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The in vitro production of ceramic implants used for cranial defect repair can be challenging and complex. In this thesis, a raw material in such a production has been mapped in order to optimize the production process. The current production leaves variations in the handling properties of the calcium phosphate cement (CPC), such as the viscosity and setting performance. The problems originate from the in-house recrystallization of the raw material monocalcium phosphate monohydrate (MCPM) with a 70% ethanol solution. The treatment of MCPM is strongly dependent on the relative humidity and the current process is not reliable and leaves unwanted fluctuations in the quality of MCPM. Various material and process parameters were investigated to get a deeper knowledge of MCPM in the specific process. The mapping resulted in new information about how the MCPM recrystallizes and how it depends on the evaporation of the ethanol solution during the treatment. Other findings were that the particle size distribution of MCPM is not the only factor controlling the viscosity of the CPC; the density and shape of the MCPM particles may also influence the handling properties. The mapping led to a process optimization suggestion where the amount of ethanol solution is adjusted to the relative humidity during the recrystallization to neutralize the effect of the humidity. The adjustment of ethanol solution volume means the evaporation can be controlled and in theory, constant quality of MCPM can be maintained. Unfortunately, the new method needs additional data to be fully effective but shows great potential.

Os Insumos farmacêuticos ativos (IFA) são em sua maioria produzidos e comercializados na forma de formulações sólidas. A eficácia terapêutica de cada IFA, no entanto, está diretamente relacionada com suas características no estado sólido. Desta forma, o controle e o entendimento da química das características físico-químicas de estado sólido dos IFAs, como produtos formulados ou substâncias puras, é uma importante parte do processo de desenvolvimento de novos medicamentos. Dentro deste marco, o presente trabalho tem o intuito de obter e caracterizar novas formas sólidas de dois compostos farmacêuticos, sendo eles, o fármaco anti-helmíntico Mebendazol e o hormônio Estradiol 17β Valerato. A caracterização destes compostos foi realizada por meio da técnica de difração de raios X de monocristais e complementada com dados provenientes de outras técnicas tais como espectroscopia Infravermelho e Raman e análise térmica. A partir da amostra de mebendazol obteve-se um novo sal, o mesilato de mebendazol monohidratado que cristaliza no grupo espacial triclínico P1. A unidade assimétrica deste composto apresenta uma molécula de MBZ, uma molécula de mesilato (metil sulfonato) e uma molécula de água. A análise estrutural mostrou que a molécula do principio ativo apresenta ligação de hidrogênio intramolecular assistida por ressonância. No que diz respeito às interações intermoleculares, a presença dos íons mesilato e da água fazem com que o empacotamento cristalino seja mais compacto que o apresentado pelas outras formas sólidas reportadas na literatura devido à presença de ligações de hidrogênio fortes. Estas ligações dão lugar à formação de cadeias infinitas nas quais as moléculas de MBZ estão unidas por interações fortes envolvendo os íons mesilato. Essas cadeias por sua vez se arranjam de maneira a formar estruturas bidimensionais unidas entre si por interações envolvendo as moléculas de água, o que estabiliza o empacotamento tridimensional. O Estradiol 17β Valerato, utilizado para tratamento de menopausa e em pílulas anticoncepcionais, não apresenta na literatura nenhuma caracterização de estado sólido. O mesmo cristalizou no grupo espacial não centrossimétrico P2₁ com duas moléculas por unidade assimétrica as quais mostram evidencias de desordem vibracional na cadeia terminal do grupo valerato. A análise térmica mostrou que este composto funde a 145°C sendo que o processo de decomposição da amostra acontece em 262°C. Analisando o comportamento térmico desse insumo a baixa temperatura constatou-se que ele apresenta uma transição de fase estrutural de primeira ordem em -22°C ao descer a temperatura e em -16°C ao subir. A caracterização estrutural deste sólido farmacêutico a 100K permitiu observar que a transição de fase está relacionada com uma forte mudança conformacional do grupo valerato. / The active pharmaceutical ingredients (API) are mostly produced and marketed in the form of solid formulations. The therapeutic efficacy of each API, however, is directly related to its characteristics in the solid state. Thus the control and understanding of the chemistry of the physicochemical characteristics of solid state APIs as pure substances or formulated products, is an important part of the process of developing new drugs. Within this framework, this paper aims to obtain and characterize new solid forms of two pharmaceutical compounds, among them, the anthelmintic drug Mebendazole and hormone 17β estradiol valerate. The characterization of these compounds was performed by means of diffraction X-ray single crystal and supplemented with data from other techniques such as infrared and Raman spectroscopy and thermal analysis. From the sample mebendazole obtained a new salt, mesylate monohydrate mebendazole which crystallizes triclinic space group P1. The asymmetric unit of this compound exhibits a MBZ molecule, a molecule of mesylate (methyl sulphonate) and one water molecule. Structural analysis showed that the molecule of the active principle presents intramolecular hydrogen bond assisted by resonance. In respect of intermolecular interactions, the presence of mesylate ion and the water cause the crystal packing is more compact than that shown by the solid forms reported in the literature by the presence of strong hydrogen bonding. These bonds give rise to the formation of endless chains in which molecules are joined by MBZ strong interactions involving ions mesylate. These chains in turn are arranged so as to form two-dimensional structures but joined by interactions between the molecules involving water which stabilizes the three-dimensional packaging. The 17β Estradiol valerate, used for treatment of menopause and in oral contraceptives, there has no literature characterization of the solid state. The same crystallized in the no centrosymmetric space group P2₁ with two molecules per asymmetric unit which show evidence of vibrational disorder in the chain terminal group valerate. Thermal analysis showed that this compound melting at 145°C and the process of decomposition of the sample occurs in 262°C. By analyzing the thermal behavior of this input at low temperature it was found that it presents a structural phase transition of first order in -22°C to lower the temperature and -16°C to rise. The structural characterization of this solid pharmacist 100K allowed observing the phase transition is related to a strong conformational change valerate group.

