (HPMC), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone vinylacetate) (PVPVA), or Soluplus. In agreement with our recently published work, all applied carriers were found to be prone to polymer degradation. Covalent bonds within the polymers were cleaved and mechanoradicals were generated. Furthermore, decomposition of indomethacin was also observed but occurred only in the presence of polymers. Hence, it is proposed that the generated mechanoradicals from the polymers are responsible for the chemical degradation of indomethacin. Our study also strongly suggests the existence of a critical polymer- and process-dependent molecular weight limit "M∞", below which only limited mechanodegradation takes place since the lower-molecular-weight polymer PVP K12PF had a less profound influence on the degradation of indomethacin in comparison to PVP K25.

Depletion stabilization in nanoparticle-polymer suspensions: multi-length-scale analysis of microstructure.

We study the mechanism of depletion stabilization and the resultant microstructure of aqueous suspensions of nanosized silica and poly(vinyl alcohol) (PVA). Rheology, small-angle light scattering (SALS), and small-angle X-ray scattering (SAXS) techniques enable us to analyze the microstructure at broad length scale from single particle size to the size of a cluster of aggregated particles. As PVA concentration increases, the microstructure evolves from bridging flocculation, steric stabilization, depletion flocculation to depletion stabilization. To our surprise, when depletion stabilization occurs, the suspension shows the stabilization at the cluster length scale, while maintaining fractal aggregates at the particle length scale. This sharply contrasts previously reported studies on the depletion stabilization of microsized particle and polymer suspensions, which exhibits the stabilization at the particle length scale. On the basis of the evaluation of depletion interaction, we propose that the depletion energy barrier exists between clusters rather than particles due to the comparable size of silica particle and the radius gyration of PVA.

Gastro-resistant encapsulation of amorphous solid dispersions containing darunavir by coaxial electrospraying.

The relatively simple technique of coaxial electrospraying allows to produce core-shell microparticles with potentially high encapsulation efficiencies. In this study, amorphous solid dispersions of a hydroxypropyl methylcellulose or polyvinlypyrrolidone based polymer matrix containing the active pharmaceutical ingredient darunavir were coated with a gastro-resistant shell polymer that does not dissolve at lower pH present in the stomach, but only later at a higher pH in the small intestine. A multitude of shell polymers were tested with the aim to identify a material that limits the drug release to less than 10% after two hours at a pH of 1 to comply with the European Pharmacopoeia regarding gastro-resistant formulations. In parallel, the core-shell structure of the particles was determined with confocal imaging and their surface morphology with SEM imaging. While the structural analysis revealed significant differences between the different formulations, all investigated shell polymers exhibited a burst drug release followed by a slow release for the remainder of a two hour period. Ultimately, the shell copolymer poly(methacrylic acid-co-methyl methacrylate), in particular for a monomer ratio 1/2, resulted consistently in darunavir release below the 10% upper limit compared to the other tested polymers, where such low releases were inaccessible. Further investigation of this shell polymer revealed that both the monomer ratio of methacrylic acid to methyl methacrylate in the copolymer and the utilized solvent are determining factors in the release performance of the final particles.

Fixed dose combinations for cardiovascular treatment via coaxial electrospraying: Coated amorphous solid dispersion particles.

As a result of an aging population, the need for fixed dose combinations in the treatment of cardiovascular diseases, that are easy to swallow and administer, has been growing remarkably. In this work, the feasibility of coaxial electrospraying (CES) was investigated to manufacture in one single step, a powder of individually coated particles containing atenolol (ATE), lovastatin (LOV) and acetylsalicylic acid (ASA). To improve the dissolution rate of the poorly water soluble LOV, an amorphous solid dispersion (ASD) of LOV with Soluplus® (SOL) was formulated and Eudragit S100®, an enteric copolymer that only dissolves above pH 7, was applied as coating to avoid LOV hydrolysis in acidic medium. Furthermore, ATE was added to the inner ASD compartment and the acidic ASA was embedded in the coating layer. With regard to the uncoated ASD particles, which were prepared with single nozzle electrospraying, the rate and extent of the LOV dissolution was increased, even to an extent of 100% for the 1/1/6 (ATE/LOV/SOL) ratio. Hence, this ratio was selected and coated particles with proper release of the three APIs could be successfully produced via CES. However, a peculiar behaviour of the coating performance was observed. Regarding LOV, the enteric layer of the particles performed as expected in acidic medium and supersaturation was obtained after the switch to a neutral pH, but in contrast, over 50% of ATE was released after 90 min in acidic medium. Nonetheless, hardly any ATE was released under acidic circumstances from ATE tablets that were, as a benchmark, manually dip-coated with Eudragit S100®. Two different model APIs, namely paracetamol (well soluble) and fenofibrate (poorly soluble) were tested as well, revealing similar discrepancy in the coating performance. The coating layer formed during CES is most likely less dense as compared to the layer produced with tablet coating and consequently, more permeable for highly soluble APIs, but not for the poorly soluble compounds.

