Formulation Development and Evaluation of Gastroretentive Floating Tablets of Cilnidipine

 Shubam Sharma and Prof. Vinayak Munde  

Dr. Vedprakash Patil Pharmacy College, Chh. Sambhajinagar, Maharashtra, India

*Correspondence: shubhamsharma83219@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2026.5624  

INTRODUCTION

Oral drug delivery is the most commonly used route for pharmaceutical administration because it is convenient, economical, non-invasive and acceptable to patients. However, conventional oral dosage forms may not provide optimum therapy for drugs with narrow absorption windows, poor aqueous solubility, instability in intestinal pH or rapid gastric emptying. Such dosage forms can pass rapidly through the stomach and upper intestine before complete drug release and absorption, causing low or variable bioavailability and fluctuations in plasma concentration [1,2].

Gastroretentive drug delivery systems (GRDDS) are designed to prolong the residence time of dosage forms in the stomach. Floating drug delivery systems are one of the most widely studied GRDDS approaches. These systems possess a density lower than gastric fluid, enabling them to remain buoyant on the gastric contents while releasing the drug in a controlled manner. Floating tablets are particularly useful for drugs that are preferentially absorbed in the stomach or upper gastrointestinal tract, drugs that show poor solubility in alkaline intestinal fluids and drugs requiring sustained plasma concentration [1,3].

Cilnidipine is an antihypertensive drug belonging to the calcium channel blocker class. It acts on L-type and N-type calcium channels and is used for the treatment of hypertension. As a BCS Class II drug, Cilnidipine exhibits low aqueous solubility and may show variable oral bioavailability. Sustained gastroretentive delivery may improve drug dissolution in the acidic gastric environment, extend the absorption period and reduce fluctuations in blood pressure control [4-6].

HPMC K100M is a hydrophilic matrix-forming polymer widely used in sustained-release tablet formulations. On contact with gastric fluid, HPMC hydrates and forms a viscous gel barrier around the tablet. Sodium bicarbonate reacts with gastric acid to generate carbon dioxide, which becomes entrapped within the hydrated matrix and provides buoyancy. The combined effect of polymer swelling, gel formation, gas entrapment and matrix diffusion can produce floating behavior and sustained drug release. Therefore, the present study was undertaken to formulate, optimize and evaluate gastroretentive floating tablets of Cilnidipine using HPMC K100M and sodium bicarbonate.

Figure 1. Principle of gastroretentive floating drug delivery system

MATERIALS AND METHODS

Materials

Cilnidipine was used as the model antihypertensive drug. HPMC K100M served as the sustained-release matrix polymer, sodium bicarbonate and citric acid were used as effervescent agents, microcrystalline cellulose was used as diluent, and magnesium stearate and talc were used as lubricant and glidant, respectively. Analytical-grade methanol, hydrochloric acid, phosphate buffer, distilled water and potassium bromide were used during analytical and compatibility studies.

Table 1. Composition of Cilnidipine gastroretentive floating tablets

Preformulation studies

The preformulation study included organoleptic evaluation, solubility analysis, melting point determination, UV-visible spectrophotometric analysis, and drug-excipient compatibility testing. Cilnidipine was observed as a white to off-white crystalline powder, odorless, fine and free-flowing. It was very slightly soluble in distilled water, slightly soluble in pH 4.5 buffer, freely soluble in ethanol and highly soluble in DMSO. The melting range was found to be 168-172 °C, indicating the identity and purity of the drug sample. The λmax of Cilnidipine was determined by scanning a suitable working solution using a UV-visible spectrophotometer. The maximum absorbance was observed at 242 nm. Calibration solutions in the range of 2-10 µg/mL showed a linear increase in absorbance, confirming the suitability of the UV method for drug estimation in dissolution and drug content studies.

