Despite the advent of alternative dosage forms, solid dosage forms constitute a major proportion of dosage forms not only on the market, but also in many pharmaceutical companies’ pipelines. This is because of their superior stability and ease of manufacturing relative to other dosage forms. Although solid dosage forms have been the topic of discussion for decades, the process of compaction of these dosage forms is considered an art rather than science because of the empiricism that exists in this area. With the introduction of Quality by Design (QbD), it is imperative that the drug development process is guided by structured scientific principles. It has been hypothesized that crystal structure of organic solids plays a pivotal role in understanding the properties, processing and eventually performance of solids. In this regard, the intermolecular interactions within a solid play a paramount role in dictating the materials response to stress. One important parameter that is weakly addressed in the literature is the concept of strength of intermolecular interactions. In the current work, we utilize the concept of elasticity as a metric for strength of intermolecular interactions. We introduce powder Brillouin light scattering; an inelastic light scattering technique to measure the elasticity of organic solids and try to correlate the mechanical moduli extracted from the spectra to the compaction performance of solids. We hypothesize that any redistribution of intermolecular interactions would be reflected in the BLS spectrum of these materials and the material properties can be used to explain the differences in compaction performance. Before we tested our hypothesis, we validated our powder BLS technique using aspirin as model system. We then applied the same analysis to four model systems that involved different ways of reorganizing the intermolecular interactions upon subtle modifications to the molecular structure. In Chapter 4, we investigated the effect of alkyl chain length and crystal structure on the mechanical properties and compaction performance of p-aminobenzoic acid (PABA) and its esters. For the entire ester series, a similar hydrogen bonding pattern was observed with strong N-H…O (carbonyl) and supportive N-H…N interactions. While the ethyl and butyl esters exhibited a layered structure, the methyl ester displayed a 3-D isotropic structure. The crystal structure for PABA exhibited a three-dimensional, quasi-isotropic distribution of the hydrogen-bonding interactions that connected the PABA dimers. The powder BLS spectra for these materials revealed low velocity shear modes for the layered structures and a spectrum consistent with an isotropic structure for Me-PABA and PABA. This was in good agreement with the compressibility behavior under load, with Et-PABA and Bu-PABA more compressible than PABA. However, due to greater particle-particle adhesion, PABA compacts showed greater tensile strength at higher pressures. The moduli calculated also showed that both Et-PABA and Bu-PABA had lower shear and Young’s modulus relative to the other materials. Attachment energies corroborated the above results. These studies showed that weak dispersive forces play an important role in understanding material properties. In Chapter 5, a series of nitrobenzoic derivatives were used to study the effect of secondary interactions on the crystal reorganization and material properties. The materials used in the study include p-nitrobenzoic acid (4-NBA), m-nitrobenzoic acid (3-NBA, 4-chloro-3-nitrobenzoic acid (Cl-NBA), 4-bromo-3-nitrobenzoic acid (Br-NBA), and 4-methyl-3-nitrobenzoic acid (Me-NBA). Crystal structures of the materials revealed different organization of C-H…O interactions. Two types of C-H…O interactions were prevalent namely C-H…O (nitro) and C-H…O (carboxy). The reorganization of these two types of interactions led to different packing motifs and different mechanical behavior. These structural features were reflected in their mechanical properties assessed by powder Brillouin light scattering. Cl-NBA and Br-NBA displayed an isotropic spectrum similar to polystyrene and aspirin. 