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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article   Research Article

Optimization and Characterization of Chlorthalidone Bilayer Tablets for Chronotherapeutic Pulsatile Drug Release

Moulindu Mondal ¹, Deepannita Roy Mukherjee ²*, Dona Biswas ³, Pinki Biswas ³, Saikat Santra ³

¹ Department of Pharmaceutics, Bengal School of Technology, Sugandha, Chinsurah, Hooghly–712102, West Bengal, India. 

² Department of Pharmacology, JRSET College of Pharmacy, Panchpota, Chakdah, Nadia–741222, West Bengal, India

³ Department of Pharmaceutics, JRSET College of Pharmacy, Panchpota, Chakdah, Nadia–741222, West Bengal, India

 

 

1. INTRODUCTION

Oral solid dosage forms constitute the most widely utilized category of drug delivery systems, accounting for more than 90% of pharmaceutical formulations intended for systemic action, with tablets being the preferred choice due to their unit-dose accuracy, mechanical strength, cost-effectiveness, ease of large-scale manufacturing, and high patient compliance¹. However, conventional immediate-release and sustained-release formulations are primarily designed to maintain relatively constant plasma drug concentrations, a pharmacokinetic approach that may not be optimal for diseases exhibiting time-dependent variation in symptom severity². Many pathological conditions, particularly cardiovascular disorders such as hypertension, follow circadian rhythms  endogenous biological cycles of approximately 24 hours regulated by the suprachiasmatic nucleus resulting in predictable fluctuations in physiological parameters, notably the early morning surge in blood pressure that occurs between 6:00 AM and noon and is strongly associated with increased risk of myocardial infarction, ischemic stroke, and sudden cardiac death³. This temporal mismatch between drug delivery and disease activity has led to the emergence of chronotherapeutic approaches, among which Pulsatile Drug Delivery Systems (PDDS) have gained considerable attention due to their ability to release drugs rapidly after a predefined lag phase, thereby synchronizing drug availability with peak pathophysiological demand⁴. Among various PDDS strategies, time-controlled systems such as bilayer press-coated tablets are particularly advantageous for cardiovascular therapy due to their formulation simplicity, reproducibility, and independence from physiological variables such as gastrointestinal pH and motility⁵. Hypertension, a major global health burden affecting over 1.28 billion individuals, is a chronic and often asymptomatic condition driven by complex mechanisms including the renin–angiotensin–aldosterone system, sympathetic nervous system activity, renal electrolyte balance, and endothelial mediators, ultimately leading to severe complications such as atherosclerosis, cardiac hypertrophy, renal failure, and stroke if left untreated⁶. In this context, Chlorthalidone, a long-acting thiazide-like diuretic classified under Biopharmaceutics Classification System (BCS) Class II, is an ideal candidate for pulsatile delivery owing to its low aqueous solubility, high permeability, prolonged elimination half-life (40–60 hours), and sustained antihypertensive effect mediated through inhibition of the Na⁺/Cl⁻ symporter in the distal convoluted tubule⁷. The present study introduces a novel chronotherapeutic approach by designing bilayer press-coated tablets of Chlorthalidone capable of providing a precisely controlled lag time of approximately 6 hours followed by rapid and complete drug release, aligning drug action with the early morning cardiovascular risk window after bedtime administration⁸. The novelty of this work lies in the systematic optimization of polymeric barrier layers using varying ratios of hydroxypropyl methylcellulose (HPMC) and ethyl cellulose (EC) to achieve reproducible and predictable pulsatile release behavior, combined with the development of a fast-disintegrating core to ensure immediate drug availability upon rupture of the coating⁹. Furthermore, the integration of advanced physicochemical characterization techniques, including ATR-IR spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM), along with comprehensive drug release kinetic modeling, provides a robust understanding of formulation-performance relationships¹⁰. This study therefore offers a scientifically rational and clinically relevant formulation strategy that enhances therapeutic efficacy, minimizes adverse effects, and advances the application of pulsatile drug delivery systems in the chronotherapeutic management of hypertension²¹.

