ISSN: 0975-766X CODEN: IJPTFI Available Online … IJPTFI Available Online through Research Article...

Deepthi A* et al. International Journal Of Pharmacy & Technology

IJPT| July-2015 | Vol. 7 | Issue No.1 | 8131-8145 Page 8131

ISSN: 0975-766X

CODEN: IJPTFI

Available Online through Research Article

www.ijptonline.com PREPARATION AND EVALUATION OF VALACYCLOVIR MICROSPHERES

Ramesh Y1, Deepthi A*

1, Madhavi C

1, Mamatha D

1, Gobinath M

1

Department of Pharmaceutics, Ratnam Institute of pharmacy, Pidathapolur (V & P), Muthukur (M),

SPSR Nellore (dist), Pin- 524346, A.P., India.

Email: [email protected]

Received on 29-06-2015 Accepted on 22-07-2015

Abstract:

The objective of the present study was prepared and evaluate valacyclovir microspheres by using emulsion solvent

diffusion technique.valacyclovir is loaded with ethyl cellulose & HPMC microspheres and it was prepared by emulsion

solvent diffusion method. The results of FTIR indicated the stable character of valacyclovir microspheres loaded with

ethyl cellulose microspheres and also absence of drug polymer interaction. The compatability studies like FTIR & DSC

were used to investigate there is no incompatability in the formulation. The Morphological particle size of valacyclovir

microspheres is carried out by SEM. The Microspheres were evaluated for total formulation codes is VM 1 to VM 9.

The Percentage Yield was found to be 73.33% to 88.88%.Drug content was 65.8 to 98.2. The Particle size of

microspheres 10 µm to 450 µm, Drug entrapment efficiency was 51.8% to 91.1 %, The drug loading capacity was

54.8% to 97.9%. The swellability studies was 0.2 sec to 1.5 sec. Invitro dissolution studies of best formulation VM8 was

found to be 88.92%. The invitro drug dissolution data obtained was fitted to various mathematical models such as zero

order, first order, Higuchi matrix & Krosmeyer peppas model. The valacyclovir microspheres follows model having

R2 value was 0.937,0.399,0.899,0.785 & m Value was 1593,0.061,11409,2.560 . The release of drug from the

microspheres extended up to 45 Mints. The valacyclovir loaded with ethyl cellulose & HPMC microspheres were

prepared under optimised conditions that shows good release characteristics.

Key words:

Valacyclovir, Microspheres, Invitro dissolution studies, FTIR & DSC.



Introduction

The Microsphere is defined as the spherical particle size varying with diameters in the micrometer ranges from 1μm to

1000μm, it containing a core substance. The microspheres containing synthetic polymers having characteristic free

flowing powders. They are biodegradable in nature, and also having a particle size is less than 200

micrometer.Microspheres is one of the multiparticulate drug delivery systems. It is prepared to obtain the prolonged (or)

controlled drug delivery, to improve the bioavailability or stability and to target the drug to specific sites. It is defined as

a solid spherical particles ranging from 1 to 1000μm, containing dispersed drug in microcrystalline form. Ethyl cellulose

is non-biodegradable, bio-compatible, non-toxic natural polymer. It is widely used in oral and topical formulation5.

Microspheres have gained wide acceptance as a means to achieve oral and parenteral controlled drug delivery systems.

Valacyclovir is an antiviral drug. It is used in the management of herpes simplex, herpes zoster (shingles), and herpes B.

It is a prodrug and it is being converted in vivo to acyclovir. Valacyclovir is a prodrug1. It incorporates the

monophosphate form into the viral DNA. It results in chain termination. It is also shown that the viral enzymes cannot

remove the aciclo-GMP from the chain, which results in the inhibition of further activity of DNA polymerase.

Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to

acyclovir which has been demonstrated the antiviral activity against HSV types 1 Herpes simplex virus (HSV-1) and 2

(HSV-2) and VZV (varicella zoster virus)both in cell culture and in vivo. The inhibitory activity of acyclovir is highly

selective due to its affinity for the enzyme thymidine kinase (TK). It is encoded by HSV and VZV2.

Materials

The pure drug of valacyclovir was obtained from Hetero drugs private limited, Hyderabad and the excipients like Ethyl

cellulose & HPMC were obtained from Tiny pharmaceuticals and the organic solvent Ethanol was obtained from

Himalaya pvt limited Nellore.

Methods

IR studies: In the preparation of drug and polymer may interact with each other, It leads to the instability of drug

preformulation studies regarding the drug and polymer interaction.They are very critical in appropriate polymer. FTIR

Spectroscopy was employed to ascertain the compatibility between Valacyclovir and the cellulose polymer3.

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

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

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

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

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

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

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

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



Differential scanning calorimetry: The output of a DSC is a plot of heat flux (rate) versus temperature at a

specified temperature rate. It provides information about the physical properties of the sample. It is in crys talline

or amorphous in nature .In formulations it demonstrates a possible interaction between the drug and

polymers,according to the thermograms4.

Morphology of the Particles:

Scanning Electron Microscopy: Scanning Electron Microscopy is a technique (SEM). It is very useful in ascetaing the

overall shape and morphology of the Microspheres. The morphology and surface appearance of both coated

microspheres and Ethyl cellulose microcapsules were found by Scanning Electron Microscopy (SEM)5. The particles

were freeze dried, and coated with gold palladium to achieve a film of 20nm thickness (Sputter coater, Balzers SCD 004,

Liechtenstein) and observed microscopically (SEM, JSM-6400, Tokyo, Japan).

Procedure of Valacyclovir Microspheres: The valacyclovir microspheres were obtained by the Emulsion solvent

Diffusion method by using distilled water as an external phase.The internal phase consists of a good solvent ethanol

including valacyclovir with concentration of polymers like HPMC& Ethyl cellulose.The drug and polymers were

codissolved in an organic solvent mixture with polymers with different ratio.The drug solution was slowly injected via

syringe in to the external water phase under agitating .The system was stirred at 800 rpm continuosly for about I

hr.Along with the good solvent diffusing in to the poor solvent. The droplets gradually solidified & formed

microspheres.The system was filtered to separate the microspheres from the preparation system.The resultant product

was washed with distilled water& dried.The whole process was carried out at room temperature6.

Evaluation of Microspheres

Percentage production yield (PY)

Practical mass of microspheres

PY (%) = × 100

Theoretical mass

Each formulation was carried out in triplicate and the PY (%) was calculated.

Entrapment efficiency: The Microspheres was prepared by Emulsion solvent diffusion technique .It was centrifuged at

14,000 rpm for 40 min at 10°C. The amount of Valacyclovir is encapsulated into the Ethyl cellulose & HPMC7. It was



the difference between the total amounts that are used to prepare the Microspheres and the amount was found in the

supernatant. The amount of free Valacyclovir in the supernatant was analyzed by UV-spectrophotometer at 250-255 nm.

It is calculated by the following equation

M Initial drug – M Free drug

%EE = X100

M Initial drug

Where

“MInitial drug” is the mass of initial drug used for the assay

“MFree drug” is the mass of free drug detected in the supernatant after centrifugation of the aqueous dispersion.

Drug loading efficiency: Drug loading efficiency was removed and the remaining sediments (precipitations) were

washed by distilled water.It is dispersed in a mixture of chloroform: acetone (2.5:2.5, v/v) in a 10 mL volumetric flask.It

is used to ensure the complete extraction of drug from Microspheres, then it was sonicated for 30 min.The volume was

made-up to 10 ml with chloroform8. The resulting solution was centrifuged at 14,000 rpm at 10°C for 30 min and

supernatants were obtained and analyzed in triplicate for the loaded drug by UV spectrophotometer at 250-255nm.

Particle size determination: Particle size of Microspheres was determined by using an optical microscopy method.

Approximately 100 microspheres were counted for particle size. The distribution of particle size was measured by

suspending in water9.

Equilibrium swelling studies of microspheres: A preweighed amount of microspheres was placed in Phosphate buffer

(pH7.4)10

. It is allowed to swell at a constant weight. The microspheres were removed and blotted with filter paper, and

their changes in weight were measured. The degree of swelling was calculated by the following formula.

α=wg-wo/wo

Where

Wo is the initial weight of the microspheres and

Wg is the weight of the microspheres at equilibrium swelling in the medium.



Drug content determination

50mg of Valacyclovir microspheres was crushed and suspended in water to extract the drug from the microspheres.

After 24 h, the filtrate was assayed spectrophotometrically at 234 nm for drug content against water as blank11

.

In-vitro drug release studies

In-vitro drug release studies were carried out by using USP XXIV dissolution apparatus type II, with 500 ml of

dissolution medium.It is maintained at 37±0.5 °C for 45 Mits, at 50 rpm, and pH 7.4 ± 0.2 phosphate buffers as

dissolution medium. It is also subjected to the In-vitro drug release studies. The results of In-vitro release

profile obtained for all the formulations were plotted in modes of data treatment as follows:

1. Log cumulative percent drug remaining versus time (first order kinetic model)

2. Cumulative percent drug release versus square root of time (Higuchi model)

3. Cumulative percent drug remaining versus time (zero order kinetic model)

4. Log cumulative Percent Drug released versus log time (korsmeyer’s model)

Results and Discussion:

Compatability studies for FT IR studies

The IR spectrum of the pure Valacyclovir sample is recorded by FTIR. This is compared with standard functional group

frequencies of Valacyclovir as shown in Table no 2. FTIR spectrum of formulation shown in Fig. 1 to 5.

Table No-1: Formulations of Valacyclovir Microspheres.

SI.

No

Ingredients VM1 VM 2 VM 3 VM 4 VM 5 VM6 VM 7 VM 8 VM 9

1 Valacyclovir 1.5 1 0.5 2 2.5 2 3 2.5 3

2 Ethyl

Cellulose

1 1.5 1 1.5 2 2.5 2 2 2.5

3 HPMC 0.5 0.5 0.5 1 1.5 1 0.5 1 1.5

4 Ethanol 10 ml 10 ml 10 ml 10 ml 10 ml 10 ml 10 ml 10 ml 10 ml

5 Distilled

water

100

ml

100

ml

100

ml

100 ml 100

ml

100

ml

100

ml

100

ml

100

ml



Table No-2: Interpretations of FTIR Spectra of Pure Drug and Excipients.

Observed

peak

Characteristic peak Bond Functional Groups

Pure Drug – VALACYCLOVIR

3462.22 3300-3500 -N-H- Amines

3342.64 3300-3500 -N-H- Amines

3236.55 2700-3300 C-H Stretch Aromatics






DRUG + ETHYL CELLULOSE + HPMC

3442.94 3300-3600

3000-3700

C=0 Stretch

O-H Stretch

Hydrogen bonded

alcohols and

phenols

3415.93 3300-3600

3000-3700

C=O Stretch

O-H Stretch

Hydrogen bonded

alcohols and phenols

3358.07 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

Hydrogen bonded


3319.49 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

Hydrogen bonded


3305.99 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

carboxylic acids or

H-Bonded alcohols

3269.34 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

Hydrogen bonded


3130.47 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

Hydrogen bonded


3111.18 2700-3300

3000-3700

C-H Stretch

O-H Stretch

Aromatics

Hydrogen bonded








Differential scanning calorimetry: The pure drug of DSC sample of spectra the Endothermic peak is 122.50c and -

10.65 mw.The mixture sample contain Drug (valacyclovir), Ethyl cellulose, HPMC the endothermic peak is 121.9oc &-

9.29 mw, the exothermic peak of the mixture 286.2 oc & -7.50 mw ,the compatibility of drug& excipients shows there

is no compatibility in the formulation. As shown in Table No.3. It is suitable for performing formulation of

microspheres. The DSC spectra as shown in fig.6& 7.

Table No-3: Interpretations of DSC Spectrum.

Morphology of the Particles: The following methods are used to determine the particle size, size distribution, and

morphology of Valacyclovir microspheres.

Scanning Electron Microscopy: Morphology and structure of Microspheres were determined by using scanning

electron microscopy (SEM) and photomicrographs were taken at suitable magnifications. The photographs of the

optimized formulation are taken by Scanning electron microscopy are shown in the Fig.no 8.

Evaluation of Valacyclovir Microspheres

Percentage Yield: The production yield of microspheres of Valacyclovir using HPMC & Ethyl cellulose results as

shown in Table no 4 and Fig.no 9

Drug entrapment efficiency (%EE) : The Percentage entrapment efficiency of VM 1- 91.1%, VM2- 87.1%, VM3-

77%, VM 4 – 66%, VM 5- 63.9%, VM 5 – 63.9%, VM 6- 60.8%, VM 7- 58.8, VM 8-54.5, VM 9- 51.8%, The VM 8

shows the good formulation & high efficiency. Results as shown in Table No 4 and Fig. No.10.

Table no-4: Characterizaton of Valacyclovir microspheres.

SI.No Drug & Excipients Endothermic

peak

Exothermic peak

1 Valacyclovir(VM1) 122.5oc & -10.65

mw

-----------------

2 Drug+ethyl cellulose+Hpmc

(VM2)

121.9oc & -9.29

mw

286.2oC & -7.50

mW

Formu

lation

code

%

yield

(%)

Drug

Content

Entrapment

Efficiency

(%)

Drug

Loading

capacity

(%)

Particle

size(µm)

Swellability

Studies

(Sec)

VM1 83.33 65.8 91.1 97.9 200 0.5

VM 2 75 69.2 87.1 87.9 50 0.4

VM 3 73.33 90.3 77 84.3 100 0.3

VM 4 78.94 89.7 66 71.9 45 0.7



Entrapment Loading (%EL): The Percentage entrapment loading of VM 1- 97.9%, VM2- 87,9%, VM3- 84.3%, VM

4 – 71.9%, VM 5- 70.4%, VM 6- 68.8%, VM 7- 64.8, VM 8-56.8, VM 9- 54.8%, The VM 8 shows the good

formulation & high efficiency. Results as shown in Table No.4 and Fig. No 11.

Particle size: The Particle size distribution of Microspheres represented by VM 1 (200µm ), VM 2 (50 µm), VM3

(100 µm), VM4 (45 µm), VM 5 (450 µm), VM 6 ( 300 µm), VM 7 (250 µm ), VM 8 ( 10 µm), VM 9 ( 100 µm),

Formula as shown in given Table No. 4 and Fig No 12.

Equilibrium swelling studies of microspheres: A preweighed amount (100 mg) of microspheres was placed in

Phosphate buffer (pH7.4) and allowed to swell to a constant weight. The microspheres were removed and blotted with

filter paper, and their changes in weight were measured results as shown in Table. no 4 and Fig. no .13.

Percentage drug content Determination: The Drug content distribution of Microspheres represented it indicated that

drug content is VM 1 ( 65.8%), VM 2 ( 69.2 %), VM3 ( 90.3%), VM4 (89.7%), VM 5 ( 75.2 %), VM 6 ( 85.2 %), VM

7 (88.5 %), VM 8 ( 98.2%), VM 9 (70.4 %), Formula as shown in given Table no 4 Fig.no 14.

In vitro dissolution Studies:

For understanding the mechanism of drug release rate kinetics of the drug from dosage forms, the invitro drug

dissolution data obtained was fitted to various mathematical models such as zero order, First order, Higuchi matrix, and

Krosmeyer Peppas model. The values are complied in Table no 6. The % drug release with data to various kinetic

models for different microspheres formulations is presented in figure no. 15.

Table no-5: In Vitro dissolution Studies.

Sl.no Time % of Drug release

VM1 VM2 VM3 VM4 VM5 VM6 VM7 VM8 VM9

1 5 1.54 3.06 6.96 7.68 11.58 13.14 14.64 15.42 11.58

2 10 4.62 6.96 9.24 12.36 15.42 16.98 19.32 27.06 16.20

3 15 6.96 8.46 11.59 14.64 19.32 23.16 23.16 34.80 22.08

4 20 7.68 11.58 14.64 19.32 23.16 23.94 27.72 38.64 23.94

5 25 11.58 15.42 19.32 23.16 27.06 36.3 37.86 46.38 30.9

6 30 15.42 27.06 30.9 35.32 37.08 38.64 42.48 50.22 7.86

VM 5 88.88 75.2 63.9 70.4 450 0.2

VM 6 81.25 85.2 60.8 68.8 300 0.3

VM 7 80 88.5 58.8 64.8 250 0.2

VM 8 86.66 98.2 54.5 56.8 10 1.5

VM 9 80 70.4 51.8 54.8 100 1.5



7 35 27.06 34.8 34.8 38.64 39.42 40.98 45.60 54.12 40.2

8 40 30.9 42.48 51.0 54.9 62.64 71.1 68.62 61.86 61.86

9 45 38.64 50.22 54.12 61.86 70.26 76.56 77.28 88.92 69.6

Table No-6: Release Order Kinetics of Valacyclovir Microspheres.

Model Equation VM 1 VM 2 VM 3 VM 4 VM 5

R2 m R

2 m R

2 M R

2 M R

2 M

Zero

order

Mo-Mt=kt 0.655 69.4 0.939 1123 0.007 15.93 0.202 72.88 0.928 1414

First

order

InM=InMo 0.494 0.061 0.540 0.067 0.257 0.038 0.352 0.044 0.438 0.062

Higuchi’s Matrix

M0−Mt =

kt1/2

0.516 4508 0.767 7420 0.023 212.0 0.189 515.5 0.803 9618

Korsmey

er-

Peppar

log (M0-

Mt)= log k

+ n logt

0.835 2.354 0.884 2.545 0.572 1.709 0.663 1.813 0.806 2.517

Formulation

Code

Zero order

First order

Higuchi

Matrix

Korsmeyer

Peppar

Best fit

Model

R2 m R2 m R2 m R2 m

VM 8 0.937 1593 0.399 0.061 0.899 1140

9

0.785 2.560 Zero

order

Model Equation VM 6 VM 7 VM 8 VM 9

R2 m R

2 m R

2 M R

2 M

Zero

order

Mo-Mt=kt 0.917 154.9 0.949 154.4 0.937 1593 0.945 139.7

First

order

InM=InMo 0.481 0.052 0.465 0.051 0.399 0.061 0.478 0.051

Higuchi’s Matrix

M0−Mt =

kt1/2

0.798 1057 0.848 1067 0.899 11409 0.836 960.9

Korsmey

er-

Peppar

log (M0-

Mt)= log k

+ n logt

0.835 2.032 0.827 2.033 0.785 2.560 0.838 2.018



Figure No-1: FTIR Spectrum of Pure drug (Valacyclovir).

Figure No-2: FTIR Spectrum of Ethyl cellulose.

Figure No-3: FTIR Spectrum of HPMC.

Figure No-4: FTIR Spectrum of Drug + Ethyl cellulose.



Figure No-5: FTIR Spectrum of Drug + EC + HPMC.

Figure No-6: DSC spectrum of pure drug valacyclovir.

Figure No-7: DSC spectrum of Mixtures (Drug + EC + HPMC).

SHAPE AND SURFACE MORPHOLOGY

Temp Cel400.0350.0300.0250.0200.0150.0100.050.0

4.00

2.00

0.00

-2.00

-4.00

-6.00

-8.00

-10.00

-12.00

-14.00

122.5Cel

-10.65mW

154mJ/mg

Temp Cel400.0350.0300.0250.0200.0150.0100.050.0

10.00

5.00

0.00

-5.00

-10.00

-15.00

-20.00

-25.00

-30.00

62.6Cel

-19.66mW

63.1mJ/mg

6.74mJ/mg

121.9Cel-9.29mW

286.2Cel

-7.50mW



Figures No-8: SEM Samples of Best formulation of VM 8.

Fig. no-9: Percentage yield of Valacyclovir microspheres.

Fig.no 10: Entrapment efficiency of Valacyclovir Microspheres.

83.33

75

73.33

78.94

88.88

81.25

80

86.66

80 VM1

VM2

VM3

VM4

VM5

VM6

VM7

VM8

VM9

Formulation codes

Percentage Yield of Valacyclovir Microspheres

0 20 40 60 80 100

Formulation code

VM2

VM4

VM6

VM8

0

91.1

87.1

77

66

63.9

60.8

58.8

54.5

51.8

Entrapment Effiiency of Valacyclovir Microspheres



Fig. No-11: Drug Loading Capacity of Valacyclovir microspheres.

Fig. No-12: Particle Size of Valacyclovir microspheres.

Fig. no-13: Swelling index of Valacyclovir microspheres.

97.9

87.9 84.3

71.9 70.4 68.8 64.8

56.8 54.8

0

20

40

60

80

100

120

VM1 VM2 VM3 VM4 VM5 VM6 VM7 VM8 VM9

formulation codes

En

tra

pm

en

t lo

ad

ing

eff

icie

ncy

Drug loading capacity of valacyclovir Microspheres

0 100 200 300 400 500

VM1

VM2

VM3

VM4

VM5

VM6

VM7

VM8

VM9

200

50

100

45

450

300

250

10

100 PARTICLE SIZE OF VALACYCLOVIR MICROSPHERES

FO

RM

ULA

TIO

N C

OD

ES

Particle size

0

0.5

1

1.5

VM1 VM 2 VM 3 VM 4 VM 5 VM 6 VM 7 VM 8 VM 9

Swelling index of Valacyclovir microspheres

FORMULATION CODES

Sw

ell

ing

In

de

x



Fig. no-14: Percentage drug content of Valacyclovir microspheres.

Fig no-15: In vitro dissolution studies of valacyclovir microspheres.

Conclusion

The purpose of present work was to develop the microspheres of Valacyclovir for sustained drug delivery system. From

the results it seem that formulation VM 8 was found to be the excellent Morphological properties, % yield of

microsphere of best formulation was found to be VM 8 (86.66%), Entrapment efficiency of best formulation was found

to be (54.5 %) , Drug loading efficiency of best formulation was found to be (56.8 %), Swelling index best formulation

was found to be (1.5 sec),Particle size of best formulation was found to be(10 µm ) ,Drug content determination of best

formulation was found to be (98.2)and in vitro drug release was fitted with various Release kinetic studies of a

sustained manner with constant fashion over extended period of time for 45 Mints. It was observed that concentration of

0 20 40 60 80 100

VM1

VM2

VM3

VM4

VM5

VM6

VM7

VM8

VM9

65.8

69.2

90.3

89.7

75.2

85.2

88.5

98.2

70.4 DRUG CONTENT DETERMINATION OF VALACYCLOVIR MICOSPHERES

FO

RM

ULA

TIO

N C

OD

ES

Drug content Determination

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

VM1

VM 2

VM 3

VM 4

VM 5

VM 6

VM 7

VM 8

VM 9

In Vitro Dissolution studies of Valacyclovir Microspheres

Times (Mints)

% D

rug

Re

lea

se



Ethyl cellulose affected all the evaluation parameter significantly. Hence the prepared microspheres of Valacyclovir may

prove to be potential candidate for safe and effective sustained drug delivery.

Acknowledgement: The author are thankful to the Guide, HOD Principal, Ratnam Institue of Pharmacy, Pidathapolur,

Nellore for providing necessary facilities to carry out this work.

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Corresponding Author:

Deepthi A*,

Email: [email protected]

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