Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243
Research Article ISSN: 0974-6943
Available online through www.jprsolutions.info
Formulation and evaluation of ranitidine loaded eudragit rs100 microspheres Gowri. R*, Narayanan. N Jaya College of Pharmacy, Thiruninravur – 602 024, Chennai, TamilNadu, India. Received on:22-02-2015; Revised on: 14-03-2015; Accepted on:18-04-2015 ABSTRACT BACKGROUND: Microencapsulation is an innovative process by which small particles like solids and liquids are entrapped in a uniform shell. Microencapsulation technique employs coating of very small particle with protecting coating by various polymers with high potential that retards the drug release. Ranitidine is a histamine H2 receptor antagonist that restrain acid secretion in the stomach. More widely it is used in the treatment of peptic ulcer and gastroesophageal disease. AIM: The rationale that lies behind this technique is to achieve a controlled and delayed release with enhancement of stability and good shelf life. In the present study ranitidine loaded Eudragit RS100 microspheres were prepared by three different methods, characterized and evaluated to get more prolonged and effective delivery of ranitidine. MATERIALS AND METHODS: Three batches of Ranitidine loaded Eudragit RS 100 were prepared by solvent evaporation technique using the drug to polymer ratio (1:4), organic phase to aqueous phase ratio (1:5) and stabilizer concentration (1% w/v). Three batches of RES3 showed reproducibility of the products. The , particle size, yield and entrapment efficiency of RES3 which show there is prominent sustained drug release attributed on the nature of polymer. RESULTS AND DISCUSSION: The particle size measured by SEM was relatively smaller than the particle size measured by Malvern particle size analyzer. The drug release from the formulation RES3 was slow and extended beyond 12 h up to 24 h . After 4 h the rapid drug release occurred due to of polymer erosion in the surface of microspheres and consequent release of drug which has been loaded near the surface of the microspheres. It obeys Higuchi and Peppas equation suggesting mechanism for drug release from the microspheres follows diffusion an dissolution. CONCLUSION: RES3 batch showed good stability makes it a promising tool for sustained drug delivery and will enhance patient compliance. Hence it is concluded that is concluded that the method of preparation of microspheres was found to be simple, reproducible, and provides good yield. KEY WORDS: Microencapsulation, Microspheres, Ranitidine HCL. INTRODUCTION Microencapsulation is one of the techniques used to prepare sustained release formulations. Microencapsulation and resulting microcapsules/microspheres have gained good acceptance and has been a widely accepted technique to achieve sustained, oral and parenteral controlled release and drug targeting1-2. Microparticles belong to multi particulate delivery systems and are used for prolonged or controlled drug delivery, to improve bioavailability, to enhance stability and to target drug to specific sites. Microparticles can also offer advantages like minimizing fluctuations of drug concentration within therapeutic range, maintaining steady state concentrations, reducing side effects, and thereby providing better and safer therapeutic management by decreasing dosing frequency and improving patient compliance.
Eudragit RS100 is commonly used for the formulation of sustained and controlled release dosage forms. It is insoluble in physiological pH and capable of swelling5. This characteristic may maximize the cellular uptake of drug-polymer complex. Eudragit RS100 has been previously applied for delivery of anti-inflammatory drugs6. In the present study ranitidine loaded Eudragit RS100 microspheres were prepared by three different methods, characterized and evaluated to get more prolonged and effective delivery of ranitidine.
