Study of the physicochemical properties of the etravirine substance

Introduction. Etravirine, being one of the most popular antiretroviral drugs, doesn't have its physicochemical properties sufficiently described in scientific publications. Detailed information on the substance properties is necessary both for organizing the synthesis and for justifying the dosage form and technology for its production, as well as for identifying bottlenecks and critical parameters that affect the quality of the finished product.

Aim. Study the etravirine physicochemical properties to model the design of studies to create an innovative dosage form

Materials and methods. Etravirine (MSN Life Sciences Pvt. Ltd., Hetero Labs Ltd.). The melting point was determined by the capillary method. Etravirine samples were studied via differential scanning calorimetry (DSC), X-ray powder diffractometry, IR and NMR spectroscopy. Particle size was determined using laser diffraction analysis. The shape and size of the crystals were determined with the help of transmission electron microscopy (TEM). The concentration of etravirine in aqueous media was determined using the HPLC method with a fluorescence detector. The concentration of etravirine in organic solvents was determined spectrophotometrically.

Results and discussion. The X-ray powder diffractometry and IR spectroscopy helped to determine the fact that the studied substances represent the same polymorphic modification. The melting point of etravirine ranges from 259 to 263 °C. Melting is accompanied by decomposition. The substance is practically insoluble in aqueous media at pH values in the range from 1.2 to 6.8, soluble in some organic solvents, readily soluble in dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide. The distribution coefficient in the "1-octanol/phosphate buffer solution pH 6.8" solvent system was 5.22. The experiment showed that the etravirine substance is lipophilic. Etravirine is found to be a highly crystalline substance and represents needle-shape prismatic crystals.

Conclusion. Etravirine is a lipophilic substance, practically insoluble in aqueous solutions, soluble in a number of organic solvents. The studied substances turned out to be the same polymorphic modification. Since the melting of the substance is accompanied by decomposition, high temperatures processes should be avoided.

Conflict of interest. The authors declare that they have no obvious and potential conflicts of interest related to the publication of this article.

1. Committee for Medicinal Products for Human Use (CHMP) Assessment report for Intellence. London: European Medicines Agency; 2008. 52 p.

2. Havens J. P., Podany A. T., Scarsi K. K., Fletcher C. V. Clinical pharmacokinetics and pharmacodynamics of etravirine: an updated review. Clinical Pharmacokinetics. 2020;59(2):137-154. DOI: 10.1007/s40262-019-00830-9.

3. Kiekens F. R. I., Voorspoels J. F. M., Baert L. E. C., inventors; Janssen Sciences Ireland UC, assignee. Process for preparing spray dried formulations of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. United States patent US9603803B2. 2017 Mar 16.

4. Tran P., Pyo Y.-C., Kim D.-H., Lee S.-E., Kim J.-K., Park J.-S. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics. 2019;11(3):132. DOI: 10.3390/pharmaceutics11030132.

5. Huang S., O'Donnell K. P., de Vaux S. M. D., O'Brien J., Stutzman J., Williams R. O. Processing thermally labile drugs by hot-melt extrusion: The lesson with gliclazide. European Journal of Pharmaceutics and Biopharmaceutics. 2017;119:56-67. DOI: 10.1016/j.ejpb.2017.05.014.

6. Rajput L., Sanphui P., Desiraju G. R. New solid forms of the anti-HIV drug etravirine: salts, cocrystals, and solubility. Crystal Growth & Design. 2013;13(8):3681-3690. DOI: 10.1021/cg4007058.

7. Bhatt-Mehta V., Hammoud H., Amidon G. L. A proposed pediatric biopharmaceutical classification system for medications for chronic diseases in children. European Journal of Pharmaceutical Sciences. 2020;152:105437. DOI: 10.1016/j.ejps.2020.105437.

8. Nyamba I., Lechanteur A., Semde R., Evrard B. Physical formulation approaches for improving aqueous solubility and bioavailability of ellagic acid: A review. European Journal of Pharmaceutics and Biopharmaceutics. 2021;159:198-210. DOI: 10.1016/j.ejpb.2020.11.004.

9. ICH guideline Q8 (R2) on pharmaceutical development. Step 5. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-11.pdf. Accessed: 19.07.2021.

10. Zolotov S. A., Demina N. B., Zolotova A. S. Influence of Water-Soluble Pharmaceutically Acceptable Polymers on the Solubility of Darunavir and Darunavir Ethanolate. Khimiko-far-matsevticheskiy zhurnal. 2020;54(12):44-47. (In Russ.) DOI: 10.30906/0023-1134-2020-54-12-44-47.

11. Markovic M., Zur M., Ragatsky I., Cvijic S., Dahan A. BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide. Pharmaceutics. 2020;12(12):1175. DOI: 10.3390/pharmaceutics12121175.

12. Murakami T. Absorption sites of orally administered drugs in the small intestine. Expert opinion on drug discovery. 2017;12(12):1219-1232. DOI: 10.1080/17460441.2017.1378176

13. ReshenieSoveta Evraziyskoyekonomicheskoykomissiiot 03.11.2016 № 78 (red. ot 14.06.2018) "O Pravilakh registratsii i ekspertizy le-karstvennykh sredstv dlya meditsinskogo primeneniya" [Eurasian Economic Commission Council Resolution No. 78 of 03 November 2016 (amended of 14 June 2018) "On the rules of marketing authorization and assessment of medicinal products for human use"]. Available at: https://docs.eaeunion.org/docs/ru-ru/01418269/cncd_20072018_55. Accessed: 19.07.2021. (In Russ.)

14. Habyalimana V., Mbinze J. K., Yemoa A. L., Waffo C., Diallo T., Tshilombo N. K., Ntokamunda J.-L. K., Lebrun P., Hubert Ph., Marini R. D. Application of design space optimization strategy to the development of LC methods for simultaneous analysis of 18 antiretroviral medicines and 4 major excipients used in various pharmaceutical formulations. Journal of Pharmaceutical and Biomedical Analysis. 2017;139:8-21. DOI: 10.1016/j.jpba.2017.02.040.

15. Taylor K., Aulton M., editors. Aulton's Pharmaceutics. Amsterdam: Elsevier; 2017. 936 p.

16. Weuts I., Van Dycke F., Voorspoels J., De Cort S., Stokbroekx S., Leemans R., Brewster M. E., Xu D., Segmuller B., Turner Y. T. A., Roberts C. J., Davies M. C., Qi S., Craig D. Q. M., Reading M. Physicochemical Properties of the Amorphous Drug, Cast Films, and Spray Dried Powders to Predict Formulation Probability of Success for Solid Dispersions: Etravirine. Journal of Pharmaceutical Sciences. 2011;100(1):260-274. DOI: 10.1002/jps.22242.

17. Mao F., Kong Q., Ni W., Xu X., Ling D., Lu Z., Li J. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery. ChemistryOpen. 2016;5(4):357-368. DOI: 10.1002/open.201600015.

18. Azad M. A., Capellades G., Wang A. B., Klee D. M., Hammersmith G., Rapp K., Brancazio D., Myerson A. S. Impact of Critical Material Attributes (CMAs)-Particle Shape on Miniature Pharmaceutical Unit Operations. AAPSPharmSciTech, 2021:22(3):1 -11. DOI: 10.1208/s12249-020-01915-6.

19. Wilson D., Bunker M., Milne D., Jawor-Baczynska A., Powell A., Blyth J., Streather D. Particle engineering of needle shaped crystals by wet milling and temperature cycling: Optimisation for roller compaction. Powder Technology. 2018;339:641-650. DOI: 10.1016/j.powtec.2018.08.023.