Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

4 Issues per year

IMPACT FACTOR 2016: 1.288
5-year IMPACT FACTOR: 1.600

CiteScore 2016: 1.55

SCImago Journal Rank (SJR) 2016: 0.353
Source Normalized Impact per Paper (SNIP) 2016: 0.854

Open Access
See all formats and pricing
More options …
Volume 65, Issue 4


Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

Sandra Urek Blatnik / Rok Dreu / Stanko Srčič
Published Online: 2015-12-17 | DOI: https://doi.org/10.1515/acph-2015-0031


During the past few years, the studies of bi- and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multilayered tablet combinations, which are commonly used in polypharmacy. For this purposes, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were monitored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablets system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It is presumed that the HCTZ dissolution rate was decreased due to formation of non-soluble substances as a result of HCTZ degradation in the presence of alkaline layer.

Keywords: hydrochlorothiazide; bi-; three-layer tablets; disintegration time; dissolution rate; stability


  • 1. R . D. Deshpande, D. V. Gowda, N. Mahammed and D. N. Maramwar, Bi-layer tablets an emerging trend: a review, Int. J. Pharm. Sci. Res. 2 (2011) 2534-2544.Google Scholar

  • 2. P. H. Ashok and T. A. Kumar, A novel approach of bilayer technology: a review, Int. Res. J. Pharm. 3 (2012) 44-49.Google Scholar

  • 3. A . Divya, K. Kavitha, M. R. Kumar, S. Dakshayani and SD Singh Jagadeesh, Bilayer tablet technology: An overview, J. Appl. Pharm. Sci. 1 (2011) 43-47.Google Scholar

  • 4. N . D. Pujara, Bilayer tablet - An emerging trend, J. Pharm. Res. Dev. 4 (2012) 102-111.Google Scholar

  • 5. Experts in solid dosage discuss the formulation and manufacture of multilayer tablets. Multilayer tablets: Key challenges and trends, Pharm. Technol. 36 (2012) 22-33.Google Scholar

  • 6. U. Conte and L. Maggi, Modulation of the dissolution profiles from Geomatrix(r) multi-layer matrix tablets containing drugs of different solubility, Biomaterials 17 (1996) 889-896; DOI: 10.1016/ 0142-9612(96)83284-4.CrossrefGoogle Scholar

  • 7. A . Kulkarni and M. Bhatia, Development and evaluation of regioselective bilayer floating tablets of atenolol and lovastatin for biphasic release profile, Iran. J. Pharm. Res. 8 (2009) 15-25.Google Scholar

  • 8. S. Abdul and S. S. Poddar, A flexible technology for modified release of drugs: multi layer tablets, J. Control. Release 97 (2004) 393-405; DOI: 10.1016/j.jconrel.2004.03.034.CrossrefGoogle Scholar

  • 9. S. B. Bagde, B. V. Bakde, M. Channawar and A. V. Chandewar, Formulation and evaluation of bilayer tablets of metoprolol succinate and ramipril, Int. J. Pharm Pharm. Sci. 3 (2011) 174-178.Google Scholar

  • 10. S. Aryal and N. Skalo-Basnet, Stability of amlodipine besylate and atenolol in multi-component tablets of mon-layer and bi-layer types, Acta Pharm. 58 (2008) 299-308; DOI: 10.2478/v10007-008-0012-5.Web of ScienceCrossrefGoogle Scholar

  • 11. S. R. Vaithiyalingam and V. A. Sayeed, Critical factors in manufacturing multi-layer tablets - Assessing material attributes, in process controls, manufacturing process and product performance, Int. J. Pharm. 398 (2010) 9-13; DOI : 10.1016/j.ijpharm.2010.07.025.CrossrefWeb of ScienceGoogle Scholar

  • 12. F. Podczeck, Theoretical and experimental investigations into the delamination tendencies of bilayer tablets, Int. J. Pharm. 408 (2011) 102-112; DOI : 10.1016/j.ijpharm.2011.02.007.CrossrefWeb of ScienceGoogle Scholar

  • 13. F. Eisenacher, A. Schadlich and K. Mader, Monitoring of internal pH gradients within multi-layer tablets by optical methods and EPR imaging, Int. J. Pharm. 417 (2011) 204-215; DOI : 10.1016/j.ijpharm. 2010.10.010.Web of ScienceCrossrefGoogle Scholar

  • 14. H. P. Deppeler, Hydrochlorothiazide, in Analitical Profiles Drug Substances, Ed. K. Florey; Academic Press. New York (1983) pp. 405- 409.Google Scholar

  • 15. J. A. Mollica, C. R. Rohm, J. B. Smith and H. R. Govan, Hydrolysis of benzothiadiazines, J. Pharm. Sci. 6 (1971) 1380-1384; DOI: 10.1002/jps.2600600920.CrossrefGoogle Scholar

  • 16. European Pharmacopeia, 7th ed., Council of Europe, Brussels 2013.Google Scholar

  • 17. S. I. F. Badaway and M. A. Hussain, Microenvironmental pH modulation in solid dosage forms, J. Pharm. Sci. 96 (2007) 948-959; DOI: 10.1002/jps.20932.CrossrefWeb of ScienceGoogle Scholar

  • 18. K . Moodly, V. Pillay, Y. E. Choonara, L. C. du Toit, V. M. K. Ndesendo, P. Kumar, S. Cooppan and P. Bawa, Oral drug delivery systems comprising altered geometric configurations for controlled release drug delivery, Int. J. Mol. Sci. 13 (2012) 18-43; DOI : 10.3390/ijms13010018.CrossrefGoogle Scholar

  • 19. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Guideline on the Investigation of Bioequivalence, London, 20 January 2010; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf.Google Scholar

  • 20. A . N. Elmeshad and M. K. Darwish, Stability studies of the effect of crosslinking on hydrochlorothiazide release, Drug Dis. Ther. 3 (2009) 136-142.Google Scholar

  • 21. C. R. Rehm and J. B. Smith, The photometric determination of hydrochlorothiazide and its hydrolysis product, J. Am. Pharm. Assoc. Am. Pharm. Assoc. 49 (1960) 386-389.CrossrefGoogle Scholar

  • 22. A . Crouter and L. Briens, The effect of moisture on the flowability of pharmaceutical excipients, AAPS PharmSciTech. 15 (2014) 65-74; DOI: 10.1208/s12249-013-0036-0.Web of ScienceCrossrefGoogle Scholar

  • 23. United States Pharmacopoeia 38, NF 33, USP Convention, Rockville 2015, pp. 3773-3774. Google Scholar

About the article

Accepted: 2015-07-07

Published Online: 2015-12-17

Published in Print: 2015-12-01

Citation Information: Acta Pharmaceutica, Volume 65, Issue 4, Pages 383–397, ISSN (Online) 1846-9558, DOI: https://doi.org/10.1515/acph-2015-0031.

Export Citation

© by Sandra Urek Blatnik. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Naoya Matsuzaki, Yousuke Yamamoto, Daisuke Murayama, Yoshifumi Katakawa, Hisashi Mimura, Shin-ichiro Kimura, Yasunori Iwao, and Shigeru Itai
CHEMICAL & PHARMACEUTICAL BULLETIN, 2017, Volume 65, Number 5, Page 478

Comments (0)

Please log in or register to comment.
Log in