Abstract
Tibolone, a synthetic steroid, is used in the treatment of natural or surgical menopause disturbs resultant of estrogenic deficiency. Isotibolone (Δ4-tibolone) is one of the three active metabolic degradation products of tibolone that displays progestagenic effects on carcinoma cell growth and gene regulation. Isotibolone can be present in raw material of tibolone due to some inadequate synthesis or storage. Its presence is necessary to be identified and quantified in active pharmaceutical ingredients (API), before its use in the manufacturing of medicines. After a recent study on the crystal structure determination of isotibolone, quantitative phase analyses of both tibolone and isotibolone in raw materials and tablets became possible to be conducted. X-ray powder diffraction is one recommended tool for this purpose, but it can be highly frustrating due to the extreme peak overlap when conventional laboratory equipments are used. In this work we show that the use of Brazilian Synchrotron Light Source X-ray powder diffraction data and the Rietveld method can be successfully applied to identify and quantify the isotibolone in two samples of tibolone raw materials.
Highlights
Tibolone is a synthetic steroid used to relieve hypooestrogenic symptoms and protect against bone loss in post-menopausal women
In this work we show that the use of Brazilian Synchrotron Light Source X-ray powder diffraction data and the Rietveld method can be successfully applied to identify and quantify the isotibolone in two samples of tibolone raw materials
The crystals obtained were filtered and washed with hexane at 0 ̊C and dried under vacuum at 40 ̊C. They were characterized as being indicative of pure tibolone with a triclinic structure (TRI) as per the methodology described in the literature
Summary
Tibolone is a synthetic steroid used to relieve hypooestrogenic symptoms and protect against bone loss in post-menopausal women. Tibolone itself has no biological activity; its effects are the results of the activity of its metabolites on various tissues [1]. Tibolone is quickly metabolized into 3-hydroxytibolone (3-OH-tibolone) and 3β-OH-tibolone compounds, which are present in an inactive, sulfated form. A third compound, the isotibolone ( known as 4 isomer or Org OM38) (Figure 1) is formed from tibolone directly or from the 3β-OH-metabolites and it functions as a progestagenic in endometrial tissue, whereas in the brain and liver it has androgenic effects [1]. The isotibolone is considered the major degradation product of tibolone [2]. The potential for significant degradation of tibolone to isotibolone makes it difficult to formulate and provide a pharmaceutical composition with acceptable storage life time for a marketed product. The isomerization mechanism involves the rearrangement on the A-ring of the double bound from carbon atoms 5 - 10 to 4 - 5 [3]
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