Enhancement of Dissolution Rate of Ritonavir: A ...8)/G0480044058.pdfEnhancement of Dissolution Rate of Ritonavir: A Comparative study using various Carriers and Techniques 1A. Sarada,

International Journal of Pharmaceutical Science Invention

ISSN (Online): 2319 – 6718, ISSN (Print): 2319 – 670X

www.ijpsi.org Volume 4 Issue 8 ‖ August 2015 ‖ PP.44-58

www.ijpsi.org 44 | P a g e

Enhancement of Dissolution Rate of Ritonavir: A Comparative

study using various Carriers and Techniques

1A. Sarada,

2D. Lohithasu,

3V. Chamundeswari,

1D.Midhun Kumar and

3 S. Ramya

1Division of Pharmaceutical Technology, A.U. College of Pharmaceutical Sciences, Andhra University,

Visakhapatnam, Andhra Pradesh, India. 2Division of Pharmaceutics, GITAM Institute of Pharmacy, GITAM University, Visakhapatnam, Andhra

Pradesh, India. 3Maharajah’s College of Pharmacy, Phoolbaugh, Vizianagaram, Andhra Pradesh, India.

Abstract: Aim of study: The aim of present work is to study the release of Ritonavir from solid dispersions

with different grades of PEGs and cyclodextrins using various techniques like physical mixing, solvent

evaporation, melting technique and kneading.

Material and methods: Different drug-to-polymer ratios were prepared to investigate the appropriate

concentration of polymer required to enhance the solubility of the drug and improve its release kinetics. The

physicochemical properties of dispersions were evaluated by using Fourier transform infrared spectroscopy

(FTIR), the study of FTIR could not show significant interaction between Ritonavir and the polymers

incorporated i.e., PEGs and cyclodextrins. The Polymeric dispersions prepared were evaluated for the release

of ritonavir over a period of 1 hour in 0.1N HCl using USP type II dissolution apparatus. The in vitro drug

release study revealed that the dispersion techniques have increased the dissolution rate.

Conclusions: It concluded that the various grades of PEGs (PEG 4000, PEG 6000, PEG 8000, PEG 20000),

beta cyclodextrins and hydroxyl propyl beta cycldextrins were used in preparation of polymer dispersions for

improving the dissolution and physical stability by various techniques. The in vitro release profile and the

mathematical models indicate that release of Ritonavir can be effectively increased from a formulation

containing polymeric dispersion of PEG grade 20,000 and inclusion complexes of Hydroxy propyl beta

cyclodextrins.

Keywords: Polymeric dispersion, Ritonavir, Polyethylene glycols (PEGs), Cyclodextrins.

I. INTRODUCTION Ritonavir shows more release than that of pure drug due to nano size dispersion and the solid

dispersion prepared by solvent evaporation method is a promising approach for the bioavailability enhancement

of Ritonavir [1].The approaches used to overcome the insufficient bioavailability are reduction of particle-size

which includes microsizing and nanosizing, salt formation, solubilization, use of surfactants, polymorphism,

liquisolid technique [2,8] and complexation with β cyclodextrins to increase the oral bioavailability of poorly

water-soluble drugs[3]. Solid dispersion can produce a solid dosage form having the active in an amorphous

state or in a molecular dispersion state. The solid dispersion is used to enhance the dissolution rate by drug

particle size reduction, solublization effect of the carrier, invention of amorphous state and molecular interaction

between the drug and carrier [4]. Ritonavir is practically insoluble in water. It is used for the treatment of

human immune deficiency disease. The selected drug belongs to BCS class II basing on their solubility and

permeability. Ritonavir is an anti HIV drug which acts by inhibiting the protease enzymatic action. Ritonavir

pure drug is known to have high purity and satisfactory stability. However, it has low solubility in water and

thus is not suitable for oral administration. Conversion of Ritonavir pure drug into an amorphous form leads to

high water solubility and improves the usefulness of Ritonavir in the therapy of disease. But amorphous

materials are thermodynamically unstable and therefore show some tendency to crystallize spontaneously to

variations in the pH, temperature and moisture[5-7]. Hence in the present work it was planned to prepare

