Pharmaceutical nanocrystals: production by wet milling and applications.

Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form of nanosuspensions, which are subsequently dried to prepare drug-laden nanocomposites. In this comprehensive review paper, the term “nanocomposites” is used in a broad context to cover drug nanoparticle-laden intermediate products in the form of powders, cakes, and extrudates, which can be incorporated into final oral solid dosages via standard pharmaceutical unit operations, as well as drug nanoparticle-laden strip films. The objective of this paper is to review studies from 2012–2017 in the field of drug-laden nanocomposites. After a brief overview of the various approaches used for preparing drug nanoparticles, the review covers drying processes and dispersant formulations used for the production of drug-laden nanocomposites, as well as various characterization methods including quiescent and agitated redispersion tests. Traditional dispersants such as soluble polymers, surfactants, other water-soluble dispersants, and water-insoluble dispersants, as well as novel dispersants such as wet-milled superdisintegrants, are covered. They exhibit various functionalities such as drug nanoparticle stabilization, mitigation of aggregation, formation of nanocomposite matrix–film, wettability enhancement, and matrix erosion/disintegration. Major challenges such as nanoparticle aggregation and poor redispersibility that cause inferior dissolution performance of the drug-laden nanocomposites are highlighted. Literature data are analyzed in terms of usage frequency of various drying processes and dispersant classes. We provide some engineering considerations in comparing drying processes, which could account for some of the diverging trends in academia vs. industrial practice. Overall, this review provides rationale and guidance for drying process selection and robust nanocomposite formulation development, with insights into the roles of various classes of dispersants.

https://www.mdpi.com/1999-4923/10/3/86/pdf

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation⁻Processing Aspects and Challenges.

The solid-form screening of active principal ingredients is a challenge for pharmaceutical drug development, as more than 80 % of marketed drugs are formulated in the solid form. A broad and comprehensive study of the various solid forms of drugs is needed to enhance their translation into the clinic. Therefore, the most suitable solid form must be taken into consideration regarding ex vivo and in vivo stability, targeting, solubility, dissolution rate, and bioavailability. In this review, techniques of solid-form screening are covered, including differences in solid forms such as polymorphs, solvates, salts, co-crystals, and amorphous particles. Moreover, solid drug size reduction is also discussed, with insight into the emergence of drug nanocrystal formulations. An overview of the smallest nanocrystals reported in the literature and on the market is also provided, along with their applications and routes of administration.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201800612

State of the Art of Pharmaceutical Solid Forms: from Crystal Property Issues to Nanocrystals Formulation

To improve the bioavailability of the poorly water-soluble fungicide, an azoxystrobin nanosuspension was prepared by the wet media milling method. Due to their reduced mean particle size and polydispersity index, 1-Dodecanesulfonic acid sodium salt and polyvinylpyrrolidone K30 were selected from six conventional surfactants, the content only accounting for 15% of the active compound. The mean particle size, polydispersity index, and $$\zeta$$
 potential of the nanosuspension were determined to be 238.1 ± 1.5 nm, 0.17 ± 0.02 and − 31.8 ± 0.3 mV, respectively. The lyophilized nanosuspension mainly retained crystalline state, with only a little amorphous content as determined by powder X-ray diffraction. Compared to conventional fungicide formulations, the nanosuspension presented an increased retention volume and a reduced contact angle, indicating enhanced wettability and adhesion. In addition, the azoxystrobin nanosuspension showed the highest antifungal activity, with a medial lethal concentration of 1.4243 μg/mL against Fusarium oxysporum. In optical micrographs, hyphal deformations of thinner and intertwined hyphae were detected in the exposed group. Compared to the control group, the total soluble protein content, superoxide dismutase, and catalase activities were initially increased and then decreased with prolonged exposure time. The azoxystrobin nanosuspension reduced the defensive antioxidant capability of Fusarium oxysporum and resulted in the generation of excessive reactive oxygen species. This study provides a novel method for preparing nanosuspension formulation of poorly soluble antifungal agents to enhance the biological activity and decrease the negative environmental impact.

/pdf/preparation-characterization-and-evaluation-of-azoxystrobin-2lc39sm7xo.pdf

Preparation, characterization, and evaluation of azoxystrobin nanosuspension produced by wet media milling

Nano-scale and molecular-level understanding of wet-milled indomethacin/poloxamer 407 nanosuspension with TEM, suspended-state NMR, and Raman measurements.

Effect of polymer species and concentration on the production of mefenamic acid nanoparticles by media milling.

An industrially feasible formulation approach combining media milling and spray-drying was applied to improve dissolution characteristics of the poorly soluble drug mefenamic acid (MA). The approach was studied for two MA polymorphs at different stressing and pH conditions. It was found that final MA product particle sizes are rather determined by the solid-liquid equilibrium than by mechanical fracture. Obtained drug particles are only composed of the most stable polymorph. Direct compressed tablets containing MA nanocrystals exhibit a significant improvement of in vitro dissolution kinetics as compared to tablets with micronized drug particles.

Formation of Mefenamic Acid Nanocrystals with Improved Dissolution Characteristics

Importance of Controlling Particle Size in Nasal Powder Formulation of Influenza Vaccine for Target Site Delivery Ratio

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Papers

Effect of polymer species and concentration on the production of mefenamic acid nanoparticles by media milling.

Formation of Mefenamic Acid Nanocrystals with Improved Dissolution Characteristics

Importance of Controlling Particle Size in Nasal Powder Formulation of Influenza Vaccine for Target Site Delivery Ratio