INTRODUCTION:

Apixaban is a novel oral anticoagulant widely recommended for the prevention and treatment of strokes and blood clots suffering from nonvalvular atrial fibrillation by suppressing factor Xa. Moreover, it is also useful in minimizing deep vein thrombosis and pulmonary embolism in patients after knee replacement surgery¹. The prompt suppression of factor Xa and prothrombinase helps in the minimization of thrombus, thus the anticoagulant action is achieved. Apixaban has a log P of 2.71 with poor solubility and reported maximum bioavailability of approximately 50 %².

The solubility is the rate-determining phase concerning the bioavailability of active therapeutic agents³. Liquisolid compact technique (LCT) is gaining tremendous significance for the enrichment of solubility and dissolution proportion of poorly water-soluble molecules⁴. LCT practice is mostly implemented for the potent active ingredients by incorporating the non-volatile solvent (NVS) approved by the US FDA. The quality-by-design (QbD) is the process of development of dosage form by randomizing the formulation parameters with minimal trial runs. Moreover, this process also prevents potential errors in the formulation and also indicates a toxic profile. The current research aimed to enhance the therapeutic efficacy of Apixaban by improving its solubility, dissolution rate, and bioavailability^5,6.

MATERIALS AND METHODS:

Apixaban was gifted by the Natco Pharma, Kothur, Telangana, India. Microcrystalline cellulose and Aerosil 200 were purchased from Loba Chemicals, Mumbai. Cross povidone was supplied by Ajanta Pharma, Aurangabad. All other chemicals utilized were of analytical grades only.

Selection of best non-volatile solvent:

An accurately well-chosen extent of Apixaban was shifted into the 2 ml of several NVS such as Tween 20, Tween 80, Span 80, Polyethylene glycol 200 and 400 grades, propylene glycol, glycerin, etc. Further, these test tubes were placed on the vortex mixer to dissolve the Apixaban solid sample into the solvents. Finally, all the test tubes were examined by scanning the sample with a UV-visible spectrophotometer (Shimadzu 1900, Japan)⁷.

FTIR studies:

The identity of Apixaban was checked with the ATR-FTIR (IRAffinity-1s, Shimadzu). Moreover, the physical interaction between active ingredients with MCC 102, Aerosil 200, and cross-povidone was also analyzed⁸.

Optimization design:

The development of the Liquisolid Compact of Apixaban required a carrier, coating agent, and superdisintegrant. Whereas, the CQA for tablets were disintegration time and dissolution release. Hence, according to the formulation concept, there were 3-independent factors and 2-dependent factors. The Box-Behnken model was chosen for the optimization analysis due to the lesser number of trial runs⁹.

Evaluation of flow property:

The quantities mentioned in the optimization table were weighed accurately for every batch and judged for their flowing behavior such as bulk density, tapped density, Carr’s index, Angle of repose, and Hausner’s ratio^10,11.

Preparation of Liquisolid Compaq Tablets of Apixaban:

In each batch, 30 tablets were prepared, and accordingly, Apixaban was carefully relocated into the mortar. Thereafter, PEG 200 was added dropwise and converted into the liquid medicament. The predetermined quantity of MCC 102 followed by Aerosil 200 was added to the liquid medicament. Finally, cross-povidone, magnesium stearate, and talc were blended just before compression^12,13. The ingredients are described in Table 1.

Evaluation of Liquisolid Compaq Tablets:

Weight variation test:

The 20 tablets were preferred unevenly and assessed precisely. Thereafter, the average was certified according to I.P. 2022¹⁴.

Crushing strength:

The pressure generated on the tablet until it breaks was established by the Monsanto hardness tester¹⁵.

Friability:

The tablet's extent corresponding to 6.5 g was taken and sited in the friabilator with a velocity of 25 rpm for 100 turnings^16,17.

Disintegration time (DT):

The arbitrarily labelled 6 tablets were retained in the equipment at 37±0.5°C expending 900ml of simulated gastric fluid. When the entire material screen out that time was considered¹⁸.

Table 1: Composition of LCT of Apixaban

Code	Apixaban	PEG 400	MCC 102	Aerosil 200	CP	MS	Talc	TOTAL
	mg	mg	mg	mg	mg	mg	mg
A1	2.5	16	200	50	7.5	3	3	282
A2	2.5	16	180	50	12	3	3	267
A3	2.5	16	180	40	9.75	3	3	254
A4	2.5	16	180	60	9.75	3	3	274
A5	2.5	16	190	40	7.5	3	3	262
A6	2.5	16	190	40	12	3	3	267
A7	2.5	16	190	60	7.5	3	3	282
A8	2.5	16	190	60	12	3	3	287
A9	2.5	16	180	50	7.5	3	3	262
A10	2.5	16	200	60	9.75	3	3	294
A11	2.5	16	200	40	9.75	3	3	274
A12	2.5	16	200	50	12	3	3	287

In-vitro dissolution:

The process was accomplished with Paddle equipment using pH 6.8 phosphate buffer (0.05 M). The paddle was permitted to revolve at a velocity of 50 rpm, at 37±0.5° C. The samples were quiet at a break of 5 minutes, diluted, and investigated spectrophotometrically at 241 nm¹⁹.

