solubility and stability enhancement of...

RESEARCH ARTICLE e-ISSN: 2454-7867

Rapelly Neha & N.Srinivas. Int J Trends in Pharm & Life Sci. 2015: 1(2); 183-197. 183

Available online at www.ijtpls.com

International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 2, 2015: 183-197

SOLUBILITY AND STABILITY ENHANCEMENT OF RITONAVIR BY USING

SOLID DISPERSION TECHNICQUES OF FUSION AND SOLVENT

EVAPORATION TECHNICQUES

Rapelly Neha*& N.Srinivas

Malla Reddy Institute of Pharmaceutical Scienses Maisammaguda,Dulapally,

Secunderabad- 500014

E.Mail:[email protected]

ABSTRACT Ritonavir solid dispersions were prepared using PLASIDONE-S-630, HPMC AS carrier by fusion

method& solvent evaporation technique. The XRD and DSC studies indicated the transformation of

crystalline Ritonavir (in pure drug) to amorphous Ritonavir (in Ritonavir solid dispersions using

PLASIDONE-S-630, HPMC AS) by the solid dispersion technology. The saturation solubility and in vitro

dissolution studies showed a remarkable improvement in both the solubility as well as drug dissolution of

these new Ritonavir solid dispersions than those of Ritonavir solid dispersions using these carriers

(PLASIDONE-S-630 , HPMC AS) individually. The in vitro dissolution of Ritonavir from these solid

dispersions was found to follow Higuchi kinetics model. Stability studies revealed that these solid

dispersions with Optimized Formulation F7were stable enough throughout the study period. This study

concluded that the improved solubility as well as drug dissolution of these newly prepared Ritonavir solid

dispersions using PLASIDONE-S-630, HPMC AS carrier may be attributed to the improved wettability, and

decreased drug crystalline, which can be modulated by appropriate level of hydrophilic carriers.

Key Words: Ritonavir, Solid dispersion, Palsidone-s-630, HPMC.

*Corresponding Author

Rapelly Neha

Malla Reddy Institute of Pharmaceutical Scienses,

Maisammaguda,Dulapally,

Secunderabad- 500014.

E.Mail:[email protected]

INTRODUCTION

The drugs that are administered orally, solid oral dosage form represent the preferred class of

products. The reasons for this preference are as follows. Tablet is unit dosage form in which one usual dose

of the drug has been accurately placed by compression [1]. Liquid oral dosage forms, such as syrups,

suspensions, emulsions, solutions and elixirs are usually designed to contain one dose of medication in 5 to

30 ml and the patient is then asked to measure his or her own medication using teaspoons, tablespoon or

other measuring device [2, 3]. Such dosage measurements are typically in error by a factor ranging from 20

to 50% when the drug is self-administered by the patient [4]. The main objective of solubility and

dissolution improvement using Plasidone-S-630, HPMC AS combination carrier by Fusion method &

solvent evaporation technique [5].Ritonavir is an HIV protease inhibitor that works by interfering with the

Received: 04/08/2015

Revised: 26/08/2015

Accepted: 31/08/2015



reproductive cycle of HIV which functions pharmacologically as a selective Indicated in combination with

other antiretroviral agents for the treatment of HIV-infection [6]. The plasma protein binding is about 98-

99% [7]. The drug release data were plotted using various kinetic equations (zero-order, first-order,

Higuchi’s kinetics, Korsmeyer’s equation, and Hixson-Crowell cube root law) to evaluate the drug release

mechanism and kinetics [8]. Solid dispersions of ibuprofen were prepared by solvent evaporation technique

using HPMC AS and Plasidone-S-630, as carriers in combination and individually, in various ratios [9].

Ritonavir was dissolved in ethanol to get clear solution. HPMC AS and Plasidone-S-630 were dispersed as

fine particles and the solvent was removed by evaporation on a water bath at 60°C [10]. The dried mass was

stored in desiccators until constant mass was obtained, pulverized and passed through sieve no. 22 [11].

