1. INTRODUCTION:

Ulcers are crater-like sores (generally 1/4 inch to 3/4 inch in diameter, but sometimes 1 to 2 inches in diameter) which form in the lining of the stomach (called gastric ulcers), just below the stomach at the beginning of the small intestine in the duodenum (called duodenal ulcers) or less commonly in the esophagus (called esophageal ulcers). In general, ulcers in the stomach and duodenum are referred to as peptic ulcers

An ulcer is the result of an imbalance between aggressive and defensive factors. On one hand, too much acid and pepsin can damage the stomach lining and cause ulcers. On the other hand (and more commonly), the damage comes first from some other causes, making the stomach lining susceptible to even an ordinary level of gastric acid¹ .

Hence, ulcers are sores on the lining of the digestive tract. The digestive tract consists of the esophagus, stomach, duodenum (the first part of the intestines) and intestines.

An ulcer may arise at various locations:

• Stomach (called gastric ulcer)

• Duodenum (called duodenal ulcer)

• Oesophagus (called Oesophageal ulcer)

• Meckel's Diverticulum (called Meckel's Diverticulum ulcer)².

Peptic ulcer

A peptic ulcer, also known as ulcus pepticum, peptic ulcer disease (PUD),³ is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. As may as 80% of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach. Ulcers can also be caused or worsened by drugs such as aspirin and other non-steroid anti-inflammatory drugs (NSAIDs)4.

Types of peptic ulcers

• Type I: Ulcer along the lesser curve of stomach

• Type II: Two ulcers present - one gastric, one duodenal

• Type III: Prepyloric ulcer

• Type IV: Proximal gastroesophageal ulcer

• Type V: Anywhere along gastric body, NSAID induced

Figure 1. Deep gastric ulcer

Epidemiology

The lifetime risk for developing a peptic ulcer is approximately 10%5. In Western countries the prevalence of Helicobacter pylori infections roughly matches age (i.e., 20% at age 20, 30% at age 30, 80% at age 80 etc). Prevalence is higher in third world countries. Transmission is by food, contaminated groundwater and through human saliva (such as from kissing or sharing food utensils). A minority of cases of Helicobacter infection will eventually lead to an ulcer and larger proportion of people will get non-specific discomfort and abdominal pain or gastritis⁴.

Pathophysiology of peptic ulcer

Classical causes of ulcers (tobacco smoking, blood groups, spices and a large array of strange things) are of relatively minor importance in the development of peptic ulcers. A major causative factor (90% of gastric and 75% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori, a spirochete that inhabits the antral mucosa and increases gastric production. Gastric, in turn, stimulates the production of gastric acid by parietal cells.

The gastric mucosa protects itself from gastric acid with a layer of mucous, the secretion of which is stimulated by certain prostaglandins. Non-steroid anti-inflammatory drugs (NSAIDs) block the function of cyclooxygenase 1, which is essential for the production of these prostaglandins. Newer NSAIDs (celecoxib and rofecoxib) only inhibit cox-2, which is less essential in the gastric mucosa, and roughly halve the risk of non-steroid anti-inflammatory drugs (NSAID) related gastric ulceration.

Glucocorticoids lead to atrophy of all epithelial tissues. Their role in ulcerogenesis is relatively small. Stress in the psychological sense has not been proven to influence the development of peptic ulcers. Burns and head trauma, however, can lead to "stress ulcers" and it is reported in many patients who are on mechanical ventilation. Smoking leads to atherosclerosis and vascular spasms, causing vascular insufficiency and promoting the development of ulcers through ischemia. A family history is often present in duodenal ulcers, especially when blood group O is also present. Inheritance appears to be unimportant in gastric ulcers6.

Signs and symptoms

Symptoms of a peptic ulcer can be

Ø Abdominal pain, classically epigastric with severity relating to mealtimes, after around 3 h of taking a meal (duodenal ulcers are classically relieved by food, while gastric ulcers are exacerbated by it)

Ø Bloating and abdominal fullness

Ø Water brash (rush of saliva after an episode of regurgitation to dilute the acid in esophagus)

Ø Nausea and copious vomiting

Ø Loss of appetite and weight loss

Ø Vomiting of blood; this can occur due to bleeding directly from a gastric ulcer, or from damage to the esophagus from severe/continuing vomiting

Ø Melina (tarry, foul-smelling feces due to oxidized iron from hemoglobin)

Ø Rarely, an ulcer can lead to a gastric or duodenal perforation. This is extremely painful and requires immediate surgery.

A history of heartburn, gastroesophageal reflux disease (GERD) and use of certain forms of medication can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer include non-steroid anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase and most glucocorticoids (e.g. dexamethasone and prednisolone).

The timing of the symptoms in relation to the meal may differentiate between gastric and duodenal ulcers. A gastric ulcer would give pain during the meal, as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux into the stomach. Symptoms of duodenal ulcers would manifest mostly before the meal when acid (production stimulated by hunger) is passed into the duodenum. However, this is not a reliable sign in clinical practice⁴.

Treatment

Younger patients with ulcer-like symptoms are often treated with antacids. Bismuth compounds may actually reduce or even clear organisms, though it should be noted that the warning labels of some bismuth subsalicylate products indicate that the product should not be used by someone with an ulcer. Patients who are taking non-steroid anti-inflammatory drugs (NSAIDs) may also be prescribed a prostaglandin analogue (Misoprostol) in order to help prevent peptic ulcers, which may be a side-effect of the NSAIDs. When Helicobacter pylori infection is present, the most effective treatments are combinations of two antibiotics (e.g. clarithromycin, amoxicillin, tetracycline and metronidazole) and one proton pump inhibitor (PPI), sometimes together with a bismuth compound. In complicated, treatment-resistant cases, three antibiotics (e.g. amoxicillin + clarithromycin + metronidazole) may be used together with a proton pump inhibitor and sometimes with bismuth compound. An effective first-line therapy for uncomplicated cases would be amoxicillin + metronidazole + pantoprazole (proton pump inhibitor). In the absence of Helicobacter pylori long-term higher dose proton pump inhibitors (PPIs) are often used. Treatment of Helicobacter pylori usually leads to clearing of infection, relief of symptoms and eventual healing of ulcers. Recurrence of infection can occur and retreatment may be required, if necessary with other antibiotics. Since the widespread use of proton pump inhibitors (PPIs) in the 1990s, surgical procedures (like "highly selective vagotomy") for uncomplicated peptic ulcers became obsolete.

