Stability of Docetaxel Solution: RESULTS

Taxotere

Accelerated Degradation and Assay Validation

Degradation of docetaxel with sodium hypochlorite occurred relatively quickly, such that less than 53% of the initial docetaxel concentration remained after 23 min. At least 4 degradation products were observed in the chromatograms (Figure 1, chromatogram B). None of these degradation products interfered with quantification of docetaxel. Degradation of docetaxel at 80°C occurs more slowly, and 56% remained after 5 h. At least 6 degradation products were observed in the chromatograms (Figure 1, chromatogram C). Although the relative amounts differed, the primary degradation products obtained with heat were identical with those obtained through degradation with sodium hypochlorite. None of these degradation products interfered with quan­tification of docetaxel. As a result of the chromatographic separation of these degradation products from docetaxel and the similarity of the ultraviolet spectrum (200 to 320 nm) between a fresh docetaxel sample and docetaxel in a degraded sample, it was concluded that this analytical method was suitable for indicating stability.

Assay validation demonstrated that deviation from the known concentration for quality control samples and standards on any day averaged less than 2%. Analytical error observed with repeated measurements averaged less than 1% within days and less than 2.5% between days. Apcalis Oral Jelly

Table 1. Observed Concentration (as Mean Percent of Initial Concentration)* of Docetaxel after Dilution in Ethanol-Polysorbate 80 and Storage in Vials


Study Day


Room Temperature (23°C)


Refrigerated (4°C)


Initial concentration (mg/mL)


10.0±0.03


10.2±0.20


Day 1


101.0±1.6


101.1±1.2


Day 3


96.5±1.1


96.2±1.7


Day 4


101.8±0.6


100.7±1.2


Day 7


99.8±1.2


101.9±1.2


Day 10


103.7±1.0


102.5±0.5


Day 14


101.7±0.8


101.3±0.8


Day 17


101.3±1.1


100.5±1.7


Day 21


100.0±0.4


99.6±1.1


% remaining on
day 21t


101.5


100.9


Lower limit of
95%
CI for
% remaining on
day
21Ф 96.6


96.3

Analysis of accuracy and reproducibility during the study period indicated that the docetaxel concentration was measured accurately and reproducibly. For accuracy, the mean of duplicate determinations of standards over the study period showed less than 2% deviation from the expected concentration. For analytical reproducibility, the mean of duplicate determinations of standards (as measured by CV) averaged less than 2% within a day and less than 2.5% between days. These results indicate that differences of 10% or more can be confidently detected with acceptable error rates13 with duplicate analysis. System suitability criteria developed to ensure continued acceptable chromatographic performance during the study period required that on each study day the concentration of the mobile phase be adjusted to ensure a retention time for docetaxel between 8.2 and 10 min.

Stability of Docetaxel (10 mg/mL) in Vials

During the 21-day study period, all samples retained more than 95.0% of the initial concentration(Table 1). On day 21, the lowest limit of concentration, with 95% confidence, was calculated as 96.3% (Table 1). Multiple linear regression showed no differences in percent remaining due to temperature (p = 0.21) or time (p = 0.26), which indicates that there was no trend for the concentration to consistently change from day to day during the study. Inspection of chromatograms during the stability study failed to reveal any of the degradation products that were observed during assay validation. viagra 50 mg

Figure 1. Chromatogram A represents

Figure 1. Chromatogram A represents a solution of docetaxel 0.5 mg/mL in methanol and water. The sample that generated chromatogram B was applied to the column 92 min after addition of 1% sodium hypochlorite to the 0.5 mg/mL solution. At 92 min, 35% of the initial concentration remained. Degradation produced at least 4 degradation products (DPs). The sample that generated chromatogram C was applied to the column after 25 h of incubation at 80°C, at which time 39% of the docetaxel remained. Degradation using heat produced some additional degradation products, but none of them interfered with quantification of docetaxel at 10 min. Chromatogram D represents docetaxel 0.4 mg/mL in 0.9% sodium chloride stored at room temperature and subjected to chromatography on study day 35. The degradation products that were observed during the accelerated degradation study (see chromatograms B and C) were not observed.

All solutions were initially clear and colourless and remained so for the duration of the study. No visible particles were observed in any of the solutions through­out the study period.

Stability of Docetaxel (0.4 and 0.8 mg/mL) in PABs

During the 35-day study period, all samples retained more than 95.0% of the initial concentration (Table 2). On day 35, the lowest limit of concentration, with 95% confidence, was calculated as 95.9%. Multiple linear regression showed no differences in percent remaining due to formulation (new versus old; p = 0.16) or time (p = 0.34), which indicates that there was no trend for the concentration to consistently change from day to day during the study. However, a statistically significant difference as small as 2.4% (in terms of docetaxel concentration remaining) was detected (p = 0.041). canadian antibiotics

Table 2. Observed Concentration (as Mean Percent of Initial Concentration)* of Docetaxel after Dilution in 0.9% Sodium Chloride and Storage in Polypropylene-Polyethylene Copolymer Bags at Room Temperature (23°C)


New Formulation


Old Formulation


Study Day


0.4 mg/mL
(first bag)


0.4 mg/mL (second bag)


0.8 mg/mL


0.8 mg/mL


Observed initial concentration (mg/mL)


0.376±0.0005


0.393±0.0025


0.634±0.0005


0.778±0.0003


Day 3


100.3±0.7


100.9±0.7


98.0±0.5


97.1±0.2


Day 7


103.5±0.8


103.9±0.0


99.9±0.4


98.2±0.1


Day 14


106.0±0.4


106.9±0.6


102.2±0.4


98.7±0.3


Day 25


99.5±0.3


99.1±1.6


99.8±0.2


98.2±0.6


Day 35


104.9±0.2


105.0±0.9


100.8±0.4


97.2±1.7


% remaining on
day 35t


103.9


103.9


100.9


97.5


Lower limit of
95%
CI for
% remaining on
day
35Ф


99.6


99.1


98.9


95.9

Inspection of chromatograms during the stability study revealed no measurable amounts of the degradation products that were observed during the accelerated portion of the study (Figure 1, chromatograms B and C). Therefore, degradation could not be detected after storage at room temperature. Because no degradation was detected, estimates of the degradation rate for docetaxel at room temperature could not be determined with confidence for any solution at either concentration. We were therefore unable to detect differences in degradation rates between the new and the older formulation or between solutions stored at room temperature and at 4°C.

All solutions remained clear and colourless for the duration of the study. With the new formulation, the initial pH values for the 0.4 mg/mL solutions in NS ranged from 5.13 to 5.16, whereas those for the 0.8 mg/mL solutions had an initial pH of 4.80. In contrast, with the old formulation, the initial pH for docetaxel 0.8 mg/mL in NS was 6.71. Over the 35-day study period the pH changed by less than 0.06 of a pH unit in the 4 solutions of docetaxel in NS. generic cialis soft tabs

Category: Main

Tags: docetaxel, stability, Taxotere

Leave a Reply

Your email address will not be published.

CAPTCHA image
*