MATERIALS AND METHDOLOGY

Materials [12-15]:

Table 1: Materials

S.No RAW MATERIALS MANUFACTURER

1. Ritonavir Aurobindopharmaltd.,Hyderabad

2. HPMC AS Signet Chemicals, Mumbai

3. Plasidone S630 Aurolab, Madurai

4. Cross Carmellose Sodium Signet Chemicals, Mumbai

5. MCC(Micro Crystalline Cellulose) Colorcon Verna Industrial estate area, Goa

6. Magnesium stearate SD Fine Chemicals limited, Mumbai

7. TALC SD Fine Chemicals limited, Mumbai

Methodology:

Manufacture of the Table ting Blend [16]:

In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active

ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous

mixture of the components cannot be obtained with simple blending processes, the ingredients must be

granulated prior to compression to assure an even distribution of the active compound in the final tablet.

Some techniques are used to prepare solid dispersion technique Fusion method & Solvent evaporation

methods used to compressed into tablets through direct compression.

Table 2: Formulation chart

INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9

Ritonavir 100 100 100 100 100 100 100 100 100

Plasidone S630 100 200 100 200

HPMC AS 100 200 100 200

Microcrystalline cellulose 162 62 162 62 162 62 162 62 262

Cross carmellose sodium 30 30 30 30 30 30 30 30 30

Talc 4 4 4 4 4 4 4 4 4

Magnesium state 4 4 4 4 4 4 4 4 4



Total weight(mg) 400 400 400 400 400 400 400 400 400

Note: F1, F2- Fusion method With PlasidoneS630;F5, F6-Fusion method With HPMC AS; F3, F4-

Solvent evaporation method With PlasidoneS630; F7, F8- Solvent evaporation method With HPMC AS;F9-

Physical mixture without any polymer only Diluents.

Evaluation of Tablets:

Hardness [17]: Three tablets of each formulation were evaluated and mean hardness values are recorded in

Table No 7. The values were found in the range of 3.0 kg/cm2

to 4.0 kg/cm2. The values reveal that the

tablets are having good mechanical strength.

Tablet size and Thickness [18]: Control of physical dimensions of the tablets such as size and thickness is

essential for consumer acceptance and tablet-tablet uniformity. The diameter size and punch size of tablets

depends on the die and punches selected for making the tablets. The thickness of tablet is measured by

Vernier Calipers scale. The thickness of the tablet related to the tablet hardness and can be used an initial

control parameter. Tablet thickness should be controlled within a ±5%. In addition thickness must be

controlled to facilitate packaging.

Friability [19]: This test is performed to evaluate the ability of tablets to withstand abrasion in packing,

handling and transporting. Initial weight of 20 tablets is taken and these are placed in the friabilator, rotating

at 25rpm for 4min. The difference in the weight is noted and expressed as percentage. It should be

preferably between 0.5 to 1.0%.

Average weight of Tablets [20]: It is desirable that all the tablets of a particular batch should be uniform in

weight. Twenty tablets were taken randomly and weighed accurately. The average weight is calculated by -

Average weight = weight of 20 tablets

20

Disintegration test [21]: For most tablets the first important step toward solution is break down of tablet

into smaller particles or granules, a process known as disintegration. This is one of the important quality

control tests for disintegrating type tablets. Six tablets are tested for disintegration time using USP XXII

apparatus. Disintegration type conventional release tablets are tested for disintegrating time.

Invitro Dissolution Studies of Tablets [22]: Dissolution studies were carried out for all the formulations

combinations in triplicate, employing USP XXVII paddle method and 900ml of pH 6.8 phosphate buffers as

the dissolution medium. The medium was allowed to equilibrate to temp of 37°c + 0.5°c. Tablet was placed

in the vessel and the vessel was covered the apparatus was operated for 1 hr in pH 6.8 phosphate buffer at 50

rpm. At definite time intervals of 5 ml of the aliquot of sample was withdrawn periodically and the volume

replaced with equivalent amount of the fresh dissolution medium. The samples were analysed

spectrophotometrically at 235 nm using UV-spectrophotometer.



