Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid

Abstract

Amorphous−Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The αrelaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.

Modified Free Volume Theory for Self-Diffusion of Small Molecules in Amorphous Polymers

“…Particularly in formulation technologies, diffusion of active ingredients in polymers gains practical relevance for ensuring the physical stability of pharmaceutical amorphous solid dispersions, 1 controlled pesticide release from polymers, 2,3 design of intravaginal drug delivery systems, 4,5 and development of insecticide-impregnated mosquito nets. 6 The free volume theory (FVT) of Vrentas and Duda 7,8 offers an efficient predictive approach for estimating the self-diffusivity of small molecules in amorphous non-cross-linked polymers, proven to be consistent with experimental data on multiple occasions. 9,10 However, shortcomings such as appearance of negative values of specific hole free volume 11 and the need for at least two measured diffusivity values 12 leave room for improving this model.…”

“…38 This process was followed by inserting the obtained viscosities at each temperature into the F-SE relation according to the procedure elaborated in a previous work. 6 Figure 9 draws a comparison between the predictions of the original and modified FVT with the experimental data. In this very case, the modified FVT preditions exhibit a reasonably good agreement with the experimental data close to T g , while a relatively modest deviation is observed at larger distances to T g .…”

Molecular Dynamics and Diffusion in Amorphous Solid Dispersions Containing Imidacloprid

“…While the explicit connection of long-term stability and molecular dynamics is not addressed in the present study, it is extensively addressed for solid dispersions of imidacloprid (IMI) in another polymer matrix elsewhere. 18 This work combines dielectric and rheological spectroscopy to access the temperature evolution of the structural relaxations of ASDs containing IMI and poly(vinylpyrrolidone)-vinyl acetate (PVP/VA). The structural (α-)relaxation can be regarded as a measure for a collective mode of molecular motion involving groups of molecules and its characteristic time is considered an important microscopic parameter to describe the kinetic behavior of a system.…”

“…This emphasizes the need for the knowledge of active ingredients’ diffusion behavior in polymers and the corresponding criteria for controlling it. While the explicit connection of long-term stability and molecular dynamics is not addressed in the present study, it is extensively addressed for solid dispersions of imidacloprid (IMI) in another polymer matrix elsewhere . This work combines dielectric and rheological spectroscopy to access the temperature evolution of the structural relaxations of ASDs containing IMI and poly(vinylpyrrolidone)-vinyl acetate (PVP/VA).…”

Introducing the Molecular Pharmaceutics Special Issue on Industrial Drug Delivery─In Silico to Bedside

“…8 On the same note of pipeline operational efficiency, continuous processing has also become popular, first for drug substance but also in the drug product space and the concepts are now also being considered outside the solid-oral dosage forms space such as for topicals as reported on by Matadh et al 11 In conclusion the articles submitted to this special issue give great insight into the complex landscape of drug delivery in the pharmaceutical industry including a wide variety of modalities, dosage forms, and characterization techniques. 5 Mansuri et al 6 Mansuri et al 7 Tabriz et al 8 Pepin et al 9 Piscitelli et al 10 Matadh et al…”