Formulation Development and In vitro Characterisation of Stavudine Extended Release Matrix Tablets

 

Y. Sirisha¹*, Kurni Sai Kumar¹, Ramya Sri S²

¹Department of Pharmaceutics, Samskruti College of Pharmacy, Affiliated to JNTUH University,

Hyderabad 501301, Telangana, India.

²Department of Pharmacy, University College of Technology, Osmania University,

Hyderabad – 500007, Telangana, India.

 

ABSTRACT:

The aim of the present study was to develop Stavudine extended release tablets to maintain constant therapeutic levels of the drug for over 12 hrs. Xanthan gum, Sodium CMC and HPMC 15cps were used as polymers. All the formulations were passed various physicochemical evaluation parameters such as Bulk Density, Tapped Density, Carr’s Index, Hausners Ratio, Angle of Repose, Weight Variation, Hardness, Thickness, Friability and Drug Content. From the dissolution studies it was evident that the formulation F6 showed better and desired drug release pattern i.e., 99.12% in 12 hours. It contains the Sodium CMC as polymer. It followed Kars Mayer peppas release kinetics mechanism.

 

 

 

INTRODUCTION:

Extended release dosage forms are designed to achieve a prolonged therapeutic effect by continuously releasing drug over an extended period of time after administration of a single dose¹. To achieve better therapeutic action various types of drug delivery systems are available, out of which extended release systems are gaining much importance because of their wide advantages over others like ease of administration, convenience and non-invasiveness².

 

Extended release formulation is an important program for new drug research and development to meet several unmet clinical needs.

 

There are several reasons for attractiveness of these dosage forms viz. provides increase bioavailability of drug product, reduction in the frequency of administration to prolong duration of effective blood levels, Reduces the fluctuation of peak trough concentration and side effects and possibly improves the specific distribution of the drug³. The rationale for development of an extended-release formulation of a drug is to enhance its therapeutic benefits, minimizing its side effects while improving the management of the diseased condition⁴.

 

The sustained plasma drug levels provided by extended release products often at times eliminate the need for night dosing which benefits not only the patient but also the caregiver⁵. The extended release systems are the methods that can achieve therapeutically effective concentrations of drug in systemic circulation over an extended period of time⁶.

Stavudine (2', 3'-didehydro-3'-deoxythymidine), is a nucleoside analogue of thymidine used in the treatment of HIV5⁷. It has a molecular formula of C₁₀H₁₂N₂O₄ and a molecular weight of 224.22g/mol⁸. Stavudine is absorbed rapidly orally producing peak plasma concentration within 1hour with 86% bioavailability and elimination half life of 1 to 1.5 hour following single or multiple doses⁹. It also causes termination of DNA synthesis by incorporating into it¹⁰.

 

 

Fig 1: Chemical strcture of Stavudine¹¹

 

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a major and one of the most serious public health challenges in today’s world. An estimated 35.3 million people across the world are infected with HIV¹². NACP 2 (1999 – 2006) continued to expand the program and involved NGOs and other sectors such as education and transport, as well as the police. Under NACP 3 (2006-11), the program is dramatically scaling up targeted prevention interventions, such as promoting condom use among sex workers and their clients, implementing harm reduction among injecting drug users, and supporting peer educators to reach the vulnerable groups at highest risk.¹³

 

MATERIALS AND METHODS:

Stavudine procured from Cipla Pharmaceuticals Limited, Bangalore.  Provided by SURA LABS, Dilsukhnagar, Hyderabad. Xanthan gum from Arvind Remedies Ltd, Tamil nadu, India. Sodium CMC from SD Fine Chem. Ltd. (Mumbai, India). HPMC 15cps from Yarrow chemicals (Mumbai, India). Lactose from Chemdyes Corporation (Ahmedabad, India). Magnesium stearate from Shakti Chemicals (Mehsana, India). Aerosil from Kerry laboratories

 

 

 

 

METHODOLOGY:

Analytical method development:

Determination of Wavelength:

10mg of pure drug was dissolved in 10ml methanol (primary stock solution - 1000µg/ml). From this primary stock solution 1 ml was pipette out into 10ml volumetric flask and made it up to 10ml with the media (Secondary stock solution – 100µg/ml). From secondary stock solution again 1ml was taken it in to another volumetric flask and made it up to 10ml with media (working solution - 10µg/ml). The working solution was taken for determining the wavelength.

