Algorithm Technique For Structure Solution Research Articles

Novel anhydrous solid-state form of Azathioprine: The assessing of crystal structure by powder X-Ray diffraction, Infrared Absorption Spectroscopy and Raman scattering

Azathioprine (Imuran), one of the oldest immunosuppressants, having been used in transplantation since the early 1960`s, is known to have only two crystal forms: an anhydrous form and a dihydrate phase. We report the crystal structure of a new anhydrous solid-state form of Azathioprine, determined directly form powder X-Ray diffraction data, employing the direct-space genetic algorithm technique for structure solution, followed by Rietveld refinement. The new anhydrous polymorph is accessible only by a solid-state dehydration process of the readily obtained monohydrate form of Azathioprine, the form for which a crystal structure has not previously been reported. The IR and Raman spectra confirmed the results obtained from X-Ray diffraction indicating the presence of all functional groups involved in intermolecular hydrogen bonding which dictates different arrangement of molecules in the structural packing.

Combining the Advantages of Powder X-ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride

We report the crystal structure of the anhydrous phase of cimetidine hydrochloride, determined directly from powder X-ray diffraction data. The material was prepared by dehydration of the readily obtained monohydrate form of cimetidine hydrochloride, the only form for which a crystal structure has previously been reported. As such, solid-state dehydration processes typically yield the product phase as a microcrystalline powder, and structure determination was carried out directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. The structure determined from powder X-ray diffraction was further validated by calculating solid-state 13C NMR data for the crystal structure (using first-principles periodic DFT techniques within the GIPAW approach) and assessing the quality of agreement with the corresponding experimental solid-state 13C CPMAS NMR data. This strategy provides a robust vindication of the correctness of the crystal structure by assessing the quality of agreement of the structure both with experimental powder X-ray diffraction data and with experimental solid-state 13C NMR data.

Discovery of a New System Exhibiting Abundant Polymorphism:m-Aminobenzoic Acid

Given the importance of the phenomenon of polymorphism from both fundamental and applied perspectives, there is considerable interest in the discovery of new systems that exhibit abundant polymorphism. In the present article, the preparation strategies and structural properties of three new polymorphs (denoted Forms III, IV, and V) of m-aminobenzoic acid (m-ABA) are reported, elevating this system to the rare class of polymorphic systems with at least five known polymorphs. The crystal structures of the three new polymorphs have been determined directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement, demonstrating the opportunities that now exist for determining crystal structures when crystals of sufficient size and quality for single-crystal X-ray diffraction are not available. In two of the new polymorphs (Forms III and IV), the m-ABA molecules exist in the zwitterionic form (as in the previously known Form I), while the m-ABA molecules in the other new polymorph (Form V) are nonzwitterionic (as in the previously known Form II). Furthermore, disorder of the molecular orientation, and hence disorder in the intermolecular hydrogen-bonding arrangement, is revealed in Form V. The assignment of the tautomeric form in each polymorph is confirmed by X-ray photoelectron spectroscopy. Issues relating to the relative stabilities of the five polymorphs of m-ABA are discussed.

The crystal structure of l-arginine

We report the crystal structure of L-arginine, one of the last remaining natural amino acids for which the crystal structure has never been determined; structure determination was carried out directly from powder X-ray diffraction (XRD) data, exploiting the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement.

Structure Determination from Powder X-ray Diffraction Data of a New Polymorph of a High-Density Organic Hydrate Material, with an Assessment of Hydrogen-Bond Disorder by Rietveld Refinement

