When I first started my career in the pharmaceutical industry back in 1986, I would find lots of strange looking spray guys squirreled away in drawers no one used. Eventually, I found out that these were solvent spray guns for the film coating equipment. So, by the 80’s, it was clear that solvent processing was fading away. Now, some 30 plus years later, working for a contract development and manufacturing organization, I am surprised by the number of clients asking for solvent capabilities because they are still using solvents in their processes. This article will discuss reasons for using organic solvents in pharmaceutical processes today as well as strategies for conversion to aqueous processes.
Generally, there are a few main reasons why processes today utilize organic solvents. The obvious first reason is that the product was developed many years ago and have never been updated. Second, is potential degradation of the API due to hydrolysis. Third may be due to the use of controlled release polymers that are water insoluble to modify the drug release of the API. Some products may be very difficult to manufacture in an aqueous environment such as hydrophilic matrix or osmotic pump formulations. Lastly, many new poorly soluble drugs may utilize organic solvents in order to create amorphous solid dispersions.
In some cases, products manufactured using organic solvents can be converted to aqueous systems thereby reducing the hazard in manufacturing these products. Eliminating organic solvents may also reduce the cost to manufacture the final product thereby improving profit. In addition, residual solvent concerns are eliminated from the final product. Not every system using organic solvents can be converted to an aqueous process, but many can. I will discuss several situations where conversion is most likely to be successful.
Many older products utilized organic solvents in the wet granulation operation prior to the introduction of fluid bed dryers. These products utilized static tray dryers to remove the granulating liquid. Due to the volatility or most organic solvents compared to water, the drying process was shorter when a solvent was used. Many of these products can be converted to aqueous systems without any issue. In order to reduce drying time, conversion to fluid bed drying can greatly reduce the drying time. Alternately, these granulation processes may be able to be converted to a dry process like direct compression or roller compaction. Today, there are many more excipients created to facilitate direct compression operations.
In cases where moisture driven degradation is a concern, we can again look toward direct compression and roller compaction operations to eliminate degradation concerns. In addition, there are formulation strategies to minimize the hygroscopicity of a formulation and reduce the overall chance for hydrolysis to occur. One operation the seems to concern many formulators is film coating. They believe that spraying an aqueous solution onto their tablets will result in high rates of decomposition. I have seen many formulators reach this conclusion after they did a “quick and dirty” experiment of film coating by dipping a tablet in to a film coating solution to simulate coating. Aside from coloring your tablet, dipping doesn’t come close to simulating the film coating process. In today’s modern coating pans, the film coating process can be conducted in a dry state that does not allow moisture to penetrate the tablet core. Naturally, if the coating process is not optimized, moisture can be driven into the tablet. In addition, moisture barrier coatings can be applied to tablets to improve their shelf life by preventing moisture transmission into the core.
In the manufacture of tablets containing high levels of viscous water soluble polymers, the granulation process with water can result in the formation of large agglomerates as water is added in the high shear granulator. I have seen agglomerates larger than a person’s head come out of a high shear granulator during the manufacture of matrix formulations. Use of solvent here, produces a much more uniform granule as the solvents typically do not hydrate the polymers. This reduces stickiness and lump formation. Another way to achieve this result is to use a spray nozzle to deliver the granulating fluid in the high shear. My preference is for pneumatic nozzles, but hydraulic nozzles can be effective as well. Utilizing a spray nozzle essentially decreases the spray flux as you increase the area the liquid is distributed over. With this technique, very hydrophilic polymers can be granulated. In addition, I believe the chopper of a high shear granulator should always be running during processing. Too many formulators do not use the chopper during the dry mixing or the infusion steps. The chopper runs at high speed and its purpose it to break up lumps and disperse liquid.
As mentioned earlier, there are some products that currently do not have aqueous options. The creation of amorphous solid dispersions is one of these problem areas. To produce these, we must dissolve both the polymer matrix and the API. Another problem area is in controlled release dosage forms. The cellulose acetate coating of an osmotic pump is a good example. I am unaware of any technique to produce a cellulose acetate coating without using organic solvents. It may be possible though, to utilize different polymers to replace this coating or to build an entirely different controlled release dosage form that yields the same release profile as an osmotic pump.
There are, however, several routes to convert some organic solvent, polymer coating systems on multiparticulates or tablets producing modified drug release rates. Ethylcellulose is a very common polymer used to coat both tablets and multiparticulate to impart a sustained drug release over time. These are called barrier membrane coating systems. These systems greatly retard drug release with low coating weight gains or film thickness. Aqueous or latex versions of ethylcellulose systems are commercially available from several suppliers. In many cases, product coated with ethylcellulose from organic solvent, can be converted to an aqueous coating in a straightforward manner. Generally, higher weight gains of the latex systems will be required in order to achieve similar release profiles. Some slight tweaks to pore former levels or plasticizers may also be needed. Methacrylate polymers are also available as aqueous dispersions and very similarly the solvent based systems can be converted in a straightforward manner.
Another recent technology being explored today is powder layering of these polymers. Micronized versions of the polymers may be layered onto beads or multiparticulates utilizing a plasticizer solution. Powdered polymer is fed while spraying the plasticizer onto the substrate. Given the right formulation and process conditions, these powder particles can coalesce together to produce a barrier membrane film to control drug release without the use of organic solvents.