Development And Optimization of Hydrochlorothiazide Oral Disintegrating Tablets Using Natural Superdisintegrants and Box–Behnken Design

Hypertension is among the most common chronic cardiovascular disorders in the world and it is still a major risk factor for stroke, myocardial infarction, heart failure, chronic kidney disease and premature mortality [1–4]. Although several antihypertensive therapies are available, a large proportion of patients still have uncontrolled blood pressure, leading to increased morbidity and mortality [5]. Therefore, effective pharmacological management is critical to reduce disease burden and improve patient outcomes. The oral route of administration is still the most preferred route of administration due to convenience, safety and patient compliance [6,7]. However, traditional tablets can be a challenge for pediatric, geriatric and dysphagic patients, leading to poor medication adherence [8].

Hydrochlorothiazide (HCTZ) is a popular thiazide diuretic commonly used for treatment of hypertension and edema [18,19]. The drug produces the antihypertensive effect by inhibiting the sodium–chloride cotransporter in the distal convoluted tubule of the nephron which increases sodium and water excretion and decreases blood pressure [6]. HCTZ is a first-line therapy for treatment of hypertension [18] due to its efficacy, low cost and long history of clinical use.

Oral disintegrating tablets (ODTs) are new dosage forms developed in order to overcome the problem in swallowing associated with conventional tablets [13–15]. ODTs disintegrate rapidly in the oral cavity without the need of water, offering enhanced convenience, enhanced patient compliance, faster onset of action and potentially improved bioavailability [13]. These advantages make ODTs particularly suitable for pediatric, geriatric, bedridden and dysphagic patients [14,15]. The regulatory authorities recommend that ODTs should disintegrate rapidly and emphasize the importance of optimization of the formulation to achieve desirable characteristics of the tablet [11,12].

Natural superdisintegrants have been extensively studied in pharmaceutical formulation due to their biodegradability, biocompatibility, less toxicity, cheaper and environmental sustainability [23–26]. Locust bean gum and fenugreek seed mucilage are natural polymers which can absorb water and swell rapidly and thus aid tablet disintegration [25]. Their use in ODT formulations presents an appealing alternative to synthetic disintegrants without sacrificing formulation performance and patient acceptability [23].

Systematic formulation development is a key aspect of Quality by Design (QbD) principles that identify critical material attributes and process parameters influencing product quality [16]. Response Surface Methodology (RSM) and Box–Behnken Design (BBD) are popular optimization tools for the evaluation of individual and interactive effect of formulation variables [17]. These statistical approaches reduce the number of experimental runs and increase the generation of information, thus facilitating the optimization of pharmaceutical formulations [16,17].

Therefore, the present work was planned to develop and optimize Hydrochlorothiazide oral disintegrating tablets with natural superdisintegrants, namely locust bean gum and fenugreek seed mucilage along with crospovidone, using Box-Behnken experimental design for rapid disintegration and enhanced drug release.

2. Materials and Methods

2.1 Materials

Hydrochlorothiazide was selected as a model antihypertensive [18]. Super-disintegrants used were locust bean gum, fenugreek seed mucilage and crospovidone other excipients used for the tablet formulation include microcrystalline cellulose, mannitol, magnesium stearate, talc and other pharmaceutical-grade ingredients [25,26].

2.2 Extraction of Fenugreek Seed Mucilage

2.2 Fenugreek Seed Mucilage Extraction

The mucilage of fenugreek seeds was isolated by the conventional aqueous extraction method. 200 g of fenugreek seeds was soaked in 1.5 L of distilled water at room temperature for 12 h. The seeds were hydrated and then heated to a slury. The slurry was kept overnight in a refrigerator for sedimentation of insoluble matter. The supernatant was collected and concentrated at 60 °C. The mucilage was precipitated by adding acetone, separated, washed repeatedly with acetone, dried at room temperature, passed through an 80-mesh sieve and stored in desiccators until further use [23].

2.3 Extraction of Locust Bean Gum

Locust bean gum was extracted from carob seeds by dehusking, grinding and purification. The gum was dissolved in hot water and filtered to remove the non-soluble impurities, precipitated with alcohol, dried, milled and stored in air-tight containers for later formulation studies [23,25].

