Beyond the Pill: The Essential Role of Solvents in Pharmaceutical Formulation

Solvents play a central but often invisible role in drug formulation. Although it might appear that solvents are irrelevant in the final product, as a tablet contains no solvents, there are several stages on the way to a final tablet where solvents are not only useful, but inevitably necessary.

From Drug Synthesis to Tablet Production: Solvents at the Forefront

The journey of each drug molecule begins in a solution, in which solvents serve as a dissolution and reaction controlling medium for the intermediate molecular structures. This process, from synthesis to the formation of the desired molecule, depends on the effective and correct use of solvents. After synthesis, when the desired drug needs to be purified and crystallized, solvents are key to the formation of crystals (e.g. in solvent/antisolvent crystallization or cooling crystallization processes). By manipulating solvent composition, temperature, and other parameters, pharmaceutical scientists can achieve precise control over crystal size, shape, and polymorphic forms, directly influencing the drug’s bioavailability, stability, and solubility.Understanding all existing crystal structures is an important prerequisite for patenting, and several metastable polymorphs are more likely to occur in certain solvents only.

As we move from molecule to marketable powder, solvents continue to play an important role. Processes like spray drying engage solvents or solvent mixtures to dissolve all essential components, such as the Active Pharmaceutical Ingredient (API), polymers, and excipients, creating a uniform start mixture. During spray drying, as the solution passes through a nozzle, a fine powder is obtained, which is then processed into tablets. This step is particularly crucial in the manufacturing of amorphous solid dispersions (ASDs) to ensure complete dissolution. The subsequent complete removal of solvents is also vital to meet strict regulatory guidelines on residual solvent content in tablets and reduce toxicity risks.

Choosing the right solvent is a balancing act, considering environmental impact, solubility of the API and excipients, and regulatory compliance. The complexity of many drug molecules adds to this challenge.

Predicting and Perfecting Solvent Use with Advanced Modeling

amofor’s physics-based in-silico modelling approach marks a significant advancement in solvent selectionefforts. It allows an extensive understanding of interactions between components like APIs, polymers and excipients within various solvents. By accurately predicting solubilities, miscibilities, volatilities and phase equilibria, it reduces the need for extensive trial-and-error solubility screenings and accelerates the formulation process.

Our application of this model throughout drug development has proven its effectiveness from early phase 1 to advanced phase 3 clinical phases. Apart from typical solubility predictions, this tool anticipates even morechallenges associated with solvent use, such as varying evaporation rates and residual solvent contents. The complexities of solvent choice are manifold. For instance, in processes like spray drying, the interaction of different solvents with all involved components is critical. A solvent might dissolve the polymer effectively but not the API, requiring a balanced mixture of solvents. Afterwards, understanding the behavior of solvents during the evaporation process is vital. A mixture might contain faster evaporating components and slowerevaporating ones (e.g. acetone and water). This leads to unwanted accumulation of one solvent in the spray-dried particle within milliseconds, ultimately then to immiscibility of the formulated components.

Our approach, focused on predicting solvent interactions, eliminates the need for extensive physical testing. By understanding each solvent’s volatility and molecular interactions, we can predict the best solvent combination, ensuring that the final product is stable and devoid of unwanted residues.

Key Insights for Formulators

Utilizing thermodynamic modeling helps to more effectively tackle the challenges of choosing the right solvents. This ensures not only the efficacy and safety of the drugs but also adherence to regulatory standards. Our universal approach is applicable to any solvent-related process like spray drying, co-precipitation, membrane processes, granulation, coating, drying, and many more.

To stay updated with the latest in solvent applications, explore our recent publications in this field:

For any queries or assistance in selecting the right solvents, connect with us. We look forward to find with you the right solvent for your formulation!