Tucatinib(1) is an oral inhibitor of HER2 for clinical treatment of HER2- positive breast cancers. In this paper, the synthesis methods of 1 and its key intermediate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylaniline(2) are reviewed, and the advantages and disadvantages of each synthetic route are discussed. This review is beneficial to the future process research of tucatinib.

Oral administration is the preferred method for drug delivery. However, due to the unique properties of drugs and the gastrointestinal barrier, the bioavailability of oral administration is limited. By referencing the structural characteristics of organisms in nature and adopting a biomimetic perspective, the biomimetic nanocarriers can be designed and prepared to improve the oral absorption of drugs, which hold promising development prospects. This review summarizes the application of nanocarriers designed and prepared with various biomimetic ideas in oral drug delivery,offering insights and references for the development and clinical application of oral nanocarriers.

Paclitaxel belongs to the diterpenoid compounds and has good antitumor activity against various cancers such as ovarian cancer and breast cancer. Due to its poor solubility, paclitaxel has significant adverse reactions when it was used directly, limiting its clinical application. Serum albumin nanoparticles can compensate for the inherent defects of paclitaxel, enhance the stability of the drug in the body, improve its bioavailability and targeting ability, achieve the purpose of enhancing efficacy and reducing toxicity, and to some extent solve the problem of paclitaxel. This review summarizes the preparation process of serum albumin-paclitaxel nanoparticles, the application of modified serum albumin in paclitaxel-loaded nanoparticles, in order to provide theoretical guidance for the development of serum albumin based nanodrug delivery systems that meet actual clinical applications.

Surface modified liposomes with hyaluronic acid as a new transdermal drug delivery carrier can significantly improve the transdermal penetration of drugs by swelling the stratum corneum through the powerful hydration effect of hyaluronic acid. Due to its unique structure and tumor cell targeting, hyaluronic acid forms a mesh structure on the surface of liposomes, which can realize active targeting, prevent drug leakage, prolong drug release, improve stability, and synergistically enhance antitumor activity. This study mainly introduces the research progress of hyaluronic acid modified liposomes in the aspects of the preparation methods and related parameters, synergistic transdermal absorption of hyaluronic acid and liposomes, enhancement of tumor cell targeting of liposomes, the stability and sustained release effect of modified liposomes, as well as application prospects. It provides a reference for the further development of hyaluronic acid modified liposomes for transdermal drug delivery.

Cyclosporine A, a potent immunosuppressive agent, is extensively utilized in ophthalmic treatments. However, its high relative molecular mass and pronounced hydrophobicity pose challenges to its penetration through the physiological barriers of eyes, leading to low bioavailability. By strategically integrating innovative excipients and formulation technologies, the bioavailability of cyclosporine A can be enhanced from four aspects: increasing drug solubility, facilitating penetration through ocular mucus, boosting deep penetration into corneal tissues, and extending residence time on the ocular surface. This review focuses on the characteristics, action mechanisms, and associated formulation technologies of novel excipients employed in cyclosporine A ophthalmic formulations, to provide a reference for efficient delivery of cyclosporine A and the development of future novel formulations.

Tumor is closely related to the copper disorder in human body. In order to discover new copper ion chelating antitumor compounds, five 8-hydroxyquinoline derivatives were synthesized by C-2 aldol condensation, elimination and Michael reaction with 2-methyl-8-hydroxyquinoline as the starting material. The copper ion chelating ability and selectivity were studied by ultraviolet titration. And their cytotoxicity against human melanoma cells(A375 cells and Colo829 cells), human lung cancer cells(A549 cells), human liver cancer cells(HepG2 cells), human cervical cancer cells(HeLa cells) and human immortalized keratinocytes(HaCaT cells) was determined by MTT assay. Finally, two compounds TDMQ51 and TDMQ53 showed higher safety than the positive control fluorouracil(5-FU), while the complexation constants for copper and zinc differed by 13 orders of magnitude. These two compounds could be studied intensively as lead compounds owing to the good inhibitory activity to a wide variety of tumor cells.

To perform the quality control of arbidol hydrochloride, five potential related substances were synthesized. They were ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylsulfinyl)- methyl]-1H-indole-3-carboxylate(related substance A), ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1,2- dimethyl-1H-indole-3-carboxylate(related substance B), ethyl 6-bromo-5-hydroxy-1-methyl-4-[(methylamino)- methyl]-2-[(phenylthio)methyl]-1H-indole-3-carboxylate(related substance C), ethyl 4-[(dimethylamino)methyl]- 5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylate(related substance D) and ethyl 6,7-dibromo-4- [(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylate(related substance E). Their chemical structures were confirmed by MS, 1H NMR and 13C NMR.

