Understanding stress-induced disorder and breakage in organic crystals: beyond crystal structure anisotropy

Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H₂O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H₂O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H₂O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage.

Crystal engineering has advanced the strategies of design and synthesis of organic solids with the main focus being on customising the properties of the materials.     

Coriandrum sativum L.: A Review on Ethnopharmacology,Phytochemistry, and Cardiovascular Benefits

Coriandrum sativum (C. sativum), belonging to the Apiaceae (Umbelliferae) family, is widely recognized for its uses in culinary and traditional medicine. C. sativum contains various phytochemicals such as polyphenols, vitamins, and many phytosterols, which account for its properties including anticancer, anti-inflammatory, antidiabetic, and analgesic effects. The cardiovascular benefits of C. sativum have not been summarized before, hence this review aims to further evaluate and discuss its effectiveness in cardiovascular diseases, according to the recent literature. An electronic search for literature was carried out using the following databases: PubMed, Scopus, Google Scholar, preprint platforms, and the Cochrane Database of Systematic Reviews. Articles were gathered from the inception of the database until August 2021. Moreover, the traditional uses and phytochemistry of coriander were surveyed in the original resources and summarized. As a result, most of the studies that cover cardiovascular benefits and fulfilled the eligibility criteria were in vivo, while only a few were in vitro and clinical studies. In conclusion, C. sativum can be deemed a functional food due to its wide range of cardiovascular benefits such as antihypertensive, anti-atherogenic, antiarrhythmic, hypolipidemic as well as cardioprotective effects.     

Unprecedented Acid‐Promoted Polymerization and Gelation of Acrylamide: A Serendipitous Discovery

Dilute acid polymerizes degassed, aqueous acrylamide with concomitant gelation, without the need for added free radical initiator or cross‐linking agent. This reaction is accelerated by sonication or UV irradiation, but inhibited by adventitious oxygen or the addition of a free radical inhibitor, suggesting an acid‐accelerated free radical process. The resulting hydrogels are thixotropic in nature and partially disrupted by the addition of chaotropic agents, indicating the importance of hydrogen bonding to the 3D network. This discovery was made while trying to prepare pectin‐polyacrylamide hydrogels. We observed that pectin initiated the gelation of acrylamide, but only if the aqueous pectin samples had a pH lower than ca. 5.     

Polysorbates versus Hydroxypropyl Beta-Cyclodextrin (HPβCD): Comparative Study on Excipient Stability and Stabilization Benefits on Monoclonal Antibodies

Polysorbates (PS 20 and PS 80) are the most widely used surfactants in biopharmaceutical formulations to protect proteins from denaturation, aggregation, and surface adsorption. To date, around 70% of marketed therapeutic antibodies contain either PS 20 or PS 80 in their formulations. However, polysorbates are chemically diverse mixtures, which are prone to degradation by oxidation and hydrolysis to produce peroxides and fatty acids, which, in turn, induce protein oxidation, aggregation, and insoluble particle formation. These will negatively impact protein quality and stability. Thus, polysorbate degradation has emerged as one of the major challenges in the development and commercialization of therapeutic protein products. KLEPTOSE^® HPβCD (hydroxypropyl beta-cyclodextrin), a new multifunctional excipient, has been shown to provide protein stabilization functions in biopharmaceutical downstream processes and in their final formulations. This study aims to evaluate HPβCD, a new molecule of its class, against polysorbates as a stabilizer in biologics formulations. In this study, the chemical stability of KLEPTOSE^® HPβCDs is compared with polysorbates (20 and 80) under various stress conditions. When subjected to heat stress, HPβCDs show little change in product recovery (90.7–100.7% recovery for different HPβCDs), while polysorbates 20 and 80 show significant degradation, with only 11.5% and 7.3% undegraded product remaining, respectively. When subjected to other chemical stressors, namely, autoclave, light, and oxidative stresses, HPβCD remains almost stable, while polysorbates show more severe degradation, with 95.5% to 98.8% remaining for polysorbate 20 and 85.5% to 97.4% remaining for polysorbate 80. Further, profiling characterization and degradation analysis reveal that chemical structures of HPβCDs remain intact, while polysorbates undergo significant hydrolytic degradation and oxidation. Lastly, the physicochemical stability of monoclonal antibodies in formulations is investigated. When subjected to light stress, adalimumab, as a model mAb, formulated in the presence of HPβCD, shows a significant decrease in protein aggregation, and superior monomer and total protein recovery compared to PS 80-containing formulations. HPβCD also reduces both agitation and thermal stress-induced protein aggregation and prevents subvisible particle formation compared to PS 80.     

Development of Ultrahigh Permeance Hollow Fiber Membranes via Simple Surface Coating for CO2/CH4 Separation

Most researchers focused on developing highly selective membranes for CO₂/CH₄ separation, but their developed membranes often suffered from low permeance. In this present work, we aimed to develop an ultrahigh permeance membrane using a simple coating technique to overcome the trade-off between membrane permeance and selectivity. A commercial silicone membrane with superior permeance but low CO₂/CH₄ selectivity (in the range of 2–3) was selected as the host for surface modification. Our results revealed that out of the three silane agents tested, only tetraethyl orthosilicate (TEOS) improved the control membrane’s permeance and selectivity. This can be due to its short structural chain and better compatibility with the silicone substrate. Further investigation revealed that higher CO₂ permeance and selectivity could be attained by coating the membrane with two layers of TEOS. The surface integrity of the TEOS-coated membrane was further improved when an additional polyether block amide (Pebax) layer was established atop the TEOS layer. This additional layer sealed the pin holes of the TEOS layer and enhanced the resultant membrane’s performance, achieving CO₂/CH₄ selectivity of ~19 at CO₂ permeance of ~2.3 × 10⁵ barrer. This performance placed our developed membrane to surpass the 2008 Robeson Upper Boundary.     

Aqueous fraction of Nephelium ramboutan-ake rind induces mitochondrial-mediated apoptosis in HT-29 human colorectal adenocarcinoma cells

The aim of this study was to investigate the cytotoxic and apoptotic effects of Nephelium ramboutan-ake (pulasan) rind in selected human cancer cell lines. The crude ethanol extract and fractions (ethyl acetate and aqueous) of N. ramboutan-ake inhibited the growth of HT-29, HCT-116, MDA-MB-231, Ca Ski cells according to MTT assays. The N. ramboutan-ake aqueous fraction (NRAF) was found to exert the greatest cytotoxic effect against HT-29 in a dose-dependent manner. Evidence of apoptotic cell death was revealed by features such as chromatin condensation, nuclear fragmentation and apoptotic body formation. The result from a TUNEL assay strongly suggested that NRAF brings about DNA fragmentation in HT-29 cells. Phosphatidylserine (PS) externalization on the outer leaflet of plasma membranes was detected with annexin V-FITC/PI binding, confirming the early stage of apoptosis. The mitochondrial permeability transition is an important step in the induction of cellular apoptosis, and the results clearly suggested that NRAF led to collapse of mitochondrial transmembrane potential in HT-29 cells. This attenuation of mitochondrial membrane potential (Δψm) was accompanied by increased production of ROS and depletion of GSH, an increase of Bax protein expression, and induced-activation of caspase-3/7 and caspase-9. These combined results suggest that NRAF induces mitochondrial-mediated apoptosis.