2. MATERIALS AND METHODS

2.1 Materials

Chlorthalidone API was procured from Yarrow Chem Products. Mannitol, Microcrystalline Cellulose (MCC), Sodium Starch Glycolate (SSG), Magnesium Stearate, Talc, Lactose, and HPMC K100M were obtained from Lobe Chemie Pvt. Ltd., Mumbai. Croscarmellose Sodium (CCS) and Starch were sourced from Research-Lab Fine Chem Industries, Mumbai. Ethyl Cellulose (EC) was procured from HiMedia Laboratories. Methanol (AR grade) was used as a solvent in analytical studies. All materials were of pharmaceutical/analytical grade.

 

 

Table 1: List of Materials Used in the Study

S.No.	Ingredient	Category	Manufacturer
1	Chlorthalidone (Drug)	API	Yarrow Chem Products
2	Mannitol	Filler/Diluent	Lobe Chemie Pvt. Ltd., Mumbai
3	MCC	Diluent/Binder	Lobe Chemie Pvt. Ltd., Mumbai
4	Sodium Starch Glycolate (SSG)	Superdisintegrant	Lobe Chemie Pvt. Ltd., Mumbai
5	Croscarmellose Sodium (CCS)	Superdisintegrant	Research-Lab Fine Chem, Mumbai
6	Magnesium Stearate	Lubricant	Lobe Chemie Pvt. Ltd., Mumbai
7	Talc	Glidant	Lobe Chemie Pvt. Ltd., Mumbai
8	Lactose	Diluent	Lobe Chemie Pvt. Ltd., Mumbai
9	HPMC K100M	Polymer (Coat)	Lobe Chemie Pvt. Ltd., Mumbai
10	Ethyl Cellulose	Polymer (Coat)	HiMedia Laboratories
11	Methanol	Solvent	AR Grade

 

 

2.2 Formulation of Fast-Dissolving Core Tablets

Core tablets containing 10 mg of Chlorthalidone were prepared by the direct compression method²². All excipients listed in Table 2 were individually passed through sieve #60, accurately weighed, and blended uniformly in a closed polyethylene container for 30 minutes to ensure homogeneity²³. Magnesium stearate and talc were incorporated during the final 5 minutes of blending as lubricant and glidant, respectively²⁴. The prepared powder blend was evaluated for pre-compression parameters, including flow properties, prior to compression²⁵. The blend was then directly compressed using a 12-station rotary tablet punching machine fitted with 7 mm round flat-faced punches to obtain fast-dissolving core tablets²⁶.

 

 

 

 

 

Table 2: Composition of Core Tablet (per tablet)

 

2.3 Formulation of Press-Coated Bilayer Tablets (CHT-A to CHT-I)

Nine formulations designated CHT-A through CHT-I were prepared using varying weight ratios of HPMC K100M (hydrophilic swelling layer) and Ethyl Cellulose (hydrophobic rupturable membrane)²⁷. The formulation code nomenclature — CHT (Chlorthalidone) followed by a letter suffix — reflects increasing HPMC content (CHT-A: pure EC → CHT-I: HPMC-rich; CHT-G represents the optimized 3:5 HPMC:EC ratio)²⁸. Coat materials were passed through sieve #24 and blended uniformly for 15 minutes²⁹. For each tablet, half of the coating blend was loaded into the die cavity, the pre-formed core tablet was manually centered, and the remaining coating material was added over the core³⁰. Final compression was performed using 11 mm round punches on a 12-station rotary tablet press to obtain press-coated bilayer tablets³¹. Table 3 presents the coating layer compositions of formulations CHT-A to CHT-I.

 

 

Table 3: Coating Layer Compositions for Formulations CHT-A to CHT-I

*CHT-G = Optimized formulation. HPMC:EC weight ratio = 150:250 (3:5).

 

 

2.4 Evaluation of Tablets

2.4.1 Organoleptic Characterization

Pure Chlorthalidone API was evaluated for colour, odour, taste, and physical appearance³².

2.4.2 Melting Point Determination

The melting point was determined by the capillary tube method using a liquid paraffin bath and calibrated thermometer³³. The temperature range at which the drug melted was recorded³⁴.

2.4.3 Solubility Study

The saturation solubility of Chlorthalidone was evaluated in distilled water using UV spectrophotometric analysis at 276 nm³⁵. Solubility in methanol, ethanol, ether, and chloroform was assessed qualitatively³⁶.