Perforated peptic ulcer is a surgical emergency and requires surgical repair of the perforation. Most bleeding ulcers require endoscopy urgently to stop bleeding with cutlery, injection or clipping⁴.

The concept of tablet

A tablet is a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients include binders, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrates to ensure that the tablet breaks up in the digestive tract; sweeteners or flavours to mask the taste of bad tasting active ingredients; and pigments to make uncoated tablets visually attractive. A polymer coating is usually applied to hide the taste of the tablet's components, to make the tablet smoother and easier to swallow, to make it more resistant to the environment and extending its shelf life. The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms and half of these are compressed tablets⁷. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, rectally or intra vaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions and emulsions. It consists of an active pharmaceutical ingredient with biologically inert excipients in a compressed solid form.

Tablets are one of the most stable and commonly administered oral dosage forms. Since the later part of nineteen-century, tablets have been widespread and their popularity continues. Tablets remain popular as dosage form because of the advantages afforded both to the pharmaceutical manufacturers and patients. These includes: simplicity and economy of preparation, stable and convenient in packing, ease of transporting and dispensing, accuracy of single dosage regimen, compactness and portability, and blandness of taste and ease of administration⁷.

2. METHODS:

FT-Infrared spectroscopy to find out the compatibility of drug with polymers:

This was carried out to find out the compatibility between the drug pantoprazole sodium sesquihydrate and the polymer hydroxylpropyl methylcellulose (HPMC), Cassava starch, and polyvinyl pyrrolidone. 10 mg of the sample and 400 mg of KBr were taken in a mortar and triturated. A small amount of the triturated sample was taken into a pellet maker and was compressed at10 kg/cm2 using a hydraulic press. The pellet was kept onto the sample holder and scanned from 4000 cm-1 to 400 cm-1 in Shimadzu FT-IR spectrophotometer. Samples were prepared for drug pantoprazole sodium sesquihydrate, polymer HPMC, Cassava starch, polyvinyl pyrrolidone and physical mixture of drug and polymer. The spectra obtained were compared and interpreted for the functional group peaks.

Preparation of standard graphs:

Preparation of standard graph for pantoprazole sodium sesquihydrate using pH 1.2 acidic buffer

A. Determination of absorption maxima (λmax)

100 mg of pantoprazole sodium sesquihydrate was weighed accurately and dissolved in 100 ml of pH 1.2 acidic buffer in 100 ml volumetric flask (stock solution). 2 ml was taken from the stock solution and transferred into 100 ml volumetric flask and diluted up to 100 ml with pH 1.2 acidic buffer. The resulting solution was labeled as standard working Solution. 2 ml of the working solution was withdrawn and diluted up to 10 ml with pH 1.2 acidic buffer in 10 ml volumetric flask. The spectrum of this solution was run in 200 to 400 nm range in UV-visible spectrophotometer. The λ max of the pantoprazole sodium sesquihydrate was found to

be 283.5 nm.

B. Preparation of standard graph

From above standard working solution, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml and 6 ml was withdrawn and diluted up to 10 ml with pH 1.2 acidic buffer in 10 ml volumetric flask to get concentration of 2 μg, 4 μg, 6 μg, 8 μg, 10 μg and 12 μg respectively. The absorbance of each solution was measured by UV-visible spectrophotometer at 283.5 nm using the pH 1.2 acidic buffer as blank.

Preparation of standard graph for pantoprazole sodium sesquihydrate using pH 6.8 phosphate buffer:

A. Determination of absorption maxima (λmax)

100 mg of pantoprazole sodium sesquihydrate was weighed accurately and dissolved in 100 ml of pH 6.8 phosphate buffer in 100 ml volumetric flask (stock solution). 2 ml was taken from the stock solution and transferred into 100 ml volumetric flask and diluted up to 100 ml with pH 6.8 phosphate buffer. The resulting solution was labeled as standard working Solution. 2 ml of the working solution was withdrawn and diluted up to 10 ml with pH 6.8 phosphate buffer in 10 ml volumetric flask. The spectrum of this solution was run in 200 to 400 nm range in UV-visible spectrophotometer. The λ max of the pantoprazole sodium sesquihydrate was found to be 288.5 nm.

B. Preparation of standard graph

From standard working solution, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml and 6 ml was withdrawn and diluted up to 10 ml with pH 6.8 phosphate buffer in 10 ml volumetric flask to get concentration of 2 μg, 4 μg, 6 μg, 8 μg, 10 μg and 12 μg respectively. The absorbance of each solution was measured by UV-visible spectrophotometer at 288.5 nm using the pH 6.8 phosphate buffer as blank.

Preparation of pantoprazole sodium sesquihydrate tablets:

Preparation of granules

Pantoprazole sodium sesquihydrate granules for tabletting were prepared by wet granulation method42. Specified quantity of pantoprazole, hydroxypropyl methylcellulose (HPMC), Cassava starch, polyvinyl pyrrolidone (PVP) and Avicel PH 102 were weighed according to the formula and transferred in a mortar and pestle and mixed thoroughly. The powder mass was mixed with 5% starch paste to obtain a sluggy mass and this was passed through sieve no 12 to obtain the granules. The granules prepared were dried at 50oC for 4 h. The dried granules were screened through sieve no 22 & 44 and stored for further studies. The specified quantity of magnesium stearate and talc were finally added and mixed for the compression of tablets.