Ritonavir polymer dispersions for improving the dissolution and physical stability. For this, we have selected

various grades of Polyethylene glycol .i.e. PEG 4000, PEG 6000, PEG 8000, PEG 20000, Beta cyclodextrins

and Hydroxy propyl beta cyclodextrins. These polymer dispersions were prepared by various techniques and

evaluated for their effectiveness in improving the disolution rate and improving the physical stability of

Ritonavir.

Enhancement of Dissolution Rate of…


The primary objective of the present work was to improve the solubility of poorly soluble drug by

preparing polymeric dispersions and characterizes the properties of polymeric dispersions formulation using

analytical methods like DSC and FTIR studies. The study also includes observation of the effect of different

polymers and their concentration on the drug solubility parameters to improve the bioavailability of the drug.

The present work involves preparation and evaluation of Ritonavir polymer solid dispersions.

II. MATERIALS AND METHODS Ritonavir was received as a gift sample from Hetero drug limited (Hyderabad, India). Polyethylene

glycol 4000, 6000, 8000 and 20000 were procured from S.D. Fine Chemicals Ltd. (Mumbai, India). Beta

cyclodextrins and hydroxyl propyl beta cycldextrins purchased from Cavitron, USA. Other chemicals and

reagents used were purchased from Merck Limited (Mumbai, India) and were of analytical grade.

Methods:

In this present study, the polymeric dispersions were prepared by different methods. Polyethylene glycols (PEG

4000, PEG 6000, PEG 8000, PEG 20000), beta cyclodextrins and hydroxyl propyl beta cyclodextrins were used

for the preparation of polymeric dispersions. All the polymeric dispersions were prepared from drug to polymer

ratios about 1:0.25, 1:0.5, 1:1, 1:2, 1:3 and 1:4. Physical mixing technique is used for preparation of polymeric

dispersions in various ratios of 1:0.25, 1:0.5, 1:1 and 1:2 in a mortar and pestle for 20 minutes as well as solvent

evaporation technique (dissolved in methanol, then removed by evaporation under reduced pressure) is used for

preparation of polymeric dispersions in various ratios of 1:0.25, 1:0.5, 1:1, 1:2, 1:3 and 1:4. Melting technique

(carrier is melted and added the drug to carrier at same temperature, cooled) is used for preparation of polymeric

dispersions in various ratios of 1:0.25, 1:0.5, 1:1, 1:2 and 1:3. Hydroxy propyl beta cyclo dextrins and cyclo

dextrins were also used in various proportions.

Calibration curve of Ritonavir in 0.1 N HCl Analytical Methods: In this present study, UV spectroscopic method was employed to determine absorbance

maxima( max) and construct the standard calibration curve of Ritonavir in 0.1 N HCl.

Preparation of 0.1 N HCl : 8.5 ml of hydrochloric acid was added to 200 ml of distilled water and the final

volume was made up to the 1000 ml with water.

Estimation of Ritonavir in 0.1 N HCl

Determination of λmax

First the drug was dissolved in about 1 ml of methanol and the volume was made up to get various standard

solutions using 0.1N HCl media. Most of drugs absorbs light in UV region (200-400 nm), since they are

generally aromatic or contain double bonds. An absorption maximum was determined using 0.1 N HCl.

Solutions ranging from 10-50 µg/ml was scanned from 200-400 nm using double beam UV spectrophotometer

(SL 210, M/s Elico Pvt. Ltd., India) to determine absorption maximum of Ritonavir. The absorption maximum

was found to be 245 nm.

