Academic literature on the topic 'Polymorphism (crystallography)'

Thesis (Ph.D)--Chemical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Rousseau, Ronald; Committee Member: Meredith, Carson; Committee Member: Prausnitz, Mark; Committee Member: Teja, Amyn; Committee Member: Wilkinson, Angus. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Spectroscopy is increasingly used to investigate and monitor the solid state forms of pharmaceutical materials and products. Spectroscopy�s speed, nondestructive sampling, compatibility with fibre optics and safety also make it attractive for in-line monitoring. In this thesis, the spectroscopic techniques Fourier transform Raman spectroscopy, terahertz pulsed spectroscopy and second harmonic generation were used to characterise and quantify polymorphism and crystallinity of pharmaceutical compounds. Where possible, the multivariate analysis technique partial least squares was used for quantitative analysis. Fourier transform Raman spectroscopy detects polarisability changes mainly associated with molecular vibrations. Terahertz pulsed spectroscopy is a new spectroscopic technique that operates between the infrared and microwave regions of the electromagnetic spectrum and detects dipole moment changes mainly associated with crystalline phonon vibrations in the solid state. Second harmonic generation is a nonlinear optical phenomenon that depends on the dipole moment in crystals and crystal symmetry. Several materials capable of existing in different solid state forms were used. FT-Raman spectroscopy was able to differentiate carbamazepine forms I and III, enalapril maleate forms I and II and γ-crystalline and amorphous indomethacin. Combined with partial least squares the technique could quantify binary mixtures of CBZ forms I and III with a limit of detection as low as 1%, and mixtures of enalapril maleate with a limit of detection of as low as 2%. Terahertz pulsed spectroscopy obtained very different spectra for carbamazepine forms I and III, enalapril maleate forms I and II, γ-crystalline and amorphous indomethacin, crystalline and supercooled thermotropic liquid crystalline fenoprofen calcium, three forms of lactose, and five forms of sulphathiazole. At present the modes in the spectra cannot be attributed to specific phonon modes. Quantitation of binary mixtures of different forms of a compound using partial least squares analysis usually resulted in a limit of detection of about 1%. Second harmonic generation was used to quantify binary mixtures of different forms of enalapril maleate and lactose, as well as binary mixtures of enalapril maleate form II and polyvinylpyrrolidone. A quantitative relationship was present for each of the mixtures, however the limits of detection were usually above 10%. The high value is probably due to the machine being a prototype and univariate analysis associated with a single output variable. Future improvements to the apparatus and measurement parameters are likely to reduce the limits of detection. Ranitidine hydrochloride polymorphs could also be differentiated using second harmonic generation, however γ-crystalline and amorphous indomethacin and forms I and III of carbamazepine could not. The methods used in this thesis were successfully used for qualitative and quantitative analysis of polymorphism and crystallinity of pharmaceutical compounds. TPS and SHG are useful additions to the range of experimental techniques that can be used to investigate and monitor properties of pharmaceutical solids.