Preparation of pantoprazole sodium sesquihydrate tablets

An ideal mixture of granules were directly punched into tablets weighing about 200 mg containing 40 mg of pantoprazole sodium sesquihydrate, using rotary tablet compression machine (12 stations, Karnavati, India), using 8 mm diameter concave punches. The different batches of pantoprazole tablets were collected and stored in air tight containers. (Table-1).

Characterization of pantoprazole sodium sesquihydrate compressed tablets:

1) Pre compression parameters

a) Percentage yield

The prepared pantoprazole sodium sesquihydrate granules were completely collected and weighted. The percentage product yield was calculated from its theoretical and practical product yield.

b) Mean granules size analysis by optical microscopy

In the present study the granules particle size was determined by the optical microscopy. 1mm of the stage micrometer scale is equal to 89 eyepiece division. Therefore 1 eyepiece division is equal to (1/89) ×1000 Microns i.e. 11.2 μm. The dry granules were uniformly spread on the slide. Granules particle sizes were measured, along the longest axis and the shortest axis (cross shaped measurement). Average of these two reading given was mean diameter of particles. The diameter of a minimum number of 50 granules in each batch was calculated.

Table 1 Formula for the preparation of pantoprazole sodium sesquihydrate tablets

Batch no	Ingredients
Batch no	Pantoprazole sodium sesquihydrate (mg)	HPMC (mg)	Cassava starch (mg)	PVP (mg)	Avicel PH 102 (mg)	Starch paste 5%	Talc (mg)	Magnesium stearate (mg)
F1	40	-	-	-	154	qs	2	4
F2	40	24	-	-	130	qs	2	4
F3	40	44	-	-	110	qs	2	4
F4	40	64	-	-	90	qs	2	4
F5	40	84	-	-	70	qs	2	4
F6	40	104	-	-	50	qs	2	4
F7	40	-	24	-	130	qs	2	4
F8	40	-	44	-	110	qs	2	4
F9	40	-	64	-	90	qs	2	4
F10	40	-	84	-	70	qs	2	4
F11	40	-	104	-	50	qs	2	4
F12	40	-	-	24	130	qs	2	4
F13	40	-	-	44	110	qs	2	4
F14	40	-	-	64	90	qs	2	4
F15	40	-	-	84	70	qs	2	4
F16	40	-	-	104	50	qs	2	4

qs- quantity sufficient

c) Bulk density (Db)

Accurately weighed granules were carefully transferred into graduated measuring cylinder. The granules bed was then made uniform and the volume occupied by the granules was noted as per the graduation marks on the cylinder as ml. It is expressed in gm/ml and is calculated using the following formula44.

Where, M - Mass of the powder

Vb - Bulk volume of the powder

d) Tapped density (Dt)

It is the ratio of total mass of granule to the tapped volume of granule. The graduated measuring cylinder containing accurately weighed granule was manually tapped for 50 times. Volume occupied by the granule was noted. It is expressed in gram/ml and is calculated by following formula44.

Where, M - Mass of the powder

Vt - Tapped volume of the powder

e) Compressibility index (I) and Hausner’s ratio

Carr’s index and Hausner’s ratio measure the propensity of granule to be compressed and the flow ability of granule. Carr’s index and Hausner’s ratio were calculated using following formula.

Where, Dt – Tapped density of the powder

Db – Bulk density of the powder

Where, Dt – Tapped density of the powder

Db – Bulk density of the powder

f) Angle of repose (θ)

The frictional forces in a loose powder can be measured by the angle of repose. This is the maximum angle possible between the surface of a pile of powder and the horizontal plane. Sufficient quantities of pantoprazole granules were passed through a funnel from a particular height (2 cm) onto a flat surface until it formed a heap, which touched the tip of the funnel. The height and radius of the heap were measured. The angle of repose was calculated using the formula43.

Angle of repose (θ) = tan^-1 (h/r)

Where, h – Height of the pile in cm

r – Radius of the pile

2) Post compression parameters

a) Hardness test

The prepared tablets were subjected to hardness test. It was carried out by using hardness tester and expressed in kg/cm2.

b) Friability test

The friability was determined using Roche friabilator and expressed in percentage (%). 20 tablets from each batch were weighed separately (Winitial) and placed in the friabilator, which was then operated for 100 revolutions at 25 rpm. The tablets were reweighed (Wfinal) and the percentage friability (F) was calculated for each batch by using the following formula.

c) Weight variation test

20 tablets were selected at random from the lot, weighed individually and the average weight was determined. The percent deviation of each tablets weight against the average weight was calculated. The test requirements are met, if not more than two of the individual weights deviate from the average weight by more than 5% and none deviates more than 10%. IP limit for weight variation in case of tablets weighing more than 80 mg but less than 250 mg is ± 7.5 %.

d) Uniformity of drug content

The prepared pantoprazole sodium sesquihydrate tablets were tested for their drug content. Three tablets of each formulation were weighed and finely powdered. About 40 mg equivalent of pantoprazole sodium sesquihydrate was accurately weighed and completely dissolved in pH 6.8 phosphate buffer and the solution was filtered. 1 ml of the filtrate was further diluted to 100 ml with pH 6.8 phosphate buffer. Absorbance of the resulting solution was measured by UV-Visible spectrophotometer at 288.5 nm.

3) Coating of compressed pantoprazole sodium sesquihydrate tablets

a) Preparation of enteric coating solution

The enteric coating solution was prepared by simple solution method. It was prepared by 6% w/w of Eudragit L100 or cellulose acetate phthalate or =Drug coat L100 as an enteric polymer, 2.6% w/w of titanium dioxide as opacifier, diethyl phthalate 1.2% w/w as plasticizer and acetone and isopropyl alcohol mixture was used as solvent. Titanium dioxide was triturated in a glass motor with small amount of solvent mixture and filtered with muslin cloth into the polymer solution already prepared with one half of solvent mixture. Diethyl phthalate was added and made up the volume with rest of the solvent mixture; this mixture was constantly stirred for 1h with paddle mechanical stirrer at the rate of 1000 rpm and the stirred coating solution was again filtered through muslin cloth, a coating solution was obtained.

