Formulation and Evaluation of Floating Matrix Tablets of Acyclovir using 3² Factorial Design

 

Swati Rawat¹*, Shradha Sangali¹, Akhilesh Gupta²

¹SND College of Pharmacy, Babhulgaon, Yeola, Nashik

²Surgycare Lifescience, Sendhwa M. P.

 

ABSTRACT:

Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying rate. While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. These floating tablets mainly prepared for reduction of lag time and release the drug up to 12 hours and may also increase the bioavailability of the drugs by utilizing the drug to full extent avoiding unnecessary frequency of dosing. The study included formulation of floating tablets using polymers like Hydroxy propyl methyl cellulose K15M, PVP K30, Sodium bicarbonate, Xanthan-Gum, Guar-gum and microcrystalline cellulose as matrix forming agents.  The tablets were directly compressed using Lab Press multi station rotary punching machine. FTIR and DSC-TGA studies conformed that there was no incompatibility between the polymers and the drug. Tablet preformulation parameters were within the Pharmacopoeias limit. Tablet showed zero lag time, continuance of buoyancy for >12 h. In vivo X-ray studies depicted that tablets continued to float in the GIT for 12 h. The in-vitro drug release pattern of Acyclovir floating tablets was fitted to different kinetic models which showed highest regression for zero order kinetics with Koresmeyer-peppasand most of the formulations followed Non-fickian diffusion.

 

 

 

INTRODUCTION:

Acyclovir is the prototype antiviral agent used to treat various types of herpes infections. Since, Acyclovir [1, 2] was the first antiviral to be considered the gold standard for the treatment of herpes infections, all other anti-herpes virus medications are compared to it. Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity [3, 4].

 

It was co discovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog a cyclo-adenosine which showed promising antiviral activity. Later, Schaffer joined Burroghs-Wellcome and continued the development of Acyclovir with Pharmacologist Gertrude B. Elion.   The short biological half life of drug (2.5 to 3.3 hrs) also favors development of sustained release formulations. [5] Drugs which are easily absorbed from the gastrointestinal  tract and those with short half-lives are quickly eliminated from the systemic circulation due to which frequent dosing is required. To overcome this problem, gastro retentive drug delivery systems [6] which provide effective plasma drug concentration for longer periods thereby reducing the dosing frequency are being formulated [7,8,9]. It also has an advantage of minimizing the fluctuations in plasma drug concentration by delivering the drug in a controlled and reproducible manner. Floating drug delivery system or hydrodynamically [10,11] balanced systems has been reported for  prolonging the  residence time of drug delivery system in a particular region of the gastrointestinal tract, were first described by Davis (1968).[12] The floating of FDDS occurs due to their lower bulk density than the gastric contents or due to gaseous phase formed inside in the environment. It is applicable for those drugs which (i) act locally; (ii) have a narrow absorption window in the small intestinal region; and (iii) unstable in the intestinal environment.[ 13,14]. The present study aims in designing floating tablets of Acyclovir using Hydroxy propyl methyl cellulose K15M, PVP K30, Sodium bicarbonate, Xanthan-Gum, Guar-gum,[15] Microcrystalline cellulose and evaluating the prepared tablets for physicochemical properties, buoyancy lag time, total floating time, swelling index and in-vitro drug release.

 

Effervescent systems include use of gas generating agents, carbonates (sodium bicarbonate) and other organic acid (citric acid and tartaric acid) to produce carbon dioxide (CO2) gas, thus reducing the density of the system and making it to float on the gastric fluid [16].

 

MATERIALS AND METHODS:

Materials:

Acyclovir was obtained as a gift sample from Macleods Pharmaceuticals, Mumbai, India. HPMC K100M, Sodium PVP K30, sodium Bicarbonate and microcrystalline cellulose, Xanthan-Gum and Guar-gum were received from S D fine Chemicals, Mumbai. talc, magnesium stearate and lactose were of laboratory grade.

