In situ monitoring of pharmaceutical crystallisation

Using confocal Raman spectroscopy/microscopy, we have monitored pharmaceutical crystallisation 'in situ' in three model (well characterised polymorphic systems) Active Pharmaceutical Ingredients (APIs) and one previously unstudied system where polymorphism had not being reported prior to this study: flufenamic acid, a Non Steroidal Non-Inflammatory Drug (NSAID); nifedipine, an antihypertensive; tolbutamide, used in the treatment of type II diabetes; and imipramine hydrochloride, an antidepressant respectively. Constrained crystallisation from the solid amorphous state was utilised to kinetically trap polymorphs via the Ostwald's rule of stages. Particular emphasis was placed on the phonon-mode/low wavenumber region (4-400cm-1) of the Raman spectral window (this region provides useful information about lattice environment). In all cases our results from the Raman experiments were complemented with similar experiments using Differential Scanning Calorimetry (DSC) and Variable Temperature X-ray Powder Diffraction (VTXRPD). To reduce data complexity, principal component analysis was deployed and found to be extremely effective. In chapter two, a multi-technique study of flufenamic acid (FFA) was carried out which served as a groundwork for later chapters. A solid-solid transformation between two forms of FFA (forms I and III) was observed, due to the abrupt nature of this transition, the 'Lindemann vibrational catastrophe' was envisaged as a possible mechanism for the transformation. Using FFA as a test case in chapter three, polymorphic transformations was monitored in both FFA forms I and III using in situ Raman spectroscopy (as well as VTXRPD) by adopting the constrained crystallisation approach. The approach showed excellent promise (with the XRPD patterns of FFA form II and one unknown form uncovered) and was further explored in later chapters using a variety of pharmaceutical materials. While in chapter four, the interconversion between the different polymorphs of nifedipine was studied using the constrained crystallisation approach monitored using in situ Raman spectroscopy (together with VTXRPD and DSC), our results compared favourably well with those previously published in literature. We also reported for the first time the phonon-mode Raman spectral for this system as earlier publications focussed only on the 'traditional' fingerprint region. Similarly in chapter five, in situ Raman spectroscopy was also used to monitor the polymorphic transformations in tolbutamide (using the constrained crystallisation approach), results from the Raman analysis was compared with those obtained from VTXRPD and found to be in agreement. Thus further showing that Raman spectroscopy combined with the constrained crystallisation approach is a veritable tool for monitoring polymorphic transitions. In chapter six, preliminary results (Raman/XRPD/DSC) showed for the first time that imipramine hydrochloride exhibits polymorphism, with the possibility of at least two new polymorphs. Combination of state of the art spectroscopic techniques with appropriate statistical methods, X-ray powder diffraction and DSC was shown to be an extremely effective approach to investigating and characterising polymorphism in drugs, often using only milligram or sub-milligram sample quantities. Lastly in chapter seven, the novel technique of Transmission Raman Spectroscopy (TRS) was employed in carrying out a quantitative study of polymorphic content in a model pharmaceutical formulation and the results obtained compared with those from traditional backscattering geometry. The transmission method is shown to provide a true bulk measurement of the composition, being unaffected by systematic or stochastic sub-sampling issues that can plague traditional backscattering geometries

Ordered optimal solutions and parametric minimum cut problems

AbstractIn this paper, we present an algebraic sufficient condition for the existence of a selection of optimal solutions in a parametric optimization problem that are totally ordered, but not necessarily monotone. Based on this result, we present necessary and sufficient conditions that ensure the existence of totally ordered selections of minimum cuts for some classes of parametric maximum flow problems. These classes subsume the class studied by Arai et al. [Discrete Appl. Math. 41 (1993) 69–74] as a special case

