Influence of Diluent and Release Retardant on the Release Rate of Drug from Matrix Tablets

 

M. Teja Krishna* and V. Sai Kishore

Bapatla College of Pharmacy, Bapatla-522101.

*Corresponding Author E-mail: chowdharymandava@gmail.com

ABSTRACT:

The present study was undertaken to find out the potential of Xanthan gum to act as a release retardant in tablet formulations and the effect of calcium sulphate dihydrate (water insoluble) or lactose (water soluble) as diluent on the release of Diltiazem hydrochloride was studied. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, diltiazem hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Physical and technological properties of granules and tablets like flow rate, carr index, hausner’s ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. The drug release increased with decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent ‘n’ are between 0.37 and 0.54. This implies that the release mechanism is Fickian. The t₅₀% values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t₅₀% values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor.

 

 

 

INTRODUCTION:

The traditional view that excipients are inert and do not exert any therapeutic or biological action or modify the biological action of the drug substance has changed and it is now recognized that excipients can potentially influence the rate and/or extent of absorption of a drug. As herbal excipients are non toxic and compatible, they have a major role to play in pharmaceutical formulation.There are several reports about the successful use of hydrophilic polymers derived from plant, like guar, carrageenan, karaya, locust bean gum in pharmaceutical preparations¹. Gum karaya has been used as carrier for the dissolution enhancement of a poorly water soluble drug nimodipine². Abelmoschus esculentus gum has been used as mini matrix for furosemide and diclofenac sodium tablets³. Cashewtree exudates have been used as a novel bioligand tool⁴. Seed gum of Cassia tora has been evaluated as a binder in tablets⁵. Plantago ovata and Trigonella foenum graecum mucilages have been evaluated for its binding properties⁶. Guar gum has been investigated for its application in colon specific dosage forms⁷.

 

Xanthan gum is a high molecular weight extracellular polysaccharide, produced on commercial scale by theviscous fermentation of gram negative bacterium and is characterized Xanthomonas campesteris. The molecule consists of backbone identical to that of cellulose, with side chains attached to alternate glucose residues. It is a hydrophilic polymer, which until recently had been limited for use in thickening, suspending and emulsifying water based systems⁸. It appears to be gaining appreciation for fabrication of matrices, as it not only retards drug release, but also provides time- independent release kinetics with added advantages of biocompatibility and inertness⁹. Diltiazem hydrochloride was used as a model drug.

 

MATERIALS AND METHODS:

Diltiazem hydrochloride was obtained from Natco Pharma, Hyderabad, India. Xanthan gum was obtained from Loba Chemicals, Mumbai, India. Calcium sulphate dihydrate, lactose and magnesium stearate were purchased from SD fine Chemicals Ltd, Mumbai. All other materials used were of analytical grade.

 

Selection of excipients:

Lactose (freely water soluble), Calcium sulphate dihydrate (water insoluble) are commonly used as diluents in tablet formulations. Having opposite solubility characteristics, it is reasonable to expect that lactose and calcium sulphate dihydrate would exhibit significant differences in drug release from hydrated gum matrices. It has been reported that lactose produced increased release rates of various drugs from polymeric matrices^10,11. Lactose diffuses outwards through the gel layer increasing the porosity and decreasing the tortuosity of the diffusion path of drug, on the other hand calcium sulphate dihydrate may form porous, insoluble and non soluble matrix which may be of use in controlling the release of water soluble drug as the report about the use of calcium phosphate dihydrate¹². In the present work, various concentration of gum solution was used as binder in preparing the tablets and higher proportions of gum was used as release retardant in the matrix tablet. Calcium sulphate dihydrate and lactose were used separately as diluents, to find out their effect on the release behavior of the drug.

 

Differential scanning calorimetry:

The DSC curves of Diltiazem hydrochloride and mixture of the gum and diltiazem hydrochloride were generated by a differential scanning calorimeter (DSC 220C, SEIKO, Japan) at heating rate of 10 /min from 60 to 280 .

 

Formulation of tablets:

All the materials were passed through a sieve no. 80 before use. The tablets were prepared by wet granulation method. The compositions of the tablets are given in Tables 1. All the materials except magnesium stearate were thoroughly mixed in a tumbling mixer for 5 min and the solution of the gum of specified concentration was prepared by dispersing the gum in water. The powder mixture was granulated using sufficient quantity of gum solution till a wet mass was formed. The wet mass was then passed through a number 12 mesh sieve and dried at a temperature not exceeding 60⁰C for 1h. The dried granules were rescreened through number 16 mesh sieve. The granules were lubricated with 1% w/w magnesium stearate and compressed into tablets on a rotary multi-station tabletting machine (Cadmach Machinery Co. Pvt. Ltd., Mumbai) using 9 mm round and flat punches.

