Process Development

Spray drying technology

for better API crystals
The application of new techniques in spray drying of final product gives excellent control of particle
size in API production. Filipe Gaspar and Jorge Manuel C. Pastilha of Hovione describe the latest
technologies.

T
he interface between the manufacture of an API and its
formulation into a pill, an injectable or inhaled drug is MEET THE AUTHORS
an area fraught with complexity – API particle size and Filipe Gaspar is a process engineer at
crystal form have a direct impact on the performance of a drug, Hovione FarmaCiencia SA in Loures, Portugal and is head of the
and yet in the list of the top contractors for custom synthesis company’s Particle Design Technologies Program.
there appears to be surprisingly few that claim to have any
expertise in this area. Jorge Manuel C. Pastilha is director of the Logistics and Control
One explanation for this state of affairs may be the tradition Group at Hovione FarmaCiencia SA and is project manager of its
that large multinationals have to keep the last step of the API Spray Drying Program.
in-house. The one manufacturing strategy that all
pharmaceutical multinationals appear to have in common is the
location of the final stages of the API synthesis in Puerto Rico, API contractor be both cognisant of the importance of having
Ireland and now Singapore. This fiscal focus has caused most the product with the correct particle properties, and be able to
contract manufacturers of APIs to remain dedicated to supplying develop a process that delivers it consistently. It is well known
advanced, cGMP-compliant, intermediates to Big Pharma. They that properties such as particle size distribution and morphology
have therefore had little opportunity to develop know-how affect important parameters such as bioavailability, dose
around the physical attributes of the final API. uniformity and formulation. This is key in many galenic forms; in
The emergence of Small Pharma has inverted this trend. the field of inhalation for instance it is absolutely critical; it can
Those offering custom synthesis are now expected to deliver also be the source of many last-minute surprises and frustrations
everything related to the API – this includes analytical until the situation is well controlled.
chemistry, synthesis route innovation coordinated with raw- APIs are typically produced by extraction or chemical
material sourcing, process development, regulatory filings and syntheses and most often isolated through a multiple-step
manufacturing in an environment characterised by compliance process comprising controlled crystallisation, solid-liquid
and service orientation – included, but often neglected, is the separation and drying. A post-drying step such as micronisation
ability to speak the language of the next link in the chain: the is frequently needed to adjust particle properties such as size
formulator. Chemists and engineers do not, by training, distribution and bulk density. Some pharmaceutical compounds
recognise the challenges that formulators face in taking their API are particularly difficult to micronise by conventional grinding or
forward and turning it into a successful drug. Hovione has been jet milling. For example, materials that have low melting point
making nothing but final APIs for more than 40 years, and as or that are waxy can smear or form amorphous (and size-
such the company has been acutely sensitive to the technical unstable) particles.
requirements of those that use the APIs it makes. Spray drying is presently one of the most exciting technologies
In line with the latest developments in spray-drying for the pharmaceutical industry, being an ideal process where
technologies and with the increasing demand for highly defined the end-product must comply to precise quality standards
particle properties in the pharmaceutical industry, Hovione has regarding particle size distribution, residual moisture content,
installed and commissioned a state-of-the-art spray-drying unit bulk density and morphology. Already widely used for the
able to operate under the most stringent cGMP conditions at its manufacture of many consumer and industrial products such as
manufacturing plant in Portugal. The multipurpose unit is fit to instant food, laundry detergents, ceramics and agrochemicals,
deliver injectable grade APIs and is configured to be ‘cleaned-in- the growth in pharmaceutical spray drying was driven by a
place’, discharging into a classified clean room. number of advantages over conventional multiple-step processes
and competing particle reduction technologies. It allows not only
Benefits of spray drying in pharmaceutical the replacement, in many processes, of all the complex,
fine chemicals time-consuming and yield-reducing isolation steps, but also the
The service of an API manufacturer not only involves the production of APIs with tailor-made particle properties.
development of the chemical process and the supply of Another advantage of spray drying is the remarkable versatility
high-quality API, when and where required, but also paying of the technology, evident when analysing the multiple
close attention to those physical parameters that make up the applications and the wide range of products that can be
necessary requisites for a successful formulation. Chemical skills obtained. From very fine particles for pulmonary delivery to big
must be complemented by a pharmaceutical culture. For a agglomerated powders for oral dosages, from amorphous to
successful custom synthesis partnership it is imperative that the crystalline products and with the potential for one-step

38 JUNE 2004 www.sp2.uk.com

 Process Development

product, enhancing control over physiochemical properties and

functionality of the final product.

