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Golden rules for designing a salt screening strategy for insoluble molecules

Developing novel pharmaceutical agents for clinical trials can be challenging for any pharmaceutical innovator. In particular, many drug candidates currently emerging from the discovery stage present poor physicochemical properties, such as low solubility or permeability. Approximately 40% of currently marketed compounds and the majority of drug development candidates remain poorly water-soluble.

Failure to have a strategy in place to deal with and overcome these issues could be the difference between development project success and failure. 

Physicochemical challenges

According to the Biopharmaceutical Classification System (BCS), challenging active pharmaceutical ingredients (APIs) can fall into one of four categories depending on their physicochemical features:

  • Type I: High solubility and high permeability means the API is well absorbed, simplifying formulation.
  • Type II: Low solubility, but high permeability means that the API presents some issues that hinder easy formulation development. 
  • Type III: High solubility, but low permeability, also resulting in formulation challenges.
  • Type IV: Low solubility and permeability make the API particularly difficult to formulate.

The most challenging candidates are those classed as BSC Class II and IV. These are drugs that are practically insoluble, demonstrating microgram/millilitre (mL) aqueous solubility. They are also often confounded by poor intestinal permeability in the case of Class IV candidates.

All of this matters because of the impact of poor solubility and permeability on development success. Some 90% of drug candidates fail to pass clinical trials – and physicochemical challenges are responsible for up to 15% of these failures.

Golden rules when selecting salts to tackle formulation issues

A suitable strategy to address solubility and permeability issues needs to be in place early in the drug substance’s life cycle. But, what should an effective strategy include when the salt route has been selected? Here are some golden rules to bear in mind:

  • Always start with a solubility assessment 

The first step in developing any API should be to gain a robust understanding of its solubility and stability. This typically takes the form of a solubility assessment where, on a milligram scale, API is dosed with solvent and sequentially heated until dissolution is noted or a suspension remains. A simultaneous stability review should be conducted.

  • Ensure careful counterion selection 

It’s important to choose an appropriate number of counterions to screen against. Not every salt former is fit for pharmaceutical use. Selection of counterions and the provision of a suitable screen is best accomplished by considering multiple factors:

  • API structure and behaviours (pKa, solubility, polymorphism, solvation/hydration).
  • Salt former pKa, molecular weight and structure.
  • Intended route of administration.
  • Desired drug product characteristics requiring optimization.
  • Frequency of use in marketed drugs.
  • Consider screening approaches that enhance efficiency 

Not all salts that form will be suitable for development. A “cascade approach” to salt screening can help streamline assessment. Under this method, salts are tested with greater rigor, having passed certain gateway criteria, instead of full testing and performance evaluation of all salts as they are identified. As a result, it is possible to ignore those that are unviable, saving significant amounts of time by eliminating the need to test each and every salt that forms. 

  • Work with experts

Contract development and manufacturing organizations (CDMOs) with expertise in this area can advise on testing approaches designed to offer precision results while streamlining the screening process. In doing so, they can speed up the development of challenging molecules on their journey to the clinic.

Identifying and addressing poor solubility and permeability in drug candidates is becoming ever more pressing, but all of this can be achieved with the right screening approach. To learn more about how to build an effective salt screening strategy for molecules with poor physicochemical characteristics, read our latest whitepaper.

  1. https://pubmed.ncbi.nlm.nih.gov/23383426/#:~:text=Despite%20significant%20efforts%20to%20%22design,candidates%20remain%20poorly%20water%2Dsoluble.
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780568/#:~:text=Biopharmaceutical%20classification%20system%20(BCS)%20is,immediate%2Drelease%20solid%20oral%20forms.
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293739/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293739/