Rafael Silva Nunes Internal standard for amorphous pharmaceuticals products quantification and an application of parametric Rietveld refinement using time, temperature and relative humidity as ‘non-crystallographic’ parameters Padrão interno para quantificação de fármacos amorfos e uma aplicação do refinamento de Rietveld paramétrico usando tempo, temperatura e umidade relativa como parâmetros “não cristalográficos” Thesis submitted to Institute of Chemistry, of Paulista State University, as part of the requirements for obtaining the PhD degree in Chemistry Supervisor: Carlos de Oliveira Paiva Santos Araraquara 2014 FICHA CATALOGRÁFICA Nunes, Rafael Silva N972i Internal standard for amorphous pharmaceuticals products quantification and an application of Parametric Rietveld refinement using time, temperature and relative humidity as ‘non-crystallographic’ parameters = Padrão interno para quantificação de fármacos amorfos e uma aplicação do refinamento de Rietveld paramétrico usando tempo, temperatura e umidade relativa como parâmetros ‘não cristalográficos’/ Rafael Silva Nunes. – Araraquara : [s.n], 2014 116 p. : il. Tese (doutorado) – Universidade Estadual Paulista, Instituto de Química Orientador: Carlos de Oliveira Paiva Santos 1. Físico-química. 2. Norfloxacino. 3. Refinamento de Rietveld paramétrico. 4. Fármacos. 5. Amorfos. I. Título. Elaboração: Diretoria Técnico de Biblioteca e Documentação do Instituto de Química de Araraquara Seção Técnica de Aquisição e Tratamento da Informação Curriculum data Name: Rafael Silva Nunes email address: rafael.silvanunes@gmail.com 2010-2014 PhD degree in Chemistry. Universidade Estadual Paulista Júlio de Mesquita Filho, UNESP, Sao Paulo, Brazil with Sandwich Doctorate in Durham University (Supervisor: John S. O. Evans) Supervisor: Carlos de Oliveira Paiva Santos Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo Complementary Education 2013 - 2013 Short Term Course in: Local structure of crystalline materials using PDF. The University of Warwick, Warwick, England Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo 2013 - 2013 Short Term Course: International Workshop on Powder & Electron Crystallography (Protein). University of Patras, Rio, Greece Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo 2012 - 2012 Short Term Course: Powder Diffraction & Rietveld Refinement School. Durham University, Durham, England Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo 2011 - 2011 Short Term Course: 7th TOPAS Course, Bruker Corporation, Bruker, Germany Sydney, Australia Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo 2011 - 2011 Short Term Course in: Aplicações da teoria de grafos à cristalografia. Universidade de São Paulo, Sao Paulo, Brazil 2010 - 2010 Short Term Course: Workshop on Representation Theory of Space Groups. Universidade de la Republica do Uruguai, Montevideo, Uruguay Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo 2010 - 2010 Short Term Course: International School on Fundamental Crystallograph. Universidad de la Republica Uruguay, Montevideo, Uruguay Scholarship from: Fundação de Amparo à Pesquisa do Estado de São Paulo Professional Experience Universidade Estadual Paulista Júlio de Mesquita Filho 2011 - 2011 Contract: Bolsista Didático , Position: Bolsista , Working hours (weekly): 4, Schemes of job: Part-time 2011 - 2011 Contract: Bolsista Didático , Position: Bolsista , Working hours (weekly): 4, Schemes of job: Part-time Projects 2012 Preparation of a standard material for quantification of amorphous in crystalline drug without knowledge of the crystal structure. Description: Research propose to Brazilian Synchrotron (LNLS), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Members: Rafael Silva Nunes, Fabiano Yokaichiya, Margareth Kazuyo Kobayashi Dias Franco, Fabio Furlan Ferreira, Carlos O. Paiva Santos (responsible). 2013 Characterization of compounds with transition metals triethanolamine. Description: Research propose to Brazilian Synchrotron (LNLS), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Members: Rafael Silva Nunes, Selma Gutierrez Antonio, Carlos O. Paiva Santos, Stanlei Ivair Klein (responsible). Other activities 2010 a 2011 Alternate student representative of Board of Departamento de Físico-química, Universidade Estadual Paulista, Araraquara, Brazil. Scientific production Papers published in journals 1. Nunes, R. S., Fontoura, A. F. M., Canova, H. F., Yokaichiya, F., Franco, M. K. K. D., Paiva- Santos, Carlos O., Evans, John S. O. TUCANO: in situ experiments using x-ray powder diffraction at LNLS with temperature and relative humidity control, Journal of Synchrotron Radiation 2. Nunes, R. S., Evans, J. S. O., Paiva-Santos, C. O. Internal standard for pharmaceuticals products I: amorphous quantification at room temperature, Journal of Applied Crystallography 3. Nunes, R. S., Eliziario, S. A., Paiva-Santos, C. O., Evans, J. S. O. Internal standard for pharmaceuticals products II: in situ amorphous quantification, Journal of Applied Crystallography 4. Nunes, R. S., Paiva-Santos, C. O., Evans, J. S. O. Internal standard for pharmaceuticals products III: relative humidity application, Journal of Applied Crystallography Published works in events 1. Nunes, R. S., Fontoura, A. F. M., Evans, J. S. O., Canova, H. F., Scherer, J. A., Paiva-Santos, C. O., Yokaichiya, F., Franco, M. K. K. D. TUCANO: in situ temperature- humidity-controlled experiments using powder X-ray diffraction at LNLS. In: 24th Annual Users Meeting of LNLS/CNPEM, 2014, Campinas, Brazil. 2. Nunes, R. S., Evans, J. S. O., Paiva-Santos, C. O. Internal standard for amorphous quantification of pharmaceuticals. In: 28th European Crystallography Meeting, 2013, Warwick, United Kingdom. 3. Nunes, R. S., Sabino, J. R., Lima, E. C. O., Franco Junior, A. Application of Rietveld analysis to determine cations distribution in cobalt ferrite by X-ray dispersion effects. In: 21st Annual Users Meeting of LNLS/CNPEM, 2011, Campinas, Brazil. 4. Nunes, R. S., Paiva-Santos, C. O. Aplicar ou não aplicar a correção de Brindley? In: I Encontro dos Usuários de Técnicas de Difração da CEM, Santo Andre, Brazil. 5. Nunes, R. S., Sabino, J. R., Lima, E. C. O., Franco Junior, A. Cations distribution in ferrites by Rietveld analysis. In: Australian X-ray Analytical Association Workshops, Conference and Exhibition, 2011, Sydney, Australia. 6. Nunes, R. S., Antonio, S. G., Maia, N., Paiva-Santos, C. O. Lithium carbonate as internal standard. In: Australian X-ray Analytical Association Workshops, Conference and Exhibition, 2011, Sydney, Australia. 7. Nunes, R. S., Antonio, S. G., Maia, N., Paiva-Santos, C. O. Standard material for quantification of amorphous in pharmaceuticals. In: 20th Reunião da Associação Brasileira de Cristalografia, 2011, Campinas, Brazil. 8. Nunes, R. S., Bezzon, V. D. N., Ruiz, M. Inserção do software Mercury no ensino de cristalografia como recurso didático motivador. In: IX Evento de Educação em Química, 2011, Araraquara, Brazil. 9. Nunes, R. S., Sabino, J. R., Lima, E. C. O., Franco Junior, A. Application of Rietveld analysis to determine cations distribution in cobalt ferrite and magnesium ferrite. In: International School on Fundamental Crystallography, 2010, Montevideo, Uruguay. Presentation of lectures 1. Nunes, R. S., Evans, J. S. O., Paiva-Santos, C. O. Internal standard for amorphous quantification of pharmaceuticals; European Young Crystallographers Satellite Meeting, 2013. University of Warwick, Warwick, United Kingdom. 