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ORIGINAL ARTICLE
Year : 2011  |  Volume : 2  |  Issue : 2  |  Page : 73-77  

Antacids incorporation in immediate release tablets failed to improve the stability of omeprazole in acidic media


1 Department of Pharmaceutics and Pharmaceutical Technology, Hemchandracharya North Gujarat University, Mehsana, Gujarat, India
2 Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Hemchandracharya North Gujarat University, Mehsana, Gujarat, India

Date of Web Publication25-Nov-2011

Correspondence Address:
H V Chavda
Department of Pharmaceutics and Pharmaceutical Technology, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat - 384 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-9234.90217

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   Abstract 

Background: The stability of omeprazole (OMZ) decreases in acidic medium. In this investigation, attempts have been made to develop oral tablet containing antacids/buffers to increase the pH of dissolution media for certain time. Materials and Methods: Tablet formulations were prepared by the direct compression technique. For the selection of superdisintegrant, Croscarmellose sodium, used initially was replaced with other superdisintegrants. The prepared tablets were evaluated for hardness, weight variation, thickness, friability, drug content, disintegration time and in vitro drug release studies. During the in vitro drug release studies, the pH of dissolution media was measured. Results and Discussion: All batches showed very short disintegration time, within 0.5-2 min except F1 and S5. Batch F7 was able to provide the immediate drug release. The study showed that the incorporation of antacid improved the pH of dissolution media, but failed to maintain it. Even though the high quantities of antacids were incorporated; the stability of drug in media was not improved. Other superdisintegrants did not show any significant changes in drug release or disintegration time. Bath F7 was stable for the period of 6 months at 40 o C / 75 %RH. Conclusions: Incorporation of higher quantities of antacids failed to retain the stability of OMZ in acidic media.

Keywords: Antacids, immediate release tablets, omeprazole, superdisintegrant, superporous hydrogel particles


How to cite this article:
Chavda H V, Chaudhary T M, Patel C N. Antacids incorporation in immediate release tablets failed to improve the stability of omeprazole in acidic media. J Pharm Negative Results 2011;2:73-7

How to cite this URL:
Chavda H V, Chaudhary T M, Patel C N. Antacids incorporation in immediate release tablets failed to improve the stability of omeprazole in acidic media. J Pharm Negative Results [serial online] 2011 [cited 2019 Nov 20];2:73-7. Available from: http://www.pnrjournal.com/text.asp?2011/2/2/73/90217


   Introduction Top


Omeprazole (OMZ) is a potent inhibitor of gastric acid secretion by selectively interacting and inhibiting the gastric parietal cell proton pump. [1] OMZ was widely used in the treatment of active duodenal ulcer, active benign gastric ulcer, gastroesophageal reflux disease, erosive esophagitis and other pathological hypersecretory conditions. [2] The drawbacks are mainly related to the physicochemical instability to heat, light and acidic media, even with coated formulations. Moreover the low aqueous solubility of OMZ, ~0.4% at 25 o C, is responsible for small dissolution rates and so low bioavailability. [3] The stability of OMZ decreases in acidic medium, when it comes in contact of acidic medium leads a significant degradation of the drug and hence reduced bioavailability. [4],[5],[6] Due to its low bioavailability, short biological half life [7] and hepatic first pass metabolism, various oral formulation of OMZ such as enteric-coated granules [8],[9] and tablets [10],[11] have been developed with a subsequent 40% increase in oral bioavailability [12] of OMZ but have a wide individual variation of plasma concentration in human. [8],[9],[10],[11] To overcome this problem, alternative dosage forms such as rectal suppository [13] and buccal adhesive tablets [14] were also developed. But all the dosage form of OMZ gives only systemic effect.

In this investigation, attempts have been made to develop oral tablet containing antacids/buffers to increase the pH of dissolution media for certain time which provides stability to the drug temporarily, meanwhile the drug gets released.


   Materials and Methods Top


Materials

OMZ was generous gift from Cadila Pharmaceuticals Pvt Ltd., Ahmedabad, India. Sodium bicarbonate, magnesium hydroxide, croscarmellose sodium microcrystalline cellulose, acrylic acid, N,N'-Methylene-bis-acrylamide, Span 80, ammonium persulphate, and N,N,N',N'-Tetramethylethylenediamine were purchased from SD Fine Chem. Ltd, Mumbai, India. Acrylamide was obtained from Burgoyne Burbidges and Co. Pvt. Ltd., Mumbai, India. Double distilled water and 0.1N HCl were prepared in laboratory. All other chemicals used were of analytical grade and used as obtained.