Figure 2. UV analytical studies: λmax and calibration curve of Cilnidipine

Compatibility studies

FTIR spectroscopy was performed for pure Cilnidipine and the physical mixture of Cilnidipine with excipients. Characteristic peaks including N-H stretching, C=O stretching, C-N stretching and aromatic C=C stretching were retained in the physical mixture without major shifts or disappearance. DSC thermograms of pure Cilnidipine and drug-excipient mixture were also compared. The pure drug showed a characteristic endothermic peak, and the drug-excipient mixture did not show any major incompatibility-indicating changes. The slight shift in the thermal peak may be attributed to dilution or physical mixing effects rather than chemical interaction.

Figure 3. DSC thermograms of pure Cilnidipine and Cilnidipine-excipient mixture

Formulation development

Floating tablets were prepared by the direct compression method. Accurately weighed quantities of Cilnidipine, HPMC K100M, sodium bicarbonate, citric acid and MCC were passed through a suitable sieve and mixed uniformly. Talc and magnesium stearate were added as glidant and lubricant at the final mixing stage. The powder blend was evaluated for flow and compressibility and then compressed into tablets. A 3² factorial design was applied to study the influence of HPMC K100M and sodium bicarbonate concentrations on drug release at 12 h and total floating time.

Table 2. Factorial design batches and response values

Evaluation of powder blends and tablets

Pre-compression evaluation was performed by determining bulk density, tapped density, angle of repose, Carr’s index and Hausner ratio. These parameters were used to assess the flowability and compressibility of the powder blends before tableting. Post-compression evaluation included tablet weight variation, thickness, hardness, friability, floating time, drug content uniformity and in vitro drug release. In vitro dissolution studies were performed for 12 h in acidic medium to simulate gastric conditions. The optimized formulation was subjected to accelerated stability testing at 40 °C ± 2 °C / 75% ± 5% RH for three months.

RESULTS AND DISCUSSION

Pre-compression properties

The powder blends of all formulations showed acceptable flow and compressibility properties for direct compression. Bulk density ranged from 0.20 to 0.28 g/mL, while tapped density ranged from 0.28 to 0.36 g/mL. The angle of repose values ranged from 23.2° to 29.8°, indicating passable to good flow. Carr’s index values ranged from 21.2% to 27.2%, and Hausner ratios ranged from 1.17 to 1.28. Among all formulations, F6 showed an angle of repose of 23.2°, indicating comparatively better flow behavior. The acceptable micromeritic profile suggested that the selected excipients and blending process were suitable for direct compression.

Table 3. Pre-compression evaluation of powder blends

Post-compression evaluation

Post-compression evaluation was carried out to assess the quality, mechanical strength, uniformity, buoyancy, and suitability of the prepared gastroretentive floating tablets of Cilnidipine. These parameters are important because they directly influence the performance, stability, handling properties, and therapeutic reliability of the final dosage form. The results confirmed that all prepared formulations possessed satisfactory pharmaceutical characteristics and complied with acceptable limits for tablet dosage forms.

Table 4. Post-compression evaluation of floating tablets

The tablet weight was found to vary from 190 mg to 208 mg. This narrow variation in tablet weight indicates good uniformity among the prepared batches. Weight variation is an important quality control parameter because it reflects the accuracy of die filling during compression and ensures dose uniformity. Since each tablet must contain an accurate amount of Cilnidipine, uniform tablet weight suggests that the powder blend had acceptable flow properties and was compressed consistently. The observed values indicate that there was no major variation during the compression process.

Thickness values of the tablets ranged from 1.0 mm to 1.9 mm. Tablet thickness is influenced by tablet weight, compression force, powder density, and formulation composition. Uniform thickness is important for packaging, appearance, and patient acceptability. Minor variation in thickness among formulations may be due to differences in polymer concentration, especially HPMC K100M, and the amount of gas-generating agent used. However, the observed thickness range was acceptable and indicated proper compression of the tablet matrix.

Hardness of the prepared floating tablets ranged from 1.0 to 3.2 kg/cm². Hardness is a critical parameter because tablets should have enough mechanical strength to withstand handling, packaging, transportation, and storage. At the same time, excessive hardness may slow hydration, delay floating, and retard drug release. The obtained hardness values indicate that the tablets had adequate mechanical strength without being overly hard. This balance is particularly important in floating tablets because polymer hydration and gas entrapment are necessary for buoyancy and sustained release.