2. Nunes, R. S. Além das aplicações clássicas da difração de raios x por pó, Seminário Geral, 2012. Universidade Estadual Paulista, UNESP, Araraquara, Brazil. Participation in events 24th Annual Users Meeting of LNLS/CNPEM, March 11th-12th 2014, Campinas, Brazil. 28th European Crystallography Meeting, August 25th-29th 2013, Warwick, United Kingdom. 1st European Young Crystallographers Satellite Meeting, August 25th 2013, Warwick, United Kingdom. 22nd Annual Users Meeting of LNLS/CNPEM, February 28th-29th 2012, Campinas, Brazil. I Encontro dos Usuários de Técnicas de Difração da CEM, December 7th-8th 2011, Santo Andre, Brazil. 20th Reunião da Associação Brasileira de Cristalografia, February 24th-25th 2011, Campinas, Brazil. 21st Annual Users Meeting of LNLS/CNPEM, February 22nd-23rd 2011, Campinas, Brazil. Australian X-ray Analytical Association Workshops, Conference and Exhibition, February 6th- 11th 2011, Sydney, Australia. To my wife, my mother and my father. Acknowledgments I am grateful to all energy produced by these 4 years of PhD. Positive or negative, all evolution during this time was due to its influence; To Professor Carlos Paiva, for the opportunity to work with him (the greatest Brazilian reference in XRPD), for the unforgettable gastronomic experiences and for support my ideas; To Professor John Evans, for the greatest science discussions (classes) we’ve had and for the opportunity of learn the Parametric Rietveld method, created by him; To my beloved wife Sayonara, the greatest witness of all the difficulties and achievements during these four years and, of course, for all patience; To my family, grandparents (Marlene, Adélia and Waldivino), mother (Cristina), father (Reinaldo), brothers and sister (Rômulo, Ana and Felipe), cousin/brother (Gabriel), cousins (Brenda, Tom Jr., Fernanda, Lorena, Thais, Diego, Flávia, Flora and Luana), uncles/aunts (Ricardo, Paula, Marystela, Thomas, Marisilva, Peter, Marilene and Tom), nephews and niece (Samuel, João Vitor, Letícia and João Lucas), mother-in-law/father-in-law (Socorro and Pedro) and sisters-in-law/brother-in-law (Mariana, Aline, Érika, Quéginho and Giogio). The simple fact of their presence in my life is responsible for giving me the strength to continue my climb; To special friends present in these 4 years: Zé, Luna, Mike, Juninho, Gisele, Tarek, Mailer (in memory), Tiago, Brennda, Ludmilla, Bel and Luiz; To great friend physicists: Udson, Anderson and Tião, and all members of the "Fisicachaça forever"; To my friends in United Kingdom: Raminder, Luiza, Alec, Ivana Evans, Andrew, Mikaëlle, Matt, Chuang Hai and Victoria. To Chemistry Institute, IQ-UNESP, for the great support to the development of science in Brazil; To groups Liec, IRE/JSOE and Labcacc (Diego, Neide, Simone and Selma) for all support during these 4 years; To Vinicius, for been an unexpected friend in a hard time and for all help when necessary; To LNLS due a key contribution in this project, especially Dr. Fabiano Yokaichiya, Dra. Cristiane Rodella and technician Adalberto Fontoura; And last but not least, to FAPESP for the financial support to my PhD degree in Brazil and during the time in UK. "Man is the measure of all things: of things which are, that they are, and of things which are not, that they are not." Protagoras (490 BC – 420 BC) Abstract Recent studies on solid polycrystalline drugs by x-ray powder diffraction (XRPD) in Brazil, has demonstrated how important this technique can be, especially joined to Rietveld method, for structural understanding of these materials. Amorphous material has a higher internal energy than crystalline materials, what alters their therapeutic effects and it makes of amorphous quantification an important study. As an internal standard with international recognition for this purpose, such as NIST SRM-676a (Al2O3), can be economically unviable, a systematic characterization, mainly by XRPD, of a cheap material with liner coefficient absorption of same order of this organic products, to use as internal standard for quantitative phase analysis was made. Good results obtained with LiF, as internal standard, for amorphous pharmaceutical quantification at room temperature, shows its potential for a large-scale application (when compared to results obtained using NIST standard SRM-676a, considering microabsorption effect). Other important focus of this work was in situ XRPD applied to pharmaceutical products and had as highlights: a chamber called TUCANO, to use relative humidity in experiments of in situ XRPD, developed with cooperation of Brazilian Synchrotron Light Source (LNLS); the Parametric Rietveld refinement, pioneered applied in Brazil; the first use of relative humidity as ‘non-crystallographic’ parameter in this refinement; and the application of internal standards (SRM-676a and LiF) during experiments in function of time (at constant temperature), temperature and relative humidity (RH). Norfloxacin (NF, C16H18FN3O3), has a high structural susceptibility to RH and after crystallization of Norfloxacin sesquihydrate form (the only with known crystal structure) starts, at high RH, the behaviour of its cell parameters were parameterized to obtain a smoothly behaviour between all powder patterns collected during RH variation (0% < RH < 96%), consequently, it was possible to correct the value of the relative humidity really felt by the drug during the experiment and the behaviour of this RH correction seems to fit well to a natural logarithm function. To Mebendazole (MBZ, C16H13N3O3), also used during amorphous quantification at room temperature, a kinetic study, using Arrhenius plot, from powder patterns collected in function of time at different temperatures between 130°C and 160°C, compare the activate energy calculated, for transformation of Form C to Form A, using sequential Rietveld refinement and Parametric Rietveld refinement, with and without amorphous quantification (LiF as internal standard). This comparison demonstrates the better efficiency of Parametric refinement and shows how can be the influence of consider amorphous quantification during a kinetic study of a phase transition, which for MBZ a small difference was calculated. A recrystallization of Mebendazole Form B in Ethyl acetate, described in literature, allowed a better exploration of its structural behaviour as a function of temperature and a new crystal structure, crystallized from Form B transformation, was observed. Because of this new crystal structure and due amorphous generation during Form C transformation, new possibilities of MBZ polymorphic map were proposed. Resumo Os estudos recentes sobre fármacos sólidos por difração de raios X por pó (DRXP) no Brasil vem demonstrando o quão importante pode ser esta técnica, principalmente aliada ao método de Rietveld, para a compreensão estrutural destes materiais. Materiais amorfos tem uma energia interna maior que a energia interna de materiais cristalinos. Isto pode influenciar diretamente o efeito terapêutico de um medicamento, e isto faz da quantificação de amorfo um estudo importante. Como a utilização de um padrão com reconhecimento internacional, como o padrão NIST SRM-676a (Al2O3), pode ser economicamente inviável, foi feito uma caracterização sistemática, principalmente por DRXP, de um material barato e com coeficiente de absorção linear dos raios X da ordem destes produtos orgânicos, a ser usado como padrão interno em análises quantitativas de fases. Os bons resultados obtidos com LiF, como padrão interno, na quantificação de amorfo à temperatura ambiente, mostrou seu potencial para uma aplicação em larga escala (quando comparados