Stability of codeine phosphate in an extemporaneously compounded syrup.

PURPOSE: The stability of codeine phosphate in an extemporaneously compounded syrup is described. METHODS: Codeine phosphate 3-mg/mL syrup was prepared using commercially available Codeine Phosphate, USP, Sterile Water for Irrigation, USP, and Ora-Sweet syrup vehicle. Samples were stored in amber polyethylene terephthalate bottles with child-resistant caps. A second batch of codeine phosphate 3-mg/mL syrup was prepared and drawn into amber polyethylene oral syringes with silicon elastomer tips. All samples were stored at room temperature and in the dark. Samples were analyzed immediately and at 7, 14, 28, 42, 56, 70, and 98 days. Codeine phosphate concentrations were measured using a modified stability-indicating high-performance liquid chromatographic method. At each test interval, the density of the syrup was determined gravimetrically using a 10-mL amber oral syringe. Excessive degradation was defined as a greater than 7% loss of the initial concentration. RESULTS: The stock internal standard was stable for at least 98 days at room temperature. The compounded syrup retained more than 93% of the initial codeine phosphate concentration for at least 98 days at 22-25 degrees C. No changes in color, clarity, or odor and no visible solids or microbial growth were observed in any sample. The pH of the syrup was initially 4.2 and remained unchanged throughout the study. CONCLUSION: Codeine phosphate 3 mg/mL in Ora-Sweet syrup vehicle was stable in both amber polyethylene terephthalate bottles and amber polyethylene oral syringes for at least 98 days when stored at 22-25 degrees C and protected from light.     

Stability of acetazolamide in suspension compounded from tablets

The stability of acetazolamide in an extemporaneous suspension compounded from tablets was studied. Acetazolamide 25-mg/mL suspension was prepared by levigating the comminuted 250-mg tablets with 70% sorbitol solution. The mixture was incorporated into a suspension vehicle containing magnesium aluminum silicate and carboxymethylcellulose sodium. Appropriate sweeteners, flavoring agents, preservatives, humectants, and pH adjusters were then added. The suspension was stored in amber glass bottles at 5, 22, 30, 40, and 50 degrees C. Samples were analyzed for the concentration of acetazolamide by stability-indicating high-performance liquid chromatography on days 3, 7, 11, 18, 24, 32, 42, 54, and 79. For batches stored at 5, 22, and 30 degrees C, the initial acetazolamide concentration was maintained during the entire 79 days of the study. However, the concentrations in the batches stored at 40 and 50 degrees C were below 90% of the initial value after 79 and 32 days, respectively. The Arrhenius plot was used to predict a shelf life of the suspension at room temperature of 371 days. Acetazolamide oral suspension 25 mg/mL was stable for at least 79 days at 5, 22, and 30 degrees C. The formulation should be maintained at pH 4-5 and stored in amber glass bottles.     

Stability of alcohol-free theophylline liquid repackaged in plastic oral syringes

The stability of an alcohol-free liquid theophylline product repackaged and stored in polypropylene oral syringes was studied. A commercially available alcohol-free liquid theophylline preparation was repackaged in the following unit dose syringes: 3- and 10-mL clear polypropylene syringes and 3- and 10-mL amber polypropylene syringes. Fifty syringes of each type were prepared. The 3-mL syringes were filled with 2 mL of theophylline, while the 10-mL syringes were filled with 7 mL of the liquid. All syringes were stored at room temperature under continuous fluorescent lighting. The mean volume of theophylline delivered from six syringes of each type was determined on days 0, 14, 30, 60, 90, and 180 after repackaging. The samples were assayed for theophylline content by high-performance liquid chromatography. The theophylline dose delivered ranged from 96.2% to 101.7% of the initial repackaged dose. The difference in theophylline concentrations remaining among the types of syringes after 180 days of storage was not significant. The volume of theophylline delivered decreased and the concentration increased as a probable result of water evaporation over time. Alcohol-free theophylline liquid repackaged in 3- and 10-mL clear or amber disposable polypropylene unit dose syringes can be stored at room temperature under continuous fluorescent light for at least 180 days.     

Stability of ampicillin trihydrate suspension in amber plastic oral syringes

The stability of ampicillin trihydrate oral suspension stored in amber plastic oral syringes was studied. Commercially available ampicillin trihydrate powder for oral suspension was reconstituted according to manufacturer's instructions and drawn into 5-mL amber polypropylene plastic oral syringes. The syringes were divided into groups and stored at -20, 4, 25, 60, or 80 degrees C. Powder from two additional lots was similarly reconstituted and packaged and stored at 80 degrees C only to assess interlot variability. Immediately after reconstitution and at specified times during storage, three syringes at each storage temperature were removed and their contents analyzed for ampicillin trihydrate concentration by a spectrophotometric assay. Samples stored at frozen (-20 degrees C) or refrigerated (4 degrees C) temperature retained at least 90% of the initial ampicillin concentration throughout the 47-day study period. Samples stored at room temperature retained at least 90% of the initial ampicillin concentration for 30 days and exhibited an apparent zero-order degradation rate. Samples stored at heated temperatures (60 and 80 degrees C) exhibited an apparent first-order degradation process, with the concentration of ampicillin decreasing to less than 90% of initial concentration within two hours. Reconstituted ampicillin trihydrate powder for oral suspension is stable for at least 30 days when stored at room, refrigerated, or frozen temperature in the amber plastic oral syringes studied. The expiration dates recommended by the manufacturer for ampicillin trihydrate suspension stored in its original container can also be used for reconstituted suspension stored in these amber plastic syringes.     

