PHYSICAL CHARACTERIZATION AND ENHANCEMENT THE …

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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

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Pharmaceutical Sciences RESEARCH ARTICLE……!!!

PHYSICAL CHARACTERIZATION AND ENHANCEMENT THE

SOLUBILITY OF VALSARTAN BY SOLID DISPERSION METHOD

Nisha Upadhyay*1, Dr. Shridhar J. Pandya

1, Maulesh Vyas

1

Department of Pharmaceutics, Pioneer Pharmacy Degree College, Vadodara, Gujarat.

KEYWORDS:

β- Cyclodextrin,

Hydroxypropyl- β-

Cyclodextrin, Valsartan,

Solid Dispersion, Solvent

Evaporation, Phase

solubility Study.

For Correspondence:

Nisha Upadhyay*

Address:

Department of

Pharmaceutics, Pioneer

Pharmacy Degree

College, Vadodara,

Gujarat

Email id-

[email protected]

ABSTRACT

Solid dispersions have been widely used to enhance the solubility of

poorly water soluble drugs. In this study, solid dispersions of

valsartan (VAL) with β- Cyclodextrin and Hydroxypropyl- β-

Cyclodextrin were prepared by Solid Dispersion & Solvent

Evaporation Technique in the Molar ratios of 1:1, & 1: 0.5. The

prepared solid dispersions were investigated by X-ray diffraction,

infrared spectroscopy, differential scanning caloriemetry and Phase

solubility studies. X-ray diffraction and differential scanning

caloriemetry have shown that β- Cyclodextrin and Hydroxypropyl-

β- Cyclodextrin inhibit the crystallinity of valsartan. The infrared

spectroscopy suggests that there was no chemical interaction

between Valsartan and β- Cyclodextrin and Hydroxypropyl- β-

Cyclodextrin. Phase solubility studies showed that the drug solubility

was increased as the concentration of polymer content was increased.

The prepared solid dispersions were analysed for percentage

practical yield, drug content and dissolution studies. The results

demonstrated that the dissolution of solid dispersions was enhanced

greatly at ratios of 1:1when compared with that of remaining ratios

of 1: 0.5, which shows 97.90% of drug release within 60 minutes.

The drug release from the solid dispersions was found to follow the

drug release mechanism could be erosion.

mailto:[email protected]



INTRODUCTION:

“Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or

a sustained diastolic blood pressure (DBP) of greater than 90 mm Hg.”[1]

A family history of hypertension

increases the likelihood that an individual will develop hypertensive disease Diabetes, Stress,

Atherosclerosis, Smoking, alcohol intake, Chronic kidney disease, Species, Too much salt intake in the

diet, Disorders of adrenal glands, Obesity. These are the causes for hypertension. Hypertension affects

approximately 1 billion subjects worldwide & the prevalence in Europe has been estimated to be

approximately 44%, in some countries reaching up to 55%. [2]

Valsartan is a new potent, highly selective and orally active antihypertensive drug belonging to the family

of angiotensin-II type 1 receptor antagonists. It inhibits angiotensin-II receptors, by relaxing blood vessels

and causing them to widen, which lowers blood pressure and improves blood flow. Valsartan is available

as a white, microcrystalline powder with a melting range of 105- 110°C. The partition coefficient P is

0.033 (log P = 1.499). The half life of Valsartan is 6 hrs and the oral bioavailability is 23%. The water

solubility of Valsartan is 2.34e-02 g/l.[3]

Valsartan blocks the vasoconstrictor and aldosterone-secreting

effects of angiotensin II by selectively blocking the binding of angiotensin -II to the AT1 receptor in many

tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the

pathways for angiotensin II synthesis. May be used as a first line agent to treat uncomplicated

hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line

agent to delay progression of diabetic nephropathy. Valsartan is a specific and selective type-1 angiotensin

II receptor (AT1) antagonist which blocks the blood pressure increasing effects angiotensin II via the renin-

angiotensin-aldosterone system (RAAS).[4]

Solubility is one of the most important properties impacting bioavailability because of its role in

dissolution. It is one of two factors defining the Biopharmaceutics classification system (BCS) [5]

.