Auction algorithms for generalized nonlinear network flow problems

Thesis (Ph.D.)--Boston UniversityNetwork flow is an area of optimization theory concerned with optimization over networks with a range of applicability in fields such as computer networks, manufacturing, finance, scheduling and routing, telecommunications, and transportation. In both linear and nonlinear networks, a family of primal-dual algorithms based on "approximate" Complementary Slackness (ε-CS) is among the fastest in centralized and distributed environments. These include the auction algorithm for the linear assignment/transportation problems, ε-relaxation and Auction/Sequential Shortest Path (ASSP) for the min-cost flow and max-flow problems. Within this family, the auction algorithm is particularly fast, as it uses "second best" information, as compared to using the more generic ε-relaxation for linear assignment/transportation. Inspired by the success of auction algorithms, we extend them to two important classes of nonlinear network flow problems. We start with the nonlinear Resource Allocation Problem (RAP). This problem consists of optimally assigning N divisible resources to M competing missions/tasks each with its own utility function. This simple yet powerful framework has found applications in diverse fields such as finance, economics, logistics, sensor and wireless networks. RAP is an instance of generalized network (networks with arc gains) flow problem but it has significant special structure analogous to the assignment/transportation problem. We develop a class of auction algorithms for RAP: a finite-time auction algorithm for both synchronous and asynchronous environments followed by a combination of forward and reverse auction with ε-scaling to achieve pseudo polynomial complexity for any non-increasing generalized convex utilities including non-continuous and/ or non-differentiable functions. These techniques are then generalized to handle shipping costs on allocations. Lastly, we demonstrate how these techniques can be used for solving a dynamic RAP where nodes may appear or disappear over time. In later part of the thesis, we consider the convex nonlinear min-cost flow problem. Although E-relaxation and ASSP are among the fastest available techniques here, we illustrate how nonlinear costs, as opposed to linear, introduce a significant bottleneck on the progress that these algorithms make per iteration. We then extend the core idea of the auction algorithm, use of second best to make aggressive steps, to overcome this bottleneck and hence develop a faster version of ε-relaxation. This new algorithm shares the same theoretical complexity as the original but outperforms it in our numerical experiments based on random test problem suites

In situ monitoring of pharmaceutical crystallisation

Using confocal Raman spectroscopy/microscopy, we have monitored pharmaceutical crystallisation 'in situ' in three model (well characterised polymorphic systems) Active Pharmaceutical Ingredients (APIs) and one previously unstudied system where polymorphism had not being reported prior to this study: flufenamic acid, a Non Steroidal Non-Inflammatory Drug (NSAID); nifedipine, an antihypertensive; tolbutamide, used in the treatment of type II diabetes; and imipramine hydrochloride, an antidepressant respectively. Constrained crystallisation from the solid amorphous state was utilised to kinetically trap polymorphs via the Ostwald's rule of stages. Particular emphasis was placed on the phonon-mode/low wavenumber region (4-400cm-1) of the Raman spectral window (this region provides useful information about lattice environment). In all cases our results from the Raman experiments were complemented with similar experiments using Differential Scanning Calorimetry (DSC) and Variable Temperature X-ray Powder Diffraction (VTXRPD). To reduce data complexity, principal component analysis was deployed and found to be extremely effective. In chapter two, a multi-technique study of flufenamic acid (FFA) was carried out which served as a groundwork for later chapters. A solid-solid transformation between two forms of FFA (forms I and III) was observed, due to the abrupt nature of this transition, the 'Lindemann vibrational catastrophe' was envisaged as a possible mechanism for the transformation. Using FFA as a test case in chapter three, polymorphic transformations was monitored in both FFA forms I and III using in situ Raman spectroscopy (as well as VTXRPD) by adopting the constrained crystallisation approach. The approach showed excellent promise (with the XRPD patterns of FFA form II and one unknown form uncovered) and was further explored in later chapters using a variety of pharmaceutical materials. While in chapter four, the interconversion between the different polymorphs of nifedipine was studied using the constrained crystallisation approach monitored using in situ Raman spectroscopy (together with VTXRPD and DSC), our results compared favourably well with those previously published in literature. We also reported for the first time the phonon-mode Raman spectral for this system as earlier publications focussed only on the 'traditional' fingerprint region. Similarly in chapter five, in situ Raman spectroscopy was also used to monitor the polymorphic transformations in tolbutamide (using the constrained crystallisation approach), results from the Raman analysis was compared with those obtained from VTXRPD and found to be in agreement. Thus further showing that Raman spectroscopy combined with the constrained crystallisation approach is a veritable tool for monitoring polymorphic transitions. In chapter six, preliminary results (Raman/XRPD/DSC) showed for the first time that imipramine hydrochloride exhibits polymorphism, with the possibility of at least two new polymorphs. Combination of state of the art spectroscopic techniques with appropriate statistical methods, X-ray powder diffraction and DSC was shown to be an extremely effective approach to investigating and characterising polymorphism in drugs, often using only milligram or sub-milligram sample quantities. Lastly in chapter seven, the novel technique of Transmission Raman Spectroscopy (TRS) was employed in carrying out a quantitative study of polymorphic content in a model pharmaceutical formulation and the results obtained compared with those from traditional backscattering geometry. The transmission method is shown to provide a true bulk measurement of the composition, being unaffected by systematic or stochastic sub-sampling issues that can plague traditional backscattering geometries

