Estimation of impurity profiles of drugs and related materials. Part 16: Identification of the side-products of the ethinylation step in the synthesis of contraceptive gestogens.

A new apolar impurity (3,17 alpha-diethinyl-13-ethyl-3,5-gonadiene-17-ol, IIb) was detected and identified in norgestrel with the aid of thin-layer and high-performance chromatography and spectroscopic techniques. IIb is the product of the acid-catalysed dehydration of an overethinylated side product (Ib) of the ethinylation step in the synthesis of norgestrel. IIb can be determined by thin-layer densitometry and high-performance liquid chromatography. Another impurity (17 alpha-ethinyl-13-ethyl-4-gonene-17-ol, IV), originating from a side product of the Birch reduction step in the synthesis of norgestrel was also detected and identified. The spot of IV overlaps with that of IIb in the TLC system of USP XXIII but can be separated and quantification by more selective TLC systems and by gas chromatography.

Estimation of impurity profiles of drugs and related materials Part 15. Identification of minor impurities in cimetidine.

Besides several known impurities in cimetidine, two additional compounds at levels below 0.1% were detected by ion-pair reversed-phase high-performance liquid chromatography (HPLC). The impurities were isolated from crude cimetidine using normal-phase preparative HPLC. 1H and 13C NMR and mass spectrometric investigations revealed the structures of the impurities to be 2,5-bis[(N'-cyano-N"-methyl)guanidinoethylthiomethyl]-4-methylimid azole (VII) and 1,8-bis[(N'-cyano-N"-methyl)guanidino]-3,6-dithiaoctane (VIII). These structures were verified by synthesis of the impurities and comparison of the spectra and chromatographic (HPLC and TLC) retention data of the isolated and synthesized materials.

Estimation of impurity profiles of drugs and related materials. 12. Isolation and identification of an isomeric impurity in danazol.

We report on a new isomeric impurity of danazol. This impurity designated as isodanazol was detected by reversed-phase high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Its structure was determined after separation by preparative HPLC. Mass spectrometry revealed the isomeric nature of the impurity while the UV spectrum indicated profound difference in the isoxazole moieties. The structure of the isomeric isoxazole ring in isodanazol was determined by NMR spectroscopy using COSY, HETCOR and NOE measurements. The difference between the UV spectra of danazol and isodanazol is explained on the basis of the difference between the aromaticities of their isoxazole rings supported by quantum chemical calculations. The quantitative determination of the impurity down to the 0.05% level can be performed by HPLC, gas chromatography and TLC densitometry.

Estimation of impurity profiles in drugs and related materials. Part 11--The role of chromatographic and spectroscopic methods in the estimation of side-reactions in drug syntheses.

Impurities in drugs are classified on the basis of the types of side-reactions in drug syntheses resulting in their formation. This is shown by summarizing the authors' earlier results in the field of impurity profiling of 19-nor-steroids, ethynodiol diacetate, mazipredone, pipecuronium bromide, flumecinol, enalapril, pyridinol carbamate, phenylbutazone, thymotrinan and some new results related to danazol and famotidine.

[Analysis of steroids. Part 40. Isolation and identification of unusual impurities in ethynodiol diacetate]. / Adatok a szteránvázas vegyületek analitikájához 40. Etinodiol-diacetát szokatlan szennyezéseinek izolálása és szerkezetük felderítése.

In the course of the estimation of the impurity profile of ethynodiol diacetate, in addition to common impurities such as norethisterone acetate, ethynodiol-3-acetate and alpha-ethynodiol diacetate, two unknown impurities were detected by analytical reversed phase HPLC (C-18 silica and 80% aq. methanol as the eluent) and isolated by normal phase preparative HPLC (silica and 98:2 mixture of hexane and 2-propanol as the eluent). The 1H- and 13C-NMR spectra of the isolated impurities revealed that their structures could be characterized as the E and Z isomers of an analogue of EDDA containing "trimerised acetyl" group at the 17-hydroxy group (structures 4 and 4a). These structures were in good agreement with the extended UV spectra of the impurities and the mass spectra with the m/z 438 peak which can be derived from 4 and 4a by the loss of ketene.

Studies on the melts of alkali metal acetates.

The density, viscosity, and electrical conductivity of alkali metal acetates were measured over the temperature interval between melting and decomposition. The apparent activation energies of the equivalent conductivities and viscosities were calculated. It has been concluded from the results that alkali metal acetates, similarly to alkali metal benzenesulphonates studied earlier, exhibit properties quite unlike those of alkali metal halides. In the dependence of equivalent conductivity on the nature of the cation, the anomalous behaviour of lithium salts appears to be due to association prevailing in the melt phase.