The key to unlock new drug formulations?Roughly half of all new drugs in development are poorly soluble and often associated with low bioavailability. Among the most promising
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Figure 1. Principal of operation of Microfluidics Reaction Technology.
A new generation of nanosuspension processing equipment is enabling pharmaceutical and biotechnology companies to develop and ultimately manufacture difficult-to-formulate insoluble drugs. It has been demonstrated that Microfluidics Reaction Technology (MRT), a highly successful development program at Microfluidics Corporation (MFIC), can create high purity nano-particles to sizes not achievable with conventional particle size reduction methods. This new technology could potentially unlock numerous drugs, vaccines and drug delivery systems that could not be formulated or efficaciously administered in the past.
Bottom-Up Versus Top-DownThe MRT creates nanosuspensions through the precipitation of crystals. This solvent/anti-solvent crystallization is commonly called a “bottom-up” technique, because particles are grown, beginning with crystallization of individual molecules. To do this, the API is dissolved into a solvent, and then this solution is subsequently mixed with an anti-solvent to cause precipitation/crystallization. The technology introduces uniform mixing in the nanometer scale of species that are present in the chemical or physical processes which enables nanoparticles to be formed and the rates of the processes to be expedited.
In contrast, the conventional “top-down” process takes larger particles and breaks them apart to achieve submicron particle sizes. Various techniques are employed, such as wet-milling, homogenization, and micronization. Most often these top-down processes cannot produce enough energy to break through nature’s barrier to reduce particles smaller than the primary crystal size which varies with each material of interest. This limitation is a roadblock that prevents a growing number of critical formulations from becoming available to the marketplace.
The key to MRT is the processing conditions in the Microfluidizer® processor reaction chamber where the precipitation/crystallization takes place. The short reaction time (i.e. dwell time) inside the high speed, high pressure, and high shear environment, forces the reactants to interact at a nanoscale level. By intensifying various processes, and by expediting the rate of chemical reaction, the processor’s continuous microreactor generates high throughput.
This new technology is advantageous compared to other bottom-up techniques that already exist. For example, a laboratory technician can certainly perform solvent/anti-solvent crystallization in a glass beaker at atmospheric pressure, but this process is difficult to control and to scale. Also, the product can be inconsistent and can contain unacceptable levels of impurities and crystalline polymorphs that provide no pharmacological benefit.
The MRT ProcessTo cover a broad range of applications, the current MRT program consists of two reactors; the Microfluidics Mixer Reactor (MMR) for very fast reactions, and a coaxial
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Figure 2: Crystallization Results using Microfluidics Reaction Technology
The residence times in the Microfluidizer processor chamber can range from a few hundred microseconds to a few hundred milliseconds. It is the levels and the localized nature of the energy dissipation that create a uniform mixture of the reactants in the nanometer level.
The patented Microfluidizer Mixer-Reactor (MMR) system is a high-performing, continuous chemical reactor utilizing multiple reactant fluid streams. In most conventional chemical reactors, inadequate mixing and mass-transfer rates limit the value and performance of a fast chemical reaction. As a result, product yields are low, and unwanted by-products are produced. Building upon basic Microfluidics technology, computer controlled flow rates of multiple streams of pressurized reactants are brought together in a proprietary MMR mixing chamber with residence times of a few hundred microseconds to a few hundred milliseconds. By optimizing the fast chemical reactions required in specific chemical processes, MMR enables the production of uniform nanoparticles on a continuous basis with phase purity previously unachievable with conventional batch reaction technology.
The Co-Reactor allows for precise control of the feed rate, reactant ratios, and mixing intensity and location of liquid reactants through a coaxial feed system. For the slower reactions, which comprise the majority of applications that are encountered, the co-reactor has clearly demonstrated to be more effective in producing optimally-sized, consistent nanosuspensions than standard particle size reducing methods for a variety of drugs using solvent and anti-solvent crystallization.
