No / The crystal structure of the I-phase of quinacridone was determined from non-indexed X-ray powder data by means of crystal structure prediction and subsequent Rietveld refinement. This I-phase is another polymorph than the -phase reported by Lincke [G. Lincke and H.-U. Finzel, Cryst. Res. Technol. 1996, 31, 441¿452.]. The crystal structures of the and polymorphs were determined from single crystal data. The knowledge of the crystal structures can be used for crystal engineering, i.e., for targeted syntheses of pigments having desired properties, especially for the syntheses of new red pigments.

Yes / We report formation of polymorphs and new eutectics and cocrystals of curcumin, a sparingly water-soluble active component in turmeric, structurally similar to cinnamic acid. The curcumin polymorphs were formed using liquid antisolvent precipitation, where acetone acted as a solvent and water was used as the antisolvent. The metastable form 2 of curcumin was successfully prepared in varied morphology over a wide range of solvent-to-antisolvent ratio and under acidic pH conditions. We also report formation of new eutectics and cocrystals of curcumin with cinnamic acid acting as a coformer. The binary phase diagrams were studied using differential scanning calorimetry and predicted formation of the eutectics at the curcumin mole fraction of 0.15 and 0.33, whereas a cocrystal was formed at 0.3 mole fraction of curcumin in the curcumin–cinnamic acid mixture. The formation of the cocrystal was supported with X-ray powder diffraction, the enthalpy of fusion values, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The hydrogen bond interaction between curcumin and cinnamic acid was predicted from Fourier-transform infrared spectra, individually optimized curcumin and cinnamic acid structures by quantum mechanical calculations using Gaussian-09 and their respective unit cell packing structures.

The majority of pharmaceutical products are formulated as solids in the crystalline state. With the potential to exist in different crystalline modifications or polymorphs, each solid form bears its own physical and chemical properties, influencing directly bioavailability and manufacturability of the final dosage form. In view of the importance of crystalline form selection in the drug development process, it is imperative for pharmaceutical scientists to work arduously on various aspects of polymorphism, ranging from fundamental understanding of the phenomenon at the molecular level to practical utilization of a specific crystalline form. One common feature of organic crystals is the existence of distinct molecular conformations in different polymorphic structures, known as conformational polymorphism. Conformational polymorphs are routinely observed in drug development, produced when crystal growth conditions vary. Crystallization from solution involves nucleation and crystal growth, the mechanisms that influence the polymorphic outcome. The embryonic solute aggregate has been recognized to play a critical role in dictating the final crystal structure, and solution conditions are also known to drastically influence the self-association behavior of solute molecules during crystallization, affecting crystal packing of organic molecules. For the crystal growth of conformational polymorphs, changes in molecular conformation not only determine the growth kinetics, but also influence the nature and strength of interactions present in the crystal structures. How conformation and intermolecular interaction affect each other underlines the intricacy and the wonder of crystal growth of the organic. Thus, the overall goal of this research is to provide the fundamental understanding of the extent to which solution conditions influence the molecular conformation in the solid-state of a model drug, tolfenamic acid. By combining experimental studies with advanced computational tools, this dissertation offers novel insights into solution species during pre-nucleation and molecular packing of conformational polymorphs of tolfenamic acid. In-depth understanding of the underlying connection between molecular conformation and crystal packing will help advance the knowledge required for rational control of crystal growth.