Preparation of Ritonavir standard stock solution

Stock solution of 1000 µg/ml solutions was prepared by dissolving 100 mg of Ritonavir in 100 ml of 0.1 N HCl,

in a 100 ml volumetric flask. From this solution 10 ml was taken and diluted to 100 ml of 0.1 N HCl to give a

concentration 100 µg/ml. From the above standard stock solution, Ritonavir was subsequently diluted with

above selected solvent media to obtain a series of dilution containing 10, 20, 30, 40 and 50 µg of Ritonavir /ml.

The absorbance of the above dilutions were measured at 245 nm using double beam UV spectrophotometer (SL

210, M/s Elico Pvt. Ltd., India) at 245 nm using pure solvent as blank. The absorbance values were plotted

against concentration of Ritonavir as shown in the Fig.1. The method obeyed beer’s law in the concentration

ranges from 10-50 µg/ml. Reproducibility of the method was tested by analyzing six separately weighed

samples of Ritonavir. The relative standard deviation (RSD) in estimated values was found to be <1. The low

RSD values indicated that the method is reproducible. Thus the method was found to be suitable for the

estimation of Ritonavir contents in the dissolution fluids.

Drug-excipients compatibility studies Fourier Transform Infrared Spectroscopy (FT-IR): The pure drug and drug-excipients compatibility studies

were carried out by Fourier Transform Infrared Spectroscopy (FT-IR). The pellets were prepared on KBr under

hydraulic pressure of 150 kg/ cm2, the spectra were scanned over the wave number range of 4000 to 400 cm

-1 at

the ambient temperature. The results were shown in Fig.2.

Differential Scanning Calorimetry (DSC): DSC study was performed using DSC-60 Calorimeter. Samples

were sealed in aluminum crucibles (40 µL) and the DSC thermograms were reported at a heating rate of 20 °C/

min under dry air flow between 30 °C-300 °C. The results were shown in Fig.3.



Phase solubility studies: Phase solubility studies showed a linear increase of drug solubility with an increase of

the concentration of each examined carrier and have been attributed to the probable formation of weak

complexes. On the other hand, the enhancement of the drug solubility in the aqueous carrier solution could be

equally well explained by the co-solvent effect of the carrier. It has been found that hydrophilic carriers mainly

interact with drug molecules by electrostatic bonds(ion-to-ion, ion-to-dipole, and dipole- to –dipole bonds) even

though other types of forces, such as vander waals forces and hydrogen bonds, can frequently play a role in the

drug carrier interaction. The drug solubility increased linearly with increasing polymer concentration.

Drug content: The formulations (equivalent to 25 mg of Ritonavir) were dissolved in small amount of

methanol, then final volume made up to 100 ml of 0.1 N HCl, then filtered and diluted with 0.1 N HCl, then find

out the drug content using UV spectrophotometer at 245 nm. The percentage of drug content for all the

formulations was found to be 86.14 ± 1.09- 99.09 ± 1.98% of Ritonavir, it complies with official specifications.

The results were shown in Table 1.

In vitro studies: All the prepared formulations of Ritonavir were subjected to in vitro release studies these

studies were carried out using USP type II dissolution apparatus, 900 ml of pH1.2 hydrochloric acid buffer at

37±0.5 οC, 50 rpm and 5 ml of sample were withdrawn and replaced with fresh media to maintain sink

conditions. The results were shown in Fig. 4 to Fig. 15. The results obtained in in vitro release studies were

plotted in different model of data treatment as follows:

1. Cumulative percent drug released vs. time (zero order rate kinetics)

2. Log cumulative percent drug retained vs. time (First Order rate Kinetics)

3. Log cumulative percent drug released vs. square root of time (Higuchi’s

Classical Diffusion Equation)

