Formulation and Evaluation of Immediate Release Tablet of Efavirenz by Micellar Solubilization Technique

 

Snehal B. Kulkarni¹*, Mr. M. M. Bari¹, Dr. S. D. Barhate¹, Ashutosh Tripathi²

¹Department of Pharmaceutics, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner, Maharashtra, India, 424206

²Centurion Laboratories, Vadodara, Gujarat.

 

ABSTRACT:

The objective of the study was to prepare and evaluate immediate release tablet of efavirenz by using micellar solubilization technique to improve solubility and dissolution rate of poorly water soluble drug efavirenz. The tablets were prepared by wet granulation method using sodium lauryl sulphate as surfactant and crosscarmellose sodium and crospovidone as a superdisintegrants. Compatibility study was carried out by using FTIR and DSC found there was no drug – excipient interaction. F1-F9 batches were prepared and F9 batch showed good pre and post compression results, F9 batch showed disintegration time 1:34 min. and 98.99% drug release within 30 min. Also F9 batch was compared with marketed formulation showed better release of drug. 

 

 

 

INTRODUCTION:

Oral ingestion is the most convenient and commonly employed route of drug delivery due to its easy administration, high patient compliance, cost-effectiveness, least sterility constraints, and flexibility in the design of the dosage form. Immediate release tablets are those which disintegrate rapidly and get dissolved to release the medicaments. For the drugs which required to be released faster for the better therapeutic effect, the designing of the immediate release tablets dosage form plays a significant role in the therapy. Immediate release dosage forms are those for which ≥85% of the labeled amount dissolve within 30 min. For immediate release formulation, superdisintegrant play key component to improve the efficacy of solid dosage form. This achieved by various mechanisms, swelling, porosity and capillary action, heat of wetting, particle repulsion forces, deformation recovery, enzymatic reaction by which the tablets are broken into small particles.[1]

 

Although antiretroviral drug therapy has contributed significantly to improve patient quality of life and disease management, its use is associated with several drawbacks and inconveniences for patients. Associated severe side effects can be attributed to the high doses required to achieve a therapeutic effect, to inadequate drug concentration at the site of action, and/or to the poor bioavailability of some antiretroviral drugs. These drugs can present physico-chemical problems such as poor solubility that can lead to formulation difficulties [2]

 

Efavirenz (EFV) is an antihuman immunodeficiency virus (anti HIV) drug that works by inhibiting the non-nucleoside reverse transcriptase of HIV and is used as a part of the highly active antiretroviral therapy. EFV is freely soluble in methanol, but it is practically insoluble in water and has a bioavailability of 40 to 45%. [3]

 

The solubility of drugs plays a significant role in determining the rate and extent of its absorption, thus finally affecting its bioavailability. Therefore poorly soluble or water insoluble drugs need special consideration and strategies while designing their solid oral formulations. Rate of drug release from solid oral dosage forms is one of the leading factors, which helps to ascertain the therapeutic efficacy in view of the quantity of drug available for absorption and reaching into blood circulation. Although, the phenomenon is equally applicable and important for all active pharmaceutical ingredient(s) (API). [4]

 

Micellization have been reported to solubilize a number of poorly water soluble drugs. Surfactants (amphiphilic molecules composed of a hydrophilic moiety known as the head and a hydrophobic moiety known as the tail) do that by forming micelles (colloidal clusters) in solutions. As association colloids, micelles are formed spontaneously under certain conditions (self assembling system) and are thermodynamically more stable towards both dissociation and aggregation. Depending upon the drug hydrophobicity, it can be solubilized in the inner core of the micelle, on the surface of the micelle or at an intermediate location in the palisade layer.[5]

 

Surfactant acts as an absorption enhancer and hence increases both dissolution and permeability of the drug. Further enhancement of dissolution can be done by using superdisintegrant. Superdisintegrant, disintegrate the tablet rapidly which enhances the dissolution rate of the drug. [6]

 

MATERIALS AND METHODS:

Material

Efavirenz was obtained as a gift sample from Centurion Laboratories, Vadodara Gujarat, India. Croscarmellose sodium was gift sample from Haffkine Ajintha Pharmaceutical Ltd, Jalgaon and Crospovidone, SLS, Poloxamer 188, polysorbate 80 and 20 were gift sample from Celogen Life Science, Mumbai.

