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ORIGINAL RESEARCH ARTICLE
Year : 2015  |  Volume : 5  |  Issue : 2  |  Page : 92-100

Formulation and characterization of sustained release dosage form of moisture sensitive drug


1 Department of Pharmaceutical Sciences, Saurashtra University, Rajkot, Gujarat, India
2 Shivam Pharmaceutical Studies and Research Center, Valasan, Gujarat, India

Date of Web Publication17-Mar-2015

Correspondence Address:
Prof. Priya Patel
Department of Pharmaceutical Sciences, Saurashtra University, Rajkot, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-973X.153385

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  Abstract 

Objective: The purpose of this study was to prepare sustained release tablet of moisture sensitive drug like Ranitidine Hydrochloride for treatment of gastroesophageal reflux disease along with the improvement of moisture stability to get better therapeutic efficacy. Materials and Methods: Pan coating technique was used for coating of the tablet. Film coating was done using Eudragit RLPO and Eugragit EPO as coating polymer. 3 2 full factorial design was applied for optimization purpose, and 9 runs were conducted. In that Eudragit RLPO and Eudragit EPO taken as an independent variables and moisture gain and Cummulative Drug Release (CDR) were taken as dependent variables. Drug and excipient compatibility was done using differential scanning calorimetry and Fourier transform infrared spectroscopy study. The tablet was evaluated for precompression parameter and all postcompression parameter. Stability study was carried out at room temperature (30°C ± 2°C/65% ± 5% relative humidity). Final formulation was compared with marketed formulation RANTEC 300. Result: Tablets were passing out all precompression parameter along with postcompression parameter. Stability study shows that the parameter such as hardness, friability, and dissolution are in the range. Hence, there is no significant change shown after stability study. Our final formulation was compared with marketed formulation RANTEC 300 and result demonstrates that our final formulation have less moisture gain and give release up to 12 h. Conclusion: The result of present study demonstrates that final formulation has less moisture gain and getting desired CDR for sustained release of drug. On the basis of all study, it was concluded that the tablet was coated by combination of Eudragit RLPO 10% and Eudragit EPO 10% give better result. This formation provided promising approach for the drug release up to 12 h for moisture sensitive drug like ranitidine hydrochloride.

Keywords: Gastroesophageal reflux disease, moisture stability, pan coating technique, ranitidine hydrochloride, sustained release tablet


How to cite this article:
Patel P, Dave A, Vasava A, Patel P. Formulation and characterization of sustained release dosage form of moisture sensitive drug. Int J Pharma Investig 2015;5:92-100

How to cite this URL:
Patel P, Dave A, Vasava A, Patel P. Formulation and characterization of sustained release dosage form of moisture sensitive drug. Int J Pharma Investig [serial online] 2015 [cited 2018 May 26];5:92-100. Available from: http://www.jpionline.org/text.asp?2015/5/2/92/153385


  Introduction Top


Gastroesophageal reflux disease (GERD) is serious form of gastroesophageal reflux (GER). GER occurs when the lower esophageal sphincter opens spontaneously for varying period or does not close properly, and stomach contains rise into esophagus. GER is also called acid reflux or acid regurgitation because digestive juices called acids rise with the food. The esophagus is a tube that carries food from the mouth to stomach. The lower esophageal sphincter is a ring of muscle at the bottom of esophagus that acts like a valve between esophagus and stomach. Persistent reflux that occurs more than twice a week is considered as GERD, and it is eventually lead to more serious health problems. [1]

Ranitidine hydrochloride is widely used in the treatment of GERD. Ranitidine hydrochloride is moisture sensitive, so it is necessary to maintain its stability. It is degraded in the presence of moisture because of its hygroscopic nature. Absorb moisture can lead to the catalytic reaction like hydrolysis and oxidation which leads to degradation of the drug and hence decrease in therapeutic efficacy of the drug. [2] Hence, it is necessary to protect ranitidine hydrochloride from moisture to avoid degradation of the drug and to improve the therapeutic efficacy of the drug. [3]

Various approaches are used to increase the moisture stability of the drug are as follow:

