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The use of polar anti-solvents for the crystallisation of lactose from 10% (w/v) aqueous solutions has been investigated. Crystal growth was observed at 50-65% antisolvent content and showed a morphological transition from polyhedral to needle-like habit with increasing antisolvent content, which coincided with a polymorphic transition from alpha lactose monohydrate (t:a. H20) to beta lactose (L~). Where anhydrous dehydrating antisolvents were employed such a~ methanol and ethanol, evidence of La. H20 dehydration to form stable anhydrous alpha lactose (Las) was also observed at 95% antisolvent content. Powder X-ray diffraction (PXRD) analysis of the samples highlighted the preferred orientation effects exhibited by large crystals of this kind, indicating the difficulties experienced by the non-specialist when performing phase identification of lactose polymorphs by PXRD. Application of the same crystallisation procedures to a racemic mixture of the active pharmaceutical ingredient (API) salbutamol sulfate (SS) indicated that some conditions can promote the formation of solvated SS. Ethanolic suspensions of spray dried and micronised La. H20, with average particle size between 3 and 200~m, were prepared by static and reflux methods and compared with sub-micron lactose (SML) suspension prepared by a high pressure homogenisation approach. Dehydration behaviour as a function of time was investigated by 13C CP MAS NMR spectroscopy and in all cases, indicated that suspensions contained Las. Several approaches were employed to remove ethanol from these suspensions and the products were analysed by PXRD and scanning electron microscopy (SEM). For samples with mean particle size greater than one micron, Las was retained on removal of the ethanol, although differences in the morphology and particle size of the crystals were apparent. These data imply that while SML is stable under dry conditions it is more susceptible to rehydration than standard Las with particle size between 3 and 200~m. in-situ 13C CP MAS NMR spectroscopy, employing hand-made glass inserts, was used to investigate the dehydration behaviour of La. H20 to Las in ethanolic suspension. Strong ethanol 13C resonances were observed for some samples, indicating a liquid-solid interaction between the ethanol and lactose surface. Replacement of ethanol with anhydrous methanol, n-butanol and 3-methylbutan- 2-01 implied that the solvent mediated dehydration is sterically controlled. 13C CP MAS NMR studies of SS, fluticasone propionate (FP) and salmeterol xinafoate (SX) showed that both SS and FP exhibit very short relaxation times for a solid material (-2s). This liquid-like behaviour is particularly beneficial pharmaceutically, as these APls are often mixed with an excess of lactose in inhaled formulations. Lactose behaves as a typical crystalline solid, and therefore experiences significantly longer relaxation times (-360s). Signals from SS and FP were successfully isolated from lactose/API blends (98%/2%) simply by reducing the delay times used within the 13c CP MAS NMR experiment. |
