Dissertations / Theses on the topic 'Pharmaceutical aerosol'

The characterization of perphenazine and scopolamine aerosols generated using the capillary aerosol generator (CAG) was reported. Variables including steady state power, the formulation vehicle, the drug concentration and the formulation flow rate were studied for their effects on the chemical stability and particle size of these drug aerosols.Stability-indicating HPLC and LC-MS assays were developed and validated for perphenazine and scopolamine, respectively. The chemical stability of each compound was investigated under a variety of stress conditions and the structure of degradation products was proposed.Perphenazine aerosols were generated from propylene glycol (PG) formulations with concentrations of 9, 48 and 90mM at formulation flow rates of 2.5 and 5.0µL/s at a series of steady state powers. At higher aerosolization powers, the low concentration formulation (9mM) degraded with dehalogenation being the major pathway. The size of perphenazine aerosols was between 0.4 to 0.6µm. Changing the solute concentration produced only small changes (~0.2µm) in perphenazine aerosol particle size. The formulation flow rate did not significantly affect the aerosol size.Scopolamine degraded significantly when aerosolized in PG formulations. It was possible to generate chemically stable scopolamine aerosols from ethanol formulations. Significant amounts of degradation products were formed only at or above 4.6W at 5.0µL/s. Hydrolysis and dehydration appeared to be the major degradation pathways at higher powers and low formulation flow rate. The MMAD of scopolamine aerosols was between 0.5 and 2.0µm from 8, 20 and 40mM formulations at 5.0 and 10.0µL/s. The size of scopolamine aerosols increased as a function of increasing the solute concentration. Increasing the formulation flow rate increased the linear velocity of the spray, thus the Reynolds number was increased and smaller particles were generated.

Thesis (Ph. D.)--Virginia Commonwealth University, 2008.
Prepared for: Dept. of Mechanical Engineering. Includes bibliographical references (leaves 212-233). Also available online via the Internet.

Pharmaceutical aerosols provide a number of advantages for treating respiratory diseases that include targeting high doses directly to the lungs and reducing exposure of other organs to the medication, which improve effectiveness and minimize side effects. However, difficulties associated with aerosolized drug delivery to the lungs include drug losses in delivery devices and in the extrathoracic region of human upper airways. Intersubject variability of extrathoracic and thoracic drug deposition is a key issue as well and should be minimized. Improvements to respiratory drug delivery efficiency have been recently proposed by Dr. P. Worth Longest and Dr. Michael Hindle through the use controlled condensational growth methods, which include enhanced condensational growth (ECG) and excipient enhanced growth (EEG). These methods reduce inhaled drug loss through the introduction of an aerosol with an initial submicrometer aerodynamic diameter, which then experiences condensational growth to increase droplet size and enhance thoracic deposition. Tracheobronchial and nasal human airway computational models were developed for this study to assess drug delivery using conventional and EEG methods. Computational versions of these models are used to assess drug delivery and variability with computational fluid dynamics (CFD) simulations, which are validated with experimental data where possible. Using CFD, steady state delivery of albuterol sulfate (AS) during high flow therapy (HFT) through a nasal cannula was characterized with four nasal models developed for this study, with results indicating an increase in average delivered dose from 24.0% with a conventional method to 82.2% with the EEG technique and an initially sized 0.9 µm aerosol, with a corresponding decrease in the coefficient of variation from 15% to 3%. Transient CFD simulations of nebulized AS administration through a mask during noninvasive positive pressure ventilation (NPPV) were performed and validated with experimental data, which resulted in 40.5% delivered dose with the EEG method as compared with 19.5% for a conventional method and a common inhalation profile. Using two newly created face-nose-mouth-throat models, dry powder delivery of ciprofloxacin during NPPV was assessed for the first time with steady state CFD predictions, which showed an increase in average delivered lung dose through a new mask design of 78.2% for the EEG method as compared with 36.2% for conventional delivery, while corresponding differences in delivered dose between the two models were reduced from 45.4% to 12.8% with EEG. In conclusion, results of this study demonstrate (i) the use of highly realistic in silico and in vitro models to predict the lung delivery of inhaled pharmaceutical aerosols, (ii) indicate that the EEG approach can reduce variability in nose-to-lung aerosol delivery through a nasal cannula by a factor of five, and (iii) introduce new high efficiency methods for administering aerosols during NPPV, which represents an area of current clinical need.

PhD
Electrostatics of aerosols for inhalation is a relatively new research area. Charge properties of these particles are largely unknown but electrostatic forces have been proposed to potentially influence lung deposition. Investigation on the relationship between formulation and aerosol charging is required to understand the fundamental mechanisms. A modified electrical low pressure impactor was employed to measure the particles generated from metered dose inhalers and dry powder inhalers. This equipment provides detailed size and charge information of the aerosols. The particles were sized by impaction onto thirteen stages. The net charges in twelve of the size fractions were detected and recorded by sensitive electrometers. The drug deposits were quantified by chemical assay. The aerosol charge profiles of commercial metered dose inhalers were product-dependent, which was due to differences in the drug, formulation, and valve stem material. The calculated number of elementary charges per drug particle of size ≤ 6.06 μm ranged from zero to several ten thousands. The high charge levels on particles may have a potential effect on the deposition of the aerosol particles in the lung when inhaled. New plastic spacers marketed for use with metered dose inhalers were found to possess high surface charges on the internal walls, which was successfully removed by detergent-coating. Detergent-coated spacer had higher drug output than the new ones due to the reduced electrostatic particle deposition inside the spacer. Particles delivered from spacers carried lower inherent charges than those directly from metered dose inhalers. Those with higher charges might be susceptible to electrostatic forces inside the spacers and were thus retained. The electrostatic low pressure impactor was further modified to disperse two commercial Tubuhaler® products at 60 L/min. The DPIs showed drug-specific responses to particle charging at different RHs. The difference in hygroscopicity of the drugs may play a major role. A dual mechanistic charging model was proposed to explain the charging behaviours. The charge levels on drug particles delivered from these inhalers were sufficiently high to potentially affect deposition in the airways when inhaled. Drug-free metered dose inhalers containing HFA-134a and 227 produced highly variable charge profiles but on average the puffs were negatively charged, which was thought to be due to the electronegative fluorine atoms in the HFA molecules. The charges of both HFAs shifted towards neutrality or positive polarity with increasing water content. The spiked water might have increased the electrical conductivity and/or decreased the electronegativity of the bulk propellant solution. The number of elementary charges per droplet decreased with decreasing droplet size. This trend was probably due to the redistribution of charges amongst small droplets following electrostatic fission of a bigger droplet when the Raleigh limit was reached.

