Ind. Eng. Chem. Res. 2009, 48, 1761–1771
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Production of Norfloxacin Nanosuspensions Using Microfluidics Reaction Technology through Solvent/Antisolvent Crystallization Thomai Panagiotou,*,† Steven V. Mesite,† and Robert J. Fisher‡ Microfluidics International, 30 Ossipee Road, Newton, Massachusetts 02464, and Department of Chemical Engineering, 77 Massachusetts AVenue, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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. Introduction A large number of compounds with potentially high pharmacological value fail to pass initial screening tests because they are too hydrophobic to be effectively formulated. Most formulation strategies aim at increasing the bioavailability of such drugs by particle size reduction as described extensively by others in this field.1-4 Such strategies include the production of emulsions, liposomes, and functionalized chaporones by high shear processing, the production of nanosuspensions by milling or high shear processing, and the production of nanoporous materials. Nanoemulsions, liposomes, and other generalized cargo loaded systems can only encapsulate limited amounts of drugs; therefore they may not be the strategies of choice for drugs with high dose demands. Nanosuspensions can deliver much larger amounts of drug in a smaller volume than the solvent diluted drug systems1-4 and, therefore, have a potential advantage as a formulation strategy. Most often, nanosuspensions are produced by “top down” methods such as milling or high shear processing,5 in which the size of existing particles is reduced by impact, shear, or attrition. Unfortunately, the targeted particle sizes, usually less than 0.5 µm, are often time-consuming and expensive to produce.6 Crystallization is a method very often used to produce fine chemicals and pharmaceuticals of desired purity, or for the formation of a specific crystal polymorph with the desired crystalline structure and associated properties.1,2,7-10 However, the techniques used previously often produced particles in the range of several tens or hundreds of micrometers and therefore are not suitable for delivering highly hydrophobic drugs. * To whom correspondence should be addressed. E-mail: mimip@ mfics.com. Tel.: (617) 969-5452. Fax: (617) 965-1213. † Microfluidics International. ‡ Massachusetts Institute of Technology.
In an effort to produce submicrometer or micrometer particles during crystallization, there has been a substantial amount of work over the years.8-13 On many occasions impinging jet reactors have been proposed 8,10,12,13 in conjunction with solvent/ antisolvent crystallization. The existing impinging jet reactor designs, for example Johnson and Prud’homme,13 have fairly low velocities (in the range of 0.2-18 m/s). The low velocities limit the mixing intensity of the solvent and antisolvent, therefore limiting the ability of such devices to produce small particles. In addition, this conventional impinging jet reactor requires that the solvent and antisolvent streams have the same volume flowrate, therefore they do not allow for fine control of supersaturation. Other techniques previously explored included the exposure of a solvent and antisolvent mixture to high shear forces, as developed by Baxter.11 In such cases, crystallization may start or even complete well before the high shear mixing. In those cases high shear homogenization functions as a “top down” particle size reduction. In addition, the scalability of such a process is doubtful. Microfluidics reaction technology (MRT), which includes both hardware and process, may potentially address issues of existing technologies. MRT impinging jet reactor provides jet velocities and energy dissipation levels that are orders of magnitude higher than those of existing reactors. As a result, the mixing scales inside the MRT reaction chamber are much smaller than those of conventional designs.14 In addition, MRT allows for continuous selection of stream ratios, therefore providing fine control of supersaturation. Finally, MRT is a fully continuous process with a microreactor (reaction chamber) scalable to process tens of liters per minute. The ability to create nanosuspensions from a variety of drugs using MRT was demonstrated previously.15-18 The polymorph formation as a function of process parameters was also explored.17,18 The present work explores a variety of process
10.1021/ie800955t CCC: $40.75 2009 American Chemical Society Published on Web 01/22/2009
