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Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid



Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH∙∙∙pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state.


Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated.


The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed.


The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.

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We thank CPD (Center for Pharmaceutical Development) and CPPR (Center for Pharmaceutical Processing Research) for providing partial financial support for this study. The authors declare the following competing financial interest(s): E.J.M. is a partial owner of Kansas Analytical Services, a company that provides solid-state NMR services to the pharmaceutical industry. The results presented here are from academic work at the University of Kentucky, and no data from Kansas Analytical Services are presented.

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Correspondence to Tonglei Li.

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Guest Editors: Tony Zhou and Tonglei Li

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Kalra, A., Lubach, J.W., Munson, E.J. et al. Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid. Pharm Res 35, 51 (2018).

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Key words

  • amorphous
  • crystallization
  • intermolecular interactions
  • molecular species
  • nucleation
  • phase transition
  • solid-state NMR spectroscopy