Enhancement of Bioavailability of Diazepam IP by Using Different Surfactants

Mahendra Deshpande, Chandrashekhara S.*, Rahul Suthar, Mitul Patel and Pratik Savaliya.

Maratha Mandal’s College of Pharmacy, Belgaum (Karnataka)

ABSTRACT:

Surface active agents are most widely used in Pharma industry and are having multiple roles due to its versatile nature. In the present study, Drug surfactant delivery systems (DSDS) are prepared of the diazepam. Four different surfactants are used for preparing drug surfactant delivery systems at the two different concentrations of each, brij -30 (0.01%, 0.05%), Cetomacragol-1000 (0.01%, 0.05%), Ethoxylated cardanol-C25 (0.01%, 0.05%) and Ethoxylated cardanol-C30 (0.01%, 0.05%).Tablets are prepared with these DSDS. Evaluation tests of the tablets were done like hardness, weight variation, friability, content uniformity, disintegration test, dissolution test and stability studies.

Evaluation tests showed that the formulations having drug along with Ethoxylated cardanol-C25 and Ethoxylated cardanol-C30, were found to be the best formulations with more than 90% release data due to higher hydrophilicity and good surface tension lowering ability of the surfactants.

KEYWORDS: Drug surfactant delivery system, diazepam, surfactant

INTRODUCTION:

Surface active agents are one of the most versatile chemical having very wide application in the pharmaceutical industry. In our work, we have tried to exploit the use of surfactant in influencing the rate and extant of absorption of certain poorly soluble drugs.¹

A Surface activate agent is a compound which will get adsorbed at an air water or oil water or at surface of solids and modified the properties of the medium at the surface of interface²; it is change in interfacial energy (free) and surface charge resulting from adsorption which lead to the ability of these compounds to act as emulsifying agent, suspending agent and solubilizing agents. The surface active agents are characterized by presence of both polar and non Polar Regions of the same molecules.³ The polar and hydrophilic regions of molecules may carry positive or negative charges giving rise to cationic or anionic surfactants respectively or may be composed of polyoxyethylene chain as in case of non ionic surfactant. The non polar and hydrophobic portion of the molecule is most commonly a flexible chain hydrocarbon although there is large numbers of compounds with aromatic hydrophobic groups. This existence in the same molecules two moieties, one of which has affinity for solvent and other of which is antipathetic to it is responsible for the phenomenon of surface activity and of miscellisation and solubilization.⁴

The diazepam is benzodiazepine tranquillizer with anticoulvansant, sedative and muscle relaxant properties. It is used in the treatment of anxiety and tension states as sedative and premedicament, in the control of muscles spasm as in tetanus, and in management of alcohol withdrawal symptoms its poor aqueous solubility (1 in 400 parts ) and subsequent poor dissolution rate, was criteria for choosing diazepam as model drug in our study.^5,6

MATERIAL AND METHODS:

Diazepam I.P, Brij -30, Cetomacragol-1000, Ethoxylated cardanol-C25, Ethoxyleted cardanol C-30,lactose Starch paste, Starch I.P, Magnesium USP, Talc.

Preparation of the drug surfactant delivery system:

Different drug surfactant delivery systems prepared were:

a) Diazepam+ Brij- 30 (0.01%, 0.05%)

b) Diazepam+cetomacragol-1000(0.01%, 0.05%)

c) Diazepam+ethoxylated cardanol c-25(0.01%0.05%)

d) Diazepam+ethoxylated cardanol c-30(0.01%, 0.05%)

A stock solution of surfactant was prepared by dissolving 100mg of respective above mentioned surfactants, each in100ml of methanol so as to give 1mg/ml solution of surfactants. From this solution, a definite amount base on volume by weight was then added to the drug to give the respective delivery system.

An accurately weighed quantity of the drug diazepam was taken in the 250mL thoroughly dried conical flask with ground glass joint. The drug was dissolved by adding methanol subsequently stirring until complete dissolution of the drug. To this solution the required amount of surfactant in methanol (above prepared stock solution) was added. Two solutions were then mixed thoroughly, using magnetic bar the flask was then fitted to a vacuum pump to facilitate slow evaporation with continuous stirring until a viscous mass was formed. Once the mass turned viscous, the sitting was discontinuous, and the vacuum was disconnected the mass was then stirred with glass rod until a dried powder was obtained. the last traces of methanol were completely removed by keeping the mass in vacuum desiccators under vacuum for 3 to 4 days. This mass was then pulverized and sieved through a mesh sieve and collected over 120mesh sieve. This mixture is the drug surfactant delivery system used for further studies.

The sample of DSDS and pure drug were subjected to evaluate by melting point studies, TLC, IR spectroscopy, UV spectroscopy, DTA, X- crystallography.