EXPERIMENTAL AND COMPUTATIONAL ANALYSIS OF RELATIVE ENERGETIC STABILITIES OF CRYSTALLINE ANHYDROUS POLYMORPHS AND PSEUDOPOLYMORPHS

The stability of pharmaceutical solids is impacted by the properties of both active and inactive ingredients. Given that the aqueous solubility of solid-state medicinal products can be directly linked to the component properties, it is prudent to carefully study these materials to predict bioavailability and shelf stability. The relative energetic stabilities of the molecular crystals of interest are governed by both the intermolecular forces and the molecular conformations within the structure. In this research, the electronic origins of crystalline stability were investigated using a combination of solid-state density functional theory (ss-DFT) and terahertz time-domain spectroscopy (THz-TDS). Terahertz spectroscopy of the lattice vibrations offers a sensitive probe of solid-state interactions and serves as a rigorous benchmark for testing the quality of the applied theoretical methods. Vibrational simulations of different polymorphic forms are also useful for investigating the relative thermodynamic stabilities of these structures. Through the calculation of Gibbs free energy versus temperature trends, it was possible to not only identify enantiotropic or monotropic relationships between polymorphs, but also the precise transition temperature linking enantiotropic pairs. These combined experimental and computational methods were extended to analyzing the relative stabilities of not only pure solids, but also cocrystals. The successful use of DFT for identifying relative stabilities of known crystal structures led to its use for crystal structure prediction. Overall, this work has demonstrated the extensive applicability of ss-DFT in the analysis of electronic and thermodynamic relationships within polymorphic and pseudopolymorhic systems. Application of this methodology to pharmaceutical solids has provided new insights into the most important contributors to the stabilities of these materials

A critical review of the approaches to optimization problems under uncertainty

Ankara : The Department of Industrial Engineering and the Institute of Engineering and Science of Bilkent University, 2001.Thesis (Master's) -- Bilkent University, 2001.Includes bibliographical references leaves 58-72.In this study, the issue of uncertainty in optimization problems is studied. First of all, the meaning and sources of uncertainty are explained and then possible ways of its representation are analyzed. About the modelling process, different approaches as sensitivity analysis, parametric programming, robust optimization, stochastic programming, fuzzy programming, multiobjective programming and imprecise optimization are presented with advantages and disadvantages from different perspectives. Some extensions of the concepts of imprecise optimization are also presented.Gürtuna, FilizM.S

Exploration of elastomeric and polymeric liquid crystals with photothermal actuation: a review.

