Properties of the Sodium Naproxen-Lactose-Tetrahydrate Co-Crystal upon Processing and Storage

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Ioana Sovago, Wenbo Wang, Danwen Qiu, Dharaben Kaushikkumar Raijada, Jukka Rantanen, Holger Grohganz, Thomas Rades, Andrew D Bond, Korbinian Löbmann

Co-crystals and co-amorphous systems are two strategies to improve the physical properties of an active pharmaceutical ingredient and, thus, have recently gained considerable interest both in academia and the pharmaceutical industry. In this study, the behavior of the recently identified sodium naproxen-lactose-tetrahydrate co-crystal and the co-amorphous mixture of sodium, naproxen, and lactose was investigated. The structure of the co-crystal is described using single-crystal X-ray diffraction. The structural analysis revealed a monoclinic lattice, space group P21, with the asymmetric unit containing one molecule of lactose, one of naproxen, sodium, and four water molecules. Upon heating, it was observed that the co-crystal transforms into a co-amorphous system due to the loss of its crystalline bound water. Dehydration and co-amorphization were studied using synchrotron X-ray radiation and thermogravimetric analysis (TGA). Subsequently, different processing techniques (ball milling, spray drying, and dehydration) were used to prepare the co-amorphous mixture of sodium, naproxen, and lactose. X-ray powder diffraction (XRPD) revealed the amorphous nature of the mixtures after preparation. Differential scanning calorimetry (DSC) analysis showed that the blends were single-phase co-amorphous systems as indicated by a single glass transition temperature. The samples were subsequently tested for physical stability under dry (silica gel at 25 and 40 °C) and humid conditions (25 °C/75% RH). The co-amorphous samples stored at 25 °C/75% RH quickly recrystallized into the co-crystalline state. On the other hand, the samples stored under dry conditions remained physically stable after five months of storage, except the ball milled sample stored at 40 °C which showed signs of recrystallization. Under these dry conditions, however, the ball-milled co-amorphous blend crystallized into the individual crystalline components.

Original languageEnglish
Article number509
JournalMolecules
Volume21
Issue number4
Pages (from-to)1-13
Number of pages13
ISSN1420-3049
DOIs
Publication statusPublished - 2016

ID: 162186145