INTRODUCTION:

A drug delivery system (DDS) is defined as a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body¹. This process includes the administration of the therapeutic product, the release of the active ingredients by the product, and the subsequent transport of the active ingredients across the biological membranes to the site of action^2,3. The term therapeutic substance also applies to an agent such as gene therapy that will induce in vivo production of the active therapeutic agent.

Sustained release tablets are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect⁴. The advantage of administering a single dose of a drug that is released over an extended period of time to maintain a near-constant or uniform blood levelof a drug often translates into better patient compliance, as well as enhanced clinical efficacyof the drug for its intended use^5,6.

The first sustained release tablets were made by Howard Press in New Jersy in the early 1950's. The first tablets released under his process patent were called 'Nitroglyn' and made under license by Key Corp. in Florida.

Sustained release, prolonged release, modified release, extended release or depot formulations are terms used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

The goal in designing sustained or sustained delivery systems is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery. So, sustained release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or to a specified target organ^7,8.

Sustained release dosage forms provide a better control of plasma drug levels, less dosage frequency, less side effect, increased efficacy and constant delivery. There are certain considerations for the preparation of extended release formulations:

· If the active compound has a long half-life, it is sustained on its own,

· If the pharmacological activity of the active is not directly related to its blood levels,

· If the absorption of the drug involves an active transport and

· If the active compound has very short half-life then it would require a large amount of drug to maintain a prolonged effective dose.

AIM AND OBJECTIVE:

AIM OF WORK:

The main aim of the present study is to Formulation and in vitro Evaluation of Phenytoin Sodium Sustained release matrix tablet.

OBJECTIVES OF THE WORK:

1. To formulate Phenytoin Sodium sustained release matrix tablets for the improvement of Bioavailability.

2. To perform various quality control evaluation parameters for the prepared tablets.

Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures and focal seizures, but not absence seizures. The intravenous form is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for 24 hours. Blood levels can be measured to determine the proper dose.

MATERIALS AND METHOD:

Phenytoin Sodiumwas Provided by SURA Labs, Dilsukhnagar, Hyderabad, Carbopol 934 and HPMC K100was purchased from Elders Pharmaceuticals Pvt Ltd Dehradun, India, Eudragit was purchased from Degussa India Ltd, Mumbai, India, PVP K 30was purchased from Merck Specialities Pvt Ltd, Mumbai, IndiaLactosewas purchased from Shakti Chemicals, Mehsana, India.Magnesium stearate was purchased Signet Chemical Corp., Mumba. And Talc was purchased from S. D. Fine Chemicals Ltd., Mumbai, India.

METHODOLOGY:

Table: 1 Formulation composition for tablets

Ingredients (Mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Phenytoin Sodium	30	30	30	30	30	30	30	30	30
Carbopol 934	25	50	75	-	-	-	-	-	-
Eudragit	-	-	-	25	50	75	-	-	-
HPMC K100	-	-	-	-	-	-	25	50	75
PVP K 30	10	10	10	10	10	10	10	10	10
Lactose	123	98	73	123	98	73	123	98	73
Magnesium sterate	7	7	7	7	7	7	7	7	7
Talc	5	5	5	5	5	5	5	5	5
Total weight	200	200	200	200	200	200	200	200	200

RESULTS AND DISCUSSION:

Analytical Method:

Graphs of Phenytoin Sodium were taken in 0.1N HCl and in pH 6.8 phosphate buffer at 373 nm and 376nm respectively.

Table: 2 Observations for graph of Phenytoin Sodium in 0.1N HCl

Concentration (µg/ml)	Absorbance
0	0
5	0.138
10	0.246
15	0.357
20	0.475
25	0.598

Table: 3 Standard graph values of Phenytoin Sodium at 376nm in pH 6.8 phosphate buffer

Concentration (µg/ml)	Absorbance
0	0
5	0.134
10	0.265
15	0.386
20	0.498
25	0.624

Figure 1. Standard curve of Phenytoin Sodium

Figure 2. Standard curve of Phenytoin Sodium

PREFORMULATION PARAMETERS OF POWDER BLEND:

Table: 4 Pre-formulation parameters of Core blend

Formulation code	Angle of repose (Ө)	Bulk density (gm/cm³	Tapped density (gm/cm³)	Carr’s index (%)	Hausner’s ratio
F1	26.92 ± 0.03	0.315 ±0.04	0.365 ± 0.05	17.79 ±0.01	1.24
F2	25.98 ± 0.02	0.306 ± 0.03	0.354 ± 0.05	16.81 ± 0.01	1.18
F3	25.11 ± 0.03	0.298 ± 0.04	0.341 ± 0.04	16.55 ± 0.04	1.08
F4	26.91 ± 0.07	0.318 ± 0.02	0.361 ± 0.07	17.99 ± 0.02	1.02
F5	26.65 ± 0.03	0.313 ± 0.04	0.355 ± 0.02	16.98 ± 0.02	1.07
F6	25.47 ± 0.04	0.299 ± 0.01	0.350 ± 0.04	16.33 ± 0.04	1.16
F7	27.52 ± 0.02	0.334 ± 0.02	0.384 ± 0.01	17.00 ± 0.05	1.15
F8	26.99 ± 0.05	0.321 ± 0.04	0.375 ± 0.05	15. 81 ±0.02	1.08
F9	26.28 ± 0.08	0.313 ± 0.03	0.362 ± 0.05	15.41 ± 0.03	1.11

All the values represent n=3

Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend has good flow properties. The bulk density of all the formulations was found to be in the range showing that the powder has good flow properties. The tapped density of all the formulations powders has good flow properties. The compressibility index of all the formulations was found to be below17.99 ± 0.02 which show that the powder has good flow properties. All the formulations has shown the hausner ratio below 1.24 indicating the powder has good flow properties.

