Stability of Hydromorphone-Ketamine Solutions in Glass Bottles, Plastic Syringes, and IV Bags for Pediatric Use

Objectives:

To evaluate the stability of mixtures of hydromorphone and ketamine in 0.9% sodium chloride (normal saline [NS]) after storage for up to 7 days at room temperature (25°C).

Methods:

The stability of 3 standard mixtures of hydromorphone and ketamine (hydromorphone 0.2 mg/mL + ketamine 0.2 mg/mL, hydromorphone 0.2 mg/mL + ketamine 0.6 mg/mL, and hydromorphone 0.2 mg/mL + ketamine 1.0 mg/mL) in NS was studied. Portions of each mixture were transferred to 3 brown glass bottles (100 mL), 3 plastic syringes (50 mL), and 3 IV bags (50 mL), which were then stored at room temperature (25°C). Physical characteristics, including pH, colour, and precipitation, were evaluated daily. Three 1.5-mL samples were collected from each bottle, syringe, and IV bag at baseline, at 24, 48, and 72 hours, and on day 7. Samples were analyzed in triplicate by a stability-indicating high-performance liquid chromatography method. Solutions were considered stable if they maintained 90% of the initial concentration of each drug. Samples from syringes and IV bags were subjected to standard sterility testing by incubation for 5 days in an enriched culture media.

Results:

No notable changes in pH or colour were observed, and no precipitation occurred in any of the solutions. All formulations maintained more than 90% of the initial concentration of each drug on day 7. No bacterial growth was observed in any of the samples tested.

Conclusions:

Mixtures of hydromorphone and ketamine were stable for up 7 days at 25°C, and the sterility of the preparations was maintained. Because stability alone does not guarantee efficacy, it is recommended that clinical studies be conducted to evaluate the pharmacokinetics and pharmacodynamics of these formulations.     

Stability of celecoxib oral suspension

Background:

Celecoxib is a selective cyclo-oxygenase 2 inhibitor that relieves pain without affecting platelet function, causing gastrointestinal toxic effects, or increasing the risk of bleeding.

Objectives:

To develop a suspension formulation for oral celecoxib and to determine its physical and chemical stability when packaged in amber polyvinyl chloride (PVC) bottles and stored with refrigeration (5°C) and at room temperature (23°C).

Methods:

The contents of celecoxib capsules were used to prepare a single suspension, with Ora-Blend used as the suspending and flavouring agent. The suspension (10 mg/mL) was then packaged in amber PVC bottles and stored at either 5°C or 23°C. Samples were collected on days 0, 7, 14, 21, 27, 56, and 93. Chemical stability was determined using a validated stability-indicating high-performance liquid chromatography method. At each sampling time, the suspensions were checked visually for changes in appearance (i.e., colour, layering, caking, and ease of resuspension), odour, and pH.

Results:

All of the suspensions were stable for at least 93 days, regardless of storage conditions. There were no apparent changes in physical appearance, nor were there any substantial changes in odour or pH.

Conclusions:

Suspensions of celecoxib (10 mg/mL in Ora-Blend) packaged in amber PVC bottles were stable for up to 93 days when stored at 5°C or 23°C. A 3-month expiry date has been established for this oral suspension on the basis of physical compatibility and chemical stability.     

有机金属抗癌原料药二氯二茂钛的稳定性试验

目的考察二氯二茂钛原料药的稳定性,并预测其有效期。方法采用正相高效液相色谱法测定原料药含量和有关物质,以正己烷一二氯甲烷（50：50）为流动相考察加速和长期稳定性试验,经典恒温法预测其有效期。结果含量和有关物质测定方法的平均回收率为99．9％（n=9）,RSD为0．45％。拟市售包装,40℃加速试验6个月,长期室温试验24个月,有关物质稍有增加,其他各考察指标无明显变化。经典恒温法预测本原料药在25℃贮存时有效期大于10年。结论拟市售包装条件下二氯二茂钛稳定性较好,有效期暂定2年。     