Polymorphism can influence every aspect of the properties of a solid including the shelf life, dissolution rate, solubility, formulation properties and processing properties of a solid drug. A deeper understanding of polymorphism and related solid state properties would ensure an improved quality of the materials used throughout drug preparation, dosage form formulation and clinical trials. Therefore, determination of the existence of polymorphs and pseudopolymorphs, characterization of different solid state forms and their respective properties, and controlling the existing form in the resulting formulation all form part of a rapidly growing field within pharmaceutical research and industry. Carbamazepine (CBZ) was the model drug used in this study. FT-Raman spectroscopy was chosen as a main investigative technique in this study to evaluate its potential in monitoring (pseudo)polymorphic conversions in aqueous suspensions in the absence or presence of various pharmaceutical excipients. Partial least squares analysis (PLS) was used for quantitative analysis of the spectral data. Earlier it has been found that CBZ converts rapidly to the dihydrate (DH) when exposed to humidity or water, and this has been reported to be the main reason for the sometimes observed greatly decreased bioavailability of marketed CBZ tablets. In this study, the conversion kinetics of CBZ (forms I, II and III) to DH in aqueous suspension were found to be first order kinetics with an unconverted portion (R� [greater than or equal to] 0.95), where the crystal morphology appeared to play a more important role in its conversion kinetics than the polymorphic form. The influence of pharmaceutical excipients on the conversion of CBZ in aqueous suspension was also explored. For excipients such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) which have both a low solubility parameter (< 27.0 MPa[1/2]) and strong hydrogen bonding groups, complete inhibition of the conversion of CBZ was possible even at a very low concentration (0.1 % w/v). Raman spectroscopy showed its high applicability in investigating CBZ conversion kinetics and screening of excipient effects in aqueous environment. It was demonstrated that Raman has a robust nature in quantitative analysis since problems such as different particle size, morphology, and spatial distribution of the two solid state forms of the drug seemed not to have significant influence on Raman scattering. This study has also clarified the relative importance of many contributing factors (type of crystalline form (CBZ or DH), crystal morphology, surface area, and excipient interactions with drug particles) influencing the in vitro dissolution of CBZ. The solid state characterization approach taken in this study will provide a deeper insight into the dissolution performance of drugs and should thus lead to a better understanding of in vitro/in vivo behavior of drugs.

This thesis describes the effect of pressure on crystal structures that are in some way unusual. The aim was to investigate whether pressure could be used to force these ‘structural oddities’ to conform to more conventional behaviour. In many cases pressure-induced phase transitions were observed, and the driving forces of these are considered. L-serine monohydrate crystallises with layers of hydrogen bonded serine molecules. Layers are linked together by H-bonds from the donor atoms of water molecules. The orientation of the water molecules between the layers is uncommon for other layered hydrates in the CSD. A single crystal of serine hydrate undergoes a pressure-induced phase transition at 5 GPa, which is characterised by a rotation of the water molecules to an orientation which is more frequently observed. PIXEL calculations show that the transition is driven by the PV term in the equation G = U - TS + PV. An attempt to reproduce the transition in another layered hydrate with a similar topology was partially successful in the compression of S-4-sulfo-L-phenylalanine monohydrate, which undergoes a similar phase transition at 1 GPa. Methyl 2-(9H-carbazol-9-yl)benzoate crystallises unusually with eight molecules in the asymmetric unit (Z’ = 8). Compression of a single crystal results in a phase transition at ca. 5 GPa to give a Z’ = 2 polymorph. The PV term is an important contributor to the driving force of the transition. The geometries of the molecules in phase-II are significantly less stable than in phase-I, and as pressure is released on phase-II the need to adopt a more stable molecular conformation eventually outweighs the PV advantage. The Z’ = 8 structure is eventually re-established at 4.6 GPa. This work illustrates how low Z’ polymorphs of the same structure are not always the thermodynamically more stable forms. When recrystallised in situ from a 4:1 by volume solution of methanol and ethanol, a new polymorph of salicylamide is obtained at 0.2 GPa. The ambient pressure phase appears in the CSD to contain a number of abnormally short H…H contacts. We find this model to be incorrect, and have re-determined the structure to find no short H…H contacts. PIXEL and DFT calculations indicate that the high-pressure polymorph is favoured over the ambient phase by the PV term, the zero point energy and entropy. Low completeness that often occurs as a result of shading from the high-pressure cell was improved by the inclusion of multiple crystals within the sample chamber. Bianthrone changes colour from yellow to green on grinding, though this does not occur when subjected to hydrostatic pressure to 6.5 GPa. There is, however, a subtle colour change from bright yellow to dark orange as pressure is applied, and it is likely that this is caused by changes in the - stacking distances. This work highlights how a system can react differently to hydrostatic and non-hydrostatic conditions.

