X-Ray Crystallography

X-ray crystallography
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Imaging System The imaging system is ideal for storing crystals in incubators operating at different temperatures, and acquisition of image data for hanging and sitting drop experiments with high-resolution quality.

Welcome to the Biomolecular X-ray Crystallography Facility at the University of Colorado Boulder!

Services include but are not limited to:. Please feel free to contact us to discuss your project! Toggle Navigation. Online Inquiry. This is made possible by the EU reverse charge method. Edited by Yitzhak Mastai. Edited by Marcello Andreeta. Edited by Peter Wilson.

Edited by Kui Liu. Edited by S Neralla. Edited by Sher Bahadar Khan. Edited by Khan Maaz. Edited by Magdalena Janus. Published: December 16th DOI: Teresa Duarte Open access peer-reviewed 4. Piniella Open access peer-reviewed 6. The matrix can be either crystalline or amorphous. Solid dispersion technique is one of the most promising techniques for enhancement of drug solubility and dissolution rate consequently the bioavailability of poorly soluble drugs. The traditional techniques for micronization focus on mechanical means, such as milling and grinding.

Micronization is one of the most common techniques of particle size reduction in drug development. Physicochemical properties of an API differ from one solid form to the other which is often a consequence of the way the API molecules are arranged in the crystal lattice of that solid form. Hence, selection of a solid form has profound implications in clinical, legal, and regulatory perspective.

Poor solubility is the characteristic nature of the drugs that fall into these classes.

Drug formulators often rely on techniques such as micronization, solid dispersion, encapsulation, salt formation, amorphous forms, etc. However, these techniques have inherent drawbacks in manufacturing and additional risk of stability of resulting formulations. In addition, many solid-state problems such as physical stability, hygroscopicity, melting point, and dissolution rate could be modified by selecting an appropriate coformer. Cocrystals that show improved physicochemical properties satisfy the three criteria required for issuing a patent: 1 novelty, every cocrystal is novel as it is not possible to predict whether a combination of an API and coformer forms a cocrystal, 2 non-obviousness, the physicochemical and pharmacokinetic properties of APIs are difficult to predict unless detailed experiments were conducted, 3 utility, the main motivation in the development of cocrystals is due to their ability to improve the performance of the parent drug.

Trask puts forth the patentability aspects of pharmaceutical cocrystals. The potential applications of cocrystals in the development of drug formulations has been recognized by several pharmaceutical companies and many have even recognized the need for their screening as part of solid-form screening for identifying an optimal solid form for development. The importance of pharmaceutical cocrystals has been recognized recently by the US Food and Drug Administration FDA, 37 and European Medicines Agency EMA, , 38 which released draft guidelines on the subject of regulatory classification of pharmaceutical cocrystals.

While FDA classified pharmaceutical cocrystals as drug product intermediates and the coformers used to make the cocrystals are defined as excipients, EMA defined them as being solid-state variants of the APIs, aligning them with salts, polymorphs, hydrates, or solvates. The views of the regulatory bodies, in particular FDA, are contrary to what the current understanding of the concept of pharmaceutical cocrystals is that the second component in a cocrystal is a pharmaceutically acceptable coformer.

In addition, by classifying them as drug product intermediates, cocrystals have to comply with additional current good-manufacturing practice requirements cGMPs. Therefore, to address the industry concerns and also to ease the regulatory burden, the FDA has most recently reclassified them August as a special class of solvates in which the second component is non-volatile. Year Milestone Discovery of the first cocrystal by F. Etter are useful for predicting hydrogen-bond patterns in organic crystals including cocrystals Introduction by G.

Zaworotko in Chemical Communications : Formal beginning of the subject of pharmaceutical cocrystals An article by M. Encapsulation: It is a process in which particles of a substance are surrounded by a coating to give capsules of many useful properties. In pharmaceuticals, encapsulation of drug molecules into microspheres or nanoparticles enables controlled drug release, taste masking, improving stability, and protection of protein and peptide from degradation. Cocrystals are defined as multi-component crystals composed of two or more solid components in stoichiometric ratio.