Calculo renal, também conhecido como urolitíase, é comum com uma taxa de prevalência estimada global recente de 14,8%, a qual parece estar aumentando, com uma taxa de recorrência em cinco anos de até 50%. As várias atividades biológcas promissoras de extratos de plantas ricas em ácidos galolquínicos, como as folhas das espécies de Copaifera, levaram nosso interesse em sintetizar o éster metílico do ácido 3,4,5-tri-O-galoilquinico trissubstituído (TGAME), com o objetivo de desenvolver um composto com potencial para prevenção de cálculos renais. A síntese total incluiu seis etapas a partir dos ácidos quínico e gálico disponíveis comercialmente. O passo-chave na via sintética foi a esterificação de Steglich viável do quinato de metila com ácido 3,4,5-tribenziloxibenzóico usando diciclo-hexilcarbodiimida e N, N-(dimetilamino)piridina como reagentes de acoplamento. As estruturas químicas do composto final e seus intermediários sintéticos foram elucidados por métodos espectroscópicos, espectrométricos e espectrofotométricos de análises. O efeito potencial do composto sobre a ligação de cristal monoidratado de oxalato de cálcio (COM) à superfície de células de rim caninas tipo I de Madin-Darby (MDCKI) e o crescimento de cristais em modelo de túbulos Malpighi de Drosophila melanogaster foi investigado. As quantidades de membrana, citosólica e total de Annexina A1 (ANXA1), Alfa-enolase e HSP90 foram examinadas por análise de transferência de Western após fracionamento subcelular, as quais foram confirmadas por coloração por imunofluorescência de células cultivadas. O pré-tratamento de células MDCKI com TGAME por até 6 h diminuiu significativamente a ligação de cristal COM de uma maneira dependente da concentração. O TGAME (50 ?M) inibiu significativamente a expressão superficial de ANXA1 por microscopia de imunofluorescência, enquanto o ANXA1 intracelular aumentou. A análise de Western Blot confirmou alterações de expressão de ANXA1 na membrana e frações citosólicas de células tratadas com os compostos, enquanto a ANXA1 de células inteiras permaneceu inalterada. O TGAME também diminuiu significativamente o tamanho, o número e o crescimento de cristais de COM induzidos em um modelo de túbulos Malpighi de Drosophila melanogaster, o qual apresentou também potente atividade antioxidante em um ensaio de DPPH. Adicionalmente, realizamos estudos de biotransformação de derivados do ácido galoilquínico, utilizando fungos filamentosos, para prever seus comportamentos farmacocinéticos. Os resultados mostraram que os ácidos galoilquínicos das folhas de Copaifera lucens (fração n-butanólica, BF) foram transformados por Aspergillus alliaceus em um metabólito majoritário, o ácido 3-O-metil gálico (M1), que é um dos metabolitos conhecidos do ácido gálico estudado em humanos. O produto biotransformado foi identificado por UPLC-MS/MS. O pré-tratamento de células MDCKI com BF e seu produto transformado por 3 h diminuiu significativamente a ligação de cristal COM a estas células em concentrações de 50 ?g/mL e 5 ?M, respectivamente. Os compostos reduziram significativamente a expressão superficial das ANXA1 e HSP90 (proteínas de ligação COM) como evidenciado por microscopia de imunofluorescência, enquanto o nível intracelular aumentou. A análise por Western blot confirmou estas alterações nas frações de membrana e citosol das células tratadas com estes compostos, enquanto as células inteiras permaneceram inalteradas. M1 também apresentou atividade antioxidante promissora no ensaio DPPH. / Renal stone disease, also known as urolithiasis, is common with a recent overall estimated prevalence rate of 14.8% that appears to be rising, with a five-year recurrence rate of up to 50%. The promising diverse bioactivities of plant extracts rich in galloylquinic acids such as Copaifera species leaves prompted our interest to synthesize the tri-substituted 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME), with the goal of developing a lead compound for kidney stone prevention. The total synthesis included six steps starting from commercially available quinic and gallic acids. The key step in the synthetic pathway was through Steglich esterification of methyl quinate with 3,4,5-tribenzyloxybenzoic acid using dicyclohexylcarbodiimide and N,N-(dimethylamino) pyridine as the coupling reagents. The chemical structures of the final compound and its synthetic intermediates were elucidated by spectroscopic, spectrometric and spectrophotometric methods of analyses. The potential effect of the compound on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby Canine Kidney Cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule model were investigated. Membrane, cytosolic and total Annexin A1 (ANXA1), ?-enolase and HSP90 amounts were examined by Western blot analysis after subcellular fractionation, then confirmed by immunofluorescence staining of cultured cells. Pretreatment of MDCKI cells with TGAME for up to 6 h significantly diminished COM crystal-binding in a concentration-dependent manner. TGAME (50 ?M) significantly inhibited ANXA1 surface expression as evident by immunofluorescence microscopy, whereas intracellular ANXA1 increased. Western blot analysis confirmed ANXA1 expression changes in the membrane and cytosolic fractions of compound-treated cells, whereas the whole cell ANXA1 remained unchanged. TGAME also significantly decreased the size, number, and growth of COM crystals induced in a Drosophila melanogaster Malpighian tubule model, and possessed a potent antioxidant activity in a DPPH assay. We also have performed a biotransformation study of galloylquinic acid compounds using filamentous fungi to predict their pharmacokinetic behaviors. The results showed that galloylquinic acids from Copaifera lucens leaves (n-butanolic fraction, BF) were transformed by Aspergillus alliaceus into one major metabolite 3-O-methyl gallic acid (M1), which is one of the known metabolites of gallic acid studied in humans. The biotransformed product was identified by UPLC-DAD-MS/MS and 1H NMR. Pretreatment of MDCKI cells with BF (50 ?g/mL) and its transformed product M1 (5 ?M) for 3 h significantly diminished COM crystal-binding to these cells. The compounds significantly reduced surface expression of ANXA1 and HSP90 (COM-binding proteins) as evidence by immunofluorescence microscopy, whereas the intracellular level increased. Western blot analysis confirmed these changes in membrane and cytosolic fractions of compound-treated cells, whereas whole cells remained unchanged. M1 also showed a promising antioxidant activity in DPPH assay.

