Pulmonary and oral drug administrations are usually the preferred methods of delivery of active pharmaceutical ingredients.Generally,pulmonary drug formulations are more attractive compared to oral formulations since they consist of micron-sized powders with high surface area thus having faster onset of action,as well as minimizing the drug dosage and side effects.Oral insulin formulations,if achievable,would provide an alternative to injectable insulin,as the common drawbacks of injectable insulin are the multiple daily injections and the possibility of skin infections at the injection site. In this study,the feasibility of using dense gas particle processing techniques known as the Aerosol Solvent Extraction System (ASES),Gas Anti-Solvent (GAS)and High-Pressure Media Milling (HPMM)for pharmaceutical processing was assessed.The ASEStechnique,utilizing dense ethane,was employed to prepare insulin-lactose formulations for pulmonary administration whilst the GAS and ASES techniques,utilizing dense CO2,were employed to prepare microencapsulated formulations containing insulin and Eudragit?? S100 for oral administration.Furthermore,the HPMM technique,utilizing dense hydrofluocarbon (HFC)134a/227ea,was employed to prepare suspension Metered Dose Inhaler (MDI)formulations containing budesonide and various surfactants. The Fine Particle Fraction (FPF)of processed insulin without the presence of lactose was found to be 44%.In other words,44% of processed insulin delivered to the impactor stages (excluding the throat and neck)has aerodynamic diameter of less than 5??m.With the addition of lactose as carrier,the FPFof the insulin-lactose (1:1w/w)formulation increased to 64%.The increase in FPFwas attributed to the lower density of lactose particles compared to that of insulin particles to produce an intimate mixture with enhanced powder flowability and aerodynamic performance. Proteins for oral delivery should ideally be formulated with acid-resistant polymer as a protective coating to protect against enzymatic degradation in the stomach.Eudragit?? S100,which is insoluble or almost impermeable at pH 1-4and soluble at pH 5-7,was used to prepare oral insulin formulations.The insulin release at pH 3was sustained by the Eudragit?? S100coating and the encapsulation efficiency of insulin??Eudragit?? S100formulations varied between 6% and 24% depending on the initial drug to polymer ratio. One of the major therapies utilizing metered dose inhaler formulations in the treatment of asthma has been studied using the HPMM process.The HPMM process has been demonstrated to be an efficient milling process for the enhancement of the physical stability and aerodynamic performance of budesonide in HFC-134a/227ea propellant formulations.No significant change in physical stability was observed in the formulations for 2 weeks.

The physical stability of guaifenesin in melt-extruded acrylic matrix tablets was investigated. The initial study found that recrystallization was caused by guaifenesin supersaturation in Eudragit[Trademark] L100-55, and that the instability was confined to tablet surfaces. Drug release was not affected by crystal growth as guaifenesin is very water soluble. The addition of a polymer in which guaifenesin showed a higher solubility to the matrix blend decreased recrystallization on storage as supersaturation levels dropped. The second investigation identified heterogeneous nucleation as an additional factor in guaifenesin recrystallization. A quantitative assay showed that talc in matrix tablets accelerated the onset and extent of the recrystallization due to a nucleating effect on guaifenesin. Storage under elevated humidity conditions promoted recrystallization as well, but crystal growth was not correlated with water uptake, which implied a nucleating effect of moisture on guaifenesin. The third study investigated the effect of aqueous film-coating of the matrix tablets to stabilize amorphous guaifenesin using either hypromellose or ethylcellulose as coating polymers. The selection of the coating polymer influenced crystal morphology, and was a major factor in delaying the onset of crystallization, ranging from 1-3 weeks (ethylcellulose film-coatings) to 3-6 months (hypromellose film-coatings). Higher weight gains retarded recrystallization. Factors promoting drug and polymer diffusion, such as long curing times and elevated temperatures during both curing and storage, incomplete film coalescence and high core drug concentrations all resulted in an earlier onset of crystallization. The effects of single-screw extrusion (SSE) and twin-screw extrusion (TSE) of diltiazem hydrochloride and guaifenesin-containing blends in Eudragit[Trademark] L100-55 on drug morphology and dispersion were studied in the fourth project. Guaifenesin solubilized diltiazem hydrochloride, and plasticized Eudragit[Trademark] L100-55. Extrusion temperature influenced the drug morphology in single-screw extrudates, while TSE rendered all formulations amorphous due to higher dispersive mixing capabilities. Drug distribution improved with extrusion temperature and by TSE over SSE. Homogeneous matrices showed the slowest drug release at pH 1.0. Recrystallization was inversely correlated to drug distribution. In conclusion, the physical stability of guaifenesin in hot melt-extruded acrylic matrix tablets was shown to be affected by formulation, processing and post-processing factors. / text