Pseudomonas aeruginosa bacterial biofilms are the leading cause of mortality among cystic fibrosis (CF) patients. Biofilms contain bacteria attached to a surface and encased in a protective matrix. Since bacteria within a biofilm are less susceptible to antibiotics, a new approach is to use dispersion compounds that cause the biofilms to release free-swimming bacteria. Our approach has focused on combining nutrient dispersion compounds with antibiotics to increase eradication of bacteria within biofilms. This approach takes advantage of the enhanced susceptibility of free-swimming bacteria to antibiotics, compared to bacteria within biofilms. Ultimately, this research will guide the development of an aerosol therapy containing both antibiotic and dispersion compounds to treat bacterial biofilm infections. To study the effect of antibiotic and dispersion compound treatments on biofilm eradication, a high-throughput screening assay was used to assess the effect on young Pseudomonas aeruginosa biofilms. In addition, a Lab-Tek chambered coverglass system imaged via confocal microscopy was used to assess the effect on mature Pseudomonas aeruginosa biofilms. Seven antibiotics (amikacin disulfate, tobramycin sulfate, colistin sulfate, colistin methanesulfonate (CMS), polymyxinB sulfate, erythromycin, and ciprofloxacin hydrochloride) were tested alone or in combination with four nutrient dispersion compounds (sodium citrate, succinic acid, xylitol, and glutamic acid) to assess the level of eradication of bacteria within biofilms. For young biofilms, 15 of 24 combinations significantly eliminated more live bacteria within the biofilms (measured in colony forming units per milliliter) compared to antibiotics alone. In the more mature biofilm system, only 3 out of 26 combinations resulted in a higher percentage of live biofilm bacteria being eliminated compared to antibiotics alone, showing the importance of biofilm age in the effectiveness of these potential combination therapies. To aid in confocal microscopic analysis of biofilms, an automated quantification program called STAINIFICATION was developed. This new program can be used to simultaneously investigate connected-biofilm bacteria, unconnected bacteria (dispersed bacteria), the biofilm protective matrix, and a growth surface upon which bacteria are grown in confocal images. The program contains novel algorithms for the assessment of bacterial viability and for the quantification of bacteria grown on uneven surfaces, such as tissue. The utility of the viability assessments were demonstrated with confocal images of Pseudomonas aeruginosa biofilms. The utility of the uneven surface algorithms were demonstrated with confocal images of Staphylococcus aureus biofilms grown on cultured human airway epithelial cells and Neisseria gonorrhoeae biofilms grown on transformed cervical epithelial cells. Finally, a proof-of-concept study demonstrated that dry powder aerosols containing both antibiotic and nutrient dispersion compounds could be developed with properties optimized for efficient deposition in the lungs. A design of experiments study showed that solution concentration was the most significant parameter affecting aerosol yield, particle size, and in vitro deposition profiles. Collectively this work demonstrated that bacterial dispersion from biofilms can enhance antibiotic susceptibility and can be better quantified using the new STAINIFICATION software. Formulation of dispersion compounds and antibiotics into a dry powder aerosol could enable more effective treatment of biofilm infections in the lungs.

This research was aimed at the development and validation of new in vitro methods capable of predicting in vivo drug deposition from dry powder inhalers, DPIs, in lung-normal human adults. Three physical models of the mouth, throat and upper airways, MT-TB, were designed and validated using the anatomical literature. Small, medium and large versions were constructed to cover approximately 95% of the variation seen in normal adult humans of both genders. The models were housed in an artificial thorax and used for in vitro testing of drug deposition from Budelin Novolizer DPIs using a breath simulator to mimic inhalation profiles reported in clinical trials of deposition from the same inhaler. Testing in the model triplet produced results for in vitro total lung deposition (TLD) consistent with the complete range of drug deposition results reported in vivo. The effect of variables such as in vitro flow rate were also predictive of in vivo deposition. To further assess the method’s robustness, in vitro drug deposition from 5 marketed DPIs was assessed in the “medium” MT-TB model. With the exception of Relenza Diskhaler, mean values for %TLD+SD differed by only < 2% from their literature in vivo. The relationship between inhaler orientation and in vitro regional airway deposition was determined. Aerosol drug deposition was found to depend on the angle at which an inhaler is inserted into the mouth although the results for MT deposition were dependent on both the product and the formulation being delivered. In the clinic, inhalation profiles were collected from 20 healthy inhaler naïve volunteers (10M, 10F) before and after they received formal inhalation training in the use of a DPI. Statistically significant improvements in Peak Inhalation Flow Rate (PIFR) and Inhalation Volume (V) were observed following formalized training. The shapes of the average inhalation profiles recorded in the clinic were found to be comparable to the simulated profiles used in the in vitro deposition studies described above. In conclusion, novel in vitro test methods are described that accurately predict both the average and range of aerosol airway drug deposition seen from DPIs in the clinic.

This study is the first-ever approach to simulate particulate matter transport and deposition in the terminal bronchioles of the 17-generation, whole lung model by considering a possible entire branching pattern. The anatomically explicit, digital 17-generation conduit model is generated from the high-resolution CT data. A comprehensive size- and shape-specific particle transport and deposition study is performed for different physical conditions and finds a new deposition pattern for a realistic anatomical model. The present findings would potentially help the targeted drug delivery system design and increase the efficiency of the drug delivery to the specific positions in the pulmonary airways.

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution. The physicochemical properties of multi-component dry powder inhaler (DPI) formulation were characterized by a number of techniques. In addition, the in vitro aerosol dispersion performance, storage stability test, and in vitro drug release of selected spray-dried (SD) multi-component systems were conducted. The physicochemical study revealed that multi-component aerosol particles possessed essential particle properties suitable for deep lung delivery. In general, the multi-component particles (typically 0.5 to 2 µm) indicated that the designed SD aerosol particles could potentially penetrate deep lung regions (such as respiratory bronchiolar and alveolar regions) by sedimentation and diffusion, respectively. The essential particle properties including narrow size distribution, spherical particle and smooth surface morphologies, and low water content (or water vapor sorption) could potentially minimize interparticulate interactions. The study of in vitro aerosol dispersion performance showed that majority of SD multi-component aerosols exhibited low values (less than 5µm) of MMAD, high values (approximately above 30% up to 60.4%) of FPF, and high values (approximately above 90%) of ED, respectively. The storage stability study showed that azithromycin–incorporated multi-component aerosol particles stored at 11 and 40% RH with no partial crystallization were still suitable for deep lung delivery. Compared to SD pure azithromycin particles, the azithromycin-incorporated multi-component particles exhibited an enhanced initial release. The targeted microparticulate and nanoparticulate multi-component dry powder aerosol formulations with essential particle properties for deep lung pulmonary delivery were successfully produced by using spray drying from organic solution. The promising experimental data suggest the multi-component formulations could be further investigated in in vivo studies for the purpose of commercialization.

