Nizatidine Is H2 Receptor Antagonist Biology Essay


Nizatidine is H2 receptor antagonist. It is widely prescribed as gastric ulcer, duodenal ulcers. It has short biological half life and it is susceptible to metabolized by colonic bacteria. The current investigation concerns formulation of Nizatidine gastro retentive tablets by effervescent technique to increase the gastric retention time and control the drug release up to 12 hrs, also improve the bioavailability. In this field, optimized concentration of sodium bicarbonate (10%) used as gas generating agent. Release retarding agents used in this examination are natural polysaccharides like Xanthane gum, pectin, sodium alginate and synthetic polymers like HPMC K100M. Each polymer used in concentration range of 20%, 25%, 30%, 35%, 40% to obstruct the drug release. All prepared formulations were evaluated for weight variation, hardness, friability, drug content, In vitro buoyancy studies, swelling studies and Invitro drug release studies are performed. Except sodium alginate comprised formulation all formulations exhibits less than 1 minute of buoyancy lag time further more retain the matrix integrity up to 12hours. Invitro drug release studies displays that pectin contains formulation shows better drug release than other polymers. Drug release kinetics of all formulations shows that they follow non Fickian diffusion mechanism to release the drug from prepared matrix tablets.


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Oral route of administration is most convenient way of drug delivery in associate with better patent compliance as compared with other route of administration and more than 60% of marketed pharmaceutical products are administered through oral route(1). Over past three decades oral sustained release drug delivery systems have been gained a remarkable importance due to their therapeutic advantages as well as patient compliance(2).

The real dispute in designing of oral controlled release dosage forms is not just to retard the drug release for prolonged period of time also retain the dosage form in gastrointestinal tract until the drug is completely release from dosage form. Most of orally administered sustained release dosage forms are displacing from gastrointestinal tract before releasing the drug from dosage form due to faster gastric emptying. In order to overcome this kind of adversities, a significant interest is attained to develop gastro retentive dosage from fast few decades(3).

Gastric emptying studies are disclose that orally administered dosage forms are importantly suffering from unpredictable gastric emptying rate and short gastric residence time. Gastro retentive dosage forms are able to prolong the gastric residence time and avoid the problem of short gastric residence time by buoyant the dosage form in stomach for prolong time period(4).

The present investigation is to develop Nizatidine gastroretentive tablets by effervescent technique to avoid the obstacle of short biological half life(1.5 to 2 hrs), improve the oral bioavailability as well as Nizatidine acts locally to treat gastric and duodenal ulcers(5).

Nizatidine is histamine H2-receptor antagonist. It inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells. These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by about 70%(6).It is widely prescribed in gastric ulcers, duodenal ulcers, Zollinger- Ellison syndrome and gastroesophageal reflux disease (GERD).

Nizatidine was ready to metabolize by colonic bacteria, which reduces the therapeutic efficiency of Nizatidine. It does not induce any anti-androgenic effects and drug interactions in patients as compared to any other class of H2 Receptor Antagonists (7). Thus, it is reasonably better way to improve the therapeutic efficacy of the drug when it is formulated as gastro retentive dosage form.

In order to prepare successful gastro retentive tablets of Nizatidine, optimized concentration of sodium carbonate(10%) was incorporated which liberates carbon dioxide gas (Co2) up on contact with gastric juice present in stomach, there by tablet density was reduced to below 1.004gm/cm3then tablet become buoyant((8). Release retarding polymers used in present investigation were natural polysaccharides like Xanthane gum, Pectin, Sodium alginate and synthetic polymer of HPMC K100M to obstruct the drug release up to 12 hrs(9).

Inspite arrival of many synthetic polymers, incorporation of natural polymer in gastro retentive dosage form earning lot of importance duo to their distinguished characteristics of compatibility, inexpensive, ready availability, safe and gel forming nature. Because of this inference present work is mainly focused on natural polysaccharides(10).

Materials and methods


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Nizatidine pure drug was kindly supplied by shasun chemicals and drugs, Chennai as a gift sample. Xanthane gum, pectin were gifted by lucid colloids, Mumbai. HPMC K100M obtained as gift sample from Scope ingredients pvt Ltd, Chennai. Sodium bicarbonate was gifted by Rishi chemical works, Kolkata. Super tab 14SD as a brand of Spray dried lactose provided by DFE pharma , Bangalore.


Preparation of Nizatidine gastro retentive tablets

Nizatidine gastro retentive tablets were prepared by direct compression technique. The respective powders namely Nizatidine, Releasing retarding polymers(Xanthane gum, pectin, sodium alginate, HPMC K100M) , gas generating agent (sodium bicarbonate) ,diluents(spray dried lactose) were passed through sieve no. 60 ,separately. Then mixing of powders was carried out by using pestle, motor for 5 mints. Talc and magnesium stearate were then added to the mixed powder. Mixing was continued for another 3 mints. Finally 400mg of each mixture were weighed and fed manually in to the die of tablet compression machine, equipped with flat faced punches (10mm) to produce desire tablets(11,12).

