Method Development & Forced Degradation

High performance Liquid Chromatography (HPLC) & Gas Chromatography (GC)

High-performance liquid chromatography (HPLC) is the typical method of choice for assessing the purity and impurities of new drug candidates in process development, running control and stability studies or evaluating new formulations for development. Gas Chromatography (GC) may also be used when compounds under testing are volatile or HPLC is deemed otherwise unsuitable.

Rationale for HPLC Method Development for the API Release

  1. To harmonize the testing of starting materials, intermediates and API in a single method
  2. To use the API method for in-process-control or whether to use a shorter method (preferably with the same column and mobile phase combination / compositions to avoid error) to maximize the efficient use of each instrument.
  3. To apply a retrospective approach to method development that would start development first on the API method, then adding the starting materials and intermediates to the method to check the overall method suitability.
  4. To evaluate method specificity during process development to ensure that adequate specificity is provided for the current process.
  5. To conduct forced degradation to evaluate method specificity for the degradants.

Forced Degradation and Understanding of the Degradation Pathway

Forced degradation is an integral part of impurity evaluation in method development, which is undertaken to facilitate development and to demonstrate the suitability of stability indicating methods. This is particularly important when little information is available about potential degradation products.

Forced degradation studies generally rely upon conditions that promote thermolytic, hydrolytic, oxidative, and photolytic degradation mechanisms. The goal of these studies is to generate a primary degradation profile that mimics or exceeds what would be observed in accelerated stability studies conducted under ICH conditions.

J-Star Research scientists design experiments to generate similar amounts of degradants to those occurring in stability studies. A team of organic chemists and analytical chemists can thus achieve a comprehensive understanding of the relevant degradation pathway.

Chiral Separations

The presence of stereocenters in intermediates and Active Pharmaceutical Ingredients (APIs) add an additional layer of required analytical understanding, monitoring and control. Each enantiomer or diastereomer may have great variations in efficacy and toxicity. In 1992 the Food & Drug Administration (FDA) issued a series of guidelines for the development of single enantiomers and racemates in pharmaceuticals.

We can rapidly screen a wide selection of chiral columns on a Spiderling system and then further optimize the resulting chiral HPLC method.

Our team of analytical chemists with training in organic chemistry and extensive experience with poly-chiral compounds facilitates efficient and rational method development / optimization.

Method Development with HPLC-CAD

Charged Aerosol Detector (CAD) is a universal detector and (in conjunction with HPLC) can be used to measure all non-volatile (and some semi-volatile) compounds. This renders it extremely useful in the evaluation of purity and quantification of impurities for new drug candidates or intermediates lacking a significant UV chromophore.

J-Star Research began using HPLC-CAD in 2013 and now has multiple HPLC-CAD systems in house. As such we have a deep-rooted experience base in gaining invaluable experience with method development / optimization / troubleshooting with this mode of detection.