 

Methods:

Preparation of effervescent floating matrix tablets:

Effervescent floating matrix tablets containing Acyclovir are prepared by direct compression technique using variable concentrations of HPMC K100M, Sodium Bicarbonate, PVP K30, Xanthan-Gum, Guar-gum and Cellulose microcrystalline cellulose. The powder mixture containing drug, polymer, magnesium stearate and talc. All the ingredients are accurately weighed and passed through sieve no.40 and blended thoroughly in a mortar. Quantities of 600 mg of the mixture are weighed and were directly compressed using Lab Press multi station rotary punching machine

 

 

Table 1: Formulation of Effervescent Floating Matrix Tablets

Sr No	Ingredient	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	Acyclovir	200
2	HPMC K15M	100	150	200	100	150	200	100	150	200
3	PVP K30	5	5	5	10	10	10	15	15	15
4	NaHCO3	70	70	70	0	70	70	70	70	70
5	MCC	206	156	106	201	151	101	196	146	96
6	Magnesium stearate	14	14	14	14	14	14	14	14	14
7	Talc	5	5	5	5	5	5	5	5	5
8	Total wt	600	600	600	600	600	600	600	600	600

 

Factorial design:

3² factorial design was applied by using Design expert 8 trial version 8.0.7.1 by general factorial design and levels were selected

 

 

Table 2: Factor levels

Coded level	-1	0	+1
HPMC K15M (X1)	100	150	200
PVP K30 (X2)	5	10	15

 

 

Table no 3: Factorial design

 

EVALUATION OF FLOATING MATRIX TABLETS:

Pre compression parameters:

Color and appearance, Assay of Acyclovir (as per BP), Melting point determination, Solubility, U V spectra, IR spectra, Differential scanning calorimetry, Angle of repose, bulk density, tapped density, Carr’s(compressibility) index, Hausner’s ratio anddrug content are determined to find out the flow property of granules during formulation.[ 17,18 ]. The details of powder characteristics  are given in Table 3.

 

 

Table 3. Powder characteristics of drug

Sr no	Angle of repose (o)	Bulk density (gm/cm2)	Tappeddensity (gm/cm2)	Hausner ratio
Acyclovir	40.27± 0.12	0.497± 0.14	0.539±0.51	7.79

 

 

Evaluation of blend:

Angle of Repose, Carr’s Compressibility Index, Bulk Density and Tapped Density, Hausners ratio, Differential scanning calorimetry (DSC) studies of drug with polymer, FTIR studies of drug with polymer for incompatibilities.

 

Post compression parameters [19]

General appearance:

The formulated tablets are evaluated for general appearance. Viz., colour, odour, shape

 

Tablet Dimension:

The thickness and diameter of the tablets are carried out using digital vernier caliper. Three tablets are used from each batch and results were expressed in millimeter (mm).

 

Weight variation test:

Twenty tablets are selected at random, individually weighed in a single pan electronic balance and the average weight is calculated. The uniformity of weight is determined according to I.P. specification. As per IP (2007) not more than two of individual weights should deviate from average weight by more than 5% and none deviate more than twice that percentage.

 

Hardness test:

Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packing and shipping. Monsanto hardness tester is used to measure the hardness of tablet. Three tablets from each batch are used for hardness test and results are expressed in Kg/cm2.

 

Friability test:

It is done in Roche friabiliator apparatus. Pre-weighed samples of 20 tablets are placed in the friabiliator, which is then operated for 100 revolutions. The tablets are then dusted and reweighed. The percentage friability is calculated by the following expression,

 

                                    Weight loss

Frability=--------------------------------------------------x100

                weight of the tablet before operation

 

Drug content uniformity:

Ten tablets are weighed and taken in a mortar and crushed to make powder form. A quantity of powder weighing equivalent to 10mg of drug is taken in a 100ml volumetric flask and Acid buffer pH 1.2 is added. The solution is filtered using membrane filter (0.45μm) and 10 ml of filtrate is taken into 100 ml volumetric flask and made up to final volume with Acid buffer pH 1.2. Then its absorbance is measured at 256.2 nm using UV-Visible spectrometer. The amount of drug present in one tablet is calculated using standard graph.