 

Preparation of immediate release tablet:[7,12]

Immediate release tablets each containing 200 mg of efavirenz were prepared by wet granulation method employing SLS as a surfactant and corsscarmellose sodium, crosspovidone as a superdisintegrant as shown in the formulae given in table. The blends were granulated with water as a binder solution. Firstly all ingredients weigh accurately. Efavirenz, Microcrystalline cellulose, L-HPC 21, Crosscarmellose sodium / Crosspovidone, Sodium Lauryl Sulphate were sifted separately through 60#seive. Efavirenz ,Microcrystalline cellulose, Crosscarmellose sodium / Crosspovidone, Sodium Lauryl Sulphate ,L-HPC21 were taken in small polythene bag and mixed slowly for 5min. Mixed material was added in mortar and binder solution was added to prepare a dump mass. The dumps mass passed through sieve 8#.The wet granules were dried at room temperature. Dried granules were passed through 16# .The granule were ready for lubrication. Sifted granules were transferred to polythene bag and magnesium Stearate, Aerosil and Talc sifted through 60 # and added to dried granules and mixed for 2 min.

 

Compression of Immediate release tablet: Immediate release tablet were prepared manually using multi-tooling punching machine (CIP).9mm biconcave punch was selected. Then granules were compressed in to 300 mg tablets of hardness 3-4.5 kg/cm².

 

 

Table 1. Composition of Immediate Release Tablet of Efavirenz

Sr. No	Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	Efavirenz	200	200	200	200	200	200	200	200	200
2	Microcrystalline Cellulose PH101	48.7	48.8	48.7	53.7	50.7	47.7	50.7	42.7	28.7
3	L-HPC	30	35	40	30	35	40	30	35	40
4	Corsscarmellose Sodium	-	-	-	10	8	6	8	6	10
5	Crosspovidone	5	-	-	-	-	-	-	-	5
8	Sodium Lauryl Sulphate	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
9	Purified water	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
10	Crospovidone	10	10	5	-	-	-	5	10	10
11	Talc	3	3	3	3	3	3	3	3	3
12	Aerosil	0.30	0.30	0.30	0.30	0.30	0.30	0.30	0.30	0.30
13	Magnesium Stearate	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Average weight		300	300	300	300	300	300	300	300	300

*Note: All quantities were taken in milligram.

 

COMPOSITION OF FILM COATING SOLUTION:

Table2. Composition of Film Coating Solution for immediate Release Efavirenz Tablet

Sr. No.	Ingredient	Concentration (% w/v)
1	Sunset Yellow	5
2	Polyethylene Glycol	1
3	Isopropyl Alcohol	32
4	Methylene Chloride	62

EVALUATION OF IMMEDIATE RELEASE TABLET OF EFAVIRENZ:

1)    Hardness Testing: The hardness of tablet depends on the weight of material used, space between upper and lower punches at the time of compression. The hardness also depends on the nature and quantity of excipient used during formulation. If the finished tablet was too hard, it may not disintegrate in the required period of time and tablet was too soft it may not withstand the handling during packing and transportation. Therefore, it was very necessary to check the hardness of tablet. Hardness for immediate release tablet in order to maintain the physical strength as well as desired release, because has indirect effect on the release of immediate release tablet.10 tablets of each formulation F1 to F9 were taken and the hardness was determined. Hardness is expressed in kg/cm².[7]

 

2)    Thickness: The thickness of tablet can vary without any change in its weight. This was due to difference in density of granules, applied for compression and speed of compression. Thickness and diameter were measured by using Vernier caliper. Tablet thickness should be controlled within a ± 5% variation of standard value.[7]

 

3)    Friability: The ability of the tablet it withstands abrasion in packaging, handling and shipping. The loss due to abrasion was a measure of the tablet friability. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablet are not picked up. Friability is expressed in percentage.[8]

 

 

% Friability = Initial Weight-Final weight/Initial Weight × 100

 

4)       Weight Variation:

It is an important property to determine the drug content present in each tablet. Twenty tablets were select randomly from each batch and weighed individually. Average weight was calculated from the total weight of all tablets. The individual weights were compared with the average weight. The acceptable % of weight variation as per USP is ± 7.5 % that is ˃130 mg to ˂ 324 mg. Tablet meets the USP test if no more than 2 tablets are outside the percentage limit and if no tablet. Differs by more than 2 times the percentage limit. A little variation is allowed in weight of a tablet.[8]

 

 

Table 3. Weight variation parameters

Average weight of tablet	Percentage deviation
130 mg or less	±10
>130 mg and <324 mg	±7.5
324 mg or more	±5

*In all formulation, the tablet weight is 300 mg, hence ±7.5 % maximum difference allowed.

