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

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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.

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.

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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.

19. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Guideline on the Investigation of Bioequivalence, London, 20 January 2010;

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.

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.

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.

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

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