Permeability Behavior of Nanocrystalline Solid Dispersion of Dipyridamole Generated Using NanoCrySP Technology

Abstract

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals of improved properties. Our lab has also contributed in this field by providing a ‘novel’ platform technology, NanoCrySP, for the generation of nanocrystals. NanoCrySP-generated nanocrystals have improved the oral bioavailability of various molecules. In this study, we aim to assess the permeability behavior of nanocrystals generated by NanoCrySP. Three samples of Dipyridamole (DPM) drug were used in this study: (1) DPM (micron-sized powder), (2) nanocrystals of DPM (NS), generated by media milling (as control) and, (3) nanocrystalline solid dispersion containing DPM (NSD) in the matrix of mannitol (MAN), generated using NanoCrySP technology. In vitro (Caco-2 cell lines) and ex vivo (everted gut sac) studies were conducted in this work. Cellular permeability (Papp) from apical-to-basolateral side in Caco-2 cell monolayer was found to be in the order NS > NSD > DPM, which was the same as their apparent solubility values. Higher Papp from a basolateral-to-apical side suggested a significant contribution of the P-gp efflux transport for DPM, while NS exhibited much higher inhibition of the efflux mechanism than NSD. Both NS and NSD showed higher permeation from the jejunum region in the ex vivo everted gut sac study. Interestingly, Papp of NSD was similar to NS in ex vivo everted gut sac model, however, NSD showed higher mucoadhesion than NS and DPM in this study.

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…Furthermore, Girdhar et al propose that for increased bioavailability, mucoadhesion is an essential factor to account for based on everted gut sac model experiments using dipyridamole. Mucoadhesive particles could locally increase the supersaturation close to the membrane and therefore increase the transmembrane flux (Girdhar et al, 2018).…”

Factors Affecting Crystallization Kinetics of Fenofibrate and Its Implications for the Generation of Nanocrystalline Solid Dispersions via Spray Drying

“…Form I of FNT has a melting point of 80.5 °C, and cooling of its melt to subambient temperatures generates an amorphous phase. FNT did not crystallize in a subsequent heating cycle up to its melting point (Figure ).…”

“…FNT did not crystallize in a subsequent heating cycle up to its melting point (Figure ). FNT lacks hydrogen bonding donor, and it arranges in a crystal lattice solely by van der Waals interactions . However, in the presence of MAN as the heteronucleant, FNT crystallized during the second heating cycle in DSC.…”

“…A non-isothermal crystallization kinetics study was carried out to determine the underlying mechanism in the generation of FNT nanocrystals in the presence of native MAN. 25 and cooling of its melt to subambient temperatures generates an amorphous phase. FNT did not crystallize in a subsequent heating cycle up to its melting point (Figure 8).…”

“…In this technique, the evaporation of a solution droplet containing drug and excipient in a spray dryer leads to the formation of powder-containing drug nanocrystals embedded in the matrix of the excipient. This final spray-dried product is known as “nanocrystalline solid dispersion”. , The generated nanocrystals using NanoCrySP have shown improved dissolution, permeability, oral bioavailability, and efficacy. − The drying of the droplet in a spray-drying process involves solution-state crystallization kinetics followed by solid-state crystallization kinetics. , However, the current understanding of the NanoCrySP technology is solely based on solid-state crystallization kinetics of the drug. We have reported a few mechanisms involved in the formation of nanocrystals based on the solid-state crystallization kinetics such as (i) excipient-driven plasticization of drug in the amorphous phase and (ii) primary heterogeneous nucleation due to the matrix forming excipient .…”