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Aplicacións da difracción de Raios X á Bioloxía Estudios de sistemas polimórficos por difracción de Raios X. Universidade.

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Presentation on theme: "Aplicacións da difracción de Raios X á Bioloxía Estudios de sistemas polimórficos por difracción de Raios X. Universidade."— Presentation transcript:

1 Aplicacións da difracción de Raios X á Bioloxía Estudios de sistemas polimórficos por difracción de Raios X. http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) Bruno Dacuña Mariño http://imaisd.usc.es/riaidt/raiosx/

2 Difracción de po cristalino Vs monocristal… O polimorfismo (Exemplos)… http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X)

3 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) Monocristal Po Cristalino > 0.1mm < 0.1mm CRYSTAL GROWTH & DESIGN 2006 VOL.6,NO.10 2228-2240 Difracción de po Vs monocristal… o tipo de mostra avantaxes: poder analizar cristais pequenos e sistemas multifásicos.

4 2Ө2Ө RaiosX http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) Difracción de po Vs monocristal… o experimento desvantaxe: perda de número de datos 2Ө2Ө

5 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) Difracción de po Vs monocristal… qué se pode facer con datos de po cristalino??

6 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Pharmaceutical Research, Vol. 20, No. 4, April 2003 Scientific Considerations of Pharmaceutical Solid Polymorphism in Abbreviated New Drug Applications (Lawrence X. Yu, et al.) “…Pharmaceutical polymorphic solids of the same chemical compound differ in internal solid-state structure and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, and mechanical properties. These properties can have a direct impact on drug substance processability, drug product manufacturability, and drug product quality/ performance, including stability, dissolution, and bioavailability. Unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences, which may result in product development delay and commercial production disruption, as in the case of ritonavir…”

7 “…In mid-1998, several lots of capsules failed the dissolution requirement … a new polymorph was identified that had greatly reduced solubility compared to the original crystal form. An unusual conformation was found for form II that results in a strong hydrogen bonding network A possible mechanism for heterogeneous nucleation of form II was investigated… Ritonavir polymorphism was investigated using solid state spectroscopy and microscopy techniques including solid state NMR, Near Infrared Spectroscopy, powder X-ray Diffraction and Single crystal X-ray…. Although the polymorph (form II) corresponding to the “cis” conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersaturated solutions. The coincidence of a highly supersaturated solution and a probable heterogeneous nucleation by a degradation product resulted in the sudden appearance of the more stable form II polymorph….” http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Pharmaceutical Research, Vol. 18, No. 6, 2001 Ritonavir: An Extraordinary Example of Conformational Polymorphism (John Bauer et al.)

8 “…At this time, only the most fundamental of laboratory studies are usually done. Thermal studies such as DSC and TGA, along with microscopy and powder diffraction, will likely provide sufficient information about the identity and characteristics of the drug substance. If single crystal data are available, this is a plus, since indexing the powder pattern may be easier… …stability studies should be carried out to examine the possibility of changes in the physical state when the dosage form is subjected to various conditions. Extremes of humidity, as well as heat, may alter the crystalline form of the drug substance in the dosage form. For example, exposure of tablets of anhydrous theophylline in tablets is known to form theophylline monohydrate in a period of a few days… …To the drug developer, rapid dissolution in the stomach is often critical, so there may be good reasons to prefer to manufacture tablets or capsules from crystalline forms which are less stable, and thus more soluble. Unfortunately, this may increase the possibility of undesirable phase changes... …Following the completion of the Phase 3 studies, the New Drug Application, or NDA, in the U.S., will be submitted. This should include complete details about the drug substance, including information about the various solid-state forms of the drug substance …” (U. S. Food and Drug Administration, Wilson H. DeCamp, Presented to XVIIIth Congress of the International Union of Crystallography Glasgow, Scotland August 7, 1999 ) http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo…

9 “…Anhydrous theophylline (3,7-dihydro-1,3-dimethyl-1H-purine- 2,6-dione) is a pharmaceutical material that is used as a vasodilator and a muscle relaxant. Initial results suggested that two distinct crystal structures with different hydrogen-bonding networks, in the same given unit cell. ()…study shows how the potential for polymorphism in a “given unit cell” may be assessed successfully by combining several complementary experimental and theoretical approaches…” http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… J. Phys. Chem. B 2001, 105, 5818-5826 “The Determination of the Crystal Structure of Anhydrous Theophylline by X-ray Powder… (Elaine D. L. Smith, et al.)

