Elsevier

Powder Technology

Volume 342, 15 January 2019, Pages 642-652
Powder Technology

Development of porous spray-dried inhalable particles using an organic solvent-free technique

https://doi.org/10.1016/j.powtec.2018.10.041Get rights and content

Highlights

  • Development of spray-dried inhalable porous particle without using organic solvents.

  • Cromoglycate porous particles with adequate in vitro aerosolization properties.

  • Appropriate long term stability of porous Cromoglycate inhalable particles.

  • Stable porous Cromoglycate inhalable particles even under mechanical stress.

Abstract

A simple technique to produce spray-dried porous particles for inhalatory administration was developed. The particles were produced using water as solvent, Sodium Cromoglycate as model drug and ammonium bicarbonate as pore forming agent. A central composite design was employed to study the influence of the: pore-forming agent concentration (in the drug aqueous solution fed to the spray dryer) and air inlet temperature on: process yield and powder properties. The powder particle size distribution, moisture content, densities and estimated aerodynamic diameters were studied. Also, particles morphology, hygroscopicity, surface area, in vitro aerosolization properties, dissolution rate and stability were evaluated for some selected samples. In addition, a novel friability test was proposed for mechanical resistance evaluation of the porous materials.

A pore forming agent concentration of 1.25% (w/w) and an air inlet temperature of 170 °C were the optimal process parameters to produce porous particles suitable for inhalatory administration. The process yield was high and it was demonstrated that the particles were free of ammonium bicarbonate. The porous powder, obtained by a simple and scalable technique, exhibited low tap density, good stability even at long storage periods (12 months), appropriate mechanical resistance, high initial dissolution rate and excellent aerosolization performance.

Graphical abstract

Large porous inhalatory spray-dried particles obtained without using organic solvents and employing ammonium bicarbonate as pore forming agent.

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Introduction

The inhalatory route is a therapeutic strategy for treatment of local respiratory diseases (asthma and chronic obstructive pulmonary disease) [1]. The most common devices available for inhalation drug delivery are nebulizers, pressurized metered-dose inhalers and dry powder inhalers (DPIs). Among them, the DPIs have some advantages over other devices: lower production cost because they are propellant free, greater stability of the formulation (dried powder), easier to be transported and administered by the patient [2]. However, the therapeutic success of DPIs faces different technological challenges: i) good dispersion of the particles from the inhaler device, ii) adequate particle deposition in the respiratory tract and iii) low clearance [3]. These requirements are closely related to the particles` size, shape and density [4]. The particles suitable for pulmonary administration are usually very cohesive, basically due to the small sizes required to reach the lung. In fact, the mass median aerodynamic diameter has to be between 0.5 and 3 or 5 μm for systemic or local treatments, respectively [5]. The aerodynamic diameter of a particle is a function of its geometric size and density. Therefore, large porous particles can achieve the required aerodynamic size because the low density balances the relatively big geometrical size. Bigger particles have better dispersibility because the cohesive forces are lower and reduce the risk of phagocytosis due to the increase of the drug residence time in the lungs [6,7]. Then, porous particles are particularly attractive to be targeted to the lung.

The current techniques to produce porous inhalable particles involves a first step of emulsion formulation (containing the drug, pore forming agents, polymeric carrier and solvents) and a second stage of evaporation of the emulsion phases [8]. The methodologies that include these main formulation steps can be grouped into the following technologies: single (w/o) and multiple emulsions (w/o/w) [[9], [10], [11], [12]], precision particle production [13], antisolvent high electrostatic voltage [14] and supercritical fluid processes [15,16]. Among them, the multiple emulsion strategy is the most used technique, which requires several raw materials and production stages. The emulsion is formed by: a) a dispersed aqueous phase containing the drug, a pore forming agent and a surfactant, b) an organic continuous phase formed by a polymer dissolved in methylene chloride and an emulsifier, and c) an external aqueous phase holding the mentioned phases emulsified by homogenization. The formed emulsion is stirred to evaporate the organic solvent, in consequence porous are produced in the particles. Finally, the particles are separated by centrifugation, washed and water is removed by lyophilization or spray drying [17].

Another option to produce porous inhalable particles implies the spray drying of hydro-alcoholic solutions (e.g., water/ethanol or water/methanol) containing the drug with and without a pore forming agent (e.g., ammonium bicarbonate) and excipients to improve the powdered product dispersibility (e.g., leucine) [6,18,19]. The rapid evaporation of the organic solvent and the decomposition of the pore forming agent during the drying of the atomized droplets contributes to the production of porous particles. For example, ammonium bicarbonate decomposes in carbon dioxide and ammonia gas bubbles when the temperature is raised up to 36 °C. These gases can increase the internal pressure within the droplet to finally be released producing pores within the particles [20].

