Formation Of Drug Nanoparticles Research Articles

Fragment-based drug nanoaggregation reveals drivers of self-assembly

Self-assembled drug nanoaggregates are of interest due to their potential to form in cells, interfere with protein folding, or facilitate drug delivery approaches to improve the solubility, bioavailability, and pharmacokinetics. However, the physicochemical properties and molecular features of small molecules that mechanistically drive the formation of drug nanoparticles remain elusive. Therefore, the rational design of nanoaggregate-based carriers, and the prediction of intracellular aggregation based on drug structure, is still challenging. Inspired from fragment-based drug discovery, we systematically investigated self-assembly mechanisms using small molecule fragments in indocyanine-based nanoaggregates to identify the critical non-covalent molecular forces that contribute to self-assembly. We found that aromaticity and hydrogen bond acceptors and donors on fragments were essential for nanoparticle formation, suggesting the system is driven by both π-π stacking of the aromatic groups and hydrogen bonding. We applied fragment molecular feature analysis to a kinase inhibitor, a full-size clinical compound, and discovered that nanoparticle formability is intrinsically associated within the drug fragment substructures. We also found that these drug aggregates form core-shell structures but lack ordered internal packings and are amorphous in solution. These findings suggest that incorporation of molecular design features can address intracellular aggregation and pharmacologic or delivery challenges in conventional and fragment-based drug development processes.

Anhydrous nanoprecipitation for the preparation of nanodispersions of tenofovir disoproxil fumarate in oils as candidate long-acting injectable depot formulations.

The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.

Effects of amphiphilic diblock copolymer on drug nanoparticle formation and stability

This study systematically compares the effects of amphiphilic diblock copolymer (di-BCP) on stabilizing hydrophobic drug nanoparticles formed by flash nanoprecipitation (FNP), and provides a guideline on choosing suitable di-BCPs. Four widely used di-BCPs, i.e., polystyrene-block-poly(ethylene glycol) (PS-b-PEG), polycaprolactone-block-poly(ethylene glycol) (PCL-b-PEG), polylactide-block-poly(ethylene glycol) (PLA-b-PEG), and poly(lactic-co-glycolic acid) (PLGA-b-PEG), and β-carotene as a model drug were used. The study showed that PLGA-b-PEG was the most suitable one, whose hydrophobic block was biodegradable and noncrystallizable as well as had relatively high glass transition temperature (Tg) and a right solubility parameter (δ). The molecular weight of PLGA block over the range from 5k to 15k showed an insignificant effect on controlling the particle size. Amorphous drug particles with a high drug loading of over 83 wt% can be achieved. Much remarkable evidence supported the nanoparticles with kinetically frozen and non-equilibrium packing structures of polymer chains rather than either the micelles or micellar nanoparticles with two well segregated polymer blocks. The thermodynamic effects of the drug and BCP on the particle stability, size and structures were discussed by using solubility parameters.

Mechanism of Nanoparticle Formation from Ternary Coground Phenytoin and Its Derivatives

The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and (13)C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability.

Nanoparticle Formation and Growth During In Vitro Dissolution of Ketoconazole Solid Dispersion

The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.

Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate.

Formation, Physical Stability and In Vitro Antimalarial Activity of Dihydroartemisinin Nanosuspensions Obtained by Co-grinding Method

The purpose of this study was to investigate the formation of drug nanoparticles from binary and ternary mixtures, consisting of dihydroartemisinin (DHA), a poorly water-soluble antimalarial drug, with water-soluble polymer and/or surfactant. Binary mixtures of drug/polyvinyl pyrrolidone K30 (PVP K30), binary mixtures of drug/sodium deoxycholate (NaDC), and ternary mixtures of drug/PVP K30/NaDC were prepared at different weight ratios and then ground by vibrating rod mill to obtain ground mixtures. Nanosuspension was successfully formed after dispersing ternary ground mixtures or DHA/NaDC ground mixtures in water. The ternary ground mixtures did not give superior nanosuspension in terms of particle size reduction and recovery of drug nanoparticles, but they provided more physically stable nanosuspensions than DHA/NaDC ground mixtures. The size of drug nanoparticles was decreased with increasing grinding time and lowering amount of PVP K30 and NaDC. About 95% of drug nanoparticles were found in the nanosuspension from ternary ground mixtures. Zeta potential measurement suggested that stable nanosuspension was attributable to adsorption of NaDC and PVP K30 onto surface of drug particles. Atomic force microscopy and transmission electron microscopy with selected area diffraction indicated that DHA in nanosuspension was existed as nanocrystals. The obtained nanosuspensions had higher in vitro antimalarial acitivity against Plasmodium falciparum than microsuspensions. The results suggest that co-grinding of DHA with PVP K30 and NaDC seems to be a promising method to prepare DHA nanosuspension.

