Solubility Enhancement of Ritonavir by using Liquisolid Compact Technique

 

Dr. Sapana Ahirrao1*, Bhagyashree D. Gangode2, Dr. Sanjay Kshirsagar3

1Assistant Professor, Department of Pharmaceutics, MET’s Institute of Pharmacy, Adgaon, Nashik, Maharashtra, India, Affiliated to Savitribai Phule Pune University (SPPU), Pune

2Department of Pharmaceutics, MET’s Institute of Pharmacy, Adgaon, Nashik, Maharashtra, India, Affiliated to Savitribai Phule Pune University (SPPU), Pune

3Principal of MET’s Institute of Pharmacy, Adgaon, Nashik, Maharashtra, India, Affiliated to Savitribai Phule Pune University (SPPU), Pune

*Corresponding Author E-mail: sapana.58ahirrao@gmail.com, bhagyashreegangode43@gamil.com, sanjayjk@rediffmail.com

 

ABSTRACT:

Novel solubility enhancement technique; liquisolid compact technique is used in present research work. Ritonavir is poorly soluble drug was formulated using Avicel pH 102 and Aerosil 200 as carrier and coating material respectively. Solubility studies were conducted in different liquid vehicles, namely propylene glycol, span 20, PEG 400, tween 20, and PEG 200. From the result of saturation solubility study the liquisolid compacts were formulated using PEG 400 as non volatile vehicle. The ritonavir liquisolid formulations were obtained by allowing liquid vehicle with varying ritonavir concentration to get absorbed onto carrier and coating material taken at different ratio (R=5,10,15,20).Then the ritonavir liquisolid powder system evaluated for flow property determination and then compressed into tablet. Each batch of prepared ritonavir Liquisolid powder compact evaluated for Quality control tests, i.e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution study. Optimized batch of Liquisolid powder compact evaluated for quality control test of tablet along with FTIR, DSC and PXRD study. The tableting properties of the liquisolid compacts were within the acceptable limits and in vitro drug release rate of LS compacts were distinctly higher as compared to directly compressible tablet and pure drug alone. This was due to an increase in wetting properties and surface of drug available for dissolution. FTIR study result indicates that there is no drug excipient interaction..DSC and PXRD study suggested loss of ritonavir crystallinity upon liquisolid formulation, it indicates that drug is held within the power substrate in a solubilized, almost molecularly dispersed state, which lead to enhanced drug solubility. From significant result of solubility of ritonavir, liquisolid technique would be promising solubility enhancement technique for various poorly soluble drugs.

 

KEY WORDS: Ritonavir; Liquisolid compact; PEG 400; Carrier material; Coating material; Poorly water soluble drugs.

 

1. INTRODUCTION:

The oral route is the most preferred route of drug administration. Tablets are the most popular oral formulation available in market and are preferred by patient and physicians due to number of advantages.(1)Tablets are a unit dosage form and they offer greatest capabilities of all oral dosage form for greatest dose precision and least content variability. They are lightest and most compact of all oral dosage form with lowest cost.(2) Most of newly discovered chemical entities, in spite of high therapeutic activity, have low aqueous solubility and poor bioavailability, leading to poor absorption of drug from the gastrointestinal tracts (GIT).(3) The aqueous solubility for poorly water soluble drug is usually less than 100μg/ml.(4) As per BCS classification, drugs are classified into four classes. Out of them BCS class II and class IV drugs show major problem due to solubility and hence absorption and bioavailability problem, is the major area of reason. Hence in present research work, aim is focused on solubility enhancement. various technique of solubility enhancement can be categorized into physical chemical modification of drug substance and other techniques(5,6) shown in figure 1.Each technique having its own advantages with limitations. Out of all techniques, liquisolid compact technique is most promising and novel technique selected for solubility enhancement of poorly soluble drugs.

 

Figure 1: Technique of Solubility Enhancement

 

The goal of this study was to improve dissolution of a model hydrophobic drug, ritonavir, using liquisolid tablets containing different non-volatile liquid vehicles. Ritonavir is an antiretroviral drug used in treatment of AIDS and HBV infections. The half life of drug is 3-5 hrs and administered dose of 300mg thrice a day. Ritonavir exhibit low and variable oral bioavailability due to its poor aqueous solubility (0.00126mg/mL)(7,8,9) Various approaches have been triedto enhance the dissolution properties of ritonavir, such as formation of ritonavir solid dispersion(3,10,11,12) complexation with Cyclodextrins and use of surfactant(13), co-crystalization(14) and formation of solid solution by using hot melt extrusion technique(15), preparation of nanosuspension.(16) However, one strategy that has not been investigated to improve dissolution of ritonavir is liquisolidtablet formulations. To the best of our knowledge, there are currently no liquisolid dosage forms available in the market. However, commercial products using liquisolid technology may be available, in the future, in the market based on this research and similar studies.