2.4.4 ATR-IR Spectroscopy — Drug–Excipient Compatibility

ATR-IR spectroscopy was performed to confirm drug identity and evaluate compatibility between Chlorthalidone and excipients³⁷. Spectra were recorded over 4000–300 cm⁻¹ at 4 cm⁻¹ resolution³⁸.

2.4.5 Differential Scanning Calorimetry (DSC)

DSC analysis was conducted to investigate thermal behavior and possible drug–excipient interactions³⁹. Samples were scanned from 30°C to 300°C at 10°C/min under nitrogen atmosphere⁴⁰.

2.4.6 Scanning Electron Microscopy (SEM)

SEM was used to examine the surface morphology of pure drug crystals and the optimized formulation (CHT-G)⁴¹. Samples were gold sputter-coated and analyzed at different magnifications under 10–15 kV accelerating voltage⁴².

 

2.4.7 Post-Compression Parameters of Core Tablets

Core tablets were evaluated for physical appearance, thickness, diameter, weight variation, hardness, friability, disintegration time, and drug content according to pharmacopeial standards⁴³.

2.4.8 In Vitro Dissolution Study

Dissolution studies were performed using USP Type II apparatus at 50 rpm and 37 ± 0.5°C⁴⁴. Drug release was evaluated in 0.1 N HCl followed by pH 6.8 phosphate buffer, and samples were analyzed at 276 nm⁴⁵.

2.4.9 Drug Release Kinetics

Release data of optimized formulation CHT-G were fitted to Zero-order, First-order, Higuchi, and Korsmeyer–Peppas kinetic models to determine the release mechanism⁴⁶.

3. RESULTS

3.1 Organoleptic Properties and Melting Point

Pure Chlorthalidone is a white to off-white, odorless, and tasteless crystalline powder, as shown in Figure 1. The melting point of the compound was found to be 227°C, which is in close agreement with the reported pharmacopoeial value. This result confirms the identity and purity of the drug, as outlined in Table 4.

Table 4: Identification Tests of Pure Chlorthalidone

S.No.	Parameter	Observation
1	Colour	White to off-white
2	Odour	Odourless
3	Taste	Tasteless
4	Appearance	Crystalline powder
5	Melting Point	227°C

 

 

Figure 1: Bilayer Chlorthalidone Tablets

3.2 Solubility

Chlorthalidone was found to be soluble in methanol, slightly soluble in ethanol, and insoluble in water, ether, and chloroform — consistent with its BCS Class II classification (low aqueous solubility, high permeability).

3.3 ATR-IR Spectroscopy

The FTIR spectrum of pure Chlorthalidone Figure 2 (A) exhibited characteristic absorption bands at 3418–3248 cm⁻¹ corresponding to N–H stretching vibrations, a prominent peak at 1650 cm⁻¹ attributed to C=O stretching of the sulfonamide group, and bands in the region of 1458–1383 cm⁻¹ associated with aromatic C=C and C–N stretching vibrations. Additional peaks observed at 1167–1016 cm⁻¹ correspond to S=O stretching vibrations, while the band at 683 cm⁻¹ is characteristic of C–Cl stretching, confirming the identity of the drug.

In the Chlorthalidone–HPMC physical mixture Figure 2 (B), the characteristic peaks of Chlorthalidone were retained with only minor shifts in peak positions and slight reductions in intensity. The principal absorption bands at 2361, 1659, 1560, 1383, 1338, 1019, and 685 cm⁻¹ remained clearly visible, indicating that the drug maintained its chemical structure in the presence of HPMC. No new peaks or disappearance of major peaks were observed.

Similarly, the Chlorthalidone–EC physical mixture Figure 2 (C) showed the preservation of the characteristic drug peaks at 2361, 1650, 1458, 1398, 1363, 1167, 1076, 1017, and 683 cm⁻¹. The absence of significant peak shifts, peak broadening, or additional absorption bands suggests that no chemical interaction occurred between Chlorthalidone and ethyl cellulose.

