Diazepam is available as a 5 mg/mL injection solution in 10-mL vials and 2-mL prefilled syringes and syringe cartridges.3784; 3785; 3786 Each mL of solution also contains propylene glycol 40%, ethanol 10%, sodium benzoate and benzoic acid 5%, and benzyl alcohol 1.5% as a preservative.3784; 3785
pH
Osmolality
The osmolality of diazepam (Roche) was determined to be 7775 mOsm/kg. Diazemuls (Kabi) has an osmolality of 349 mOsm/kg.1233
Diazepam injection is administered by deep intramuscular injection or direct intravenous injection.3784 Do not use small veins for direct intravenous injection; if necessary, diazepam injection may be administered slowly through the infusion tubing as close as possible to the vein insertion.3784 Extravasation or intra-arterial administration should be avoided.3784 Intravenous injection should be made slowly at a rate not exceeding 5 mg/min.3784 For the treatment of status epilepticus in children, the dose may be administered by direct intravenous injection over 1 minute;3785 for other indications in children, manufacturers recommend the dose be administered over at least 1 minute for each 5 mg given3785 or over 3 minutes.3784 Dilution of diazepam injection is not recommended.3784
Intact containers of diazepam injection should be stored at controlled room temperature and protected from light.3784; 3785; 3786 Diazepam injection is a colorless to light yellow solution.3784; 3785; 3786 The drug should not be used if the solution is darker than slightly yellow or particulate matter is present.3786
The drug is most stable at pH 4 to 8 and is subject to acid-catalyzed hydrolysis below pH 3.643
In tropical climates, diazepam injection is subject to discoloration from degradation by an oxidative hydrolytic mechanism. The rate of degradation leading to discoloration is dependent on various factors including the polarity/dielectric constant of the vehicle, pH, oxygen and electrolyte content, access to light, and storage temperature.1749
Diazepam injection under simulated summer conditions in paramedic vehicles was exposed to temperatures ranging from 26 to 38°C over 4 weeks. Analysis found no loss of the drug under these conditions.2562
Syringes
Diazepam 5 mg/mL was filled into 3-mL plastic syringes (Becton Dickinson, Sherwood Monoject, and Terumo) and stored at -20, 4, and 25°C in the dark. Losses, presumably due to sorption to surfaces and/or the elastomeric plunger seal, ranged from 6% at 25°C to 2 or 3% at 4°C to 1% or less at -20°C in 1 day. Storage for 7 days at 4°C and 30 days at -20°C resulted in losses of 4 to 8% and 5 to 13%, respectively.1562
Diazepam (Roche) 10 mg/2 mL stored in plastic syringes composed of polypropylene and polyethylene exhibited no loss of diazepam in 4 hours.351
Diazepam (Roche) 5 mg/mL was stored in 1.5-mL disposable glass syringes with slit rubber plunger-stoppers (Hy-Pod) for 90 days at 30 and 4°C in light-resistant bags. Diazepam was gradually lost from the solution, with the disappearance being essentially complete in 60 days. At 4°C, about 5% was lost at the 60- and 90-day intervals; about 9 to 10% was lost at 30°C in this period. The loss was attributed to sorption to the rubber plunger-stoppers.794
Sorption
The stability of diazepam in several infusion fluids in glass containers321 does not extend to the solutions in polyvinyl chloride (PVC) bags, in which substantial sorption occurs. At 10 mg in 100 and 200 mL, over 24% loss occurred in 30 minutes and 80 to 90% loss occurred in 24 hours.330
Diazepam 8 mg/L in sodium chloride 0.9% in PVC bags exhibited 20% loss in 24 hours and 32% loss in 1 week at 15 to 20°C due to sorption.536
The sorption of diazepam to PVC infusion bags was evaluated at concentrations of 5 and 20 mg/100 mL in dextrose 5% and sodium chloride 0.9%. Diazepam concentration was under 45% in 2 hours and 20 to 25% in 8 hours.647
Diazepam sorption that results from plastic infusion sets was evaluated. Dilutions of 7.5 and 30 mg in 150 mL of dextrose 5% and sodium chloride 0.9% were prepared in the burette chamber of a Buretrol. The solutions flowed through the tubing at 30 mL/hr for 2 hours. Less than 10% decrease in diazepam occurred in the burette chamber. However, running the solution through the tubing resulted in steep declines to 43% of the initial amount. When diazepam 25 and 100 mg/500 mL of dextrose 5% and sodium chloride 0.9% prepared in glass bottles and 100-mL aliquots were run through the Buretrol over 1 hour, only about 60 to 70% of the diazepam was delivered. The presence of a 0.5-µm inline filter did not affect the concentration delivered.647
Over 90% loss due to sorption to the administration set (Abbott) and the extension tubing (Extracorporeal) both with and without a 0.22-µm inline filter (Abbott) was reported. Diazepam 0.02 to 0.04 mg/mL in dextrose 5% had no precipitation, and solutions in glass bottles were stable over 24 hours. However, the amount delivered through the tubing was only 40 to 55% at time zero, and this amount dropped to 2 to 7% at 24 hours. No difference was noted from the inline filter.645
