Compatibility studies for selection of excipients
Compatibility studies are usually the last activity done during pre-formulation profiling. All pre-formulation studies, except compatibility studies, are carried out on pure drug substance. Compatibility studies are aimed at studying the interactions of drug substance with other excipients. Selection of excipients is vital for development of a quality drug product. Choice of excipients is guided by the type of proposed dosage form. For example for a tablet dosage form, excipients belonging to categories of diluent, binder, disintegrant, lubricant, glidant are usually included in the compatibility studies. Based on the need, optionally solubilizer, stabilizing agent, buffer and rate controlling polymer can also be included.
Mechanisms for incompatibility
Compatibility studies aim at identifying potential physical and chemical incompatibility between drug substance and excipients. Excipients may contribute to incompatibility by (i) altering the moisture content, (ii) altering the micro-environment pH, (iii) acting as a catalyst for degradation or (iv) contributing an impurity that causes degradation.
Compatibility study protocols
Numerous experimental tools like isothermal stress testing, differential scanning calorimetry and isothermal micro calorimetry are used for conducting compatibility studies. Most commonly isothermal stress studies with various stressors like thermal, humidity, oxidation and mechanical stress, are employed. Studies can be performed between two or multi-component systems. Design of experiment and ‘mini-formulation studies’ are also employed to understand compatibility in multi-component systems. A typical protocol for isothermal stress studies involves charging the physical mixtures of drug substance and excipients(s), in powder or compacted form, usually at temperature of 50, 60 oC or even higher. Additional stressor like moisture can also be included. The samples are monitored on weekly basis (usually for a period of 4 weeks) for physical observations like color, odor, deliquescence and flow behavior. Samples are also analyzed quantitatively using UV spectroscopy or HPLC. Additional data on solid form changes can also be generated using conventional tools like powder X ray diffraction, FTIR and solid state NMR.
DSC can also be used for studying incompatibility, especially in the early stages of drug development, when drug substance is available in limited quantities. However, data of DSC based compatibility studies should be interpreted carefully, as there is always a danger of ‘over-interpretation due to presence of false positives ’.
Role of compatibility studies in formulation development
Compatibility studies thus allow in systematic selection of excipients, for formulation development. Early detection of incompatibilities also helps in developing strategies to mitigate stability related problems in the dosage forms.
Dr. Arvind Bansal[adrotate banner=”6″]
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