Factorial approach for the optimization and development of stability indicating study of the contraceptive suspension for injection(Depo-Provera®)

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Highlights

  • Optimization and validation of UV spectrophotometric study for MPA in its dosage form

  • Stability indicating and kinetic study for UV-degradation of MPA

  • Factorial design study for degradation of MPA in aqueous media and under UV light

  • Characterization of the degraded product and mechanism of degradation

  • Effect of freezing-thawing cycle on the stability of MPA

Abstract

The study involves use of factorial design for optimization of forced degradation conditions and development of stability indicating method for medroxyprogestrone acetate (MPA) or depo-provera as known in the market. MPA is an important contraceptive and anticancer drug especially for treatment of breast cancer and it is the first time to study the different conditions affecting its stability. MPA was subjected to different variables such as solvent type, pH and the time subjected to UV light. Factorial design has been used during forced degradation to determine significant factors responsible for degradation and to optimize degradation conditions reaching maximum degradation. Factors responsible for forced degradation were statistically evaluated using Bubble and Surface plots. Variables proved to be significant (p < 0.05) and the suggested model represented a perfect example for indicating the efficiency of factorial designs in optimizing the degradation conditions that give maximum percent of degradation.

We investigated also the solubility and stability profiles of MPA in aqueous solutions. Stability study results showed a very low stability profile of MPA in all the aqueous solutions with rapid degradation rate more than other solvents. The current research may contribute to enrich the knowledge of the physicochemical properties of this drug for exploring its full anticancer potential in the future.

Introduction

Forced degradation study is a complementary part of stability testing wherein the effect of the environmental stress factors like pH and light are evaluated. Medroxyprogesterone acetate (MPA), 6-methyl-3, 20-dioxopregn-4-en-17-yl acetate (Fig. 1), is a synthetic analoge of progesterone hormones used for contraception and treatment of cancers, especially breast cancer [1]. According to USP 31 [2], the current assay for MPA bulk drug and its related impurities employs an RP-HPLC, whereas the assay for MPA in an injectable suspension is a NP-HPLC assay which is a time consuming method. Up to now, several methods including spectrophotometry [[3], [4], [5], [6]], HPLC [7], LC–MS [8], GC–MS [9] and immunoassay [10] have been published for determining MPA in pharmaceutical preparations and biological fluids. There is one study for stability-indicating HPLC method for determination of medroxyprogesterone acetate in pharmaceutical preparation [7] and one study in bulk drug and injection formulation [11]. A very new approach in the field of forced drug degradation is applied to evaluate dependency of forced degradation on the different parameters by applying the concept of factorial design [12,13]. This design of experiments technique allows to elucidate, with the reduced number of experiments, various interactions between independent variables and helps to reach to the forced degradation conditions that give maximum percent of degradation and aids in the recommendations of the stability requirements for each dosage form according to the final results.

The present investigation reports the development and validation of a UV spectrophotometric method for quantification of MPA in vials and study of its kinetic degradation profile. Stress testing of MPA was carried out according to International Conference on Harmonization (ICH) guidelines [14]. Kinetic spectrophotometric method that has advantages such as high sensitivity, sufficient accuracy, simplicity, speed, and the necessity of less expensive apparatus makes it as an attractive method for the determination of trace elements in biological samples and pharmaceuticals [15].

In this report, we studied the solubility, stability and kinetics of degradation of MPA in different solutions along with the effect of pH and light. We expect this study to be helpful in future research in the field of MPA formulations that may accelerate its clinical applications. On the other hand, UV-spectrophotometry is still the technique of choice since it is simple, sensitive, economical rapid and more easily manageable.

Section snippets

Instrumentation and apparatus

The spectrophotometric measurements were carried out using a double beam UV–Visible spectrophotometer (Shimadzu, Kyoto, Japan) model UV-1601 PC connected to an IBM compatible computer, with UVPC personal spectroscopy software version 3.7. The absorption spectra were carried out using 1 cm quartz cells and recorded over the wavelength range from 200 to 400 nm. All pH-metric measurements were made on Hanna pH meter (Hanna Instruments, São Paulo, Brazil) digital pH-meter with glass combination

Spectral characteristics

The absorption spectrum of 25.0 μg mL1 MPA solution in methanol was recorded between 200 and 400 nm and showed an absorption maximum at 241 nm, and at this wavelength methanol had significant absorbance. Therefore, 241 nm was used as analytical wavelength (λmax). Fig. 2 represents the absorption spectra of MPA in methanol along with methanol blank.

Method validation

The proposed method was validated according to ICH [16] for linearity, sensitivity, precision, accuracy, robustness, ruggedness, selectivity,

Conclusions

In this research we studied the stability of the contraceptive suspension medroxyprogesterone (MPA) using factorial design approach under UV light and in different solutions. The study revealed that the drug might already have enough aqueous solubility to induce in-vivo therapeutic effects, particularly if administered via a parenteral route. Unfortunately, the solubility of the drug is compromised by its stability problems, as we demonstrated that MPA is highly unstable in aqueous solutions

Acknowledgment

The authors gratefully acknowledge Prof. Abdel Maaboud Ismail Mohamed (Pharmaceutical analytical chemistry department, Faculty of Pharmacy, Assiut University, [email protected]) for his valuable discussion regarding the factorial design approach of the presented work.

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