The structural properties of a new polymorph of a material distributed commercially as “hexaketocyclohexane octahydrate” have been determined directly from powder X-ray diffraction data, employing the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. It is shown that the molecule actually present in the crystal structure is dodecahydroxycyclohexane (C6(OH)12) rather than hexaketocyclohexane (C6O6). This assignment is also confirmed from high-resolution solid-state 13C NMR data. The crystal structure contains two molecules of water per molecule of C6(OH)12. In the asymmetric unit, there are 16 hydrogen-bond donor groups (O–H bonds) and 14 hydrogen-bond acceptors (oxygen atoms), leading to multiple permutations for intermolecular hydrogen-bonding arrangements. Detailed analysis of the results from Rietveld refinement suggests that a disordered model provides the most appropriate description of the hydrogen-bonding arrangement, in which the hydrogen atom of each OH group of C6(OH)12 and the hydrogen atoms of each water molecule are distributed among several different intermolecular O–H···O hydrogen bonds. The density of this material (1.926 g cm–3 at ambient temperature) is one of the highest ever reported densities among organic materials that contain no elements heavier than oxygen.

Structural Chemistry of a New Chiral Anhydrous Phase of Ru(bipy)3(ClO4)2Established from Powder X-ray Diffraction Analysis

A new anhydrous chiral phase of Ru(bipy)3(ClO4)2 (bipy = 2,2′-bipyridine) has been prepared both by mechanical grinding followed by annealing of the known chiral hydrate phase of this material and by solid-state dehydration of the chiral hydrate phase at high temperature. The new phase is obtained from these processes as a microcrystalline powder, thus limiting the opportunity to carry out structural characterization by single-crystal X-ray diffraction. Instead, our structure determination of the new chiral anhydrous phase has exploited the capabilities of modern powder X-ray diffraction techniques, employing the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. The structural properties of the chiral anhydrous phase are discussed, particularly with regard to assessing the structural relationship to the parent hydrate phase.

Arrays of P═O Dipoles As a Recurrent Structural Motif in Bis-Diphenylphosphine Oxides, Established from Powder X-ray Diffraction

Rationalization of the solid-state structural properties of odd members (n = 3, 5, 7) of the series Ph2P(O)(CH2)nP(O)Ph2 leads to insights concerning the structural determinants of this class of material, particularly with regard to the formation of preferred arrangements of P═O dipoles. The odd members of this series are recalcitrant to the formation of single crystals of suitable size and quality for single-crystal X-ray diffraction, and modern techniques for carrying out crystal structure determination directly from powder X-ray diffraction data were essential for determining the structural properties of these materials. In the present work, nonsolvate crystal phases of the materials with n = 3 and 5 were prepared by appropriate solid-state desolvation processes (starting from hydrate and toluene solvate phases, respectively), yielding microcrystalline powders of the nonsolvate phase in each case. Structure determination was carried out directly from powder X-ray diffraction data, employing the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement.

A Solid-State Dehydration Process in an Organic Material Associated with Substantial Hydrogen-Bond Reorganization, Investigated by Powder X-ray Diffraction

Solid tert-butylammonium acetate monohydrate undergoes a facile solid-state dehydration process under ambient conditions, in which single crystals of the monohydrate phase transform to a microcrystalline powder of an anhydrous product phase. The structural properties of the anhydrous phase have been determined directly from powder X-ray diffraction data, employing the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement, allowing rationalization of the structural changes associated with the dehydration process. The dehydration process is associated with substantial reorganization of the hydrogen bonding arrangement, although one component of the hydrogen-bonding scheme is actually preserved in the transformation.

Physicochemical Understanding of Polymorphism and Solid-State Dehydration/Rehydration Processes for the Pharmaceutical Material Acrinol, by Ab Initio Powder X-ray Diffraction Analysis and Other Techniques

The extensively used antibacterial agent acrinol is known to form a monohydrate phase (H) on crystallization from water. We demonstrate here that acrinol also forms two anhydrous polymorphs, denoted form I (AI) and form II (AII). Polymorph AI is obtained directly on heating H, by a solid-state dehydration process, and polymorph AII is obtained subsequently from AI, by a polymorphic transformation. The crystal structures of AI and AII have been determined directly from powder X-ray diffraction data, employing the direct-space genetic algorithm technique for structure solution, followed by Rietveld refinement. From the structural properties of AI and AII, mechanistic aspects of the dehydration process and the polymorphic transformation have been established. From measurements of initial dissolution rates and enthalpies of dissolution, AII is assigned as the thermodynamically stable polymorph, with a monotropic relationship between AI and AII. The hydration properties of AI and AII differ significantly, with hydration of AI occurring at substantially lower relative humidity than AII.

