Preformulation Studies: Stability analysis

Stability analysis is an area of great interest in preformulation studies. It is a complex set of procedures performed on candidate drug molecules or dosage forms that are in their final immediate packaging intended for marketing, and where appropriate, novel formulation excipients. By investigating the intrinsic stability of candidate drug molecules, useful information which is likely to improve the integrity of the drug products, as well as, prevent alteration in its physical properties, chemical properties and pharmacological effects are obtained.

Preformulation stability analysis includes solid-state stability analysis, solution-state stability analysis and drug-excipients compatibility studies. The key to a good stability analysis is to select concentrations for analysis that allow the detection of degradation product peaks that are at least 0.1% of the parent peak. The stability design and type of testing used will depend on the stage of the development process and the nature of the drug and product under test.

Why stability analysis/ testing?

1. To generate useful information on how environmental factors e.g., temperature, humidity, light etc. influence the quality of drug products over time.
2. To establish the how physical, chemical and microbiological changes influence the effectiveness, safety and stability of the final drug product.
3. To recommend storage conditions, establish a retest period, and shelf life of drug products.

Factors influencing drug stability

1. Temperature or thermal effect
2. Moisture and relative humidity
3. Light and radiation energy
4. pH
5. Presence of reacting solvents
6. Order of reaction
7. Microorganisms
8. Chemical nature of the drug or excipient
9. Ionic strength
10. General acid-base catalysis
11. Presence of trace metals, oxygen and oxidizing agents.

Significant changes that might occur during stability analysis

1. Physical changes – changes in the physical appearance of the drug product, melting point, clarity and colour of solutions, crystal modification (polymorphism) and particle size etc.
2. Chemical changes – increased degradation and decrease API (Active Pharmaceutical Ingredient) assay
3. Microbial changes – increased microbial load/ microbial contamination.

Read also: Preformulation Studies: Solubility Analysis

ICH Stability Rooms for Pharmaceutical, Cosmetics and Quality Control

Solid-state stability analysis

Solid-state stability analysis is a very important aspect of drug stability testing. It identifies the stable storage conditions for drug products and also investigates any physical or chemical properties of the drug molecule that may affect the stability of a drug product. This study requires repetitive testing of the initial bulk lot in parallel with newer bulk lots. Unlike reactions that take place when drugs are in solution, solid-state reactions are usually slower and more difficult to interpret due to a reduced number of molecular contacts between drug molecules and excipient(s) and also the occurrence of multiple phase reactions. Information generated from this analysis is influenced by temperature, pH, humidity, hydrolysis, oxidation, etc.

Solution-state stability analysis

Solution-state stability analysis provides evidence on unknown liquid incompatibilities that would likely pose a significant challenge during drug development process. It also serves as a guide for formulation processes. During solution-state stability studies, it is important to evaluate

1. The stability of the drug substance at various pH (pH 1, 2, 4, 7 and 10), at ambient and elevated temperature.
2. Photolytic stability (the influence of ICH light) and finally
3. Oxidative stability (oxidation by peroxides).

Solution-state stability analysis is capable of identifying loss of API and any consequent increment in degradation products.

Drug-excipient compatibility studies

This study is carried out to identify all forms of drug-excipient interactions which could alter the stability of a dosage form. In pharmaceutical formulations, drug substances come in direct contact with one or more excipients and therefore, can undergo chemical reactions and physical interactions under favourable conditions producing less active or inactive and toxic by-products with adverse reactions. Compatibility study is an important process in drug product development as the information generated is very useful to the formulator in selecting appropriate excipients for a drug product. Some of the most frequently used analytical techniques include but are not limited to thermal methods of analysis (e.g., Differential Scanning Calorimetry, Differential Thermal Analysis, Isothermal Titration Calorimetry etc.), spectroscopic methods of analysis (e.g., FT-IR Spectroscopy, X-ray diffraction etc.), Chromatographic methods of analysis (e.g., Thin Layer Chromatography, High-performance liquid chromatography etc.) and accelerated Stability Study.

References       

• Amir I. M., Amir M. E., Osama A. A., Suzan A. and Alaa I. M. (2017). Investigation of Drug-Polymer Compatibility Using Chemometric-Assisted UV-Spectrophotometry. Pharmaceutics, 9(7): 1-13.
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• Gibson, M. (2004). Pharmaceutical Preformulation and Formulation: A Practical Guide from candidate Drug Selection to Commercial Dosage Form. Florida: CRC Press LLC.
• Kulkarni, S., Sharma, S. and Agrawal, A. (2015). Preformulation – A Foundation For Formulation Development. International Journal of Pharmaceutical, Chemical And Biological Sciences, 5(2): 403-406.
• Kumar, P., Vaishnavi, G., Divya, K. and Lakshmi, U. (2015). An Overview on Preformulation Studies. Indo American Journal of Pharmaceutical Science, 2(10): 1399-1407.
• Leo, A., Hansch C., and Elkins D. (1971). Partition Coefficients and Their Uses. Chemical Reviews, 71(6): 525-616.
• Onyishi, I. V. (2015). Lecture on Preformulation. Personal Collection of Onyishi, University of Nigeria, Nsukka, Enugu State.
• Shayne Cox Gad (2008). Preclinical Development Handbook: ADME and Biopharmaceutical Properties. Canada: John Wiley & Sons Inc.
• Yuri V. K and Rosario L. (2007). HPLC for Pharmaceutical Scientists. Canada: John Wiley & Sons Inc.

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