A new approach to the investigation of the optical properties of polytypic minerals that combines spindle stage techniques, X-ray diffraction methods, electron microprobe analysis, and dielectric tensor calculations has been developed and applied to zinc sulfides and chloritoids. For the first time, X—ray diffraction studies of natural anisotropic zinc sulfides have documented the simultaneous occurrence of twinning and stacking disorder along more than one of the four symmetry equivalent <111> directions of sphalerite. Precession photographs of optically anisotropic zinc sulfides are characterized by twin—equivalent diffraction maxima and diffuse diffraction streaking along lattice rows with (h-k) ≠ 3n (equivalent hexagonal indices) in one or two <111> directions. A system of linear equations has been used to calculate the approximate volume fractions of each twin domain and the sphalerite host domain. Dielectric tensor calculations have been performed to illustrate that mixtures of cubic and hexagonal zinc sulfide may be optically biaxial if the intergrowth occurs along more than one of the symmetry equivalent <111> directions of sphalerite (cubic). The dependence of the optical properties upon the chemical variation and polytypic intergrowth in the Hg-Fe chloritoids has been investigated. The effects of the variation in chemical composition of specific polytypic compositions were analyzed first. The refractive indices of 10 approximately pure 2M₂ Hg-Fe chloritoids show strong correlations (R² ≥ 0.094) to the proportion of Hg cations in the H(1B) site, Hg/(Hg + Fe + Hn) - HGN. Correlations between the optical orientation angles and HGN were weaker (R² ≤ 0.87). The optical orientation is very sensitive to small variations in the polytypic composition, especially orientation angles that have fixed values in 2M₂ chloritoid. The parameter showing the most sensitivity is ∠ X ⋀ b, which is 0° in an ideal 2M₂ chloritoid, but increases to about 6° for a chloritoid containing 10% by volume 1Tc polytype. The sum of ∠ Y ⋀ c* and ∠ Z ⋀ c* for an ideal 2M₂ chloritoid has a value of 90°, whereas a chloritoid with 10% 1Tc has a sum of 92°. Although not as sensitive as ∠ X ⋀ b, this parameter can be determined with only a spindle stage or universal stage. The observed dependence of the optical properties on polytypic intergrowth and chemical variation has been modeled using dielectric tensor calculations based on the properties of a 1Tc layer and assuming that the 2M₂ polytype is derived by twinning the 1Tc polytype about [010] with an (001) composition plane.<br>Ph. D.

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

Esta tesis se basa fundamentalmente en el estudio in situ del polimorfismo de triacilgliceroles (TAGs) mayoritarios de aceites y grasas alimentarios, la determinación del comportamiento de fases de algunas de sus mezclas binarias, y la aplicación del polimorfismo como herramienta para la autentificación de productos alimentarios. Se ha llevado a cabo la caracterización polimórfica de los TAGs POP, OPO, POO, POL, SOO, OOO y OOL, básicamente utilizando una combinación de calorimetría diferencial de barrido y difracción de rayos X con radiación sincrotrón (SAXD y WAXD). Así, se han podido monitorizar los procesos dinámicos de cristalización y las transiciones polimórficas cuando las muestras se sometían a diferentes velocidades de enfriamiento y calentamiento. Los resultados obtenidos son directamente aplicables a procesos de cristalización de aceites y grasas alimentarios, con la finalidad de obtener las propiedades deseadas del producto final, utilizando los tratamientos térmicos más eficientes. Para comprender las interacciones intermoleculares que tienen lugar entre TAGs, se ha determinado los diagramas de fases de las mezclas PPO-OPO, PPO-POO y POO-OPO. Se ha observado un comportamiento eutéctico para el sistema PPO-OPO, mientras que en los sistemas PPO-POO y POO-OPO se formaba un compuesto molecular (co-cristal) metaestable, que tendía a separarse en los componentes de origen. Mediante el uso de difracción de rayos X con micro-haz de radiación sincrotrón, se han analizado las microestructuras heterogenias de mezclas de POP-OPO. El estudio de estos agregados cristalinos esferulíticos es directamente aplicable a procesos de fraccionamiento del aceite de palma. Con la finalidad de comprender muestras grasas más complejas, se ha caracterizado el complejo comportamiento polimórfico de mezclas multi-componente de 3 a 6 TAGs. Para el caso particular del aceite de oliva, el comportamiento polimórfico viene básicamente determinado por los TAGs mayoritarios, mientras que los componentes minoritarios parecen desarrollar un papel menos crucial. Finalmente, se ha aplicado el comportamiento polimórfico como herramienta para la autentificación y detección de fraudes en productos alimentarios. Ha sido posible determinar adiciones fraudulentas de aceite de avellana en aceite de oliva virgen extra en concentraciones inferiores al 5%, y se han podido establecer diferencias muy significativas en grasas de jamones Ibéricos de las categorías cebo y bellota.