Assay:

The set tablets were picked unsymmetrically and transformed into powder. The usual extent of a tablet dissolved with pH 6.8 phosphate buffer (0.05 M) was investigated spectrophotometrically at 241nm^20,21.

Stability study:

The improved batch was retained at 40⁰C and 75% RH for nearly 3 months. The contents were introverted at one month and assessed²².

RESULTS AND DISCUSSION:

Selection of non-volatile solvent:

The PEG 200 exhibited the highest extent of solubility (89µg/ml) of Apixaban comparatively with the rest NVS. Hence, PEG 200 was opted for the development of LCT.

FTIR Study:

The spectrum obtained was interpreted for the bands and the stretching. The sharp peak was noted at 3743.83 cm^-1, and 3309.85 N-H cm^-1 for N-H stretching, 2166.06 cm^-1 observed for C-H stretching, 1625.99 cm^-1, and 1595.13 cm^-1 for C=C stretching, and 1186.22 cm^-1, 1510.26 cm^-1, 1251.80 cm^-1 for C=O stretching. The compatibility of Apixaban with their formulation ingredients was analyzed and found to be compatible. The FTIR spectrums are shown in Fig. 1.

Optimization of Liquisolid Compact of Apixaban:

The Box-Behnken design model was best suited for the 3-independent and 2-dependent factors which showed 12 runs. The tablets of all the 12 batches were evaluated and data was fitted into the BBD which was illustrated in Table 2. The ANOVA model for the dependent factors was portrayed in Tables 3 and 4 respectively.

The influence of these factors was showed with 2-D Contour plots and 3-D response surface plots in the Fig. 2 and 3 respectively.

Fig. 1 The FTIR spectra of Apixaban with MCC and Aerosil 200

Table 2: The Box-Behnken design model for Apixaban Tablets

		Factor 1	Factor 2	Factor 3	Response 1	Response 2
Std	Run	A:MCC 102	B:Aerosil 200	C:Cross Povidone	Disintegration Time	Dissolution
		mg	mg	mg	min	%
6	1	200	50	7.5	2.56	98.49
7	2	180	50	12	2.42	98.95
1	3	180	40	9.75	2.48	99.03
3	4	180	60	9.75	2.5	98.66
9	5	190	40	7.5	2.53	98.47
11	6	190	40	12	2.4	99.35
10	7	190	60	7.5	2.56	98.6
12	8	190	60	12	2.41	98.99
5	9	180	50	7.5	2.55	98.58
4	10	200	60	9.75	2.49	98.87
2	11	200	40	9.75	2.51	98.68
8	12	200	50	12	2.42	99.21

Table 3: The ANOVA model of BBD for the disintegration time

Source	Sum of Squares	df	Mean Square	F-value	p-value
Model	0.0395	8	0.0049	65.78	0.0028	significant
A-MCC 102	0.0001	1	0.0001	1.50	0.3081
B-Aerosil 200	0.0002	1	0.0002	2.67	0.2010
C-Cross Povidone	0.0378	1	0.0378	504.17	0.0002
AB	0.0004	1	0.0004	5.33	0.1041
AC	0.0000	1	0.0000	0.3333	0.6042
BC	0.0001	1	0.0001	1.33	0.3318
A²	0.0008	1	0.0008	10.67	0.0469
B²	0.0001	1	0.0001	1.50	0.3081
C²	0.0000	0
Residual	0.0002	3	0.0001
Cor Total	0.0397	11

Table 4: The ANOVA model of BBD for the Dissolution release

Source	Sum of Squares	df	Mean Square	F-value	p-value
Model	0.8915	8	0.1114	20.42	0.0154	significant
A-MCC 102	0.0001	1	0.0001	0.0206	0.8949
B-Aerosil 200	0.0210	1	0.0210	3.85	0.1446
C-Cross Povidone	0.6962	1	0.6962	127.55	0.0015
AB	0.0784	1	0.0784	14.36	0.0322
AC	0.0306	1	0.0306	5.61	0.0986
BC	0.0600	1	0.0600	11.00	0.0452
A²	0.0036	1	0.0036	0.6618	0.4755
B²	0.0000	1	0.0000	0.0023	0.9648
C²	0.0000	0
Residual	0.0164	3	0.0055
Cor Total	0.9079	11