MATERIALS Ranitidine was obtained as gift sample from Central Drugs Pvt. Ltd. Chennai. Eudragit RS 100 was procured from Evonik Rohm GmbH, Darmstadt, Germany through Sandoz Ltd, Mumbai. Poly vinyl alcohol was obtained from Sigma, Mumbai. Dichloromethane and AcetoThe polymeric microparticulate systems have been considered as nitrile (HPLC grade) were obtained from Qualigens, Mumbai and Popromising carriers for the drug delivery and sustained oral drug deliv- tassium dihydrogen orthophosphate & Sodium hydroxide from SD ery will be beneficial to the patients for the long term treatment3. The Fine Chemicals, Mumbai, India. Distilled- deionized water was presub-cellular size of microspheres can improve the stability of active pared with Milli-Q plus System (Elix 10, Millipore corp. India). All substances and also allows relatively higher intracellular uptake of other reagents were of analytical grade. drug than other particulate systems4. Preparation of microspheres by solvent evaporation method *Corresponding author. The ranitidine microspheres were prepared with various ratios of drug Gowri. R and Eudragit RS100 polymer as shown in Table 1 using solvent evapoJaya College of Pharmacy, ration technique 7. The method is a modification of emulsion solvent Thiruninravur – 602 024, Chennai, TamilNadu, India. Journal of Pharmacy Research Vol.9 Issue 4.April 2015 237-243
Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243 evaporation technique and involves preparation of o/w emulsion between organic phase consisting of ranitidine and Eudragit RS 100 in dichloromethane (DCM) and aqueous phase, 1% w/v aqueous solution of polyvinyl alcohol (PVA). The dichloromethane solution of ranitidine and Eudragit RS100 was emulsified by using probe homogenizer (Virtis Cyclone IQ, USA). The dichloromethane was completely evaporated by stirring overnight (12 to 16 hrs) at room temperature (25 0C ± 2 0C). The prepared microspheres were recovered by centrifugation for 20 minutes at 15,000 rpm [Sorvall Ultracentrifuge, USA]. The precipitate was washed repeatedly with ice cold water to remove the traces of polyvinyl alcohol. Finally, the product was dispersed in cold water and recovered by lyophilisation (Labconco Lyophilisor, USA). Six batches of Eudragit microspheres were prepared keeping organic phase to aqueous phase at 1:5, and varying drug: polymer ratios.
Particle size analysis and surface morphology Particle size analysis of ranitidine microparticles were carried out using Malvern particle size analyzer (Malvern Instruments Ltd, UK). The measurements were carried out at a fixed angle of 90o. About 10 mg of microparticles were suspended in 5 ml of Milli-Q water and analyzed with an obscuration index of about 5% (Obscuration index is a measure of amount of light lost due to introduction of sample against light path). The analysis was performed at a temperature of 25°C. The mean particle diameter and size distribution of the suspension were assessed. Analysis was carried out for three times for each batch of sample under identical conditions and mean values were reported.10-11 Surface morphology of ranitidine loaded Eudragit RS100 microparticles were studied using scanning electron microscope (SEM) (JEOL JSM5610LV, Japan). Samples were prepared on 10 x 10 mm brass stub and coated with gold using sputter coater at accelerating voltage of 20 KV at high vacuum mode.
Table 1: Formulation of ranitidine Eudragit RS 100 microspheres S. No
Formulation Drug: Wt. of polymer Ranitidine (mg)
Wt. of polymer (mg)
Vol. Vol. of of OP AP (1% (ml) PVA) (ml)
% Yield
1 2 3 4 5 6
RES1 RES2 RES3 RES4 RES5 RES6
50 100 200 300 400 500
6 6 6 6 6 6
62.9 68.2 78.7 52.4 69.3 70.3
1:1 1:2 1:4 1:6 1:8 1:10
50 50 50 50 50 50
30 30 30 30 30 30
Characterization of microspheres Entrapment efficiency and drug content The entrapment efficiency of ranitidine in microparticles was estimated by UV-spectrophotometry. The standard curve of ranitidine was constructed from the serial dilution of standard stock solution. The standard stock solution was prepared by dissolving the ranitidine in hydrochloric acid. The ranitidine microspheres were extracted from microparticles with alcoholic hydrochloric acid after dissolving the microparticles in acetonitrile. After suitable dilutions, the absorbance was measured in a UV- spectrophotometer (Shimadzu, Japan) at 313 nm. The amount of ranitidine was estimated from standard curve. The entrapment efficiency (EE) and drug content (DC) were calculated using the following formula8-9
Poured Density, Tapped Density and Carr’s Index: Poured density and tapped density of prepared microparticles were measured. Carr’s Index (%) and Hausner’s Ratio were calculated12 by the following formula: Hausner’s Ratio = Tapped density / Poured density The angle of repose was also determined by funnel method and was calculated using the following formula: θ = tan -1(h/r) Where, θ = angle of repose, h = height of heap, and r = radius of base of the heap. In-vitro evaluation 4.3.1. Drug release study In-vitro release study of ranitidine from the microspheres was carried out in 900 ml of simulated gastric fluid (pH 1.2) maintained at 370C ± 0.5 0C, with stirring speed 50 rpm, using USP Dissolution test apparatus (USP TDT 06PL, Electrolab, Mumbai) type II (Paddle type) for 24 h. Microparticles, equivalent to 5 mg of ranitidine, were used for the study. At predetermined time intervals (viz. 1, 2, 4, 6, 8, 10, 12 and 24 h); 10 ml of the sample solution was withdrawn and filtered through 0.45 µm membrane filter. After suitable dilution the samples were analyzed using UV spectrophotometer at 313 nm. An equal amount of
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Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243 fresh dissolution medium, maintained at 37 0C, was replaced immediately after withdrawal of each test sample. It was diluted suitably and absorbance measured by triplicate manner 13
against square root of time graph will be linear if the release obeys Higuchi equation. If the drug release obeys Higuchi plot, it indicates that the drug release is governed by diffusion mechanism16-17
Analysis of dissolution data: It is important to understand the kinetics and mechanisms of drug release from the pharmaceutical dosage forms. To ascertain the kinetics of drug release from the formulated microspheres, in-vitro drug release data were fitted into zero order and first order kinetic models and to find out the mechanisms of drug release, the same data were fitted into Higuchi, Hixson- Crowell and Korsemeyer-Peppas equations.
