A drug must be absorbed by the body to reach its intended biological target. However, before reaching its destination, and depending on the type of delivery, a drug will be exposed to various environments [1]. For an oral delivery, the drug experiences various pH and media conditions (from enzymes to bile salts, etc), going from the mouth (pH 6.5–7.5) to stomach (pH 1.5–3.5) to small intestine (gradual pH increase from 5.5 to 8) and large intestine (6.0–7.0).
Therefore, the solubility and aggregation of drug molecules depends on multiple experimental parameters (temperature, ionic strength, salts, presence of excipients, etc) as well as on the different types of solvents and media conditions. From a formulation point-of-view, all these aspects should be considered to make sure that the drug remains potent and bioavailable [2].
The challenges with profiling
However, profiling solubility and aggregation is a challenging endeavour, for several reasons.
1. Profiling is resource intensive
- It requires excess drug substance, which is problematic for expensive or scarce APIs
- It requires skilled labor with extensive hands-on work
- It requires expensive and complex instrumentation
The cost of producing new drugs has steadily increased in the past years [3]. Especially with new drug modalities, such as biologics, gene therapies, and cell therapies which are generally more expensive to develop [4]. Moreover, the analytical development for these types of drugs is at an early stage. New tools and method developments are needed to address the solubility and aggregation profile of new drug modalities with particular focus on miniaturization, universality and flexibility (studying drugs in their native environment), and sensitivity.
2. Profiling is slow, uncertain and risky
- It is necessary before project initiation
- Current technologies are slow and stifle the development
Ideally, before any drug development occurs, the solubility and aggregation landscape should have been profiled. However, this challenge is overwhelming because of the enormous the amount of material needed to profile the solubility and aggregation landscape of a drug. A technology is needed that requires the least amount of compound – especially for expensive drugs where it is almost impossible to perform any type of solubility/aggregation profiling.
3. Profiling is constraint by production:
- There is pressure to develop, but many potential formulations pathways to choose
- Aggregation curbs manufacturing
Indeed, once the drug enters the drug product phase, there is a pressure to increase its production. However, if the aggregation profile is not yet optimized, the yield will be low and process improvements must be a top priority. To optimize the process, aggregation profiling is a must and should be obtained with speed and precision.
These difficulties are important; hence scientists and technicians are left with little coping strategies. Either by measuring only a few conditions assumed to be key, or by delaying the study only when problems happen. In a nutshell: you have to make tough choices by sacrificing either knowledge or resources.
Rethinking solubility and aggregation profiling: Oryl’s solution
Oryl has developed a groundbreaking technology to measure drug aggregation and solubility using a patented ultrafast laser-based second harmonic scattering (SHS) method. This optical phenomenon measures how the solvent redistributes around the solute molecules (what we call the Solvent Redistribution method) to follow the dynamics of solubility and aggregation in an accurate, fast and resource-saving way. The key advantage of this method is its minimal sample requirement, using only 10 µg per solubility datapoint.
Unlike HPLC-based systems that require over 1 mg of compounds, Oryl’s method allows you to obtain around 100 solubility datapoints from the same amount. This enables large-scale solubility and aggregation profiling. Additionally, since the technology uses light-scattering and standard well-plates without destroying the sample, you can perform time-lapse and dynamic measurements and reuse the sample for other complementary techniques.
In a nutshell, Oryl’s method allows rapid, accurate and actionable feedback to orient the drug development using as little compound as possible. This versatile technology works with both small and large molecules in any dipolar solvent, allowing you to profile conditions across various salt concentrations, excipients, and solvents.
References
[1] https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00524/full
[2] https://www.mdpi.com/1999-4923/15/2/484
[3] https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820562
[4] https://pharmaoffer.com/blog/small-molecules-vs-biologics-understanding-the-differences/