Thesis. 1978. Ph.D.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Includes bibliographical references. / Ph.D.

Polymorphism and crystallinity are now recognised as important issues in drug development. This is shown by the increased amount of research in this area over recent years. In pharmaceutical development milling is an important unit operation for size reduction to improve powder handling, processing and dissolution rate. The aim of this thesis was to investigate the effect of ball milling (and cryo-milling) on the solid state properties, including amorphous drug formation, of pharmaceutical solids. Milling was carried out using an oscillatory ball mill (Mixer Mill MM301, Retsch GmbH & Co., Germany). In cryo-milling the milling jars were immersed in liquid nitrogen for three min before milling. XRPD was used as the main technique to evaluate the milled samples. Ranitidine hydrochloride (RAN) and indomethacin (INDO) were the model drugs used in this study. It was found that upon milling, RAN form 1 converts to RAN form 2 via an amorphous phase. A faster amorphization rate was observed when the crystalline samples were cryo-milled. Amorphous ranitidine hydrochloride was characterized to have a glass transition (T[g]) range of 13 to 30 �C and a crystallization exotherm (T[c]) between 30 and 65 �C. Conversion was found to occur faster when the temperature of the solid powder was greater than the T[c]. Under various storage conditions, similarly, crystallization of the amorphous phase mainly led to RAN form 2. However, some form 1 and amorphous phase was also detected on the XRPD diffractograms. Using partial least squares regression, the amount of solid form components in the ternary RAN mixtures were successfully quantified. RAN form 2 did not convert to form 1 under any milling (including cryo-milling) or storage conditions used in this study. Overall, RAN form 2 was found to be the thermodynamically stable form and the two (RAN) polymorphs are likely to be a monotropic pair. In a co-milling study of INDO and RAN, the two crystalline drugs were successfully converted into a single amorphous phase after 60 min of co-milling in a cold room (4 �C). The T[g] range (26-44 �C) was also characterized for these mixtures. DRIFTS spectra of the co-milled amorphous samples indicated an interaction had occurred between the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (NC=O) of the INDO molecule with the aci-nitro (C=NO₂) of RAN. Depending on the ratio of INDO to RAN, in general, the amorphous mixtures were stable at 4 �C after 30 days of storage. Crystallization was faster when the binary mixtures were stored at higher temperature or contained higher amounts of RAN in the mixture. Although XRPD and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between INDO and RAN. Ball milling can be used to produce amorphous drug. The rate and extent of amorphization is dependent on the milling conditions. A faster rate of amorphization was observed when the crystalline drugs were cryo-milled. Amorphous drug formation can be made either alone or in combination with another crystalline drug. Amorphization could offer a significant improvement on the dissolution profile and the bioavailability of the poorly water soluble drug - indomethacin. Furthermore, ball milling can also be used to produce a homogenous mix between solids. The �goodmix� effect can be used for seed-induced crystallization or, when the XRPD or Raman data were combined with partial least squares regression, to create a reliable calibration model for quantitative analysis.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 135-138).

For 40% of currently discovered drugs which are poorly water soluble, engineering amorphous nanoparticles with rapid dissolution and enhanced solubility can improve their absorption. Antisolvent precipitation by mixing organic drug solutions with aqueous solutions produced sub-300 nm amorphous nanoparticle dispersions. Polymeric stabilizers increased the nucleation rate by lowering the interfacial tension and adsorbed to particle surfaces to inhibit growth by condensation and coagulation. An increase in the stabilizer concentration decreased the average particle size until reaching a threshold where the particles were < 300 nm for the poorly water soluble drug, itraconazole. The amorphous itraconazole nanoparticle dispersions dissolved at pH 1.2 to produce high supersaturation levels up to 90-times the equilibrium solubility. The supersaturation increased with particle curvature, as described qualitatively by the Kelvin equation. A thermodynamic analysis indicated the stabilizer maintained amorphous ITZ in the solid phase with a fugacity 90-times the crystalline value, while it did not influence the activity coefficient of ITZ in the aqueous phase. Recovery of the amorphous nanoparticles from water was achieved by adding salt to desolvate the polymeric stabilizers and flocculate the particles, which could then be rapidly filtered. The flocculation under constant particle volume fraction produced open flocs which were redispersible in water to their original ~300 nm size, after filtration and drying. Amorphous particles were preserved, as flocs were formed below the drug's glass transition temperature. After flocculation/filtration, medium surface area (2-5 m²/g) particles dissolved rapidly in pH 6.8 buffer with 0.17% surfactant to an unusually large supersaturation up to 17, comparable to that for high surface area (13-36 m²/g) particles. However, the decay in supersaturation was much slower for the medium surface area particles, as the smaller excess surface area of undissolved particles produced slower nucleation and growth from solution. In contrast, the maximum supersaturation was far lower for more conventional low surface area solid dispersions of drug in polymers, because of crystallization of undissolved solid during slow dissolution. The ability to design the particle morphology to manipulate the level in supersaturation in pH 6.8 media, offers new opportunities in raising bioavailability in gastrointestinal delivery. / text

