From Drugdeliverytech.com:
Breakthrough Ultraturbulent Reaction Technology Opens Frontier for Developing Life-Saving Nanometer-Scale Suspensions & Dispersions
By: Irwin J. Gruverman, PE, MS
INTRODUCTION
One of the greatest challenges in the race for cures and more effective therapies for life-threatening diseases is balancing pharmaceutical formulations with advances in drug delivery technology. Technological breakthroughs in the form of microdevices that painlessly inject vaccines and protein therapeutics into the skin are dependent on the availability of active drug particles small enough to pass through these new delivery systems. Exciting developments in aerosol and topical treatments cannot come to market if the drugs they would administer cannot be reduced to micron and submicron sizes. Or development of potent lipophilic drugs must be tabled because slow-dissolving aqueous nanosuspensions cannot be achieved.
This lag between drug development and drug delivery often can be traced to formulation equipment limitations at pharmaceutical research and production facilities. If uniform nanometer-scale dispersions or suspensions are the drug developers’ objectives, their end formulations’ properties are governed by the starting material’s history. Dispersion or mixing equipment is not designed to reduce the primary crystallite size because the equipment’s mixing energy densities cannot disrupt covalent or ionic bonds. Pharmaceutical companies must therefore find a way to control the starting material history to manufacture predictable nanoparticle preparations.
There is a new way for processing in chemical reactor technology — Multi-Stream Mixer Reactor (MMR) — which does allow for total control of material history. This development conducts controlled, continuous reactions of two or more streams of pure starting materials in an ultraturbulent collision zone to produce nanometer-scale structures that can be separated, purified, and redispersed in a desired medium. These new, smaller primary crystallites can be maintained in a solid material for further processing. Or, precipitation products can be recovered and processed into desired formulations using high-shear fluid processors.
The development of the first continuous MMR prototype was funded by a matching grant from the Advanced Technology Program sponsored by the National Institute of Science and Technology. The project was a joint effort of Microfluidics™, a division of MFIC™ Corporation, and Catalytica, Inc. This article presents original information derived from the project’s breakthrough in ultraturbulent reactor technology — an advancement that can open new frontiers for drug development and delivery.
One frontier could be the creation of pharmaceutical nanoparticles for injection. Many promising drug developments have been stalled or abandoned because the lipid-soluble material cannot be dissolved in water. Lipid formulations of these active ingredients are not blood miscible, and the lipid components may coalesce and block blood vessels. A potential solution is to prepare a stable, nanoparticle suspension. Nanoparticles of active drugs could be injected as an aqueous colloid or suspension and slowly dissolved into the blood stream. The MMR technology discussed can produce these nanoparticles. It also can be used to process microemulsions, another approach to enabling injectable lipidic pharmaceuticals.
MMR TECHNOLOGY BUILDS ON CORE HIGH-SHEAR FLUID PROCESSING TECHNOLOGY
For two decades, pharmaceutical researchers and manufacturers have relied on the Microfluidics™ patented Microfluidizer® high-shear fluid processing system to disperse particles throughout stabilizing media (Figure 1). In this process, a premixed solution pressurized anywhere between 1,500 to 40,000 psi is pumped into the Microfluidizer® materials processor. As the product stream flows through a patented interaction chamber, it passes through channels with cross-sections smaller than a human hair. The stream is divided in two and forced to collide at supersonic velocity in a small interaction zone under ultraturbulent conditions, extreme energy density levels, and high turbulent energy dissipation. This subjects the stream to shear densities up to ten times greater than any other processor available on the market. This high-shear fluid process creates small structures with unmatched uniformity and disperses them in highly stable and reliable emulsions and suspensions.
In early work on chemical reaction systems, reactant streams were mixed at the feed inlet to the Microfluidizer® materials processor. The flow time from the inlet to the interaction zone was approximately 1 second. With a premixed solution, that flow time permitted significant reaction completion prior to it reaching the interaction zone. When reaching the collision zone, the system remodeled already formed precipitate, often modifying crystal structure and phase purity. While useful in some reaction systems, this often produced low product yields and unwanted byproducts. MMR technologists concluded that controlling the pre-interaction zone mixing would allow for more predictable and different properties of precipitated products.
To control the precipitation event in the MMR, two streams were mixed just upstream of the interaction zone. This allowed for homogeneous nucleation of microcrystals to take place in the flow channels prior to reaching the interaction zone. Virtually perfect mixing thus occurred in the interaction chamber and completed the fast precipitation reaction within the ultraturbulent, high-energy density environment. Changes in process parameters could be made to control particle size, distribution, and crystal and phase purity.
SETTING MMR DEVELOPMENT OBJECTIVES
Based on these findings, several objectives were set to develop the MMR technology:
Perfect mixing in the interaction zone with mixing times in the millisecond range;
Adequate homogeneous nucleation prior to precipitation reaction;
Ultraturbulent mixing in the reaction zone to facilitate perfect mixing;
Absolute control of reactant stoichiometry to achieve uniform, continuous reaction mixture composition in the reaction zone;
Low capital cost relative to conventional batch reaction technology;
Predictable scale-up to production level systems; and
Continuous flow to allow optimization of capital cost, energy usage, and product yield.