aos obtidos pelo padrão NIST SRM-676a, considerando o efeito de microabsorção). Outro importante foco deste trabalho foi a DRXP in situ aplicada aos produtos farmacêuticos e teve como destaques: uma câmara chamada TUCANO, para aplicar umidade relativa em experimentos de difração de raios x por pó in situ, desenvolvida em colaboração com o Laboratório Nacional de Luz Síncrotron (LNLS); a aplicação, pioneira no Brasil, do refinamento de Rietveld Paramétrico e o primeiro uso da umidade relativa como parâmetro “não cristalográfico” neste refinamento; e aplicação dos padrões internos (SRM- 676a e LiF) em experimentos em função do tempo (com temperatura constante), temperatura e umidade relativa (UR). Norfloxacino (NF, C16H18FN3O3), possui uma alta suscetibilidade estrutural à umidade relativa e depois da cristalização da forma sesquihidratada do Norfloxacino (única estrutura cristalina conhecida) começa, em alta UR, o comportamento dos seus parâmetros de rede foram parametrizados para obter um comportamento suave entre todos os difratogramas coletados durante a variação da UR (0% < UR < 96%), consequentemente, foi possível corrigir o valor da umidade relativa realmente sentida pelo fármaco durante o experimento e o comportamento desta correção da UR parece se ajustar bem à uma função de logaritmo natural. Para o Mebendazol (MBZ, C16H13N3O3), também utilizado na quantificação http://en.wikipedia.org/wiki/Carbon http://en.wikipedia.org/wiki/Hydrogen http://en.wikipedia.org/wiki/Nitrogen http://en.wikipedia.org/wiki/Oxygen de amorfo à temperatura ambiente, um estudo cinético, usando a equação de Arrhenius, a partir dos difratogramas coletados em função do tempo em diferentes temperaturas entre 130°C e 160°C, compara a energia de ativação calculada para transformação da Forma C em Forma A, usando o refinamento de Rietveld sequencial e o refinamento de Rietveld Paramétrico, com e sem quantificação de amorfo (LiF como padrão interno). Esta comparação demostra a melhor eficiência do refinamento Paramétrico e mostra como pode ser a influência de considerar a quantificação de amorfo durante um estudo cinético de transição de fase, que para o MBZ uma pequena diferença foi calculada. Uma recristalização do Mebendazol Forma B em acetato de etila, descrito na literatura, permitiu uma melhor exploração do seu comportamento estrutural em função da temperatura e uma nova estrutura cristalina foi observada. Por causa desta nova estrutura cristalina e devido a formação de amorfo durante a transformação da Forma C, novas possibilidades de mapa polimórfico do MBZ são propostos. List of figures Figure 2.1: Cubic morphology of LiF with particle size distribution……………………………...…….9 Figure 2.2: Li2CO3 morphology with many defects in its surface layer and size distribution……………9 Figure 2.3: α-Al2O3 with particle size distribution……………………………….…………………….10 Figure 2.4: Microabsorption effect on mixtures of: a) LiF/SRM-676a (errors bars are smaller than plotted points); b) LiF/Al2O3.; c) Error on assuming LiF 100% crystalline…………………………….12 Figure 2.5: a) QPA behaviour of mixtures SRM-676a/Li2CO3 (errors bars are smaller than plotted points); b) Amorphous quantity in 100% of Li2CO3 for each ratio of mixtures with SRM-676a collected in D8, RINT2000 and LNLS…………………………………………………………………………...13 Figure 2.6: Interaction test at room temperature, for mixtures: (a) MBZ/LiF (50/50) and (b) MBZ/Li2CO3 (50/50) using XRD in function of time collected over 10 hours…………………………14 Figure 2.7: a) Amorphous quantification from internal standard method in samples with 50% LiF + x% (C8H8)n + (50 – x)% MBZ (error bars are smaller than plotted points); b) MBZ amorphous quantified in each mixture……………………………………………………………………………………………16 Figure 3.1: Schematic of the furnace with its electronic and gas flow connections…………………….20 Figure 3.2: (a) Schematic draw of constituents of sample holder support; (b) Schematic draw of components inside the chamber………………………………………………………………………...21 Figure 3.3: Heating simulation of the sample holder from 25 °C to 250 °C: (a) time = 0.0 s; (b) time = 1.5 s; (c) time = 3.0 s; (d) time= 7.0 s…………………………………………………………………...22 Figure 3.4: Rietveld refinement of Al2O3 recorded at 28 °C from TUCANO’s set-up. Observed data is in black, calculated in red, difference in grey…………………………………………………………...23 Figure 3.5: (a) Comparison between cell volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement with Taylor volume expected for each temperature; (b) Difference of temperature (TA - TS) behaviour due temperature applied……………………………….24 Figure 3.6: Maximum RH achievable as a function of true sample temperature……………………….25 Figure 3.7: Deliquescence effect of NaCl observed at RH = 90%, T = 28 °C…………………………..26 Figure 3.8: a) Deliquescence effect of NaCl observed from rise in background; b) NaCl scale factor behaviour from Rietveld refinement……………………………………………………………………27 Figure 4.1: a) Neutral anhydrous Norfloxacin; b) Zwitterionic hydrate Norfloxacin..………………...29 Figure 4.2: Rietveld analysis of SRM676a/NF-API without identify any crystal structure already known…………………………………………………………………………………………………..31 Figure 4.3: SRM-676a/NF data set plotted in 2D-film and 3D………………………………………...32 Figure 4.4: Comparison between first scan and the last scan of each cycle during RH variation (RH going up and going down), in sequence………………………………………………………………...32 Figure 4.5: a) Comparison between NF sesquihydrate volumes calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) RHC behaviour in function of RHA fitted by a natural logarithm function…………………………………………………………..33 Figure 4.6: LiF/NF API data set plotted in 2D-film and 3D……………………………………………34 Figure 4.7: Comparison between first scan and the last scan of each cycle during RH variation (RH going up and going down), in sequence…………………………………………………...……………34 Figure 4.8: a) Comparison between NF sesquihydrate volumes calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) RHC behaviour in function of RHA fitted by a natural logarithm function………………………………………………...………...35 Figure 4.9: LiF/NF API data set (4% ≤ RH ≤ 97%) plotted in 2D-film and 3D………………………...35 Figure 4.10: Comparison between first scan and the last scan of each cycle during RH variation (RH going up and going down), in sequence. for LiF/NF API data set (4% ≤ RH ≤ 97% ).………………………………………………………………………………..……36 Figure 4.11: a) Comparison between NF sesquihydrate volumes calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) RHC behaviour in function of RHA fitted by a natural logarithm function…………………………………………………………..36 Figure 4.12: LiF/NF tablet data set plotted in 2D-film and 3D………………………………………...37 Figure 4.13: Comparison between first scan and the last scan of each cycle during RH variation (RH going up and going down), in sequence for LiF/NF tablet data set……….……………..……………...38 Figure 4.14: a) Comparison between NF sesquihydrate volumes calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) RHC behaviour in function of RHA fitted by a natural logarithm function…………………………………………………………..38 Figure 5.1: Flat isomerism between Mebendazole form C and Mebendazole form A…………………40 Figure 5.2: Mebendazole packing: a) form C along a axis; b) form A along a axis…………………….41 Figure 5.3: Comparison between XRD patterns of form B……………………………………………43 Figure 5.4: Comparison between TG curves of pure samples and mixture samples: (a) MBZA; (b) MBZC…...………………………………………………………………………………………….46 Figure 5.5: Comparison between DSC curves of pure samples and mixture samples: (a) MBZA; (b) MBZC…...