6,6’-Dimethoxygossypol (DMG) is a natural product of the cotton variety Gossypium barbadense and a derivative of gossypol. Gossypol has been shown to form an abundant number of clathrates with a large variety of compounds. One of the primary reasons why gossypol can form clathrates has been because of its ability to from extensive hydrogen bonding networks due to its hydroxyl and aldehyde functional groups. Prior to this work, the only known solvate that DMG formed was with acetic acid. DMG has methoxy groups substituted at two hydroxyl positions, and consequently there is a decrease in its ability to form hydrogen bonds. Crystallization experiments were set up to see whether, like gossypol, DMG could form clathrates. The following results presented prove that DMG is capable of forming clathrates (S1 and S2) and two new polymorphs (P1 and P2) of DMG have been reported.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-04-04T15:05:19Z No. of bitstreams: 1 SAMARA MARQUES DOS REIS .pdf: 1152921 bytes, checksum: 30f5b5e9c3afbab29666da7f6e7c9033 (MD5) / Made available in DSpace on 2016-04-04T15:05:19Z (GMT). No. of bitstreams: 1 SAMARA MARQUES DOS REIS .pdf: 1152921 bytes, checksum: 30f5b5e9c3afbab29666da7f6e7c9033 (MD5) Previous issue date: 2015-03-04 / Estudos de associação gene-doença mostraram uma relação entre TPH2 e a depressão em diferentes populações, estudos, no entanto, têm sido produzidos resultados contraditórios, sendo a Triptofano hidroxilase-2 (TPH2) uma enzima limitante da taxa na via sintética para a serotonina do cérebro, vários estudos relatam os polimorfismos da enzima TPH2. Dois grandes projetos, o HapMap e o 1000 genomas, organizaram a maioria dos polimorfismos a partir do estudo de várias populações disponibilizando estes dados. Este trabalho tem como objetivo desenvolver um método de estudo para obtenção de possíveis marcadores de predisposição a doença a partir da correlação entre os dados epidemiológicos e frequências populacionais de polimorfismos, baseado na hipótese de que se numa população existe maior frequência de uma determinada patologia determinada geneticamente, então as variantes envolvidas deveriam estar em maior frequência e vice-versa. O modelo usado foi o envolvimento de variantes do gene TPH2 na predisposição à depressão. Os dados obtidos com correlação positiva em um dos genótipos homozigotos e também no alelo deste homozigoto sugeriram a presença de 10 polimorfismos (14,49% do total) possivelmente envolvidos no desenvolvimento do processo depressivo. Estes dados foram comparados com dados da literatura envolvendo estudos do tipo caso controle. Nestes trabalhos foram estudados 20 dos 69 polimorfismos descritos para o gene TPH2. Com exceção de um único polimorfismo, todos os dados obtidos com a nossa estratégia apresentaram-se iguais aos dados da literatura, inclusive quanto ao alelo que determinaria predisposição à depressão quando demonstrada associação. Portanto, propomos esta estratégia como uma forma alternativa de se realizar estudos do tipo Genome-Wide Association sem a necessidade de estudos caso-controle, apenas usando dados epidemiológicos da doença, diminuindo o tempo e custo destes estudos. / Disease-gene association studies reported a relation between the TPH2 and depression in different populations, however some studies have produced contradictory results, being the tryptophan hydroxylase-2 (TPH2) a limiting enzyme in the rate of synthetic route of serotonin in the brain, many studies reported the polymorphisms of the TPH2 enzyme. Two big projects, HapMap and 1000 genomes, organized the major part of these polymorphisms from the study of several populations becoming these data available. This work is aimed to develop a system to obtain possible predisposition markers of a disease from the correlation between epidemiological data and population frequencies of polymorphism, based in the hypothesis that if in a population there is more frequency of a certain kind of pathology genetically determined, the variables involved should be more frequent and vice-versa. The model used was the involvement of variables of the TPH2 gene in the predisposition of depression. The data obtained with positive correlation in one of homozygous genotypes and in the allele of this homozygous suggested the presence of 10 polymorphisms (total 14,49%) possibly related to the development of depression. These data were compared to literature data involving case control studies. In these work were studied 20 from 69 polymorphisms described to the TPH2 gene. With the exception of only one polymorphism, all the data obtained through the strategy proposed in this work have been equals to the literature data, including the allele that is determinant to the predisposition of depression when it is demonstrated the association. Therefore, it is proposed this strategy as an alternative to realize this kind of Genome-Wide Association studies without the necessity of a case control study, only using the epidemiological data from the disease, decreasing the time and the cost of this study.

