Polymorphic forms of bisoprolol fumarate

Bisoprolol fumarate is a beta blocker-type drug substance which has been well known for several decades. However, no relevant data can be found in the literature about its crystal polymorphism. The purpose of this paper was to present two anhydrous forms (Form I and Form II) and a hydrate of bisoprolol fumarate substance. Crystalline forms were studied by various solid-state analytical methods: Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and thermoanalytical methods (thermogravimetry and differential scanning calorimetry). Thermodynamic stability and solubility of the presented polymorphs were also investigated. Both FT-IR and XRPD methods were found to be suitable for the characterization of the different crystal structures. Thermoanalytical measurements showed that (1) Form I and Form II own clearly different melting points and (2) both Form II and hydrate forms can transform into Form I at higher temperature values. Results of the DVS measurements prove that both Form I and Form II became metastable under extremely humid conditions (>?80% RH) and converted into the hydrate. Thermodynamic stability studies showed that Form I and Form II polymorphs are in enantiotropic relationship with an enantiotropic point at about 40–45 °C. Solubility studies indicated that all of the prepared forms are highly soluble, and no difference was found between them. Considering the recommendations of the corresponding International Conference of Harmonization guideline, it can be stated that no specification is required for crystal polymorphism in case of this substance.

     

Enantiomeric deoxycholic acid: total synthesis, characterization, and preliminary toxicity toward colon cancer cell lines

Deoxycholic acid (DCA) is an endogenous secondary bile acid implicated in numerous pathological conditions including colon cancer formation and progression and cholestatic liver disease. DCA involvement in these disease processes results partly from its ability to modulate signaling cascades within the cell, presumably through both direct receptor activation and general detergent mediated membrane changes. To further explore DCA induced changes in cell signaling, we completed a total synthesis of enantiomeric deoxycholic acid (ent-DCA) from achiral 2-methyl-1,3-cyclopentanedione. Using a modified method of the synthesis of ent-testosterone that proceeds through the (R)-(-)-Hajos-Parrish ketone, we have completed the successful synthesis of ent-DCA in 25 steps with a yield of 0.3% with all stereochemical assignments of the product confirmed by X-ray crystallography. Our studies toward this synthesis also uncovered the methodology for the development of a novel A,B-cis steroidal skeleton system containing a C3-C9 single bond as well as conditions to selectively ketalize the typically less reactive 12-carbonyl in poly-keto A,B-cis androgens. The critical micelle concentration (cmc) of ent-DCA, determined by a dye solubilization method, was identical to the cmc of natural DCA. Toxicity studies toward HT-29 and HCT-116 human colon cancer cell lines demonstrated that ent-DCA had similar effects on proliferation, yet showed a markedly decreased ability to induce apoptosis as compared to natural DCA.     

Elementary Graphs with Respect to <Emphasis Type="Italic">f</Emphasis>-Parity Factors

This note concerns the f-parity subgraph problem, i.e., we are given an undirected graph G and a positive integer value function \({f : V(G) \rightarrow \mathbb{N}}\), and our goal is to find a spanning subgraph F of G with deg _F ≤ f and minimizing the number of vertices x with \({\deg_F(x) \not\equiv f(x) \, {\rm mod} \, {2}}\) . First we prove a Gallai–Edmonds type structure theorem and some other known results on the f-parity subgraph problem, using an easy reduction to the matching problem. Then we use this reduction to investigate barriers and elementary graphs with respect to f-parity factors, where an elementary graph is a graph such that the union of f-parity factors form a connected spanning subgraph.     

Molecular topology

General formulas for calculating the Wiener index (W) ² and the hyper-Wiener index (R)³ in spiro-graphs containing three- to six-membered rings are proposed. They are derived on the basis of Hosoya's formula⁴ and the Klein-Lukovitz-Gutman⁵ formula for evaluatingW andR, respectively, in cycle-containing graphs, by using the layer matrix of cardinality (LC). ⁶ An extension of the Wiener number, theW ^* number of Gutman⁷ is also evaluated for these spiro-graphs.For Part 23, see Ref. 1.Dedicated to Academician of the RAS N. S. Zefirov (on his 60th birthday).Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1674–1679, September, 1995.