Comparison between solvent evaporation and supercritical CO2 technology in taste-masking of Azithromycin bitter-taste using pH-sensitive Eudragit EPO or Eudragit S100 polymers

Hadeia Mashaqbeh; Rana Obaidat; Mo’tasem M. Alsmadi; Tamara Athamneh

doi:10.7324/JAPS.2024.171403

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Abstract

Despite the broad spectrum of the antibiotic Azithromycin, its extremely bitter taste after oral dosing decreases patient compliance. This bitter taste can be masked by minimizing Azithromycin interaction with the tasting buds using polymers that are insoluble at salivary pH (6.8–7.4), like the cationic polymers Eudragit EPO and Eudragit S100. The purpose of this study was to employ two different techniques (solvent evaporation (SE) and supercritical fluid technology (SFT)) for encapsulating Azithromycin into Eudragit microparticles to mask its bitter taste. The formulations were characterized using Fourier-transform infrared spectroscopy (FTIR(, powder X-ray diffraction (PXRD), Differential scanning calorimetry (DSC), and scanning electron microscope (SEM). Also, the Azithromycin in vitro release and in vivo assessment of bitter taste masking were conducted. The present work showed promising results in veiling the bitter taste of Azithromycin. Taste panel scores for the in vivo clinical taste study of the formulation prepared using SE was 0.3 after 30 seconds compared to Azithromycin, resulting in a score of 3 owing to its palpable bitter taste. Whereas drug-Eudragit EPO showed no interaction, FTIR results indicated azithromycin interaction with Eudragit S100. The formulation prepared by the SE method and Eudragit EPO showed efficient taste masking, within-matrix encapsulation, lower drug release in simulated salivary fluid (SSF, <2% released over 60 seconds), and loss of Azithromycin’s crystallinity. On the contrary, SFT had higher encapsulation efficiency (91%) but faster in vitro release (6% released over 60 seconds). Thus, SE was better than SFT in Azithromycin taste masking using Eudragit EPO.

Keyword: Azithromycin dihydrate taste masking eudragit solvent evaporation supercritical CO2 technology

Citation:

Mashaqbeh H, Obaidat R, Alsmadi MM, Athamneh T. Comparison between solvent evaporation and supercritical CO2 technology in taste-masking of Azithromycin bitter-taste using pH-sensitive Eudragit EPO or Eudragit S100 polymers. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.171403