Η χρήση των βιοϋλικών ως εμφυτεύματα στην Ουρολογία και ιδιαίτερα στις ενδοουρολογικές επεμβάσεις είναι πράξη ρουτίνας τις τελευταίες δεκαετίες. Παρ’ όλα αυτά τα προβλήματα που προκύπτουν από την ευρεία χρήση τους μπορεί να θέσουν σε κίνδυνο τη υγεία του ασθενή που τις φέρει (λοιμώξεις ή και επανεπεμβάσεις). Αναφορικά με τις επικαθίσεις δυσδιάλυτων αλάτων στην επιφάνεια των ενδοπροθέσεων αυτών υπάρχει εκτεταμένο πεδίο έρευνας αλλά οι μηχανισμοί του φαινομένου δεν έχουν διαλευκανθεί πλήρως. Ο βασικός στόχος της παρούσας διατριβής είναι η προσομοίωση του φαινομένου στο εργαστήριο με ασταθή διαλύματα συνθετικών ούρων υπέρκορα ως προς το οξαλικό ασβέστιο καθώς και η μελέτη της κινητικής και των θερμοδυναμικών παραμέτρων του φαινομένου. Το πειραματικό πρότυπο που χρησιμοποιήθηκε κρίνεται ικανοποιητικό για την κινητική μελέτη των επικαθίσεων (εναποθέσεων) σε βιοϋλικά του ουροποιητικού συστήματος. Η γραφική παράσταση της συνάρτησης της αρχικής ταχύτητας κρυστάλλωσης του μονοένυδρου οξαλικού ασβεστίου με το γινόμενο των ιοντικών ενεργοτήτων ασβεστίου και οξαλικών στην παρούσα διατριβή είναι γραμμική και σε καλή συμφωνία με αποτελέσματα από τη βιβλιογραφία. Η επιφάνεια του καθετήρα καταλύει την πυρηνογένεση ενώ οι χαμηλές τιμές επιφανειακής ενέργειας που υπολογίστηκαν υποδηλώνουν μηχανισμό ετερογενούς πυρηνογένεσης. Η αντίδραση για τον γυάλινο καθετήρα φαίνεται να ελέγχεται από την διάχυση δομικών μονάδων από το διάλυμα των συνθετικών ούρων ενώ για τους καθετήρες Foley ισχύουν διεργασίες επιφανειακής διάχυσης. Δεν φαίνεται να υπάρχει σημαντική διαφοροποίηση μεταξύ του γυαλιού και του καθετήρα Foley όσον αφορά στην επιφανειακή ενέργεια του σχηματιζόμενου στερεού. Η συμβατότητα των πυρήνων του μονοένυδρου οξαλικού ασβεστίου (COM) οι οποίοι αναπτύσσονται στους αντίστοιχους κρυσταλλίτες με τις επιφάνειες των καθετήρων Foley και των γυάλινων καθετήρων (control) – γωνία θ- βρέθηκε ότι ήταν παραπλήσια. Οι μικρές διαφοροποιήσεις στην επιφανειακή ενέργεια των υλικών τα οποία μελετήθηκαν, υποδεικνύουν ότι υλικά με μεγάλη επιφανειακή ενέργεια της αναπτυσσόμενης φάσης μπορούν να αναστείλουν τον σχηματισμό επικαθίσεων σε ενδοπροθέσεις. Η ποιοτική ανάλυση των επικαθίσεων των δυσδιάλυτων αλάτων μέσω της φασματοσκοπίας υπερύθρου είναι σημαντική για τη λήψη πληροφοριών σχετικά με τις συνθήκες σχηματισμού καθώς και του ρυθμού ανάπτυξής τους. Σε όλα τα πειράματα που πραγματοποιήθηκαν, από την ανάλυση των στερεών που ελήφθησαν διαπιστώθηκε ότι καταβυθίζεται αποκλειστικά μονοένυδρο οξαλικό ασβέστιο (COM). Η ηλεκτρονική μικροσκοπία σάρωσης μας παρείχε πληροφορίες για τη μορφολογία των στερεών. Παρατηρείται αλλαγή της μορφολογίας των κρυστάλλων του μονοένυδρου οξαλικού ασβεστίου παρουσία συνθετικών ούρων σε σχέση με τη μορφολογία του κρυστάλλου απουσία των συνθετικών ούρων. Η ποιοτική ταυτοποίηση 63 ουρητηρικών καθετήρων (stents) ανέδειξε πιο συχνά απαντώμενη την επικάθιση του μονοένυδρου οξαλικού ασβεστίου μόνη ή σε συνδυασμό με άλλες (36,5%). Στους καθετήρες κύστης (12) ήταν πιο συχνές οι επιμολύνσεις και οι επικαθίσεις στρουβίτη-απατίτη. Από τον μεταβολικό έλεγχο των ούρων όλων των παραπάνω ασθενών βρέθηκε σε υψηλό ποσοστό συνύπαρξη υποκιτρικουρίας (50 - 85,71%) καθώς και άλλες μεταβολικές διαταραχές όπως υπεροξαλουρία και υπομαγνησιουρία. Είναι πιθανό τέτοιοι μεταβολικοί παράγοντες να υπεισέρχονται στους μηχανισμούς ανάπτυξης των κρυσταλλικών επικαθίσεων. Τέλος, χρησιμοποιήθηκε το λογισμικό Phreeqc Interactive v 2.6 για τον υπολογισμό του υπερκορεσμού των ούρων ασθενών όσον αφορά στο μονοένυδρο οξαλικό ασβέστιο, στον υδροξυαπατίτη και στον βρουσίτη με ικανοποιητικά αποτελέσματα. Δεδομένου ότι ο υπερκορεσμός είναι μία αναγκαία αλλά όχι και ικανή συνθήκη για την καταβύθιση ενός άλατος η βάση δεδομένων του λογισμικού χρήζει τροποποιήσεων ώστε να έχει ακριβέστερη εφαρμογή στην βασική έρευνα και στην κλινική λιθίαση. Η ανάλυση των επικαθίσεων δυσδιάλυτων αλάτων σε βιοϋλικά του ουροποιητικού συστήματος είναι σημαντική για τη λήψη πληροφοριών σχετικά με τις συνθήκες σχηματισμού καθώς και του ρυθμού ανάπτυξής των. Οι πληροφορίες για τη διαδικασία σχηματισμού εναποθέσεων είναι σημαντικές για το σχεδιασμό νέων βιοϋλικών ανθεκτικών στα φαινόμενα των εναποθέσεων οργανικού υλικού (biofilm), μικροοργανισμών, και δυσδιάλυτων αλάτων. / The use of biomaterials as devices in Urology