International Journal of Innovative Pharmaceutical ... AND EVALUATION OF SOLID ... similar...

RESEARCH ARTICLE Kritika Thakur et.al / IJIPSR / 2 (8), 2014, 1793-1812

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com August Issue 1793

DEVELOPMENT AND EVALUATION OF SOLID DISPERSION

USING BINARY AND TERNARY COMPLEXES

1Kritika Thakur

*,2Meenu Nagpal

,3Geeta Aggarwal,

4Rupinder Kaur,

5Upendra Kumar Jain

1,2,4,5Department of Pharmaceutics, Chandigarh College of Pharmacy, Landran, Mohali,

Punjab- 140307, INDIA 3

Rayat and Bahra College of Pharmacy, Mohali, Punjab, INDIA

Corresponding Author:

Kritika Thakur

Department of Pharmaceutics,

Chandigarh College of Pharmacy,

Landran, Mohali,

Punjab- 140307, INDIA

Email: [email protected]

Phone: +91 7837909163

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Improving oral bioavailability of drugs those given as solid dosage forms remains a challenge

for the formulation scientists due to solubility problems. The dissolution rate could be the rate-

limiting process in the absorption of a drug from a solid dosage form of relatively insoluble

drugs. Therefore increase in dissolution of poorly soluble drugs by solid dispersion technique

represents a challenge to the formulation scientists. Solid dispersion techniques have attracted

considerable interest of improving the dissolution rate of highly lipophilic drugs thereby

improving their bioavailability by reducing drug particle size, improving wettability and

forming amorphous particles. The term solid dispersion refers to a group of solid products

consisting of at least two different components, generally a hydrophilic inert carrier or matrix

and a hydrophobic drug.

Keywords: Poorly soluble drug; solid dispersion; solubility enhancement.




INTRODUCTION

Oral bioavailability of drugs depends on its solubility and/or dissolution rate, therefore major

problems associated with these drugs was its very low solubility in biological fluids, which

results into poor bioavailability after oral administration.

[1-5] A drug with poor aqueous

solubility will typically exhibit dissolution rate limited absorption, and a drug with poor

membrane permeability will typically exhibit permeation rate limited absorption [6]. Therefore,

pharmaceutical researchers’ focuses on two areas for improving the oral bioavailability of drugs

include: (i) enhancing solubility and dissolution rate of poorly water-soluble drugs and (ii)

Enhancing permeability of poorly permeable drugs [7].

It has been estimated that 40% of new

chemical entities currently being discovered are poorly water soluble. [8, 9] unfortunately, many

of these potential drugs are abandoned in the early stages of development due to the solubility

problems.

It is therefore important to realize the solubility problems of these drugs and methods for

overcoming the solubility limitations are identified and applied commercially so that potential

therapeutic benefits of these active molecules can be realized [10,11].Therefore lots of efforts

have been made to increase dissolution of drug. Methods available to improve dissolution

include salt formation, micronization and addition of solvent or surface active agents. Solid

dispersion (SD) is one of such methods and involves a dispersion of one or more active

ingredients in an inert carrier or matrix in solid state prepared by melting, dissolution in solvent

or melting-solvent method.[11]

The formulation of drugs having low aqueous solubility using

solid dispersion technology has been an active area of research since 1960.[12]

The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline

particles..The first drug whose rate and extent of absorption was significantly enhanced using the

solid dispersion technique was sulfathiazole by Sekiguchi and Obi [1].This technique has been

used by many researchers/scientists for a wide variety of poorly aqueous soluble drugs to

enhance the solubility of the drugs and hence bioavailability [13, 14, 15]

Clarithromycin is used for the treatment of infections including those of the chest, skin and ear. It

is also used for some types of stomach ulcer. Even if your condition improves, it is important to

complete the prescribed course unless you are told to stop. Otherwise your infection could come

back. Any side-effects are usually mild. The most common are feeling or being sick, indigestion,




and diarrhea. Clarithromycin is used to treat a variety of bacterial infections. It works by killing

the bacteria that cause the infection [16,17].

Clarithromycin is stable in gastric medium and has a narrow absorption in gastrointestinal tract,

rapid intestinal absorption, highly solute at gastric pH, no effect of food on absorption and it has

higher eradication rate in vivo to H.pylori. Based on this, an attempt was made through this

investigation to formulate floating matrix tablets of clarithromycin using different polymers and

their combinations. [18.19]

Clarithromycin is a macrolitic antibiotic used to treat pharyngitis, tonsillitis, acute maxillary

sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia (especially atypical

pneumonias associated with Chlamydia pneumonia or TWAR), skin and

skin structure infections. In addition, it is sometimes used to treat Legionellosis,Helicobacter

pylori, and Lyme disease.[20]

Clarithromycin prevents bacteria from growing by interfering with their protein synthesis. It

binds to the subunit 50S of the bacterial ribosome and thus inhibits the translation of peptides.

Clarithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against

certain Gram-negative bacteria, particularly Legionella pneumophila. Besides this bacteriostatic

effect, Clarithromycin also has bactericidal effect on certain strains, such as Haemophilus

influenzae, Streptococcus pneumoniae and Neisseria gonorrhoeae. [21]

To reduce the development of drug-resistant bacteria and maintain the effectiveness of

clarithromycin extended-release tablets and other antibacterial drugs, clarithromycin extended

release tablets should be used only to treat or prevent infections that are proven or strongly

suspected to be caused by susceptible bacteria. When culture and susceptibility information are

available, they should be considered in selecting or modifying antibacterial therapy. In the

absence of such data, local epidemiology and susceptibility patterns may contribute to the

empiric selection of therapy. [21-25].

MATERIALS AND METHODS

Materials

Clarithromycin was a kind gift from Torrent Pharmaceuticals Pvt. Ltd., India. Citric acid was

procured from (Loba chemie, Mumbai, India). Sodium Starch glycolate (Signet Chemicals

(Thomas baker(chemicals) pvt limited), Citric acid (Thomas baker (chemicals) Pvt Ltd).

http://en.wikipedia.org/wiki/Bacteria

http://en.wikipedia.org/wiki/Protein_synthesis

http://en.wikipedia.org/wiki/Ribosome

http://en.wikipedia.org/wiki/Peptide

http://en.wikipedia.org/wiki/Legionella_pneumophila

http://en.wikipedia.org/wiki/Haemophilus_influenzae

http://en.wikipedia.org/wiki/Haemophilus_influenzae

http://en.wikipedia.org/wiki/Streptococcus_pneumoniae

http://en.wikipedia.org/wiki/Neisseria_gonorrhoeae




Equipments

Melting point apparatus( PERFIT, India), Hot air oven(Microsil, India) , Electronic Weighing

Balance (Shimadzu Japan), U.V spectroscopy (Shimadzu, Japan).

API characterization

Characterization of API was done by development of calibration curve and also pre-formulation

studies. This was mainly done to ensure that the API which is to be used is of the optimum

quality and its properties could be judged.

Calibration curve of Clarithromycin

Calibration curve of Clarithromycin: Calibration curve was prepared in two solvents for

the API. These were Methanol and HCl. The procedure for determining absorbance maxima

was done by using two solvents explained as follows:

Methanol – 100 mg clarithromycin was dissolved in 100 ml methanol to prepare stock

solution. Now take out 1ml, 2ml, 3ml, 4ml, 5ml 6ml, 7ml, 8ml, 9ml and 10ml of stock

solution to prepare different concentrations of 100µg/ml, 200µg/ml, 300µg/ml, 400µg/ml,

500µg/ml, 600µg/ml, 700µg/ml, 800µ/ml, 900µg/ml and 1000µg/ml respectively. The base

line was corrected and lambda max was determined on UV spectrophotometer at 282 nm.

Absorbance of drug at different concentrations was calculated and graph was plotted.

Hydrochloric acid (HCl) -100 mg Clarithromycin acid was dissolved in 100 ml HCl to

prepare stock solution. Now take out 1ml, 2ml, 3ml, 4ml, 5ml 6ml,7ml, 8ml, 9ml and 10ml

of stock solution to prepare different concentrations of 100µg/ml, 200µg/ml, 300µg/ml,

400µg/ml, 500µg/ml, 600µg/ml, 700µg/ml, 800µ/ml, 900µg/ml and 1000µg/ml

respectively. The base line was corrected and lambda max was determined on UV

spectrophotometer at 288 nm. Absorbance of drug at different concentrations was

calculated and graph was plotted.

Pre-formulation Studies

Before starting with the formulation development the pre-formulation studies were conducted to

characterize the drug and the selection of Excipients was also based on the pre-formulation

studies. [27,28] It mainly involved two parameters Organoleptic and physicochemical properties

of the API used. This was mainly done to check the purity of the drug and any deviation could

also help to know if there is any detoriation involved.




a) Organoleptic properties (API)

Appearance

Colour

Odour

All the above studies were carried out by using no special equipment these were done by visual

assessment.

b) Physicochemical Properties (API)

Melting point:

For determination of melting point of Clarithromycin a melting point apparatus of

capillary type was used. The capillary filled with API was inserted and the temperature at

which the API started to melt was noted down as melting point of the API.

