formulation and evaluation of dexlansoprazole …

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Jahnavi et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF DEXLANSOPRAZOLE

SOLID DISPERSIONS USING HYDROPHILIC CARRIER

V.N.S. Jahnavi1, S. Bhagya Laxmi

1, B. Sireesha

1, K. Geetha Sri

1, K. Preethi Sobha Sri

1,

P.M.M. Naga Lakshmi Varma*1 and K. Padmalatha

2

1Department of Pharmaceutics, Vijaya Institute of Pharmaceutical Sciences for Women,

Vijayawada.

2Department of Pharmacology, Vijaya Institute of Pharmaceutical Sciences for Women,

Vijayawada.

ABSTRACT

The main objective of this study was to investigate the dissolution

behaviour of D-lansoprazole Solid dispersion which was prepared

using Mannitol as hydrophilic carrier by Fusion method and solvent

evaporation method. The solubility studies, Fourier transform infra-red

(FTIR) spectroscopy, percentage practical yield, drug content and in

vitro drug release studies were evaluated. The Solid dispersion was

prepared in 1:1, 1:2 and 1: 3 weight ratios of the drug to carrier. FTIR

studies showed that there was no interaction between the drug and

carrier. In vitro release profiles of all Solid dispersions (F1 to F6) were

comparatively evaluated and also compared with pure lansoprazole.

Among the Solid dispersions, F6 (1:3) using Mannitol showed maximum drug release of

100.2% compared with the other formulations. So, the solid dispersion containing Mannitol

(1:3) by solvent evaporation method may offer suitable formulation because of its faster drug

release among all formulations. The development of solid dispersion of lansoprazole could be

a promising approach to enhance its dissolution rate and solubility property, which may

subsequently minimize the variation in its bioavailability.

1. INTRODUCTION

The oral route of administration is the most common and preferred method of delivery due to

convenience and ease of ingestion. Even though the oral drug route is preferred, it can be

problematic for number of reasons the most significant contributors being poor aqueous

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 7, 1353-1364 Research Article ISSN 2278 – 4357

*Corresponding Author

P.M.M.Naga Lakshmi

Assistant Professor in Vijaya

Institute of Pharmaceutical

Sciences for Women,

Vijayawada.

Article Received on

02 May 2020,

Revised on 23 May 2020,

Accepted on 12 June 2020

DOI: 10.20959/wjpps20207-15944


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solubility and or poor membrane permeability of the drug molecule which results into poor

bioavailability after oral administration (Abdul Hasan Sathali A., et al 2013 and Appa Rao

B., et al 2010). Solid dispersions traditionally have been used as an effective method to

improve the dissolution properties and bioavailability of poorly water soluble drugs.

Molecular dispersion of the drug in polymeric carriers may lead to particle size reduction and

surface area enhancement, which result in improved dissolution rates (Sarifulislam Howlader

Md., et al 2012 and Deshmukh D B., et al 2010).

Dexlansoprazole sold under the trade name Dexilant which is an R-enantiomer of

lansoprazole and a new-generation proton pump inhibitor that decreases the amount of acid

produced in the stomach. Dexlansoprazole is used to treat heartburn caused by

gastroesophageal reflux disease (GERD), and to heal erosive esophagitis (damage to the

esophagus from stomach acid).

According to their Biopharmaceutical Classification System (BCS), Lansoprazole belongs to

class II compound having poor aqueous solubility and high permeability (Brahmankar D M.,

et al 2009). Therefore, solid dispersion technology may offer suitable approach to improve

the poor solubility of Lansoprazole and subsequently reduces the variation on its

bioavailability and difficulties in its solid formulation (Karnik Priyanka et al., 2016).

The main objective of this work was to investigate the possibility of improving the solubility

and dissolution rate of lansoprazole by preparing solid dispersions. Fusion and solvent

evaporation methods with water-soluble carrier Mannitol were investigated. The prepared

solid dispersions was tested for practical yield (%), drug content, infrared (IR) spectroscopic

and in vitro dissolution behaviour.

2. MATERIALS AND METHODS

The D-lansoprazole pure drug obtains as gift sample from Therdose Pharma Pvt. Ltd.,

Hyderabad. Methanol, Mannitol, Hydrochloric acid, Sodium hydroxide and Potassium

dihyrogen phosphate were of analytical grade.