3-NBA, 4-NBA and Me-NBA displayed different spectra from Cl-NBA and Br-NBA with high frequency tailing in the longitudinal mode distribution indicating a specific direction of extended molecular interactions. The Young’s modulus and shear modulus followed the order: 3-NBA < Me-NBA< 4-NBA < Cl-NBA < Br-NBA. The maximum longitudinal modulus Mmax was the highest for 3-NBA and was significantly greater than rest of the materials. From the compaction studies, it was observed that the tabletability followed the rank order 3-NBA > 4-NBA > Me-NBA ≈ Br-NBA ≈ Cl-NBA which is the same order as Mmax. 3-NBA by virtue of its low shear and Young’s modulus to be the most compressible material, but the compressibility rank order was 4-NBA > Me-NBA ≈ 3-NBA > Cl-NBA > Br-NBA. However, 3-NBA by virtue of its greater particle-particle adhesion was the most compactable material. The yield pressures obtained from Heckel plots revealed that 4-NBA and Me-NBA were relatively more plastic when compared to the other materials. This study demonstrated that subtle changes to the molecular structure can result in drastically different crystal packing which in turn would influence the mechanical properties and the compaction performance of organic solids. In Chapter 6, we investigated the effect of cocrystallization on the compaction performance of caffeine(CAF). The series of halo-nitrobenzoic acids (F-NBA, Cl-NBA and 3-NBA) were used as coformers. The cocrystals CAF: F-NBA, CAF: Cl-NBA and CAF: NBA Form 1 adopted a flat layered structure that can undergo deformation with ease. This increased the compressibility of the cocrystals relative to CAF. In addition to the improved compressibility, by virtue of increased particle-particle contacts, the cocrystals also displayed superior tabletability. In contrast to the layered structures adopted by the three cocrystals, the CAF: NBA Form 2 displayed a columnar structure that exhibited resistance to stress. The compressibility and the tabletability of CAF: NBA Form 2 was significantly compromised when compared to that of Form1. All the compaction characteristics of the cocrystals were in good agreement with moduli and parameters obtained from powder BLS spectra. The layered materials showed the presence of low velocity shear modes corroborating the earlier studies. There was a clear difference in the spectra of the polymorphs, indicating that powder BLS can be used for mechanical screening of polymorphs. In Chapter 7, we examined the effects of crystal structure and coformer functionality on the compaction performance of theophylline (THY). The coformers employed include 4-fluoro-3-nitrobenzoic acid (FNBA), acetaminophen (APAP), and p-aminobenzoic acid (PABA). While THY-APAP and THY-FNBA exhibited layered structures, the THY-PABA displayed a interdigitated columnar structure. Powder BLS spectra showed the presence of low frequency shear modes relative to THY for all the three cocrystals. However, the order of frequencies followed: THY-FNBA < THY-APAP < THY-PABA. The shear modulus calculated followed the order THY-APAP≈ THY-FNBA < THY < THY-PABA which is in agreement with the crystal structures discussed. The Young’s modulus followed the order THY-FNBA < THY-APAP < THY < THY-PABA. The two layered structures (THY-APAP, THY-FNBA) showed distinct compaction performance (similar compressibility but different compactability and tabletability). The layered structures were more compressible than THY which is hypothesized to undergo deformation through multiple mechanisms. THY-PABA showed poor compaction properties. This highlights the fact that although the coformer (PABA) is molecularly similar to FNBA, the resultant cocrystals are structurally and mechanically distinct. These observations were well supported by the moduli calculated from powder BLS studies. The order of yield pressures obtained from Heckel analysis followed the same order as shear modulus. The tensile strength of the compacts of the cocrystals level off at around 150 MPa but the tensile strength of THY compacts continues to increase. From a manufacturing perspective the cocrystals can prove to be a better option as they as more compactable at higher porosities or they possess greater tabletability at low compaction pressures. Overall, we have used model systems to demonstrate that the redistribution of intermolecular forces upon point substitution or cocrystallization have a dramatic effect on the material properties. It is also worth noting that elasticity along with plasticity can provide important information about the strength of interactions which would help in understanding the role of weak intermolecular forces in the performance of organic materials. To gain a better perspective of the compaction process and move towards a QbD approach, it is also imperative to understand the link between crystal structures, intermolecular interactions which is possible with the help of novel characterization techniques (BLS, AFM).