 

1.1.Liquisolid Technique:

The term liquisolid technique refers to immediate release or sustained release tablets or capsules, combined with the inclusion of appropriate adjuvant required for tabletting or encapsulating. Liquisolid compacts are acceptably free flowing and compressible powder forms of liquid medications.(17) The liquid portion, which can be an oily liquid drug, suspension or solution of water insoluble solid drugs in suitable non-volatile liquid vehicles, is incorporated into the porous carrier material. Once the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles.(18) Thus, an apparently dry, free flowing, and compressible powder is obtained. The concentrations of the carriers, coating materials, disintegrants, lubricants and glidants are optimized to get a non-sticky easily compressible blend.(19)

 

1.2.Theory of Liquisolid Systems:

The powder can retain only certain limited amount of liquid while maintaining the flow ability and compressibility. To calculate the quantities of powder excipients required for the formulation of liquisolid system, a mathematical approach is required and it has been developed by Spireas et. al. This approach is based on flowable (Ø-value) and compressible (Ψ-number) liquid retention potential.(20)

 

Flowable liquid retention potential (ϕ-value) is defined as the maximum weight of liquid that can be retained per unit weight of powder material in order to produce an acceptably flowing liquid/powder admixture.(21)

 

Compressible liquid retention potential (ѱ-value) The Ѱ-number of a powder is defined as the maximum amount of liquid that a powder can retain inside its bulk (w/w) while maintaining acceptable compact ability, namely, producing cylindrical compacts of adequate crushing strengths and acceptable levels of friability without presenting any ‘liquid-squeezing-out’ phenomena during compression.(21)

 

According to the new theories, the carrier and coating powder materials can retain only certain amounts of liquid while maintaining acceptable flow and compression properties.

 

Depending on the excipient ratio (R) of the powder substrate, where:

R = Q/q …………. (1)

which is the fraction of the weights of the carrier (Q) and coating (q) materials present in the formulation, an acceptably flowing and compressible liquisolid system can be prepared only if a maximum liquid load on the carrier material is not exceeded. Such a characteristic amount of liquid is termed the liquid load factor (Lf) and defined as the weight ratio of the liquid medication (W) and carrier powder (Q) in the system, i.e.:

 

Lf = W/Q………... (2)

 

It has been established (Spireas, 1993) that, for a given powder substrate consisting of a certaincarrier and coating powders mixed at various powder excipient ratios (R), there are specific maximum liquid load factors (Lf) which must be employed in order to produce acceptably flowing liquisolid systems. Such flowable Lf values, denoted as ФLf, are related to the R-values of their powder blends by:

 

ФLf=Ф +ф(1/R) ………(3)

 

where, as mentioned earlier, Ф and ф are the Ф -values of the carrier and coating powder materials, respectively.

Similarly, the compressible liquid load factors, Ѱ Lf, required to produce liquisolid compacts with acceptable compaction properties, are related to the excipient ratios (R) of their powder substrates as follows:

 

Ѱ Lf= Ѱ + ѱ (1/R)………… (4)

 

where Ѱ and ѱ are the C-numbers of the carrier and coating powders, respectively.

 

Therefore, for any liquid medication incorporated onto a given powder substrate consisting of certain carrier and coating materials (e.g. microcrystalline cellulose and silica) blended at a specific excipient ratio (R), there exists an optimum liquid load factor, LO, required to produce acceptably flowing and, simultaneously, acceptably compressible liquisolid preparations. In essence, the LO value required at a given powder excipient ratio for any system is equal to either its ФLf or ѰLf value, whichever is less; thus:

 

LO=фLf when: ФLf<ѰLf……………(5)

or

LO_ѱLf when: ФLf\ѰLf ………….(6)

 

Based on Eqs. (1) and (2), as soon as the optimum liquid load factor of a given excipient ratio system is established, the appropriate quantities of carrier (QO) and coating (qO) powder materials required to convert a given amount of liquid medication (W) into an acceptably flowing and compressible liquisolid system, may be calculated as follows(22)

QO=W/LO ……….(7)andqO=QO/R ………….(8)

 

2. MATERIAL AND METHODS:

Ritonavir was obtained from Mylan Laboratories Ltd., Sinnar, Nashik, microcrystalline cellulose (Avicel PH102) was gift sample from DFE Pharma, Mumbai, colloidal silicon dioxide (aerosil200) obtained from Research lab. Fine chem. industries, Mumbai, polyethylene glycol 400 obtained from Thomas Baker (chemicals) pvt.ltd. Mumbai. All other materials used were of analytical grade.