and particularly in endourological interventions is an ordinary practice in the last decades. Unfortunately problems that result from their wide use can get patient’s health into risk (with infections or even reoperation). There is an extensive field of research concerning encrustations (deposits) from undissolved salts in the surface of the endourological devices (stents, catheters) but the mechanisms of this phenomenon has not been cleared up completely till now. The main objective of the present study is the simulation of the phenomenon in the laboratory dealing with unstable solutions of synthetic urine supersaturated with respect to calcium oxalate monohydrate as well as the study of kinetics and thermodynamic parameters of the phenomenon. The experimental model that was used was characterised satisfactory for the kinetic study of salt deposits in biomaterials of the urinary system. The graphic representation of the function of initial rate of crystallization of calcium oxalate monohydrate with ion activity product of calcium oxalate monohydrate in the present study is linear and in accordance with results from the bibliography. The surface of catheter catalyses the formation of the nuclei of crystals while the low values of surface energy that were calculated imply mechanism of heterogeneous nucleation. The reaction in the surface of the glass catheter seems to be depended upon the diffusion of structural units from the solution of synthetic urine but the one in the Foley catheters suggests a surface diffusion mechanism. There is no important differentiation between the glass catheter and Foley catheter with respect to the surface energy of the formatted solid phase. The compatibility of calcium oxalate monohydrate nuclei which developed on the surfaces of Foley catheters and glass catheters (control) was found to be similar. The small differentiations concerning the surface energy of the materials were studied, indicate that materials with high surface energy of the developing solid phase could minimize the formation of encrustations in endourological devices. The qualitative analysis of salt encrustations via infrared spectroscopy is important for informing the conditions of nucleation as well as the rate of nuclei growth. The analysis of the solid phase took place in all experiments show exclusively calcium oxalate monohydrate formation(COM). The Scanning Electron Microscopy (SEM) provided us information about the morphology of the solid phase developed in the biomaterials surface. There was a differentiation on the crystal morphology of calcium oxalate monohydrate in the presence of synthetic urine comparing with other solutions in the bibliography. Presenting results from 11 samples– stents and catheters- was found that calcium oxalate monohydrate (COM) was the undissolved salt identified more often in such deposits. The qualitative identification of other 53 stents also showed increased calcium oxalate monohydrate deposits alone or in combination with other salts (36,5%). In 11 bladder catheters studied, the bacterial colonization was more often and the crystalline deposits were consisted mostly of struvite or apatite. Metabolic evaluation of urine of all above patients showed the coexistence of hypocitruria in high percentage (50-85,71%) as well as other metabolic disturbances such as hyperoxaluria and hypomagnesuria. It is supposed that such metabolic factors inside into the mechanisms of growth of crystal deposits. Finally, software Phreeqc Interactive v 2.6 was used for the calculation of patients’ urine supersaturation. The results were satisfactory with respect to calcium oxalate monohydrate, brushite and apatite. Since supersaturation is a necessary but not the unique factor for a salt precipitation seems that this software database requires modifications so that it has more sophisticated applications in basic research and clinical urolithiasis in future. The analysis of encrustations of undissolved salts in biomaterials used in the urinary system is important for collecting information concerning the conditions of crystal formation as well as their crystal growth. This is also important for planning new materials could resist in the phenomenon of deposits of either organic material (biofilm) and microorganisms or salts.

