Tableting is a critical process in the manufacture of pharmaceutical tablets that directly influences product quality. Ensuring consistent quality between the research and development phase and commercial-scale production is essential during scale-up. In this study, we investigated methods for evaluating time-dependent deformation behavior using four excipients that exhibit different compression deformation behaviors. Dicalcium phosphate dihydrate (DCPD) shows no viscoelasticity, whereas lactose monohydrate (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) exhibit viscoelasticity and viscoplasticity, although the degree of viscosity varies between them. In addition to investigating the known strain rate sensitivity (SRS), we performed mechanical energy evaluation based on the area under the force–displacement curve and stress relaxation tests. A trapezoid waveform was applied during the test, with loading punch speeds of 0.5 and 100 mm/s, and a dwell time of 4.5 s. The SRS value for DCPD approached approximately one, indicating no speed dependence, and the SRS increased in the order of LAC < MCC < CS, consistent with previous studies that used a saw-tooth waveform. Among the mechanical energies, the ratio of plastic flow energy to plastic energy, which depends on dwell time, followed a similar trend to SRS for the three materials other than DCPD. We conclude that axial stress relaxation is affected by machine deformation, whereas radial stress relaxation provides insight into the viscous behavior of the material. Under the test conditions, the effects of the punch-displacement profile and compression pressure on the mechanical energy and stress relaxation were more pronounced than those of SRS.

Multivariate statistical process control (MSPC) has attracted considerable attention as a monitoring method for pharmaceutical continuous manufacturing. However, there are few examples of its application in pharmaceutical manufacturing, and previous studies have shown high false-positive rates. One of the reasons is the use of inappropriate scaling factors. In pharmaceutical processes, the number of experiments for MSPC modeling tends to be small because the active pharmaceutical ingredients are expensive. Subsequently, the standard deviation, a common scaling factor for some variables, becomes too small, and the model may become sensitive to small variations. In this study, we have proposed methods for determining the appropriate scaling factors. These methods were applied to granulation and drying processes in pharmaceutical continuous manufacturing. The MSPC model can detect changes in the process parameters and raw materials used during continuous wet granulation and fluidized bed drying using the proposed scaling method.

The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared to the μ-opioid receptor (MOR), which is commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, a DOR-selective agonist with a morphinan skeleton, offers analgesic and antidepressant benefits without inducing convulsions at therapeutic doses, unlike the conventional DOR agonist SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, a signaling pathway implicated in adverse opioid effects, the ligand structural basis for this biased signaling remains unclear. In this study, we explored the structure–signal relationships of KNT-127, focusing on its quinoline moiety, which is known to serve as an address domain responsible for DOR selectivity. Modifying the quinoline moiety by removing the aromatic rings reduced DOR selectivity and potency in relation to G-protein activation while diminishing both the potency and efficacy of β-arrestin recruitment. These results suggest that the morphinan skeleton is critical for reduced β-arrestin recruitment, while the quinoline moiety differentially modulates G-protein activation and β-arrestin recruitment. Together, our study expands the message-address concept, previously limited to receptor selectivity, by providing structural insights into the G-protein-biased agonism of DOR agonists, thereby guiding the design of safer DOR-targeting therapeutics.

Building on our previously reported techniques, we developed a concise and highly stereoselective synthesis method for β,β-disubstituted α,β-unsaturated esters. This synthesis comprises 3 reactions: the aldol reaction of acetic ester derivatives with ketones, the acetylation of tert-alcohols, and an elimination reaction utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). During the acetylation process, acetic anhydride and 4-dimethylaminopyridine (DMAP) facilitated the smooth acetylation of bulky tert-alcohols; however, employing DBU as a base reduced the yields. Additionally, the removal of excess DMAP effectively suppressed the formation of unwanted byproducts during the elimination step.