FORMULATION & EVALUATION OF BUFFERED PANTOPRAZOLE SODIUM TABLET

FORMULATION & EVALUATION OF BUFFERED PANTOPRAZOLE SODIUM TABLET

Mukesh P. Ratnaparkhi*, Pravin S. Pongale and Shilpa P. Chaudhari

Department of Pharmaceutics, Marathwada Mitra Mandal’s College of Pharmacy, Thergaon (Kalewadi), Pune- 411 033, Maharashtra, India

ABSTRACT: The aim of this study was to prepare buffered tablets of acid labile drug, Pantoprazole sodium for oral administration using buffering agents to protect a drug from gastric fluid. Its mechanism of action was inhibition of H+/K+-adenosine triphosphate, an enzyme present in the gastric parietal cells. The tablets were prepared by wet granulation method. The formulations contain sodium carbonate, sodium bicarbonate as buffering agents and crospovidone as superdisintegrant. The formulation were prepared, optimized and evaluated by 3² factorial design. In this design independent variables were   sodium carbonate, sodium bicarbonate, cross povidone and dependent variables were pH and disintegration time. The tablets were evaluated for friability, hardness, disintegration, dissolution and drug content. The formulation F6 was selected by factorial design it was selected due to results as this formulation maintain neutral pH of stomach  and drug release simultaneously within 50 seconds after administration.

Pantoprazole sodium, Buffered tablet, Superdisintegrants, Buffering agents

INTRODUCTION:Peptic ulcer disease comprises a group of chronic ulcerative conditions that primarily affect the gastric mucosa and proximal duodenum.

The drug like H₂ blockers cimetidine, ranitidine and famotidine reduce the amount of acid produced by stomach. But Proton Pump Inhibitors (PPIs) are a group of drugs whose main action is pronounced and long-lasting reduction of gastric acid production.

The key action mechanism of the PPIs is inhibition of H+/K+-adenosine triphosphate, an enzyme present in the gastric parietal cells.

These drugs are metabolized in the parietal cells to active sulfonamide metabolites that inactivate the sulfhydryl group of the proton pump, thus reducing the hydrogen ion secretion ^{1, 2}.

Pantoprazole is a lipophilic weak base with poor aqueous solubility at low pH. It is unstable in low pH solutions and undergoes rapid acid-catalyzed degradation, though it is relatively stable at neutral or high pH. Due to the pH sensitivity of Pantoprazole Sodium, effective drug delivery is problematic.

Most of the PPIs are formulated in an enteric-coated solid dosage form (either a delayed-release capsule or tablet) or as an intravenous solution. There are some problems associated with enteric-coated preparations as dissolution of the enteric coating is pH-dependent and gastric empting time. pH profile of the gastrointestinal tract in an individual is variable at different times and is dependent on numerous physiological factors (e.g., the fed or fasted state), variable dissolution times for the enteric coat and variable pharmacokinetic profiles of individuals may affects ^{3, 4, 5}.

The acid-labile drugs for oral administration may also be protected from gastric acidity by neutralizing the pH of the gastric fluid. So the current frontier in PPI therapy is immediate-release tablet combined with buffering agents which prevent degradation of drug by neutralizing the pH of stomach before absorption and protect the drug from low pH. Such dosage forms are known as buffered tablet and such tablet is advantageously devoid of any enteric coating or delayed or sustained-release delivery ^{6, 7}_.

MATERIAL AND METHOD:

Materials: Pantoprazole sodium, mannitol, colloidal silicon dioxide, calcium stearate, sodium bicarbonate, sodium carbonate, crospovidone received from Genpharma International Pvt. Ltd Pune.

Method:

Drug Excipients Compatibility Study: Sample of pure drug, coating, physical mixture of coating material and drug in 1:1 ratio was placed at accelerated stability condition 40±2°C and 75±5% relative humidity for a period of 3 month. At the end of 3 month samples were evaluated for drug–excipients compatibility using Fourier transformed infrared spectroscopy (FT-IR) (Shimadzu Corporation, Japan, 8400s).

Preparation of buffered tablet of pantoprazole sodium: Buffered tablets were prepared by wet granulation technique using varying proportion of Ingredients.  The detail process is as follows:-

• Sifting: The Drug, Mannitol, Sodium carbonate, sodium bicarbonate, Crosspovidone, Polyvinyl   pyrrolidone K-30 (PVPK-30) were sifted through sieve # 40.
• Mixing: The sifted ingredients were mixed thoroughly in a polybag for 15min.
• Preparation of Granules: The Isopropyl alcohol was added in well mixed powder till the desired wet mass was formed. This wet mass was sifted through sieve #10.
• Drying: The prepared granules were dried in an oven at 45⁰C for 1 hr and sifted through sieve #20. Loss on drying was done.
• Lubrication: Calcium stearate were sifted through sieve #40 and mixed with the prepared granules in a polybag for 5min.