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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3. Patil V, Tambe V, Pathare B, Dhole S. Modern taste concealing techniques in pharmaceuticals: a review. WJPPS. 2014;3:293-316.
4. Jyothi NVN, Prasanna PM, Sakarkar SN, Prabha KS, Ramaiah PS, Srawan G. Microencapsulation techniques, factors influencing encapsulation efficiency. J Microencapsul. 2010;27(3):187-97. https://doi.org/10.3109/02652040903131301
5. Al-kasmi B, Alsirawan MB, Bashimam M, El-zein H. Mechanical microencapsulation: the best technique in taste masking for the manufacturing scale-effect of polymer encapsulation on drug targeting. J Control Release. 2017;260:134-41. https://doi.org/10.1016/j.jconrel.2017.06.002
6. Patra CN, Priya R, Swain S, Jena GK, Panigrahi KC, Ghose D. Pharmaceutical significance of Eudragit: a review. Future J Pharm Sci. 2017;3(1):33-45. https://doi.org/10.1016/j.fjps.2017.02.001
7. Thakral S, Thakral NK, Majumdar DK. Eudragit®: a technology evaluation. Expert Opin Drug Deliv. 2013;10(1):131-49. https://doi.org/10.1517/17425247.2013.736962
8. Cantor SL, Khan MA, Gupta A. Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride. Drug Dev Ind Pharm. 2015;41(7):1156-64. https://doi.org/10.3109/03639045.2014.935392
9. Jelvehgari M, Valizadeh H, Kiafarab F, Afandipourc L. Taste masking and characterization of chlorpheniramine maleate by using enteric polymers carrier system. J Rep Pharm Sci. 2013;2(1):45-58. https://doi.org/10.4103/2322-1232.222236
10. Ghorab MM, Zia H, Luzzi LA. Preparation of controlled release anticancer agents I: 5-fluorouracil-ethyl cellulose microspheres. J Microencapsul. 1990;7(4):447-54. https://doi.org/10.3109/02652049009040466
11. Lee C-W, Kim S-J, Youn Y-S, Widjojokusumo E, Lee Y-H, Kim J, et al. Preparation of bitter taste masked cetirizine dihydrochloride/β-cyclodextrin inclusion complex by supercritical antisolvent (SAS) process. J Supercrit Fluids. 2010;55(1):348-57. https://doi.org/10.1016/j.supflu.2010.05.028
12. Obaidat R, Aleih H, Mashaqbeh H, Altaani B, Alsmadi MtM, Alnaief M. Development and evaluation of cocoa butter taste masked ibuprofen using supercritical carbon dioxide. AAPS PharmSciTech. 2021;22:1-13. https://doi.org/10.1208/s12249-021-01962-7
13. Machado ND, Mosquera JE, Martini RE, Goñi ML, Gañán NA. Supercritical CO2-assisted impregnation/deposition of polymeric materials with pharmaceutical, nutraceutical, and biomedical applications: a review (2015-2021). J Supercrit Fluids. 2022;191:105763. https://doi.org/10.1016/j.supflu.2022.105763
14. AlSheyyab RY, Obaidat RM, Altall YR, Abuhuwaij RT, Ghanma RR, Ailabouni AS, et al. Solubility enhancement of nimodipine through preparation of Soluplus® dispersions. J Appl Pharm Sci. 2019;9(9):030-7. https://doi.org/10.7324/JAPS.2019.90905
15. Obaidat RM, Alnaief M, Mashaqbeh H. Investigation of carrageenan aerogel microparticles as a potential drug carrier. Aaps Pharm. 2018;19:2226-36. https://doi.org/10.1208/s12249-018-1021-4
16. Bagheri H, Notej B, Shahsavari S, Hashemipour H. Supercritical carbon dioxide utilization in drug delivery: experimental study and modeling of paracetamol solubility. Eur J Pharm Sci. 2022;177:106273. https://doi.org/10.1016/j.ejps.2022.106273
17. Joshi J. Azithromycin drug profile. Indian J Otolaryngol Head Neck Surg. 1995;47(4):331-3. https://doi.org/10.1007/BF03048008
18. Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles of drug substances, excipients and related methodology. Elsevier, Amsterdam, The Netherlands, pp 1-40, 2014. https://doi.org/10.1016/B978-0-12-800173-8.00001-5
19. Harrison TS, Keam SJ. Azithromycin extended release. Drugs. 2007;67(5):773-92. https://doi.org/10.2165/00003495-200767050-00010
20. Fiese E, Steffen S. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother. 1990;25(suppl_A):39-47. https://doi.org/10.1093/jac/25.suppl_A.39
21. Tung N-T, Tran C-S, Nguyen T-L, Hoang T, Trinh T-D, Nguyen T-N. Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. Eur J Pharm Biopharm. 2018;126:187-200. https://doi.org/10.1016/j.ejpb.2017.03.017
22. Amin F, Khan S, Shah SMH, Rahim H, Hussain Z, Sohail M, et al. A new strategy for taste masking of azithromycin antibiotic: development, characterization, and evaluation of azithromycin titanium nanohybrid for masking of bitter taste using physisorption and panel testing studies. Drug Design Dev Ther. 2018:3855-66. https://doi.org/10.2147/DDDT.S183534
23. Hu L, Pan J, Liu C, Xu H, Luo L. Preparation, characterization and taste-masking properties of microspheres containing azithromycin. J Pharm Pharm. 2009;61(12):1631-5. https://doi.org/10.1211/jpp.61.12.0007
24. Chen Y, Liu Y, Wu C, Pan X, Peng T. Dry suspension containing coated pellets with pH-dependent drug release behavior for the taste-masking of Azithromycin. AAPS PharmSciTech. 2022;24(1):21. https://doi.org/10.1208/s12249-022-02484-6
25. Siddiqui F, Shoaib MH, Ahmed FR, Qazi F, Yousuf RI, Usmani MT, et al. Formulation development and optimization of taste-masked azithromycin oral suspension with ion exchange resins: Bioanalytical method development and validation, in vivo bioequivalence study, and in-silico PBPK modeling for the paediatric population. J Drug Deliv Sci Technol. 2023;79:104048. https://doi.org/10.1016/j.jddst.2022.104048
26. Mashaqbeh H, Obaidat RM, Alsmadi MtM. Solvent-free method for masking the bitter taste of azithromycin dihydrate using supercritical fluid technology. Drug Dev Indust Pharm. 2024;50:1-10. https://doi.org/10.1080/03639045.2023.2298892
27. Budisa N, Schulze-Makuch D. Supercritical carbon dioxide and its potential as a life-sustaining solvent in a planetary environment. Life. 2014;4(3):331-40. https://doi.org/10.3390/life4030331
28. Alnaief M, Obaidat R, Mashaqbeh H. Effect of processing parameters on preparation of carrageenan aerogel microparticles. Carbohydr Polym. 2018;180:264-75. https://doi.org/10.1016/j.carbpol.2017.10.038
29. Guhmann M, Preis M, Gerber F, Pöllinger N, Breitkreutz J, Weitschies W. Development of oral taste masked diclofenac formulations using a taste sensing system. Int J Pharm. 2012;438(1-2):81-90. https://doi.org/10.1016/j.ijpharm.2012.08.047
30. Waghule SN, Jain NP, Patani CJ, Patani AC. Method development and validation of HPLC method for determination of azithromycin. Der Pharma Chemica. 2013;5(4):166-72.
31. Ali M, Walboomers XF, Jansen JA, Yang F. Influence of formulation parameters on encapsulation of doxycycline in PLGA microspheres prepared by double emulsion technique for the treatment of periodontitis. Jf Drug Deliv Sci Technol. 2019;52:263-71. https://doi.org/10.1016/j.jddst.2019.04.031
32. Adeli E. Preparation and evaluation of azithromycin binary solid dispersions using various polyethylene glycols for the improvement of the drug solubility and dissolution rate. Braz J Pharm Sci. 2016;52(1):1-13. https://doi.org/10.1590/S1984-82502016000100002
33. Montejo-Bernardo J, García-Granda S, Bayod-Jasanada M, Llorente I, Llavonab L. An easy and general method for quantifying Azithromycin dihydrate in a matrix of amorphous Azithromycin. Arkivoc. 2005;9:321-31. https://doi.org/10.3998/ark.5550190.0006.927
34. Braga ME, Pato MTV, Silva HSC, Ferreira EI, Gil MH, Duarte CM, et al. Supercritical solvent impregnation of ophthalmic drugs on chitosan derivatives. Jf Supercr Fluids. 2008;44(2):245-57. https://doi.org/10.1016/j.supflu.2007.10.002
35. Champeau M, Thomassin JM, Tassaing T, Jerome C. Drug loading of sutures by supercritical CO2 impregnation: effect of polymer/drug interactions and thermal transitions. Macromole Mater Eng. 2015;300(6):596-610. https://doi.org/10.1002/mame.201400369
36. Champeau M, Thomassin J-M, Tassaing T, Jérôme C. Drug loading of polymer implants by supercritical CO2 assisted impregnation: a review. J Control Release. 2015;209:248-59. https://doi.org/10.1016/j.jconrel.2015.05.002
37. Timoumi S, Mangin D, Peczalski R, Zagrouba F, Andrieu J. Stability and thermophysical properties of azithromycin dihydrate. Arabian J Chem. 2014;7(2):189-95. https://doi.org/10.1016/j.arabjc.2010.10.024
38. Alnaief M, Obaidat R, Mashaqbeh H. Loading and evaluation of meloxicam and atorvastatin in carrageenan microspherical aerogels particles. J Appl Pharm Sci. 2019;9(1):083-8. https://doi.org/10.7324/JAPS.2019.90112
39. Alsayad R, Laham A. Investigation of the effects of some process variables on the azithromycin microencapsulation by the quasi-emulsion solvent evaporation method. Res J Pharm Technol. 2023;16(8):3909-14. https://doi.org/10.52711/0974-360X.2023.00643