Η υδροχλωρική δονεπεζίλη (Donepezil.HCl, DPZ) είναι ένα φάρμακο που λαμβάνεται για τη θεραπεία της νόσου Altzheimer. Δρα ως ανασολέας της ακετυλοχοληστερινάσης, ενός ενζύμου υπεύθυνου για την καταστροφή του νευροδιαβιβαστή ακετυλοχολίνη, αυξάνοντας το ποσό της ακετυλοχολίνης στον εγκέφαλο. Παρουσιάζει διάφορες κρυσταλλικές μορφές, συμπεριλαμβανομένων δύο ένυδρων, καθώς και μια άμορφη φάση. Τα δισκία Υδροχλωρικής Δονεπεζίλης λαμβάνονται από το στόμα και μπορεί να αποθηκευθούν για κάποιο χρονικό διάστημα πριν χρησιμοποιηθούν. Τα δισκία DPZ ισχύος 10 mg περιέχουν 3.6 % API, ενώ στις περιπτώσεις όπου λαμβάνει χώρα πολυμορφική μετατροπή, η επιμέρους περιεκτικότητα κάθε πολυμόρφου είναι ακόμα μικρότερη. Η ταυτοποίηση και ποσοτική ανάλυση των πολυμόρφων ή ένυδρων μορφών είναι δυνατή μόνο με τη χρήση περίθλασης ακτίνων Χ και δονητικών φασματοσκοπικών τεχνικών. Λόγω του μικρού ποσοστού της δραστικής ουσίας στα δισκία και της πιθανής παρουσίας περισσοτέρων του ενός πολυμόρφου αλλά και του μεγάλου σχετικά ορίου ανίχνευσης αυτών των τεχνικών η ταυτοποίηση και ποσοτική ανάλυση είναι μια αναλυτική πρόκληση. Στην παρούσα εργασία έγινε προσπάθεια ταυτοποίησης των κρυσταλλικών μορφών του DPZ σε δισκία και έλεγχος της σταθερότητάς τους μετά από διάφορες διαδικασίες παρασκευής των δισκίων, καθώς και μετά από αποθήκευση σε διάφορες συνθήκες υγρασίας και θερμοκρασίας, χρησιμοποιώντας τις πειραματικές τεχνικές XRD, FT-IR και FT-Raman. Παρατηρήθηκε ότι η προέλευση του API, οι συνθήκες αποθήκευσης και κυρίως η μέθοδος παρασκευής των δισκίων επηρεάζουν τη σταθερότητα των φαρμακευτικών σκευασμάτων. Με στόχο τη διερεύνηση της δυνατότητας ανάπτυξης ποσοτικών αναλυτικών μεθόδων προσδιορισμού των πολυμόρφων Ι και ΙΙΙ του DPZ σε δισκία, οι παραπάνω τεχνικές χρησιμοποιήθηκαν για τον υπολογισμό των ορίων ανίχνευσης των δύο πολυμόρφων (0.35% κ.β. για το πολύμορφο Ι και 0.44 % κ.β. για το πολύμορφο ΙΙΙ με την τεχνική Raman, 0.95% κ.β. για το πολύμορφο Ι και 1.3 % κ.β. για το πολύμορφο ΙΙΙ με την τεχνική XRD, 1.2% κ.β. για τη μορφή Ι και 1.0 % κ.β. για τη μορφή ΙΙΙ με την τεχνική IR, όπως προέκυψαν μετά από στατιστική επεξεργασία των πειραματικών δεδομένων των διαφόρων τεχνικών), καθώς και για τον ποσοτικό τους προσδιορισμό. Η τεχνική Raman φαίνεται να μπορεί χρησιμοποιηθεί για ποσοτική ανάλυση των πολυμόρφων Ι και ΙΙΙ του DPZ σε δισκία, ενώ επιπλέον η ποσοτική μέθοδος που παρουσιάσθηκε εδώ είναι απλή και μη καταστροφική για τα δείγματα. Η μέθοδος XRD μπορεί πιθανόν να χρησιμοποιηθεί για την ποσοτική ανάλυση δισκίων DPZ, με μεγαλύτερο όμως σφάλμα σε σύγκριση με την τεχνική Raman, ενώ η μέθοδος FT-IR ATR, παρέχει τα λιγότερο καλά ποσοτικά αποτελέσματα, ακόμα και στην περίπτωση που το δισκίο περιέχει αποκλειστικά το ένα από τα δύο πολύμορφα. Τέλος, με στόχο την ερμηνεία των φασμάτων δόνησης που καταγράφησαν στην παρούσα εργασία, υπολογίστηκαν η σταθερή δομή του μορίου της Δονεπεζίλης και της ένυδρης Δονεπεζίλης (με ένα μόριο νερού ανά μόριο Δονεπεζίλης) και τα φάσματα δόνησης (IR και Raman) με τις μεθόδους Hartree-Fock ab-initio και DFT (Density Functional Theory) και χρήση του υπολογιστικού πακέτου Gaussian09. / Donepezil hydrochloride (DPZ) is a medication used to treat Altzheimer’s disease. It acts as an inhibitor of acetylcholisterinase, an enzyme responsible for the destruction of the neurotransmitter acetylcholine, thus increasing the level of acetylcholine in the brain. As most of the pharmaceutical solids, DPZ exhibits polymorphism. Donepezil hydrochloride has different crystalline forms, including two hydrates, as well as an amorphous phase. DPZ is available for oral administration in tablets which can be stored for some time before use. In the present study, an effort was made to identify the crystal form of DPZ in tablets, as well as to test its stability against time, temperature and humidity, after various manufacturing processes, using XRD, FT-IR and FT-Raman techniques. The data showed that the origin of the API, the storing conditions and mainly the manufacturing process of the tablets affect the stability of the API. Quantitative determination of polymorphs I and III of DPZ in tablets was also attempted using the above experimental