Why Organic Solvents Matter in Freeze Drying: Solubility, Stability, and Structure
Welcome back to the “Colorful Researchers” blog. In my last post, I discussed how our spray-drying solutions are used to create the types of modern batteries required for the green energy revolution. In this post, I’d like to turn my attention back to freeze-drying, particularly how to work with solvent mixtures.
Using solvent mixtures is a development made possible with modern instruments that can achieve lower temperatures. In our Lyovapor™ line, the L-200 can achieve a stable condenser temperature of -55ºC, which is ideal for working with water, but products not soluble in water are out of bounds. Achieving a condenser temperature of -85ºC was a goal for our new Lyovapor™ L-250 to ensure the instrument could handle applications that require organic-based solvents. Energy efficiency was essential when designing this new instrument because it requires more energy to achieve lower temperatures.
Why are solvents required to freeze-dry specific samples?
Freeze-drying, or lyophilization, is a process that removes water (or another solvent) from a sample by first freezing it and then sublimating the solid phase into a gas under reduced pressure. The use of water versus organic solvents in freeze-drying depends mainly on the samples' properties and the solvent’s characteristics. While water is the most used solvent in freeze-drying, there are many situations where water isn’t suitable. In fact, for certain products, especially those in the pharmaceutical sector, organic solvents are not just beneficial but essential.
But why is that the case? Let’s dive into why organic solvents, such as acetonitrile, acetone, methanol, and ethanol, are required for freeze-drying specific samples and why water can sometimes fall short.
Solubility: Why are organic solvents necessary for dissolving hydrophobic compounds during freeze-drying?
One of the primary reasons for using organic solvents in freeze-drying is the limited solubility of certain compounds in water. Many active pharmaceutical ingredients (APIs) are hydrophobic, meaning they don’t dissolve well in water. Attempting to freeze-dry these substances from an aqueous solution can result in incomplete dissolution, poor distribution, and uneven drying — all of which can impact the quality and effectiveness of the final product.
Organic solvents, on the other hand, can dissolve hydrophobic compounds more effectively. Solvents like acetone, ethanol, and methanol are commonly used as co-solvents in these cases. They allow the product to form a homogenous solution that can be uniformly freeze-dried, preserving the integrity and efficacy of the drug. In some cases, neat dimethyl sulfoxide has been used to achieve maximum solubility.
Solvent Mixtures: What are the advantages of using solvent mixtures for advanced formulations like nanoparticles or liposomal drugs?
In some freeze-drying applications, a mixture of water and organic solvents is used to create a solution that balances the benefits of both. These mixtures can be tailored to suit the needs of complex materials or formulations. For example, in cases where a compound is partially soluble in water but requires an organic solvent to dissolve completely, a mixed-solvent approach allows for more flexibility.
This is particularly useful in advanced drug formulations like nanoparticles or liposomal drugs, where a combination of water and organic solvents can optimize the final product's stability and performance.
In some cases, the use of short-chain alcohols such as butanol, and isopropyl alcohol can help the chemical stability of the solute in the dry product. Their impact on the crystallization behavior of the solute seems to be the main factor for this result.
Drying process: How can organic solvent as co-solvent be used to optimize the process?
Organic solvents and their aqueous mixtures have higher vapor pressures than water. This creates a higher pressure gradient between the condenser surface and the sample. Since the sublimation rate and, subsequently, the drying time depends on this gradient as a driving force, one can observe a faster drying process.
As the freezing step in freeze drying has such a significant impact on the sublimation rate, the specific addition of solvent to the aqueous sample can initiate different freezing behaviors in the sample. The result is large and needle-like ice crystals. The formation of big ice crystals facilitates the sublimation due to a more significant channel inside the product by which the vapor can leave the sample. In other words, product resistance decreases with increasing ice crystals. A well-exploited candidate/co-solvent is tert-butanol.
Final Product Quality: Why do organic solvents produce superior product quality, especially in pharmaceuticals?
The physical properties of the final freeze-dried product, such as porosity, surface area, and reconstitution time, can be significantly influenced by the choice of solvent. A more porous freeze-dried “cake” structure is often desirable for pharmaceuticals because it reconstitutes more quickly and evenly when mixed with a solvent for administration. In these cases, choosing an organic solvent can make a big difference in the performance and usability of the product.
Since ice crystal formation during freezing is linked to porosity, a.k.a. the surface area, freeze-dried' cakes’ with different surface areas show different stability behaviors. The presence of an organic solvent in a mixture contributes to a larger area, leading to a larger distance between the molecules and, finally, a smaller degradation rate.
How do you work with organic solvent mixtures and maximize efficiency?
Understanding why organic solvents are necessary for certain applications is one thing, but working with them effectively is another thing entirely. When working with organic samples, you need to know:
- How can a solvent be frozen, and which method can reach a low enough temperature to freeze the sample fully?
- At what concentration can the solvent be frozen? Does the solvent need to be diluted?
- Can the ice condenser collect the solvent?
- Will the samples remain frozen during the process?
Understanding all these things is essential for effective method development and endpoint determination. Luckily, our specialists have put together a webinar that answers each of these questions, allowing you to maximize efficiency in freeze-drying solvent mixtures.
Bueno Chao,
Bruno