Phase Solubility Study: [6.7,8,9]

The most widely used approach to study inclusion complexation is phase solubility method, described by

Higuchi and Connors. Higuchi and connor method is used to confirm that actual complex is formed or not.

[8]



Fig. no. -1: phase solubility diagram

[9]

A type curves indicate, the formation of soluble inclusion complexes

B type suggests the formation of inclusion complexes with poor solubility.

BS type response denotes complexes of limited solubility and a BI curve indicates insoluble

complexes.

„A‟ type -curves are subdivided into AL (linear increases of drug solubility as a function of CD

concentration), AP (positively deviating isotherms) and AN (negatively deviating isotherms)

Subtypes.

The phase solubility study for my dissertation is carried out for Valsartan: β-CD and Valsartan:

HP-β-CD

Techniques Of Solubility Enhancement: [10]

A. Inclusion Complex: Kneeding, Co-Precipitation, Mixture

B. Solid Dispersion

C. Spray Drying Technique

D. SCF Technology

E. Solvent Evaporation Method

F. Freeze Drying Method

G. Self Micro Emulsifying Drug Delivery System

H. Particle Size Reduction



MATERIAL AND METHOD:

Valsartan was procured from Alembic Pharmaceuticals, Vadodara as gift sample. Β- Cyclodextrin &

Hydroxypropyl- Β- Cyclodextrin, procured from Balaji Drugs, Surat. All other reagents used were of

analytical grade.

Solubility study of Valsartan in different pH medium:

The solubility studies in different pH [11]

of valsartan were determined in various fluids such as pH 1.2, pH

6.8 and pH 7.4 buffers. The similar procedure was followed as per above saturation solubility studies.

Phase solubility studies:

Phase solubility studies of valsartan, was carried out to evaluate the possible solubilising effect of the

carrier by adding an excess of drug to 10 ml of aqueous solutions containing increasing concentrations of

β- Cyclodextrin & Hydroxypropyl- β- Cyclodextrin (0.001-0.005 M) and shaken at 25°C in a temperature

controlled bath for 72 hrs. Drug concentrations were assessed spectrophotometrically. The apparent

stability constant (Kc) of the drug was calculated according to the following equation.

slope

Kc = --------------------------

Intercept (1-Slope)

PREPARATION OF SOLID DISPERSIONS:

Solid Dispersion:

Materials Used: Valsartan Drug, β-Cycledextrin, Hydroxypropyl- β- Cyclodextrin, water.

Procedure: Drug was weighed accurately in their molar ratio and poured in porcelain dish, β-cd And hp β-

Cd were also weighed in their molar ratio and poured in that porcelain dish. Then lable it with val:β-cd

(1:1), (1:0.5) And, Val:hp-β-cd (1:1), (1:0.5) Respectively. Then in each porcelain dish, little amount of

water was added to prepare the dough mass, and then that dough mass was dried in oven at 30◦c. after

drying of it the complex was scrapped & passed through sieve no 80. The complexes were packed in Zip

lock bag with appropriate label. & the % practical yield was calculated.

Solvent Evaporation:

Materials Used for the Solid Dispersion: Valsartan Drug, β-Cycledextrin, Hydrodypropyl- β-

Cyclodextrin, water, Methenol.

Procedure: Weigh accurately Valsartan, β-cd (1:1), (1:0.5) and hp-β-cd (1:1), (1:0.5) respectively in their

molar ratios. The drug was dissolved in 20 ml methanol, and β-cd & hp-β-cd were dissolved in 20 ml

distilled water. The solution of β-cd was stirred on magnetic stirrer add the drug solution was added drop



wise in that solution and stirred until the whole solvent was evaporated. Then the dried complex was

scrapped out and collected in the zip lock bag. The complex was dried and the % practical yield was

calculated.