The FTIR spectrum of Chlorthalidone with all excipients, Figure 2 (D), displayed the major characteristic peaks of the drug along with peaks attributable to the excipients. Although minor variations in peak intensity and broadening were observed due to physical mixing and possible hydrogen-bond interactions, the fundamental functional group frequencies of Chlorthalidone remained unchanged. Importantly, no new absorption bands or disappearance of characteristic drug peaks were detected. The FTIR analysis demonstrated in Table 5 that the characteristic functional groups of Chlorthalidone remained intact in all physical mixtures and in the formulation containing all excipients. The absence of significant spectral changes indicates good compatibility between Chlorthalidone and the selected polymers/excipients, confirming the lack of chemical interaction and supporting their suitability for formulation development.

 

 

 

 

Table 5: ATR-IR/FTIR Peak Assignment and Interpretation of Chlorthalidone and Physical Mixtures

 

 

Figure 2. ATR-IR spectra of (a) pure Chlorthalidone, (b) Chlorthalidone-HPMC (1:1), (c) Chlorthalidone-EC (1:1), and (d) Chlorthalidone with all excipients.

 

 

3.4 Differential Scanning Calorimetry (DSC)

The DSC thermogram of pure Chlorthalidone (Figure 3 a) exhibited a sharp endothermic peak at approximately 238°C, corresponding to the melting point of the crystalline drug. The sharp and intense peak confirms the crystalline nature and thermal stability of Chlorthalidone.

In the Chlorthalidone–HPMC physical mixture (Figure 3 b), the characteristic melting endotherm of 

Chlorthalidone was retained with a slight shift toward a lower temperature (approximately 236°C). A broad endothermic event observed between 70–120°C can be attributed to the loss of absorbed moisture from HPMC. The preservation of the drug melting peak without the appearance of any new thermal events suggests the absence of significant interaction between Chlorthalidone and HPMC.

Similarly, the Chlorthalidone–EC physical mixture (Figure 3 c) showed the characteristic melting endotherm of Chlorthalidone at approximately 238°C with only a minor variation in peak intensity. A slight baseline deviation observed in the range of 100–150°C is associated with the polymeric characteristics of ethyl cellulose. No additional peaks or disappearance of characteristic drug peaks were observed, indicating good compatibility between Chlorthalidone and EC.

The retention of the characteristic melting endotherm of Chlorthalidone in both physical mixtures, along with only minor shifts in peak temperature and enthalpy values, indicates that no significant drug-excipient interactions occurred during mixing. These findings confirm the compatibility of Chlorthalidone with HPMC and EC, supporting their suitability for formulation development and indicating that there are no interactions or polymorphic conversions, as shown in Figure 3 and Table 6.

 

 

 

Figure 3: DSC thermograms of (a) pure Chlorthalidone, (b) Chlorthalidone-HPMC physical mixture (1:1), and (c) Chlorthalidone-EC physical mixture (1:1), showing characteristic melting endotherm and absence of drug-excipient interaction. 

 

Table 6: DSC Parameters of Chlorthalidone and Physical Mixtures

Sample	Onset Temperature (°C)	Peak Temperature (°C)	ΔH (J/g)
Pure Chlorthalidone	233.6	238.4	96.8
Chlorthalidone + HPMC (1:1)	230.8	236.3	82.4
Chlorthalidone + EC (1:1)	232.6	237.8	89.7

Note: ΔH values scaled to drug proportion. No new peaks or exotherms observed.

 

 

 

3.5 Scanning Electron Microscopy (SEM)

Figure 4 (A) (Pure Chlorthalidone): The SEM image of pure Chlorthalidone reveals well-defined, elongated rod-shaped crystals with smooth surfaces and sharp edges, indicating the crystalline nature of the drug. The uniform crystal habit and absence of surface irregularities suggest high crystallinity of the untreated drug material. Figure 4 (B) (Hydrated Matrix after Dissolution): The cross-sectional SEM image shows the formation of a distinct swollen polymeric layer surrounding the drug core. Numerous pores and channels are visible within the matrix, indicating penetration of dissolution medium and gradual erosion of the hydrated polymer network. The presence of the swollen HPMC layer demonstrates gel formation, which acts as a diffusion barrier and contributes to the controlled release of Chlorthalidone. The rupturable ethyl cellulose membrane remains partially intact around the hydrated core, supporting a membrane-controlled release mechanism. Figure 4 (C) (Optimized Formulation Surface): The surface morphology of the formulated tablet appears relatively smooth, compact, and homogeneous, with only a few minor surface imperfections. No visible drug crystals or phase separation are observed on the tablet surface, suggesting uniform dispersion of Chlorthalidone within the polymer matrix. The absence of cracks or large pores indicates good film-forming properties and effective compression characteristics of the formulation.

