Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics

Abstract

Low-concentration polymers can strongly influence crystal growth in small-molecule glasses, a phenomenon important for improving physical stability against crystallization. We measured the velocity of crystal growth in two molecular glasses, nifedipine (NIF) and o-terphenyl (OTP), each doped with four or five different polymers. For each polymer, the concentration was fixed at 1 wt % and a wide range of molecular weights was tested. We find that a polymer additive can strongly alter the rate of crystal growth, from a 10-fold reduction to a 10-fold increase. For a given polymer, increasing molecular weight slows down crystal growth and the effect saturates around DP = 100, where DP is the degree of polymerization. For all the systems studied, the polymer effect on crystal growth rate forms a master curve in the variable (T - T)/T, where T is the glass transition temperature and T is the crystallization temperature. These results support the view that a polymer's effect on crystal growth is controlled by its segmental mobility relative to the host-molecule dynamics. In the proposed model, crystal growth rejects impurities and creates local polymer-rich regions, which must be traversed by host molecules to sustain crystal growth at rates determined by polymer segmental mobility. Our results do not support the view that host-polymer hydrogen bonding plays a controlling role in crystal growth inhibition.

Advances in coamorphous drug delivery systems

“…Nevertheless, the mechanism of crystallization inhibition by small-molecules polymer analogues could be different from those of the polymer based solid dispersions. Compared to the coamorphous systems, in addition to molecular interactions, the segmental mobility of polymer chains relative to host-molecule dynamics is suggested to control its effect on crystal growth in polymer-based amorphous solid dispersions 13 . Despite the additional cost and complexity by introducing a third component into binary systems, the ternary coamorphous systems sometimes show advantages over the binary systems in terms of physical stability52., 80., 102., 103..…”

“…Furthermore, some polymers with low glass transition temperatures might accelerate rather than inhibit crystallizations of amorphous solids dispersions 12. , 13. , 14.…”

“…In addition, the increased volume of final product may cause a problem for a high-dose drug formulation10., 11.. Furthermore, some polymers with low glass transition temperatures might accelerate rather than inhibit crystallizations of amorphous solids dispersions12., 13., 14., 15..…”

In situ solid‐state NMR characterization of pharmaceutical materials: An example of drug‐polymer thermal mixing

“…[2] In recent years, there are increasing Food and Drug Administration approved amorphous solid dispersions for poorly soluble drugs to enhance bioavailability, [3] and the presence of polymer in amorphous solid dispersion (ASD) is able to stabilize APIs against crystallization. [4][5][6][7][8] As one of the major preparation methods, hot melt extrusion (HME) has been proven to be an effective and convenient way to produce drug-polymer ASDs. [9][10][11][12] For the HME method, the processing temperature is mainly determined to ensure crystalline APIs are fully melted, and it is also required to avoid the chemical decomposition of APIs and excipients.…”

“…In order to enhance oral bioavailability of those pharmaceuticals, various approaches have been proposed, including micro‐ and nanonization, self‐microemulsion, cyclodextrin complexation, lipid encapsulation, cocrystallization, salt formation, and amorphous solid dispersion . In recent years, there are increasing Food and Drug Administration approved amorphous solid dispersions for poorly soluble drugs to enhance bioavailability, and the presence of polymer in amorphous solid dispersion (ASD) is able to stabilize APIs against crystallization . As one of the major preparation methods, hot melt extrusion (HME) has been proven to be an effective and convenient way to produce drug‐polymer ASDs .…”