 

In vitro buoyancy study [20]:

The in-vitro buoyancy studies are performed for two parameters such as floating lag time (FLT) and total floating time (TFT). These parameters are determined for all the formulations of Valsartan. The randomly selected tablets from each formulation are kept in a 100 ml beaker containing acid buffer pH 1.2. The time taken for each tablets to rise on the surface and float is taken as floating lag time (FLT).

 

The total floating time of all tablets are performed by using dissolution test apparatus USP type II paddle method with a stirring speed of 50 rpm at 37°C ± 0.5°C in 900 ml of acid buffer pH 1.2 for 12 hours. The duration of time the floating tablets constantly remain on surface of medium is taken as total floating time (TFT).

 

Swelling Index study:

For each formulation, one tablet is weighed and placed in a USP type II paddle dissolution test  apparatus containing 900 ml of acid buffer pH 1.2 with the paddle speed of 50rpm. After pre determined time the tablet is removed from apparatus, blotted to remove excess of water and weighed on digital balance. The increase in the wet mass represents the medium uptake (swelling index).The percentage weight gain by the tablet is taken as swelling index and expressed in terms of percentage, and it is calculated from the following equation

 

                                Wt- W_o

SI (%)= ---------------------------- X 100

                                W_o

 

Where, SI is swelling index, Wt is weight of tablet at time t, W0 is weight of tablet before immersion.

 

In vitro drug release studies:

Dissolution characteristics of the formulated floating tablets of Acyclovir are carried out using USP type II (paddle) dissolution test apparatus for 12hrs [21,22]  

 

Method:

Acid buffer pH 1.2 (900 ml) is filled in dissolution apparatus and temperature of the medium is set at 37°C ± 0.5°C. One tablet of different batch is placed in each dissolution vessel and the rotational speed of paddle was set at 50rpm. 5 ml of sample is withdrawn at predetermined time interval of every one hour for up to 12 hours and same volume of fresh medium is replaced immediately. The withdrawn sample is diluted to 25ml in volumetric flask and filtered through 0.45μ membrane filter. The resultant samples are analyzed for drug content at 256.2 nm using UV-Visible spectrophotometer.

Buoyancy (Floating) duration[23]:

Water uptake study, Stability studies of the optimized formulation.

 

Invitro release kinetics studies:

The dissolution data are fitted to four popular release models such as a zero order, first order, higuchi and Koresmeyer-Peppa’s equations. The order of drug release from matrix systems is studied by using Higuchi equation and Erosion equation.[19] For finding out the mechanism of drug release from floating matrix tablets, the dissolution data obtained from the above experiments are treated with the different release kinetic models.

Zero order release equation: Q = K0t

 

Higuchi’s square root of time equation: Q = KHt1/2

Peppa’sequation: F = Mt/M = K t

 

RESULTS AND DISCUSSION:

Preparation of Calibration Curve:

UV spectrum of 20 μg/ml solution of the drug powder in 0.1 N aqueous hydrochloric acid solution and Phosphate buffer pH 6.8 was recorded in the range of wavelengths from 200 nm to 400 nm using UV-visible Double beam Spectrophotometer (UV-Chemito-2600). The λmax’s were found to be at 256.2nm and 253.6nm in 0.1 N aqueous hydrochloric acid solution and Phosphate buffer pH 6.8 respectively. The calibration curve prepared between the concentrations ranges of 2-20μg/mL. The standard calibration curve of drug in solvent 0.1 N HCl was as depicted in Figure:1. Standard calibration curve followed Beer-Lambert’s law in the range y = 0.0491x+0.0069 with high correlation coefficient of (R2) 0.9994 The standard calibration curve of drug in pH 6.8 Phosphate buffer was taken. Standard calibration curve followed Beer-Lambert’s law in the range y = 0.055x+ 0.0037 with high correlation coefficient of (R2) 0.9987 and was depicted in Graph 4

 

 

Figure: No.1 Standard calibration curve of Acyclovir in solvent 0.1N HCl at λmax 256.2 nm

 

 

Figure: No.2 Standard Calibration curve of Acyclovir in Phosphate buffer of Ph 6.8 at λmax 253.6

 

DRUG-POLYMER COMPATIBILITY STUDIES:

1. Fourier Transform Infrared Spectroscopic studies (FTIR):

FTIR spectra’s of pure Acyclovir blend of polymers with drug were determined. Acyclovir showed that the principle IR peaks 3299 cm^-1, 129.33 cm-1, 118.43 cm-1 and172486.12 cm-1. All the major peaks present in the spectrum of pure drug were clearly observed in the spectrum of physical mixtures with negligible changes. The obtained results clearly showed that there was no interaction between the drug and polymers.

