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    Evaluation of the Effect of Critical Process and Formulation Parameters on the Attributes of Nanoparticles Produced by Microfluidics. Design of Experiments Approach for Optimisation of Process and Formulation Parameters Affecting the Fabrication of Nanocrystals of Poorly Water-Soluble Drug Using Anti-solvent Precipitation in Microfluidic

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    PhD Thesis (7.747Mb)
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    Publication date
    2021
    Author
    Obeed, Muthana M.
    Supervisor
    Assi, Khaled H.
    Isreb, Mohammad
    Keyword
    Microfluidics
    Nanocrystal
    Particle size
    Solubility
    Polymers
    Nanoprecipitation
    Anti-solvent
    Bioavailability
    Formulation parameters
    Nanoparticles
    Ibuprofen (IBU)
    Salmeterol (SAL)
    Drug delivery
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    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    School of Pharmacy and Medical Sciences
    Awarded
    2021
    
    Metadata
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    Abstract
    Advanced drug delivery systems have shown immense success through nanotechnology which overcomes the challenges posed by large sized particles such as poor solubility, bioavailability, absorption, and target-specific delivery. This study focuses on nano sizing by application of microreactor technology and nanoparticles to obtain polymeric particulate with a selection of model drugs for inhalation drug delivery routes. The development of nanoparticles of two challenging compounds in terms of solubility and permeability, namely Ibuprofen (IBU) and Salmeterol (SAL), was conducted using a continuous, controlled, and scalable system offered by microfluidic reactor with the incorporation of anti-solvent approach. The research explores the potential of this technology to enhance absorption rate and hence bioavailability of IBU via oral route, and SAL via inhalation. IBU, an anti-inflammatory drug, is classified as BCS Class II drug with low solubility and high permeability. SAL is a selective long acting β2-agonist which is co-dispensed along with a short-acting β2-agonist for quick relief of acute bronchoconstriction due to its long onset of action. This lack of the ‘kick’ effect in SAL can be attributed to its relatively higher lipophilicity which causes a delay in the diffusion to the β2 receptors on the smooth muscles. It is therefore feasible to assume that increasing the dissolution and/or diffusion rate of SAL in the interstitial fluids would reduce the delay between administration and the onset of action of this drug which would be beneficial to patients. Process and formulation parameters were investigated to optimize the production and stability of nano particles of both drugs using Y shaped microfluidic reactors. IBU results show that the smaller the angle between the two inlets were the smaller the particle size achieved. Moreover, the particle size increased with increasing the concentration of IBU solution. The effect of the polymer mixture ratio (PVP/HPMC) on the initial particle size was not clear though. The smallest particle size (113 nm) was achieved using 10° Y shaped chip with IBU concentration of 1 mg/mL and a polymer mixture of 0.3% w/v PVP and 0.5% w/v HPMC. Using a polymer mixture of 0.5% w/v of each polymer though yielded a better PDI (140nm and PDI of 0.5). Same observations were noted when the syringe pumps were replaced with a non-pulsatile pressure pump. Particle size though dropped significantly to 33nm. Stability data showed that all systems were practically stable regardless of the process or formulation parameters. In addition, a considerable 2.5 fold increase in dissolution rate was observed in the first 20 minutes when compared to the raw material. The optimized parameters were applied to SAL to produce nanocrystals with best result (59 nm) were obtained using 50µg/mL Salmeterol with microfluidics inlet angle 10° with non-pulse syringe pump. The stabilizing mixture was PVP 0.8% w/v and Tween 80 at a concentration of 0.02%. This approach offered a basis for the generation of nano sized SAL particles with higher fine particle fraction and better deposition in NGI than currently marketed formulations, thus providing a more efficient drug dose delivery and lung deposition.
    URI
    http://hdl.handle.net/10454/19273
    Type
    Thesis
    Qualification name
    PhD
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