 

2.1.Saturation solubility studies:

The solubility of ritonavir determined in distilled water and 0.1 N HCl. To select non volatile solvent solubility of ritonavir determined in six non volatile vehicle namely polyethylene glycol200,propylene glycol, polyethylene glycol400,span20,tween20.The ritonavir was added in excess amount into 5 mL of each vehicle in conical flask separately and stirred for 48 hours at room temp in incubator orbital shaker. Then equilibrated samples were removed from shaker and centrifuged at 3000 rpm for 15 min to remove the excess drug. The supernatant was taken and filtered through a 0.45 μm membrane filter. The concentration of drug in supernatant was measured by UV spectrophotometer after appropriate dilution with 0.1N HCl at 246nm. Then drug solubility (mg/mL) was calculated.(10,23,24)

 

2.2. Drug Excipients Compatibility Study:

To assess physical and chemical incompatibilities, it was customary to make a small mixture of Ritonavir with excipients. Ritonavir and each excipients placed in vials in 1:1 ratio. also prepared physical mixture to assess incompatibility. Rubber stoppers were placed in the vial and kept vials at temperature 400c, Humidity-75% RH for Period of 1 month in Environmental Stability chamber.(25)

 

2.3.Method for Preparation of liquisolid powder compact:

1.    Based on saturation solubility study PEG 400 was selected as liquid vehicle for preparation of liquisolid powder system. Several liquisolid compacts were prepared as follows.

2.    The formulations batches of liquisolid compacts, F-1 to F-8 was prepared by varying excipients ratio 5,10,15 and 20 at drug concentration 60%w/w and 70%w/w. liquid load factor and amount of carrier and coating material calculated as per Spireas mathematical model shown in Table 1.

3.    The desired quantities of the previously weighed Ritonavir and the liquid vehicle (PEG 400) was mixedto obtain solution. The solution was then sonicated for 15 min until a homogeneous drug solution was obtained.

4.    Then the calculated weight (W) of the resulting liquid medications (equivalent to 100 mg drug) were incorporated into the calculated quantities of the carrier material (Avicel PH102) (Q) and mixed thoroughly.

5.    The resulting wet mixture was blended with the calculated amount of the coating material (Aerosil 200) (q) using a standard mixing process to form simple admixture.

6.    The required quantity of disintegrants (Sodium starch glycolate) was mixed with the Liquisolid powder system for 10 min. Then liquisolid compact were formed by direct compression method by using Rotary Tablet punching machine (Karnavati).(4,26)


 

Table 1: Formulation Batches of Ritonavir liquisolid tablet formulations

Formulation code

Drug conc. in liquid medication (%w/w)

Carrier coating ratio (R)

Liquid load factor (Lf)

Liquid vehicle (mg)

Drug (mg)

Carrier material (Q)(mg)

Coating material (q) (mg)

Disintegrant  (mg)

Unit dose (mg)

F1

60

5

0.657

66.66

100

101.46

20.20

14.41

302.73

F2

70

5

0.657

42.85

100

65.22

13.04

11.05

232.16

F3

60

10

0.331

66.66

100

201.38

20.13

11.15

399.32

F4

70

10

0.331

42.85

100

129.45

12.94

14.26

299.05

F5

60

15

0.222

66.66

100

300.27

20.01

24.34

511.28

F6

70

15

0.222

42.85

100

193.01

12.86

17.43

366.15

F7

60

20

0.168

66.66

100

396.78

19.83

29.16

612.43

F8

70

20

0.168

42.85

100

255.05

12.75

20.53

431.18

 


2.4. Preparation of Ritonavir Tablet by Direct Compression Technique:

Tablet containing Ritonavir was prepared by mixing 100mg Ritonavir with microcrystalline cellulose (Avicel PH102) and Sodium starch Glycolate as disintegrant and mix for 10 min. Glidant and lubricant added and then compressed by Tablet punching machine. The composition of directly compressible tablet is given in table 2.

 

Table 2: Composition of directly compressible tablet

Sr. No.

Ingredient

Quantity

1

Ritonavir

100mg

2

Sodium Starch Glycolate

75mg

3

Microcrystalline cellulose

135mg

4

Magnesium Stearate

30mg

5

Talc

60mg

 

2.5. Characterization of liquisolid compact:

2.5.1. Pre-compression study:

The flow property of all liquisolid formulation were studied such as bulk density, tapped density, carr’s index, hausnars ratio and angle of repose.(23)

 

1) Bulk density:

Bulk density refers to the measure used to describe a packing of particles or granules. Bulk density is defined as the mass of powder divided by the bulk volume and is expressed in grams per milliliter (g/mL). The equation for determining bulk density (ρb) is

 

                                    ρb = M / Vb

 

where ρb = Bulk density

M = Mass of sample in g

Vb = Total volume of packing in mL

 

 

2) Tapped density:

Tapped density can be defined as mass of blend in the measuring  cylinder divided by its tapped volume.

ρt = M / Vt

Where ρt = Tapped density

M = Mass of blend in g

Vt = Tapped volume of blend in cm3

 

3) Angle of Repose:

Angle of repose for blend of each formulation was determined by fixed funnel method. The funnel is secured with its tip with height ‘h’ above a plane of paper kept on a flat horizontal surface. The powders were carefully poured through the funnel until the apex of the conical pile so formed just reaches the tip of funnel. Angle of repose was determined by substituting the values of the base radius ‘r’ and height of the pile ‘h’ in the given equation below. (table 3)

 

Tanθ = h/r

 

Table 3: Angle of repose as an indication of powder flow properties(36)

Sr. No.

