Small-molecule drug candidates often encounter challenges related to physicochemical properties, such as poor solubility and stability. Modifying the crystal form of these compounds is a promising approach to overcoming these challenges. Herein, trimethoprim (TMP), a biopharmaceutics classification system (BCS) class II drug with low water solubility, and sulfathiazole (STZ), a polymorphic sulfa drug, were selected as model active pharmaceutical ingredients. A TMP-STZ complex was prepared using liquid-assisted grinding, yielding anhydrous and ethanol-solvated forms. Physicochemical analyses confirmed that the complexes formed stable salt crystals, reducing hygroscopicity and improving thermal stability. An ethanol solvate demonstrated enhanced stability but exhibited a decreased melting point due to desolvation. Single-crystal structure analysis revealed strong hydrogen-bonding interactions between TMP and STZ, contributing to the stability of the crystal. Structural analysis confirmed proton transfer between TMP and STZ, forming a stable salt. Reduced hygroscopicity and improved thermal stability indicate enhanced solid-state robustness of TMP. These results provide a structural basis for controlling the solid-state stability of TMP by salt formation.

Amorphous solid dispersions (ASDs) are an effective formulation approach for improving the solubility of poorly water-soluble drugs. Nevertheless, their drug-release performance depends on the phase separation morphology during the dissolution process. Although the addition of surfactants has been experimentally reported to improve the dissolution behavior of ASDs, experimental methods alone are insufficient to resolve the complex and heterogeneous intermolecular interactions between drugs and excipients in multicomponent systems at the molecular level. In this study, we used dissipative particle dynamics simulations, which efficiently analyze mesoscopic phenomena such as phase separation, to elucidate the mechanisms of drug aggregation, water uptake, and phase separation, and to discuss their potential implications for drug-release behavior. Interaction parameters (χ) were derived from quantum chemical calculations and used to parameterize the coarse-grained model. We compared binary ASDs composed of felodipine and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) with ternary ASDs that additionally contained the surfactant d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), focusing on the functional role of the surfactant. Results suggested that the balance between water uptake and drug aggregation may influence drug release behavior from ASDs, potentially through interfacial liquid-liquid phase separation (LLPS)-related organization. In particular, simulations of the ternary system containing TPGS showed reduced mesoscale drug aggregation through accelerated hydration, suppression of interfacial energy growth, and steric stabilization by TPGS molecules. These structural features may facilitate drug diffusion into the aqueous phase. These simulation-derived behaviors are consistent with previous experimental observations. Overall, this study provides a mechanistic, simulation-based framework for understanding phase separation behavior and its potential influence on drug release processes in ASDs, drug release processes in ASDs, thereby guiding formulation design, particularly for surfactant-containing systems.

Objectives: We investigated the compression mechanisms for loxoprofen sodium (LXP), which is known to occur as a dihydrate, and identified parameters that influence the tablet hardness of LXP tablets prepared by the wet granulation method. Method: LXP granules were prepared with water or ethanol as the solvent, dried under various conditions and sieved for particle size control, with 1% Mg-st added before tablet compression. Results: The findings indicated that both the granulation solvent and drying temperature significantly impacted the tablet hardness. Granules prepared with ethanol exhibited higher hardness as compared with those prepared with water. The tablet hardness varied with varying drying temperatures. Discussion: Principal component analysis (PCA) identified positive correlations between the tablet hardness and the surface free energy (SFE), polar component (γ(p)), and cohesion, and a negative correlation with the dispersive component (γ(d)). Granules prepared with ethanol exhibited a higher γ(p), likely due to the differing solubility in ethanol and water, leading to enhanced interparticle binding. This study confirmed that use of the eutectic mixture of LXP and Mg-st exerted no significant influence. Crystal structure analysis indicated that the hydration states varied according to the drying temperature, suggesting the higher γ(p) in anhydrous forms, due to the lower hydrophobicity, contributed to increased tablet hardness. Conclusion: This research offers insights for optimizing the formulation conditions to improve the LXP tablet hardness. Appropriate selection of the solvent and drying temperature mitigates tablet hardness issues, while assessment of SFE can help in the selection of suitable additives.

The flowability of powders in pharmaceutical formulations is critical for manufacturing robustness and content uniformity. Shear cell measurements aid in assessing flowability under consolidation and provide useful parameters for predicting powder behavior in real manufacturing. However, some of the parameters vary with void fraction (indentation load), thereby necessitating specification of the consolidation conditions under which the value was obtained; moreover, the given single value still cannot be used to predict flowability under different conditions. If flowability could be expressed using a parameter that reflects an intrinsic property of the powder, it would be useful for quality control of raw materials and for efficient formulation design. Therefore, we investigated the relationship between various parameters obtained from constant-volume shear cell measurements and consolidation conditions using pharmaceutical powders with different particle sizes and shapes. We found that, when the substance of the sample is the same, the preshear points align on a single straight line passing through the origin, regardless of differences in indentation load, particle size, or shape. In other words, the slope of the critical state line (ϕCSL) connecting the preshear points was relatively insensitive to particle size and shape, indicating high robustness. These findings reveal that ϕCSL could serve as an intrinsic flowability parameter of the powder. The ϕCSL values of several fine powders with particle sizes <10 µm deviated from this trend, suggesting that interparticle cohesive forces may have influenced their flowability.