10 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Dunitz: “…are crystal structures predictable?”, with the opening line response, “The one word answer to the title question is still ‘No’, although at certain levels of discussion a ‘Maybe’ or even a conditional ‘Yes’ may be entertained as possible responses…” http://www.a-star.edu.sg/astar/exploit/index.do http://www.avantium.com/ http://www.pharmorphix.com/ http://www.ipi.ac.uk/services/polymorph-screening/ http://www.zinsserna.com/crissy.htm http://imaisd.usc.es/riaidt/raiosx/ 1.…as similitudes estruturais entre os polimorfos… polymorph-screening…haberá que analizar… Walter McCrone: “…the number of forms of a given compound is proportional to the time and money spent on research on the compound…” High-Throughput crystallization CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 927-933

11 CRYSTAL GROWTH & DESIGN 2003 VOL.3, NO.6 897-907 “Anhydrates and Hydrates of Olanzapine: Crystallization, Solid-State Characterization, and Structural Relationships” (Susan M. Reutzel-Edens et al.) http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) “…Olanzapine, a novel benzodiazepine agent used in the treatment of schizophrenia and related psychoses, crystallizes in 25+ crystal forms, seven of which are pharmaceutically relevant: three anhydrates (I-III), three dihydrates (B, D, and E), and a higher hydrate…. Olanzapine has been crystallized in a number of anhydrous and hydrated forms, wherein a centrosymmetric dimer, stabilized by van der Waals interactions between the complementary surfaces of the most stable conformational enantiomers, has been identified as the crystal building block. The dimeric aggregates likely prevail because the hydrogen bond donors and acceptors of olanzapine remain accessible for hydrogen bonding…” O polimorfismo… o estudo das similitudes estruturais entre os polimorfos

12 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Dunitz: “…are crystal structures predictable?”, with the opening line response, “The one word answer to the title question is still ‘No’, although at certain levels of discussion a ‘Maybe’ or even a conditional ‘Yes’ may be entertained as possible responses…” http://www.a-star.edu.sg/astar/exploit/index.do http://www.avantium.com/ http://www.pharmorphix.com/ http://www.ipi.ac.uk/services/polymorph-screening/ http://www.zinsserna.com/crissy.htm http://imaisd.usc.es/riaidt/raiosx/ 1.…as similitudes estruturais entre os polimorfos… 2.…os efectos termodinámico e cinético que controlan o proceso de crecido… polymorph-screening…haberá que analizar… Walter McCrone: “…the number of forms of a given compound is proportional to the time and money spent on research on the compound…” High-Throughput crystallization CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 927-933

13 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) “… [e.g., 60 mass % polyethylene glycol 300 (PEG300) in water] is more viscous than the antisolvent (e.g., water)…in crystallization from a quasi-emulsion, where diffusion becomes important, the nucleation and growth rate are slowed and formation of the stable polymorphic form is favored. The crystalline phase that is formed will be primarily governed by thermodynamics… On the other hand, rapid, homogeneous mixing with high supersaturation will favor the formation of a metastable form in accordance with Ostwald’s Rule of Stages, which hypothesizes that metastable (higher free energy) phases are first formed in a crystallization process, i.e., the crystalline form obtained is governed by kinetics. Solvent polarity/nonpolarity is also known to affect polymorphism, especially through influences on hydrogen bond formation… as quasi-emulsion formation will occur when mixing solvent and antisolvent liquids that have different polar/nonpolar properties in addition to viscosity differences, care will be taken to distinguish the effect of the quasi-emulsions from other solvent effects…” CRYSTAL GROWTH & DESIGN 2006 VOL.6,NO.10 2228-2240 Quasi-Emulsion Precipitation of Pharmaceuticals. 2. Application to Control of Polymorphism (Xing Wang and Donald J. Kirwan) O polimorfismo… os efectos termodinámico e cinético que controlan o proceso de crecido

14 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) “…This is the case for example for glucocorticoids, which belong to the most effective and versatile drugs and used in therapy for several years. Triamcinolone for example is a synthetic glucocorticoid agonist and is an inducer of gene expression and apoptosis… we have conclusively shown the existence of two polymorphic solvent-free forms and one pseudopolymorphic form for the glucocorticoid triamcinolone. Surprisingly, the commercially available form A is metastable and transforms in most solvents into form B, which represents the thermodynamically most stable form at room temperature. Only in water the formation of a monohydrate (form C) is observed. If the water is removed from the hydrate by heating, a transformation into the metastable form A is observed…” CRYSTAL GROWTH & DESIGN 2003 VOL.3, NO.6 897-907 Investigations on the Polymorphism and Pseudopolymorphism of the Glucocorticoid Triamcinolone: New Findings for a Well-Known Drug (Viktor Suitchmezian et al.) O polimorfismo… os efectos termodinámico e cinético que controlan o proceso de crecido