 

Evaluation of the formulation:

The granules were evaluated for their flow properties, the flow rate through a funnel, the Carr’s index (compressibility index) and Hausner’s ratio. Using the glass funnel specified in the European Pharmacopoeia-III the flow rate (g/s) was calculated from the time needed for the entire sample (60 g) to empty from the funnel. Bulk density was calculated from the amount of granules poured into a 100 ml graduated cylinder up to a total volume of 50 ml while for the tap density determination the cylinder was tapped until no measurable change in the volume was observed. Based on bulk and tap density both the Carr’s Index (%) [(tapped–bulk)×100/tapped] and Hausner’s ratio (tapped/bulk) were calculated. Angle of repose was determined by fixed funnel method^13,14. Funnel with the end of the stem cut perpendicular to the axis of symmetry was secured with its tip at a given height (H) above a graph paper placed on a flat horizontal surface. The material was carefully poured through the funnel until the apex of the conical pile so formed just touches the tip of the funnel. The mean diameter (2R) of the base of the powder cone was determined and the tangent of the angle of repose is given by Tan α = H/R, where α is the angle of repose.

 

The tablets were evaluated for hardness using Monsanto hardness tester. The hardness reported is an average of three measurements. Twenty numbers of tablets were weighed and placed in a (Roche friabilator). After rotating for 4 min that is 100 revolutions. The percentage loss of weight was determined as an indicator of friability. The disintegration test was performed in water at 37 C using a disintegration testing machine. The disintegration times reported are average of three determinations.

 

In vitro dissolution study:

In vitro dissolution study was carried out on tablets, where gum has been used as release retardant. Release of diltiazem was determined using a six panel, USPXXIII dissolution apparatus-2 at 100 rpm. The dissolution was studied using 900 ml of water as dissolution medium. The medium was allowed to equilibrate to temperature of 37 + 0.5 C. The apparatus was operated for 12 hours. At definite time intervals 5 ml of the receptor fluid was withdrawn, filtered, suitable dilutions were done with distill water and analyzed spectrophotometrically at 237 nm using Elico UV-Visible spectrophotometer¹⁵. Triplicate studies were performed, the cumulative percentage of drug release was calculated and plotted against time.

 

Data analysis:

The rate and the mechanism of release of diltiazem hydrochloride from the prepared matrix tablets were analyzed by fitting the dissolution data into¹⁶, zero-order equation, Q=Q₀ –k₀t(1),where Q is the amount of drug released at time t, and k₀ is the release rate. First order equation, Ln Q = Ln Q₀ – k₁t (2), where k₁ is the release rate constant and Higuchi’s equation, Q= k₂t^1/2 (3) where Q is the amount of the drug released at time t and k₂ is the diffusion rate constant. The dissolution data was further analyzed to define the mechanism of release by applying the dissolution data following the empirical equation , M_t/M_∞ =Ktⁿ (4), where Mt/M_a is the fraction of drug released at time t. K is a constant and n characterizes the mechanism of drug release from the formulations during dissolution process.

 

Fig. 1: DSC thermogram of Diltiazem hydrochloride

 

 

TABLE 1: Composition of tablets containing the gum as release retardant

Ingredient	F1	F2	F3	F4	F5	F6
Diltiazem HCl	60 mg	60 mg	60 mg	60 mg	60 mg	60 mg
Calcium sulphate dihydrate q.s	250 mg	250 mg	250 mg	---	---	---
Lactose q.s	---	---	---	250 mg	250 mg	250 mg
Gumsolution (2ml)	10% w/v	20% w/v	30% w/v	10% w/v	20% w/v	30% w/v
Magnesium stearate	1%	1%	1%	1%	1%	1%

 

TABLE 2: Physical and technological properties of the granules and tablets

PROPERTIES	F1	F2	F3	F4	F5	F6
Flow rate(g/s)	7.4	6.7	6.4	7.6	6.8	6.5
Carr’s index (%)	11.0	7.4	12.3	7.2	8.9	11.4
Hausner’s ratio	1.04	1.11	1.08	1.06	1.02	1.07
Angle of repose	18	19	22	21	19	20
Hardness (kg)	7	7.5	8	7.5	7.5	8
Friability (%)	0.54	0.48	0.34	0.32	0.43	0.46

