Differential scanning calorimetry (DSC) is one of the most important Analytical techniques in the Pharmaceutical Industry. However, a suitable method is required in order to Develop a Robust Analytical method. Hence, the DSC method development procedure is provided here for reference purposes.
Differential scanning calorimetry Principle
Differential scanning calorimetry (DSC) is a “Thermo-analytical technique” in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature.
The sample and reference material are maintained at the same temperature during the experiment.
Differential scanning calorimetry (DSC) Method Development
The Analytical Method Development Procedure for the “DSC” analytical technique is illustrated as guidance. Hence, refer to this never-before article to achieve Method Development goals.
Precautions during DSC instrument operation & Method Development
Warm-up Time and Environment: It is recommended that, ensure that the Instrument (Electronics) stabilize for at least one hour after the system is turned off (important samples).
Avoid Areas such as hoods or near an air conditioner. Ensure to perform the Calibration prior to the operation in case of Cooling accessories used.
Crimped pans vs Hermetic pans (sealed) for DSC instrument
Use a Hermetic pan if the sample loses approximately 0.5 % or more.
Excessive decomposition will contaminate DSC cells between runs (This will help in the selection of Experimental conditions).
Take appropriate care, as the bottom of all pans, shall be flat. This is to improve heat transfer/ Resolution.
Sample Preparation for DSC Method Development
Keep the sample in a thin film. Cut rather than crush.
Weigh 10 to 15 mg for polymers, Approximately 3-5 mg for metals or chemical meltings, or as specified in the individual monograph, for existing methods in the patents, customers, or other literature.
The goal is to achieve a change of 0.1 to 10 J/gram heat flow in going through the transition.
If a sample contains volatiles, put pinholes in the lid of the pan before crimping in order to permit a continuous evaporation process.
Selection of Purge Gas
| Parameter | To increase Sensitivity | To Increase Resolution |
| Sample weight | Increase | Decrease |
| Heating Rate | Increase | Decrease |
| Purge Gas | Nitrogen | Helium |
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DSC Method Optimization
Always do TGA method optimization experiments before beginning DSC tests on new materials.
Heat approx 10 mg sample at 10°C/min to determine the volatile content.
Note: Unbound water or solvent is usually lost over a broader temperature range and a lower temperature than a hydrate/Solvate (Pseudo-polymorphs).
Decomposition temperature: This gives an idea to know whether the material is decomposing or not. The measured decomposition temperature will shift to lower temperatures at lower heating rates.
Note: Pseudo-polymorphs: All hydrated or solvated forms are pseudo-polymorphs.
All the products shall analyze at different heating rates by applying the typical approximate experimental conditions as mentioned below.
Sample weight: About 2-5 mg
Starting temperature: About 40°C or specified as per monograph.
End temperature: Depending on the melting point/decomposition
Rate : 1°C/min, 2°C/min, 5°C/min, 10°C/min and 20°C/min
Nitrogen/Helium flow: As per the developed conditions (30ml/min or 50ml/min).
Compare the data at various heating rates and select the appropriate conditions.
Finalize the analytical conditions by using the data generated above, in case the same was not available with the literature/patents/ Pharmacopoeia.
If the literature is available, then use the data generated above to evaluate the various changes observed with different heating rates.
Run the sample by using finalized conditions. In the case of certain new products, the sample weight may affect the thermal changes. The sample weight decrease or increase depending on the observations from the thermogram.
Quantification of unwanted polymorphs
Always develop the quantification method if the polymorph shows a difference in melting points (approx 5 °C).
Spike the undesired polymorph in the desired one with different spiking concentrations and observe the increase in peak area wrt the desired one.
Fix the LOD, and at what concentrations, we are observing the peak.
Draw the calibration curve with respect to concentration vs peak area of the undesired form.
Note: Select the unwanted standard form by applying different techniques like XRD, IR, TGA, etc. So because there is no interference of other unwanted forms during the quantification along with the desired form.
Perform a study on micronized samples as a fresh sample and make a correlation with before micronization. Studies like Endotherm temperature variation, additional endotherms/ exotherms observation, etc….
Finalize the method once after satisfactory results and justification.
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