With the background of health issues regarding the consumption of tobacco, the widespread availability of safer nicotine products and a harm reduction policy is encouraged. A cigarette alternative is designed to deliver a dose of medicinal nicotine within a timeframe comparable to that of a cigarette, and gives much of what smokers expect from a cigarette without the risks of smoking tobacco. The general purpose of this Ph.D. project is to study the process of flashing atomization and dispersion, with a view to supporting the development of a cigarette replacement device. In order to test the effectiveness of the nicotine formulations, the analysis is carried out sizing the droplets of the aerosols at the position where human oropharynx locates, to support the further research on the deposition of droplets in the human respiratory tract. A mechanical lung has been assembled and programmed to trigger the ‘cigarette-like’ devices with different inhalation profiles, and a dual laser system has been designed to measure the global actuation flow characteristics (e.g. spray velocity and opacity). In order to efficiently acquire sufficient droplet information (e.g. diameter and aspect ratio) from images of in and out of focus droplets, a multi-threshold algorithm is developed and successfully implemented in the automatic particle/droplet image analysis (PDIA) system. It increases the depth of field (DoF) of small particles with diameters smaller than 50μm, and it performs more efficiently than the dual threshold methods which are widely used in the commercial software. A numerical multi-component two-phase actuation flow model has been developed, in order to test different formulations within various flow domains of the cigarette replacement devices. The simulated results of the numerical model have been validated with the experimental measurements and the results of previous researchers. In order to acquire an aerosol with relatively low and steady mass flow rate of nicotine, it is recommended that the mass fraction of propellant (HFA 134a) should be kept around 75%~90% to avoid the sharp temperature drop causing the sensation of freezing. The actuator nozzle diameter should be 0.2mm~0.3mm to produce a flow with relatively low mass flow rate. Furthermore the numerical model is capable of predicting the residual mass median diameter (MMD) of the spray, by using evaporation model of multicomponent liquid droplets, to quantify the sprays. Two different formulations with 95% and 98% mass fraction of HFA 134a, and two prototype cigarette alternatives with different expansion chamber volumes, have been analyzed by the numerical model and compared with the dual laser measurements. In addition, it considers the spray character by high speed imaging, with the special interest in the flashing phenomena and droplet sizes. It concludes that a larger expansion chamber volume enhances the propellant evaporation, recirculation, bubble generation and growth inside the chamber, and it made a significant improvement to produce finer sprays. Although the formulation with 98% of HFA 134a can generate smaller droplets, the formulation with 95% of HFA 134a produces more steady puffs with relatively low mass flow rate.

Dry powders for inhalation, although clinically effective, tend to be inefficient in terms of the extent and reproducibility of drug delivery. In part at least this is due to an inadequate understanding of the relevant particle-particle interactions between drug and drug, and drug and carrier. Electrostatic charge interactions are one of several factors influencing the overall efficiency of an inhalation powder. The practical significance of such interactions is considered to be critical in every aspect of the powder formulation, including the formation of an ordered mix and, more importantly, the timely disruption of drug - carrier agglomerates, allowing the reproducible delivery of respirable particles. The principal aim of this study was to provide a more fundamental understanding of electrostatic interactions of poured, packed and aerosolised powders for inhalation. Electrostatic properties of drug and excipient powders were studied using a deep Faraday pail static charge detector. The surface charge developed when adhered drug particles were detached from carrier particles was investigated using two dynamic measurement systems: a) an Airstream Faraday cage, and b) a differential charge-to-mass test system, The electric field attributable to the particle cloud generated by a dry powder inhaler was assessed using a fieldmeter, located at the base of a specially constructed flow tube, through which aerosolised particles were drawn. Characterisation of the electrostatic properties of the respirable fraction of the aerosol generated by high efficiency and commercial inhalers was also achieved. Adhesion forces between drug and carrier particles were measured using a modified centrifuge system. Deposition characteristics of powder mixes were studied using an invitro pharmacopoeial method. Hypotheses relating to particle interactions were established from the data obtained. Electrostatic characterisation of powders following detachment from carrier surfaces showed that they exhibit charges of increased magnitude, and in some cases opposite polarity to those observed following contact. Dynamic charge measurements were considered much more relevant to the performance of dry powder formulations for inhalation than corresponding static determinations. Aerosols generated from dry powders for inhalation were shown to exhibit bipolar charging characteristics, which could result in reagglomeration of charged aerosol particles, and contribute to the reduced efficiency of these systems. Aerosol properties were found to be dependent upon the physical and chemical properties of the material studied and the construction and deaggregation mechanism of the dry powder inhaler (DPI) device. A combination of centrifugation, in-vitro deposition studies using the twin stage impinger (TSI) and electrostatic detachment charges indicated the relative contribution of centrifugal and electrostatic elements toward the deaggregation of drug-carrier complexes in dry powder formulations for inhalation. Good correlation was demonstrated between electrostatic detachment charge measurements and TSI deposition studies for binary and ternary powder blends. In-vitro performance characteristics of dry powder formulations were found to improve upon the addition of ternary and quaternary components. A 'chain breaker' theory has been proposed for the mechanism of interaction between carrier, drug, ternary and quaternary components of the attached chain of constituents, based upon their electrostatic characteristics.

Dry powder inhalers (DPIs) are commonly used to deliver drugs to the lungs. The drug particles used in these DPIs should possess a number of key properties. These include an aerodynamic particle size < 5μm and particle crystallinity for long term formulation stability. The conventionally used micronization technique to produce inhalation particles offers limited opportunities to control and optimize the particle characteristics. It is also known to induce crystalline disorder in the particles leading to formulation instability. Hence, this research project investigates and optimizes a solvent/anti-solvent crystallization process capable of directly yielding inhalation particles using albuterol sulfate (AS) as a model drug. Further, the feasibility of the process to produce combination particles of AS and ipratropium bromide monohydrate (IB) in predictable proportions and in a size suitable for inhalation is also investigated. The solvent / anti-solvent systems employed were water / ethyl acetate (EA) and water / isopropanol (IPA). Investigation and optimization of the crystallization variables with the water / EA system revealed that particle crystallinity was significantly influenced by an interaction between the drug solution / anti-solvent ratio (Ra ratio), stirring speed and crystal maturation time. Inducing a temperature difference between the drug solution and anti-solvent (Tdrug solution > Tanti-solvent) resulted in smaller particles being formed at a positive temperature difference of 65°C. IPA was shown to be the optimum anti-solvent for producing AS particles (IPA-AS) in a size range suitable for inhalation. In vitro aerosol performance of these IPA-AS particles was found to be superior compared to the conventionally used micronized particles when aerosolized from the Novolizer®. The solvent / anti-solvent systems investigated and optimized for combination particles were water / EA, water / IPA, and water / IPA:EA 1:10 (w/w). IPA was found to be the optimum anti-solvent for producing combination particles of AS and IB with the smallest size. These combination particles showed uniform co-deposition during in vitro aerosol performance testing from the Novolizer®. Pilot molecular modeling studies in conjunction with the analysis of particle interactions using HINT provided an improved understanding of the possible interactions between AS and IB within a combination particle matrix.

Cascade impactors, routinely used for in vitro particle size characterization of pharmaceutical aerosols, are calibrated using dilute, charge-neutralized, monodisperse aerosols. But pharmaceutical aerosols are known to generate concentrated, inherently charged, polydisperse aerosol clouds. A computational model of the Andersen Cascade Impactor (ACI) suggested that the presence of charge on aerosol particles may influence their deposition within the ACI, but experimental validation of the model is warranted. This dissertation investigates the influence of electrostatic charge upon the deposition behavior of aerosols within cascade impactors, to address the impact of charge on particle size characterization. The influence of applied charge upon the deposition pattern and aerodynamic particle size distribution (APSD) of commercially available pressurized metered dose inhalers (pMDIs) within the Electrical Low Pressure Impactor (ELPI) was examined. Electrostatic properties were modified using an external voltage source in conjunction with the ELPI corona charger and observed to be dependent on the formulation and device packaging. Induced artificial charge on the aerosol particles influenced the deposition pattern within the impactor, but did not result in a significant change in the apparent APSD. An experimental apparatus capable of producing charge neutralized and charged aerosol, with targeted deposition on the CFD predicted ‘charge sensitive’ ACI stages, was developed. In vitro results were observed to be in partial agreement with the CFD predictions. While charge influenced the deposition pattern in the ACI with increased deposition observed in the charger and on the upper stages of the ACI, it did not influence the apparent APSD of the aerosol. Electrostatic charge effects on deposition behavior within cascade impactors were delineated with respect to space charge and image charge effects by investigating the influence of impactor grounding, particle size, stage coating and loading. While the deposition pattern within the ACI was influenced by charge, only stage coating and stage loading resulted in a small, significant difference in the apparent APSD, which may not be practically relevant due to the variability associated with in vitro aerosol testing. Similar trends were observed in the deposition behavior of charge neutralized and charged aerosol within an abbreviated ACI system compared to the full resolution ACI.

