1. 3M Drug Delivery Systems 3 Introduction The headspace of pressurized metered dose inhaler (MDI) canisters is filled by the vapor of volatile components, mainly propellant, contained in the formulation. Following multiple actuations of the MDI, the headspace of the canister increases and more propellant evaporates to fill the headspace, which causes the concentration of non-volatile components, mainly the active drug, in the liquid phase of the formulation. If there are no confounding variables, as seems likely in a formulation containing dissolved drug, the delivered dose drug per actuation from the MDI would be expected to increase through the container life. The significance of such impacts had been proposed on the regulatory specification limits of MDI dose content uniformity (1-3). A solution formulation HFA MDI product has been developed. This formulation contains one active drug at 1 mcg/actuation, 15% w/w ethanol as a co-solvent, a non-volatile mineral acid as a stabilizer, and HFA-134a as a propellant. The objective of this study is to assess the influences of the canister headspace on the drug concentration in the container, drug delivery, and particle size distribution of the MDI product. Shuguang Hou, Kimberly Kriesel, Todd Alband, Lisa Dick and David Heisler 3M Drug Delivery Systems Division, 3M Center Building 260-4N-12, St Paul, MN 55144 The Influence of Canister Headspace on the Pharmaceutical Performance of a Solution Metered Dose Inhaler Product Results Dose Delivery (DD): For the 7.3 g fill weight units (with a larger initial canister headspace), the delivered dose increased approximately 13% at the end of container life (Table 1), which agreed with the literature (1 - 2). This was explained by the continuous equilibration of the liquefied propellant into the headspace of the canister following the actuations. For the 11.0 g fill weight units (with a smaller initial canister headspace), no significant change was observed for the delivered dose through container life (Table 1). Theoretically, the 11.0 g fill weight unit has more doses (120 actuations), thus should show a more significant increase for the delivered dose per actuation at the end of container life. The reason for no change of the delivered dose through container life for the 11.0 g fill weight unit remains unclear. Particle Size Distribution: No significant change was observed for the fine particle fraction (FPF) through container life for either fill weight (Table 1). Parameters7.3 g Fill Weight11.0 g Fill Weight BeginningMiddleEndBeginningMiddleEnd % of Drug Conc. 100.0 (0.9) NA94.5 (0.0) 100.0 (0.0) 99.5 (0.4) 86.3 (1.9) DD (mcg/act.) 0.77 (0.06) 0.81 (0.06) 0.87 (0.00) 0.80 (0.02) 0.79 (0.03) 0.81 (0.02) FPF (%) 46.8 (0.5) NA48.6 (3.2) 48.3 (4.9) NA48.7 (3.9) Mean (Standard Deviation) NA: Not Tested. n = 3 for FPF and n = 9 for drug concentration and DD Conclusions The initial canister headspace and fill weight had an effect on the active drug concentration remaining in the container and the delivered dose. The behavior of a solution formulation allows the detection of such effects. Under both headspace conditions, the delivered dose through the container life should meet the regulatory guidance of within 80 - 120% of label claim (4). To achieve a more consistent pharmaceutical performance for solution MDIs, a smaller initial canister headspace and smaller fill weight are suggested. References 1.Howlett, D., Drug Delivery to Lungs VII, 105-109, 1996. 2.Lewis, D., Brambilla, G., Ganderton, D., Howlett, D. and Meakin., B., Respiratory Drug Delivery VII, 373- 375, 2000. 3.Zhang L and Adjei A., Respiratory Drug Delivery IX, 673-676, 2004. 4.FDA Draft Guidance for Industry, “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products”, October 1998. Table 1 Summary of Drug Concentration in the Container, Drug Delivery and Fine Particle Fraction through Container Life The authors thank Mike Sivigny and Jane M. Pamperin for providing the computer model program. Acknowledgement The MDI solution formulation was filled in 3M aluminum 15-mL canisters with Bespak BK357 63-µL valves. The fill weight was either 7.3 grams (60 actuations) or 11.0 grams (120 actuations), resulting in different head space volumes in the canister. The drug concentration in the container through container life was determined by a validated HPLC method with UV detection. The method precision was 0.5% relative standard deviation (RSD). The delivered dose (ex ‑ actuator) and particle size distribution through container life were measured with the Bespak 0.22 mm orifice diameter actuator. The dose delivery was tested using a dose unit spray apparatus (DUSA) tube and the particle size distribution was measured using Andersen cascade impactor (ACI). The flow rate was 28.3 liters per minute for both tests. The drug content in the DUSA tube and ACI plates was assayed by a validated HPLC method with UV detection. The method precision was 1.7% RSD and the limit of quantitation (LOQ) was 0.14 mcg/actuation. Methods Drug Concentration in Container: The drug concentration in the container decreased to 94.7% and 86.6% of the beginning at the end of container life for units with fill weights of 7.3 g (60 actuations) and 11.0 g (120 actuations) (Figure 1 and Table 1). The 11.0 g fill weight unit showed a larger decrease of drug concentration through container life due to its larger fill weight (i.e. larger number of actuations). Interestingly, the drug concentration at the middle of the container life (i.e. after 60 actuations) did not change for the 11.0 g fill weight unit, while the drug concentration decreased to 94.7% after 60 actuations for the 7.3 g fill weight unit. This might be explained by the smaller initial canister headspace for the 11.0 g fill weight unit. A computer model, developed based on the ideal gas law and Raoult’s law, was applied to estimate these impacts. The experimental results had a good agreement with the theoretical data (Figure 1). These results indicate that both the initial canister headspace and fill weight have impacts on the drug concentration remaining in the canister through container life. Results Figure 1 Plot of Drug Concentration in the Canister through Container Life