Angle of repose (degrees)

Flow property

1

25 – 30

Excellent

2

31 – 35

Good

3

36 – 40

Fair-aid not needed

4

41 – 45

Passable – may hang up

5

46 – 55

Poor – must agitate, vibrate

6

56 – 65

Very poor

7

>66

Very, very poor

 

4) % Compressibility (Carr’s index):

It is used to evaluate flow ability of powder by comparing the bulk density and tapped density of a powder. The percentage compressibility of a powder is direct measure of the potential of powder arch or bridge strength is calculated according to the equation given below(table 4)

 

% Compressibility (Carr’s index)

 

 

Table 4: Carr’s index as an indication of powder flow(35)

Sr. No.

Carr’s index (%)

Type of Flow

1

5-15

Excellent

2

12 – 16

Good

3

18 – 21

Fair

4

21 – 25

Passable

5

23 – 35

Poor

6

33 – 38

Very poor

7

>40

Very, very poor

 

5) Hausner’s ratio

Hausner found that the ratio tapped density/bulk density was related to inter particle friction as such, could be used to predict powder flow properties. He showed that the powder with low inter particle friction had ratio of approximately 1.2, whereas more cohesive less free flowing powders have Hausner’s ratio greater than 1.6. Hausner’s ratio less than 1.25 indicate good flow.(table 5)

 

 

Table 5: Hausner’s ratio as an indication of powder flow(35)

Sr. No.

Hausner’s  ratio

Type of Flow

1

1.05 – 1.18

Excellent

2

1.14 – 1.20

Good

3

1.22 – 1.26

Fair

4

1.26 – 1.29

Passable

5

1.30 – 1.54

Poor

6

1.50 – 1.61

Very poor

7

>1.67

Very, very poor

 

2.5.2. Post compression study:

1. Tablet dimensions:

Thickness and diameter were measured using vernier calipers. Three tablets from each formulation were used and average values were calculated. (23)

 

2.Tablet hardness:

The hardness of the liquisolid compacts prepared was evaluated using Pfizer hardness tester. It is expressed in kg/cm2. The mean hardness of each formulation was determined. (23)

 

3.Friability:

Roche friabilator was used for testing the friability using following procedure. The tablet samples of each batch were weighed accurately and placed in drum. Drum was rotated for 100 revolutions (i.e. 25 rpm) and then tablets were removed. Any loose dust from the tablets was removed and accurate weight was taken. Friability was calculated by using following formula.(23)

 

 

4.Weight variation test:

The weight of tablet is measured to ensure that a tablet contain the proper amount of drug. Weight variation test was performed as per IP 2007. Twenty tablets were selected randomly and weighed. Average weight of the tablet was determined. Not more than the two tablets should deviate from the percentage deviation as shown in table 6.(23)

 

Table 6: IP Standards for uniformity of weights

Sr. No.

%Deviation

Avg. weight of Tablet

1

± 10

80 mg or less

2

± 7.5

More than 80mg or Less than 250mg

3

± 5

250mg or more

 

5. Content uniformity:

20 tablets were weighed and powered. Quantity of powder equivalent to 10 mg of drug was weighed and transferred to 100 ml volumetric flask containing 60 ml of methanol. The flask was shaken to dissolve the drug and adjusted to volume with methanol. 1 ml of this solution was diluted to 10 ml with methanol and absorbance of resulting solution was measured at maximum absorption wavelength of 246 nm.(23, 27)

 

6. Disintegration test:

The assembly was suspended in the liquid medium in the suitable vessel, preferably in 1000 ml beaker. The volume of the liquid such that the wire mesh at its highest point is at least 25 mm below the surface of liquid and its lower point is at least 25 mm above the bottom of the beaker. A thermostatic arrangement was made for heating the liquid and maintaining the temperature at 37 ± 2oC. Assembly was suspended in beaker containing 900 ml of distilled water and the apparatus was operated for specified time. The assembly was removed from liquid. The tablet passes the test if all of them have disintegrated within specified time. If 1 or 2 tablets fail to disintegrate repeat the test for 12 additional tablets, not less than 16 of the total of 18 tablets tested disintegrate, finally observe the disintegration time of the tablets.(23)

 

7. In-vitro drug release:

Test Parameters:

Volume of Dissolution medium - 900 ml, RPM- 50 rpm, temperature of dissolution medium- 37.0 ± 0.5 o C, Apparatus type - USP Apparatus II, Dissolution media - 0.1 N HCl. For all batches of Ritonavir the same media were used.

