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

Pharmaceutical Research volume 35, Article number: 51 (2018) Cite this article

Abstract

Purpose

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.

Methods

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

Results

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.

Conclusions

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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ACKNOWLEDGMENTS AND DISCLOSURES

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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Authors and Affiliations

  1. Department of Industrial & Physical Pharmacy, College of Pharmacy, Purdue University, RHPH Building, Room 124B, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907-2091, USA

    Arjun Kalra & Tonglei Li

  2. Genentech, Inc., South San Francisco, California, 94080, USA

    Joseph W. Lubach

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40508, USA

    Eric J. Munson

Authors
  1. Arjun Kalra
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  2. Joseph W. Lubach
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  3. Eric J. Munson
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  4. Tonglei Li
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Corresponding author

Correspondence to Tonglei Li.

Additional information

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). https://doi.org/10.1007/s11095-018-2346-0

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  • DOI: https://doi.org/10.1007/s11095-018-2346-0

Key words

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