Reinhard Vehring

Pharmaceutical Particle Engineering via Spray Drying

This review covers recent developments in the area of particle engineering via spray drying. The last decade has seen a shift from empirical formulation efforts to an engineering approach based on a better understanding of particle formation in the spray drying process. Microparticles with nanoscale substructures can now be designed and their functionality has contributed significantly to stability and efficacy of the particulate dosage form. The review provides concepts and a theoretical framework for particle design calculations. It reviews experimental research into parameters that influence particle formation. A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts.

Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery

Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg.

Spray-dried Respirable Powders Containing Bacteriophages for the Treatment of Pulmonary Infections

Myoviridae bacteriophages were processed into a dry powder inhalable dosage form using a low-temperature spray-drying process. The phages were incorporated into microparticles consisting of trehalose, leucine, and optionally a third excipient (either a surfactant or casein sodium salt). The particles were designed to have high dispersibility and a respirable particle size, and to preserve the phages during processing. Bacteriophages KS4- M, KS14, and cocktails of phages ΦKZ/D3 and ΦKZ/D3/KS4-M were spray-dried with a processing loss ranging from 0.4 to 0.8 log pfu. The aerosol performance of the resulting dry powders as delivered from an Aerolizer® dry powder inhaler (DPI) exceeded the performance of commercially available DPIs; the emitted mass and the in vitro total lung mass of the lead formulation were 82.7% and 69.7% of filled capsule mass, respectively. The total lung mass had a mass median aerodynamic diameter of 2.5-2.8 µm. The total in vitro lung doses of the phages, delivered from a single actuation of the inhaler, ranged from 10(7) to 10(8) pfu, levels that are expected to be efficacious in vivo. Spray drying of bacteriophages into a respirable dry powder was found to be feasible.

Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers.

Engineered porous phospholipid microparticles with aerodynamic diameters in the respirable range of 1-2 μm were cosuspended in 1,1,1,2-tetrafluoroethane, a propellant, with microcrystals of glycopyrrolate, formoterol fumarate dihydrate, or Mometasone furoate-three drugs with different solubilities in the propellant, and different physical, chemical, and pharmacological attributes. The drug microcrystals were added individually, in pairs, or all three together to prepare different cosuspensions, contained in a pressurized metered dose inhaler (pMDI). The drug microcrystals irreversibly associated with the porous particles, and the resultant cosuspensions possessed greatly improved suspension stability compared with suspensions of drug microcrystals alone. In general, all cosuspensions showed efficient dose delivery of the drugs, with fine particle fractions of more than 60% for a wide range of doses, including those as low as 300 ng per inhaler actuation. In the cosuspension pMDIs, comparable fine particle fractions were delivered for all tested drugs, whether or not they were emitted from an inhaler containing one, two, or three drugs. We demonstrate that the cosuspension approach solves at least three long-standing problems in the clinical development of pMDI-based products: (1) dose and drug dependent delivery efficiency, (2) inability to formulate dose strengths below 1 μg to fully explore drug efficacy and safety, and (3) combination suspensions delivering a different fine particle fraction than individual drug suspensions.

Optical Determination of the Temperature of Transparent Microparticles

We present a noncontact temperature-sensing method for microdroplets of water, which relies on temperature dependence of the OH stretching band of the spontaneous Raman spectrum. Temperatures of freely moving evaporating droplets with mean particle diameters of approximately 35 µm have been measured with an accuracy of ±1°C in the range from 10 to 65°C. The method allows the observation of droplet cooling during the initial unsteady phase of evaporation.

ELECTRODYNAMIC TRAPPING AND MANIPULATION OF PARTICLE CLOUDS

Apparatus and techniques were developed to electrodynamically trap and manipulate groups of microparticles. The equipment consists of a vibrating orifice aerosol generator, an inductive particle charger, a plenum chamber, and a double-ring electrodynamic balance. Salt particles (NaNO3) of controllable and measurable mass and charge were produced and introduced into the balance in nitrogen at flow rates up to 25 cm3/min. Ordered arrays of any number of particles up to 26 were assembled and manipulated. Methods for compressing the arrays are presented, and controlled ejection of single particles from a trapped array is demonstrated. Particles of opposite polarity were successfully levitated and kept apart, and aggregation of these particles was then induced by changing the electric field. Raman spectra were recorded for multiple salt particles, each having a diameter of 3.5 μm, by aligning them in a laser beam. The enhanced Raman signal is compared with that from a single particle isolated from the array. F...

The characterization of fine particles originating from an uncharged aerosol: Size dependence and detection limits for Raman analysis

A new experimental method for chemical in situ analysis of ambient aerosol particles is presented. Aerosol particles from the atmosphere with diameters > 1 μm were charged and subsequently captured in an electrodynamic balance. Raman scattering from the particles was excited with an argon ion laser. Raman spectra were taken with a CCD detector through a spectrograph and used to identify chemical substances in the particles. Test particles of sodium sulfate and diethyl sebacate (DES) were employed to determine the detection limit of the method and the size dependence of Raman scattering. The detection limit for sodium sulfate was 0.27 pg, corresponding to a particle diameter of 580 nm. The size-averaged Raman scattering was found to be approximately proportional to volume for particles with diameters > 500 nm using excitation in the visible region.

Linear Raman Spectroscopy on Droplet Chains: A New Experimental Method for the Analysis of Fast Transport Processes and Reactions on Microparticles

A new experimental method for the analysis of mass and energy transport and reactions on microparticles is presented. A chain of microdroplets from a vibrating orifice generator was injected into a quiescent gas phase. Linear Raman spectra from the microparticles and the surrounding gas were taken at different distances from the generator. Concentration changes were measured as a function of droplet lifetime. A period of time of up to 20 ms could be studied with a resolution of 10 μs. An argon-ion laser in a 90° scattering geometry was used for excitation. Spectra were taken through a modified double monochromator with a two-dimensional charge-coupled device (CCD) detector, one axis of which was used for spatial resolution. Profiles of gaseous components near the droplets could be measured with a resolution of 50 μm. The method has been applied to analysis of absorption, dissociation, and isomerization in the SO2–H2O system and to the investigation of the desorption process of CO2 from water droplets. Chemical components in gas and liquid phase could be separated. The detection limit in aqueous media was 1 mmol/L.

Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma.

Pressurized metered dose inhaler is the most common inhaled dosage form, ideally suited for delivering the highly potent compounds that medicinal chemists typically discover for respiratory therapeutic targets. The clinical benefit of combination therapy for asthma and chronic obstructive pulmonary disease has been well established, and many of the new discovery candidates are likely to be studied in the clinic as combination drugs even at early stages of development. We present a novel pressurized metered dose inhaler formulation approach to enable consistent aerosol performance of a respiratory therapeutic whether it is emitted from a single-, double- or triple-therapy product. This should enable rapid nonclinical and clinical assessment whether alone or in combination with other drugs, without the challenge of in vitro performance dissimilarity across product types.

Red-Excitation Dispersive Raman Spectroscopy is a Suitable Technique for Solid-State Analysis of Respirable Pharmaceutical Powders

Dispersive Raman spectroscopy with excitation by a red diode laser is suitable for quantitative crystallinity measurements in powders for pulmonary drug delivery. In spray-dried mixtures of salmon calcitonin and mannitol, all three crystalline polymorphs of mannitol and amorphous mannitol were unambiguously identified and their mass fractions were measured with a limit of quantification of about 5%. The instrument design offered high sensitivity and adequate background suppression, resulting in a low limit of detection in the range of 0.01% to 1%. This spectroscopy method has significant advantages over established techniques regarding specificity, sensitivity, and sample requirements.