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1. Pediatrics AAO. Periodic Survey# 44: patient compliance with prescription regimens. 2015.

2. Chirag JP, Tyagi S, Dhruv M, Ishita M, Gupta A, Mohammed Usman M, et al. Pharmaceutical taste masking technologies of bitter drugs: a concise review. J Drug Discov Ther. 2013;1(5):39-46.

3. Patil V, Tambe V, Pathare B, Dhole S. Modern taste concealing techniques in pharmaceuticals: a review. WJPPS. 2014;3:293-316.

4. Jyothi NVN, Prasanna PM, Sakarkar SN, Prabha KS, Ramaiah PS, Srawan G. Microencapsulation techniques, factors influencing encapsulation efficiency. J Microencapsul. 2010;27(3):187-97. https://doi.org/10.3109/02652040903131301

5. Al-kasmi B, Alsirawan MB, Bashimam M, El-zein H. Mechanical microencapsulation: the best technique in taste masking for the manufacturing scale-effect of polymer encapsulation on drug targeting. J Control Release. 2017;260:134-41. https://doi.org/10.1016/j.jconrel.2017.06.002

6. Patra CN, Priya R, Swain S, Jena GK, Panigrahi KC, Ghose D. Pharmaceutical significance of Eudragit: a review. Future J Pharm Sci. 2017;3(1):33-45. https://doi.org/10.1016/j.fjps.2017.02.001