4. Log of cumulative % release Vs log time (Peppas Exponential Equation)

8. Cubic root of unreleased fraction of drug verses time (Hixon Crowel)

III. RESULTS AND DISCUSSION

Fig.1: Standard graph of Ritonavir pure drug

Fourier Transform Infrared Spectroscopy (FT-IR) studies: When FT-IR was performed, the drug spectrum

indicated characteristic peaks at 3,480 cm−1

(N–H stretching amide group), 2,964 cm−1

(hydrogen-bonded acid

within the molecule), 1,716 cm−1

(ester linkage), 1,645, 1,622, and 1,522 cm−1

(–C═C– stretching aromatic

carbons). The FT-IR spectra of solid dispersion of Ritonavir prepared by solvent evaporation and melt method

was taken and analyzed. Two main band formations were observed between drug and carrier on the basis of FT-

IR spectra. Intermolecular hydrogen bonding was observed due to the peak at 3,380 cm−1

. A number of

indistinguishable peaks appeared in the region of 3,400–4,000 cm−1

in the solid dispersion which was absent in

the crystalline drug. A broad and strong absorption peak at 1,108 cm−1

indicated formation of secondary

hydrogen bond which was absent in pure drug. The presence of strong absorption peak at 1,735 cm−1

and

2,720 cm−1

were indicative of characteristic C–H stretching band and C═O stretching band of aliphatic

aldehydic group. This band was absent in the spectra of the crystalline drug. The hydrogen bonding and

aldehydic group formation between drug and carrier indicated interaction between the two, which could be

attributed to the cause of enhanced dissolution rate of the solid dispersion as compared to pure drug. In case of

melt method, both the aldehydic group and hydrogen bond peaks were present but were very broad as compared

to that obtained in solvent evaporation. The interaction between drug and carrier was due to hydrogen bond and

aldehydic linkages resulting in the increase solubility of drug.



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47.2

116

18.2

815

21.8

414

58.1

814

11.8

913

59.8

213

42.4

612

80.7

312

42.1

612

01.6

511

88.1

511

45.7

211

11.0

010

60.8

510

31.9

296

2.48

947.

0588

3.40

842.

8979

0.81

765.

7473

8.74

704.

0267

3.16

663.

5164

4.22

599.

8658

2.50

569.

0055

5.50

530.

42 514.

9948

0.28

455.

20

R 5 Fig.2 : FT-IR Spectra of A) pure drug Ritonavir; B) Kneading 1:0.5 HP Beta CD;C) Kneading 1:3 Beta

CD;D) 1:3 Melting PEG 20,000; E) 1:4 Solvent evaporation PEG 20,000; F)1:4 Solvent evaporation PEG

4000

Differential Scanning Calorimetry (DSC): DSC studies of various solid dispersion of Ritonavir were taken. It

was concluded on the basis of scans that DSC of the sample prepared by the solvent method, kneading, physical

mixing and melt method showed absence of any significant drug peak at 120°C but presence of prominent peak

of carrier with no change in melting point. This suggested the formation of a monotectic system where the

melting point of the carrier is unchanged in the presence of drug. The results suggested formation of the eutectic

solid dispersion where the drug is present as ultrafine crystals in polymer matrix.



A)

50.00 100.00 150.00 200.00

Temp [C]

-15.00

-10.00

-5.00

0.00

mW

DSC

118.08 x100COnset

126.47 x100CEndset

122.95 x100CPeak

-438.12 x100mJ

-219.06 x100J/g

Heat

File Name: R 0.tad

Detector: DSC-60

Acquisition Date 12/11/09

Acquisition Time 11:50:35(+0530)

Lot No: RIPS0164

Sample Name: R 0

Sample Weight: 2.000[mg]

Cell: Aluminum

Operator: CIR,RIPS,Berhampur

Thermal Analysis Result-RIPS

B)

50.00 100.00 150.00 200.00

Temp [C]

-10.00

-5.00

0.00

mW

DSC

117.81 x100COnset

124.69 x100CEndset

121.40 x100CPeak

-197.87 x100mJ

-98.93 x100J/g

Heat

File Name: R 1.tad

Detector: DSC-60



Lot No: RIPS0163

Sample Name: R 1


Cell: Aluminum


[Temp Program]