A Solid-State Dehydration Process Associated with a Significant Change in the Topology of Dihydrogen Phosphate Chains, Established from Powder X-ray Diffraction

The anhydrous crystalline phase of chloroquine bis-(dihydrogen phosphate) is obtained by dehydration of the corresponding hydrate phase, but in common with many solid-state dehydration processes, the product is obtained as a polycrystalline powder, thus limiting the opportunity to carry out structural characterization using single crystal X-ray diffraction techniques. Instead, structure determination of the anhydrous phase has exploited the capabilities of modern powder X-ray diffraction techniques, employing the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The results reveal that the dehydration process is associated with a significant change in the topology of hydrogen bonded chains of dihydrogen phosphate anions, arising from a change in the hydrogen bonding arrangement within the chains, together with a significant change in the conformation of the chloroquine cation.

Multiple-fragment representations of molecular geometry in direct-space structure solution from powder X-ray diffraction data using genetic algorithms

Structure determination of organic molecular solids from powder X-ray diffraction data is nowadays carried out widely, in particular using the direct-space strategy for structure solution. In our implementation of this approach, structure solution involves the use of a genetic algorithm to explore the powder-profile R-factor hypersurface Rwp(Γ) to locate the global minimum, where Γ represents the set of variables that define trial structures. Conventionally, the set of variables comprises, for each molecule in the asymmetric unit, the position {x, y, z} and orientation {θ, φ, ψ} of the molecule, and a set of n variable torsion angles {τ1, τ2,...,τn}. An alternative definition of variable-space has been explored recently, based on a multiple-fragment representation of molecular geometry, and has been demonstrated to be successful in solving the structures of conformationally complex molecules. This paper explores details of the methodology for the definition of multiple-fragment representations of molecular geometry within the context of the application of the direct-space genetic algorithm technique for structure solution.

Enhanced Efficiency of Direct-Space Structure Solution from Powder X-ray Diffraction Data in the Case of Conformationally Flexible Molecules

A strategy is reported for assessing the feasibility of molecular conformations within direct-space structure-solution calculations of organic molecular crystal structures from powder X-ray diffraction data, focusing in particular on the genetic algorithm technique for structure solution in which fitness is defined as a function of the whole-profile figure-of-merit Rwp. The strategy employs a readily computed distance-based function to assess the feasibility of the molecular conformation in each trial structure generated in the genetic algorithm calculation, and structures considered to have low-feasibility conformations are penalized within the evolutionary process. The strategy is shown to lead to significant improvements in the success rate of structure-solution calculations in the case of flexible molecules with a significant number of conformational degrees of freedom.

Structural properties of a family of hydrogen-bonded co-crystals formed between gemfibrozil and hydroxy derivatives of t-butylamine, determined directly from powder X-ray diffraction data

We report the formation and structural properties of co-crystals containing gemfibrozil and hydroxy derivatives of t-butylamine H 2NC(CH 3) 3− n (CH 2OH) n , with n=0, 1, 2 and 3. In each case, a 1:1 co-crystal is formed, with transfer of a proton from the carboxylic acid group of gemfibrozil to the amino group of the t-butylamine derivative. All of the co-crystal materials prepared are polycrystalline powders, and do not contain single crystals of suitable size and/or quality for single crystal X-ray diffraction studies. Structure determination of these materials has been carried out directly from powder X-ray diffraction data, using the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The structural chemistry of this series of co-crystal materials reveals well-defined structural trends within the first three members of the family ( n=0, 1, 2), but significantly contrasting structural properties for the member with n=3.

Understanding the Structural Properties of a Dendrimeric Material Directly from Powder X-ray Diffraction Data

Complete structure determination of an early-generation dendrimeric material has been carried out directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. This work represents the first application of modern direct-space techniques for structure determination from powder X-ray diffraction data in the case of a dendrimeric material and paves the way for the future application of this approach to enable complete structure determination of other dendrimeric materials that cannot be prepared as single crystal samples suitable for single crystal X-ray diffraction studies.