7. Thakral S, Thakral NK, Majumdar DK. Eudragit®: a technology evaluation. Expert Opin Drug Deliv. 2013;10(1):131-49. https://doi.org/10.1517/17425247.2013.736962

8. Cantor SL, Khan MA, Gupta A. Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride. Drug Dev Ind Pharm. 2015;41(7):1156-64. https://doi.org/10.3109/03639045.2014.935392

9. Jelvehgari M, Valizadeh H, Kiafarab F, Afandipourc L. Taste masking and characterization of chlorpheniramine maleate by using enteric polymers carrier system. J Rep Pharm Sci. 2013;2(1):45-58. https://doi.org/10.4103/2322-1232.222236

10. Ghorab MM, Zia H, Luzzi LA. Preparation of controlled release anticancer agents I: 5-fluorouracil-ethyl cellulose microspheres. J Microencapsul. 1990;7(4):447-54. https://doi.org/10.3109/02652049009040466

11. Lee C-W, Kim S-J, Youn Y-S, Widjojokusumo E, Lee Y-H, Kim J, et al. Preparation of bitter taste masked cetirizine dihydrochloride/β-cyclodextrin inclusion complex by supercritical antisolvent (SAS) process. J Supercrit Fluids. 2010;55(1):348-57. https://doi.org/10.1016/j.supflu.2010.05.028

12. Obaidat R, Aleih H, Mashaqbeh H, Altaani B, Alsmadi MtM, Alnaief M. Development and evaluation of cocoa butter taste masked ibuprofen using supercritical carbon dioxide. AAPS PharmSciTech. 2021;22:1-13. https://doi.org/10.1208/s12249-021-01962-7

13. Machado ND, Mosquera JE, Martini RE, Goñi ML, Gañán NA. Supercritical CO2-assisted impregnation/deposition of polymeric materials with pharmaceutical, nutraceutical, and biomedical applications: a review (2015-2021). J Supercrit Fluids. 2022;191:105763. https://doi.org/10.1016/j.supflu.2022.105763

14. AlSheyyab RY, Obaidat RM, Altall YR, Abuhuwaij RT, Ghanma RR, Ailabouni AS, et al. Solubility enhancement of nimodipine through preparation of Soluplus® dispersions. J Appl Pharm Sci. 2019;9(9):030-7. https://doi.org/10.7324/JAPS.2019.90905

15. Obaidat RM, Alnaief M, Mashaqbeh H. Investigation of carrageenan aerogel microparticles as a potential drug carrier. Aaps Pharm. 2018;19:2226-36. https://doi.org/10.1208/s12249-018-1021-4

16. Bagheri H, Notej B, Shahsavari S, Hashemipour H. Supercritical carbon dioxide utilization in drug delivery: experimental study and modeling of paracetamol solubility. Eur J Pharm Sci. 2022;177:106273. https://doi.org/10.1016/j.ejps.2022.106273

17. Joshi J. Azithromycin drug profile. Indian J Otolaryngol Head Neck Surg. 1995;47(4):331-3. https://doi.org/10.1007/BF03048008

18. Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles of drug substances, excipients and related methodology. Elsevier, Amsterdam, The Netherlands, pp 1-40, 2014. https://doi.org/10.1016/B978-0-12-800173-8.00001-5

19. Harrison TS, Keam SJ. Azithromycin extended release. Drugs. 2007;67(5):773-92. https://doi.org/10.2165/00003495-200767050-00010

20. Fiese E, Steffen S. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother. 1990;25(suppl_A):39-47. https://doi.org/10.1093/jac/25.suppl_A.39

21. Tung N-T, Tran C-S, Nguyen T-L, Hoang T, Trinh T-D, Nguyen T-N. Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. Eur J Pharm Biopharm. 2018;126:187-200. https://doi.org/10.1016/j.ejpb.2017.03.017

22. Amin F, Khan S, Shah SMH, Rahim H, Hussain Z, Sohail M, et al. A new strategy for taste masking of azithromycin antibiotic: development, characterization, and evaluation of azithromycin titanium nanohybrid for masking of bitter taste using physisorption and panel testing studies. Drug Design Dev Ther. 2018:3855-66. https://doi.org/10.2147/DDDT.S183534

23. Hu L, Pan J, Liu C, Xu H, Luo L. Preparation, characterization and taste-masking properties of microspheres containing azithromycin. J Pharm Pharm. 2009;61(12):1631-5. https://doi.org/10.1211/jpp.61.12.0007

