Optimization and Characterization of Chlorthalidone Bilayer Tablets for Chronotherapeutic Pulsatile Drug Release
Abstract
Pulsatile Drug Delivery System (PDDS) is defined as the rapid and transient release of drug molecules within a short time period immediately after a predetermined lag (off release) period. Blood pressure exhibits a well-documented circadian surge in the early morning hours — a window associated with peak cardiovascular morbidity. Chlorthalidone, a BCS Type-II thiazide-like diuretic with a plasma half-life of 40–60 hours, was selected as the model drug for a chronopharmacological pulsatile formulation. Nine bilayer press-coated tablet formulations (CHT-A through CHT-I) were prepared using Hydroxypropyl Methylcellulose K100M (HPMC) as the hydrophilic swelling polymer and Ethyl Cellulose (EC) as the hydrophobic rupturable membrane at varying weight ratios. Preformulation studies — including ATR-IR spectroscopy, Differential Scanning Calorimetry (DSC), and powder flow characterization — confirmed drug identity, thermal behaviour, and excipient compatibility. Scanning Electron Microscopy (SEM) was employed to characterize surface morphology. The core tablet exhibited a disintegration time of 185 seconds and 95.8% drug content. Formulation CHT-G (HPMC 150 mg: EC 250 mg) demonstrated the optimal 6-hour lag time followed by a burst release of 83.20% at hour 7. Korsmeyer-Peppas modelling (R² = 0.8545; n = 2.2082) identified super case-II swelling-controlled transport as the dominant release mechanism. The developed system offers a clinically promising chronopharmacological strategy for the management of morning-surge hypertension.
Keywords: Pulsatile Drug Delivery; Chlorthalidone; Bilayer Tablet; HPMC; Ethyl Cellulose; DSC; SEM; Lag Time; Chronopharmacology; Hypertension
Keywords:
Pulsatile Drug Delivery, Chlorthalidone, Bilayer Tablet, HPMC, Ethyl Cellulose, DSC, SEM, Lag Time, Chronopharmacology, HypertensionDOI
https://doi.org/10.22270/jddt.v16i6.7813References
1. Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019; 11(3): 129. https://doi.org/10.3390/pharmaceutics11030129
2. Sarkar R, Biswas P, Mukherjee DR, Tanbir S, Biswas B, Rahaman MM, Santra S. Chrono-Colonic Delivery in Engineering Time-Responsive Systems for Site-Specific Therapy. Journal of Drug Delivery and Therapeutics. 2025; 15(10): 148–171. https://doi.org/10.22270/jddt.v15i10.7398
3. Smolensky MH, Hermida RC, Castriotta RJ, Portaluppi F. Role of sleep-wake cycle on blood pressure circadian rhythms and hypertension. Sleep Medicine. 2007; 8(6): 668–680. https://doi.org/10.1016/j.sleep.2006.11.011
4. Maroni A, Zema L, Del Curto MD, Loreti G, Gazzaniga A. Oral pulsatile delivery: Rationale and chronopharmaceutical formulations. International Journal of Pharmaceutics. 2010; 398(1–2): 1–8. https://doi.org/10.1016/j.ijpharm.2010.07.026
5. Sungthongjeen S, Puttipipatkhachorn S, Paeratakul O, Dashevsky A, Bodmeier R. Development of pulsatile release tablets with swelling and rupturable layers. European Journal of Pharmaceutics and Biopharmaceutics. 2004; 58(2): 369–374. https://doi.org/10.1016/j.ejpb.2004.03.031
6. World Health Organization. Global report on hypertension: the race against a silent killer. Geneva: World Health Organization; 2023. Available from: https://www.who.int/publications/i/item/9789240081062
7. Sica DA. Chlorthalidone: has it always been the best thiazide-type diuretic? Hypertension. 2006; 47(3): 321–322. https://doi.org/10.1161/01.HYP.0000203147.75714.ba
8. White WB. Cardiovascular risk and therapeutic intervention for the early morning surge in blood pressure and heart rate. Blood Pressure Monitoring. 2001; 6(1): 63–72. https://doi.org/10.1097/00126097-200102000-00013
9. Sungthongjeen S, Paeratakul O, Limmatvapirat S, Puttipipatkhachorn S. Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique. International Journal of Pharmaceutics. 2007; 324(2): 136–143. https://doi.org/10.1016/j.ijpharm.2006.06.032
