Nanosuspensions of a poorly soluble investigational molecule ODM-106: Impact of milling bead diameter and stabilizer concentration

Abstract

Aqueous solubility of a drug substance is an important attribute affecting oral bioavailability.Nanonization, particle size reduction to submicron level, is an elegant approach to improve drug solubility and dissolution by increasing the surface energy, which in turn necessitates the use of stabilizers. The purpose of this study was to develop a nanosuspension of a practically water-insoluble investigational molecule by nanomilling approach using wet media milling. A variety of polymeric and surface active excipients were tested for their wettability. A combination of hydroxypropyl methylcellulose and sodium lauryl sulfate (SLS) were selected as stabilizers on the bases of compatibility studies and efficient wettability behaviour in contact angle measurements (≈80˚). A factorial design set-up was used to study the effect of milling bead diameter and stabilizer concentration on the efficiency of particle size reduction.Nanonization outcome was different when milling beads of 0.5 mm and 1 mm diameter were used at different concentrations of the stabilizers, which demonstrated the complex nature of the whole system. Storage of the nanosuspensions under different temperature conditions resulted only in minor changes of the particle size fractions.

Naringenin nanocrystals for improving anti-rheumatoid arthritis activity

“…NARNCs were prepared using a planetary ball mill. The grinding time and stabilizer concentrations were critical to determining particle sizes and PDIs [ 14 , 25 ]. Thus, the milling time and the amount of stabilizer were determined.…”

“…In the initial stages of grinding (0 to 125 min), the particle sizes and PDIs decreased rapidly with an increase in milling time because the stabilizers could quickly cover the surface of NAR and facilitate the breakage of crude particles into nanoparticles [14] . However, in the late stages (125 to 175 min), the excess energy due to over-grinding could also disrupt repulsive forces, induce the aggregation of small particles, and affect the physical stability of the system [26] .…”

“…However, for chronic diseases treatment, chronic patients need long-term medication, organic solvents, and surfactants in the preparation will bring a series of adverse reactions and side effects. Compared with the ethanol/Cremophor solution formulation, although the preparation of NCs is slightly complex and the cost is a bit high, almost negligible surfactants and/or polymers used in the formulation will not bring safety concerns and can be used for long-term administration [ 14 , 36 ]. Despite the oral bioavailability of NARNCs is lower than the solution, it may be critical sufficient to make a NAR, a poorly water-soluble drug, clinically effective.…”

“…To address these problems, several systems have been developed, including liposomes [9] , emulsions [10] , solid dispersions [11] , nanoparticles [12] , and cosolvents [13] . However, the positive effects of these systems are compromised by low drug loading, potential toxicity, high cost, and other disadvantages [14] .…”

Systematic Screening Study for the Selection of Proper Stabilizers to Produce Physically Stable Canagliflozin Nanosuspension by Wet Milling Method

“…But the drug-excipient compatibility study showed that there was a high degradation risk between PVP K30 and the related drug. In addition, it is well known that the risk of degradation is higher in liquid formulations such as nanosuspensions and also that a high energy input from grinding media will increase the rate of active ingredient degradation [17]. The optimization study was rebuilt after removing PVP K30 and PVP/VA.…”