The loss On Drying (LOD) Test is the most important Quantitative analytical technique in the Pharmaceutical Industry. However, a suitable LOD method is required for each and every Pharma product or Material. Hence to simplify our work, a good Method Development procedure for the determination of “Loss on Drying” was provided step-by-step.
Loss on drying Principle
The Loss on drying (LOD) test parameter determines the amount of volatile matter and the content of Water present in a drug substance/ drug product/ any material, under the specified conditions. LOD is a thermogravimetric analysis technique.
Determination of Loss on Drying
Accurately weigh the uniform material about 1 to 2 g (based on the method reference). Ensure the particle size of the substance is about 2 mm by gentle crushing.
Take a pre-dried glass-stoppered LOD bottle (dried for 30 minutes under the same conditions as the test sample). Transfer the test sample to a LOD bottle, keep the bottle cover, and accurately weigh the bottle and the contents. Ensure to distribute the test sample by gentle, sidewise shaking, as evenly as practicable to a depth of about 5 mm (not more than 10 mm).
Keep the LOD bottle in a hot oven at the required temperature by removing/ leaving the bottle stopper in the same oven. Hold and dry the test sample for an appropriate time interval. The acceptance criteria of the temperature are ±2°C of the set temperature. Once after completion of the drying, open the oven and close the LOD bottle properly, and cool it to room temperature in a desiccator before weighing.
If the test sample melts during the “Loss on drying” process, then the set temperature adjusts to 5 to 10°C below the melting temperature. Then re-perform the drying activity.
LOD of Capsules: Use mixed contents of 4 capsules and more.
LOD of Tablets: Use powder from 4 tablets and more (ensure, ground to a fine powder).
Drying in vacuum over a desiccant: Use a vacuum desiccator or a vacuum drying pistol, or other suitable vacuum drying apparatus.
In a desiccator: Ensure that the desiccant is kept fully effective and replaced recently.
Capillary-stoppered bottle in a vacuum: Use a bottle or tube fitted with a stopper having a 225 ± 25 µm diameter capillary, and maintain the heating chamber at a pressure of 5 mm or less of mercury.
Loss on drying test procedure – Simple Guidance
Set the temperature of the oven (Vacuum/ Hot air) to the required temperature (in °C). Heat the Stoppard bottle to set the temperature for 30 minutes. After this period, remove it from the oven and cool the Stoppard bottle in the desiccator. Accurately determine the weight of the bottle and record it as “A” mg. Transfer the sample to the weighing bottle and stopper it (in grams/mg). Weigh the bottle accurately and record it as “B” mg.
Spread the sample evenly by gentle side-wise shaking. Place the bottle in the oven with the stopper still in place. Dry the sample in the oven at a set temperature for 3-4 hours (based on requirement). Remove the bottle after the drying period, and with the stopper still in place allow it to cool to room temperature in a desiccator before weighing. Weigh the bottle accurately and record it as “C” mg. Repeat this up to a constant weight.
Loss on drying formula / Calculation
Loss on drying Method Development Procedure
The below basic requirements shall fulfil for the best LOD Method development.
Melting Range of the material
Chemical Structure and synthetic scheme
Melting range of the material
Search for literature (USP, EP, etc) for the same molecule or for similar molecules having similar structures.
Chemical structure:
Based on the chemical structure, ensure that the product may be degradable or dehydrated, etc.
Loss on drying Method Development Procedure
Check the loss on drying on a minimum of about 1 gram (1 to 2 grams) of the sample.
Observe the sample description, whether it is changing or not. If the description is changing from dull to dark in any color indicates the product is degraded. Check the purity as per the existing related substances method. If any degradable impurities are found when compared to initial purity. Discord this method of analysis. Try at lower temperatures with a vacuum (20 mm Hg), as per USP General chapters and Assays <731>.
Basics to ensure during Method Development
If the test substance is in the form of large crystals, reduce the particle size to about 2mm by quickly crushing. Take a “glass stopper, shallow weighing bottle” that has been dried for 30 minutes under the same conditions to be employed in the determination. Transfer the test specimen to the bottle, replace the cover, and accurately weigh the bottle and the contents. Place the loaded bottle in the chamber. Dry the test specimen at the temperature and time specified as per the method development. The temperature specified in the development method or as per the individual monograph is to be regarded within the range of + 2°C of the stated figure. Up on opening the chamber, close the bottle promptly, and allow it to come to room temperature in the desiccator before weighing.
Optimize the analysis time by studying with different heating times at the same temperature, so as to result will remain unchanged by about 10-20 % of the specification limit or justify the variation. A similar way optimizes the analysis temperature also.
If the material is hydrated, compare the water content with the Loss on drying. If the results are not comparable with respect to the water by KF, go for the TGA analysis.
Note: If the substance melts at a lower temperature than that specified for the determination of LOD, maintain the bottle with its contents for one to two hours at a temperature of 5°C to 10°C below the melting temperature, then dry at the specified temperature.
VACUUM: As per USP, the term ‘in a vacuum ‘ denotes a pressure of less than 20 mm of mercury unless otherwise indicated.
Other reference or guidance on Loss on drying technique
USP General Chapters and Assays: Loss on drying <731>
European Pharmacopoeia, Physical and physicochemical methods <2.2.32>.
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