 

Determination of Calibration Curve:

10mg of pure drug was dissolved in 10ml methanol (primary stock solution - 1000µg/ml). From this primary stock solution 1ml was pipette out into 10 ml volumetric flask and made it up to 10ml with the media (Secondary stock solution – 100µg/ml). From secondary stock solution required concentrations were prepared (shown in Table 10.1 and 10.2) and those concentrations absorbance were found out at required wavelength.

 

Preformulation parameters:

The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing and all these can affect the characteristics of blends produced. The various characteristics of blends tested as per Pharmacopoeia.

 

Formulation development of Tablets:

All the formulations were prepared by direct compression. The compositions of different formulations are given in Table 9.3. The tablets were prepared as per the procedure given below and aim is to prolong the release of Stavudine. Total weight of the tablet was considered as 150mg.

 

Procedure:

1)   Stavudine and all other ingredients were individually passed through sieve   no ¹ 60.

2)   All the ingredients were mixed thoroughly by triturating up to 15 min.

3)   The powder mixture was lubricated with talc.

4)   The tablets were prepared by using direct compression method.

Table 1: Formulation composition for tablets

Ingredients	Formulation Chart
	F1	F2	F3	F4	F5	F6	F7	F8	F9
Stavudine	30	30	30	30	30	30	30	30	30
Xanthan gum	10	20	30	-	-	-	-	-	-
Sodium CMC	-	-	-	10	20	30	-	-	-
HPMC 15cps	-	-	-	-	-	-	10	20	30
Lactose	99	89	79	99	89	79	99	89	79
Magnesium stearate	6	6	6	6	6	6	6	6	6
Aerosil	5	5	5	5	5	5	5	5	5
Total Weight	150	150	150	150	150	150	150	150	150

All the quantities were in mg

RESULTS AND DISCUSSION:

The present study was aimed to developing Extended release tablets of Stavudine using various polymers. All the formulations were evaluated for physicochemical properties and in vitro drug release studies.

 

Analytical Method:

Graphs of Stavudine were taken in 0.1N HCl and in pH 6.8 phosphate buffer at 238nm and 245nm respectively.

 

 

Figure 1: Standard graph of Stavudine in 0.1N HCl

 

 

Figure 2: Standard graph of Stavudine pH 6.8 phosphate buffer (245 nm)

Preformulation parameters of powder blend:

Table 2: Pre-formulation parameters of Core blend

Formulation Code	Angle of Repose	Bulk density (gm/ml)	Tapped density (gm/ml)	Carr’s index (%)	Hausner’s Ratio
F1	29.35	0.538	0.649	17.10	1.20
F2	30.30	0.546	0.665	17.89	1.21
F3	31.65	0.576	0.672	14.28	1.16
F4	29.98	0.524	0.657	20.24	1.25
F5	29.66	0.564	0.677	16.69	1.20
F6	29.98	0.536	0.635	15.59	1.18
F7	30.32	0.576	0.650	11.38	1.12
F8	27.33	0.547	0.657	16.74	1.20
F9	30.62	0.567	0.678	16.37	1.19

 

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 of   0.524 to 0.576(gm/cm3) showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range of 0.635 to 0.678 showing the powder has good flow properties. The compressibility index of all the formulations was found to be below 17 which show that the powder has good flow properties. All the formulations has shown the hausner ratio below 1.20 indicating the powder has good flow properties.

 

Quality Control Parameters For tablets:

Tablet quality control tests such as weight variation¹⁶, hardness¹⁴, and friability¹⁶, thickness, drug content¹⁵ and drug release studies¹⁷ in different media were performed on the compression coated tablet.