………………………………………………………………………………………….47 Figure 5.6: Comparison between quantitative phase analysis by sequential Rietveld refinement: a) without amorphous quantification; b) with amorphous quantification…………………………………48 Figure 5.7: Natural logarithm of MBZC quantity in function of time for temperatures from 130°C to 160°C with respective linearity factor, R2: a) MBZC without correction; b) MBZC corrected by amorphous quantification………………………………………………………………………………49 Figure 5.8: Arrhenius plot for transformation of Mebendazole form C corrected (black) or not (red), by the amorphous quantity………………………………………………………………………………...49 Figure 5.9: Comparison between quantitative phase analysis by parametric Rietveld refinement: a) without amorphous quantification; b) with amorphous quantification…………………………………50 Figure 5.10: Natural logarithm of MBZC quantity (from parametric Rietveld refinement) in function of time for temperatures from 130°C to 160°C with respective linearity factor, R2: a) MBZC without correction; b) MBZC corrected by amorphous quantification………………………………………….50 Figure 5.11: Arrhenius plot for transformation of Mebendazole form C, quantified from parametric Rietveld refinement, corrected (black) or not (red), by the amorphous quantity………………………..51 Figure 5.12: Mebendazole form B recrystallized from Ethyl acetate at room temperature…………….52 Figure 5.13: Form B phase transformation with geometry in transmission mode…………………….53 Figure 5.14: Form B phase transformation with geometry in flat mode………………………………..54 Figure 5.15: MBZ polymorphic map according MBZB phase transition obtained in experiment with transmission mode……………………………………………………………………………………...54 Figure 5.16: MBZ polymorphic map according MBZB phase transition obtained in experiment with flat mode……………………………………………………………………………………………….55 Figure 5.17: MBZ polymorphic map according MBZB phase transition obtained by Villiers and co- workers…………………………………………………………………………………………………55 Figure A.1: Graphical Rietveld refinement obtained on data ‘d7_03348’ for mixture Al2O3/LiF (85/15). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………67 Figure A.2: Graphical Rietveld refinement obtained on data ‘d7_03350’ for mixture Al2O3/LiF (70/30). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………67 Figure A.3: Graphical Rietveld refinement obtained on data ‘d7_03352’ for mixture Al2O3/LiF (60/40). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………67 Figure A.4: Graphical Rietveld refinement obtained on data ‘d7_03344’ for mixture Al2O3/LiF (50/50). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………68 Figure A.5: Graphical Rietveld refinement obtained on data ‘d7_03354’ for mixture Al2O3/LiF (40/60). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………68 Figure A.6: Graphical Rietveld refinement obtained on data ‘d7_03356’ for mixture Al2O3/LiF (30/70). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………68 Figure A.7: Graphical Rietveld refinement obtained on data ‘d7_03358’ for mixture Al2O3/LiF (15/85). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………69 Figure A.8: Graphical Rietveld refinement obtained on data ‘d7_04585’ for mixture SRM-676a/LiF (95/5). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………73 Figure A.9: Graphical Rietveld refinement obtained on data ‘d7_04920’ for mixture SRM-676a/LiF (85/15). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..74 Figure A.10: Graphical Rietveld refinement obtained on data ‘d7_04625’ for mixture SRM-676a/LiF (70/30). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..74 Figure A.11: Graphical Rietveld refinement obtained on data ‘d7_04997’ for mixture SRM-676a/LiF (60/40). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..74 Figure A.12: Graphical Rietveld refinement obtained on data ‘d7_04656’ for mixture SRM-676a/LiF (50/50). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..75 Figure A.13: Graphical Rietveld refinement obtained on data ‘d7_05016’ for mixture SRM-676a/LiF (40/60). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..75 Figure A.14: Graphical Rietveld refinement obtained on data ‘d7_04658’ for mixture SRM-676a/LiF (30/70). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..75 Figure A.15: Graphical Rietveld refinement obtained on data ‘d7_05040’ for mixture SRM-676a/LiF (15/85). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..76 Figure A.16: Graphical Rietveld refinement obtained on data ‘d7_05044’ for mixture SRM-676a/LiF (5/95). Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………..76 Figure A.17: Graphical Rietveld refinement obtained on data ‘d7_05177’ for mixture SRM- 676a/Li2CO3 (85/15). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………………………………………………………………………………………84 Figure A.18: Graphical Rietveld refinement obtained on data ‘d7_04730’ for mixture SRM- 676a/Li2CO3 (70/30). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………84 Figure A.19: Graphical Rietveld refinement obtained on data ‘d7_05116’ for mixture SRM- 676a/Li2CO3 (60/40). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………84 Figure A.20: Graphical Rietveld refinement obtained on data ‘d7_04733’ for mixture SRM- 676a/Li2CO3 (50/50). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………85 Figure A.21: Graphical Rietveld refinement obtained on data ‘d7_05132’ for mixture SRM- 676a/Li2CO3 (40/60). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………85 Figure A.22: Graphical Rietveld refinement obtained on data ‘d7_04740’ for mixture SRM- 676a/Li2CO3 (30/70). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………85 Figure A.23: Graphical Rietveld refinement obtained on data ‘d7_05159’ for mixture SRM- 676a/Li2CO3 (15/85). Blue dots – observed data; red curve – calculated data; grey curve – residual…………………………………………………………………………………………………86 Figure B.1: Graphical Rietveld refinement obtained on data ‘d7_04801’ for mixture SRM-676a/MBZ. Blue dots – observed data; red curve – calculated data; grey curve – residual curve……………………93 Figure B.2: Graphical Rietveld refinement obtained on data ‘d7_04902’ for mixture Li2CO3/MBZ. Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………………………93 Figure B.3: Graphical Rietveld refinement obtained on data ‘d7_04894’ for mixture LiF/MBZ. Blue dots – observed data; red curve – calculated data; grey curve – residual curve…………………………94 Figure B.4: Graphical Rietveld refinement obtained on data ‘d7_05197’ for mixture LiF/MBZ/(C8H8)n (50/45/5). Blue dots – observed data; red curve – calculated data; grey curve – residual curve………...98 Figure B.5: Graphical Rietveld refinement obtained on data ‘d7_05198’ for mixture LiF/MBZ/(C8H8)n (50/40/10). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……….99 Figure B.6: Graphical Rietveld refinement obtained on data ‘d7_05202’ for mixture LiF/MBZ/(C8H8)n (50/35/15). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……….99 Figure B.7: Graphical Rietveld refinement obtained on data ‘d7_05205’ for mixture LiF/MBZ/(C8H8)n (50/30/20). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……….99 Figure B.8: Graphical Rietveld refinement obtained on data ‘d7_05212’ for mixture LiF/MBZ/(C8H8)n (50/25/25). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……...100 Figure B.9: Graphical Rietveld refinement obtained on data ‘d7_05213’ for mixture LiF/MBZ/(C8H8)n (50/20/30). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……...100 Figure B.10: Graphical Rietveld refinement obtained on data ‘d7_05219’ for mixture LiF/MBZ/(C8H8)n (50/15/35). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……...100 Figure B.11: Graphical Rietveld refinement obtained on data ‘d7_05220’ for mixture LiF/MBZ/(C8H8)n (50/10/40). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……...101 Figure B.12: Graphical Rietveld refinement obtained on data ‘d7_05221’ for mixture LiF/MBZ/(C8H8)n (50/5/45). Blue dots – observed data; red curve – calculated data; grey curve – residual curve……….101 Figure C.1: a) Comparison between lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement with Taylor equation for each temperature; b) Comparison between lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement with Taylor equation for each temperature………………………………………103 Figure C.2: a) Comparison between cell volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement with Taylor equation for each temperature; b) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement with Taylor equation………………………………………………………………….......103 Figure C.3: Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement with Taylor equation…………………………………………………………….104 Figure C.4: All graphical Rietveld refinements obtained on SRM-676a heating from 33 °C up to 25°C. Black curve– all observed data; red curve – all calculated data; grey curve – all residual curves……...104 Figure C.5: Graphical Rietveld refinements obtained on SRM-676a at 33 °C. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………105 Figure C.6: Graphical Rietveld refinements obtained on SRM-676a at 114 °C. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………105 Figure C.7: Graphical Rietveld refinements obtained on SRM-676a at 173 °C. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………105 Figure C.8: Graphical Rietveld refinements obtained on SRM-676a at 232 °C. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………106 Figure C.9: Graphical Rietveld refinements obtained on SRM-676a at 250 °C. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………106 Figure D.1: a) Comparison between NF sesquihydrate lattice parameter ‘a’, in sample SRM-676a/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘b’, in sample SRM-676a/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….108 Figure D.2: a) Comparison between NF sesquihydrate lattice parameter ‘c’, in sample SRM-676a/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘beta’, in sample SRM- 676a/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………...108 Figure D.3: a) Comparison between NF sesquihydrate volume, in sample SRM-676a/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate phase, in sample SRM-676a/NF, calculated by sequential Rietveld refinement and surface Rietveld refinement…………………………………………………109 Figure D.4: a) Comparison between Rwp (%) obtained, for SRM-676a/NF sample, by sequential Rietveld refinement and surface Rietveld refinement; b) Comparison between gof obtained, for SRM- 676a/NF sample, by sequential Rietveld refinement and surface Rietveld refinement………………..109 Figure D.5: All graphical Rietveld refinements obtained for SRM-676a/NF during RH variation. Black curve– all observed data; red curve – all calculated data; grey curve – all residual curves…………….110 Figure D.6: Graphical Rietveld refinements obtained for SRM-676a/NF at RH = 97%. Blue curve – observed data; red curve – calculated data; grey curve – residual curve………………………………110 Figure D.7: Graphical Rietveld refinements obtained for SRM-676a/NF at RH = 95%. Blue curve – observed data; red curve – calculated data; grey curve – residual curve………………………………110 Figure D.8: Graphical Rietveld refinements obtained for SRM-676a/NF at RH = 3%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………111 Figure D.9: Graphical Rietveld refinements obtained for SRM-676a/NF at RH = 91%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………111 Figure D.10: Graphical Rietveld refinements obtained for SRM-676a/NF at RH = 3%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………111 Figure D.11: a) Comparison between NF sesquihydrate lattice parameter ‘a’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘b’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….112 Figure D.12: a) Comparison between NF sesquihydrate lattice parameter ‘c’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘beta’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….112 Figure D.13: a) Comparison between NF sesquihydrate volume, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate phase, in sample LiF/NF, calculated by sequential Rietveld refinement and surface Rietveld refinement…………………………………………………………..113 Figure D.14: a) Comparison between Rwp (%) obtained, for LiF/NF sample, by sequential Rietveld refinement and surface Rietveld refinement; b) Comparison between gof obtained, for LiF/NF sample, by sequential Rietveld refinement and surface Rietveld refinement…………………………………..113 Figure D.15: All graphical Rietveld refinements obtained for LiF/NF during RH variation. Black curve– all observed data; red curve – all calculated data; grey curve – all residual curves…………………….114 Figure D.16: Graphical Rietveld refinements obtained for LiF/NF at RH = 82%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..114 Figure D.17: Graphical Rietveld refinements obtained for LiF/NF at RH = 52%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..114 Figure D.18: Graphical Rietveld refinements obtained for LiF/NF at RH = 68%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..115 Figure D.19: Graphical Rietveld refinements obtained for LiF/NF at RH = 72%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..115 Figure D.20: Graphical Rietveld refinements obtained for LiF/NF at RH = 8%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..115 Figure D.21: a) Comparison between NF sesquihydrate lattice parameter ‘a’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘b’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….116 Figure D.22: a) Comparison between NF sesquihydrate lattice parameter ‘c’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘beta’, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….116 Figure D.23: a) Comparison between NF sesquihydrate volume, in sample LiF/NF, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate phase, in sample LiF/NF, calculated by sequential Rietveld refinement and surface Rietveld refinement…………………………………………………………..117 Figure D.24: a) Comparison between Rwp (%) obtained, for LiF/NF sample, by sequential Rietveld refinement and surface Rietveld refinement; b) Comparison between gof obtained, for LiF/NF sample, by sequential Rietveld refinement and surface Rietveld refinement…………………………………..117 Figure D.25: All graphical Rietveld refinements obtained for LiF/NF during RH variation. Black curve– all observed data; red curve – all calculated data; grey curve – all residual curves…………………….118 Figure D.26: Graphical Rietveld refinements obtained for LiF/NF at RH = 96%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..118 Figure D.27: Graphical Rietveld refinements obtained for LiF/NF at RH = 94%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..118 Figure D.28: Graphical Rietveld refinements obtained for LiF/NF at RH = 63%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..119 Figure D.29: Graphical Rietveld refinements obtained for LiF/NF at RH = 4%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..119 Figure D.30: Graphical Rietveld refinements obtained for LiF/NF at RH = 89%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………..119 Figure D.31: a) Comparison between NF sesquihydrate lattice parameter ‘a’, in sample LiF/NF tablet, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘b’, in sample LiF/NF tablet, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….120 