[Are ultraviolet and visible spectroscopy and spectrophotometry obsolete methods in pharmaceutical analysis?]. / Elavult módszereknek tekinthetók-e az ultraibolya spektroszkópia és spektrofotometria a gyógyszeranalitikában?

It has been investigated if UV-VIS spectroscopy and spectrophotometry can be regarded to be obsolete methods in pharmaceutical analysis. The conclusions are as follows. As a consequence of the introduction and spreading of highly efficient spectroscopic methods in the structural analysis of organic compounds the importance of UV-VIS spectroscopy as a structure elucidation tool has greatly decreased. At the same time, however, diode-array UV spectrophotometers used as HPLC detectors have created very convenient possibilities for the identification of minor components (impurities, degradation products, etc.) in drugs. This statement is illustrated by several practical examples. On the basis of some data taken from the British Pharmacopoeia 1998 it is stated that UV spectrophotometry as a quantitative analytical method still belongs to the most frequently used analytical techniques in pharmaceutical analysis. At the same time, however, the authors are of negative opinion about the up-to-dateness and usefulness of colorimetric methods still very often published for the determination of drug substances.

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 9: HPLC investigation of flumecinol.

Two HPLC systems have been developed for the investigation of flumecinol (3-trifluoromethyl-alpha-ethyl-benzhydrol). The reversed-phase system (LiChrosorb RP-18; methanol-water, 7:3, v/v) enables the isolation and identification of the impurities. The chiral system (Chiralcel OD; hexane-2-propanol, 98:2, v/v) separates the enantiomers of flumecinol and its impurities. The potential of spectral convolution in peak identification in HPLC impurity profiling is demonstrated by an example involving the identification of the 4'-methyl-analogue of flumecinol.

[Analysis of steroids. Part 45: Analytical investigation of pipecuronium bromide (Arduan)]. / Adatok a szteránvázas vegyületek analitikájához 45. Pipecuronium bromid (Arduan) analitikai vizsgálata.

The following methods are described for the analytical investigation of pipecuronium bromide. 1. HPLC method. Of the several systems tried for the separation and quantification of impurities and degradation products the best results were obtained using silica as the stationary phase and 43:43:14 mixture of methanol, acetonitrile and concentrated aqueous ammonia containing 0.1 mole/l each of ammonium chloride and ammonium carbonate as the eluent. The validation of this method is presented. The above described aggressive eluent can be successfully replaced by an ion-pairing system using silica as the stationary phase and 96:4 mixture of acetonitrile and water containing 0.1 mole/l sodium perchlorate as the eluent. 2. Thin-layer chromatography. TLC systems are described for the separation and densitometric quantification of the impurities and degradation products of pipecuronium bromide. 3. Spectrophotometry. Two methods are described. The ester groups of the molecule can be determined by the iron(III)-hydroxamate method while for the ion-pair extraction of the quaternary ammonium steroid picric acid or bromthymol blue are used as the reagents. 4. Titrimetry. In addition to the titration with acetous perchloric acid for the assay of the bulk material a microtitration method is described for the determination of pipecuronium bromide in individual lyophylized ampoules (potentiometric titration with 0.1 M silver nitrate).

[Determination of 3,3'-dichlorodibenzoyl peroxide impurity in 3-chloroperbenzoic acid]. / 3,3'-diklór-dibenzoil-peroxid szennyezés meghatározása 3-klór-perbenzoesavban.

An ultraviolet spectrophotometric method has been developed for the determination of 3,3'-dichloro dibenzoyl peroxide impurity in 3-chloroperbenzoic acid, an important epoxidation agent in drug (especially steroid) syntheses. The method is based on the selective extraction of the main component by aqueous alkali from a chloroformic solution. The solution of the test substance (0.05-0.1 g in 50 ml chloroform) is extracted four times with 20 ml portions of 0.1 M aqueous sodium hydroxide and the absorbance of the resulting chloroformic solution in measured at 286 nm to calculate the content of 3,3'-dichloro dibenzoyl peroxide impurity. Beer's law is obeyed in the 0-10% impurity range. The A10/01 cm.value is 77.9 and the correlation coefficient of the regression equation was found to be 0.995. The relative standard deviation of the measurement in the case of 2% impurity was +/- 0.43%.

The changing role of ultraviolet spectroscopy in drug analysis.

New applications in the identification of minor components in drugs by rapid scanning diode-array UV spectrophotometers as high-performance liquid chromatographic (HPLC) detectors are exemplified by (a) identification and quantification of alpha-chloro-4-methoxycinnamic acid methyl ester as the byproduct of the Darzens reaction between 4-methoxybenzaldehyde and chloroacetic acid methyl ester; and (b) identification of 4-androsten-17-one and 3 beta-phenyl-5 alpha-androstan-17-one as impurities in 5 alpha-androst-2-en-17-one. The advantages of the use of derivative spectrophotometry are illustrated by the following examples: (a) determination of flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol) in an oily emulsion formulation; (b) determination of RGH-6148 (2-benzylthiazolidinone) in a suspension used in toxicological studies; and (c) determination of mestranol as an impurity in norethisterone.

New derivatization reactions in pharmaceutical analysis.

The application of chemical reactions in conjunction with spectrometric and chromatographic methods is exemplified by the formation of 2-nitrophenylhydrazide derivatives for the spectrometric assay of carboxylic acids; silylation and trifluoroacetylation of drugs for gas chromatography; selective reduction of steroid ketones for their IR spectrometric identification; the use of epoxidation in discriminating between saturated and unsaturated steroids in gas chromatography; increasing the selectivity and sensitivity of the spectrometric and gas chromatographic determination of isomeric Delta4- and Delta5-3-ethylenedioxy steroids by treatment with hydrochloric acid; and the use of the same reagent in the difference spectrometric determination of 2,5-dimethyl-alpha-ethyl benzhydrol.

Analytical methods based on transformations with hydrochloric acid.

Ultraviolet spectrophotometric methods are described for alpha-ethyl benzhydrol derivatives, 3-trifluoromethyl-alpha-ethyl benzhydrol (flumecinol), 2,5-dimethyl-alpha-ethyl benzhydrol (RGH-3395) an impurity of the latter, (1,4-di-(2,5-dimethyl-phenyl)-1,4-diphenyl-butan-1,4-diol). The methods are based on dehydrations catalysed by hydrochloric acid yielding unsaturated aromatic chromophores. The determination of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (RGH-4615) is also based on treatment with hydrochloric acid; the chromophoric compound is a benzaldoxime derivative. The hydrochloric acid-catalysed transformation of ethynodiol diacetate to its 3,5-diene derivative enables the parent compound to be determined by gas chromatography.