Partition coefficient:

The partition coefficient is the parameter used to determine the lipophilicity of the API. The

API with high lipophilic nature has high lipophilicity and thus a high partition coefficient and

vis-versa. The logarithm of the ratio of the concentrations of the un-ionized solute in the

organic and aqueous solvents is called log P: The log P value is also known as a measure of

lipophilicity (partition coefficient). It provides a means of characterizing the

lipophilic/hydrophilic nature of the drug. [29-32]

Drugs having values of P much greater than 1 are classified as lipophilic, whereas those with

partition coefficient much less than 1 are indicative of a hydrophilic drug. [33, 34] The partition

coefficient is commonly determined using an oil phase of n-Octanol and water.

It can be determined by the formula: [35]

Ko/w

Solubility Studies:

These pre-formulation studies formed the most important part of the formulation development;

as it formed the base for selection of excipients which had high solubility of the API. The

procedure followed was the shake flask method. [36-38] The solubility of Clarithromycin in

various solvents was determined by dissolving excess amount of API in 5ml of each of the

selected solvents in 10ml capacity stoppered vials separately. The mixture vials were then kept at




37±1.0 ◦C in a shaker bath for 24 h to get equilibrium.. The concentration of API was determined

in each solvent by UV spectrophotometer by scanning from 200-400nm (wavelength 282nm).

[39-42].

Method of preparation of Solid dispersion

Preparation of solid dispersion (kneading technique)

Preparation of Binary System

Binary mixtures was prepared by mixing accurate weight of Clarithromycin with sodium starch

glycolate in drug: polymer ratio of 1:1, 1:2, 1:3, 1:4, and 1:5 for 5 min using glass mortar and

pestle. The physical mixture was triturated using a small volume of water and Hcl (1:1) solution

to give a thick paste, which was kneaded for 30 minutes, and then dried at 45°C in an oven. The

dried mass was pulverized, passed through 60 mesh sieve size, then weighed, transferred to

airtight container and stored, and the percentage drug content was determined.

Preparation of Ternary system

Ternary mixtures was prepared by mixing accurate weight of Clarithromycin with sodium starch

glycolate and citric acid in Drug: polymer ratio of 1:5:2,1:5:4, and 1:5:5 for 5 min using glass

mortar and pestle. The physical mixture was triturated using a small volume of water and Hcl

(1:1) solution to give a thick paste, which was kneaded for 30 minutes, and then dried at 45°C in

an oven. [43,44] The dried mass was pulverized, passed through 60 mesh sieve size, then

weighed, transferred to airtight container and stored, and the percentage drug content was

determined.

Characterization of Solid Dispersion

Percentage yield

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

method, thus it helps in selection of appropriate method of production. Solid dispersions were

collected and weighed to determine practical yield (PY) from the following equation [45-49 ].

Percentage yield = Practical mass (solid dispersion) × 100

Theoretical mass (drug + carrier)

Drug content

The Physical mixture of solid dispersion equivalent to 50 mg of drug were taken and dissolved

separately in100 ml of Hcl. The solutions were filtered and were further diluted such that the

absorbance falls within the range of standard curve. [50-52] The absorbance of solutions were




determined at 288 nm by UV‐visible spectrophotometer. The actual drug content was calculated

using the following equation as follows

% Drug content = Practical drug content × 100

Theoretically drug content

Fourier Transform Infra red spectroscopy (FTIR)

The IR analysis of sample drug was carried out for qualitative compound identification. The

infrared spectra of Clarithromycin was performed on Fourier transformed infrared

spectrophotometer. This technique shines a beam containing many frequencies of light at once,

and measures how much of that beam is absorbed by the sample. Next, the beam is modified to

contain a different combination of frequencies, giving a second data point. This process is

repeated many times [53-58].

X-Ray Diffraction (XRD)

X-ray powder diffraction patterns were recorded on X-ray powder diffraction system, PAN

analytical spectris Pvt.Ltd., [59,60] Singapore using copper target, a voltage of 40 Kv and a

current of 30 mA. The scanning was done over 2θ range of 5º to 60º.

