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Particle Surface Roughness Improves Colloidal Stability of Pressurized Pharmaceutical Suspensions

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Abstract

Purpose

The effects of particle size and particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were investigated using monodisperse spray-dried particles.

Methods

The colloidal stability of multiple suspensions in the propellant HFA227ea was characterized using a shadowgraphic imaging technique and quantitatively compared using an instability index. Model suspensions of monodisperse spray-dried trehalose particles of narrow distributions (GSD < 1.2) and different sizes (MMAD = 5.98 μm, 10.1 μm, 15.5 μm) were measured first to study the dependence of colloidal stability on particle size. Particles with different surface rugosity were then designed by adding different fractions of trileucine, a shell former, and their suspension stability measured to further study the effects of surface roughness on the colloidal stability of pressurized suspensions.

Results

The colloidal stability significantly improved (p < 0.001) from the suspension with 15.5 μm-particles to the suspension with 5.98 μm-particles as quantified by the decreased instability index from 0.63 ± 0.04 to 0.07 ± 0.01, demonstrating a strongly size-dependent colloidal stability. No significant improvement of suspension stability (p > 0.1) was observed at low trileucine fraction at 0.4 % where particles remained relatively smooth until the surface rugosity of the particles was improved by the higher trileucine fractions at 1.0 % and 5.0 %, which was indicated by the substantially decreased instability index from 0.27 ± 0.02 for the suspensions with trehalose model particles to 0.18 ± 0.01 (p < 0.01) and 0.03 ± 0.01 (p < 0.002) respectively.

Conclusions

Surface modification of particles by adding shell formers like trileucine to the feed solutions of spray drying was demonstrated to be a promising method of improving the colloidal stability of pharmaceutical suspensions in pressurized metered dose inhalers.

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Acknowledgments and Disclosures

The authors acknowledge financial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Alberta Ingenuity Fund and the Canadian Foundation for Innovation (CFI). Hui Wang gratefully acknowledges the scholarship support of Alberta Innovates and Alberta Advanced Education.

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Authors and Affiliations

  1. Department of Mechanical Engineering, 10-269 Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, Alberta, T6G 1H9, Canada

    Hui Wang, David S. Nobes & Reinhard Vehring

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  1. Hui Wang
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Correspondence to Reinhard Vehring.

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Appendix

Appendix

The Brunauer-Emmett-Teller (BET) Method

According to the BET Eq. 11,

$$ \frac{1}{m\left(\frac{P_0}{P}-1\right)}=\frac{C-1}{m_0C}\left(\frac{P}{P_0}\right)+\frac{1}{m_0C} $$
(11)

where m is the weight of adsorbed gas at a relative pressure P/P0, m0 is the weight of adsorbate constituting a monolayer of surface coverage for each unit mass of sample, and C is the BET constant that is indicative of the adsorbate-adsorbent interaction energy, the krypton adsorption isotherm is plotted as \( 1/m\left(\frac{P_0}{P}-1\right) \) against P/P0, leading to a linearized BET plot shown in Appendix Fig. 15. From Eq.(11), the slope, s, and intercept, i, of the plot can be obtained as:

$$ s=\frac{C-1}{m_0C} $$
(12)

and

$$ i=\frac{1}{m_0C} $$
(13)

The weight of adsorbate gas for a monolayer coverage can therefore be calculated by combining Eqs. (12) and (13) that:

$$ {m}_0=\frac{1}{s+i} $$
(14)

and the BET constant is:

$$ C=1+\frac{s}{i} $$
(15)

Specific surface area of the tested sample, S, can therefore be determined as:

$$ S=\frac{m_0{N}_{\mathrm{A}}{A}_{\mathrm{cr}}}{M_{\mathrm{Kr}}} $$
(16)

in which NA is the Avogadro’s constant, Acr and MKr is the cross-sectional area of a single adsorbate gas molecule and the gas molecular weight respectively. Listed in Appendix Table IV is the measured data and calculated results.

Table IV Data Used for the Determination of Particle Specific Surface Area and BET Constant
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Fig. 15
figure 15

Linear region of the krypton adsorption isotherm used for the determination of specific surface area and BET constant

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Morphology of Particles Extracted from the Propellant

Fig. 16
figure 16

Images of particles extracted from the propellant showing no significant changes of morphology

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Wang, H., Nobes, D.S. & Vehring, R. Particle Surface Roughness Improves Colloidal Stability of Pressurized Pharmaceutical Suspensions. Pharm Res 36, 43 (2019). https://doi.org/10.1007/s11095-019-2572-0

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