The compositions of the tablet formulations were listed in table 1.

TABLE 1: TABLET FORMULATIONS

Selection of buffering agent and there combinations in 500 ml SGF: Different buffering agents and alkaline agents are used for neutralizing pH of SGF and there combination also tried for same shown in table 2.

TABLE 2: COMBINATION OF BUFFER

 Evaluation of Tablets ^{8, 9, 10}:

Bulk density: LBD (Loose Bulk Density) and TBD (Tapped Bulk Density) were determined by 44 gm of powder from each formula, previously lightly  shaken to break any agglomerates formed, was  placed into a 100 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 5 cm at 2 second intervals. The reading of tapping was continued until no further change in volume was noted using the following equation.

LBD and TBD were calculated:

LBD = Weight of the powder / volume of the packing.

TBD = Weight of the powder / Tapping volume of the packing.

Compressibility index: The compressibility index of the granules was determined by Carr’s compressibility index:

Carr’s index (%) = {(TBD – LBD) X 100}/TBD

Angle of Repose: The angle of repose of granules was determined by the funnel method. The accurately weighed granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation;

Angle of Repose θ = tan-1 h/r

Where, h = height of the powder cone, r = radius of the powder cone

Thickness measurement: It  is  carried  out  on  20  tablets  by  measuring  thickness  using Vernier’s calipers. Mean and standard deviation were determined.

Hardness determination: 20  tablets  were  taken  randomly  and  hardness  was  measured  using  Hardness  tester  (Electrolab  India  Ltd).  The mean hardness of 20 tablets of each formulation was determined.

Friability test: Friability was determined on 20 tablets. Tablet  samples  were  weighed  accurately  and  placed  in  friabilator  (Electrolab  India  Ltd).  After  100  rotations  (4 min  at  25  rpm)  loose  dust  was  removed  from  the  tablets.  Finally tablets were weighed.  The  loss  in  weight  indicates  the  ability  of  the  tablets  to  withstand  the  wear.  The percentage friability was determined by using following formula:

Disintegration test: Disintegration  time  was  determined  to  ensure  that  the  drug  substance  is  fully  available  for  dissolution  and absorption  from  the  gastrointestinal  tract. The  tablets  were  examined  using  the  USP-  XXIV  disintegration  apparatus  (Electrolab  India).  Six tablets were tested for each batch.

In vitro dissolution studies: In vitro dissolution studies were carried out using USP 30 dissolution apparatus type II  at 25 rpm in an Electrolab TDT-08L  dissolution tester,

The dissolution was conducted for a total period of 30 mint using 500ml simulated gastric fluid pH 1.2 at 37.0 ± 0.5ºC. Samples were withdrawn from each vessels at 5,10,15,20,25,30 from starting the amount of drug present was determined according to the USP monograph for Pantoprazole sodium tablets using UV at 294nm.

Full Factorial Design: A 3²randomized full factorial design was used in this study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations.

The ratio of Intra granulation Crosspovidone (X₁) and Amount of intra granulation Crosspovidone (X₂) in tablet were selected as independent variables. The time required to Disintegration of tablet (Y) was selected as dependent variables. The experimental design with corresponding formulation outline in Table 3.

TABLET 3: COMPOSITION OF TABLET

 Stability Studies: One selected formulation was packaged into ALU-ALU strip and kept for stability study at both room condition (30±2ºC / 65±5%RH) and accelerated condition (40±2ºC / 75±5 %RH) according to ICH Guideline [ICH Q1A (R2)].13 Samples were withdrawn at 0, 1st, 3rd and month for evaluation of physical condition, drug content and in vitro release and accelerated condition.

RESULT AND DISCUSSION

Compatibility study:

Drug-Excipient Interactions: The IR spectra of Formulation were compared with the standard spectrum of Pantoprazole sodium (Fig. 1). IR spectrum of Pantoprazole sodium was characterized by the absorption of -S=O group at 1037 cm⁻¹ & - C-F group at 1105. In spectra of Formulation, band was same absorption pattern as that of pure drug. Mentioned evidences thus lead to the conclusion that changes were not seen as there was no physical interaction between the drug and polymers.

FIUGRE NO.1 IR SPECTRUM OF DRUG AND FORMULATION

Preparation of Tablets: Tablets were prepared by using 2 independent variables as different concentrations of polymers by using 3² factorial design. In the preparation of tablet, Sodium bicarbonate, sodium carbonate, Crosspovidone, mannitol cab-o-sil, PVPK -30 were used. In this formulation, Mannitol was used as a filler and PVPK-30 as a binder. Sodium bicarbonate, sodium carbonate were generally used in pharmaceutical formulations as a source of carbon dioxide in effervescent tablets and granules. But here they were used to produce or maintain an alkaline pH in a preparation. Crosspovidone is used in a variety of pharmaceutical formulations; it is primarily used in solid-dosage forms. In tableting, Crosspovidone solutions are used superdisintegrating agent in wet-granulation processes.

