Amino acids as stabilizers for spray-dried simvastatin powder for inhalation

Background

The use of amino acids as excipients is a promising approach to improve the physical stability and powder dispersibility of spray-dried powders for inhalation.

Objectives

The aim of this study was to investigate the stabilizing effect of different amino acids on spray-dried amorphous powders for inhalation using simvastatin (SV) as a model compound.

Methods

Two hydrophobic amino acids (leucine, LEU and tryptophan, TRP), and one hydrophilic amino acid (lysine, LYS) were spray dried from 1% (w/v) solutions with SV at a molar ratio of 1:1 into dry powders for inhalation. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the morphology, solid form and potential intermolecular interactions of the spray-dried powders. X-ray photoelectron spectroscopy (XPS) was used to analyse the chemical composition of the surface of the particles. The physical stability of the dry powders was examined upon storage in controlled conditions. A next-generation impactor (NGI) was applied to assess the in vitro aerosol performance of the powders.

Results

XRPD and DSC results confirmed that the spray-dried SV-LEU was composed of crystalline LEU and amorphous SV, the spray-dried SV-LYS was co-amorphous, and the spray-dried SV-TRP was an amorphous system with two phases. XPS analyses revealed that the surface of the spray-dried SV-LEU particles were LEU rich, indicating surface-enrichment of LEU in these particles. In contrast, an almost even distribution of TRP and SV at the surface of spray-dried SV-TRP was observed. FTIR results indicated no intermolecular interaction between SV and the amino acids used in the present study. The three spray-dried samples were physically stable after eight months storage in a desiccator (12% RH, ca. 22 °C). Nevertheless, spray-dried SV-LEU exhibited the best storage stability as compared to the other two spray-dried samples when the samples were stored at 60% RH, 25 °C. Both, the spray-dried SV-LEU and SV-TRP exhibited higher fine particle fractions than the spray-dried SV-LYS.

Conclusion

Both the spray-dried SV-LEU and SV-TRP exhibited better aerosol performance and storage stability compared to the spray-dried SV-LYS. Compared to TRP, LEU exhibited better protection of spray-dried amorphous SV from re-crystallization, which could be attributed to the formation of a LEU crystalline shell covering SV upon the spray drying process.