 

 

 

Figure 4: SEM micrographs: (a) Pure Chlorthalidone drug crystals (×500); (b) cross-section of optimized formulation CHT-G showing core, HPMC swelling layer, and EC rupturable outer membrane (×100); (c) coat surface of CHT-G at ×1000.

 

 

3.6 Post-Compression Parameters of Core Tablets

Core tablets met all pharmacopoeial and in-house specifications as summarized in Table 7. Hardness (4.2–4.5 kg/cm²) was appropriate for the subsequent press-coating step. Disintegration time (185 s; ~3 minutes) confirms rapid core disintegration once the coat ruptures. Drug content (95.8%) and friability (0.45%) are within IP 2010 limits.

 

 

Table 7: Post-Compression Parameters of Core Tablet 

Weight (mg)	Thickness (mm)	Hardness (kg/cm²)	Friability (%)	Disintegration (s)	Drug Content (%)
150.7 ± 2.67	3.4	4.2–4.5	0.45	185	95.8

±SD and number of replicates (n) for Thickness, Hardness, Friability, Disintegration Time, and Drug Content per IP 2010 / USP standards.

 

 

3.7 In Vitro Dissolution of Press-Coated Tablets (CHT-A to CHT-I)

All nine formulations exhibited a complete lag phase (0% drug release) during the first 2 hours in 0.1 N HCl. Following medium change to pH 6.8 buffer, drug release commenced at varying time points according to the HPMC:EC ratio (Table 8, Figure 5). 

 

 

Table 8: Cumulative % Drug Release from Formulations CHT-A to CHT-I

Time (h)	CHT-A	CHT-B	CHT-C	CHT-D	CHT-E	CHT-F	CHT-G*	CHT-H	CHT-I
0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
1	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
2	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
3	101.04	12.29	8.13	61.38	12.29	73.13	13.13	18.96	13.96
4	100.00	17.31	22.31	69.47	15.64	77.27	12.31	20.22	17.72
5	100.00	22.32	31.49	80.65	17.74	82.29	18.99	24.82	31.49
6	100.00	31.92	81.51	90.67	22.34	93.60	20.26	31.51	79.01
7	100.00	34.45	88.20	94.03	25.28	98.32	83.20	34.03	86.53

CHT-G = Optimized formulation containing HPMC K100M (150 mg) and Ethyl Cellulose (250 mg). For CHT-A, cumulative drug release values exceeding 100% were observed after 3 h. Since cumulative drug release cannot physically exceed the total amount of drug present in the dosage form, these values were attributed to normal analytical variability associated with dissolution sampling, dilution procedures, spectrophotometric measurement, and calibration curve estimation. Therefore, values above 100% were interpreted as complete drug release and reported as 100%. This adjustment does not alter the dissolution behavior or comparative performance of the formulation, but ensures compliance with the fundamental mass-balance principle governing drug release studies.

Figure 5: Comparative in vitro dissolution profiles of formulations CHT-A to CHT-I showing cumulative % drug release vs. time (hours). CHT-G exhibits the desired 6-hour lag time followed by rapid burst release.

 

 

3.8 Drug Release Kinetics of Optimized Formulation CHT-G

Kinetic analysis of CHT-G dissolution data revealed the Korsmeyer-Peppas model as the best fit (Figure 6, Table 9), with R² = 0.8545 and release exponent n = 2.2082, indicating super case-II transport (n > 1.0). Zero-order (R² = 0.6394), first-order (R² = 0.5078), and Higuchi (R² = 0.5581) models showed poor fit.

 

Table 9: Drug Release Kinetics Parameters-Optimized Formulation CHT-G

 

Figure 6: Kinetic release plots for optimized formulation CHT-G: (a) Zero-order; (b) First-order; (c) Higuchi; (d) Korsmeyer-Peppas-best fit model (R² = 0.8545). 

