INTRODUCTION:

Oral drug delivery offers the convenience of administration, low cost, and high patient compliance. When medications are taken orally, they dissolve in the gastrointestinal tract before being absorbed into the bloodstream. The rate-governing element for oral medication absorption with limited water solubility is dissolution^1,2. Only 40% of recently developed drugs exhibit significant biopharmaceutical challenges due to poor aqueous solubility and restricted intestinal permeability, ultimately leading to poor drug absorption and submaximal therapeutic effects ³.

The availability of modern drug discovery tools has greatly accelerated the entry of drug molecules into the clinic. There are various techniques for the enhancement of drug water solubility These include the employment of techniques such as solid dispersion⁴, crystal engineering⁵, micronization⁶, complexation⁷, emulsification⁸, mesoporous carriers⁹. Liquisolid compact formulations have demonstrated encouraging potential for enhancing the medicines' oral bioavailability and dissolving performance¹⁰. In this method, the coating and carrier materials are mixed to dissolve the medications into solids that can be readily compressed or into liquisolid compacts. The medicine is more easily dissolved and loaded onto the carrier with the assistance of the non-volatile solvent. Liquisolid compacts speed up the wetting and dissolution of the medication, improving the properties of oral bioavailability. From the powder compact, which allows the medications to be loaded in the adsorbed liquid form, liquisolid tablets are made ^11,12. ADP receptor inhibitor drug of a new generation is Ticagrelor. When a P2Y12 inhibitor that isn't a metabolite and has a quicker onset of action is sought, it is used to treat acute coronary syndrome and to avert thrombotic events like stroke and heart attack. Despite prior statistics showing that ATP prevented ADP-induced platelet aggregation, ATP is incredibly unstable.

The goal was to create an ATP analogy that was more potent and persistent. This analogue had a very short half-life because the triphosphate groups persisted, so they had to be fed intravenously¹³. “Ticagrelor” is a crystalline powder with a very low water solubility of about 10 g/ml and a modest intrinsic permeability, making it a biopharmaceutical Class IV drug. The absolute bioavailability of ticagrelor after oral administration is about 36%. The Solubility of Ticagrelor must therefore be addressed. After being absorbed into the body, the T_max for Ticagrelor was a median of 1.5 hours with a range of 1.0 to 4.0. Therefore, the current study concentrated on enhancing Ticagrelor's therapeutic performance and dissolution rate using the liquisolid compact technology ¹⁴. The liquisolid powder compacts were optimized by using Design expert software.

MATERIAL AND METHODOLOGY:

Materials:

Ticagrelor was procured from Mylan Pharma as a gift sample, Bangalore, India. Neusilin US2 was obtained as a gift sample from Gangwal Chemicals, Mumbai, India. Colloidal silicon dioxide (Aerosil 200), Croscarmellose sodium, Magnesium stearate, ween 80, PEG (Polyethylene Glycol) 200, PEG (Polyethylene Glycol) 400, PEG(Polyethylene Glycol) 600 and Propylene Glycol (PG) were procured from GattefossePvt. Ltd. Mumbai India.

Methods

1. Preparation of Liquisolid Compacts ^{15,16,17,18,19}

The weighed quantity of the drug and non-volatile solvent was taken in a glass beaker. The mixture was heated slowly until the entire quantity of the drug dissolved. The liquid component was added in the fixed amount of carrier and coating materials by the three-step procedure, and liquisolid compacts were obtained.

The first procedure involved making a liquid drug by mixing precisely weighed Ticagrelor with the specified quantity of PEG 600. The liquid drug was permitted to absorb in the second stage on a calculated amount of carrier material (Neusilin US2) in the mortar. Aerosil 200 coating material was added in a predetermined amount to the blended mixture and continuously stirred for five minutes to create a dry powder admixture in the final step. The final powder mixture also contained 1% Magnesium stearate and 3% Sodium Starch Glycolate. The powder mixture was finally compacted using a single-station punch press.