Unlike other multi-stream mixer reactor systems, the co-reactor pumps the multiple streams of pressurized reactants (the API dissolved into the solvent and the anti-solvent) through a coaxial feed system to the Microfluidizer processor reaction chamber. The flow of each of the reactants is metered by a peristaltic positive-displacement pump, and the precisely-controlled mixing ratio can vary from 1:1 to 40:1. ?Each stream in the Microfluidizer processor is pressurized in the range of 5,000 to 40,000 psi and led into an inlet channel a few millimeters long with a cross-sectional area in the range of 75-200 microns. Fluid velocities between three and 30 m/sec are achieved. Jets are then formed, reaching velocities in the 200-400 m/sec range. The channels are formed in diamond or ceramic constructs to handle a wide variety of product media.
Both systems are scalable. Parallel jets can be employed – operate under identical conditions – and should process tens of liters per minute.
The technology is designed to prevent any reacting prior to the reactants entering the interaction chamber. However, for some applications, it may be desirable to allow the controlled mixing of the inlet streams in a macromixing zone before entry into the inlet channels. Liquid mixing occurs for a few milliseconds in these channels, creating a small amount of microcrystalline product nuclei to seed the reaction in the reaction zone, if necessary.
Requirements of the pressures, channel dimensions, reaction zone dimensions and exit channel dimensions are experimentally optimized to accommodate the specific kinetics of the reaction being conducted. Bulk fluid temperature rise in the system between five and 20 Celsius depending on process pressure, and heating or cooling either before or after reaction can be provided. ?Post-reaction processing may be necessary or desirable for some reactions to prevent crystal growth or to alter crystal morphology (length/diameter ratios of needle-shaped crystals, for example). Agglomeration is a natural post-reaction event. It can be minimized by dilution of the product stream. Alternately, the product can be redispersed at a later time.
Experimental ResultsMRT has been successful in producing stable nanosuspensions with exceptionally small particle sizes for several drugs, including two antibiotics, an antihistamine, an anticonvulsant and a non-steroidal anti-inflammatory, with molecular weights ranging from 228-750 Amu.
Control experiments were performed for comparison purposes, using conventional “top-down” particle reduction methods. These conventional methods were not able to achieve particle sizes as small as those created using MRT, regardless of the number of processing cycles.
The experiments used the solvents DMSO or NMP, and water served as the antisolvent. The surfactants, Solutol (BASF) and INUTEK (Orafti) were also used.
The process achieved considerably smaller median particle size (see Figure 2), as well as more uniformity as exemplified in narrow Azithromycin particle size distribution. The MRT process also provided better crystalline structure than the control methods, and a reduction in quantity of polymorphs that provide no pharmacological benefit.
Nanosuspensions Development RoadmapMicrofluidics recommends a three step process in development a pharmaceutical nanosuspension:
The first step is to conduct screening experiments to determine the best solvent, anti-solvent and surfactant systems, considering issues such as solubility, toxicity and compatibility for the particular application. Analysis should be conducted to select the most suitable materials and to optimize the concentrations.
The next step is to use the MRT to produce nanosuspensions. The goal at this stage is to determine the optimal processing parameters, such as feed rates of reactants, reaction chamber geometry, process pressure, super-saturation ratio, and number of passes.
The final step is to purify nanosupension, if necessary, using methods such as centrifuging, filtering, rinsing, and lyophilizing.
Next Generation Nanosuspension ProcessingWith the introduction of MRT, pharmaceutical and biotechnology companies now have a powerful and flexible tool to develop and ultimately manufacture difficult-to-formulate insoluble drugs. The coaxial feed system and the Microfluidizer processor reaction chamber provide precise control of critical processing parameters, including mixing ratio and reaction time, to produce nanosuspensions containing optimally- and uniformly-sized drug particles.
It has been demonstrated that MRT can create high purity nano-particles to sizes not achievable with conventional particle size reduction methods. Conventional processors cannot produce enough energy to break through nature’s barrier to reduce particles smaller than the primary crystal size which varies with each material of interest. This limitation is a roadblock that prevents a growing number of critical formulations from becoming available to the marketplace.