 

Table 3: In vitro quality control parameters for tablets

Formulation codes	Average Weight (mg)	Hardness (kg/cm2)	Friability (%loss)	Thickness (mm)	Drug content (%)
F1	149.25	5.2	0.16	3.14	98.32
F2	147.52	4.8	0.61	3.26	97.56
F3	149.10	5.1	0.58	3.47	99.34
F4	150.0	4.6	0.46	3.62	96.87
F5	147.96	4.9	0.28	3.59	98.24
F6	148.58	4.2	0.72	3.47	97.89
F7	149.72	5.3	0.39	3.95	96.75
F8	149.18	5.9	0.58	3.58	99.27

 

In Vitro Drug Release Studies

Table 4: Dissolution Data of Stavudine Tablets Prepared with Xanthan gum

Time (hr)	Cumulative Percent Drug Dissolved
	f1	f2	f3	f4	f5	f6	f7	f8	f9
0	0	0	0	0	0	0	0	0	0
0.5	12.19	7.98	10.9	9.85	11.52	15.59	18.19	21.82	18.79
1	16.62	12.75	19.02	14.67	16.63	20.76	22.34	26.42	22.64
2	22.34	21.68	24.63	19.72	23.92	27.42	26.73	30.92	26.18
3	35.52	28.34	29.98	26.14	28.41	36.10	34.59	36.22	30.27
4	40.19	36.65	34.80	32.92	36.75	45.34	40.96	43.72	37.21
5	53.75	42.89	40.51	39.30	43.64	53.47	49.82	47.36	42.65
6	57.68	54.72	48.63	45.43	50.79	61.93	53.97	53.24	56.72
7	64.54	58.49	52.24	49.98	56.62	67.16	60.84	62.87	58.87
8	70.47	62.34	58.72	54.67	61.93	75.26	69.46	68.16	64.31
9	76.85	68.97	62.47	58.71	67.44	82.59	72.12	75.45	75.45
10	84.36	73.58	65.63	63.24	78.39	88.73	79.57	82.93	80.94
11	91.52	78.14	70.75	69.14	82.40	92.69	84.21	88.32	83.62
12	95.14	85.60	74.20	74.96	89.22	99.12	96.62	90.59	87.10

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

 

Formulations prepared with Sodium CMC retarded the drug release in the concentration of 30mg (F6 Formulation) showed required release pattern i.e., retarded the drug release up to 12 hours and showed maximum of 99.12% in 12 hours with good drug release.

 

The Formulation Containing HPMC 15cps in 10mg Concentration Showed good retarding nature with required drug release in 12 hours i.e., 96.62%.

 

From the above results it was evident that the formulation F6 is best formulation with desired drug release pattern extended up to 12 hours.

 

Application of Release Rate Kinetics to Dissolution Data:

 

Fig 3: Kars Mayer peppas graph

 

From the above graphs it was evident that the formulation F6 was followed Kars mayer peppas release kinetics.

 

Drug – Excipient compatability studies

Fourier Transform-Infrared Spectroscopy:

From Below the FTIR data it was evident that the drug and excipients doses not have any interactions.  Hence they were compatible.

 

Fig 4: FTIR graphs

 

CONCLUSION:

The present study was carried out on Stavudine. It has half life about 0.8-1.5hrs. The main aim of this study is to extend the drug release up to 12 hrs. Drug wavelength and calibration curve was developed in 0.1N HCl and pH 6.8 Phosphate buffer.

 

The drug and excipient compatability studies were shown good compatability between drug and excipients. Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose, bulk density, tapped density, compressibility index and hausner ratio powder has good flow properties.

 

Post compression studies like Weight variation, Hardness, thickness, friability, drug content was determined within IP limits. From the dissolution data it was evident that the formulation F6 is best formulation with desired drug release pattern extended up to 12 hours. The formulation F6 was followed Kars Mayer peppas release kinetics.

 

ACKNOWLEDGEMENT:

Thе Authors arе thankful to the Management and Principal, Department of Pharmacy, Samskruti College of Pharmacy, Hyderabad, for extending support to carry out the research work. Finally, the authors express their gratitude to the Sura Labs, Dilsukhnagar, Hyderabad, for providing research equipment and facilities.

 

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Received on 24.10.2022       Modified on 28.11.2022

Accepted on 22.12.2022   ©AandV Publications All Right Reserved