Morphology and Surface States of Colloidal Probucol Nanoparticles Evaluated by Atomic Force Microscopy

Morphology and surface states of colloidal probucol nanoparticles after dispersion of probucol/polyvinylpyrrolidone (PVP)/sodium dodecyl sulphate (SDS) ternary ground mixture into water were investigated by atomic force microscopy (AFM). The observed particles had core-shell structure, i.e. drug nanocrystals were covered with PVP and SDS complex. The AFM phase image and the force curve analyses indicated that probucol nanoparticles with PVP K17 showed layer structure, compared to those with PVPK12. The structural difference was explainable in terms of the molecular states of PVP-SDS complex on the particle surface. These findings support not only the mechanism of drug nanoparticle formation but also the in vivo absorption results with the almost same particle size of ca. 40 nm.

Preparation of Drug Nanoparticles by Co-grinding with Cyclodextrin: Formation Mechanism and Factors Affecting Nanoparticle Formation

The aim of this study was to investigate the factors affecting the formation of pranlukast nanoparticle prepared by co-grinding with beta-cyclodextrin (beta-CD) and to elucidate the mechanism of nanoparticle formation. The effects of grinding time, moisture content and CD content on the nanoparticle formation were evaluated by means of UV quantitative determination and particle size analysis. High-resolution scanning electron microscopy (HRSEM) was employed to observe drug nanoparticles in the ground mixture. Nanoparticle recovery was higher than 95% for 2 : 1 molecular mixtures of beta-CD : pranlukast which had been ground for 10 min with moisture levels between 10 and 15%. While that of the 1 : 2 ground mixture prepared at 8% moisture level was only 57%. Nanoparticle recovery from beta-CD : pranlukast 2 : 1 mixture ground for 1 min was 2.5%, while that of the 10 min ground mixture was as high as 95%. HRSEM demonstrated that primary drug nanoparticles having a particle size around 50 nm were observed in the ground mixture. The grinding time, the moisture content, and the CD content had significant influences on the formation of drug nanoparticles. The CD matrix may form and stabilize primary particles by its interaction with the particle surface through water molecules. Primary nanoparticles existed in the ground mixture as 50 nm drug nanocrystallites.

Investigation of Drug Nanoparticle Formation by Co-grinding with Cyclodextrins: Studies for Indomethacin, Furosemide and Naproxen

Drugs with poor water solubility were co-ground with cyclodextrins (CDs) to create nanoparticles with improved solubility characteristics. Indomethacin (IDM), furosemide (FRM) and naproxen (NAP) were co-ground with β-CD at the molar ratio of 2:1 (CD:drug). Co-grinding of a drug with CD resulted in not only the formation of drug nanoparticles but also the solubilization of the drug by inclusion complex formation with CD in aqueous media. The nanoparticle fraction of IDM, and FRM from ground mixtures prepared with β-CD was as high as 60–70% while the solubilization fraction was less than 10%. In contrast, β-CD–NAP ground mixture showed a large fraction, 48%, for drug solubilization and only 4% for nanoparticle formation. Furosemide ground mixtures prepared with α-CD, β-CD and γ-CD showed comparatively high nanoparticle fraction while the solubilization fraction was around 10%. Both the nanoparticle fraction and the solubilization fraction were greater in the IDM–β-CD system than those in γ-CD and α-CD systems. The nanoparticle formation of NAP depended on the types of CD used as a co-grinding additive. Naproxen nanoparticles could be prepared by co-grinding NAP and α-CD, while the solubilization of NAP tended to improve when β-CD or γ-CD was used.

Formation and stability of drug nanoparticles obtained from drug/PVP/SDS ternary ground mixture

The purpose of this study was to investigate the stability and the formation mechanism of drug nanoparticles obtained from a ternary system consisting of poorly water-soluble drug, polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS). The physical state of drug nanoparticles was investigated by powder X-ray diffraction and zeta potential measurements. Poorly water-soluble drug, PVP K17 and SDS were mixed at a weight ratio of 1:3:1 and ground for 30 min by vibrational rod mill. Most of the poorly water-soluble drugs used in this study provided the nano- particle formation in the submicron region after the ternary ground mixtures (GMs) were dispersed into distilled water. Stability and mechanism of drug nanoparticle formation were investigated by focusing on phenytoin, probucol and griseofulvin. The drug nanoparticle formation was also observed when the ternary GMs were dispersed in the dissolution media. The mean particle size of the dispersed particles was still less than 250 nm after storage at 25°C for one month, indicating the long-term stability of drug nanoparticles. The quantitative determination of drug content demonstrated that more than 93% of the drug was recovered as fine particles smaller than 0.8 ^m from the ternary GMs, whereas the nanoparticles were hardly gained from binary GMs, drug with PVP K17 or SDS. Powder X-ray diffraction analysis for the dispersed particles accumulated by ultracentrifugation indicated that the dispersed particles existed as fine crystals. The zeta potential measurement revealed that the obtained nanoparticles were stable in aqueous media because the particle agglomeration was effectively inhibited by the adsorption of both PVP and SDS onto the particle surface.