Stability and Beyond-Use Date of a Compounded Thioguanine Suspension

Background: Thioguanine (TG) is available only in the form of 40 mg tablets in the United States, and the patient population in which TG is used comprises mostly children. Recognizing its importance as a therapeutic agent and limited stability data for its compounded preparation, the United States Pharmacopoeia has listed TG in its priority list of compounded preparations monographs. Objective: The goal of the present study was to generate stability data and establish a beyond-use date for compounded TG suspension. Methods: Suspensions were compounded using TG tablets and ORA-Plus and ORA-Sweet as vehicles. A robust high-performance liquid chromatography method was developed and validated. TG and guanine (G) in suspensions were quantified immediately after compounding and at regular intervals for 90 days. Physical stability of suspensions was evaluated by observation of organoleptic properties. Results: Results from the study indicate that average TG levels in suspensions remained above 90% of the starting concentration and G formation was less than 2.5% for 90 days. There was no statistically significant difference in the amount of TG degraded over 90 days between suspensions stored at room temperature and in refrigerated conditions. There was also no statistically significant difference in G concentration of suspensions between day 0 and day 90. Conclusion: TG suspensions are stable for 90 days when stored at room temperature or refrigerated conditions and the beyond-use date can be set to 90 days.     

Disposition of synthetic glucocorticoids I. Pharmacokinetics of dexamethasone in healthy adults

The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid Chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest poly exponential equation that is consistent with the data. The terminal phase half-lifet _1/2 was significantly greater (p<0.05) in males (mean 201.5 min) than in females (mean 142.3 min). The prolongedt _1/2 in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 247.5ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation betweent _1/2 and among the 12 adults (r=0.92, p<0.001). There were also significant correlations between and body weight (r=0.67, p<0.05) andt _1/2 (r=0.80, p<0.01).The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t _1/2. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.     

Stability of aseptically prepared tazocin solutions in polyvinyl chloride bags

Background:

Tazocin, a mixture of piperacillin and tazobactam, has recently been reformulated to include edetate disodium (EDTA) and citric acid. Since the introduction of this new formulation, there have been no studies of stability in polyvinylchloride (PVC) bags.

Objective:

To complete a physical compatibility and chemical stability study of the new formulation of Tazocin, prepared at 2 concentrations in each of 2 diluents and stored in PVC bags.

Methods:

Tazocin, at 22.5 or 90 mg/mL, was compounded in dextrose 5% in water (D5W) or 0.9% sodium chloride (normal saline [NS]) in PVC bags. The bags were stored at 5°C with protection from light for 14, 21, or 28 days, followed in each case by storage at 23°C with exposure to light for 72 h. Triplicate samples collected at each of the 7 time points were analyzed in duplicate using a stability-indicating high-performance liquid chromatography method. Physical compatibility was determined by monitoring the solutions for changes in colour, clarity, and pH.

Results:

The amount of each drug remaining for each concentration in each diluent was above 95% of the initial concentration after storage at 5°C with protection from light and above 94% of the initial concentration after an additional 72 h at 23°C with exposure to light. The pH of the solutions changed only slightly over the course of the study, and all solutions remained clear and colourless.

Conclusions:

Tazocin solutions at 22.5 and 90 mg/mL, prepared in PVC bags of either D5W or NS, were chemically stable after storage for up to 28 days at 5°C with protection from light followed by 72 h at 23°C with exposure to light.     

Stability of ciprofloxacin in polyvinylchloride minibags

Background:

Ciprofloxacin is a fluoroquinolone antibiotic used to treat infections caused by both gram-positive and gram-negative organisms.

Objective:

To determine the physical and chemical stability of ciprofloxacin diluted in 5% dextrose in water (D5W) or 0.9% sodium chloride (normal saline [NS]) and stored in polyvinylchloride (PVC) minibags at various temperatures.

