Supersaturation-driven self-assembly formation of ceftriaxone sodium spherulites:From amorphous form to spherulites

Drug particles with spherical morphology possess amazing advantages in terms of particle flowability,mechanical properties,drug solubility,and bioavailability.The growth mechanism of drug spherulite is of great importance for the preparation and regulation of spherulites.Herein,ceftriaxone sodium spherulites were fabricated by the antisolvent crystallization method using dropwise addition of ceftriaxone sodium solution to acetone.Online observation of the whole crystallization process combined with electron microscopy technique revealed the spherical growth process from amorphous form to spherulites.As the supersaturation of the crystallization system was adjusted,the ceftriaxone sodium crystals transformed from amorphous form to spherulites.In the process of antisolvent crystallization with acetone as antisolvent,when the theoretical supersaturation degree S was higher than 2.62,the crystallization system tended to appear amorphous form;when S was between 2.57 and 2.62,the amorphous form transformed into clustered spherulites;when S was less than 2.57,the surface of spherulites will be covered with flaky crystal,which transformed into urchin-like type.With the understanding of the spherical growth mechanism,the ceftriaxone sodium spherulites prepared in this research with modified supersaturation control had a low residue of antisolvent acetone,and the flowability was significantly improved.

Effect of different additives on the phase separation behavior and thermodynamics of p-tert-alkylphenoxy poly (oxyethylene) ether in absence and presence of drug

Cloud point （CP） determinations of 4-（1,1,3,3-tetramethylbutyl）phenyl-polyethylene glycol （TX-100 （nonionic surfactant）） was carried out in aqueous as well as in the attendance of drug （ceftriaxone sodium trihydrate （CFT））/（CFT ＋ different inorganic salts） and discussed thoroughly. Nonionic surfactants are employed exten- sively in different formulations. In aqueous solution, the values of CP of TX-100 are obtained to increase by means of enhancing of their concentration in the solution. The CP values of TX-100 solutions were found to de- crease in the presence of drug and their values decrease more with rising concentrations of the drug. The values of CP of CFT and TX-100 mixtures were found to further decrease in the attendance of inorganic salts in compar- ison to their absence. The effect of different sodium salts in decreasing CP values of TX-100 was achieved in the following order： NaCO3 〉 Na2SO4 〉 NaCl. However, in the case of potassium and ammonium salts, the decreasing order obtained is K2SO4 〉 KCO3 〉 KCI and （NH4）2SO4 〉 Na2CO3 〉 NH4Cl respectively. Various thermodynamic pa- rameters for example standard free energy （△G c）, standard enthalpy （△H c） as well as standard entropy （△S c） changes of phase separation were also evaluated and discussed in detail on the basis of their behavior.

Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein

Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.