methods. Calibration models were constructed and applied in DPZ tablets. The detection limits of polymorphs I and III of DPZ for each technique, derived after statistical treatment of the experimental data, were calculated. Raman spectroscopy exhibited the lower detection limit (0.35 weigh % for polymorph Ι and 0.44 % weigh % for polymorph ΙΙΙ) compared with XRD (0.95% weigh % for polymorph Ι and 1.3 % weigh % for polymorph ΙΙΙ) and IR spectroscopy (1.2% weigh % for polymorph Ι and 1.0 % weigh % for polymorph ΙΙΙ). The data suggest that Raman spectroscopy could be applied to quantify polymorphs I and III in DPZ tablets; moreover, the Raman quantitative method presented in this work is simple and non-destructive for the tablets. The application of the X ray diffraction method for the quantitative analysis of polymorphs I and III in tablets yielded larger errors compared with Raman spectroscopy, while the FT-IR ATR technique yielded poor quantitative results, even in the case that only one polymorph was present in DPZ tablets. Finaly, in order to facilitate the assignment of the vibrational spectra recorded in this study, the optimized structure and the vibrational spectra (IR and Raman) of Donepezil and Donepezil hydrate (Donepezil:H20 = 1:1) molecules were calculated at the Hartree-Fock and DFT (Density Functional Theory) level of theory using the Gaussian 09 program package. The weigh % of the API in the tablets containing 10 mg of DPZ is 3.6 %. In cases where two or more polymorphs are present, the weigh % of each polymorphic form is lower. The difficulty in the identification and quantification of the crystal phase of DPZ is stemming from the small percentage of the API in the tablets, the considerable overlapping of DPZ XRPD patterns and IR and Raman spectra of the polymorphs and the excipients and the availability of various polymorphs.

The vast majority of pharmaceutical drug products are developed, manufactured, and delivered in the solid-state where the active pharmaceutical ingredient (API) is crystalline. With the potential to exist as polymorphs, salts, hydrates, solvates, and cocrystals, each with their own unique associated physicochemical properties, crystals and their forms directly influence bioavailability and manufacturability of the final drug product. Understanding and controlling the crystalline form of the API throughout the drug development process is absolutely critical. Interfacial properties, such as surface energy, define the interactions between two materials in contact. For crystal growth, surface energy between crystal surfaces and liquid environments not only determines the growth kinetics and morphology, but also plays a substantial role in controlling the development of the internal structure. Surface energy also influences the macroscopic particle interactions and mechanical behaviors that govern particle flow, blending, compression, and compaction. While conventional methods for surface energy measurements, such as contact angle and inverse gas chromatography, are increasingly employed, their limitations have necessitated the exploration of alternative tools. For that reason, the first goal of this research was to serve as an analytical method development report for atomic force microscopy and determine its viability as an alternative approach to standard methods of analysis. The second goal of this research was to assess whether the physical and the mathematical models developed on the reference surfaces such as mica or graphite could be extended to organic crystal surfaces. This dissertation, while dependent upon the requisite number of mathematical assumptions, tightly controlled experiments, and environmental conditions, will nonetheless help to bridge the division between lab-bench theory and successful industrial implementation. In current practice, much of pharmaceutical formulation development relies on trial and error and/or duplication of historical methods. With a firm fundamental understanding of surface energetics, pharmaceutical scientists will be armed with the knowledge required to more effectively estimate, predict, and control the physical behaviors of their final drug products.