Polymorphism and crystallinity are now recognised as important issues in drug development. This is shown by the increased amount of research in this area over recent years. In pharmaceutical development milling is an important unit operation for size reduction to improve powder handling, processing and dissolution rate. The aim of this thesis was to investigate the effect of ball milling (and cryo-milling) on the solid state properties, including amorphous drug formation, of pharmaceutical solids. Milling was carried out using an oscillatory ball mill (Mixer Mill MM301, Retsch GmbH & Co., Germany). In cryo-milling the milling jars were immersed in liquid nitrogen for three min before milling. XRPD was used as the main technique to evaluate the milled samples. Ranitidine hydrochloride (RAN) and indomethacin (INDO) were the model drugs used in this study. It was found that upon milling, RAN form 1 converts to RAN form 2 via an amorphous phase. A faster amorphization rate was observed when the crystalline samples were cryo-milled. Amorphous ranitidine hydrochloride was characterized to have a glass transition (T[g]) range of 13 to 30 �C and a crystallization exotherm (T[c]) between 30 and 65 �C. Conversion was found to occur faster when the temperature of the solid powder was greater than the T[c]. Under various storage conditions, similarly, crystallization of the amorphous phase mainly led to RAN form 2. However, some form 1 and amorphous phase was also detected on the XRPD diffractograms. Using partial least squares regression, the amount of solid form components in the ternary RAN mixtures were successfully quantified. RAN form 2 did not convert to form 1 under any milling (including cryo-milling) or storage conditions used in this study. Overall, RAN form 2 was found to be the thermodynamically stable form and the two (RAN) polymorphs are likely to be a monotropic pair. In a co-milling study of INDO and RAN, the two crystalline drugs were successfully converted into a single amorphous phase after 60 min of co-milling in a cold room (4 �C). The T[g] range (26-44 �C) was also characterized for these mixtures. DRIFTS spectra of the co-milled amorphous samples indicated an interaction had occurred between the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (NC=O) of the INDO molecule with the aci-nitro (C=NO₂) of RAN. Depending on the ratio of INDO to RAN, in general, the amorphous mixtures were stable at 4 �C after 30 days of storage. Crystallization was faster when the binary mixtures were stored at higher temperature or contained higher amounts of RAN in the mixture. Although XRPD and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between INDO and RAN. Ball milling can be used to produce amorphous drug. The rate and extent of amorphization is dependent on the milling conditions. A faster rate of amorphization was observed when the crystalline drugs were cryo-milled. Amorphous drug formation can be made either alone or in combination with another crystalline drug. Amorphization could offer a significant improvement on the dissolution profile and the bioavailability of the poorly water soluble drug - indomethacin. Furthermore, ball milling can also be used to produce a homogenous mix between solids. The �goodmix� effect can be used for seed-induced crystallization or, when the XRPD or Raman data were combined with partial least squares regression, to create a reliable calibration model for quantitative analysis.

Thesis (Ph. D.)--Ohio University, June, 1997. / Title from PDF t.p.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

No description available.

No description available.

M.Sc. / Thin film solar cell devices based on amorphous silicon absorber films are promising candidates for the efficient conversion of sunlight into useable, cheap electrical energy. However, typical device structures are rather complex and consist of semiconductor/metal contacts as well as a complicated p-i-n junction. Against this background, the present study focussed on the optimization of certain key components of the device, including the transparent conductive oxide, amorphous silicon absorber layers and substrate/metal structures. These thin films were deposited by direct current (DC) magnetron sputtering and radio frequency (RF) capacitativecoupled gas discharge. In each case, a systematic study was conducted in which all the relevant processing parameters were varied over a broad range. The material quality of the respective films was subsequently correlated against the growth parameters. In the case of DC magnetron sputtered ZnO, w hich is generally used as a transparent conductive oxide in the device structure, the material quality were critically influenced by geometric orientation of the sample with respect to the target, the substrate-target distance, deposition power, working pressure and substrate temperature. Optimum structural, optical and electrical properties were obtained in the case of samples deposited at an angle of 80° with respect to the surface of the target. Bombardment damage was to a large extent prevented when the samples were placed at a vertical substrate-to-target distance of 70 mm, 75 mm away from the center zone of the plasma. The optimum substrate temperature, deposition power and working pressure was experimentally found to be 100°C; 600 mW/cm2 and 5.25 ´ 10-3 Torr, respectively. The structural features of the substrates influenced the morphology and optical properties of the DC sputtered metallic films. In general, the surface roughness increased when the glass substrates were replaced by kapton. The glass/silver structures were characterized by relatively smooth surface morphologies, while glass/aluminium films exhibited spike-like growth features. The material properties of intrinsic amorphous silicon were influenced by the RF power, substrate temperature and deposition pressure. A systematic study revealed optimum structural, optical and electrical properties at depositions powers around 43 mW/cm2, substrate temperatures close to 200°C and deposition pressures in the order of 500 mT. / Professor V. Alberts