James W. Ivey

Use of a Fundamental Approach to Spray-Drying Formulation Design to Facilitate the Development of Multi-Component Dry Powder Aerosols for Respiratory Drug Delivery

PurposeA fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach.MethodsFormulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured.ResultsThe design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations.ConclusionsTheoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.

The use of modeling in spray drying of emulsions and suspensions accelerates formulation and process development

Abstract In respiratory drug delivery, porous, lipid-based microparticles have shown performance advantages over microcrystalline particles ( Hirst et al., 2002 ). These engineered particles are manufactured by spray drying of emulsions or suspensions. The purpose of this work is to combine an understanding of underlying mechanisms with particle characterization data to develop models in support of a quality-by-design (QbD) approach to drug development. Powders were manufactured using a laboratory scale spray dryer. A thermodynamic model was developed for the spray drying process, allowing prediction of outlet temperature and powder residual water content. A stochastic model based on a Monte-Carlo simulator was developed to analyze the effects of relevant parameters on the aerodynamic size of the particles; modeled results were verified by comparison to measured aerodynamic size distributions of spray-dried powders. These modeling techniques allowed rank-ordering of the relative importance of formulation and process variables, and aided in developing an understanding of the drying unit operation.

Understanding pressurized metered dose inhaler performance.

Introduction: Deepening the current understanding of the factors governing the performance of the pressurized metered dose inhaler (pMDI) has the potential to benefit patients by providing improved drugs for current indications as well as by enabling new areas of therapy. Although a great deal of work has been conducted to this end, our knowledge of the physical mechanisms that drive pMDI performance remains incomplete. Areas covered: This review focuses on research into the influence of device and formulation variables on pMDI performance metrics. Literature in the areas of dose metering, atomization and aerosol evolution and deposition is covered, with an emphasis on studies of a more fundamental nature. Simple models which may be of use to those developing pMDI products are summarized. Expert opinion: Although researchers have had good success utilizing an empirically developed knowledge base to predict pMDI performance, such knowledge may not be applicable when pursuing innovations in device or formulation technology. Developing a better understanding of the underlying mechanisms is a worthwhile investment for those working to enable the next generation of pMDI products.

Manufacturing and device options for the delivery of biotherapeutics.

Biotherapeutic aerosol formulations are an intense area of interest for systemic and local drug delivery. This article provides a short overview of typical factors required specifically for biotherapeutic aerosol formulation design, the processing options open for consideration, and the issue of inhalation device selection. Focusing on spray drying, four case studies are used to highlight the relevant issues, describing investigations into: (1) the mechanical stresses occurring in bacteriophage formulations during spray-dryer atomization; (2) modeling of the spray-dryer process and droplet drying kinetics, to assist process design and predictions of formulation stability; (3) a predictive approach to the design and processing of a five-component dry powder aerosol formulation; and (4) the survival of bacteriophages after pressurized metered dose inhaler atomization.

A correlation equation for the mass median aerodynamic diameter of the aerosol emitted by solution metered dose inhalers

A correlation equation for the mass median aerodynamic diameter (MMAD) of the aerosol emitted by solution metered dose inhalers (MDIs) is presented. A content equivalent diameter is defined and used to describe aerosols generated by evaporating metered dose inhaler sprays. A large set of cascade impaction data is analyzed, and the MMAD and geometric standard deviation is calculated for each datum. Using dimensional analysis, the mass median content equivalent diameter is correlated with formulation variables. Based on this correlation in combination with mass balance considerations and the definition of the aerodynamic diameter, an equation for prediction of the MMAD of an inhaler given the pressure of the propellant in the metering chamber of the MDI valve and the surface tension of the propellant is derived. The accuracy of the correlation equation is verified by comparison with literature results. The equation is applicable to both HFA (hydrofluoroalkane) propellants 134a and 227ea, with varying levels of co-solvent ethanol.

Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers

The effects of propellant type, cosolvent content, and air humidity on the morphology and solid phase of the particles produced from solution pressurized metered dose inhalers containing the corticosteroid beclomethasone dipropionate were investigated. The active ingredient was dissolved in the HFA propellants 134a and 227ea with varying levels of the cosolvent ethanol and filled into pressurized metered dose inhalers. Inhalers were actuated into an evaporation chamber under controlled temperature and humidity conditions and sampled using a single nozzle, single stage inertial impactor. Particle morphology was assessed qualitatively using field emission scanning electron microscopy and focused ion beam-helium ion microscopy. Drug solid phase was assessed using Raman microscopy. The relative humidity of the air during inhaler actuation was found to have a strong effect on the particle morphology, with solid spheroidal particles produced in dry air and highly porous particles produced at higher humidity levels. Air humidification was found to have no effect on the solid phase of the drug particles, which was predominantly amorphous for all tested formulations. A critical level of air relative humidity was required to generate porous particles for each tested formulation. This critical relative humidity was found to depend on the amount of ethanol used in the inhaler, but not on the type of propellant utilized. The results indicate that under the right circumstances water vapor saturation followed by nucleated water condensation or ice deposition occurs during particle formation from evaporating propellant-cosolvent-BDP droplets. This finding reveals the importance of condensed water or ice as a templating agent for porosity when particle formation occurs at saturated conditions, with possible implications on the pharmacokinetics of solution pMDIs and potential applications in particle engineering for drug delivery.