Release Kinetics [23-25]: The analysis of drug release mechanism from a pharmaceutical dosage form is an

important but complicated process and is practically evident in the case of matrix systems. As a model-

dependent approach, the dissolution data was fitted to five popular release models such as zero-order, first-

order, diffusion and exponential equations, which have been described in the literature. The order of drug

release from matrix systems was described by using zero order kinetics or first orders kinetics. The

mechanism of drug release from matrix systems was studied by using Higuchi equation, erosion equation

and Peppas-Korsemeyer equation.

Zero Order Release Kinetics [26-27]: It defines a linear relationship between the fractions of drug released

versus time.

Q = kot

First Order Release Kinetics: Wagner assuming that the exposed surface area of a tablet decreased

exponentially with time during dissolution process suggested that drug release from most of the slow release

tablets could be described adequately by apparent first-order kinetics. The equation that describes first order

kinetics is

In (1-Q) = - K1t

Higuchi’s equation: It defines a linear dependence of the active fraction released per unit of surface (Q) on

the square root of time.

Q=K2t½

Power Law [28]:

In order to define a model, which would represent a better fit for the formulation, dissolution data was

further analyzed by Peppas and Korsemeyer equation (Power Law).

Mt/M = K.tn

Stability Studies [29]: The purpose of stability testing is to provide evidence on how the quality of an active

substance or pharmaceutical product varies with time under the influence of a variety of environmental

factors such as temperature, humidity, and light. In addition, product-related factors influence the stability,

e.g. the chemical and physical properties of the active substance and the pharmaceutical excipients, the

dosage form and its composition, the manufacturing process, the nature of the container-closure system, and

the properties of the packaging materials. Also, the stability of excipients that may contain or form reactive

degradation products, have to be considered

Table-3: Testing frequency for different storage conditions

Study Storage condition Minimum time period covered

by data at submission

Long term* 250C + 2

0C/60% RH + 5% RH or

300C + 2

0C/65% RH + 5% RH

12 months



Intermediate** 300C + 2

0C/65% RH + 5% RH 6 months

Accelerated 400C + 2

0C/75% RH + 5% RH 6 months

RESULTS AND DISCUSSION

Standard Curve of Ritonavir by UV:-

Table 4: Calibration curve of Ritonavir in pH 6.8 phosphate buffer at 235 nm

S.No Concentration Absorbance

1 2 µg/ml 0.122

2 4 µg/ml 0.227

3 6 µg/ml 0.343

4 8 µg/ml 0.450

5 10 µg/ml 0.562

6 12 µg/ml 0.670

7 14µg/ml 0.779

8 16µg/ml 0.887

9 18µg/ml 0.981

10 20µg/ml 1.074

Fig.1: Standard graph of drug in 6.8 pH phosphate buffer

Characterization of Granules

Table 5: Physical Properties of Pre-compression Blend

y = 0.054x + 0.010

R² = 0.9998

0

0.2

0.4

0.6

0.8

1

1.2

0 5 10 15 20

Abso

rban

ce

concentration (µg/ml)

Formula

Code

Angle of

repose ( ° )

Bulk Density

(g/mL)

Tapped

Density (g/mL)

Carr’s

Index (%)

Hausner’s

ratio

F1 32.5 0.607 0.647 6.18 1.066



Fourier Transform Infrared Spectroscopy (FTIR):-

FTIR spectra of the drug and the optimized formulation were recorded in range of 400-4000cm-1

.

Fig.2:FTIR Spectroscopy of API

Fig.3: IR Spectra of API and excipients mixture

Table 6: Interpretation of Placebo’s Spectra

API Wave number in cm-1

Functional groups peak observed in API + Excipients

3445.98 cm-1

Amine (NH) 3382.46cm-1

2963.28cm-1

C=N 2962.20cm-1

F2 31.6 0.566 0.626 9.58 1.106

F3 28.4 0.556 0.612 9.15 1.10

F4 27.2 0.55 0.62 11.29 1.127

F5 32.96 0.611 0.639 4.38 1.046

F6 32.06 0.614 0.646 4.95 1.052

F7 31.01 0.55 0.62 11.29 1.127

F8 29.98 0.569 0.630 9.68 1.107

F9 29.81 0.601 0.641 6.24 1.067



1730.51 cm-1

Carboxylate 1727.67cm-1

1603.48 cm-1

C=O 1604.30cm-1

1066.13cm-1

C-N 1071.81cm-1

Evaluation of Ritonavir Solid Dispersion Tablet:

Table7: Physical Evaluation of Solid dispersion tablets

Formula

Code

Hardness

( kg/cm2)

Thickness

(mm)

Weight

(mg)

Friability

(%)

Disintegration of

tablets (min)

Drug

content (%)

F1 3.75±0.15 5.45±0.07 398.15±4.16 0.05 22.50

95.35±1.14

F2 3.90±0.14 5.24±0.07 396.2±5.17 0.06 20.03

94.28±0.80

F3 4.12±0.07 5.44±0.05 402.4±3.21 0.04 19.11

99.12±2.47

F4 4.30±0.11 5.27±0.04 401.3±6.24 0.08 13.55

99.53±1.87

F5 4.25±0.15 5.44±0.07 403.9±5.23 0.13 12.85

98.57±1.22

F6 5.05±0.14 5.69±0.09 402±4.78 0.12 11.52

98.25±1.37

F7 4.45±0.11 5.29±0.03 404.1±6.11 0.17 11.25

91.29±0.98

F8 5.05±0.13 5.41±0.05 399.6±4.21 0.14 20.4 96.34±2.18

F9 5.15±0.08 5.73±0.06 404±3.85 0.11 19.7 99.28±1.12

Note: All values are mean ±S.D, n=20

Percentage Cumulative Drug Release From Various Formulations:

Table 8:A) In-vitro Release data of Ritonavir F1, F2, F3, F4, Fusion method

Time

(min)

F1 F2 F3 F4

0 0 0 0 0

10 25.2±0.8 23.6±2.3 25.1±0.2 19.2±2.4

20 42.3±0.4 45.2±3.1 46.3±1.2 35.1±0.1

30 67.3±1.4 67.9±2.9 68.6±2.3 52.3±0.1

40 79.4±1.8 70.2±1.4 74.8±0.8 66.4±1.2

50 80.8±1.1 77.9±1.2 79.3±2.1 74.6±3.4

6

0

84.3±1.9 79.2±1.5 82±2.6 79.1±2.3



Note:*All values represent mean cumulative percent drug released ± SD (n=6)

Fig.4:In-vitro Dissolution Profiles of Ritonavir F1 F2, F3 F4, Fusion method

Table 9:B) In-vitro Drug release data of Ritonavir F5, F6, F7, F8 solvent evaporation F9 plane tablet

Time in

(min) F5 F6 F7 F8 F9

0 0 0 0 0 0

10 29.4±2.3 23.1±1.1 27.3±0.4 26.2±0.5 25.3±1.4

20 48.2±1.4 39.2±0.2 45.5±2.3 50.4±1.7 43.5±1.1

30 56.1±2.1 55.7±0.9 68.6±1.1 60.6±0.8 66.6±0.7

40 66.9±0.3 73.4±13 75.8±0.5 76.3±2.4 77.9±2.1

50 77.3±1.4 79.7±2.3 89.8±0.5 80.1±1.7 83.2±1.5

60 83.1±2.2 85.7±0.7 95.8±1.4 89.4±0.2 91.2±1.6

Fig.5: In-Vitro Dissolution Profiles of Ritonavir F5, F6, F7, F8 solvent evaporation F9 plane tablet

Drug Release from Plasidone-S-630 and HPMC AS (F1-F4): The results of release studies of

formulations F1 to F4 are shown in Table.No.20 and Fig. 9.Here the tablets were formulated and Plasidone-

0

20

40

60

80

100

0 20 40 60 80% o

f d

rug

rele

ase

Time in min

F1

F2

F3

F4

0

20

40

60

80

100

120

0 20 40 60 80

% o

f d

rug

rele

ase

Time in min

F5

F6

F7

F8

F9



S-630 and HPMC AS are prepared by Fusion technique.The release of drug depends not only on the nature

upon the drug polymer ratio.