Preparation of immediate release tablets

Tablet formulations were prepared by the direct compression technique. The drug and additives were passed through 80# sieve, and mixed thoroughly by geometric mixing. Croscarmellose sodium was used as a superdisintegrant. Talc and magnesium stearate were then added as glidant and lubricant, respectively. The blend was compressed using flat-faced round-shaped punch (11 mm diameter) for tablets with weight 700 mg (F1-F3) and deep concave capsule shaped punch for tablets with weight more than 700 mg (F4-F9) using a rotary tablet compression machine (Rimek, Ahmedabad, India). Each tablet contained 40 mg OMZ. The composition for single tablet is shown in [Table 1].
Table 1: Composition for single immediate release Omeprazole tablet


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Batch F1-F9 was prepared to select best immediate release formulation. Thereafter for the selection of superdisintegrant that provides fast immediate release, the superdisintegrant, Croscarmellose sodium, used in selected batch from F1-F9 was replaced with other superdisintegrants, as shown in [Table 2] (Batch S1-S5). Other superdisintegrants used were sodium starch glycolate, starch 1500, cross povidone and superporous hydrogel particles. Superporous hydrogel particles were prepared as reported in our previous studies. [15],[16],[17] Batch S5 was prepared as a control batch without addition of superdisintegrant.
Table 2: Composition for single immediate release Omeprazole tablet containing different superdisintegrants


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Evaluation of tablets

The prepared tablets were evaluated for hardness, weight variation, thickness, friability, drug content and disintegration time. For each formulation, the hardness (5 tablets) and friability (10 tablets) of OMZ tablets were determined using the Pfizer type hardness tester (Janki Impex, Ahmedabad) and the Roche friabilator (Electrolab, India), respectively. The thickness of the tablets was determined using a thickness gauge (Mitutoyo, Japan). Five tablets from each batch were used, and average values were calculated. To study weight variation 20 tablets of each formulation were weighed and the test was performed according to Indian Pharmacopoeia 2007. For estimation of drug content, 10 tablets were crushed, and the aliquots of powder equivalent to 100 mg of drug were extracted in 0.1N HCL. The solutions were passed through 0.45-μm membrane filter and after suitable dilutions the absorbance was measured at 302 nm using the UV-1800 UV/Vis Double Beam Spectrophotometer (Shimadzu, Japan). The disintegration time test was carried out on the 6 tablets using the Disintegration Test Apparatus USP (Electrolab, India). Distilled water and 0.1N HCL at 37 o C ± 2 o C were used as disintegration media. The time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

In vitro drug release studies

The release rate of OMZ from immediate release tablet (n = 3) was determined using USP XXIV Dissolution Testing Apparatus II (dissolution tester model TDT-08 L, Electrolab, India). The dissolution test was performed using 900ml of 0.1N HCL at 37 ± 0.5 o C and 100 rpm. At the regular time interval of 5 min samples (5 ml) were withdrawn from the dissolution apparatus for 1 hr; and the fluid removed was replaced with fresh dissolution medium, immediately. The samples were filtered and diluted to suitable concentrations with 0.1N HCL. The absorbance of these solutions was measured at 302 nm using UV-1800 UV/Vis Double Beam Spectrophotometer. The cumulative percentage of drug release was calculated using an equation obtained from a standard curve.

pH check for dissolution media

OMZ is unstable at acidic pH. [4],[5],[6] If the pH of dissolution media is raised beyond 4 the stability of drug can be improved up to certain extent. And so, in prepared tablets antacids were used to maintain the pH of dissolution media above 1.2. During the in vitro drug release studies, the pH of dissolution media was also measured at the time of each sampling up to 45 min.

Stability studies

The optimized batch was kept in airtight containers and stored in stability chamber (TH-90S, Thermolab, India) at 40 o C/75%RH for 6 months. [18] Results for in vitro dissolution studies obtained after 6 months were compared with the data obtained at the time of preparation. The similarity factor (f2 ) was applied to study the effect of storage on optimized batch. The f2 value is calculated from the equation 1:




   Results and Discussion Top


Preparation of immediate release tablets

To accommodate the different weights of tablets viz. 700, 950 and 1200 mg, tablets with two shapes were prepared by the direct compression technique. All tablets with weight 700 mg were compressed using flat-faced round-shaped punch. And tablets with weight 950 mg and 1200 mg were compressed using deep concave capsule-shaped punch.

