Influence of small amorphous amounts in hydrophilic and hydrophobic APIs on storage stability of dry powder inhalation products

• Standard pharmaceutical operations led to small amorphous amounts.
• Determination of amorphous content by dynamic vapor sorption (DVS) method.
• Impact of amorphous content on storage stability over 6 months.
• Investigation of the different drug’s FPF with a Next Generation Impactor.
• Explanation of different mechanisms which have influence on FPF values.

The effects of different manufacturing methods to induce formation of amorphous content, changes of physico-chemical characteristics of powder blends and changes of aerodynamic properties over storage time (6 months) analyzed with the Next Generation Impactor (NGI) are investigated. Earlier studies have shown that standard pharmaceutical operations lead to structural disorders which may influence drug delivery and product stability. In this investigation, fully amorphous drug samples produced by spray-drying (SD) and ball-milling (BM) as well as semi-crystalline samples (produced by blending and micronization) are studied and compared to fully crystalline starting material. The amorphous content of these hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was determined using a validated one-step DVS-method. For the conducted blending and micronization tests, amorphous amounts up to a maximum of 5.1% for salbutamol sulfate (SBS) and 17.0% for ciclesonide (CS) were measured. In order to investigate the impact of small amorphous amounts, inhalable homogenous powder mixtures with very high and low amorphous content and a defined particle size were prepared with a Turbula blender for each API. These blends were stored (6 months, 45% RH, room temperature) to evaluate the influence of amorphous amounts on storage stability. The fine particle fraction (FPF: % of emitted dose < 5 μm) was determined with the NGI at defined time points. The amorphous amounts showed a major effect on dispersion behavior, the mixtures of the two APIs showed differences at the beginning of the study and significant differences in storage stability. The FPF values for SBS decreased during storage (FPF: from 35% to <27%) for the blend with high amorphous amounts, in contrast the initially re-crystallized sample achieved a comparable constant level of about 25%. For the hydrophobic CS a constantly increasing FPF (from 6% to >15%) over storage time for both types of blends was determined. Therefore, prolonged stability of amorphous parts and an incalculable behavior for CS blends are supposed, in contrast, SBS showed a controllable FPF after conditioning.

Figure optionsDownload high-quality image (75 K)Download as PowerPoint slide