Formation of Isomorphic Desolvates: Creating a Molecular Vacuum

Stephenson, Gregory A.; Groleau, Edward G.; Kleemann, Rita L.; Xu, Wei; Rigsbee, Daniel R.

doi:10.1021/js970449z

Cited by 158 publications

(163 citation statements)

References 15 publications

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“…There is some¯exibility in the amide backbone, with the OÐCÐCÐN(H 3 ) torsion angles ranging from 27.3 (6) to 44.5 (6) . The geometry of the related species cefadroxil (Shin & Cho, 1992) has a similar conformation, ®tting within the range found here for CEX, as does CEX complexed with -napthol (Kemperman et al, 1999), although here the amide backbone is more eclipsed (equivalent angle = 16.2 ).That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Stephenson et al (1998) in the moisture adsorption isotherms of CEX. Only above 70% relative humidity does CEX begin to approach a genuine dihydrate.…”

supporting

confidence: 65%

“…That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Stephenson et al (1998) in the moisture adsorption isotherms of CEX. Only above 70% relative humidity does CEX begin to approach a genuine dihydrate.…”

Section: Commentmentioning

confidence: 99%

“…The characterization of the solid-state properties of CEX has, however, been hampered by uncertainty over the exact nature of its hydration behaviour. CEX can form a range of hydrates in the solid state, all with essentially identical unit cells, and has thus been identi®ed as part of the class of compounds known as isomorphic desolvates (Stephenson et al, 1998). Indeed, CEX is known to go further and reversibly replaces water with other small, polar, solvent molecules (Pfeiffer et al, 1970).…”

mentioning

confidence: 99%

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Cephalexin: a channel hydrate

et al. 2003

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The antibiotic cephalexin [systematic name: d-7-(2-amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid] forms a range of isomorphic solvates, with the maximum hydration state of two water molecules formed only at high relative humidities. The water content of the structure reported here (C 16 H 17 N 3 O 4 SÁ1.9H 2 O) falls just short of this con®guration, having three independent cephalexin molecules, one of which is disordered, and 5.72 observed water molecules in the asymmetric unit. The facile nature of the cephalexin solvation/desolvation process is found to be facilitated by a complex channel structure, which allows free movement of solvent in the crystallographic a and b directions. CommentThe cephalosporin derivative cephalexin (CEX) is an antibiotic useful for treating a variety of infections, including those of the respiratory tract, of the skin and of other soft tissues. The characterization of the solid-state properties of CEX has, however, been hampered by uncertainty over the exact nature of its hydration behaviour. CEX can form a range of hydrates in the solid state, all with essentially identical unit cells, and has thus been identi®ed as part of the class of compounds known as isomorphic desolvates (Stephenson et al., 1998). Indeed, CEX is known to go further and reversibly replaces water with other small, polar, solvent molecules (Pfeiffer et al., 1970). Powder diffraction studies show that the isomorphic solvates have similar unit-cell dimensions but, despite their crystallographic similarities, their commercially important physical properties (such as their solubilities and dehydration behaviour) vary considerably. Despite considerable interest in CEX, no single-crystal structure determination had previously been achieved, and so the structural basis of its ready solvation/desolvation process remained unknown. However, we have overcome the problems of small crystal size and loss of (single) crystallinity upon facile dehydration by utilizing careful sample preparation methods (see Experimental) and the extra intensity of synchrotron radiation to report here the ®rst crystal structure of any CEX hydrate, that of CEXÁ1.9H 2 O, (I).The asymmetic unit of (I) was found to contain three CEX molecules and, spread over ten sites, 5.72 water molecules. The three crystallographically independent molecules of CEX (Fig. 1) were found to exist in the zwitterionic form, with no signi®cant differences in their bond lengths or angles. One CEX molecule is disordered. There is some¯exibility in the amide backbone, with the OÐCÐCÐN(H 3 ) torsion angles ranging from 27.3 (6) to 44.5 (6) . The geometry of the related species cefadroxil (Shin & Cho, 1992) has a similar conformation, ®tting within the range found here for CEX, as does CEX complexed with -napthol (Kemperman et al., 1999), although here the amide backbone is more eclipsed (equivalent angle = 16.2 ).That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Ste...

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supporting

confidence: 65%

Section: Commentmentioning

confidence: 99%

mentioning

confidence: 99%

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Cephalexin: a channel hydrate

et al. 2003

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“…This shows the significance of using solvate formation during crystal form discovery, as has been frequently shown for organic compounds. 17,20,47,49 I-TPI results in the same crystal form independent from the solvent/solvate, which again points towards one energetically favoured modification.…”

Section: Unsolvated Crystal Formsmentioning

confidence: 67%

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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“…There are many examples of drugs that are formulated as a hydrate form, such as cephalexin, cefaclor, ampicillin and theophylline. [4][5] Hydrates (water solvates) are of special concern, because they occur more frequently than other solvates. Another factor that makes hydrates particularly important is the fact that water is a non-toxic solvent.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Hydrate and Solvate Formation Using Statistical Models

Takieddin

Khimyak

Fábián

2015

Crystal Growth & Design

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Novel, knowledge-based models for the prediction of hydrate and solvate formation are introduced, which require only the molecular formula as input. A dataset of more than 19,000 organic, non-ionic and non-polymeric molecules was extracted from the Cambridge Structural Database. Molecules that formed solvates were compared with those that did not using molecular descriptors and statistical methods, which allowed the identification of chemical properties that contribute to solvate formation. The study was conducted for five types of solvates: ethanol, methanol, dichloromethane, chloroform and water solvates. The identified properties were all related to the size and branching of the molecules and to the hydrogen bonding ability of the molecules. The corresponding molecular descriptors were used to fit logistic regression models to predict the probability of any given molecule to form a solvate. The established models were 2 able to predict the behavior of ~80% of the data correctly using only two descriptors in the predictive model.

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Formation of Isomorphic Desolvates: Creating a Molecular Vacuum

Cited by 158 publications

References 15 publications

Cephalexin: a channel hydrate

Cephalexin: a channel hydrate

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

Prediction of Hydrate and Solvate Formation Using Statistical Models

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