Drug Formulation: Lipophilic Compound Q&A

Break away from historical suspicion to uncover opportunities which leverage compounds with high lipophilicity.

Lipophilic compounds have a notorious reputation for being challenging to formulate, but, with the help of today’s technology and excipients, we’re here to disprove this notion. Be it poor aqueous solubility, variable absorption, or instability, drug developers hoping to achieve acceptable lipophilic drug products have been plagued for decades with consistent challenges.

Break away from historical suspicion to uncover opportunities which leverage compounds with high lipophilicity. While these compounds are often passed over given the characteristics above, our team has overcome these obstacles and outlined the materials and thought processes to create a more straightforward approach.

Dave Barnes, Ph.D., Vice President of Scientific Affairs, has answered questions below directly from our industry colleagues, themselves. For more in-depth background, check out his latest webinar, "Developing Liquid Formulations for The Oral Dosing of Lipophilic Drugs."

Is it feasible to administer a lipid formulation as a liquid, without needing to fill into capsules?

Based on published knowledge from Gattefosse, known to work with these materials often, the taste and mouth feel of lipid excipients is very off putting to humans and should not be dosed as a liquid. These should be filled into capsule shells.

To what extent does daily intake limit of lipid excipients restrict their usage for oral delivery?

With pure lipids this is rarely an issue. In my experience, it is the surface-active compounds that can cause issues and that's why we tend to formulate products with both a lipid in which the drug is dissolved and an emulsifying agent, rather than simply dissolving the drug in a surface-active excipient. Clinically, the volumes being dosed are typically small enough, this is not a concern.

What precautions would you consider regarding storage? For example, many of these lipid compounds are commonly stored at -20 or -80 degrees Celsius depending on the compound.

As a dry powder, many lipid drugs are unstable and must be stored at frozen temperatures. In my experience, once the compound is dissolved in a suitable lipid vehicle that also contains an antioxidant, the chemical stability of the compound is much improved and low temperatures are no longer required.  

When developing a strategy for solubility studies, how would you recommend narrowing down excipient choices?

Typically, we conduct a solubility screen in pure lipids rather than in surface active materials which cuts down the number of excipients needing to be considered.  Once we've decided which lipid to utilize, we use hydrophilic lipophilic balance (HLB) values to determine the best emulsifying agents for the product.

How can you avoid crystallization of an amorphous drug in a lipophilic system?

While not having experienced this firsthand, highly lipophilic compounds usually don't crystallize on their own accord.  In more conventional circumstances, we have inhibited the crystallization of drugs in a liquid formulation by the addition of nucleation inhibitors such as polyvinyl pyrrolidone (PVP).  If you are seeing crystallization, I'd suggest adding a nucleation inhibitor.

Is it possible to solubilize the lipid molecule with a high HLB emulsifying agent for a systemic drug product?

Yes, there are several products on the market containing the drug plus Gelucire filled into capsule shells.  The various grades of Gelucire all have high HLB values, usually 11 and above.

What are your thoughts on the use of SLS to make pharmaceutical solutions, emulsions, or suspensions?

Most of our clients shy away from using Sodium Lauryl Sulphate (SLS) as an emulsifier or solubilizer due to the large amounts required.  Alternatively, SLS has great value as a wetting agent. When developing aqueous formulations of hydrophobic drugs, the addition of a small amount of SLS (typically <1%) greatly improves the dispersal of the drug crystals within the product.

In closing, the understanding and application of lipophilic compounds is still in reprieve from former challenges, but new strategies create a wealth of opportunities. High lipophilicity was once a factor for elimination and now this feature no longer inhibits progress. 

For more on lipophilic drug formulations, watch our webinar, "Developing Liquid Formulations for The Oral Dosing of Lipophilic Drugs."

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