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Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps 6 7

Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol

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Q1

Waseem Kaialy a,⇑, Ali Nokhodchi b a b

School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK

a r t i c l e

i n f o

Article history: Received 15 October 2014 Received in revised form 1 December 2014 Accepted 2 December 2014 Available online xxxx Keywords: Dry powder inhaler Fine particle fraction Freeze-dried mannitol Homogeneity Overall desirability Particle size

a b s t r a c t The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., freeze-dried mannitol (FDM). FDM was prepared and sieved into four size fractions. FDMs were then characterized in terms of micromeritic, solid-state and bulk properties. Dry powder inhaler (DPI) formulations were prepared using salbutamol sulphate (SS) and then evaluated in terms of drug content homogeneity and in vitro aerosolization performance. The results showed that the crystalline state of mannitol was maintained following freeze-drying for all size fractions of FDM. All FDM particles showed elongated morphology and contained mixtures of a-, b- and d-mannitol. In comparison to small FDM particles, FDMs with larger particle sizes demonstrated narrower size distributions, higher bulk and tap densities, lower porosities and better flowability. Regardless of particle size, all FDMs generated a significantly higher (2.2–2.9-fold increase) fine particle fraction (FPF, 37.5 ± 0.9%–48.6 ± 2.8%) of SS in comparison to commercial mannitol. The FPFs of SS were related to the shape descriptors of FDM particles; however, FPFs did not prove quantitative apparent relationships with either particle size or powder bulk descriptors. Large FDM particles were more favourable than smaller particles because they produced DPI formulations with better flowability, better drug content homogeneity, lower amounts of the drug depositing on the throat and contained lower fine-particlemannitol. Optimized stable DPI formulations with superior physicochemical and pharmaceutical properties can be achieved using larger particles of freeze-dried mannitol (FDM). Ó 2014 Published by Elsevier B.V.

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Abbreviations: ANOVA, one way analysis of variance; CI, Carr’s compressibility index; CL, commercial lactose; CM, commercial mannitol; Copt, optical concentration; CV, coefficient of variation; Dae, theoretical aerodynamic diameter; D10%, particle size at 10% volume distribution; D50%, particle size at 50% volume distribution (median diameter); D90%, particle size at 90% volume distribution; Dequi, equivalent diameter; DPI, dry powder inhaler; DSC, differential scanning calorimetery; ER, elongation ratio; FDM, freeze-dried mannitol; FPD, fine particle dose; FPF, fine particle fraction; FPM, fine particle mannitol; FR, flakiness ratio; FTIR, Fourier transform infrared; GSD, geometric standard deviation; HSD, Honestly Significant Difference; I + M, inhaler with mouthpiece adaptor; IP, induction port; MMAD, mass median aerodynamic diameter; MSLI, Multi-Stage Liquid Impinger; OD, overall desirability; PSD, particle size distributions; PXRD, powder X-ray Diffraction; r2, correlation coefficient; RD, recovered dose; RH, relative humidity; SD, standard deviation; SEM, scanning electron microscopy; SM, supplementary material; SS, salbutamol sulphate; TSE, transmissible spongiform encephalopathy; USP, United States Pharmacopeia; VMD, volume mean diameter; Yi, the actual observed values; Ymax, the maximum acceptable values; Ymin, the minimum acceptable values. ⇑ Corresponding author. Tel.: +44 1902 321139. E-mail addresses: [email protected], [email protected] (W. Kaialy).

1. Introduction

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Pulmonary drug delivery is one of the most ancient and successful methods of drug delivery systems (Washington et al., 1989). This delivery route is globally expected to grow to a reasonable market size of around $44 billion by 2016 (Nagavarapu, 2012), which contributes to its popularity within the pharmaceutical world. Good inhalation performance requires many characteristics such as stability, ease of processing, reproducibility and availability at the site of action. Particle deposition in the respiratory tract is affected by many physical properties of the aerosol such as size, shape, density and flowability (Telko and Hickey, 2005). Dry powder inhalers (DPIs) are delivery devices that have been introduced in the 1970s. These dosage forms are stable, friendly to the environment, easy to formulate and cost-effective (Borgström et al., 2002). However, the relatively high variation in dose delivery was one disadvantage associated with DPIs that may lead to

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Please cite this article in press as: Kaialy, W., Nokhodchi, A. Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.12.005