Methods:

Solutions of ciprofloxacin (1 and 2 mg/mL) were prepared by diluting a commercially available concentrate (10 mg/mL) with either D5W or NS. The prepared solutions were then packaged in PVC mini-bags. Three minibags of each concentration–diluent combination were stored at 2°C to 8°C with protection from light, at 21°C to 24°C with exposure to light, and at 29°C to 31°C with protection from light. Samples were collected from each minibag on days 0, 7, 14, and 30 and then analyzed. Colour, clarity, and pH were monitored when the samples were collected. On each day of analysis, the samples were accurately diluted before duplicate analysis with a stability-indicating high-performance liquid chromatography assay. A solution was considered stable if the concentration remained above 90% of the initial values.

Results:

There were no changes in the physical characteristics of any of the solutions. At both concentrations (1 and 2 mg/mL), the ciprofloxacin solutions prepared in D5W remained above 93.9% of the initial concentration over the 30-day study period under all 3 storage conditions. Similarly, at both concentrations, solutions diluted in NS remained above 95.9% of the initial concentration over the 30-day study period under all 3 storage conditions.

Conclusions:

Ciprofloxacin prepared in either D5W or NS and stored in PVC minibags was stable for 30 days under 3 separate storage conditions: 2°C to 8°C with protection from light, 21°C to 24°C with exposure to light, and 29°C to 31°C with protection from light.     

Stability of trisodium citrate and gentamicin solution for catheter locks after storage in plastic syringes at room temperature

Background:

Catheter-related infections are a major problem for hemodialysis patients with central venous catheters for vascular access. Catheter lock solutions containing an anticoagulant are used to maintain the patency of the catheter between hemodialysis sessions. There is evidence that the use of lock solutions containing an antibiotic is associated with lower rates of infection but also that these solutions can kill microbes in colonized catheters and thus avoid the risks and costs associated with replacing the catheter.

Objective:

This stability study was conducted to determine whether an extemporaneously prepared gentamicin–citrate catheter lock solution would retain its potency over time, thus allowing for advance preparation of the solution.

Methods:

Catheter lock solutions containing gentamicin alone, citrate alone, and the combination of gentamicin and citrate were prepared aseptically and packaged in polyethylene syringes. The syringes were stored at room temperature. At timed intervals over 112 days, samples were withdrawn for analysis by means of validated high-performance liquid chromatography.

Results:

None of the 3 lock solutions showed any evidence of degradation during the 112-day observation period. In the formulation containing both gentamicin 2.5 mg/mL and sodium citrate 40 mg/mL (4%), there was no change in the concentration of either gentamicin (p = 0.34) or citrate (p = 0.55). Linear regression analysis of the concentration–time data for the combined formulation showed that 99.97% of the labelled amount of gentamicin and 101.30% of the labelled amount of citrate remained at day 112. The lower limit of the 95% confidence intervals indicated that more than 98.17% of the gentamicin and more than 99.57% of the citrate remained on day 112.

Conclusion:

The results of this study will allow pharmacies to extemporaneously compound the combined gentamicin–citrate catheter lock solution in advance of use. The method described here will yield a stable product for use in clinical applications.     

Stability of cefazolin sodium in polypropylene syringes and polyvinylchloride minibags

Background:

Cefazolin is a semisynthetic penicillin derivative with a narrow spectrum of activity covering some gram-positive organisms and a few gram-negative aerobic bacteria.

Objective:

To determine the physical and chemical stability of cefazolin sodium reconstituted with sterile water for injection and stored in polypropylene syringes or diluted with either 5% dextrose in water (D5W) or 0.9% sodium chloride (normal saline [NS]) and stored in polyvinylchloride (PVC) minibags.

Methods:

Reconstituted solutions of cefazolin (100 or 200 mg/mL) were packaged in polypropylene syringes. More dilute solutions (20 or 40 mg/mL) were prepared in D5W or NS and packaged in PVC minibags. For each concentration–diluent–container combination, 3 containers were designated for each day of analysis (days 7, 14, 21, and 30). Containers were stored under refrigeration (5°C) with protection from light until the designated day of analysis, at which time one 5-mL sample was collected from each the designated container. The designated containers were then stored at room temperature (21°C to 25°C) with exposure to light for an additional 72 h, and additional samples were drawn. The samples were assayed using a validated, stability-indicating high-performance liquid chromatography method. The colour and clarity of the solutions, as well as their pH, were also monitored on each sampling day.

