INTRODUCTION:

An ideal dosage regimen in the drug therapy of any disease is the one, which immediately attains the desire therapeutics concentration of drug in plasma (or at the site of action) and maintains it constant for the entire duration of treatment¹. Drugs are frequently taken by oral administration, although a few drugs taken orally are intended to be dissolved within the mouth, majority of drugs taken orally are swallowed. Compared with alternate routes, the oral route of drug administration is the most popular and has been successfully used for conventional delivery of drug. It is considered as most natural, convenient means of administering drugs².

Oral Dispersible Tablet is an innovative tablet technology where the dosage form containing active pharmaceutical ingredients disintegrates rapidly, usually in a matter of seconds, without the need for water, providing optimal convenience to the patient³. The basic methods used to prepare solid dispersions are Melting method or fusion method, Solvent evaporation method, Kneading method. supercritical Fluid Process^4,5,6,7. Mechanical strength, disintegration time, Taste masking, are the different challenges to develop oral dispersible tablet^8,9. Shape and Color, Uniformity of Thickness) Hardness test, Friability test, Content uniformity test etc. are the Post-compression evaluation parameters for formulation of tablet¹⁰. The basic approach to the development of fast dissolving tablets (FDT) is the use of superdisintegrants. ODT shows less sensitivity to environmental conditions and temperature^11,12,13,14.It produces quick onset of action due to rapid disintegration, dissolution and absorption of tablets^15,16. Aprepitant is insoluble in water so to enhance the solubility solid dispersion method (by full 3² factorial design) is used¹⁷. Drugs with relatively larger doses are difficult to formulate into FDT¹⁸.Freeze Drying, Tablet Molding, Spray drying are the conventional technologies for fast dissolving tablet¹⁹.Few properties of fast dissolving tablets such as no bitter taste, dose lower than 20mg, small to moderate molecular weight, good stability in water and saliva^20,21. Various superdisintegrant like Croscarmellose sodium (Ac-Di-Sol), crospovidone (CP), PolyplasdoneXL XL, sodium starch glycolate (SSG) can be used in formulation of fast dissolving tablets.^22,
23,24. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors^25,²⁶. Aprepitant is a morphine-based antiemetic, which is the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy²⁷. Hence, it was concluded that fast‐dispersible Apripatent tablet could be prepared by direct compression using superdisintegrant²⁸.

MATERIALS AND METHODS:

Materials:

Aprepitant drug was obtained as gift sample from R.K Pvt. Ltd. (Baroda), Mannitol, Polyplasdone Xl, Polyplasdone XL10, Polyplasdone INF 10, Cross carmeloss sodium, other chemicals were procured from market.

Method of Precipitation (Direct Compression):

Mixtures of Aprepitant and SSG/CP / Polyplasdone (1:1, 1:3 and 1:5 by weight) were wetted with acetone: water (1:1 ratio) kneaded thoroughly for about 60min in a glass mortar till the acetone: water mixture gets evaporated. The obtained dispersion is then placed in a desiccator for24hrs and then the dry dispersion was passed through #100 sieves and is stored in a desiccator till further use. Physical mixtures (PM) were obtained by pulverizing in a glass mortar and carefully mixed accurately in a glass mortar Apripatentand SSG/CP (1:5 by weight).

Identification of variables and fixing the levels of variables

All ingredients Aprepitant, Mannitol, lactose, Aerosil 200, Magnesium Stearate Powder flavor strawberry were weighed accurately and passed through sieve 60#. The materials were transferred to mortar and triturate until mixed it uniformly. The resulting powder mixture was compressed in to tablets using single punch tablet machine. Here, Polyplasdone XL10 use as superdisintegrant for preparation of ODT of Aprepitant by this method. (Table-1).

Evaluation of formulation:

a) Angle of repose (Ɵ)

Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and horizontal

Plane. The frictional force in a loose powder or granules can be measured by angle of repose.

Ɵ = tan'1(h/r)

Where, Ɵ = angle of repose h = height of pile r = radius of the base of pile

b) Bulk density and tapped density:

Bulk density is defined as the mass of a powder divided by the bulk volume. Tapped density is defined by tapping the mass

Volume with help of cylinder.

c) Carr’s Compressibility Index:

The compressibility index of the granules was determined by Carr’s compressibility index. Grading of the powders for their flow properties according to Carr’s Index is given in below formula

Tap density – Bulk density

Carr’s INDEX = --------------------------------- X 100

Tap density

d)Hausner’s ratio:

Hausner found that the ratio of bulk density to tapped density was related to inter particle friction and, as such, could be used to predict powder flow properties. He showed that powders with low inter particle friction, such as coarse spheres, have ratios of approximately 1.2, whereas more cohesive, less free-flowing powders such as flakes have Hausner’s ratio greater than 1.6.

Hausner’s ratio= tapped density/ bulk density.

