Progress in the development of stabilization strategies for nanocrystal preparations

Abstract

In recent years, nanocrystal technology has been extensively investigated. Due to the submicron particle size and unique physicochemical properties of nanocrystals, they overcome the problems of low drug solubility and poor bioavailability. Although the structures of nanocrystals are simple, the further development of these materials is hindered by their stability. Drug nanocrystals with particle sizes of 1∼1000 nm usually require the addition of stabilizers such as polymers or surfactants to enhance their stability. The stability of nanocrystal suspensions and the redispersibility of solid nanocrystal drugs are the key factors for the large-scale production of nanocrystal preparations. In this paper, the factors that affect the stability of drug nanocrystal preparations are discussed, and related methods for solving the stability problem are put forward.

Stabilizing Effect of Soluplus on Erlotinib Metastable Crystal Form in Microparticles and Amorphous Solid Dispersions

“…Another method to improve aqueous solubility of poorly water-soluble drugs is to reduce the particle size to micron or nanometer level. Only some products need to be prepared into nanoparticles (NPs) to enhance therapeutic efficacy, such as Rapamune ®® , Emend ®® and Tricor ®® , approved by the FDA for marketing [ 11 ]. Most drugs can achieve high bioavailability as microparticles (MPs).…”

Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach

“…The benefit of combining the two stabilization mechanisms to achieve a stable colloidal dispersion is explained through the reduction in the self-repulsion between the ionic surfactant molecules in the presence of steric stabilizers, leading to closer packing of the molecules [ 17 ]. SLS was used in concentration below the critical micelle concentration, thus not influencing DK-I-60-3 solubility, as recommended for successful stabilization [ 18 ]. Indeed, the solubility of DK-I-60-3 in medium containing SLS and PVP in concentrations as in F5, F6, and F8 was 5.52 ± 1.22, 3.47 ± 0.25, and 3.05 ± 0.82 µg/mL, respectively, i.e., similar to the solubility in water.…”

“…For that reason, amphiphilic substances or polymers in proper concentrations are added to cover these regions and ensure the preservation of small particle size [ 19 ]. If the stabilizer concentration is insufficient, the drug particles cannot be effectively coated, while excessive stabilizers concentration could lead to particle aggregation and bridging due to the attachment of several drug particles to the same stabilizer molecule [ 18 ]. It was clear that stabilizers’ concentration in formulations F1–F4 was not enough to ensure particle stabilization, which resulted in higher particle size after preparation.…”

“…Therefore, for samples in which non-spherical particles are expected, visualization by some microscopic technique is significant for the right interpretation of the results. Atomic force microscopy is considered a valuable tool for nanocrystal characterization as it can provide information about the shape and structure of the particles in nano-range resolution [ 18 ]. AFM images of samples F5, F6, and F8 are presented in Figure 3 .…”

“…An increase in saturation solubility is expected according to the Ostwald-Freundlich equation[30], due to reduced particle size but also as a consequence of changes in crystal lattice energy[29].In the other two media, however, the solubility decreased significantly, which indicated stability impairment due to low pH value and/or high ionic strength (Figure6b). Electrostatic repulsion of nanocrystals can be inhibited by high acid concentrations, leading to particle agglomeration[18]. It was interesting that the solubility in 0.1 M HCl in nanosuspensions decreased to the values similar to the ones in the corresponding suspensions (p = 0.563 and 0.965 for F5 vs. S5, and F6 vs. S6, respectively, Student t-test) except in the case of F9 (p < 0.01, Student t-test).…”