Rapid Insights - Mitigating Salt Disproportionation Risks

Welcome to 'Microgram Minute', the one-minute read that may save you a year in development.

Salt formation is a well-established strategy for increasing the solubility of ionizable drug candidates; however, the possible conversion of salts to their free acid or base forms through disproportionation can have detrimental effects on the stability, manufacturability and regulatory compliance of a drug product by causing variability in drug content, unexpected changes in particle size, or the formation of undesirable polymorphs. These issues can derail a development program by complicating scale-up and causing batch-to-batch inconsistencies.

Most importantly, however, disproportionation causes a drop in the solubility of the active ingredient, leading to less bioavailable forms with reduced therapeutic efficacy.

During the salt selection process, understanding and mitigating salt disproportionation risks is essential for developing robust, stable, and effective pharmaceutical products. This includes assessing the chemical stability of the salt form under various environmental conditions such as pH, temperature, and the presence of interacting excipients.

Concerns around salt disproportionation are also not limited to the API, and for example chemical intermediates are often converted to salts for isolation, purification, ease of handling, and improved stability. 

Using The Solubility Company SPA® optical technology, surprises like salt disproportionation can be identified early – from the first mg of material – while generating a robust data package evaluating solubility, dissolution, excipients, and the impact of particle size to jumpstart de-risked formulation efforts.    

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In case you missed our earlier Microgram Minutes, you can read them here:

• Jumpstarting Formulation Development
• The Data Package You Wish You Had but Don't Have Time to Collect
• Unleashing Bioavailability: A Synergistic Approach for the Race Against Disproportionation
• The Critical Role of Solubility in Saving Time and Cost in the Development of Antibody-Drug Conjugates (ADCs)
• What is 'True Solubility'?
• Solubility in Chemical Synthesis Process Scaling
• Formulate First Time Right