Development and optimization of mucoadhesive sustained-release chlorothiazide pellets for improved bioavailability: A response surface methodology based approach
Abstract
Chlorothiazide (CTZ), a widely used thiazide diuretic, exhibits poor and variable oral bioavailability due to site-specific absorption and carrier-mediated saturable transport in the upper gastrointestinal tract. This study aimed to develop mucoadhesive controlled-release pellets of CTZ to overcome these limitations and improve bioavailability. The pellets were prepared using the extrusion-spheronization technique, with critical formulation parameters optimized using a 32 full factorial design. The concentrations of hydroxypropyl methylcellulose (HPMC K15M) and polycarbophil were selected as independent variables, while the percentage drug release at 1 h, percentage drug release at 6 h, and ex-vivo mucoadhesion time (hours) were chosen as dependent variables. Results revealed that higher HPMC K15M concentrations significantly reduced drug release due to its gel-forming properties, while polycarbophil contributed to enhanced mucoadhesion. The optimized batch exhibited sustained drug release over 12 h and prolonged gastric retention, with over 90 % mucoadhesion in-vivo after 8 h. Pharmacokinetic studies demonstrated a 2.93-fold improvement in bioavailability compared to conventional CTZ formulations in rat. Fourier Transform Infrared Spectroscopy (FTIR) and Powder X-ray Diffraction (PXRD) analyses confirmed the stability of CTZ in the formulation. This study highlights the potential of mucoadhesive controlled-release systems in addressing absorption challenges associated with CTZ, providing a promising strategy for enhancing therapeutic outcomes.
Introduction
Chlorothiazide (CTZ), 6-chloro-4H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (C7H6ClN3O4S2), is a thiazide diuretic commonly administered orally as tablets or oral suspensions [1]. It is widely used to treat edema (fluid retention) caused by conditions such as congestive heart failure, severe liver disease (cirrhosis), kidney disorders, or long-term steroid or hormone treatments. CTZ inhibits the sodium/chloride cotransporter in the distal tubules, leading to increased excretion of sodium and water [2]. This mechanism not only helps in reducing edema but also in managing high blood pressure (hypertension), which is important for preventing complications like stroke, heart attacks, heart failure, and kidney failure. The typical oral dosage for edema is 500–1000 mg once or twice daily, while for hypertension, the dosage is 500–1000 mg per day, either as a single dose or divided doses, with adjustments made by the prescribing doctor as needed [3]
While literature classifies CTZ as a BCS Class IV drug, in-vitro dissolution studies reported in published research articles present a contradictory perspective. Shah et al. have compared the dissolution profile of various CTZ tablets with different dose and release patterns. The authors reported more than 70 percent drug release in 60 min at pH 7.4 at all the tested rpm with 250 mg conventional tablet [4]. Similarly, Teng et al. have prepared cocrystals and hydrate cocrystals of the CTZ for improving the dissolution. Here also the authors have reported that dissolution of the prepared cocrystal was only marginally higher than the pure CTZ (1.05 and 1.03 times) [5]. Although CTZ is safe and effective on oral administration and have good dissolution profile, absorption of CTZ from the gastrointestinal tract is incomplete and variable depending on the dose administration [6]. Studies have indicated that bioavailability decreases with increasing doses, with a reported decline of 56 %, 33 %, and 16 % for administered doses of 50 mg, 250 mg, and 500 mg, respectively [7]. This variability in bioavailability is attributed to site-specific absorption (limited segment of the upper segment of the small intestine) and carrier-mediated saturable absorption mechanisms. [8].
In conventional tablet formulations of CTZ, drug release is rapid, with absorption being the rate-limiting step governed by two primary factors: 1. Site-Specific Absorption: The absorption of CTZ in the gastrointestinal (GI) tract depends on specific transport mechanisms, primarily mediated by transport proteins or carriers, which are localized to upper segment of the small intestine. As a result, the drug can only be effectively absorbed in these limited regions, making the timing and rate of drug release critical [9,10]. 2. Carrier-Mediated Saturation: Since the absorption of these drugs is carrier-mediated, a rapid increase in drug concentration following the disintegration of conventional tablets can saturate the available transporters. When the drug concentration rises quickly, the transporters become saturated, reaching their maximum capacity for absorption. This saturation prevents further absorption, causing a significant proportion of the drug to remain unabsorbed and be excreted from the body. This results in reduced drug bioavailability as a substantial amount is lost before it can be absorbed into systemic circulation [11,12].