Design and pharmaceutical applications of a low-flow-rate single-nozzle impactor

A new low-flow-rate (0.5L/min) single-nozzle impactor for the concentration of dilute aerosol particles with selected pharmaceutical applications is described in this paper. The impactor can be configured up to 11 stages with a wide range of cutoff diameters from 0.6μm to 21.1μm, enabling convenient sampling of inhalable drug particles from inhalation devices and drug production processes. Its unique single-nozzle design and removable impaction plate allow direct sample transfer for subsequent compositional, morphological, solid-state, and other analysis. Agreement between the measured size distribution of fluticasone propionate particles actuated from commercial pMDI Flixotide® 250 Evohaler® and reported data in the literature verified that the impactor stages have accurate cutoff diameters as designed. The multi-stage configuration of the impactor allows rapid separation of polydisperse aerosol particles into different size classes for further characterization. Overlapping of the Raman spectra of the double-component powders from the Seretide® 250 pMDI collected using two different methods demonstrated the applicability of the impactor for a representative sampling of multi-component aerosol particles for bulk composition analysis. A time-dependent and size-dependent stability study was conducted consuming only a single sample canister with 80mg of amorphous indomethacin particles suspended in HFA-134a. It was found that amorphous indomethacin particles converted to the γ crystalline polymorph upon storage at 45°C and that the crystallization rate is strongly size dependent. With its highly effective aerosol collection capability and accurate cutoff diameters for aerosol classification, the impactor will have various applications in the pharmaceutical industry.

Performance of Pressurized Metered-Dose Inhalers at Extreme Temperature Conditions

The performance of pressurized metered-dose inhalers (pMDIs) under a variety of temperature conditions was investigated. The effects of both inhaler temperature and ambient temperature were considered. The inhaler temperature ranged from -13.0°C to 41.7°C and the ambient temperature ranged from -12.0°C to 41.7°C. The in vitro lung dose was measured for four widely available pMDIs: Airomir(TM) , QVAR(TM) , Symbicort(®) , and Ventolin(®) . The in vitro lung dose through an Alberta Idealized Throat was measured by gravimetric assay, which was verified by UV spectroscopic assay. A decrease in the in vitro lung dose was observed for all evaluated pMDIs when ambient temperature and device temperature were simultaneously reduced, decreasing on average by 70% at the coldest temperatures, whereas increasing on average by 25% at the elevated temperature condition. In vitro lung dose is strongly dependent on both inhaler temperature and ambient temperature with the tested pMDIs.

Experimental investigations of particle formation from propellant and solvent droplets using a monodisperse spray dryer

ABSTRACT Experimental studies of particle formation from solution droplets were conducted using a newly developed monodisperse spray drying process. Solutes beclomethasone dipropionate and caffeine were dissolved in ethanol, pressurized hydrofluoroalkane propellant 134a, and mixtures thereof. Solutions were atomized into monodisperse microdroplets using a custom droplet generator installed in a laboratory scale spray dryer, enabling drying and collection of the resulting monodisperse microparticles. The effects of droplet diameter, solution concentration, solvent composition, and drying rate on the physical properties of the dried particles were evaluated. Particle morphology and size were assessed using ultramicroscopy and image analysis of micrographs. Extent of crystallinity and polymorphism were investigated using Raman spectroscopy. The drying temperature was found to have a large effect on the morphology of amorphous beclomethasone dipropionate particles. Particles dried near room temperature were spheroidal to ellipsoidal with prevalent surface concavities and evidence of shell buckling; increasing the drying temperature for fixed droplet size and composition resulted in a transition to more spherical, smooth-surfaced particle morphologies. Crystalline caffeine microparticles were made up of assemblies of multiple crystallites. The measured length and breadth of these crystallites was found to be correlated with the time available for crystal nucleation and growth as calculated using a particle formation model. The results highlight the abilities and limitations of currently available particle formation models in elucidating the relationships between the size, composition, and evaporation rate of drying solution droplets and the physical properties of the resulting particles. The work demonstrates the suitability of monodisperse spray drying as an experimental technique for investigating the fundamentals of particle formation from solution droplets.