Summarizing, for the currently techniques, the production of porous inhalable particles involves the formulation of a liquid sample (i.e.,w/o/w emulsions or hydro-alcoholic solutions) and the subsequent evaporation of solvents. In general, spray drying is the most widely used process for solvent evaporation because allows to produce particles in the inhalable size range and also is a rapid, continuous, reproducible, cost-effective and scalable technology [21]. However, an appropriate design of porous inhalable particles by spray drying requires finding the adequate liquid sample formulation and the operating conditions.

In this work Sodium Cromoglycate (SC), an antiasthmatic and antiallergenic drug usually used in inhalation therapy, was selected as a model drug to produce porous inhalable particles. For a DPI commercial formulation of SC (i.e., 20 mg micronized powder per capsule) is reported that only between 5 and 15% of the dose is absorbed from the respiratory tract. The remaining fraction is exhaled or deposited in the oropharynx, swallowed and eliminated via the gastrointestinal tract. The velocity of absorption in the lung is lower than the velocity of elimination, thus the SC absorption is limited by its elimination half-time (about 90150 min). Due to the low respirable fraction and the high drug elimination rate, the recommended dosage for pulmonary SC administration is four to eight intakes daily [22]. It is well known that the use of large porous particles (LPPs) has the following advantages: reduces the particles aggregation tendency, improve the aerosolization performance and decrease the risk of phagocytosis increasing the drug residence time in the lung [7,8,23,24]. In this sense, Nolan et al. [25] found an optimum liquid feed composition for the production of SC porous inhalable particles by spray drying. The inlet feed was a water:methanol:n-butyl acetate mixture (1:15:15, v/v) and the obtained powder presented higher respirable fraction than the micronized drug. Dellamary et al. [26] produced SC spray-dried porous particles (Platform PulmoSpheres®) with geometric diameters smaller than 5 μm and low density of 0.06 g/cm3. However, the preparation of such particles implies a complex emulsion technique that requires organics solvents, various compounds and several steps of formulation. Although the quality of these products is widely recognized, to our best knowledge, the production of porous inhalable particles containing SC and without using organic solvents was not previously studied. In this context, the aim of this work is the production of spray-dried porous particles for inhalatory administration of SC based on a simple technique without using organic solvents. To this end, the influence of the concentration of the pore forming agent in an aqueous feed solution and the spray drying operating conditions on the powder quality were studied by means of a central composite experimental design. The product yield, particles' size, moisture content, densities and estimated aerodynamic diameter were evaluated. For some selected particulate systems, the properties: hygroscopicity, surface area, in vitro deposition, dissolution rate and stability were also assessed. In addition, to study the mechanical resistance of the porous particles (i.e., friability) a novel measurement method was developed.

Section snippets

Materials

The following materials were used as received from the supplier: crystalline SC (99.57% purity), size 2 gelatine capsules, spectroscopic grade potassium bromide (Parafarm, Saporiti, Buenos Aires, Argentina), ammonium bicarbonate, silica gel (Cicarelli, Buenos Aires, Argentina) and glycerin (Anedra, Buenos Aires, Argentina). Sieved DC-lactose monohydrate (Parafarm, Saporiti, Buenos Aires, Argentina) with particle sizes between 77 and 451 μm was also employed. Distilled water was used for the

Response surface analysis

For all the tested process parameters, the PYs were between approximately 67 and 76% (Table 1), which are high values for a lab-scale spray dryer [21]. The statistical analysis showed that the air inlet temperature (X1) and the pore forming agent concentration (X2) in the aqueous feed solution did not significantly affect the PY. The ANOVA test showed a not significant model for the PY as a function of the studied factors (p = 0.1130), in fact the R2 value was low (0.66).

Regarding the moisture

Conclusions

Very porous inhalatory SC spray-dried powders were obtained by using ammonium bicarbonate as pore forming agent and water as solvent. The spray drying process conditions: atomization air flowrate = 600 l/h, feed flowrate = 6 ml/min, drying air flowrate = 35 m3/h, air inlet temperature = 170 °C, SC content = 1% (w/w) and pore forming agent concentration n = 1.25% (w/w) allowed to produce relatively large porous particles with: high product yield, low tap density, good stability even at long

Acknowledgements

The authors express their gratitude for the financial support granted by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), the Universidad Nacional del Sur (UNS) and the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT). The authors thank Lic. F. Cabrera (PLAPIQUI) for her technical assistance.

