Arjun Kalra1, Joseph W Lubach2, Eric J Munson3, Tonglei Li4. 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. 2. Genentech, Inc., South San Francisco, California, 94080, USA. 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40508, USA. 4. Department of Industrial & Physical Pharmacy, College of Pharmacy, Purdue University, RHPH Building, Room 124B, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907-2091, USA. tonglei@purdue.edu.
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.
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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