Os Insumos farmacêuticos ativos (IFA) são em sua maioria produzidos e comercializados na forma de formulações sólidas. A eficácia terapêutica de cada IFA, no entanto, está diretamente relacionada com suas características no estado sólido. Desta forma, o controle e o entendimento da química das características físico-químicas de estado sólido dos IFAs, como produtos formulados ou substâncias puras, é uma importante parte do processo de desenvolvimento de novos medicamentos. Dentro deste marco, o presente trabalho tem o intuito de obter e caracterizar novas formas sólidas de dois compostos farmacêuticos, sendo eles, o fármaco anti-helmíntico Mebendazol e o hormônio Estradiol 17β Valerato. A caracterização destes compostos foi realizada por meio da técnica de difração de raios X de monocristais e complementada com dados provenientes de outras técnicas tais como espectroscopia Infravermelho e Raman e análise térmica. A partir da amostra de mebendazol obteve-se um novo sal, o mesilato de mebendazol monohidratado que cristaliza no grupo espacial triclínico P1. A unidade assimétrica deste composto apresenta uma molécula de MBZ, uma molécula de mesilato (metil sulfonato) e uma molécula de água. A análise estrutural mostrou que a molécula do principio ativo apresenta ligação de hidrogênio intramolecular assistida por ressonância. No que diz respeito às interações intermoleculares, a presença dos íons mesilato e da água fazem com que o empacotamento cristalino seja mais compacto que o apresentado pelas outras formas sólidas reportadas na literatura devido à presença de ligações de hidrogênio fortes. Estas ligações dão lugar à formação de cadeias infinitas nas quais as moléculas de MBZ estão unidas por interações fortes envolvendo os íons mesilato. Essas cadeias por sua vez se arranjam de maneira a formar estruturas bidimensionais unidas entre si por interações envolvendo as moléculas de água, o que estabiliza o empacotamento tridimensional. O Estradiol 17β Valerato, utilizado para tratamento de menopausa e em pílulas anticoncepcionais, não apresenta na literatura nenhuma caracterização de estado sólido. O mesmo cristalizou no grupo espacial não centrossimétrico P2₁ com duas moléculas por unidade assimétrica as quais mostram evidencias de desordem vibracional na cadeia terminal do grupo valerato. A análise térmica mostrou que este composto funde a 145°C sendo que o processo de decomposição da amostra acontece em 262°C. Analisando o comportamento térmico desse insumo a baixa temperatura constatou-se que ele apresenta uma transição de fase estrutural de primeira ordem em -22°C ao descer a temperatura e em -16°C ao subir. A caracterização estrutural deste sólido farmacêutico a 100K permitiu observar que a transição de fase está relacionada com uma forte mudança conformacional do grupo valerato. / The active pharmaceutical ingredients (API) are mostly produced and marketed in the form of solid formulations. The therapeutic efficacy of each API, however, is directly related to its characteristics in the solid state. Thus the control and understanding of the chemistry of the physicochemical characteristics of solid state APIs as pure substances or formulated products, is an important part of the process of developing new drugs. Within this framework, this paper aims to obtain and characterize new solid forms of two pharmaceutical compounds, among them, the anthelmintic drug Mebendazole and hormone 17β estradiol valerate. The characterization of these compounds was performed by means of diffraction X-ray single crystal and supplemented with data from other techniques such as infrared and Raman spectroscopy and thermal analysis. From the sample mebendazole obtained a new salt, mesylate monohydrate mebendazole which crystallizes triclinic space group P1. The asymmetric unit of this compound exhibits a MBZ molecule, a molecule of mesylate (methyl sulphonate) and one water molecule. Structural analysis showed that the molecule of the active principle presents intramolecular hydrogen bond assisted by resonance. In respect of intermolecular interactions, the presence of mesylate ion and the water cause the crystal packing is more compact than that shown by the solid forms reported in the literature by the presence of strong hydrogen bonding. These bonds give rise to the formation of endless chains in which molecules are joined by MBZ strong interactions involving ions mesylate. These chains in turn are arranged so as to form two-dimensional structures but joined by interactions between the molecules involving water which stabilizes the three-dimensional packaging. The 17β Estradiol valerate, used for treatment of menopause and in oral contraceptives, there has no literature characterization of the solid state. The same crystallized in the no centrosymmetric space group P2₁ with two molecules per asymmetric unit which show evidence of vibrational disorder in the chain terminal group valerate. Thermal analysis showed that this compound melting at 145°C and the process of decomposition of the sample occurs in 262°C. By analyzing the thermal behavior of this input at low temperature it was found that it presents a structural phase transition of first order in -22°C to lower the temperature and -16°C to rise. The structural characterization of this solid pharmacist 100K allowed observing the phase transition is related to a strong conformational change valerate group.