Table no.1. 3 full factorial design batches

Ingradient (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
APREPITANT	80	80	80	80	80	80	80	80	80
Mannitol	50	56	62	50	56	62	50	56	62
Spray dried lactose	44	40	44	40	44	40	44	40	44
Polydapsone XL 10	26	26	26	30	30	30	34	34	34
Aerosil 200	5	5	5	5	5	5	5	5	5
Magnesium Stearate	2	2	2	2	2	2	2	2	2
Powder flavor strawberry	1	1	1	1	1	1	1	1	1
Total	220	220	220	220	220	220	220	220	220

Post-compression evaluation parameters for formulated tablets:

a) Shape and Color:

Round and off white

b) Uniformity of Thickness:

The crown thickness of individual tablet may be measured with Vernier calipers, which permits accurate measurements and provides information on the variation between tablets. Other technique employed in production control involves placing 5 or 10 tablets in a holding tray, where their total crown thickness may be measured with a sliding caliper scale. The tablet thickness was measured using Vernier calipers.

c) Hardness test:

Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in 2 Kg/cm. Three tablets were randomly picked from each formulation and the mean and standard deviation values were calculated.

d) Friability test:

It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or attrition. The friability of tablets was determined by using Roche Friabilater. It is expressed in percentage (%). Ten tablets were initially weighed (W initial) and transferred into Friabilater. The Friabilater was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (Final). The percentage friability was then calculated by,

Initial -final

%friability = -------------------- x100

Initial

Friability of tablets less than 1% is considered acceptable.

e) Weight variation test:

The tablets were selected randomly from each batch and weighed individually to check for weight variation.

f) Content uniformity test:

The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch. Due to increase awareness of physiological availability, the content uniformity test has been included in the monographs of all coated and uncoated tablets intended for oral administration where the range of size of the dosage form available includes 50 mg or smaller sizes. For content uniformity test, representative samples of 30 tablets were selected and 10 are assayed individually. At least 9 must assay within ± 15% of the declared potency.

g) In- vitro dissolution study:

For dissolution in USP apparatus were used in which drug was released in 6.8 buffer pH solution. In this 900ml solution of 6.8 buffer pH was prepare. The rotational speed of paddle was 50 rpm at 37±0.5ºc. The 5 ml aliquots were withdrawn for predetermined time interval. The Aprepitant was analyzed using double beam UV spectrophotometer at 240-256nm.

h) Stability study:

Reproduce large scale batch was placed for stability study at 40˚C/75% RH for1 month. Sample was collected at 1 month and evaluated for dissolution study (ICH) Guidelines Q1C. At the end of the study period, the tablets were observed for change in physical appearance, color, drug content and swelling index. The tablets were also subjected to in vitro dissolution studies. There should be no change in physical appearance, color, drug content, and In vitro dissolution.

RESULT AND DISCUSSION:

Pre-Compression Parameters:

A) Physical Appearance:

Colour: Off white crystalline powder, Odour: odourless.

b) Solubility: Soluble in DMSO (Dimethyl sulphoxide)

c) Melting point:

The melting point method was measured by capillary fusion method. One sided closed capillary filled with drug and tie the capillary with thermometer with the help of thread. Solid drug measured in to liquid at 245.23◦c.

Table no. 2. Evaluation for solid dispersion (KNEADING mehod):

Time (min)	Cumulative % Drug Release
Time (min)	S1	S2	S3	S4	S5	S6	P1	P2	D	D
5	91.81±1.01	98.04±0.11	87.82±0.13	97.28±0.27	94.26±0.61	99.55±0.19	34.59±0.93	24.39±0.79	0	0
10	102.01±0.13	98.04±0.58	91.25±0.95	101.43±0.89	103.55±1.16	97.34±0.87	41.25±0.48	39.89±0.19	10.57±0.77	10.57±0.77
20	101.67±0.56	101.0±0.91	95.02±0.78	99.55±0.61	101.85±1.07	98.85±0.29	42.99±0.19	41.25±0.48	19.78±0.37	19.78±0.37
30	98.79±0.49	100.32±1.01	94.26±0.79	98.79±0.94	100.98±0.58	97.33±0.64	52.79±0.63	49.02±0.87	30.11±0.93	30.11±0.93
45	98.63±0.69	100.32±0.35	95.77±1.17	97.74±1.06	100.98±0.48	92.62±0.35	63.35±0.17	55.81±0.58	45.59±0.18	45.59±0.18
60	99.29±1.12	100.32±0.51	91.25±0.95	98.5±0.73	99.56±0.83	94.12±1.03	76.18±0.49	64.11±0.49	52.68±0.83	52.68±0.83

Table No. 3. Pre-Compression Para Meter of Preliminary Screening Batches

	Bulk density(g/mL)	Tapped density(g/mL)	Hausner ratio	Carr’s Index	Angle of repose
A1	0.51±0.01	0.60±0.01	1.31±0.01	23.71±0.01	23.29±0.01
A2	0.45±0.01	0.52±0.01	1.15±0.01	14.41±0.01	22.47±0.02
A3	0.45±0.03	0.54±0.04	1.18±0.01	15.6±0.02	20.18±0.01
A4	0.49±0.01	0.55±0.01	1.13±0.02	11.76±0.02	21.8±0.03
A5	0.43±0.02	0.51±0.03	1.19±0.01	16.38±0.01	23.89±0.01
A6	0.41±0.01	0.49±0.01	1.18±0.02	15.83±0.01	23.8±0.02
A7	0.42±0.02	0.53±0.01	1.17±0.01	17.23±0.02	22.57±0.02
A8	0.47±0.01	0.57±0.02	1.19±0.01	13.52±0.01	20.42±0.01
A9	0.44±0.01	0.56±0.01	1.21±0.01	18.21±0.01	24.2±0.01
A10	0.46±0.02	0.59±0.03	1.23±0.01	12.29±0.02	21.56±0.03