Characterization of Solubility Improvised Complex:

Saturation Solubility Study:

The saturation solubility studies were carried out to determine the solubility of solid dispersions. Weighed

amount of solid dispersions were added to 250 ml conical flasks containing 15 ml of 1.2 pH buffer. The

sealed flasks were shaken for 24 hrs at 37±0.5ºC.Then aliquots were filtered through whatmann filter

paper. The concentration of Valsartan was determined by UV spectrophotometer at 250 nm.

% Practical yield:

Percentage practical yield is calculated to know about percent yield or efficiency of any method, thus its

help in selection of appropriate method of production. Solid dispersions were collected and weighed to

determine practical yield (PY) from the following equation.

Practical Yield

PY(%) = -------------------------- ×100

Theoretical Yield

% Drug content:

10 mg of solid dispersions were weighed accurately and dissolved in 10 ml of methanol. The solution was

filtered, diluted suitably and drug content was analyzed at 216nm by UV spectrophotometer. Each sample

analyzed in triplicate. Actual drug content was calculated for all batches using the equation as follows in

solid dispersion Actual Valsartan content in weight:

Quantity of solid dispersion

%Drug Content = ---------------------------------------------- ×100

Theoretical amount of Valsartan

In vitro dissolution studies

In vitro release profile for each solid dispersion as well as pure drug was performed using USP Type II

dissolution apparatus. Sample equivalent to 80 mg of Valsartan was added to 900ml of 1.2 pH buffer at

37+ 0 .5°C and stirred at 50 rpm aliquot of 5 ml was withdrawn at time intervals of 15, 30, 45, 60,90, &125

min. The withdrawn volume was replenished with the same volume of dissolution medium in order to keep

the total volume constant. The absorbance of the samples was measured at λmax 250 nm after suitable



dilution if necessary, using appropriate blank. Results of in vitro drug release studies obtained from

absorbance data were shown in table.

FT-IR studies : ( Furier Transform Infra Red Spectroscopy)

Procedure: FTIR spectra for drug alone and with excipients were recorded using a FTIR

spectrophotometer with KBR pellets to study drug-excipients and excipient-excipient compatibility. Drug

excipient interaction was determined by performing infrared spectroscopy using FTIR (Bruker α ,

Mumbai).

The FTIR studies were carried out by the pressed pellet technique using a KBr press in which the KBr was

taken and kept in a hot air oven for two hours for the removal any moisture. The above dried KBr was

taken for the preparation of pellets of drug, and the selected formulations. The prepared pellet was placed

in the sample holder and kept in the instrument to record the FTIR peaks.

DSC of Complex: (Differential scanning calorimetery)

Procedure: Assessment of possible incompatibilities between an active drug substance and different

excipients forms an important part of the preformulation stage during the development of solid dosage

form. Differential Scanning Calorimeter (DSC TA- 60WS) allows the fast evaluation of possible

incompatibilities, because it shows changes in the appearance, shift of melting endotherms and exotherms,

and/or variations in the corresponding enthalpies of reaction. The DSC thermograms of pure drug and

complex were recorded. The thermal analysis was performed in a nitrogen atmosphere at a heating rate of

100 C/min over a temperature range of 25

0 C to 150

0 C. DSC study was performed for Valsartan and

complex of drug.

XRD of Complex (X-Ray Diffraction)

Procedure: With the help of a spatula place the finely ground powder on to an open hole aluminum holder

and fill it. With the help of a microscopic slide press the sample gently to prepare an absolutely flat

diffracting surface. Place the sample plate (ready for analysis) in the sample holder of the instrument, X-

Ray Diffractometer (Philips Holland/X‟Pert MPD Model ). Set the required conditions and start analysis to

collect the diffractogram.



RESULT AND DISCUSSION:

Saturated Solubility Study pH 1.2, % Drug Content & % practical Yeild:

Table No: 1 Saturated Solubility Study pH 1.2, % Drug Content & % practical Yeild of Complex:

CODE %DRUG CONTENT SOLUBILITY % PRACTICAL

YEILD

VBSD1 94.15% 3.04

97.03%

VHSD2 91.54% 2.30

89.54%

VBSE1 97.40% 3.17

98.43%

VHSE2 96.69% 2.61

86.49%

From the above results of Solid Dispersion and Solvent Evaporation it was found that the solubility of

Valsartan was improvised using Different polymers with different solubility enhancing techniques, among

them the Solvent Evaporation Method with β- Cyclodextrin in the Drug : Polymer Ratio 1: 1 shows the

highest solubility , % Drug Content & % Practical Yeild.

Solubility Study of Valsartan in Various pH medium:

Weakly basic drugs and weakly acidic drugs or salts thereof demonstrated pH-dependent solubility. For

weak acids, as the pH value increases, the solubility of the acid also increases due to the contribution from

the ionizedform. If log P of any drug is exceeding 1, indicating that the compound has a rather hydrophilic

character at physiological pH.

In case of valsartan, it contains two weakly acidic functions with pKa values of 3.9 and 4.7 and one

asymmetric centre and (co) exists in solution at physiological pH values as the undissociated acid, the

monoanion and the di-anion.

In pH dependent solubility studies of valsartan (Table.No.1) the solubility was low at pH 1.2 and high at

pH 7.4. Proportionate increase in solubility was observed at pH 6.8.

Table No.2: pH dependent solubility of Valsartan

Sr.No. Solubility Reported solubility(mg/ml) Performed

solubility(mg/ml)

1 Distiled water 0.567 0.632

2 1.2 pH buffer 0.116 0.588

3 6.8 pH buffer 0.304 0.740

4 7.4 pH buffer 0.598 0.776



Phase Solubility Study:

Phase solubility Diagrams obtained could be classified as AL type, Solubility of Valsartan increase as the

concentration of β-CD & HP- β-CD (1-5mM) , as slope of all these diagram was less than 1.0, it was

possible to assess a 1:1 stoichiometry & Kc, the value of Kc is more in VAL: HP- β-CD( 0.458 M-1 )

, than

VAL: β-CD ( 180M-1

), which shows that VAL forms more stable complex with : HP- β-CD than β-CD,

may be due to extension of hydrophobic cavity without steric hinderence and provision of greater inclusion

ability.

Fig. no.2 - phase solubility study of VAL:β-CD & VAL: HP-β-CD.

Micromeritics properties of drug, excipients and complexes:

There are different micromeritics properties which are used for the flow property of the drug, polymer and

complex. which are given below:

Table No.3: Bulk & Tapped Density, Angle of Repose, Hausner’s ratio, Carr’s compressibility

index:

Sr.

No

Drug/Polymer/

Complex

Bulk

Density[B.D]

Tapped

Density[T.D]

Angle of

Repose θ

H.R= [T.D/

B.D]

C. I. =

[(T.D – B.D/ T.D) * 100]

1 Valsartan pure 0.23 0.34 32.92 1.47 76.87

2 β-CD

pure

0.28 0.33 30.22 1.17 71.79

4 Solid

Dispersion

Val:β-CD (1:1)

0.52 1.0 13.03 1.92 47.91

5 Solvent

Evaporation

Val:β-CD (1:1)

0.46 0.65 20.47 1.41 53.90

0

1

2

3

4

AB

SO

RB

AN

CE

CONCENTRATIONTION

PHASE SOLUBILITY STUDY

ABS HP-B-CD(250 NM)

ABS B-CD(250NM)



In-Vitro Dissolution Studies:

Dissolution study complex ofValsartan have exhibited varied release profiles and shown in Fig. no. 3.

in which it was found that the Drug release from VAL: β-CD Complex is Higher than VAL: HP- β-CD

Complex , which are prepared by Solvent Evaporation Technique.AS per the Phase solubility Study HP- β-

CD shows more stable complex than β-CD Complex, which interferes with the Drug Release of the

Valsartan. VAL: β-CD complex shows more drug release from the complex as compared with the VAL:

HP- β-CD complex.

Fig. no. 3 –Drug Release profile of VAL: β-cd and VAL: HP-: β-cd

Table no.4: Drug release of VAL: β-CD Drug Release

FT-IR Spectrophotometry:

FT-IR spectra of solid dispersions of VAL and β-CD , HP- β-CD prepared by Solvent Evaporation & Solid

Dispersion are shown in Fig. no.: 4-7 . The principal absorption peaks of VAL were observed at 1166 cm-

0

10

20

30

40

50

60

70

80

90

100

15 30 45 60 90 120

% D

RU

G R

EL

EA

SE

TIME (MIN)

DISSOLUTION PROFILE

%Drug Release of Valsartan pure Drug

% Drug Release (β-CD)

% Drug Release (HP- β-CD)

Time

(min)

%Drug Release of

Valsartan pure Drug

% Drug

Release (β-CD)

% Drug Release

(HP- β-CD)

15 5.12 48.08 40.33

30 21.34 69.00 58.54

45 29.67 76.16 68.00

60 37.56 83.75 72.87

90 41.45 92.54 76.41

120 48.56 94.39 78.75



1 (N-N stretch), 1596 cm-1 (N-H bending), 1729 cm-1 (C=O stretch), 1204 cm-1 (C-N stretch) and 2963

cm-1 (methyl bond). Same peaks of N-N and methyl bond were present without much shifting in the

spectra of solid dispersion & Solvent Evaporation of VAL and carriers suggested no interaction between

the drug and the carriers.

Fig.no.4- FT-IR spectra of pure Valsartan

Fig. no. 5- FT-IR spectra of VAL: β-CD(solid Dispersion)



Fig. no.6- FT-IR spectra of VAL: HP-β-CD (Solid Dispersion)

Fig. no.7- FT-IR spectra of VAL: β-CD( Solvent Evaporation)

DSC Thermal Analysis:

From DSC thermograms the melting point of pure drug valsartan was found to be 104°C which is the

nearer value reported in literature hence the procured drugs are pure forms. The solid dispersion of DSC

thermograms of valsartan indicated that there are no interactions between the drugs and selected polymers

which can be accessed from the peaks in the DSC thermograms. The DSC graphs of the solvent

Evaporation were shown in Fig. no. 8-9.



Fig. no.8- DSC of Pure Valsartan Drug

Fig. no. 9- DSC of VAL: β-CD complex (Solvent Evaporation)

X-Ray Diffraction Study (XRD):

Valsartan exhibited characteristic diffraction pattern, whereas in the case of solvent Evaporation with all

the carriers, the sharp diffraction peaks have been changed. The intensity of sharp peaks in the

diffractograms of solvent Evaporation is reduced considerably indicating the reduced crystallinity of the

drug in all the cases of solvent Evaporation when compared to pure drugs. This may be due to partial

conversion of the drugs to amorphous state from crystalline state. In regards to the studies of complexes

between β-CD and VAL prepared using the solid dispersion & Solvent Evaporation, there was no solid

residue generation at the end of analyses. This indicates complete decomposition of the substances. (Fig.

no. 10-11)



Fig. no. 10- XRD of Pure Valsartan Drug.

Fig. no.11- XRD of VAL: β-CD complex (Solvent Evaporation)

CONCLUSION:

The results of the present study clearly demonstrated that suitability of selection of β-CD & HP- β-CD in

the preparation of solid dispersions. These prepared solid dispersions are showing promising results in

enhancing the solubility of poorly soluble drug such as valsartan. Amongst the solid dispersions prepared,

solid dispersions prepared using sVAL: β-CD shown the better release of valsartan (80.76%) within 60 min

in comparison with that of VAL: HP- β-CD. Thus, the selected polymers (β-CD & HP- β-CD) are

considered to be very good carriers in increasing the solubility, dissolution rate and thereby bioavailability

of poorly soluble drug candidates. Further studies are required to confirm the applicability of these

polymers in formulation technology. DSC & XRD also shows good properties of the complex, they shows

that the complex is converted in to the amorphous form, which shows better solubility profile.



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http://www.emea.europa.eu/

http://www.drugbank.ca/drugs/DB00966

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