Effect of Primary Packaging Material on the Stability Characteristics of Diazepam and Midazolam Parenteral Formulations

Abstract

Diazepam and midazolam are formulated in autoinjectors for parenteral administration to decrease seizures in the case of emergency. However, the compatibility of these lipophilic drugs with the primary packaging material is a key part of drug formulation development. In this work, diazepam and midazolam were packaged in glass syringes as parenteral solutions using two different elastomeric sealing materials (PH 701/50 C BLACK and 4023/50 GRAY). Syringes were stored at three different storage temperatures: 4, 25, and 40 °C. At different time points over 3 years, physical appearance, benzodiazepine sorption on the sealing elastomeric materials, and drug content in solution were assayed. A detailed study on the adsorption profile of both benzodiazepines on the elastomeric gaskets was performed, indicating that the novel rubber material made of bromobutyl derivatives (4023/50 GRAY) is a better choice for manufacturing autoinjectors due to lower drug adsorption. Diazepam showed a better stability profile than midazolam, with the latter solubilised as a hydrochloride salt in an acidic pH that can affect the integrity of the elastomer over time. The amount of drug adsorbed on the surface of the elastomer was measured by NIR and correlated using chemometric models with the amount retained in the elastomeric gaskets quantified by HPLC.

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics)

“…The t 90 midazolam values at 25 ± 2 °C were lower than 1 month for F1 in all tested conditions and below 2 months for F2 formulations. The stability of autoinjector monocomponent formulations containing only midazolam stored at 25 °C in similar conditions as those described in this work was about two years [ 14 ]. This shows evidence of the effect of temperature on accelerating the degradation kinetics of midazolam.…”

“…Formulation 2 (F2) was prepared in a similar way to formulation 1, but the 180.0 g of pralidoxime hydrochloride was replaced with 66.0 g of obidoxime hydrochloride. The liquid formulations were packed in 3 mL cartridge syringe glass Type I (Schott, Schott Pharma, Mainz, Germany) with two different sealing materials described previously [ 14 ].…”

“…Although the chemical stability of monocomponent parenteral formulations containing pralidoxime [ 9 , 10 ], obidoxime [ 11 ], atropine [ 12 ], and midazolam [ 13 , 14 ] has been reported as stable, the combination of many of them in the same autoinjector formulation has never been explored and may lead to physicochemical interactions and a loss of stability. Apart from drug chemical stability in solution, another crucial point to identify is the drug adsorption within the elastomeric gasket materials used to manufacture the autoinjectors.…”

“…Higher adsorption rates can detrimentally reduce the amount of drug available in a solution that is administered to the patient. In a previous work, based on benzodiazepine autoinjector formulations, diazepam demonstrated a more stable profile compared to midazolam but 2-fold greater adsorption on the elastomeric gaskets [ 14 ]. This suggested that midazolam may be a better candidate for multicomponent autoinjector formulations.…”

“…The adsorption of the drugs in the sealing gaskets was also studied. In a previous work [ 14 ], the bromobutyl—4023/50 GRAY sealing gasket proved to be a better option than older materials such as chlorobutyl—PH 701/50 BLACK, especially for midazolam monocomponent formulations. In this work, the compatibility of this new sealing gasket with pralidoxime, obidoxime, and atropine was also studied.…”