Korsmeyer- Peppas equation To illustrate a more desirable release of drug for the formulation, dissolution data was further analyzed by Peppas and Korsemeyer equation.18-20
Zero Order Release kinetics: It defines a linear relationship between the cumulative % drug released vs. time14 and is expressed as Q(t) = K0t Where, Q is the cumulative percentage of drug released against time t and it will be linear if the release obeys zero order kinetics. Values of release constant K0 were obtained from the slope of % drug released versus time plot. First order Release Kinetics It defines linear relationship between the log % drugs remaining to be released vs time. According to Wagner 15, the exposed surface area of a particle decreases exponentially with time during the dissolution process. The equation used to describe first order kinetics islog (Q0 - Q) =
log Q0 - K1t/2.303
Where, Q0 = % drug remaining to be released at zero time (t=0), Q = % drug remaining to be released at time t (t= t), K1 = first order rate constant for drug release. Thus, a plot of the log % drug remaining to be released vs. time will be linear, if the release obeys first order release kinetics. Higuchi model It defines a linear relationship between fraction released per unit of surface (Q) and square root of the time. Q = KH t½ Where, KH is the release rate constant. Values of release constant KH were obtained in each case from the slope of % drug released versus square root of time plots. The cumulative percentage drug released
Mt / Ma = k. t n Where, Mt is the amount of drug released at time (t) and Ma is the amount of drug released at time a, thus the Mt / Ma against log time will be linear if the release obeys Korsmeyer- Peppas equation and the slope of this plot represents ‘n’ value. All the equations used to analyze the first 60% of a release curve where the release is linearly related to “t”. According to Korsmeyer- Peppas the value of diffusion exponent, n, is indication of mechanism of drug release from spherical particles. The value of ‘n’ is 0.43, indicates that the mechanism of drug release follows fickian diffusion; when ‘n’ > 0.43 and < 1.00, drug release follows non- fickian (anomalous) diffusion. A value of n=1 means that the drug release is independent of time, regardless of geometry and follows zero order. Stability study Decomposition or degradation of the pharmaceutical formulations may develop due to environmental factors like temperature, humidity, radiation, light, air etc. and due to interaction with other chemical constituents/excipients in formulation or due to the nature of container used for packing. Hence, it is necessary to perform stability testing for assuring safety and efficacy and acceptability of the pharmaceutical formulations. To perform the stability study, ranitidine microparticles was kept in glass vials and placed in three different storage conditions [ICH Q1A (R2)] viz. long term study (25 ± 2 °C / 60% RH ± 5% RH) for one year, intermediate study (30 ± 2 °C / 65% RH ± 5% RH) for six months and accelerated study (40 ± 2 °C / 75% RH ± 5% RH) for six months. The microparticles were evaluated at intervals of 0, 3, 6 and 12 months for long term study and 0, 3 and 6 months for intermediate study and accelerated study. During stability testing samples were evaluated for physical appearance, particle size and drug content and drug release study. Statistical analysis Experimental results were tested by one-way analysis of variance and Student’s t-test. Data represented as mean values ± SD (standard
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Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243 deviation). The values of p < 0.05 (*) were indicative of significant difference and very significant difference if p < 0.01 (**).
by solvent evaporation technique with drug: polymer ratio 1:4 was selected for further in-vitro and in-vivo evaluation.
RESULTS AND DISCUSSION The ranitidine microspheres with Eudragit RS100 were prepared with solvent evaporation technique. Eudragit RS100 was selected because of its good sustained action and mucoadhesive properties. Eudragit contains quaternary ammonium group which may provide positive surface charge and effective adhesion of microspheres to the negatively charged mucous membrane in the GI tract. The solvent evaporation method was simple and comparatively easy than other methods like double emulsion (w/o/w) and coacervation-phase separation method. Moreover, the yield of microspheres produced was comparatively high in the solvent evaporation method.