15 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Dunitz: “…are crystal structures predictable?”, with the opening line response, “The one word answer to the title question is still ‘No’, although at certain levels of discussion a ‘Maybe’ or even a conditional ‘Yes’ may be entertained as possible responses…” http://www.a-star.edu.sg/astar/exploit/index.do http://www.avantium.com/ http://www.pharmorphix.com/ http://www.ipi.ac.uk/services/polymorph-screening/ http://www.zinsserna.com/crissy.htm http://imaisd.usc.es/riaidt/raiosx/ 1.…as similitudes estruturais entre os polimorfos… 2.…os efectos termodinámico e cinético que controlan o proceso de crecido… 3.…os primeiros pasos do proceso de cristalización… polymorph-screening…haberá que analizar… Walter McCrone: “…the number of forms of a given compound is proportional to the time and money spent on research on the compound…” High-Throughput crystallization CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 927-933

16 “…we show that the mechanism of polymorphic transformation involves inclusion of the stable form of a polymorph within the metastable form… R-Nucleation. In agreement with Ostwald’s law of stages, as the supersaturated amino acid L-Glu solution decreases to the solubility of the R-form, primary homogeneous nucleation of the R-form occurs. â-Nucleation. This is followed successively by secondary nucleation of â-L-Glu nuclei advantageously on the R-surface, followed by slight growth of â-nuclei. R-Growth. Growth of R-crystals occurs (kinetics favors this), until the solubility of the R-form is attained, thereby encapsulating the â-crystals in the R-crystals, by R-form overgrowth. On surface inspection, this may appear as though the â-crystals are nucleating on the R-surface, and not in the crystal interior as evidenced by FIB crosssections. R-Dissolution. Once the R-solubility is reached, the solution is only supersaturated with respect to the â-form... The R-form therefore redissolves, providing an increased local supersaturation for simultaneous continued growth of the â-crystals, formed at the initial nucleation stage. â-Growth. As the solution continues to crystallize, new â-nuclei form advantageously on the R-crystal surface, and the encapsulated â- nuclei continue to grow, once they emerge from the dissolving R-crystals and contact the supersaturated solution …” http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 869-872 Inclusion of the Stable Form of a Polymorph within Crystals of Its Metastable Form (Caitriona Cashell, et al.) O polimorfismo… o estudo dos primeiros pasos do proceso de cristalización

17 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… Dunitz: “…are crystal structures predictable?”, with the opening line response, “The one word answer to the title question is still ‘No’, although at certain levels of discussion a ‘Maybe’ or even a conditional ‘Yes’ may be entertained as possible responses…” http://www.a-star.edu.sg/astar/exploit/index.do http://www.avantium.com/ http://www.pharmorphix.com/ http://www.ipi.ac.uk/services/polymorph-screening/ http://www.zinsserna.com/crissy.htm http://imaisd.usc.es/riaidt/raiosx/ 1.…as similitudes estruturais entre os polimorfos… 2.…os efectos termodinámico e cinético que controlan o proceso de crecido… 3.…os primeiros pasos do proceso de cristalización… 4.…controla-las variables nos procesos de nucleazón e crecido cristalino polymorph-screening…haberá que analizar… Walter McCrone: “…the number of forms of a given compound is proportional to the time and money spent on research on the compound…” High-Throughput crystallization CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 927-933

18 “…A number of factors can affect the crystal formed either by influencing the hydrogen-bonded aggregate precursors in solution or influencing one of the many other factors involved in crystallization… these include (1) solvent composition or polarity, (2) concentration or degree of supersaturation, (3) temperature including cooling rate and the cooling profile, (4) additives, (5) seeds and the presence of seeds, (6) pH (pH is important for crystallization of salts), and (7) agitation…” Chem. Mater. 1994,6, 1148-1158, Solid-state Pharmaceutical Chemistry (S. R. Byrn et al.) http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… cómo controla-las variables nos procesos de nucleazón e crecido cristalino “…Current approaches for discovery and selection of polymorphic forms of a compound include crystallization with tailor made soluble additives, epitaxial growth, laser induced nucleation, crystallization in capillaries, confinement within porous materials, and more traditional methods, such as varying solvent, temperature, and extent of supersaturation…” J. AM. CHEM. SOC. 2005, 127, 5512-5517 Crystalline Polymorph Selection and Discovery with Polymer Heteronuclei (Christopher P. Price et al.)

19 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) “…the crystal engineering design strategy facilitates supramolecular synthesis of 13 new crystalline phases of carbamazepine (CBZ), an analgesic and anticonvulsant with known problems related to solubility and polymorphism… CBZ forms supramolecular complexes with the following molecules, all of which are complementary to CBZ in terms of hydrogen bonding and can therefore act as cocrystal formers: acetone (1a); DMSO (1b); benzoquinone (1c); terephthalaldehyde (1d); saccharin (1e); nicotinamide (1f); acetic acid (1g); formic acid (1h); butyric acid (1i); trimesic acid (1j); 5-nitroisophthalic acid (1k); adamantane-1,3,5,7-tetracarboxylic acid (1l); and formamide (1m). O polimorfismo… cómo controla-las variables nos procesos de nucleazón e crecido cristalino CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.6 909-919 Crystal Engineering of the Comp. of Pharmaceutical Phases: Multiple-Component Crystalline Solids Involving CBZ (Scott G. Fleischman et al.)