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significant dose uniformity problems (Cegla, 2004). In addition, DPIs demonstrated low efficiency of drug delivery to the lower airway regions (Islam and Cleary, 2012). High drug-carrier adhesive forces and the consequent inadequate separation (drug re-dispersion) was one of the most important explanations for poor drug deposition efficiency of DPI formulations (Zhou and Morton, 2012). DPI performance is essentially affected by particle–particle interactions (Xu et al., 2011). Therefore, engineered drug (Muhammad et al., 2013) and/or engineered carrier (Kaialy et al., 2012a) particles have been used to improve DPI performance. Recently, mannitol with promising aerosolization performance from a DPI was engineered by freeze-drying (Kaialy and Nokhodchi, 2013a). Freeze-drying process, also known as lyophilisation, is a particle-engineering technical procedure that encompasses three distinctive stages after the pre-treatment step, i.e., freezing, primary drying and secondary drying. In general, the procedure works by freezing the sample material, followed by reduction of the surrounding atmospheric pressure. This permits the frozen water in the product to sublimate directly from its solidstate to the gaseous state without liquid phase transition (Mellor, 1978). Several process and formulation factors should be optimized during the application of freeze-drying technique in order to insure stability of active ingredients (Carpenter et al., 1997). Sublimation is an endothermic process and therefore energy has to be supplied, by the heat transfer fluid in the channels within the shelves, in order to sustain the sublimation rate. The temperature of the shelf has to be maintained below the glass transition temperature (or ‘collapse temperature’) of the sublimate in order to avoid the formulation of amorphous (glassy) phase during freeze-drying (Adams and Ramsay, 1996). Lactose is recognized as the excipient of choice for pulmonary delivery (Kou et al., 2012; Pilcer et al., 2012). However, lactose has some disadvantages when it is used as excipient for DPIs. For example, lactose is incompatible with drugs that have a primary amine group (e.g. budesonide and formoterol) and therefore it is less suitable for the next generation of inhalable products (e.g. proteins and peptides) (Patton and Platz, 1992). Lactose may demonstrate unpredictable physicochemical properties during pharmaceutical processing (Steckel et al., 2006). Moreover, lactose may carry a potential risk of transmissible spongiform encephalopathy (TSE) because it may be produced with traces of biovine (EC Statement, 2002). Therefore, engineering alternative carriers for DPI formulations appears to be scientifically warranted. Mannitol is a polyol broadly used in freeze-drying (Al-Hussein and Gieseler, 2012). Unlike lactose, mannitol does not have a reducing effect, and furthermore, it displays desirable properties for DPI formulations such as high crystallinity, non-hygroscopicity, excellent mechanical properties and chemically inert nature (D’Addio et al., 2013). Particle size is an important design variable of DPI formulations. Several researchers highlighted that the presence of fine carrier particles had a positive influence on DPI performance (Jones and Price, 2006; Kaialy and Nokhodchi, 2013b). The mechanism by which fine particle excipients improve the performance of drugcarrier DPI formulations remains speculative; nevertheless, several Q2 hypotheses have been suggested including the active-sites theory (e.g. Zeng et al., 1998), agglomeration theory (e.g. Louey and Stewart, 2002), fluidisation theory (e.g. Shur et al., 2008) and buffer hypothesis (e.g. Dickhoff et al., 2006). However, caution should be kept in mind on the development of the latter formulations since the long-term safety of fine excipient particles is not established yet, which may induce concerns among regulatory authorities (Jones and Price, 2006; Chan and Chew, 2003). Inhaled fine carrier particles may lead to annoyance, irritation, coughing and even bronchoconstriction (Karhu et al., 2000). Inhaled fine mannitol could increase bronchial hyperresponsiveness (Rademacher et al., 2013). Therefore, we believe that preparing engineered carrier

particles that would enhance the performance of drug-carrier binary DPI formulations without the use of a ternary additive of fine carrier is significantly justified. To this end, aerodynamically light powders of freeze-dried mannitol were prepared and the influence of physicochemical properties of freeze-dried mannitol on the performance of a DPI was investigated.

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2. Materials and methods

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2.1. Materials

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Commercial mannitol (CM) was purchased from Fisher Scientific, UK. Micronized salbutamol sulphate (SS, D10% = 0.5 ± 0.0 lm, D50% = 1.7 ± 0.1 lm, D90% = 3.1 ± 0.3 lm, SM–1)) was supplied from LB Bohle, Germany. Commercial lactose (CL, Pharmatose 100 M) was obtained from DMV International, Netherlands. Methanol (Fisher Scientific, UK) and 1-heptane sulfonic acid sodium salt (Sigma–Aldrich, Chemical Co., USA) used for HPLC experiments were obtained from the named sources.

