Mechanism of Dissolution-Induced Nanoparticle Formation from a Copovidone-Based Amorphous Solid Dispersion

Abstract

Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 μm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70-80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0-10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term "hydrophobic capture". Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.

Incomplete Loading of Sodium Lauryl Sulfate and Fasted State Simulated Intestinal Fluid Micelles Within the Diffusion Layers of Dispersed Drug Particles During Dissolution

“…Anacetrapib hot melt extrudate (HME) was prepared previously and its preparation is described elsewhere. 30 Acetonitrile, SLS, sodium chloride, sodium phosphate monobasic monohydrate, 85% o-phosphoric acid, and HPLC grade water were obtained from Fisher Scientific (Fair Lawn, NJ).…”

“…This HME amorphous solid dispersion forms 110 nm (D 50 ) nanoparticles at 3.5% TPGS and 190 nm nanoparticles at 2% TPGS in water; the details of this mechanism are described elsewhere. 30 Approximately 20 mg of milled HME was weighed into a scintillation vial with 10 mL of stirring HPLC grade water at 37 C (300 rpm) for 1 h. An aliquot of the solution was spiked into 250 mL of FaSSIF as well as 250 mL of 0.3% SLS stirring at 300 rpm so that the total concentration was 0.6 ug/mL. Ultracentrifugation (Optima TLX ultracentrifuge, TLA 110 rotor, 10 min at 348,000 Â g (rmax)) was used to remove nanoparticles to measure molecularly dissolved anacetrapib.…”

“…A total of 110 and 190 nm (D 50 ) anacetrapib nanoparticles are created from an anacetrapib HME formulation previously described. 30 Anacetrapib has approximately 4-fold higher solubility in 0.3% SLS media than in FaSSIF media, and the SLS micelles have nearly 4-fold higher diffusivity values due to their smaller size (Table 3). Figure 10 shows the dissolution data over the first 30%-50% of the 0.6 mg/mL anacetrapib nanoparticles added to both micellar solutions.…”

Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

“…LLPS is most commonly observed to occur in dissolution media where there is rapid generation of supersaturation. [37][38][39][40] The drug-rich LLPS typically has a size of 100-500 nm. As concluded by multiple reports on this subject, the LLPS phenomenon demonstrate the formation of noncrystalline drug-rich phase occurs under the condition that the critical supersaturation threshold is exceeded.…”

“…As concluded by multiple reports on this subject, the LLPS phenomenon demonstrate the formation of noncrystalline drug-rich phase occurs under the condition that the critical supersaturation threshold is exceeded. 30,37,38 The HME tablet contains FEN in its amorphous state. In principle, this formulation may yield LLPS provided that a high degree of supersaturation of FEN is encountered.…”