Conformational analysis of intramolecular hydrogen-bonded amino alcohols. Determination of the NH/N-electron pair equilibrium and assignment of conformational free energies for interactions in decahydroquinoline and piperidine compounds in a dilute nonpolar medium

Aaron, Herbert S.; Ferguson, C. P.

doi:10.1021/ja00438a045

Cited by 11 publications

(1 citation statement)

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“…31 The higher reactivity of COP toward esterificaton with CA could be mainly due to the higher nucleophilicity of the allyl alcohol of COP compared to the alkyl alcohol of CAR. 32 Moreover, intramolecular hydrogen bonding between the vicinal alcohol and amine groups 33 in solid state CAR could provide a smaller fraction of available alcohol for the esterification with CA. In contrast, the structure of COP does not seem to favor the formation of such intramolecular hydrogen bonds.…”

Section: ■ Discussionmentioning

confidence: 99%

Drug–Excipient Interactions in the Solid State: The Role of Different Stress Factors

et al. 2017

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Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

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Section: ■ Discussionmentioning

confidence: 99%

Drug–Excipient Interactions in the Solid State: The Role of Different Stress Factors

et al. 2017

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Conformational Analysis of Intramolecular‐Hydrogen‐Bonded Compounds in Dilute Solution by Infrared Spectroscopy

Aaron

1979

Topics in Stereochemistry

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ChemInform Abstract: Conformational Analysis of Intramolecular Hydrogen‐Bonded Amino Alcohols. Determination of the NH/N‐Electron Pair Equilibrium and Assignment of Conformational Free Energies for Interactions in Decahydroquinoline and Piperidine Compounds in a Dilute Nonpolar Medium.

Aaron¹,

Ferguson²

1977

Chemischer Informationsdienst

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Conformational analysis of intramolecular hydrogen-bonded amino alcohols. Determination of the NH/N-electron pair equilibrium and assignment of conformational free energies for interactions in decahydroquinoline and piperidine compounds in a dilute nonpolar medium

Abstract: Die Konformationsgleichgewichte der epimeren Hydroxychinoline (II) und (III) in Tetrachlorkohlenstoff wurden IR‐spektroskopisch ermittelt und daraus die Gleichgewichtsposition der NH‐Gruppe in trans‐Decahydrochinolin (I) zweifelsfrei abgeleitet.

Cited by 11 publications

References 5 publications

Drug–Excipient Interactions in the Solid State: The Role of Different Stress Factors

Drug–Excipient Interactions in the Solid State: The Role of Different Stress Factors

Conformational Analysis of Intramolecular‐Hydrogen‐Bonded Compounds in Dilute Solution by Infrared Spectroscopy

ChemInform Abstract: Conformational Analysis of Intramolecular Hydrogen‐Bonded Amino Alcohols. Determination of the NH/N‐Electron Pair Equilibrium and Assignment of Conformational Free Energies for Interactions in Decahydroquinoline and Piperidine Compounds in a Dilute Nonpolar Medium.

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