Information Bulletin Number 59/2010
Laboratory Scale Spray Drying Of Inhalable Drugs:
A Review

Mini Spray Dryer B�290
Figure 1: Mini Spray Dryer B-290 The Mini Spray Dryer B-290 from Büchi a compact spray dryer. The residence The adjustable process parameters Labortechnik AG is a laboratory scale time of the drying air within the spray instrument to perform spray drying chamber is about 1.5 seconds. The processes down to 30 mL batch volume powder col ection is provided by a • inlet and outlet temperature, and up to 1 litre of water or organic glass-made cyclone separator, which • sample feed rate, solvent per hour. Thanks to the glass- is internal y coated with a thin nanosize • drying gas flow rate and ware, the complete drying process antistatic film to reduce powder • spray gas flow from the two-fluid nozzle down to the adhesion to the glass wall. The powder col ection vessel is visible.
separation works by centrifugal forces Fine particles are produced because by virtue of inertia of the solid of the short residence time in such Features and benefits
Mini Spray Dryer B-290
Main benefit
for traditional spray drying, established process Max. inlet temperature
1.0 kg/h, higher for solvents Nozzle types
two-fluid nozzle, three-fluid nozzle typical y around 50% - 70% Min. sample volume
Max. sample viscosity
300 cps (viscous samples and juices possible) possible to scale-up to kg- and tons-scale Table 1: Features and benefits of the Mini Spray Dryer B-290

Nano Spray Dryer B�90
Figure 2: Nano Spray Dryer B-90 The new Nano Spray Dryer B-90 is The liquid sample is fed to the spray membrane to vibrate, ejecting mil ions based on a new spray drying concept. nozzle via a peristaltic pump in a re- of precisely sized droplets per second The drying gas enters the apparatus circulation mode. with a very narrow distribution. These from the top where it is heated to the set The generation of droplets is based on extremely fine droplets are dried inlet temperature, flows then through a piezoelectric driven actuator, vibrating into solid particles and col ected by the drying chamber, and exits the spray a thin, perforated, stainless steel electrostatic charging and subsequent dryer at the bottom outlet. The gas is membrane in a small spray cap. The deflection to the collecting electrode. additional y fine filtered before leaving the membrane (spray mesh) features an Final y the resulting powder is col ected instrument. The inlet temperature and array of precise, micron-sized holes using a rubber spatula. outlet temperature are measured just (4.0, 5.5 or 7.0 μm). The actuator is after the heater and before the fine filter. driven at around 60 kHz, causing the Features and benefits
Nano Spray Dryer B-90
Main benefit
for small quantities, finest particles, highest yields Max. inlet temperature
Nozzle type
piezoelectric driven vibrating mesh electrostatic particle col ector Min. sample volume
Max. sample viscosity
10 cps (diluted samples) limited by spray head and electrical particle col ector Table 2: Features and benefits of the Nano Spray Dryer B-90 Laboratory Scale Spray Drying Of Inhalable Drugs: A Review
Author: Dr. Cordin Arpagaus, Dr. Nina [3, 4]. It has the potential to generate particles, based on the available RDD Schafroth and Marco Meuri highly dispersible powders for inhalation online proceedings database. The liter- in the range from 1 to 5 μm size with a ature review showed breakthrough R&D particle morphology that can more eas- innovations in the field of respiratory The pharmaceutical industry addresses ily be influenced compared to for exam- drug delivery with key information about a number of demands on novel respira- ple jet mil ing [5].
available spray drying parameters and ble particulates, which from a process technology perspective can be broadly This study reports a review, regarding Spray drying applications focused categorized into the areas of: perfor- research work on particles for inhalation especial y on anti-asthmatic drugs mance (e.g. total/local lung deposition, that have been published in the RDD [2, 5-9], antibiotics [1, 9-12], proteins, immediate versus controlled release), proceedings database, using laboratory such as insulin [13-15], bovine serum processing (e.g. achieve flow properties) scale Büchi Mini Spray Dryer models albumin [16] or human serum albumin and stability (e.g. physical/chemical sta- B-190, B-191 and B-290 [17], antibodies [18] and tuberculosis bility and activity).