Friability values were found to range from 0.30% to 0.92%. All formulations showed friability below the generally accepted limit of 1%, confirming good resistance to abrasion and mechanical stress. Low friability indicates that the tablets did not break, chip, or lose excessive powder during handling. This suggests that the selected excipients and compression conditions produced tablets with suitable structural integrity. Drug content was observed in the range of 95.4% to 99.6%, demonstrating uniform distribution of Cilnidipine within the tablet matrix. This result confirms that the drug and excipients were properly mixed before compression. Uniform drug content is essential for consistent therapeutic effect and patient safety, especially for antihypertensive drugs where dose accuracy is important for maintaining blood pressure control.

Total floating time ranged from 10 to 12 hours, confirming the successful performance of the effervescent floating system. The floating ability was mainly due to the reaction of sodium bicarbonate with acidic gastric medium, producing carbon dioxide gas. This gas was entrapped within the hydrated HPMC K100M gel matrix, reducing tablet density and allowing the tablet to remain buoyant. Prolonged floating time indicates that the formulation can remain in the stomach for an extended period, providing sustained drug release and potentially improving the bioavailability of Cilnidipine. The post-compression evaluation confirmed that the prepared floating tablets exhibited acceptable weight uniformity, suitable thickness, adequate hardness, low friability, uniform drug content, and prolonged floating behavior. These findings indicate that the formulations were physically stable, mechanically strong, and capable of providing gastroretentive sustained drug delivery.

In vitro drug release study

The in vitro drug release profile showed gradual and sustained release of Cilnidipine from all formulations over 12 h. This sustained release behavior is attributed to hydration and swelling of HPMC K100M, formation of a gel barrier and diffusion-controlled movement of dissolved drug through the hydrated matrix. Formulations containing lower polymer concentration released drug comparatively faster but had lower overall sustained matrix control, whereas higher polymer concentration increased matrix density and could restrict drug diffusion. Sodium bicarbonate assisted buoyancy by generating carbon dioxide, which was entrapped in the hydrated polymer network.

Among the formulations, F6 demonstrated the highest and most balanced drug release profile. F6 released 6% drug at 0.5 h, 30% at 3 h, 55% at 6 h, 70% at 8 h, 80% at 10 h and 89% at 12 h. This indicated that the combination of 100 mg HPMC K100M and 40 mg sodium bicarbonate provided an optimum balance between gel strength, buoyancy and diffusion pathways. The release from F6 was higher than other batches at 12 h while still maintaining controlled release behavior throughout the study period.

Table 5. In vitro cumulative drug release profile (%)

Figure 4. In vitro cumulative drug release profile of Cilnidipine floating tablets

Optimization by factorial design

The factorial design confirmed that polymer concentration and gas-generating agent concentration influenced the critical formulation responses. The model for drug release at 12 h was significant, and HPMC K100M concentration showed a marked effect on release behavior. Sodium bicarbonate contributed to floating performance by improving carbon dioxide generation and buoyancy. A balanced level of polymer and sodium bicarbonate was essential because inadequate polymer may produce weak matrix integrity, while excessive polymer may retard drug diffusion. Based on drug release, total floating time, mechanical strength, friability and drug content, F6 was selected as the optimized formulation.

Figure 5. The Design of Experiments (DoE) contour and 3D surface plots

The Design of Experiments (DoE) contour and 3D surface plots illustrate the effect of two independent formulation variables, HPMC K100M concentration and sodium bicarbonate concentration, on two important responses: drug release at 12 hours and total floating time. HPMC K100M acts as a release-retarding polymer, while sodium bicarbonate acts as a gas-generating agent responsible for tablet buoyancy.