2.4 Experimental Setup

The Box–Behnken Design [16,17] of three factors at three levels was carried out using Design-Expert® software. Independent variables selected were locust bean gum (X1), fenugreek seed mucilage (X2) and crospovidone (X3). Fifteen experimental runs with three center points were generated to evaluate the effects of formulation variables on tablet properties. Selected responses were tablet hardness, disintegration time and dissolution behavior.

2.5 Preparation of Fast Dissolving Tablets

Direct compression was used to prepare Hydrochlorothiazide oral disintegrating tablets [7,8]. Drug and excipients were uniformly mixed in accurately weighed quantities. The powder mixture was lubricated and compressed with tablet compression machine to get the uniform weight and size of the tablets.

2.6 Tablets evaluation

Pre-compression Parameters

The flow properties and compressibility of powder blends were assessed using bulk density, tapped density, Carr’s index, Hausner ratio and angle of repose [7,8].

Post-compression Parameters

The compressed tablets were evaluated for weight variation, thickness, hardness, friability, drug content uniformity, wetting time, water absorption ratio, disintegration time and in vitro dissolution as per pharmacopeial guidelines [9,11,12].

In Vitro Release Study.

Drug release studies were conducted using USP dissolution apparatus under specified condition. Samples were withdrawn at predetermined time intervals and analyzed spectrophotometrically for cumulative drug release [12].

Statistical Analysis

The Design-Expert® software was used to analyze the responses obtained. Significant formulation factors were identified and optimized tablet characteristics were attained by using the analysis of variance (ANOVA), polynomial modeling and response surface methodology [16,17].

3. RESULTS AND ANALYSIS

3.1 Discussion and Results

The aim of the present investigation was to formulate and optimize Hydrochlorothiazide Oral Disintegrating Tablets (ODTs) using natural superdisintegrants. The aim of the present study was to improve patient compliance by developing a dosage form which can disintegrate quickly and deliver improved drug release, with acceptable mechanical properties. Similar approaches have been reported in the development of ODTs for antihypertensive and other therapeutic agents where rapid disintegration and patient acceptability were improved by incorporation of suitable super disintegrants and optimization techniques. [31,32]

3.2 Pre-compression Evaluation

Flow properties of all powder blends like angle of repose, bulk density, tapped density, Hausner’s ratio and Carr’s compressibility index were determined before compression of tablets. These parameters are important for uniform die filling and consistent tablet production. [33]

The tested formulations showed good flow properties and were therefore found suitable for direct compression. The values obtained indicated good compressibility and flowability of the powder blends. The flow properties should be adequate to reduce the variation in weight and to provide content uniformity of the final dosage form. Similar observations were also reported by researchers who developed ODTs by direct compression techniques. Acceptable flow properties contributed to uniform tablet characteristics.[34]

Figure 3.2 Reduction in disintegration time achieved after optimization

 

Figure 3.3: Cumulative percentage drug release of optimized formulation.

 

Figure 3.4 Mechanism of Action of Superdisintegrants

3.9 Discussion

This research clearly shows that Hydrochlorothiazide Oral Disintegrating Tablets were formulated very well using all-natural super disintegrants. Another important finding is that the use of Box-Behnken Design allowed for the formulation variables to be optimized systematically, which resulted in the rapid disintegration of the tablets and also the tablets having very good mechanical properties and improved drug release.

Furthermore, the optimized formulation found the correct balance between the strength of the ODTs, and also that they could be disintegrated rapidly, which is a significant challenge when developing ODTs. Additionally, direct compression was shown to be an easy, cost-effective way to manufacture ODTs when considering reasonable scalability for large-scale production. Lastly, these results agree with previous research highlighting the benefits of both direct compression and the use of statistical optimization techniques when developing ODT formulations. [49,50]

In summary, the ODT formulation developed during this research had excellent overall pharmaceutical performance and therefore has the opportunity to improve patient compliance with and the effectiveness of drug therapy for managing hypertension.

4. CONCLUSION

The present study was successfully prepared and optimize Hydrochlorothiazide Oral Disintegrating Tablets using Crospovidone, Fenugreek Seed Mucilage and Locust Bean Gum as super disintegrants. The utilization of Box-Behnken design enabled a systematic assessment of all the formulation variables and the development of an optimized formulation possessing desired pharmaceutical properties. 