This dissertation examines three different aspects of groundwater contamination by immiscible liquids, both at laboratory and field scale. The first component incorporates a study of denser than water immiscible-liquid dissolution at the laboratory scale that aims to describe the effects of immiscible liquid source-zone saturation, distribution, and length on dissolution rates. It was observed that overall immiscible-liquid saturation, distribution, and source zone length did not influence initial dissolution rates under the condition of the experiments. However, transient phase dissolution behavior, primarily observed by the heterogeneously packed columns, was significantly different to that of the homogeneously packed columns. This indicates that initial dissolution rates are comparable for these different systems, however it is demonstrated that immiscible liquid distributions (e.g., heterogeneity) can significantly effect transient dissolution rates. The second component investigates the effectiveness of a field-scale partitioning tracer test (PTT) for the measurement of the amount of denser than water immiscible liquid in the subsurface. It was demonstrated that the effectiveness of partitioning tracer test may be significantly limited by factors contributing to nonideal transport such as sorption, tracer mass, and immiscible liquid distribution. The third component examines the effectiveness of a field-scale remediation technology for the enhanced removal of denser than water immiscible liquid in the subsurface. An important component of this project was the implementation of reagent recovery and reuse, which improved the efficiency of the technology. It was demonstrated that the effectiveness of enhanced solubilization technologies for groundwater remediation may be significantly limited by the distribution of immiscible liquid in the subsurface. However, the nature of cyclodextrin (enhanced-solubilization agent) makes it an attractive option for subsurface remediation of immiscible-liquid contaminants, especially for situations where mobilization is undesirable and where the use of higher-toxicity agents is not possible.

Pulmonary and oral drug administrations are usually the preferred methods of delivery of active pharmaceutical ingredients.Generally,pulmonary drug formulations are more attractive compared to oral formulations since they consist of micron-sized powders with high surface area thus having faster onset of action,as well as minimizing the drug dosage and side effects.Oral insulin formulations,if achievable,would provide an alternative to injectable insulin,as the common drawbacks of injectable insulin are the multiple daily injections and the possibility of skin infections at the injection site. In this study,the feasibility of using dense gas particle processing techniques known as the Aerosol Solvent Extraction System (ASES),Gas Anti-Solvent (GAS)and High-Pressure Media Milling (HPMM)for pharmaceutical processing was assessed.The ASEStechnique,utilizing dense ethane,was employed to prepare insulin-lactose formulations for pulmonary administration whilst the GAS and ASES techniques,utilizing dense CO2,were employed to prepare microencapsulated formulations containing insulin and Eudragit?? S100 for oral administration.Furthermore,the HPMM technique,utilizing dense hydrofluocarbon (HFC)134a/227ea,was employed to prepare suspension Metered Dose Inhaler (MDI)formulations containing budesonide and various surfactants. The Fine Particle Fraction (FPF)of processed insulin without the presence of lactose was found to be 44%.In other words,44% of processed insulin delivered to the impactor stages (excluding the throat and neck)has aerodynamic diameter of less than 5??m.With the addition of lactose as carrier,the FPFof the insulin-lactose (1:1w/w)formulation increased to 64%.The increase in FPFwas attributed to the lower density of lactose particles compared to that of insulin particles to produce an intimate mixture with enhanced powder flowability and aerodynamic performance. Proteins for oral delivery should ideally be formulated with acid-resistant polymer as a protective coating to protect against enzymatic degradation in the stomach.Eudragit?? S100,which is insoluble or almost impermeable at pH 1-4and soluble at pH 5-7,was used to prepare oral insulin formulations.The insulin release at pH 3was sustained by the Eudragit?? S100coating and the encapsulation efficiency of insulin??Eudragit?? S100formulations varied between 6% and 24% depending on the initial drug to polymer ratio. One of the major therapies utilizing metered dose inhaler formulations in the treatment of asthma has been studied using the HPMM process.The HPMM process has been demonstrated to be an efficient milling process for the enhancement of the physical stability and aerodynamic performance of budesonide in HFC-134a/227ea propellant formulations.No significant change in physical stability was observed in the formulations for 2 weeks.

Thesis (M. Pharmacy ((Pharmaceutics)) -- University of Limpopo, 2022 / According to the biopharmaceutical classification system, Clarithromycin is considered a class II molecule with low solubility. Poorly soluble drugs result in low bioavailability. Various techniques have been studied to improve the solubility of drugs and subsequently bioavailability. Of these techniques, preparation of amorphous form is the preferred method because it is a more effortless and convenient way to improve the aqueous solubility and dissolution of poorly water soluble drugs. The only disadvantage of amorphous materials is that they are less thermodynamically stable and can recrystallize during processing and storage. Aim: The aim of this study is to prepare amorphous form of clarithromycin to improve its solubility, dissolution rate, and, subsequently, bioavailability. Methods: In this study, preparation of amorphous form of clarithromycin was conducted using the quench cooling method in which the purchased anhydrous crystalline clarithromycin was spread on an aluminum foil and heated to a melting point (217˚C - 220˚C) and then rapidly cooled. Various techniques were conducted to characterize the prepared amorphous clarithromycin, and these include Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Spectroscopy (FTIR), and X-Ray Powder Diffraction (XRPD). In addition, tablets were formulated using the amorphous clarithromycin mixed with selected excipients from compatibility studies, and in vitro dissolution and stability studies were conducted over a period of 6 months. Results: The DSC thermogram results confirmed that the material prepared using the quench cooling process is an amorphous solid-state. Furthermore, the XRPD confirmed an amorphous solid-state with scattering halo peaks. The FTIR also depicted some broader and lower intensity peaks that indicated a formation of an amorphous material. The dissolution rate of amorphous clarithromycin tablets improved by more than 30% when compared to commercial crystalline clarithromycin tablets. The study revealed a drop in dissolution rate at months 3 to 6 under accelerated conditions due to recrystallization. The 6 monthly stability study at long term conditions showed no change in the integrity of the tablets and their contents. Conclusion: As indicated by the study, it can be concluded that the amorphous clarithromycin remained stable during processing and storage under long-term stability for 6 months. Furthermore, based on dissolution results, it can be concluded that amorphous solids have an improved dissolution rate. / Medical Research Council CHIETA