Scanning Electron Microscopy (SEM)

Photomicrographs of clarithromycin and Best ternary SD formulation were obtained by SEM

(JSM-6360; JEOL Ltd., Japan). The powder were mounted on double-sided adhesive tape and

sputtered with gold for 2 min using SPI sputter. Scanning Electron photographs were taken at an

accelerating voltage of 15 kV [61,62].

In vitro release studies

The drug release rate from solid dispersion was determined using USB apparatus Type II paddle

type dissolution apparatus. Weighed amount of formulation was filled into the capsule then it

was being placed in the basket. 0.1N Hcl was used as dissolution medium at 37±5ºc at a rotating

speed of 100 rpm.

Volume of dissolution media was kept at 900ml .5ml sample was withdrawn at predetermined

time. First sample was withdrawn at 10 min interval.

The samples were analysed specrtophotometrically at 288 nm to determine the concentration of

drug present. The initial volume of dissolution fluid was maintained by adding 5ml of fresh

dissolution [63-66].




RESULT AND DISCUSSION

Calibration curve of Clarithromycin

Calibration curve was prepared in two solvents for the API these were Methanol and Hcl. These

were determined in 100ug/ml-1000ug/ml for both the solvents.

Determination of absorbance maxima:

The procedure for determining absorbance maxima was done by using two solvents explained as

follows:

Methanol

100 mg clarithromycin was dissolved in 100 ml methanol to prepare stock solution. Now

take out 1ml, 2ml, 3ml, 4ml, 5ml 6ml, 7ml, 8ml, 9ml and 10ml of stock solution to prepare

different concentrations of 100µg/ml, 200µg/ml, 300µg/ml, 400µg/ml, 500µg/ml,

600µg/ml, 700µg/ml, 800µ/ml, 900µg/ml and 1000µg/ml respectively. The base line was

corrected and lambda max was determined on UV spectrophotometer at 282 nm.


Hydrochloric acid (Hcl)

100 mg Clarithromycin acid was dissolved in 100 ml HCl to prepare stock solution. Now

take out 1ml, 2ml, 3ml, 4ml, 5ml 6ml, 7ml, 8ml, 9ml and 10ml of stock solution to prepare

different concentrations of 100µg/ml, 200µg/ml, 300µg/ml, 400µg/ml, 500µg/ml,

600µg/ml, 700µg/ml, 800µ/ml, 900µg/ml and 1000µg/ml respectively. The base line was

corrected and lambda max was determined on UV spectrophotometer at 288 nm.





Pre-formulation studies

The Preformulation studies were carried out for the API in use which involved the organoleptic

and physicochemical properties of the drug. The results obtained were used in the formulation

development process.

a) Organoleptic properties: The basic properties of the API were tested as appearance, colour

and odour. It was observed as a powder which was white in colour having no odour and bitter in

taste.

b) Physico-chemical properties: The physicochemical properties were analysed to estimate its

ability to be used in the formulation. The various properties studied were as follows;

Melting point:

There is a linear correlation between log flux and reciprocal of melting point, indicating

that the lower melting point the better penetration [68]. The melting point of

Clarithromycin was found to be 210-222ºC.

Table1: Melting Points of Clarithromycin

Partition coefficient:

Partition coefficient was determined as ratio of concentration of drug in octanol to the

concentration of drug in water and the value were reported as log P. [69,70]

Concentration of drug in non aqueous phase

KO/W =

Concentration of drug in aqueous phase

Drug Melting point observed Reported value

Clarithromycin 217-220°C 210 -222°C




Table 2: Partition coefficient of Clarithromycin

Solubility studies:

The solubility studies conducted have the following results. The shows the solubility

results and also as per IP have been determined. The highlighted solvents are selected for

further study. The saturation solubility of Clarithromycin was calculated.

Table3: Solubility profile of Clarithromycin in different solvents

Evaluation of solid dispersion

Percentage Drug yield

Percentage drug content was in the range of 90 % to 98 %

Table 4: Percentage drug yield of solid dispersion

TD-Ternary solid dispersion

Percentage drug content

Percentage drug content was in the range of 60% to 97.5%

Table 5: Percentage drug content of solid dispersion

Drug Partition coefficient observed Reported value

Clarithromycin 2.91±01 2.92

S.no Solvent Amount in mg/ml Inference

1 Acetone 136.36±0.22 Soluble

2 Water 1.09±0.17 Insoluble

3 Methanol 4.27±0.46 Partially soluble

4 Ethanol 3.85±0.15 Partially soluble

S.no Batch no % yield

1 TD1 98%

2 TD2 89%

3 TD3 85%

S.no Batch no % drug content

1 TD1 97.5%

2 TD2 60.0%

3 TD3 85.6%




Scanning electron microscopy (SEM)