<br>Lipids, together with proteins and carbohydrates are major nutrients and also employed as lipophilic materials in food, cosmetic and pharmaceutical industries. Alimentary and industrial fats and oils (such as vegetable oils, margarine, chocolate, and confectionery fats) mainly consist of triacylglycerols (TAGs), whose molecules involve different types of fatty acid moieties. TAGs show a complicated crystallization behavior. The physicochemical properties of a TAG molecule are determined by the nature and compositions of the three fatty acid moieties. These properties must be studied not only in their pure systems but also in mixed systems. In particular, studies on binary mixture systems provide valuable information about molecular interactions among different lipid materials. This PhD thesis is based on the study of the in situ polymorphic characterization of the main TAGs of some vegetable and animal fats and oils, some of their mixtures and the use of the polymorphic behavior of edible fats and oils as a tool to determine their authentication. The polymorphic study of the triacylglycerols POP, OPO, POO, POL, SOO, OOO and OOL was in situ characterized by mainly using differential scanning calorimetry (DSC) and synchrotron radiation X-ray diffraction (SR-XRD) with SAXD and WAXD simultaneous measurement. The combined usage of DSC and SR-XRD or laboratory-scale X-ray diffraction enabled us to monitor the occurrence and transformation behavior at different rates of cooling and heating. The results obtained are closely related to actual crystallization processes of edible fats and oils, in which most functional polymorphic forms can be obtained by applying the most efficient thermal treatments. We also determined the phase behavior of binary mixtures of mixed-acid TAGs containing palmitic and oleic fatty acids (i.e. PPO-OPO, PPO-POO and POO-OPO). PPO-OPO system revealed an eutectic behavior, whereas PPO-POO and POO-OPO were molecular compound-forming. Long incubation periods were needed in order to thermodynamically stabilize the binary mixtures, and the results demonstrated that molecular compounds of PPO-POO and POO-OPO were metastable and tended to separate into the pure TAG components. On the other hand, microstructures of spherulites of POP-OPO binary mixtures were analyzed in neat liquid and solution (n-dodecane) systems by using synchrotron radiation microbeam X-ray diffraction (SR-mu-XRD). Due to a molecular compound formation at the 50:50 concentration ratio, 75POP:25OPO and 25POP:75OPO compositions were characterized to study how the microstructures of spherulites of the TAGs mixtures are determined when the molecular compound crystals and POP or OPO component crystals can be formed competitively. Studies of these heterogeneous microstructures in neat liquid and solution are applicable to palm oil fractionation processes by dry and solvent methods. In an attempt to make an approach to complex natural fatty samples, such as olive oil, the polymorphism of multicomponent mixtures (from 3 to 6 TAG components) was analyzed and discussed. Thus, we observed that the polymorphic behavior of an extra virgin olive oil from the Arbequina olive variety was mainly influenced by its main TAGs, whereas apparently minor components did not develop a crucial role. Furthermore, we also used the polymorphic behavior of natural fat and oils (virgin and extra virgin olive oil, and Iberian ham fat) as a tool to determine authenticity (different ham categories depending on the fattening system used) and detection of adulterations (fraudulent additions of hazelnut oil in olive oil). The combined use of DSC and preliminary chemometric calculations permitted determining fraudulent additions of raw hazelnut oil in an extra virgin olive oil (Arbequina) at concentrations below 5%. On the other hand, highly significant differences were detected in the polymorphic behavior of Iberian ham fat from the bellota and cebo categories.