Class of 2012 Abstract / Specific Aims: To evaluate the in vitro throat deposition and respirable mass of the QVAR® pressurized metered-dose inhaler (pMDI) alone or coupled to an accessory device, such as the AeroChamber Valved Holding ChamberTM or various nonconventional accessory devices. Methods: The performance of the AeroChamber and nonconventional accessory devices, including a toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, plastic bottle reverse-flow holding chamber, and nebulizer reservoir tubing, were compared to no accessory device. Throat deposition and respirable mass were evaluated using a United States Pharmacopeia (USP) inlet ("throat") coupled to instrumentation for particle size analysis. Each configuration was tested with three actuations and repeated in quadruplicate. The amount of drug deposition was quantified using high-performance liquid chromatography. The data were analyzed using multiple independent t-tests assuming unequal variances. An a priori α-threshold of 0.05 was used with a Bonferroni corrected α of 0.007. Main Results: Compared to the pMDI alone, all of the accessory devices had significantly lower throat deposition (p < 0.001) and significantly higher respirable fraction (p < 0.001). Differences in respirable mass were not significant for any accessory device (p ≥ 0.049), except the paper towel roll and the nebulizer reservoir tubing (p < 0.001). Conclusions: Under these testing circumstances, nonconventional accessory devices, such as the toilet paper roll, rolled paper, plastic bottle spacer, and plastic bottle reverse-flow holding chamber, effectively reduce throat deposition and maintain respirable mass compared to a QVAR pMDI alone. Therefore, they may be suitable alternatives to commercial spacers.

Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist/antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form/morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR®/Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS/β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide®/Symbicort®, GlaxoSmithKline/AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery.

Class of 2012 Abstract / Specific Aims: To evaluate the in vitro throat deposition and respirable mass of the QVAR® pressurized metered-dose inhaler (pMDI) alone or coupled to an accessory device, such as the AeroChamber Valved Holding ChamberTM or various nonconventional accessory devices. Methods: The performance of the AeroChamber and nonconventional accessory devices, including a toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, plastic bottle reverse-flow holding chamber, and nebulizer reservoir tubing, were compared to no accessory device. Throat deposition and respirable mass were evaluated using a United States Pharmacopeia (USP) inlet ("throat") coupled to instrumentation for particle size analysis. Each configuration was tested with three actuations and repeated in quadruplicate. The amount of drug deposition was quantified using high-performance liquid chromatography. The data were analyzed using multiple independent t-tests assuming unequal variances. An a priori α-threshold of 0.05 was used with a Bonferroni corrected α of 0.007. Main Results: Compared to the pMDI alone, all of the accessory devices had significantly lower throat deposition (p < 0.001) and significantly higher respirable fraction (p < 0.001). Differences in respirable mass were not significant for any accessory device (p ≥ 0.049), except the paper towel roll and the nebulizer reservoir tubing (p < 0.001). Conclusions: Under these testing circumstances, nonconventional accessory devices, such as the toilet paper roll, rolled paper, plastic bottle spacer, and plastic bottle reverse-flow holding chamber, effectively reduce throat deposition and maintain respirable mass compared to a QVAR pMDI alone. Therefore, they may be suitable alternatives to commercial spacers.

Class of 2015 Abstract / Objectives: To evaluate the in vitro performance of various pressurized metered dose inhaler (pMDI) formulations by cascade impaction primarily focusing on throat deposition, fine particle fraction (FPF), and mass-median aerodynamic diameter (MMADR) measurements Methods: Ten solution pMDIs were prepared with varying cosolvent species in either low (8% w/w) or high (20% w/w) concentration. The chosen cosolvents were either alcohol (ethanol, n-propanol) or acetate (methyl-, ethyl-, and butyl acetate) in chemical nature. All formulations used HFA-134a propellant and 0.3% drug. The pMDIs were tested by cascade impaction with three different inlets to determine the aerodynamic particle size distribution (APSD), throat deposition, and FPF of each formulation. Theoretical droplet evaporation time (DET), a measure of volatility, for each formulation was calculated using the MMADR. Results: Highly volatile formulations with short DET showed consistently lower throat deposition and higher FPF than their lower volatility counterparts when using volume-constrained inlets. However, FPF values were not significantly different for pMDI testing with a non-constrained inlet. The MMADR values generated with volume-constrained inlets did not show any discernible trends, but MMADR values from the non-constrained inlet correlated with DET. Conclusions: Formulations with shorter DET exhibit lower throat deposition and higher FPF, indicating potentially better inhalational performance over formulations with longer DET. There appear to be predictable trends relating both throat deposition and FPF to DET. The shift in MMADR values for volume-constrained inlets suggests that large diameter drug particles are preferentially collected in these inlets.