Atom transfer radical polymerisation (ATRP) technique was used to synthesize poly(methacrylic acid-block-methyl methacrylate) (P(MAA₁₀₂-b-MMA₁₀)) copolymer in order to study the aggregation behavior in aqueous solution over the course of neutralization. A combination of static and dynamic light scattering (SLS, DLS) and potentiometric titration techniques were used to investigate the size and shape of the micelle at various degrees of neutralization. The hydrodynamic radius (Rh) determined from dynamic light scattering increases from ~26nm (for unneutralized) to ~42nm (for completely neutralized sample). Both potentiometric and laser light scattering studies indicate the formation of a core shell micelle. The weighted average molecular weights of the polymer and micelle are 1.18x10⁴ and 2.25 x 10⁵ g/mol respectively, which suggests that the aggregation number of the micelle is ~20. / Singapore-MIT Alliance (SMA)

Di-block copolymer of poly[methacrylic acid-block-2-(diethylamino)ethyl methacrylate] [P(MAA-b-DEA)] with narrow molecular weight distribution was synthesized using the atom transfer radical polymerization (ATRP) technique. The micellization behavior of the P(MAA-b-DEA) copolymer in aqueous solution at room temperature and different pH values were examined by potentiometric and conductivity titration, UV-Visible spectrophotometry, ¹H-NMR, static and dynamic laser light scattering. At low pH (< 4.2), core-shell micelles were formed with MAA core and protonated DEA shell. At moderate pH values, the polymer precipitated from water and formed a cloudy solution, where the polymer chains aggregated into larger particles resembling that of a hard sphere induced by electrostatic interactions. At high pH (> 9.5), core-shell like micelles consisting of hydrophobic DEA core and ionized MAA shell were re-established. / Singapore-MIT Alliance (SMA)

<p>Cancer is now the leading cause of death in developed countries. Despite advances in strategies aimed at the prevention and treatment of the disease, early detection of precancerous growths remains the most effective method of reducing associated morbidity and mortality. Pathological examination of physical tissues that are collected via systematic biopsy is the current "gold standard" in this pursuit. Despite widespread acceptance of this methodology and high confidence in its performance, it is not without limitations. Recently, much attention has been given to the development of optical biopsy techniques that can be used clinically and are able to overcome these limitations. This dissertation describes one such optical biopsy technique, angle-resolved low coherence interferometry (a/LCI), its adaptation to a clinical technology, and its evaluation in clinical studies.</p><p> The dissertation presents the theory that underlies the operation of the a/LCI technique, the design and validation of the clinical instrument, and its evaluation by means of two clinical trials. First, an account of the manner in which the depth-resolved angular scattering profiles that are collected by a/LCI can be used to determine nuclear characteristics of the investigated tissues is given. The design of the clinical system that is able to collect these scattering profiles through an optical fiber probe that can be passed through the accessory channel of an endoscope for <italic>in vivo</italic> use is presented. To demonstrate the ability of this system to accurately determine the size of cell nuclei, a set of validation experiments are described.</p><p> In order to evaluate the clinical utility of this a/LCI system, two clinical trials intended to assess the ability of a/LCI to detect the presence of early, pre-cancerous dysplasias in human tissues are presented. The first of these, an <italic>in vivo</italic> study of Barrett's esophagus (BE) patients undergoing routine surveillance for the early signs of esophageal adenocarcinoma, is described. This study represents the first use of the a/LCI technique in vivo, and confirms its ability to provide clinically useful information regarding the disease state of the tissue that it examines, with performance that compares favorably to other optical biopsy techniques. Next, an <italics>ex vivo</italics> study of resected intestinal tissue is presented. The results of this study demonstrate the ability of a/LCI to provide information that can be used to detect dysplasia in the lower gastrointestinal tract with high accuracy. This study will enable future development of the technology to allow conduction of <italic>in vivo</italic> trials of intestinal tissue. The results of these two clinical studies demonstrate the clinical utility a/LCI, illustrating its potential as an optical biopsy technique that has great potential to provide diagnostically relevant information during surveillance procedures. This is particularly relevant in the case of BE, where its successful use has been demonstrated <italic>in vivo</italic>.</p> / Dissertation

No description available.