Figure D.32: a) Comparison between NF sesquihydrate lattice parameter ‘c’, in sample LiF/NF tablet, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate lattice parameter ‘beta’, in sample LiF/NF tablet, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement…………………………………………………………………………………………….120 Figure D.33: a) Comparison between NF sesquihydrate volume, in sample LiF/NF tablet, calculated by sequential Rietveld refinement (in function of RHA and RHC) and surface Rietveld refinement; b) Comparison between NF sesquihydrate phase, in sample LiF/NF tablet, calculated by sequential Rietveld refinement and surface Rietveld refinement…………………………………………………121 Figure D.34: a) Comparison between Rwp (%) obtained, for LiF/NF tablet sample, by sequential Rietveld refinement and surface Rietveld refinement; b) Comparison between gof obtained, for LiF/NF tablet sample, by sequential Rietveld refinement and surface Rietveld refinement…………………...121 Figure D.35: All graphical Rietveld refinements obtained for LiF/NF tablet, during RH variation. Black curve– all observed data; red curve – all calculated data; grey curve – all residual curves…………….122 Figure D.36: Graphical Rietveld refinements obtained for LiF/NF tablet at RH = 95%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………………...…122 Figure D.37: Graphical Rietveld refinements obtained for LiF/NF tablet at RH = 96%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………...122 Figure D.38: Graphical Rietveld refinements obtained for LiF/NF tablet at RH = 93%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………...123 Figure D.39: Graphical Rietveld refinements obtained for LiF/NF tablet at RH = 79%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………...123 Figure D.40: Graphical Rietveld refinements obtained for LiF/NF tablet at RH = 0%. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………………...123 Figure E.1: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………………………………………...125 Figure E.2: a) Comparison between sample amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………...125 Figure E.3: a) Comparison between LiF scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………………...126 Figure E.4: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………...126 Figure E.5: a) Comparison between MBZC scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………...127 Figure E.6: a) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………………………………………………………………127 Figure E.7: a) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……...128 Figure E.8: a) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C…………………………………………………………………………………………………128 Figure E.9: a) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……...129 Figure E.10: a) Comparison between MBZA scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………...129 Figure E.11: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……………………………………………………………………………130 Figure E.12: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……...130 Figure E.13: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C…………………………………………………………………………………………………131 Figure E.14: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C.; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 130°C……...131 Figure E.15: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves……………………..132 Figure E.16: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 14.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..132 Figure E.17: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 29 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..132 Figure E.18: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 43.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..133 Figure E.19: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 58 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..133 Figure E.20: Graphical Rietveld refinements obtained for LiF/MBZ at T = 130 °C and t = 72.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..133 Figure E.21: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………………………………………...134 Figure E.22: a) Comparison between sample amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C………………….134 Figure E.23: a) Comparison between LiF scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C………………………...……135 Figure E.24: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………...135 Figure E.25: a) Comparison between MBZC scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………...136 Figure E.26: a) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………………………………………………………………136 Figure E.27: a) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……...137 Figure E.28: a) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C…………………………………………………………………………………………………137 Figure E.29: a) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……...138 Figure E.30: a) Comparison between MBZA scale factor behaviour calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………...138 Figure E.31: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……………………………………………………………………………139 Figure E.32: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……139 Figure E.33: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C………………………………………………………………………………………………....140 Figure E.34: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C.; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 135°C……...140 Figure E.35: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………..………...141 Figure E.36: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 10 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..141 Figure E.37: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 19.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..141 Figure E.38: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 29.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..142 Figure E.39: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 39 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..142 Figure E.40: Graphical Rietveld refinements obtained for LiF/MBZ at T = 135 °C and t = 48.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..142 Figure E.41: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………………………………………...143 Figure E.42: a) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………………...143 Figure E.43: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………...144 Figure E.44: a) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………………………………………………………………………144 Figure E.45: a) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……...145 Figure E.46: a) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……...145 Figure E.47: a) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………………………………………………………………………………….146 Figure E.48: a) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………...146 Figure E.49: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……………………………………………………………………………147 Figure E.50: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……...147 Figure E.51: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C…………………………………………………………………………………………………148 Figure E.52: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 140°C……...148 Figure E.53: Graphical Rietveld refinements obtained for LiF/MBZ at T = 140 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………......149 Figure E.54: Graphical Rietveld refinements obtained for LiF/MBZ at T = 140 °C and t =11.