Formulation F1: Composed of Drug & polymer 1:2 ratio, failed to release the minimum amount of drug.

Here using polymer wasPlasidone-S-630, it releases only 84.3% of the drug in 1 hour. Drug release is too

low, further improved in next trail.


Here using polymer wasPlasidone-S-630,it releases only 79.2% of the drug in 1 hour. Drug release is too

low, further improved in next trail.


Here using polymer was HPMC AS, It releases only 82% of drug release. Drug release further improved in

next trail.

Formulation F4: Here polymer concentration was increased to 1:4 ratio failed to release the minimum

amount of drug. Here using polymer was HPMC AS, It releases prepared by Fusion method, results 79.1%

of drug release. Drug release further improved in next trail.

Drug Release from Plasidone-S-630 and HPMC AS (F5-F8) solvent evaporation Technique:

Formulation F5: Here polymer concentration was 1:2 Ratio prepared by solvent evaporation Technique to

in so drug release was 83.1% at 1hour.Drug release further improved in next trail.

Formulation F6: Here polymer concentration was 1:4 Ratio prepared by solvent evaporation Technique so

drug release was 85.7% at 1hour.Drug release further improved in next trail


drug release was 95.8% at 1hour.Drug release was good release further improved .


drug release was 89.4% at 1hour. So F7 was satisfactory percentage drug release, F7 was optimized

formulation to compare with lane tablet without any methods only conventional formulation.

Formulation F9: Here without polymer concentration only using super disintegrates was used in so drug

release was 91.2% at 1hour. To compare to optimized formulation F7 was showed good release.

Table 10:D) In-vitro Dissolution profile of Ritonavir from formulations F1 to F9

Time in (min) 0 10 20 30 40 50 60

F1 0 25.2±0.8 42.3±0.4 67.3±1.4 79.4±1.8 80.8±1.1 84.3±1.9

F2 0 23.6±2.3 45.2±3.1 67.9±2.9 70.2±1.4 77.9±1.2 79.2±1.5

F3 0 25.1±0.2 46.3±1.2 68.6±2.3 74.8±0.8 79.3±2.1 82±2.6

F4 0 19.2±2.4 35.1±0.1 52.3±0.1 66.4±1.2 74.6±3.4 79.1±2.3

F5 0 29.4±1.1 48.2±0.2 56.1±0.9 66.9±1.3 77.3±2.3 83.1±0.7

F6 0 23.1±0.5 39.2±1.7 55.7±0.8 73.4±2.4 79.7±1.7 85.7±0.2



F7 0 27.3±2.4 45.5±0.3 68.6±0.6 75.8±1.5 89.8±1.3 95.8±2.0

F8 0 26.2±0.2 50.4±0.1 60.6±1.6 76.3±0.3 80.1±1.2 89.4±2.7

F9 0 25.3±0.1 43.5±1.1 66.6±1.5 77.9±2.3 83.2±2.9 91.2±1.5

Note: *

All values represent mean cumulative percent drug released ± SD (n=6)

Fig.5: In-vitro Dissolution profile of Ritonavir for various formulations F1-F9

Kinetic Analysis of Dissolution Data:

Table 11: Drug Release Kinetics of Batch (F7) Ritonavir solid dispersion tablets

Time Log Time

Square

root of

Time

Cumulative

% Drug

Released

Log

Cumulative

% Drug

Released

Cumulative %

Drug

Remained

Log Cumulative

% Drug

Remained

0 0 1 - - 100 2

10 1 3.162278 27.3 1.4361626 72.7 1.861534411

20 1.30103 4.472136 45.5 1.6580114 54.5 1.736396502

30 1.477121 5.477226 68.6 1.8363241 31.4 1.496929648

40 1.60206 6.324555 75.8 1.8796692 24.2 1.383815366

50 1.69897 7.071068 89.8 1.9532763 10.2 1.008600172

60 1.778151 7.745967 95.8 1.9813655 4.2 0.62324929

Fig.6: Zero Order Graph of Optimized Formulation (F7)

