(M1230-09-61) Careful Management of the Salt Disproportionation Risk of an In-House Developed Mono-Tartrate Salt (Compound 1)

Purpose: Disproportionation is a known risk associated with pharmaceutical salts. Failure to identify this risk early in development can lead to the in-situ formation of the poorly soluble free base, compromising bioavailability. An in-house developed compound 1 was selected as our salt API for the assessment of salt disproportionation (SD) risk.

Methods: This work outlines the investigation of SD tendencies of compound 1 using four different approaches (Figure 1). Through the use of integrated in silico and in vitro evaluations, early detection of disproportionation risks is expected to enable better formulation strategies and prevent unexpected failures in development.

Results: Based on the disproportionation solid-state risk plot (Approach A), the theoretical risk assessment for Biogen compound 1 (pKa 6.42 vs. solubility difference (Salt: Free Base 11 mg/mL:0.05 mg/mL in log) is predicted as a high-risk salt for disproportionation.  The pH_max of this salt candidate was modeled as 4.08 (Approach B), which is in good agreement with experimental value of 4.1. When the native pH is < pHmax, salt will not disproportionate. When the native pH is >pHmax, salt will likely disproportionate. Lower pHmax values generally suggest a higher risk of disproportionation given the narrower pH range that salt is stable in. Since compound 1 was identified with high disproportionation risk, selecting excipients in the formulation should be carefully considered. The microenvironmental pH shifts farther away from salt stable pH region at low pHmax are most likely to occur at water-sorbed layers on the surface of the API in contact with basic excipients. When the microenvironmental pH remains below pHmax, the salt remains stable; however, if the microenvironment pH rises above pHmax, these interactions can promote disproportionation over time, leading to the formation of a lower-solubility neutral form (free acid or free base), ultimately affecting the stability and performance of the drug product. Therefore, SD propensity was further evaluated with a comprehensive in-vitro risk assessment including both aqueous slurry (Approach C) and at solid-state (Approach D) in the presence of candidate excipients to ensure the selection of excipients that maintain the API's integrity throughout its lifecycle. Both approaches required a limited amount of API, time, and resources providing critical insights to guide excipient selection. The SD quantification was achieved via a Raman technique in Figure 2. It is generally used as the worst-case scenario to inform the risk of salt disproportionation in drug product development. This, in turn, ensures optimal formulation performance by minimizing the risk of disproportionation and its impact on the drug product's stability, solubility, and overall product quality and bioperformance. Our studies demonstrated that basic excipients increased the microenvironmental pH above the modeled pH_max, promoting conversion to the free base. As a result, all basic excipients were excluded from the formulation. Our data demonstrated that Opadry TF (barrier coating) and magnesium stearate (lubricant) were specifically identified as accelerating SD under stressed conditions leading to elevated pH beyond pH_max. Thereby they should be subsequently eliminated from further consideration (Figure 3). To further mitigate moisture-driven disproportionation, a direct-compression process was adopted, and wet-processing methods such as wet granulation were avoided. A long-term stability program under ICH-relevant conditions was initiated to confirm the robustness of the final tablet formulation.

Conclusion: The SD risk assessment, implementation of learnings toward de-risking SD, mitigation strategies for processing, rational selection of excipients and form monitoring from stability / storage condition experiments using Raman spectroscopy for quantitative analysis of SD provided a sound scientific foundation during drug substance and drug product oral dosage form development.

References: 1Serajuddin, ATM, “Salt Formation to Improve Drug Solubility”, 2007. Adv. Drug Del. Rev. 59:603-616
2Merritt JM, Viswanath SK, Stephenson GA, Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. Pharm Res. 2013 Jan:30(1):203-217
3Stephenson GA, Aburub A, Woods TA “Physical Stability of Salts of Weak Bases in the Solid-State”, J Pharm Sci, 2011, 100(5): 1607-1617
4Weldeab AO, McElderry JD, Lin Y “The Effect of In-Situ-Generated Moisture on Disproportionation of Pharmaceutical Salt”, Mol. Pharmaceutics 2023, 20,

Figure 1. Workflow for compound 1 mono-tartrate salt disproportionation (SD) assessment using theoretical modeling and empirical in vitro approaches

Figure 2. Quantification of SD in drug substance by Raman Spectroscopy

Figure 3. Empirical in vitro risk assessment in the presence of excipients leading to the excipients selection in the drug product