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2.2. Preparation of freeze-dried mannitols in different size fractions

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Mannitol (5%, w/v in distilled water) was freeze-dried (SCANVAC CoolSafe™ freeze-dryer, CoolSafe 110-4, Lynge, Denmark) and then sieved (vibratory mechanical shaker, Endecotts Ltd, England) in different size fractions. The bulk fluffy FDM powder (the yield was >99% w/w) was poured above 125 lm sieve that was placed on top of different sieves (RetschÒ Gmbh Test Sieve, Germany) with smaller aperture sizes above each other as follows: 90 lm, 63 lm, 45 lm, 20 lm and a metal collection plate. The mechanical shaker was tightened closely and then operated for 15 min. When the sieving process was complete, particles with different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm), were collected and stored in sealed glass vials in laboratory (22 °C, 50% RH) until required. The sieved FDMs were stored for at least 7 days before further analyses to allow any possible charge relaxation to occur. The commercial mannitol (CM) and commercial lactose (CL) were as well sieved to separate the 63–90 lm fractions. The physicochemical properties of the sieved CM (Kaialy and Nokhodchi, 2013b) and CL (Kaialy and Nokhodchi, 2012b) were described previously.

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2.3. Particle size measurements

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Sieving is a rough method in determining particle size because it does not give exact measurements of any dimension of the particle. Therefore, volume-weighted particle size analysis of all mannitols was conducted using a Sympatec HELOS/RODOS (Clausthal-Zellerfeld, Germany) laser diffraction particle size analyser. The dispersion of air pressure was adjusted to 2.0-bar and a feed rate of 50% was applied. The particle size distributions (PSDs), i.e., particle size at 10% (D10%), 50% (D50%, median diameter), 90% (D90%) of the volume distribution and volume mean diameter (VMD) (mean ± SD, n = 9), were all calculated automatically using the WINDOX software based on Fraunhofer theory. Approximately 1 g of each powder was hand-fed into the VIBRI RODOS disperser through a funnel placed above the u-shaped groove of the rotating table. The sample container was cautiously tapped against the funnel to make sure the material was flowing through the vibrating chute into the groove of the rotary table. A background measurement was taken as the reference test. The measurements were set to trigger when the optical concentration (Copt) was higher than 1.1% and to end when the Copt fell below 1% for 5 s. The timebase was 100 ms and the obstruction was 10–30%. The span

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(calculated from Eq. (1)) of the volume distribution was used as a measure of the width of the distribution of size relative to the median diameter.

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Span ¼

D90%  D10% D50%

ð1Þ

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2.4. Image analysis optical microscopy

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Laser diffraction does not take into account apparent particle density and dynamic shape factors. Therefore, quantitative number-weighted particle size and shape analyses were conducted using a computerized morphometric image analyzing system, i.e., Leica DMLA Microscope; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany; Leica Q Win Standard Analyzing Software. For each mannitol product, a small amount of powder (20 mg) was homogeneously dispersed on a microscope slide to form a thin powder, and then a minimum of 1000 particles were detected randomly from different positions and measured. Particle size and shape were quantified using subjective descriptors including the equivalent diameter (Dequi), elongation ratio (ER, Eq. (2)) and flakiness ratio (FR, Eq. (3)).

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Length Elongation ration ¼ Breadth

ð2Þ

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Breadth Flakiness ratio ¼ Thickness

ð3Þ

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where ‘length’ is the longest Feret diameter, ‘breadth’ is the shortest Feret diameter (maximum and minimum Feret diameters were calculated from 16 calliper measurements at 6° intervals around the particle), ‘thickness’ is Feret diameter in the 90° direction and Dequi is the equivalent circle diameter derived from area measurements.

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2.5. Scanning electron microscopic observations

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Elongation ratio and flakiness ratio measurements are function of the particle orientation and contact area with other particles, thus they may not necessarily be sufficient to evaluate particle shape of different mannitols. Therefore, all mannitol samples were characterized by scanning electron microscopy (SEM). Scanning electron micrographs of mannitol samples and SS–mannitol formulations were obtained using a field emission scanning electron microscope (SEM, HITACHI SU 8030, Japan) operating at an acceleration voltage of 0.5 kV and a probe current of 10 lA. A sputter coating apparatus (Edwards S 150B, 12 nm layer thickness) was applied under vacuüm with chromium in an argon atmosphere to increase the electric conductivity on the surface of the samples. The specimens were sprinkled gently on aluminium pin stubs (G301, Agar Scientific Ltd, Essex, England) with double-sided adhesive carbon tabs (G3347N, Agar Scientific, Essex, England). Different magnifications were used to observe the size, shape and surface morphology of different mannitols. SEM images were attained with extreme care to ascertain their representativeness.

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2.6. Helium pycnometry

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True density of all mannitols (defined as particle mass divided by its volume excluding both open pores and closed pores) was measured using Ultrapycnometer 1000 (Quantachrom, USA) under helium gas. The input gas pressure was 20 psi and the equilibrium time was 1 min. The sample volume was calibrated with a calibration sphere (Quantachrome Corp.) and then determined from the difference in pressure when a defined volume of helium gas was introduced into the sample-chamber. The mean of three

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3

determinations of each sample was recorded with a run standard deviation of 0.05%.