10. Bussemer T, Otto I, Bodmeier R. Pulsatile drug-delivery systems. Critical Reviews in Therapeutic Drug Carrier Systems. 2001; 18(5): 433–458. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v18.i5.10
11. Kario K, Pickering TG, Hoshide S, Eguchi K, Ishikawa J, Morinari M, Hoshide Y, Shimada K. Morning blood pressure surge and hypertensive cerebrovascular disease: role of the α-adrenergic sympathetic nervous system. American Journal of Hypertension. 2004; 17(8): 668–675. https://doi.org/10.1016/j.amjhyper.2004.04.011
12. Sunil SA, Srikanth MV, Rao NS, Uhumwangho MU, Latha K, Murthy KV. Chronotherapeutic drug delivery systems: an approach to circadian rhythms diseases. Current Drug Delivery. 2011; 8(6): 622–633. https://doi.org/10.2174/156720111797635559
13. Mandal U, Chatterjee B, Cecilie VL. Current strategies in development of pulsatile drug delivery systems: an overview. Journal of Scientific and Innovative Research. 2020; 9(1): 1–8. https://doi.org/10.31254/jsir.2020.9101
14. Mukherjee DR, Tanbir S, Mondal S, Tarafder S, Biswas D, Dutta S, Santra S, Biswas P. Exploring the Gut Microbiome's Influence on Peptic Ulcer Disease: Mechanistic Insights, Pharmacological Implications, and Emerging Therapeutic Strategies. Journal of Drug Delivery and Therapeutics. 2025; 15(4): 209–218. https://doi.org/10.22270/jddt.v15i4.7088
15. Hermida RC, Ayala DE, Mojón A, Fernández JR. Sleep-time blood pressure as a therapeutic target for cardiovascular risk reduction in type 2 diabetes. American Journal of Hypertension. 2012; 25(3): 325–334. https://doi.org/10.1038/ajh.2011.231
16. Karia C, Bhatt N, Pandya V, Sheth N, Shelat P. Chronotherapy and pulsatile drug delivery system. The Scitech Journal. 2015; 2(3): 5–9.
17. Youan BB. Chronopharmaceutics: science and technology for biological rhythm-guided therapy and prevention of diseases. Advanced Drug Delivery Reviews. 2010; 62(9–10): 875–897. https://doi.org/10.1016/j.addr.2010.02.001
18. Lemmer B. Chronobiology, drug-delivery, and chronotherapeutics. Advanced Drug Delivery Reviews. 2007; 59(9–10): 825–827. https://doi.org/10.1016/j.addr.2007.07.001
19. Langer R. New methods of drug delivery. Science. 1990; 249(4976): 1527–1533. https://doi.org/10.1126/science.2218494
20. Gazzaniga A, Palugan L, Foppoli A, Sangalli ME. Oral colon-specific drug delivery systems for highly soluble drugs: an approach to slow-release formulations. European Journal of Pharmaceutics and Biopharmaceutics. 2008; 68(3): 553–559. https://doi.org/10.1016/j.ejpb.2007.07.006
21. Hermida RC, Ayala DE, Fernández JR, Calvino C. Comparison of the effects of morning vs. evening treatment with the calcium-channel blocker amlodipine in patients with essential hypertension. Journal of Human Hypertension. 2002; 16(9): 675–681. https://doi.org/10.1038/sj.jhh.1001453
22. Bhalla S, Rathore H, Garg M, Dua K. The review on direct compression tabletting as a convenient method for tablet formulation. World Journal of Pharmaceutical Research. 2017; 6(4): 196–212. https://doi.org/10.20959/wjpr20174-8250
23. Patel S, Kaushal AM, Bansal AK. Compression physics in the formulation development of tablets. Critical Reviews in Therapeutic Drug Carrier Systems. 2006; 23(1): 1–65. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v23.i1.10
24. Hussain A, Smith G, Khan KA, Bukhari NI, Pedge NI, Ermolina I. Investigation of the effect of magnesium stearate on the flow properties of lactose by surface energy and cohesion analyses. European Journal of Pharmaceutics and Biopharmaceutics. 2016; 109: 11–22. https://doi.org/10.1016/j.ejpb.2016.09.016
25. Aulton ME, Taylor KMG. Aulton's Pharmaceutics: The Design and Manufacture of Medicines. 5th ed. Edinburgh: Elsevier; 2018. ISBN: 978-0702073694.