 

TABLE 3: Correlation coefficient (r) values of diltiazem hydrochloride tablets

FORMULATION	CORRELATION COEFFICIENT (R) VALUES
	ZERO-ORDER MODEL	FIRST ORDER MODEL	HIGUCHI MODEL	PEPPAS MODEL
F1	0.9688	0.9491	0.9866	0.9903
F2	0.9579	0.8870	0.9866	0.9970
F3	0.9330	0.8893	0.9901	0.9957
F4	0.9196	0.9122	0.9915	0.9955
F5	0.9314	0.8808	0.9928	0.9981
F6	0.9435	0.8728	0.9906	0.9985

 

TABLE 4: Dissolution parameters of dilteazem hydrochloride tablets

TABLETS	DISSOLUTION PARAMETERS
	DIFFUSION EXPONENT (n)	ZERO ORDER K (mg/h)	T50 (h)
F1	0.43	4.5	6.66
F2	0.36	3.8	7.89
F3	0.042	3.3	9.09
F4	0.046	4.9	6.12
F5	0.048	4.2	7.14
F6	0.040	3.6	8.33

 

 

 

 

 

 

 

 

 

 

Fig. 2: DSC thermogram of mixture of Diltiazem hydrochloride and gum

 

RESULT AND DISCUSSION:

DSC thermograms of diltiazem hydrochloride and mixture of the gum and diltiazem hydrochloride are depicted in figs.1 and 2, respectively. The thermogram of the pure drug exhibited a sharp endothermic peak at 213.17⁰C corresponding to its melting point, while the mixture of the gum and diltiazem hydrochloride exhibited a broad endothermic peak at 211.74 C. The DSC thermogram of the gum and drug mixture showed identical peaks corresponding to pure drug indicated the absence of well defined chemical interaction between the drug and the gum. Flow properties (Table 2) of the granules were determined as good flowability is prerequisite for the preparation of the tablets with an acceptable weight variation. For all the formulations the flow rate of the granules was between 6 and 9 g/s. According to literature data excellent flow properties are seen for powders with a Carr Index between 5 and 15% and a Hausner’s ratio below 1.25¹⁷. All the formulations tested had a Carr’s Index ranging between 7.4 and 11.8% while their Hausner’s ratio was below 1.25. The angle of repose was found to be between 16 and 22. The excellent flow properties were also proved by the narrow weight distribution of the tablets, as all the formulations had coefficient of variation values of less than 6% relative to their mean weight. The hardness of the tablet varies between 6 and 8 kg clearly indicating that they are strong tablets and they can withstand the mechanical shocks. This is combined with the friability (less than 1%) of all the formulations demonstrated the effectiveness of the gum for use as binder. The present work involves the evaluation of the xanthan gum for its ability to retard the release of diltiazem hydrochloride from tablets and the effect of excipients of opposite solubility on the release of the drug. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar and much variation was not observed.

Fig. 3: In vitro release profile of drug from tablets containing calcium sulphate dihydrate.

 

F5 containing 10% gum (─♦─), F6 containing 20% gum (─■─) and F7 Containing 30% gum (─▲─) (n=3).

 

Fig. 4: In vitro release profile of drug from tablets containing lactose.

 

F8 containing 10% gum (─♦─), F9 containing 20% gum (─■─) and F10 containing 30% gum (─▲─) (n=3).

 

The drug release increased with decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The typical release profile of the tablets containing calcium sulphate dihydrate and lactose are shown in figs. 3 and 4. To ascertain the mechanism of drug release, the dissolution data was analyzed by zero order, first order, and Higuchi and peppas equations. The correlation coefficient values (r) were reported in Table 3. These values revealed that the dissolution profiles follows zero order kinetics and the mechanism of drug release was governed by peppas model. The release exponent n and R² values for the formulations are given in the Table 4. The tabulated data shows that values of n are between 0.36 and 0.48. This implies that the release mechanism is Fickian. Much variation was not observed in the n value. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t_50% values for tablets containing calcium sulphate dehydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t_50% values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor. Lower gum content would result reduced swelling with corresponding decrease in diffusional path length. Moreover the excipient would either enhance dissolution or erosion mechanism, depending on the solubility of the excipient, which compensates for the slowing diffusion rate through the gradually increasing gel layer by creating greater porosity for the drug pathway.

 

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Received on 02.07.2010          Modified on 23.07.2010

Accepted on 31.07.2010         © RJPT All right reserved