The optimized formulation was found to have satisfactory hardness (2.76 kg/cm 2), low friability (0.52%), uniform thickness (1.86mm) and an extremely rapid disintegration time (16 sec). The in vitro dissolution study showed that the formulation released about 97.41% of the drug in 15 minutes, indicating a very high rate of drug dissolution and rapid disintegration of the tablet. 

Natural super disintegrants were found to be advantageous because of their good safety profile, biocompatibility, easy availability and inexpensive. Their manufacture by direct compression provides an easy and effective way for their large-scale production.
In conclusion, the developed Hydrochlorothiazide Oral Disintegrating Tablets provides a good alternative to conventional oral dosage forms for children, elderly and patients with swallowing difficulties. The optimized formulation has potential to improve patient compliance due to the rapidity of drug release and the formulation has sufficient mechanical strength for effective management of hypertension. 

Future research involving clinical studies of bioavailability and in-vivo evaluation will provide further evidence for the utility of the developed formulation. In conclusion, the study shows that ODT offers a convenient and effective method of medication for the patients with hypertension.

REFERENCES

1. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2019: a systematic analysis. Lancet. 2020;395(10225):709–733.
2. Hall JE, Guyton AC. Guyton and Hall Textbook of Medical Physiology. 14th ed. Philadelphia: Elsevier; 2021.
3. Katzung BG. Basic and Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, et al. Resistant hypertension: Detection, evaluation, and management. Hypertension. 2018;72(5):e53–e90.
5. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635–1642.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill; 2022.
7. Aulton ME, Taylor KMG. Aulton's Pharmaceutics: The Design and Manufacture of Medicines. 6th ed. London: Elsevier; 2022.
8. Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 4th ed. New Delhi: CBS Publishers; 2019.
9. Indian Pharmacopoeia Commission. Indian Pharmacopoeia. Ghaziabad: IPC; 2022.
10. Ansel HC, Allen LV, Popovich NG. Pharmaceutical Dosage Forms and Drug Delivery Systems. 11th ed. Philadelphia: Wolters Kluwer; 2021.
11. European Pharmacopoeia Commission. European Pharmacopoeia. 11th ed. Strasbourg: Council of Europe; 2023.
12. United States Pharmacopeial Convention. United States Pharmacopeia 47–National Formulary 42. Rockville (MD): USP; 2024.
13. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug Carrier Syst. 2004;21(6):433–476.
14. Siddiqui MN, Garg G, Sharma PK. Fast dissolving tablets: preparation, characterization and evaluation. Int J Pharm Sci Rev Res. 2010;4(2):87–96.
15. Nagar P, Singh K, Chauhan I, Verma M, Yasir M, Khan A, et al. Orally disintegrating tablets: formulation, preparation techniques and evaluation. J Appl Pharm Sci. 2011;1(4):35–45.
16. Montgomery DC. Design and Analysis of Experiments. 10th ed. New York: Wiley; 2020.
17. Myers RH, Montgomery DC, Anderson-Cook CM. Response Surface Methodology: Process and Product Optimization Using Designed Experiments. 5th ed. Hoboken (NJ): Wiley; 2023.
18. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus other antihypertensive agents. Hypertension. 2004;43(1):4–9.
19. Sica DA. Diuretic use in hypertension. J Clin Hypertens. 2004;6(11):661–664.
20. Dobetti L. Fast disintegrating tablet. US Patent 6,596,311 B1; 2003.
21. Gandhi AS, Sharma PK, Patel MM. Orally disintegrating tablet comprising co-processed excipient. US Patent Application 2009/0208576 A1; 2009.
22. Towa Pharmaceutical Co Ltd. Orally disintegrating tablet. US Patent 11,564,916 B2; 2023.
23. Bhise SB, Chaulang GM, Mahajan MP. Textbook of Pharmaceutics. 4th ed. Pune: Nirali Prakashan; 2022.
24. Banker GS, Rhodes CT. Modern Pharmaceutics. 5th ed. New York: CRC Press; 2020.
25. Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 9th ed. London: Pharmaceutical Press; 2020.
26. Allen LV. Pharmaceutical Excipients and Their Applications. 2nd ed. Washington (DC): American Pharmacists Association; 2021.
27. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug Carrier Syst. 2004;21(6):433–476.
28. Siddiqui MN, Garg G, Sharma PK. Fast dissolving tablets: preparation, characterization and evaluation. Int J Pharm Sci Rev Res. 2010;4(2):87–96.
29. Aulton ME, Taylor KMG. Aulton's Pharmaceutics: The Design and Manufacture of Medicines. 5th ed. London: Elsevier; 2018.
30. Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 3rd ed. Mumbai: Varghese Publishing House; 2009.
31. Montgomery DC. Design and Analysis of Experiments. 9th ed. New York: John Wiley & Sons; 2017.
32. Patel DM, Patel MM. Optimization of fast-dissolving tablets using response surface methodology. Int J Pharm Pharm Sci. 2011;3(2):85–89.
33. Deshmukh VN. Mouth-dissolving drug delivery system: a review. Int J PharmTech Res. 2012;4(1):412–421.
34. Indian Pharmacopoeia Commission. Indian Pharmacopoeia. Ghaziabad: IPC; 2022.
35. Dhahir RK, Al-Kotaji MY. Formulation of orally disintegrating tablets of cinnarizine by using direct compression method. Int J Appl Pharm. 2019;11(1):117–123.
36. United States Pharmacopeia 47–National Formulary 42. Rockville (MD): United States Pharmacopeial Convention; 2024.
37. Kulkarni AP, Gowthamarajan K, Suresh B. Evaluation of binding properties of Plantago ovata and fenugreek seed mucilage. Indian Drugs. 2002;39(8):422–425.
38. Prajapati VD, Jani GK, Moradiya NG, Randeria NP. Pharmaceutical applications of various natural gums, mucilages, and their modified forms. Carbohydr Polym. 2013;92(2):1685–1699.
39. Zhang Y, Li Z, Tang H, Ren W, Gao X, Sun Y, et al. Development and optimization of orally disintegrating tablets by response surface methodology. Drug Dev Ind Pharm. 2020;46(1):42–49.
40. Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 8th ed. London: Pharmaceutical Press; 2017.
41. Malviya R, Srivastava P, Kulkarni GT. Applications of mucilages in drug delivery systems: a review. Adv Biol Res. 2011;5(1):1–7.
42. Shihora H, Panda S. Superdisintegrants, utility in dosage form: a quick review. J Pharm Sci Biosci Res. 2011;1(3):148–153.
43. Kumar R, Patil MB, Patil SR, Paschapur MS. Isolation and evaluation of disintegrant properties of fenugreek seed mucilage. Int J PharmTech Res. 2009;1(4):982–996.
44. ICH Harmonized Guideline Q1A(R2). Stability Testing of New Drug Substances and Products. Geneva: International Council for Harmonisation; 2003.
45. Juan C, Gallo L, Gonzalez Vidal N. Development of Losartan orally disintegrating tablets by direct compression: a cost-effective approach to improve pediatric patient compliance. AAPS PharmSciTech. 2024;25(4):79.
46. Tafere C, Yilma Z, Abrha S, Yehualaw A. Formulation, in vitro characterization and optimization of taste-masked orally disintegrating co-trimoxazole tablets by direct compression. PLoS One. 2021;16(3):e0246648.
47. Juan C, Rodriguez D, Ceballos L, Lanusse C, Gallo L, Vidal NG. Development of ivermectin orally disintegrating tablets using factorial design: in-vitro evaluation and in vivo absorption pattern in rats. J Drug Deliv Sci Technol. 2023;87:104757.
48. Alburyhi MM, Saif AA, Noman MA, Yahya TA, Al-Ghorafi MA. Formulation and Evaluation of Drotaverine Orally Disintegrating Tablets. World J Pharm Res. 2023;12(18):66–79.
49. Gunda RK, Manchineni PR, Reddy CG. Formulation development and in vitro evaluation of oral disintegrating tablets for newer anticonvulsant agent. J Anal Pharm Res. 2019;8(2):85–89.
50. Zhang Y, Li Z, Tang H, Ren W, Gao X, Sun Y, Zhao QX, Wang F, Liu J. Development and optimization of levodopa and benzylhydrazine orally disintegrating tablets by direct compression and response surface methodology. Drug Dev Ind Pharm. 2020;46(1):42–49.