In vitro characterization of prepared tablets

Prepared tablets were tested for weight variation, thickness measured by vernire calipers, hardness determined by Monsanto hardness tester, By using roche friabulator friability was determined, all values are expressed as mean values ± SD (13, 14).

Drug content

Accurately weighed equivalent to 15 mg of Nizatidine transferred to a 50 ml volumetric flask dissolve in sufficient quantity of methanol then make up the final volume with methanol and mix. Then filter the solution, collect the filtrate and made suitable dilutions with methanol, then measure the absorbance by using UV visible spectrophotometer at λmax of 320nm wavelength, there by calculate the amount of drug being in tablet (15)

In vitro buoyancy studies:

In vitro buoyancy studies include buoyancy lag time, floating duration time.

Buoyancy lag time test was performed to determine whether the tablets were float on dissolution medium or not. In this test the tablet was assigned on beaker consist of 200ml of 0.N HCl, then observe visually how much time is taken by tablets to emerge on the surface of dissolution medium i.e. 0.1N HCl.

Floating duration time was determined by placing the tablets on beaker includes 200ml of 0.N HCl, then conclude how much time taken by tablet to possess on surface of 0.1N HCl medium(3,15,16).

Swelling studies:

A Tablet was weighed (W1) and placed in a glass beaker, containing 200 mL of 0.1 N HCl. At regular time intervals, the tablet were displaced and the excess surface liquid was carefully removed by a filter paper. The swollen tablet was then reweighed (W2). The swelling index (SI) was calculated using below formula (17, 18).

Swelling index =Ã-100

In vitro drug release studies:

In vitro drug release studies were carried out by USP TYPE II dissolution tester apparatus (paddle type). 0.1N HCl was taken as a dissolution medium which was placed on beakers of apparatus and maintained the temperature 37+ 0.50c. The paddles are allowed to rotate at a speed of 50 rpm, then tablet was placed on beaker containing dissolution medium. Aliquots of 5 mL were detach from the dissolution apparatus at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 hrs time intervals, At each time of withdrawal, 5 mL of fresh medium was replaced into the dissolution flask. Then the drug content was determined spectrophotometrically at λmax of 228 nm wavelength (19).

Drug release kinetics

In order to study kinetics of drug release, the obtained data was analyzed by different model dependent kinetics. Tease studies are based on different mathematical functions, which describe the dissolution profile. The model dependent approaches include zero order(20), First order, Higuchi, korsmeyer-peppas models (21, 22).

Drug - Excipient interaction studies

Drug - Excipient interaction are determined by Fourier transform infrared (FT IR) spectroscopy. As a part of this work, KBr disc method was preferred to record the spectra of samples. In this way each sample was gently triturated with recrystalized KBr powder in proportion of 1:100 then pressed by hydrostatic press to form disc. Then the disc was placed on sample holder scanned from 4000 to 400cm-1, then spectra of Nizatidine pure drug, Xanthane gum, pectin, sodium alginate, HPMC K100M and optimized formulation (Nizatidine & pectin) was recorded (23).

Tablet preparation for In vivo studies

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All the ingredients used in preparation of Nizatidine gastro retentive tablets were transparent to X-rays. In order to opaque the administered tablet in stomach by X-rays, incorporation of radio contrast agent is necessary. Barium Sulphate (BaSO4) is most often used in imaging of the GI tract. but it has high density (4.4777 gm /cm3) and poor floating property. So 12% concentration of BaSO4 is enclosed in tablet on behalf of 12% of Nizatidine to ensure the tablet float on stomach. In addition to BaSO4, 30%pectin, 5% PVP K30, 2% Talc, 1% magnesium stearate were accurately weigh and mix to form uniform blend then compress by using tablet compression machine.

In vivo studies was carried out in 3 healthy subjects. Subjects were allowed to fasted for overnight. BaSO4 enclosed prepared tablets were administered to subjects were allowed to expose X radiations to get abdominal X ray imaging. At regular time intervals of 0.15, 2,4,6,8 hrs, X ray images were taken in standing position of subjects by maintaining constant distance between X- rays and subjects. Gastric retentive time of Nizatidine gastro retentive tablets was estimated from the pictures of X- ray radiography studies(24).

Results and discussion

In the present study nizatidine gastro retentive tablets were favorably formulated by using different ratios of Xanthane gum, pectin, sodium alginate, and HPMC K100M along with sodium bicarbonate as gas generating agent.

Matrix tablet characterization

The Nizatidine gastro retentive tablets were prepared have off white, smooth, and flat shaped in appearance. All the prepared tablets shows agreeable weight variation range of 397 to 405mg with standard deviation range of <3, and not more than two tablets were allowed to deviate from percent weight variation range as specified in Indian pharmacopoeia(IP). Thickness of prepared tablets were measured by varnier calipers. It was shown between the range of 3.2±0.05 to 3.4±0.46. Hardness of prepared tablets shows between the range of 3.8±0.96 to 4.46±0.115 with standard deviation of <2.

In vitro buoyancy studies

All formulations of Nizatidine gastro retentive tablets were prepared by effervescent technique. In all formulations optimized concentration (10%) of sodium bicarbonate used as effervescent agent which induces buoyancy to prepared tablets without effecting matrix integrity for up to 12 hrs, with maximum possible lag time.