 

 

4. DISCUSSION

The present study successfully developed and characterized a chronotherapeutic pulsatile drug delivery system of Chlorthalidone using bilayer press-coated tablets (CHT-A to CHT-I). The formulation strategy was designed to address the early morning surge in blood pressure, a period associated with an increased risk of adverse cardiovascular events such as myocardial infarction and stroke. By providing a predetermined lag phase followed by rapid drug release, the developed system aims to synchronize drug availability with the circadian rhythm of hypertension. 

Preformulation studies confirmed the suitability of Chlorthalidone for incorporation into the pulsatile delivery system. The drug exhibited characteristic physicochemical properties consistent with reported literature values. ATR-IR spectroscopy demonstrated the retention of all major characteristic absorption bands of Chlorthalidone in the presence of HPMC, EC, and other formulation excipients, indicating the absence of significant chemical interactions. Similarly, DSC analysis revealed the preservation of the characteristic melting endotherm of Chlorthalidone with only minor shifts in peak temperature, confirming the thermal compatibility of the drug with the selected polymers. These findings indicate that the formulation components are compatible and unlikely to adversely affect drug stability during processing and storage.

SEM analysis provided valuable insight into the structural characteristics of the optimized formulation. The pure drug exhibited well-defined crystalline morphology, whereas the optimized tablet displayed a compact and homogeneous surface without visible drug crystals or major defects. The cross-sectional micrograph revealed a distinct multilayer structure comprising the drug core, swelling HPMC layer, and rupturable EC outer membrane. This architecture supports the proposed mechanism of pulsatile release, in which water penetration into the tablet causes swelling of HPMC, generating internal pressure that eventually ruptures the surrounding EC layer and triggers rapid drug release.

The dissolution profiles of formulations CHT-A through CHT-I clearly demonstrated the influence of polymer composition on lag time and drug release behavior. Formulation CHT-A, containing only ethyl cellulose (400 mg), exhibited premature drug release beginning at the third hour, indicating failure of the hydrophobic barrier to maintain the desired lag phase. The absence of a swelling polymer component prevented the generation of controlled internal pressure and resulted in rapid penetration of dissolution medium through the coating. Consequently, complete drug release was achieved much earlier than required for chronotherapeutic delivery. In contrast, formulation CHT-B, containing only HPMC K100M (400 mg), exhibited only 34.45% cumulative drug release after 7 h. The extensive swelling and gel-forming properties of HPMC produced a strong diffusion barrier that significantly retarded drug release and prevented the abrupt burst effect required for pulsatile therapy. These observations demonstrate that neither EC nor HPMC alone can provide an optimal pulsatile release profile. 

A clear relationship between polymer ratio and drug release characteristics was observed among the intermediate formulations. Increasing the proportion of HPMC enhanced water uptake and swelling, thereby increasing the internal pressure generated within the coat. Excessive HPMC content led to early rupture and shorter lag times, as observed with CHT-D (300 mg HPMC:100 mg EC), which released 61.38% of drug by the third hour. Conversely, increasing the proportion of EC strengthened the hydrophobic barrier and delayed water penetration, resulting in prolonged lag times and slower release. Formulations containing high EC content, such as CHT-E and CHT-H, exhibited extended release retardation due to the greater resistance of the hydrophobic membrane to medium penetration. These results confirm that the lag phase and subsequent release pattern can be effectively modulated by adjusting the HPMC-to-EC ratio. 

Among all formulations, CHT-G (HPMC 150 mg: EC 250 mg) exhibited the most desirable pulsatile release profile. The formulation maintained a lag phase for approximately 6 h, with only limited drug release during this period, followed by a rapid increase in drug release at the seventh hour. Such behavior is characteristic of a successful rupturable pulsatile system, where swelling-induced pressure gradually accumulates within the coating until mechanical failure of the EC membrane occurs. The abrupt release observed after the lag period demonstrates that the balance between the swelling force of HPMC and the mechanical resistance of EC was optimized in this formulation. The dissolution behavior of CHT-G closely matches the intended chronotherapeutic objective of delivering Chlorthalidone during the early morning hours following bedtime administration. 

