Stability of ceftazidime in a viscous eye drop formulation.

OBJECTIVE: To assess the stability of an extemporaneously prepared ceftazidime eye-drop. METHOD: Ceftazidime was formulated at a concentration of 5% w/v as an eye drop, using Sno Tears, an artificial tear solution containing polyvinyl alcohol, as a vehicle. Two batches of the formulation were stored in 10 ml eye drop bottles at 7 and 25 degrees C for up to 14 days. Ceftazidime and pyridine, its degradation product, were determined at intervals by HPLC. RESULTS: A yellow coloration was evident after 7 days at 7 degrees C and after 24 h at 25 degrees C. Ceftazidime lost approximately 35% after 7 days storage at 25 degrees C. At 7 degrees C, the mean time to 10% degradation, determined by linear regression, was 11 and 8 days for the two batches. However, the lower 95% confidence limits were 8 and 5 days, respectively. Pyridine levels increased during storage. The mass balance between ceftazidime remaining and pyridine formed was close to 100% during the early part of storage. By the end of storage, the balance had reduced to around 95% at 7 degrees C and 80% at 25 degrees C. This discrepancy may be due to sorption of pyridine to the butyl rubber bottle closure. The pH remained in the range 6-7 throughout the storage period. CONCLUSION: The formulation may be stored for 5 days in the refrigerator.

Near-patient stability studies.

Approaches to performing stability tests on formulations developed in hospitals, defined as the near-patient situation, are reviewed. Emphasis is placed on the selection and validation of storage conditions and the statistical methodology necessary to ensure confidence in the results obtained.

Compatibility of a commercially available low-density polyethylene eye-drop container with antimicrobial preservatives and potassium ascorbate.

The compatibility of the 7 ml size of Steri-Dropper, a commercially available low-density polyethylene sterile eye-drop container, was studied for use with solutions containing the antimicrobial preservatives benzalkonium chloride and phenylmercuric acetate. For benzalkonium chloride, there was no difference between the Steri-Dropper and the glass eye-drop bottles throughout the study period of 84 days. However, there was less phenylmercuric acetate present in the Steri-Dropper compared to the glass containers by the end of the study. The suitability of the Steri-Dropper bottle was also studied for use with potassium ascorbate eye drops; these degraded more in Steri-Dropper compared to glass containers and a yellow discoloration of the product was also seen in these containers. The Steri-Dropper bottle is therefore potentially compatible with dispensed formulations containing benzalkonium chloride and, for short periods only, with phenylmercuric acetate. The container would only be suitable for use with oxygen-sensitive drugs for short periods. Further validation of the suitability of the Steri-Dropper bottle would be required for use with any specific formulation.

Chemical stability of fluocinolone acetonide ointment and fluocinonide cream diluted in emollient bases.

The chemical stability of fluocinolone acetonide ointment and fluocinonide cream was studied when diluted in emollient bases. Fluocinolone acetonide ointment was diluted 1 in 4 with Unguentum Merck and Lipobase. Fluocinonide cream was also studied in these bases, with the addition of Metosyn Diluent, at dilutions of 1 in 4 and 1 in 10. Regression analysis gave the time for 5% degradation of fluocinolone acetonide at a dilution of 1 in 4 in Unguentum Merck and in Lipobase as 12 weeks in both cases. The lower 95% confidence bound of each regression line was used to set shelf lives, for additional safety, and gave values of 1 month for the Unguentum Merck dilution and 2 months for the Lipobase dilution. Fluocinonide dilutions were more stable than the corresponding fluocinolone acetonide dilutions, with no degradation detectable during the study. The base made no observable difference to stability. Shelf lives, based on the lower 95% confidence bound of the regression data, of more than 6 months would be feasible for all of the fluocinonide 1 in 4 dilutions studied and for the 1 in 10 dilution in Unguentum Merck. However, for fluocinonide 1 in 10 in Metosyn Diluent, a shelf life of only 6 weeks could be assured, due to there being more variation in the analytical results. There were insufficient data to determine a storage life based on the lower 95% confidence bound of the regression for fluocinonide 1 in 10 in Lipobase. More data would be required to determine if there was significant interbatch variation in the stability of the dilutions.

Stability of bupivacaine hydrochloride with diamorphine hydrochloride in an epidural infusion.

The stability of diamorphine (0.02 mg/ml as the hydrochloride) in 250 ml bupivacaine hydrochloride (0.15% wt/vol infusion) was studied by high pressure liquid chromatography at temperatures in the range 7 to 45 degrees C. Diamorphine hydrochloride was degraded by approximately 0.13% per day at 7 degrees C. No bupivacaine hydrochloride degradation was detectable during the study. The storage life of the combination at 7 degrees C, based on the lower 95% confidence limit of the time to 5% diamorphine hydrochloride degradation, was 14 days. The stability at 25 degrees C was adequate to allow transport and administration over 24 h at ambient temperature. Stability was also maintained for at least 24 hr at 32 and 45 degrees C. Infusion of the mixture with an ambulatory infusion pump which uses a standard polyvinyl infusion bag is therefore possible. A study of its compatibility with different infusion pump medication reservoirs was not undertaken. The drugs were also stable on frozen storage at -18 degrees C for up to 6 months.

Stability of caffeine oral formulations for neonatal use.