Table 2: Composition of coating solution

Ingredients	Quantity (%w/w)
Cellulose acetate phthalate / Eudragit L100 / Drug coat L100	6.0
Titanium dioxide	2.6
Diethyl phthalate	2.0
Acetone	59.4
Isopropyl alcohol	30.0

b) Enteric coating of pantoprazole sodium sesquihydrate compressed tablets by dipping method

The compressed tablets were coated with enteric coating polymer (Eudragit L100 or cellulose acetate phthalate or Drug coat L100) solution by dipping method. Desired tablet coating continued the dipping and weight gain was achieved. The coated tablets were studied for its weight variation, thickness, uniformity of drug content and in vitro dissolution study.

4) Physicochemical evaluation of coating films

The same polymer solution was used to prepare the polymeric films and was subjected for

Ø film thickness

Ø film weight

Ø film solubility

The polymeric films were prepared by casting the acetone –isopropyl alcohol (2:1), the polymer solution was poured on the glass plate. The film was dried for 24 h at room temperature under a special cover with reduced solvent evaporation to obtained smooth homogenous films. The dried films were cut in to 1cm2 area the prepared polymeric film were studied for film thickness, film weight and film solubility. The thickness of dried films was determined by thickness Digital micrometer. The 1 cm2 coating film was selected and separately weighed using the digital balance; the average films weight was calculated. The film solubility was studied with pH 1.2 and pH 6.8. The 1×1 cm2 coating film was selected, weighed and transferred in a beaker containing 20 ml of specified pH medium, which was mixed in a magnetic stirrer for 1 h at 37 ± 1°C and finally film solubility was examined.

5) In vitro drug release studies

USP dissolution apparatus type II was employed to study the in vitro drug release from various formulations prepared. The dissolution medium used was 900 ml of acidic buffer of pH 1.2 for 2 h and phosphate buffer of pH 6.8 for 10 h. The tablet was kept in to the basket. The temperature was maintained at 37°C ± 0.5°C and the stirring rate was 100 rpm. Samples were withdrawn at regular time intervals and the same volume was replaced with fresh dissolution medium. The samples were measured by UV- visible spectrophotometer at 283.5 nm (pH 1.2) and at 288.5 nm (pH 6.8) against a blank. The release studies were conducted in triplicate and the mean values were plotted versus time.

6) Stability studies

A study was carried out to assess the stability of the pantoprazole sodium sesquihydrate cellulose acetate phthalate coated tablet formulation (ECF3). Generally, the observation of the rate at which the product degrades under normal room temperature requires a long time. To avoid this undesirable delay, the principles of accelerated stability studies are adopted. The tablets were packed in glass container. Stability studies were carried out at 40°C and 75% RH over a period of 1 month. Samples were evaluated at 10th, 20th and 30th days for different parameters such as physical appearance, hardness, weight variation, drug content and dissolution.

3. RESULTS:

Drugs Polymer Interaction Study by FTIR spectrophotometer:

FT-IR spectroscopy study was carried out separately to find out, the compatibility between the drug pantoprazole and the polymers hydroxypropyl methylcellulose, Cassava starch, polyvinyl pyrrolidone used for the preparation of tablets. The FT-IR was performed for drug, polymer and the physical mixture of drug-polymer. The spectral obtained from FT-IR spectroscopy studies at wavelength between 4000 cm-1 to 400 cm-1 are given below.

Table 3 : IR interpretation of drug, polymer and physical mixture of drug-polymer

Sr. No	Interpretation	IR absorption bands (cm^-1)
Sr. No	Interpretation	Pure drug	Drug + HPMC	Drug + Cassava starch	Drug + PVP
1	N-H	3483.56	3487.42	3498.99	3497.06
2	O-H	3358.18	3363.97	3248.23	3362.04
3	CH₂	3176.87	3194.23	3196.15	3203.87
4	CH₃	2960.83	2953.12	2939.61	2945.40
5	C-O	1591.33	1591.33	1591.33	1591.33
6	C-F	1373.36	1373.36	1377.22	1373.36
7	S=O	1049.31	1039.67	1116.82	1033.88

Figure 2:- IR spectrum of pantoprazole sodium sesquihydrate

Figure 3 :- IR spectrum of hydroxypropyl methylcellulose

Figure 4:- IR spectrum of physical mixture of pantoprazole sodium sesquihydrate and hydroxypropyl methylcellulose

Figure 5:- IR spectrum of polyvinyl Pyrrolidone

Figure 6:- IR spectrum of physical mixture of pantoprazole sodium sesquihydrate and polyvinyl Pyrrolidone

Figure 7:- IR spectrum of Cassava starch

Figure 8:- IR spectrum of physical mixture of pantoprazole sodium sesquihydrate and Cassava starch

Preparation of standard graphs

Standard graph for the drug pantoprazole sodium sesquihydrate was done separately in pH 1.2 acidic buffer and pH 6.8 phosphate buffer. Tables show the concentrations of pantoprazole sodium sesquihydrate in pH 1.2 acidic and pH 6.8 phosphate buffers and the respective absorbance. The Figures show the calibration curves of pantoprazole sodium sesquihydrate in pH 1.2 acidic buffer and pH 6.8 phosphate buffer respectively.

