Core in Cup Ethylmorphine Hydrochloride Tablet for Dual Fast and Sustained Pain Relief: Formulation, Characterization, and Pharmacokinetic Study.

Ethylmorphine hydrochloride (EtM) is a derivative of morphine used as analgesic to treat severe pain in case of cancer and bone injury. This study aimed to formulate and evaluate core in cup tablets containing 2 doses of EtM, the cup was formulated as lyophilized oro-dispersible tablet (ODT) for immediate release (IR), and the core was formulated as directly compressed tablet for sustained release (SR). Factorial design was adopted for the optimization of tablets prepared via lyophilized form and direct compression techniques: a 41.22 design was used for the former, while a 32 one was used for the latter. All prepared tablets showed acceptable physical properties which were in accordance with pharmacopeial standards. Two lyophilized ODTs (F9 and F10) formulae were selected as the cup for instant release. While one directly compressed tablet formula (S6) was selected based on the in vitro release profile to represent the sustained core, the outcome was 2 core in cup tablets, namely B1 and B2 which were evaluated for their in vivo absorption and showed a maximum plasma concentration (Cpmax) of 354.12 ± 17.55 ng/mL and 350.82 ± 12.15 ng/mL respectively attained after 3.0 h which were twofolds significantly higher in comparison to the market tablet with Cpmax of only 172.05 ± 12.53 ng/mL attained after 2.20 ± 0.24 h.

Insights into hydrate formation and stability of morphinanes from a combination of experimental and computational approaches.

Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl(-) counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compounds except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to estimate the heat of the hydrate ↔ anhydrate phase transformations, indicating an enthalpic stabilization of the respective hydrate of 5.7 to 25.6 kJ mol(-1) relative to the most stable anhydrate. These results are in qualitative agreement with static 0 K lattice energy calculations for all systems except morphine hydrochloride, showing the need for further improvements in quantitative thermodynamic prediction of hydrates having water···water interactions. Thus, the combination of a variety of experimental techniques, covering temperature- and moisture-dependent stability, and computational modeling allowed us to generate sufficient kinetic, thermodynamic and structural information to understand the principles of hydrate formation of the model compounds. This approach also led to the detection of several new crystal forms of the investigated morphinanes.

Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones as human chymase inhibitors using structure-based drug design.

A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.

Synthesis, cytotoxic activities and cell cycle arrest profiles of naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides.

Naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD glycosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not only the indolocarbazole framework as well known before but the sugar moiety can have a profound impact on the mechanism of action for these types of compounds.

Friedländer synthesis of the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine has been prepared in 26% yield from 3-amino-2-phenylpropenal and creatinine which were heated with N,O-bis(trimethylsilyl)acetamide at 120 degrees C for 2 h. Under certain other conditions, the main product was a pyrimidine derivative.