Saccharides, a class of organic materials, are potential candidates for nonlinear optical applications. Ascorbic acid is a sugar acid and is classified as a monosaccharide. The molecule of ascorbic acid has two chiral centers and, therefore, four stereoisomers. Among them, two are naturally occurring compounds; L-ascorbic acid and D-isoascorbic acid. From these two acids various salts and other derivatives could be synthesized. In this thesis, four compounds of the ascorbic acid family were selected for detailed study based on their nonlinearity, chemical and physical stability and their crystallization characteristics. The thesis is organized into seven chapters. The first chapter covers the theoretical background of nonlinear optics, especially, second harmonic generation. Second chapter details the experimental techniques and methodology adopted. Chapter 3 discusses the crystal structure, growth, physical and nonlinear optical properties of Lithium Disoascorbate monohydrate (LDAM). Detailed analysis of refractive index measurements employing Brewsters angle method and determination of phase matching curves, effective nonlinear coefficient, walk off angle etc are given. In Chapter 4, investigations on Sodium D-isoascorbate monohydrate (NDAM) are presented. Detailed characterization of the crystals including thermal, optical, dielectric properties are carried out. Analyses of dielectric dispersion based on Cole-Cole equation are discussed. Comprehensive studies on laser damage of the crystals are discussed. Chapter 5 discusses the nonlinear optical properties of the monoclinic D-isoascorbic acid (DIA). Chapter 6 presents studies on the triclinic Lithium L-ascorbate dihydrate (LLA) crystals. The crystals exhibit intense non-collinear second harmonic rings as they possesses large birefringence coupled with high second order nonlinear coefficients. The SHG conversion efficiency of these crystals is 15 times that of KDP. In the final chapter, a comprehensive summary of the work carried out is presented along with scope for further investigations.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-05-05T19:45:04Z No. of bitstreams: 1 RicardoSousaFerreira.pdf: 2802747 bytes, checksum: 0d4bf284379fe32714f3b112e464cf64 (MD5) / Made available in DSpace on 2017-05-05T19:45:04Z (GMT). No. of bitstreams: 1 RicardoSousaFerreira.pdf: 2802747 bytes, checksum: 0d4bf284379fe32714f3b112e464cf64 (MD5) Previous issue date: 2016-03-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / Currently, the amino acid salt crystals are extensively studied, primarily because of their possible application in opto-electronic devices. Many amino acids complexed with chlorine crystals were synthesized and characterized, and suggested as promising materials in frequency conversion. However, the characterization of L-isoleucine hydrochloride monohydrate crystals (L-Ile.H2O.HCl) is poor because to date, one article has been published and only the authors determined the crystal structure of the synthesized material. Thus, the objective of this study was to synthesize crystals of L-Ile.HCl.H2O by the method of slow evaporation and characterize them by X-Ray Fluorescence (XRF), Differential Thermal Analysis (DTA), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TG), X-Ray diffraction (XRD) as a function of temperature and time, Raman scattering as a function of temperature and heat treating the material in a sealed glass tube with argon atmosphere for 24h at 170 °C. The XRF confirms the presence of chlorine. The XRD at 25 oC shows that the crystal belongs to orthorhombic system with lattice parameters a = 5.873 (3) Å, b = 24.814 (4) Å, c = 6.873 (5) Å. The TG, DTA and DSC indicated that the material loses water of solvation and crystallization at approximately 55 °C and 132 °C, respectively .The DRX a function of temperature, the material shows phase transformation starts at 60 oC and 155 oC extends to. The XRD at 140 oC shows that after 32h, the crystal loses water and chlorine. Raman spectra as a function of temperature, confirm the phase transformation at 60 °C and 100 °C. The material when subjected to 170 °C, for a period of 24 sealed in a glass tube with an inert atmosphere (Ar) and undergoes vaporization sublimate the same orthorhombic phase, when it has its temperature reduced to 25 °C. Therefore, the L-Ile.HCl.H2O crystal is not a material suitable for use in optical devices due to their low thermal stability. / Atualmente, os cristais de sais de aminoácidos são amplamente estudados, principalmente devido à sua possível aplicação em dispositivos opto eletrônicos. Muitos cristais de aminoácidos complexados com cloro foram sintetizados, caracterizados e sugeridos como materiais promissores na conversão de frequência. No entanto, a caracterização de cristais de L-isoleucina hidroclorídrica monohidratada (L-Ile.H2O.HCl) é deficiente, pois até o momento, um único artigo foi publicado e os autores apenas determinaram a estrutura cristalina do material sintetizado. Dessa forma, o objetivo do presente trabalho foi sintetizar cristais de L-Ile.HCl.H2O pelo método de evaporação lenta e caracterizá-los por Fluorescência de Raios-X (FRX), Análise Térmica Diferencial (DTA), Calorimetria Exploratória Diferencial (DSC), Análise Termogravimétrica (TG), Difração de Raios-X (DRX) em função da temperatura e do tempo, espalhamento Raman em função da temperatura e tratar termicamente o material em um tubo de vidro selado com atmosfera de argônio por 24h a 170 oC. A FRX confirmou a presença de cloro. O DRX a 25 oC mostrou que o cristal pertence ao sistema ortorrômbico, com parâmetros de rede a = 5,873(3) Å, b = 24,814(4) Å, c = 6,873(5) Å. O TG, DTA e DSC indicaram que o material perde água de solvatação e cristalização em aproximadamente 55 oC e 132 oC, respectivamente. O DRX em função da temperatura, revelou que o material inicia transformação de fase em 60 oC e se estende até 155 oC. O DRX a 140 oC mostrou que após 32h, o cristal perdeu água e cloro. Os espectros Raman em função da temperatura, confirmaram as transformações de fase em 60 oC e 100 oC. O material quando submetido a 170 oC, por um período de 24h selado em um tubo de vidro com atmosfera inerte (Ar), sofreu vaporização e ressublimou na mesma fase ortorrômbica, quando teve sua temperatura reduzida a 25 oC. Portanto, o cristal de L-Ile.HCl.H2O não é um material indicado para ser utilizado em dispositivos ópticos devido a sua baixa estabilidade térmica.