Temp Rate Hold Temp Hold Time

[C/min ] [ C ] [ min ]

10.00 300.0 0


C)

100.00 200.00

Temp [C]

-15.00

-10.00

-5.00

0.00

mW

DSC

100.58 x100COnset

121.56 x100CEndset

114.97 x100CPeak

-1.32 x100J

-660.28 x100J/g

Heat

File Name: R 2.tad

Detector: DSC-60



Lot No: RIPS0162

Sample Name: R 2


Cell: Aluminum


[Temp Program]


[C/min ] [ C ] [ min ]

10.00 300.0 0


D)

50.00 100.00 150.00 200.00

Temp [C]

-15.00

-10.00

-5.00

0.00

mW

DSC

45.16 x100COnset

58.58 x100CEndset

53.57 x100CPeak

-678.32 x100mJ

-339.16 x100J/g

Heat120.36 x100COnset

135.96 x100CEndset

124.91 x100CPeak

-258.68 x100mJ

-129.34 x100J/g

Heat

File Name: R 3.tad

Detector: DSC-60



Lot No: RIPS0159

Sample Name: R 3


Cell: Aluminum


[Temp Program]


[C/min ] [ C ] [ min ]

10.00 200.0 0


E)

50.00 100.00 150.00 200.00

Temp [C]

-10.00

0.00

mW

DSC

50.92 x100COnset

65.52 x100CEndset

61.35 x100CPeak

-675.28 x100mJ

-337.64 x100J/g

Heat

164.08 x100COnset

192.20 x100CEndset

163.13 x100CPeak

-75.98 x100mJ

-37.99 x100J/g

Heat

File Name: R 4.tad

Detector: DSC-60



Lot No: RIPS0160

Sample Name: R 4


Cell: Aluminum


[Temp Program]


[C/min ] [ C ] [ min ]

10.00 300.0 0




F)

100.00 200.00 300.00

Temp [C]

-20.00

-10.00

0.00

mW

DSC

49.98 x100COnset

62.48 x100CEndset

57.91 x100CPeak

-1.01 x100J

-502.68 x100J/g

Heat

151.01 x100COnset

162.40 x100CEndset

153.26 x100CPeak

-32.04 x100mJ

-16.02 x100J/g

Heat

File Name: R 5.tad

Detector: DSC-60



Lot No: RIPS0161

Sample Name: R 5


Cell: Aluminum


[Temp Program]


[C/min ] [ C ] [ min ]

10.00 300.0 0


Fig.3 : DSC thermograms of A) pure drug Ritonavir; B) Kneading 1:0.5 HP Beta CD;C) Kneading 1:3 Beta

CD;D) 1:3 Melting PEG 20,000; E) 1:4 Solvent evaporation PEG 20,000; F)1:4 Solvent evaporation PEG

4000

Phase solubility studies: Phase solubility diagrams showed a linear increase in drug solubility with an increase

in the concentration of each examined carrier. At 2%, 6% & 8% w/v concentration of β-CD, HP β-CD, and

PEGs, the solubility of Ritonavir increased significantly. Analogous results were found for these same carriers,

probably due to the formation of weakly soluble complexes. Hydrophilic carriers mainly interact with drug

molecules by electrostatic bonds (ion-to-ion, ion-to-dipole, and dipole-to-dipole bonds), even though other types

of forces, such as Vander Waals forces and hydrogen bonds, can frequently play a role in the drug–carrier

interaction .The drug solubility increased linearly with increasing polymer concentration. The values of Gibbs

free energy (ΔG) associated with the aqueous solubility of Ritonavir in presence of carrier were all negative for

carriers at various concentrations, the spontaneous nature of drug solubilization. The values decreased with

increasing carrier concentration, demonstrating that the reaction became more favorable as the concentration of

carrier increased.