Amorphous solid dispersions of darunavir: Comparison between spray drying and electrospraying.

The interest in using electrospraying as a manufacturing method for amorphous solid dispersions has grown remarkably. However, the impact of formulation and process parameters needs further clarification. In this study, amorphous solid dispersions of darunavir and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS) and polyvinylpyrrolidone K-30 (PVP) were prepared with electrospraying and spray drying, in order to compare both solvent based manufacturing techniques. Our results revealed that electrospraying was as successful as spray drying. The formulations prepared with the two methods were amorphous and had similar characteristics concerning the residual solvent and drug release. Although differences in the morphology and the particle size distributions were observed, this was not reflected in the pharmaceutical performance of the formulations. Electrosprayed amorphous solid dispersions made up of darunavir and PVP were studied in more detail by means of a full factorial experimental design. The impact of two process and two formulation parameters on the properties of the amorphous solid dispersions was determined. The feed flow rate had a significant effect on the diameter and morphology of the particles whereas the tip-to-collector distance had no significant impact within the tested range. The drug loading influenced the homogeneity and the residual solvent, and the total solids concentration had an impact on the homogeneity and the morphology.

Electrospraying of polymer solutions: Study of formulation and process parameters.

Over the past decade, electrospraying has proven to be a promising method for the preparation of amorphous solid dispersions, an established formulation strategy to improve the oral bioavailability of poorly soluble drug compounds. Due to the lack of fundamental knowledge concerning adequate single nozzle electrospraying conditions, a trial-and-error approach is currently the only option. The objective of this paper is to study/investigate the influence of the different formulation and process parameters, as well as their interplay, on the formation of a stable cone-jet mode as a prerequisite for a reproducible production of monodisperse micro- and nanoparticles. To this purpose, different polymers commonly used in the formulation of solid dispersions were electrosprayed to map out the workable parameter ranges of the process. The experiments evaluate the importance of the experimental parameters as flow rate, electric potential difference and the distance between the tip of the nozzle and collector. Based on this, the type of solvent and the concentration of the polymer solutions, along with their viscosity and conductivity, were identified as determinative formulation parameters. This information is of utmost importance to rationally design further electrospraying methods for the preparation of amorphous solid dispersions.

Encapsulating darunavir nanocrystals within Eudragit L100 using coaxial electrospraying.

Electrospraying is renowned for its simplicity and versatility, and which can effectively produce particles with well-controlled size, size distribution, particle shape, morphology and microstructure at the nano/microscale. In this study, coaxial electrospraying was used to investigate its feasibility for preparing nanoparticles made up of nanocrystals encapsulated within a polymer shell. Firstly, aqueous nanosuspensions of darunavir were prepared by wet media milling. Then the nanosuspension and solutions of an enteric polymer, Eudragit L100, were used as the inner/core liquid and outer/shell liquid in a coaxial electrospraying setup, respectively. As long as a sufficiently high voltage was applied, a stable Taylor cone-jet mode was obtained to produce very fine core-shell structure nanoparticles with high darunavir encapsulation efficiency of approximately 90%. The influence of the starting nanosuspension and the flow rates on the characteristics of the final electrosprayed particles was also evaluated. Using an optimized nanosuspension with reasonable size, size distribution and flow rates, the enteric coating layer reduced the percentage of DRV release in acidic medium in the in vitro dissolution test to ca. 20%. This study indicates that coaxial electrospraying is a potential and unique technique for encapsulating drug nanocrystals within a polymeric shell.