MACRO-, MESO- & MICRO-MIXING REDUCES PARTICLES TO NANOMETER-SCALE & IMPROVES PRODUCT HOMOGENEITY & PHASE PURITY
Keys to MMR technology achieving these objectives are its high operating pressures and the fixed geometry of the proprietary interaction chamber. Using separate inlets, the system continuously feeds two or more reactant streams of pure starting materials to the interaction chamber (Figure 2). Pressure, temperature, and position sensors ensure constant mixing conditions. A computer adjusts the flow from the two or more pumps so that they operate in phase (they start and stop at the same times, but may pump at different rates). This helps ensure that the correct stoichiometry is achieved throughout all phases of the pump stroke.
The independent streams of reactants flow through the interaction zone within the mixing chamber. This zone is about the size of a pencil eraser and is made of either ceramic or polycrystalline diamond material to minimize abrasion of the microfine channels.
Depending on the optimum condition for a given chemical reaction, the MMR can achieve macro-, meso-, and micro-mixing regimens within this interaction zone (Figure 3).
As the individual reactant streams move at 2 to 20 meters/second through each channel, they converge on each other (A) and macro-mix for hundreds of milliseconds.
Next, the reactant mixture moves downstream, then splits into separate flow channels that narrow to diameters no greater than those of a human hair. In the process, the solution is accelerated to velocities of 30 to 60 meters/second for tens of milliseconds, and then meso-mixing occurs (B).
Finally, in the area of the mixing chamber where the flow channels are narrowest, the separate streams collide and micro-mixing (C) takes place. This generates energy dissipation values on orders of magnitude 1010W/kg, greater than the energy dissipation achieved near the impeller in any stirred tank reactor or in commonly used homogenizer or rotor/stator mixers [Figure 4].
For fast reactions requiring maximum micro-mixing, a Direct Impingement Chamber is used instead of the Macro-Meso-Micro Chamber. In this configuration, separate reactant streams are pressurized and accelerated to velocities of 80 to 300 meters/second, then collide to mix and react in a fraction of a millisecond in the Direct Impingement Chamber.
This novel MMR technology has been secured with U.S. process and application patents and worldwide applications are in various stages of prosecution. Prototypes have proven their superior mixing and reaction capabilities for future use in several applications. Projected uses include the production of pharmaceuticals, ultrapure chemicals, superconductors, abrasives for planarization, photographic and recording media, and ceramics (Figure 5).
THE POSSIBILITIES
With MMR technology, drug developers can conduct and control a number of reactions to get results never before achieved. They can use precipitation reactions and recrystallization processes to control product size, phase purity, and product uniformity and scale it to production-level quantities.
The MMR also conducts and controls homogeneous reactions to minimize undesirable competing reactions. By selecting proper flow parameters, developers can optimize either slow or fast reaction product yields.
Biphasic reactions also can be conducted with the MMR. The ultraturbulent conditions in the interaction zone create maximum interfacial area for rapid reaction kinetics. This helps reduce structures to near-molecular sizes, resulting in nanoparticle products.
Multiple component reactions where more than two reactants are required can be conducted in the MMR. Three or more independent reaction material streams can be introduced to the mixing chamber for optimal product size, phase purity, and yield results.
The MMR can also be used for controlled recrystallization. This can create pure nanoparticles. In this application, a solution of a sparingly soluble product is mixed with a precipitating liquid stream to create a recrystallized nanometer-scale product.
SUMMARY
With the advent of MMR technology, the challenge now is to find drug developers who have either been stalled or stopped in their research due to equipment limitations. Several companies have begun discussions for developing partnerships with MFIC Corporation to see if MMR technology can advance their efforts. Other innovative companies are being sought to collaborate with Microfluidics™ to augment the development of this breakthrough technology. But the greatest hope lies within the people whom MMR technology will benefit most — those waiting for this new technology to align drug formulations with delivery systems, leading to less painful, more effective cures and therapies.
BIOGRAPHY
Irwin J. Gruverman, PE, MS, is the Founder, Chairman, and Chief Executive Officer of MFIC Corporation, a world leader in high-performance applications of fluid processing and mixing systems. He is also Chairman and a Founder of North American Scientific, Inc., a company that produces brachytherapy radiation sources for cancer treatment and develops imaging radiopharmaceuticals for management of cancer therapy and transplant rejection. Mr. Gruverman earned his BS in Chemical Engineering from The Cooper Union in 1954 and his MS in Nuclear Engineering from MIT in 1955. In his nearly 50-year career, he has authored more than 100 technical articles, presentations, and papers on isotope methodology, engineering and biotechnology applications, and analysis of business/high-technology funding options. |
