Influence of Annealing in the Close Vicinity of T_g on the Reorganization within Dimers and Its Impact on the Crystallization Kinetics of Gemfibrozil

Abstract

In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature ( T g ), reveal the presence of two secondary relaxations (β, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (β) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, T c ), as well as annealing at two temperatures in the vicinity of T g and further heating up to T c , showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. ( Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-T g Temperature Tominaka S. Kawakami K. Fukushima M. Miyazaki A. Tominaka S. Kawakami K. Fukushima M. Miyazaki A. 10.1021/acs.molpharmaceut.6b00866 28043129 Mol. Pharm. 2017 14 264 273 ), who demonstrated that the sub- T g annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differen...

Mesoporous Matrices as a Promising New Generation of Carriers for Multipolymorphic Active Pharmaceutical Ingredient Aripiprazole

“…In the case of the bulk sample, the amplitude of the α-relaxation peak decreases rapidly at higher T (Figure (a)) indicating the occurrence of the crystallization process. Such a situation is commonly observed for many APIs. ,, On the other hand, this phenomenon was much less pronounced for the API infiltrated into native SiO 2 (Figure (b)) and other confined systems, regardless of the applied measurement protocol. This suggests a much lower degree of crystallization of APZ in mesopores, with respect to the bulk sample at higher temperatures.…”

“…Such a situation is commonly observed for many APIs. 33 , 64 , 65 On the other hand, this phenomenon was much less pronounced for the API infiltrated into native SiO 2 ( Figure 4 (b)) and other confined systems, regardless of the applied measurement protocol. This suggests a much lower degree of crystallization of APZ in mesopores, with respect to the bulk sample at higher temperatures.…”