The sorption of diazepam to administration sets from solutions of diazepam 25 and 50 mg/500 mL in glass bottles of dextrose 5% and Ringer’s injection, lactated or 12.5 and 25 mg/250 mL of these same solutions in Soluset burette chambers was tested. The admixtures showed no evidence of physical incompatibility over 4 hours at room temperature. The solutions in glass bottles were run through Venosets composed of PVC drip chambers and tubing at 2.5 and 5 mg/hr. The solutions stored in the cellulose propionate burette chambers of the Solusets were also run through their PVC tubing at the same rates. The solution delivered through the Venosets contained about 91 to 97% of the initial concentration, with the more dilute solution having slightly more drug remaining. However, the Soluset delivered only about 50 to 60% in 2 hours and about 35 to 45% of the initial concentration after 4 hours. Most of the loss was due to sorption to the cellulose propionate burette chamber. This result was attributed to the larger surface area of the burette compared with the tubing and/or the difference in plastic composition. Almost all of the lost diazepam could be recovered through desorption from the burettes. The use of 0.45-µm inline filters had no effect on the drug concentration.646
Diazepam 50-mg/500 mL solution in dextrose 5% prepared in glass bottles and run through an administration set (Travenol) at 100 mL/hr was assessed. Only 63% of the diazepam was initially delivered but gradually climbed to 81% at the end of 5 hours.649
A 27 to 33% diazepam loss was noted from admixtures in both dextrose 5% and sodium chloride 0.9% in PVC bags. Diazepam concentrations ranged from 0.05 to 0.2 mg/mL. No drug decomposition could be detected. Diazepam solutions in dextrose 5% were also run through a 70-inch Travenol set. A steep decline to under 70% was delivered during the first 15 minutes, after which the delivered amount increased to between 80 and 90% over the next 85 minutes as saturation of the tubing occurred. A quantitatively smaller, but qualitatively similar, effect was observed when diazepam was administered by intravenous push through an intravenous catheter (Abbott Venocath-18) of 11.5-inch total length. The decline in delivered diazepam reached a nadir of 95% in about 8 minutes before returning to 100% at 10 minutes. The smaller effect of the intravenous catheter relates to its relatively shorter length.650
Diazepam 8 mg/L in sodium chloride 0.9% in glass bottles exhibited a cumulative 7% loss due to sorption during a 7-hour simulated infusion through an infusion set (Travenol). The set consisted of a cellulose propionate burette chamber and 170 cm of PVC tubing. Diazepam sorption was attributed mainly to the tubing. The extent of sorption was found to be independent of concentration.606
Diazepam was also tested as a simulated infusion over at least 1 hour by a syringe pump system. A glass syringe on a syringe pump was fitted with 20 cm of polyethylene tubing or 50 cm of Silastic tubing. A negligible amount of drug was lost with the polyethylene tubing, but a cumulative loss of 21% occurred during the 1-hour infusion through the Silastic tubing.606
Storage of a 25-mL aliquot of the 8-mg/L diazepam solution in all-plastic syringes composed of polypropylene barrels and polyethylene plungers for 24 hours at room temperature in the dark did not result in any drug loss due to sorption.606
Diazepam 20 mg/500 mL in dextrose 5% was delivered at 4 mL/hr through PVC tubing by means of an infusion pump. Under 20% of the diazepam was delivered at any time point over 24 hours. Increasing the concentration to 50 mg/500 mL in dextrose 5% and increasing the infusion rate to 20 mL/hr decreased the amount of diazepam lost from the solution. After 30 minutes of solution delivery, the diazepam in the tubing effluent was about 30% of the initial concentration. Subsequently, the delivered diazepam concentration climbed to about 60% over 24 hours.351
The partition coefficients of diazepam with various plastics from intravenous containers and administration sets were determined. PVC bags and tubings from a variety of suppliers were all similar in partitioning and hundreds of times greater than polyolefin containers. Volume-control chambers made from cellulose propionate had partition coefficients smaller than those of PVC but still sufficient to cause serious depletion of diazepam from the chambers.644
The uptake of diazepam into PVC is absorption into the plastic matrix rather than adsorption to the surface. The absorption is independent of concentration but related to contact time with the plastic. Decreasing the flow rate or increasing the tubing length increases the amount of diazepam absorbed.
