When API content drops under accelerated stability conditions and known degradation products don’t account for the loss, development teams need answers quickly. This Ardena application note shows how SOLFORD®, a solid-state degradation technology developed and patented by RD&C, was applied to forced degradation and drug-excipient compatibility screening. The approach confirmed a stability-indicating method and identified the formulation components linked to impurity formation, generating relevant data within days rather than weeks.
Application note by Ana Lobo González, Analytical Scientist, and Marta Agúndez Salinas, Analytical Development Expert, Ardena.
The challenge: unexplained API loss during formulation development
During formulation development of an encapsulated product manufactured with a wet granulation step, a significant decrease in API content was observed under accelerated stability conditions. The increase in known degradation products did not fully explain this decrease.
The team needed to answer three questions quickly:
- Was the impurity method truly stability-indicating, capable of detecting all degradation formed during manufacturing and shelf life?
- What are the main degradation pathways of the API?
- Which formulation components contribute to product degradation?
A stability-indicating method requires an acceptable mass balance: every species in the sample, the API plus its degradation products, must be reflected in the chromatogram. Conventional forced degradation and excipient compatibility studies can take weeks to deliver this evidence, which slows early CMC decisions.
The approach: mechanochemical stress testing with SOLFORD®
SOLFORD® is RD&C’s patented solid-state degradation technology. It uses mechanochemistry, specifically ball milling, to accelerate degradation, offering an efficient alternative to conventional stress testing. Beyond forced degradation, its applications include drug-excipient compatibility screening, formulation design within Quality by Design (QbD) frameworks, and assessment of packaging, storage conditions and polymorphic transformations.
Two complementary studies were run.
Forced degradation of API, drug product and placebo
The API, drug product and placebo were each subjected to acidic, alkaline and oxidative stress by ball milling, then analysed by HPLC to quantify degradation and characterise impurity profiles. Including the placebo made it possible to distinguish API-related peaks from excipient-related peaks.
Excipient compatibility screening that mimics the process
Because the manufacturing process includes wet granulation, a modified SOLFORD® approach was used. The API was incorporated in solution form to better reflect real manufacturing conditions. Two experimental designs were combined:
- Binary API:excipient mixtures to assess direct drug-excipient interactions.
- Component omission (“formulation minus one”), in which each excipient was removed in turn, to evaluate each component’s contribution to the overall degradation profile.
Key results
- Stability-indicating method confirmed. Satisfactory mass balance across the forced degradation and compatibility studies confirmed the suitability of the analytical method.
- Oxidation is the main degradation pathway. Under oxidative stress, API content fell to 52.2%, while acidic and alkaline conditions showed limited impact. The major degradation products were identified.
- Origin of impurities clarified. Differentiating API-related from excipient-related peaks gave a clearer picture of the degradation products seen in stability studies.
- Mannitol flagged as a likely key contributor. No impurities were detected when mannitol was excluded from the formulation, while impurities were present in every mixture containing it. The capsule material also showed a significant influence on API stability.
Why it matters for early CMC decisions
Knowing early which pathway drives degradation, and which excipients are involved, de-risks both the analytical and the formulation workstreams. A confirmed stability-indicating method gives confidence in stability data. Identifying problematic excipients allows formulation adjustments to be considered before they become late-stage issues.
Compared with conventional approaches, mechanochemical ball milling significantly reduced study timelines and experimental effort. This supports faster development of robust analytical methods and optimised formulations.
At Ardena, our [analytical development] and [formulation development] scientists integrate approaches like this into CMC programmes, helping clients take decisions on solid data from the earliest stages. We know development™.
Download the full Application Note
The full application note includes the complete experimental design, forced degradation results for API, drug product and placebo, mass balance data, and the binary and component-omission impurity profiles.
Subject Matter Experts
Ana Lobo González
Analytical Scientist
Ana Lobo González is Analytical Scientist at Ardena, where she is part of the Analytical Development team. As part of her doctoral research, she is developing a forced degradation technology and a universal method for analytical development, aimed at streamlining the development of stability-indicating methods, making it more time and cost effective. Her work involves the use of HPLC/UPLC and SOLFORD technologyapplied to solid oral dosage. Ana joined the Pamplona site in 2023 to begin her industrial PhD in collaboration with the University of Navarra, after two years working in community pharmacy. Ana attended CAI 2026 where she defended a poster: “Accelerating Drug Stability Studies: Comparison using HPLC Between Conventional and Mechanochemical Stress” Ana holds a degree in Pharmacy from the University of Navarra.
Marta Agundez Salinas
Analytical Development Expert
Marta Agúndez Salinas is Analytical Development Expert at Ardena, where she provides technical leadership for the Analytical Development area, delivering innovative and efficient analytical solutions for drug development in line with regulatory requirements. Marta brings more than 24 years of experience in the pharmaceutical industry, all of them at the Pamplona site, which she joined in 2001, well before it became part of Ardena. Over this time, she has contributed to the implementation of GMP systems, the introduction of new technologies and the consolidation of the analytical area, progressing from hands-on laboratory work to leading analytical development projects and coordinating teams. Her career is built on commitment, continuous improvement and the conviction that people are key to sustainable, high-quality results. Marta holds a degree in Pharmacy and a PhD in Organic Chemistry from the University of Navarra, and complemented her scientific training with studies in Business Administration. She also collaborates with the University of Navarra, supervising master’s projects and two doctoral theses.