Multiple regression analysis (MRA) and principal component analysis (PCA) have been used in the present study to examine the relationships between the operational conditions of a unique multi-functional rotor processor, material attributes such as water content during granulation, and a series of associated micromeritics, including the flowability, granule mean size and granule density values. A variety of different operational conditions were tested, including the binder flow rate, atomization pressure, slit air flow rate, rotating speed and temperature of the inlet air. The results of MRA revealed several trends, including (1) the granule mean size was negatively affected by the atomization pressure, and positively affected by the binder flow rate; (2) the granule flow property, Carr’s index was positively affected by the atomization pressure, and negatively affected by the slit air flow rate; and (3) the granule density was positively affected by the rotating speed. Taken together, these results suggested that the binder flow rate, atomization pressure and slit airflow rate were critical process parameters for the preparation of fine globular granules. Using PCA, it was possible to examine each relationship of all 19 batches and 10 variables, as well as determine which process parameters or material attributes impacted on the quality of the final product. The PCA results revealed that the roundness was positively correlated with the water content. Therefore, we believe this fundamental information will be important for the development of processes for the facile manufacture of fine globular granules.

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The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (k_obs) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0–7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).

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In the dispensing process, powdered medicines are often blended with diluents or different kinds of powder. With blending, the mass percent of the medicine in the mixture is unknown until the active pharmaceutical ingredient is determined with techniques such as spectroscopy and chromatography. However, pharmacists need to confirm the exact blending ratio of the dispensing mixture in pharmacies. We aimed to develop a precise and concise method to measure the mass percent of powdered medicine mixtures without an expensive analytical apparatus. Digital photographs of three kinds of mixture of lactose powder, as diluents, with Adona®, Anginal®, or Asverin® powder were taken with a microscope at a 30× magnification. Thereafter, the mass percent was calculated from digital images of the mixture using calibrated color information in the YCbCr color space. A linear regression, between the mass percent and color difference signal, Cb, value was obtained from 10 to 90% of the medicines (r²=0.9806–9993) in all systems. The intra-day accuracy and precision were 0.67–12% (relative error) and <5% (relative standard deviation), respectively. Moreover, the mass percent measured using image analysis was consistent with the concentration of the active pharmaceutical ingredient determined spectrophotometrically. This effective image analysis method enables pharmacists to nondestructively ensure the exact mass percent of the medicine in the dispensing mixture in pharmacies.

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In this study, green tea compounds (flavonoids, alkaloids, and phenolic acids) were analyzed in green tea-containing dentifrices, and their stability at different pH levels was evaluated. The compounds were separated under 0.01% phosphoric acid–acetonitrile gradient conditions and detected by photodiode array detector at 210, 280, 300, 335 nm. Column temperature was set at 20°C based on the results of screening various temperatures. Each compound showed good linearity at optimized wavelength as well as showing good precision and accuracy in dentifrices. Using this method, the stability of compounds was investigated in pH 4, 7, 8, and 10 solutions for 96 h, and in pH 7 and pH 10 solutions for 6 months. The green tea compounds were more stable at low pH levels; purine alkaloids were more stable than flavonoids. In particular, gallocatechin (GC), epigallocatechin (EGC), epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), and myricetin almost disappeared in pH 10 solutions after 96 h. In dentifrices, the compounds were gradually decreased until 6 months in both pH types, while gallic acid was increased because of production of galloyl ester of other green tea compounds. Therefore, it is beneficial to adjust to as low a pH as possible when produce green tea-containing dentifrices.

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A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.

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Novel hybrids 8a–j and 9a–j were designed and synthesized by coupling the carboxyl group of hydroxylcinnamic acids with tetrahydro-β-carboline alkaloids which were linked with different substituted nitrogen-containing heterocycles at the positions-N9, and their in vitro biological activities were evaluated. It was found that most hybrids showed good to moderate anti-tumor activities. Especially, compound 9j had a great potency superior to 5-fluorouracil (5-FU) and comparable to adriamycin in human cancer cells, and could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. More importantly, apoptosis assay indicated that 9j could significantly induce tumor cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new hybrids for the intervention of human cancers.

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For the purpose of obtaining a creatinine-specific antibody, a creatinine derivative with 4-aminobutyl, which was served as a linker for preparing the creatinine–bovine serum albumin (BSA) conjugate, was synthesized from 4-benzylaminobutan-1-ol in 8 steps. Production of anti-creatinine antibodies was observed in two rabbits using the creatinine–BSA conjugate, although their titer was rather low.

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Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.

