1. INTRODUCTION:

Majority of the drugs are having problem with solubility in water^[2]. It is accounted for that about 40% of the recently created medications and almost 60% of the integrated substance elements have dissolvability difficulties^[3,4]. The amount of drug reaching to the blood stream was hindered by the solubility issue of the drug^[5,
6]. Many methods have been adopted to enhance the solubility of medications. Micronizationis used for increase the solubility of drugs because of increased surface area and increased interaction of molecules on the surface of the particle with solvent molecules. The challenge in this method is that, the increased surface area will increase surface free energy and particle start agglomerating, hence it will be difficult to increase solubility especially when the formulation was tablet^[7].

Another method was solid dispersion method, but due to less stability and improper knowledge on structure of solid state makes its less commercial application^[8]. Soft Gel formulation is also a method to improve solubility but due to the requirement of sophisticated equipment, this process becomes costly^[9]. The approaches like complexation^[10], microencapsulation, and nanosuspensions^[12], self-nanoemulsions^[13]and solid lipid nanoparticles^[14] have high production cost and demand for advanced machinery even though they increase solubiliy. Liquisolid procedure, a recently created and propelled strategy for disintegration upgrade, can defeat numerous a fore referenced hindrances^[15–
17].

This procedure was first presented by Spireas et al. what's more, connected to consolidate water insoluble medications into quick discharge strong dose frames. The structure standard of liquisolid framework is to contain fluid medications (i.e., fluid medications tranquilize preparations or suspensions) in powdered shape and conveyance sedate comparably to delicate gelatin cases containing fluids. Liquisolid strategy alludes to the transformation of liquid drug into evidently dry, free flowing and compressible powder blends by mixing the fluid meds with appropriate excipients, which are by and large named as bearers and covering materials^[18,19]. The fluid medicine is first consumed into the inside system of the bearer. When the inside of the bearer is soaked with fluid drug, a fluid layer is shaped on the outside of transporter particles, which is in a split second adsorbed by the fine covering materials. Subsequently, a clearly dry and free streaming and compressible powder blend is shaped. The component of liquisolid framework development is shown in Fig. 1. For the most part, orally sheltered, and ideal water miscible natural solvents with high breaking point, for example, propylene glycol and polyethylene glycol (PEG) 400, are utilized as the fluid vehicles. Bearers allude to permeable materials with expansive explicit surface region and high fluid assimilation ability to ingest fluid prescription^[20]. Various evaluations of cellulose, starch and lactose can be received as transporters. Notwithstanding, just excipients with fine molecule estimate and profoundly adsorptive property, for example, silica powder, can be utilized as covering materials^[21]. Even however the medication inside liquisolid framework is in a strong state, it exists precisely in a totally or halfway molecularly scattered state^[22,23]. In this way, a liquisolid framework may show upgraded disintegration rate because of the expanded disintegration territory, upgraded watery solvency, or enhanced wetting properties^[24]. Aside from disintegration upgrade, liquisolid method has as of late been explored as a device to impede medicate discharge ^[25–27], to limit the impact of pH minor departure from disintegration profile^[28,29], and to enhance sedate photostability^[30]. At long last, it merits referencing that liquisolid frameworks are not related with soundness issues^{[15,31– 33]}.

2. MATERIALS AND METHODS:

Table 1: List of API and Polymers Used

Material Used	Manufactured By
Clopidogrel bisulfate	A to Z Pharmaceuticals
Microcrystalline cellulose	Himedialaboraties
Sodium starch glycolate	Qualigens laboratories
Polyethylene glycol (PG) 400	Merck laboratories
Aerosil 200	K .Mohan and company
Propylene glycol	Merck laborites
Glycerin	Merck laborites

2.1 Solubility studies:

The high solubility of drug in non-volatile solvents was known by conducting solubility. The non-volatile solvents should get dissolved in a 0.1N HCl. The non-solvent like Tween 80, Propylene glycol (PG), Polyethylene glycol (PEG 400), and glycerin, the drug was added until the solution gets supersaturated and transferred it into a rotating shaker with constant vibration for 48 hrs at 25˚c, then it was filtered through a 0.45µm Millipore filter, diluted and analyzed by UV spectrophotometer at λ_max 220nm.

