Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules

Abstract

The purpose of this study was to understand how different polymers affect the crystal growth rates of two chemically diverse organic drug molecules (bifonazole and nimesulide) from the undercooled melt regime close to the glass transition temperature. Bifonazole is an antifungal drug that contains no traditional hydrogen bond donors, only acceptors. In contrast, nimesulide contains both hydrogen bond donor and acceptor groups. Therefore, the potential hydrogen bonding interactions with polymers vary between the two compounds. For bifonazole, poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone-vinyl acetate) (PVP/VA) and poly(acrylic acid) (PAA) were investigated, while for nimesulide, PVP, PVP/VA and poly(vinyl acetate) (PVAc) were probed. Polymers were incorporated at a level of 5%w/w by cryomilling followed by melt quenching. Linear crystal growth rates in the presence and absence of polymers were measured as a function of temperature (18-100 C for bifonazole and 18-80 C for nimesulide) using optical microscopy. Differential scanning calorimetry (DSC) and infrared spectroscopy were performed for further characterization. All of the polymers decreased the growth rates of both drugs, however large differences could be observed between polymers in terms of the extent of crystal growth inhibition. For bifonazole, PAA was a notably better crystal growth inhibitor compared to the other polymers. This may be related to formation of specific interactions between the drug and the polymer. For nimesulide, the order of effectiveness was PVP$PVP/VA>PVAc and, compared to bifonazole, differences seen between polymers were more modest. Infrared (IR) spectroscopy and density functional calculations strongly suggested that amorphous nimesulide formed an intramolecular hydrogen bond. IR spectroscopy showed that drug-polymer intermolecular hydrogen bonding did occur, but was hampered by the partial loss of the hydrogen bond donor to the intramolecular hydrogen bond. Hence the effectiveness of a polymer appears to depend not only on the chemistry of the drug, but also on the availability of hydrogen bonding groups.

Enhancement of docetaxel solubility using binary and ternary solid dispersion systems

“…The viscosity of the medium does increase due to Kollidon 12PF but it is for sure, going to be lesser than the PVP K30 at the equivalent concentration. And also, there is a high potential of hydrogenbonding interaction between PVP hydrogen bond acceptors 35 and DTX hydrogen bond donors. So, it is not difficult to surmise that the overall increment could be a combined effect of viscosity 34 , hydrogen-bonding interactions 36 and shielding of DTX by PVP 3 .…”

An Investigation of Nifedipine Miscibility in Solid Dispersions Using Raman Spectroscopy

“…One of the underpinning mechanisms which helps prevent the drug molecule from recrystallizing is the molecular interaction between drug and polymer. The intermolecular interactions (which may be specific such as hydrogen bonding and/or non-specific such as van der Waals force (5)) increase kinetic barriers by lowering molecular mobility (6,7). The strength of intermolecular interaction is a key factor governing the physical stabilization of solid dispersions and it may be related to the miscibility of the drug in the polymer matrix (7).…”

“…The intermolecular interactions (which may be specific such as hydrogen bonding and/or non-specific such as van der Waals force (5)) increase kinetic barriers by lowering molecular mobility (6,7). The strength of intermolecular interaction is a key factor governing the physical stabilization of solid dispersions and it may be related to the miscibility of the drug in the polymer matrix (7). To date, there have been several attempts to apply analytical methods to characterize drug-polymer miscibility, e.g., differential scanning calorimetry (DSC) (3,(8)(9)(10)(11)(12)(13)(14)(15)(16), infrared spectroscopy (IR) (8)(9)(10)(11)(12)(13)(17)(18)(19), solid state-nuclear magnetic resonance (ss-NMR) (14,16), Xray powder diffractometry (XRD) (10), X-ray photoelectron spectroscopy (XPS) (14) and Raman spectroscopy (15,(19)(20)(21)(22)(23).…”

Application of Vibrational Spectroscopy to Study Solid-state Transformations of Pharmaceuticals

“…IR and Raman spectroscopy are also important tools to study changes in intermolecular interactions upon amorphization and the presence of drug-polymer or drugcoformer interactions that stabilize the system [202][203][204][205][206][207][208]287]. H bonding between the drug and the polymer or coformer can affect the molecular mobility of the API, inhibit H bonding between two API molecules and can impact on the crystallization driving force due to the relative strength of API-polymer/coformer and API-API H bonds.…”