Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low-Concentration Poly(ethylene oxide)

Abstract

Physical stability of pharmaceutical amorphous solid dispersions is one of the critical attributes to the successful development of the formulation. Herein, we studied the impact of low-concentration poly(ethylene oxide) (PEO) on the crystallization rates of three polymorphs of indomethacin (IMC, γ-, α-, and δ-form). We observed that the addition of 3% w/w PEO significantly increased the crystal growth rates of γ-form and α-form of IMC, but had a negligible effect on the δ-form. The reduction of the activation energy for the crystal growth of IMC polymorphs after adding the PEO follows the order γ-form > α-form > δ-form, which is consistent with the trend toward the accelerating effects of PEO on the crystal growth rates of three polymorphs. With the addition of low-concentration PEO, there is an increase of molecular mobility of IMC as evidenced by the decreased structural relaxation times and viscosities. This study suggests that the substantially different effects of PEO on the crystal growth rates of IMC polymorphs are attributable to the different adsorption of PEO on the crystal surface of those polymorphs, which in turn exerts a selective accelerating effect on IMC molecules to organize into the different crystalline phases. These findings are relevant for understanding the crystallization behavior of amorphous solid dispersions containing polymorphic drugs.

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound

“…In the case of SIL + 25 wt.% PVAc, the acceleration of the molecular mobility, exerted by the addition of a low-T g polymer, decreased the temperature of the crystallization onset (see Figure 1A). This result is consistent with the data reported for the binary mixture of indomethacin and PEO, where the polymer addition accelerated the crystallization process [46]. However, as can be seen in Figure 1A, with a further increase in the concentration of this polymeric additive (PVAc), the onset of the SIL recrystallization process shifts towards higher temperatures.…”

“…Moreover, based on the collected dielectric spectra the ASD systems containing up to 50 wt.% of PVAc are characterized by the lower temperature of the crystallization onset than amorphous SIL (see Figure 3). This would support the hypothesis that the acceleration of the molecular dynamics of the system would increase its tendency towards recrystallization [46]. On the other hand, it should be emphasized that with each subsequently measured concentrations of the polymer additive, the T C shifts towards higher temperatures, which indicates an improvement of the physical stability.…”

“…In contrast to the above, a polymer with a low T g (well below the T g of the amorphous l) will decrease the T g of the system-the so-called plasticization effect-which corresponds to the acceleration of the molecular mobility. It has been demonstrated, using the example of a binary mixture of the model drug, indomethacin, with a polymer, poly(ethylene oxide) (PEO), that the plasticization effect can, indeed, accelerate its crystallization [46].…”

Flow‐based reactor design for the continuous production of polymeric nanoparticles

“…NPs were produced via batch nanoprecipitation and continuous nanoprecipitation in the CJM (Figure a). After production, the NPs were stored for 24 h at room temperature and 24 h at 4 °C to promote crystallization of non‐encapsulated indomethacin, which were removed via centrifugation . NPs were further purified from non‐encapsulated drug in solution, dissolved polymer, and residual solvents by ultrafiltration.…”

Advances in coamorphous drug delivery systems

“…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..…”