2. Experimental design ^20,21,22

Design and development of Ticagrelor's liquisolid compacts used a 3² full factorial technique. PEG 200 was selected as the non-volatile solvent for the current investigation, Neusilin US2 as the carrier material, and Aerosil 200 as the coating material. Based on the liquid load factor calculation and a literature study, Neusilin dosages of 100 mg, 150 mg, and 200 mg and Aerosil 200 dosages of 30 mg, 60 mg, and 90 mg were administered. Acceptable flowability and compressibility are significantly influenced by the addition of carrier and coating powder material.3² full factorial designs were used to determine each variable's individual and combined effects on the overall performance of liquisolid compacts, as shown in Table 1. The angle of repose, percent CDR in 30 minutes, and percent CDR in 60 minutes were chosen as the dependent variables. Neusilin US2 and Aerosil 200 amounts were chosen as the independent variables. The control variables that substantially impact response variables were identified using regression analysis. composition of all factorial batches created with Aerosil 200 as the coating material and Neusilin US2 as the carrier.

Table 1: Coadded and Transformed Value for Design Batches

Formulation code	Coded value		Decoded values
Formulation code	X1 (Neusilin US2)	X2 (Aerosil 200)	X1 (Neusilin)	X2 (Aerosil)
F1	0	-1	150	30
F2	0	0	150	60
F3	-1	0	100	60
F4	1	-1	200	30
F5	-1	-1	100	30
F6	-1	1	100	90
F7	0	1	150	90
F8	1	1	200	90
F9	1	0	200	60

3. Characterization of the liquisolid compact ^23,24,25

The micrometric characterization of the powder mixture of all the batches was performed. Flow properties like tapped and bulk density, Hausner's ratio, angle of repose and Carr's Consolidation index were performed in accordance with the procedures explained in USP-NF 40

4. Evaluation of liquisolid compact tablets^26,27,28

All liquisolid tablets were subjected to various evaluation parameters like friability, hardness and disintegration time according to the standard procedures reported in USP-NF

5. In vitro dissolution study ²⁹

As a dissolving medium for Ticagrelor, the USFDA suggests IPA+ Phosphate buffer 8. However, in vitro drug release research in pH 1.2 buffer was conducted to predict the drug release from all formed formulations in gastric pH. The USP type II (paddle) dissolving apparatus (Labindia® DS 8000) was utilized to conduct dissolution research on all of the prepared formulations and marketed conventional tablets. pH 1.2 buffer was used as the dissolution medium at a temperature of 37°C and a rotating speed of 50 rpm. Throughout the course of the investigation, the gastric state was maintained by adding 5ml of pH 1.2 buffer after each aliquot withdrawal (5, 10, 15, 30, 45, & 60 min). The acquired samples were divided, filtered, and subjected to UV spectrophotometric analysis at a wavelength of 254 nm (Shimadzu UV 1900). Similar dissolution studies were conducted using pH 1.2 buffer as the dissolution medium for tablets with improved formulations and direct compressibility. The experiment was carried out three times.

6. Optimization data analysis and response surface mapping^30,31

Fitting the experimental data to an appropriate mathematical model for each of the investigated response variables, optimization data analysis was carried out. After doing a multiple linear regression analysis, the model's parameters were chosen. The statistical significance of the ANOVA model, lack of fit, and correlation coefficient were then used to gauge the model's applicability. Response surface mapping was also carried out. The factor-response relationship was analyzed using 2D and 3D plots. The model diagnostic plots were used to assess the data's fitness.

7. Selection of optimized liquisolid compact^32,33

The optimized liquisolid compacts were selected by numerical optimization. The desirability function was chosen by "trading-off" responses to achieve desired goals. Additionally, graphical optimization was done to choose the best formulation for the design space.

