Spray Drying Enhances Solubility And Bioavailability Of Poorly Soluble Drugs
By Marianne Spaene, EVP Global Business Development, Siegfried Ltd.
In spray drying, a liquid feed (solution or suspension) is sprayed into a hot gas stream with the intent to isolate products in a solid form state as well-defined powder. By application of spraying, the liquid evolves as small droplets with precisely defined volume(s). These droplets are then transported with the gas flow along a drying chamber (referred to as ‘flight time’). During the flight time, the solvent evaporates from the droplets until only residual solids remain. The hot gas becomes saturated with solvent vapor during this process. The powder is then separated from the drying gas stream and collected. Evaporating solvent from the droplets consumes energy which is delivered by the hot gas around the droplet, so that the droplet stays cold and the gas becomes cooled. Due to these physical principles, the product stays at a well-defined temperature range during the drying process even though the gas temperature at the inlet is much higher. Temperature is only applied for a short period of the flight time to the product allowing spray drying to run as a gentle continuous drying operation, with minimal thermal stress on a product.
Varying spray drying conditions affects the size of the droplet(s) which define the remaining particle size overall. In addition, the spray drying conditions influence the physical properties of the final particles. Thus, the particles can be isolated as individual particles of defined size and shape, which can also be agglomerated when needed.
Over the last three decades, improved R&D has provided for modernized spray drying equipment to better meet the necessary requirements to produce powder with tailor-made properties for the end-user.
In summary, Spray Drying transforms a product from a liquid to solid state in one step, replacing up to three unit operations (crystallization, drying and milling).
The Benefits of Spray Drying - High precision control over:
- Particle size
- Bulk density
- Degree of crystallinity
- OVIs and residual solvents
Typical application in pre-formulated products - Micro encapsulations
- Solid solutions
- Improved bioavailability
- Improved product stability
For products with unusual or difficult characteristics - Difficult to isolate products
- Rapid drying with low temperature stress for sensitive materials
- Particle design
What is the fastest growing application? What is driving the increased interest in spray drying and what are the benefits?
Spray drying is growing in two fields of applied use. In one use, spray drying is applied to isolate APIs which are thermo-labile, or hard to crystallize like biomolecules or large molecules with complex structures. The demand of spray drying seems to have increased with this particular application, especially for the large molecule NCEs. A second rapidly growing use is the enhancement of bioavailability by spray drying the API together with excipients such as polymers in order that the API becomes isolated and stable in an amorphous form, which results in higher solubility and bioavailability than the crystalline form.
An additional advantage of spray drying is the remarkable versatility of the technology itself, which is evident when analyzing the multiple applications and the wide range of products that can be obtained. Examples include the fine particles for pulmonary delivery, to big agglomerated powders for oral dosages, and, amorphous to crystalline products as potential one-step formulations. Overall, spray drying offers multiple opportunities that no other single drying technology can deliver.
How does spray drying enhance the solubility and bioavailability of poorly soluble drugs?
There appears to be a real issue with newly developed products lacking acceptable levels of bioavailability due to the poor solubility achieved in stomach fluids. Therefore the absorption in the gastrointestinal tract remains low and the un-dissolved drug cannot reach its molecular target. In general, the amorphous form of an API is much more soluble than the crystalline form. Unfortunately, an amorphous API has a high tendency to crystallize over time, thus decreasing bioavailability and reducing the shelf life. Simply said, if a drug cannot dissolve and pass through a patient’s system, they will not benefit from it.
When applying spray drying, the API is dissolved together with a tailored polymer in an organic solvent and can then be isolated to the amorphous form. The amorphous form is encapsulated in a polymer matrix, which prevents crystallization from occurring, resulting in a stable amorphous form. The final product is more soluble and ultimately much more bioavailable. Achieving the improved bioavailability, the daily dose can be reduced, further reducing probable side effects. In addition, the improved bioavailability creates greater access to molecules, which previously could not be marketed without this new technology.
Could you use spray drying in-lieu of freeze drying?
Yes. Lyophilization, commonly referred to as freeze drying, is the most common processing method for removing moisture from temperature sensitive biopharmaceuticals. It can increase stability, temperature tolerance and shelf life of most products. Lyophilization is well established within the industry; however it does require expensive equipment which can take up a great deal of space within a production facility.
Spray drying is a technique that can be applied in lieu of Lyophilization. Spray drying, like lyophilization, is additive in that you can control the pH or salts in order to stabilize the structure. One advantage of spray drying is that it requires much less energy than lyophilization, and the particles can be designed to the needs of the downstream process(s).
What prompted Siegfried to expand its spray drying capabilities and capacity, and why in the US?
As an integrated supplier Siegfried is well suited for this sort of bridging technology that combines both know how from drug substance production (solvents) and drug product development (particle engineering). Siegfried already has the experience to spray dry a commercial GMP process in its US facility (Pennsville NJ). Our US site is a full cGMP chemical site, thus we are able to handle large amounts of flammable solvents like those needed for amorphous spray dried dispersions. Therefore; Siegfried decided first to expand our capability with spray drying at our US site. Siegfried has also installed a laboratory spray dryer in our global headquarter site in Zofingen Switzerland, where we currently support the combined chemical and pharmaceutical development activities.
What do you see as key success factors for Siegfried’s spray drying activities?
Siegfried’s key success factor is our inherent knowledge of both drug product and drug substance. Siegfried’s integrated offering fits perfectly with the spray drying capabilities that will become enhanced at the US site, and later at our Chinese Nantong site and Zofingen site, which further support our dual sourcing strategy.
What equipment did you purchase and why?
Siegfried’s spray drying large scale equipment was purchased via GEA/Niro and SPX/ Anhydro. For the development work, we choose the ProCept Spray dryer, because it has the possibility to produce already large particles which can be used for early stage formulation development. The type and scale of equipment available at Siegfried will make it possible to assume responsibility for a process at various stages of development, commercial scale and/or to develop a new process.
Did you need to expand your facility?
Yes. We believe we needed to do so in order to further support our long term integrated offering under the transform strategy of Siegfried. Currently we maintain two spray drying suites at Siegfried’s US facility in Pennsville, NJ. Our new additional suite will be commissioned during the first quarter of 2014.
About the author:
Marianne Späne (1962) joined the Siegfried Group in 2004 and was appointed as Head of Business Development & Sales in March 2010. She headed the Siegfried Generics Division from 2008 to 2010 and was previously responsible for the Classical Generics Business Unit. Between June 2004 and January 2008, Marianne Späne managed the Business Development Department and the Supply Chain for Generics. Prior to joining Siegfried, she worked in logistics, business development and as site manager for Boucheron, a cosmetics company. Later, she switched to the pharmaceutical industry and joined the pharma division of Schweizerhall as head of the sales and marketing department. Subsequently, she joined Aceto, a US-based company, where she developed European expansion strategies. Marianne Späne holds degrees in finance, business administration and marketing from the Business Management School (KFS) in Basel and the Marketing & Business School in Zurich (MBSZ). Marianne Späne is a German citizen.