Surface characteristics of ternary solid dispersion were analysed using a scanning electron

microscope. This technique is useful in the examination of internal and external morphology of

solid dispersions. The SEM analysis of the samples was performed to investigate the surface

morphology and homogeneity of the particles. The samples of optimized solid dispersion were

sputter-coated with gold at room temperature before examination to render the surface of

particles Electroconductive [71-76].The SEM analysis of the sample was done by Jeol JSM-840

(Japan) scanning electron microscope. SEM analysis of clarithromycin was shown in fig 510 and

SEM of final formulation (1:5:2) ternary solid dispersion was shown in fig 5.11.

.

Fig 1: Scanning electron micrographs Fig 2: Scanning electron micrographs

of final formulation of Clarithromycin

XRD ( X-ray Diffractometry)

X-ray diffracometry (XRD) spectra Drug and ternary systems with carriers are presented in

Figure 3. The x-ray diffractogram of clarithromycin has sharp peaks at diffraction angles (2θ)

12.26-, 15.88-, 19.88-, 22.08-, and 23.92- showing a typical crystalline pattern. However, all

major characteristic crystalline peaks appear in the diffractogram of both physical mixtures and

solid dispersion system. Moreover, the relative intensity and 2θ angle of these peaks remains

practically unchanged [77-80]. Thus it can be clearly suggestive from x-ray data that there is no

amorphization of clarithromycin and aliquots were withdrawn, filtered (0.22 μm pore size) and

spectrophotometrically assayed if it is still in its original crystalline form.




Fig 3: XRD of Clarithromycin

Fig 4: XRD of ternary solid dispersion (1:5:2)

Table 6:In vitro release studies

S.no Time (in

min)

% cumulative drug

release(1:5:2)

% cumulative drug

release(1:5:4)

% cumulative drug

release(1:5:5)

0 0 0 0 0

1 10 67.85±1.02 20.743±0.63 33.7±0.57

2 20 69.86±0.04 23.23±1.09 36.13±1.08

3 30 70.19±0.51 26.22±1.87 38.61±1.93

4 40 72.07±1.07 28.9±0.27 39.27±2.08

5 50 75.95±0.08 29.23±1.71 40.5±1.52

6 60 77.72±1.6 32.78±1.77 41.5±0.57

7 70 79.611±1.12 36.12±0.18 42.21±0.48

8 60 80.5±1.08 41.81±0.71 52.69±0.67

9 90 83.49±0.07 44.4±0.61 61.2±0.51

10 100 84.49±1.73 45.39±0.34 65.12±0.98

11 110 89.38±.092 45.44±0.77 71.01±1.1

12 120 90.34±0.52 45.49±1.09 75.6±1.52

13 130 91.38±0.19 46.47±0.55 76.9±1.5

14 140 94.49±0.05 46.99±0.67 78.8±0.26

15 150 95.6±0.12 47.51±0.78 80.83±1.1

16 160 96.8±1.15 48.97±0.89 83.0±0.57

17 170 98.62±0.09 52.69±1.21 85.06±0.32

Position [°2Theta] (Copper (Cu)) 10 20 30 40

Counts

0

500

1000

1500

FORMULATION 1-5-2-CK

Position [°2Theta] (Copper (Cu))

10 20 30 40

Counts

0

2000

4000

6000

8000

PURE DRUG-CK




Fig 4 : Cumulative Percent Release of Clarithromycin from ternary Solid Dispersions

Series1: Ternary solid dispersion 1:5:2



CONCLUSION

The result of the present study showed that the solid dispersion had enhanced the dissolution of

drug . Solid dispersions of Clarithromycin were prepared by using sodium starch glycolate and

citric acid showed better drug release. On the basis of result of Clarithromycin, sodium starch

glycolate and citric acid solid dispersions in 1:5:2 ratio (TD1) revealed better solubility and

dissolution rate. This study was started to establish the possibility of preparing solid dispersions

with improved aqueous solubility and dissolution rate, which will solve the difficulties in the

development of pharmaceutical dosage forms of Clarithromycin, poorly water soluble drug due

to their limited water solubility, slow dissolution rate and low bioavailability. Solid dispersion

was prepared by Kneading method thus may be an ideal means of drug delivery system for

poorly water soluble drugs.

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