Table 2: Particle size, entrapment efficiency, drug content and % yield of ranitidine loaded Eudragit RS100 microspheres prepared by solvent evaporation method
The particle size of the prepared microspheres was estimated by Malvern particle sizer. The various formulation and process parameters like, drug to polymer ratio, stirring speed, and speed homogenization are taken into consideration for getting the particle sizes from 2 to 8 µm. The microspheres were constituted to be distinct, freely flowable and spherical in shape. The size of microspheres was increased with increasing of polymer content in the formulations due to increased in viscosity of the coating solution phase. Dissimilarities in the formulation parameters failed to reduce particle size as well as size range. The drug-polymer ratio in the formulation played an important role in the formation of microspheres. It was observed that the sizes of the microspheres were increased in formulations with drug: polymer ratios beyond 1:4. The particle size showed relatively larger in size at drug to polymer ratio 1:10. Eudragit RS100 produced relatively larger sized microspheres in higher concentration. The larger particle size of the microspheres is the increased concentration of polymer in the coating solution which results the agglomeration of the particles. Yield and entrapment efficiency The product yield was in the range of 52.4 to 78.7% for solvent evaporation method, The entrapment efficiency was in the range of 65.3 ± 0.55 to 84.31 ± 0.62 % for solvent evaporation method The encapsulation efficiency was increased with increase in proportion of polymer in the microspheres. The low yield in some cases could be attributed to losses occurring during various steps of processing, such as adherence of polymeric solution to glass container and due to washing steps 21. . Considering the facts like ease of operation, various steps involved, number of additives, effectiveness and yield of microspheres, the solvent evaporation technique was selected for further preparation of microspheres. The formulation RES3 prepared
S. No
Formulation Drug: polymer
Particle size ( µm )*
Entrapment Drug efficiency content (%w/w)* (%)*
% Yield
1 2 3 4 5 6
RES1 RES2 RES3 RES4 RES5 RES6
2.64 ± 2.10 2.79 ± 3.34 2.99 ± 1.33 21.52 ± 2.87 35.02 ± 4.58 42.12 ± 3.98
65.3 ± 0.55 67.43 ± 0.83 73.19 ± 1.19 76.12 ± 0.61 82.32 ± 0.88 85.31 ± 0.62
62.9 68.2 78.7 52.4 69.3 70.3
1:1 1:2 1:4 1:6 1:8 1:10
32.76 ± 0.76 28.35 ± 0.33 16.59 ± 0.24 12.78 ± 0.77 9.66 ± 0.42 8.82 ± 0.13
Poured Density, Tapped Density and Carr’s Index The poured density, tapped density and Carr’s Index were measured for selected formulations based on the particle sizes and yield. It was observed that both poured density and tapped density increased with increase of polymer ratio which is justified with relatively higher bulk density of the polymer. Angle of repose (between 24º and 28º) of the microparticles indicates good flowability of the products. Carr’s compressibility scale also determines the flowability of the particles. The Carr’s index between 5 and 15 is the indication of excellent flowability22. Table 3: Physical Characteristics of ranitidine loaded Eudragit RS100 microspheres S1. No
Form. Poured Code Density* (g/cm3)
1
RES3
Tapped Density* (g/cm3)
Carr’s * Index (%)
Hausner’s Ratio *
Angle of Repose * (degrees)
0.196 ± 0.002 0.213 ± 0.002 7.981 ± 0.019 1.086 ± 0.001 26.24 ±1.18
Note: The values are expressed as mean ± SD for n=3
Particle size and surface morphology of ranitidine microspheres (RES3) The particle size of the ranitidine loaded microspheres was measured by Malvern instrument. The size distribution plots (Malvern Particle Sizer, UK) of formulation RES3 showed sharp and steep peak specifies narrow size distribution . The surface morphology and shape of the ranitidine loaded microspheres (RES3) was measured using scanning electron microscopy. The SEM image of microspheres revealed that the particles are of spherical in shape with relative smooth surface . The particle size measured by SEM was relatively smaller than the particle size measured by Malvern particle size analyzer. The electron microscope measures only the size of microspheres, whereas the Malvern particle sizer measures the particles inclusive of hydrodynamic layer.
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Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243 Fig 1: Particle size distribution of ranitidine-Eudragit RS 100 microspheres (RES3) measured in Malvern particle sizer
Fig 4. Ranitidine loaded Eudragit RS100 microspheres (RES3) – first order release in simulated gastric fluid (pH 1.2).