Results:

All samples remained clear for the duration of the study; they had a slight yellow colour that darkened over time, and there was an increase in pH. Solutions diluted with sterile water for injection and stored in polypropylene syringes retained at least 94.5% of the initial concentration after 30 days of refrigerated storage and at least 92.1% after an additional 72 h at room temperature with exposure to light. Samples diluted in D5W or NS and stored in PVC minibags retained at least 95.8% of the initial concentration after 30 days of refrigerated storage and at least 91.8% after an additional 72 h at room temperature with exposure to light.

Conclusions:

Cefazolin at various concentrations stored in polypropylene syringes or PVC minibags was stable for up to 30 days with storage at 5°C with protection from light, followed by an additional 72 h at 21°C to 25°C with exposure to light.     

Rapid High-Performance Liquid Chromatographic Analysis and Stability Study of Hydrocortisone 17-Butyrate in Cream Preparations

Pharmaceutical Research -     

皮炎速灵软膏中醋酸地塞米松的HPLC测定

用ＳｈｉｍｐａｃｋＣＬＣ－ＯＤＳ色谱柱，采用高效液相色谱外标法测定醋酸地塞米松的含量，甲醇－水（７０∶３０）为流动相，紫外检测波长为２４０ｎｍ，方法简便、灵敏，重现性好，平均回收率１００．５４％，ＲＳＤ为０．８５％。     

Silicone Oil-Free Polymer Syringes for the Storage of Therapeutic Proteins

Prefilled syringes are a popular choice for the delivery of biopharmaceuticals. However, glass syringes might not be the optimal primary packaging material for all biopharmaceuticals. There is evidence that the necessary lubricant silicone oil in glass syringes can interact with proteins and can be shed from the surface into the product solution. In recent years, silicone oil-free polymer syringes were developed. Despite several advantages, however, a major shortcoming of these polymer systems is their relatively high gas permeability, which might be a limitation for the storage of oxygen sensitive biopharmaceuticals. So far, no long-term protein stability studies regarding such polymer systems have been published. In this study, 2 therapeutic proteins were stored in glass syringes and in silicone oil-free polymer syringes. In addition, polymer syringes stored in nitrogen-filled aluminum pouches or covered with oxygen-tight labels were included. Similar chemical protein stability was achieved at 4°C for all syringes. However, in contrast to the polymer syringes, high particle counts were observed in the glass syringes. Polymer syringes stored in nitrogen-filled aluminum pouches presented a promising alternative for the storage of biopharmaceuticals as they do not expose patients to silicone oil and silicone oil-protein aggregates.     

Comparative pharmacokinetics of vitamin A (retinol) in rats and hamsters

The absorption and elimination of all-trans-retinol in the plasma of rats and hamsters were studied after an oral dose of 45 mg/kg body weight. The hamsters exhibited a higher pretreatment mean circulating retinol concentration than rats maintained on an identical diet. The increase in plasma retinol after a single oral dose was much greater in hamsters than rats. The area under the plasma concentration v. time curve was approximately 60% greater for rats than for hamsters. The elimination half-times for rats were much longer than for hamsters. Plasma retinol uptake and disappearance were consistent with a two-compartment open model with first-order absorption.     

HPLC法测定眼药水中的地塞米松磷酸钠及分解产物

提出了用高效液相色谱法同时测定限药水中的地塞米松磷酸钠及其分解产物地塞米松含量的方法。采用ＭｉｃｒｏｐａｋＭＣＨ－５－Ｎ－ＣＡＰ（１５０×４ｍｍ）色谱柱,以乙腈－磷酸水溶液（３２：６８）为流动相,地塞米松磷酸钠和地塞米松得到了很好分离,其保留时间分别为６．３和１１．３ｍｉｎ。采用紫外光度检测器检测（波长为２４０ｎｍ）分离后的两组分。