Stability of midazolam hydrochloride in a flavored, dye-free oral solution.

The stability of injectable midazolam hydrochloride in a solution for oral use was studied at three temperatures over 56 days. A 2.5-mg/mL oral solution was prepared from injectable midazolam hydrochloride and a flavored, dye-free syrup. Samples of solution were stored in amber glass bottles at 7, 20, or 40 degrees C. Duplicate samples were analyzed by high-performance liquid chromatography on days 0, 1, 3, 5, 14, 21, 35, and 56. Samples were also visually inspected on each sampling day. The concentrations of all samples remained greater than 90% of the original concentration and there were no visual signs of microbial growth or changes in color, turbidity, or odor throughout the 56-day period. A 2.5-mg/mL solution of injectable midazolam in syrup was stable for 56 days at 7, 20, or 40 degrees C.     

Stability and availability of cyclosporine stored in plastic syringes

The stability and availability of cyclosporine from the oral dosage form when stored in plastic syringes were examined. Solutions of cyclosporine were stored in plastic syringes for 28 days at 25 degrees C. Half of the solutions remained in room light, and samples were obtained at 3, 6, and 12 hours and 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28 days. The remaining samples were protected from light, and samples were obtained at 1, 3, 5, 7, 14, 21, and 28 days. Samples stored in plastic were compared with control solutions stored in the original amber bottle. All samples were analyzed for unchanged cyclosporine by high-pressure liquid chromatography. Cyclosporine was stable and completely available from the oral dosage form when stored in plastic syringes for up to 28 days. There was no difference in the stability of cyclosporine between the solutions exposed to room light and those protected from light. Solutions of the oral dosage form of cyclosporine may be stored in plastic syringes without protection from light for up to 28 days.     

Stability of ganciclovir in extemporaneously compounded oral liquids.

The stability of ganciclovir in extemporaneously prepared sugar-containing and sugar-free oral liquids was studied. The contents of 80 250-mg capsules of ganciclovir were combined with Ora-Sweet or Ora-Sweet SF (sugar free) (Paddock Laboratories) to produce 200 mL of suspension with a ganciclovir concentration of 100 mg/mL. Five 1-mL samples were analyzed immediately, and the rest of the suspension was poured into five 60-mL amber polyethylene terephthalate bottles and stored at 23-25 degrees C. Samples were removed and analyzed with stability-indicating high-performance liquid chromatography on days 15, 35, 60, 91, and 123. The suspensions retained at least 96% of the initial ganciclovir concentration for 123 days. The pH of the suspensions was initially 4.5 and remained unchanged throughout the study. There was no detectable change in color or odor and no visible microbial growth in any sample. Ganciclovir 100 mg/mL was stable for 123 days in sugar-containing and sugar-free oral liquids stored at 23-25 degrees C in amber polyethylene terephthalate bottles.     

Stability of carbamazepine suspension after repackaging into four types of single-dose containers

The stability of carbamazepine in commercially available suspension that had been repackaged in various single-dose containers was studied. Carbamazepine suspension was repackaged in 2-mL and 8-mL aliquots in amber glass vials, polypropylene vials, and amber polypropylene syringes and in 2-mL aliquots in amber glass oral syringes. Containers were stored at room temperature and continuously exposed to fluorescent light for up to 12 weeks. Samples from each container type and volume were assayed for carbamazepine content by high-performance liquid chromatography at various intervals during storage. Carbamazepine concentrations in the samples were compared with the carbamazepine concentration in the original manufacturer's container. The pH of the samples was also determined, and the suspensions were inspected for color, odor, and large particles. There was no significant decrease in carbamazepine concentration of more than 10% in samples stored for up to eight weeks. After 12 weeks, significant decreases in concentration were observed in all but one container type. No changes in color, odor, or consistency were observed during the 12 weeks, and there were no significant changes in pH. In commercially available suspension repackaged in volumes corresponding to common pediatric doses, carbamazepine (20 mg/mL) is stable for at least eight weeks when stored at room temperature in the containers tested.     