A new trend in pulmonary drug delivery Literature Review Various excipients were applied to is to move from the liquid or pressurised stabilize drugs during formulation, formulations to dry powder inhalation A search query in the RDD online data- predominately mannitol [13, 14, 17, 18, formulations. This, in part, is due to the base with the key word "spray drying" 20], poly(lactic-co-glycolic-acid) PLGA advantages of dry powder systems, in- revealed 53 hits. Figure 3 visualizes the [8, 10, 19, 21], lactose [5, 8, 16] and cluding breath-actuated inhalation, lim- distribution of these published papers chitosan [7]. SEM photographs of ited coordination requirements, no pro- over the last several years. It seems the spray dried powders exhibited pel ant requirement and short treatment that the ful potential of the spray drying mostly spherical shapes with corrugated process for dry powder aerosols has surfaces, resin-like or even hol ow Spray drying is a simple, rapid, repro- not been ful y exploited yet. Spray structures, depending on the sub- ducible, economic and easy to scale-up drying has become a well established stance material and drying conditions production process [2] that has been in- technology in pulmonary drug delivery.
(Table 3A and 3B). tensively studied for pharmaceuticals The produced particles were in the respi- and excipients for pulmonary drug de- Table 3A and 3B reviews the spray rable size range with roughly 1 - 5 μm livery in dry powder inhalation systems drying research with regard to inhalable aerodynamic diameters. High fine parti- online database

ber of abstracts
ord "spray drying" 4
ith keyw
published in R
Figure 3: Number of abstracts published in the RDD online database (, visited January 8, 2010) with key word "spray drying" (total 53 abstracts) Particle size, shape,
Carrier and
Spray drying
yield, fine particle
Reference and
fraction (FPF) and
emitted dose (ED)
Spherical particles Cook et al. 2004 sulphate
University of London Matrix forming exipients throat impaction 23.9 % Dryer B-191 School of Pharmacy, UK 4% w/w terbutaline 1 - 15 μm particle size Terbutaline
Learoyd et al. 2006a sulphate
6-36% w/w leucine and gas spray 600 L/min Aston University, 25-50% w/w chitosan Hol ow to porous Salbutamol
particles, reduced phosphatidylcholine, Brandes et al. 2004 sulphate
agglomeration tendency Mini Spray Christian Albrecht compared to jet-mil ed calcium chloride University, Germany powders, 40% drug dihydrate, Solkane 227 Spherical particles Salbutamol
Learoyd et al. 2006b PLGA, beclomethasone sulphate
spray gas 600 L/min Aston University, dipropionate, PVA, feed rate 3.2 mL/min Dryer B-290 Birmingham, UK Spherical particles Weiler et al. 2008 Salbutamol
3.2 μm , FPF around Johannes Gutenberg- sulphate
Lactose monohydrate 70 %, dispersion University Mainz, Boehringer Ingelheim, Cabral Marques and Spherical particles University of Lisbon, feed rate 5 - 11 mL/min Raisin-like particles Hydrochloric acid, Cagnani et al. 2004 T in < 140 °C sodium hydroxide, University of Parma, respirable particles polyalcohols, mannitol Particle diameter < 5.8 μm Najafabadi et al. 2007 sponge-like morphology Aqueous solution of University of Medical T out 62 - 65°C suitable for respiratory insulin and additives Sciences, Tehran, Iran spray gas 550 NL/h (mannitol, polymer) Pasteur Institute of Iran, feed rate 3 mL/min ED 59 - 81% dispersability 57 - 60 % Drying air humidity <20% Maltensen and van de Aqueous solution T in 75 - 220°C Resin-like morphology spray gas 7 - 17 L/min particle size of 4 μm University of Copenhagen, feed rate 2 - 5 mL/min suitable for inhalation aspirator 80 - 100% Spherical to corrugated Gentamicin
shape particles of Lechuga-Ballesteros et al. Gentamicin with small amounts of trileucine Nektar Therapeutics, USA Table 3A: Literature review of spray dried inhalable products using the laboratory scale Büchi Mini Spray Dryer models B-190, B-191 and B-290. "Part 1" Particle size, shape,
Carrier and
Spray drying
yield, fine particle
Reference and
fraction (FPF) and
emitted dose (ED)
Traini et al. 2007 Corrugated particles University of Sydney, Monash University, Victoria, Australia Bain et al. 2002 Quintiles (UK) Ltd, Rifampicin
Spherical particles Poly(D,L-lactide) (PDLLA) University of Strathclyde, Glasgow, Scotland John Moores University, Liverpool, England Cefotaxime