Electrostatic properties of formulation component materials and blends play an important role in dry powder inhalation (DPI) products, and that valid measurement of charge distribution will lead to more precise control of powder behavior in DPI manufacturing processes. Ultra-fine powders are known to be bipolarly charged, have non-spherical shapes and tend to be highly cohesive. Real time, non-invasive techniques need to be developed to obtain a precise and accurate time-history characteristic of electrically charged powders as they aerosolize from a DPI product, and how this measure relates to materials behavior throughout the various steps of a manufacturing process i.e. from drug micronisation, blending with lactose, through to filling dose units. A novel non-invasive technique for simultaneous measurement of size and charge of pharmaceutical powders is considered which employs the Phase Doppler Anemometry (PDA) system. Previous research demonstrated the advantages of this technique in measuring the bipolar charge distribution on a population of particles. These findings led to significant improvements in understanding performance of dry powder formulations, manufacturing processes and development of new platforms for inhaled drug delivery. The main aim of this research is to perform an investigation of electrostatic propertiesof pharmaceutical dry aerosols using the PDA system. The PDA technique was used to track the motion of charged particles in the presence of an electric field. The magnitude as well as the polarity of the particle charge can be obtained by solving the equation of particle motion in DC and AC fields combined with the simultaneous measurement of its size and velocity. The results show the capability of the technique to allow real-time size and charge distribution in the control of dry powder attributes that are critical to fully understanding manufacturing design space. The data obtained from initial investigations of electrical properties of pharmaceutical powders and bipolar charge measurements was used to perform an in-depth study of electrostatic properties of pharmaceutical aerosols dispensed by dry powder inhaler (DPI) devices. The delivery of a drug to the lungs can only be achieved by a combination of inhaler device and drug formulation which is capable of producing an aerosol of an aerodynamic diameter smaller than 5 μm and of appropriate charge. The aerosols generated by these devices are often bipolarly charged and can influence specific site deposition in human lung. By controlling the electrostatic charge generated by tribielectrification, it may be possible to achieve the desired drug deposition in the airways. Bipolary charged dispensed ultrafine particles are inhaled through the extrathoracic and tracheobronchial airways down into the alveolar region. Anatomically realistic respiratory airways and computation fluid dynamics (CFD) models have been created to study airflow structures and predict aerosol deposition within the human respiratory system using visible human data sets, human casts and morphometric data. Many theoretical studies of charged aerosol deposition in human respiratory systems have been developed, however getting real time, non-intrusive data of bipolar charge levels on aerosols dispensed from DPI’s within the human respiratory system represents a challenging issue. This research project presents a simplified human upper airway model which combined with the modified Phase Doppler Anemometry (PDA) system is able to provide real time bipolar charge distributions of aerosols delivered from several commercially available DPI devices. A three dimensional (3D) reconstruction of the upper respiratory system was performed from two dimensional (2D) images obtained from computerized tomography (CT), magnetic resonance imaging (MRI) and cryosectioned images available from Visible Human Server data set (Ecole Polytechnique Fédérale de Lausanne). The resulting dimensions of the model were consistent with morphometric data from the literature from which the simplified upper airway model consisting of two connected segments, i.e., the oral airways from the mouth to trachea (Generation G0), was created. The findings of this study provided a better understanding of the interaction between specific active ingredients and DPI devices. These results may be used in designing future generation DPI devices and a better understanding of aerosol transport and deposition efficiency within the human airways.

The administration of pharmaceutical aerosols to infants on mechanical ventilation needs to be improved by increasing the efficiency of delivery devices and creating better ways of evaluating potential therapies. Aerosolized medicines such as surfactants have been administered to ventilated infants with mixed results, but studies have shown improvement in respiratory function with a much lower dose than with liquid instillation through an endotracheal tube (ETT). An aerosolized medicine must be transported through the ventilation tubing and deposit in the lungs to have the desired therapeutic response. This work has taken a systematic approach to (i) develop new devices for the efficient production of small sized charged pharmaceutical aerosols, (ii) adapt a lead device to an infant ventilation system, (iii) develop a novel breathing infant lung (BIL) in vitro model capable of capturing lung delivery efficiency in an infant without the need for human subjects testing, and (iv) evaluate the hypothesis that small sized charged pharmaceutical aerosols can improve drug delivery efficiency to the lungs of a ventilated infant. Three new devices were developed and screened for the efficient generation of small sized charged pharmaceutical aerosols, which were: wick electrospray, condensational vapor, and a modified vibrating mesh nebulizer in a streamlined low flow induction charger (LF-IC). Of these devices, only the LF-IC produced a small [mean(SD) = 1.6(0.1) micrometers] and charged (1/100 Rayleigh limit) aerosol at a pharmaceutically relevant production rate [mean(SD) = 183(9) micrograms per minute]. The LF-IC was selected as a lead device and adapted for use in an infant ventilation system, which produced an increase in in vitro lung filter deposition efficiency from 1.3% with the commercial system to 34% under cyclic ventilation conditions. The BIL model was first shown to produce a realistic pressure-volume response curve when exposed to mechanical ventilation. The optimized LF-IC was then implemented in the BIL model to demonstrate superior reduction in inspiratory resistance when surfactant was delivered as an aerosol compared to liquid instillation. For the delivery of an aerosolized medication, the lung deposition efficiency increased from a mean(SD) 0.4(0.1)% when using the conventional delivery system to 21.3(2.4)% using the LF-IC in the BIL model, a 59-fold increase. The charged aerosol produced by the LF-IC was shown to have more depositional loss in the LF-IC than an uncharged aerosol, but the charge decreased the exhaled fraction of aerosol by 17%, which needs additional study to achieve statistical significance. Completion of this work has produced a device that can achieve lung delivery efficiency that is 59-fold greater than aerosols from conventional vibrating mesh nebulizers in invasively ventilated infants using a combination of small particle size, synchronization with inspiration and appropriate charge. The BIL model produced in this work can be used to test clinically relevant methods of administering medications to infants and can be used to provide more accurate delivery estimates for development of new nebulizers and inhalers. The LF-IC developed in this work could be used for controlled and efficient delivery of aerosolized antibiotics, steroids, non-steroidal anti-inflammatories, surfactants, and vasodilators.