In this study, a series of denim fiberboards are fabricated using two different resins, malamine urea formaldehyde (MUF) and polymeric methylene diphenyl diisocyanate (pMDI). Two experimental design factors (1) adhesive content and (2) MUF-pMDI weight ratio, were studied. All the denim fiberboard samples were fabricated following the same resin blending, cold-press and hot-press procedures. The physical and mechanical tests were conducted on the fiberboard following the procedures described in ASTM D1037 to obtain such as modulus of elasticity (MOE), modulus of rupture (MOR), internal bond (IB), thickness swell (TS), and water absorption (WA). The results indicated that the MOE was significantly affected by both factors. IB was affected significantly by weight ratio of different glue types, with 17 wt% more MDI resin portion in the core layer of the denim boards, the IB for total adhesive content 15% fiberboard was enhanced by 306%, while for total adhesive content 25% fiberboard, enhanced by 205%. TS and WA, with higher adhesive content used in denim boards' fabrication, and more pMDI portion in the core layer of the boards, the boards' TS and WA was reduced by up to 64.2% and 78.8%, respectively.

Phenol Formaldehyde (PF) and polymeric isocyanate (pMDI) are the two main types of adhesives used in the production of structural wood-based composites. Much is unknown about various aspects of adhesion between these two types of resins and wood. The present research describes the development of techniques which will permit an enhanced understanding of 1.) the extent of cure of PF within a wood based composite, 2.) the scale of molecular level interactions between PF and pMDI and wood, 3.) mechanical performance and durability of wood-adhesive bonds. Correlations were established between conventional methods of characterization of neat PF (thermomechanical analysis, swelling studies) and measurements made using 13C CP/MAS NMR. These correlations were then utilized to characterize PF cured in the presence of wood. The use of 13C labeled PF allowed estimates of relative degrees of resin conversion to be made. The use of 13C and deuterium labeled PF allowed qualitative estimates of resin molecular rigidity to be made. The scale of molecular level interactions between PF and pMDI and wood was probed using NMR relaxation experiments. Evidence was shown to suggest the formation of an interpenetrating polymer network (IPN) morphology existing at both types of wood-resin interphases. The formation of the IPN morphology was strongly influenced by resin molecular weight, cure temperature and the presence of solvent. A new test geometry for the evaluation of the fracture toughness of wood-adhesive bonds was developed. Consistent and reliable results were obtained. It was found that low molecular weight PF possessed enhanced durability over high molecular weight. / Ph. D.