Therefore, knowledge of intermolecular interactions between the molecular components is a prerequisite for a successful cocrystal design. In this regard, G. Recurring intermolecular interactions in a crystal structure are termed supramolecular synthons and are further classified into two basic types.

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The angle of the cross and the distance between the spots contains information about the thickness of the wire and tightness of the spring, compressing the spring, for instance, changes the pattern produce. Encapsulation: It is a process in which particles of a substance are surrounded by a coating to give capsules of many useful properties. Acta Cryst B Google Scholar. The technique of single crystal X-ray crystallography has three basic steps. This model can be applied to refine the phases, atomic positions and respective Debye-Waller factors with the aim of fitting the observed diffraction data, thus getting an improved model and ideally yielding a better set of phases. X-ray diffraction is based on constructive interference of monochromatic X-rays and a crystalline sample.

One that involves the same functional groups is called supramolecular homosynthon and the one that involves different but complementary functional groups is called supramolecular heterosynthon. As the cocrystals are formed due to intermolecular interactions between two or more different molecules, the supramolecular heterosynthons of the type that involve functional groups of different molecules play an important role in the design of cocrystals.

Hydrogen bonds: It is an attractive interaction between a hydrogen atom from a molecule or a molecular fragment X—H in which X is more electronegative than H, and an atom or a group of atoms in the same or a different molecule, in which there is evidence of bond formation. Hydrogen-bonding rules: 1 All good proton donors and acceptors are used in hydrogen bonding. These rules correlate functional groups in neutral organic molecules with hydrogen-bond patterns in crystals and useful for selection of suitable coformers for the design of cocrystals.

Design of cocrystals generally relies on identification of robust supramolecular synthons between the constituents of the cocrystal. Pharmaceutical cocrystals have proven to be valuable for addressing solubility and dissolution rate issues of several BCS Class II and IV drug substances, for which low solubility is a serious concern in development of drug formulations. While a large number of cocrystals have been reported that showed improved solubility of API, attempts to reduce the solubility of an API through cocrystallization are seldom reported.

One such study that has demonstrated the application of cocrystallization technique in controlling the solubility of an API was reported by A. Nangia and coworkers using an antibiotic, sulfacetamide SACT. Such a limitation necessitates frequent dosing, which is often inconvenient to patients and amounts to excess drug loading.

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The authors have hypothesized that if the weaker hydrogen-bonding synthons in the crystal structure of SACT are replaced with stronger hydrogen bonds by way of cocrystallization, then the resulting stable cocrystal may be useful to lower the solubility of the parent drug. By employing a crystal engineering strategy, the authors have prepared a series of cocrystals and analyzed crystal structures and evaluated the physicochemical properties. Interestingly, the cocrystals showed low solubility and dissolution rate compared to the parent API. The heteromeric interactions afford the cocrystal better packing efficiency and stronger crystal lattice, which showed lower solubility and dissolution rate of SACT.

It has also been found that the cocrystal is stable under slurry and accelerated test conditions—a consequence of the stronger crystal lattice of the cocrystal. Cocrystallization of APIs for improving aqueous solubility has been a well-established technique; however, studies on improving drug permeability through cocrystallization have been reported only recently. The solubility and permeability product best represents the impact of cocrystallization on pharmacokinetic properties of HCT.

The observed improvement in solubility and permeability of the cocrystals is due to the disruption of sulfonamide—sulfonamide homosynthon in API by the coformer molecules. The authors proposed that the higher concentration of cocrystals in solution leads to amorphous cocrystal formation in solution with moderate or weak hydrogen bonds, which could generate high concentration gradient at the membrane site. Thus, the resulting high transient concentrations overcome lipophilicity and particle size effects and provide improved permeation.

Metaxalone MTX is a muscle relaxant used to relieve discomfort associated with acute and painful musculoskeletal conditions.

Its effects have been reasoned to depression of central nervous system. It has also been reported that the oral bioavailability of MTX is greatly influenced by food, which impacts dosing needs of a patient. The previous attempts to make a sufficiently bioavailable form of MTX have not been successful.