Drug release kinetic analysis further supported the proposed release mechanism. The Korsmeyer–Peppas model provided the best fit to the dissolution data of CHT-G (R² = 0.8545), whereas zero-order, first-order, and Higuchi models exhibited comparatively lower correlation coefficients. The release exponent (n = 2.2082) indicated super case-II transport, suggesting that drug release was governed predominantly by polymer relaxation, swelling, and pressure-induced membrane rupture rather than simple diffusion. This finding is consistent with the SEM observations and dissolution profile of the optimized formulation and confirms the suitability of the selected polymer combination for pulsatile drug delivery. 

From a therapeutic perspective, the optimized formulation offers significant potential for chronotherapy of hypertension. Following bedtime administration, the approximately 6-hour lag phase would delay drug release until the early morning period, coinciding with the time of greatest cardiovascular risk. Once released, the fast-disintegrating core rapidly liberates Chlorthalidone, while the drug’s long elimination half-life helps maintain antihypertensive activity throughout the day. Therefore, the developed pulsatile system may improve therapeutic effectiveness, enhance patient compliance, and provide better protection against early morning cardiovascular events compared with conventional immediate-release formulations. 

Overall, the study demonstrates that precise modulation of HPMC K100M and ethyl cellulose ratios can successfully control lag time and burst release behavior in press-coated tablets. The optimised formulation CHT-G achieved the optimal balance between swelling-pressure generation and membrane resistance, resulting in a pulsatile drug-delivery system capable of meeting the chronotherapeutic requirements of hypertension management.

5. CONCLUSION

A time-controlled pulsatile drug delivery system for Chlorthalidone was successfully developed, characterised, and optimised in the form of bilayer press-coated tablets designated CHT-A through CHT-I. The formulation employs HPMC K100M as a hydrophilic swelling layer and Ethyl Cellulose as a hydrophobic rupturable membrane, leveraging the swelling-pressure-driven rupture mechanism to achieve precisely timed drug release.

Comprehensive preformulation evaluation including melting point determination, ATR-IR spectroscopy, DSC thermal analysis, and SEM morphological characterization — confirmed drug identity (melting point 224°C), thermal stability (DSC endotherm at 238.4°C), crystalline purity, and excipient compatibility with both HPMC and EC, with no evidence of chemical interaction or polymorphic conversion. Core tablet evaluation demonstrated satisfactory fast-dissolving character (disintegration time 185 s) and adequate drug content (95.8%), with friability (0.45%) and weight variation within IP 2010 pharmacopoeial limits.

Among the nine formulations, CHT-G (HPMC 150 mg: EC 250 mg) was identified as the optimized formulation, exhibiting an approximately 6-hour lag phase (≤20.26% at hour 6) followed by a rapid burst release of 83.20% at hour 7. Drug release kinetics followed the Korsmeyer–Peppas model (R² = 0.8545; n = 2.2082), consistent with super case-II transport — a swelling-pressure-driven membrane rupture mechanism characteristic of rupturable bilayer press-coated systems. SEM cross-sectional analysis of CHT-G confirmed the three-layer architectural integrity of the bilayer press-coated system, with a clearly defined core, HPMC swelling layer, and EC outer membrane.

The developed CHT-G formulation presents a pharmacologically rational and patient-friendly chronopharmacological strategy for managing morning-surge hypertension: a single bedtime dose undergoes a 6-hour lag before delivering its antihypertensive payload precisely during the early morning cardiovascular high-risk window, without requiring an additional morning dose. Future studies should include in vivo pharmacokinetic validation in animal models, accelerated stability testing per ICH Q1A guidelines, and Phase I clinical pharmacokinetic assessment to confirm the chronotherapeutic benefit of CHT-G over conventional immediate-release Chlorthalidone tablets.

Conflict of Interest: The authors declare no potential conflict of interest concerning the contents, authorship, and/or publication of this article. 

Author Contributions: All authors have equal contributions in the preparation of the manuscript and compilation. 

Source of Support: Nil 

Funding: The authors declared that this study has received no financial support. 

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data supporting this paper are available in the cited references. 

Ethical approval: Not applicable.

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