2.1. Calibration curve of lansoprazole

A standard curve was prepared with different concentrations (1 to 10μg/ml) using pH 6.8

phosphate buffer solution. The absorbance of these solutions were measured at 271.5nm by


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UV- spectrophotometer. This standard curve was used to measure the concentration of the

drug release from the formulation during the in vitro dissolution studies.

2.2 Fourier Transform Infra red spectroscopic studies

FTIR Spectroscopic study was carried out to check the compatibility between drug and

carrier. The spectrum of Lansoprazole (pure drug) and physical mixtures were recorded using

Fourier transform infrared spectrometer.

2.3 PREPARATION OF SOLID DISPERSIONS

2.3.1. Melting or Fusion Method: Solid dispersion were prepared by melting the accurately

weigh amount of carrier in china dish on water bath and drug were dispersed in a molten

solution, & cooling immediately on ice bath with continuous stirring to dry mass (or) melted

mixture was poured on a ceramic tile and cooled. The resulted solidified mass was powdered

(pulverized) and passed through sieve no. (No: 100 or 80 or 60). Then the powder stored in

airtight container (desiccator) for further studies (Mohammed Gulzar Ahmed, et al., 2010).

2.3.2 Solvent Evaporation Method: In this technique drug was dissolved in a Methanol

solvent and obtained a clear solution. After getting a clear solution the carrier were added to

that solution until the thick slurry is formed and transfer it in to the petri plate & allow the

solvent to evaporate and dry it. The resulted solidified mass was powdered (pulverized) and

passed through sieve no. (No: 100 or 80 or 60). Then the powder stored in airtight container

(desiccator) for further studies (Irin Dewan Md. Ayub Hossain, et al., 2012).

Table No 1: Formulation Plan of Dexlansoprazole Solid dispersion.

Method Formula Composition Drug : carrier

Fusion method

F1 Drug: Mannitol 1:1



Solvent

evaporation

method




3. EVALUATION OF FORMULATION

3.1 Percentage Practical Yield

Percentage practical yield was calculated to know about percent yield or efficiency of any

method, thus its help in selection of appropriate method of production. SDs were collected

and weighed to determine practical yield (PY) from the following equation (Appa Rao. B, et


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al., 2010). According to Vogel's Textbook of Practical Organic Chemistry, yields around

100% are called quantitative, yields above 90% are called excellent, yields above 80% are

very good, yields above 70% are good, yields above 50% are fair, and yields below 40% are

called poor.

3.2 Particle size analysis

The prepared Solid dispersion was evaluated for particle size distribution and average

diameter by optical microcopy. Small quantity of the formulation was dispersed using liquid

paraffin and spread into a thin film on a microscopic slide. Particles were observed under

high power (45X) and the size of randomly selected 150 particles from different locations

were measured and average size of the particles was calculated (shin. S et al., 1998).

3.3 Loss on Drying (LOD)

100 mg of solid dispersion was dried at a temperature of 40±2ºC for 7 days and final weight

was taken to Wt after drying. The LOD of solid dispersion was calculated by using following

equation.

% LOD = (Weight of water in sample / Total weight of wet sample) x 100

[(WO - Wt)/ WO] X 100

Where,

Wo = is initial weight of Sample

Wt= is weight of sample after drying

3.4. Solubility Study

A modification method of solubility determination was used to determine the solubility of

different D-Lansoprazole solid dispersions. The solid dispersion equivalent to 0.5 gm of D-

Lansoprazole was introduced in to the 15 ml stopper conical flask containing 5 ml of

phosphate buffer solution (pH 6.8). The sealed flask was agitated on magnetic stirrer over a

night at 37°C. The same procedure followed for the pure D-Lansoprazole sample. The

solution was filtered & the filtrate was suitably diluted (1ml in 10ml PBS) and analyzed on a

UV-Visible spectrophotometer at 271.5 nm (Leunar C et al., 2000).