Pre-compression characteristics for powder blend:           The  drug  content  was  found  to  be  optimum  in  all  the  cases.  The blend  of  the  optimized  formulation  containing  Pantoprazole sodium and tablet were evaluated  for  parameters like  angle  of  repose was  found  to  be 39.58 Bulk  density was  found  to  be  0.780 g/cm³ and  tapped density 1.0789 g/cm³. Hausner’s ratio was found to be 1.38 as shown in table 4.

TABLE 4: PRE-COMPRESSION PARAMETERS FOR POWDER BLEND

 Post-compression characteristics of tablets: In the present study, Pantoprazole sodium   Buffered   tablets were prepared using buffering agent such as sodium bicarbonate and sodium carbonate. The  hardness  of  the  tablets  was  found  to  be  between  16 to 18  kg/cm² and  friability was found to be below 1%  indicating good mechanical resistance as shown  in Table 5.

TABLE 5: POST-COMPRESSION PARAMETERS FOR TABLETS

In vitro dissolution studies: In the present study, pH of F 6 batch was found to be optimum and disintegration time is 40 sec. In-vitro drug release studies were done for the selected formulations from each batch. The drug release was found to show maximum drug release in case of F6 with 99.99% in 30 minutes as shown in table 6 and figure 2, 3.

Stability study: The stability  of  this  optimized  formulation  was  known  by  performing  stability  studies  for  three months at accelerated conditions of 30±2ºC /75%RH and  40°C±75 % RH on optimized  formulation. The formulation was found to be stable, with insignificant change in the hardness, disintegration time as shown in Table 7.

TABLE 6: IN VITRO DISSOLUTION STUDIES FOR FORMULATIONS F1-F9

FIGURE 2, 3: DISSOLUTION CHART FOR F1 TO F9

TABLE 7: STABILITY STUDY OF OPTIMIZED FORMULATION

 Factorial Design: Full factorial design was constructed to study the effect of the amount of Intra-granular Crosspovidone (X₁) and the amount of Extra-granular Crosspovidone (X₂) on the Disintegration of tablet. The dependent variables chosen were times required to disintegration of tablet within 40 seconds. A statistical model incorporating interactive and polynomial terms was utilized to evaluate the response where Y is the dependent variable, b₀ is the arithmetic mean response of the 9 runs, and b₀ is the estimated coefficient for the factor X₁ The main effects (X₁) and (X₂) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X₁, X₂) show how the response changes when 2 factors are changed simultaneously. The polynomial terms (X₁₂) and (X₂₂) are included to investigate nonlinearity. The statistical analysis of the factorial design batches was performed by multiple linear regression analysis using Microsoft Excel. The time of disintegration of tablets of each batch (F1 to F9) showed a wide variation the result is shown in figure 3. The fitted equations relating the response Disintegration time, shown in Equation1, and Equation 2, respectively;

Y = b₀ + b₁X₁ + b₂X₂ + b₁₂X₁X₂ + b₁₁X₁² + b₂₂X²₂,……………………………………….….(1)

Y=35.56-8.33X₁31X₂+20.00X₁X₂+31.67A²+41.67B²….. (2)

The values of the correlation coefficient indicate a good fit. The polynomial equation can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries, (i.e., positive or negative).

Figure 3 shows the plot of the amount of Intra-granular povidone (X₁) and amount of extra granular povidone (X₂) versus Disintegration time. The plot was drawn using Sigma Design Expert 8. The data demonstrate that both X1 and X2 affect the Disintegration time. It may also be concluded that the low level of X1 and the higher level of X2 favor the preparation to disintegration of tablets. The results in table indicate that batches F2, F3, F6, fulfill the above criteria. But batch F6 showed the best among all the batches.

FIGURE 3: RESPONSE SURFACE PLOT FOR DISINTEGRATION TIME 

CONCLUSION: In the present work, an attempt was made to develop Buffered tablet of Pantoprazole sodium by wet granulation method using sodium carbonate, sodium bicarbonate as a buffering agent, Crosspovidone as Super-disintegrants and mannitol as a diluents. Nine   formulations (F1-F9) were prepared, the optimum concentration were identified based on the disintegration time and in vitro drug release results.

Based on the observation, it was concluded that formulation F6 had obtain the pH 7 and disintegrated within 40 second, optimized combination due to its fast in vitro disintegration time. The  results  demonstrated  the  effective  use  of buffered tablet Pantoprazole  tablets  and  as  an  ideal  drug  release  formulation for treatment of peptic ulcers and different acidic conditions .

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    How to cite this article:

    Ratnaparkhi MP, Pongale PS and Chaudhari SP: Formulation & evaluation of buffered Pantoprazole sodium tablet. Int J Pharm Sci Res 2013; 4(12): 4708-14. doi: 10.13040/IJPSR. 0975-8232.4(12).4708-14

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