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parameters that affect both the particle size and crystalline structure of a drug. In addition, it provides the roadmap for the process development of drug nanosuspensions using MRT. Norfloxacin (NFN), which is a highly hydrophobic pharmaceutical ingredient, was selected as a model drug to demonstrate the applicability of this technology in proof of concept experiments. The solvent/antisolvent system selected for this model drug was dimethylsulfoxide (DMSO) and water. The metrics used to evaluate performance are associated with the particle size, distribution, structure, and percent recovery. Light scattering, scanning electron microscopy (SEM), and X-ray diffraction (XRD) techniques were used for both qualitative and quantitative analysis of the material that was produced. Gravimetric analysis was used for solubility and recovery determinations. The main process variables are system pressure (energy input), feed rates (for solution composition and thus supersaturation ratio), drug concentration, and chamber configuration (determines shear rates and energy dissipation mechanisms). Although long-term stability of the particles produced was not the focus of this work, limited testing was done to determine stability of the particles in the solvent/antisolvent stream and also during possible post processing steps to remove the solvent. Experimental Apparatus and Procedure 1. Microfluidics Reaction Technology. A. Technology. Microfluidics reaction technology can be used to produce nanoparticles and/or expedite the rate of chemical reactions by minimizing diffusion limitations between single-phase and multiphase reactant streams. The technology involves high shear, continuous fluid processing through a fixed geometry which provides intense and uniform mixing in the meso- and micromixing range and generates nanometer scale eddies and products. These Kolmogorov length scale eddies are responsible for the enhanced transport observed.14 In addition, the technology allows for control of mixing rates and energy input with respect to intensity and location. MRT is based on the microfluidizer processor technology which has been used commercially for decades for particle size reduction (“top down” processing) of suspensions and emulsions to submicrometer levels. Microfluidizer processor technology has been demonstrated to be scalable to tens of liters/min.5 MRT evolved from the standard technology by controlling the feed rates of multiple reactant streams and also by controlling the location and mixing intensity of these streams. With such controls the technology is applicable to a wide variety of physical and chemical processes. B. Reaction Chamber. The core of the technology is the reaction chamber that exploits impinging jet technology to provide the micro-mixing environment inside a volume with dimensions at the microliter scale, see Figure 1a. A combination of shear and impact disperse the reactants streams into submicrometer eddies that intermingle and have very high interfacial/ surface area. This promotes rapid development of homogeneous conditions within the microliter chamber. Using the micromixing models reported in the literature 12,14 turbulent energy dissipation rates attainable in standard microfluidizer interaction chambers are on the order 107 W/kg and higher. The estimated mixing scales are in the order of 25-50 nm. This achieves rapid micromixing (time scale 4 µs) and meso-mixing (time scale 20 µs). Note that nominal residence times in the interaction chamber are of the order 1 ms. The chamber (see Figure 1a) consists of channels with depths and widths typically in the range of 50-150 µm, which are several times smaller than the channels in other impinging jet
designs.8,13,14 The design used for these tests employ channels with a minimum dimension of 75 µm. The combined feed stream is split equally prior to entering these feed channels to the impingement zone. The fluids accelerate up to 500 m/s, forming two opposing jets that impact one another (see Figure 1a). The jets collide with sufficient energy to develop the desired dissipation levels. Arrays of such channels, (Figure 1b) ensure the linear scalability of the technology. Nominal shear rates developed within the channels are calculated by assuming a 1-D flow field representation. The deformation rate tensor, composed of the various velocity component spatial derivatives is thus approximated as the ratio of the average velocity inside the channels, uavg, and the smallest dimension of the channel, dmin. For a Newtonian fluid this is related to the nominal shear stress (τ) and the dynamic viscosity of the fluid (µ) as:
||
uavg τ ) (1) µ dmin The shear rates for the conditions of the present experiments are estimated to be (5-8) × 106 s-1. C. Processor. Figure 2 shows the principal of operation of the particular processor type used in this work. Multiple reactant streams are fed into an intensifier pump separately at controlled rates, forming a coarse premix. The intensifier pump is used to pressurize the reactant mixture to 207 MPa (30000 psi) and introduce them to the reaction chamber in which a fine reactant mixture is formed. After the reaction chamber the products are introduced into a heat exchanger for heat removal. If required, the products are passed through the processor for an additional number of passes. In this type of processor there is some mixing of the reactants prior to introduction into the reaction chamber. However, prior to the interaction chamber, the contact duration is small (