8. Evaluation of the optimized liquisolid compacts:

a) FT-IR Spectroscopy:

An IR spectrum of Ticagrelor, physical mixture without liquid, and optimized liquisolid formulation were checked using an FT-IR spectrophotometer and was scanned in the range of 4000-400 cm for comparing any significant change between drug and excipients. The given samples were mixed with KBr, pressed to form a pellet, and then analyzed using an FTIR instrument.

b) Differential Scanning Calorimetry (DSC):

Melting, exothermic decompositions, and phase transitions are all studied using differential scanning calorimetry. It can determine the sample's purity and find impurities in a drug formulation. On a DSC 60 (TA60) detector, a differential scanning calorimetry (DSC) analysis was carried out. DSC established the pure drug and the physical mixture of the drug with the carrier and coating material The sample was sealed after being put into an aluminium pan. The thermogram was recorded when the DSC sample was scanned from 25 to 200⁰C at a heating rate of 10⁰C /min while being purple with nitrogen.

c) Stability study:

According to ICH guidelines, the stability study of the improved formulation (F-8) was conducted for one month at an accelerated temperature of 40 °C ± 2°C and 75 % +5 % RH and room temperature 250°C + 20°C/RH 60% ± 5% using a stability chamber where the tablets were stored in amber-coloured bottles and sealed. The quality of prepared liquisolid tablets was examined for a number of criteria, including hardness, friability, drug content, and drug release, to see how time and environmental conditions affected the tablets' quality.

RESULTS:

Formulation and optimization of liquisolid compacts:

The various solvent solubility data of the drug were enlisted in Table 2. PEG 600 was selected as the vehicle for liquisolid compact from various non-volatile solvents. The Formulation of the Liquisolid compact was carried out using Neusilin US2 and Aerosil 200 carriers as these exhibit porous characteristics and high surface adsorption. Initial experimental tests were carried out using a few excipients, including colloidal silicon dioxide powder (Aerosil 200) as a coating material and Neusilin US2 as a carrier. Additionally, the liquisolid compact formulations (F1-F9) composition is depicted in Table 1 whereas the trial batches were formulated in accordance with the chosen experimental design, as shown in Table 3.

Table 2: Solubility Analysis

Solvent	Solubility in mg/ml
Isopropyl Alcohol	46.81±0.632 mg/ml
pH Buffer 1.2	43.136±0.432 mg/ml
Methanol	41.64 ±581 mg/ml
Dimethyl sulfoxide	33.38 ±0.119 mg/ml
Ethanol	24.9067±0.404 mg/ml

Table 3: Composition of design batch.

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Ticagrelor	60 mg	60 mg	60 mg	60 mg	60 mg	60 mg	60 mg	60 mg	60 mg
PEG 600	0.5 ml	0.5 ml	0.5 ml	0.5 ml	0.5 ml	0.5 ml	0.5 ml	0.5 ml	0.5 ml
Neusilin	150 mg	150 mg	100 mg	200 mg	100 mg	100 mg	150 mg	200 mg	200 mg
Aerosil 200	30 mg	60 mg	60 mg	30 mg	30 mg	90 mg	90 mg	90 mg	60 mg
Magnesium Stearate	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg
R	5	2.5	1.6	6.6	3.3	1.1	1.6	2.2	3.3
LF	0.003	0.003	0.005	0.002	0.005	0.005	0.003	0.002	0.002
Total Weight	245.5 mg	275.5 mg	225.5 mg	295.5 mg	195.5 mg	255.5 mg	305.5 mg	355.5 mg	325.5 mg

All formulation contains 3% sodium starch glycolate, and 1% dibasic calcium phosphate.

Excipient ration (R) = Q/q [Q- weight of the carrier, q- weight of coating]

Lf – Liquid load factor

Table 5: Post-compression study analysis

Formulation	Wetting Time (sec)	Hardness (Kg/cm²)	Friability (%)	Drug Content (%)	Disintegration Time(min)	Weight Variation (%)
F1	60 ±1.12	2.9 ±0.46	0.88 ±0.51	97.91± 91	7.1 ±0.023	1.56±0.33
F2	68 ±2.29	2.9 ±0.82	0.88 ±0.02	97.91 ±27	2.6 ±0.011	1.31± 0.02
F3	71 ±3.43	3.1 ±0.10	0.92 ±0.05	94.90 ±90	6.9 ±0.016	1.53 ±0.004
F4	74 ±0.94	2.8±0.122	0.81± 0.02	93.80 ±80	6.7± 0.019	1.31± 0.46
F5	74 ±1.15	2.8 ±0.48	0.51 ±0.01	98.46 ±46	5.9± 0.020	2.14 ±0.02
F6	83 ±3.33	3.2 ±0.19	0.56±0.08	91.06 ±06	6.6 ±0.014	1.39± 0.03
F7	92 ±3.24	3.2 ±0.25	0.78± 0.11	92.71 ±71	6.9± 0.016	1.27± 0.22
F8	101 ±1.52	2.9 ±0.44	0.81±0.06	99.01± 01	6.6± 0.009	1.22 ±0.01
F9	118 ±1.26	3.1 ±0.41	0.88 ±0.14	96.54 ±54	7.5± 0.011	1.24 ±0.04

standard deviation from the mean (n=3)