In vitro dissolution studies: All formulations of Ritonavir were subjected to in vitro dissolution studies using

0.1N HCl as the dissolution medium to assess various dissolution properties. All SD formulations with various

polymers exhibited higher rates of dissolution than Ritonavir pure drug and corresponding physical mixtures.

The pure drug showed up to 48 % dissolution over 60 min, but its solid dispersions prepared by solvent

evaporation 1:4 w/w) showed dissolution of greater than 80% .Solid dispersions of β-CD and HP β-CD prepared

by kneading and physical mixture showed nearly similar dissolution. The dissolution enhancing effect of various

carriers used in this study followed the order: 20,000PEG>4000 PEG>8000PEG>6000 PEG and HP β-CD > β-

CD. Among various ratios of drug with PEG, ratio at 1:4 w/w solid dispersions prepared by solvent evaporation

technique showed better enhancement of solubility. Among various ratios of drug with HP β-CD at ratio 1:0.5

w/w inclusion complexes in the form of solid dispersions by kneading technique at room temperature exhibited

improved aqueous solubility leading to superior in vitro dissolution profile. Among various ratios of drug with

β-CD at ratio 1:3 w/w solid dispersions prepared by kneading technique at room temperature exhibited

improved aqueous solubility leading to superior in vitro dissolution profile. The dissolution rate enhancing

effect of various grades of PEG carriers used in this study followed the order 20,000

PEG>4000PEG>8000PEG>6000PEG. The solubility enhancing effect in the case of complex forming polymers

HP β-CD showed relatively higher dissolution enhancement in comparison with β-CD. The dissolution

enhancing effect of various SD preparation methods followed the order solvent evaporation technique>kneading

technique>melting technique>physical mixing technique. Experience with solid dispersions indicates that this is

a very fruitful approach to improve the release rate and oral bioavailability of poorly soluble drugs. This could

potentially lead to an increase in the bioavailability that is so great that that the dose administered can be

lowered.

Pure drug dissolution profile:



Fig. 4: In vitro dissolution profile of Pure drug

In vitro dissolution profile of formulations prepared by Physical Mixing:

Fig. 5: In vitro dissolution profile of PM1 (1:0.25), PM 2 (1:0.5), PM 3 (1:1) and PM 4 (1:2) containing PEG

4000 by Physical Mixing.

Fig. 6: In vitro dissolution profile of PM5 (1:0.25), PM 6 (1:0.5), PM 7 (1:1) and PM 8 (1:2) containing PEG

6000 by Physical Mixing.



Fig. 7: In vitro dissolution profile of PM9 (1:0.25), PM 10 (1:0.5), PM 11 (1:1) and PM 12 (1:2) containing

PEG 8000 by Physical Mixing.

Fig. 8: In vitro dissolution profile of PM 13(1:0.25), PM 14 (1:0.5), PM 15 (1:1) and PM 16 (1:2) containing

PEG 20000 by Physical Mixing.

In vitro dissolution profile of formulations prepared by Solvent Evaporation:

Fig. 9: In vitro dissolution profile of SE1 (1:0.5), SE2 (1:1), SE3 (1:2), SE4 (1:3) and SE5 (1:4) containing PEG

4000 by Solvent Evaporation.



Fig. 10: In vitro dissolution profile of SE 6(1:0.5),SE7 (1: 1), SE8 (1:2),SE 9 (1:3) and SE 10 (1:4) containing

PEG 6000 by Solvent Evaporation.

Fig. 11: In vitro dissolution profile of SE 11(1:0.5),SE12 (1: 1), SE13 (1:2),SE 14 (1:3) and SE 15 (1:4)

containing PEG 8000 by Solvent Evaporation

Fig. 12: In vitro dissolution profile of SE 16(1:0.5), SE17 (1: 1), SE18 (1:2), SE 19 (1:3) and SE 20 (1:4)

containing PEG 20000 by Solvent Evaporation.



