Advancing the art of spray drying

Conventional spray drying is a useful process but has its limitations. John Polidoro, Mark Ketner and Carl Sahi, Engineered BioPharmaceuticals, explain how the field of dry powder processing can be advanced by the newer technique of atmospheric spray freeze drying.

Scientists and engineers manufacture dry powder pharmaceuticals for many reasons, including increasing stability and shelf life of drug formulations; for storing at room temperatures; reducing weight and bulk; and for facilitating the development of novel self-administration methods of delivery, such as nasal and pulmonary delivery.

The mainstay method for liquid-to-dry-powder conversion is lyophilisation. Also known as freeze drying, lyophilisation involves freezing a bulk liquid solution and subliming off the solvent using temperature and vacuum. Pharmaceutical companies worldwide have used this method for decades to produce dry powder pharmaceuticals, even though it is slow, has significant energy requirements and often necessitates post processing to produce a powder suitable for its end-use application.

With pressure on pharmaceutical companies to increase manufacturing efficiency and produce products with higher activity and longer shelf lives, including the manufacture of complex and fragile dry powder biologics, bulk processing lyophilisation may have reached its limitations.

New methods exist that provide the reliability and performance of lyophilisation, yet offer the scientist and engineer a dashboard of opportunity to fabricate intricate features and properties into each particle. One of the advanced technologies leading the charge into ‘engineered’ dry powder pharmaceuticals is atmospheric spray freeze-drying (ASFD).

ASFD is a hybrid process of lyophilisation and conventional spray drying, without many of the limitations. In this process, a liquid formulation is atomised and the individual droplets are rapidly cooled to suspend solute streaming and molecular motion, and lock in the spherical droplet shape. The frozen particles are then dried in a cold, dry gas flow to the desired, predetermined low moisture content.

The resulting particles are porous, spherical and aerodynamically light – making them ideal powders for a variety of end-use applications. A flow diagram of the ASFD process is shown in Figure 1. A better understanding of the advantages of ASFD powders first requires a review of the older, basic, predicate technologies in the field of dry powder processing.

Lyophilisation is a dehydration process common in both the food processing and pharmaceutical industries. For pharmaceuticals, a moisture-containing material (i.e. a liquid solution of active pharmaceutical ingredient (API) and excipients) is bulk frozen, after which the ambient pressure is reduced and enough heat is added to allow the frozen aqueous portion in the material to sublime. There are typically three stages in the process: freezing, primary drying and secondary drying.¹

The freezing process is accomplished by lowering the temperature to between –50°C and –80°C, slowly enough to avoid thermal gradients and subsequent damage to the API. The specific temperature is selected to be below the solution’s triple point to ensure sublimation rather than melting. During primary drying heat is minimally added until 95% of the aqueous portion has been removed. This drying process is slow and may take several days because of the inherent thermodynamic properties of the process and to avoid stressing the active ingredients.

In secondary drying the molecular water is removed, resulting in a dry powder with final moisture content generally between 1% and 8%. This phase of the process is governed by the solutes’ isothermal adsorption profiles. The ambient pressure is kept low to encourage desorption of water molecules and heat is slowly added to attain temperatures slightly above primary drying.² The result of the process is a ‘cake’ of powder that can be reconstituted at time of use or post-processed to improve surface area properties for inhalation or faster reconstitution times. The particles are typically non-porous, irregularly shaped and cover a wide size distribution. Their aerodynamic performance, i.e. those properties needed for predictable flight in an airstream, are less than ideal for nasal and pulmonary pharmaceutical delivery applications and their non-porous nature means reconstitution times can be long.

The bulk nature of the process can lead to non-homogeneous powders, particularly if the bulk solution is a suspension or the active solute concentration is low. Lyophilisation is a standard method for protecting pharmaceutical proteins as the air/liquid interface can be minimised, crystal growth can be controlled and the inclusion of cryoprotectants is straightforward. However, the inability to make homogeneous particles in size, shape and content and engineer intricate features into the particles, limits its ability to progress with the advancement of the pharmaceuticals themselves.

The pharmaceutical industry currently relies on lyophilisation because the years of producing lyophilised dry powders have created a body of knowledge and a comfort level with the technology.

Spray drying is the process of atomising a liquid into a warm/hot gas stream to evaporate the solvent and collect the solid. The formulation (comprising proteins, excipients, solvents, etc.) is fed by a pump through a small orifice nozzle to produce fine droplets that fall through a drying chamber. A warm gas stream vortex is created in the chamber to suspend the particles and evaporate the liquid solvent. As the droplet falls, evaporation occurs until the final desired moisture content is reached.^3,7

Spray-dried particles tend to be semi-spherical or raisin-shaped, allowing enhanced aero-dynamic performance compared with lyophilised powders. Unlike lyophilisation, particle size can be controlled through the choice of the nozzle. Perhaps the greatest benefit spray drying offers is that spraying and drying happen in one continuous and rapid process. However, collection efficiency can be poor and for protein-based pharmaceuticals, spray drying can be detrimental to proteins due to their inherent sensitivity to the heat required by the process.

Overall, the multiple process variables of spray drying offer challenges in controlling and validating the process and maintaining sterility of the complex spray dry chambers.