 

 

Figure: No3 :IR of Acyclovir drug

 

 

2. Differential Scanning Calorimetric (DSC) with TGA Studies:

The DSC thermogram of the drug depicts a sharp endothermic peak at 257.24 °C corresponding to the melting transition temperature and decomposition of acyclovir. Such sharp endothermic peak signifies that Acyclovir used was in pure state.

 

PRE-COMPRESSION EVALUATIONS:

The present study was carried out to develop floating drug delivery system of acyclovir in order to enhance absorption and bioavailability by increasing the gastric retention time of the drug. In concern to this approach, the primary necessity is to float the tablet in gastric environment. In this case the formulations were prepared. The detailed composition of each formulation is given in the All the observations of pre-compression parameters were within the prescribed limits of IP.(2007) and the observations for the powder blend were given in Table 4.

 

Table No. 4 Pre-compression Evaluation parameter of powder blend     n=3,

Formulation Code	Angle of Repose (o)	LBD (gm/cm2)	TBD(gm/cm2)	Compressibility index (%)	Hausner’s ratio
F1	35.53±0.45	0.375±0.006	0.479±0.025	21.42±4.47	1.27±0.07
F2	36.76±0.55	0.387±.005	0.506±0.005	23.54±1.76	1.30±0.03
F3	37.13±0.32	0.394±.009	0.504±0.007	21.75±0.62	1.27±0.01
F4	35.13±0.40	0.349±0.005	0.456±0.004	23.44±0.81	1.30±0.01
F5	36.00±0.26	0.366±0.004	0.482±0.004	23.98±1.69	1.31±0.02
F6	36.53±0.45	0.375±0.004	0.482±0.026	21.97±4.32	1.28±0.06
F7	33.30±0.81	0.338±0.002	0.440±0.001	23.23±0.44	1.30±0.007
F8	34.50±0.70	0.337±0.003	0.458±0.003	26.41±0.38	1.35±0.007
F9	35.13±0.25	0.353±0.005	0.470±0.002	24.92±1.42	1.33±0.02

 

POST-COMPRESSION EVALUATIONS:

FORMULATION DESIGN:

3² factorial design was applied by using Design expert 8 trial version 8.0.7.1 by general factorial design. The levels selected and actual values taken were depicted in Table no5 and 6.

 

Table No 5 :  Factorial design

 

Table No.6: Actual values of ingredients taken for floating tablet.

 

Table 7.Post Compressional Evaluation of Acyclovir Floating Matrix Tablets

Formulation Code	Evaluation parameter
	Thickness ± S.D. (mm) (n = 5)	Hardness ± S.D.(kg/cm2) (n = 5)	Friability (%)	Average weight variation (n=10)	Drug content (%)
F1	4.21±0.01	5.22±0.03	0.47±0.005	600.3±0.35	98.73
F2	4.16±0.06	5.23±0.02	0.24±0.01	599.01±0.27	97.31
F3	4.24±0.04	5.35±0.03	0.27±0.03	599.01±0.27	98.50
F4	5.16±0.04	5.27±0.03	0.36±0.015	599.38±1.02	98.60
F5	4.26±0.06	5.32±0.02	0.36±0.03	599.25±0.39	98.23
F6	4.18±0.07	5.37±0.02	0.46±0.03	598.26±0.37	98.80
F7	4.26±0.08	5.21±0.02	0.62±0.02	597.3±0.6	98.89
F8	4.22±0.05	5.23±0.01	0.52±0.03	600.3±0.27	98.80
F9	4.28±0.07	5.28±0.01	0.48±0.03	599.2±0.39	98.16

 