Recent research in soft materials is an exhilarating category which has been transcending boundaries for variety of functional applications. This category also stems liquid crystals whose stimuli-responsive feature has fantasized researchers for application arrays in actuators and biomedical. Liquid crystals evince dual characteristics of liquid and solids empowering them to reversibly transit on external actuation. The after-effect of irradiating photons on liquid crystals (LC) facilitate outlying functioning and are engineered with gold nanorods, dyes, graphene and carbon nanotubes among others which greets to incoming stimulus and participates in transference of light energy to perceivable transformation through heat drive. This is progressively explored in medical domain for drug delivery, tissue engineering, cancer treatment, and other disciplines of medicine and bio-mimicking. Additionally, photothermal trigger equips localized punctilious treatment outshining diffusion assisted heating and enables spot treatment. However, LC utilization is burgeoning towards 3D printing, characterizing it as 4D Printing. Present review framework probes LC and its photothermal actuation chemistry in the medical domain. Furthermore, it reflects on LC potential in smart manufacturing in 3D/4D printing, its challenges (limited concentration of filler, its miscibility, and actuation cycle fatigue) and future likelihood

Polymorphic Crystallization Process Development

Ph.DDOCTOR OF PHILOSOPH

Procedural-Reasoning Architecture for Applied Behavior Analysis-based Instructions

Autism Spectrum Disorder (ASD) is a complex developmental disability affecting as many as 1 in every 88 children. While there is no known cure for ASD, there are known behavioral and developmental interventions, based on demonstrated efficacy, that have become the predominant treatments for improving social, adaptive, and behavioral functions in children. Applied Behavioral Analysis (ABA)-based early childhood interventions are evidence based, efficacious therapies for autism that are widely recognized as effective approaches to remediation of the symptoms of ASD. They are, however, labor intensive and consequently often inaccessible at the recommended levels. Recent advancements in socially assistive robotics and applications of virtual intelligent agents have shown that children with ASD accept intelligent agents as effective and often preferred substitutes for human therapists. This research is nascent and highly experimental with no unifying, interdisciplinary, and integral approach to development of intelligent agents based therapies, especially not in the area of behavioral interventions. Motivated by the absence of the unifying framework, we developed a conceptual procedural-reasoning agent architecture (PRA-ABA) that, we propose, could serve as a foundation for ABA-based assistive technologies involving virtual, mixed or embodied agents, including robots. This architecture and related research presented in this disser- tation encompass two main areas: (a) knowledge representation and computational model of the behavioral aspects of ABA as applicable to autism intervention practices, and (b) abstract architecture for multi-modal, agent-mediated implementation of these practices

Advanced Imaging Techniques for Point-Measurement Analysis of Pharmaceutical Materials

Drugs are an essential element protecting human lives from many diseases such as cancer, diabetes, and cardiovascular disorders. One of the highlights in drug development in recent years is the establishment of rational drug design: a collection of various multi-disciplinary approaches that at the core, focus on designing molecules with specific properties for identified targets and biomolecules with known functional roles and structural information. The candidate molecules will then go through a series of examinations to characterize their physiochemical properties, and an iterative process is used to improve the design of the drug to achieve desirable attributes. The time consuming and highly expensive nature of drug development constantly calls for new analytical techniques that have increasingly higher throughput, faster analysis speed, richer chemical and structural information, and lower risk and cost. Conventional analytical methods for pharmaceutical materials, such as X-ray diffraction analysis and Raman spectroscopy, often suffer from prolonged measurement time. In many cases, the identification of regions of interest within the sample is non-trivial in itself. Nonlinear optical imaging techniques, including second harmonic generation (SHG) microscopy and two-photon excited ultraviolet fluorescence (TPE-UVF) microscopy were developed as fast, real-time, and non-destructive methods for selective identification and characterization of crystalline materials present in pharmaceutical samples. These techniques were integrated with synchrotron X-ray diffraction analysis and Raman spectroscopy to significantly reduce the overall measurement time of these structure characterization techniques. In the meanwhile, with the now increased speed of measurement, the amount of experimental data acquired per unit time has also drastically increased. The rate at which data are analyzed, digested, and interpreted is becoming the bottleneck in data-driving decision-making. Novel electronics that only collect data at the most information-rich time points were employed to significantly increase the signal-to-noise ratio (SNR) during data acquisition, reducing the total amount of data needed for material characterization. Advanced sampling algorithms to reduce the total amount of measurements required for perfect data space reconstruction, automated programs for data acquisition and analysis, and efficient data analysis algorithms based on machine learning were developed for accelerated data processing for nonlinear optical imaging analysis, Raman spectra processing, and X-ray diffraction indexing