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2.7. Differential scanning calorimetry

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A differential scanning calorimeter (DSC822e, Mettler Toledo, Switzerland) was used to characterise the solid-state of different mannitols. An accurately weighed sample of each mannitol powder (4–5 mg) was placed in a crimped 40-lL aluminium DSC pan and sealed non-hermetically. Each sample was heated from 25 °C to 300 °C at a ramp rate of 30 °C/min. An empty aluminium pan was used as a reference. The equipment was calibrated using pure indium. A purge gas of nitrogen was passed over the pans with a flow rate of 50 mL/min. The temperature and enthalpies readings were calculated by the software (Mettler, Switzerland) by integrating the transition areas associated and normalizing the weight of each sample.

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2.8. Fourier transform infrared spectroscopy

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All mannitols were analysed using a SPECTRUM-ONE Fourier transform infrared (FT-IR, PerkinElmer, Massachusetts, USA) spectrometer, at a scanning range between 650 and 4000 cm1 with a 1 cm1 resolution. A sample of each mannitol (few milligrams) was placed on the middle of the sample stage and a force was applied (50 arbitrary units of the device’s pressure meter) by twisting the top of the arm of the sample stage clockwise to make the necessary contact to yield a characteristic spectrum. After obtaining sharp peaks with reasonable intensities, the spectra acquired were the results of averaging four scans.

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2.9. Powder X-ray diffraction

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The powder X-ray diffraction (PXRD) patterns of all mannitols were collected on a Siemens DIFFRACplus 5000 powder diffractometer with Cu Ka radiation (1.54056 Å). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for illumination on the 20 mm area on the sample. Each sample was scanned from 5° to 40° 2h, with a step size of 0.02° at 2 step/s. The sample stage was spun at 30 rpm. The instrument was pre-calibrated using a silicon standard. Estimated quantitative mannitol crystal form analysis (% a-, % b- and % d-mannitol, mean ± SD, n = 4) were performed by Rietveld refinement using Topas v4 (Bruker) and Cif structural models obtained from the Cambridge Structural Database. The reproducibility of the obtained diffraction patterns was ascertained by analysing four different samples from each mannitol.

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2.10. Water content

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Moisture content for each mannitol product was determined by Karl–Fisher titration method (Metter Toledo, C20 Coulometric KF Titrator, Switzerland). Following equilibration of the instrument, samples (20 mg) were added rapidly into the titrator vessel. The Fischer reagent solution (HydranalÒ Coulomat AF, Sigma– Aldrich, USA) was standardized with a known amount of water. Each sample was titrated five times.

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2.11. Characterization of bulk properties of freeze-dried mannitol powders

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Bulk density, tap (effective) density and porosity (Eq. (4)) of each mannitol powder were measured as important descriptors of powder bulk cohesive properties. Mannitol samples were gently poured into a measuring cylinder using a glass funnel. After

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recording of the bulk volume, the cylinder was tapped 200 times (22 °C, 50% RH) and then the tap volume was recorded. No significant additional reduction in the powder volume was attained when more than 200 taps were applied. Tap density was calculated as powder weight over powder tap volume. The Carr’s compressibility index (CI, Eq. (5)) was calculated as an indication of powder flowability, and defined as the percentage change in volume of constant mass of powder as a result of tapping.

Poosity ¼



1



Bulk density  100 Tue density

  Tap density Bilk density  100 CI ¼ TAp density

ð4Þ

ð5Þ

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Based on the obtained CI values, powder flowability was described as good (CI: 12–18%), fair (CI: 18–21%) or poor (CI: 23–28%). Each sample was analysed five times.

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2.12. Preparation of DPI formulations

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Each mannitol powder (2 g) was blended with SS powder at a constant ratio of mannitol: SS 67.5:1 (w/w), which was the same ratio used in commercially available Ventolin RotacapsÒ. This blending was performed in cylindrical aluminium container (6.5  8 cm) using a TurbulaÒ mixer (Maschinenfabrik, Basel Switzerland) at a constant speed of 100 rpm for 30 min. Once prepared, all formulations were stored in tightly sealed glass vials until used.