20 http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) Some impurities inhibit crystallization, and more specifically some additives will selectively inhibit undesired polymorphs. For intermediates in a chemical synthesis, the focus is on the degree of purity obtained during a crystallization, rather than the polymorph obtained. Yet, there is little known about how polymorphism affects crystal purity…. “Piperidene” is an intermediate in the manufacture of a novel antibacterial pharmaceutical… The N-linked impurity could not form this hydrogen bond. The molecule is fully extended to enable the oxygen atom to take part in this hydrogen bond, and if the N-linked ring is substituted it is not possible to place a nitrogen or oxygen atom this close to the water molecule… Consideration of the strong and weak hydrogen bonding in the hydrate structure suggests that this may be the origin of the enhanced selectivity of this structure… O polimorfismo… cómo controla-las variables nos procesos de nucleazón e crecido cristalino CRYSTAL GROWTH & DESIGN 2004 VOL.4,NO.3 539-544 Increased Chemical Purity Using a Hydrate (Simon N. Black et al.)

21 “…Cocoa butter was crystallized statically from the melt to various temperatures in the range of -20 to 26 °C and annealed for up to 45 days. During this period, the polymorphism of the solid state was monitored using differential scanning calorimetry and powder X-ray diffraction… Triglycerides are known to crystallize in a number of different polymorphic forms depending on processing conditions (heat, mass, and momentum transfer) and chemical composition. Cocoa butter, the main structuring material in chocolate and confections, displays complex crystallization behavior in that six different polymorphs have been identified. These solid phases have characteristic melting ranges and wide angle X-ray reflections. In a few cases, distinct microstructures have been associated with particular polymorphic forms. Essential to the manufacturing of good quality chocolate is the ability to induce the formation and stabilization of certain polymorphic forms in cocoa butter. This in turn will lead to the formation of a fat crystal network with desirable mechanical and thermal properties… The crystallization behavior of cocoa butter was followed by measuring the change in solid fat content (SFC) as a function of time. http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… cómo controla-las variables nos procesos de nucleazón e crecido cristalino CRYSTAL GROWTH & DESIGN 2003 VOL.3,NO.1 95-108 Relationship between Crystallization Behavior andStructure in Cocoa Butter (Alejandro G. Marangoni* and Sara E. McGauley)

22 “… Jadarite' s chemical formula is very close to the formula invented for the fictional substance kryptonite in the 2006 film Superman Returns. This coincidence attracted mass-media attention, and jadarite was covered by ABC, BBC, CNN, Washington Post, and Yahoo, among others…. The new mineral, unlike the fictional material in the movie, does not contain fluorine, does not emit electromagnetic radiation, and is white rather than green (although, in the Superman comics, there is a white colored variety of kryptonite). In all other respects the chemistry matches that of the rock containing kryptonite in the movie. The jadarite fluoresces a pinkish-orange color when exposed to UV light… … Jadarite is a white, powdery, non-radioactive monoclinic mineral whose chemical formula is sodium lithium boron silicate hydroxide: LiNaSiB3O7(OH) or Na2OLi2O(SiO2)2(B2O3)3H2O. It was discovered in November 2006, in a mine at the Jadar Valley (Serbian Cyrillic: Јадар, Yaddar) in Serbia, from which it is named. It was confirmed as a new mineral after scientists at the Natural History Museum in London and the National Research Council of Canada conducted tests on it. Jadarite was first found by Dr. Chris Stanley from the Natural History Museum. Researchers from the dual listed company Rio Tinto Exploration discovered the mineral, and after being unable to match it with previously known minerals enlisted the expertise of Dr. Stanley, from the Natural History Museum, who later described it as being unique to mineralogy.…" http://imaisd.usc.es/riaidt/raiosx/ Universidade de Santiago de Compostela Servizo de difracción de RaiosX ED. CACTUS Campus sur Aplicacións da difracción de Raios X á Bioloxía (Estudios de sistemas polimórficos por difracción de Raios X) O polimorfismo… cómo controla-las variables nos procesos de nucleazón e crecido cristalino Acta Crystallographica Section B Structural Science, International Union of Crystallography. LiNaSiB3O7(OH) a novel structure of the new borosilicate mineral jadarite determined from laboratory powder diffraction data. Whitfield, Pamela.


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