 

 

Procedure:

The tablets from each formulation batch were placed in dissolution medium and apparatus was run maintaining above stated test conditions. Five-milliliter aliquots were withdrawn at time intervals of 0, 5, 10, 15, 20, 30, 40 and 60 minutes. Every time the equal volume of fresh dissolution medium was added to the bulk of the solution and temperature was maintained. Samples were filtered through whattman filter paper no. 41, dilutions were carried out as per calibration curve and the absorbances were recorded at 246 nm. Percentage of labeled amount of drug released at each time point was calculated. The study was carried out in triplicate. (23)

 

8.Wetting time:

The wetting test conducted for 3 tablet of each formulation. Use of a piece of double folded tissue paper placed in a petridish containing 6 ml of water. One tablet was placed on this paper and the time for complete wetting of tablet was noted as wetting time. (28)

 

2.5.3. Differential scanning calorimetry:

The thermal behavior and the thermotropic properties of the drug, physical mixture (DCT) and the prepared liquisolid system were determined by DSC. It also shows any possible interaction between excipients used in the formulas. This was done by using Shimadzu differential scanning calorimeter Mettler. The thermal behaviors of the samples were investigated at a scanning rate of 10°C/ min, covering a temperature range of 0 -300°C.(15,29)

 

2.5.4. Fourier transforms spectroscopy (FTIR):

FTIR spectra were performed by the KBr pellet method using the fourier transform infrared spectrophotometer (Shimadzu, Japan). A baseline correction was made using dried potassium bromide, and then the spectra of Ritonavir, DCT and liquisolid system were obtained. (30, 31)

 

2.5.5. Powder X-ray diffractometery (PXRD):

The crystallinities of pure Ritonavir and liquisolid formulation were evaluated by XRD measurement. It has been seen that polymorphic changes of the drug are important factors, which may affect the drug dissolution rate and bioavailability. XRD patterns were studied using X-ray diffractometer. Samples were exposed to1.540 ˚A Cu radiation wavelength and analyzed over the 2θ range of 2–801. XRD patterns were determined for Ritonavir and liquisolid system with drug. (32, 33)

 

2.5.6. Stability study:

To assess the drug and formulation stability, stability studies were done according to ICH guidelines Q1C. The optimized formulation wrapped in aluminum foil in and kept in humidity chamber maintained 40 ± 2°C / 75 ± 5 % RH for 3 month. At the end of studies, samples were analyzed for the drug content, friability, hardness and in vitro drug release.(34)

 

3.RESULT AND DISCUSSION:

3.1. Solubility study:

Solubility of Ritonavir determined in different vehicle is shown in table7 and graphical representation of effect of solvent on solubility of ritonavir given in figure 3. Solubility of ritonavir in distilled water was found to be 0.50 mg/mL. From this it was conclude that ritonavir has low solubility in water. Among the various non volatile solvent, solubility of PEG 400 was found to be 15.98 mg/mL. As PEG 400 showed greater solubility of the drug than the other solvents, it was selected as the suitable non volatile solvent for preparing Ritonavir liquisolid compacts in this study.

 

Table 7: Solubility of Ritonavir in different solvent system

Sr. No.

Solvent

Solubility(mg/ml)

1

Distilled water

0.50±0.023

2

0.1N HCl

0.952±0.028

3

Polyethylene Glycol (PEG)-200

11.43±0.012

4

Polyethylene Glycol (PEG)-400

15.98±0.018

5

Propylene Glycol

11.24±0.024

6

Span-20

7.83±0.015

7

Tween-20

5.29±0.026

 

 

Figure 3: effect of various solvent on solubility of ritonavir

 

3.2. Drug excipient compatibility study:

The mixture for compatibility study were removed after 1 month and analyzed by FTIR spectroscopy to determine incompatibility between drug and excipients. FTIR Spectra of compatibility study is shown in figure 2.In given  FTIR spectra of physical mixture shows the principle peaks such as C=O at 1608.63cm-1 and N-H at 3321.42 cm-1, C-N at 1338.60 cm-1 indicate that confirmation of Ritonavir which is identified and proved. The physical mixture showed that there were no changes in important peaks from the pure Ritonavir and Excipient IR results show the presence of the above groups in the IR spectra of drug and polymer which confirmed that the drug and polymer have not found any compatibility problems. When IR spectra of physical mixture was compared with individual spectra of drug and polymer it was observed that there is no significant change in peaks.

 

3.3. Evaluation of liquisolid compacts formulation batches:

3.3.1. Pre-compression parameter:

Powder flow is a complicated matter and is influenced by so many interrelated factors. Flow properties includes angle of repose, Carr’s index, Hausner’s ratio as it may affect compressibility, tablet porosity and dissolution. As a general guide angle of repose greater than 40o has unsatisfactory flow properties whereas minimum angle close to 25o correspond to very good flow property. Powders showing Carr’s index up to 21 are considered of acceptable flow property. Flow property of Liquisolid formulation batches F1-F8 evaluated as shown in table 8.

 

3.3.2. Post compression parameter:

1.Tablet dimensions:

Thickness of liquisolid compacts were ranged as mean 5.64 ± 0.03 mm given in table 9.The thickness of the tablet is determined by the diameter of die, the amount of fill permitted to enter the die, the compaction characteristic of the fill material and the force applied during compression.


