The term coacervation derives from the Latin verb “coacervare”, meaning “to crowd together”. The technique of coacervation was first characterised by Bungenberg de Jong in 1931, although the earliest reports of this technique go back to Tiebackx in 1911. Over the last 2-3 decades complex coacervation has been deployed in industries as diverse as food, cosmetics, agriculture and functional materials, as well as, more recently, generating an increasing interest in the pharmaceutical industry as a drug delivery mechanism.
There are two methods for coacervation.
Complex coacervation is manifest in many microencapsulated products. The first recorded major use was in the 1950s in the carbonless copying paper industry. Microcapsules consist of a core surrounded by a wall or barrier of a designed thickness. The thickness of this shell ranges from several to hundreds of micrometres (2 - 300 μm) and protects the core against degradation and enables control over payload delivery under specific conditions.
Despite the wide uptake of complex coacervation, the fundamental science has been poorly understood until recently. The limitations of the earliest theory, by Voorn–Overbeek, have long been acknowledged and alternative models are now being advanced . This is opening up the field to novel systems.
A wide range of naturally derived polymers are suitable candidates for complex coacervation. The commonest of these include gelatin, chitosan, alginates, pectin and albumin although, with a plethora of grades for each product it is easy for the inexperienced to struggle to achieve their desired product performance. Some drugs formulated by complex coacervation include
There have been demonstrations of the ability to tune the shell to release under certain conditions. Examples include:
Manufacture of complex coacervates
Traditional manufacturing approaches involve dissolution of the two polymeric materials in water, with stirring. Typically an amphoteric biopolymer, gelatine (porcine or piscine are preferred) and gum acacia (or alternate polymers such as sodium carboxy methyl cellulose) Dissolution is performed at elevated temperature (50°C), at high pH (~9) to ensure no unwanted interaction between the polymers. The internal phase is then added to the tank. At this point either a recirculating homogeniser or an in-tank homogeniser is used to emulsify the mix to the specified target droplet size. Careful monitoring is required at this stage as droplet size has a profound effect on final capsule mechanical stability. Oversized capsules may be fragile and smaller capsules hard to control the release properties. In addition, the generation of foam from the applied high shear can be problematic, so the use of a defoamer is advised. Once the droplet size has been achieved the homogeniser can be deactivated and a lower stirrer speed can be used.
The pH is carefully adjusted to below the isoelectric point of the gelatine, (~pH 4) wherein the gelatine becomes cationic in nature and interacts with the anionic gum acacia, thus forming the coacervate phase. This polymer rich phase can be observed as droplets of clear polymer dispersed in the aqueous phase.
By reducing the temperature of the batch, slowly, over time, the coacervate comes out of solution and begins to deposit at the interface of the oil and water, making up the capsule wall. Different grades of gelatine have different ‘working temperatures’ where the rate of deposition is critical, allowing, by process design and formulation, differing amounts of wall material to deposit and influencing the final capsule wall thickness.
Variation in particle size distribution also affects how much coacervate deposits, with larger capsules having thinner walls than the smaller capsules. Overall droplet surface area can have an effect on how much coacervate is available.
Taking the temperature down to 10-13°C should ensure that all available coacervate have been utilised before the crosslinking step, wherein chemical or enzymatic approaches can be taken to ‘set’ the capsule walls. This process takes time and the batch can usually be left overnight to complete crosslinking. After the requisite time has passed, some post processing may be required, depending on the application, such as dewatering, pH adjustment or filtering and resuspension.
Alternative approaches to coacervation, broadly involve the same process steps but with some modifications, e.g. using chitosan with gum acacia, starts at low pH and is slowly increased to the isoelectric point of the gum acacia, which then forms coacervate with the cationic chitosan. This process can be done at ambient temperatures.
Whilst complex coacervation is a uniquely versatile encapsulation technique, it is often referred to the ‘science and art’ of encapsulation. Batch to batch variations can be challenging. Inherent differences in naturally derived biopolymers, can influence the effective pH at which coacervation occurs. A small adjustment in particle size can have a profound impact on surface area and coacervate deposition. Polymer ratios, concentration or dilution at various stages can all effect the overall quality.
The Micropore difference
Achieving an accurate target capsule size in an industrial setting can be a challenge While the homogeniser is running, samples are taken and sized via electrozone sensing (Coulter principle) or laser diffraction. These techniques take time to run, and in the meantime the homogeniser continues to reduce the size of the emulsion droplets in the batch. This makes accurate sizing unpredictable.
A preferred approach is a system where the desired size characteristics can be defined in advance and the emulsion produced in a single pass.
Membrane emulsification makes this possible, by injecting the internal phase through the membrane pores and, by applying a known shear force, droplet sizes can be controlled precisely. A combination of membrane design and control of the degree of shear force applied to the surface of the membrane deforms and detaches the uniform droplets as they form on the surface.
This single pass continuous technique can provide 10 µm droplets with a coefficient of variation as low as 10% at emulsion concentrations approaching 50%. The formation of this mono-dispersed emulsion ensures that every droplet will pick up a consistent volume of coacervate, will have a uniform mechanical stability and therefore a predictable release profile.
By reducing variability as much as possible a more consistent final product can be obtained. Membrane emulsification technologies now provide the repeatability, reproducibility and fine control not previously offered by historical emulsification techniques.
We’re ready to help you with your core-shell coacervation challenges.
Working with Micropore was a very positive experience for us. The speed with which we progressed reflects how user-friendly we found the Micropore equipment.