T3/T4 Formulations - Compounding Issues and Recommendations

Liothyronine Sodium (T3) and Levothyroxine Sodium (T4) are iodonated 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 these 3 issues: microgram concentrations, iodination of the compound, and water.

Three Common Compounding Issues

1. Microgram concentrations

In the preparation of a powder blend to be use for preparation of T3/T4 capsules, typically the active ingredients are mixed with microcrystalline cellulose and perhaps methyl cellulose as well, to provide the correct dilution and desired slow release properties. Sometimes a coloring agent is also included to provide a visual indication of completeness of mixing. Normally, these are blended according to the technique of geometric additions and mixed/stirred in the same fashion as many of the other capsule formulations. Blending micrograms is more difficult than blending milligrams, since microgram is 1/1000th of a milligram. A few particles of the API powder may equal a microgram. These few particles must be evenly distributed throughout the powder blend. It takes longer to evenly blend micrograms of an ingredient than it does milligrams.

If the particle size of the API is significantly different from that of the other ingredients, even when the particles are well-mixed, they may not stay mixed. 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

Halogens are electronegative because of their electron rich outer shell orbital.

T3 and T4 both contain iodine atoms which are members of the halogen group. 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. Th faster the powder blend is mixed, the stronger the static charge will be. ARL has observed T3T4 API clinging 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 made to account for this. 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 API powders.

• Both the active and inactive ingredients should be micronized to approximately the same particle size to 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 make sure the actives are well mixed. Mortar and pestle mixing may not be enough or effective.

• The time required will vary depending upon batch size and mixing speed, but a 2-hr. mixing time would not be unusual.