Formulation And Evaluation of a Novel Floating Pulsatile Delivery System of Nizatidine Tablets for Chronotherapeutic Release

Gastrointestinal physiology and drug pharmacokinetics follow circadian rhythms, influencing both disease manifestation and therapeutic response. The circadian clock, governed by the suprachiasmatic nuclei of the hypothalamus, regulates numerous biological processes such as sleep wake cycles, hormone secretion, and gastric acid production [1]. Conditions like peptic ulcers and gastroesophageal reflux disease (GERD) exhibit nocturnal exacerbations of acidity, typically between midnight and early morning hours [2,3]. Hence, chronotherapeutics the alignment of drug release with biological rhythms has become a promising approach for enhancing efficacy and minimizing side effects [4,5].

Nizatidine is a selective histamine H? receptor antagonist indicated for the treatment of gastric and duodenal ulcers. It exhibits a short half-life (1–2 hours) and undergoes extensive first-pass metabolism, necessitating multiple daily doses for effective acid suppression [6,7]. However, conventional formulations fail to maintain therapeutic levels during the nocturnal acid breakthrough phase, leading to incomplete acid control [8].

To address this limitation, floating pulsatile drug delivery systems (FPDDS) have been developed. These systems combine gastro-retentive mechanisms with time-controlled drug release, ensuring the release of drug at a predetermined lag time after ingestion [9]. Floating systems remain buoyant in the gastric environment due to gas generation (effervescent) or low-density matrices (non-effervescent) [10].

In the present study, Nizatidine floating pulsatile tablets were formulated to synchronize drug release with circadian patterns of gastric acid secretion. The effervescent method utilized sodium bicarbonate as the gas-generating agent and HPMC as a swellable matrix to achieve buoyancy. The rupturable coating composed of ethyl cellulose and HPMC E15 controlled the lag phase before the second pulse of release [11]. The non-effervescent (low-density) method using Compritol 888 wax was explored but found unsuitable due to inadequate floating behavior.

This innovative dual-mechanism approach aimed to achieve:

1. Immediate drug release for postprandial acid suppression,

2. A programmed lag phase (≈4 hours), and

3.A subsequent sustained-release pulse maintaining therapeutic levels during nocturnal periods.

4. Such a system offers improved chronotherapeutic management of ulcers, reduces dosing frequency, and enhances patient compliance [12,13].

2. MATERIALS AND METHODS

2.1 MATERIALS

Nizatidine was received as a sample from Natco Pharma Ltd., Hyderabad. Excipients included HPMC K4M, HPMC E15, ethyl cellulose (EC, 50 cps), Carbopol 934P, crosspovidone, sodium bicarbonate, magnesium stearate, talc, lactose, dibutyl phthalate, and Compritol 888 (glyceryl behenate) obtained from reputed pharmaceutical suppliers [7,10]. All solvents were of analytical grade and used as received.

2.1.1 Equipment

1. Formulation and evaluation were performed using:

2. Tablet compression machine (Rimek Minipress II)

3. Pharma R&D coater (VJ Instruments Ltd.)

4. UV spectrophotometer (Lab India UV-3000 Plus)

5. USP Dissolution Apparatus II (Lab India DS-8000)

6. FT-IR Spectrophotometer (Shimadzu)

7. Differential Scanning Calorimeter (Perkin Elmer)

8. Hardness tester (Monsanto) and Roche Friabilator.

All instruments were calibrated before use.

2.2 Methods

2.2.1 Determination Of Λmax And Calibration Curve

A stock solution of Nizatidine (1000 µg/mL) was prepared in 0.1 N HCl. Absorbance was measured at 314 nm using UV–VIS spectrophotometer, and a standard calibration curve (50–250 µg/mL) was plotted [8].

2.2.2 Formulation of Floating Pulsatile Tablets

2.2.2.1 Effervescence Method

This approach involved three sequential steps:

Step 1 – Preparation of Floating Core Tablets:

Nizatidine and HPMC K4M were mixed in ratios of 1:1, 1:1.5, and 1:2 with sodium bicarbonate (10% w/w) as effervescent agent. The blends were lubricated with magnesium stearate and talc and compressed using 9 mm punches (Rimek Minipress II). Each tablet contained 75 mg of Nizatidine.