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2.13. HPLC quantification of salbutamol sulphate

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device (sourced from Novartis, Switzerland and supplied by Vectura, UK) and Multi-Stage Liquid Impinger (MSLI, apparatus 4 in pharmacopoeia) equipped with a USP induction port (IP, Copley Scientific, Nottingham, UK). AerolizerÒ was selected as a model inhaler because it is extensively used in the market and is relatively less efficient than many of the newly developed devices in terms of drug dispersion. A flow rate that corresponds to a pressure drop of 4 kPa across the device (92 L/min, flow meter: Copley Scientific Ltd., Nottingham, UK) was used. At this flow rate, the effective cut-off diameters of stage 1, 2, 3 and 4 of the MSLI become 10.50 lm, 5.49 lm, 2.50 lm and 1.37 lm respectively. Ten capsules were aerosolized for the deposition experiment of each formulation. Four deposition experiments were carried out for each formulation. The fine particle dose (FPD) was defined as the amounts of SS with aerodynamic size less 65 lm. The recovered dose (RD) was the total amounts of SS recovered from the inhaler device with its fitted mouthpiece adaptor, induction port and all stages of the impactor. The fine particle fraction (FPF) was defined as the percentage of FPD to RD. The mass median aerodynamic diameter (MMAD) was calculated as the 50th percentile of the aerodynamic % cumulative particle size distribution by mass plotted on log probability paper. The geometric standard deviation (GSD) was calculated as the square root of the ratio of particle size at the 84.13th percentile to the 15.87th percentile. Mass distribution profiles of the SS were expressed as percentages to RD. Theoretical aerodynamic diameter (Dae, Eq. (6)) was estimated according to the geometrical mean particle diameter (based on volume, VMD) and particle tap density (q) (Bosquillon et al., 2004).

 12 q Dae ¼ VMD

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ð6Þ

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Salbutamol sulphate (SS) was analysed using HPLC method (Waters, USA). A mixture of methanol and 0.25% (w/v) 1-heptane sulfonic acid sodium salt (45:55 v/v) was used as the mobile phase. The flow rate of the mobile phase was 2 mL/min and the assay wavelength was 200 nm. The HPLC system consisted of a pump (CM4000 Multiple Solvent Delivery System, LDC Analytical Inc., FL, USA), a multiple wavelength UV detector (SpectroMonitor 3100, LDC Analytical Inc., FL, USA) and a 25 cm  4.6 mm i.d. column packed with 5 lm Novapack C18 (Waters, Milford, MA, USA). The retention time for salbutamol sulphate was 3.2 min and the limits of detection and quantification were 0.10 and 0.23 lg/mL respectively. The calibration curve of SS was linear (r2 = 0.9989) over the concentration range 5–500 lg/100 mL.

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2.14. Drug homogeneity assessment

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After blending, ten randomly selected samples were taken from different spots of each formulation powder for the quantification of SS content. Each sample weighed 27.5 ± 0.5 mg (which is equivalent to a unit dose of SS, 400 lg, in accordance with Ventolin RotacapsÒ) and was dissolved in 100 mL distilled water in a volumetric flask. For each formulation, % potency was calculated as the percent amount of SS to the nominal dose, whereas the degree of SS content homogeneity was expressed in terms of percent coefficient of variation (% CV). Drug content is considered uniform when % CV is below 6% (Tee et al., 2000).

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2.15. In vitro aerosolization study

2.16. Statistical analysis

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After blending, each formulation was manually filled into hard gelatine capsules (size 3) with 27.5 ± 0.5 mg formulation powder. Prior to investigation, the filled capsules were stored in sealed glass vials for at least 48 h (to allow possible charge-relaxation). Deposition profiles of all formulations were assessed in vitro (airconditioned laboratory, 22 °C, 50% RH) using an AerolizerÒ inhaler

One way analysis of variance (ANOVA) test was applied to compare mean results in this study considering P values less than 0.05 as indicative of significant difference. When appropriate and when ANOVA indicated significant difference, Tukey’s Honestly Significant Difference (HSD) test was performed. The data were expressed as the mean ± standard deviation (SD).

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q1

where q1 = 1 g/cm3. To perform a quantitative comparison of different formulations simultaneously, a desirability function (di) was defined as follows.

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Y i  Y min di ¼ Y max  Y min

ð7Þ

where Yi, Ymax, and Ymin are the actual observed, the maximum acceptable and the minimum acceptable values for the response variable respectively. A good DPI formulation is required to demonstrate maximal deposition on the lower airway regions (high % FPF), good drug content homogeneity (low % CV, essential to achieve uniform metering doses by the patient), good flow properties (low % CI, essential for handling, dose metering, fluidization and processing on an industrial scale) and low content of fine ( 0.05) (Table 4). As the volume mean diameter of FDM particles increased, bulk density (r2 = 0.9212) and tap density (r2 = 0.9103) of FDM powders increased, whereas porosity (r2 = 0.9004) and CI (r2 = 0.8976) of FDM powders decreased (Table 4, SM–6). This indicated that decreasing the size of FDM particles was accompanied by increased cohesive properties of FDM powders and ‘step-wise’ decreases in flowability. Additionally, the slightly lower true densities for small FDM particles in comparison to large FDM particles could contribute to their relatively poorer flow properties, because the effect of gravity will be lower for the former particles (SM–7).