  1. Melt granulation
  2. Moisture resistance packaging
  3. Coating approach.


Melt granulation technique has the disadvantage like it requires high energy input and meltable binder used in this technique should have appropriate melting point in correlation. In this study, coating approach were selected and evaluated for moisture stability. Coating with nonaqueous polymeric coating deals with regulatory restrictions, cumbersome procedures, and pollution. Sugar coating has disadvantage of long processing time and high water influx during coating. [4] Hence, it was decided to select aqueous moisture barrier film coating system for the current study. For coating solution, combination of Eudragit RLPO and Eudragit EPO were selected. [5]


  Materials and Methods Top


Materials

Ranitidine hydrochloride was obtained as a gift sample from Orchev Pharma Pvt. Ltd. Rajkot, India. Microcrystalline cellulose, titanium dioxide, polyvinyl alcohol were obtained as a gift sample from Loba Chemicals, Mumbai, India. Eudragit RLPO and Eudragit EPO were also obtained as a gift sample from Evonik Degussa Industries, Mumbai, India. Glyceryl monostearate was obtained as a gift sample from JRS Pharma, USA.

Methods

Drug-excipient compatibility studies


Fourier transform infrared spectroscopy study


Drug and excipient compatibilities were analyzed by IR spectral studies. IR spectra of drug, polymer, drug polymer physical mixture and formulation were obtained using Fourier transform infrared spectroscopy (FT-IR) spectrophotometer. 1-2 mg of sample was gently triturated with KBr powder and compress into disc by applying pressure for 10 min in a hydraulic press. The disc was placed in the sample holder and scanned from 4000 cm−1 to 400 cm−1 . [6]

Differential scanning calorimetry study

Weigh the sample to the nearest 1-5 mg with the analytical balance. Record the weight. Use forceps to place the sample in the bottom half of an aluminum differential scanning calorimetry pan. Use forceps to place the lid on top of your sample. Place the sample into sample encapsulating press. Align the sample in the encapsulating press, and press down on the handle to seal aluminum pan. Crimp an empty aluminum pan and lid. You are using the empty pan as a reference sample, and scanning speed was 10°C/min over temperature range of 40-250°C. [6]

Loss on drying studies

The determination of the amount of moisture or volatile compound adsorbed by the surface of fumed oxides is obtained by drying the sample in an oven for 3 h at 60°C.

Place the crucible with tilted lid in the oven at 105°C for 2 h. Place the crucible in desiccator and allow cooling for 30 min. Weigh a prepared crucible with lid and record weight (Wtare). Place approx. 1 g of sample into the crucible and tap carefully, record the weight (Wstart). Place the crucible with lid in drying oven for 3 h. After 3 h time period, take crucible out of the oven and being careful not to create turbulence. Replace the lid to the closed position. Place the crucible in a desiccator and allow cooling for 30 min. Reweigh the crucible with closed lid and record as (Wdry) and calculate the % loss on drying by using formula: [7]

%LOD = Wstart - Wdry/Wstart - Wtare × 100

Moisture uptake study

Moisture uptake study was carried out at three different level of 22, 57, and 75% relative humidity (RH). A controlled humidity environment was produced using laboratory desiccators containing a saturated solution of various salts. Potassium acetate, sodium bromide, and sodium chloride were used to provide 22, 57, and 75% RH, respectively, at 25°C. %RH was measured by hygrometer. [8]

Preparation of core tablet

Weigh all the material accurately as per the formula given below in [Table 1]. Melt the glyceryl nitrate in china dish and allow to liquefy the material. Add accurate amount of drug and mix well. Allow the mixture to cool. Add microcrystalline cellulose and remaining excipient into dish, mix well and prepare lump mass using PVP K-30 as a binder and pass through sieve and allow granules to dry. After drying, again pass through sieve and compress granules to prepare tablets. [9]
Table 1: Formulation table of tablet


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Optimization of formulation using 3 2 full factorial design

A 3 2 full factorial design was employed to systemically study the joint influence of the effect of independent variables on dependent variables. Variables are depicted in below [Table 2]. In this study, 2 factors are evaluated, each at 3 levels, and experimental trials are performed at all 9 possible batches. On the basis of preliminary trial batches Eudragit RLPO (X 1 ) and Eudragit (X 2 ) were selected as independent variables and moisture gain (Y1) and Cummulative Drug Release (CDR) (Y2) were selected as dependent variables. [9] 3 2 full factorial design with coded value given in [Table 3] for coating of core tablet.
Table 2: Variables and their level in 3 2 design


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Table 3: Formulation as per 3 2 full factorial design with coded value (all value in mg)


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  Evaluation Parameter Top


Precompression parameter

The powder mixture is evaluated for precompression parameter such as angle of repose, bulk density (BD), tapped density (TD), Carr's index (CI), and Hausner ratio (HR).