Table 4:- Spectrophotometric data for standard graph of pantoprazole sodium sesquihydrate in pH 1.2 acidic buffer

Concentration (μg/ml)	Absorbance
2	0.06
4	0.12
6	0.182
8	0.237
10	0.306
12	0.365

Figure 9:- Standard curve of pantoprazole sodium sesquihydrate in pH 1.2 acidic buffer

Table 5:- Spectrophotometric data for standard graph of pantoprazole sodium sesquihydrate in pH 6.8 phosphate buffer

Concentration (μg/ml)	Absorbance
2	0.071
4	0.145
6	0.215
8	0.287
10	0.357
12	0.430

Figure 10:- Standard curve of pantoprazole sodium sesquihydrate in pH 6.8 phosphate buffer

Characterization of pantoprazole sodium sesquihydrate tablets:

1) Pre compression parameters

The pantoprazole sodium sesquihydrate granules were prepared by wet granulation method. The granules were evaluated for percentage yield, granules particle size, angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index, and the results are shown in Table. The percentage yield was ranged between 86.13 to 97.82%. The particle size of the granules was ranged between 0.498 ± 0.05 mm to 0.559 ± 0.12 mm. The bulk densities of the granules were found to be in the range of 0.306 ± 0.03 to 0.418 ± 0.03 gm/ml. The angle of repose varied from 25.47 ± 0.12 to 30.79 ± 0.26. The tapped densities were ranged between 0.313 ± 0.04 to 0.472 ± 0.05 gm/ml. Hausner’s ratio was ranged between 1.055 ± 0.04 to 1.129 ± 0.07, while the compressibility index was in the range of 5.28 ± 0.16 to 11.44 ± 0.12. (table-6)

Table 6:- Physicochemical evaluations of pantoprazole sodium sesquihydrate granules

Batch no	Yield (%)	Mean patricle size (mm)	Bulk density (gm/ml)	Tapped density (gm/ml)	Carr’s Index (%)	Hausner’s ratio	Angle of repose (θ)
F1	97.82	0.498	0.306	0.326	6.13	1.065	25.79
F2	94.82	0.545	0.312	0.335	6.86	1.073	26.95
F3	95.37	0.527	0.358	0.358	7.01	1.075	26.33
F4	94.12	0.542	0.357	0.384	7.03	1.075	28.31
F5	93.43	0.533	0.359	0.394	8	1.097	27.2
F6	91.68	0.535	0.384	0.429	10.48	1.117	30.27
F7	94.23	0.512	0.312	0.334	6.58	1.07	29.52
F8	95.89	0.548	0.286	0.313	8.62	1.094	26.13
F9	97.14	0.536	0.306	0.334	8.38	1.091	26.78
F10	94.42	0.559	0.294	0.324	9.25	1.102	28.09
F11	93.57	0.538	0.307	0.34	9.7	1.107	28.74
F12	94.6	0.507	0.384	0.406	5.41	1.057	25.47
F13	94.86	0.537	0.394	0.416	5.28	1.055	28.47
F14	96.13	0.523	0.416	0.457	8.97	1.098	29.79
F15	97.37	0.567	0.384	0.41	6.34	1.067	26.32
F16	86.13	0.545	0.418	0.472	11.44	1.129	30.79

(n=3 ± S.D)

Post compression parameters

The pantoprazole sodium sesquihydrate tablets were prepared by wet granulation method. The results of physicochemical evaluation of prepared tablets are shown in Table 7. The tablets were evaluated for Average weight, hardness, friability and drug content. The drug content was found to be between 95.42 ± 0.38% to 99.42 ± 0.26%. The hardness was found to be from 4.73 ± 0.42 to 8.40 ± 0.002 kg/cm2 and in all the cases the friability was less than 1%. (table-7).

Table 7:- Physicochemical evaluations of pantoprazole sodium sesquihydrate tablets

Batch no	Parameter
Batch no	Hardness (kg/cm2 )*	Friability (%)**	Average weight (g)**	Drug content (%)***
F1	8.4	0.011	0.201	98.85
F2	5.8	0.012	0.199	97.71
F3	6.2	0.016	0.204	98.85
F4	4.9	0.005	0.203	97.42
F5	4.93	0.023	0.208	96.85
F6	4.73	0.024	0.205	97.14
F7	5.66	0.24	0.199	98.55
F8	8.2	0.017	0.209	99.42
F9	5.6	0.11	0.198	96.85
F10	5.73	0.11	0.203	96.28
F11	5.12	0.09	0.206	95.78
F12	8.06	0.011	0.198	94.57
F13	7.66	0.019	0.207	95.42
F14	5.56	0.051	0.206	95.71
F15	5.83	0.032	0.204	95.71
F16	6.21	0.023	0.199	96.01

*(n=5 ± S.D)

**(n=20 ± S.D)

***(n=3 ± S.D)

In vitro drug release studies

The in vitro dissolution studies were carried out for the prepared tablets using USP apparatus type II. The in vitro release profiles of pantoprazole sodium sesquihydrate tablets are shown in Tables. The cumulative percentage of release of pantoprazole sodium sesquihydrate from the prepared tablets was varied from 65.02 ± 0.42% to 99.26 ± 0.16% depends upon the drug polymer ratio for 12 h. (table-8, Fig.- 11).