In the contour and 3D surface plots for drug release at 12 hours, the percentage drug release was found to be influenced mainly by the concentration of HPMC K100M. As the concentration of HPMC K100M increased, the drug release decreased gradually. This may be due to the formation of a thicker and more viscous gel layer around the tablet, which slows the penetration of dissolution medium and retards drug diffusion from the matrix. Lower polymer concentration produced comparatively faster drug release because of reduced matrix resistance. Sodium bicarbonate also affected drug release by generating carbon dioxide and creating pores within the hydrated polymer matrix, which may facilitate medium penetration and drug diffusion. The contour and 3D surface plots for total floating time show that floating duration increased with increasing HPMC K100M concentration. This is because HPMC K100M rapidly hydrates in gastric fluid and forms a strong gel barrier capable of trapping carbon dioxide gas generated by sodium bicarbonate. Entrapment of gas reduces tablet density and helps the tablet remain buoyant for a prolonged period. Sodium bicarbonate concentration also contributed to floating behavior by producing sufficient gas for buoyancy. The plots indicate that an optimized balance between HPMC K100M and sodium bicarbonate is necessary to achieve both sustained drug release and prolonged floating time. Excess polymer may retard drug release too much, while insufficient polymer may reduce matrix strength and floating stability. The DoE plots therefore helped in selecting the optimized formulation with desirable controlled release and gastroretentive floating characteristics.

Stability study

The optimized formulation F6 was subjected to accelerated stability studies for a period of three months to assess its physical stability, mechanical strength, drug retention, floating ability, and sustained-release performance during storage. Stability testing is an important part of formulation development because it helps to determine whether the optimized dosage form can maintain its quality, safety, and performance under stress conditions. The results obtained after three months indicated that the optimized gastroretentive floating tablet formulation remained stable, with only minor changes observed in the evaluated parameters.

Table 6. Stability study of optimized formulation F6

No significant change was observed in the physical appearance of formulation F6 during the stability study period. The tablets retained their original shape, color, and surface characteristics, and there was no evidence of cracking, chipping, discoloration, swelling, or visible degradation. This indicates that the selected excipients, including HPMC K100M, sodium bicarbonate, citric acid, microcrystalline cellulose, magnesium stearate, and talc, were physically compatible and did not produce any undesirable changes during storage. Maintenance of physical appearance is important because visible instability may indicate moisture absorption, chemical degradation, or structural weakening of the tablet matrix.

The hardness of formulation F6 showed a marginal decrease from 2.6 kg/cm² to 2.5 kg/cm² after three months. This slight reduction may be attributed to minor moisture uptake or relaxation of the compressed tablet matrix during storage. However, the change was very small and remained within acceptable limits. Adequate hardness is necessary to ensure that the tablet can withstand handling, packaging, transportation, and administration without breaking. The observed hardness value after storage confirmed that the optimized formulation maintained sufficient mechanical strength.

Friability increased slightly from 0.30% to 0.34%, but the value remained well below the pharmacopeial limit of 1%. This indicates that the tablets retained good resistance to abrasion and mechanical stress. The slight increase in friability may be due to minor weakening of surface particles during storage, but it was not significant enough to affect the quality of the formulation. Similarly, the thickness changed from 1.4 mm to 1.5 mm, which represents only a minor variation and may be due to slight hydration or expansion of the polymeric matrix. This change did not affect tablet performance.

Drug content decreased slightly from 99.6% to 98.9% after three months, indicating good chemical stability of Cilnidipine in the optimized formulation. The minimal reduction in drug content suggests that no significant degradation occurred during storage. The floating time decreased marginally from 12 hours to 11.55 hours, which still indicates prolonged buoyancy. This confirms that the gas-generating system and HPMC K100M gel-forming matrix retained their functional ability. The drug release at 12 hours changed slightly from 89% to 88%, demonstrating that the sustained-release behavior of the formulation was maintained.

Overall, the stability study confirmed that optimized formulation F6 remained physically stable, mechanically strong, chemically consistent, and functionally effective under accelerated storage conditions. The minor variations observed in hardness, friability, thickness, drug content, floating time, and drug release were within acceptable limits. Therefore, formulation F6 can be considered a stable gastroretentive floating tablet system capable of maintaining prolonged gastric retention and sustained Cilnidipine release during storage.