26. Goswami R, Santra S, Pal B, Basu B, Prajapati B. Improvement of pharmacokinetic properties and release of aceclofenac swellable matrix tablets utilizing okra (Abelmoschus Esculentus) and Hibiscus Leaf (Hibiscus Rosa-Sinensis) natural polymer mucilage. IP International Journal of Comprehensive and Advanced Pharmacology. 2024; 9(2): 130–138. https://doi.org/10.18231/j.ijcaap.2024.019
27. Bodmeier R, Paeratakul O. A novel multiple-unit drug delivery system. I. Compression of theophylline pellets with and without the addition of retarding polymers. Drug Development and Industrial Pharmacy. 1994; 20(9): 1517–1533. https://doi.org/10.3109/03639049409038387
28. Bussemer T, Dashevsky A, Bodmeier R. A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. Journal of Controlled Release. 2003; 93(3): 331–339. https://doi.org/10.1016/j.jconrel.2003.09.001
29. Dashevsky A, Bussemer T, Bodmeier R. Pharmaceutical press-coated tablets with pulsatile drug release. European Journal of Pharmaceutics and Biopharmaceutics. 2001; 51(2): 123–128. https://doi.org/10.1016/S0939-6411(00)00151-3
30. Santra S, et al. Development of Ionically Crosslinked Microspheres Containing Acyclovir Using Natural Polymers for Sustained Release. International Journal of Zoological Investigations. 2026; 12(1). https://doi.org/10.33745/ijzi.2026.v12i01.042
31. Nagaraju R, Kaza R. Recent developments in pulsatile drug delivery systems: a review. International Journal of Research in Pharmaceutical and Biomedical Sciences. 2011; 2(2): 501–511.
32. Anand O, Lawrence X, Yu L, Hussain AS. Dissolution testing for generic drugs: an FDA perspective. AAPS Journal. 2011; 13(3): 328–335. https://doi.org/10.1208/s12248-011-9272-y
33. Pharmacopoeia of India (IP). 7th ed. New Delhi: Indian Pharmacopoeia Commission; 2018.
34. United States Pharmacopeia and National Formulary USP 46-NF 41. Rockville: United States Pharmacopeial Convention; 2023.
35. Kakhi M. Classification of the fluid dynamics in the USP apparatus 2. International Journal of Pharmaceutics. 2009; 376(1–2): 22–34. https://doi.org/10.1016/j.ijpharm.2009.04.024
36. Santra S, et al. Isolation and characterization of flavonoid fractions from orange peel with antioxidant properties. International Journal of Basic & Clinical Pharmacology. 2026; 15(3): 519–525. https://doi.org/10.18203/2319-2003.ijbcp20261118
37. Silverstein RM, Webster FX, Kiemle DJ. Spectrometric Identification of Organic Compounds. 7th ed. New York: Wiley; 2005. ISBN: 978-0471393627.
38. Dymek K, Wiercigroch E, Malek K, Stepanenko Y, Bryła A, Jarosz M. Characterization of a chlorthalidone raw material and pharmaceutical formulations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2023; 297: 122736. https://doi.org/10.1016/j.saa.2023.122736
39. Ford JL, Mann TE. Fast-scan DSC and its role in pharmaceutical physical form characterisation and selection. Advanced Drug Delivery Reviews. 2012; 64(5): 422–430. https://doi.org/10.1016/j.addr.2011.11.010
40. Chadha R, Bhandari S. Drug-excipient compatibility screening—role of thermoanalytical and spectroscopic techniques. Journal of Pharmaceutical and Biomedical Analysis. 2014; 87: 82–97. https://doi.org/10.1016/j.jpba.2013.06.016
41. Saber-Samandari S, Khatibi M, Doliati S, Ahmadi H. Scanning electron microscopy (SEM) applications in pharmaceutical manufacturing. Pharmaceutical Bioprocessing. 2014; 2(4): 211–219.
42. Thakur N, Sharma B, Bishnoi S, Thakur S. Ethyl cellulose: a suitable polymer for drug encapsulation and controlled release. Drug Delivery Letters. 2020; 10(3): 209–218. https://doi.org/10.2174/2210303109666190326103139
43. Indian Pharmacopoeia Commission. Indian Pharmacopoeia (IP) 2018. Ghaziabad: Government of India; 2018.
44. FDA. Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Guidance for Industry. Rockville: US Food and Drug Administration; 1997. Available from: https://www.fda.gov/media/70936/download
45. Emami J. In vitro - in vivo correlation: from theory to applications. Journal of Pharmacy and Pharmaceutical Sciences. 2006; 9(2): 169–189.
46. Ritger PL, Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Journal of Controlled Release. 1987; 5(1): 37–42. https://doi.org/10.1016/0168-3659(87)90035-6
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