Biofilm-induced changes to the composite surface.

OBJECTIVES: Composites may undergo biodegradation in the oral cavity. The objective was to investigate the effect of single- and multi-species biofilms on the surface roughness and topography of two composites. METHODS: Disk-shaped specimens of a paste-like, Bis-GMA-free (Gradia Direct Anterior, GC), and a flowable, Bis-GMA-based composite (Tetric EvoFlow, Ivoclar-Vivadent) were prepared. After ethylene-oxide sterilization (38°C), specimens (n=3) were incubated with Streptococcus mutans or mixed bacterial culture (Streptococcus mutans, Streptococcus sanguinis, Actinomyces naeslundii and Fusobacterium nucleatum). As negative controls, unexposed specimens and specimens exposed to sterile medium (BHI) were used. Specimens exposed to acidified BHI medium (pH=5) and enzymatic solution of cholesterol esterase served as positive control. Following 6-week incubation, the attached biofilms were collected for real-time PCR assessment, after which the surface roughness and topography of the specimens were analyzed with atomic force microscopy. Surface hydrophilicity/hydrophobicity was determined by contact angle measurements. Biofilm structure was analyzed with scanning electron microscopy. RESULTS: Even though multi-species biofilms were thicker, with more cells attached, they did not significantly affect the surface roughness of the composites. On the other hand, S. mutans alone significantly increased the roughness of Tetric by 40.3%, while its effect on Gradia was lower (12%). The total amount of attached bacteria, however, did not differ between the composites. CONCLUSIONS: S. mutans can increase the surface roughness of composites, depending on their composition. This ability of S. mutans is, however, mitigated in co-culture with other species. In particular, bacterial esterases seem to be responsible for the increased composite surface roughness upon biofilms exposure. CLINICAL SIGNIFICANCE: Cariogenic bacteria can degrade composites, thereby increasing the surface roughness. Increased roughness and subsequent improved bacterial accumulation may facilitate the development of secondary caries around composites, which is the most common reason for the restoration failure.

Pharmaceutical Applications of Electrospraying.

The electrohydrodynamic atomization technique, or simply called electrospraying, has been extensively studied for biomedical as well as for pharmaceutical applications over the past years. The simplicity, flexibility, and efficiency of producing particles at the microscale or nanoscale, with tailored size, shape, morphology, and microstructure, make electrospraying to become one of the most promising and well-practiced approaches to be applied in many biomedical and pharmaceutical fields, from improving the bioavailability of poorly aqueous soluble drugs, preparing targeted drug delivery systems, and controllable drug release systems to delivering sensitive therapeutic agents such as protein-based drugs or even living cells. Nevertheless, some issues still remain with respect to low throughput as well as the complex interplay between a great number of processing and formulation factors. A comprehensive understanding of these fundamental aspects is essential for the successful application of electrospraying for the production of particulate formulations with desired properties.

One-step production of darunavir solid dispersion nanoparticles coated with enteric polymers using electrospraying.

OBJECTIVES: The aim of this work was to investigate the feasibility of producing darunavir (DRV) solid dispersion nanoparticles coated with an enteric polymer in one single step using electrospraying. METHODS: The core-shell nanoparticles were made using coaxial electrospraying. A solution of DRV with hydroxypropyl methylcellulose in a mixture of organic solvents formed the core, while the shell was produced from an enteric polymer (Eudragit L100) dissolved in an organic solvent. The final particles were evaluated in terms of morphology, physical state, encapsulation efficiency and in-vitro dissolution. KEY FINDINGS: Nanoparticles of encapsulated DRV solid dispersions within Eudragit L100 were successfully prepared with high encapsulation efficiency (90%). The enteric coating layer reduced the percentage of DRV release in acidic medium in the in-vitro dissolution test to less than 20%. CONCLUSIONS: This study showed the potential of coaxial electrospraying for encapsulating solid dispersions within core-shell structured nanoparticles.