(125e) Integrated Continuous Crystallization and Spray Drying of Beclomethasone Dipropionate for Pulmonary Drug Delivery

Pulmonary drug delivery can offer improved bioavailability of active pharmaceutical ingredients (APIs) compared to oral drug delivery for both the treatment of systemic and local diseases due to the large surface area of the lungs, direct delivery to the site of action, and reduced metabolism. Delivery of the API in dry powder form through inhalation is beneficial compared to other aerosol forms, because a dry powder requires no propellant, has superior chemical stability and resistance to bacterial, and is portable and easy to use. However, the manufacture of dry powders for pulmonary drug delivery is challenged by stringent requirements for the solid-state properties.(1) Small particles (< 1 µm) do not deposit sufficiently fast within a single breathing cycle and large particles (> 5 µm) impact in the back of the throat followed by swallowing. Crystalline particles offer advantages related to stability and flowability compared to amorphous particles. Finally, needle-like particles have a better aerosolization behavior compared to spherical particles. Drug particles that do not deposit effectively in the lungs increase the cost of a single dose and may lead to side-effects for the patient. Therefore, the design and operation of pharmaceutical processes that can produce pulmonary drugs with optimal properties reliably is of critical importance to minimize costs and enhance therapeutic efficacy. Micronization such as milling is often needed after conventional batch crystallization processes to reduce the size of the API crystals for pulmonary drug delivery. However, micronization lowers the process yield and typically leads to poorer aerosolization behavior.

Continuous manufacturing offers inherent advantages to improve the manufacture of APIs for dry powder inhalation. A high supersaturation is needed to create a large number of nuclei that can grow into the optimal size range with high attainable yield. Anti-solvent crystallization can create such high supersaturation, which works well in continuous flow due better mixing conditions compared to batch operation. Furthermore, continuous crystallization can be integrated with spray drying, which inherently operates in continuous flow, to minimize work-up steps and transfer time.

An integrated continuous process combining plug-flow crystallization and spray drying for the improved manufacture of pulmonary drugs is presented.(2) A segmented-flow crystallizer(3-5) is integrated with spray drying to produce crystals with optimal properties for pulmonary drug delivery in a single step. The process is illustrated for the case of beclomethasone dipropionate, which is a commercial pulmonary drug used, for example, for the treatment of asthma. First, the continuous anti-solvent crystallization is optimized by screening suitable solvent/anti-solvent pairs and varying common operational variables such as residence time, temperature, and initial supersaturation. Subsequently, spray drying is optimized by varying the inlet temperature and atomizer gas flow rate. Finally, both steps are integrated into a single process, which has been optimized by varying the most critical process parameters.

The dry powder is analyzed in terms of solid-state form, morphology and drug delivery performance using a Next Generation Impactor^TM and commercial dry powder inhaler. The results demonstrate that under optimal conditions the integrated process produces a dry powder consisting of needle-like crystalline particles with an emitted fraction (i.e., the fraction of the powder leaving the capsule in the inhaler device) of 75% and a fine particle fraction of 33% (i.e., the fraction of the powder expected to deposited at the intended sites in the lungs) without any size correction steps or addition of excipients, which represents a good performance compared to commercial products. Furthermore, the overall process yield is 65% and the total residence time is only 10 minutes. The presented process is simple and flexible due to continuous operation and the clear separation of process functions. Future work may focus on the extension towards other applications, dedicated equipment design to further improve process yield, process modeling, control, and alignment with quality-by-design principles and recently published regulatory guidelines for continuous pharmaceutical manufacturing to enable commercial implementation.(6)

Acknowledgment

This research is funded by the Hong Kong Innovation and Technology Commission, under ITSP Tier 3 Scheme (Project No. ITS/137/16).

References

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