A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery

Abstract

The present study evaluates the effect of L-leucine concentration and operating parameters of a laboratory spray dryer on characteristics of trehalose dry powders, with the goal of optimizing production of these powders for inhaled drug delivery. Trehalose/L-leucine mixtures were spray dried from aqueous solution using a laboratory spray dryer. A factorial design of experiment (DoE) was undertaken and process parameters adjusted were: inlet temperature, gas flow rate, feed solution flow rate (pump setting), aspiration setting and L-leucine concentration. Resulting powders were characterised in terms of particle size, yield, residual moisture content, and glass transition temperature. Particle size was mainly influenced by gas flow rate, whereas product yield and residual moisture content were found to be primarily affected by inlet temperature and spray solution feed rate respectively. Interactions between a number of different process parameters were elucidated, as were relationships between different responses. The leucine mass ratio influenced the physical stability of powders against environmental humidity, and a high leucine concentration (30% w/w) protected amorphous trehalose from moisture induced crystallization. High weight ratio of leucine in the formulation, however, negatively impacted the aerosol performance. Thus, in terms of L-leucine inclusion in a formulation designed for pulmonary delivery, a balance needs to be found between physical stability and deposition characteristics.

Keywords: DPI; Design of experiments; Dry powder for inhalation; Leucine; Pulmonary formulation; Spray drying; Trehalose.

Fig. 1.

Bar plots showing F-value and associated p-value determining statistical significance of the main effects and interactions for the response: A, d₅₀; B, d₉₀; C, yield; D, RMC; E, T_out. Only terms with p-values equal to or less than 0.05 were plotted. *, p<0.0001; **, p<0.001; §, p<0.005; §§, p<0.05. Factors: (A), T_in; (B), airflow rate; (C), pump setting; (D), aspiration setting; (E), LL concentration.

Fig.2.

Response surface plots showing the effects of the two main parameters having the greatest influence on the given response.

Fig.3.

Volumetric particle size distribution of formulations: A) TFD22; B) TFD8 and C) TFD17. d₅₀, d₉₀, d₁₀ and span values are shown in table 1s.

Fig.4.

SEM micrographs of: A) formulation TFD22 (10% LL concentration); B) formulation TFD8 (20% LL concentration); C) TFD 17 (30% LL concentration)

Fig. 5.

Relationships between: A) RMC and yield, B) yield and T_out; C) yield and d₅₀; D) RMC and yield; E) T_out and RMC; F) T_g and RMC.

Fig.6.

Water vapor sorption and desorption isotherms of formulations: A) TFD22; B) TFD8 and C) TFD17. Solid line: sorption isotherm; dotted line: desorption isotherm.

Fig. 7.

XRPD diffractograms of formulations TFD22 pre (A) and post (A’) DVS analysis; TFD8 pre (B) and post (B’) DVS analysis and TFD17 pre (C) and post (C’) DVS analysis.

Fig.8.

Cumulative mass deposition percentage, A, and NGI stage mass deposition profile, B, of formulations TFD8, TFD17 and TFD22. MOC: micro-orifice collector