Formation of Inhalable Rifampicin–Poly(l-lactide) Microparticles by Supercritical Anti-solvent Process

Abstract

Abstract. Formation of inhalable microparticles containing rifampicin and poly(L-lactide) (L-PLA) by using supercritical anti-solvent process (SAS) was investigated. The solutions of drug and polymer in methylene chloride were sprayed into supercritical carbon dioxide. The effect of polymer content and operating conditions, temperature, pressure, carbon dioxide molar fraction, and concentration of solution, on product characteristics were studied. The prepared microparticles were characterized with respect to their morphology, particle size and size distribution, drug content, drug loading efficiency, and drug release characteristic. Discrete, spherical microparticles were obtained at high polymer:drug ratios of 7:3, 8:2, and 9:1. The shape of L-PLA microparticles became more irregular and agglomerated with decreasing polymer content. Microparticles with polymer content higher than 60% exhibited volumetric mean diameter less than 5 μm, but percent drug loading efficiency was relatively low. Drug-loaded microparticles containing 70% and 80% L-PLA showed a sustainable drug release property without initial burst release. Operating temperature level influenced on mean size and size distribution of microparticles. The operating pressure and carbon dioxide molar fraction in the range investigated were unlikely to have an effect on microparticle formation. An increasing concentration of feed solution provided larger size microparticles. Rifampicin-loaded L-PLA microparticles could be produced by SAS in a size range suitable for dry powder inhaler formulation.

Application of supercritical antisolvent method in drug encapsulation: a review

“…23,60 By decreasing the ratio of the polymer to drug, supercritical fluid is saturated with the drug and the drug loading efficiency will be enhanced. 11 Drug loading in drug encapsulation is explained by the ratio of mass fraction of a nanoencapsulated drug to the total mass of the sample, according to the following equation: 4,9,11,[61][62][63] …”

“…22,33,34,36,38,63,77 Besides, increasing the concentration enhances the viscosity and surface tension of the solution, producing larger droplets; therefore, particles of larger diameter will be formed. 11,27,33,36,52,75,77 Conversely, in some cases, by increasing the concentration, the particle size decreases because the increased initial concentration enhances the maximum supersaturation and, therefore, smaller particle size will be formed. 32,33 Actually, when the initial solution is of a higher concentration, the concentration of the solvent is reduced and then the solvent is removed more easily.…”

“…Thus, the microparticles production process shifts toward the growth process and therefore larger particles would be produced. 11,52 For production of the spherical microparticles, mole fraction of CO 2 must be larger than the mole fraction at which the binary mixture CO 2 -liquid solvent shows the mixture critical point (MCP). Mixture critical point depends on the temperature and the nature of the liquid phase.…”

“…The particle size must be between 1 and 5 µm for inhalation delivery, between 0.1 and 0.3 µm for intravenous delivery, and between 0.1 and 100 µm for oral delivery. 1,4,[10][11][12] Therefore, drug nanoencapsulation becomes crucial in successful drug delivery. The usage of supercritical fluid for the purpose of drug nanoencapsulation is a clean and effective method compared with other techniques.…”

Development of a Novel and Customizable Two-Solution Mixing Type Spray Nozzle for One-Step Preparation of Nanoparticle-Containing Microparticles

“…These droplets are mixed and the drug begins to crystallize and form its core through the "anti-solvent effect," which means the effect of nano-sized drug crystallization by decreasing the solubility after the drug solvent is mixed with other drug-insoluble solvent. [12][13][14] We have previously utilized this nozzle to prepare drug/microparticle formulations for inhalation [6][7][8] as a dry powder and to prepare two-drug composite microparticles 9,11) and microspheres containing polymeric nanoparticles. …”