In vitro dissolution profile of formulations prepared by Melt Fusion:

Fig. 13: In vitro dissolution profile of MF1(1:3), MF2(1:3), MF3(1:3) and MF4(1:3) containing by PEG

4000,6000,8000 and 20000 respectively (Melt fusion technique).

In vitro dissolution profile of formulations prepared by Kneading Method:

Fig. 14: In vitro dissolution profile of KF1 (1:0.5), KF2(1:1), KF3(1:2) KF4(1:3) (Kneading Method)and KF5

(1:0.5-Physical Mixing method) containing by Beta cyclodextrins

Fig. 15: In vitro dissolution profile of KF6 (1:0.5), KF7 (1:1), KF8(1:2) KF9(1:3) (Kneading Method) and KF10

(1:3-Physical Mixing method) containing by Hydroxy propyl Beta cyclodextrins.



Table 1: Drug content estimation of Ritonavir polymeric dispersions by various carriers

Formulations code Method % Drug Content ± SD

PM 1 Physical Mixing Technique 91.01 ± 1.34

PM2 Physical Mixing Technique 92.01 ± 1.29















MF1 Melt Technique 93.24 ± 1.94




SE1 Solvent Evaporation Technique 92.12 ± 1.77






















KF1 Kneading Method 96.42 ± 1.01




KF5 Physical Mixing Technique 95.42 ± 2.34





KF10 Physical Mixing Technique 93.88 ± 1.06

Table 2: Kinetics data for various polymeric dispersions

Formulations

code

Higuchi

Krosmeyer-Peppas model

Hixon

Crowell

First

order

Zero

order

R R K n R R R

PM1 0.997 0.974 25.70 0.069 0.994 0.994 0.993

PM2 0.978 0.985 26.66 0.065 0.945 0.946 0.942

PM3 0.972 0.923 27.16 0.070 0.997 0.997 0.997

PM4 0.895 0.835 25.50 0.128 0.946 0.944 0.951

PM5 0.968 0.926 11.22 0.117 0.980 0.980 0.979

PM6 0.928 0.868 11.48 0.116 0.972 0.972 0.973

PM7 0.906 0.861 10.37 0.160 0.952 0.951 0.954

PM8 0.965 0.960 3.53 0.467 0.993 0.922 0.996

PM9 0.897 0.832 9.74 0.156 0.955 0.954 0.956

PM10 0.970 0.933 12.35 0.129 0.993 0.993 0.994

PM11 0.939 0.910 12.50 0.178 0.968 0.966 0.970

PM12 0.958 0.962 6.19 0.386 0.928 0.930 0.923

PM13 0.913 0.912 10.81 0.153 0.913 0.913 0.913

PM14 0.970 0.994 12.82 0.143 0.919 0.920 0.915

PM15 0.965 0.936 14.02 0.175 0.986 0.985 0.987

PM16 0.956 0.928 17.10 0.194 0.960 0.962 0.957

MF1 0.955 0.905 34.43 0.135 0.985 0.982 0.991

MF2 0.946 0.982 33.34 0.123 0.982 0.979 0.987

MF3 0.973 0.929 37.15 0.113 0.992 0.992 0.992

MF4 0.993 0.972 40.27 0.123 0.994 0.995 0.989

SE1 0.982 0.957 27.03 0.137 0.982 0.983 0.979

SE2 0.951 0.890 48.97 0.083 0.985 0.982 0.990

SE3 0.968 0.921 49.09 0.093 0.985 0.985 0.985

SE4 0.949 0.887 52.23 0.082 0.982 0.980 0.983

SE5 0.961 0.990 55.08 0.093 0.924 0.934 0.900

SE6 0.994 0.984 25.31 0.290 0.991 0.993 0.985

SE7 0.978 0.997 46.77 0.087 0.942 0.947 0.929

SE8 0.939 0.896 46.77 0.095 0.962 0.956 0.972



SE9 0.988 0.977 48.97 0.086 0.978 0.980 0.971

SE10 0.910 0.853 48.97 0.086 0.943 0.936 0.958

SE11 0.982 0.960 26.85 0.160 0.993 0.992 0.993

SE12 0.958 0.925 45.91 0.082 0.965 0.965 0.964

SE13 0.988 0.953 52.48 0.076 0.998 0.998 0.998

SE14 0.998 0.983 53.70 0.079 0.990 0.993 0.983

SE15 0.991 0.963 56.23 0.075 0.993 0.994 0.989

SE16 0.984 0.957 23.98 0.222 0.995 0.995 0.993

SE17 0.917 0.921 47.86 0.103 0.887 0.892 0.877

SE18 0.976 0.938 48.97 0.094 0.985 0.986 0.983

