Continuous wavelet transform and integration of discrete wavelet transform with principal component analysis and fuzzy inference system for the simultaneous determination of ethinyl estradiol and drospirenone in combined oral contraceptives.

In this study, the spectrophotometric method integrated with continuous wavelet transform (CWT) and coupled discrete wavelet transform (DWT) with fuzzy inference system (FIS) was developed for the simultaneous determination of ethinyl estradiol (EE) and drospirenone (DP) in combined oral contraceptives (COCs). The CWT approach was performed in the linearity range of 0.6-6 µg/mL for EE and 0.9 to 18 µg/mL for DP. Biorthogonal with an order of 1.3 (bior1.3) at a wavelength of 216 nm and Daubechies with an order of 2 (db2) at a wavelength of 278 nm were selected as the best wavelet families for obtaining the best zero crossing point for EE and DP, respectively. The limit of detection (LOD) of 0.7677 and 0.3222 µg/mL and the limit of quantification (LOQ) of 2.326 and 0.9765 µg/mL were obtained for EE and DP, respectively. The mean recovery of 103.24% and 99.77%, as well as root mean square error (RMSE) of 0.1896 and 0.1969, were found for EE and DP, respectively. In the DWT, the absorption of the mixtures was decomposed using different wavelets named db4, db2, Symlet2 (sym2), and bior1.3. Each of the wavelet outputs was dimension reduced by the principal component analysis (PCA) method and considered as FIS input. The wavelet of db4 with the coefficient of determination (R2) of 0.9979, RMSE of 0.0968, and mean recovery of 100.63% was chosen as the best one for the EE, while bior1.3 with R2 of 0.9955, RMSE of 0.4055, and mean recovery of 101.93% was selected for DP. These methods were successfully used to analyze the EE and DP simultaneously in tablet pharmaceutical formulation without any separation step. The suggested methods were compared with a reference method (HPLC) using analysis of variance (ANOVA) at a 95% confidence level, and no significant difference was observed in terms of accuracy. The suggested chemometric methods are reliable, rapid, and inexpensive, and can be used as an environmentally friendly alternative to HPLC for the simultaneous estimation of the mentioned drugs in commercial pharmaceutical products.

Recency, duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer (Washington, USA).

Women who have used combined oral contraceptives (COC) have a reduced risk of endometrial cancer relative to that of women who have never used oral contraceptives, but it is unclear whether the size of the reduction is influenced by the progestin content of the preparation. We analyzed data from two population-based case-control studies of endometrial cancer to investigate this question. Among women aged 40 to 59 years who were residents of King or Pierce Counties, Washington (United States), incident cases who were diagnosed during 1975-77 or 1985-87 were identified. Personal interviews were conducted with 316 such women and their responses compared with those of 501 controls who were selected by household surveys or random-digit dialing. A reduced risk of endometrial cancer associated with COC use was present only among users of five or more years' duration, and even then only in women who were not long-term users of unopposed postmenopausal estrogens. Among these women, the relative risk (RR) of endometrial cancer did not differ according to the progestin potency of the COC used: it was equally low for women who had used a COC with low progestin content (RR = 0.2, 95 percent confidence interval [CI] = 0.1-0.8) as for women who had used a COC with high progestin content (RR = 0.3, CI = 0.1-0.9). Our results argue that, if the reduced risk of endometrial cancer in long-term users of COCs is due to the progestins contained in these preparations, that amount of progestin in most COCs exceeds the threshold amount needed to produce this beneficial effect.

Modification of the U.S.P. dissolution method for the analysis of norethindrone and ethinyl estradiol tablets.

A modification of the U.S.P. dissolution method for the quantitation of norethindrone and ethinyl estradiol tablets is proposed. This modification consists of the use of distilled water as the dissolution medium instead of 0.1 N hydrochloric acid (HCl) and/or neutralization of 0.1 N HCl with sodium carbonate prior to analysis. Statistical analysis of the results indicate that there are no significant differences between the dissolution in 0.1 N HCl and the dissolution in distilled water (p < 0.05) for norethindrone and ethinyl estradiol.

Quantitative analysis of ethynodiol diacetate and ethinyl estradiol/mestranol in oral contraceptive tablets by high-performance liquid chromatography.

A procedure is described for the assay of ethynodiol diacetate and ethinyl estradiol/mestranol by HPLC using two UV detectors at 210 and 280 nm. The system was acetonitrile 38% (v/v) in water as mobile phase on a 250 x 3.2-mm i.d. RP-2 column, with butylated hydroxytoluene as the internal standard. There was greater than 99% recovery from synthetic preparations and the coefficient of variation was greater than 2.0% for formulations.

Simple high-performance liquid chromatographic assay for norethindrone--mestranol in combination tablets.

A simple, sensitive, and specific high-performance liquid chromatographic procedure was developed to assay norethindrone--mestranol combination tablets. The method involves a chloroform extraction of a single pulverized tablet. After centrifugation, and aliquot of the supernate was injected into a modular high-performance liquid chromatograph. The effluent from the silica column was monitored serially with a fixed-wavelength UV detector (254 nm) for norethindrone quantitation and a fluorescence detector (230 nm for excitation and 280 nm cutoff filter for emission) for mestranol quantitation. Progesterone was used as an internal standard. The method was employed successfully in content uniformity studies of several brands of commercially available tablets.

Effect of varying amounts of ethinyl oestradiol in the combined oral contraceptive on plasma sex hormone binding globulin capacity in normal women.

The plasma sex hormone binding globulin (SHBG) capacity has been measured in 52 normal women, 11 women on various oral contraceptives containing 50 micrograms of ethinyl oestradiol and 11 women on oral contraceptives containing less than 35 micrograms of ethinyl oestradiol. The results show that women on oral contraceptives containing 50 micrograms of ethinyl oestradiol have a significantly raised SHBG capacity (p less than 0.005) whereas those patients on oral contraceptives containing 35 micrograms or less of ethinyl oestradiol have SHBG capacities which do not differ significantly from normal ovulating women (p greater than 0.05). Thus the 35 micrograms pill interferes less with bound/unbound sex steroid ratios than does the 50 micrograms pill.

Collaborative study of an assay for progestational steroids in individual contraceptive tablets.

A single tablet assay method has been developed for determining norethindrone, norethynodrel, and norgestrel in commercial contraceptive tablets. The steroid is separated from the tablet constituents on a diatomaceous earth column, the chloroform eluate is reacted with isonicotinic acid hydrazide, and the steroid is determined by colorimetry. Norethynodrel is isomerized to a conjugated ketosteroid before the colorimetric determination. Fourteen laboratories collaboratively tested the method. The average recoveries in 3 brands of tablets were as follows: 102.6% for the sample labeled as containing 0.35 mg norethindrone/tablet, 99.4% for the 2.5 mg norethynodrel/tablet, and 98.2% for the 0.5 mg norgestrel/tablet. The assay method has been adopted as official first action.