1. Introduction

X-ray crystallography (XRC) is a technique used to determine the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of. x Ray crystallography is currently the most favoured technique for structure determination of proteins and biological macromolecules. Increasingly, those.

MTX exists in two polymorphic forms. Oxazolidone group of the MTX was exploited to form a series of cocrystals with dicarboxylic acids such as, succinic acid, fumaric acid, maleic acid, adipic acid, and salicylic acid. The presence of coformer in the crystal lattice resulted in a significant change in the bioavailability of the MTX.

Pharmacokinetic PK studies in beagle dogs using cocrystals with succinic and fumaric acids revealed higher plasma concentration and the area under the curve AUC for cocrystals than the MTX. Materials undergo deformation on applying stress; this includes elasticity, plasticity, viscoelasticity, brittle fracture, fragmentation, or a combination of these based on the nature of applied stress and internal structure of the material.

A proper understanding of these mechanical properties and material deformation phenomena is important for powder compaction and secondary processes such as milling. The previous studies on single-component systems are aimed at correlating compaction properties and plasticity of materials. The presence of slip planes and crystallographic planes with weakest interactions or adjacent planes with higher d-spacing in the crystal structure affords greater plasticity and better tabletability.

Studies concerning mechanical properties of cocrystals have been conducted only recently. For example, W. Jones and coworkers have found that the cocrystals of paracetamol PRA showed better tabletability than the marketed polymorph.

X-ray crystallography instrumentation

Velaga et al. A closer look into the crystal structures of the cocrystals and Form I revealed that the crystal structure of Form I has no slip plane and consisted primarily of interlocked PRA molecules held strongly by hydrogen bonds. The rigid hydrogen-bonded network affords poor tableting properties that resulted in brittleness to the compressed tablets. On the other hand, the cocrystal with oxalic acid features catemeric arrangement of oxalic acid and PRA molecules that generate layers parallel to and planes. The perfect layered structure of the cocrystal explains the greater plastic deformation and better tabletability.


These studies underscore the role of crystal packing and the strength of intermolecular bonding in determining tablet formation and its mechanical strength. Marketability of a solid form depends on several factors and its promising physicochemical properties are undoubtedly the prime consideration.

As detailed in Sects. The adoptability of cocrystallization technology to a wide range of APIs, including the ones that are non-ionizable, has tremendous implications in drug development. The inherent characteristics of cocrystals such as novelty, usefulness, and non-obviousness provide additional means for patenting cocrystals as novel composition of matter.

A close inspection of the marketed drugs and their composition revealed that some of them contain the API in cocrystal form. For example, well-known drugs such as caffeine citrate, sodium valproate—valproic acid, and escitalopram oxalate—oxalic acid, all comply with the cocrystal definition and marketed even before the concept of pharmaceutical cocrystals came to existence. Some other promising cocrystals that are under late- stage development are: a drug—drug cocrystal containing a non-steroidal anti-inflammatory drug, celcoxib, and an opiod drug, tramadol, which has superior analgesic efficacy compared to comparable doses of tramadol, 57 and a cocrystal of an anti-diabetic drug ertugliflozin with 5-oxo-proline.

Acknowledgements S. Deschamps JR The role of crystallography in drug design.

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He J, Kunitake T Are ceramic nanofilms a soft matter?. Nature Google Scholar. Nature CrossRef Google Scholar. Science CrossRef Google Scholar. Acta Cryst B Google Scholar. Phys Zeit Google Scholar. Hull AW A new method of X-ray crystal analysis. Pharmaceutical applications of X-ray powder diffraction. Spectroscopy Google Scholar. Bolla G, Nangia A Pharmaceutical cocrystals: walking the talk. Wiley, Weinheim, pp 19—38 Google Scholar. Trask AV An overview of pharmaceutical cocrystals as intellectual property. European Medicines Agency.

Desiraju GR Supramolecular synthons in crystal engineering—a new organic synthesis. Etter MC Encoding and decoding hydrogen-bond patterns of organic compounds. Bolton O, Matzger AJ Improved stability and smart-material functionality realized in an energetic cocrystal. Toth PE, Urtis J Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxaloone.

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