The objective of this research was to develop efficient, non-invasive separation systems for various biological and non-biological substances. One of the major technological pushes in modern bioanalysis instrumentation development is the realization of efficient, miniaturized bioanalysis systems. In this work, three sizes of micromachined electrical field-flow fractionation (m-ElFFF) systems, with complementary on-column electrical and optical detection modalities were fabricated to achieve this objective. Field-flow fractionation (FFF) technology is capable of fractionating (or separating) a wide variety of materials and is capable of hundreds of consecutive analysis runs using a single system. A highly promising sub-technique, particularly for the analysis of biological / biochemical materials, is electrical field-flow fractionation (ElFFF). In this work, microfabrication technologies were used to fabricate m-ElFFF systems that have smaller system volumes, require smaller sample volumes and have shorter run times than their macro-scale counterparts. Direct, on-column detection within the miniaturized separation device improved the resolution, decreased the band broadening, lowered the plate height, and shortened the overall analysis time. Also, the information obtained from these detection systems can be used to elucidate information on the electrical and physical characteristics of a sample. Therefore, complimentary on-column detection systems, were designed, fabricated and characterized. Additionally, the data from the two detection systems was compared and a quantitative correlation was performed, enabling the independent use of each detection system.

In this research, hills-like hierarchical structured TiO2 photoanodes for dye-sensitized solar cells (DSSCs) have been prepared. We expected these appropriately aggregated TiO2 clusters in photoanode layer could cause stronger light scattering and higher dye loading that increased efficiency of photovoltaics. For detailed light-harvesting study, different molecular weight of polyvinyl alcohol (PVA) polymers were used as binders for TiO2 nanoparticles (P-25 Degussa) aggregation. After preparing a series of TiO2 films with dissimilar morphology, the reflection of TiO2 films, absorbance of attached dye, amount of dye loading, and performance of fabricated DSSC devices were measured and investigated. An optimized device had higher dye loading and well light harvesting at the same time that induced a 23% increase of short-circuit current Jsc in DSSCs. Moreover, we found that electrolyte could penetrate or diffuse easily in this higher porous structure. We fabricated dye-sensitized solar cells with MPN-based liquid electrolyte and gel polymer electrolyte. From this structure, the short-circuit current Jsc was increased around 16% and 19% respectively compared to conventional layers with liquid electrolyte and gel polymer electrolyte devices. The increase in highly viscous system of gel polymer electrolyte is due to easier penetration by such hills-like hierarchical structure.

The single scattering properties of atmospheric particles are fundamental to radiative simulations and remote sensing applications. In this study, an efficient technique, namely, the pseudo-spectral time-domain (PSTD) method which was first developed to study acoustic wave propagation, is applied to the scattering of light by nonspherical particles with small and moderate size. Five different methods are used to discretize Maxwell’s equations in the time domain. The perfectly matched layer (PML) absorbing boundary condition is employed in the present simulation for eliminating spurious wave propagations caused by the spectral method. A 3-D PSTD code has been developed on the basis of the five aforementioned discretization methods. These methods provide essentially the same solutions in both absorptive and nonabsorptive cases. In this study, the applicability of the PSTD method is investigated in comparison with the Mie theory and the T-matrix method. The effects of size parameter and refractive index on simulation accuracy are discussed. It is shown that the PSTD method is quite accurate when it is applied to the scattering of light by spherical and nonspherical particles, if the spatial resolution is properly selected. Accurate solutions can also be obtained from the PSTD method for size parameter of 80 or refractive index of 2.0+j0. Six ice crystal habits are defined for the PSTD computational code. The PSTD results are compared with the results acquired from the finite difference time domain (FDTD) method at size parameter 20. The PSTD method is about 8-10 times more efficient than the conventional FDTD method with similar accuracy. In this study, the PSTD is also applied to the computation of the phase functions of ice crystals with a size parameter of 50. Furthermore, the PSTD, the FDTD, and T-matrix methods are applied to the study of the optical properties of horizontally oriented ice crystals. Three numerical schemes for averaging horizontal orientations are developed in this study. The feasibility of using equivalent circular cylinders as surrogates of hexagonal prisms is discussed. The horizontally oriented hexagonal plates and the equivalent circular cylinders have similar optical properties when the size parameter is in the region about from 10 to 40. Otherwise, the results of the two geometries are substantially different.

