Homogeneity is essential for ensuring appropriate dosing of medications. Active pharmaceutical ingredients that have been appropriately weighed or measured and are known to be stable in a given preparation may still be dosed inappropriately if the resultant compounded preparation lacks homogeneity.
An excellent way to ensure homogeneity is spot testing compounded products from various locations, such as testing the top, middle, and bottom of a cream after mixing or testing capsules from different areas of the capsule machine,, Hhowever, this level of testing is not possible to complete on all compounded preparations, and there is a need for the development of standardized mixing protocols to ensure repeatability of a homogenous mixture. This need is especially acute for dilutions that are used to compound products for several different prescriptions and those that involve the use of narrow therapeutic index drugs.
Levothyroxine sodium and liothyronine sodium are narrow therapeutic index drugs and are commonly compounded into dilution formulas to allow for accurate measurement consistent with the minimum weighable quantity of scales typically used by compounders. To achieve appropriate minimum weighable quantities and simplify calculation, levothyroxine sodium and liothyronine sodium are often compounded as a 1:1000 (1mcg/mg) dilutions. The extreme API to excipient ratio makes levothyroxine sodium and liothyronine sodium dilutions excellent proof of concept for a mixing study and homogeneity test.
We set out to evaluate homogeneity of levothyroxine sodium and liothyronine sodium mixed into capsule excipient vehicles (SimpleCap) by testing the top, middle, and bottom of a dilution product and submitting to an independent FDA registered, cGMP compliant laboratory for testing.
Formulation Tested
Homogeneity was evaluated by testing the top (sample taken from top 10%), middle (sample taken from middle 40-60% of the jar), and bottom (sample taken from bottom 10%) after mixing. Quantitative assessment of relative standard deviation (RSD) was used as a measurement of homogeneity. RSD calculations are used to determine the standard deviation of a set of data to the mean. Levothyroxine sodium 1mcg/mg (1:1000) in SimpleCap came back with an average of 96.6% potency and an RSD of 2.35%. Liothyronine sodium 1mcg/mg (1:1000) in SimpleCap came back with an average of 97.6% and an RSD of 4.62%. These results indicate a high degree of homogeneity throughout the dilution product for levothyroxine sodium and liothyronine sodium with the indicated mixing program on the Invomatic.
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References
1. Rosch M, Gutowski T, Baehr M et al. Development of an immediate release excipient composition for 3D printing via direct powder extrusion in a hospital. International Journal of Pharmaceutics. 2023; 643: 123218
2. Marianni B, Polonini H, Oliveira M. Ensuring homogeneity in powder mixtures for pharmaceuticals and dietary supplements: evaluation of a 3-axis mixing equipment. Pharmaceutics. 2021; 13(563): doi: 10.3390/pharmaceutics13040563
