Miscibility of Amorphous Solid Dispersions: A Rheological and Solid-State NMR Spectroscopy Study.

Miscibility is critical in the prediction of stability against crystallization of amorphous solid dispersions (ASDs) in the solid state. However, currently available approaches for its determination are limited by both theoretical and practical considerations. Recently, a rheological approach guided by the polymer overlap concentration (c*) has been proposed for miscibility quantification of ASDs [J. Pharm. Sci., 112 (2023) 204-212] and shown to be useful in predicting both accelerated and long term physical stability in the absence of moisture. However, this approach can only be performed at high temperatures (slightly above the melting temperature, Tm, of drugs), and little is known about the difference in miscibility between high and low temperatures (e.g., below the glass transition temperature, Tg). Here we compare the miscibility of nifedipine (NIF)/polyvinylpyrrolidone (PVP) ASDs as determined by the rheological approach at 175°C (∼3°C above Tm of NIF) and solid state NMR (ssNMR) 1H T1 and T1ρ relaxation times at -20°C (∼66°C below Tg of NIF). Our results indicate agreement between the two methods. For low molecular weight (Mw) PVP, T1ρ measurements are more consistent with the rheological approach, while T1 measurements are closer for relatively high Mw PVP. Our findings support the use of the c* based rheological approach for inferring miscibility of deeply cooled ASDs.

Delaying the First Nucleation Event of Amorphous Solid Dispersions Above the Polymer Overlap Concentration (c*): PVP and PVPVA in Posaconazole.

A thorough understanding of effects of polymers on crystallization of amorphous drugs is essential for rational design of robust amorphous solid dispersion (ASD), since crystallization of the amorphous drug negates their solubility advantage. In this work, we measured the first nucleation time (t0, time to form the first critical nucleus in fresh liquid/glass) in posaconazole (POS)/polyvinylpyrrolidone vinyl acetate (PVPVA) and POS/polyvinylpyrrolidone (PVP K25) ASDs and showed that the polymer overlap concentration (c*, concentration above which adjacent polymer chains begin to contact) is critical in controlling crystallization of ASDs. When polymer concentration c < c*, t0 of POS ASDs is approximately equal to that of the neat amorphous POS, but it increases significantly when c > c*. This observation supports the view that the effective inhibitory effect of crystallization in ASDs above c* is primarily correlated with delay in the first nucleation event. Our finding is useful in efficient polymer selection and performance prediction of high drug loaded ASD formulations.

Asiaticasics A-O, structurally intriguing coumarins from Toddalia asiatica with potential inflammatory inhibitory activity.

Ethyl acetate fraction of Toddalia asiatica was fractionated to yield fifteen previously undescribed prenylated coumarins, asiaticasics A-O (1-15) along with nine (16-24) known derivatives. The structures of these undescribed coumarins were established by spectroscopic analysis and reference data. Biological activity evaluation showed that compound 3 with the IC50 value of 2.830 µM and compound 12 with the IC50 value of 0.682 µM owned anti-inflammatory activity by detecting the rate of lactate dehydrogenase release in pyroptosis J774A.1 cells. The results showed that the expression of Caspase-1 and IL-1ß was decreased in a dose-dependent manner in the compound 12 treatment group, suggesting that compound 12 may reduce pyroptosis by inhibiting NLRP3 inflammasome. To further determine that compound 12 treatment can inhibit macrophage pyroptosis, morphological observation was performed and the results were consistent with the bioactivity evaluation.

Crystallization Inhibition in Molecular Liquids by Polymers above the Overlap Concentration (c*): Delay of the First Nucleation Event.

Low concentration polymer additives can significantly alter crystal growth kinetics of molecular liquids and glasses. However, the effect of polymer concentration on nucleation kinetics remains poorly understood. Based on an experimentally determined first nucleation time (time to form the first critical nucleus, t0), we show that the polymer overlap concentration, c*, where polymer coils in the molecular liquid start to overlap with each other, is a critical polymer concentration for efficient inhibition of crystallization of a molecular liquid. The value of t0 is approximately equal to that of the neat molecular liquid when the polymer concentration, c, is below c*, but increases significantly when c > c*. This finding is relevant for effective polymer screening and performance prediction of engineered multicomponent amorphous materials, particularly pharmaceutical amorphous solid dispersions.

Diverse diterpenoids from Callicarpa rubella Lindl. as natural inhibitors of macrophage foam cell formation.

Ten undescribed diterpenoids namely rubellawus E-N of structural types pimarane (1, 3-4), nor-abietane (2), nor-pimarane (5-6), isopimarane (7-9), and nor-isopimarane (10), along with eleven known compounds, were isolated and identified from the aerial parts of Callicarpa rubella Lindl. The structures of the isolated compounds were confirmed by comprehensive spectroscopic analyses and quantum chemical computations. Pharmacologically, almost all the compounds exhibited a potential inhibitory effect on oxidized low-density lipoprotein-induced macrophage foam cell formation, which suggests that these compounds may be promising candidates in the treatment of atherosclerosis.

A Rheological Approach for Predicting Physical Stability of Amorphous Solid Dispersions.

Miscibility is an important indicator of physical stability against crystallization of amorphous solid dispersions (ASDs). Currently available methods for miscibility determination have both theoretical and practical limitations. Here we report a method of miscibility determination based on the overlap concentration, c*, which can be conveniently determined from the viscosity-composition diagram. The determined c* values for ASDs of two model drugs, celecoxib and loratadine, with four different grades of polyvinylpyrrolidone (PVP), were correlated strongly with the physical stability of ASDs. This result suggests potential application of the c* concept in guiding the design of stable high drug loaded ASD formulations. A procedure is provided to facilitate broader adoption of this methodology. The procedure is easy to apply and widely applicable for thermally stable binary drug/polymer combinations.

Callicarpnoids A-C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

Efficient development of sorafenib tablets with improved oral bioavailability enabled by coprecipitated amorphous solid dispersion.

An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.

In vivo irreversible albumin-binding near-infrared dye conjugate as a naked-eye and fluorescence dual-mode imaging agent for lymph node tumor metastasis diagnosis.

Tumor metastases account for about 90% of cancer-related death, among which lymphatic metastases play a pivotal role. Therefore, high-efficiency sentinel lymph node (SLN) identification is significant for lymph node (LN) metastasis diagnosis in clinic. Herein, a novel in vivo covalent albumin-binding near-infrared (NIR) fluorescent IR820-maleimide conjugate (IR-Mal) is firstly designed as a SLN dual-mode imaging agent. The IR-Mal conjugate exhibits bright blue appearance and its large Stokes shift (over 100 nm) increases the fluorescent imaging resolution effectively. The fluorescence intensity of covalent albumin-binding IR-Mal (BSA-IR-Mal) complex is considerably stronger than that of IR-Mal. In vivo, IR-Mal could rapidly covalently bind the tissue interstitial albumin following subcutaneous administration and BSA-IR-Mal complexes could specifically accumulate on LN, and detect both normal and metastatic SLN through naked-eye and fluorescence imaging with high resolution. Moreover, the light stability and enhanced fluorescence intensity of BSA-IR-Mal complex facilitates its diagnosis accuracy. These findings suggest that such in vivo irreversible albumin-binding fluorescence conjugates could serve as a new agent for dual-mode imaging and have a great potential to be applied in the SLNs imaging and diagnosis.