Angle of repose

The angle of repose was determined by funnel method. The accurately weigh granules were taken in funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the heap of the blends. An accurately weighed sample of the powder was allowed to pass through the funnel freely on to a flat surface. The height (h) and radius (r) of the powder cone were measured and the angle of repose (θ) calculated using formula as follow:

θ = tan−1 (h/r).

Bulk density

Bulk density is determined by pouring powder into a graduated cylinder via a large funnel and measure the volume and weight.

Tapped density

A known weight of the powder was transferred to a measuring cylinder, tapped manually 100 times, and the ratio of weight to volume of the powder gives the TD.

Carr's index

The CI of powder was measured by using below equation:

CI = (TD - BD)/TD×100.

Hausner ratio

Tapped and BD were determined and HR was calculated as follow:

HR = TD/BD.

Postcompression parameter

Prepared tablet were evaluated for postcompression parameter such as tablet thickness, hardness, diameter, friability, weight variation test, and percentage drug content.

Tablet thickness

The thickness of the tablets was determined using Vernier caliper. Five tablets were used, and average values were calculated.

Tablet diameter

The diameter of the tablet was measured using Vernier caliper.

Tablet hardness

Hardness indicates the ability of the tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm 2 .Three tablets were randomly picked, and hardness of the tablets was determined.

Friability

The friability of tablets was determined using Roche friabilator. It is expressed in percentage (%). Ten tablets were initially weighed and transferred into friabilator. The friabilator was operated at 25 rpm for 4 min. The tablets were weighed again. The %friability was then calculated by:



% Friability of tablets <1% are considered acceptable.

Weight variation test

To study weight variation 20 tablets of the formulation were weighed using a digital balance and the test was performed according to the official method. Twenty tablets were selected randomly and weighed individually to check for weight variation. Take average weight of 20 tablets. No >2 tablet deviate from the average weight.

Drug content

This test is performed to check the uniformity of amount of active medicament in the whole batch. Totally, 10 tablets were selected randomly, weighed a tritured. A quantity of triturate equivalent to 90 mg of ranitidine hydrochloride was dissolved in 0.1 N HCl in 100 ml volumetric flask. The solution formed was suitably diluted to get 10 μg/ml, and the absorbance was measured at 325 nm using 0.1 N HCl as a blank. Amount of drug present in one tablet was calculated.

In vitro dissolution study

The release rate of ranitidine hydrochloride tablet was determined using USP apparatus type 2 (USP rotating paddle method). The dissolution test was performed during 900 ml 0.1 N HCl (pH-1.2) at 37°C at 100 rpm. 5 samples were withdrawn hourly for 2 h and replaced with fresh medium. After 2 h, dissolution was performed in 900 ml of pH 6.8 phosphate buffer for 12 h. The sample was filtered through Whattman filter paper No. 41. After that, absorbance was taken at 325 nm by ultraviolet (UV) spectrophotometer using 0.1 N HCL as a blank for 2 h sampling and 12 h sampling take 6.8 pH buffer as a blank. [10]

Moisture uptake study

Uncoated and coated tablet was taken into 2 different glass containers and spread uniformly in container. The container was placed in constant humidity (75% RH) and at room temperature. The weight increase due to moisture absorption was measured by taking weight at different intervals such as 1, 2, 3, 4, 5, 6, 7, 20, 32, 44, 56, 68, and 92 h. [3]

Stability study

The purpose of stability study is to provide evidence on how quality of the drug substance or a drug product varies with time under the influence of environmental factors such as temperature, humidity, and light. The storage condition used for stability study was room temperature (30°C ± 2°C/65% ± 5% RH). Tablets of optimized formulation were packed in aluminum foil and kept in plastic zip bags for 30 days. After this time period, tablets were analyzed for parameter such as moisture uptake study, weight variation, hardness, friability, and in vitro dissolution. [11],[12]