Increasing the flow rate from 10 to 264 mL/hr through 198 cm of PVC tubing decreased the amount of diazepam absorbed from 88 down to 28%. Increasing the tubing length from 100 to 350 cm increased the amount absorbed from 17 to 59%. However, it was noted that absorption is not markedly affected by tubing length within the range of lengths commercially available.644
Diazepam 50 mg/L in sodium chloride 0.9% in a glass bottle was delivered through a polyethylene administration set (Tridilset) over 8 hours at 15 to 20°C. The flow rate was 1 mL/min. No appreciable loss due to sorption occurred. This finding is in contrast to a 20% loss using a conventional administration set.769
The sorption of diazepam 40 and 120 mg/L in sodium chloride 0.9% was evaluated in 100- and 500-mL PVC infusion bags. After 8 hours at 20 to 24°C, 58 to 60% of the diazepam was lost in the 100-mL bag and 31% was lost in the 500-mL bag. The extent of sorption was independent of concentration but was influenced by the size of the PVC container. This difference results from the ratio of the surface area of plastic to the volume of solution. As the volume of solution in the bag decreases, the extent of sorption increases.770
Diazepam showed negligible (3%) loss when aqueous solutions were stored in polypropylene bags.770
Extensive sorption of diazepam in dextrose 5% and sodium chloride 0.9% to PVC containers was found. Solutions of 10 to 80 mg/L showed a 12 to 20% diazepam loss in 1 hour. In 6 hours, the loss was 30% at 5°C and 40% at room temperature. Over 30% of the missing diazepam could be recovered by washing the PVC with methanol. Sorption did not occur to glass or polyethylene containers, which showed losses of about 6 to 8% in 24 hours.796
No loss of diazepam occurred to glass or polyethylene containers in 200-mg/L concentrations in dextrose 5% or sodium chloride 0.9%. In PVC containers, drug losses of 37 to 43% occurred in 24 hours at 25°C.797
Testing the administration of diazepam with a glass syringe on an infusion pump connected with high-density polyethylene tubing resulted in negligible drug loss.795
Plastic syringes having polypropylene barrels and polyethylene plungers (Pharma-Plast, AHS Australia) and all-glass containers were compared for the possible sorption of diazepam. After 24 hours of storage, no drug loss was found in either container. The authors indicated that these plastic syringes could be used with syringe pumps.782
The effect of several factors on the rate and extent of sorption of diazepam by PVC was evaluated. Sorption proved to be independent of changes in ethanol-propylene glycol concentrations in the vehicle, pH changes in the admixtures over 4.2 to 7.5, and the diazepam concentration. The rate and extent of sorption could be minimized by decreasing the storage temperature, minimizing the storage time, and increasing the surface area to volume ratio by storing the largest possible fluid volume in a given PVC bag and using short lengths of small diameter infusion tubing. Use of glass or polyolefin solution bottles and polyolefin infusion tubing avoids the loss of diazepam.880
The sorption of diazepam 20 mg/500 mL in sodium chloride 0.9%, run at 1 mL/min through PVC and polybutadiene (PBD) administration sets (Avon Medicals, U.K.), was reported. The delivered concentration through the PVC set was 80% initially and then climbed to 90% after 4 hours. For a concentration of 10 mg/120 mL prepared in a cellulose propionate burette, 10 to 15% sorption occurred in the burette. Use of the PBD set, with or without a methacrylate butadiene styrene burette chamber, resulted in no loss of diazepam.1027