Nifedipine stability in cardioplegic solution

The stability of nifedipine in cardioplegic solution was studied. Cardioplegic solutions containing nifedipine at 275 and 500 micrograms/liter were stored in plastic bags covered in brown plastic wrappers (1) under normal room light at 25 degrees C and (2) in a dark refrigerator at 4 degrees C. Samples were removed periodically for 48 hours. Infusions of cardioplegic solution containing 275 micrograms/liter were simulated using tubing and flow rates of 100, 200, and 300 ml/min; bags were covered with aluminum foil, while tubing was exposed to normal room lighting or yellow lighting, which does not degrade nifedipine. Gas chromatography was used for nifedipine assays. Nifedipine degraded more rapidly at 25 degrees C than at 4 degrees C. However, even when protected from light and refrigerated, nifedipine concentrations declined to less than 90% of original potency by approximately six hours after preparation. There was no significant degradation during the simulated infusion regardless of light exposure or flow rate. Cardioplegic solutions containing nifedipine should be prepared immediately before the surgical procedure, refrigerated until use, and protected from light until administration.     

Extended stability of iobenguane under simulated clinical conditions.

PURPOSE: The stability of iobenguane sulfate stored at 4-7 degrees C over 91 days was studied. METHODS: An iobenguane sulfate solution at a concentration of 2.2 mg/mL was prepared in a top-fill i.v. bag using 143 mg of iobenguane sulfate and 65 mL of Sterile Water for Injection, USP. The solution was poured through a 0.22- microm filter assembly for sterilization into 60 1-mL polycarbonate plastic syringes. Each syringe was filled with 0.9 mL of the iobenguane sulfate solution and stored in amber plastic bags at 4-7 degrees C. The stability of iobenguane sulfate was analyzed using high-performance liquid chromatography immediately after solution preparation and on days 7, 14, 28, 42, 56, 70, and 91. Samples were inspected for chemical purity by observing for particulate formation and color change. RESULTS: The mean concentration of ioben-guane exceeded 93% of the initial concentration in all samples throughout the 91-day study period. No changes in color or turbidity were observed. CONCLUSION: Iobenguane sulfate 2.2 mg/mL was stable for 91 days when stored in polycarbonate syringes at 4-7 degrees C.     

Stability of dolasetron in two oral liquid vehicles.

The stability of dolasetron 10 mg/mL over 90 days when prepared as an oral liquid formulation from commercially available tablets in both strawberry syrup and a sugar-free vehicle was studied. A liquid suspension of dolasetron mesylate 10 mg/mL was prepared from commercially available dolasetron tablets, OraPlus, and Ora-Sweet or strawberry syrup. Six samples of each formulation were prepared and stored in amber plastic bottles. Three samples of each formulation were refrigerated (3-5 degrees C) and three were stored at room temperature (23-25 degrees C). A 1-mL sample was withdrawn from each of the 12 bottles immediately and after 7, 14, 30, 60, and 90 days. After further dilution to an expected concentration of 10 micrograms/mL with sample diluent, the solutions were assayed in duplicate using high-performance liquid chromatography. The samples were also inspected for color and odor changes, and the pH of each sample was determined. The stability-indicating capability of the dolasetron assay was determined by forced degradation of four separate 10-mg/mL samples exposed to direct sunlight for 90 days. There were no detectable changes in color, odor, or taste and no visible microbial growth in any sample. At least 98% of the initial dolasetron concentration remained throughout the 90-day study period for all samples. An extemporaneously compounded oral liquid preparation of dolasetron mesylate 10 mg/mL in a 1:1 mixture of Ora-Plus and strawberry syrup or Ora-Sweet was stable for at least 90 days when stored at 3-5 or 23-25 degrees C.     

Stability of valacyclovir hydrochloride in extemporaneously prepared oral liquids.

The stability of valacyclovir hydrochloride in three commonly used syrups was studied. Triplicate suspensions of valacyclovir (from caplets) in Ora-Sweet (Paddock Laboratories), Ora-Sweet SF (Paddock), and Syrpalta Humco Laboratory) syrups were extemporaneously compounded to yield a final concentration of valacyclovir 50 mg/mL (as the hydrochloride salt). The nine suspensions were stored at 4 degrees C in amber glass bottles. At intervals up to 60 days, the liquids were visually inspected for color change, cloudiness, gas formation, and precipitation, and samples were assayed in duplicate for valacyclovir concentration by stability-indicating high-performance liquid chromatography. Also tested were pH, particle size, and microbial growth. During the first 21 days of storage, mean valacyclovir concentrations in all liquids were >90% of the initial concentration, but concentrations were <90% by day 21 in some individual samples of suspensions prepared with Ora-Sweet and Ora-Sweet SF. Mean valacyclovir concentrations in the Syrpalta-based suspensions met the 90% cutoff for at least 35 days. Solution pH and particle size remained unchanged in all liquids through day 60, and there were no changes in physical appearance. There was no evidence of microbial growth on the days when microbial growth was tested (0 and 28). Valacyclovir 50 mg/mL (as the hydrochloride salt) in three oral liquids stored in amber glass bottles at 4 degrees C was stable for at least 21 days when prepared with two of three syrups and for at least 35 days when prepared with the third syrup. All the liquids were free of microbial growth for at least 28 days.