 

 

Figure 2: Compatibility study of drug and excipient (overlay of spectra)

 


 


 

 

Table8: Precompression properties of liquisolid Formulation batches

Formulation Code

Bulk Density (gm/ml) (Mean± SD)*

Tapped Density (gm/ml) (Mean± SD)*

Hausner’s Ratio (Mean± SD)*

Carr’s Index (%) (Mean± SD)*

Angle of Repose (Mean± SD)*

F1

0.352±0.23

0.419±0.28

1.19±0.12

15.9±0.23

29.20±0.26

F2

0.703±0.24

0.826±0.24

1.17±0.23

11.62±0.15

30.23±0.25

F3

0.553±0.15

0.616±0.21

1.11±0.25

10.2±0.32

25.40±0.16

F4

0.769±0.21

0.952±0.25

1.23±0.26

19.22±0.23

35.73±0.32

F5

0.621±0.23

0.766±0.24

1.23±0.27

18.92±0.25

30.34±0.34

F6

0.619±0.29

0.772±0.21

1.16±0.13

14.26±0.21

39.08±0.27

F7

0.806±0.22

0.961±0.25

1.19±0.24

16.1±0.23

32.15±0.28

F8

0.608±0.24

0.695±0.23

1.14±0.25

12.5±0.45

38.76±0.31

* All values expressed as Mean ± SD (n=3)

 


 

 

2. Hardness:

Hardness was found to be in the range as mean of 4.6 ± 0.2 kg/cm2. The hardness of all batches given in table9.The hydrogen bonds between hydrogen groups on adjacent cellulose molecules in avicel PH 102 may account almost exclusively for the strength and cohesiveness of compacts. The high compressibility and compactness of Avicel PH 102 can be explained by the nature of the microcrystalline cellulose particles themselves which are held together by hydrogen bonds, when compressed, such particles are deformed plastically and a strong compact is formed due to the extremely large number of surfaces brought in contact during the plastic deformation and the strength of the hydrogen bonds formed. Tablets with low hardness were not considered because they were not able to withstand abrasion in handling.

 

3. Friability:

Tablet hardness is not an absolute indicator of strength. Since, some formulations compressed into very hard tablet tend to capon attrition losing their crown portions. Therefore another measure of tablets strength is friability which can be measured by Roche Friability test apparatus. All the liquisolid compacts had acceptable friability as none of the tested formulae had percentage loss in tablet’s weights that do not exceed 1% as shown in table9. Friability below 1% is an indication of good mechanical resistance of the tablets. This ensures that tablets could withstand the pressure, shocks during handling, transportation and manufacturing processes

 

4. Weight variation test:

Weight variation test revealed that the tablets were within the range of Pharmacopoeial specifications. All the formulations passes weight variation test. Result listed in Table 9.

 

5. Drug content:

A fundamental quality attribute for all pharmaceutical preparations is the requirement for a constant dose of drug between individual tablets. Uniform drug content was observed for the formulation which is as per the IP specification (90%-110%) given in table 10.

 

6. Disintegration time:

The disintegration time test revealed that the liquisolid tablet formula disintegrated within 3 min which is as per specifications given for the dispersible tablets in the IP and result of the test are shown in table 10. Microcrystalline cellulose has disintegration property which could facilitate disintegration of tablets and dissolution of drug. Because of the presence of a nonvolatile solvent acting as a binding agent in the liquisolid formulation, delayed disintegration time is expected. However, in the liquisolid tablets containing microcrystalline cellulose, a fast disintegration of tablet occurred which can be explained by the disintegrating property of microcrystalline cellulose. In addition, use of Sodium starch glycolate accelerates the disintegration of tablets by virtue of its ability to absorb a large amount of water when exposed to an aqueous environment. The absorption of water results in breaking of tablets and therefore faster disintegration.

 

7. Wetting time

Wetting time for formulation batches given in table 10.Wetting time of optimized batch found to be 3 min. It indicate enhanced wettability of liquisolid compact.PEG 400 facilitated wetting of drug by decreasing interfacial tension between water and surface of tablet.


 

Table 9: Post compression parameter of formulation batches

Formulation Code

Avg. Weight (mg) (Mean± SD)*

Thickness (mm) (Mean± SD)*

Hardness (kg/cm2) (Mean± SD)*

Friability (%) (Mean± SD)*

F1

302.73±0.9

5.52±0.03

2.7±0.2

0.49±0.1

F2

232.16±1.2

5.61±0.02

4.8±0.3

0.38±0.2

F3

399.32±1.8

5.64±0.03

4.4±0.2

0.41±0.2

F4

299.05±2.1

5.38±0.02

4.7±0.3

0.59±0.2

F5

511.28±1.6

5.47±0.02

4.6±0.3

0.68±0.1

F6

366.15±2.1

5.54±0.03

4.6±0.3

0.59±0.1

F7

612.43±0.5

5.55±0.04

4.5±0.3

0.54±0.1

F8

431.18±0.98

5.57±0.04

4.4 ±0.2

0.56±0.3

* All values expressed as Mean ± SD (n=3)

 


Table 10: Table for results of Disintegration and wetting time and drug content of liquisolid formulation

Formulations code

Disintegration Time (min) (Mean± SD)*

Wetting Time (min) (Mean± SD)*

Drug Content (%) (Mean± SD)*

F1

4±0.3

2±0.5

87.45±0.41

F2

5±0.6

3±0.4

84.67±0.46

F3

4±0.2

3±0.7

99.76±0.45

F4

6±0.3

5±0.3

86.92±0.51

F5

5±0.5

6±0.5

92.11±0.52

F6

8±0.3

8±0.4

87.54±0.45

F7

15±0.4

12±0.3

98.11±0.41

F8

20±0.3

15±0.4

82.8±0.46

* All values expressed as Mean ± SD(n=3)


