Polymer-Mediated Drug Supersaturation Controlled by Drug-Polymer Interactions Persisting in an Aqueous Environment.

We investigated the drug-polymer interactions in nonaqueous and aqueous environments between a poorly water-soluble drug, BAY1161909 (909), and two commonly used polymers in amorphous solid dispersions, i.e., PVP and HPMC-AS. In an nonaqueous state, with a drug-polymer Flory-Huggins interaction parameter, solution NMR and FT-IR results revealed that strong specific interactions existed between 909 and PVP, while not between 909 and HPMC-AS. After prolonged moisture exposure under 95% RH, 909/PVP intermolecular interaction no longer existed, while hydrophobic interaction between 909 and HPMC-AS occurred and persisted. In an aqueous supersaturation study of 909, codissolved PVP significantly outperformed predissolved PVP in maintaining 909 supersaturation. We hypothesized that the codissolved PVP formed a specific interaction with 909, and thus, it was able to prolong 909 supersaturation before disruption of the interaction in aqueous medium, while predissolved PVP formed hydrogen bonds with water, and thus, it was no longer able to form specific interactions with 909 to prolong its supersaturation. In contrast, HPMC-AS effectively mediated 909 supersaturation through hydrophobic interaction, which became pronounced in an aqueous environment and was independent of how HPMC-AS was added. This hypothesis was supported by dynamic light scattering analysis, wherein the formation of nanosized drug/polymer aggregations was found to be correlating with the supersaturation of 909. In summary, we concluded that polymer-mediated drug supersaturation was controlled by drug-polymer interactions persisting in an aqueous environment. Therefore, the physical nature of the drug-polymer interaction as well as the dissolution kinetic of the drug and polymer are all critically important to achieve an optimal ASD formulation design.

Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers.

We aim to understand the potential impact of a modest chemical modification of a drug molecule on the downstream design of its amorphous solid dispersion (ASD) formulation. To this end, we used sorafenib (SOR) and its fluorinated form, regorafenib (REG), as model drugs, to assess the impact of a single hydrogen substitution by fluorine on the molecular interaction and miscibility between drug and PVP or PVP-VA, two commonly used polymers for ASDs. In this study, we observed that the Tg values of PVP or PVP-VA based ASDs of SOR deviated positively from the Gordon-Taylor prediction, which assumes ideal mixing, yet the Tg of REG ASDs deviated negatively from or matched well with the ideal mixing model, suggesting much stronger drug-polymer interactions in SOR ASDs compared with the REG ASDs. Using solution NMR and computational methods, we proved that a six-member-ring formed between the carbonyl groups on the polymers and the uramido hydrogen of SOR or REG, through intermolecular hydrogen bonding. However, steric hindrance resulting from fluorination in REG caused weaker interaction between REG-polymer than SOR-polymer. To further confirm this mechanism, we investigated the molecular interactions of other two uramido-containing model compounds, triclocarban (TCC) and gliclazide (GCZ), with PVP. We found that TCC but not GCZ formed a hexatomic ring with PVP. We concluded that PVP based polymers can easily interact with N, N'-disubstituted urea compounds with a trans-trans structure in the form of hexatomic rings, and the interaction strength of the hexatomic ring largely depended on the chemistry of drug molecules. This study illustrated that even a slight chemical modification on drug molecules could result in substantial difference in drug-polymer interactions, thus significantly impacting polymer selection and pharmaceutical performance of their ASD formulations.

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

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 CDCl3 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.

Oral bioavailability enhancement of ß-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion.

The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for ß-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM. USP II and intrinsic dissolution studies were used to compare the in vitro dissolution of these formulations, and a crossover dog pharmacokinetic study was used to compare their in vivo bioavailability. An 1:1 LPC-resorcinol cocrystal with higher solubility and faster dissolution rate was obtained, yet it converted to LPC crystal rapidly in solution. LPC/HPMC-AS ASD was confirmed to be amorphous and uniform, while the crystal and crystallite sizes of LPC in CSD were found to be ∼1-3 µm and around 40 nm, respectively. These formulations performed similarly during USP II dissolution, while demonstrated dramatically different oral bioavailability of ∼32%, ∼5%, and ∼1% in dogs, for CSD, co-crystal, and ASD, respectively. CSD showed the fastest intrinsic dissolution rate among the three. The three formulations showed poor IVIVC which could be due to rapid and unpredictable crystallization kinetics. Considering all the reasons, we conclude that for molecules with extremely high crystallization tendency that cannot be inhibited by any pharmaceutical excipients, size-reduction technologies such as CSD could be advantageous for oral bioavailability enhancement in vivo than technologies only generating transient but not sustained supersaturation.

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance.

Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.