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3.5 Drug Content

Formulation containing D-Lansoprazole was taken in a mortar and triturated properly until

fine powder was formed. 10 mg equivalent of fine powder was taken in a 100 ml volumetric

flask and makeup the final volume by using pH 6.8 PBS. Sonicated in a sonicator to make a

clear solution and then finally was filtered. From this solution 1 ml drug solution was

withdrawn and taken in a 10 ml volumetric flask and the volume of drug solution was

adjusted up to 10 ml with pH 6.8 PBS. Absorbance value was determined using UV-

spectrophotometer (UV-3000+, Lab India.) and reagent blank, at 271.5 nm. Using the

absorbance value, the amount of D-Lansoprazole entrapped was determined with the help of

standard curve (Appa Rao. B, et al., 2010).

3.6 In vitro Dissolution Study

An accurately weighed sample of solid dispersions (equivalent to 30 mg Lansoprazole) was

placed into 900 ml of phosphate buffer (pH 6.8), maintained at a temperature of 37ºC ± 0.5ºC

and stirred at a speed of 75 rpm. 10 ml samples were withdrawn at different time intervals

(10, 20, 30, 45, 60, 90 and 120 min) and absorbance was measured at 271.5 nm, then the

amount of D-Lansoprazole was calculated.

4. RESULTS

4.1 Standard curve of D-lansoprazole

Figure No – 1: Standard curve of D-Lansoprazole in pH 6.8 PBS.


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4.2 Drug and Excipient Compatibility Studies by FTIR

The FTIR studies for drug with each excipient were performed and spectral peaks recorded

between the wavelengths from 4000 cm-1 to 400 cm-1. Obtained graphs depicted that there

was no interaction between the drug and excipients.

Figure No 2: FTIR Spectra for the Pure D-lansoprazole.

Figure No 3: FTIR Spectra for D-Lansoprazole + Mannitol.


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4.3 EVALUATION STUDIES

I. Percentage Practical Yield

Table No 2: Percentage Practical Yield.

Method Formula Theoretical

mass(gm)

Practicle

Mass(gm) % practical yield

Fusion method

F1 2 1.83 91.5%

F2 3 2.88 96%

F3 4 3.92 98%

Solvent

evaporation

method

F4 2 1.88 94%

F5 3 2.90 96.6%

F6 4 3.91 97.75%

Theoretical yield is defined as the amounts of products calculated from the complete reaction

of the limiting reagent while practical yield is the exact amount produced of a product.

Usually, practical yield is less than the theoretical yield. The results of % practical yield

studies are shown in above table. Percent practical yield for all formulations of solid

dispersions found to be 91.5 - 98%. Maximum yield was found to be 98% in formulation F3.

According to Vogel's Practical Organic Chemistry, yields around 100% are called

quantitative, yields above 90% are called excellent, yields above 80% are very good, yields

above 70% are good, yields above 50% are fair, and yields below 40% are called poor

method.

II. Particle Size Analysis

Table No -3: Particle Size Analysis.

Method Formula Average Particle Size (µM)

Fusion method

F1 75.6

F2 79.3

F3 70.7

Solvent evaporation

method

F4 74.0

F5 73.0

F6 72.6

Average diameter of Particles =∑nd/∑n

The particle size of solid dispersions with mannitol ranged from 15 - 130 µm and the average

diameter was found out to be in the range of 70.7 to 79.3 µm. The formulation F3 showed

minimum average particle size of 70.7 µm and maximum solubility due to reduction in the

average particle size.


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III. Loss on Drying (LOD)

Table No 4: Loss on Drying (LOD).

Method Formula WO (mg) Wt (mg) [(WO- Wt)/ WO] X 100

Fusion method

F1 100 97 3%

F2 100 98 2%

F3 100 99 1%

Solvent

evaporation

method

F4 100 96 4%

F5 100 97 3%

F6 100 99 1%

The all batches of solid dispersions were studied for % LOD. According the IP this procedure

was followed and all batches showed the satisfactory results the data are shown in Table no.

4. The loss on drying for each formulations were found less than 5%, this could help to

maintain concentration of water that helps to wet the drug particles.

IV. Solubility Study

Table No 5: Solubility Study.