Post-compression analysis of liquid-solid compacts:

All of the developed liquid-solid compacts underwent post-evaluation criteria like hardness, friability, wetting time, drug content, disintegration time and weight variation test as shown in Table 5.

Selection of optimized formulation and validation studies:

The nearest numerical optimization and desirability function values help in choosing the best formulation by trading off the Angle of Repose, % CDR in 30 mins and % CDR in 60 mins. When compared to the other prepared formulations, F8 showed all the response variables to be relatively close to the target values. The yellow colour zone represents the design space, and the marked point displays the makeup of the optimized formulation as well as the projected values of the responses.

The cumulative drug release of all formulations in the above dissolution media varies from 82% to 96% and Formulation F9 exhibit a maximum cumulative drug release of around 96%, F8 optimized batch exhibited around 95% and the conventional tablet exhibited a cumulative drug release of about 80%. It can thus be concluded that drug release increases with liquisolid technology, all the formulations exhibit higher cumulative drug release compared to a conventional tablet.

Statistical analysis and graphical presentation of the obtained results:

The primary objective of preparing the liquisolid compact was to improve the dissolution profile of Ticagrelor so Angle of repose (Y1), cumulative drug release in 30 min (Y2) and 60 min (Y3) were selected as the response variables. The obtained R² value for all response variables YI, Y2 and Y3 were 0.98, 0.98 and 0.98 respectively which confirmed the excellent predictability of the regression model. For all the variables, Calculated >Tabulated, with an F significant value of less than 0.05 which proved the validity of the overall models. The polynomial equations generated from the Y1 Y2 and Y3 are mentioned below.

Y₁(Angle of repose) = 28.48+2.72x(X1)+1.32x(X2)-0.2650x(X1X2)-0.6867x((X1)²)-(1.21)x(X2)²

Y₂(%CDR in 30 mins) = 67.35+3.13x(X1)+10.29x(X2)

Y₃(%CDR in 60 mins) = 90.06= 1.65x(X1)+5.80x(X2)

For responses Y1, Y2 and Y3, it was observed that independent variables X1 and X2, with an increase in the values of X1 and X2 there is a proportional increase in the values of Y1, Y2 and Y3.

(A)

(B)

(C)

(D)

Figure 2: Results of Regression Analysis for Response A) Y1(Angle of Repose) B) Y2 (%CDR in 30 mins) and C) Y3 (%CDR in 60 mins), D) Desirability plot for optimized liquisolid formulation of Ticagrelor Liquisolid compacts.

Stability study:

There was no significant change in the physicochemical properties of the liquisolid tablet after the stability period. There was a slight increase in disintegration time for the stored formulation but it was well within the acceptable limit of 15 min. DSC study suggested that there was slight recrystallization of the drug in liquisolid tablets at the end of the stability period, but it had no significant effect on the dissolution profile of the optimized formulation shown in Table 6.

After the stability period, there was no discernible change in the physicochemical characteristics of the liquisolid compacts. The disintegration time for the stored formulation increased slightly, but it was still well under the 15-minute permissible limit. At the end of the stability period, DSC research revealed that the liquisolid tablets had mild recrystallization, but this did not significantly affect the dissolution profile of the optimized formulation. shown in Table 6.

Table 6: Stability data of optimized formulation (f8) at the accelerated temperature of 40±2°C/ relative humidity of 75±5% and room temperature 25°C± 2°C /relative humidity 60±5%.