Step 2 – Time-Lagged Coating:

Coating dispersion (8% w/w) containing ethyl cellulose and HPMC E15 in weight ratios of 37.5:62.5, 50:50, and 67.5:32.5 was prepared using isopropyl alcohol and water. Dibutyl phthalate (20% w/w) and talc (5% w/w) were added as plasticizer and glidant. Tablets were coated in a Pharma R&D coater to weight gains of 5%, 10%, and 15%, followed by drying at 40°C for 2 hours.

Step 3 – Compression Coating:

An immediate-release layer comprising Nizatidine (75 mg), Carbopol 934P, crosspovidone, sodium bicarbonate, and lactose was used to compression-coat the optimized core tablets. Crosspovidone enhanced rapid disintegration for the first pulse release, while sodium bicarbonate ensured buoyancy [12,13].

2.2.2.2 Non-Effervescence (Low-Density) Method

In this method, Compritol 888 (glyceryl behenate) was used as a low-density matrix former. Direct compression was employed, but tablets failed to float due to inadequate buoyancy; hence, this approach was discontinued [10].

2.2.3 Evaluation Parameters

Preformulation Studies: FT-IR and DSC confirmed absence of drug–excipient interaction.

Post-Compression Evaluation: Tablets were assessed for weight variation, hardness, friability, thickness, and drug content as per USP guidelines.

Buoyancy Studies: Conducted in 0.1 N HCl (pH 1.2, 37 ± 0.5°C) to determine floating lag time and total floating duration.

In Vitro Dissolution Studies: Using USP Apparatus II at 100 rpm in 900 mL of 0.1 N HCl, samples were withdrawn at predetermined intervals and analyzed spectrophotometrically at 314 nm.

Kinetic Modelling: Release data were fitted to zero-order, first-order, Higuchi, and Korsmeyer–Peppas models. The optimized formulation (CCF3) followed Higuchi diffusion-controlled zero-order kinetics [9-13].

2.2.4 Statistical and Stability Evaluation

All experiments were conducted in triplicate (n = 3) and results expressed as mean ± SD. Stability testing was performed for 60 days at 40°C ± 2°C/75% ± 5% RH per ICH Q1A(R2) guidelines [12].

3. RESULTS AND DISCUSSION

3.1 Determination of Lambda Max of Nizatidine:

After scanning 10 µg/ml solution of Nizatidine the lambda max of Nizatidine was found to be 314nm (absorbance-0.106).

Fig.no.1: Spectrum of Nizatidine 10µg/ml Solution in 0.1n HCL

The scanning of the volumetric solution of Nizatidine in the ultraviolet range (200- 400nm) against 0.1 N HCl blank gave the λmax as 314 nm. The standard concentrations of Nizatidine (50-250µg/ml) prepared in 0.1N HCl showed good linearity with R2 value of 0.998, which suggests that it obeys the Beer-Lamberts law

Fig.no.2: Standard graph of Nizatidine in 0.1N HCl

3.3.1  Fourier Transform Infrared Spectroscopic Studies (FTIR)

The FTIR spectra of drug and optimised formulation were recorded. The characteristic peaks of the optimized formulation followed the same trajectory as that of the drug alone with minor differences. Thus there may be no drug-excipient interactions.

Fig.no.3: FTIR spectra of Nizatidine pure drug

Fig.no.4: FTIR spectra of optimised formulation (CCF3)

DSC study was conducted for Nizatidine and optimised formulation (CCF3). DSCthermogram of pure Nizatidine shows sharp exothermic peak at 138.4°C. Similar exothermic peak wasobtained at 136°C for the optimised formulation.

Table no.3.: DSC melting points of the selected formulations

Fig.no.5: DSC thermogram of pure drug Nizatidine

Fig.no.6: DSC thermogram of optimised formulation

The powder blends of floating tablets (F1-F3) and compression coated tablets were evaluated for their flow properties, the results were shown in Table 24. Angle of repose was in the range from 21.8 to 28.14 which indicates good flow of the powder for all formulations. The values of bulk density were found to be in the range from 0.51 to 0.623 gm/cc; the tapped density was in the range of 0.597 to 0.684 gm/cc. The Carr’s index was found to be in the range from 11.10 to 17.25. The Hausner ratio was found to be in the range from 1.16 to 1.37. These results indicate that the powdered blends exhibited good flow properties and have good compressibility.