The bitter taste of drugs is an important impediment to medication adherence for pediatric patients. To develop a formulation that can be easily taken by pediatric patients, we prepared film-coated molded tablets to mask their bitterness and investigated their properties. We manufactured 5 and 3 mm film-coated tablets, which were easy for children to swallow. The tablets also exhibited rapid disintegration (≤30 s), making them suitable for tube administration. The formulation of the film-coating layer was experimentally optimized. Tablets (measuring 5 and 3 mm thick) containing the model drug dextromethorphan hydrobromide were film-coated by weight of the uncoated tablets (4% by weight). These tablets rapidly disintegrated and masked the bitterness for 10 s. An examination of the coated tablets revealed that the film covered the periphery, which may mask the bitterness. The findings demonstrate that coating small molded tablets with a film enables the manufacture of tablets that could be more tolerable for pediatric patients and suitable for tube administration.

Magnesium stearate (MgSt), which is often used as a lubricant in the production of solid formulations, has different stearic acid and palmitic acid contents depending on the lot and manufacturer, resulting in differences in mixability and lubricating effect. However, there are few reports on the effect of the different physical properties of MgSt samples on mixing and tablet formation. Additionally, it is known that the triboelectric properties of components affect the mixability. Overmixing of formulations can decrease tablet hardness. In this study, the triboelectric properties and mixability of MgSt samples with different lots and manufacturers were evaluated. Tablet hardness was used as an index of the mixability of the MgSt samples with various excipients. The triboelectric properties of the MgSt samples depended on the production lot. Mixability was higher when the triboelectric properties of the excipient and MgSt were different. By evaluating the charge properties of MgSt, it should be possible to select the optimum lot and manufacturer of MgSt for specific formulations.

Remdesivir was developed as a nucleoside analogue inhibitor targeting the RNA-dependent RNA polymerase (RdRp) of the Ebola virus. It was shown to be an effective treatment for coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir is incorporated into the RdRp of SARS-CoV-2, and it becomes inactivated when remdesivir comes to the -3 position by adding three nucleotides behind. However, the detailed molecular mechanism of its inactivation remains unknown. In this study, we performed dynamic interaction analysis combining classical molecular dynamics (MD) simulations and fragment molecular orbital (FMO) calculations on the structures of RdRp and RNA complexes with remdesivir at four different positions. The results showed that the interaction between remdesivir at position -3 and Lys593 has significant importance in inhibiting RNA elongation of RdRp. Therefore, the combination of MD and FMO calculations is a useful method to clarify the molecular recognition mechanism in the biological environment.

The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance the sampling efficiency of the deposition/sublimation phase transition. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.

Ionic liquids (ILs) exhibit very diverse physicochemical properties, such as non-volatility, stability, and miscibility, which render them excellent candidate excipients for multi-purpose use. Six novel arginine (Arg)-based ILs were obtained using a one-step ultrasound method. Salt formation was confirmed by Fourier-transform infrared (FTIR), Raman, and nuclear magnetic resonance (NMR) spectroscopies. Moreover, the effects of anions and molar ratio on the molecular states and thermal properties of Arg-ILs were investigated. In addition, the solubilization of drugs with different pKa and LogP values was attempted using Arg-ILs consisting of asparagine, proline, octanoic acid, and malic acid, respectively, and a comparative study was performed. Furthermore, the interaction mode between the drugs and ILs was determined by FTIR and Raman spectroscopy. Presumably, partial interaction between the component of ILs and drugs such as ofloxacin and valsartan occurred, whereas flurbiprofen and isosorbide mononitrate were dispersed in the viscous IL. The development of strategies for the application of ILs as solubilizers or carriers of active pharmaceutical ingredients is an extremely promising and wide avenue of research

A novel in silico drug design procedure is described targeting the Main protease (Mpro) of the SARS-CoV-2 virus. The procedure combines molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. The binding structure and properties of Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through drug repositioning, targeting Mpro. Several poses of the Mpro and NFV complexes were generated by docking, from which four docking poses were selected by scoring with FMO energy. Then, each pose was subjected to MD simulation, 100 snapshot structures were sampled from each of the generated MD trajectories, and the structures were evaluated by FMO calculations to rank the pose based on binding energy. Several residues were found to be important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NFV. Asn142 is presumably regarded to form hydrogen bonds or CH/pi interaction with NFV; however, in the present calculation, their interactions were transient. Moreover, the tert-butyl group of NFV had no interaction with Mpro. Identifying such strong and weak interactions provides candidates for maintaining and substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Besides the interaction between NFV and the amino acid residues of Mpro, the desolvation effect of the binding pocket also affected the ranking order. A similar procedure of drug design was applied to Lopinavir, and the calculated interaction energy and experimental inhibitory activity value trends were consistent. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained.

