Future applications for spray drying in pharmaceuticals

Spray drying is one of the most remarkable technologies currently to be applied to pharmaceuticals. It is a continuous process that converts, in a single step, a liquid feed into a powder and is an ideal process when precise attributes such as particle size, morphology and stability are required. This review describes the technology, current and future applications and how the present level of understanding and modeling tools enable a process development stage that is both lean and risk-free.

Spray drying is a drying method that was firstly described more than 140 years ago as an improvement in drying and concentrating liquids1. But it was not until the beginning of the 20th century that the level of sophistication and knowledge of the process allowed its industrial use. The production of milk powder was the first commercial application and still remains one of the most important uses of the technology.

Spray drying involves the atomisation of a liquid feed into very small droplets within a hot drying gas leading to flash drying of the droplets into solid particles. The particles are then separated from the drying gas, using a cyclone and/or a filter bag, as a final spraydried product. The feed can be a solution, a suspension or an emulsion and the resulting product can be classified as a powder, granules or agglomerates.

In a single continuous step, spray drying therefore converts a liquid feedstock into a powder with well-defined properties. Properties such as level of moisture or residual solvent in the powder, particle morphology or size and powder density can be manipulated to a great extent to target levels. The remarkable flexibility in tailoring the properties of the final powder, the gentleness of the process and its economics when compared with competing technologies such as freeze drying led to its proliferation in multiple industrial applications including cosmetics, fine chemicals, detergents, polymers, excipients and pharmaceuticals.

The key driver for this expansion was the need to formulate oral drugs in the amorphous state as a means to increase the bioavailability of many modern drugs. Due to spray drying’s rapid evaporation process this has become an ideal way to precipitate drugs from solutions in an amorphous state. This formulation platform, known as “amorphous solid dispersions”, is the fastest growing formulation approach to overcome the poor bioavailability of many drugs. Spray Drying and Hot Melt Extrusion are the main manufacturing process to obtain these amorphous materials. Other drivers for the more widespread use of spray drying in the pharmaceutical industry include the production of microcapsules for controlled-release formulations or taste masking and advanced powder forms such as direct compressible and readily wet-able powders. So it is no surprise to see that every two years, or more recently every year, a new chemical entity is formulated using spray drying technology.

Equipment types and scales

Spray dryers differ in many different ways: for example, whether or not the drying gas recirculates (close vs. open loop systems), the type of drying gas utilised (air, nitrogen or argon), the type of atomiser or nozzle (pressure, two-fluid, ultrasonic or rotary), the powder recovery system used (often through a cyclone and/or a filter bag), the degree of finishing (namely the level of polish of the internal surfaces), the existence or not of clean-in-place (CIP) or sterilisation-in-place systems as well as the level of instrumentation and automation.

Pharmaceutical spray dryers often combine the highest degree of finishing and the most sophisticated control systems with the simplest hardware designs that provide for easier cleaning. In many cases nitrogen is the preferred drying gas to air, not only because it allows the safe drying of organic solvents but also to reduce oxidation in the product. Pressure and two-fluid nozzles are mostly used in pilot and large scale equipment and their selection often depends on the type of feed and the target particle size of the final product. Rotary nozzles are less often used due to poor cleanability. Very interesting is the use of ultrasonic nozzles in small scale equipment since they allow for the formation of large droplets which very closely resemble those of larger equipment.

For amorphous solid dispersions, close system spray dryers using nitrogen as the drying gas are typically used because of the need to handle organic solvents.

Pressure nozzles are also favoured because they result in powders with better flow characteristics (as a result of the narrower particle size distribution), which simplifies the downstream processes of tableting or capsule filling.

Spray dryers in the pharmaceutical industry are available in a wide range of scales: from lab units where a gram or less of final material can be produced, to very large commercial units capable of producing several tons per day .

Using process understanding for lean and risk-free development

The modelling and simulation tools described above, together with the ability to generate commercial scale-like powders from lab units have reduced considerably the level of experimentation, as well as the quantities of typically very expensive APIs, required to develop a robust commercial spray-drying process. Process understanding and prior knowledge with similar processes are also crucial to minimise testing. Moreover, the description of the process and its design space through meaningful and scale-independent parameters (such as relative saturation of the drying gas and mean droplet size, accurately estimated by modelling tools) facilitates scale-up and can reduce initial experimentation to a handful of lab-scale runs using only a few grams of material.

Today the development of a spray drying process can be accomplished with a fraction of the material that was required 10 years ago and can be done in days instead of months. This is a paradigm shift in spray drying development and one that is being led by the pharmaceutical industry because the quantities of novel drugs are often limited and very expensive to produce.