The fingerprints of decoction pieces and dispensing granules of Bupleurum chinense DC. were established by HPLC coupled with evaporative light scattering detector according to the “Similarity Evaluation system of TCM Chromatographic Fingerprint(2012 edition)”. The similarity was evaluated and the common characteristic peaks were determined. Softwares of SPSS 22.0 and SIMCA 14.1 were used for cluster analysis(CA), principal component analysis(PCA) and orthogonal partial least square discriminant analysis to screen the different components that affected the quality of decoction pieces and dispensing granules. The results showed that there were twenty-four common peaks in ten batches of decoction pieces, with a similarity of no less than 0.985. And there were sixteen common peaks in twenty batches of dispensing granules, with a similarity of 0.858 - 0.998. Six common peaks were identified, including saikosaponin c(peak 6), saikosaponin f(peak 7), saikosaponin a(peak 9), saikosaponin d(peak 18), saikosaponin b2(peak 28) and saikosaponin b1(peak 29). The results of CA and PCA showed that Bupleurum chinense DC. decoction pieces and Bupleurum chinense DC. dispensing granules were clustered into two categories. The variable importance in the projection(VIP) values of sixteen common peaks were all high than 1, which meant the difference between decoction pieces and dispensing granules. The established fingerprint and chemical pattern recognition analysis method can be used to evaluate the quality of decoction pieces and dispensing granules of Bupleurum chinense DC.

The study utilized a fluidized bed method to prepare Sheyin pharyngitis granules. The Box-Behnken design was used to optimize the process parameters, with the fluidized bed atomization pressure, fluidization temperature, and spray liquid rate as the investigation indicators, and the qualification rate(namely the proportion of the granules with the particle size of 180 - 2 000 μm to total granules) and dissolution time as the evaluation indicators. Additionally, the high-performance liquid chromatography method coupled with a diode array detector(HPLC-DAD) was established to determine contents of chlorogenic acid, harpagide, harpagoside and irisflorentin in the granules. The results indicated that the optimized process parameters were as follows: an atomization pressure of 22 kPa, an inlet air temperature of 66 ℃, and a spray liquid rate of 1.55 mL/min. The qualification rate and dissolution time of the obtained granules were 91.51％ and 42.87 s, respectively. The contents of chlorogenic acid, harpagide, harpagoside and irisflorentin in the granules were 3.22, 0.72, 0.63 and 0.16 mg/g, respectively.

A high drug-loading solid dispersion of nimodipine was prepared via a hot-pressing extrusion method by mixing the bulk drug and a polymer carrier in a mass ratio of 4∶1. The process parameters, namely the carrier material type, rotational speed of the extrusion machine, extrusion temperature, and preparation method, were optimized with the dissolution behavior of the product in hydrochloric acid(pH 1.0) as the evaluation indicator. The results showed that the high drug-loading solid dispersions with Eudragit® EPO as the carrier prepared at 80 ℃ which was far below the melting point of nimodipine and the rotational speed of 30 r/min by hot-pressing extrusion method could significantly improve the dissolution of nimodipine. The dissolution rate at 15 min was over 80％. The characteristic results of differential scanning calorimetry, powder X-ray diffraction, particle size determination and scanning electron microscopy showed that nimodipine was existed in the form of nanocrystals in the solid dispersion. In the accelerated test, nimodipine in the solid dispersion changed from crystal form Ⅰ to crystal form Ⅱ, but the dissolution behavior in vitro remained basically unchanged.

Due to the temperature sensitivity of some ion channel drugs, the testing temperature might be an important influencing factor in their safety evaluation. Therefore, this study compared the effects of some drugs on the voltage-gated sodium channel(Nav1.5) under different temperature(29, 33, 35, and 37 ℃)] conditions. The whole-cell patch clamp technique was used to record the changes in sodium channel current(INa) after the temperature-sensitive drugs(mexiletine, quinidine, and ranolazine) functioned on Nav1.5-human embryonic kidney(HEK) 293 cells at different temperatures. The study investigated the influence of temperature on the concentration-dependence of INa and the halfmaximal inhibitory concentration(IC50) of the aforementioned drugs. The results showed that mexiletine, quinidine, and ranolazine could inhibit INa in a concentration-dependent manner at different temperatures(29, 33, 35, and 37 ℃). Compared to 29 ℃, the inhibitory effects of these drugs on INa was more significant at 35 ℃. This study evaluated the effects of three drugs on the sodium channel Nav1.5 under four temperature conditions, which was benefit to improve the accuracy of preclinical cardiac toxicity screening and evaluation of drugs, providing a reference for GLP institutions to conduct ion channel drug evaluation tests.