Contrasting Solid-State Structures of Trithiocyanuric Acid and Cyanuric Acid

Although trithiocyanuric acid (TTCA) has been investigated widely as an agent in the formation of molecular cocrystals, the crystal structure of pure TTCA has never been determined. Attempts to grow crystals of pure TTCA by crystallization from solution invariably lead to the formation of solvate cocrystals, and desolvation of these materials leads to polycrystalline powder samples. In this paper, we report the structure determination of pure TTCA directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. The structure presents interesting contrasts to that of the oxygen analogue, cyanuric acid, and alludes to the possibility that both compounds might be capable of exhibiting polymorphism.

Structural properties of methoxy derivatives of benzyl bromide, determined from powder X-ray diffraction data

Structure determination of 3,5-dimethoxybenzyl bromide and 3,4,5-trimethoxybenzyl bromide has been carried out from laboratory powder X-ray diffraction data using the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. These two compounds are of interest for their potential use as building blocks for the synthesis of dendritic materials. Although the two molecules differ only in the presence/absence of the methoxy group at the 4-position of the aromatic ring, the structural properties of the two materials are significantly different.

Developments in genetic algorithm techniques for structure solution from powder diffraction data

Abstract This paper presents an overview of developments that have taken place in recent years in the genetic algorithm technique for structure solution from powder diffraction data. After a brief resumé, of the essential features of the genetic algorithm technique for structure solution, the paper highlights recent developments in fundamental aspects of the technique, including the development of parallel computing concepts, the analysis of the evolutionary history in genetic algorithm structure solution calculations and the combination of energy information together with the powder diffraction data in structure solution. Several examples are also given to illustrate the application of the genetic algorithm technique to solve crystal structures of different types of organic molecular materials, including oligopeptides and multi-component co-crystals.

Structural Aspects of a Dendrimer Precursor Determined Directly from Powder X-ray Diffraction Data

The structure of 3,5-dimethoxybenzyl alcohol has been determined directly from powder X-ray diffraction data using the genetic algorithm technique for structure solution followed by Rietveld refinement. This material is the precursor to a family of dendrimer materials, and structural features exhibited by 3,5-dimethoxybenzyl alcohol in the solid state may be important in the rationalization of higher generation dendrimer materials within this family.

Rationalizing the Structural Properties of Bupivacaine Base—A Local Anesthetic—Directly from Powder X-Ray Diffraction Data

Bupivacaine belongs to a family of 1-alkyl-2′,6′-pipecoloxylidides, which has shown promise as reversible action potential blockers that can introduce prolonged local anesthetic effects. The crystal structure of the free-base form of bupivacaine has been determined directly from powder X-ray diffraction data using the Genetic Algorithm technique for structure solution, followed by Rietveld refinement. This work further emphasizes the scope and utility of ab initio structure solution directly from powder X-ray diffraction data for tackling structural problems within the biomedical field, leading to opportunities for the investigation of structure–property relationships. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Polymorphism of a Novel Sodium Ion Channel Blocker

2‐{[4‐(4‐Fluorophenoxy)phenyl]‐methylene}‐hydrazinecarboxamide, a member of the semicarbazone family which has shown potential therapeutic use as anticonvulsants, has been found to exist in two polymorphic forms denoted A and B. In addition to reporting aspects of the physical characterization of both forms, the crystal structure of polymorph A has been determined directly from powder X‐ray diffraction data using the Genetic Algorithm technique for structure solution, followed by Rietveld refinement. This structure is compared with that of polymorph B, which was determined previously from single crystal X‐ray diffraction data. Knowledge of the crystal structures of the two polymorphs provides the opportunity for establishing structure‐property relationships. This work further emphasizes the scope and utility of ab initio structure solution from powder X‐ray diffraction data in the pharmaceuticals field. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2017–2026, 2003