Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate

Abstract

Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR, using CDCl as the solvent, and the drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the nonaqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained that NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite the lack of specific interactions in the nonaqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hindering the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

“…Pinto et al (2019) emphasized the relevance of biorelevant media, as they revealed specific interactions between polymer and surfactants, which led to a decreased supersaturation performance in FaSSIF compared to plain buffer [43]. In line with this, Pui et al also found a decreased supersaturation ability of a polymer due to competitive interactions with surfactants [44]. Consequently, the HPMCAS concentration needed to be increased to 3.6 mg/mL in presence of FaSSIF.…”

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…Furthermore, the authors reported enhanced dissolution profiles for Eudragit EPO with the NSAIDs (non-steroidal anti-inflammatory drugs) indomethacin and piroxicam. There are also indications that a nonspecific binding can result in a crystallization inhibition effect (Baghel et al, 2018): an NMR study on nimodipine with PVP (polyvinylpyrrolidone) as a polymer in solution showed nonspecific hydrophobic interactions between the hydrophobic moieties of the polymer and the drug (Pui et al, 2018). A study investigating the higher degree of crystallization inhibition by PAA (polyacrylic acid) compared to PVP concluded that this effect is attributed to strong specific interactions between drug and polymer as observed with NMR measurements.…”

Impact of Matrix Surface Area on Griseofulvin Release from Extrudates Prepared via Nanoextrusion

“…Compared to its crystalline counterpart, an amorphous drug exhibits higher “kinetic solubility” owing to its high free energy and metastable nature [ 20 ]. Despite this beneficial aspect, the amorphous drug can undergo precipitation upon wetting–dissolution of ASD particles, which detrimentally affects its physical stability and sustained supersaturation capability [ 20 , 21 ]. Supersaturation is desirable for the absorption and bioavailability of the drug if it is sustained over a gastrointestinal transition time of 4–5 h. Supersaturation, albeit desirable on its own, is also the driving force for primary or secondary nucleation (in the presence of residual crystals) [ 22 ], followed by growth and aggregation of precipitated particles, which can cause depletion of initially high supersaturation or a lower extent of dissolution [ 20 , 21 , 23 , 24 , 25 ].…”

“…Despite this beneficial aspect, the amorphous drug can undergo precipitation upon wetting–dissolution of ASD particles, which detrimentally affects its physical stability and sustained supersaturation capability [ 20 , 21 ]. Supersaturation is desirable for the absorption and bioavailability of the drug if it is sustained over a gastrointestinal transition time of 4–5 h. Supersaturation, albeit desirable on its own, is also the driving force for primary or secondary nucleation (in the presence of residual crystals) [ 22 ], followed by growth and aggregation of precipitated particles, which can cause depletion of initially high supersaturation or a lower extent of dissolution [ 20 , 21 , 23 , 24 , 25 ]. Depending on their concentration and interactions with the drug, polymers in ASDs can inhibit drug precipitation, affording the sustainment of the drug supersaturation [ 23 , 24 ] besides their role in ASD formation through polymer–drug miscibility.…”