Pharmaceutical application of spray drying: application in APIs or excipients

Spray drying process can render a dried product with desirable characteristics for subsequent processing e.g. direct compression. As an example, spray-dried lactose was introduced to the pharmaceutical market in the 1960s as an excipient that enables direct compression of formulations in a simple manufacturing process8. Prior to the spray drying process, lactose can be suspended in a saturated aqueous solution. The drying process converts them into free flowing granules with a mixed solid state of crystal form and amorphous form. The resulting unique internal structure can confer the dry powder a good plasticity and binding during the process of direct tableting. To date, lactose remains one of the most popular excipients for active pharmaceutical ingredients (APIs) whose dose makes them suitable for direct compression. Other direct compressible excipients produced from spray drying include EMDEX (spray dried dextrose), Avicel HFE-102 (co-spray dried microcrystalline cellulose and mannitol), Karion Instant (spray dried sorbitol), TRI-CAFOS (spray-dried tricalcium phosphate) and Advantose 100 (spray-dried maltose)9. Besides excipients, APIs can also be spray-dried in order to obtain some of following properties such as improved flowability, adherence or agglomeration for tableting and wettability in water. Due to the almost instantaneous transition between liquid and solid phases, spray drying usually results in predominately amorphous material for small molecule substances, especially when particle temperature during the process is typically lower than the glass transition temperature of the material. This is often desirable, as it may be used to increase the bioavailability of the resulting drug product. However, the physicochemical stability of the dry product is always a concern due to the high tendency of transformation from metastable amorphous form to stable solid form. Hence, a suitable packaging has to be applied to minimise the physicochemical degradation of the drug product during its shelf life.

Application in pharmaceutical formulations: solid dispersion

APIs are often co-spray dried with some excipients in order to achieve desirable functionality for the final pharmaceutical formulations. Producing solid dispersion by spray drying may be one of the main applications of this technique in the pharmaceutical industry. Nowadays, approximately 40 per cent of NCEs have low solubility in water, and possess poor bioavailability. One of the strategies to improve oral absorption is to improve the dissolution rate of the NECs by formulating them into solid dispersion. Spray drying and melt-quenching are regarded as the two most established approaches that can highly disperse the poorly-water soluble drug substances into solid dispersion carriers (mostly polymeric matrix). Nevertheless, as compared to melt-quenching, the thermal decomposition of drugs or carriers can be prevented by using spray drying since solvent is evaporated rapidly and dry product undergoes a low temperature10.

A general procedure of preparing solid dispersion using spray drying consists of dissolving the drug and polymeric carrier in an organic solvent, e.g. ethanol, chloroform, or a mixture of ethanol and dichloromethane, then spraying it into a stream of heated nitrogen gas flow to remove the organic solvent. The use of organic solvents, the high preparation cost and the difficulties in completely removing the solvent are some of the disadvantages associated with this method10. Moreover, physical stability of molecularly dispersed drugs still presents a major challenge in the development of solid dispersions12.

Microencapsulation

The goals of microencapsulation in the pharmaceutical industry are to stabilise active compounds, mask the bitter taste of the drug substance or design modified release pharmaceutical formulations. Through selecting suitable excipients and feed solvents, the active drug substances can be encapsulated by a polymer shell or coat. The feed can be an emulsion, suspension or polymer solution containing active substances. Microencapsulation can also be achieved through spray congealing where the materials are melted and sprayed into cold air to congeal the particles instead of being dissolved in a solvent medium prior to atomisation.

Taste masking

For bitter drug substances, a taste masking formulation will certainly improve patient compliance. Taste masking may be more significant when formulating an orally disintegrating tablet system for drug substances of this type. Bora et al developed taste-masked microspheres for the intensely bitter drug ondansetron hydrochloride by spray drying14. Both chitosan and Eudragit E100 were shown to mask the bitter taste of the drug but did not compromise the drug release. Sollohob et al also used spray drying to obtain the roxithromycin containing microcapsules with high taste masking efficiency, and Eudragit L30D-55 was chosen as a barrier coating15.

Modified release formulation

Modified release formulations designed using spray drying can be in a form of micro capsule, microsphere or microparticle. A microcapsule can be defined as an active substance which is covered by a shell or coat by forming a core-shell reservoir structure. The release of the drug substance from the microcapsule is mainly controlled by the diffusion rate of dissolved drug through the shell or the coat. In contrast, the drug release rate of microspheres or microparticles can be controlled by the dissolution rate of the drug or the carriers and diffusion rate of drug from an insoluble matrix. Microcapsules are more likely achieved by spray drying of an emulsion or a suspension rather than a solution. The excipients, often polymeric materials, dissolved in the dispersion phase may form a shell during spray drying to encapsulate the active substances. Microcapsule can render delayed release profiles to the drug, whereas microparticle and microsphere are more likely suitable for the design of sustained release formulations. The selection of one of these forms is dependent on the therapeutic aspects and physicochemical properties of the drug substance. Varshosaz et al developed colontargeted microcapsule of budesonide for ulcerative colitis by spray drying of the drug with dextran, and demonstrated that the microcapsules could target the drug to colon. And its efficacy in reducing macroscopic damage score was higher than mesalasine suspension16.