Evaluation of tablets

The evaluation parameters for tablets are shown in [Table 3]. The thickness of the tablets ranged from 4.02 ± 0.03 to 6.23 ± 0.04 mm. The hardness and percentage friability of the tablets of all batches ranged from 4.0 ± 0.21 to 4.2 ± 0.16 kg/cm 2 and 0.74 ± 0.04 to 0.89 ± 0.05, respectively. For weight variation test, the average percentage deviation of 20 tablets of each formulation was less than ± 5%. Drug content was found to be uniform among different batches of the tablets and ranged from 98.38 ± 0.04 to 99.65 ± 0.05. Disintegration time was ranged from 30 ± 3 to 106 ± 7 and 58 ± 4 to 211 ± 9 second in distilled water and 0.1N HCL, respectively. Batch F9 was found to be fast disintegrating formulation. Disintegration time was on of the important parameters in case of immediate release formulation. All batches showed very short disintegration time, within 0.5-2 min except F1 and S5.
Table 3: Evaluation parameters for Omeprazole matrix tablets


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In vitro drug release studies

The drug release profiles (n=3) from batches containing different proportions of antacids, and different superdisintegrants are shown in [Figure 1] and [Figure 2], respectively. Although Batch F9 was fast disintegrating, however, Batch F7 was able to provide the immediate drug release as was able to release more than 90% of drug within 40 min. Except Batch F5 and F9, all other batches showed immediate release and release more than 99% of OMZ within 60 min.
Figure 1: Drug release profiles from immediate release Omeprazole tablets (n = 3)

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Figure 2: Drug-release profiles from immediate release Omeprazole tablets containing different superdisintegrants (n = 3)

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Here an attempt was made for the selection of superdisintegrant that provides fast immediate release. The superdisintegrant, Croscarmellose sodium, used in Batch F7 was replaced with other superdisintegrants. Other superdisintegrants viz. cross povidone, sodium starch glycolate, starch 1500, and superporous hydrogel particles [15] were not shown any significant changes in drug release or disintegration time. The presence of superdisintegrant provided less disintegration time in distilled water and 0.1N HCL compared to control batch S5. Compared to commonly used superdisintegrants, superporous hydrogel particles, newly tried and recently reported, played an equivalent and important role as a superdisintegrant. The superporous hydrogel particles, having a high tendency of swelling and hence impart quick breakage of tablets as the dissolution media penetrates, may be other option for a superdisintegrant for future formulations.

pH check for dissolution media

It is reported that OMZ degrades very rapidly in aqueous solutions at low pH values. [4],[5],[6] In aqueous solutions, the degradation rate proceeds with a half life of less than 10 min at pH values below 4, 18 h at pH 6.5 and about 300 days at pH 11. [19] The process of OMZ degradation is acid catalyzed. An increase in the pH values decreases the rate of degradation. In this formulation this stability problem was tried to minimize/overcome by addition of buffers/antacids in the formulation which help in providing and maintaining the pH of dissolution media beyond 4. Here immediate formulation was tried, so the drug was immediately released in this media and hence might be have less chance of degradation.

[Table 4] shows the pH of dissolution media at the time of each sampling up to 45 min. Incorporation of antacids, sodium bicarbonate and magnesium hydroxide, helped in raising the pH of dissolution media beyond 1.2 for all batches. However, the antacids failed to raise it beyond 4, which was necessary to improve the stability of drug in media. As the disintegration of tablet proceeded, the antacids were released in dissolution media which raised the pH beyond 1.2 initially, but afterwards as the time passed it gets lowered, but still beyond 1.2. Antacids were able to raise the pH but failed to maintain it. Different proportions of antacids changes the pH of dissolution media, but was not able to provide significant difference.
Table 4: Average pH of dissolution media at the time of each sampling


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Stability studies

Batch F7 was selected for reference in order to calculate similarity factor (f2 ). After 6 months of applied stability conditions Batch F7 showed the similarity factor 83.64. The stability studies showed that there were no significant changes observed for in vitro dissolution studies after 6 months. Bath F7 was stable for the period of 6 months at 40 o C / 75%RH.


   Conclusions Top


The study showed that the incorporation of antacid improved the pH of dissolution media, but failed to maintain it. Even though the high quantities of antacids were incorporated; the stability of drug in media was not improved. Croscarmellose sodium was the best suited superdisintegrant suitable for the immediate release OMZ tablet. Replacement of croscarmellose sodium with the other superdisintegrants did not show any improvement in drug release. From this study, both the parameters dissolution and disintegration time are very important and play an important role in the immediate release formulations.