Comparison with marketed formulation

Moisture uptake study


Coated and marketed tablet (RANTEC 300) was taken into 2 different glass containers and spread uniformly in container. The container was placed in constant humidity (75% RH) and at room temperature. The weight increase due to moisture absorption was measured by taking weight at different intervals such as 1, 2, 3, 4, 5, 6, 7, 20, 32, 44, 56, 68, and 92 h. [7]

In vitro dissolution study

The release rate of Prepared Ranitidine Hydrochloride tablet and marketed tablet (RANTEC 300) was determined using USP apparatus type 2 (USP rotating paddle method). The dissolution test was performed during 900 ml 0.1 N HCl (pH - 1.2) at 37°C at 100 rpm. 5 samples were withdrawn hourly for 2 h and replaced with fresh medium. After 2 h, dissolution was performed in 900 ml of pH - 6.8 phosphate buffer for 12 h. The sample was filtered through Whattman filter paper No. 41. After that absorbance was taken at 325 nm by UV spectrophotometer using 0.1 N HCL as a blank for 2 h sampling and 12 h sampling take 6.8 pH buffer as a blank. [7]


  Result and Discussion Top


Drug-excipient compatibility study

Fourier transform infrared spectroscopy study


The FT-IR spectra of pure drug, excipient, and physical mixture (drug + excipient) are shown in below [Figure 1]. All principal peak of ranitidine hydrochloride were found in the physical mixture which indicates that there was no interaction between drug and excipient.
Figure 1: Fourier transform infrared spectroscopy spectra of Ranitidine Hydrochloride, Microcrystalline cellulose, Glyceryl monostearate, Eudragit RLPO, Eudragit EPO and physical mixture


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Differential scanning calorimetry study

As shown in [Figure 2], the endothermic peak of Ranitidine Hydrochloride was observed at 146.19°C and this peak is also observed in the final formulation. It indicates that there was no interaction between drug and excipient.
Figure 2: Differential scanning calorimetry thermograph of final formulation Loss on drying study


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Loss on drying study

Not >0.75% determined on 1 g by drying in an oven at 60°C at a pressure not exceeding 2.75 kPa for 3 h.

  • Wstart = 40.528 mg
  • Wtare = 39.528
  • Wdry = 40.451
  • %LOD = Wstart - Wdry/Wstart - Wtare × 100
  • %LOD =7.7%.


From the result, we can conclude that the drug can absorb the moisture up to 7.7% of its weight. Hence, the drug cannot be able to full fill the criteria.

Moisture uptake study

[Figure 3] shows that moisture uptake profile for 1 g ranitidine hydrochloride at three different levels of RH such as 75, 57, and 22% RH. The figure indicates that Ranitidine Hydrochloride exposed to high RH, absorbed maximum amount of moisture.
Figure 3: Moisture uptake study of Ranitidine at various %RH


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  Optimization of Formulation Using 3 2 Full Factorial Designs Top


The 3 2 full factorial design was used to optimize the amount of Eudragit RLPO and Eudragit EPO for sustained release tablet of ranitidine hydrochloride. The amount of coating material was selected on the basis of the preliminary study. 3 2 full factorial designs was used and prepared total 9 batches (F1 to F9). In those two factors, amount of Eudragit RLPO (X 1 ) and the amount of Eudragit EPO (X 2 ) were used, and all two factors had three levels (0, −1 and 1). Then all batches are evaluated by moisture uptake study by at 75% RH and at room temperature and dissolution of all batches are carried out for 12 h to optimize the best batch.


  Regression Analysis Top


Effect of independent variable on moisture gain

Moisture gain (Y 1 ) = 20.89 − 1.83 X 1 − 3.33 X 2 + 0.25 X 1 X 2 +0.17 X 1 2 − 0.33 X 2 .