The final tablets were white, smooth, and flat, round shaped in appearance. The thickness was measured by vernier calipers and was ranged between 4±0.20and 4.1±0.09 mm. The diameter was measured and ranged between 11.04 ± 0.11 to 11.12 ± 0.11 mm. The weight variation for different formulations (F1 to F3) showed satisfactory results as per United States Pharmacopoeia (USP) limit (average weight ± 5%). The hardness was measured by Monsanto tester and was found to be ranged from 4.66 ± 0.28to 5.16 ± 0.28kg/cm2. Thefriability was found to be ranged from 0.472 to 0.76 which was below 1% indicating goodmechanical resistance of the tablets. Thepercentage of drug content for all formulations wasfound to be inbetween 98.1 ± 1.21 to 103.03 ± 0.45 of Nizatidine, it complies withofficial specifications (95to 110%).

All the tablets were prepared by effervescent approach. The results of floating study were shown in table 27. On immersion in 0.1N HCL solution pH (1.2) at 37?C, the tablets floated, and remained buoyant without disintegration. Sodium bicarbonate was used as the effervescent base. When the floating matrix tablets containing gas generating agent were exposed to 0.1N HCl, hydrochloric acid reacted with sodium bicarbonate in the floating tablet inducing CO2 formation. The generated gas was entrapped into the matrix of swollen polymer matrix and was well protected by gel formed by hydration of polymers, which led to floating of the dosage forms.

Table no.6.: Results of In vitro Buoyancy study

In core tablet formulations as the HPMC K4M level increasing the FLT increased. As the polymer concentration increases it takes more time for the polymer matrix to hydrate and swell and then float, so FLT increased. In compression coated formulations, FLT decreased in the order CCF1>CCF2>CCF3. This is due to addition of cross povidone to CCF2 and CCF3 which has higher swelling index than carbopol and helps in floating along with carbopol. So floating lag time decreased.

3.7 In Vitro Dissolution Studies Of Core, Spray Coated, And Compression Coated Tablets Of Nizatidine:

In vitro dissolution studies of all the formulations of Nizatidine were carried out in 0.1 N HCl and percentage drug release was calculated.

No. 7 Table. Results of In vitro dissolution studies of Nizatidine floating core tablets

Fig.no.7: DSC thermogram of optimised formulation

Table no.8.: Results of In vitro dissolution studies of Nizatidine floating core tablets spray coating (CF1-CF9)

Fig.no.8: Comparative drug release profiles of Nizatidine floating pulsatile tablets (CF1- CF9)

In CCF only Carbopol was used. The floating lag time and floating time were good for CCF1 but took two hours to release the immediate release dose of Nizatidine. So to enhance fast release of immediate dose the super disintegrant, cross povidone was added in CCF2(5mg), CCF3(10mg). Target release of immediate dose within 30min was achieved with CCF3 followed by lag time up to fourth hour and sustained release up to 8hrs. Cross povidone worked both to enhance the release of Nizatidine immediately and also decreased the floating lag time due to its instant high swelling.

Fig.no.9: Comparative drug release profiles of Nizatidine floating pulsatile tablets with immediate release dose-compression coating.

Fig.no.10: Kinetic release plots of optimised floating core tablet (F3) - Zero order, First order

Kinetics were applied only to floating core tablets(matrix) because there is no drug release for certain time in floating pulsatile tablets. The in vitro dissolution data were fitted in different kinetic models viz. zero order, first order, Higuchi and Korsemeyer-Peppas equation. Correlation coefficients of all formulations showed higher correlation with zero order plots than first order. So, predominant drug release order is controlled release. To confirm theexact  mechanism of drug release from thesetablets, the data were fitted toHiguchi and Korsemeyer- Peppas equation. All three formulations showed higher regression values for Higuchi model indicating the release mechanism was Higuchi matrix diffusion.The causes for diffusion may be due to the swollen insoluble hydrogel matrix, which entrapped the drug.According to peppas kinetics based on n value the mechanism of drug release for F1, F2 was fickian diffusion and F3 was non fickian or anomalous transport.

Fig.no.11: Kinetic release plots of optimised floating core tablet (F3) - Zero order, First order

Fig.no.12: Kinetic release plots of optimised floating core tablet (F3)- Higuchi, peppas model