Esterification of pseudoephedrine hydrochloride by citric acid in a solid dose pharmaceutical preparation

Goel, Alok; Zhao, Zhicheng; Sørensen, Dan; Zhou, Jay; Zhang, Fa

doi:10.1016/j.jpba.2016.07.038

Cited by 4 publications

(2 citation statements)

References 15 publications

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“…These experimental findings are in agreement with a previous degradation study of CAR in physical mixtures with CA, where the central ester was reported to form fastest, as well . Also for pseudoephedrine, it was found that the central ester is the main reaction product . It is likely that CA is activated via anhydride formation between the central and a terminal carboxylic group before reacting with the API under ester formation .…”

Section: Discussionsupporting

confidence: 92%

“…6 Also for pseudoephedrine, it was found that the central ester is the main reaction product. 36 It is likely that CA is activated via anhydride formation between the central and a terminal carboxylic group before reacting with the API under ester formation. 37 In this case, the central carbonyl carbon can experience the electrophilic activation due to hydrogen bonding between carbonyl oxygen and the hydrogen of the free acid group, thus act as a preferential activation site (see Supporting Information).…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 92%

Section: Molecular Pharmaceuticsmentioning

confidence: 99%