Physical Compatibility

After 91 days of storage at 23°C or 5°C, there were no visible signs of particulate matter in any of the samples. Each solution remained colourless over the course of the study. The pH increased by only about 0.4 units over the 91 days; this change was considered insignificant.

Figure 1. Sample chromatograms of ketamine

Figure 1. Sample chromatograms of ketamine and its degradation products. A: Fresh sample of ketamine at time zero. B: Acidified ketamine sample after heating at 60°C for 245 h. C: Alkaline-degraded ketamine sample after heating at 60°C for 245 h. D: Oxidized ketamine sample after 245 h at room temperature

Chemical Stability Study Assay Validation

Chromatograms of ketamine and morphine at time zero appear in Figures 1A and 2A, respectively. Acidification and heating for 245 h resulted in a 7% decrease in the concentration of ketamine (Figure 1B) and a 10% decrease in the concentration of morphine (Figure 2B). Alkaline conditions produced more dramatic changes in concentration, with reductions of 22% for ketamine (Figure 1C) and 28% for morphine (Figure 2C), relative to starting concentrations, after 245 h of heating. Oxidation resulted in nearly 18% destruction of ketamine (Figure 1D) and 22% destruction of morphine (Figure 2D). None of the degradation peaks interfered with the parent compounds. The purity of all parent peaks in the degradation samples was confirmed by multichannel and UV spectral analysis. Spectral comparisons between the parent compounds and the reference material yielded good correlation (> 0.990).
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Table 1. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (2 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 23°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.4 ±0.05

2.1 ± 0.04

Day7

100.2 ±1.4

99.8 ±1.1

Day 14

100.2 ±0.8

99.6 ± 0.6

Day 28

100.3 ±1.7

100.2 ±1.0

Day 56

101.4 ±1.7

100.2 ±0.7

Day 91

99.7 ±1.2

99.2 ± 0.9

SD= standard deviation. *Except where indicated otherwise. tMean of 6 replications.

Table 2. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (2 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 5°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.4 ±0.03

2.0 ±0.01

Day 7

100.1 ±1.5

100.6 ±1.1

Day 14

99.9 ±1.1

100.4 ±0.9

Day 28

98.9 ±1.0

100.3 ±1.4

Day 56

99.7 ± 0.7

100.4 ±0.6

Day 91

99.1 ±1.3

100.8 ±0.6

SD= standard deviation. *Except where indicated otherwise. tMean of 6 replications.

The intraday CV for the ketamine assay was 0.68%, whereas the intraday variance for the morphine assay was 0.81% over 30 h. When slopes, linear coefficients, and average areas from 5 separate days were compared, the CVs for interday testing were 1.82%, 0.06%, and 1.27%, respectively, for ketamine and 0.92%, 0.06%, and 0.87%, respectively, for morphine. The accuracy of the methods, as determined by a recovery study for each drug, was 99.7% ± 1.02% for ketamine and 100.9% ± 1.03% for morphine (means and standard deviations). The sensitivity of the ketamine and morphine assays was 620 ng and 635 ng, respectively. cheap cialis canadian pharmacy

Table 3. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (5 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 23°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.3 ±0.08

5.0 ± 0.03

Day 7

100.1 ±1.2

100.1 ±1.3

Day 14

100.6 ±0.4

99.3 ± 0.5

Day 28

100.3 ±0.7

99.5 ± 0.6

Day 56

99.8 ±1.0

99.6 ±1.1

Day 91

99.9 ± 0.6

98.4 ±0.4

SD= standard deviation. *Except where indicated otherwise. tMean of 6 replications.

Table 4. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (5 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 5°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.4 ±0.03

5.1 ± 0.03

Day 7

99.9 ± 0.8

100.7 ±1.4

Day 14

99.2 ± 0.4

99.9 ± 0.7

Day 28

99.8 ± 0.9

99.9 ± 0.4

Day 56

99.1 ±1.4

99.6 ± 0.3

Day 91

100.9 ±1.2

100.3 ±0.6

SD= standard deviation. *Except where indicated otherwise. tMean of 6replications.

Stability Study

The results of the chemical stability study for the admix­tures of ketamine and morphine are summarized in Tables 1 to 6. Neither the concentration of drug nor the storage conditions seemed to have a significant effect on the stability of either ketamine or morphine in these mixtures over the 91-day study period.
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Figure 2. Sample chromatograms of morphine

Figure 2. Sample chromatograms of morphine and its degradation products. A: Fresh sample of morphine at time zero. B: Acidified morphine sample after heating at 60°C for 245 h. C: Alkaline-degraded morphine sample after heating at 60°C for 245 hours. D: Oxidized morphine sample after 245 h at room temperature.

Table 5. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (10 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 23°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.4 ±0.01

10.2 ±0.03

Day 7

98.5 ± 0.6

99.0 ± 0.5

Day 14

98.8 ±1.0

99.0 ± 0.5

Day 28

98.3 ± 0.8

98.7 ± 0.4

Day 56

98.6 ± 0.4

98.6 ± 0.4

Day 91

99.1 ±1.1

98.4 ±0.6


SD = standard deviation. *Except where indicated otherwise. tMean of 6 replications.

Table 6. Stability of Mixture of Ketamine (2 mg/mL) and Morphine (10 mg/mL) in 0.9% Sodium Chloride Stored in Polypropylene Syringes at 5°C

% of Initial Concentration Remaining* (Mean ± SD)t

Storage Period

Ketamine

Morphine

Initial concentration (mg/mL)

2.4 ±0.01

10.2 ±0.09

Day 7

98.6 ± 0.8

100.0 ±1.7

Day 14

100.5 ±0.6

101.3 ±0.4

Day 28

99.5 ± 0.5

101.0 ±0.3

Day 56

100.5 ±0.5

101.5 ±0.5

Day 91

99.7 ±1.2

100.0 ±1.0

SD= standard deviation. *Except where indicated otherwise. tMean of 6 replications.