Safer solvent use in the pharmaceutical industry

Solvent waste treatments

Given that (1) a lot of solvent is used in the synthesis of a typical active pharmaceutical ingredient (API), and (2) the solvent is not an inherent part of the final product, solvents are responsible for a considerable amount of avoidable waste. The cost of standard solvents is low per litre but cumulatively the outgoing is significant enough to warrant attention. Additionally, the cost of disposing solvent waste is increased by the legal obligation to safely contain and treat hazardous waste using specialised processes by trained operators. For these reasons alone it is worth considering waste-reducing actions, even without the environmental arguments.

Solvents and the waste hierarchy

Through the lens of the Waste Hierarchy (EC, 2008), the preferred approach is waste prevention, which can be achieved with a reduction in solvent use. If the volume of solvent cannot be reduced, solvent recovery practices may be used to regain some value from spent solvent. Primarily, solvent recovery is understood to mean purification of used solvents by distillation. The distillation can be performed in-house and the solvent recirculated into the same process. Alternatively, the solvent may be taken to a specialised facility. The other common solvent recovery practice is incineration. Many solvents are flammable, and their combustion creates heat energy that can be harnessed in the same way that some municipal waste is incinerated to produce energy (in preference to landfill). This form of solvent recovery is only recovering some of the energy that was required to produce the solvent. The solvent itself is not recovered, instead, incineration produces carbon dioxide, water, and other gases depending on the elemental composition of the solvent. Incineration, as a form of energy recovery, is lower on the Waste Hierarchy. Recycling does not preclude later incineration.

The decision to recover the solvent or its energy can be informed by an energy balance. Distillation requires energy, but not as much as is needed to make the same volume of replacement virgin solvent. Therefore, an energy saving is made with the positive benefit of saving carbon emissions. Incinerating a solvent produces carbon dioxide emissions, but the energy that is created offsets demand that would have had its own emissions associated with it. Using this purely energy-based argument, incineration is only preferable for hydrocarbons (with a few exceptions, as visualised below).

The high energy penalty of distillation has motivated research into membrane filtration for solvent purification. In this context, a membrane is typically a porous polymer barrier that permits certain molecules to pass through and blocks the passage other molecules. This process can be applied to the purification of mixed solvents and the separation of pharmaceutical ingredients from impurities (e.g. residual solvent or synthetic by-products). The effectiveness of membrane separation is governed by the concentration and pressure of the solvent solution on one hand, and the permeability and selectivity of the membrane on the other hand. The selectivity of a solvent-purification membrane is due to the molecular size of the solvent molecules. The use of membranes is especially valuable for the separations of solvents that form an azeotropic mixture, meaning those solvents cannot be completely separated by conventional distillation. Pervaporation (membrane separation combined with distillation) is a well-studied approach to the separation of azeotropes.

In the pharmaceutical industry, the use of solvents (and all chemical substances) is strictly controlled. There are specific tolerance levels for residual solvents in final pharmaceutical products. If a solvent is recycled by distillation or pervaporation, it will typically be reused in the same process. In doing so, any contamination may be monitored and not introduced into another process. Degradation of the solvent and accumulation of impurities must be checked, and at some point the solvent will not be considered to be of acceptable purity anymore and will be sent for incineration. Although it is possible, solvent recovery is not a default practice in the pharmaceutical industry because of the restrictions on purity, and the economic arguments are not compelling enough given the high value of the APIs.