The Power of Excipient Purity in API Stability – Maximise the Performance of Your Active Pharmaceutical Ingredients

Discover the Benefits of Super Refined Excipients

Active Pharmaceutical Ingredient (API) stability is one of the most important factors in pharmaceutical formulation development. Degradation and instability are common problems that can lead to extended development timescales, additional regulatory hurdles and reduced product shelf life. API degradation can have a significant impact on product efficacy, with breakdown products causing potential safety and toxicity issues.

The choice of pharmaceutical excipients can play a critical role in enhancing formulation stability. At Croda, our highly purified ingredients are designed to reduce the risk of product degradation, improving the chances of successful formulation development.

Our exclusive range of Super RefinedTM excipients has been specially developed to optimise API stability and improve the performance of pharmaceutical formulations. Super Refined materials demonstrate clear benefits, adding real value to the drug development process.

Benefits of Super Refined Excipients

• Enhanced API and formulation stability
• Fewer formulation degradation products
• Minimised analytical complexity
• Simplified formulations
• Reduced resource, time and development costs
• Improved chance of formulation success
• Multi-compendial – NF, PhEur, JPE

What are Super Refined excipients?

Croda’s Super Refined products are a range of highly purified pharmaceutical excipients in which impurities commonly found in standard compendial grade excipients have been removed. Super Refined excipients are manufactured using a proprietary process to reduce the level of impurities such as peroxides, aldehydes, moisture and catalyst residues, which are known to have an adverse effect on formulation stability. The Super Refined excipients comprise a wide range of polysorbates, polyethylene glycols and oils, making them suitable for parenteral, oral and topical applications.

Super Refined excipients are highly purified to remove impurities
found in standard compendial grades.

Initial API stability screening study

A study was carried out using 10 widely used APIs to assess their stability in standard compendial grade excipients. The APIs were selected to represent a range of different chemistry types and therapeutic areas. The excipients chosen to investigate the problem are some of the most commonly utilised in pharmaceutical formulations and include those found in the formulations of the API products.

Experimental details

Each API was dissolved in a standard compendial grade excipient at a concentration of 1 or 10 mg/g, depending on the API solubility. The API/excipient solutions were prepared in glass vials with plastic caps with a small air headspace above each sample. After an initial measurement of API concentration by high performance liquid chromatography (HPLC), samples were stored at temperatures of 4, 25 and 40ºC. At timepoints of 4, 8 and 12 weeks, samples were removed and the API concentration determined. The API recovery rate was calculated as a percentage of the initial concentration. An API was considered “unstable” if the percentage recovery was less than 90% after incubation for 12 weeks at 40ºC.

Results

The stability screening results (Table 1) show API degradation in a variety of excipients. Most of the APIs showed instability in at least two excipients, with two APIs (haloperidol decanoate and ritonavir) being unstable in all excipients tested. In polysorbate 80, a widely used excipient, 70% of APIs demonstrated instability.

Conclusion

API instability is a common problem and can have a significant impact on formulation development.

70% of APIs were unstable in at least one

standard compendial grade excipient.

Further API stability studies

For selected APIs shown to be unstable in standard grade compendial excipients, further studies were carried out to
investigate the effect of excipient purity and source on API stability. APIs were dissolved in either Super Refined excipients or standard compendial grade excipients from different sources. In each case, degradation studies were carried out at 4, 25 and 40ºC. API recovery rates were determined by HPLC as described in the screening study. In addition, the chromatograms were analysed to determine the presence of any additional peaks arising during the stability study, indicating the formation of API degradation products. In selected cases, identification of these degradation products was carried out by liquid chromatography – mass spectrometry (LC-MS) with reference to known standards.

Case Study: Docetaxel Stability in Polysorbate 80 and PEG API recovery

Docetaxel is more stable in Super Refined excipients than in standard compendial grade products.

API degradation – epimerisation and oxidation

Analysis of docetaxel samples in Super Refined and standard compendial grade excipients was carried out by HPLC (Figures 4 and 5) at each time point. In both Super Refined Polysorbate 80 and Super Refined PEG 400 docetaxel appears as a single peak at a retention time of 3.8 minutes, even after 12 weeks at 40ºC. This demonstrates excellent stability of the API in the Super Refined excipients.

In standard compendial grade polysorbate 80, two additional peaks are observed at retention times of 5.3 and 9.4 minutes. In standard compendial grade PEG 400, additional peaks are observed at 4.3, 5.3, 5.9 and 9.4 minutes. The intensity of each of these peaks increases during the study, indicating progressive formation of several API degradation products in the standard compendial grade excipients.

Key Findings

• Docetaxel stability is enhanced in Super Refined excipients in comparison with standard compendial grade products
• Multiple API degradation products are formed in standard compendial grade products that are not seen in Super Refined excipients

See the full brochure on Croda´s “Maximise the Performance of Your Active Pharmaceutical Ingredients“ here

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Source: Croda brochure “Maximise the Performance of Your Active Pharmaceutical Ingredients”

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