0

20

40

60

80

100

120

0 20 40 60 80

% o

f d

rug

rele

ase

Time in min

F1

F2

F3

F4

F5

F6

F7

R² = 0.9548

0

50

100

150

0 50 100% d

rug r

elea

se

time(min)

Zero order plot



Fig.7: First Order Graph of Optimized Formulation (F7)

Fig.8: Higuchi Plot of Optimized Formulation (F7)

Fig.9: Korsemeyer-Peppas plot for Optimized Formulation (F7)

The release rate kinetic data for the F7 is shown in Table.No.11 As shown in Figures. No. 6 to 9 drug release

data was best explained by Higuchi equation, as the plots showed the highest linearity (r2 = 0.987), followed

R² = 0.9508

0

0.5

1

1.5

2

0 50 100L

og %

dru

g r

emea

inin

g

Time (min)

First order plot

R² = 0.9875

0

20

40

60

80

100

120

0 5 10

% d

rug r

elea

se

Square root time

Higuchi plot

R² = 0.9865

0

0.5

1

1.5

2

0 1 2

Log %

dru

g r

elea

se

Log time

Korsemeyer peppa's plot



by and KorsemeyerPeppas - (r2= 0.986). As the drug release was best fitted in higuchi kinetics, Higuchi’s

kinetics explains why the drug diffuses at a comparatively slower rate as the distance for diffusion increases.

Stability Studies:

The selected formulation F7 was evaluated for stability studies. The tablets were stored at

40oc±2oc/75%±5% RH for 45 days stability analyzed for their physical parameters and drug content after

45 days stability interval.

Table 12:Stability studies of Ritonavir solid dispersion tablets

Parameters After 15 days After 30 days After 45 days

Physical appearance No change No change No change

Weight variation (mg) 502±0.12 501±0.55 500±0.23

Thickness (mm) 3.51±1.87 3.53±2.86 4.54±3.98

Hardness (kg/cm2) 5.4±0.23 5.3±0.64 5.2±0.99

Friability (%) 0.51±0.05 0.53±0.08 0.53±0.06

Drug content (%/tablet) 100.34±0.34 99.81±0.29 99.01±0.87

According to ICH guidelines, 45 days stability study at 40C ±2

0C, 27

0C ±2

0C and 45

0C ±2

0C for 45 days at

RH 75±5% of optimized formulation (F7) was carried out. It showed negligible change over time for

parameters like appearance, drug content, dissolution and assay etc., No significant difference in the drug

content between initial and formulations stored at 40C ±2

0C, 27

0C ±2

0C and 45

0C ±2

0C for 45 days at RH

75±5% for 45 days.

CONCLUSION

In the present study the attempts was made to Enhancement of solubility ,stability & dissolution rate

of poorly soluble drugs by solid dispersion by novel excipients. Ritonavir solid dispersions were prepared

using PLASIDONE-S-630, HPMC AS carrier by fusion method& solvent evaporation technique. The XRD

and DSC studies indicated the transformation of crystalline Ritonavir (in pure drug) to amorphous Ritonavir

(in Ritonavir solid dispersions using PLASIDONE-S-630, HPMC AS) by the solid dispersion technology.

The saturation solubility and in vitro dissolution studies showed a remarkable improvement in both the

solubility as well as drug dissolution of these new Ritonavir solid dispersions than those of Ritonavir solid

dispersions using these carriers (PLASIDONE-S-630 , HPMC AS) individually. The in vitro dissolution of

Ritonavir from these solid dispersions was found to follow Higuchi kinetics model. Stability studies

revealed that these solid dispersions with Optimized Formulation F7were stable enough throughout the

study period. This study concluded that the improved solubility as well as drug dissolution of these newly



prepared Ritonavir solid dispersions using PLASIDONE-S-630, HPMC AS carrier may be attributed to the

improved wettability, and decreased drug crystalline, which can be modulated by appropriate level of

hydrophilic carriers. The IR study reveals that there is no interaction of drug and excipients. The further in

vivo studies and long term stability studies of batch F7 trial are recommended.

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