Anke Müller-Fahrnow

Use of X-ray crystallography for the characterization of single crystals grown in steroid containing transdermal drug delivery systems.

Target of the study was to characterize crystals which had grown in steroid-containing matrix patches during short-term storage and to thereby establish a rationale for the inhibition of crystal formation in those patches in general. Matrix type transdermal drug delivery systems (TDDS) containing either 2.2% gestodene or 3.3% estradiol were free of crystals directly after their production. However, crystals of up to 800 microns in length grew during 3 months of storage at ambient temperature. The application of several analytical methods did not help to identify the crystals. This was mainly due to the fact that the adhesive matrix surrounding the crystals could not be fully removed in the course of sample preparation with routine laboratory methods and thus impaired DSC, FTIR microscopy and hot stage polarized microscopy. However, within X-ray diffractometry, the residual amorphous patch matrix did not hamper the measurement of the crystals. Thus, they were identified as estradiol hemihydrate and gestodene form I, respectively. These results suggest that steroid-containing matrix TDDS should be stabilized against drug recrystallization e.g. by the addition of suitable crystallization inhibitors. Furthermore, systems containing estradiol may be stabilized by efficient removal water.

11β-Aryl Steroids in the Androstene Series. The Role of the 11β-Region in Steroid Progesterone Receptor Interaction

Abstract The syntheses of 11β-arylandrost-4-en-3-one 24 and the corresponding 9β,19-cyclo derivative 8 are described. Steric interaction between C-19 and the aryl residue effects conformational changes of the steroid ring system that result in reduced affinity for the progesterone receptor. The conformation of 11β-arylandrostenes is discussed in comparison with known antiprogestational steroids.

Cycloaddition-fragmentation route to 14β-allylestrone and the derived 14α,17α-ethano analogue of estriol

Abstract 3-Methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate (1) undergoes efficient boron trifluoride catalysed cycloaddition at 20 °C with acrolein to

Cloning, purification, and crystallization of Escherichia coli cystathionine β-lyase

The metC gene coding for cystathionine β‐lyase of Escherichia coli has been cloned and used to construct an overproducing E. coli strain. An efficient purification scheme has been developed and the purified enzyme has been crystallized by the hanging drop vapour diffusion method using either ammonium sulfate or polyethyleneglycol 400 as precipitating agent. The crystals belong to the orthorombic space group C2221. Their unit cell parameters are . Consideration of the possible values of V M accounts for the presence of one dimer per asymmetric unit. The crystals are suitable for X‐ray analysis and a complete native date set to 1.83 Å resolution has been collected using synchrotron radiation.

A radical approach to the synthesis of 9(10→19) abeo-steroids

Abstract Tributyltin hydride reduction of a 19-iodo-9(11)-androstene derivative stereoselectively produces B-homosteroids of the 9(10→19)abeo-type.

7α,15α-Ethano bridged steroids. Synthesis and progesterone receptor interaction

Abstract The synthesis of 7α,15α-ethano bridged steroids is described. Diels-Alder reaction of 3-methoxyestra-1,3,5(10),7,14-pentaen-17-one 4 with ethylene under high pressure provides efficient synthetic access to this class of steroids. Compounds 15 and 17 were tested for their binding affinities to the progesterone receptor (PR). Two low energy conformations 17a and 17b could be identified by force field calculations of compound 17. Both conformations were analysed in complex with the ligand binding domain of the human progesterone receptor (hPR LBD).

Synthesis of 20-fluorovitamin D analogues

Abstract A synthetic approach to novel 20-fluorovitamin D analogues is described. Introduction of fluorine has been performed by electrophilic fluorination followed by elaboration of biologically interesting side chain substructures.

Detection and characterization of polymorphic modifications of the anxiolytic drug ABECARNIL

Abstract Polymorphism is of special interest in pharmaceutical research since the stability and the biological activity of a drug substance are influenced by its solid state form. For the anxiolytic β-carboline compound ABECARNIL (isopropyl 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylate, C24H24N2O4) three different modification have been observed. Single crystal X-ray structure analyses and a variety of physicochemical methods as well as energy minimizations have been carried out in order to characterize the three solid state forms and to find at least one method capable of differentiating between the polymorphic forms. Due to nearly identical conformations and very similar packings of the molecules within their crystal lattices, polymorphs A and B show a pronounced resemblance in most physicochemical properties. Nevertheless, both forms can be distinguished by X-ray power diffraction and differential scanning calorimetry. In the crystal, molecules belonging to polymorph C show altered conformation and packing characteristics compared to forms A and B. Polymorph C can therefore be distinguished from the other solid state form by means of X-ray powder diffraction, differential scanning calorimetry and by IR spectroscopy. The relative energy of C in the crystalline environment is significantly lower than for the other two modifications.

Cycloaddition mediated synthesis and rearrangement of 16-functionalised 14α,17α-etheno-19-norsteroids

Abstract Estra-1,3,5(10),14,16-pentaen-17-yl acetates ( 1 ) undergo cycloaddition with 2-acetoxyacrylonitrile to give the corresponding 16α,17β-diacetoxy