Spherical particles Najafabadi et al. 2005 University of Medical T out 87 - 89 °C better aerolisation Sciences, Tehran, Iran compared to jet mil ing Spherical particles with Tobramycin
corrugated surfaces Parlati et al. 2008 0.25 - 2.0 % sample < 3.0 μm size yield 60 % University of Sydney, in vitro drug deposition Corrugated particles Bovine Serum
Lactose / Brij 76 5.4 / 12.8 μm size Li and Sevil e 2008 Aston University, recovery of drug after spray gas 600 L/h inhalation >95 % Schüle et al. 2004 No change in secondary Mini Spray University of Munich, spray gas 670 L/h proteins structure Dryer B-290 Boehringer Ingelheim, feed rate 3 mL/min Protein/mannitol ratio Zimontkowski et al. 2005 (antibody) and
Spherical particles University of Bonn, Human Serum
spray gas 700 L/h Boehringer Ingelheim, feed rate 9 mL/min Garcia-Contreras et al. Proteins secreted Poly
1.95 μm particle size (lactic-co-glycolic acid) feed rate 7 ml/min University of North activity > 93 % Spherical particles Lysozyme
200 mL solutions of 5 μm particle size Shoyele et al. 2008 (enzyme for
University of Bradford, UK T out 50 ± 2°C 3M Drug Delivery spray gas 500 L/h phosphate buffer 12 weeks storage feed rate 5 mL/min 66% retained enzymatic Mean size 4 - 10 μm Colombo et al. 2008 Morphine
concentration of morphine satisfactory morphine University of Parma spray gas 600 L/h HCl, mannitol and lecithin stability in agglomerated Dryer B-191 University of Salerno feed rate 3.2 mL/min University of Ferrara, Italy Mannitol
concentrations up Morton et al. 2008 Mannitol with 1 - 10% to 35 ppm in air Monash University, w/w different additives feed rate 0.1 mL/s mean particle size Victoria, Australia Table 3B: Literature review of spray dried inhalable products using the laboratory scale Büchi Mini Spray Dryer models B-190, B-191 and B-290. "Part 2"

cle fractions were achieved, ranging sulphate nanoparticles (an anti-asthma- acting inhaled drug particles (about from 30 - 60% [6-8, 16] to over 85% tic drug) into microparticles [2]. 0.5 - 3.3 μm which represents [13]. Inhaler emitted powder doses of Physically and chemically stable deposition in the lung alveoli). over 90% were reported [2, 7, 8]. Amor- non-cohesive spray dried particles, The key benefits of this technology are phous powders were typical y generated with smal aerodynamic diameters the possibilities to control the size and due to the short drying time in the labo- were designed to be efficiently delivered morphology of the particles under a ratory scale spray dryers [3, 22]. Aero- as a dry powder aerosol [11]. Spray relatively gentle processing method. solized powder clouds with maximal drying produced powders with superior Indeed, this method has been proven volume concentrations of up to 35 ppm biochemical stability upon formulation for the preparation of heat-sensitive particles in air were achieved [20]. compared to spray freeze drying; materials such as protein based drugs.
Cefotaxime sodium (Bain et al. 2002) (Cagnani et al. 2004) (Najafabadi et al. 2005) (Traini et al. 2007) (Brandes et al. 2004) (Cook et al. 2004) (Learoyd et al. 2004) (Weiler et al. 2008) Figure 3: SEM photographs of inhalable spray dried powder from literature. Compared to jet mil ed samples, higher although with less efficient aerosol While the traditional bench-top spray fractions of potential y inhalable aerosol properties [24]. Sustained release of dryers have been shown capable particles of antibiotic cefotaxime highly dispersible amino acid leucine tools for the laboratory aim generation sodium were measured for spray dried incorporated PLGA powders was of respiratory sized particles, the area formulations [23]. Deagglomeration exhibited over several days [8].
of process technology is ever-evolving. of spray dried protein formulations The Nano Spray Dryer B-90 offers new was possible [17]. Higher powder possibilities in the field of laboratory dispersibility of spray dried powders scale spray drying and eliminates compared to jet mil ed particles was Spray drying is a very useful technique some weak points of traditional spray explained by their spherical shape to produce inhalable dry powders with dryers; including increased recovery and therefore smaller surface contact predetermined specifications. There (up to 90%), smal quantity production is significant research activity in dry (100 mg amounts) and highly definable powder aerosol formulation to treat particle size ranges (300 nm - 5 μm) [25].
