We have identified a co-crystal of tramadol hydrochloride−celecoxib (ctc; E-58425/MR308), a novel active pharmaceutical ingredient (API)−API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol•HCl and celecoxib, which displays favorable physicochemical and dissolution profiles. Adequate treatment of pain represents an unmet medical need that is often addressed via combination therapy. API−API co-crystals represent a new approach with potential to improve physicochemical properties, bioavailability, stability, or formulation capacity, which may translate into optimized pharmacokinetic profiles and clinical benefits compared with individual APIs or their combination. ctc showed a well-defined differential scanning calorimetry profile, and its single-crystal X-ray diffraction structure demonstrated a supramolecular 3D network in which the two active enantiomers of tramadol and celecoxib are linked via hydrogen bonding and chloride ions. Oversaturation studies indicated that the saturation effect for highly insoluble celecoxib occurred at a higher concentration in ctc than in celecoxib alone. Comparative intrinsic dissolution rate studies showed that the release of celecoxib was faster, and the release of tramadol was slower, from ctc than from the individual APIs, predicting an improved pharmacokinetic behavior for ctc. Together with findings from preclinical studies, these data support the clinical development of ctc for the treatment of pain.

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]­undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

The title compound, (C7H70)2TeI2 (or Ci4Hi41202Te), crystallizes in space group Pi, either with Z = 8, (Ia), or Z = 4, (Ib). The six independent molecules [four in (Ia) and two in (Ib)] have very similar structures. The geometry at the Te atoms is pseudo-trigonal bipyramidal, with the I atoms in the axial positions and the anisyl groups and the lone pair of electrons in the equatorial plane. The Te--C and Te--

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