Below [Table 4] depicted full and reduced model for moisture gain. From [Table 4], P values are in the range so we can conclude that all the data are significant.
Table 4: Regression coefficients and polynomial equations for moisture gain


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In [Figure 4], the multiple regression analysis reveals that the increase in the concentration of Eudragit RLPO and Eudragit EPO leads to decrease in moisture gain because the coefficient b 1 and b 2 bears a negative sign. When higher percentage of Eudragit RLPO and Eudragit EPO is used, the more moisture proof tablet was produced.
Figure 4: Contour plot showing effect of variables on moisture gain


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In [Figure 5], Response surface plot shows that as the concentration of the Eudragit RLPO (X 1 ) and Eudragit EPO (X 2 ) increases leads to decreases in moisture gain (Y 1 ).
Figure 5: Response surface plot showing effect of variables on moisture gain


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Effect of independent variable on Cumulative Drug Release

CDR (Y 2 ) = 78.98 − 3.86 X 1 + 7.58 X 2 + 0.057 X 1 X 2 + 0.81 X1 2 − 1.07 X2 2 .

Below [Table 6] depicted full and reduced model for cummulative drug release. From the table, P values are in the range so we can conclude that all the data are significant.

In [Figure 6], the multiple regression analysis reveals that the increase in the concentration of Eudragit RLPO and Eudragit EPO leads to decrease in CDR because the coefficient b 1 and b 2 bears a negative sign. When higher percentage of Eudragit RLPO and Eudragit EPO is used we get the CDR for a longer time. Hence, we get more sustained release effect of the drug as we increase the concentration of the drug.
Figure 6: Counter plot showing effect of variables on competent Person's Report


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Model validation using ANOVA for both Moisture gain or cumulative drug release data depicted in [Table 5] and [Table 7] respectively. It shows that Fcal < Ftab Hence model is validated for both moisturegain as well as Cummulative Drug Release.
Table 5: Model validation using ANOVA for moisture gain


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Table 6: Regression coefficients and polynomial equations for CDR


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Table 7: Model validation using ANOVA for CDR


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In [Figure 7], Response surface plot shows that as the concentration of the Eudragit RLPO (X 1 ) and Eudragit EPO (X 2 ) increases leads to decreases in CDR (Y 2 ).
Figure 7: Response surface plot showing effect of variables on Cumulative Drug Release


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In [Figure 8], overlay plot showing that two different checkpoint batch and [Table 8] mention the formula of check point batch was selected for the validation of the design.
Figure 8: Overlay plot showing combined effects of factors X 1 and X 2 on Y 1 , Y 2


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Table 8: Formula for check point batch


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The % relative error for the checkpoint batch was in the range of 5.04-4.54 which is <8%, so statistically acceptable. It was concluded that the experimental value and predictive value show good agreement between each other.

Evaluation parameter

Precompression parameter


From the precompression parameter of all batches shown in [Table 9], angle of repose is within the range and shows that good flow property. CI and HR also in the range and shows good flow property.
Table 9: Precompression parameter


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All post compressional parameters like thickness, Diameter, Hardness, Weight variation, Friability and % Drug content depicted in [Table 10]. All parameters complies within Range, Drug content complies between 98.28 % to 102.72%.
Table 10: Postcompression parameter


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Postcompression parameter

In vitro dissolution of 3 2 batches


From [Figure 9], dissolution data show that F6 batch gives 86.03% release of the drug at 12 h and other batches gives less release as compared to the F6 batch because it contains 10% Eudragit RLPO and Eudragit EPO 10% while other batches gives less release of the drugs because of the higher amount of the polymer.
Figure 9: Dissolution profile of all 3 2 design batches


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Moisture uptake study

Moisture uptake study was carried out at 75% RH for 15 days and result shows in [Figure 10] that F7 batch has less moisture gain because it contains 12% of Eudragit RLPO and 6% Eudragit EPO and all other batches show higher moisture gain than F7 batches it contains higher amount of Eudragit RLPO and Eudragit EPO.
Figure 10: Moisture uptake study of all 3 2 batches at 75% RH


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Moisture uptake study at room temperature

Moisture uptake study was carried out at room temperature for 8 days. In [Figure 11], that F8 batch has less moisture gain because it contains 12% of Eudragit RLPO and 10% Eudragit EPO and all other batches show higher moisture gain than F8 batches it contains higher amount of Eudragit RLPO and Eudragit EPO.
Figure 11: Moisture uptake study of all 3 2 batches at room temperature


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Stability study

Result of stability study shown in [Table 11] and [Figure 12], it was observed that the prepared sustained release tablet was stable for 1-month at (30°C ± 2°C/65% ± 5% RH). No significant change was found in the tablet parameter such as weight variation, friability, hardness, drug content, and in vitro dissolution.
Figure 12: In vitro dissolution of F6 batch before and after stability study


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Table 11: Stability study of batch F6


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Comparison with marketed formulation

Comparison was carried out with marketed formulation RANTEC 300 and final formulation by dissolution and moisture uptake study.