NLO materials have been researched for nearly five decades from the point of view of understanding the basic mechanisms and also in the pursuit of new materials possessing improved properties. Materials satisfying a set of physico-chemical properties such as wide transmission range, good mechanical hardness, high po-larizablity, noncentric crystal structure, good chemical stability, etc are the ones which are sought after. Several organic and inorganic molecules have been synthe-sized with the hope of finding materials that possess the desired NLO properties. Most of the organic materials are known to possess high figure of merit. However, their poor mechanical strength and needle like growth habit are hindrances to practical applications. Inorganic NLO materials have better mechanical properties but many of them possess small deff and laser induced damage threshold. Semi-organic NLO materials are intended to have the merits of both organic and inorganic counterparts. In this investigation, three important NLO crystals, viz cesium hydrogen L-malate monohydrate (CsLM, CsH[C4H4O5]H2O), cesium lithium borate(CLBO,CsLiB6O10)and near stoichiometric lithium niobate codoped with Nd and Zn (Nd:Zn:LiNbO3)are chosen for detailed study. The thesis is organized into 6 chapters. First chapter contains the theoretical background of the physical and chemical phenomena including a review of nonlin-ear optics, second harmonic generation, multiphoton absorption & refraction con-cepts, single crystal growth, principles of ferroelectricity and the scope of the work involved. For better connectivity, a brief review of the earlier work carried out on the chosen materials is given in the beginning of each chapter. The second chapter discusses the methodology of work and experimental details used in the present study. The third chapter deals with studies on CsLM, the new organometallic NLO crystal. Its structure, electro-optical properties and dielectric properties in FIR region are reported very recently. This material is also reported to show a phase transition at 50 0C though not much is understood about its nature. Further details of crystal growth conditions, nonlinear optical properties and laser damage thresholds are little known on this newly discovered NLO material. In this chapter detailed crystal growth studies and investigations of physical properties are presented. During growth, CsLM crystals manifest in platy and prismatic morphologies depending on level of super saturation invoked. The maximum dimensions of the grown crystal are 20 x15 x35 mm3. It has very good transmission in the range, 250-1300 nm and dislocation density of ≈104/cm2 . The dc conductivity measurements place this crystal between an ionic conductor and a dielectric. Dielectric properties show considerable frequency dispersion and axial anisotropy with є′ being the highest along the polar b axis. Maker fringes experiment reveals that CsLM possesses good second harmonic generation efficiency, an order of magnitude higher than KDP. It also has high laser damage threshold for fundamental and second harmonic wavelengths of Nd:YAG pulsed laser. TGA/DTA experiments are performed on the crystals grown below and above the reported transition temperature(labelled as CsLM and Anhydrous-CsLM respectively). The present investigations on Anhydrous-CsLM show that it crystallizes in a structure different from that of CsLM and the nature of the reported ′phase transition ′is driven by sluggish hydration and dehydration processes. Recently UV transparent nonlinear optical materials were evaluated for the fab-rication of all solid state UVlasers and CLBO is one such NLO material. It crystal-lizes in non-centrosymmetric tetragonal space group, I42d. It is highly transparent in the wide range of wavelengths from 180 to 2500 nm and has good deff. It pos-sesses very good angular and spectral bandwidth tolerances compared to its contemporaries such as lithium triborate(LBO) and beta barium borate(β-BBO). There is, however, a problem associated with this material that it cracks when exposed to atmosphere due to its hygroscopic nature. This chapter details the fabrication of the required instrumentation to grow single crystals of this material and the study of possible solutions to avoid cracking problem besides its new nonlinear properties. Since the melts of borate materials are known to be highly viscous, the crystal growth apparatus should have the options for tuning the parameters like seed and crucible rotation rates, temperature isotherms, slow pulling rate, etc. Keeping the above in mind, a high temperature top seeded solution growth unit was designed and fabricated inhouse. Highly transparent single crystals of CLBO were grown using the above unit which were characterized for the defects/dislocations using X-ray topography. The average dislocation density estimated is ≈103/cm2. The nonlinear optical absorption(NLA) and refraction(NLR) properties are studied. Z-scan experiments reveal that five photon absorption(5PA )is responsible for nonlinear absorption when the wavelength and pulse width are 800 nm and 110 fs respectively. For 532 nm and 6 ns pulses, dielectric breakdown occurs before NLA could occur due to high pulse influence. CLBO is found to show negative nonlinear refraction under high intensities. Hygroscopicity of CLBO is attributed to the entry of water through the channels that are present along a and b axes, which in turn, cause cracking. Doping, is expected to modify the size of the channels. Since certain dopants are found to improve the stability of CLBO, substitution of Cs site with Zn and Gd is carried out to reduce the size of channels. As there was no significant improvement with doping experiments, an alternate approach is attempted by coating with SiO2 thin films on the optical elements to prevent the water molecules from entering lattice through the channels. The results and discussion of the above studies are presented in the chapter 4. Lithium niobate is the most widely used single crystal for fabricating optical modulators, waveguides, SAW devices and optical parametric oscillators. Although single crystals of this ferroelectric material were grown way back in 1965 by Ball-man and Fedulov independently, most of the work till the beginning of 90’s was concentrated on crystals with congruent composition(CLN) because there were no suitable methods available for growing homogeneous single crystals of stoichiomet-ric lithium niobate(SLN). Recently, Double Crucible Czochralski method with au-tomatic powder feeding technique and top seeded solution growth technique with Li2O and K2O fluxes are shown to produce SLN crystals. In this work, top seeded solution growth technique with58.6 mol% Li2O composition(self flux) is adopted to grow SLN crystals and the details of the growth and investigations are presented in chapter 5. Initially, crystal growth of SLN, and Zn & Nd codoped SLN are de-scribed. The maximum dimesions of the SLN crystals are 20 mm diameter and 35 mm length. CLN crystals(30mm diameter and 70 mm length) are also grown for comparison. The growth rate for SLN crystals is approximately 25 times lower than that for CLN. The maximum amount of Zn added to the melt is 2.5 mol%. For Nd codoping, four concentrations (0.2, 0.5, 0.9, 1.5 mol%) have been chosen with Zn concentration in the melt fixed at 2.5 mol%. Addition of Zn is to enhance the pho-torefractive damage threshold and Nd to use SLN as laser host. Structural studies on the grown crystals using powder X-ray diffraction show no additional phases. The domain structure analysis by chemical etching studies reveal that it is sensitive to doping and temperature gradient above the melt surface. The grown crystals possess good transmission in the UV-Vis-NIR region. Apparent increase in the dielectric constant found in doped crystals is attributed to space charge effect. In Nd:Zn codoped SLN, the parameters corresponding to lasing (Judd-Ofelt parameters, radiative transition probabilities, branching ratios) have been evaluated and found to be better than those obtained for codoped CLN. Surface laser damage and photorefractive damage thresholds are enhanced by 2 and 4 orders of magnitude respectively for the crystals grown with 2.5 mol% Zn in the melt. Nonlinear absorption and refraction studies using femtosecond Z-scan experiments reveal a correlation between the nonstoichiometric defects and nonlinear absorption & refraction coefficients. Polarization switching studies carried out on pure and Zn doped samples indicate an enhancement in switching rate at elevated temperatures. In the sixth and final chapter, a comprehensive summary of the present work and the scope for further investigations related to this work are given.