In acid environment sodium bicarbonate release carbon dioxide gas which was enclosed and protected with gel barrier formed by swelling of hydrated barrier, thus the tablet density decreased to below 1.004gm/cm3. As decreases the tablet density tablet become buoyant.

Buoyancy study values of all formulations are mentioned in table. Formulations prepared with Xanthane gum, pectin, and HPMC K100M shows buoyancy lag time <1 minuet with standard deviation range of <2 and retain the matrix integrity almost 12 hrs. But formulation prepared with sodium alginate shows floating lag time 1 to 2 minutes and failed to retain matrix integrity up to 12 hrs as low swelling rate of polymer unable to form gel barrier.

Swelling study

Swelling index is one of the foremost factor, plays a meaningful role to ensure buoyancy to prepared tablets as well as to bear matrix integrity up to desired period. Based on swelling nature of polymer used tablet, gel layer is formed which represents the drug release.

Swelling index values of all formulation were expressed in table. In case of tablet prepared with Xanthane gum(F1 to F5), HPMC K100M(F15 to F20) swelling index values are gradually increase up to 12 hrs, comparatively formulation prepared with HPMC K100M shows high swelling index value than other polymers. Indeed, Tablets prepared with pectin(F6to F10) exhibits swelling index values are gradually increase in first 6 hrs than slightly decreases because rapid hydration of polymer in initial hours. Formulations prepared with sodium alginate(F11 to F15) shows low swelling index values because it has poor swelling and hydration nature. Graphical representation of swelling index values of all formulations are shown in fig.

Invitro dissolution study

In vitro dissolution study was carried out in 0.1N HCl dissolution medium using usp type II dissolution apparatus, dissolution was carried out up to 12hrs by withdrawing samples every one hour.

In vitro drug release values of Nizatidine gastro retentive tablets are mentioned in table no. Formulations prepared with 20% concentration of xanthane gum(F1) release 99.57% of drug with in 10 hours. 25% concentration of xanthane gum(F2) release98.7% of drug in 11 hours. But remaining 30%(F3), 35%(F4), 40%(F5) concentrations Xanthane gum release 97.9%,97.2%, 95.97% of drug respectively at 12th hour. Which denotes that the 20%, 25% concentration of Xanthane gum was not acceptable to obstruct the drug release up to 12 hours.

Formulation developed with 20%(F6), 25%(F7) concentration of pectin exhibits 99.26%, 98.72% of drug release up to 11 hrs. whereas 30%(F8), 35%(F9), 40%(F10) concentrations of pectin shows 99.1%, 97.38%, 96.78% of drug release respectively. Among all formulations of F6 to F10, Formulation prepared with 30% concentration of pectin show better drug release, so it is desire concentration to get Nizatidine floating tablets.

Formulations prepared with 20% to 35% (F11 to F14) concentration of sodium alginate failed to retard the drug release up to 12 hrs because it have limited swelling and low gel forming property. Formulations prepared with HPMC K100M shows very slow drug release, unable to deliver 70% of drug in 8hrs. But 98%, 97.3%, 96%, 96.7%, 94.4% of drug release was shown by formulation contain 20%, 25%,30%,35%,40% concentrations of HPMC K100M. this is due to HPMC K100M produce high viscosity of gel barrier around the tablet which takes longer time to erode. Among all polymers pectin enclosed formulation shows better drug release than others, this may be due to increase the solubility of sparingly soluble Nizatidine by pectin which can able to increase the solubility. Graphical Representation of in vitro drug release profile of all formulations is shown in fig.

Drug release kinetics

To understand the drug release kinetics and mechanism of drug release from prepared tablets in vitro drug release data was analyzed by different model depend kinetics like zero order, First order, Higuchi, krosmeyer-peppas models. Regression coefficient (R2) values obtained by kinetic models are illustrates in table. Dissolution profile of most of formulations follows zero order kinetics, formulation prepared with 35% of xanthane gum, 30% of pectin regression values shows linear drug release profile. From the kinetic data of krosemeyer - peppas model, we can confirm the mechanism of drug release. In this model release exponent 'n' explains the mechanism of drug release from prepared tablets. If n values is <0.45, that follows Fickian diffusion. Similarly, n value is in between 0.45 -0.89 which follows non Fickian transport mechanism. If 'n' is More than 0.89 which follows case II transport. As for this present work concerns, drug release profile of all formulations follows non Fickian transport to release the drug from prepared tablets.

In vivo floating behavior

In vivo floating behavior of prepared gastro retentive tablets were observed by radiographic imaging technique in 3 healthy subjects. Tablets prepared with 12% concentration of BaSo4 can able to opaque in X-ray image which inference that 12% concentration of BaSo4 is enough to prepare tablet for In vivo X-ray imaging studies to predict the gastric retention time.

Tablet can able to visualize in x-ray image taken in 0.15hr indicates that the administered tablet was float on stomach with in 15 minuts. X ray images taken in 2nd ,4th and 6th hour disclose that the tablet being in stomach up to 6hrs and alteration in tablet position reveals that the tablet did not adhere to stomach mucosa.