Structure, Solubility, Screening, and Synthesis of Molecular Salts

Black, Simon; Collier, Edwin A.; Davey, Roger J.; Roberts, R.J.

doi:10.1002/jps.20927

Cited by 153 publications

(152 citation statements)

References 23 publications

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Section: Research Papers 2 Publcifsupporting

confidence: 47%

“…The angle N1C2C3C4 is 158.84 (17) ° for (II) and this too shows a modest conformational change from the range found for the cations of (I). These small differences do not however amount to evidence of two or more dramatically distinct conformer geometries as has been previously described for salt forms of related phenylethylamine species such as methylephedrine, psuedo-ephedrine and tyramine (Kennedy et al, 2011;Black et al, 2007;Briggs et al, 2012).All six crystallographically independent NH 3 groups in structure (I) utilise all three H atoms as single hydrogen bond donors. Both the H 2 PO 4 salt and the room temperature phase of the SO 4 salt show similar hydrogen-bonding behaviour by the amphetamine cation (Pogorzelec-Glaser et al, 2009;Hebert, 1978).…”

mentioning

confidence: 51%

“…Studies on systematic series of crystal structures of phenylethylamine salts have been instigated with a view to determining relationships between crystal structure and the physicochemical properties of APIs (see for example Kennedy et al, 2011;Black et al, 2007;Briggs et al, 2012;Cruickshank et al, 2013). The ultimate goal of such studies is to understand and improve the pharmaceutical salt selection process.…”

Section: Commentmentioning

confidence: 99%

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The hydrochloride and hydrobromide salt forms of (S)-amphetamine

2015

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This version is available at https://strathprints.strath.ac.uk/54364/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. Abstract(S)-Amphetamine hydrochloride, C 9 H 14 ClN, has a Z′ = 6 structure with six independent cation, anion pairs. That these are indeed crystallographically independent is supported by different packing orientations of the cations and by observation of a wide range of cation conformations generated by rotation about the phenyl-CH 2 bond. The supramolecular contacts about the anions also differ such that both a wide variation in the geometry of the three N-H···Cl hydrogen bonds formed by each chloride anion and differences in C-H···Cl contacts are apparent. (S)-Amphetamine hydrobromide, C 9 H 14 BrN, is broadly similar to the chloride in terms of cation conformation, the existance of three N-H···X hydrogen bond contacts per anion and the overall 2 dimensional hydrogen bonded sheet motif. However, only the chloride structure features organic bilayers and Z′ > 1. CommentSalt selection or salt screening is a common technique used in the pharmacuetical industry to improve the physicochemical properties of potential Active Pharmaceutical Ingredients (APIs, Stahl & Wermuth 2008). Studies on systematic series of crystal structures of phenylethylamine salts have been instigated with a view to determining relationships between crystal structure and the physicochemical properties of APIs (see for example Kennedy et al., 2011;Black et al., 2007;Briggs et al., 2012;Cruickshank et al., 2013). The ultimate goal of such studies is to understand and improve the pharmaceutical salt selection process. A member of the phenylethylamine class of molecules, amphetamine is popularly known as a stimulant and as a drug of abuse (Kilminster et al., 1977), but it also has legitimate pharmaceutical roles for instance in the treatment of attention defecit hyperactivity disorder and of narcolepsy (Wood et al., 2014). Despite the high pro...

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Section: Research Papers 2 Publcifsupporting

confidence: 47%

mentioning

confidence: 51%

Section: Commentmentioning

confidence: 99%

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The hydrochloride and hydrobromide salt forms of (S)-amphetamine

2015

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“…ΔpKa (ΔpKa= pKa base−pKa acid) is widely used to predict the outcome of adduct products of acids and basic molecules. It is generally assumed that the resulting adduct would be a salt if ΔpKa>3, whereas if ΔpKa<0, it would be a cocrystal (24,25). Adduct could be either salt or cocrystal or complex with partial proton transfer if ΔpKa is between ΔpKa>0 and ΔpKa<3 (26).…”

Section: Introductionmentioning

confidence: 99%

Improvement of Physicochemical Properties of an Antiepileptic Drug by Salt Engineering

et al. 2012

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Abstract. The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ( 1 H) and carbon ( 13 C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products.

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“…Recently, a number of studies have been dedicated to improving salt selection strategies and to developing predictive capabilities for the properties of the final form through better understanding the crystallization behavior of salts and interrelationships between structure and physical properties (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The importance of this knowledge is also obvious in the emerging discipline of crystal engineering (12,13).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Relationships Between Solid-State Properties, Counterion, and Developability of Pharmaceutical Salts

Guerrieri

Rumondor

et al. 2010

AAPS PharmSciTech

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Abstract. The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts.

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Structure, Solubility, Screening, and Synthesis of Molecular Salts

Cited by 153 publications

References 23 publications

The hydrochloride and hydrobromide salt forms of (S)-amphetamine

The hydrochloride and hydrobromide salt forms of (S)-amphetamine

Improvement of Physicochemical Properties of an Antiepileptic Drug by Salt Engineering

Analysis of Relationships Between Solid-State Properties, Counterion, and Developability of Pharmaceutical Salts

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