Preparation of tablets:

Exactly weight amount of the drug or DSDS was taken in the small vessel and mixed wall with known quantity of lactose and disintegrate starch. The mass was thoroughly mixed and then using a starch paste as a binder, the mixture was kneaded in to dough. This dough was then force through a 12 mesh sieve. The granules obtain were dried at 45 ˚C for the period of the 4 to 5 hrs. The dried granules were then passed through a 20mesh sieve, and the excess fines were removed by sieving the granules on 80mesh sieve. The dry screened granules were then bended with remaining amount of disintegrant and lubricant. The granules were then mixed with 10% of the fines and were compressed on a single stroke power driven tabletting machine (cadmach) using 5/16” punch size (Table-1). ⁷

Table1: Formulation of the DSDS.

Ingredients	Pure drug	SD 1	SD 2	SD 3	SD 4	SD 5	SD 6	SD 7	SD 8
Diazepam IP	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg	5 mg
Lactose	93.925 mg	93.925 mg	93.925 mg	93.925 mg	93.925 mg	93.925 mg	93.925 mg	93.925 mg	93.925 mg
Starch paste	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg
Starch IP	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg	0.5 mg
Magnesium stearate USP	0.05 mg	0.05 mg	0.05 mg	0.05 mg	0.05 mg	0.05 mg	0.05 mg	0.05 mg	0.05 mg
Talc	0.025 mg	0.025 mg	0.025 mg	0.025 mg	0.025 mg	0.025 mg	0.025 mg	0.025 mg	0.025 mg
Cetamacragol	------	0.01%	0.05%	------	------	------	------	------	------
Brij-30	------	------	------	0.01%	0.05%	------	------	------	------
Ethoxylated cardanol C30	------	------	------	------	------	0.01%	0.05%	------	------
Ethoxylated cardanol C25	------	------	------	------	------	------	------	0.01%	0.05%

Table2: Results of the hardness, disintegration test, weight variation test, friability test, % drug contents

Formulation Code	Conc of surfactant %v/w	Hardness in kg/cm^2	Disintegration time in sec	Weight variation data				% friable loss	% content of drug
				Avg wt mg	Max wt mg	Min wt mg	±% diff
Pure drug	------	3.16	273	106	108	103	2	0.0301	102.6
SD 1	0.01	3.5	154	103	110	95	6	0.0210	96.1
SD 2	0.05	3.3	79	98	102	94	4	0.0361	97.2
SD 3	0.01	3.5	151	109	112	105	4	0.0410	96.2
SD 4	0.05	3.5	164	108	112	105	4	0.0580	97.0
SD 5	0.01	3.33	230	123	128	114	7	0.067	98.3
SD 6	0.05	3.16	203	121	124	110	8	0.042	97.9
SD 7	0.01	3.16	60	108	112	103	5	0.081	96.4
SD 8	0.05	3.25	38	113	105	115	6	0.098	95.95

Evaluation of DSDS tablets:

1. Hardness: From each batch of the 5 tablets were selected at random and subjected to hardness test using the monsanto hardness tester. Result recorded in table 2.⁸

2. Weight variation test: As per the pharmacopoeial specifications, 20tablets were selected at random from each batch. The weight of these 20 tablets taken and average weight was determined. These 20 tablets were then weighed individually and the deviation from the average weight was observed. Since theoretical average weight of diazepam tablets was 100mg, the maximum percentage differences allowed was 105 of average weight the result are recorded in table 2.⁹

3. Friability: About 10 tables were selected from the each batch and were weight. These were revolved in the “Roche friabilator “for 4min. and then weighed again. The percentage friable loss was thus determined. The possible limit is about 1% loss in weight. Results are recorded in table2.¹⁰

4. Content uniformity test: In this test, 5 tablets were selected from different batch and then assayed individually determined the drug content by pharmacopoeial procedure. Weighed and powdered 20 tablet and a quantity equivalent to 10mg of diazepam was weighed. To this 5 ml of distilled water was added, mixed and allowed to stand for 15min. then, about 90ml of 0.5%w/v H₂SO₄ in methanol was added, shaken well and volume made up to 100 ml with 0.5%w/v of H₂SO₄ in methanol. This solution was then filtered and 10ml of filtrate was diluted to 100mL with same acidic methanol solution and absorbance of this solution measured al 284nm using acidic methanol solution as blank. The concentration is then obtained from standard curve and drug content determine. The results were recorded in table 2.¹¹

