1. 3M Drug Delivery Systems 3 Introduction A combination MDI product has been developed containing two active drug substances (designated as A and B) in solution, 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 was to assess the influences of drug, ethanol and acid concentration on the pharmaceutical performance of the product in order to assess the impact of manufacturing variability and to establish appropriate product specifications. Shuguang Hou, Todd Alband, Kimberly Kriesel, Lisa Dick and David Heisler 3M Drug Delivery Systems Division, 3M Center Building 260-4N-12, St Paul, MN 55144 The Influence of Formulation Factors on the Pharmaceutical Performance of a Solution Metered Dose Inhaler Product Results Dose Delivery:The delivered dose is defined as the drug amount collected downstream from the mouthpiece of the actuator. For both active drugs A and B, all formulations delivered within ± 20% of their target dose over the ethanol and acid concentration variability in the tested ranges studied (Table 2). The FDA guidance suggests that the dose content should not be outside of 80 - 120% of label claim (2). The delivered dose of both drugs A and B decreased following an increase in ethanol concentration in the formulations. This is primarily due to the decrease in formulation density following the increase in ethanol concentration, which results in a reduced shot weight and drug mass delivered per actuation. The acid level did not influence the delivered dose for either active drugs. The delivered dose of drug A was not affected by the concentration of drug B either. The delivered dose of drug B was proportional to its concentration in the formulations. Conclusions The dose delivery and particle size distribution of a solution HFA MDI product were influenced by the ethanol and drug concentration in the formulation. The non- volatile mineral acid did not have an effect on the pharmaceutical performance. Methods Two separate 2 2 factorial experiments, shown in Table 1, were designed to assess the influence of drug B, ethanol and acid concentration on MDI product performance. The concentration of drug A was 1 mcg per actuation in all the tested formulations, while drug B concentration was varied from 100 mcg to 200 mcg per actuation. The ethanol and acid concentrations were assessed at  20% and  50% of their respective target levels. A total of 12 formulations were prepared, including 2 duplicate target composition formulations at each concentration level for drug B. All formulations were filled in 3M aluminum 15- mL canisters with Bespak BK357 63-µL valves. Testing was conducted using Bespak 0.22 mm orifice diameter actuators. 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 (1). The drug content was assayed by validated HPLC methods with UV detection. The method precision for delivered dose and fine particle dose is 3.2% and 6.8% relative standard deviation (RSD), respectively. The method limit of quantitation (LOQ) is 0.2 mcg and 0.4 mcg per actuation, respectively, for drugs A and B. References 1. USP24 General Chapters, 2000. 2. FDA Draft Guidance for Industry, “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products”, October 1998. 3. Stein, S.W. and Myrdal, P.B. (2004), J. Pharm. Sci., 93 (8), 2158-2175. Drug B Conc. (mcg/act.) Ethanol Conc. (% w/w)Acid Conc. (% w/w) 12.015.018.0 100 Lot A1Lot D1Low Lots C11 & C12Target Lot B1Lot E1High 200 Lot A2Lot D2Low Lots C21 & C22Target Lot B2Lot E2High Table 1 Factorial Design of Experiments Particle Size Distribution: The fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) for both drugs A and B were identical, as shown in Table 2 and Figure 1, indicating the co- deposition of the two active drugs in the solution formulation. The FPF was influenced by both the ethanol and drug B concentration in the formulation. As the ethanol concentration was increased, the FPF decreased and more residual drug was observed in the actuator mouthpiece and USP throat inlet. A lower FPF was observed for formulations with a higher drug B concentration. The drug concentration effect on the FPF was less obvious for formulations with higher ethanol concentration levels, such as lots E1 and E2, suggesting that the ethanol concentration plays a more prominent role on the particle size distribution of solution MDIs. The MMAD for both active drugs was not sensitive to the ethanol concentration levels in the formulation. It is believed that the depositions of large particles in the actuator mouthpiece and USP throat inlet mask the ethanol effect on MMAD (3). A larger MMAD was observed for all formulations with a higher drug B concentration, shown in Figure 1. Theoretically the MMAD is proportional to the total non-volatile drug concentration to the 1/3 power (3). The ratio of measured MMAD between these two drug concentration formulations (MMAD 200mcg/act / MMAD 100mcg/act ) was 1.24, which agreed well with the theoretical ratio of 1.25. LotDelivered Dose (mcg/act.) FPF (%) Residual in Actuator and Throat (mcg/act.) Drug ADrug BDrug ADrug BDrug ADrug B A10.95 (0.03)95 (3)60.2 (0.6)60.8 (1.4)0.43 (0.02)38 (2) B10.90 (0.05)90 (2)57.2 (1.8)56.5 (1.9)0.40 (0.02)39 (1) C110.91 (0.01)92 (2)49.0 (2.7)49.2 (2.6)0.48 (0.01)48 (5) C120.90 (0.03)91 (4)48.7 (2.3)48.2 (2.5)0.49 (0.02)47 (3) D10.85 (0.04)85 (4)42.9 (2.0)42.9 (1.8)0.51 (0.01)49 (1) E10.80 (0.03)85 (2)40.1 (2.5)40.2 (2.5)0.54 (0.05)51 (5) A20.89 (0.06)179 (12)54.6 (2.0)55.0 (1.9)0.46 (0.01)91 (3) B20.88 (0.02)184 (4)53.5 (1.8)53.3 (1.5)0.48 (0.02)93 (4) C210.91 (0.02)182 (3)44.0 (2.0)43.4 (1.4)0.51 (0.01)104 (4) C220.88 (0.02)180 (4)44.9 (0.9)44.6 (0.9)0.54 (0.01)106 (1) D20.83 (0.02)173 (4)40.2 (2.3)37.9 (2.0)0.55 (0.02)111 (4) E20.84 (0.04)175 (4)40.8 (1.1)39.9 (1.2)0.53 (0.02)101 (5) Table 2 Summary of Dose Delivery and Particle Size Distribution Figure 1 Plot of MMAD versus Drug B Concentration Mean (Standard Deviation) n = 15 for delivered dose and n = 5 for particle size distribution