Quality Control Parameters For tablets:

Tablet quality control tests such as weight variation, hardness, and friability, thickness, and drug release studies in different media were performed on the compression tablet.

Table: 5. In vitro quality control parameters for tablets

Formulation codes	Average Weight (mg)	Hardness (kg/cm²)	Friability (%loss)	Thickness (mm)	Drug content (%)
F1	198.24	4.5	0.16	3.12	99.45
F2	196.56	5.1	0.32	3.26	97.53
F3	197.06	4.6	0.44	3.39	98.75
F4	199.51	5.3	0.76	3.54	96.36
F5	198.28	4.8	0.68	3.67	97.86
F6	197.50	5.7	0.83	3.46	99.87
F7	198.42	4.7	0.48	3.69	97.62
F8	199.79	5.9	0.22	3.86	98.46
F9	200.05	5.6	0.36	3.94	99.74

Weight variation test:

Tablets of each batch were subjected to weight variation test, difference in weight and percent deviation was calculated for each tablet. The average weight of the tablet is approximately in range of 196.56 to 200.05 mg, so the permissible limit is ±7.5% (>200 mg). The results of the test showed that, the tablet weights were within limit.

Hardness test:

Hardness of the three tablets of each batch was checked by using Pfizer hardness tester and the data’s were shown in Table 5. The results showed that the hardness of the tablets is in range of 4.5 to 5.9 kg/cm², which was within IP limits.

Thickness:

Thickness of three tablets of each batch was checked by using Micrometer and data shown in Table-5. The result showed that thickness of the tablet is raging from 3.12 to 3.94mm.

Friability:

Tablets of each batch were evaluated for percentage friability and the data were shown in the Table 5. The average friability of all the formulations was less than 1% as per official requirement of IP indicating a good mechanical resistance of tablets.

Drug content:

Drug content studies were performed for the prepared formulations. From the drug content studies it was concluded that all the formulations were showing the % drug content values within 96.36-99.87%.

All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits.

In Vitro Drug Release Studies:

Table: 6 Dissolution data of Phenytoin Sodium tablets

Time(hrs)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
0.5	12.14	14.25	17.32	13.21	12.52	14.85	14.23	10.56	16.23
1	17.36	21.15	21.65	18.2	20.92	21.41	19.32	18.32	19.56
2	21.86	26.22	28.15	28.2	23.65	23.35	24.65	26.62	29.36
3	27.36	34.49	36.45	36.78	30.56	29.26	28.16	30.25	31.47
4	33.56	40.12	39.55	42.25	46.87	37.67	32.47	34.58	38.54
5	45.89	47.84	44.87	57.49	53.42	45.51	49.36	41.15	42.85
6	49.56	59.17	54.25	69.65	64.98	58.19	58.45	46.69	50.51
7	53.21	63.5	58.32	74.46	71.25	69.78	64.98	52.78	56.65
8	59.22	69.48	65.63	86.87	76.87	75.62	76.74	57.41	58.12
9	63.27	75.26	73.52	96.55	82.36	80.87	79.85	63.65	62.56
10	72.12	81.65	81.41		91.33	83.3	84.32	68.14	67.14
11	76.97	84.41	87.54		98.45	87.71	88.65	75.36	72.69
12	79.34	88.54	91.36			99.84	94.56	86.32	79.65

Figure 3. Dissolution profile of Phenytoin Sodium (F1- F9 formulations)

From the dissolution data it was evident that the formulations prepared with Carbopol 934 as polymer were retard the good drug release up to desired time period i.e., 12 hours.

Formulations prepared with Eudragit retarded the drug release in the concentration of 75 mg (F6 Formulation) showed required release pattern i.e., retarded the drug release up to 12 hours and showed maximum of 99.84% in 12 hours with good retardation.

Whereas the formulations prepared HPMC K100 with retarded the drug release in the concentration of 25mg (F7 Formulation) retarded the drug release (94.56 %) up to 12 hours (Required Time).

Finally Concluded that F6 formulation was considered as optimized formulation.

DRUG – EXCIPIENT COMPATIBILITY STUDIES:

Figure 4. FT-TR Spectrum of Phenytoin Sodiumpure drug

Figure: 5. FT-IR Spectrum of optimised Formulation

There was no disappearance of any characteristics peak in the FTIR spectrum of drug and the polymers used. This shows that there is no chemical interaction between the drug and the polymers used. The presence of peaks at the expected range confirms that the materials taken for the study are genuine and there were no possible interactions.

Phenytoin Sodiumare also present in the physical mixture, which indicates that there is no interaction between drug and the polymers, which confirms the stability of the drug.

CONCLUSION:

The present study was undertaken with an aim to formulate and evaluate sustained-release matrix tablets of Phenytoin Sodium by using different types of polymers. Compatibility study revealed that there was no interaction between the drug and the excipients in the formulation. The pre-compression and the post compression parameters are found to be within the limits. All the formulations were passed various physicochemical evaluation parameters and they were found to be within limits. It can be concluded that the present study indicates that the sustained release tablets of Phenytoin Sodium provides a better option for therapy of the several formulations investigated. Among 9 formulations, F-6 is optimized based on the cumulative % drug release is 99.84 % in 12 hours. The in vitro drug release data was plotted for various kinetic models. The R²value for optimized formulation F6 for zero order was found to be 0.975.

АCKNOWLEDGEMENT:

The Authors arе thankful to Sura Labs, Dilshukhnagar, Hydеrabad for providing thе necessary facilities for the research work.

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Received on 17.02.2020 Modified on 15.03.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(2): 68-72.

DOI: 10.5958/0975-4377.2020.00012.9