8. In-vitro drug release:

The in vitro drug release of all liquisolid formulation at different time interval was shown in table 11.The results of in vitro percentage amount of drug released at different time intervals plotted against time to obtain the release profiles shown in figure 4. Kinetic model observed for all liquisolid formulation batches given in table 12. From in vitro drug release and value of dissolution kinetic model, F3 selected as optimized batch. The optimized batch F3 had 98.02% and follows higuchi dissolution kinetic model (figure 5). The enhanced dissolution rates of liquisolid compact compared to directly compressible tablet formulation may be attributed to the fact that, the drug is already in solution form in PEG 400 while at the same time, it is carried by the powder particles (Avicel PH102 and Aerosil200). Thus, its release is accelerated due to its markedly increased wettability and surface availability to the dissolution medium. The wettability of the compacts by the dissolution media is one of the proposed mechanisms for explaining the enhanced dissolution rate from the liquisolid compact. PEG facilitates wetting of drug particles by decreasing interfacial tension between dissolution medium and tablet surface.

 

3.3.3.Comparative in-vitro drug release study:

The liquisolid tablet compared with directly compressible tablet of ritonavir and plain ritonavir to observed the enhancement solubility of liquisolid tablet formulation. The dissolution profiles of the selected Ritonavir liquisolid tablet formulation together with the dissolution profile of directly compressible tablet formulation tablets (DCT) and Ritonavir drug alone are presented in table 13.From In-vitro drug release study, Plain drug gives 39.80% release at 60 min where as Directly compressible Tablet gives 56.51% drug release in 0.1N HCl at 60 min. Optimized liquisolid compact gives highest drug release i.e. 98.58% in 0.1N HCl at 60min.Therefore it shows enhancement of solubility as compared to plain drug and DCT. Comparative study of Cumulative percent drug release against time for liquisolid formulation, DCT and plain ritonavir was shown in figure 6.

 


 

Table 11: In-vitro Drug Release of all liquisolid batches

Time (min)

Drug Release (%) (Mean± SD)*

F1

F2

F3

F4

F5

F6

F7

F8

0

0

0

0

0

0

0

0

0

5

16.52±1.4

12.02±1.3

34.77±1.4

17.24±1.2

21.04±1.2

8.30±0.5

31.93±1.0

10.69±1.2

10

24.96±1.2

17.08±1.4

37.52±2.1

26.32±2.3

32±2.0

19.46±1.7

33.42±1.9

15.91±1.9

15

38.51±0.5

30.87±1.4

45.12±1.6

37.86±1.7

44.91±1.2

27.55±2.1

43.05±2.4

29.13±2.1

20

42.78±2.0

40.54±2.1

55.70±1.4

49.02±1.6

56.01±1.6

40.47±1.8

51.06±1.8

38.50±1.3

30

51.49±1.6

48.89±1.8

69.92±2.1

54.56±0.7

61.99±1.6

44.10±2.1

62.37±2.0

45.47±2.1

40

60.82±1.7

60.96±1.3

82.97±1.8

66.15±2.4

75.05±2.7

57.99±3.3

76.29±2.3

58.19±2.1

50

75.12±2.5

74.83±1.4

92.36±2.0

74.12±2.9

84.18±2.0

63.22±2.3

89.16±2.1

62.13±1.3

60

85.46±2.3

78.64±2.1

98.02±3.0

83.48±1.8

89.06±2.0

77.98±2.1

94.18±3.2

72.39±1.9

* All values expressed as Mean ± SD (n=3)

 

Figure 4: Graphical representation of in vitro drug release of formulation batches

 

Table 12: Kinetic Model Study for in-vitro drug release study of Formulation batches.

Formulation code

Zero order

First order

Hixon Crowell

Higuchi model

Korsemeyer Peppas

F1

0.980

0.978

0.981

0.986

0.943

F2

0.970

0.966

0.986

0.988

0.952

F3

0.980

0.976

0.982

0.993

0.922

F4

0.960

0.955

0.987

0.991

0.973

F5

0.945

0.937

0.984

0.988

0.982

F6

0.965

0.961

0.975

0.984

0.956

F7

0.978

0.985

0.986

0.987

0.906

F8

0.958

0.953

0.979

0.987

0.964

 

 


Table 13: Comparative in-vitro drug release study

Time

(min)

Drug Release (%) (Mean± SD)*

Plain Drug

Directly Compressible Tablet

Optimized Batch (F3)

0

0

0

0

5

1.33±1.2

3.74±2.1

19.17±1.2

10

7.01±1.3

13.11±1.8

27.15±1.3

15

10.37±1.2

18.62±1.3

40.30±1.1

20

14.01±1.3

23.44±1.5

57.80±1.6

30

18.23±1.5

35.17±1.6

62.22±1.3

40

29.60±2.1

39.13±2.3

74.05±1.2

50

34.44±2.5

45.36±2.1

83.70±1.3

60

39.80±2.1

56.51±2.6

98.58±1.2

* All values expressed as Mean ± SD (n=3)

