Expanding the Solid-State Landscape of <scp>l</scp>-Phenylalanine: Discovery of Polymorphism and New Hydrate Phases, with Rationalization of Hydration/Dehydration Processes

Williams, P. Andrew; Hughes, Colan E.; Buanz, Asma; Gaisford, Simon; Harris, Kenneth David Maclean

doi:10.1021/jp401547f

Cited by 39 publications

(59 citation statements)

References 79 publications

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“…A similar conformation is found in other 2-methyl-substituted amino acids, for example, isoVal monohydrate, CISNUP [ = 177.0 (3) ; Butcher et al, 2013] and DMTYRS [ = À176.58 (1) ], while the cis conformation is observed in other cases, as in QABCAX. This slightly distorted data reports conformation is also comparable to that found in the crystal structures of phenylalanine derivatives, for example in l-Phe monohydrate (GOFWOP; Williams et al, 2013).…”

Section: Structure Descriptionsupporting

confidence: 83%

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

Fujii

2016

IUCr Data

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The title compound, C 10 H 13 NO 2 ÁH 2 O, crystallizes in a zwitterionic form as a monohydrate, involving the propylbenzene group with a trans conformation. It is a non-natural amino acid, and has attracted attention as an inhibitor of phenylalanine hydroxylase. In the crystal, molecules are linked by N-HÁ Á ÁO hydrogen bonds, forming C(5) chains along the c-axis direction. Two chains are linked by another N-HÁ Á ÁO hydrogen bond, forming an R 3 3 (11) ring motif. Further O-HÁ Á ÁO hydrogen bonds link these motifs via the water molecules, to form a three-dimensional framework.

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Section: Structure Descriptionsupporting

confidence: 83%

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

Fujii

2016

IUCr Data

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“…The symmetry of the resulting unit cell corresponded to the space group P 2 with four molecules in the asymmetric unit. Recently Williams et al 6. used powder X‐ray diffraction to elucidate the structure of a second polymorph, form II ( F‐II , QQQAUJ04), “stable only under rigorously dry conditions”, which can be reversibly converted to the hemihydrate and monohydrate upon increased relative humidity.…”

Section: Crystallographic Unit Cells Of L‐phementioning

confidence: 99%

The Polymorphs of L‐Phenylalanine

et al. 2014

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The solid-state structure of the amino acid phenylalanine (Phe) offers a potential key to understanding the behavior of a large class of important aromatic compounds. Obtaining good single crystals is, however, notoriously difficult. The structure of the common polymorph of Phe, form I, was first reported by Weissbuch et al. (as D-Phe) in 1990, but the correctness of the published C2 unit cell with two disordered molecules in the asymmetric unit was later questioned and other space groups suggested. The identity of form I of L-Phe is here established to be P21 with Z'=4, based on data from a well-diffracting single crystal grown from an acetic acid solution of the amino acid. A second new polymorph, form IV, together with the two recently described forms II and III provide unprecedented information on the structural complexity of this essential amino acid. It is furthermore documented that the racemate, dl-Phe, does not grow proper single crystals.

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“…16 On the other hand, solvates represent a route to obtain novel unsolvated crystal forms, which are not accessible by direct crystallisation. [17][18][19][20][21][22] The inclusion of solvent molecules into crystal forms has been widely studied, not only in the pharmaceutical field. The influence of solvate formation has been studied in a co-crystal system that has been crystal-engineered to undergo photodimerisation.…”

Section: Introductionmentioning

confidence: 99%

Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

Kitchen

Melvin

Najib

et al. 2016

Crystal Growth & Design

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Bio-isosteric replacement is a frequently used tool in medicinal chemistry. While the pharmacological activity is not influenced by the exchange of substituents, the solid-state characteristics and formation of different crystal forms may well be altered dramatically, jeopardizing the processability and safety of the drug compound. In this study we investigate a series of triphenylimidazole (TPI) derivatives as model compounds with the bio-isosteric exchange of only one halogen position (F, Cl, Br, I). Crystallization from two industrially used solvents (methanol and acetonitrile) reveals solvate formation of all TPIs, for which the basic hydrogen bonded motif does not change. The three-dimensional packing depends on the size of the substituent and changes from fluoroto chloro-and bromo-substitution but remains the same for the larger iodo-substituent. From acetonitrile, only F-TPI and Cl-TPI form an isomorphic channel solvate, which in both cases desolvates reversibly to an isomorphic crystal form. Due to the halogen atom lining of the channels, bromine and iodine are too large to generate a stable packing. This study illustrates the importance of understanding the influence of bio-isosteric substitution on the solid state, in order to best utilize this common tool.

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Expanding the Solid-State Landscape of l-Phenylalanine: Discovery of Polymorphism and New Hydrate Phases, with Rationalization of Hydration/Dehydration Processes

Cited by 39 publications

References 79 publications

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

The Polymorphs of L‐Phenylalanine

Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

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