Assessment of excipient compatibility with an active pharmaceutical ingredient (API) is an essential step prior to formulation development for a drug. Although pharmacologically inert in a formulation, excipients can interact with the API physically or chemically which may significantly impact the therapeutic efficacy and safety profile of the API, or the stability of the drug product. Isothermal stress testing (IST) followed by HPLC analysis is commonly employed to evaluate drug-excipient compatibility. While this technique provides reliable results, it requires long term stress studies and typically involves significant numbers of sample combinations to properly manage risk.
Any incompatibility between an API and an excipient resulting in decomposition of the drug produces a small amount of heat. Microcalorimetry is an ultra-sensitive technique allowing for the detection of minute thermal changes, and is therefore useful as a compatibility screening test. In this study, isothermal microcalorimetry (IsoCal) was employed for quick assessment of drug-excipient incompatibility. The IsoCal results are comparable to those evaluated using the typical IST/HPLC approach.
Indomethacin was selected as the model compound (API) for the compatibility study with five excipients including magnesium stearate (MgSt), polyethylene glycol (PEG) 3350, sodium lauryl sulfate (SLS), stearic acid, and glyceryl monostearate.
Figure 1: Chemical structure of API – indomethacin
API solids were mixed with an excipient at a 50:50 (w/w) ratio, along with H2O added into the sample (350 ± 1 mg for each component with 200 μL H2O). Mixtures were sealed in clean glass ampoules, and loaded to the instrument, TAM III 4 mL static minicalorimeters. The basic assumption of the technique is that the rate of heat production is proportional to the chemical or physical process occurring in the sample. Thermal activities of the mixtures were therefore monitored at a constant temperature and compared to the theoretical responses, i.e., “non-interaction” curves constructed from the individual components (350 ± 1mg with 100 μL H2O). If an experimentally significant difference is observed between the mixture and the “non-interaction” curve, the excipient is considered to be potential incompatible with the API. The mixture and the individual components were evaluated at the same experimental conditions since the instrument is 6-pack minicalorimeters which provides six simultaneous measurements and increases measuring capacity and productivity.
Figure 2: A sketch of IsoCal working principle for excipient compatibility testing
Results and Discussion
Compatibility of Indomethacin/Magnesium Stearate
Indomethacin/MgSt system is a known “not compatible” system by multiple analytical techniques, including DSC , DSC/TG [3, 4], FTIR and XRPD . Therefore, this system was investigated initially in this study to identify appropriate conditions for IsoCal testing. Heat flow signals of samples including indomethacin-only, MgSt-only, and 50:50 (w/w) indomethacin/MgSt physical mixtures in sealed ampoules were monitored for 3 days at 2 temperatures, 25 °C and 45 °C. Water was added into each sample prior to testing .
At each temperature, the IsoCal data showed clear interactions between indomethacin and MgSt confirming the materials’ incompatibility, consistent with the conclusions from the literature [2, 3, 4]. The heat output at 45 °C is significantly larger than the one at 25 °C, and therefore 45 °C was selected as the temperature condition for IsoCal testing of indomethacin with other excipients.
The typical IST/HPLC approach for excipient compatibility study was also carried out for comparison. Indomethacin/MgSt mixtures were exposed to 40 °C/75%RH for a total of 3 months. Stressed samples were analyzed by HPLC for indomethacin potency at t= 2 weeks and t=3 months; n=2 at each time-point and the reported indomethacin recovery is an averaged value. Based on the results, all other indomethacin/excipient pairs were analyzed at t= 3 months.
Table 1: HPLC analysis for Indomethacin/MgSt samples post-stress at 40 °C/75% RH
Compatibility of Indomethacin with Other Excipients
Based on IsoCal data, samples containing indomethacin and PEG 3350 or SLS also displayed heat flow signals that are significantly different from the corresponding “non-interaction” responses, indicating possible incompatibility between indomethacin and these excipients. Heat flow signals indicate that the reactions between indomethacin and PEG or SLS occurred much faster compared to indomethacin/MgSt system; and heat outputs from mixtures quickly matched with the “non-interaction” responses. Since very rapid reactions may lead to a false “compatible” result, API/excipient mixtures that are deemed “compatible” by IsoCal should be followed by typical IST/HPLC testing.
Stearic acid and glyceryl monostearate were found to have no interactions with indomethacin at the IsoCal testing conditions and therefore are potentially compatible with indomethacin.
Conclusions drawn from HPLC data on samples exposed to 40 °C/75%RH/3 months are consistent with IsoCal studies.
Table 2: Indomethacin excipient compatibility by IST/HPLC approach, stress condition 40 °C/75% RH
|Material||Indomethacin recovery, t= 3 months||Compatibility|
|Indomethacin/PEG 3350||97.0%||Not compatible|
In this study, compatibility between indomethacin and excipients including MgSt, PEG 3350, SLS, stearic acid, and glyceryl monostearate, were examined by IsoCal and IST/HPLC approaches, and conclusions from the two approaches are qualitatively in good agreement. The study proves that IsoCal provides a rapid and easy approach to identify potential incompatibility between API and excipients. IsoCal results were obtained in a fairly short period of time, 3-days versus 3-months using the IST/HPLC approach. When IsoCal is used in conjunction with IST/HPLC approach, the number of sample combinations for time-consuming IST/HPLC evaluation can be substantially decreased and appropriate excipients for use in a formulation can be identified more efficiently.
: TA Instruments, Microcalorimetry Brochure, 2010
: S. Venkataram, et.al., Drug Development and Industrial Pharmacy, 21 (7), 847-855, 1995
: A. Marini, et.al., Journal of Thermal Analysis and Calorimetry, 73, 529-545, 2003
: Bogdan Tita, et.al., Journal of Thermal Analysis and Calorimetry, 118, 1293-1304, 2014
: Eric A. Schmitt, et. al., Thermochimica Acta, 380, 175-183, 2001
(Originally presented by Jing Teng, Justin Guerra, and Yizheng Cao at the 2017 AAPS Annual Meeting and Exposition in San Diego, CA)
Appendix 1: TAM III, 6-pack minicalorimeter  and testing ampoules 
Appendix 2: Indomethacin/MgSt excipient compatibility by IsoCal at (a) 25 °C and (b) 45 °C
Appendix 3: Indomethacin excipient compatibility by IsoCal at 45 °C with (a) PEG 3350 and (b) SLS
Appendix 4: Indomethacin excipient compatibility by IsoCal at 45 °C with (a) stearic acid and (b) glyceryl monostearate