5)       Drug Content:

Then 10 tablet from each formulation from F1-F9 were taken, crushed and then accurately weight was taken according to the 16 mg of pure drug and dissolve in the 2% SLS solution and value were observed in spectrophotometer (UV-VIS-1800 Shimadzu) at 247 nm, these will be the values of sample, after that with the help of the following formula content uniformity was calculated.[8,15]

 

Content Uniformity = (Absorbance of sample /Absorbance of standard) ×100

6)       Disintegration Time:

The disintegration test was carried out using an Electrolab disintegration test apparatus (model ED2L, Electrolab). The volume of disintegration medium (distilled water) used was 900 ml. 1 tablet in each of 6 tubes of basket was carefully placed and if prescribed add a disc. Operate the apparatus using water maintained at 37⁰c ±0.2⁰c. At the end of the time specified basket was lifted from the fluid and observes the tablets. All of the tablets have disintegrated completely within 2 min. [9,16]

 

7)       In-Vitro Dissolution Studies:

The USP dissolution test apparatus (apparatus II paddle type) was used to study the drug release from the tablets. The dissolution medium was 900 ml of 2% SLS. The release was performed at 37 ± 0.5°C, with a rotation speed of 50 rpm.5ml samples were withdrawn at predetermined time intervals and replaced with fresh medium. The samples were analyzed after appropriate dilution by UV spectrophotometer 1800 at 247 nm and drug release was determined by following formula [8,9,17]

 

% Drug Release = (Sample abs Std.abs) × Standard dilution × Test dilution × (Purity Lable claim)

RESULT AND DISCUSSION:

1)       Determination of Wavelength:

Spectrum of 10 µg solution was taken on UV-Visible spectrophotometer (Shimadzu 1800), the spectra of efavirenz in 2% w/v SLS solution scanned in the range of 400-200 nm and λmax was observed at 247 nm.

 

Figure 1. UV Spectrum of Efavirenz

 

2)       Standard Calibration Curve of Efavirenz in 2% SLS Solution:

An accurately weighed quantity of efarevinz (100mg) was dissolved in 2% SLS and volume was made upto 100 ml to get solution of 1000 µg/ml. From this solution 10 ml was withdrawn and diluted up to 100 ml with 2% SLS solution to get stock solution of 100 µg/ml.Standard solution from above  stock solution different aliquot were prepared in the range of 0.3 µg/ml, 0.6 µg/ml, 0.9 µg/ml, 1.2 µg/ml, 1.5 µg/ml, 1.8 µg/ml. Absorbance of each solution was measured at 247 nm using UV/VIS spectrophotometer (Shimadzu 1800) and 2% SLS as reference standard and the standard curve was generated.

 

 

Figure 2. Standard calibration curve of efavirenz

 

DSC and FTIR Estimation of Efavirenz:

 

Figure3. FTIR Spectrum of Efavirenz

 

Figure4. DSC graph of Efavirenz pure drug

DRUG EXCIPIENT COMPATIBILITY STUDY:

1) FTIR Study:

FTIR spectrum of efavirenz with SLS, Crosscarmellose sodium, Crosspovidone and L-HPC

The FTIR spectrums of all these samples were compared to that pure efavirenz spectrum. It indicates that there was no interaction with excipients.

 

 

Figure 5. FTIR spectrum of Efavirenz + SLS

 

 

Figure 6. FTIR spectrum of Efavirenz + Crosspovidone

 

 

Figure 7. FTIR spectrum of Efavirenz + Croscarmellose sodium

 

 

Figure 8. FTIR spectrum of Efavirenz + L-HPC

 

2) DSC Study:

The melting point of efavirenz (142⁰C) matches with the standard value (138⁰C-141⁰C). The DSC graph of efavirenz was also showed the melting point at 142⁰C indicate that the drug was pure.

 

 

Figure 9. DSC graph of efavirenz with Excipient

 

Solubility of Efavirenz at Various Concentration of Surfactant [18]

 

Table 4. Solubility of Efavirenz at Various Concentration of Surfactant

Sr. No.	Surfactant	concentration	% Solubility (mg/ml)
1.	Tween 80	0.5	0.53
2.	Tween 20	0.5	0.78
3.	Poloxamer -188	0.5	0.91
4.	SLS	0.5	1.3
		0.4	1.04
		0.3	0.78
		0.2	0.52

 

From the above result was concluded that significant increase in solubility of efavirenz was observed in 0.5% SLS, compared to other 0.5% tween 80, tween 20 and Poloxamer 188.

 

 

 

Pre-compression parameters of efavirenz granules: [7,8,9]

 

Table 5. Pre-compression Parameter of Efavirenz Tablet Batches

Batch	Parameters
		Bulk Density  (g/ml)*	Tapped Density (g/ml)*	Carr’s Index (%)*	Hausner’s Ratio	Angle of repose (degree)
F1		0.61± 0.005	0.71± 0.02	18.41± 0.004	1.23± 0.015	33.10± 0.762
F2		0.59± 0.005	0.72± 0.03	21.66± 0.045	1.25± 0.011	35.66± 0.762
F3		0.62± 0.0005	0.71± 0.006	19.23± 0.002	1.18± 0.010	30.76± 0.467
F4		0.62± 0.005	0.71± 0.0020	17.21± 0.002	1.17± 0.010	33.07± 0.098
F5		0.63± 0.000	0.72± 0.040	20.65± 0.003	1.26± 0.000	31.38± 0.710
F6		0.64± 0.005	0.74± 0.003	15.38± 0.005	1.24± 0.0050	30.81± 0.884
F7		0.62± 0.000	073.± 0.006	17.61± 0.060	1.29± 0.010	34.35± 0.282
F8		0.62± 0.005	0.70± 0.004	21.14± 0.013	1.21± 0.011	32.07± 0.05
F9		0.62± 0.005	0.71± 0.006	14.58± 0.002	1.17± 0.011	28.87± 0.713