Dissolution study

Comparison with marketed and final formulation was performed and from result show in [Figure 13] that marketed formulation gives release up to 8 h and our final formulation gives release up to 12 h.
Figure 13: Dissolution study comparison with marketed formulation


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Moisture uptake study

Moisture uptake study of final and marketed formulation was carried out at 75% RH and result shown in [Figure 14] that our final formulation gain less moisture as compared to marketed formulation.
Figure 14: Moisture uptake study comparison with marketed formulation


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  Conclusion Top


The result of the present study demonstrates moisture gain was decreased and getting desired CDR for sustained release tablet. Therefore, this formulation provides better treatment for Gastric esophageal Reflux diseases along with the improvement of moisture stability to get better therapeutic efficacy. Thus, on the basis of all the studies, it was concluded that the batch having Eudragit RLPO 10% and Eudragit 10% having less than moisture gain and give drug release up to 12 h. Hence, this formulation composition provided promising approach for the drug release up to 12 h for moisture sensitive drug like ranitidine hydrochloride.


  Acknowledgment Top


Author wishes to thank Orchev Pharma Pvt. Ltd. Rajkot, India for gift sample of Ranitidine Hydrochloride and Evonik Degussa Industries Mumbai, India for providing gift sample of Eudragit polymer. Author also wishes to thank Head of Department of Pharmaceutical Science, Saurashtra University, Rajkot for providing necessary facilities.

 
  References Top

1.
Available from: http://www.en.wikipedia.org/wiki/gastroesophageal reflux disease. [Last assessed on 2014 Oct 19]  Back to cited text no. 1
    
2.
British Pharmacopoeia. Properties of Ranitidine Hydrochloride. 2002;1:1481-2.  Back to cited text no. 2
    
3.
Islam SM, Hossain A, Kabir H, Kabir S, Hossain MK. Study of moisture absorption by ranitidine hydrochloride: Effect of % RH, excipients, dosage forms and packing materials. Dhaka Univ J Pharm Sci 2008;7:59-64.  Back to cited text no. 3
    
4.
Bley O, Siepmann J, Bodmeier R. Protection of moisture-sensitive drugs with aqueous polymer coatings: Importance of coating and curing conditions. Int J Pharm 2009 13;378:59-65.  Back to cited text no. 4
    
5.
Thakre S, Bhople A, Deshpande S, Thakre A, Patild S, Shekh T. Optimization and validation of process for formulation and coating of ranitidine. World J Pharm Res 2013;2:382-409.  Back to cited text no. 5
    
6.
Doshi MM. Controlled release formulations of Ranitidine, Patent No. US5853756 A; 1995.  Back to cited text no. 6
    
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Franz RM. Film coated tablet of ranitidine HCl Patent No. US4880636 A; 1989.  Back to cited text no. 7
    
8.
Yadav NR, Ansari IK. Moisture barrier application of selected commercial coating systems. Int J Pharm Res Dev 2013;5:162-70.  Back to cited text no. 8
    
9.
Khan S, Giradkar P, Yeole P. Formulation design of ranitidine hydrochloride to reduce its moisture absorption characteristics. PDA J Pharm Sci Technol 2009;63:226-33.  Back to cited text no. 9
    
10.
Tadros MI. Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development, optimization and in vitro-in vivo evaluation in healthy human volunteers. Eur J Pharm Biopharm 2010;74:332-9.  Back to cited text no. 10
    
11.
Zahn M. Global stability practices. In: Huynh-Ba K, editor. Handbook of Stability Testing in Pharmaceutical Development. USA: Springer; 2009. p. 90.  Back to cited text no. 11
    
12.
Nakabayashi K, Shimamoto T, Mima H. Stability of packaged solid dosage forms. II. Shelf-life prediction for packaged sugar-coated tablets liable to moisture and heat damage. Chem Pharm Bull (Tokyo) 1980;28:1099-106.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]


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