SE19 0.990 0.963 51.28 0.089 0.993 0.994 0.989

SE20 0.981 0.950 60.25 0.070 0.990 0.989 0.988

KF1 0.944 0.970 74.64 0.123 0.923 0.935 0.892

KF2 0.931 0.949 25.88 0.224 0.914 0.927 0.881

KF3 0.946 0.957 38.01 0.314 0.935 0.951 0.893

KF4 0.955 0.963 36.30 0.113 0.935 0.940 0.925

KF5 0.990 0.979 21.37 0.298 0.994 0.994 0.989

KF6 0.782 0.798 48.30 0.382 0.826 0.817 0.843

KF7 0.871 0.922 29.58 0.265 0.820 0.839 0.779

KF8 0.686 0.778 20.13 0.166 0.604 0.619 0.576

KF9 0.757 0.824 36.39 0.186 0.712 0.736 0.664

KF10 0.960 0.964 21.57 0.322 0.954 0.959 0.934

IV. CONCLUSION Although numerous methods are available to improve the solubility of pure drugs, the most

promising method for promoting dissolution is the formation o solid dispersions. The negative values of Gibbs

free energy of transfer from water to an aqueous solution of hydrophilic carriers indicated the spontaneity of

drug solubilization. Increased solubility was also observed with all types of hydrophilic carriers used in the

preparation of solid dispersions. Highest solubilizing power of HP β-CD and 20,000 grade of poly ethylene

glycol towards Ritonavir were shown by Phase solubility and dissolution studies. The solubility and dissolution

rate of ritonavir can be enhanced by the formulations of SDs of Ritonavir with Poly ethylene glycol 8000, Poly

ethylene glycol 4000, Poly ethylene glycol 6000 and β-CD. The solubilization effect of PEGs may be

contributed due to reduction of particle aggregation of the drug, absence of crystallinity , increased wettability,

dispersibility and alteration of the surface properties of the drug from its solid dispersion. Among the various

ratios, drug: PEG 20,000 and drug: HP β-CD showed satisfactory solubility enhancement. From FTIR

spectroscopy studies, it was concluded that there was no well defined chemical interactions between Ritonavir -

PEG 20,000 and Ritonavir-HP β-CD.

ACKNOWLEDGEMENT

Authors are highly thankful to GITAM Institute of Pharmacy, GITAM University Visakhapatnam, India for

providing library facility during literature survey and also thankful to RIPS for conducting thermal analysis.

Conflict of Interest: Authors have no conflict of interest.

REFERENCES

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[3] Dannenfelser. R, He H, Joshi.Y, Bateman. S, Serajuddin.A.T.M.,2004. Development of clinical

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[4] Sushilkumar S. P., Shirish U. N. and Dinesh. K. S., 2011. Designing of Ritonavir Solid Dispersion

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solubility and dissolution of Ritonavir by solid dispersion. Journal of Pharmaceutics and Scientific

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[6] Md. Gulshan, S. Subhashini, M. Prathyusha and N. Rama Rao,2014. Dissolution rate enhancement

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Enhancement of Dissolution Rate of Ritonavir: A ...8)/G0480044058.pdfEnhancement of Dissolution Rate of Ritonavir: A Comparative study using various Carriers and Techniques 1A. Sarada,

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