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3.5. Evaluation of SS:FDM formulations

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3.5.1. Homogeneity In pulmonary drug delivery, the high variability in drug content could be more worrying than the low efficiency (Pauwels et al., 1997). Therefore, the homogeneity of all DPI formulations under investigated was evaluated. The potency of SS content within formulations ranged between 88.0 ± 3.9% and 110.2 ± 11.6% (Fig. 4), which fell within the acceptable range of 85–115% (USP criteria), suggesting that the overall blending, sampling and analyses were reasonably accurate and reproducible. The formulation containing CL demonstrated inhomogeneous drug content (CV: 9.9% (Fig. 4), which could be due to the relatively high degree of drug–drug agglomeration (Kaialy and Nokhodchi, 2013b). Nevertheless, the blending process was not altered in order to meet the purpose of

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Table 3 Water content (mean ± SD, n > 4) and polymorphic form for commercial mannitol (CM) and freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90– 125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm). Physicochemical property

Water content (%) Polymorphic form

CM

0.2 ± 0.0 b-

Freeze-dried mannitol product FDM-A

FDM-B

FDM-C

FDM-D

0.3 ± 0.0 a- + b- + d-

0.4 ± 0.1 a- + b- + d-

0.7 ± 0.2 a- + b- + d-

0.9 ± 0.2 a- + b- + d-

Fig. 3. Powder X-ray Diffraction (PXRD) patterns (a), % crystal form (b) and relationship between % d-mannitol content (determined by PXRD) and melting enthalpy of dmannitol (determined by DSC) (c) for commercial mannitol (CM) and freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63– 90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm).

Table 4 True density, bulk density, tap density, porosity, Carr’s index (CI), flow character (mean ± SD, n > 3) for commercial mannitol (CM) and freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm). Physicochemical property

True density (g/cm3) Bulk density (g/cm3) Tap density (g/cm3) Porosity (%) CI (%) Flow

CM

1.52 ± 0.02 0.54 ± 0.01 0.63 ± 0.01 63.9 ± 0.9 17.7 ± 1.7 Good

Freeze-dried mannitol product FDM-A

FDM-B

FDM-C

FDM-D

1.54 ± 0.02 0.24 ± 0.01 0.31 ± 0.02 84.3 ± 0.5 17.7 ± 1.4 Good

1.47 ± 0.01 0.19 ± 0.01 0.26 ± 0.01 86.9 ± 0.8 24.5 ± 3.4 Poor

1.45 ± 0.01 0.08 ± 0.00 0.11 ± 0.00 94.6 ± 0.5 26.0 ± 0.8 Poor

1.42 ± 0.03 0.09 ± 0.00 0.12 ± 0.00 93.7 ± 0.4 27.5 ± 1.7 Poor

Please cite this article in press as: Kaialy, W., Nokhodchi, A. Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.12.005

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Fig. 4. % potency ( ) and % coefficient of variation (d, CV) for dry powder inhaler (DPI) formulations composed of salbutamol sulphate (SS) blended with commercial lactose (CL), commercial mannitol (CM) and freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm). Freeze-dried mannitol particles with a smaller particle size generated formulations with poorer drug content homogeneity.

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this study, i.e., comparing all formulation blends under investigation under similar protocol. Unlike FDM-D (coefficient of variation, CV: 6.9%), FDM-A, FDM-B and FDM-C produced ordered-DPI formulations with a CV 6 6% (ranging from 2.2% to 5.8%) (Fig. 4), with large FDM particles producing lower variations in SS content in comparison to smaller particles (Fig. 4). This could be attributed to the better distribution of drug particle on the surface of large FDM particles in comparison to small FDM particles due to their relatively narrower size distributions (Table 1) and better flow properties (Table 4). The % CV of drug content produced linear relationships when plotted against CI (r2 = 0.8953) or span (r2 = 0.8875) of FDMs (SM–8), demonstrating that SS:FDM formulations containing FDMs with better flowability (as indicated by lower CI) or lower span