Lung cellular disposition and anti-inflammatory pharmacology of inhaled corticosteroids (ICSs) is complex, comprised of a cascade of aerosol deposition and dissolution, followed by cellular uptake for local pharmacological action. This project hypothesized that the kinetics of dissolution for certain ICS aerosols generated from inhaler products were kinetically rate-determined for their cellular uptake and local pharmacological action. A novel dissolution testing system was developed to determine the dissolution kinetics for the ICS aerosols. A total of 5 ICSs aerosols generated from 6 inhaler products were collected in 2.1-3.3 or 4.7-5.8 µm of aerodynamic diameters at 0.7-19.8 µg on filter membranes by impaction using the Andersen cascade impactor. The filter membrane was then placed on the donor side of the transwell insert, with its face down, and the ICS dissolution in the limited 40 µL of the donor fluid was monitored over time. The dissolution kinetics overall conformed to the rank order of the aqueous solubility, while also being affected by ICS aerosol’s mass, size, formulation and dosage forms. For the readily soluble triamcinolone acetonide (TA), the kinetics was first-order, reaching ≥89 % dissolution in 5 h. In contrast, for the least soluble fluticasone propionate (FP), the kinetics was zero-order, reaching only 3 % dissolution in 10 h. The project then developed an air-interface culture of human bronchial epithelial cell line, Calu-3. Well-differentiated monolayers were formed with sufficiently “tight” barrier for restrictive solute diffusion while their mucosal surface was maintained semi-dry with 39.7±12.1 µL of the mucosal lining fluid in the 4.5 cm2 transwells. These monolayers were transfected with reporter plasmid of pNFκB-Luc to assess in vitro anti-inflammation via repression of pro-inflammatory NFκB by direct FP or TA aerosol deposition. The FP aerosols at 0.9 µg successfully exhibited significant 35.7±6.3 % repression. Notably, however, an identical ~0.5 µg of FP and TA aerosols caused comparable 15.5±2.2 and 10.4±2.6 % repression, respectively, despite FP’s 10-fold greater “intrinsic” anti-inflammatory potency over TA, reported in the literature. This was attributed to FP’s slow dissolution resulting in only 4.7 % cellular uptake, compared to 32.6 % for the TA aerosols. Hence, the FP aerosols were shown to be rate-determined by dissolution on the lung cell surface, resulting in reduced anti-inflammatory actions, which was not the case for the readily soluble TA aerosols.

The overall aim of this research project was to develop surfactant dry powder formulations and devices for efficient delivery of aerosol formulations to infants using the excipient enhanced growth (EEG) approach. Use of novel formulations and inline delivery devices would allow for more efficient treatment of infants suffering from neonatal respiratory distress syndrome and bronchiolitis. A dry powder aerosol formulation has been developed using the commercial product, Survanta ® (beractant) and EEG technology to produce micrometer-sized hygroscopic particles. Spray drying and formulation parameters were initially determined with dipalmitoylphosphatidylcholine (DPPC, the dominant phospholipid in pulmonary surfactant), which produced primary particles 1 um in size with a mass median aerodynamic diameter of 1-2 um. Investigation of dry powder dispersion enhancers and alcohol concentration on the effect of powder aerosol characteristics were performed with the Survanta-EEG formulation. The optimal formulation consisted of Survanta ® , mannitol and sodium chloride as hygroscopic excipients, and leucine as the dry powder dispersion enhancer, prepared in 20% v/v ethanol/water. The powders produced primary particles of 1 um with >50% of the particles less than 1 um. The presence of surfactant proteins and surface activity were demonstrated with the Survanta-EEG formulation following processing. A novel containment unit dry powder inhaler (DPI) was designed for delivery of the surfactant-EEG formulation using a low volume of dispersion air. Studies explored optimization of air entrainment pathway, inlet hole pattern, delivery tube internal diameter and length. With 3- 10 mg fill masses of spray dried surfactant powder, the DPI enabled delivery of >2 mg using one 3-mL actuation of dispersion air. Overall, it was possible to deliver >85% of the loaded fill mass using three actuations. Nebulized aerosol formulations are characterized with low delivered doses. Using a novel mixer-heater delivery system, the highest estimated percent lung dose achieved during realistic in vitro testing of a Survanta-EEG formulation aerosolized with a commercial mesh nebulizer was when nebulization was synchronized with inhalation of the breathing profile. Design changes to the mixer-heater system eliminated the need for synchronization, achieving an estimated percent lung dose of 31% of the nominal, an improvement compared with existing systems that achieve approximately <2% lung dose.

Most current models for the deposition of aerosol particles in the human lung are based on a Lagrangian reference frame, which is ill-suited for modeling transient eects. Deposition models based on an Eulerian reference frame are much better at capturing instantaneous time-dependent eects, though they are dicult to create. In the interest of developing such models, mathematical techniques were used to describe the velocity elds of simple particle ows. Analytic expressions describing the time-dependent ow of particles through a curved pipe were created and implemented numerically. The numerical simulations were used to determine which ow regimes required the use of Eulerian modelling for deposition prediction.