24. Chen Y, Liu Y, Wu C, Pan X, Peng T. Dry suspension containing coated pellets with pH-dependent drug release behavior for the taste-masking of Azithromycin. AAPS PharmSciTech. 2022;24(1):21. https://doi.org/10.1208/s12249-022-02484-6

25. Siddiqui F, Shoaib MH, Ahmed FR, Qazi F, Yousuf RI, Usmani MT, et al. Formulation development and optimization of taste-masked azithromycin oral suspension with ion exchange resins: Bioanalytical method development and validation, in vivo bioequivalence study, and in-silico PBPK modeling for the paediatric population. J Drug Deliv Sci Technol. 2023;79:104048. https://doi.org/10.1016/j.jddst.2022.104048

26. Mashaqbeh H, Obaidat RM, Alsmadi MtM. Solvent-free method for masking the bitter taste of azithromycin dihydrate using supercritical fluid technology. Drug Dev Indust Pharm. 2024;50:1-10. https://doi.org/10.1080/03639045.2023.2298892

27. Budisa N, Schulze-Makuch D. Supercritical carbon dioxide and its potential as a life-sustaining solvent in a planetary environment. Life. 2014;4(3):331-40. https://doi.org/10.3390/life4030331

28. Alnaief M, Obaidat R, Mashaqbeh H. Effect of processing parameters on preparation of carrageenan aerogel microparticles. Carbohydr Polym. 2018;180:264-75. https://doi.org/10.1016/j.carbpol.2017.10.038

29. Guhmann M, Preis M, Gerber F, Pöllinger N, Breitkreutz J, Weitschies W. Development of oral taste masked diclofenac formulations using a taste sensing system. Int J Pharm. 2012;438(1-2):81-90. https://doi.org/10.1016/j.ijpharm.2012.08.047

30. Waghule SN, Jain NP, Patani CJ, Patani AC. Method development and validation of HPLC method for determination of azithromycin. Der Pharma Chemica. 2013;5(4):166-72.

31. Ali M, Walboomers XF, Jansen JA, Yang F. Influence of formulation parameters on encapsulation of doxycycline in PLGA microspheres prepared by double emulsion technique for the treatment of periodontitis. Jf Drug Deliv Sci Technol. 2019;52:263-71. https://doi.org/10.1016/j.jddst.2019.04.031

32. Adeli E. Preparation and evaluation of azithromycin binary solid dispersions using various polyethylene glycols for the improvement of the drug solubility and dissolution rate. Braz J Pharm Sci. 2016;52(1):1-13. https://doi.org/10.1590/S1984-82502016000100002

33. Montejo-Bernardo J, García-Granda S, Bayod-Jasanada M, Llorente I, Llavonab L. An easy and general method for quantifying Azithromycin dihydrate in a matrix of amorphous Azithromycin. Arkivoc. 2005;9:321-31. https://doi.org/10.3998/ark.5550190.0006.927

34. Braga ME, Pato MTV, Silva HSC, Ferreira EI, Gil MH, Duarte CM, et al. Supercritical solvent impregnation of ophthalmic drugs on chitosan derivatives. Jf Supercr Fluids. 2008;44(2):245-57. https://doi.org/10.1016/j.supflu.2007.10.002

35. Champeau M, Thomassin JM, Tassaing T, Jerome C. Drug loading of sutures by supercritical CO2 impregnation: effect of polymer/drug interactions and thermal transitions. Macromole Mater Eng. 2015;300(6):596-610. https://doi.org/10.1002/mame.201400369

36. Champeau M, Thomassin J-M, Tassaing T, Jérôme C. Drug loading of polymer implants by supercritical CO2 assisted impregnation: a review. J Control Release. 2015;209:248-59. https://doi.org/10.1016/j.jconrel.2015.05.002

37. Timoumi S, Mangin D, Peczalski R, Zagrouba F, Andrieu J. Stability and thermophysical properties of azithromycin dihydrate. Arabian J Chem. 2014;7(2):189-95. https://doi.org/10.1016/j.arabjc.2010.10.024

38. Alnaief M, Obaidat R, Mashaqbeh H. Loading and evaluation of meloxicam and atorvastatin in carrageenan microspherical aerogels particles. J Appl Pharm Sci. 2019;9(1):083-8. https://doi.org/10.7324/JAPS.2019.90112

39. Alsayad R, Laham A. Investigation of the effects of some process variables on the azithromycin microencapsulation by the quasi-emulsion solvent evaporation method. Res J Pharm Technol. 2023;16(8):3909-14. https://doi.org/10.52711/0974-360X.2023.00643