Practical and scalable synthesis of beclomethasone dipropionate.

Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16ß-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C17 and C21 demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.

Spray-Congealing and Wet-Sieving as Alternative Processes for Engineering of Inhalation Carrier Particles: Comparison of Surface Properties, Blending and In Vitro Performance.

PURPOSE: Traditionally, α-lactose monohydrate is the carrier of choice in dry powder inhaler (DPI) formulations. Nonetheless, other sugars, such as D-mannitol, have emerged as potential alternatives. Herein, we explored different particle engineering processes to produce D-mannitol carriers for inhaled delivery. METHODS: Wet-sieving and spray-congealing were employed as innovative techniques to evaluate the impact of engineering on the particle properties of D-mannitol. To that end, the resulting powders were characterized concerning their solid-state, micromeritics and flowability. Afterwards, the engineered carrier particles were blended with inhalable size beclomethasone dipropionate to form low dose (1 wt%) DPI formulations. The in vitro aerosolization performance was evaluated using the NEXThaler®, a reservoir multi-dose device. RESULTS: Wet-sieving generated D-mannitol particles with a narrow particle size distribution and spray-congealing free-flowing spherical particles. The more uniform pumice particles with deep voids and clefts of wet-sieved D-mannitol (Pearl300_WS) were beneficial to drug aerosolization, only when used in combination with a ternary agent (10 wt% of 'Preblend'). When compared to the starting material, the spray-congealed D-mannitol has shown to be promising in terms of the relative increase of the fine particle fraction of the drug (around 100%), when used without the addition of ternary agents. CONCLUSIONS: The wet-sieving process and the related aerosolization performance are strongly dependent on the topography and structure of the starting material. Spray-congealing, has shown to be a potential process for generating smooth spherical particles of D-mannitol that enhance the in vitro aerosolization performance in binary blends of the carrier with a low drug dose.

Proliposome powders prepared using a slurry method for the generation of beclometasone dipropionate liposomes.

A novel "slurry method" was described for the preparation of proliposome powders using soya phosphatidylcholine (SPC) with cholesterol (1:1) and for incorporation of beclometasone dipropionate (BDP) at 2mole% of the total lipid phase. Proliposomes made with a range of lipid to sucrose carrier ratios were studied in terms of surface morphology using scanning electron microscopy (SEM) and thermal properties using differential scanning calorimetry (DSC). Following hydration of proliposomes, the resultant vesicles were compared to liposomes made using the traditional proliposome method, in terms of vesicle size and drug entrapment efficiency. SEM showed that sucrose was uniformly coated with lipid regardless of lipid to carrier ratio. Liposomes generated using the slurry proliposome method tended to have smaller median size than those generated with the conventional proliposome method, being in the range of 4.72-5.20µm and 5.89-7.72µm respectively. Following centrifugation of liposomes using deuterium oxide (D2O) as dispersion medium, vesicles entrapping BDP were separated as a floating creamy layer, whilst the free drug was sedimented as crystals. Drug entrapment was dependent on formulation composition and preparation method. When 1:15 w/w lipid to carrier was used, liposomes generated using the slurry method had an entrapment efficiency of 47.05% compared to 18.67% for those generated using the conventional proliposome method. By contrast, liposomes made by the thin-film hydration method had an entrapment efficiency of 25.66%. DSC studies using 50mole% BDP demonstrated that the drug was amorphous in the proliposome formulation and tended to crystallize on hydration, resulting in low drug entrapment. In conclusion, a novel approach to the preparation of proliposomes using a slurry method has been introduced, offering higher entrapment for BDP than liposomes made using the conventional proliposome method and those prepared by thin-film hydration technique.