Test	Initial	After 30 days (Room temperature 25°C±2°C/RH 60±5%)	After 30 days (Accelerated temperature 40°C±2°C/RH 75±5%)
Appearance	White colour	No change in appearance	No change in appearance
Hardness (kg/cm2)	2.9	2.9	2.6
Drug content (%)	99.01	98.76	98.05
Drug release (%)	95.41	94.33	92.83

DISCUSSION:

The drug and the formulation's excipients were subjected to pre-formulation research. A study on the solubility of ticagrelor in several non-volatile solvents revealed that PEG 600 had the highest solubility (120 mg/ml). As a result, PEG 600 was employed as the medium for creating the liquisolid system.

By using FTIR and DSC, the interaction of the drug excipient was identified. The results of FTIR and DSC did not reveal any indications of drug and excipient incompatibility.

To investigate the impact of several independent factors (Aerosil 200 and Neusilin US2) on the dependent variables software (angles of repose, percent CDR in 30mins, percent CDR in 60mins), the experimental design was carried out using a Design expert. 32 factorial designs were used to create a total of 9 liquisolid system formulations in accordance with the mathematical model.

On each and every one of the formulated formulations, pre- and post-compression parameters were applied. Characteristics of the material prior to compressions, such as angle of repose, Carr's index, and Hausner's ratio, were evaluated. F-8 formulations outperformed other batches I in terms of flow and compressibility across all formulations.

The physical characteristics of the tablet, "its hardness, friability, weight variation, wetting time, content uniformity, disintegration test, and in vitro dissolution study" were examined as post-compression parameters. All formulations' findings were determined to fall under the IP limit. All nine of the liquisolid formulations tested in an in vitro dissolution study revealed a higher rate of dissolution than marketed conventional tablets. In pH 1.2 medium, formulation F-9 had the highest drug release of 96,78 %.

The similarity factor in pH 1.2 medium was used in a comparative study between the optimized F-8 formulation and commercially available conventional tablets, and the similarity factor f2 value was determined to be larger than 50.

One-way ANOVA was used in the statistical analysis to determine whether all the variables had p-values under 0.05 that made them statistically significant. A signal-to-noise ratio was also established, indicating adequate precision.

The optimized formulation F-8 was then subjected to a stability study for a month at 40℃ ± 2℃, 75% ± 5% relative humidity, with the room temperature being 25℃ ± 2℃, the relative humidity being 60%. The tablets underwent evaluations for a number of factors, including hardness, drug content, and time till breakdown The stability study's findings indicated that, in comparison to freshly made liquisolid tablets, ageing of the tablet did not lead to any substantial shifts in the parameters being studied.

CONCLUSION:

The study proved that the liquisolid technique can be an enticing approach for improving the dissolution profile of drugs having low water solubility. The addition of PEG 600 in the liquisolid compact was able to improve drug release. Applying the DoE approach has revealed that the carrier-to-coating ratio and mixing of Aerosil 200 with Neusilin US 2 significantly affect drug release from the formulation. The design batches have acceptable tableting properties such as flow property, compatibility, hardness, friability, content uniformity and disintegration time. The design batches had a significantly higher dissolution rate than marketed conventional tablets at all defined time intervals. The results of DSC and FTIR studies suggested that the no interaction. After a month of storage, stability testing showed that none of the formulation's key features had changed significantly.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank KLE College of Pharmacy, Belagavi, Karnataka for providing facilities to conduct this research work. The authors are thankful to Mylan Pharma, Bangalore for providing a gift sample of Ticagrelor (API) and Gangwal Chemicals, Mumbai, India for providing a gift sample of Neusilin US2 for research work.

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Received on 22.11.2022 Modified on 25.04.2023

Research J. Pharm. and Tech 2024; 17(4):1453-1460.

DOI: 10.52711/0974-360X.2024.00230

Formulation Batch	Carr’s Index (%)	Hausner’s ratio	Angle of repose in degree
F1	9.27	1.10	22.33±0.97
F2	9.39	1.10	25.64±0.91
F3	10.79	1.11	28.53±0.39
F4	9.52	1.14	28.29±0.41
F5	9.85	1.10	28.53±0.43
F6	10.03	1.09	30.25±0.95
F7	10.07	1.10	25.2±0.95
F8	10.14	1.11	28.86±0.01
F9	10.44	1.11	30.34±0.21