The delivery of diazepam 50 and 100 mg/500 mL in dextrose 5% and sodium chloride 0.9% through a PVC administration set (Accuset 9210, IMED) and a set composed of ethylene vinyl acetate with a polyethylene inner wall (Accuset 9630, IMED) was evaluated. The solutions were run through the sets at 50 and 100 mL/hr. The delivered diazepam concentration varied between 44 and 71% at 50 mL/hr and between 62 and 89% at 100 mL/hr, increasing from the lower to the higher percentage over the 5-hour study period. The non-PVC set exhibited no sorption of diazepam, delivering 100% of the diazepam.1096
The percentage of diazepam delivered through PVC administration sets varied with the length of the tubing; the longer the tubing, the smaller was the percentage delivered. For a 25-mg/500 mL admixture in sodium chloride 0.9%, delivery through PVC tubing in lengths from 23 to 185 cm varied from 88% of the theoretical amount for the shortest length to 53% for the 185-cm length.1097
The effect of container type and flow rate on the sorption of diazepam was evaluated. Glass and polyethylene containers showed 0 and 5% sorption, respectively, of the diazepam content of a 25-mg/500 mL admixture in sodium chloride 0.9% in 7 days at 25°C. PVC containers showed a 75% loss in this time period. Simulated infusion of this solution from glass bottles through PVC sets at flow rates of 30 to 120 mL/hr showed that a greater percentage of diazepam was lost at the slower infusion rates. At 30 mL/hr, 63% was lost after 4 hours, while only 23% was lost after 4 hours at 120 mL/hr.1098
A rapid diazepam loss from a 40-mcg/mL solution in sodium chloride 0.9% in a PVC container at 21°C was reported. A 15% loss occurred in 2 hours, and a 55% loss occurred in 24 hours. Little or no diazepam loss occurred in 24 hours in glass bottles or polyethylene-lined laminated bags.1392
Diazepam 100 mcg/mL in sodium chloride 0.9% exhibited no loss due to sorption in 24 hours at 21°C in glass bottles and polypropylene trilayer bags (Softbag, Orion). However, about a 70% loss occurred due to sorption in PVC bags.1796
Diazepam 40 mcg/mL in 0.9% sodium chloride and in pH 7 buffer also underwent sorption to ethylene vinyl acetate (EVA) plastic bags. Losses exceeding 25% occurred within 24 hours stored at 30°C. The solutions appeared to reach equilibrium after 96 hours of storage.1917
Diazepam 0.04 mg/mL in dextrose 5% and sodium chloride 0.9% in PVC, polyethylene, and glass containers exhibited only 4 to 5% loss in glass and polyethylene containers but 66% loss due to sorption in PVC containers stored at 4 and 22°C for 24 hours.2289
To minimize the sorption of diazepam, glass or polyolefin containers should be used. If PVC bags are used, the lowest possible surface-to-volume ratio should be selected and storage time should be minimized. The use of non-PVC administration sets will reduce loss. If PVC tubing is used, it should be the shortest possible length with a small diameter, and the set should not contain a burette chamber. More rapid flow rates (consistent with safe clinical use) will also reduce the loss of diazepam.
Filtration
Diazepam (Roche) 50 mcg/mL in dextrose 5% and sodium chloride 0.9% was delivered over 7 hours through 4 kinds of 0.2-µm membrane filters varying in size and composition. Diazepam concentration losses of 7 to 17% were found during the first 60 minutes; subsequent diazepam levels returned to the original concentration when the binding sites became saturated.1399
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Infusion Solutions
Although product labeling for diazepam injection contains a caveat against dilution of the product,3784; 3785; 3786 interest in the intravenous administration of diluted diazepam has been expressed in the literature.
