Background and importance The scientific literature was reviewed in order to investigate metronidazole 1% topical solution for treatment of ulcers infected by anaerobic bacteria, and whether refrigerated storage is recommended. However, the samples formulated in the Hospital Pharmacy Department presented a crystalline precipitate, which could not be redispersed. Therefore, a compounding improvement was necessary.
Aim and objectives Design and analyse, by galenic validation, different compounding improvement to increase the solubility of metronidazole in water in three storage environments.
Material and methods A bibliographic search found that metronidazole base solubility in water is 10.5 mg/mL (25°C) and 17 mg/ml (20°C) in propyleneglycol. The 1% solution in water is a saturated solution that initially presents an oversaturation stage whose intensity and duration are determined by solid particle size and its solubility increases progressively over the time.
Thereby, we formulated three metronidazole solutions in different vehicles: water (M1), water+glycerin (M2) and water+propyleneglycol (M3). They were stored in refrigeration, room temperature (RT) and Tª>25°C conditions. A galenic validation was carried out, monitoring organoleptic characteristics, sedimentation time, redispersability, homogeneity, crystal growth and pH on days 0, 1, 5, 7, 11, 14, 18, 30 in a 30-day follow-up.
Results The three solutions had a pH=5.5 and showed neither colour nor odour throughout the 30-day analysis.
With refrigeration, in less than 24 hours, the three solutions crystallised and could not be resuspended. Therefore, follow-up was stopped and refrigeration was discarded.
At RT, M1 and M2 presented crystals and vigorous hand shaking and heating for several minutes was necessary to resuspend them. M3 maintained the physical characteristics and was no longer oversaturated from day 18.
At Tª>25°C, the three solutions started as oversaturated solutions (no crystals were observed at any time). Subsequently, M3 became a saturated solution on day 4 and M1/M2 on day 7.
Conclusion and relevance Metronidazole base in solution cannot be stored in a refrigerator due to an irreversible crystallisation. Glycerin as a humectant does not provide any advantage compared with water as a single vehicle. Propyleneglycol allows a compounding improvement because it increases the solubility of metronidazole in water, allowing the solution to be preserved at RT without crystal formation and to reach the saturation phase quickly at Tª>25°C. The hospital pharmacists’ knowledge allows the resolution of compounding difficulties derived from the physicochemical characteristics of raw materials.
Conflict of interest No conflict of interest
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