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of particle size distribution demonstrated relatively lower variations in drug content (as indicated by lower CV). Such results could be explained as follows. The efficiency of blending is deeply affected by the flow properties of the powder components. Depending on particle size of the FDM product, free flowing (non-cohesive) or non-free flowing (cohesive) mixtures will be formed. Large FDM particles (FDM-A) demonstrated a good flow character (Table 4) and thus SS:FDM-A mixture could be potentially described as a free flowing mixture. Such mixtures are favorable in terms of minimal need of lubricant and good homogeneity. On the other hand, SS:FDM-D could be described as cohesive mixture due to the poor flowability of FDM-D product (Table 4). Such mixtures are characterized by non-free flowing properties and ‘stick–slip’ characteristics (Deveswaran et al., 2009). Additionally, good mass distribution of particle size (low span) is important because it relates directly to the uniformity of the dose. Small FDM particles have a relatively higher polydispersity of size (higher span value) (Table 1) and lower bulk density (Table 4) than large particles, thus could contain different amounts of absorbed drug per unit mass due to possible induced ‘percolation’ segregation concurrently with powder consolidation (Twitchell, 2013). Consequently, drug-rich areas may form within formulations containing small FDM particles surrounded by small congregates of drug particles. In addition, large FDM particles can be weighed more reproducibly than small particles due to their higher bulk density (Table 4). Furthermore, as small FDM particles produced powders with increased cohesive properties (Table 4), some the energy introduced during the blending process might be expended in breaking up the FDM–FDM particle agglomerates rather than SS–SS agglomerates within the SS:FDM formulations. A good DPI ordered mixture should be homogenous (low % CV) to ensure uniform metered doses and thus therapeutic effect during aerosol delivery. Additionally to homogeneity, a good DPI ordered mixture should easily separate into its primary components (drug and carrier) during aerosolization. Therefore, in vitro aerosolization performance of all SS:mannitol formulations were evaluated.

Fig. 5. Scanning electron microscope (SEM) images for dry powder inhaler (DPI) formulations composed of salbutamol sulphate (SS) blended with freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm).

Please cite this article in press as: Kaialy, W., Nokhodchi, A. Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.12.005

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3.5.2. Comparative in vitro aerosolization studies DPI formulations were depicted as interactive unites consisting of small SS particles adhered to FDM carrier particles (Fig. 5). Mass distribution profiles of SS deposited on the capsule shells, inhaler with mouthpiece adaptor (I + M) and throat (IP) are shown in Fig. 6a. All mannitols deposited similar (P > 0.05) amounts of SS on capsules (drug residue, 1.6 ± 0.7%–3.0 ± 1.3%) and on the inhaler with mouthpiece adaptor (I + M, 3.9 ± 1.0%–5.5 ± 1.5%) (Fig. 6a). Such low amount of drug residue suggested the dispersible nature of all mannitols, which is advantageous in term of efficiency and economy standpoint, and minimizes the potential for possible local side effects. In comparison to CL and CM, all FDMs deposited higher amounts of drug on the throat (IP) (Fig. 6a). Direct linear relationship (r2 = 0.9531) was established indicating that mannitols with a higher porosity deposited higher amounts of drug on the throat (Fig. 6a). This could be due to the small size and poor flowability of FDMs with increased porosity (Tables 1 and 4), thus interparticle forces between SS:FDM particles will potentially be higher leading to the formation of aggregates depositing on the 90 °C blend of the throat (IP) upon aerosolization. The adrenoreceptors exist in high concentrations in the small airways, thus the target site of SS (b2 agonist) is mostly in the lower airways (Hensley et al., 1978). In comparison to CL and CM, all FDMs produced higher fine particle fractions (FPF: 19.9 ± 1.0% (CL); 16.8 ± 1.3% (CM) versus 37.5 ± 0.9%–48.6 ± 1.4% (FDMs)) of SS (Fig. 6b), and higher amounts of SS with aerodynamic size 610.5 lm, 65.5 lm, 62.5 lm and 61.4 lm (SM–9), indicating their

Fig. 6. Amounts of salbutamol sulphate (SS, % recovered dose) deposited on capsules, inhaler + mouthpiece adaptor (I + M) and induction port (IP); % SS deposited on IP VS porosity of mannitol carrier (a); fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of SS (b) for dry powder inhaler (DPI) formulations composed of SS blended with commercial lactose (CL), commercial mannitol (CM) or freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45–63 lm) and FDM-D (20–45 lm) (mean ± SD, n = 4).

