Liothyronine Sodium (T3) and Levothyroxine Sodium (T4) are iodinated amino acids and are typically formulated in microgram concentrations. These active pharmaceutical ingredients (APIs) contain water: up to 4% in the T3 powder and up to 11% in the T4 powder. The primary reasons for the difficulty in preparing formulations containing T3 and/or T4 arise from 3 common issues: microgram concentrations, iodination of the compound, and water.
Three Common Compounding Issues
1. Microgram concentrations
In the preparation of a powder blend of T3/T4 capsules, typically the active ingredients are mixed with microcrystalline cellulose and, potentially, other excipients like methyl-cellulose, to provide the correct dilution and desired slow-release properties. Sometimes additional materials are added, such as a coloring agent, to provide a visual indication of completeness of mixing. Normally, these ingredients are blended through the technique of geometric addition and mixed or stirred in the same fashion as other capsule formulations. This becomes an issue is treated the same as other capsule formulations as blending microgram quantities is significantly more difficult than blending milligrams, due to a microgram being 1/1000th of a milligram. A few particles of the API powder may equate to a microgram, thus these few particles must be evenly distributed throughout the powder blend for a homogenous preparation. To achieve this desired microgram distribution it often takes longer to blend in comparison to a milligram distribution preparation and may require different handling techniques. In T3/T4 blends the particle size of the API is significantly different from that of the other ingredients, so even when the particles are well-mixed, they may not stay mixed due to this difference. During handling, the vibrations generated in the process will cause the smaller particles to move toward the bottom of the container while the larger ones will migrate to the top.
2. Static charge
T3 and T4 both contain iodine atoms which are members of the halogen group. Halogens are electronegative because of their electron rich outer shell orbital. If the powder blend is mixed in a plastic container, the agitation of the cellulose along with the T3/T4 actives will develop a strong static charge on the walls of the container which will attract these microgram amounts of ingredients out of the blend and onto the surface of the container. The faster the powder blend is mixed, the stronger the static charge will be, and the more the API will migrate out of the blend. ARL has observed, through several rinse studies, T3T4 API migrating and staying attached to the walls of containers.
3. Water Content
Since a portion of the weight of the T3 and T4 powder is water, adjustments in the desired amounts of these ingredients must be considered to offset this content. An appropriate extra amount of the API powder should be included in the formulation so the final product will not be sub-potent.
Compounding Suggestions:
- Make sure your formulation appropriately accounts for the water content in the raw, starting material API powders.
- Both the active and inactive ingredients should be micronized to approximately the same particle size to help prevent stratification.
- Blends containing microgram amounts of T3 and or T4 actives must be blended longer and more completely than usual.
- Avoid using plastic containers for mixing and storage. The blending should be accomplished in either glass or metal containers and should have a tumbling action of side over side and end over end to ensure the actives are well mixed. Mortar and pestle mixing may not be enough or as effective by comparison.
- The time required for thorough mixing will vary, depending upon batch size and mixing speed, but a 2-hr. mixing time would not be unusual to achieve proper dispersion.