   Acknowledgments Top


The authors thankfully acknowledge the help of Cadila Healthcare Ltd, Ahmedabad, Gujarat, for providing gift sample of OMZ.

 
   References Top

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2.Martindale-The complete drug reference. In: Sweetman SC, editor. London: Pharmaceutical Press; 2005.   Back to cited text no. 2
    
3.Arias MJ, Moyano JR, Mun˜oz P, Gine´s JM, Justo A, Giordano F. Study of omeprazole-c- cyclodextrin complexation in the solid state. Drug Dev Ind Pharm 2000;26:253-9.   Back to cited text no. 3
    
4.Davidson AG, McCallum A. A survey of the stability of omeprazole product from 13 countries. Drug Dev Ind Pharm 1996;22;1173-85.  Back to cited text no. 4
    
5.Mathew M, Gupta VD, Bailey ER. Stability of omeprazole solutions at various pH values as determined by high performance liquid chromatography. Drug Dev Ind Pharm 1995;21:965-71.  Back to cited text no. 5
    
6.Jee UK, Lee GW, Jeon UJ. Stability and dissolution enhancement of omeprazole by pharmaceutical technology. Kor Pharm Sci 1992;22:281-2.   Back to cited text no. 6
    
7.Hoogerwerf WA, Pasricha PJ. Agents used for control of gastric acidity and treatment of peptic ulcers and gastroesophageal reflux disease. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw Hill; 1996. p. 1007- 9.   Back to cited text no. 7
    
8.Andersson T, Bergstrand R, Cederberg C. Influence of acid secretory status on absorption of omeprazole from enteric supcoated granules. Br J Clin Pharmacol 1991;31:275-8.   Back to cited text no. 8
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9.Pilbrant A. Development of an oral formulation of omeprazole. Can J Gastroenterol 1985;20:113-9.   Back to cited text no. 9
    
10.Kim CK, Jeong EJ, Lee EJ, Shin HJ, Lee WK. Bioequivalence of enteric coated omeprazole products. J Korean Pharm Sci 1993;23:41-9.   Back to cited text no. 10
    
11.Thomson AB, Kirdeikis P, Lastiwka R, Rohss K, Sinclair P, Olofsson B. Pharmacokinetics and pharmacodynamics during treatment with the omeprazole 20 mg enteric coated tablet and 20 mg capsule in asymptomatic duodenal ulcer patients. Can J Gastroenterol 1997;11:657-60.   Back to cited text no. 11
    
12.Choi HG, Jung JH, Yong CS, Rhee CD, Lee MK, Han JH, et al. Formulation and in vivo evaluation of omeprazole buccal adhesive tablet. J Control Release 2000;68:405-12.   Back to cited text no. 12
    
13.Choi MK, Chung SJ, Shim CK. Rectal absorption of omeprazole from suppository in humans. J Pharm Sci 1996;85:893-4.   Back to cited text no. 13
    
14.Choi HG, Kim CK. Development of omeprazole buccal adhesive tablets with stability enhancement in human saliva. J Control Release 2000;68:397-404.  Back to cited text no. 14
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15.Chavda HV, Patel CN, Prajapati ST, Patel CV. A Newer Formulation Approach Based on Superporous Hydrogel Particles for Gastroretentive Drug-Delivery System: Preparation and In Vitro Evaluation. Inventi Impact: NDDS [serial on the Internet]. 2010 [cited 2010 July 15]; 1: Inventi:Med Chem/70/10. Available from: http://www.inventi.in/Impact/NDDS/CurrentIssue.aspx?Vol=2010&Issue=1&From=Past  Back to cited text no. 15
    
16.Chavda HV, Patel CN, Karen HD. Preparation and characterization of chitosan-based superporous hydrogel composite. J Young Pharm 2009;1:199-204.  Back to cited text no. 16
    
17.Chavda HV, Patel CN. Preparation and characterization of swellable polymer-based superporous hydrogel composite of poly (Acrylamide-co-Acrylic Acid). Trends Biomat Artif Organs 2010;24:83-9.  Back to cited text no. 17
    
18.Mathews BR. Regulatory aspects of stability testing in Europe. Drug Dev Ind Pharm 1999;25:831-56.  Back to cited text no. 18
    
19.Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole. Scand J Gastroenterol 1985;20;113-20.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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