CONCLUSION

The present study successfully formulated gastroretentive floating tablets of Cilnidipine using HPMC K100M as the release-retarding polymer and sodium bicarbonate-citric acid as the effervescent floating system. The direct compression method produced tablets with acceptable flow, compressibility, weight variation, hardness, friability and content uniformity. The optimized formulation F6 provided the best overall performance with satisfactory mechanical strength, minimum friability, highest drug content, prolonged total floating time of 12 h and sustained drug release of 89% at 12 h. Stability testing confirmed that F6 remained stable under accelerated storage conditions with no significant changes in critical quality attributes. Therefore, HPMC K100M-based gastroretentive floating tablets of Cilnidipine may be considered a promising sustained-release oral delivery system for improving gastric residence time, enhancing therapeutic efficacy and reducing dosing frequency in hypertension management.

ACKNOWLEDGEMENT

The authors are thankful to Dr. Vedprakash Patil Pharmacy College, Chh. Sambhajinagar, for providing laboratory facilities, guidance and support during the research work.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

REFERENCES

1.      Swain S, Patra CN, Rao MEB. Gastroretentive drug delivery systems: A review. Asian Journal of Pharmaceutical and Clinical Research. 2021;14(3):12-20.

2.      Pawar HA, Gavasane AJ, Choudhary PD. Formulation and evaluation of floating matrix tablets of antihypertensive drugs using hydrophilic polymers. International Journal of Pharmaceutical Sciences and Research. 2022;13(4):1450-1459.

3.      Jagdale SC, Jadhav VN, Chabukswar AR. Development and optimization of gastroretentive floating tablets for controlled release of antihypertensive drugs. Journal of Drug Delivery and Therapeutics. 2023;13(2):75-84.

4.      Firoz S, Audinarayana N, Riyazullah MS. Development and assessment of gastroretentive floating tablets of Celiprolol using natural polymers. International Journal of Pharmaceutics and Drug Analysis. 2023;11(1):18-27.

5.      Patel R, Shah P, Patel D. Formulation and evaluation of Cilnidipine gastroretentive floating tablets. International Journal of Pharmaceutical Research and Applications. 2021;6(4):92-101.

6.      Kumar S, Verma A, Singh R. Gastro-retentive delivery systems for poorly soluble antihypertensive drugs: A review. International Journal of Pharmaceutical Sciences Review and Research. 2022;74(1):55-63.

7.      Sharma P, Yadav K, Mishra N. Novel polymers for floating antihypertensive tablets and their influence on drug release behavior. Journal of Pharmaceutical Innovation. 2020;9(3):145-153.

8.      Jagtap S, Patil P, More S. Sustained release floating tablets for BCS Class II drugs using Cilnidipine as a model drug. Asian Journal of Pharmaceutics. 2022;16(2):220-228.

9.      Kaur H, Sharma R, Kaur G. Influence of polymers on floating drug delivery systems of antihypertensive drugs. International Journal of Pharmaceutical Investigation. 2023;13(1):88-96.

10.  Reddy K, Rao M, Kumar P. Floating matrix tablets of Cilnidipine: In-vitro optimization using factorial design. International Journal of Applied Pharmaceutics. 2023;15(4):134-142.

11.  Rosa M, Zia H, Rhodes T. Dosing and testing in-vitro of a bioadhesive and floating drug delivery system for oral application. International Journal of Pharmaceutics. 1994;95(1):65-70.

12.  Mridanga RR, Bose SK, Sengupta K. Formulation and evaluation of gastroretentive floating tablets. Research Journal of Pharmacy and Technology. 2008;1(3):175-178.

13.  Gohel MC, Mehta PR, Dave PK, Bariya NH. A more relevant dissolution method for evaluation of floating drug delivery system. Dissolution Technologies. 2005;11:22-25.

14.  Yadav KS, Satish CS, Shivkumar HG. Formulation and evaluation of floating tablets. Indian Journal of Pharmaceutical Sciences. 2007;69(1):91-95.

