Influence of micronization on the physical properties of salbutamol sulfate as a model drug used in dry powder inhalation

Abstract

Purpose: Investigation of the crystallinity of salbutamol sulfate a model drug used in the dry powder inhalation formulation. Materials and Methods: Salbutamol sulfate was supplied kindly by Lindopharm (Hilden, Germany). Salbutamol sulfate was milled using an air jet milling process, the particle size and morphology were determined using laser diffraction and the scanning electron microscopy. The drug was subjected to conditioning through storage at 52.8% and 75% relative humidity for 24 h, 1 week, and 2 weeks, respectively. The drug crystallinity was investigated using differential scanning calorimetry (DSC), X-ray diffraction, and water vapor sorption techniques. Results and Discussion: Conditioning of salbutamol sulfate after micronization lowers the glass transition (Tg) temperature of the amorphous parts present at particle surface, which enhances particle mobility for more rearrangement associated with water expelling. This transformation may result in deviation from the original particle size obtained after milling out of respirable range. DSC and X-ray diffraction show no detectable amorphous drug since no detectable Tg observed. Alternatively, water vapor sorption shows a small amount of amorphous salbutamol sulfate at the particle surface, which recrystallizes at 52.8% relative humidity after approximately 2 weeks of conditioning. Conclusion: The amorphous regions can be generated in crystalline materials during processing. The level of amorphous materials can affect every step of pharmaceutical formulation, storage, and stability. However, quantification of low levels of amorphous content still poses considerable challenge. This study confirms that, the water vapor sorption technique is useful in the quantification of a small amount of drug amorphous content.

Physical stability of dry powder inhaler formulations

“…Using isothermal microcalorimetry it was observed that the micronized revatropate hydrobromide recrystallized at RH >30% [48]. Boshhiha et al made a similar observation on salbutamol [49]. They found that amorphous regions can be generated in crystalline materials during the jet milling process, which had significant impacts on physical stability [49].…”

“…Boshhiha et al made a similar observation on salbutamol [49]. They found that amorphous regions can be generated in crystalline materials during the jet milling process, which had significant impacts on physical stability [49]. Thus, re-crystallization of the amorphous regions can lead to changes in the physico-chemical properties of the micronized particles and formation of strong agglomerates, which has the potential to significantly impact the aerosol performance of the formulation [50,51,52].…”

“…To overcome these limitations of conventional DSC, the modulated DSC (mDSC) was introduced more than two decades ago and has been used to characterize amorphous solids [184]. Both DSC and PXRD can quantify moderate-to-high levels of amorphous materials whereas DVS is more sensitive and can detect very low amounts of amorphous content [49].…”