When the finite-difference time-domain (FDTD) method is applied to light scattering computations, the far fields can be obtained by either a volume integration method, or a surface integration method. In the first study, we investigate the errors associated with the two near-to-far field transform methods. For a scatterer with a small refractive index, the surface approach is more accurate than its volume counterpart for computing the phase functions and extinction efficiencies; however, the volume integral approach is more accurate for computing other scattering matrix elements. If a large refractive index is involved, the results computed from the volume integration method become less accurate, whereas the surface method still retains the same order of accuracy as in the situation of a small refractive index. In my second study, a fourth order symplectic FDTD method is applied to the problem of light scattering by small particles. The total-field/ scattered-field (TF/SF) technique is generalized for providing the incident wave source conditions in the symplectic FDTD (SFDTD) scheme. Numerical examples demonstrate that the fourthorder symplectic FDTD scheme substantially improves the precision of the near field calculation. The major shortcoming of the fourth-order SFDTD scheme is that it requires more computer CPU time than the conventional second-order FDTD scheme if the same grid size is used. My third study is on multiple scattering theory. We develop a 3D Monte Carlo code for the solving vector radiative transfer equation, which is the equation governing the radiation field in a multiple scattering medium. The impulse-response relation for a plane-parallel scattering medium is studied using our 3D Monte Carlo code. For a collimated light beam source, the angular radiance distribution has a dark region as the detector moves away from the incident point. The dark region is gradually filled as multiple scattering increases. We have also studied the effects of the finite size of clouds. Extending the finite size of clouds to infinite layers leads to underestimating the reflected radiance in the multiple scattering region, especially for scattering angles around 90 degrees. The results have important applications in the field of remote sensing.

The light scattering problem and its application in atmospheric science is studied in this thesis. In the first part of this thesis, light scattering theory of single irregular particles is investigated. We first introduce the basic concepts of the light scattering problem. T-matrix ansatz, as well as the null-field technique, are introduced in the following sections. Three geometries, including sphere, cylinder and hexagonal column, are defined subsequently. Corresponding light scattering properties (i.e., T-matrix and Mueller Matrix) of those models with arbitrary sizes are simulated via the T-matrix method. In order to improve the efficiency for the algorithms of single-light scattering, we present a user-friendly database software package of the single-scattering properties of individual dust-like aerosol particles. The second part of this thesis describes this database in detail. Its application to radiative transfer calculations in a spectral region from ultraviolet (UV) to far-infrared (far-IR) is introduced as well. To expand the degree of morphological freedom of the commonly used spheroidal and spherical models, triaxial ellipsoids were assumed to be the overall shape of dust-like aerosol particles. The software package allows for the derivation of the bulk optical properties for a given distribution of particle microphysical parameters (i.e., refractive index, size parameter and two aspect ratios). The array-oriented single-scattering property data sets are stored in the NetCDF format. The third part of this thesis examines the applicability of the tri-axial ellipsoidal dust model. In this part, the newly built database is equipped in the study. The precomputed optical properties of tri-axial models are imported to a polarized addingdoubling radiative transfer (RT) model. The radiative transfer property of a well-defined atmosphere layer is consequently simulated. Furthermore, several trial retrieval procedures are taken based on a combination of intensity and polarization in the results of RT simulation. The retrieval results show a high precision and indicate a further application in realistic studies.