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Cold Reconstitution of Unstable Drugs
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Introduction and Background
Reconstitution is defined as "constituted again," especially of a liquid product made by adding water to dry solids from which the water has been evaporated; also, to return to the liquid state by adding water. A number of drug products with stability issues are available as dried solids that must be reconstituted prior to use.
The majority of sterile drug products for reconstitution are sufficiently stable that they can be reconstituted with sterile water for injection (SWFI) at room temperature. However, very unstable drugs present issues that must be considered. For example azacitidine, a lyophilized powder, is reconstituted in SWFI and the labeling states that the reconstituted suspension is stable for up to 1 hour at 25°C and up to 8 hours when stored at 2°C to 8°C.
Stability Considerations
There are a number of factors affecting stability, including:
- pH
- Temperature
- Solvent
- Light
- Air (oxygen)
- Carbon dioxide
- Moisture or humidity
- Particle size
Of these, we are interested in temperature in this issue. Temperature affects the stability of a drug by increasing the rate of reaction speed about two to three times with each 10°C rise in temperature, as first suggested by the Arrhenius equation.
| log k = log A – | Ea
2.3030 | X | 1
T |
The equation shows that an increase in temperature will result in an increase in the specific reaction rate, or the degradation rate of the drug. Temperature effects can be minimized by selecting the proper storage temperature (room, refrigerated, freezing). It seems reasonable, in the case of poorly stable drugs, to reconstitute with "cold" SWFI to prolong the potential time for administration of the drug. Some studies support this activity, as described in the following section.
One other consideration, since some studies have reported on the stability of a drug when frozen, is that there may be a redistribution of the powder particle size in the freeze-thaw process. It is important to confirm that the particle size distribution of the drug is still appropriate after thawing.
Results of Studies
A study by Legeron et al concludes that azacitidine 25-mg/mL suspensions reconstituted with refrigerated SWFI and stored in propylene syringes were chemically stable during the first 48 hours when stored protected from light.1
A study by Walker et al concludes that at 23°C, 15% of the initial concentration was lost after 9.6 hours; at 4°C, 32% was lost after 4 days; and at -20°C, less than 5% was lost after 23 days.2
The study by Tutino and Lai demonstrated that reconstitution of azacitidine with cold SWFI together with subsequent refrigerated storage is associated with a threefold prolongation in the stability time of the drug from 8 to 22 hours.3
A study using frozen SWFI in an isolator was recently reported using 20-mL plastic ampules. Using just refrigerated SWFI in 20-mL (plastic) and 50-mL and 250-mL (glass) containers, the temperature of the SWFI increased from 2°C to 8°C to 16.6°C, 11.9°C, and 10.3°C, respectively. When the 20-mL (plastic) ampules were frozen, decontaminated, and used in an isolator, the temperature was 5.7°C to 7.4°C after thawing for 30 minutes. They recommended freezing the plastic SWFI ampules, thawing for 30 minutes, agitating for 30 seconds, and removing 4 mL for reconstitution of the drug.4
Summary
The increase in azacitidine stability by cold reconstitution allows for prolonged in-use time that may be of convenience to pharmacists, physicians, and patients.
References
- Legeron R, Xuereb F, Djabarouti S et al. Chemical stability of azacitidine suspensions for injection after cold-chain reconstitution of powder and storage. Am J Health Syst Pharm 2013; 70(23): 2137-2142.
- Walker SE, Charbonneau LF, Law S et al. Stability of azacitidine in sterile water for injection. Can J Hosp Pharm 2012; 65(5): 352-359.
- Tutino A, Lai M. Cold water reconstitution of Vidaza® with subsequent refrigerated storage prolongs drug stability. EJHP Practice 2011; 17(5): 24-25.
- Savry A, Correard F, Villano LG et al. Keeping sterile water for injection cold enough for reconstitution of azacitidine in isolators. Am J Health Syst Pharm 2014; 71(3): 180.
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