2.2 Mathematical model for design of liquisolid systems:

The definition plan of liquisolid frameworks was done as per new numerical model depicted by Spireas et al. clopidogrel bisulfate was dissolved in PEG 400. MCC and Aerosil 200 were utilized as the carrier and coating materials, individually. The grouping of the medication in the fluid vehicle were (40, 50 and 60% w/w) and the bearer: covering proportion were (R = 20:1, 15:1 and 10:1). Flow able fluid maintenance potential (Φ value) of powder excipients was utilized to ascertain the required fixing amounts. In PEG 400, the Φ-value was (0.16) for the transporter MCC and (3.33) for the covering material Aerosil200. The fluid burden factor (Lf) was processed from the Φ -value of the bearer and covering materials with various proportions (R) in agreement to condition (1):

Lf = Φ Cr + Φ Co (1/R) (1)

Where, Φ Cr and Φ Co are the flow able fluid maintenance possibilities (Φ - values) of carrier (MCC) and coating (Aerosil 200) powder materials, individually.

Be that as it may, fluid burden factor (Lf) is characterized as the proportion of the heaviness of fluid medicine (W) to the heaviness of the bearer powder (Q) in the framework, which ought to be controlled by an acceptably streaming and compressible liquisolid framework. The most appropriate amounts of transporter (Q) were determined utilizing condition (2):

Lf = W/Q (2)

The ideal amounts of covering material (q) were gotten from condition (3):

R = Q/q (3)

Where, R is the proportion by weight of bearer (Q) and covering (q) materials present in the detailing (13, 14).

Arrangement of clopidogrel bisulfate liquisolid conservative Liquisolid compacts (LS) spoken to by recipe 1–9, each containing 98mg of clopidogrel bisulfate (proportional to 75mg clopidogrel). Diverse medication fixations in PEG 400 (40, 50 and 60% w/w) were set up by scattering the medication in the non-volatile vehicle (PEG 400). Additionally, a bindery blend of the bearer (Micro crystalline cellulose) and covering material (Aerosil 200) was set up at a proportion R of (20:1, 15:1 and 10:1). At that point after, it was blended with the fluid medicine. The blending procedure was completed in three phases. In the principal organize, the paired powder blend was mixed with fluid prescription utilizing a porcelain mortar with the guide of a pestle at a blending rate of one revolution for every second for roughly one moment so as to uniformly disperse the fluid medicine into the powder. In the second blending stage, the fluid/powder admixture was equally spread as a uniform layer on the surfaces of the mortar and was left representing around ten minutes to enable the fluid prescription to be caught up in the inside of the powder particles, and after that immersion adsorption happened on the outside of these particles. In the third stage, sodium starch glycolate (SSG) alongside poly vinyl pyrolydine (PVP K30) as a super-disintegrant was included at 5% w/w and blended for 10 minutes. The schematic representation of liquisolid compact is shown in figure 1. The last blend was compacted utilizing a tablet punching machine^(34,35). The creation and qualities of liquisolid minimal were exhibited in the table 2

Table 2 Formulation Table

Formula number	Drug (mg)	Drug conc. In PEG400 (%w/w)	Carrier coating ratio(R)	Liquid loading factor(Lf)	Liquid vehicle (PEG400)	Carrier (MCC)	Coating (aerosol 200mg)	Super disintigrant (SSG+PVPk30)	Compact weight (mg)
F-1	98	40	20	0.326	147	751.5	37.5	51.7	1085
F-2	98	50	20	0.326	98	601.2	30	41.3	868.5
F-3	98	60	20	0.326	65.3	500.9	25	34.4	723.6
F-4	98	40	15	0.397	147	646.4	43	46.7	981.2
F-5	98	50	15	0.397	98	517.1	34.4	37.3	784.8
F-6	98	60	15	0.397	65.3	430.8	46.7	31.1	653.9
F-7	98	40	10	0.493	147	496.9	37.3	39.5	831.1
F-8	98	50	10	0.493	98	397.5	31.1	31.6	664.9
F-9	98	60	10	0.493	65.3	331.2	39.5	26.3	553.9

2.3 Fourier transforms infrared spectroscopy (FTIR):

To know the compatibility of drug with excipient, Pure drug and drug with excipient were mixed with dry potassium bromide powder and compressed into transparent discs then scanned over a range of 4000-400 cm^-1 using the Infrared spectrophotometer.