The peptide mapping and disulfide linkages of ranibizumab(including one batch of reference preparation and two batches of samples) were simultaneously characterized by the online partial reduction of tris- (2-carboxyethyl)phosphine(TCEP) after a single injection by LC-MS/MS for the first time. The results showed that the sequence coverage of peptide mapping could reach 100％, and the identified post translational modifications were mainly oxidation, deamidation and pyroglutamic acid cyclization. The five pairs of disulfide bonds were confirmed to be consistent with the theoretical connection. In addition, free cysteine and three pairs of scrambled disulfide bonds were identified by this method, and the probability of artifacts could be effectively reduced by adding a certain amount of alkylation reagents. This online method shortened the processing and analysis time, reduced the uncontrollable factors introduced by humans, and provided references for high-throughput antibody structure characterization.

The complex disulfide crosslinking structure of recombinant hirudin protein was analyzed by joint enzyme digestion with UPLC Q-TOF high resolution mass spectrometry. It was verified whether the recombinant hirudin protein contained free cysteine from the protein level by high resolution mass spectrometry and the free thiol quantitative detection. Then, single enzyme method was used to label the position of each or each group of disulfide bonds in the protein sequence. Finally, according to the results of the single enzyme, the specific disulfide bond pairing method was designed and verified by dithiothreitol reduction method, and the disulfide bond position of recombinant hirudin protein was finally confirmed. It was showed that there were ten cysteine residues included in recombinant hirudin protein sequence, they could establish five pairs of disulfide bonds, including Ṩ1(Cys1-Cys2), Ṩ2-Ṩ3(Cys3-Cys5/Cys4-Cys6 or Cys3-Cys6/Cys4-Cys5), Ṩ4(Cys7-Cys9) and Ṩ5(Cys8-Cys10).

Qipi pills, a traditional Chinese medicine formulation composed of raw medicinal herb powder, are highly susceptible to microbial contamination. In this study, 149 batches of samples from 10 different manufacturers were tested in accordance with current standards and the results were analyzed. Subsequently, exploratory research was conducted to establish a microbial limit detection method for Qipi pills. The detected microorganisms were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF-MS) or 16S rRNA gene sequencing technology, and their microbial contamination status was assessed. The results revealed that all 149 batches of samples complied with the regulations upon microbial limit inspection. The established microbial limit inspection method for Qipi pills was 1∶20 for total aerobic bacteria count, 1∶10 for total mold and yeast count, while standard methods were employed for specified microorganisms including Escherichia coli, bile salt-tolerant Gram-negative bacteria, and Salmonella. Among the identified contaminating bacteria, 90％ were Bacillus spp., suggesting an enhancement in process control over microorganisms by manufacturers was necessary.

An HPLC-charged aerosol detector(CAD) method for the analysis of the related substances of 1,2-dierucoyl-sn-glycero-3-phosphocholine(1), dimyristoyl phosphatidylethanolamine(2) and dipalmitoyl phosphatidylglycerol(3) was established respectively, and the main phospholipid degradation impurities of three synthetic phospholipids were identified as Sn-1-lysophospholipids, Sn-2-lysophospholipids and fatty acids by LC-MS method and specialized phospholipase A1 combined with ACD/Labs software(version 2021), and identified in which the Sn-1- lysophospholipids was found as the dominant degradation product. The results provided a reference for the quality control and preparation process of synthetic phospholipid pharmaceutical excipients.

A GC method was established for the determination of the five residual organic solvents (tetrahydrofuran, ethanol, acetonitrile, pyridine, N,N-dimethylformamide) and a related substance(1,3-propanediol) in perampanel raw materials. Tetrahydrofuran, ethanol, acetonitrile, pyridine, N,N-dimethylformamide and 1,3-propanediol were quantitatively determined by direct sampling on DB-WAX column, with DMSO as the solvent and temperature programmed control. The above five organic solvents and 1,3-propanediol were completely separated. Their average recoveries were 97.65％ - 112.88％, with RSDs less than 5.0％. In the linearity test, good linear relationships between peak areas and mass concentrations of the analytes were achieved, and all the correlation coefficients were more than 0.998.