All formulations had average tablet weight in the range of 598.26±0.37 mg to 600.3±0.35 mg. Thickness ranged between 4.16±0.06 mm and 5.16±0.04 mm. The mean hardness for all formulation was between 5.21±0.02 Kg/cm2 and 5.35±0.03 kg/cm2.The friability of all gastro retentive floating tablets of acyclovir was found between 0.24% and 0.62%. Drug content ranged between 97.31percent to 98.80 %.The thickness depends upon the size of the punch (13 mm) and the weight of the tablet (600mg). Friability is needed for tablets to withstand force of compression applied during the manufacture of tablets and all the formulated floating tablets of acyclovir were shown the percentage friability within the official limits (i.e. not more than 1 %). Formulations showed favorable drug content which were within the limits of specifications.

 

In vitro BUOYANCY and SWELLING TEST:

a) In-vitro buoyancy studies [24].

The in-vitro buoyancy studies are performed for two parameters such as floating lag time (FLT) and total floating time (TFT). These parameters are determined for all the formulations of Acyclovir. The randomly selected tablets from each formulation are kept in a 100 ml beaker containing acid buffer pH 1.2. The time taken for each tablets to rise on the surface and float is taken as floating lag time (FLT).

 

The total floating time of all tablets are performed by using dissolution test apparatus USP type II paddle method with a stirring speed of 50 rpm at 37°C ± 0.5°C in 900 ml of acid buffer pH 1.2 for 12 hours. The duration of time the floating tablets constantly remain on surface of medium is taken as total floating time (TFT).

b) Buoyancy (Floating) duration [24]:

Duration of buoyancy is the time for which the tablet constantly floats on the surface of the medium. The duration of buoyancy was measured using a 500 ml beaker containing 0.1N HCl. Results are shown in  figure:4  and In vitro floating ability and swelling index of floating matrix tablets are given in Table no 8.

 

Table 8. In vitro Floating Ability of Floating Matrix Tablets

 

 

FLT(immediately)  

 

 

FLT After 12h

Fig 4. In-vitro buoyancy and swelling behavior of best formulation

 

In-vitro Dissolution Study [25]:

In-vitro drug release study of the samples was carried out using USP – type II dissolution apparatus (Peddle type). The dissolution medium, 900 ml of simulated gastric fluid (without enzyme), was placed into the dissolution flask maintaining the temperature of 37±0.5oC and rpm of 50. One tablet from each preliminary batch was placed in each basket of the dissolution apparatus. The apparatus was allowed to run for 12 hours. Samples measuring 5 ml were withdrawn after every 1 hour up to 12 hrs manually and samples were filtered. The fresh dissolution medium was replaced every time with the same quantity of the sample withdrawn. Collected samples were analyzed at 256.2 nm using 0.1N HCl as blank. The cumulative percentage drug release was calculated using PCP Disso v3 software. Results are mentioned in (Table no 4).

 

In vitro DRUG RELEASE:

In-vitro dissolution characteristics of the formulated floating tablets of Acyclovir are carried out using USP type II (paddle) dissolution test apparatus for 12 hrs. Acid buffer pH 1.2 (900ml) is filled in dissolution apparatus and temperature of the medium is set at 37°C ± 0.5°C. One tablet of different batch is placed in each dissolution vessel and the rotational speed of paddle was set at 50rpm. 6ml of sample is withdrawn at predetermined time interval of every one hour for up to 12 hours and same volume of fresh medium is replaced immediately. Release rate studies showed that the minimum drug release was observed in F3,F6 andF9 formulations up to 87.67%,88.68,89.20 with matrix integrity because of increase in polymer concentration as PVP K30 concentration increases drug release rate increases. Drug release rate improves in F2,F5 and F8 i.e 92.42%, 93.60%, 94.15% and release rate is better in F1,F4 andF6 i.e, 96.35%, 97.35%, 98.71%. In F3,F6 andF9; F2,F5 and F8; F1,F4 andF6 polymer concentration is similar in each three formulation but there is increase in PVP K30 concentration shows improved drug release rate hence conclude that as polymer concentration increases drug release rate decreases and solubilizing agent i.e PVP K30 increases drug release rate increases.