Figure 11:- In vitro drug release profile of pantoprazole sodium sesquihydrate from various tablet formulations (F1 to F16)

Table 8:- In vitro drug release profile of pantoprazole sodium sesquihydrate from various tablet formulations (F1 to F16)

Time (h)	Cumulative percentage of drug released
Time (h)	F1	F2	F3	F5	F6	F7	F8	F9	F10	F11	F12	F13	F14	F15	F16
0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
0.5	17	19	15	9	9	15	5	9	20	16	10	11	10	11	8
1	36	24	21	16	10	27	15	17	28	25	15	20	15	17	11
1.5	51	29	23	22	17	37	25	28	43	41	31	30	31	24	19
2	65	36	28	35	25	51	37	39	50	52	38	43	38	38	28
3	85	42	39	41	34	55	53	49	59	58	53	51	48	44	36
4	87	52	42	48	40	64	61	56	69	66	60	57	54	51	46
6	92	62	53	55	49	70	72	66	73	80	69	68	64	58	54
8	95	72	67	61	59	82	77	93	81	84	77	74	71	64	64
10	97	81	74	66	62	91	84	80	87	89	89	82	78	70	71
12	98	97	87	69	65	99	91	85	91	91	98	90	82	75	75

4. DISCUSSION:

FT-Infrared spectroscopy to find out the compatibility of drug with polymer

This was carried out to find out the possible interaction between selected drug pantoprazole and polymers hydroxypropyl methylcellulose, Cassava starch and polyvinyl pyrrolidone. FT-IR of pantoprazole showed the following peaks at 3483.56, 3358.18, 3176.87, 2960.83, 1591.33, 1373.36 and 1049.31nm due to N-H, O-H, CH2, CH3, C-O, C-F and S=O functional groups. The physical mixture of drug with polymer hydroxypropyl methylcellulose, Cassava starch and polyvinyl Pyrrolidone clearly shows the retention of these characteristic peaks of pantoprazole thus revealing no interaction between the selected drug and polymers.

Preparation of pantoprazole tablets

This method produced granular particles and very less fines. The pantoprazole sodium sesquihydrate tablets were prepared by wet granulation method. Hydrophilic matrix systems are widely used in oral sustained drug delivery because they make it easier to achieve a desirable drug release profile, they are cost effective and they have broad US FDA acceptance. The Cassava starch and PVP also used as polymer in the other formulation49. The hydrophilic polymer matrix system consists of hydrophilic polymer, drug and other excipients distributed throughout the matrix. Sustained delayed release can be achieved by formulating drugs as matrix devices using HPMC, PVP and/ or other polymers50,51,52. The solubility of HPMC is pH independent. In this study HPMC, Cassava starch and PVP was used as a hydrophilic release retarding polymer in different concentrations and the Avicel PH 102 (MCC) as filler and starch paste (5%) as binding agent.

During the optimization of granules, less moisture sluggy masses were found to have more fines and high friability and the high moisture sluggy masses were sticky in sieving process. Hence, optimum moisture (paste 5%) was used for preparing the granules. Drying of granules was performed at 50°C temperature. This method produced narrow shaped granular particles with very less fines. The obtained granules were smooth and almost uniform sized.

Characterization of pantoprazole sodium sesquihydrate tablets

a) Precompression parameters

The prepared pantoprazole granules for tabletting were prepared by wet granulation method. The prepared pantoprazole granules were evaluated for percentage yield, mean granule particle size, angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index. This method was able to produce narrow shaped granular particles with fewer fines. The obtained granules were smooth and almost uniform sized The percentage yield of the granules was ranged between 86.13 to 97.82% w/w. This could be considered satisfactory product yield value of granules and these was due to polymer binding properties of granules. The particles were found to possess a narrow range of size distribution and have average particle size in the range of 0.498 ± 0.05 to 0.559 ± 0.12 mm. The bulk densities of the granules were found to be in the range of 0.306 ± 0.03 to 0.418 ± 0.03 gm/ml, while the tapped densities were ranged between 0.313 ± 0.04 to 0.472 ± 0.05 gm/ml. The flow characteristics of the granules were assessed by determining their angle of repose and Carr’s Index. The low values of compressibility (5.28 ± 0.16 to 11.44 ± 0.12%) signify good flowability. The angle of repose of all formulation was less than 30° (25.47 ± 0.12 to 30.79 ± 0.26) also indicate the good flowability of the prepared granules. This shows that the granules had smooth flow properties ensuring homogenous filling of the die cavity during the compression (punching) of tablets⁴⁴.

b) Post compression parameters

The pantoprazole tablets were prepared by wet granulation method and shown in Figure. The tablets were evaluated for their hardness, weight variation, content uniformity, friability and in vitro drug release. The hardness test is one of the control parameter during the manufacturing of tablets. Generally the tablet prepared with low compression force was dissolved faster than that with high compression force. Hardness must be controlled to ensure that th product is firm enough to withand handling without breaking or crumbling and not so hard that the disintegration time is unduly prolonged. The recommended value for tablet is 4 to 8 kg/cm2. The average hardness of the tablets to be in range was found within 4.73 ± 0.42 to 8.40 ± 0.002 kg/cm2. The average weight variation of tablets was found within the limits of 7.5% (I.P.)Friability value which also affected by the hardness value of tablets should be in the range of 0.5 to1% limits, which is the usual friability range of tablets. The friability of the prepared tablets was found less than 1% w/w. The uniformity of drug pantoprazole sodium sesquihydrate present in tablets formulation ranged from 95.42 ± 0.38 to 99.42 ± 0.26%. The physicochemical parameters of the prepared tablets were compared with the marketed tablet (Pantosec 40 mg, Cipla, India) containing 40 mg of pantoprazole. It was found that the physicochemical parameters of the prepared tablets as well as the marketed tablets comply with the standards.

5. CONCLUSION:

Ulcers are crater-like sores which form in the lining of the stomach, just below the stomach at the beginning of the small intestine in the duodenum. An ulcer is the result of an imbalance between aggressive and defensive factors. Pantoprazole is a substituted benzimidazole derivative that targets gastric acid proton pumps, the final common pathway for gastric acid secretion. The drug covalently binding to the proton pumps, causing prolonged inhibition of gastric acid secretion. The stability of pantoprazole is a function of pH and it rapidly degrades in acid medium of the stomach, but has acceptable stability in alkaline conditions. Therefore, pantoprazole should be delivered into the intestine. Hence, an attempt was made to formulate a delayed release drug delivery system for pantoprazole by using various enteric coating polymers.

The main objective of the study was to develop delayed release tablets of pantoprazole. The study led the following conclusions:

Ø The drug pantoprazole was selected for the study, because of its availability, proved activity and better clinical applications.