5. Disintegration test: This test is very important because the dissolution rate and availability of the drug to some extant depend on time for disintegration. The disintegration test of the tablet of pure diazepam and diazepam surfactant system were done as per B.P method. 5 tablets from each batch were selected randomly and the disintegration test carried out in distilled water maintains at 37 ± 0.5 ˚C on the Campbell disintegration apparatus, B.P 1973. The results were recorded in table 2¹¹

6. Dissolution studies: The drug release characteristics of pure drug and DSDS in the dissolution medium (0.01N HCL) were studied In-vitro using dissolution apparatus specified by USP XIX3.900mL of dissolution medium taken in dissolution vessel. The dissolution medium maintain at tem of 37 ± 0.5 ̊ C. weighed quantity of the pure drug equivalent of 5mg of diazepam and DSDS tablet was transferred in to muslin bag . The opening of bag tied and then placed in wire basket or mesh. The basket, immersed to a depth of 2± 0.2cm from the bottom of the dissolution vessel, was rotated with the help of the vertical rode attached to motor at the speed of the 100rpm. At regular intervals, 5mL aliquots from the dissolution medium in the vessel were withdrawn in 50mL volumetric flask and volume made up to the dissolution medium. Fresh dissolution medium of the equal volume as that of the aliquot withdrawn was quickly added to vessel so as to maintain its volume at 900mL. The absorbances of the solution in the flask were then read out at 284nm on UV spectrophotometer using dissolution medium as blank. The results are recorded in table 3.¹²

7. Stability studies: The pure drug as well as tablets was subjected to stability studies according to the following conditions. Pure drug and tablets were kept at three different temperature, i.e. room temperature, 40 ˚C and 60 ̊C. Pure drug and tablets expose to constant humidity in special desiccators maintaining 45% RH, 75%RH and kept at room temperature.¹³

RESULTS AND DISCUSSION:

The tablets of diazepam and those containing the various drug surfactant delivery systems were subjected to the various quality control tests.

From the results of the tablets characteristic recorded in the table (2) it can be absorbed that the hardness of the tablets were found to be in the range of 3.16 to 3.5kg/cm². The hardness of the tablets from the different batches was kept same, so that the comparison of the drug release from the each batch could be made.

Table 3: Results of the dissolution test of the DSDS

Time in minute	%release from diazepam tablets	% drug released from DSDS containing
		SD1	SD2	SD3	SD4	SD5	SD6	SD7	SD8
10	11.02	23.3	49.2	28.4	60.60	67.2	74.9	39.5	59.07
15	30.68	42.7	72.6	56.9	88.29	70.4	77.5	45.5	61.5
20	58.31	70.4	84.6	72.5	95.49	73.6	80.8	58.7	66.7
30	69.18	80.8	90.0	84.6	98.46	82.8	86.8	83.3	84.8
40	75.05	89.4	95.9	89.3	100	87.4	90.0	94.7	98.6
50	79.27	94.2	98.8	95.9	100	90.62	91.6	98.0	99.21
60	81.83	93.3	99.7	98.8	100	91.4	92.9	98.6	99.64
70	82.13	94.3	100.0	100	100	94.1	96.2	99.0	100
80	92.09	95.3	100.1	100	100.1	97.4	100	99.23	100
90	86.24	94.3	100.0	100	100.4	99.3	100	99.45	100

This is essential because drug release patent to a large extent are influenced by the hardness of the tablets. The results of the disintegration test as in a table(2) reveals that the tablet of the all batches disintegrated with in a 5min. the tables of the DSDS had less disintegration time as compare to that of pure diazepam tablets. This may be attributed to the fact that the surfactant present in the formulation (though in low concentration) being hydrophilic in nature, aids in the process of disintegration. The weight various of the tablets are within the permissible limits, i.e. ±10% of the average weight. The %friable loss are also within limits (1%) thus approving the quality of the tablets punched.

The results of the dissolution studies carried out with diazepam tablets and tablets containing DSDS are presented in table (3) and figure (1,2,3,4). It is obvious from the tables and the graphs the release of the drug was significantly more in case of tablets of DSDS as compare to the tablets containing pure diazepam. It is also reveals that with increase in concentration of surfactant, there is an increase in the percentage of the drug release.

The results of the stability studies of the DSDS at a room temperature and humidity shows results: there was absolute no changes in the color and the percentage change in the weight was very little.

CONCLUSION:

As per the above result, tablets containing diazepam+ethoxylated cardenol C-25 and containing diazepam+ethoxylated cardenol C-30 shows better release of the diazepam then those containing diazepam +cetamacragol and diazepam+ brij-30. This may be, as discussed before due to the fact that the ethoxylated cardenols are comparatively more hydrophilic and have better surface tension lowering ability than cetamacragol and brij-30, were by weighting of the drugs occurs faster.

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Received on 31.08.2011

Accepted on 11.09.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 281-284