Table NO.33: in vitro drug release of formulation:

Sr No	F1	F2	F3	F4	F5	F6	F7	F8	F19
1	9.84 ±0.02	9.65 ±0.06	8.10 ±0.68	13.58 ±0.60	9.93 ±0.79	8.40 ±0.55	12.76 ±0.83	10.50 ±0.71	9.01 ±0.62
2	16.31 ±0.19	14.85 ±0.12	14.13 ±0.72	16.24 ±0.79	16.31 ±0.79	14.85 ±0.86	18.14 ±0.75	17.50 ±0.73	15.13 ±0.62
3	22.43 ±0.08	23.43 ±0.04	21.15 ±0.02	24.07 ±0.58	23.61 ±0.006	22.15 ±0.82	25.17 ±0.66	24.07 ±0.68	22.98 ±0.83
4	28.36 ±0.04	27.90 ±1.08	26.63 ±0.85	29.82 ±0.55	28.82 ±0.66	27.26 ±0.89	31.01 ±0.74	29.27 ±0.63	28.27 ±0.77
5	34.20 ±0.06	32.01 ±0.05	31.01 ±0.81	35.57 ±0.76	33.74 ±1.09	31.83 ±0.69	44.24 ±0.56	35.57 ±0.73	33.65 ±0.86
6	44.24 ±0.11	43.51 ±0.14	34.20 ±0.66	45.33 ±0.77	42.96 ±0.81	39.40 ±0.96	51.08 ±0.56	43.51 ±0.68	41.59 ±0.87
7	50.26 ±0.07	48.53 ±0.14	44.33 ±0.59	52.36 ±0.70	49.53 ±1.02	44.78 ±0.72	53.82 ±0.93	52.92 ±0.56	49.35 ±0.74
8	57.56 ±0.13	56.19 ±0.12	52.63 ±0.20	59.66 ±0.72	58.93 ±0.90	53.45 ±0.87	60.66 ±0.55	57.92 ±0.74	9.84 ±0.63
9	68.78 ±0.06	67.60 ±0.58	62.30 ±0.66	72.16 ±0.65	68.78 ±0.89	63.03 ±0.79	72.89 ±0.59	69.88 ±0.60	66.89 ±0.50
10	75.81 ±0.16	74.99 ±0.09	69.49 ±0.70	78.55 ±0.72	77.18 ±0.85	69.88 ±0.50	79.92 ±0.79	78.18 ±0.60	72.89 ±0.44
11	88.31 ±0.66	87.03 ±0.03	80.01 ±0.53	80.04 ±0.71	87.95 ±0.02	81.74 ±1.15	89.50 ±0.45	88.77 ±0.66	86.30 ±0.32
12	96.35 ±0.50	92.42 ±0.11	87.67 ±0.67	97.35 ±0.62	93.60 ±0.54	88.68 ±0.78	98.68 ±1.11	94.15 ±0.61	89.20 ±0.33

 

 

Fig 5. In-vitro drug release profile of F1 – F9 Formulation

 

Slope value (n) in Korsemeyer-Peppas equation for formulation was found as 0.745 which is greater than 0.5 (n= >0.5) suggested that the release of Acyclovir floating tablets followed the Non-Fickian transport mechanism.

 

RELEASE KINETICS:

Invitro release kinetics studies:

The dissolution data are fitted to four popular release models such as a zero order, first order, higuchi and Koresmeyer-Peppa’s equations. The order of drug release from matrix systems is studied by using Higuchi equation and Erosion equation. For finding out the mechanism of drug release from floating matrix tablets, the dissolution data obtained from the above experiments are treated with the different release kinetic models, Zero order release equation: Q = K0t,Higuchi’s square root of time equation: Q = KHt1/2., Peppa’sequation: F = Mt/M = K tn.The release data (1-12 hrs) were analyzed as per zero order, first order, Higuchi and Korsemeyer-Peppas equation. The r2value of best formulation for zero order and first order equation was found 0.986 and 0.942 respectively. It shows that the formulation follow Zero order release. To confirm the exact mechanism of drug release from the tablets, the data were subjected to  Korsemeyer-Peppas equation and Higuchi’s diffusion equation. The r2- values for Korsemeyer-Peppas equation and Higuchi’s diffusion equation for the best formulation was found as 0.745 and 0.958 respectively. It shows that the best fit model for the formulation is Korsemeyers-peppas model.