Submitted by Diego Luiz Tita (diego.tita@gmail.com) on 2018-05-11T17:51:31Z No. of bitstreams: 1 DR_TITA_DL_FINAL_A.pdf: 8672085 bytes, checksum: af81639f689b5a5fc78999ae952240a8 (MD5) / Approved for entry into archive by Ana Carolina Gonçalves Bet null (abet@iq.unesp.br) on 2018-05-15T12:53:22Z (GMT) No. of bitstreams: 1 tita_dl_dr_araiq_int.pdf: 8328482 bytes, checksum: be0fe77b0059e1880c4d517105e2c2f6 (MD5) / Made available in DSpace on 2018-05-15T12:53:22Z (GMT). No. of bitstreams: 1 tita_dl_dr_araiq_int.pdf: 8328482 bytes, checksum: be0fe77b0059e1880c4d517105e2c2f6 (MD5) Previous issue date: 2018-04-20 / O refinamento de estruturas cristalinas pelo método de Rietveld (MR) consiste em ajustar um modelo estrutural a uma medida de difração. Essa é uma ferramenta eficiente para identificação e quantificação de estruturas polimórficas presentes em fármacos e excipientes. Uma forma avançada do método é o refinamento sequencial por Rietveld (RSR) que visa, a partir de um conjunto de difratogramas de uma mesma amostra, estudar o comportamento do material em função de uma variável externa (e.g. temperatura, pressão, tempo ou ambiente químico). No presente trabalho, com o objetivo de estudar as transições polimórficas e as expansões/contrações dos parâmetros de cela unitária (PCU) dos insumos farmacêuticos: espironolactona (SPR), lactose monoidratada (LACMH) e lactose anidra (LACA), empregou-se o RSR em medidas obtidas em diferentes temperaturas. O RSR foi eficiente para que os PCU fossem refinados até temperaturas próximas ao ponto de fusão dos materiais. Após o RSR, a partir da análise matemática dos PCU obtidos, foram propostas funções que regem a tendência desses parâmetros quando submetidos à variação de temperatura. Com essas funções modelaram-se os PCU em uma outra modalidade de refinamento, o refinamento paramétrico por Rietveld (RPR), assim, os PCU seguem a modelagem imposta pelas equações obtidas via RSR. O RPR mostrou-se mais eficiente nas análises, o que evitou perda de fases ou problemas de ajustes, resultando assim em informações mais precisas do sistema. Embora o RSR e RPR serem métodos sofisticados para a caracterização dos materiais, a preparação das rotinas de programação dos refinamentos não é trivial, assim, nesse trabalho desenvolveu-se uma planilha (i.e. planilha SP-DLT) que facilita o emprego dos métodos. A planilha mostrou-se eficiente e rápida para programar todas as rotinas de refinamentos apresentadas nesse trabalho. Com os estudos dos insumos farmacêuticos observou-se que na amostra SPR a forma I, com o aumento da temperatura, se converte para forma II. A alfalactose monoidratada sofre desidratação e se converte para alfalactose, na amostra LACMH, e para betalactose, na amostra LACA. E, ainda com aumento de temperatura, a betalactose não sofre mudança de fase polimórfica. Assim, entende-se que o meio pode causar influência na rota de transição polimórfica. / The crystal structural refinement by the Rietveld method (MR) consists of fitting a structural model to a diffraction measure. This is an efficient tool for identification and quantification of polymorphic structures present in drugs and excipients. An advanced way to use this method is the Sequential Rietveld Refinement (RSR), which aims, from a set of data of the same sample, to study the behavior of the material as a function of an external variable (e.g. temperature, pressure, time or chemical environment). In the present work, with the objective of studying the polymorphic transitions and the expansions / contractions of the unit cell parameters (PCU) of the pharmaceutical ingredients: spironolactone (SPR), lactose monohydrate (LACMH) and anhydrous lactose (LACA), the RSR in measurements obtained at different temperatures. The RSR was efficient so that the PCU were refined to temperatures close to the melting point of the materials. After the RSR, from the mathematical analysis of the obtained PCU, functions were proposed that govern the trend of these parameters when submitted to the temperature variation. With these functions the PCU were modeled in another modality of refinement, the Parametric Rietveld Refinement (RPR), thus, the PCU follow the modeling imposed by the equations obtained via RSR. The RPR was more efficient in the analyzes, which avoided loss of phases or problems of adjustments, resulting in more accurate information of the system. Although RSR and RPR are sophisticated methods for characterization of materials, preparation of refinement programming routines is not trivial, so a spreadsheet (i.e. SP-DLT spreadsheet) has been developed in this paper to facilitate the use of methods. The worksheet proved to be efficient and quick to program all the refinement routines presented in this paper. With the studies of the pharmaceutical inputs it was observed that in the SPR sample, the form I, with the increase in temperature, converts to form II. Alfalactose monohydrate undergoes dehydration and converts to alfalactose in the LACMH sample and to betalactose in the LACA sample. And, even with temperature increase, the betalactose does not undergo polymorphic phase change. Thus, it is understood that the medium may cause influence on the polymorphic transition route.