While Amorphous solid dispersion is an effective method for improving the solubility of pharmaceutical formulations, it presents stability challenges, as moisture absorption can accelerate crystallization. In this study, we employed a model system using four drug molecules (Droperidol, Nifedipine, Indomethacin, Ketoprofen) and the carrier polymer Polyvinylpyrrolidone, where molecular distribution was simulated using MD methods, and interaction energies were calculated using the FMO method. We analyzed the changes in interaction energies due to moisture absorption, clarifying the differences in crystallization tendencies and stability of the drugs.

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid–base neutralization reactions. The successful synthesis was validated by attenuated total reflection–Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of −43.4 °C–−13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs.

Curcumin, a bioactive compound derived from turmeric, possesses numerous pharmaceutical properties; however, its poor aqueous solubility and permeability result in low bioavailability. This study aims to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) using different lactose types as solid carriers for the oral administration of curcumin to enhance its solubility. The system comprised curcumin, an oil phase, and a surfactant. Jasmine oil, as the oil phase, and Cremophor® RH40, as the surfactant, were selected due to their superior ability to solubilize curcumin. A microemulsion was then prepared using a ternary phase diagram. The liquid SNEDDSs were converted into S-SNEDDSs by employing three solid carriers: Tablettose® 80, FlowLac® 100, and GranuLac® 200. Dissolution studies conducted in simulated gastric fluid demonstrated a significant improvement in curcumin solubility in the S-SNEDDS formulations compared to curcumin powder. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses confirmed the appearance of curcumin in the S-SNEDDS, while Fourier-transform infrared (FTIR) spectroscopy indicated compatibility between the excipients and curcumin. Additionally, an accelerated stability study conducted over four weeks at 40 °C and 75% relative humidity showed no significant changes in the physical appearance of the S-SNEDDS formulations. These findings suggest that the S-SNEDDS formulation effectively enhances curcumin’s solubility, potentially improving its bioavailability for oral administration.

The seventh blind test of crystal structure prediction (CSP) methods substantially increased the level of complexity of the target compounds relative to the previous tests organized by the Cambridge Crystallographic Data Centre. In this work, the performance of density-functional methods is assessed using numerical atomic orbitals and the exchange-hole dipole moment dispersion correction (XDM) for the energy-ranking phase of the seventh blind test. Overall, excellent performance was seen for the two rigid molecules (XXVII, XXVIII) and for the organic salt (XXXIII). However, for the agrochemical (XXXI) and pharmaceutical (XXXII) targets, the experimental polymorphs were ranked fairly high in energy amongst the provided candidate structures and inclusion of thermal free-energy corrections from the lattice vibrations was found to be essential for compound XXXI. Based on these results, it is proposed that the importance of vibrational free-energy corrections increases with the number of rotatable bonds.

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Two ethanol-solvated adipate and succinate salts of carvedilol (CVD), a Biopharmaceutics Classification System class 2 drug, were synthesized by crystallizing ethanol with adipic acid (ADP) and succinic acid (SUA). Proton transfer from ADP and SUA to CVD and the presence of ethanol in the two novel compounds were confirmed using powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and single-crystal X-ray diffraction measurements. The two novel ethanol-solvated salts exhibited enhanced solubility and dissolution rates compared with pure carvedilol in phosphate buffer (pH 6.8). Additionally, the morphologies and attachment energies of the two novel compounds and pure CVD were calculated based on their single-crystal structures, revealing a correlation between attachment energy and dissolution rate.

For powder compaction, the Kawakita equation has been used to estimate the powder behavior inside the die. The compression pressure exerted on powders is not homogeneous because of the friction on the die wall. However, the yield pressure and porosity estimated using the Kawakita equation are defined based on the assumption that homogeneous voids and compression pressure are distributed throughout the powder bed. In this study, an extended Kawakita equation was derived by considering the variation in the compression pressure as it corresponds to the distance from the loading punch surface. The yield time section estimated from the extended Kawakita equation was wider than that which was estimated via the classical equation. This result is consistent with the assumptions used to derive the extended Kawakita equation. Furthermore, a comparison of the porosity changes before and after the yield pressure was applied indicate that the direct cause of the yield is the spatial constraints of the powder particles. Equivalent stresses were defined to clarify the critical factor that constitutes the extended Kawakita equation. As a result, "taking into account the die wall friction" was considered to be the critical factor in the extended Kawakita equation. As these findings were theoretically determined by the extended Kawakita equation, a useful model was derived for a better understanding of powder compaction in die.

The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5 mm to 1.5 mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system.

The Drucker-Prager cap (DPC) model is useful for estimating stress and strain distributions in compacted powders; however, it requires numerous stress state parameters, which are obtained from various tests, thus requiring significant time and effort, and a large number of samples. In addition, there is room for improvement in the reproducibility of DPC model simulations with respect to realistic behavior. This study develops a simple method for estimating DPC model parameters, and it can accurately reproduce the pressures measured during tableting. This objective is achieved by estimating the onset of particle deformation using the powder compaction equation and including the shear stress that results from die wall friction in the stress tensor. (c) 2023 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology, Japan. All rights reserved.