2.4 Preparation of Co – processed superdisintegrant:

Solvent evaporation method was employed for the preparation of co-processed super-disintegrants. Into the 10ml of methanol a blend of PVP K30 and sodium starch glycolate (1:1) were added and mixed thoroughly until the evaporation of ethanol. The wet mass was passed through #44 mesh sieve for granulation and granules were dried at 60˚C for 20 min in hot air oven. The wet granules were dried in a hot air oven at 60˚C for 20min. the dried granules were passed through #44 mesh sieve and stored in an airtight container until further use. The co – processed superdisintigrates at a ratio (1:1 ) was used in the preparation of liquisolid compacts to study the effect of co-processed super-disintegrants on the disintigration and dissolution rate of clopidogrel bisulphate compacts.

2.5 Pre-compression studies of the prepared liquisolid Powder system:

2.5.1 Angle of repose (θ)^[36]

Angle of repose can be determined by glass funnel method.10mg of dried powder mass was passed through a glass funnel on the white paper which was previously placed on a flat surface. The radius (r) and height (h) of the pile is measured and the angle of repose was calculated from the formula (4):

tan θ = h/r - (4)

θ = tan-1 h/r- (5)

Where,

h = Height of the the powder cone.

r = Radius of the powder cone

2.5.2 Bulk density^[37]

The weighed (20-50g) amount of powder was transferred to 100ml measuring cylinder and volume occupied (bulk volume) by powder was noted. The bulk density was calculated by following equation.

Bulk density = Weight of powder/Bulk volume (6)

2.5.3Tapped density^[37]

Tapped density was carried out using tapped density apparatus (USP). The weighed (20-50g) amount of powder was transfferd to 100ml measuring cylinder and tapped until there is no further decreasing in volume of powder(tapped volume).tapped density was calculated by following formula.

Tapped density = Weight of powder/Tapped Volume (7)

2.5.4 Carr's index and Hausner's ratio^[21]

Carr’s index and the Hausner’s ratio were calculated by bulk and tapped density equation 6 and 7. They give an idea about flow property of a powder.

Carr’s Index = (tapped density – bulk density) × 100/ tapped density) (8)

Hausner ratio = tapped density/bulk density) (9)

2.5.5 Scanning electron microscopy (SEM) study:

Scanning electron microscopy (SEM) is utilized to assess the morphological characteristics of the pure drug and the liquisolid system. Samples were first loaded on sample stub using double side carbon tape then coated with gold and examined in the Zeiss Supra 55 VP Scanning electron microscope^[25]

2.6 POST COMPRESSION STUDIES:

2.6.1 Hardness:

The hardness of LS compacts was measured by using a pharma test hardness. The units for the expression of hardness of the tablet is force in kg/cm² required to crush the compact^[38].

2.6.2 Friability:

Pharma test friabilator was used in this study by taking 20 liquisolid compacts from each formula. These compacts were weighed accurately (Wt initial) then after, rotated in the friabilator for 4 min at 25rpm. The compacts were re-weighed (Wt final). The friability was calculated as a percentage according to equation^].

Friability % = [(Wt initial – Wt final)/Wt initial] × 100- (10)

The acceptable friability value is up to 1%.

2.6.3 Weight variation test:

The collective and individual weight of 20 LS compacts was determined by using digital weighting balance. from the collective weight the average weight of individual LS compact was determined and compared with individual weight to average weight variation tolerance according to pharmacopoeia^[28] .

2.6.4 Content uniformity:

This test was carried out by applying USP method. Ten compacts were individually assayed for their content. Each compact was grinded and the powder placed in 50ml of 0.1N HCl, sonicated for 5min. and cooled. Then, transfer 5ml of this solution to volumetric flask, dilute with 0.1N HCl to 50ml. Then after, filter and discard the first 5ml of filtrate. After that, the amount of clopidogrel was determined spectrophotometrically by measuring the absorbance at appropriate λmax. The percent of content uniformity for each compact was0 calculated and compared with the mean for each formula according to the USP specification^[39].

2.6.5 Disintegration time study:

Tablet disintegration test apparatus was utilized for in-vitro disintegration test. To the each of six basket tubes one LS compacts was placed ith added plastic disc on it. The basket assembly was immersed in 0.1N HCl pH (1.2) maintained at 37±2⁰C in one litre beaker, which was moved up and down through a distance of 5 to 6 cm at a frequency of 32 cycles per min. The time required for complete disintegration of the compact was recorded ^[40].