Method Formula Drug solubility (mg /ml)

Fusion method

F1 2.62

F2 2.85

F3 3.25

Solvent evaporation

method

F4 2.63

F5 2.83

F6 3.97

UV-VIS Spectrophotometric assay method identified the amount of drug in prepared solid

dispersion. Table no.5 shown the percentage of drug present in the solid dispersion. The data

indicated that the drug in carrier dispersed uniformly. Pure D-lansoprazole showed 1.4 mg/ml

of saturation solubility. All the solid dispersions of D-lansoprazole showed an increase in

drug solubility. All solid dispersion showed higher saturation solubility as compared with

pure D-lansoprazole. The maximum solubility was found to be 3.97 mg/ml in formulation F6.

This could be due to use of water soluble carrier Mannitol which has the good wettability and

increased surface area.


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V. Drug Content

Table No-6: Drug Content.

Method Formula Drug Content ( µG/ML)

% Drug Content Theoretical value Practical value

Fusion

method

F1 10 9.7 97%

F2 10 9.5 95%

F3 10 9.6 96%

Solvent

evaporation

method

F4 10 9.5 95%

F5 10 9.6 96%

F6 10 9.8 98%

Figure No 3: Drug content of different formulations.

The drug content in different formulation of solid dispersions was found and confirmation

with the theoretically calculated values, which indicate the reliability of the analytical method

used. The formulation F6 showed maximum drug content value 9.8 µg/ml and which is more

reliable with theoretical value.

VI. IN VITRO RELEASE STUDIES

Table No 14: Comparative Dissolution Profile.

Time interval

(min)

%Cumulative amount of drug dissolved

F1 F2 F3 F4 F5 F6 Pure Drug

F7

0 0 0 0 0 0 0 0

10 10.07 13.95 16 11.09 15.04 16.38 6.13

20 22.54 28.65 31 23.31 29.88 31.73 12.19

30 34.76 42.96 45.48 35.9 44.26 46.48 18.36

45 47.21 57.19 59.79 48.24 58.42 60.7 24.52

60 59.69 70.78 73.43 60.88 72.04 74.38 30.83

90 72.65 84.1 86.73 74.06 85.58 87.62 45

120 85.65 96.37 98.21 87.7 98.88 100.5 60


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Figure No - 11: Comparative Dissolution Profile.

From the above studies solid dispersions with 1:3 of drug and Mannitol in solvent

evaporation method was found to give higher dissolution rate than the fusion method.

Maximum release rate was found out (100.5%) with solid dispersions prepared with Mannitol

and solvent evaporation method. The enhancement of dissolution rate may be due to increase

in the effective surface area made available to the dissolution media. Further it may be

attributed that the use of water-soluble carriers improves the wettability of the drug particles

and hence high dissolution rate. On the basis of in vitro release studies, if the carrier

concentration increases the release of drug was increases and it was found that the rate of

dissolution was increased in solid dispersion as compare to pure drug.

5. DISCUSSION

From the FTIR spectral studies, it was suggested that there was no interactions between the

drug and polymer.

In Solubility studies, it was found that the solubility was increased with increasing the

proportion of Mannitol in the formulation. The highest solubility was shown when the ratio

of drug & Mannitol was 1:3 prepared by solvent evaporation method.

The dissolution study was carried out in phosphate buffer (pH 6.8) at 37°C+ 0.5°C up to 120

minutes and it was found that the rate of dissolution was increased in solid dispersion as

compare to pure drug.


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On the basis of In Vitro release studies, if the carrier concentration increases the release of

drug increases. The dissolution rate is increased approximately double fold to the pure drug

when solid dispersion in the ratio of 1:3 (Drug: Mannitol).When the dissolution profiles

compare between the solvent evaporation and fusion method then it was found that

dissolution rate is better in solvent evaporation method so it was concluded that dissolution of

poorly soluble drug can be effectively increased by the solid dispersion methods.

As per the release studies F6 formulation is considered to be the best formulation, the drug

was released up to 100.5% for 2 hours.

6. CONCLUSION

The solid dispersions of a poorly water soluble drug Lansoprazole by fusion method and

solvent evaporation methods were used in order to improve the solubility.

The objective achieved and the result suggested that solvent evaporation method can be

employed successfully for improvement of dissolution profile and solubility of solid

dispersions of poorly water soluble drug.

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Second Edition, 2009; 349-357.


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