ASFD, like lyophilisation and spray drying, starts with the proper formulation to ensure the active ingredients will be protected during processing and perform together to produce the desired final product properties.⁶ As with spray drying, ASFD’s liquid formulation is atomised to create a fine mist of liquid particles of the desired final shape and size. The individual droplets are then quickly cooled in liquid nitrogen or a cold gas flow to suspend solute motion and yield generally spherical solid particle shapes in a tight size distribution.

Because vacuum pressures may add physical stress to protein formulations and since sublimation can occur at atmospheric pressures, ASFD utilises the flow of cold gas to drive convective heat transfer and particle drying.¹ Nitrogen gas, at temperatures between –40°C and –20°C, depending on the glass transition temperature of the solution, is typically used in the drying process. At these low temperatures sublimation dominates the drying cycle and due to the increased surface area exposure of the particles to the gas stream, the entire drying process typically takes less than 24 hours.

Similar to lyophilisation, an annealing step can be implemented prior to drying to reduce the stress on the solutes and reduce freezing-induced heterogeneity in sublimation rates.³

Unlike spray-drying, where evaporation dominates the drying process, ASFD does not allow solute streaming and eventual collapse of particle shape. The resulting particles are compositionally and morphologically homogeneous (see Figure 2).

powder engineering

A significant advantage of the ASFD process over lyophilisation and spray drying is that it allows pharmaceutical powders to be ‘engineered’ for a wide variety of final use applications. A specific final particle size is easily achieved by adjusting the droplet diameter via the spray nozzle. In addition, the density, and thereby the aerodynamic size, can be adjusted independent of the geometric diameter by altering the starting solute concentration.

For example, a starting solution with a 5% solute concentration will make a less dense particle than one with a 15% solute concentration. In fact, two particles with the same geometric diameter can have vastly different aerodynamic diameters simply based on the starting solute concentration (active plus excipients).

Figure 2: Typical particle morphology resulting from ASFD process

This is particularly important for targeted drug delivery within the respiratory tract. If deep lung delivery is desired, particles with a tight aerodynamic diameter size distribution centred on 5.8µm can facilitate alveolar delivery and minimise errant deposition. Asthma and other allergy medicines that benefit from targeted delivery to inflamed and constricted bronchioles require a slightly larger aerodynamic diameter to maximise targeting, while minimising misplaced or systemic absorption of the medicines. Targeted nasal deposition of therapeutics requires an even larger aerodynamic particle size to maximise nasal deposition and minimise pass-through and olfactory receptor deposition.

Dry powders engineered for reconstitution of drugs for injection delivery are also substantially enhanced by ASFD particles that optimise surface area for faster dissolution rates. Table 1 summarises the advantages and disadvantages of each of the three methods discussed.

As exciting as the new opportunities ASFD processing provides to enhance dry powder pharmaceuticals, its ‘new technology’ status can work against it in a field that has remained somewhat stagnant for many years. In the heavily regulated and consequently conservative pharmaceutical industry, new technologies must be sufficiently vetted prior to adoption for widespread use.

For this reason, Engineered BioPharmaceuticals is currently in the process of scaling ASFD manufacturing to a commercially feasible and economically attractive level. This process involves both the manufacturing of the engineered dry powders and the filling of the powders into their final form packaging, all within a contained aseptic environment under cGMP control. The main picture is a view of the current laboratory-scale drying vessel being used for cycle development.

With demand for sophisticated therapeutics to extend life expectancy and improve quality of life, contrasted with the dire need to reduce spiralling healthcare costs, there is enormous pressure and opportunity for the industry to embrace new technologies that answer the call. The growth in biotechnology-based therapeutics and the repositioning of older approved drugs into new more efficient delivery modes are testament to the changing times. Protein-based pharmaceuticals are rapidly being developed that will transform and challenge traditional drug manufacturing. Unlike most small molecules, fragile proteins must be carefully handled and shielded from potential denaturing environments to ensure their activity is maintained long-term.⁸

The standard methods of making suitable dry powders have served the industry well, though these technologies leave a lot of opportunity for improvement in manufacture, therapeutic efficacy and user-palatable administration. Engineered BioPharmaceuticals is excited about this work and that of others to advance the field of novel engineered dry powders and looks forward to the opportunity to share its experience with ASFD and its impact on the future of pharmaceutical medicine.

references

1. M. Mumenthaler, H. Leuenberger, Int. J. Pharm. 1991, 72:97–110.

2. S. Behme, (2009) Manufacturing Pharmaceutical Proteins, Wiley VCH Verlag GmbH, Germany.

3. R. Vehring, Pharm. Research 2008, 25:990–1022.

4. C. Arpagaus, et al, Laboratory Scale Spray Drying of Lactose: A Review, Best@Buchi 2010, Vol 59.

5. J.A. Searles, et al, J Pharm Sci. 2001 Jul; 90(7):872–87.

6. W. Wang, Int. J. Pharmaceuticals. 2000, 203:1–60.

7. Y.F. Maa, et al, Pharm. Research.I 1998 15(5):768–775.

8. T. Arakawa, et al, Advanced Drug Delivery. 2001 46:307–326.

acknowledgement

Funding for this work was provided by NIST Technology Innovation Project Grant 11H003 and the Virginia Tobacco Indemnification and Community Revitalisation Commission R&D Grant #2279.

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