Fig. 2. 2-D Contour plots and 3-D Surface for the Disintegration time

Fig. 3. 2-D Contour plots and 3-D response for the dissolution release

Table 5 Flowing characteristics of powder blends

Batch	BD	TD	CI	Angle of repose	HR
A1	0.46±0.16	0.54±0.15	14.81±0.33	25.63±0.52	1.17±0.09
A2	0.45±0.22	0.54±0.19	16.66±0.29	27.42±0.40	1.2±0.17
A3	0.45±0.14	0.56±0.11	19.64±0.36	30.78±0.46	1.24±0.20
A4	0.43±0.10	0.52±0.14	17.30±0.39	27.67±0.37	1.20±0.15
A5	0.42±0.17	0.54±0.22	22.22±0.32	23.54±0.45	1.28±0.22
A6	0.44±0.12	0.53±0.16	16.98±0.27	28.32±0.41	1.20±0.14
A7	0.44±0.09	0.52±0.11	15.38±0.30	26.41±0.38	1.18±0.08
A8	0.43±0.18	0.5±0.21	14±0.36	24.57±0.44	1.16±0.06
A9	0.43±0.21	0.54±0.17	20.37±0.24	32.38±0.38	1.25±0.17
A10	0.45±0.25	0.52±0.13	13.46±0.20	23.9±0.33	1.15±0.16
A11	0.43±0.20	0.51±0.10	15.68±0.28	26.62±0.28	1.18±0.20
A12	0.44±0.19	0.51±0.21	13.72±0.34	24.27±0.42	1.15±0.16

All values n= 3±SD

Table 6 The evaluation of LCT of Apixaban

Code	Weight variation	Hardness	Friability	DT	Assay
A1	282±0.52	3.9±0.04	0.51±0.05	2.56±0.08	98.69±0.69
A2	267±0.66	3.8±0.09	0.50±0.08	2.42±0.10	98.84±0.72
A3	254±0.58	3.7±0.05	0.54±0.09	2.48±0.06	98.56±0.57
A4	274±.46	3.7±0.07	0.55±0.06	2.5±.014	99.06±0.80
A5	262±0.42	3.7±0.10	0.54±0.10	2.53±0.11	98.94±0.78
A6	267±0.56	3.6±0.08	0.57±0.07	2.4±0.16	98.91±0.86
A7	282±0.48	3.8±0.08	0.53±0.06	2.56±0.07	98.46±0.94
A8	287±0.70	3.9±0.05	0.52±0.12	2.41±0.09	98.58±0.65
A9	262±0.62	3.6±0.06	0.56±0.10	2.55±0.12	98.77±0.78
A10	294±0.50	4.0±0.11	0.48±0.08	2.49±0.08	99.20±0.81
A11	274±0.67	3.7±0.09	0.55±0.07	2.51±0.06	98.96±0.73
A12	287±0.46	3.9±0.12	0.51±0.09	2.42±0.12	98.85±0.79

In-vitro dissolution release:

The dissolution studies revealed that drugs from the tablets were liberated speedily as existed in a liquid state than the conventional tablets. The maximum time taken was 40 min from the LCT. Conventional tablets are available in powder form whereas Liquisolid compact renders the active ingredient in liquid form. Due to this reason, the process of dissolution was quicker. The drug release profile was showed in Fig. 4.

Fig. 4. In-vitro drug release profile of A1-A12 LCT

Stability studies:

The optimized batch A6 was tested as per the ICH stability guidelines under 40⁰C at 75% relative humidity maintained in the stability chamber (Remi, Mumbai, India). The tablet samples were quitted at 30 days and further assessed and outcomes were displayed in Table 7.

Table 7: Stability assessment of an optimized batch A6

Parameters	Original	30 Days	60 Days	90 Days
Hardness	3.6±0.08	3.6± 0.10	3.5±0.06	3.4±0.11
Friability	0.57± 0.07	0.58± 0.14	0.60± 0.16	0.62± 0.11
DT	2.4±0.16	2.40± 0.14	2.37± 0.16	2.35± 0.18
Content uniformity	98.91± 0.86	99.89± 0.60	98.81± 0.62	98.77± 0.52

CONCLUSION:

The Liquisolid Compact technique is a simple and inexpensive process for the enrichment of the solvability, dissolution, and bioavailability of the active ingredients. The optimized batch A6 was suggested for large-scale manufacturing which showed a minimal DT of 2.40 min and dissolution of 99.35 % within 30 min. These batches showed the best results with minimum involvement of material compared with the remaining batches. Hence, the outcome decided LCT is a very significant process for the enlargement of solubility dissolution and for attaining good beneficial fruitfulness.

ABBREVIATIONS:

LCT: Liquisolid Compact Technique, BBD: Box-Behnken design, NVS: non-volatile solvent, CQA: critical quality attributes.

ACKNOWLEDGMENT:

The authors are thankful to Natco Pharma Kothur, Telangana for providing the gift sample of the drug and also to the SVKM NMIMS SPTM Shirpur for providing all necessary chemicals and research facilities to carry out this research project.

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Received on 07.01.2024 Revised on 11.07.2024

Accepted on 04.12.2024 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):1945-1950.

DOI: 10.52711/0974-360X.2025.00278

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