The Corona® charged aerosol detector (CAD) is an aerosol-based detector first de-scribed by Dixon and Peterson in 2002. It is capable of detecting compounds inde-pendent from their physico-chemical properties presumed the analyte is sufficiently non-volatile. Consequently, the CAD is often applied to the analysis of substances that do not possess a suitable UV chromophore. Major drawbacks are however, the detector signal is non-linear and depending on the content of organic solvent in the mobile phase. This thesis tried to explore possible applications of the CAD for pharmaceutical analysis. Therefore, several substances from different compound classes were in-vestigated. Newly developed or existing methods were validated. Thus the perfor-mance of the CAD could be examined. Both assay and impurity determination were evaluated for their compliance with ICH Q2(R1) “Validation of Analytical Proce-dures” and the “Technical Guide for the Elaboration of Monographs”. In the course of the establishment of reference substances at the EDQM, a generic screening method for the identification of organic and inorganic pharmaceutical counterions was needed. An HPLC-CAD method developed by Zhang et al. was therefore investigated for its suitability for pharmacopoeial purpose. Method valida-tion was performed. It was found that 23 ions could be separated and detected. Iden-tification was achieved via retention time of an authentic standard of the corre-sponding ions. Alternatively, peak assignment was performed by determination of the exact mass using TOF-MS. Ions could be quantified as impurities or for stoichi-ometric purpose. For the impurity control in topiramate, the performance characterstics of the CAD were compared to that of an ELSD. CAD was superior to ELSD in terms of repeata-bility, sensitivity and linearity. However, impurities could be quantified with satisfac-tory accuracy with both detectors. The application of the ELSD was not feasible due to non-reproducible spike peaks eluting after the principle peak in the chromatogram of the test solution. One of the impurities, topiramate impurity A (diacetonide), gave no or a vastly diminished signal in the ELSD and the CAD, respectively. It is evapo-rated during the detection process due to its relatively high vapor pressure. The re-sponse could be enhanced by a factor of nine via post-column addition of acetoni-trile and a lower nebulizer temperature. As the response of topiramate impurity A was still about thousand-fold lower than the response of all other impurities, its quantification was not feasible. Additionally, the HPLC-CAD was successfully vali-dated as an assay procedure for topiramate. There seems to be a great potential in the application of the CAD to the analysis of excipients as most compounds do not possess a suitable UV chromophore. Here, a simple and rapid HPLC-CAD method for the determination of polidocanol (PD) was developed. The method was successfully validated as a potential assay procedure for the Ph. Eur. as none is described in either of the two PD monographs. The same method was applied to the determination of the PD release from a pharmaceutical polymer matrix. A method for the determination of the fatty acid (FA) composition of polysorbate 80 (PS80) was developed and validated. Using the CAD and mass spectrometry, we were able to identify two new FAs in 16 batches from four manufacturers. All batch-es complied with pharmacopoeial specification. Furthermore, the overall composi-tion of the different PS80 species (“fingerprinting”) and the peroxide content were determined. In addition to the chemical characterization, functionality related charac-teristics (FRCs) were determined. Correlations between chemical composition and FRCs were found. The validation data of the above mentioned methods suggests that the CAD repre-sents a viable detection technique for pharmaceutical analysis. The CAD was suffi-ciently sensitive for non-volatile analytes. Impurity control down to concentrations of 0.05 or 0.03%, as demanded by ICH Q3A (R2), is achievable. However, the response of semi-volatile compounds may be drastically diminished. It could be confirmed that the response of the CAD is linear when the range does not exceed two orders of magnitude. Exceptions may be observed depending on the actual method setup. When the measuring range is sufficiently narrow, quantification can be done using single-point calibration which is common practice in pharmaceutical anlysis. Impuri-ties may also be quantified against a single calibration solution. However, correction factors may be needed and the accuracy is considerably lower compared to an as-say method. If a compound is to be quantified over a large concentration range, log-log transformation of the calibration curve is needed and a decreased accuracy has to be accepted
Der “Corona® charged aerosol detector” (CAD) ist ein aerosol-basierter Detektor, welcher 2002 von Dixon und Peterson vorgestellt wurde. Damit lassen sich nicht-flüchtige Substanzen unabhängig von ihren physiko-chemischen Eigenschaften detektieren. Daraus folgt, dass der CAD oft zur Analyse von Substanzen ohne UV-Chromophor angewandt wird. Großes Manko ist jedoch, dass das Signal nicht linear und abhängig vom Anteil organischen Lösemittels in der mobilen Phase ist. Ziel dieser Arbeit war es, mögliche Anwendungen des CAD in der pharmazeuti-schen Analytik zu erschließen. Dies wurde anhand von Beispielen aus unter-schiedlichen Substanzklassen untersucht. Dabei wurden neu entwickelte oder be-stehende Methoden validiert um die Leistung des CAD beurteilen zu können. So-wohl Gehaltsbestimmungen als auch Methoden zur Erfassung von Verunreinigun-gen wurden hinsichtlich ihrer Konformität mit dem Europäischen Arzneibuch (Ph. Eur.) geprüft. Im Zuge der Charakterisierung von Referenzsubstanzen beim EDQM wurde eine Methode zur Identifikation von pharmazeutischen Gegenionen benötigt. Zu diesem Zweck wurde eine HPLC-CAD-Methode von Zhang et al. hinsichtlich ihrer Eignung für das Ph. Eur. überprüft. Mit dieser Methode ließen sich 23 pharmazeutisch rele-vante Ionen trennen und detektieren. Die Ionen wurden durch Vergleich der Re-tentionszeiten eines Standards erreicht. Zusätzlich wurde die Peakzuordnung mit-tels der Bestimmung der Präzisionsmasse des Gegenions oder des Arzneistoffes durch ein TOF-MS durchgeführt. Die Methode ließ die Quantifizierung von Ionen als Verunreinigung oder zur Bestimmung der Stöchiometrie eines Salzes zu. Bei der Bestimmung von Verunreinigungen von Topiramat wurde ein Vergleich zwischen CAD und ELSD angestellt. Es zeigte sich, dass der CAD in den Punkten Wiederholbarkeit, Empfindlichkeit und Linearität überlegen war. Mit beiden Detekto-ren wurde eine ähnlich gute Richtigkeit erzielt. Durch das Auftreten von nicht re-produzierbaren Peaks, welche nach dem Hauptpeak im Chromatogramm der Testlö-sung auftraten, war die Anwendung des ELSD hier auszuschließen. Eine der Ver-unreinigungen, Topiramat Verunreinigung A (Diacetonid) lieferte kein bzw. ein ver-ringertes Signal in ELSD und CAD. Aufgrund des relativ hohen Dampfdrucks der Substanz wurde sie während des Detektionsvorgangs verdampft. Das Signal konn-te durch Zugabe von Acetonitril nach der Säule und durch eine Verringerung der Temperatur des Vernebler um das neunfache vergrößert werden. Da aber die Emp-findlichkeit für alle anderen Verunreinigungen dennoch um das tausendfache hö-her war, war eine Quantifizierung von Topiramat Verunreinigung A nicht möglich. Die HPLC-CAD Methode wurde zusätzlich als Gehaltsbestimmungsmethode für Topiramat validiert. Die Anwendung des CAD zur Analyse von Hilfsstoffen birgt großes Potenzial, da viele Substanzen nicht über ein Chromophor verfügen. Im Zuge dieser Arbeit wurde eine einfache und schnelle Methode zur Gehaltsbestimmung von Polidocanol (PD) entwickelt. Diese wurde als mögliche Methode für das Ph. Eur. validiert. Zusätzlich wurde die Methode zur Bestimmung der Freisetzung von PD aus einer pharmazeu-tischen Matrix verwendet. Es wurde eine Methode zur Bestimmung der Fettsäurezusammensetzung von Poly-sorbat 80 (PS80) entwickelt und validiert. Mittels CAD und Massenspektrometrie war es möglich zwei neue Fettsäuren in 16 Chargen von vier verschiedenen Herstellern zu identifizieren. Alle Chargen entsprachen den Anforderungen des Ph. Eur. Wei-terhin wurde die Zusammensetzung der einzelnen PS80-Spezies („fingerprinting“) sowie der Peroxidgehalt untersucht. Neben dieser chemischen Charakterisierung wurden auch funktionalitätsbezogene Eigenschaften (FRCs) bestimmt. Korrelatio-nen zwischen chemischen Zusammensetzung und FRCs wurden gefunden. Die Validierungsdaten der genannten Methoden legen nahe, dass der CAD sinn-voll zur pharmazeutischen Analytik angewendet werden kann. Für nicht-flüchtige Substanzen wurde stets eine ausreichende Empfindlichkeit erreicht. Somit können Verunreinigungen bis zu einer Konzentration von 0.05 bzw. 0.03%, wie von der ICH Richtlinie Q3A (R2) gefordert, quantifiziert werden. Jedoch kann das Detektorsignal bei halb-flüchtigen Substanzen stark erniedrigt sein. Es konnte bestätigt werden, dass sich das Detektorsignal über zwei Größenordnungen linear verhält. Abwei-chungen davon sind in Abhängigkeit der jeweiligen Methode möglich. Ist der Mess-bereich genügen klein, so kann ein Stoff mittels Einpunkt-Kalibrierung quantifiziert werden. Dieses Vorgehen sollte bei Gehaltsbestimmungen angewandt werden. Ebenfalls mittels Einpunkt-Kalibrierung können Verunreinigungen erfasst werden. Jedoch kann es notwendig sein, Korrekturfaktoren zu bestimmen. Die Richtigkeit ist hier deutlich niedriger als bei einer Gehaltsbestimmungsmethode. Über einen gro-ßen Konzentrationsbereich muss eine Ausgleichskurve mit log-log-Transformation verwendet werden. Die Richtigkeit ist hierbei ebenfalls geringer als bei einer Ge-haltsbestimmung

Dry Powder inhalers (DPIs) have been one of the most promising developments in pulmonary drug delivery systems. In general, DPIs are more effective than systemic administrations and convenient to use. However, delivering high-dose antibiotics through a DPI is still a challenge because high powder load may need a very large inhaler or increase the incidence of local adverse effects. Spray drying has been increasingly applied to produce DPI formulations for high-dose antibiotics; nevertheless, many spray-dried particles are amorphous and physically unstable during storage, particularly under the humid environment.