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..149 Figure E.55: Graphical Rietveld refinements obtained for LiF/MBZ at T = 140 °C and t =23 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..149 Figure E.56: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………………………………………...150 Figure E.57: a) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………………...150 Figure E.58: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………...151 Figure E.59: a) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………………………………………………………………………151 Figure E.60: a) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……...152 Figure E.61: a) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……...152 Figure E.62: a) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………………………………………………………………………………….153 Figure E.63: a) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………...153 Figure E.64: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……………………………………………………………………………154 Figure E.65: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……154 Figure E.66: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C…………………………………………………………………………………………………155 Figure E.67: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 145°C……...155 Figure E.68: Graphical Rietveld refinements obtained for LiF/MBZ at T = 145 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………...156 Figure E.69: Graphical Rietveld refinements obtained for LiF/MBZ at T = 145 °C and t = 22.5 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..156 Figure E.70: Graphical Rietveld refinements obtained for LiF/MBZ at T = 145 °C and t = 45.5 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..156 Figure E.71: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………………………………………...157 Figure E.72: a) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………………...157 Figure E.73: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………...158 Figure E.74: a) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………………………………………………………………………158 Figure E.75: a) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……...159 Figure E.76: a) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……...159 Figure E.77: a) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………………………………………………………………………………….160 Figure E.78: a) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………...160 Figure E.79: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……………………………………………………………………………161 Figure E.80: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……..161 Figure E.81: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C…………………………………………………………………………………………………162 Figure E.82: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 150°C……...162 Figure E.83: Graphical Rietveld refinements obtained for LiF/MBZ at T = 150 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………...…...163 Figure E.84: Graphical Rietveld refinements obtained for LiF/MBZ at T = 150 °C and t = 13 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..163 Figure E.85: Graphical Rietveld refinements obtained for LiF/MBZ at T = 150 °C and t = 26.5 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..163 Figure E.86: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………………………………………...164 Figure E.87: a) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………………...164 Figure E.88: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………...165 Figure E.89: a) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………………………………………………………………………165 Figure E.90: a) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……...166 Figure E.91: a) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……...166 Figure E.92: a) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………………………………………………………………………………….167 Figure E.93: a) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………...167 Figure E.94: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……………………………………………………………………………168 Figure E.95: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……...168 Figure E.96: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C…………………………………………………………………………………………………169 Figure E.97: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 155°C……...169 Figure E.98: Graphical Rietveld refinements obtained for LiF/MBZ at T = 155 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………...170 Figure E.99: Graphical Rietveld refinements obtained for LiF/MBZ at T = 155 °C and t = 8 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………...170 Figure E.100: Graphical Rietveld refinements obtained for LiF/MBZ at T = 155 °C and t = 16 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………170 Figure E.101: a) Comparison between Rwp (%) behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between gof behaviour obtained by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………………………………………...171 Figure E.102: a) Comparison between MBZ amorphous quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between LiF phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………...171 Figure E.103: a) Comparison between LiF lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between LiF volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………...172 Figure E.104: a) Comparison between MBZC phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZC phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………………………………………………………………………172 Figure E.105: a) Comparison between MBZC lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZC lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……...173 Figure E.106: a) Comparison between MBZC lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZC lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……...173 Figure E.107: a) Comparison between MBZC lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZC lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………………………………………………………………………………….174 Figure E.108: a) Comparison between MBZC volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZA phase quantification calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………...174 Figure E.109: a) Comparison between MBZA phase quantification corrected by internal standard method and calculated by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZA lattice parameter ‘a’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……………………………………………………………………………175 Figure E.110: a) Comparison between MBZA lattice parameter ‘b’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZA lattice parameter ‘c’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……...175 Figure E.111: a) Comparison between MBZA lattice parameter ‘alpha’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C.; b) Comparison between MBZA lattice parameter ‘beta’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C…………………………………………………………………………………………………176 Figure E.112: a) Comparison between MBZA lattice parameter ‘gamma’ behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C; b) Comparison between MBZA volume behaviour determined by sequential Rietveld refinement and surface Rietveld refinement in function of time, for sample LiF/MBZ at 160°C……...176 Figure E.113: Graphical Rietveld refinements obtained for LiF/MBZ at T = 160 °C and t = 0 hour. Blue curve – observed data; red curve – calculated data; grey curve – residual curves…………………...177 Figure E.114: Graphical Rietveld refinements obtained for LiF/MBZ at T = 160 °C and t = 5.5 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..177 Figure E.115: Graphical Rietveld refinements obtained for LiF/MBZ at T = 160 °C and t = 11 hours. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………..177 Figure F.1: Graphical Pawley fit obtained for MBZB with: Space group P-1, a = 28.738894 Å, b = 9.489889 Å, c = 11.002775 Å, α = 92.65931°, β = 84.45296°, γ = 106.03827°, volume = 2869.864 Å3, Rwp = 4.87%, ,gof = 1.426. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………………………………………………………...178 Figure F.2: Graphical Pawley fit obtained for MBZB with: Space group P-1, a = 29.989282 Å, b = 9.933344 Å, c = 11.002775 Å, α = 90°, β = 98.13515°, γ = 90°, volume = 2585.597Å3, Rwp = 5.91%, ,gof = 1.661. Blue curve – observed data; red curve – calculated data; grey curve – residual curves….179 Figure F.3: Graphical Pawley fit obtained for MBZB with: Space group P2, a = 9.545668 Å, b = 27.465567 Å, c = 10.746676 Å, α = 96.31460°, β = 72.55161°, γ = 75.02921°, volume = 2888.733 Å3, Rwp = 4.90%, ,gof = 1.434. Blue curve – observed data; red curve – calculated data; grey curve – residual curves………………………………………………………………………………………...179 List of tables Table 1.1: World subdivided by WHO into four zones according temperature and relative humidity…..2 Table 2.1: LiF calculated from mixtures with SRM-676a and average Rwp (%) and g.o.f. values from Rietveld analysis for different ratios (30/70; 50/50; 70/30) collected in three different set-ups: D8, RINT2000 and LNLS……………………………………...…………………………………………...11 Table 2.2: Amorphous (%) quantification for Li2CO3 in three different set-ups with average values of Rwp (%) and g.o.f., for data collected in D8, RINT2000 and LNLS……………………………………..13 Table 2.3: Amorphous (%) in Mebendazole, quantified using three different internal standards, Al2O3, LiF and Li2CO3, with respectively Rwp (%) and g.o.f., obtained in each set-up (*Brindley correction).………………………………………………………………………………….………….15 Table 2.4: Amorphous (%) quantified in each sample LiF/MBZ/(C8H8)n and the respective MBZ amorphous (%) calculate……………………………………………………………………………….16 Table 3.1: Summary of the specifications for the chamber described in the text……………………….21 Table 3.2: Gas temperature (TG), relative humidity (RH), applied temperature (TA) and sample temperature (TS)………………………………………………………………………………………..25 Table 5.1: Comparison between cell parameters of form C (Martins et al., 2009) and form A (Ferreira et al., 2010)……………………………………………………………………………………………..41 Table 5.2: Mebendazole form C hydrogen bond geometry (Å, °)…………………………………...…42 Table 5.3: Mebendazole form A hydrogen bond geometry (Å, °)……………………………………...42 Table 5.4: Solubility values of MBZ in different solvents and respective (pseudo)polymorph recrystallized…………………………………………………………………………………………...44 Table 5.5: Thermal events observed from DSC for MBZA pure, LiF/MBZA, MBZC pure and LiF/MBZC (Ti – intial temperature of thermal event, Tf – final temperature of thermal event, Tm – peak position, H – Entalpy variation)…………………………………………………………………..…..47 Table 5.6: Space groups indexed with respective lattice parameters, Rwp(%) and gof values calculated from Pawley method…………………………………………………………………………………...52 Table A.1: 1st data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...63 Table A.2: 1st data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained………………………………………………………………………………………………...63 Table A.3: 2nd data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...64 Table A.4: 2nd data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained………………………………………………………………………………………………...64 Table A.5: 3rd data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...65 Table A.6: 3rd data set for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained………………………………………………………………………………………………...65 Table A.7: Average values for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...66 Table A.8: Average values for Al2O3/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………66 Table A.9: 1st data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...69 Table A.10: 1st data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………70 Table A.11: 2nd data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...70 Table A.12: 2nd data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………71 Table A.13: 3rd data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...71 Table A.14: 3rd data set for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………72 Table A.15: Average values for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………72 Table A.16: Average values for SRM-676a/LiF mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..73 Table A.17: Data set for SRM-676a/LiF mixture, from LNLS (Arara furnace) – atmospheric pressure, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………...76 Table A.18: Data set for SRM-676a/LiF mixture, from LNLS (Arara furnace) – atmospheric pressure, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained………………………………………………………………….77 Table A.19: Data set for SRM-676a/LiF mixture, from LNLS (Arara furnace) – vaccum, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………77 Table A.20: Data set for SRM-676a/LiF mixture, from LNLS (Arara furnace) – vaccum, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..77 Table A.21: Data set for SRM-676a/LiF mixture, from LNLS (Tucano furnace), with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...78 Table A.22: Data set for SRM-676a/LiF mixture, from LNLS (Tucano furnace), with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………78 Table A.23: Average values for SRM-676a/LiF mixture, from LNLS data sets, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………………...78 Table A.24: Average values for SRM-676a/LiF mixture, from LNLS data sets, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained……………………………………………………………………………………………79 Table A.25: Data set for SRM-676a/LiF mixture, from Rigaku RINT2000 equipment, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………………79 Table A.26: Data set for SRM-676a/LiF mixture, from Rigaku RINT2000 equipment, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..79 Table A.27: 1st data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for Li2CO3 phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained…………………………………………………………………………………80 Table A.28: 1st data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for Li2CO3 phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..80 Table A.29: 2nd data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for Li2CO3 phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………….81 Table A.30: 2nd data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for Li2CO3 phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..81 Table A.31: 3rd data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for Li2CO3 phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………….82 Table A.32: 3rd data set for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for Li2CO3 phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..82 Table A.33: Average values for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement, for Li2CO3 phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained………………………………………………………………………………….83 Table A.34: Average values for SRM-676a/Li2CO3 mixture, from Bruker D8 equipment, with values calculated from Rietveld refinement with Brindley correction, for Li2CO3 phase quantification (%) and respective e.s.d. (%) obtained…………………………………………………………………………..83 Table A.35: Data set for SRM-676a/Li2CO3 mixture, from LNLS (Arara furnace) – atmospheric pressure, with values calculated from Rietveld refinement, for LiF phase quantification (%) and respective e.s.d. (%), gof and Rwp (%) obtained……………………………………………………….86 Table A.36: Data set for SRM-676a/Li2CO3 mixture, from LNLS (Arara furnace) – atmospheric pressure, with values calculated from Rietveld refinement with Brindley correction, for LiF phase quantification