 

OPTIMIZATION:

Multiple Linear Regression Analysis:

Optimization was done using Design Expert 8.0.7.1 with 32 Factorial design taking 3 response i.e. % Drug Release at 1 hr., % Drug release at 10 hrs. and floating lag time. 3² factorial design was applied in which two factors, concentrations of HPMC K15M and PVP K30 were varied between -1 to +1 level. 3 different responses were recorded at these levels of polymers as shown in (Table 2 and 3).

 

Factorial models and Response surface analysis:

Based on the 3² factorial designs, the factor combinations resulted in different cumulative drug release and floating lag time. Various models, such as Linear, 2FI, Quadratic and Cubic, were fitted to the data for two responses simultaneously using Design Expert software and adequacy and good fit of the model was tested using analysis of variance (ANOVA). Mathematical relationships generated for the studied response variables are expressed as equations  (5), and (6). Positive or negative signs before a coefficient in quadratic models indicate a synergistic effect or an antagonistic effect for the factor.

 

Response surface plots for measured responses:

Three-dimensional response surface plots are presented in (Figure14) shows that cumulative drug release increases with decrease in concentrations of polymer and increase in PVP K30 concentration. The Contour plots showing the effect of polymer concentration on the Y1 (cumulative drug release ) is shown in( Figure 14). The different r2 values for Y1 are shown (Table 37).

 

Polynomial equation for response surface quadratic model:

Quadratic Equation for Y1 in Terms of Actual Factors

Y1 = +44.66+5.05 * X1-0.18 * X12+3.88 * X2+0.023* X22+1.19* X1X2 -2.36* X12X2-0.47 * X1X22-0.14 * X12X22 (1)

 

Polynomial equation for response surface quadratic model:

Quadratic Equation for Y1 in Terms of Actual Factors

Y1 =214.83-75.0 X1+12.5 X12-35.00 X2-6.67X22 +19.17X1 X2-29.83X12+5.83X1X22 +0.83 X12 X22           (2)

 

Among F1 to F9 batches, F4 batch showed highest Cumulative drug release and lowest Floating lag time as (20 Sec.). From the above study it can be seen that F7 is the optimized batch and was evaluated furtherstudies.

 

CONCLUSION:

For the formulation of floating tablets HPMC K15M, and PVP K30 was used as matrix forming agent and floating enhancer. Other excipients used are sodium bicarbonate (gas generating agent), MCC, talc and Magnesium stearate (lubricating agent). Fourier transform Infrared spectroscopy confirmed the absence of any drug/polymers/excipients interactions. One of the simplest means of improving the bioavailability of an active substance is to improve its dissolution by adding olubilizing agents, such as povidone. It forms water-soluble complexes with many active. With some such substances, it may be sufficient to produce a physical mixture. The tablets were directly compressed using Lab Press multi station rotary punching machine.

 

The prepared floating tablets were evaluated for hardness, Weight variation, thickness, friability, drug content uniformity, buoyancy lag time, total floating time, water uptake, (swelling index),in-vitro dissolution studies. F7 formulation showed good floating property and a controlled drug release. Stability studies were carried out for F7 formulation, they had showed good stability when stored at accelerated stability state as per the ICH guideline and the values were within permissible limits. It was observed that Formulations F7 showed good drug release upto 12 hrs with minimum FLT. All formulations were subjected for four different models viz. Zero order, First order, Higuchi matrix and Peppas model equations and F1 to F9 formulation best fit in into the Peppas model .

 

It was revealed that polymers and sodium bicarbonate ratios had significant influence on drug release. Thus conclusion can be made that stable floating dosage form can be developed for acyclovir for the controlled release by floating tablets

 

REFERENCES:

1.     Moffat, A. C, Osselton, M. D, Widdop, B. Clarke’s Analysis of Drugs and Poisons. Pharma ceutical   Press, London, 2004 2(3), 582.

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Received on 23.12.2017          Modified on 19.01.2018

Accepted on 21.02.2018       ©AandV Publications All right reserved