This work reports the elucidation of the structure of a copolymer generated by the cross- catalyzed reactions of PF and pMDI prepolymers.  The electronic behavior of phenolic monomers as perturbed by alkali metal hydroxides in an aqueous environment was studied with 1H and 13C NMR.  Changes in electronic structure and thus reactivity were related to solvated ionic radius, solvent dielectric constant, and their effect on ion generated electric field strength. NMR chemical shifts were used to predict order of reactivity for phenolic model compounds with phenyl isocyanate with good success.  As predicted, 2-HMP hydroxymethyl groups were more reactive than 4-HMP in forming urethane bonds under neutral conditions and 2-HMP hydroxymethyl groups were more reactive than 4-HMP in forming urethane bonds under alkaline conditions. The structure of the reaction products of phenol, benzyl alcohol, 2-HMP, and 4-HMP with phenyl isocyanate were studied using 1H and 13C NMR under neutral organic and aqueous alkaline conditions.  Reactions in THF-d8 under neutral conditions, without catalyst, were relatively slow, resulting in residual monomer and the precipitation of 1,3-diphenyl urea from the carbamic acid reaction.  The reactions of phenol, 2-HMP, and 4-HMP in the presence of TEA catalyst favored the formation of phenyl urethanes (PU). Reactions with benzyl alcohol, 2-HMP, and 4-HMP in the presence of DBTL catalyst favored the formation of benzyl urethanes (BU).  Reactions of 2-HMP and 4-HMP led to formation of benzylphenyldiurethane (BPDU).  DBTL catalysts favored formation of BDPU strictly by a benzyl urethane pathway, while TEA favored its formation mostly via phenyl urethane, although some BU was also present.  Under aqueous alkaline conditions, 2-HMP was more reactive than 4-HMP, exhibiting an enhanced reactivity that was attributed to intramolecular hydrogen bonding and a resulting resonance stabilization of the phenolic aromatic ring. ATR-FTIR spectroscopic studies generated real time structural information for model compound reactions of the cross-catalyzed system, differentiating among reaction peaks generated by the carbamic acid reaction, PU and BU formation.  ATR-FTIR also permitted monitoring of propylene carbonate hydrolysis and accelerated alkaline PF resole condensation.  ATR-FTIR data also showed that the overall reaction stoichiometry between the PF and pMDI components drove copolymer formation.  Benzyl urethane formation predominated under balanced stoichiometric conditions in the presence of ammonium hydroxide, while phenyl urethane formation was favored in its absence.  Accelerated phenolic methylene bridge formation became more important when the PF component was in excess in the presence of sufficient accelerator.  A high percentage of free isocyanate was present in solid copolymer formed at ambient temperature. The combination of ammonium hydroxide and tin (II) chloride synergistically enhanced the reactivity of the materials, reducing the residual isocyanate. From 13C CP/MAS NMR of the copolymer, the presence of ammonium hydroxide and tin (II) chloride and the higher PF concentration resulted in substantial urethane formation.  Ammonium hydroxide favored formation of benzyl urethane from the 2-hydroxymethyl groups, while phenyl urethane formed in its absence.  The low alkalinity PF resole with ammonium hydroxide favored benzyl urethane formation.  Comparison of these results with the 13C NMR model compound reactions with phenyl isocyanate under alkaline conditions confirmed high and low alkalinity should favor phenyl and benzyl urethane formation respectively.  These cross catalyzed systems are tunable by formulation for type of co-polymer linkages, reactivity, and cost. / Ph. D.

Rice straw is a global and proliferate agricultural waste whose production grossly outstrips viable uses. Current disposal methods are not sustainable, and more convenient methods – such as incineration – exude poor environmental stewardship. Although the direct use of straw bales in building construction presents a practical and sustainable alternative, engineering challenges associated with using it prevent its wide adoption. The Stak Block – a composite formed from compressed rice straw and a heat-cured adhesive – may overcome challenges associated with straw bale building. However, the times and temperatures needed to cure the binder with straw are not well understood. Therefore, the goal of this thesis was to study straw cubes (in lieu of the full-scale Stak Block) to discern a time-temperature relationship. A finite element (FE) model of the Stak Block was created to simulate the heating process. The results of this study indicated that the adhesive may actually cure at temperatures less than 100°C. This data influenced the times and temperatures that binder-treated straw cubes were baked at for the first of several iterations. A chemical dye was used to discern if cubes had cured or not. In addition, mechanical testing was used to inspect cubes for curing and to support the results obtained from using a chemical dye. Results from cubes inspected with the chemical dye method were then used to develop an inverse relationship between time and temperature needed to cure the cubes – with the lowest observed cure temperature to be 65°C for 2 hours and the fastest cure time of 30 minutes at 150 and 125°C. Following the iterative experiments, an FE model of the cube was created and fitted to the results of the iterative experiments. Values for thermal conductivity (k = 0.1 W/m-K)and specific heat (Cp = 2000 J/kg-K) used to fit the FE cube model were applied appropriately to the Stak Block FE model in order to estimate curing times at different temperatures.

Embargoed until July 2016. / Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist / antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form / morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR® / Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS / β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide® / Symbicort®, GlaxoSmithKline / AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery.