4694 Int J Pharm Sci Nanotech Vol 12; Issue 4 • July− August 2019

Research Paper

Improvement of Solubility and Dissolution Rate of Simvastatin by Solid Dispersion Technique

D.V.R.N. Bhikshapathi1*, M. Vishwaja2, R. Suthakaran2, B. Usha Sri2 and M. Ratan Seshagiri Rao3

1Teegala Ram Reddy College of Pharmacy, Pragathi Colony, Meerpet, Hyderabad- 500097, Telangana, India; 2Vijaya College of Pharmacy, Hayath Nagar, Hyderabad - 501511, Telangana, India; and 3Keele University, Newcastle-under-Lyme, ST5 5BG, United Kingdom. Received August 15, 2019; accepted September 20, 2019

ABSTRACT The aim of present work is to enhance the solubility and bioavailability of Simvastatin by solid dispersion technique and characterize the same. Preliminary solubility studies were conducted to check the solubility in different polymers. Based on the results 20 formulations prepared by solvent evaporation method with varying ratios of Kleptose HPB, Soluplus, Kolliwax GMS II, Kolliphor P188 and PVPK-30. All the formulations were analyzed for solubility, percentage yield, drug content and in vitro drug release. The formulation SD20

with enhanced solubility of 20.05 ± 0.02μg/mL in Kolliwax GMS II, percentage yield of 99.13% and dissolution rate of 99.2 ± 2.3% within 90 min is chosen as optimized formulation. The formulation is further Characterized for Drug excipient interaction by FTIR, PXRD and SEM studies. The stability studies for 6 months indicated no significant changes in drug content or drug dissolution rate. Hence, improve dissolution characteristics of Simvastatin achieved by increasing its release and solubility through solid dispersion technique.

KEYWORDS: Simvastatin; Lipid lowering agent; Solid dispersions; Solubility.

Introduction The low solubility of Biopharmaceutical Classification System (BCS) class II drugs influence their absorption, metabolism, distribution and in vivo efficacy (Mohd et al., 2010). The decrease in dissolution rate will impact the complete uptake of drug by GI track, which further leads to drug decomposition (Baghel et al., 2011). Researchers including formation of salts, solubilization, micronization and solid dispersion techniques employed various methods. Among all of these techniques, the solid dispersion (SDs) provides a challenging solution for enhancement of dissolution characteristics of the drug. SDs are the dispersions of drug in a matrix comprising of polymers or small molecules. The solid dispersions (SDs) mainly constitute hydrophilic matrix and hydrophobic drug (Huda et al., 2011). The technique of solid dispersions has been employed in the formulation of drugs that are poorly soluble like Nimsulide, Ketoprofen, Tenoxicam, Lornoxicam using several carriers that are hydrophilic in nature like polyvinylpyrrolidone, hydroxypropyl, polyethylene glycol, mannitol, sugar etc. Different grade of polyvinylpyrrolidone (PVPs), polyethylene glycols (PEGs), Labrasol, Gelucire 44/14,

HPMC grades, urea and sugars are the mostly employed as carriers in solid dispersions preparation. The interaction between drug and polymer is an ascertaining factor in performance and design of solid dispersion as it is two-component system of a drug and polymer.

The simvastatin calcium component is chemically described as [R- (R*, R*)]-2-(4- fluorophenyl)-β, a-dihydroxy-5-(1-methylethyl)-3-phenyl-4[(phenylamino) carb-onyl]-1Hpyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Simvastatin is HMG-CoA reductase inhibitors belonging to statins group that slows down the synthesis of cholesterol that arrests the biosynthesis of cholesterol in liver by a causing reduction of blocks in arterial walls. Simvastatin is a lipid lowering drug used for reduction in lipid concentration along with diet and exercise. Simvastatin possess the disadvantages of low solubility thus affecting the dissolution of drug. Simvastatin bioavailability is only 25% and biological half-life is 6h.

The aim of present work was to formulate simvastatin, BCS class II drug as solid dispersion to improve its solubility and in vitro dissolution rate of the same.

 

ABBREVIATIONS: SD, Solid dispersion; SEM, Scanning electron microscopic; PEGs, Polyethylene glycols; VPs, Polyvinyl pyrrolidone; PDI, Polydispersion index; BCS, Biopharmaceutical classical system, HPB, Hydroxypropyl beta- cyclodexatrin; GMS, Glycerol mono-stearate; XRD, X-ray diffraction; FTIR, Fourier transform infrarerd spectroscopy; HPMC, Hydroxy propyl methylcellulose.

 

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 12 • Issue 6 • November – December 2019MS ID: IJPSN-8-15-19-BIKSHAPATHI

4694

Bhikshapathi et al: Improvement of Solubility and Dissoution Rate of Simvastatin by Solid Dispersion Technique 4695 

 

Materials and Methods Materials

The simvastatin calcium drug is kindly gifted by Aurobindo Pharma Ltd, Hyderabad, India. Mannitol, Kleptose HPB, P188 and Kolliphor were purchased from BASF, Mumbai. PEG 4000, PEG 6000 and Kolliwax GMS were procured from Signet Chemical Corp. Pvt. Ltd, Mumbai. Soluplus is purchased from BASF, Germany. PVP K-30 and Urea were obtained from Dow Chemicals, USA.

Instrumentation

UV/Visible spectrophotometer (Shimadzu), pH meter (ELICO U120), Electronic Balance (Shimadzu), X-ray diffraction (Bruker, Germany), DSC (Perkin Elmer, USA.) Dissolution Apparatus (Electro lab) and FTIR (Perkin Elmer, USA.) were used for analysis.

Solubility studies of Simvastatin

Solubility studies were carried out by addition of an excess Simvastatin to 25ml aqueous solution of water-soluble carriers like Kleptose HPB, Urea, Kolliwax GMSII, PEG 6000, PVPK-30, Soluplus, Kolliphor P188, PEG4000 and Mannitol in screw capped bottles. The samples were shaken at room temperature for a period of 24 h followed by filtration using a Whatman filter paper no 1 that were then analyzed in UV at 247nm for Simvastatin after proper dilution (Higuchi and Connors, 1965).

Preparation of Simvastatin SD

Solvent evaporation method was used in preparation of 20 different Simvastatin solid dispersions by mixing calculated amount of Simvastatin and the polymers under study (Kleptose HPB, Soluplus, Kolliphor P188, Kolliwax GMS II, and PVPK-30) in porcelain dish in

ratios (1:1 and 1:3) along with SLS employed as surfactant (0 / 2%) (Table 1 and 2) (Dhirendra et al., 2009).

Solubility of Simvastatin SD

This technique was performed by shaking the samples for 48 hours at room temperature which were then filtered through Whatman filter paper no 1 and analyzed for Simvastatin in UV 247nm (Higuchi and Connors, 1965).

Evaluation of % Practical Yield Simvastatin SD

Collected SDs was weighed for determination of percentage practical yield (Lakshmi et al., 2012).

Drug content

Solid dispersions that were equivalent to about 20 mg Simvastatin were dissolved in 100 ml of methanol after accurate weighing followed by solution filtration and dilution after which drug content was analysed in a UV spectrometer at λmax 244 nm against blank [Shingala et al., 2013].

% Drug content =

Actucal amt of drug in solid dispersion (SDs)×100

The theoretical - amount of drug in solid dispersion 

In vitro drug dissolution of Simvastatin SD

Pure drug and the solid dispersions of Simvastatin were subjected to dissolution studies in Type II (paddle type) USP dissolution test apparatus operated at a paddle speed of 75rpm maintaining the temperature at 37±5oC. The test was performed on sample that was equivalent to 20mg of Simvastatin calcium in 900 mL of pH buffer pH 6.8. At regular intervals, approximately 5mL of dissolution medium was withdrawn using filter (0.45 μm), assayed at 247 nm (Valizadeh et al., 2004).

TABLE 1

Formulation table for Simvastatin solid dispersions SD1-SD10.

S. No Ingredients (g) SD1 SD2 SD3 SD4 SD5 SD6 SD7 SD8 SD9 SD10

1 Simvastatin 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 2 PVP K30 0.6 0.6 1.0 1.0 - - - - - - 3 Soluplus - - - 0.6 0.6 1.0 1.0 - - 4 Kolliphor P 188 - - - - 0.6 0.6 6 Kleptose HPB - - - - - - - - - 7 Kolliwax GMS - - - - - - - - - - 8 SLS 0% 2% 0% 2% 0% 2% 0% 2% 0% 2% 9 Methanol (ml) Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs

TABLE 2

Formulation table for the Simvastatin solid dispersions (SD 11 – SD 20).

S. No Ingredients(g) SD11 SD12 SD13 SD14 SD15 SD16 SD17 SD18 SD19 SD20

1 Simvastatin 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 2 PVP K30 - - - - - 3 Soluplus - - - - - 4 Kolliphor P 188 0.6 0.6 - - - 6 Kleptose HPB 0.2 0.2 0.6 0.6 7 Kolliwax GMS - - 0.2 0.2 0.6 0.6 8 SLS 0% 2% 0% 2% 0% 2% 0% 2% 0% 2% 9 Methanol (ml) Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs

4696

Chara

CharadispersionScanningstability s

ResuSolub

Selectsolid disppreliminasolubilityKolliwax solubilitycomparisby manniwhich thformulati

Fig. 1. Simv

Prepa

Kolliw30, and Sand 1:5) employedsamples wand pestafter whiThe finastored insieve (Fig

TABLE 3

Preliminar

Physic

Pure DruDrug + MDrug + SoDrug + KDrug + K

Solub

Solubilitydifferent solubilityKolliwax

acterization of

acterization on was done

g Electron mistudies (Higu

ults and Discility of Simva

tion of water-persion’s prepary solubilityy was observe GMS in ra

y i.e. 15.17 on to pure dritol, PEG 400

he above-specion of Simvast

vastatin physica

aration of Sim

wax GMS, KolSoluplus in tw

in addition td in solid dwere mixed w

tle followed bich product wal product wn a desiccator gure 2).

ry solubility stud

cal Mixture

g Mannitol

oluplus Kolliwax GMS Kolliphor P188

ility of Simva

y studies wer formulationsy was observe GMS in rat

f Simvastatin

of the prepar by FTIR [icroscope (Brchi and Conn

cussion astatin

-soluble carriparation wasy studies ind as 2.09μg/m

atio of 1:1 sμg/ml, almosrug. Minimal 00, PEG 6000ified carrierstatin solid dis

al mixture Solub

mvastatin SD

lliphor P188, Ko different drto SLS surfadispersion fowith a suitablby proper eva

was collected bwas packed in

after passing

dies of Simvastat

Solubility (μg/m

1.201 ± 0.042.52 ± 0.13

9.27 ± 0.00315.17 ± 0.028.32 ± 0.01

astatin SD

re carried outs using suitabed for formulatio of 1:3 wi

SD

red Simvastat[Yang et al.

reitenbach, 20ors, 1965).

ers that weres done by pern which pu

ml (Table 3). Dshowed highest 8-fold incr solubility wa0 and urea bes were excludspersions. (Fig

bility.

Kleptose HPBug-polymer ractant (0 or 2

ormulations. le solvent in aaporation andby through scn airtight cog it through

tin in different p

ml)

4

3 2

t after preparble polymers. ation SD20 coith SLS i.e.

Int J Pharm

tin solid ., 2010], 002) and

e apt for rforming

ure drug Drug and est drug rease in as shown ecause of ded from gure 1).

B, PVP K atios (1:3 2%) were

All the a mortar d drying crapping. ontainer, a 45 μm

polymers.

ration of Highest

ontaining 20.05 ±

0drere

F

T

S

F

bfo

m Sci Nanotec

0.02μg/mL, almdrug (Pure desults are epresentation

Fig. 2. Simvastati

TABLE 4

olubility studies

S. No. Fo1 Pure d2 3 4 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21

Fig. 3. Solubility

Percent pra

Percent prbetween 84.88ormulation sh

ch Vol 12; Issue

most 10-fold drug solubilit

shown in n shown in Fig

in Solid Dispers

s of Simvastatin

ormulation code drug (Simvastati

SD1 SD2 SD3 SD5 SD6 SD7 SD8 SD9

SD10 SD11 SD12 SD13 SD14 SD15 SD16 SD17 SD18 SD19 SD20

studies of Simva

actical yield a

ractical yield 8% - 99.13% howed maximu

e 6 • November

high in comty is 1.201±0

Table 4 gure 3.

ion.

solid dispersion

Solubility (in) 1.201 ±

4.96 ± 5.63 ± 6.98 ± 10.21 ± 11.22 ± 13.01 ± 14.33 ± 8.37 ± 9.16 ± 10.86 ± 11.55 ± 6.26 ± 8.15 ± 9.76 ± 12.16 ± 15.26 ± 17.56 ± 18.12 ± 20.05 ±

astatin SD.

and drug conte

of all formuas shown in

um yield of 99

er− December 2

mparison to p0.04μg/mL). T

and graph

s (SD).

μg /ml)* 0.04 0.04 0.15 0.22 0.02 0.03 0.02 0.04 0.03 0.04 0.01 0.03 0.04 0.03 0.04 0.07 0.02 0.03 0.02

± 0.02

ent

ulations weren Table 5. SD9.13%.

2019

pure The ical

e in D20

Bhikshapa

 

TABLE 5

Percent pra

S.No

1 S

2 S

3 S

4 S

5 S

6 S

7 S

8 S

9 S

10 S

11 S

12 S

13 S

14 S

15 S

16 S

17 S

18 S

19 S

20 S

In vitr

A maSimvastawith pureof drug: higher diother forform condrug wsolubilizaof solid dwith pure

Fig. 4. In v

FTIR

The FTIRcharacter

athi et al: Impro

actical yield and

Formulation

SD1

SD2

SD3

SD4

SD5

SD6

SD7

SD8

SD9

SD10

SD11

SD12

SD13

SD14

SD15

SD16

SD17

SD18

SD19

SD20

tro dissolution

arked enhancatin from alle drug was ob Kolliwax GMissolution ratrmulations thnversion to awettability aation of the ddispersions SDe drug was de

vitro drug dissolu

studies

R spectra of ristic peaks

rovement of So

drug content for

% Practical Yield

95.21

92.46

93.68

84.88

96.55

91.68

91.98

96.22

91.87

94.26

91.99

96.12

91.87

93.27

94.26

94.88

89.23

85.23

86.33

99.13

n studies

cement in ra solid disper

bserved. KolliwMS II with sute i.e. 99.2±2.hat may be aamorphous foand hydrophdrug. The graD1-SD8, SD9

epicted in Figu

ution of SD1-SD8

pure Simvast at 2955.

olubility and Dis

r Simvastatin SD

% Drug conten

91.47

94.77

87.62

90.33

92.47

94.92

93.50

94.52

91.53

92.56

94.57

91.64

92.43

89.37

92.52

95.08

91.01

90.99

93.88

99.03

ate of dissolrsions in comwax GMS II (urfactant) ha.3 % in contr

ascribed to crorm, enhancehilic carrieraphical-repres9-SD14 & SDures 4-6.

8 and pure drug.

tatin calcium15 cm-1 310

issoution Rate

D.

nt

lution of mparison (1:5 ratio

ad shown rast with rystalline ement in r aided sentation

D15-SD20

.

m showed 0 (C-N-

st(Cst1stdapid

F

F

co(Fspmd

fosuPehin

of Simvastatin

tretching), 30C-HO-stretchitretching ami

1656.97 cm-1 (Ctretching), 11

due to interadjacent Simvpure drug andentical (Figu

Fig. 5. In vitro dr

Fig. 6. In vitro dr

Distinctiveonfirmed thFigure 10) whpectra of opt

modification oduring the form

The scanni

SEM photormulation SDurface appear

Porous naturevident in SEM

homogenous ncorporate dru

n by Solid Disp

059.15 cm -1 (Cing alcoholic idic group), 3C=C-bending),104.39 cm -1 (rmolecular h

vastatin calciund that of

ure 7-9).

rug dissolution of

rug dissolution of

nature of muhe crystallinhereas absentimized formf crystalline dmulation proc

ng electron m

tographs for D 20 are showred smooth, ie of solid disM photographmass. Poly

ug crystals.

persion Techniq

C-H-stretchin group), 156

3403.27 cm-1 (, 751.62 cm-1 6(O-H-bendinghydrogen boum moleculesoptimized fo

f SD9-SD14.

f SD15-SD20.

ultiple peaks ine nature nce of any dif

mulation SD20drug to amorpcess. (Figure 1

microscope (SE

pure drug wn in Figure 1irregularly shspersions wahs and appea

ymer particl

que 46

ng), 1313.56 c64.97 cm-1 (C=(N-H-stretchin696.95 cm-1 (C

g) that mightonding betws. The spectraormulation w

in XRD spectrof Simvasta

ffraction peak0 confirmed phous compou11).

EM) Studies

and optimi12. Drug crysthaped and sizas seemed to ared as wrinkles seemed

697 

cm-1

=O-ng),

C-F-t be

ween a of

were

rum atin k in the

und

ized tals zed. be

kled to

4698 Int J Pharm Sci Nanotech Vol 12; Issue 6 • November− December 2019

Fig. 7. Simvastatin pure drug FTIR.

Fig. 8. Kolliwax GMS II FTIR.

Fig. 9. SD20 FTIR Spectrum.

Bhikshapa

 

Fig. 10. PX

Fig. 11. PX

Fig. 12. Pu

athi et al: Impro

XRD of Simvastat

XRD of Simvastat

re drug of Simva

rovement of So

tin pure drug.

tin optimized for

astatin and Simv

olubility and Dis

rmulation (SD20

vastatin optimiz

issoution Rate

0).

zed formulation (

of Simvastatin

(SD20).

n by Solid Disppersion Techniq

que 46

699 

4700 Int J Pharm Sci Nanotech Vol 12; Issue 6 • November− December 2019

Stability Studies

Optimized formulation (SD20) due to its comparatively greater drug release percent was selected for stability studies. SS were done for 6 months according to ICH guidelines Drug content, in vitro drug release profile and XRD characterization after 6 months storage was performed for physical state evaluation. The systems were stable during the 6-month period. The results clearly implicated the stability of optimized formulation (SD20) and its ability to retain their original properties with minor differences as depicted in Table 6.

TABLE 6

Evaluation parameters optimized formulation (SD20) stored at 40 ± 2oC /75 ±5%RH.

Retest time for optimized formulation (SD20)

% Drug content In-vitro drug release (%)

0 days 99.03 99.21 30 days 97.29 98.45 60 days 96.75 97.51

120 days 95.05 96.35 180 days 94.52 96.05

Simvastatin solid dispersions of twenty formulations prepared with Kolliphor P188, Kolliwax GMS, PVP K 30, Kleptose HPB, and Soluplus in two different drug-polymer ratios (1:3 and 1:5). The solubility of Simvastatin in purified water at 25°C was 2.09 ± 0.04μg/ml. An increase in solubility up to 10-fold i.e. 20.05 ± 0.02μg/mL in for SD20 formulation was achieved in comparison to pure drug. The increase in solubility with increasing Kolliwax GMS concentration indicates the solvent properties of Kolliwax GMS for the drug.

SD20 formulation showed maximum yield of 99.13% with maximum drug content i.e. 99.03%. Drug and excipient interaction were nil as revealed by FTIR. SEM studies confirmed the modification of crystalline Simvastatin to an amorphous form. Finally, a conclusion can be drawn that solid dispersion of Simvastatin using novel carriers would improve the dissolution rate by increasing solubility and thereby enhancing its systemic-availability.

Dissolution rate of Simvastatin from all the solid dispersions was greater than pure Simvastatin itself as observed during in vitro release studies. SD20 containing Kolliwax GMS II (1:3 ratio of drug: Kolliwax GMS II

with surfactant) showed developed dissolution rate of 99.2 ± 2.3 % when compared to other formulations. This may be accredited to the rise in drug wettability, hydrophilic carrier aided solubilization and conversion to amorphous form.

Conclusions As per the method and results cited above, an

optimized solid dispersion of simvastatin formulation prepared and characterized with increased solubility and higher dissolution rates.

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Address correspondence to: D.V. R. N. Bhikshapathi, Teegala Ram Reddy College of Pharmacy, Pragathi Colony, Meerpet, Hyderabad- 500097, Telangana, India. Tel +91-9848514228 E-mail: dbpathi71@gmail.com