The stability of an oral formulation of 10 mg/ml caffeine citrate (equivalent to 5.03 mg/ml caffeine free base), which was preserved with potassium sorbate, was assessed at a range of temperatures. There was no appreciable change in pH or caffeine content over 1 year, even at storage temperatures of 32 degrees C and 45 degrees C. A batch-to-batch difference in the stability of potassium sorbate was detected, with losses over 1 year of 2% and 11% for two batches at 25 degrees C and 10% and 30%, respectively, at 45 degrees C. The formulation complied with the Antimicrobial Preservative Efficacy test of the British Pharmacopoeia throughout a period of storage at 25 degrees C for 1 year. There was no detectable benefit to preservative efficacy by adding 20% w/v sorbitol as an osmotic agent. The formula with no sorbitol may be preferable due to the potential for sorbitol to cause gastrointestinal upset. A shelf-life of 1 year at room temperature is feasible. The additional precaution of limiting the in-use storage life to 1 month after opening is recommended to ensure acceptable microbiological quality.

Preservative efficacy in cefuroxime and ceftazidime eye drop formulations.

The efficacy of various common antimicrobial preservatives was tested in eye drop formulations containing the cephalosporin antibiotics cefuroxime and ceftazidime. The British Pharmacopoeia test for the efficacy of antimicrobial preservatives was used and the formulations were challenged with Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The survival of organisms was monitored over 14 days. Cefuroxime sodium, 50 mg/ml, was studied in simple aqueous solution, and dissolved in an artificial tear formulation, Sno Tears (Smith and Nephew Pharmaceuticals), which contains benzalkonium chloride 0.004% w/v. Ceftazidime (50 mg/ml) was also studied in these two vehicles and, in addition, in a phenylmercuric acetate solution (0.002% w/v) and chlorhexidine acetate (0.02% w/v). Cefuroxime and ceftazidime contributed little, in the short-term, towards a microbicidal preservative effect in the unpreserved aqueous formulations, even against organisms for which they were active. Cefuroxime was adequately preserved in a vehicle of Sno Tears, which contains benzalkonium chloride as the antimicrobial preservative. Ceftazidime was less well preserved in this vehicle, but it was superior to phenylmercuric acetate (0.002% w/v) or chlorhexidine acetate (0.02% w/v).

Stability of bendrofluazide in a low-dose extemporaneously prepared capsule.

The stability of bendrofluazide 1.25 mg in capsules was studied. The formulation is intended to provide a unit dose powder for administration by dispersing the contents in liquid. The capsules were prepared from ground bendrofluazide tablets 5 mg from two different manufacturers, diluted with lactose and packed manually by weight into hard gelatin capsule shells. The capsules were stored at ambient temperature exposed to light or 75% relative humidity, and at 45 or 60 degrees C. The ambient temperature and 60 degrees C conditions were studied for up to 1 year. Bendrofluazide was determined by a stability-indicating HPLC method. The capsule contents remained easy to disperse in liquid by the end of the study. The weight of contents which could be extracted from the capsules also remained satisfactory. A 7-month storage life at ambient temperature would be feasible, based on the lower 95% confidence limits of the time to 5% degradation.

Stability of steroid ointments diluted with Compound Zinc Paste B.P.

The chemical stability of a range of corticosteroid ointments diluted with Compound Zinc Paste B.P. was studied by high-performance liquid chromatography (HPLC). Betamethasone dipropionate degraded by first-order kinetics at both 25 degrees C and 32 degrees C. At 25 degrees C the mean first-order reaction rate constant was 9.58 x 10(-3)/day, with a t90 (time to reach 90% of the original concentration) of 11.0 days. At 32 degrees C the mean first-order reaction rate constant was 2.42 x 10(-2)/day, with a t90 of 4.4 days. Of the other steroids studied, Fluocinolone acetonide was the least stable, with 33.8% remaining after a 7-day storage period at 25 degrees C. Betamethasone-17-valerate and fluocinonide were of intermediate stability between betamethasone dipropionate and fluocinolone acetonide. None of the steroid ointments studied had adequate stability in Compound Zinc Paste B.P. to allow extemporaneous dilution with this base.

Chemical stabilities of cefuroxime sodium and metronidazole in an admixture for intravenous infusion.

The chemical stabilities of cefuroxime sodium and metronidazole, when mixed together for intravenous infusion, were studied by high-performance liquid chromatography (HPLC). The critical factor in the stability of the admixture was the degradation of cefuroxime sodium. At 25 degrees C, cefuroxime degraded by first-order kinetics with a rate constant of 7.04 x 10(-2)/day and a t90 (time to reach 90% of the original concentration) of 36 h. At 4 degrees C the rate constant was 5.23 x 10(-3)/day with a t90 of 20 days, however, over the time-scale studied, the kinetics approximated to zero-order at this temperature. The mixture was also stable with respect to metronidazole, nitrite ion and appearance. A 7-day storage life at 4 degrees C can be given to the mixture.

Comparison of colourimetric methods for ammonia determination.

The precision of the Berthelot and Nessler methods of ammonia determination are compared at various ammonia concentrations. Recommendations are made regarding the most appropriate technique to use, dependent on the range of ammonia concentration expected. The effect of microdiffusion separation on the precision of ammonia determination is studied, together with an evaluation of a water soluble lid sealant and of the effect of a model amine contaminant.

Onset-offset effects of the human brainstem auditory-evoked response.

Brainstem auditory-evoked responses (BSAER's) were obtained from 4 normal-hearing young adults to a 2-kc/s tonal stimulus of 2-, 3-, 4-, 5-, 6-, 7- or 8-msec duration at 60 db sensation level. Latency of Jewett Wave V was recorded averaging 4096 sweeps; stimuli had a 1-msec rise-fall time, with a 65-msec interstimulus interval. A Wave V response to the onset transient was present for all durations. For stimulus durations of less than 5 msec no reliable offset response was noted. Latency measures indicated the onset response to be much less variable than the offset response. The onset response latency of Wave V remained stable over a stimulus duration range of 2-8 msec. The BSAER of a single S demonstrated the intrasubject variability of the offset response as a function of stimulus duration.