Ø The compatibility studies using FT-IR revealed that there was no interaction between the selected drug pantoprazole and the polymers HPMC.

Ø The pantoprazole granules were prepared by wet granulation method. The physicochemical parameters of the granules observed support the ideal flow nature of the formulated granules.

Ø The pantoprazole tablets were prepared by wet granulation method. The physicochemical evaluation of the prepared tablets was found within the standards Pharmacopeial limits.

Ø The effect of enteric coating on the in vitro drug release, none of the CAP enteric coated tablets showed drug release during the first 2 h in pH 1.2. While the Drug coat L100 and Eudragit L100 coated formulation showed a drug release of 0.5% to 1% during the first 2 h in pH 1.2.

Ø Release of drug from the tablets was first order diffusion controlled as indicated by higher r² values in First order kinetic and higuchi model. The n value of Korsmeyer Peppas equation indicated that the release mechanism was super case-II transport.

Ø The optimized formulation was stable and retained the pharmaceutical properties at room temperature and 400C / 75% RH over a period of 1 month.

Ø The pantoprazole sodium sesquihydrate coated tablet formulation ECF3 showed its antiulcer activity.

Based on the observations, it can be concluded that the formulated delayed release tablets of pantoprazole using widely accepted and physiologically safe polymers and other excipients was capable of exhibiting sustained release properties for a period of 12 h. The enteric coated, especially the CAP coated tablets, did not release the drug in the acidic pH 1.2 for a period of 2 h. They are thus may be reducing the dose intake, prevent the degradation of drug in acidic pH 1.2, minimize the blood level oscillations, dose related adverse effects and cost and ultimately improve the patient compliance and drug efficiency.

6. SUMMARY:

The aim of the present study was to formulate and evaluate delayed release drug delivery system of pantoprazole sodium sesquihydrate tablets by using HPMC, Cassava starch and polyvinyl pyrrolidone.

FT-IR study was carried out to check any possible interactions between the drug and the polymers HPMC, Cassava starch and polyvinyl pyrrolidine, the study conformed that no interaction between the selected drug and the polymers. Pantoprazole sodium sesquihydrate granules were prepared by wet granulation method using different concentration of HPMC, Cassava starch and PVP as release retarding polymers, Avicel PH 102 (MCC) as filler and starch paste (5%) as binding agent. Magnesium stearate and talc was used as a glidant and lubricant respectively. The granules were evaluated for percentage yield, mean particle size, angle of repose, bulk density, tapped density and compressibility index. The flow characteristics of the granules were assessed by determining their angle of repose and Carr’s Index. The values of compressibility index and angle of repose signify good flowability of the granules for all the batches. This shows that the granules had smooth flow properties ensuring homogenous filling of the die cavity during the compression (punching) of tablets.

The compressed tablets were evaluated for its hardness, weight variation, content uniformity and friability.

The in vitro dissolution studies were carried out for compressed and coated tablets using USP dissolution apparatus type II. The cumulative percentage of drug release from the tablets varied and depends on the type of polymer used and its concentration.

7. REFERENCE:

1. Health encyclopedia diseases and conditions. http://www.healthscout.com. (Accessed on 14/11/2009)

2. American academy of family physicians. http://familydoctor. org/online/famdocon/home/common/digestive/disorders/186.html

3. http://www.emedmag.com/html/pre/gic/consults/071503.asp. (Accessed on 01/12/2009)

4. http://en.wikipedia.org/wiki/Peptic_ulcer. (Accessed on 14/11/2009)

5. Snowden FM. Emerging and reemerging diseases: a historical perspective. Immunol October 2008; 225: 9–26.

6. http://www.experiencefestival.com/a/Peptic_ulcer__ Pathophysiology. (Accessed on 14/11/2009)

7. Rowley FA. The Air war in the compressing room, part 1, tablets & capsules magazine. 2005.

8. Gennaro AR. Remington: The science and Practice of Pharmacy. (NY): Lippincott Williams and Wilkins 1990; 2: 1660-62.

9. Chein YW. Novel drug delivery systems. (NY): Marcel Dekker, INC; 2nd ed. New York: 1992; 140.

10. Swarbick J, Boylan JC. Encyclopedia of pharmaceutical technology. (NYand Basel): Marcel Dekker, ING; 1990; (3).

11. Hoffman A. Pharmacodynamics aspects of sustained release preparations. Advance Drug Deliv Rev 1998; 33: 185-99.

12. Ehrlich P. Immunology and cancer research. In collected papers of Paul Ehrlich, London: Pergamon Press; 1902; 442.

13. Lipowski. Australian Patent 109. 1938; 438.

14. Banker GS, Rhodes CT. Modern pharmaceutics. (NY and BASEL): Marcel Deckker, Inc; 3rd ed. 2005; 501-09.

15. http://en.wikipedia.org/wiki/Enteric_coating. (Accessed on 12/11/2009)

16. http://www.peakatp.com/pdf/peak_delivery.pdf. (Accessed on 12/11/2009)

17. Laine L, Peterson WL. Bleeding peptic ulcer. N Eng J Med 1994; 331: 717- 27.

18. Gibinski K. Step by step towards the natural history of peptic ulcer disease. J Clin Gastroenterology 1983; 5: 299-302.

19. Lai KC, Lam SK, Hui WM. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in NSAIDs users. Gastroenterology 2000; 118: 251.

20. Duvnjak M, Supanc V, Troskot B, Kovacevic I, Antic Z, Hrabar D, et al. Comparison of intravenous pantoprazole with intravenous ranitidine in prevention of re-bleeding from gastroduodenal ulcers. Gut 2001; 49(3): 2379.

21. Raffin RP, Colomé LM, Schapoval EES, Pohlmann AR, Guterres SS. Increasing sodium pantoprazole photostability by microencapsulation: Effect of the polymer and the preparation technique. Eur J Pharm Biopharm 2008; 3:1014-18.

