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Processes 2016, 4(4), 49; doi:10.3390/pr4040049

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

1
Department of Physics Chemistry and Pharmacy, University Southern Denmark, Odense 5230, Denmark
2
EmulTech b.v., Eindhoven 5600 AB, The Netherlands
3
Nature Science and SUND, University Southern Denmark, Odense 5230, Denmark
4
Department of Mechanical Engineering and Material Science, Pratt School of Engineering, Duke University, Durham, NC 27708-0300, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Andreas Håkansson
Received: 30 October 2016 / Revised: 18 November 2016 / Accepted: 25 November 2016 / Published: 30 November 2016
(This article belongs to the Special Issue Emulsification Processes)
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Abstract

The micropipette manipulation technique is capable of making fundamental single particle measurements and analyses. This information is critical for establishing processing parameters in systems such as microfluidics and homogenization. To demonstrate what can be achieved at the single particle level, the micropipette technique was used to form and characterize the encapsulation of Ibuprofen (Ibp) into poly(lactic-co-glycolic acid) (PLGA) microspheres from dichloromethane (DCM) solutions, measuring the loading capacity and solubility limits of Ibp in typical PLGA microspheres. Formed in phosphate buffered saline (PBS), pH 7.4, Ibp/PLGA/DCM microdroplets were uniformly solidified into Ibp/PLGA microparticles up to drug loadings (DL) of 41%. However, at DL 50 wt% and above, microparticles showed a phase separated pattern. Working with single microparticles, we also estimated the dissolution time of pure Ibp microspheres in the buffer or in detergent micelle solutions, as a function of the microsphere size and compare that to calculated dissolution times using the Epstein-Plesset (EP) model. Single, pure Ibp microparticles precipitated as liquid phase microdroplets that then gradually dissolved into the surrounding PBS medium. Analyzing the dissolution profiles of Ibp over time, a diffusion coefficient of 5.5 ± 0.2 × 10−6 cm2/s was obtained by using the EP model, which was in excellent agreement with the literature. Finally, solubilization of Ibp into sodium dodecyl sulfate (SDS) micelles was directly visualized microscopically for the first time by the micropipette technique, showing that such micellization could increase the solubility of Ibp from 4 to 80 mM at 100 mM SDS. We also introduce a particular microfluidic device that has recently been used to make PLGA microspheres, showing the importance of optimizing the flow parameters. Using this device, perfectly smooth and size-homogeneous microparticles were formed for flow rates of 0.167 mL/h for the dispersed phase (Qd) and 1.67 mL/h for the water phase (Qc), i.e., a flow rate ratio Qd/Qc of 10, based on parameters such as interfacial tension, dissolution rates and final concentrations. Thus, using the micropipette technique to observe the formation, and quantify solvent dissolution, solidification or precipitation of an active pharmaceutical ingredient (API) or excipient for single and individual microparticles, represents a very useful tool for understanding microsphere-processes and hence can help to establish process conditions without resorting to expensive and material-consuming bulk particle runs. View Full-Text
Keywords: microparticle; PLGA; micropipette manipulation; ibuprofen; encapsulation; drug dissolution; microfluidic emulsification microparticle; PLGA; micropipette manipulation; ibuprofen; encapsulation; drug dissolution; microfluidic emulsification
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kinoshita, K.; Parra, E.; Hussein, A.; Utoft, A.; Walke, P.; de Bruijn, R.; Needham, D. From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres. Processes 2016, 4, 49.

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