Table No. 4. Post Compression Parameter of preliminary Screening Batches

	Avg. Wt(mg)	Hardness (kp)	Thickness (mm)	Friability (%w/w)	Drug content%
A1	220.12±0.01	4.91±0.77	3.91±0.05	0.64±0.01	98.19±0.01
A2	219.85±.001	4.88±0.79	3.87±0.05	0.69±0.01	97.23±0.01
A3	219.82±0.04	4.18±0.96	3.89±0.06	0.79±0.01	97.76±0.01
A4	220.05±0.01	4.67±1.08	3.92±0.06	0.94±0.01	97.89±0.04
A5	219.78±0.02	4.62±2.97	3.91±0.04	0.89±0.02	97.26±0.03
A6	219.83±0.01	4.09±1.10	3.90±0.04	0.97±0.03	97.48±0.02
A7	219.95±0.01	4.52±0.85	3.63±0.03	0.75±0.02	98.02±0.01
A8	220.10±0.01	4.65±0.72	3.85±0.04	0.93±0.01	97.65±0.02
A9	219.87±0.02	4.95±0.81	3.73±0.05	0.72±.0.01	98.15±0.01
A10	219.98±0.01	4.23±0.73	3.78±0.04	0.86±0.02	97.59±0.03

Table No. 5. In vitro dissolution

Factorial batches	Disintegration time (sec)	Wetting time (sec)
F1	74.58±1.26	80.30±1.45
F2	72.92±1.45	78.42±1.19
F3	70.43±1.56	76.19±1.04
F4	66.25±2.24	74.26±1.53
F5	62.72±1.58	70.33±1.28
F6	56.66±1.17	67.64±1.10
F7	52.18±2.36	63.57±2.13
F8	44.32±2.50	54.79±2.30
F9	49.39±1.66	60.24±0.99

TIME (min)

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

0.000

± 0.0

46.51

± 0.65

52.16

± 0.25

52.69

± 0.65

45.34

± 0.41

54.18

± 0.99

54.42

± 0.56

48.38

± 0.75

55.67

± 0.55

56.13

±0.89

60.49

± 0.83

62.45

± 0.91

63.99

± 0.29

65.12

± 0.47

65.44

± 0.59

65.86

± 0.53

66.87

± 0.63

67.23±

0.45

69.85

± 0.31

74.43

± 0.43

74.97

± 0.87

76.56

± 0.95

77.86

± 0.91

78.15

± 0.74

79.12

± 0.65

79.16

± 0.61

80.49

± 0.54

82.53±

0.78

82.67

± 0.52

83.69

± 0.32

85.20

± 0.86

85.25

± 0.82

86.45

± 0.38

86.72

± 0.25

86.86

± 0.28

89.2 ±

0.55

90.23

± 0.67

89.49

± 0.67

91.52

± 0.85

93.64

± 0.45

94.61

± 0.49

95.79

± 0.86

96.27

± 0.65

97.20

± 0.12

98.42±

0.64

99.25

± 0.3

90.52 ±

0.89

93.21±

0.42

96.56±

0.78

97.40±

0.25

97.98±

0.02

98.34±

0.85

99.51±

0.42

99.83±

0.25

99.99±

0.48

Stability study:

The study was performed at 40°C/75% RH for 1 month. Average weight, hardness, thickness, friability, disintegration time and wetting time were evaluated during each station of stability. Data of stability study reveals that optimized formulation is stable during accelerated stability testing. The data related to stability studies of optimized batch was shown in Table 6.

Table no.6 Stability studies of optimized batch

Stability at 40ºc /75%RH
Batch no F8 optimsed	Initial	After 30 days
Average. weight	220.0.2	219.98
Hardness	4.30	4.19
Thickness	3.91	3.89
Friability	0.484	0.462
Disintegration time (sec)	20.83(1.23)	21.45(1.86)
Wetting time(sec)	21.56(1.47)	20.63(0.75)

CONCLUSION:

An optimized formulation of Aprepitant orally disintegrating tablets was found and prepared in this study by direct compression method. Here, 3² full factorial design method was used to prepare it. physico-chemical characteristics and accelerated stability results of the optimum formulation also met all pharmaceutical requirements. Concentration of polyplasdone XL10 has opposite effect on disintegration time and wetting time; as the concentration increased disintegration time and wetting time decreased. Mannitol initially decreases disintegration time and wetting time but at high concentration it increases disintegration time and wetting time.

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Received on 04.02.2022 Modified on 09.06.2022

Research J. Pharm. and Tech 2023; 16(5):2375-2380.

DOI: 10.52711/0974-360X.2023.00391