Loreana Gallo is a practical applications teacher of the Department of Biology, Biochemistry, Pharmacy at Universidad Nacional del Sur and a Scientific Researcher of CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina). She received her B·S degree from the same university and the Ph. D. degree from Universidad Nacional de Córdoba (Córdoba, Argentina). She held a postdoctoral research fellow position at the University of Salento, Lecce, Italy. Her research interests

References (54)

  • M.M. Arnold et al.

    NanoCipro encapsulation in monodisperse large porous PLGA microparticles

    J. Control. Release

    (2007)
  • D.S. Dhanda et al.

    Supercritical fluid technology based large porous celecoxib-PLGA microparticles do not induce pulmonary fibrosis and sustain drug delivery and efficacy for several weeks following a single dose

    J. Control. Release

    (2013)
  • A.M. Healy et al.

    Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide

    Eur. J. Pharm. Biopharm.

    (2008)
  • L.M. Nolan et al.

    Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

    Eur. J. Pharm. Sci.

    (2009)
  • L. Cruz et al.

    Formulation and in vivo evaluation of sodium alendronate spray-dried microparticles intended for lung delivery

    J. Control. Release

    (2011)
  • R. Sun et al.

    Preparation and characterization of hollow hydroxyapatite microspheres by spray drying method

    Mater. Sci. Eng. C

    (2009)
  • A. Sosnik et al.

    Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers

    Adv. Colloid Interf. Sci.

    (2015)
  • L.M. Nolan et al.

    Particle engineering of materials for oral inhalation by dry powder inhalers. II - Sodium cromoglicate

    Int. J. Pharm.

    (2011)
  • L. Gallo et al.

    Influence of spray-drying operating conditions on Rhamnus purshiana (Cáscara sagrada) extract powder physical properties

    Powder Technol.

    (2011)
  • T.C. Kha et al.

    Microencapsulation of Gac oil: optimisation of spray drying conditions using response surface methodology

    Powder Technol.

    (2014)
  • S.P. Tan et al.

    Effects of the spray-drying temperatures on the physiochemical properties of an encapsulated bitter melon aqueous extract powder

    Powder Technol.

    (2015)
  • R. Salama et al.

    Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics

    Eur. J. Pharm. Biopharm.

    (2008)
  • F. Palazzo et al.

    Development of a spray-drying method for the formulation of respirable microparticles containing ofloxacin-palladium complex

    Int. J. Pharm.

    (2013)
  • L. Gallo et al.

    A comparative study of spray-dried medicinal plant aqueous extracts. drying performance and product quality

    Chem. Eng. Res. Des.

    (2015)
  • D. Lamešić et al.

    Spherical agglomerates of lactose with enhanced mechanical properties

    Int. J. Pharm.

    (2017)
  • J.S.G. Cox et al.

    Solid-state chemistry of cromolyn sodium (disodium cromoglycate)

    J. Pharm. Sci.

    (1971)
  • N.Y.K. Chew et al.

    Effect of particle size, air flow and inhaler device on the aerosolisation of disodium cromoglycate powders

    Int. J. Pharm.

    (2000)
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    Loreana Gallo is a practical applications teacher of the Department of Biology, Biochemistry, Pharmacy at Universidad Nacional del Sur and a Scientific Researcher of CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina). She received her B·S degree from the same university and the Ph. D. degree from Universidad Nacional de Córdoba (Córdoba, Argentina). She held a postdoctoral research fellow position at the University of Salento, Lecce, Italy. Her research interests are based on the use of spray-drying technology to generate powders from medicinal plants extracts and inhalable particles with improved aerosolization properties, particularly mucoadhesive and porous ones.

    M. Verónica Ramírez-Rigo is a professor of the Department of Biology, Biochemistry, Pharmacy at Universidad Nacional del Sur and a Scientific Researcher of CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina). Dipl.-Pharmaceutics and Ph. D. in Chemical Science, Universidad Nacional de Córdoba (Córdoba, Argentina). She held a postdoctoral research fellow position at the University of Texas, Austin, USA. Research Interests: Pharmaceutical materials and processing, Drug delivery.

    Verónica Bucalá is professor of chemical engineering at Universidad Nacional del Sur (Bahía Blanca, Argentina) and a Scientific Researcher in CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina). She received her B.S. and Ph. D. degrees in chemical engineering from the same university. She held a postdoctoral research fellow position at Massachusetts Institute of Technology, Cambridge, USA. Her research interests are in the area of particle technology, particularly applied to pharmaceutical, fertilizer and food industries.

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