Roche indicated that an ampul of diazepam should be diluted in no more than 5 mL or, alternatively, all the way to 20 mL to avoid precipitation. Between these concentrations, a fine white precipitate may occur.379
Dilution of diazepam in a volume of 25% or more of the diazepam volume is stated to result in the immediate precipitation of diazepam. No precipitation was observed if aqueous dilution was made with a volume of less than 25% of the diazepam volume.2082
Diazepam injection added to sodium chloride 0.9% caused the immediate formation of a light yellow to white precipitate. The maximum dilution that produced such a precipitate was 15-fold, representing a mixture of about 0.3 to 0.4 mg/mL. Analysis of the diazepam injection-sodium chloride 0.9% precipitate showed that it was almost entirely diazepam. A precipitate also formed in human plasma. A solution composed of all ingredients of diazepam injection except diazepam was tried, but dilution yielded no precipitate. It was estimated that injection of 5 mg/min into the tubing of an intravenous infusion of sodium chloride 0.9% would result in a precipitate unless the solution rate exceeded 17 mL/min.381
It was determined that the precipitate induced by adding 2 mL of sterile water for injection to 1 mL of diazepam injection is only diazepam. The precipitate appeared to be oily and adhered to the walls of the container, leaving a clear solution. This may explain the reports of the clearing of cloudy solutions with time.641; 642
As little as 10 mg of diazepam in 100 mL of dextrose 5% resulted in a precipitate. It was also found that an infusion rate of over 15 to 20 mL/min was required to prevent precipitation of diazepam being injected at a rate of 5 mg/min in running infusions of dextrose 5% and sodium chloride 0.9%.382
Nevertheless, interest in infusing diazepam has persisted because of bioavailability problems associated with intramuscular injection121; 383; 384; 638 and a belief in the utility of diazepam infusions.386; 387; 388; 389; 390; 391; 392; 1099
Diazepam 10 mg in 250 mL and 5 mg in 50 mL of sodium chloride 0.9% resulted in no observable precipitate.385
A transient cloudiness occurred when 100 mg of diazepam was added to 500 mL of Ringer’s injection, lactated. The solution thereafter remained clear, and the clinical response to the diazepam infusion was good.392
A study was conducted on the compatibility and stability of diazepam in a variety of intravenous infusion solutions. Results indicate that a visible precipitate is produced in dilutions of 1:1 to 1:10. Haziness was reported at 1:15, and delayed precipitates forming after 6 to 8 hours were seen in some solutions at 1:20. Dilutions of 1:40 to 1:100 remained clear for 24 hours. Further, the concentration of the 1:40 to 1:100 dilutions was retained for 24 hours.321
The equilibrium solubilities of diazepam in water for injection, sodium chloride 0.9%, dextrose 5%, and Ringer’s injection, lactated were determined. The equilibrium solubilities were found to be about 0.04 to 0.05 mg/mL in all of the solutions at 25°C. This finding corroborated the work of others which indicated the solubility to be about 0.05 to 0.06 mg/mL. It was concluded that a more conservative 1:100 dilution should be used for diazepam infusion to guarantee solubility for 24 hours.643
The aqueous solubility of diazepam over a pH range of approximately 3 to 8 in phosphate buffer adjusted with hydrochloric acid or sodium hydroxide as well as dextrose 5%, sodium chloride 0.9%, and Ringer’s injection, lactated was determined. In the pH range of 4 to 8, which included all 3 infusion solutions, the solubility was approximately 0.05 to 0.06 mg/mL at 25°C. Dilution to at least 0.04 mg/mL was recommended to ensure rapid and complete re-solution upon addition to the infusion solution.644
Various dilutions of diazepam in water for injection and sodium chloride 0.9% were tested. The observations are tabulated here:1095
| Diazepam Concentration | Diluent | Observation |
|---|---|---|
| 10 mg/5 mL | W, NS | Clear for 1 min but then precipitate forms |
| 10 mg/10 mL | W, NS | Precipitates immediately |
| 10 mg/20 mL | NS | Precipitates immediately |
| 10 mg/25 mL | NS | Precipitates immediately |
| 10 mg/30 mL | NS | Clear for 30 min but then precipitate forms |
| 10 mg/50 mL | NS | Clear for 10 days |
| 10 mg/100 mL | NS | Clear for 10 days |
Order of Mixing
It has been reported that addition of diazepam to dextrose 5% and sodium chloride 0.9% to form concentrations of 50 and 200 mg/L results in an immediate and persistent yellow precipitate. However, addition of the diluent to the diazepam injection to these same concentrations results initially in a cloudy solution which clears before the completion of admixture. It was recommended that admixtures of diazepam be prepared by adding the infusion solution to the diazepam injection.647; 648
For a list of references cited in the text of this monograph, search the monograph titled References.