2.6.6 In-vitro dissolution test:

This study was conducted in a dissolution Type-II USP apparatus. The dissolution medium consists of a 900ml (0.1N HCl pH 1.2) maintained at 37±0.5°C and with a rotation speed of 50 rpm throughout the experiment. At predetermined intervals (5, 10, 15, 30, 45, 60, 90 and 120 min.) a sample of 5ml was withdrawn. The amount of drug present in 5ml sample was determined by UV-visible spectrophotometer (Shimadzu) at λmax of drug. The sink condition and constant volume was maintained by replacing with the equal volume of fresh dissolution media. Each preparation was tested in triplicate and the mean value of reading was calculated^[31].

3. RESULTS AND DISCUSSION:

3.1 solubility studies:

Table 3 Solubility studies

Solvents	Solubility(mg/ml)
0.1NHCl	34.23±0.25 mg/ml
Phosphate buffer (pH 6.8)	0.23±0.34mg/ml
PEG 400	0.65±0.42mg/ml
Water	0.75±0.56mg/ml

Results as mean± S.D, n = 3

The solubility of clopidogrel in different solvents was given in table 3. Clopidogrel exhibited the highest solubility in PEG 400 (48.9 mg/ml). Since, the aim of this study was to increase the dissolution rate of clopidogrel, PEG 400 was exploited as a nonvolatile solvent in preparation of liquisolid systems.

Figure 1 schematic representation of Liquisolid compact3.2

Compatibility studies:

Figure 2 FT-IR Spectrum of Clopidogrel Bisulphate

Table 4FT-IR Interpretation of Clopidogrel Bisulphate:

Wave number (cm^-1)	Functional group
2950.177	C-H Stretch Alkane
2732.106	O-H Stretch Acid
1438.54	-C=C stretch Aromatic
1317.407	-C-N stretch Amine
770.684	C-Cl Strech Alkyl halide
850.240	=C-H Bending Alkene

Figure 3 FT-IR Spectrum of Drug + Excipients

Table 5FT-IR Interpretation of Drug + Excipients

Wave number (cm^-1)	Functional group
2878.021	C-H Stretch Alkane
2501.911	O-H Stretch Acid
1436.193	-C=C- Stretch Aromatic
1313.084	-C-N- Stretch Amine
1065.654	-C-O Stretch Ether
862.069	=C-H Bending alkene

FTIR studies were carried out for pure drug and polymer blend mixture as shown in fig 2 and 3.There is no major shift in the peaks of pure drug in formulation indicating the compatibility of blend.

3.3 Pre compression studies

Table 6 Micromeretic properties of powder blend

Formula number	Bulk density (gm/cm³)	Tapped density(gm/cm³)	Angle of repose(Ѳ)	Carr’s index	Hausner’s ratio	Type of flow
F-1	0.24±0.01	0.28±0.02	36.02±0.254	18.16±0.687	1.215±0.021	Fair
F-2	0.23±0.02	0.28±0.02	33.09±0.535	15.87±0.09	1.178±0.087	Good
F-3	0.23±0.02	0.27±0.01	31.11±0.265	14.61±0.15	1.161±0.018	Good
F-4	0.28±0.04	0.33±0.04	36.94±0.403	19.05±0.64	1.2±0.062	Fair
F-5	0.23±0.01	0.28±0.08	34.01±0.854	17.25±0.7	1.191±0.044	Good
F-6	0.25±0.03	0.31±0.01	32.76±0.403	15.79±0.47	1.185±0.028	Good
F-7	0.27±0.02	0.32±0.03	37.71±0.2	19.61±0.45	1.242±0.031	Fair
F-8	0.25±0.04	0.33±0.15	35.89±0.0415	17.43±0.346	1.197±0.056	Fair
F-9	0.28±0.01	0.31±0.05	33.07±0.867	15.98±0.194	1.184±0.02	Good