Particularly, high values of respirable several diseases including asthma, fractions were found for insulin because tuberculosis, diabetes and bacterial of the spray dried particle size [13]. The infection in the lung. Spray drying offers capability for inhalation with relatively great potential to these applications high drug loading was shown, for because of the easy achievement of the example by incorporation of terbutaline accepted optimum size range for local y [10] Bain, D. F. et al. (2002), formulations for spray drying", "Biodegradable microspheres for RDD 4 , 377-380.
[1] Parlati, C. et al. (2008), "In vitro control ed intra-pulmonal delivery of evaluation of co-processed antibiotic Rifampicin to treat tuberculosis", [19] Garcia-Contreras, L. et al. (2004), for inhalation", RDD, 907-910.
RDD 8, 561-563.
"Formulation strategies for a novel inhaled tuberculosis vaccine", [2] Cook, R. O. et al. (2004), "Sustained [11] Lechuga-Bal esteros, D. et al. RDD 4, 877-880.
release microparticles containing (2004), "Designing stable and high drug nanoparticles for pulmonary performance respirable particles of [20] Morton, D.A.V. et al. (2008), administration", RDD 4, 777-780.
pharmaceuticals", RDD IX, 565-568.
"Investigating Effects of Surface modifications on an Mannitol Dry [3] Dem, C. et al. (2006), [12] Traini, D. et al. (2007), "Co-spray Powder Inhaler Plume by Laser "Understanding the spray dry design dried antibiotics for dry powder Diffraction", RDD, 649-653.
process through single droplet inhalation delivery", RDD Europe, investigations", RDD, 257-265.
[21] Arpagaus, C. and Schafroth, N. (2009), "Laboratory scale spray [4] Hickey, A.J. et al. (1996), [13] Cagnani, S. et al. (2004), "A novel drying of biodegradable polymers", Pharmaceutical inhalation aerosol spray dried formulation for RDD Europe 2009, 269-274.
technology, Marcel Dekker, pulmonary administration of Insulin", RDD 4, 813-816.
[22] Colombo, P. et al. (2006), "Nasal powders of morphine microcrystal [5] Weiler, C. et al. (2008), "Dispersibility [14] Najafabadi, A.R. et al. (2007), "The agglomerates", RDD, 885-887. of jet mil ed vs. spray dried powders ", effect of polymer on the properties RDD Europe, 571-575.
of insulin/mannitol spray dried [23] Najafabadi, A.R. et al. (2005), powder for inhalation", RDD Europe, "Evaluation of cefotaxime sodium [6] Brandes, H.G. et al. (2004), microparticles for respiratory drug "Particle design to improve delivery", RDD Europe, 265-268.
pulmonary delivery of powdered [15] Maltesen, M.J. and Van de Weert, medications," RDD 4, 229-231.
M. (2008), "Particle size of spray [24] Shoyele, A.S. et al. (2008), "A dried insulin evaluated by NIR comparative study on the bio- [7] Learoyd, T.P. et al. (2006a), spectroscopy", RDD, 827-830.
chemical stability and pharmaceutical "Sustained drug delivery from performance of excipient-free chitosan-based respirable spray- [16] Li, H.Y. and Sevil e, P.C. (2008), spray dried and spray freeze dried dried powders ", RDD, 441-444.
"Preparation of pMDI protein protein pMDIs", RDD, 823-826.
formulations using surfactant- [8] Learoyd, T.P. et al. (2006b), coated spray dried powders", RDD, [25] Schmid, K. et al. (2009), "Leucine-modified PLGA-based "Evaluation of a vibrating mesh respirable spray-dried powders for spray dryer for preparation of sustained drug delivery", RDD, [17] Zimontkowski, S. et al. (2005), submicron particles", RDD Europe, "Dispersion characteristics of spray dried protein powder formulations [9] Cabral Marques, H. M. and Almeida assessed by laser diffraction and Coimbra, R. N. M. A. (2009), SEM", RDD Europe, 273-276.
"Preparation and in vitro evaluation of cyclodextrin/beclomethasone [18] Schüle, S. et al. (2004), complexes as dry powder inhaler "Determination of the secondary formulations", RDD Europe, 413-417.
protein structure of IgG1 Antibody BÜCHI Labortechnik AG
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