 

 

Figure 5: Release kinetic model of optimized batch (F3)

 

Figure 6: Comparative in-vitro drug release study

 

 

3.3.4. Differential Scanning Calorimetric (DSC) studies:

DSC spectra of pure Ritonavir Drug and optimized liquisolid powder compact is shown in figure 7 and figure 8 respectively.DSC Thermogram of pure Ritonavir showed a sharp endothermic peak (Tonset =121.80 C, Tm=126.80C, ΔHfusion=53.3mJ/mg) due to melting. The sharp endothermic peak indicated that the Ritonavir was in crystalline anhydrous state. The optimized liquisolid system illustrated no characteristic peak of Ritonavir;a fact agrees with formation of molecular dispersion of drug within the liquisolid matrix. From the Thermogram of DCT formulation, the characteristic melting peak of Ritonavir was presented at 122.70C, indicating that there are no changes in crystallinity or interaction between drug and excipients in the conventional formulation (figure 9). The DSC data clearly indicates the conversion in native crystalline form of drug to amorphous state which can be well correlated with the improved dissolution characteristics of liquisolid systems.

 

Figure 7: Differential scanning Calorimetry (DSC) of pure Ritonavir drug

 

Figure 8: Differential Scanning Calorimetry (DSC) of Ritonavir liquisolid compact

 

Figure 9:DSC spectra of Ritonavir Directly compressible Tablet

 

3.3.5. Powder X-ray Diffraction (PXRD):

In PXRD spectra of pure ritonavir (figure 10) numerous instance peaks observed. The highest peak of intensity of 1450 observed at diffraction angle (2θ) at 22.There were numerous sharp peak observed at diffraction angle (2θ) of 8.9, 14, 16.1, 18.5, 20, 25.7 suggests the crystalline nature of Ritonavir. In PXRD spectra of optimized liquisolid compact powder (figure 11) there is decreased in intensity of peaks observed. The diffraction pattern of liquisolid powder compact revealed that absence of typical Ritonavir peaks, confirms the transformation of the physical state of the drug .i.e. Crystalline to amorphous/molecular state. A fall in degree of crystallinity indicates improvement in the amorphousness of sample. Hence, from above discussion it was conclude that the liquisolid powder compact technique resulted in amorphous form of ritonavir with suitable excipients, which led to improved dissolution release profile.


 

 

Figure 10:PXRD spectra of pure Ritonavir

 

 

Figure 11:PXRD spectra of optimized liquisolid compact powder

 

Table 14: Stability study

Evaluation parameters

Sample Points

1 month

2 month

3month

Appearance

No change

No change

No change

Hardness (kg/cm2­)

No change

No change

No change

Friability (%)

0.41±0.1

0.41±0.2

0.40±0.3

Weight of Tablet (mg)

400.2±1.8

400.2±1.6

400.2±1.6

Uniformity of content (%)

99.38±0.1

99.12±0.2

98.32±0.3

Disintegration time (min)

3±0.4

3±0.5

3±0.5

Wetting time (min)

3±0.4

3±0.5

3±0.4

Drug Release (%)

98.02±2.5

98.21±3

98±3.5

* All values expressed as Mean ± SD (n=3)


3.3.6. Stability study:

From the stability data (Table 14) it can be concluded that stability of pure ritonavir and liquisolid compact did not differed significantly in any parameter, so optimized batch are said to be stable. Hence, this product can be kept for a period of one year or more.

 

4. CONCLUSION:

In conclusion, the present study showed that liquisolid powder compact technique could be a promising strategy in improving dissolution of poorly water soluble ritonavir and wettability was improved by making a solution in polyethylene glycol 400 which used as nonvolatile solvent. Liquisolid powder compact could be prepared using avicel PH 102 as a carrier, and aerosil 200 as a coating material. The FTIR studies revealed that excipients were compatible with the drug. DSC and PXRD studies showed that there is a decrease in crystallinity of the ritonavir in liquisolid compact formulation. A fall in crystallinity means improved dissolution release profile. The optimized formulation (F3) showed higher dissolution rate when compared with that of pure drug and directly compressible tablet of ritonavir.

 

5. ACKNOWLEDGEMENT:

All authors are thankful to Trustee, MET’S Bhujbal Knowledge City, Institute of Pharmacy, Adgaon, Nashik for providing infrastructure and all the necessary facilities for this research work also Mylan laboratories Ltd, Sinner, Nashik for providing gift sample of ritonavir and MIT College of Pharmacy, Pune for providing facility of DSC and Pune University for providing facility of PXRD study and KTHM College, Nashik, for FTIR analysis.

 

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Received on 07.07.2017                Accepted on 18.08.2017               

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2017; 7 (4):189-201  .

DOI:  10.5958/2231-5713.2017.00030.7