Fig 2: SEM image of ranitidine-Eudragit RS 100 microspheres (RES3) In vitro drug release study Among all formulations formulation RES3 showed nearly 90% drug release after 24 h. After 4 h the rapid drug release was identified and this could be as a result of polymer erosion in the surface of microspheres and consequent release of drug which has been loaded near the surface of the microspheres. It suggests that the combination of dissolution, diffusion and erosion are the possible mechanism for drug release from the microspheres.
Fig 5. Ranitidine loaded Eudragit RS100 microspheres (RES3) – first order release in simulated gastric fluid (pH 1.2).
Drug release kinetics: To estimate drug release pattern the data are plotted in different kinetic models, viz. zero order, first order, Higuchi and Korsmeyer-Peppas equation respectively.
Fig 6. Drug release from ranitidine loaded Eudragit RS100 microspheres (RES3) in simulated gastric fluid pH 1.2 – Higuchi kinetic.
Fig 3. Ranitidine loaded Eudragit RS100 microspheres (RES3) Zero order release in simulated gastric fluid (pH 1.2). Journal of Pharmacy Research Vol.9 Issue 4.April 2015
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Gowri. R et al. / Journal of Pharmacy Research 2015,9(4),237-243 The results of stability studies for microspheres formulation (RES3) showed no visible physical changes (colour and cake formation) for the microspheres stored in 25 °C/60% RH and 30 °C/65% RH. But some clumping was observed when stored in 40 °C/75% RH after 6 months. This may be due to the absorption of moisture on the surface of microspheres. The in vitro drug release study also showed no noticeable difference after storage in different storage conditions.
Fig 7. Drug release from ranitidine loaded Eudragit RS100 microspheres (RES3) in simulated gastric fluid pH 1.2 – Peppas model. Model fitting of the drug release data into zero and first order model indicate that the drug release from the microspheres followed zero order and first order kinetics during 1 to 24 h. The kinetic results were consistent with the previous finding by Jain and saraf, 2009). Drug release from the microspheres also obeyed Higuchi as well as Peppas models, indicating that the drug release was by diffusion mechanism (Tab. 4). The release exponent ‘n’ value (0.433) was calculated from the slope of the Peppas model and indicates that the mechanism of drug release follows fickian diffusion. The model fitting of the drug release data suggests that the drug release from the microspheres followed the zero order kinetics and further drug release followed diffusion and dissolution mechanism. Table 4: Régression coefficient (r2) values obtained from the drug release kinetic data of ranitidine - Eudragit RS100 microspheres (RES3) Formulation Zero
1st order
Higuchi Korsmeyer
order
RES3
0.925
Peppas ‘n’
-Peppas
0.998
0.913
0.941
0.433
Stability study Stability plays an important role in the product development process. Changes in drug stability could risk patient safety and its requirements in unmet condition. Instability may also lead to formation of toxic degradants. The stability study was carried out to access the suitability of the micro-particulate system and its storage condition.
Fig 8. Drug release from ranitidine loaded Eudragit RS100 microspheres (RES3) in simulated gastric fluid pH 1.2 placed in three different storage conditions,( 25ºC ± 2ºC/60% RH ± 5% , 30ºC ± 2ºC/65% RH ± 5%RH, 40 ºC ± 2ºC/75% RH ± 5% RH). CONCLUSION Ranitidine microspheres were prepared by solvent evaporation method using Eudragit RS 100 polymer. The aim was to enhance the absorption and bioavailability by prolonging the gastric residence time. The ranitidine release from the microspheres was slow, sustained and dependent on the nature of polymer. RES3 showed nearly 90% drug release after 24 h. It also reveals that the nature of polymer influenced the physical characteristics and adhesive nature of microspheres. The optimized formulation RES3 was stable in various environmental conditions. Hence the ranitidine loaded polymeric microspheres were prepared and characterized. The microspheres further need the in vivo study for the suitability of the formulation. REFERENCES 1. Kondo A, Eds. In; Microcapsule processing and technology, Marcel Decker inc., New York, 1979: 18 2. Leung SS and Robinson JR. In; Robinson J.R. and Lee V.H.L. eds., Controlled Drug Delivery, Fundamentals and Applications, 2 nd Edn. Marcel Decker, Inc, New York. 1987. 448. 3. Brigger, C., Dubernet, P., Couvreur, P., 2002. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 54, 631651. 4. Ourique, A.F., Pohlmann, A.R., Guterres, S.S., Beck, R.C., 2009. Tretinoin-loaded nanocapsules: Preparation, physi-
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Source of support: Nil, Conflict of interest: None Declared
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