(18f) Effects of Co-Milling on Crystallinity of Salbutamol Sulphate Using Adipic Acid

Particle size in pharmaceuticals is important in defining drug delivery and bioavailability in an increasing range of pharmaceutical applications. This formulation aspect affects performance of a drug product. It governs for instance, sedimentation and flocculation rates in suspensions, therapeutic effect of dry powder inhalations (DPI) and good powder homogeneity in tablets. Comminuition is commonly used for this purpose and also to reduce particle size as it is difficult to achieve a narrow particle size distribution (PSD) via crystallization alone. However, milling also induces disorder in the crystal structure leading to the formation of amorphous regions, which are concentrated particularly at the surfaces of the particles (1-4). During post-milling storage, these amorphous regions are unstable and may transform back to the crystalline state.

Salbutamol sulphate (SS), a pharmaceutical active used in DPI, typically transforms from the crystalline to the amorphous form during milling. Amorphous SS does not remain stable and tends to undergo agglomeration under normal storage conditions for pharmaceutical powders. Pfeiffer and co-workers (5, 6) suggested that the increase in particle size of micronized SS was caused by re-crystallisation of amorphous regions produced during micronization. The purpose of this study is to stabilize the crystalline form of SS by co-milling with a pharmaceutically acceptable excipient - adipic acid (AA).

Different mass ratios (1:1, 1:2, 1:3, 2:1, 3:1) of SS and AA were co-milled at 300 rpm in a planetary ball mill for different durations. The duration was optimized and set at a period of 1 hr. The co-milled mixtures were characterized and compared with the individual components and physically blended components using Powder X-Ray Diffraction (PXRD). PXRD patterns of co-milled mixtures of SS and AA showed that the characteristic crystalline peaks of SS were retained on co-milling. This indicated that co-milling stabilized the crystalline form of SS. It was also observed that all AA:SS ratios indicated similar intensity of peaks for SS suggesting that a minimum ratio of AA:SS is useful in maintaining the stable crystalline form of SS on co-milling. This was different from the amorphous halo observed in the diffractogram of SS after it was ball-milled for 1 hr. The prominent crystalline peaks characteristic of SS were also absent from the physically blended mixtures of SS and AA. The amorphous content, surface and thermal properties of these co-milled mixtures are further analyzed using Dynamic Vapor Sorption (DVS), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA).

References:

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