better inhalation behavior. Such improvement could be due to the more elongated particle shape (ER: 2.20–2.79 versus 1.87) (Table 2) and more porous powder of FDMs (porosity: 84.3–94.6%) in comparison to CL (porosity: 59.8 ± 2.3%) and CM (porosity: 63.9%) (Table 4), leading to unstable interparticle contact area and thus enhanced deaggregation properties upon aerosolization. FDM particles have irregular morphologies and therefore SS particles adhering to the microscopic projections of FDM particles (Fig. 5) could have reduced SS–FDM interactive forces (e.g. van der Waals forces) leading to easier SS detachment upon aerosolization (Heng et al., 2000). Moreover, in comparison to CL (Kaialy and Nokhodchi, 2012b) and CM, FDM particles were more aerodynamically light as indicated by their small bulk and tap densities (Table 4). For example, despite that FDM-A (VMD: 113.0 ± 1.2 lm) had a larger physical geometric size than CL (VMD: 91.1 ± 0.3 lm) and CM (VMD: 94.8 ± 4.6 lm) (Table 1, Fig. 1a and b), FDM-A had a smaller theoretical aerodynamic size (62.9 ± 1.1 lm) than both CL (79.4 ± 0.4 lm) and CM (75.0 ± 4.2 lm). Additionally, the elongated shape and low bulk density of FDM particles give them more ability to stay airborne in the airflow in comparison to CL or CM particles, and therefore drug particles may have more ability to detach from their surfaces during aerosolization and thus travel further into the lower airways. All formulations demonstrated a statistically similar GSD (2.1 ± 0.1, P > 0.05) indicating a polydispersed distribution of particle size of the aerosolized drug (GSD > 1.2). Linear relationships were obtained when plotting FPF of SS against the elongation ratio (direct, r2 = 0.9714) and flakiness ratio (indirect, r2 = 0.9305) of FDM (Fig. 7). This concurs with a previous study which showed that (to a cretin limit, elongation ratio of 4.8) the FPF of SS increased as the elongation ratio of carrier particles increased (Kaialy et al., 2011). In fact, when the flat region on carrier surface increases, a higher degree of drug-drug agglomeration and drugcarrier adhesion could be expected (Iida et al., 2003). In comparison to FDM-A particles, despite that smaller FDM particles (FDM-B, FDM-C and FDM-D) contained slightly higher amount of fine particulates (FPM SS:FDMB > SS:FDM-C > SS:FDM-D (Fig. 8). This suggested that FDM particles with a larger mean diameter generated formulations with higher overall desirability (Fig. 8). Future studies should be directed to engineer stable carrier particles that will produce desirable inhalation performance of several drugs from several DPI devices both in vitro and in vivo without necessarily adding fine excipient to the DPI system.

Fig. 7. Fine particle fraction (FPF) of salbutamol sulphate (mean ± SD, n = 4) VS elongation ratio (ER) and flakiness ratio (FR) of freeze-dried mannitol (FDM, mean ± SE, n > 1000).

Please cite this article in press as: Kaialy, W., Nokhodchi, A. Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.12.005

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Fig. 8. Overall desirability (OD) for dry powder inhaler (DPI) formulations composed of salbutamol sulphate (SS) blended with freeze-dried mannitol products sieved to different size fractions, i.e., FDM-A (90–125 lm), FDM-B (63–90 lm), FDM-C (45– 63 lm) and FDM-D (20–45 lm) and relationship between OD and volume mean diameter (VMD) of freeze-dried mannitol particles. The overall desirability of DPI formulations increased with the mean diameter of freeze-dried mannitol. 714

3.6. Conclusion and outlook

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All size fractions of freeze-dried mannitol powders demonstrated promising aerosolization performance from a dry powder inhaler due to their low density and elongated particle shape. The use of smaller freeze-dried mannitol particles did not generate a higher fine particle fraction of drug upon aerosolization. In comparison to smaller particles, larger freeze-dried mannitol particles produced formulations with a higher desirability because of their better flowability, better drug content homogeneity, lower fineparticle-mannitol content, in addition to lower amounts of drug deposited on the throat and slightly lower content of surface (free) moisture. The complete understanding of the relationships between carrier physicochemical properties and DPI performance remains challenging because the relative importance of different factors influencing DPI performance remains uncertain. Nevertheless, it can be suggested that the poor aerosolization performance is a not a property inherent to the large size of carrier particles. The use of formulations containing carriers with increased amount of fine particles might not always be effective to generate better dispersion of drug from dry powder inhalers. The use of aerodynamically light large freeze-dried mannitol particles could play an important role in the design and development of dry powder inhalation formulations that would generate superior performance without considering the addition of fine particle additive to the formulation. Future opportunities for application of freeze-drying in the preparation of pharmaceutical dry powder inhaler formulations should be considered. This study was conducted using a low-pressure drop inhaler device, and therefore future studies should consider high-pressure drop inhaler devices. Additionally, batch-to-batch reproducibility studies should be conducted to ensure reproducible aerodynamic properties of the mannitol particles engineered in this study. Future studies may also consider the determination of dynamic shape factors in terms of the settling velocity of a single freeze-dried mannitol particle.

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Acknowledgement

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Waseem Kaialy thanks the University of Wolverhampton for providing ERAS grant.

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Appendix A. Supplementary material

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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejps.2014.12.005.

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Dry powder inhalers: physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol.

The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., ...
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