15.  Praveen G. Floating drug delivery systems: A review. The Pharma Innovation. 2012;1(5):63-70.

16.  Shanmugan S, Chakrahari R, Sundaramoorthy K, Ayyappan T. Gastroretentive drug delivery systems: A review. International Journal of PharmaTech Research. 2012;3(1):526-534.

17.  Kumar YG, Sreekanth J, Satyavati D, Chaitanya P, Swetha B. Formulation and evaluation of floating matrix tablets. International Journal of PharmaTech Research. 2013;5(3):332-344.

18.  Dehghan MH, Khan FN. Gastroretentive drug delivery systems: A patent perspective. International Journal of Health Research. 2009;2:23–44.

19.  Rocca JG, Omidian H, Shah K. Progress in gastroretentive drug delivery systems. Business Briefing: Pharma Tech. 2003;5:152–156.

20.  Mathur P, Saroha K, Syan N, Verma S, Kumar V. Floating drug delivery systems: An innovative acceptable approach in gastroretentive drug delivery. Archives of Applied Science Research. 2010;2:257–270.

21.  Shah SH, Patel JK, Patel NV. Stomach specific floating drug delivery system: A review. International Journal of PharmTech Research. 2009;1:623–633.

22.  Hagemann RC, Threlkeld DS, editors. Drug Facts and Comparisons. 50th ed. St. Louis, MO: Wolters Kluwer Co.; 1996. p. 1862–1876.

23.  Coffin MD, Parr AF, inventors. Glaxo Inc., assignee. Ranitidine solid dosage form. United States Patent 5407687. 1995.

24.  Kortejarvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, et al. Biowaiver monographs for immediate release solid oral dosage forms: Ranitidine hydrochloride. Journal of Pharmaceutical Sciences. 2005;94:1617–1625. doi:10.1002/jps.20392.

25.  Basit A, Lacey L. Colonic metabolism of ranitidine: Implications for its delivery and absorption. International Journal of Pharmaceutics. 2001;227:157–165. doi:10.1016/S0378-5173(01)00794-3.

26.  Dave BS, Amin AF, Patel MM. Gastroretentive drug delivery system of ranitidine hydrochloride: Formulation and in-vitro evaluation. AAPS PharmSciTech. 2004;5 34. doi:10.1208/pt050234.

27.  Kaza R, Usharani E, Nagaraju R, Haribabu R, Reddy PV. Design and evaluation of sustained release floating tablets for the treatment of gastric ulcers. Journal of Pharmaceutical Sciences and Research. 2009;1:81–87.

28.  Khemariya P, Mishra S, Shukla A, Bhargava M, Singhai K, Goswami S. An emerging trend in tablet technology: Floating tablets of ranitidine HCl. International Journal of Drug Delivery. 2010;2:154–158.

29.  Choudhary A, Das S, Bahadur S, Saha S. Development and characterization of extended release gastroretentive drug delivery. Journal of Pharmaceutical Research. 2009;2:1557–1560.

30.  Gusler G, Berner B, Chau M, Padua A, inventors. DepoMed Inc., assignee. Optimal polymer mixtures for gastric retentive tablets. United States Patent 6723340. 2004 Apr 20.

31.  Tiwari SB, Siahboomi AR. Applications of complementary polymers in HPMC hydrophilic extended release matrices. Drug Delivery Technology. 2009;9:20–27.

32.  Roy P, Shahiwala A. Statistical optimization of ranitidine hydrochloride floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough. European Journal of Pharmaceutical Sciences. 2009;37:363–369. doi:10.1016/j.ejps.2009.03.006.

33.  Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modelling on drug release from controlled drug delivery systems. Acta Poloniae Pharmaceutica. 2010;67:217–223. Gambhire MN, Ambade KW, Kurmi SD, Kadam VJ, Jadhav KR. Development and in vitro evaluation of an oral floating matrix tablet formulation of diltiazem hydrochloride. AAPS PharmSciTech. 2007;8. doi:10.1208/pt0803073.