Hydrophobic active pharmaceutical ingredients (APIs) are often difficult to deliver effectively because of formulation limitations. Nanosuspensions of such drugs may be used to increase bioavailability and offer a variety of delivery options including injection, inhalation, oral, and transdermal. Microfluidics reaction technology (MRT) was used successfully to produce submicrometer API suspensions via a continuous process that involves solvent/antisolvent crystallization. As proof of concept, nanosuspensions of norfloxacin (NFN), an antibacterial agent, were produced varying the key parameters of the technology. The nanosuspensions had narrow particle size distributions and median particle sizes in the range of 170-350 nm. The particle size depends on the supersaturation ratio and energy dissipation expressed as processing pressure. However, the particle size was found to be insensitive to the presence of the surfactant used. The crystalline structure of NFN was not affected by the mixing intensity but by the solvent/antisolvent system. This "bottom up" process for creating nanosuspensions was compared to a "top down" process, in which NFN nanosuspensions were created as a result of particle size reduction. It was found that the "bottom up" process was substantially more efficient and resulted in smaller particles than the "top down" process. MRT is based on an impinging jet reactor design with jet velocities and energy dissipation that is orders of magnitude higher than those of conventional impinging jet reactors. The technology provides precise control of the feed rates and the subsequent location and intensity of mixing of the reactants. It may be the best choice economically due to its process intensification character that minimizes energy requirements and the proven scalability of the reactor.
The Clean Air Act Amendments of 1990 identify a number of hazardous air pollutants (HAPs) as candidates for regulation. Should regulations be imposed on HAP emissions from coal-fired power plants, a sound understanding of the fundamental principles controlling the formation and partitioning of toxic species during coal combustion will be needed. With support from the Federal Energy Technology Center (FETC),
Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drug's life cycle, inception to delivery, is
rapidly expanding. As the industry moves more aggressively toward continuous
manufacturing modes, utilizing Process Analytical Technology (PAT) and Process
Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated.
The ability to transfer energy, mass, and momentum with directed purposeful outcomes is
a worthwhile endeavor in establishing higher production rates more economically.
Furthermore, the ability to obtain desired drug properties, such as size, habit, and
morphology, through novel manufacturing strategies permits unique formulation control
for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals
is an excellent example. Formulation and delivery are intimately coupled in improving
bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing
side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish.
Microfluidics Reaction Technology (MRT is a continuous processing technology used to produce stable nano-scale materials through crystallization, precipitation, emulsification, and chemical reactions. High purity materials with controlled structure and desired properties were produced successfully using this platform technology. The principles upon which this platform is based are the fundamental rates of mass, heat, and momentum transfer coupled with chemical reaction phenomena. The essential physical component is a continuous and scalable micro-reactor utilizing impinging jets. Flow throughput is characterized by high fluid velocities, up to 500 m/s, resulting in highly turbulent conditions and interactions at the nano-scale. In addition to size control, the technology offers control of morphologies and reaction selectivity. The unique design of this micro-reactor provides precise control of feed rates, mixing location and its intensity, and process time scales. Successful implementations of this platform technology include: (a) formation of drug nano-suspensions through crystallization, (b) nano-encapsulation of actives in polymers, and (c) chemical reacting systems that produce and/or utilize nano-species, such as suspensions and emulsions. The focus here is on the production of nano- emulsions and global system optimization. Results indicate that they can be formed in one step using MRT as opposed to the two step conventional process that requires the initial formation of a micro-emulsion. Also demonstrated are the reduced amounts of surfactants required for certain formulations to obtain stable nano-emulsions. Dependent upon process parameters, sizes in the range of 50-800 nm are easily obtained.
Entrapment of sub-micron scale emulsions containing active ingredients into macro-scale matrices has exhibited great potential as a delivery vehicle with controlled release capabilities, however optimization remains unrealized. Reported here are methods used to improve product quality by optimizing the emulsion formation steps. These methods are in conjunction with the precepts of Process Intensification (PI). Success with pharmaceutics and chemical reacting systems provides a strategy for a wide range of applications; the emphasis here being nutraceutics. Use of a nano-technology platform assists in: (a) product quality improvements through better nutrient dispersion, and thus bio-efficacy; and (b) production efficiencies through implementation of PI concepts. A continuous methodology, utilizing these PI concepts, that approximates a bottom-up approach to the creation of sub-micron and nano-emulsions is the basis of the technology presented here. Note that solid particles may result during post-processing. The metrics of successful processing include obtainment of nano-scale species with minimal input energy, reduced processing steps at higher throughput rates, and improved quality without over-usage of key ingredients. In addition to flavor and wellness characteristics, product stability for extended shelf life along with an appreciable cargo load in the entrapped emulsion is a major concern. Experimental protocols and path forward recommendations to overcome challenges and meet expectations in these emerging opportunities are also presented.
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