Results as mean± S.D, n = 3

3.5. Post compression study:

Figure 6. Photograph of tablet formulations from F1 to F9

Table 7 post compression studies

Formula Number	Hardness (kg/cm²)	Friability % (w/w)	Weight variation (mg)	Content Uniformity %	Disintigration time (sec)
F-1	4.4 ± 0.264	0.41	1.065 ± 0.556	94.4±2.4	42.6 ± 2.16
F-2	4.36 ± 0.251	0.25	867.63 ± 0.32	99.58±3.15	55.3 ± 1.92
F-3	4.73 ± 0.152	0.28	722.83 ± 0.29	95.83±1.57	68.5 ± 3.87
F-4	5.3 ± 0.153	0.23	980.53 ± 0.51	97.5±2.18	61.3 ± 2.28
F-5	5.86 ± 0.15	0.26	784.03 ± 0.55	97.05±4.72	83.1 ± 4.14
F-6	6.73 ± 0.23	0.42	653.2 ± 0.721	91.6±3.87	95.6 ± 3.62
F-7	6.4 ± 0.2	0.52	830.5 ± 0.458	98.16±2.1	89.6 ± 2.18
F-8	6.33 ± 0.251	0.19	664.16 ± 0.42	96.25±1.2	107.8± 1.57
F-9	6.3 ± 0.173	0.41	552.8 ± 0.2	95±1.25	112.3± 4.72

Results as mean± S.D, n = 3

3.5.1 Hardness test:

LS compacts average hardness ranged from (4.3 ± 0.173) to (6.46 ± 0.251) kg/cm2 (Table 7). As excipients ratio increased the hardness of the tablets increased. This was may be due to the formation hydrogen bonds between groups on adjacent cellulose molecules in MCC ^[43]

3.5.2 Friability:

All LS compacts had acceptable friability, as none of the tested formulas had percentage loss in weight that exceeded 1%(Table 7). Also, no compact cracked, split or broken in either formula^[43]

3.5.3 Weight variation:

Compacts of each formula were subjected to weight variation test, the difference in weight and percent deviation was calculated. The results of the test demonstrated in (Table 7) showed that, the compact weights were within the limit^[44].

3.5.4 Content uniformity:

Percentages of content uniformity for all clopidogrel formulas ranged from (95 – 100.8%) as shown in table 7. This complied with USP content uniformity specification that is 85%-115% of content in each individual compact indicating that, the processing method were convenience^[44].

3.5.5 Disintegration time:

The disintegration time for the prepared clopidogrel LS compacts was shown in Table 7. The disintegration time of less than two mins was found for all the LS Compacts, because of co-processed super disintegrates. It was found that the powder excipient proportion (R) was inversely proportional to the disintegration time of the compacts^[45].

Figure 7. Dissolution profiles of clopidogrel liquisolid compacts in 0.1N HCl

Figure 8. Dissolution profiles of Clopidogrel Bisulphate and Marketed drug formulation in 0.1N HCl

3.5.6 Dissolution:

The dissolution profiles of clopidogrel LS compacts Figure 4 in 0.1 N HCl. The percentage of clopidogrel bisulfate released from liquisolid compacts (F1-F9) was varying from 89.6% – 99.5%with in 100 mins. The results indicated fast release of the drug was observed from the LS compacts. Such enhanced drug dissolution rate may be mainly attributed to the fact that, sssssavailability poorly drug in PEG 400 as a molecular dispersed form in LS compacts^[46]. The release of clopidogrel bisulfate from F-2 compacts was compared with that of marketed tablets (Plavix®) in 0.1N HCl (pH 1.2) figure 8. The difference in the percent of drug release was found to be significant, may be due to fact that after the disintegration of LS compact, its primary particles suspended in the dissolution medium which had the drug particles in molecular dispersion state. In contrary, there was a limited surface area of the plain drug exposed to the dissolution medium in the marketed tablets (Plavix®), because of the hydrophobic nature of the drug particles.

4. CONCLUSION:

The liquisolid technique succeeded to enhance the dissolution rate of the practically insoluble drug (clopidogrel bisulfate). Among the LS Compact formulations (F1-F9), F-2 that was prepared by using PEG 400 as a non- volatile liquid vehicle exhibited highest dissolution rate. F-2 Liquisolid compact tablets exhibited the best dissolution as compared to marketed (Plavix®) tablets.

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Received on 25.09.2019 Modified on 09.11.2019

Research J. Pharm. and Tech 2020; 13(5):2427-2434.

DOI: 10.5958/0974-360X.2020.00435.7