Impact of Leucine and Magnesium Stearate on the Physicochemical Properties and Aerosolization Behavior of Wet Milled Inhalable Ibuprofen Microparticles for Developing Dry Powder Inhaler Formulation

Shahjabeen Sharif; Saiqa Muneer; Emad L Izake; Nazrul Islam

doi:10.3390/pharmaceutics15020674

Impact of Leucine and Magnesium Stearate on the Physicochemical Properties and Aerosolization Behavior of Wet Milled Inhalable Ibuprofen Microparticles for Developing Dry Powder Inhaler Formulation

Pharmaceutics. 2023 Feb 16;15(2):674. doi: 10.3390/pharmaceutics15020674.

Authors

Shahjabeen Sharif¹, Saiqa Muneer², Emad L Izake², Nazrul Islam^{1

3}

Affiliations

¹ Pharmacy Discipline, School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4000, Australia.
² School of Chemistry and Physics, Science and Engineering Faculty, Queensland University of Technology, Brisbane, QLD 4000, Australia.
³ Centre for Immunology and Infection Control (CIIC), Queensland University of Technology, Brisbane, QLD 4000, Australia.

Abstract

This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and TGA. Using a Twin-Stage Impinger (TSI), the in vitro aerosolization of the formulations with and without carrier lactose was studied at a flow rate of 60± 5 L/min and the IBF was determined using a validated HPLC method. The flow properties were determined by the Carr's Index (CI), Hausner Ratio (HR) and Angle of Repose (AR) of the milled IBF with 4-6.25% leucine and leucine containing formulations showed higher flow property than those of formulations without leucine. The fine particle fraction (FPF) of IBF from the prepared formulations was significantly (p = 0.000278) higher (37.1 ± 3.8%) compared to the original drug (FPF 3.7 ± 0.9%) owing to the presence of leucine, which enhanced the aerosolization of the milled IBF particles. Using quantitative phase analysis, the XPRD data revealed the crystallinity and accurate weight percentages of the milled IBF in the formulations. FTIR revealed no changes of the structural integrity of the milled IBF in presence of leucine or MgSt. The presence of 2.5% MgSt in the selected formulations produced the highest solubility (252.8 ± 0.6 µg/mL) of IBF compared to that of unmilled IBF (147.4 ± 1.6 µg/mL). The drug dissolution from all formulations containing 4-6.25% leucine showed 12.2-18.6% drug release in 2.5 min; however, 100% IBF dissolution occurred in 2 h whereas around 50% original and dry milled IBF dissolved in 2 h. The results indicated the successful preparation of inhalable IBF microparticles by the wet milling method and the developed DPI formulations with enhanced aerosolization and solubility due to the presence of leucine may be considered as future IBF formulations for inhalation.

Keywords: DPI formulations; Twin-Stage Impinger (TSI); aerosolization; dissolution; fine particle fraction; ibuprofen wet milling homogenization; leucine; saturated solubility.

Grants and funding

This research received no external funding.