Research paperParticle size control and the interactions between drug and stabilizers in an amorphous nanosuspension system
Graphical abstract
Introduction
An active pharmaceutical ingredient (API) that demonstrates poor water solubility and low oral bioavailability will likely face significant challenges during the drug development process. Among the factors influencing dissolution properties of a given API molecule, particle size is of considerable importance. The significant increase in surface energy and area obtained by particle size reduction greatly improves the dissolution velocity and saturation solubility, hence the bioavailability.
Nanosuspension, which is defined as colloidal dispersion of nano-sized particles of water-insoluble drug(s), has obtained great success in addressing the dissolution problems [1], [2]. Unlike other nanoparticle-based drug delivery systems, in which the drug is confined to a cavity surrounded by a polymer membrane or physically dispersed in a matrix, nanosuspension involves pure drug nanoparticles dispersed in a liquid medium without any membrane or matrix material. Nevertheless, some suitable stabilizers (surfactants or polymer stabilizers) are usually added to inhibit the aggregation of drug nanoparticles [3], [4]. The interactions between drug and stabilizers are believed to exist in nanosuspension systems but difficult to be revealed because the stabilizers would cause significant interference, although raw materials of stabilizers were usually taken as control in current practice.
The solid drug particles in nanosuspensions can exist in two forms: crystalline state and amorphous state. Crystalline nanoparticles, also called nanocrystals, are usually prepared by top-down approaches, including wet milling [5], [6] and high pressure homogenization [7]. Amorphous nanosuspensions are often produced by bottom–up techniques, among which, antisolvent precipitation [6], [7], [8], [9], [10], [11], [12] are typically used. Nanocrystals could also be formed in a bottom–up process in case the crystallization is not inhibited effectively [13]. Accordingly, polymer stabilizers that can interfere with crystallization in a competitive manner, are indispensable for amorphous nanosuspensions. In most cases, ultrasonication [6], [8], [9] or high-speed stirring [10], [11], [12] should be incorporated in a precipitation procedure to minimize the particle size, which adds to the complexity and difficulty of scale-up.
Amorphous solids, because they exhibit a higher energy state than crystalline solids, often have higher solubility and dissolution velocity. Both the amorphous and crystalline particles suffer from unsatisfactory stability due to Ostwald ripening. However, for an amorphous suspension, Ostwald ripening can be inhibited by incorporating a small amount of additive [14]. Therefore, amorphous nanosuspension should be extensively concerned.
Particle size is one of the most important properties of any nanosuspension system, because it greatly affected the physical stabilities and biological performances as well as the dissolution properties. The influence of particle size on the in vivo tissue distribution [15], [16], [17] and mucoadhesion [18], [19] has been demonstrated in nanoparticle drug delivery systems, which also can be reasonably expected in nanosuspension systems. During the preparation of nanosuspension, particle size control can be accomplished by adjusting the time and/or strength of milling or homogenization for “top–down” approach, but it is still a hurdle for “bottom–up” approach.
Here we prepared amorphous nanosuspensions of resveratrol using a simple precipitation method, and investigated the size control of drug solid particles using a pair of polymers PVA/PVP. Hydrogen bond induced aggregation and agglomeration could be a possible mechanism for the variation of particle size.
The drug we used here is trans-resveratrol, a poorly water-soluble stilbenoid, which is found in the skin of grapes and is well known for the French paradoxon [20]. We have reported the preparation of amorphous resveratrol nanosuspension [12], and its crystalline counterpart has also been reported [21]. Here we placed emphasis on the simplification of preparation method, the solid state confirmation and its related change in spectra, the interaction between drug and stabilizers, and most importantly, the particle size control of this nanosuspension system.
Section snippets
Materials
The commercial trans-resveratrol (98.9% pure, needle crystal) was purchased from Tianjin Jianfeng Nature Product R&D Co., Ltd. (Tianjin China). Absolute ethanol, polyvinyl alcohol (PVA-0588, Mw 24500–29500), Tween-80 and poloxamer 188 (P188) were purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China); Polyvinylpyrrolidone (PVP, Kollidon 17PF, Mw7000–11000) was obtained from BASF Corporation of Germany (Local Agent in Shanghai, China). All the chemical reagents were used as
Optimization of stabilizers
Resveratrol nanosuspensions here were obtained by a precipitation method which is in the category of “bottom–up” approach. When ethanol diffused to the aqueous phase containing stabilizer, the dissolved drug begins to precipitate and form nanoparticles due to the size limitation effect afforded by stabilizer. Fig. 1 shows the resveratrol nanosuspensions respectively stabilized by four different stabilizers. Surfactants are more effective than hydrophilic polymers in reducing Gibbs free energy
Conclusions
A simple precipitation method was developed to prepare amorphous nanosuspension of resveratrol. This method is not attached with homogenization or ultrasonication so it is effective for large scale preparation and for drug delivery. The amorphous state of nanoparticles, as well as the interactions between drug and stabilizers, were revealed by PXRD, TEM, IR spectra and DSC. The nonionic polymer PVP, which was frequently used as a stabilizer in nanosuspension systems, was used to control the
Acknowledgment
This work was supported by the National Natural Science Foundation of China (No. 81102820), the Research Award Fund for Outstanding Middle-Aged and Young Scientists of Shandong Province, China (No. BS2013YY061), Shandong Provincial Natural Science Foundation, China (Nos. ZR2011BL007X and ZR2014HP020), and Taishan University Foundation (No. Y-01-2014013).
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2018, Journal of Drug Delivery Science and TechnologyCitation Excerpt :From the particle size analysis (as shown in Figs. 5 and 6) it was observed that in polymeric stabilized nanosuspension formulation containing PVP K-30 (batch: b25) showed higher particle size (500 nm) as compared to formulation containing HPMC (batch: b26, 468 nm) and formulation containing PVA (batch: b24, 377 nm). The results are in accordance with several other studies which shows that the difference in particle size may be due to structural difference i.e. PVA and HPMC has flexible long chain like structure while PVP K-30 has coiled like structure thus surface absorption property of PVA and HPMC is better than PVP K-30 [26,27]. Amongst the nonionic surfactants, minimum particle size distribution was observed with Vitamin E TPGS (252 nm, batch: b29) which may be due to its low viscosity and high surface activity [26].