Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.

Pharmaceutical powders are often milled to achieve the optimum particle size. These size reduction processes can introduce dislocations and/or defects onto particle surfaces affecting the overall crystallinity of the powder. If enough energy is imparted, amorphous regions on the particle surfaces may be produced. These amorphous regions have the propensity to absorb significant quantities of water. In this study the effect of sorbed water on the physical characteristics of albuterol sulfate is investigated. Physical properties of this compound are studied in both micronized and unmicronized states using scanning electron microscopy, differential scanning calorimetry, powder x-ray diffraction, solution microcalorimetry, laser diffraction particle size analysis and water vapor sorption analysis. Subtle differences in crystallinity induced by air jet micronization are detected by several analytical methods. Amorphous to crystalline conversions are observed, the kinetics of which are found to be both temperature and relative humidity dependent. These experiments show the dynamic nature of micronized albuterol sulfate and aid in the determination of the actual physical state of this pharmaceutical powder.

New albuterol-containing metered-dose inhaler (MDI) formulations were under development to replace chlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkane (HFA) propellants. To achieve good chemical and physical stability of MDI formulations with HFA propellants, different drug forms were evaluated in model formulations (drug, oleic acid, and one of the following: P12/P11, P12/ethanol, P12, P134a/ethanol, P134a). The effects of drug form (base versus sulfate), propellant type (P12 versus P134a), and cosolvent type (P11 or ethanol versus none) on the chemical and physical stability were examined. The chemical stability of the formulations was determined by monitoring the percent drug remaining in the formulations using HPLC. The physical stability of the formulations was followed by visually assessing the suspension appearance, and by determining the mass median diameter (MMD) of the suspended particles using laser diffraction analysis. The drug form has a great impact on the chemical and physical stability of the formulations. The sulfate formulations were chemically stable up to 12 months when stored at 30 degrees C and 40 degrees C/85% relative humidity (RH). Poor chemical stability was observed for the base formulations, except for ethanol-free formulations (P12/P11, P12, and P134a) at 30 degrees C and a P134a formulation at 40 degrees C/85% RH. The chemical instability of albuterol base formulations at 30 degrees C correlates with its solubility. The presence of a cosolvent greatly improved the dispersion characteristics of both sulfate and base formulations. The sulfate formulations in the presence of a cosolvent (P12/P11, P12/ethanol, and P134a/ethanol) showed good physical stability when stored for up to 12 months at 30 degrees C and 40 degrees C/85% RH. The physical stability of the base formulations was not acceptable due to crystal growth/agglomeration in all formulations, except for the P12/P11 formulation. The physical instability of both sulfate and base formulations not only correlates with the drug solubility, but also with particle agglomeration. In conclusion, good chemical and physical stability of albuterol-containing suspension formulations can be achieved with the appropriate choice of drug form and formulation constituents.

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Product performance test data are presented on Glycopyrrolate (GP), a LAMA, and Formoterol Fumarate (FF), a LABA, and their combination in Pearl's HFA MDI format (GP MDI, FF MDI, and GP/FF combination MDI). GP and FF MDIs consistently deliver 18 and 2.4 µg GP and FF per actuation, respectively, with over 50% of the delivered dose in a particle size range suitable for uniform deposition in human airways. Their aerodynamic particle size distributions show excellent long term stability when stored at refrigerated (2-8°C), room temperature (25°C/60% RH) or stressed (40°C/75% RH) conditions. The delivered doses and aerosol properties of GP MDIs remain unchanged upon repeat thermal excursions between-5°C and 40°C for several weeks, demonstrating the robustness of Pearl's novel HFA MDI suspensions. GP/FF MDIs also show excellent stability without any physical or chemical interaction between the two actives under a broad range of test conditions. The overall performance attributes for the two drugs in GP/FF MDI combination remain unchanged from the monotherapy GP and FF MDIs. Conclusions Pearl is well positioned to further develop its MDI products. Pearl's MDI products demonstrate the following characteristics:  Physical and chemical stability even under stressed conditions across a wide range of products  Ability to develop very low doses of potent molecules  High fine particle fraction (>50%) with low throat deposition for all products  Excellent dose content uniformity  No pharmaceutical effect observed when developing combination drug products  High speed of development; < 9 months from first formulation to dosing patients Pearl's porous particle platform is ideal for the development of robust MDI products in timelines not previously attainable.