22. Oliveira HP, Albuquerque JJF, Nogueiras C, Rieumont J. Physical chemistry behavior of enteric polymer in drug release systems. Int J Pharm 2009; 45: 432-39.

23. Harris MS, Javeria T, Hamid AM. Evaluation of drug release kinetics from Ibuprofen matrix tablets using HPMC. Pak J Pharma Sci. 2006; 19(2): 19–24.

24. Cronlein J, Fegely K, Young C. Characterization of Delayed Release Lansoprazole Multiparticulates: Impact of Biorelevant Dissolution Media.5^th world meeting on pharmaceutics 2006.

25. Basak SC, Kumar PS, Manavalan R, Narendranath, KA. Preparation and evaluation of enteric coated pancreatin tablets. Ind J Pharm Sci 2002; 64: 260- 64.

26. Turkoglu M, Varol H, Celikok M. Tableting and stability evaluation of enteric coated omeprazole pellets. Eur J Pharm and Biopharm 2004; 57: 279- 86.

27. Pandey VP, Phanindrudu A, Manavalan R, Livingston J. In vitro study on capsule formulations of omeprazole containing enteric coated granules. Boll Chim Farm 2002; 141: 419-22.

28. Raffin RP, Pohlmann AR, Guterres SS. Preparation, characterization, and in vivo anti-ulcer evaluation of pantoprazole-loaded microparticles. Eur J Pharm and Biopharm 2006; 63: 198-204.

29. Brunner G, Harke U. Long-term therapy with pantoprazole in patients with peptic ulceration resistant to extended high-dose ranitidine treatment. Aliment Pharmacol Ther 1994; 8(1): 59-64.

30. Comoglu T, Gonul N, Dogan A, Basci N. Development and In vitro evaluation of pantoprazole-loaded microspheres. Drug delivery 2008; 15: 295-302.

31. Colomé LM, Haas SE, Jornada DS. Development of HPMC and Eudragit S100 blended microparticles containing sodium pantoprazole. Pharmazie 2007; 62: 361-64.

32. Matsuo M, Arimori K, Nakamura C. Delayed release tablets using hydroxyl ethyl cellulose as a gel forming matrix. Int J Pharm 1996; 138: 225-33.

33. Hua D, George R, Scott V, Ali R. In-vitro dissolution testing of delayed release multi-particulate systems. Controlled release society annual meeting July 2008.

34. Fan LF, Du Q, Xiang B, Li CL, Bai M, Chang YZ, Cao DY. Design and in vitro/in vivo evaluation of multi-layer film coated pellets for omeprazole. Int J Pharm 1996; 18: 25-33.

35. Ravi KP, Prakash B, Murali KM, Santha YM, Asha DC. Simultaneous Estimation of domperidone and pantoprazole in solid dosage form by UV spectrophotometry, July 2006; 3(12): 142-145.

36. Saini V. Antiulcer activity of pantoprazole from multiple-unit tablet dosage form. Int J PharmTech Res Oct-Dec 2009; 1(4): 1092-1093.

37. Mahesh DC, Paras J, Sachin C, Rajesh S, Pradeep RV. Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin. Int J Pharma January 2006; 316: 86-92.

38. Reddy KR, Mutalik S, Reddy S. Once-daily sustained release matrix tablets of nicorandil Formulation and in vitro evaluation. AAPS Pharmsci Tech 2003; 4: E61.

39. Pantoprazole sodium sesquihydrate available at: http:// www Rx list.com. (Accessed on 24/11/2009)

40. Indian Pharmacopoeia. Delhi: The controller of publications. 1996; (1).

41. British Pharmacopoeia. London: The stationary office. 2003; (1).

42. Wade A, Weller P. Handbook of pharmaceutical excipients. London: Pharmaceutical press 1994; 4: 151-52.

43. Cooper J, Gunn C. Powder flow and compaction. IN: Carter SJ, eds. Tutorial pharmacy, New Delhi: CBS publishers and distributors; 1986; 211-33.

44. Lachman L, Liberman HA, Nicholas Gl. Sustained release dosage forms, in; 2nd ed, Varghese publishing house, Mumbai, 1987; 439-40.

45. Levin M. Changing Tabletting Machines in Scale-Up and Production: Ramifications for SUPAC Background Notes for FDA CDER DPQR Seminar April 3, 2000.

46. Vueba ML, Carvalho LB, Veiga F, Sousa JJ, Pina ME. Influence of cellulose ether polymers on ketoprofen release from hydrophilic matrix tablets. Eur J Pharm and Biopharm 2004; 58: 51-59.

47. Bonin EA, Campos AC, Coelho JC, Matias JE, Malafaia O, Jonasson TH. Effect of Pantoprazole Administered Subcutaneously on the Healing of Sutured Gastric Incisions in Rats. Eur Surg Res 2005; 37: 250-256.

48. Malairajan P, Gopalkrishnan G, Narasimhan S, Jessi KV. Evaluation of anti ulcer activity of polyalthia longifolia (sonn.) thwaites in experimental animals. Ind J Pharmacol 2008; 40(3):125-128.

49. Alderman DA. A review of cellulose ethers in hydrophillic matrices for the oral controlled release dosage froms. Tech Prod Mfr 1984; 5: 1-9.

50. Carstensen JT. Pharmaceutics of solids and solid dosage forms. New York: John Wiley and Sons; 1977; 100.

51. Mockel JE, Lippold BC. Zero-order drug release from hydrocolloid matrices. Pharm Res 1993; 10: 1066-70.

52. Swarbrick J. Advances in controlled drug delivery. STP Pharma 1996; 6: 53- 56.

Received on 10.04.2013 Accepted on 14.05.2013

Asian J. Res. Pharm. Sci. 2013; Vol. 3: Issue 2, Pg 95-106