Suitability for heat-sensitive products

Contrary to a general misconception, spray drying is a very
gentle drying technology when dealing with thermally labile
compounds. The shielding effect of the solvent during drying
protects the product contained in the core of the fine droplets
from the bulk temperature in the drying chamber, typically
between 70 and 150ºC. In addition, exposure time is extremely
low, usually a few seconds, minimising the heat ‘shock’ and the
potential degradation of the product molecules. The gentleness
of the drying process together with the ability to provide highly
defined particles with tunable properties and the lower
processing costs makes spray drying a true and economic
alternative to freeze drying when handling heat-sensitive
products.
Discharge of final product into a classified clean room.
Fig 1. Very fine
particles from spray
formulations, spray drying offers multiple opportunities that no drying.
other single drying technology can claim.

From very fine particles to agglomerates

Spray drying involves the continuous atomisation of the feed
solution into a hot drying gas, most commonly air or nitrogen.
The fine droplets resulting from the atomisation of the feed
solution are immediately exposed to the drying gas leading to
supersaturation and resulting in the formation of ultra-fine
particles, typically below 5 microns and with a tight particle size
distribution, which are collected via a cyclone (Fig 1). These
highly defined particles have promoted spray drying as a Fig 2. Agglomerates
method of choice for the production of powders for inhalation. from a fluidised spray
drying system.
Moreover, technological developments in the construction of
spray dryers have also stimulated the application of this
technology in the production of agglomerates for the
pharmaceutical industry. In the early 1990s, the spray dryer
cGMP spray drying – multipurpose application
with integrated fluid bed became the most important spray
across a range of scales
Hovione’s fully automated unit operates under the most stringent
drying concept in the food and chemical industries for producing
cGMP conditions and can be configured both as a conventional
agglomerated powders. Several large-scale plants were
spray dryer for the production of very fine particles (< 5 to 10
commissioned for the production of milk powder and soluble
micron) and as a fluidised spray dryer when producing
coffee and the concept was extended to the pharmaceutical fine
agglomerated, free-flowing dustless materials (100 to 400
chemical industry with the preparation of Captisol, a leading
micron). The facility allows continuous production of dry solids
proprietary cyclodextrin that Pfizer uses in the formulation of its
in either powder, granulated or agglomerated form from liquid
compounds Geodon and Vfend. The agglomerated powders are
feedstocks such as solutions, emulsions and pumpable
produced by re-introduction of the very fine particles into the
suspensions.
drying chamber (Fig 2). The dry fine particles in contact with
Hovine’s services in process chemistry and manufacturing
wet particles form agglomerates with enhanced handling
span the complete range of scales – from lab to pilot to
properties. These dust-free agglomerates are free-flowing
commercial scale, and spray drying can be carried out across all
powders, which are far easier to dissolve in their final
of them at the company’s sites. sp2
application, thus avoiding the formation of suspended lumps of
product. Captisol is a registered trademark of CyDex Inc. Vfend and Geodon are registered
trademarks of Pfizer Inc
From amorphous to crystalline products
When starting from a product solution, spray drying is known to
produce predominately amorphous material due to the almost FURTHER INFORMATION
instantaneous transition between liquid and solid phases. This is Hovione FarmaCiencia SA
often desirable, as it may be used to increase the bioavailability Sete Casas
of the resulting product. However, spray drying can also be used 2674-506 Loures
to obtain crystalline products with defined sizes and controlled Portugal
residual solvent contents. To achieve such a goal, the product is Tel: +351 21 982 9200
fed in a crystalline suspension, instead of a solution, to the Fax: +351 21 982 9388
drying chamber. Feeding the crystals in the right form allows
spray drying to fine tune crystal size distribution and final
content of residual solvents. In between these two extremes it is Internet Links: Email: [email protected]
also possible to manipulate the degree of crystallinity of the Web: www.hovione.com

www.sp2.uk.com JUNE 2004 39