How To Optimize Lyophilization with Thermal Analysis

Neil Demarse | Nicie Murphy | Morgan Ulrich
July 22, 2022

Lyophilization, also called freeze-drying, is the process of removing water from a sample, often for preservation. Lyophilization involves the sublimation of a sample’s water content, usually through a rapid freezing process. Freezing materials quickly helps avoid the destruction of the cell walls in the sample from the formation of large ice crystals.

Common applications of lyophilization include the preservation of materials, especially when transporting pharmaceutical products. Parenteral pharmaceuticals can become unstable or lose efficacy if they are shipped as liquids. Lyophilization is used to create a drug product that is easier to transport and reconstitute before administering to patients.

Additionally, many new therapeutic treatments have poor solubility and are difficult to incorporate into conventional drug delivery methods without losing bioavailability. Lyophilization is used to create amorphous solid dispersions that can be delivered in their solid state.1

Even as lyophilization is routinely used in the pharmaceutical industry, the process is highly specific and requires a very controlled protocol. Improper procedures can lead to insufficient freezing, overload, or equipment or sample damage. Biological samples are particularly vulnerable to freezing-induced damage that reduces the efficacy and potency of the drug product. Therefore, detailed characterization is crucial to optimize the sample preparation, lyophilization, and product delivery.

Quantifying Lyophilization

Researchers need to measure critical parameters and material properties throughout lyophilization to optimize their process and products. Thermal analysis is used to measure how changes in temperature affect a sample’s material properties.

Glass Transition and DSC

The glass transition temperature (Tg) is the point at which there is increased mobility of a lyophilized sample as it transitions from its frozen, brittle state to a more viscous state.3 Researchers need to identify the glass transition temperature to optimize the process of reconstituting samples after freeze drying.

Differential scanning calorimetry measures the temperatures and heat flows associated with thermal transitions in a material, including glass transition. For complex cases where crystallization temperatures are similar to the glass transition of the sample, temperature modulated differential scanning calorimetry can help identify these material properties. Modulating the sample temperature with a linear temperature ramp enables measurement of the sample’s heat capacity as well as the total heat flow during the test.

TA Instruments offers the only modulated dynamic scanning calorimeters for thermal analysis, including the Multi-Sample X3 DSC that can run 3 samples simultaneously to offer more data in less time. The X3 DSC makes use of TA Instruments’ patented Fusion Cell design to provide the highest level of performance for the most accurate and robust thermal analysis measurements.

Nano Differential Scanning Calorimetry is also used after a sample is reconstituted to see if the product’s stability or efficacy changed. Nano DSC can efficiently characterize molecular stability, determine high affinity ligand binding, and devoncolute multi-domain structures.

Drying and TGA

Once you have freeze dried your sample, how can you confirm that it is completely dry? Thermogravimetric Analyzers (TGA) can reliably detect even the smallest amounts of residual moisture. This analysis can be used to evaluate the quality of the lyophilization process, predict how stable a product is likely to remain, and determine optimal parameters for lyophilization.2

Karl Fischer titration is the most widely used method to detect residual moisture and can be performed on a TGA instrument; alternatively, TGA can be used to test chemicals that are not compatible with Karl Fischer titration.2 TGA also offers data on how freeze dried samples will behave in different temperatures and pressures.

TA Instruments offers a range of Thermogravimetric Analyzers built for every lab’s needs. The TGA 55 is a rugged, reliable, and cost-effective option with proprietary Tru-Mass balance for the most accurate measurements across competitive models. The TGA 550 offers enhanced performance and flexibility with add-on features and optional expansion. The TGA 5500 provides ultimate performance with less drift than any competitive TGA, plus the fastest heating and cooling rates available. For any lab and lyophilization process, there is a TGA to meet your needs and propel your research forward.

Choosing Your Instrument

Since the lyophilization process is tightly controlled, leading labs need thermal analysis instruments that are highly accurate and efficient to improve procedures without wasting precious time. Thermogravimetric Analysis and Differential Scanning Calorimetry are the standard methods for optimizing lyophilization, but there are numerous instruments to choose from, as outlined previously.

At TA Instruments, we live up to our name as the world leader in the design and production of thermal analysis instruments, including TGA and DSC. TA is solution-focused and has helped more customers successfully integrate TGA and DSC into their lab than any other supplier.

Leading laboratories rely on our DSC and TGA to enhance the productivity and suitability of their lyophilization process. From the most cost-effective to the highest capability available on the market, our wide range of instruments is sure to have a match for your lab.

Contact TA Instruments today to speak with our experts and learn how our thermal analysis instruments will improve your lyophiliztion.


  1. Kasper, J. C., Winter, G., & Friess, W. (2013). European Journal of Pharmaceutics and Biopharmaceutics Recent advances and further challenges in lyophilization. European Journal of Pharmaceutics and Biopharmaceutics, 85(2), 162–169.
  2. Matejtschuk, P., Duru, C., Malik, K., Ezeajughi, E., Gray, E., Raut, S., & Mawas, F. (2016). Use of Thermogravimetric Analysis for Moisture Determination in Difficult Lyophilized Biological Samples. American Journal of Analytical Chemistry, 7, 260–265. https://org/10.4236/ajac.2016.73023
  3. Horn, J., & Friess, W. (2018). Detection of Collapse and Crystallization of Saccharide , Protein , and Mannitol Formulations by Optical Fibers in Lyophilization. Frontiers in Chemistry, 6, 1–9.