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From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Grevillea robusta, new arbutin derivatives and related compounds, named grevillosides J–Q (1–8), together with eight known compounds (9–18) were isolated. Various kind of acyl groups were attached to β-D-glucose at the 6-position through an ester linkage. Their structures were mainly elucidated from one- and two-dimensional NMR spectroscopic data. For exploitation as skin-lightening and anti-chloasma agents, the inhibitory activities of the isolated compounds as well as ones isolated in previous experiments (19–31) toward tyrosinase and melanin-producing B16 cells were assayed. Several compounds showed promising activity.

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A series of novel cyano oximino sulfonate derivatives were prepared from the reaction of arylsulfonyl chloride with different cyanoacetamide-based oximes ranging from the simplest unsubstituted amide to analogues containing N-ethyl (mimicking the Oxyma template), N-piperidinyl and N-morpholinyl chains. In addition, the cyano oximes, N-hydroxybenzimidoyl cyanide and N-hydroxypicolinimidoyl cyanide were also used in the synthesis of the novel cyano oximino sulfonate derivatives. The structures of the prepared compounds were confirmed by ¹H-NMR, ¹³C-NMR, and elemental analysis. The preliminary bioassays showed that some of the title compounds, such as 2-oxo-2-(piperidin-1-yl)-N-(tosyloxy)acetimidoyl cyanide (TsPipOx), N-(tosyloxy)benzimidoyl cyanide (TsPhOX), N-(naphthalen-2-ylsulfonyloxy)-2-oxo-2-(piperidin-1-yl)acetimidoyl cyanide (NpsPipOx), 2-amino-N-(naphthalen-2-ylsulfonyloxy)-2-oxoacetimidoyl cyanide (NpsAmOx), N-(naphthalen-2-ylsulfonyloxy)benzimidoyl cyanide (NpsPhCN), and N-(naphthalen-2-ylsulfonyloxy)picolinimidoyl cyanide (NpsPyCN), showed anti-proliferation effect on the mouse fibroblast L929. The calculated IC₅₀-values were ranging between 36.5 µg/mL and 0.235 mg/mL. However the anti-proliferation effects seem to be cytostatic rather than cytotoxic. The compounds only minimize the growth activity without completely killing the cells.

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The aim of present study was to evaluate the qualities of chaste berry (fruit of Vitex agnus-castus L.) preparations using HPLC fingerprint analysis. Seven medicinal products 1 from Japan and 6 from Europe, and 17 health foods, 6 from Japan and 11 from the United States were analyzed. HPLC profile and 26 authentic peaks were compared medicinal products and health foods. Whereas medicinal products had similar HPLC profiles, health foods had various profiles and each peak was also greatly different. The measured amounts of two markers in 5 traditional medicinal products, agnuside and casticin specified in the European Pharmacopoeia (EP), the U.S. Pharmacopoeia (USP) or the WHO monographs of chaste berry, were much lower than those in 2 medicinal products defined as “well-established use” by the European Medicines Agency. The amounts of two markers for 17 health foods differed in a great deal from 14–5054% and 3–1272%, respectively. Furthermore the amount ratios of two markers, agnuside/casticin, in about half of the health foods were remarkably larger than the standard crude drug and the ratios were closer to one of the related Chinese herbs, Vitex negundo L. It is concluded that a combination of HPLC fingerprints and the amount ratios of the marker compounds of chaste berry preparations serves as a useful tool to evaluate the qualities of these preparations.

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The two subtypes of estrogen receptor (ER), ERα and ERβ, differ greatly in expression pattern and biological functions, and ERβ-selective ligands candidates to treat immune-related disorders. ERβ-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand’s interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERβ is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERβ-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERβ selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERβ selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.

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Chemical investigation of a Formosan sponge Axinyssa sp. has led to the isolation of five nitrogenous bisabolene-type sesquiterpenes 1–5, including two new compounds axinysalines A (1) and B (2). The structures of new compounds were elucidated by analysis of high resolution (HR)-MS and two dimensional (2D)-NMR spectra and comparison of its NMR data with those of known analogues. Compound 1 exhibited moderate to weak cytotoxicity against Molt 4 and K562 cancer cell lines.

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The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0.08 to 40 ppm (µg/g API), with a R² value of 0.9999. The DL and quantitation limit (QL) obtained were 0.05 ppm and 0.08 ppm (0.13 ng/mL and 0.20 ng/mL as the 4-chloro-1-butanol concentration), respectively. These DL and QL values are well over the threshold specified in the guidelines. The accuracy (recovery) of detection ranged from 90.5 to 108.7% between 0.4 ppm and 20 ppm of 4-chloro-1-butanol. The relative standard deviation in the repeatability of the spiked recovery test was 6.0%. These results indicate the validity of the GC-MS method developed in this study. The GC-MS method was applied for the determination of 4-chloro-1-butanol in the API (Compound A), which is under clinical trials. No 4-chloro-1-butanol was found in Compound A (below QL, 0.08 ppm).

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