*Where, all values were mean ± SD, n=3

 

The value of bulk density indicates good packing character. The compressibility index of the formulation F9 below 15, indicating excellent flow properties of granules. The hausner’s ratio of the formulation F9 was also within the specification. The angle of repose for F9 batches was in between 25⁰ to 30⁰ which indicate good flow properties of granules.

 

Evaluation of Post Compression Parameter: [7,8,9]

Table 6. Evaluation of Immediate Release Tablet

Evaluation Parameter   Batches	Appearance	Weight variation (mg)	Thickness (mm)	Hardness (kg/cm2)	Friability (%)
F1	White colored round shaped uncoated tablet	298± 0.13	4.7	3.5	0.73
F2		294± 0.53	4.7	3.5	0.51
F3		299± 0.63	4.86	3.5	0.78
F4		300± 0.11	4.82	4	0.61
F5		295± 0.16	4.9	4	0.81
F6		302± 0.17	4.7	4	0.58
F7		298± 0.18	4.8	4	0.74
F8		298± 0.10	4.78	4.5	0.86
F9		299± 0.11	4.7	4.5	0.55
Coated F9	Yellow	307± 0.8	4.9	4.5	0.57

 

 

From the results obtained it was concluded that all the batches passed weight variation test and found to be within the range. All immediate release tablet formulation had acceptable hardness. All the batches showed the friability less than 1% indicates the surfaces were strong enough to withstand mechanical shock during storage, transportation. Among these formulations F9 coated showed that good post compression parameter.

 

Disintegration time: [9,10,11]

Tablet: Disintegration Time

 

Batches showed disintegration time NMT 15 min. The disintegration time of batch coated F9 was found to be 1:34.

 

Drug content: [10,11]

Table: Drug content

 

All batches shows drug content within the range 95-99%. The drug content of batch F9 was found to be 98.68 % efavirenz.

 

% In-vitro Drug Release: [11]

 

The tablets were evaluated for in vitro drug release was carried out using USP-II (paddle) dissolution apparatus.

 

 

 

 

Table 7. % In-vitro drug release profile of immediate release tablet.

Batch   Time min	% Drug Release
	F1	F2	F3	F4	F5	F6	F7	F8	F9	F9 coated	Marketed Tablet
5	19.61	22.20	25.18	21.79	22.54	28.13	22.89	29.50	33.29	36.17	35.00
10	27.45	29.67	32.77	29.21	29.35	36.17	29.36	37.62	46.66	51.48	49.50
15	38.43	39.02	40.75	40.53	45.78	49.80	38.89	50.75	63.86	67.16	65.86
20	58.48	60.75	61.63	61.27	59.06	60.46	58.89	65.07	77.76	79.28	78.07
25	70.63	72.77	72.33	72.11	75.97	73.92	74.97	76.23	87.10	92.69	87.09
30	79.28	80.77	80.85	80.98	81.08	83.12	85.10	87.79	95.99	98.99	96.28

 

 

 

 

 

Figure 10. In-vitro drug release profile of immediate release tablet F1-F3

 

 

 

Figure 11. In-vitro drug release profile of immediate release tablet F4-F6

 

 

Figure 12. In-vitro drug release profile of immediate release tablet F7-F9

 

 

Figure13. In-Vitro drug release profile of immediate release tablet F9 coated-Marketed Formulation

 

CONCLUSION:  

Immediate release tablet of efavirenz were successfully enhanced the solubility by using micellar solubilization technique to improve solubility and dissolution rate of poorly water soluble Efavirenz. Drug-excipient compatibility study was performed by using FTIR and DSC. No drug-excipient incompatibility was observed in both FTIR and DSC study hence, concluded that drug was compatible with excipient. Various Post compression parameter like general appearance, thickness, hardness, weight variation, uniformity content, disintegration time and in-vitro drug release were determined. Among these coated F9 batch gave best result. Coated F9 batch showed better disintegration time 1:30 and in-vitro drug release 98.99%.

 

ACKNOWLEDGEMENT:

I would like to acknowledgment, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner, Maharashtra, India for supporting for the fulfillment of this work and also thanks to Mr. Ashutosh Tripathi, Centurion Laboratories, Vadodara, Gujarat.

 

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Received on 17.07.2018          Accepted on 08.09.2018

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Asian J. Pharm. Res. 2019; 9(1): 12-18.