My research focuses on addressing critical challenges in physical stability of DPIs for spray-dried high-dose antibiotics. The effects of moisture-induced crystallization on physical stability and aerosol performance of spray-dried amorphous Ciprofloxacin DPI formulations stored at different humidity conditions were studied. Our study not only provided a mechanistic understanding in the impact of crystallization on aerosol performance but also developed novel approaches for improving stability of spray-dried formulations used in DPI.

Our work has shown that recrystallization of amorphous spray-dried Ciprofloxacin led to significant changes in aerosol performance of DPIs upon storage, which cause critical quality and safety concerns. These challenges have been solved through co-spray-drying Ciprofloxacin with either excipient such as leucine or synergistic antibiotic like Colistin. Co-spray-drying Ciprofloxacin with Colistin not only improved physical and aerosol stability but also enhanced antibacterial activity which is a great advantage for treating ‘difficult to cure’ respiratory infections caused by multidrug resistant bacteria.

My research work is a sincere effort to maximize the utility and efficacy of high-dose DPI, an effective delivery tool for treating severe resistant bacterial respiratory infections.

Liu Hua.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.
Includes bibliographical references (leaves 139-143).
Abstracts in English and Chinese.
Table of Contents --- p.I
Acknowledgement --- p.VII
Abstract --- p.VIII
Abstract (Chinese) --- p.X
List of Tables --- p.XV
List of Figures --- p.XXIV
List Symbols and Abbreviations
Chapter Chapter One --- Introduction
Chapter 1.1. --- Rationale of study --- p.2
Chapter 1.2. --- Drug Delivery to the lungs --- p.5
Chapter 1.3. --- Particle transport and deposition mechanisms --- p.8
Chapter 1.4. --- Factors affecting particulate interactions --- p.9
Chapter 1.4.1. --- Particle size --- p.9
Chapter 1.4.2. --- Particle shape --- p.10
Chapter 1.4.3. --- Surface texture --- p.10
Chapter 1.4.4. --- Surface energy --- p.11
Chapter 1.4.5. --- Contact area --- p.12
Chapter 1.4.6. --- Relative humidity --- p.12
Chapter 1.4.7. --- Electrical properties --- p.13
Chapter 1.5. --- Fine powder production technologies applicable to dry powder inhalation formulations --- p.13
Chapter 1.5.1. --- Batch crystallization and micronization --- p.14
Chapter 1.5.2. --- Spray drying --- p.15
Chapter 1.5.3. --- Supercritical fluid crystallization --- p.17
Chapter 1.6. --- Physical characterization of aerosol powders --- p.18
Chapter 1.6.1. --- Microscopy and particle size analysis --- p.19
Chapter 1.6.2. --- Powder X-ray diffractometry --- p.19
Chapter 1.6.3. --- Thermal analysis --- p.20
Chapter 1.6.4. --- In-vitro deposition assessment --- p.20
Chapter 1.6.5. --- Surface energy measurement by inverse gas chromatography (IGC) --- p.21
Chapter 1.7. --- Scope of study --- p.22
Chapter Chapter Two --- Materials and Methods
Chapter 2.1. --- Materials --- p.25
Chapter 2.2. --- Equipment --- p.25
Chapter 2.3. --- Methods --- p.27
Chapter 2.3.1. --- Determination of aqueous solubility of salbutamol sulphate in water --- p.27
Chapter 2.3.2. --- Preparation of spray-dried salbutamol sulphate powders under different operating conditions --- p.27
Chapter 2.3.3. --- Preparation of spray-dried salbutamol sulphate powders at various lecithin concentrations --- p.30
Chapter 2.3.4. --- Preparation of spray-dried salbutamol sulphate powders at various oleic acid concentrations --- p.32
Chapter 2.3.5. --- Physical characterization of spray-dried salbutamol sulphate powders --- p.34
Chapter 2.3.5.1. --- Scanning electron microscopy --- p.34
Chapter 2.3.5.2. --- Specific surface area determination --- p.34
Chapter 2.3.5.3. --- Particle size distribution measurements --- p.35
Chapter 2.3.5.4. --- Water content determination --- p.36
Chapter 2.3.5.5. --- Isothermal water vapour sorption studies --- p.37
Chapter 2.3.5.6. --- Powder X-ray diffraction --- p.37
Chapter 2.3.5.7. --- Thermal analysis --- p.38
Chapter 2.3.5.8. --- Surface energy measurement by inverse gas chromatography --- p.39
Chapter 2.3.5.8.1. --- Calculation of surface thermodynamic parameters --- p.40
Chapter 2.3.5.8.1.1. --- Standard Free Energy of Adsorption and Related Thermodynamic Parameters --- p.40
Chapter 2.3.5.8.1.2. --- Dispersive Component of Surface Free Energy and Related Thermodynamic Parameters --- p.41
Chapter 2.3.5.8.1.3. --- Specific Interactions and Associated Acid-Base Properties --- p.42
Chapter 2.3.5.9. --- In-vitro deposition measurement by multi-stage liquid impinger --- p.43
Chapter Chapter Three --- Results and discussion
Chapter 3.1. --- Influence of spray drying operating parameters --- p.46
Chapter 3.1.1. --- Drying temperature --- p.46
Chapter 3.1.1.1. --- "Particle size, particle morphology, and specific surface area" --- p.46
Chapter 3.1.1.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.53
Chapter 3.1.1.3. --- Surface thermodynamic properties --- p.60
Chapter 3.1.1.4. --- Aerodynamic properties and in-vitro deposition --- p.64
Chapter 3.1.2. --- Feed solution concentration --- p.67
Chapter 3.1.2.1. --- "Particle size, particle morphology and specific surface area" --- p.69
Chapter 3.1.2.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.69
Chapter 3.1.2.3. --- Surfacethermodynamicproperties --- p.70
Chapter 3.1.2.4. --- Aerodynamic properties and in-vitro deposition --- p.70
Chapter 3.1.3. --- Feed speed --- p.72
Chapter 3.1.3.1. --- "Particle size, particle morphology, and specific surface area" --- p.72
Chapter 3.1.3.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.73
Chapter 3.1.3.3. --- Surfacethermodynamicproperties --- p.73
Chapter 3.1.3.4. --- Aerodynamic properties and in-vitro deposition --- p.73
Chapter 3.2. --- Influence of formulation additives --- p.78
Chapter 3.2.1. --- Influence of lecithin as additive --- p.78
Chapter 3.2.1.1. --- "Particle morphology, particle size and specific surface area" --- p.79
Chapter 3.2.1.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.84
Chapter 3.2.1.3. --- Surfacethermodynamicproperties --- p.90
Chapter 3.2.1.4. --- Aerodynamic properties and in-vitro deposition --- p.94
Chapter 3.2.2. --- Influence of oleic acid as additive --- p.101
Chapter 3.2.2.1. --- "Particle morphology, particle size and specific surface area" --- p.101
Chapter 3.2.2.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.106
Chapter 3.2.2.3. --- Surfacethermodynamicproperties --- p.123
Chapter 3.2.2.4. --- Aerodynamic properties and in-vitro deposition --- p.127
Chapter Chapter Four --- Conclusion and Future Work
Chapter 4.1. --- Conclusion --- p.134
Chapter 4.1.1. --- Influence of spray drying operating parameters --- p.134
Chapter 4.1.2. --- Influence of formulation additives --- p.135
Chapter 4.2. --- Future Work --- p.137
References --- p.139