Dry powder for inhalation

An obvious advantage of spray drying over milling to produce dry powder for inhalation lies in its unique feature of particle engineering. Distinct from other formulations, for dry aerosol formulation, the particle characteristics are extremely important, which determine the lung deposition efficiency of the dry aerosols, thus their therapeutic efficacies. Even though technologies like supercritical fluid technology, spray freeze drying, crystal engineering, electrospray etc are emerging for particle design with different functionalities, spray drying is still regarded as the most adopted method in the pharmaceutical industry to produce dry aerosol formulations besides the milling process. Nevertheless, in terms of pulmonary delivery of biopharmaceuticals, spray drying may be more attractive than milling. In fact, the first inhalable insulin product, Exubera? for Type 1 and 2 Diabetes was produced by spray drying.

When spray drying of biopharmaceuticals, cryo- or lyo-protectants such as disaccharides is often employed to not only protect the liable compounds from degradation during the process but also to render them desired particle properties. Most of the research has been focused on the effect of the disaccharides on the stability of the biopharmaceuticals. Less work has been done on investigating the effect of biopharmaceuticals on solid state of disaccharides, which influences physical stability of dry particles. Our recent research has clearly demonstrated that the polymorphic form of spray drying mannitol can be changed upon proteins and different drying rate. Further particle dependence of polymorphism in spray dried mannitol was also observed when a model protein lysozyme was added in the formulation18.

Aseptic production with spray drying

Aseptic spray drying production is required for producing dry aerosol formulations, injectable depot formulations and also biopharmaceutical formulations. Biopharmaceuticals, like protein and peptide drugs, have become more and more important classes of therapeutic agents in the pharmaceutical industry19. They are often kept in a solid form due to stability concern. Currently, lyophilisation is the most commonly used method to produce dry protein products. But it is time-consuming and a high energy consuming technique. In contrast, aseptic spray drying production, which is more economical in terms of installation and operation compared with lyophilisation, may be an alternative to producing dry protein product20. After all, spray drying is also superior to lyophilisation with respect to engineering particle property and facilitating subsequent processing. It should be mentioned that the only process difference of aseptic spray drying from non-aseptic spray drying is the requirements for sterilisation. However, different equipments are required20.

Other applications of spray drying in pharmaceutical research

Besides the aforementioned pharmaceutical applications, spray drying has also been attempted to design many other pharmaceutical formulations. For example, liposomal formulations21, lipid based self-emulsifying drug delivery systems, dispersions of porous and non-porous silica, solid-in-oil dispersion, pre-prepared nanoparticle suspension and dry extracts of active raw materials from plants have also been treated using spray drying for various purposes like inhalation, controlled release, stabilisation, targeting drug delivery. In short, pharmaceutical scientists are continuously exploring to expand the pharmaceutical application of spray drying.

Perspectives of spray drying pharmaceuticals

Spray drying of pharmaceuticals is no longer just an approach to obtain dry product. The last decade has been a shift from empirical formulation efforts to a particle design approach based on a better understanding of particle formation in the spray drying process. In order to design sophisticated drug delivery systems, particle engineering via spray drying has been one of the most studied areas in pharmaceutical research field. To this end, various experimental techniques like levitation techniques and droplet chain techniques have been introduced to investigate single droplet drying kinetics and the physical and chemical mechanisms that control particle formation, which is the key to successful particle engineering via this method. Additional innovation may lie in understanding biological processes of the newly engineered particles, e.g. in vivo release, cellular targeting, intracellular trafficking, drug absorption and biological compatibility.

From an industrial point of view, spray drying will slowly but surely become part of the pharmaceutical industry’s standard. Further advances in spray drying may be achieved by combining the spray drying process with additional processing steps and the application of computational fluid dynamics (CFD). One of the obstacles in the pharmaceutical application of spray drying lies in the limited knowledge of this technology in many pharmaceutical companies. Luckily, more and more pharmaceutical organisations now realise both process and formulation equally determine critical quality attributes of drug products. Pharmaceutical technologists are starting to get involved in decision-making at an early stage of drug development, which may be able to bring this powerful technology into a full play in a short futur

Refrences :

• https://www.europeanpharmaceuticalreview.com/article/27768/spray-drying-pharmaceutical-industry/#:~:text=Spray%20drying%20involves%20the%20atomisation,as%20a%20final%20spraydried%20product.
• https://www.europeanpharmaceuticalreview.com/article/10406/spray-drying-pharmaceuticals/