Effects of chemical and physical parameters in the generation of microspheres by hydrodynamic flow focusing
Graphical abstract
. Uniform biodegradable polymer microspheres can be generated by hydrodynamic flow focusing. Size adjustment is possible by changing the flow ratio of the continuous to the disperse phase.
Highlights
► Hydrodynamic flow focusing to generate 1–5 μm biodegradable polymer microspheres. ► Size distribution minimally effected by solvent composition & polymer concentration. ► Size distribution strongly effected by total flow rate. ► Physical process parameters give rise to uniform particles with high mass throughput.
Introduction
The mass production of uniform and size-defined micro- and nanoparticles is a challenge in many fields, and especially in the pharmaceutical industry. Here, the production of particles that are not only biodegradable, but are also of small enough size to be used for in vivo drug delivery and large enough to remain sufficiently long in the blood stream (e.g., particles in the 1–5 μm diameters) gains more and more importance [1]. Current methods lack the ability to produce such particles with a narrow size distribution and in a single step approach. In order to achieve particle batches with similar particle sizes, many technologies (e.g., spray drying, milling techniques, or oil-in-water emulsion technologies) require additional methods to reduce the particle size to a range demanded by the customer (i.e., sieving, capillary electrophoresis, size-exclusion chromatography, or SPLITT fractionation) [2], [3], [4], [5], [6]. The use of additional methods for particle size reduction and, as a result, the significant increase in costs is justified by the demand of such particle batches.
In drug delivery applications, particle size has two important consequences. Firstly, it can determine the final site of particle accumulation within the body and secondly, it can effect the release rate and release profile of a drug and thereby its therapeutic efficacy. Employing micro- and nano-particles which are uniform in size will allow for maximal control over particle biodistribution, followed by a precisely regulated drug release [7], [8].
To meet the demand for uniform size, various particle preparation methods have been proposed and tested. In batch crystallization, a traditional method of direct drug particle generation, homogeneous size is achieved after the product undergoes labour- and cost-intensive processing steps, such as filtration/sieving, drying, and micronization (e.g., by milling). Despite these procedures, the powders produced are often of poor quality, exhibit broad distributions in shape and size, and often contain electrostatic charges which were introduced during the milling process [9]. More control is gained over size, shape, and active component distribution (e.g., drug) with the methods of spray drying [10], solvent evaporation/emulsification [11], [12], phase separation [11], [13], and rapid freeze drying [14]. An additional advantage of these methods for the preparation of drug-loaded microspheres, and particularly of the freeze drying method, is their high throughput. None of the methods mentioned, however, allow for the production of monosized particles in a single step approach, and the size can be adjusted in general only over a very limited range.
A particle preparation method that gives rise to uniform, monodisperse polymeric micro- and nanospheres in a single step is flow focusing [15]. In hydrodynamic flow focusing, two or more phases of liquid are co-axially focused and then forced through a small orifice (Fig. 1). The flow rate of the outer phase, called the continuous phase (CP), exceeds that of the inner disperse phase (DP), typically by ten to thousand times. The DP is thus forced into a narrow jet and focussed at the orifice. Due to the rapid change in pressure from the pressure chamber to the outlet and the prevailing shear stress, the jet breaks up into droplets after passing the orifice. In order to generate drug-containing polymer particles, the DP must contain the polymer(s) and drug(s). Immediately after droplet formation, the DP solvent starts to evaporate or is extracted by the surrounding fluid, leaving behind solid micro- or nanospheres. Maintaining precise control over the initial droplet size allows the formation of close to monosized particles.
Research on flow focusing and droplet disintegration is not a new topic. Studies with different orifice arrangements were already conducted in the late 19th century by Lord Rayleigh [16], [17]. Applications of flow focusing, however, have only matured during the past 20–30 years, alongside the advances in microfabrication and measurement technology. A well-established patented flow focusing technology which involves the mass production of droplets on demand with defined size is ink jet printing [18]. Flow cytometry also employs a similar flow focusing technology to focus cells or particles in a single-file fashion [19], [20]. More recent applications of the flow focusing method include not only the controlled preparation of bubbles, droplets, and capsules [21], [22], but also the preparation of uniform polystyrene microspheres, some of which contain fluorochrome dyes [23], [24]. So far, however, most applications focused on polymers that had either short chain lengths, were unbranched, or non-biodegradable.
The use of biodegradable polymers with the flow focusing method would allow the microsphere generation of specific size, which could be used in vivo and would then slowly disintegrate without toxic side effects. Recent studies have shown the successful preparation of biodegradable drug loaded particles for drug delivery studies with diameters on the order of 8–10 μm [1], [25]. Here we investigate the potential of flow focusing for the preparation of biodegradable microspheres, with diameters below 5 μm. Particles of such a small size will improve the drug delivery when compared to larger particles as a result of better distribution in small blood capillaries. As a biodegradable polymer material, poly(lactide-co-glycolide) (PLGA) was used as it allows for controlled (slow) drug release, is biocompatible and non-toxic, and can remain in the body after therapy since it degrades slowly over time [26]. In this work, we evaluated the influence of various parameters on the final particle size and their size distribution. The parameters included fluid flow velocities and ratios, injector position and orifice size, as well as the liquid properties and polymer concentrations. While the main focus is not the generation of uniform monodisperse particles, the current work can be used as a guide in the optimization of process parameters to achieve better uniformity and reduce dispersity in microspheres generated by this method.
Section snippets
Sources of materials
PLGA (85/15, intrinsic viscosity 0.61, MW 24 kDa, Lot# D96056) was purchased from Durect Corp. (Pelham, AL, USA), polyvinyl alcohol (PVA; 87–89% hydrolized, MW 13 kDa–23 kDa) from Sigma Aldrich Ltd. (Oakville, ON, Canada), dichloromethane and chloroform from Fisher Scientific (Ottawa, ON, Canada). All chemicals were of reagent grade and were used as received. 2 Ton® Clear Epoxy glue was from ITW Devcon (Danvers, MA, USA). Corrosion resistant TEFZEL tubing in various dimensions was purchased from
Solvent composition and polymer concentration in the disperse phase
Pharmaceutical substances, such as drugs, show different solubilities in (organic) solvents typically used in the generation of biodegradable polymer particles. The substances to be incorporated in the polymer have to be taken into account in the selection of a suitable solvent. The use of solvent mixtures, so-called co-solvents, can enhance the solubility of a pharmaceutical substance in a polymer, but may also effect the particle generation due to changes in density, viscosity, or interfacial
Conclusions
In the present parameter study, we showed the advantages and limitations of flow focusing for the continuous generation of user defined polymer microspheres. The motivation of our study was the generation of biodegradable microspheres in the challenging 1–5 μm diameter range. The results from our parameter study confirm some of the general advantages of the flow focusing method, as described for example by Martin-Banderas et al. [23]. Methods that allow the generation of uniform microspheres
Acknowledgements
We appreciate the work by Bikaramjit Mann, Didier Hayem, and Berwin Song, whose preliminary efforts made these results possible, and of Shona Robinson who helped in editing this paper. Furthermore we acknowledge the support by Prof. Helen Burt and John Jackson in the Faculty of Pharmaceutical Sciences at UBC, as well as the support of Prof. Daniel T. Chiu at UW. We also are grateful for helpful discussions with Prof. Boris Stoeber and Markus Fengler in Mechanical Engineering, and Prof. Fariborz
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