An in vivo study with 19 rabbits was completed. Half of the exposed rabbits had a magnetic field placed externally over their right lung. Magnetic resonance images of the lungs were acquired to determine the iron concentrations in the right and left lung of each animal. The right/left ratio increased in the middle and basal regions of the lung. With further optimization, this technique could be an effective method for targeted drug delivery. Additionally, the feasibility of increasing the length of high aspect ratio particles for improved targeted drug delivery was explored. An ultrasonic nozzle was pulsed into a large evaporation chamber. Individual particles were found to be double the original length. However, due to locally increased humidity the droplets were not dried, except with the use of an orifice to rapidly accelerate and break apart the larger droplets. The complications associated with this method make it an undesirable and unfeasible method of creating longer particles.

Dissertação de Mestrado Integrado em Engenharia Química apresentada à Faculdade de Ciências e Tecnologia
O principal objetivo desta dissertação de mestrado foi incorporar nanotubos de carbono (CNTs) em aerogéis de sílica para obtenção de materiais compósitos com boas propriedades de adsorção. Metiltrimetoxissilano (MTMS) e (3-aminopropil) trimetoxissilano (APTMS) foram utilizados como precursores de sílica, os quais, em diferentes proporções molares e utilizando a metodologia sol-gel, levaram à formação de aerogéis compósitos de CNTs-sílica.O surfactante utilizado foi escolhido entre brometo de hexadeciltrimetilamónio (CTAB), dodecil sulfato de sódio (SDS) e polietilenoglicol (PEG). Quando a síntese foi realizada com PEG, não foi obtido um gel, no entanto, o uso dos outros dois surfactantes produziu monólitos que não apresentaram diferenças significativas nos valores da massa volúmica bulk. Em relação ao tempo de gelificação, o CTAB apresentou os melhores resultados, com menor tempo de gelificação, o que é favorável para evitar a sedimentação dos CNTs na suspensão.O próximo parâmetro estudado foi o método de agitação e, embora a agitação mecânica proporcionasse menor massa volúmica bulk, o banho de ultrassom permitiu uma melhor dispersão dos CNTs na solução. Um estudo sobre a necessidade de uma etapa de lavagem para remover o surfactante dos géis foi também realizado. Comparando os resultados para a mesma formulação, com e sem lavagem, foi possível concluir que esta etapa foi fundamental, permitindo uma melhoria significativa na massa volúmica bulk, levando a uma redução de 5 a 10 kg m-3. A análise termogravimétrica confirmou que a etapa de lavagem removeu praticamente todo o surfactante da estrutura dos materiais.Os aerogéis com diferentes proporções de precursores (100% MTMS, 90% MTMS/10% APTMS e 80% MTMS/20% APTMS) foram caracterizados química, física e microestruturalmente. As amostras com 100% de MTMS apresentaram menores valores de massa volúmica bulk. A presença de grupos amina levou a um aumento em termos de tamanho dos poros, mas uma redução da área superficial específica. As técnicas de microscopia permitiram a visualização da microestrutura dos materiais, sendo visíveis grandes partículas secundárias, além de ser possível verificar a matriz de sílica à volta dos CNTs.Os testes de adsorção revelaram que a presença de CNTs levou a uma ligeira melhoria nas propriedades de adsorção dos adsorventes. Em relação aos compostos orgânicos voláteis (VOC), para os melhores materiais, com xileno e benzeno, foram obtidos elevadas percentagens de remoção (para benzeno superior a 80% e para xileno maior que 90%), enquanto para fenol foi removido apenas no máximo 30%. Para os fármacos, os melhores resultados foram obtidos para o naproxeno, com percentagens de remoção de até 96,9%, enquanto para a amoxicilina o melhor resultado de remoção foi em torno de 67%. Num estudo mais aprofundado do processo de adsorção, foi possível concluir que a presença de CNTs melhorou os parâmetros cinéticos (maior velocidade de adsorção), assim como os parâmetros das isotérmicas (maior afinidade entre a fase líquida e a fase sólida).
The main goal of this master’s dissertation was to incorporate carbon nanotubes (CNTs) in silica aerogels with the aim of obtaining composites with good adsorption properties. Methyltrimethoxysilane (MTMS) and (3-aminopropyl) trimethoxysilane (APTMS) were used as silica precursors, which, in different molar proportions and using the sol-gel methodology, led to the formation of CNTs-silica aerogel composites. The used surfactant was chosen among hexadecyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS) and polyethylene glycol (PEG). When the synthesis was performed with PEG, the gelation did not occur, however, the use of the other two surfactants produced aerogel monoliths that did not show significant differences in the values of bulk densities. Regarding the gelation time, CTAB showed the best results, with lower time, which is favorable to avoid CNTs sedimentation in the suspension. The next studied parameter was the agitation method and, even though the mechanical stirring provided lower bulk density, the ultrasound bath allowed a better CNTs dispersion in the solution. A study concerning the need of a washing step to remove the surfactant was also accomplished. Comparing the results for the same formulation, with and without washing, it was possible to conclude that this step was crucial, and allowed a significant improvement in the bulk density, leading to a decrease of 5 to 10 kg m-3. The thermogravimetric analysis confirmed that the washing step removed practically all the surfactant from the materials structure.The aerogels with different molar ratio of precursors (100% MTMS, 90% MTMS/10% APTMS and 80% MTMS/20% APTMS) were characterized chemical, physical and microstructurally. The samples with 100% MTMS presented lower values of bulk density. The presence of amine groups led to an increase in terms of pore size and a reduction regarding the specific surface area. The microscopy techniques allowed the visualization of the materials microstructure, showing large secondary particles, besides enabling the verification of the silica matrix around the CNTs. The adsorption tests revealed that the presence of CNTs led to a slight improvement in the adsorption properties of the adsorbents. Regarding volatile organic compounds (VOC), for the best materials, with xylene and benzene, high removal percentage rates were obtained (for benzene superior to 80% and for xylene higher than 90%), while for phenol a maximum of 30% was removed. For the pharmaceuticals, the best results were obtained for naproxen, with removal rates of up to 96.9 %, while for amoxicillin the best result was around 67% of removal. In a more in-depth study of the adsorption process, it was possible to conclude that the presence of CNTs improved the kinetic parameters (higher adsorption velocity), as well as the parameters of the adsorption isotherms (higher affinity between liquid phase and solid phase).