Erik Mogalian

Comparison of the TSI Model 3306 Impactor Inlet with the Andersen Cascade Impactor: solution metered dose inhalers.

The product performance of a series of solution Metered Dose Inhalers (MDIs) were evaluated using the TSI Model 3306 Impactor Inlet and the Andersen Cascade Impactor (ACI). The goal of the study was to test whether the fine particle and coarse particle depositions obtained using the Model 3306 were comparable to those results obtained by ACI testing. The analysis using the Model 3306 was performed as supplied by the manufacturer as well as with 20 cm and 40 cm vertical extensions that were inserted between the Model 3306 and the USP Inlet. Nine different solution formulations were evaluated. The drug concentrations ranged from 0.08 to 0.8% w/w and the ethanol cosolvent concentration varied between 5 and 20% w/w. In general, it was found that good correlations between the two instruments were obtained. However, for formulations containing 10–20% w/w ethanol it is shown that an extension fitted to the Model 3306 yielded an improved correlation to those obtained from the ACI.

Preformulation and pharmacokinetic studies on antalarmin: A novel stress inhibitor

The preformulation, solubilization and pharmacokinetic evaluation of antalarmin, a stress inhibitor, have been conducted. Antalarmin has a poor water solubility of less than 1 microg/mL and is weakly basic with an experimentally determined pK(a) of 5.0. Multiple solubilization approaches including pH-control either alone or in combination with cosolvents, surfactants and complexing agents have been investigated. The applicability of lipid-based systems has also been explored. Four formulations, each with a targeted drug loading capacity of 100 mg/mL, show potential for oral administration. Three of these formulations are aqueous solutions (10% ethanol + 40% propylene glycol; 20% cremophor EL; 20% sulfobutylether-beta-cyclodextrin) each buffered at pH 1. The fourth formulation is a lipid-based formulation comprising of 20% oleic acid, 40% cremophor EL and 40% Labrasol. No precipitation was observed following dilution of the four formulations with water and enzyme free simulated gastric fluid. However, only the lipid-based formulation successfully resisted drug precipitation following dilution with enzyme free simulated intestinal fluid. Pharmacokinetic analysis conducted in rats revealed that the 20% cremophor EL solution formulation has a fivefold higher oral bioavailability compared to a suspension formulation. The lipid-based formulation resulted in over 12-fold higher bioavailability as compared to the suspension formulation, the highest amongst the formulations examined.

Application of USP Inlet Extensions to the TSI Impactor System 3306/3320 Using HFA 227 Based Solution Metered Dose Inhalers

ABSTRACT The objective of this study was to further evaluate the need for a vertical inlet extension when testing solution metered dose inhalers using the TSI Model 3306 Impactor Inlet in conjunction with the TSI Model 3320 Aerodynamic Particle Sizer (APS). The configurations tested using the TSI system were compared to baseline measurements that were performed using the Andersen Mark II 8-stage cascade impactor (ACI). Seven pressurized solution metered dose inhalers were tested using varied concentrations of beclomethasone dipropionate (BDP), ethanol, and HFA 227 propellant. The inhalers were tested with the cascade impactor, and with the TSI system. The TSI system had three different configurations as the manufacturer provided (0 cm) or with inlet extensions of 20 and 40 cm. The extensions were located between the USP inlet and the Model 3306 Impactor Inlet. There were no practical differences between each system for the stem, actuator, or USP inlet. The fine particle mass (aerodynamic mass < 4.7 µm) was affected by extension length and correlated well with the ACI when an extension was present. APS particle size measurements were unaffected by the extension lengths and correlated well to particle size determined from the ACI analysis. It has been confirmed that an inlet extension may be necessary for the TSI system in order to give mass results that correlate to the ACI, especially for formulations having significant concentrations of low volatility excipients. Additionally, the results generated from this study were used to evaluate the product performance of HFA 227 based solution formulations that contain varying concentrations of ethanol as a cosolvent.

Accounting for the Effects of Moderately Increased Pressure on the Energetics of Melting and Solubility in Metered Dose Inhalers

The purpose of this study is to account for thermodynamic variations due to changes in the physical environment of propellant-based systems, particularly metered dose inhalers (MDIs). Twenty organic compounds were measured via differential scanning calorimetry under ambient pressure, 60 psi, and 90 psi. The increase in pressure did not affect the melting point of any of the compounds. A modest increase (∼8%) in enthalpy of fusion was noted. This correlates to a modest increase in entropy of fusion, and thus ideal crystalline solubility, though the magnitude of this change depends primarily on the melting point of the given compound. Because the relationship between melting point and solubility is logarithmic, compounds with higher melting points are affected more by this increased energy of melting. Based on the findings, modest changes can be made to predictive models to estimate solubility in propellant systems to account for changes in the physical environment of MDIs.

Modeling and Understanding Combination pMDI Formulations with Both Dissolved and Suspended Drugs

A simulation model has been established to predict the residual aerodynamic particle size distribution (APSD) of dual-component pressurized metered dose inhalers (pMDIs). More specifically, this model estimates the APSD of pMDI formulations containing dissolved and suspended compounds for various formulations, and has been verified experimentally. Simulated and experimental data illustrate that APSDs of the dissolved and suspended components of the pMDI are influenced by concentrations of the dissolved and micronized suspended drugs, along with suspended drug size. Atomized droplets from such combination formulations may contain varying number of suspended drug particles and a representative concentration of dissolved drug. These sub-populations of atomized droplets may explain the residual APSDs. The suspended drug follows a monomodal, lognormal distribution and is more greatly impacted by the size and concentration of the suspended drug in comparison to the concentration of dissolved drug. On the other hand, dissolved drug illustrates a bimodal, lognormal residual particle size distribution both theoretically and experimentally. The smaller mode consists of residual particles made of dissolved drug only, while the larger mode consists of residual particles that contain both dissolved and suspended drugs. The model effectively predicted the size distributions of both the dissolved and suspended components of combination formulations (r(2) value of 0.914 for the comparison of simulated versus experimental MMAD values for the formulations examined). The results demonstrate that this model is a useful tool that may be able to expedite the development of combination pMDI formulation.