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Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-β-CD) with various molecular weights (M w ) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-β-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-β-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (E cr ) in ASDs with the oligosaccharide having a greater M w (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs' core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-β-CD. Therefore, this modified saccharide is a better stabilizer of the examined API., (Copyright © 2022. Published by Elsevier B.V.)

In this paper, we propose one-step synthetic strategies for obtaining well-defined linear and star-shaped polyvinylpyrrolidone (linPVP and starPVP). The produced macromolecules and a commercial PVP K30 with linear topology were investigated as potential matrices for suppressing metronidazole (MTZ) crystallization. Interestingly, during the formation of binary mixtures (BMs) containing different polymers and MTZ, we found that linear PVPs exhibit maximum miscibility with the drug at a 50:50 weight ratio (w/w), while the star-shaped polymer mixes with MTZ even at a 30:70 w/w. To explain these observations, comprehensive studies of MTZ-PVP formulations with various contents of both components were performed using Fourier-transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results clearly showed that the polymer's topology plays a significant role in the type of interactions occurring between the matrix and MTZ. Additionally, we established that for MTZ-PVP 50:50 and 75:25 w/w BMs, linear polymers have the most substantial impact on inhibiting the crystallization of API. The star-shaped macromolecule turned out to be the least effective in stabilizing amorphous MTZ at these polymer concentrations. Nevertheless, long-term structural investigations of the MTZ-starPVP 30:70 w/w system (which is not achievable for linear PVPs) demonstrated its complete amorphousness for over one month. [ABSTRACT FROM AUTHOR]

Poly(1-vinyl-2-pyrrolidone) (Povidone, PVP) is one of the most interesting and versatile synthetic polymers utilised in the pharmaceutical and cosmetic industries. Its large-scale commercial production offers an assortment of products in a wide range of molecular weights but poorly-controlled (macro)structural parameters (i.e., dispersity, functionality) limiting the efficiency of PVP-based drug delivery systems (DDS). In this work, synthesised linear and star-shaped PVPs with a strictly defined structure and functionality were compared with the linear, commercially-supplied product and explored as potential vehicles for physical entrapment of metronidazole (MTZ). Here, a question is addressed how differences in their macromolecular properties affect the amorphisation of MTZ, drug encapsulation, the stability of drug-loaded micellar structures and their in vitro release from the carrier. The X-ray diffraction studies and calorimetric measurements revealed that MTZ crystallises in all investigated herein systems reducing the glass transition temperature of the binary mixture significantly. Transmission electron microscopy and dynamic light scattering analysis revealed that MTZ-loaded DDS are able to form ultrasmall regular nanocarriers with an increasing effect of regularity and sphericity from star-shaped DDS to linear-based ones. We founded that synthesised linear-based DDS is the most effective for MTZ entrapment (PVP:MTZ = 1:1 weight ratio) due to their smallest hydrodynamic radius d h = 14.7 nm, the highest stability of micellar structures −2.37 mV, and the highest values of loaded drug 76.5%. Moreover, all applied PVP-based DDS revealed an initial burst release effect of MTZ (pH = 7.4) reaching up to 60% of drug released within the first 5 h (the first-order release model fits). The marked efficiency of MTZ-loaded DDS of strictly defined structural parameters indicates the great importance of polymer preparation strategy in the targeted therapy. [Display omitted] • Metronidazole-polyvinylpyrrolidone (MTZ-PVP) drug delivery systems were obtained using polymers of various topology. • Commercial linear pvp has been compared with synthesised linear and star ones in terms of ability to form stable micelles and solubilize MTZ. • MTZ-loaded DDS are able to form ultrasmall regular nanocarriers with an increasing effect of regularity and sphericity from star-shaped DDS to linear-based ones. • MTZ crystallises in all investigated herein systems reducing the glass transition temperature of the binary mixture significantly. • Synthesised linear-based DDS is the most effective for MTZ entrapment. [ABSTRACT FROM AUTHOR]