The full crystal structures of three polymorphs of 4-methyl-2-nitroacetanilide (MNA) are described. The white form (MNA-l), is the most stable form. The least stable form is the amber farm (MNA-2). The yellow form (MNA-3) has been found to change in a topotactic manner into the white form. The relationships between the three polymorphs are discussed and possible mechanisms to account for the topotactic phase changes are presented. The polymorphs show different i.r. and Raman spectra in the solid state. These spectra, and those of deuterated analogues are interpreted and their differences explained. A study of the proton and 13-C n.m.r. spectra show that the conformation of flexible MNA molecules is markedly dependent on the nature of the solvent. The ability of other o-nitroacetanilides to exist in a white (intermolecular) and yellow (intramolecular hydrogen bonded) forms has been examined. Finally, details of the synthesis of these compounds and an account of the examination of MNA polymorphs by differential scanning calorimetry (d.s.c) are described. A description of computer programs used, including one in BASIC which will enable the contents of unit cell(s) to be viewed, is given.

xxi, 134 p. : ill. (some col.) / Hydrogenated nanocrystalline silicon (nc-Si:H) is a semiconducting material that is very useful as a thin film photovoltaic. A mixture of amorphous and crystalline silicon components, nc-Si:H shows good carrier mobilities, enhanced infrared response, and high resilience to light-induced degradation of its electronic properties, a thermally reversible degenerative phenomenon known as the Staebler-Wronski Effect (SWE). However, production of nc-Si:H is difficult in part because the structural and electronic properties of this material are not well understood. For example, its electronic properties have even been observed by some authors to improve upon prolonged light exposure, in direct opposition to the SWE observed in purely amorphous thin film silicon. We used several junction capacitance based measurements together with characterization methods such as Raman spectroscopy and secondary ion mass spectroscopy to better understand the structure/function relationships present in nc-Si:H. Drive level capacitance profiling (DLCP) was used to determine densities, spatial distributions, and energies of deep-gap defects. Transient photocapacitance (TPC) and transient photocurrent (TPI) were used to characterize optical transitions and the degree of minority carrier collection. Materials had crystallite volume fractions between 20% and 80% and were deposited using RF and modified VHF glow discharge (PECVD) processes at United Solar Ovonic, LLC. Measurements were made as a function of metastable state: annealed states were produced by exposing the material to temperatures above 370K for 0.5h and the lightsoaked state was produced by exposure to 200mW/cm 2 610nm long-pass filtered light from an ELH halogen source for 100h. We identified two deep defects in nc-Si:H. A primary defect appearing throughout the material at an electronic transition energy of roughly 0.7eV below the conduction band, and a second defect 0.4eV below the conduction band which was localized near the p/i junction interface. Results suggested that the deeper defect is related to the presence of oxygen and is located in grain boundary regions. The energy depth of this defect appears also to be somewhat dependent on metastable state. This phenomenon, and the universal decrease in minority carrier collection upon lightsoaking are accounted for in a model of electronic behavior we have developed over the course of this study. / Committee in charge: Dr. Miriam Deutsch, Chairperson; Dr. J. David Cohen, Advisor; Dr. Roger Haydock, Member; Dr. Heiner Linke, Member Dr. Mark Lonergan Outside Member

The knowledge of the packing behaviour of small organic compounds in crystal lattices is of great importance for industries dealing with solid state materials. The properties of materials depend on how the molecules arrange themselves in a crystalline environment. Crystal structure prediction provides a theoretical approach through the application of computational strategies to seek possible crystal packing arrangements (or polymorphs) a compound may adopt. Based on the chemical diagrams, this thesis investigates polymorphism of several small organic compounds. Plausible crystal packings of those compounds are generated, and their lattice energies are minimised using molecular mechanics and/or quantum mechanics methods. Most of the work presented here is conducted using two software packages commercially available in this field, Polymorph Predictor of Materials Studio 4.0 and GRACE 1.0. In general, the computational techniques implemented in GRACE are very good at reproducing the geometries of the crystal structures corresponding to the experimental observations of the compounds, in addition to describing their solid state energetics correctly. Complementing the CSP results obtained using GRACE with isostructurality offers a route by which new potential polymorphs of the targeted compounds might be crystallised using the existing experimental data. Based on all calculations in this thesis, four new potential polymorphs for four different compounds, which have not yet been determined experimentally, are predicted to exist and may be obtained under the right crystallisation conditions. One polymorph is expected to crystallise under pressure. The remaining three polymorphs might be obtained by using a seeding technique or the utilisation of suitable tailor made additives. / University of Bradford