Unlike conventional formulations that release the drug rapidly and risk saturating transporters, controlled-release systems ensure a gradual and sustained drug release. In these systems, the drug release rate becomes the rate-limiting step for absorption, effectively mitigating the limitations of carrier-mediated transport [13]. By modulating drug release, sustained-release formulations maintain consistent and prolonged drug availability throughout the GI tract, ensuring optimal concentrations within the absorption window and enhancing overall bioavailability. An oral sustained-release system can be developed using various strategies, including Floating Drug Delivery Systems (FDDS), mucoadhesive systems, swelling and expanding systems, and high-density systems [14,15]. Among these strategies, mucoadhesive systems stand out as particularly promising, as they directly adhere to the mucosal lining of stomach, unlike FDDS, which rely on sufficient gastric fluid levels to remain buoyant. This adhesion helps maintain the dosage form in place, even when the stomach empties or fluid levels are low, overcoming a key limitation of FDDS. Swelling and expanding systems can be bulky and may face challenges in uniform expansion, while high-density systems require precise formulation to ensure they remain at the bottom of the stomach. In contrast, the mucoadhesive approach provides a more stable and consistent gastric retention by directly interacting with the mucus layer, ensuring prolonged drug release and absorption [16,17].
All these advantages associated with mucoadhesive system have enticed formulation scientists to overcome carrier-mediated saturation and site-specific absorption by allowing a steady and sustained absorption over an extended period in the stomach thus enhancing the overall bioavailability [18,19]. Abouelatta et al. designed a gastro-retentive system to extend the gastric residence time of gabapentin, an antiepileptic drug with carrier-mediated absorption and a narrow absorption window, both of which necessitate frequent dosing and contribute to poor patient compliance. In-vivo experiments on rats confirmed prolonged gastric retention of the gel. Moreover, the optimized formula significantly improved the oral bioavailability of GBP compared to the commercially available Neurontin® immediate-release solution, with a 1.7-fold increase in Cmax and AUC parameters, indicating its potential for enhanced therapeutic outcomes [12].
A multiparticulate drug delivery system (MPDS) uses small, discrete particles such as granules, pellets, beads, or microspheres, typically ranging in size from 0.1 to 2 mm [20,21]. Pelletization, a key technique in MPDS, involves the size-enlargement of powdered active pharmaceutical ingredients and excipients into small, spherical, free-flowing units called pellets, usually between 0.5 and 2.0 mm [22]. Compared to traditional tablets and capsules, pellets provide several therapeutic benefits as follow. 1. Their ability to disperse uniformly throughout the gastrointestinal tract leads to more consistent drug absorption and reduces the risk of localized side effects. 2. Pellets can be customized to release drugs at different rates, allowing for precise control over peak plasma levels while maintaining bioavailability. 3. Additionally, the even dispersion of pellets minimizes the risk of dose dumping and can reduce gastric irritation from certain medications [[23], [24], [25]].
Response Surface Methodology (RSM) is a vital statistical tool in pharmaceutical formulation development, optimizing processes by analyzing the effects of multiple variables on a response with minimal experimentation. It enhances efficiency by systematically identifying interactions between factors such as excipient type and concentration, which significantly impact drug performance. A 32 full factorial design was chosen to systematically evaluate the impact of formulation variables on the key quality attributes of the pellets while minimizing the number of experimental runs. This approach enables the identification of significant factors and their interactions, ensuring an optimized formulation with judicious resource utilization [25,26].
In the light of above-mentioned facts, the present investigation aimed to formulate mucoadhesive sustained release pellets of chlorothiazide to overcome its carrier-mediated saturable and site-specific absorption limited poor bioavailability. The present investigation also applies the RSM to decode the effect of critical formulation parameters on the key characteristics of the formed pellets.
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Materials
CTZ, received as gift from Cambrex Profarmaco, Italy. NOVEON AA-1 (polycarbophil), provided as a generous gift by Lubrizol Advanced Material India Pvt. Ltd. Hydroxypropyl methylcellulose (HPMC K15M), microcrystalline cellulose (MCC), and polyvinylpyrrolidone (PVP) K30 were purchased from Molychem India Limited. All chemicals and reagents used were of analytical grade.
Nandlal savaliya, Chetan Borkhataria, Kiran Dudhat, Sunny shah, Trupesh Pethani, Chintankumar Tank, Viral Shah, Chintan Kalsariya, Mori Dhaval, Development and optimization of mucoadhesive sustained-release chlorothiazide pellets for improved bioavailability: A response surface methodology based approach, Journal of Drug Delivery Science and Technology, Volume 108, 2025, 106951, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.106951.
Read also our introduction article on Microcrystalline Cellulose here:
