(402a) Use of Co-Milling to Improve Physical Stability of Amorphous Salbutamol Sulphate

In recent years, co-milling of active pharmaceutical ingredients (APIs) with excipients is being investigated as a promising technique to improve physicochemical properties such as solubility[1], bioavailability[2], aerosolization[3] and physical stability[4] of various APIs. Excipients are added to a drug formulation to enhance the manufacture process or product quality, e.g. improving tablet compactibility, solubility or bioavailability[5]. However, the milling process also induces structural disorders leading to the formation of amorphous regions, particularly at the surfaces of the particles[6]. Stabilization of this amorphous form is important as it tends to revert back to a lower energy and more stable crystalline state upon storage. This transition can be detrimental to the drug performance as it affects critical particle properties such as morphology, particle size distribution, specific surface area, chemical and physical reactivity and dissolution rates[7].

In this study, salbutamol sulphate (SS) was selected as a model API as it typically transforms from its crystalline to the amorphous forms during milling. Amorphous SS is unstable and tends to undergo agglomeration under normal storage conditions. Pfeiffer and co-workers[8,9] suggested that an increase in particle size of micronized SS occurred due to re-crystallization of the amorphous regions. In our previous work, a co-milling method was devised to minimize the amorphization of SS with the aid of crystalline excipients [10,11]. Upon co-milling, the unstable amorphous form of SS was avoided. However, though the amorphous form is unstable, it can sometimes be highly desired because of its higher reactivity and better dissolution properties. This study aims to stabilize the amorphous form of SS by co-milling with pharmaceutically acceptable excipients like polyvinyl pyrrolidone (PVP).

Different mass ratios (1:1, 1:2, 1:3, 1:5, 2:1, 3:1, 5:1) of SS and PVP were co-milled at 300 rpm in a planetary ball mill for 1 h. The co-milled (CM) mixtures along with their individual components and physically blended (PB) mixtures were subjected to storage conditions of 75%RH/22°C and 15%RH/22°C for 7 days. Powder X-Ray Diffraction (PXRD) and Scanning Electron Microscopy (SEM) analyses prior and after storage were carried out to evaluate changes in crystallinity and morphology. Before storage, PXRD patterns of all CM and PB mixtures showed an amorphous halo, which indicated that SS was present in the amorphous state. After storage at 75%RH/22°C, only CM mixtures with ratios of SS:PVP greater than or equal to 1:2 retained their X-ray amorphous character. All other mixtures including PB mixtures were found to be unstable and re-crystallized under 75%RH/22°C, which was similarly observed in milled SS. The results showed that co-milling of SS with PVP with ratios greater than or equal 1:2 was effective in stabilizing the amorphous form of SS. As a control, all CM and PB mixtures remained X-ray amorphous when stored at 15%RH/22°C as the humidity conditions were not sufficient to induce re-crystallization. The PXRD results were further supported by SEM analysis, as no agglomeration behavior was observed in CM mixtures having higher mass ratios. The thermal properties of these CM mixtures were also analyzed using Differential Scanning Calorimetry (DSC).

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