Formulation and Evaluation of Gastroretentive Drug Delivery System of Cefixime Trihydrate.

 

Sadanand N. Chandewad*, M. A. Bhutkar, S. K. Mohite.

Rajarambapu College of Pharmacy, Kasegaon, Tal-Walva Dist – Sangli, Maharashtra

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

 

The study was aimed at preparing an expandable gastroretentive drug delivery system for the model drug cefixime trihydrate, and evaluating the various parameters including the buyouncy studies, in vitro drug release and expansion properties of tablet. 9 formulations (F1 to F9) were prepared by direct compression by employing 32 factorial design by varying concentration of two hydrophilic polymer viz. HPMC and sodium CMC. Formulation F5 showed maximum swelling index at 6hrs and 12 hrs and gave slow and maximum drug release up to 12 hrs and showed good expansion (diameter) increased up to 15 -16 mm which didn’t pass through the pylorus.

 

 

INTRODUCTION:

Various orally administered dosage forms have been showed that incomplete absorption and less gastric residence time leads to undermedication. So to overcome these limitations various gastroretentive drug delivery systems have been developed among those expandable gastroretentive drug delivery system is most efficient system of drug delivery¹. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach². Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable systems.

 

These systems are also called as “Plug type system”, since they exhibit tendency to remain logged in the pyloric sphincters. These polymeric matrices remain in the gastric cavity for several hours even in fed state.

 

Expandable gastroretentive drug delivery system²:

Principle: The expandable GRDFs are usually based on three configurations: a small (collapsed) configuration which enables convenient oral intake; expanded form that is achieved in the stomach and thus prevent passage through pyloric sphincters; and finally another small form that is achieved in the stomach when retention is no longer required i.e. after the GRDFs has released its active ingredient, thereby enabling evacuation.

 

Expansion can be achieved by swelling or by unfolding in the stomach. Swelling usually occurs because of osmosis. Unfolding take place due to mechanical shape memory i.e. GRDFs is fabricated in a larger size and is folded into a pharmaceutical carrier e.g. gelatine capsule, for convenient intake. In stomach, the carrier is dissolved and opens out, to achieve extended configuration. Cefixime trihydrate is a 3^rd generation cephalosporin β lactum antibiotic used in the treatment of urinary tract infection and various β lactamase resistance infections. It has oral bioavailability of 40-60% and highly soluble in acidic PH and absorbed in the upper part of GIT i.e. stomach⁶. In order to improve the absorption and its bioavailability and to reduce dosing frequency we have attempted to formulated an expandable gastroretentive drug delivery system using cefixime trihydrate as model drug with HPMC K100M and sodium CMC as polymers.     

 

MATERIALS AND METHODS:

Materials: Cefixime trihydrate was obtained as gift sample from Okasa Pharmaceutical Ltd Satara, HPMC K100M and sodium CMC was obtained as gift sample from Wockhardts research centre Aurangabad and all the other reagent and solvent used were of analytical grade.

 

Methods:

1.     Drug-excipient compatibility:

By FTIR Spectroscopy:

 

Table 1: IR Interpretation For Cefixime Trihydrate

Sr. No.	Observed Peaks (cm-1)	Groups
1	3394	N-Hstr
2	571	C-S
3	1078	C=Cstr
4	1434	C=Nstr
5	1492	C=O keto
6	1652	C=O acid
7	2924	O-Hstr

 

Figure 1: IR spectrum of cefixime trihydrate

 

The major IR peaks observed in cefixime trihydrate were 3394(N-H), 571(C-S), 1078(C=C), 1434(C=N), 1492(C=O ketone), 1652(C=O acid),2924(O-H).  In FTIR study of drug and polymers, they show all prominent peaks. As per IR spectrum given in fig.no.1.

 

Table 2: IR Interpretation For physical mixture

Sr. No.	Observed Peaks (cm-1)	Groups
1	3296	N-Hstr
2	583	C-S
3	1095	C=Cstr
4	1381	C=Nstr
5	1542	C=O keto
6	1670	C=O acid
7	2930	O-Hstr

 

IR spectrum of physical mixture:  

IR spectrum of mixture of drug, Hpmc K100m,Sod Cmc, shown all the Prominent peak for major Functional group as 3296(N-H), 583(C-S), 1095(C=C), 1381(C=N), 1542(C=O ketone), 1670(C=O acid),2930(O-H).as per IR spectrum given in fig.no.2.             

 

Figure 2: IR spectrum for physical mixture

 

Preparation of expandable gastroretentive tablet by direct compression: required quantity of polymer i.e. HPMC K100M and sodium CMC was weighed and uniformly mixed in mortar and resulting mixture added to previously weighed quantity of drug and mixed well. After thorough mixing the powder mixture was lubricated with the talk and magnesium stearate was added to improve flow properties. The powder was then compressed using rotary tablet press 8 station with 13 mm diameter punch. The composition of expandable gastroretentive tablet is given in the table no.5, as per the 3² factorial design formulas given in table no.3, by converting the coded value into the actual value as shown in table no.4.

 

Table 3: 3² factorial design of the formulation⁴

Batch code	Coded Values
	X1	X2
F1	-1	-1
F2	-1	0
F3	-1	+1
F4	0	-1
F5	0	0
F6	0	+1
F7	+1	-1
F8	+1	0
F9	+1	+1

 

Table 4: Translation of coded values to actual values

Coded values	Actual values
	X1 (mg)	X2 (mg)
-1	30	10
0	40	20
+1	50	30

Where X₁ - Amount of HPMC K100M

X₂ - Amount of Sodium CMC

 

Table 5: Composition of Expandable Tablets of cefixime trihydrate

Ingredient (mg)	Batch
	F1	F2	F3	F4	F5	F6	F7	F8	F9
Cefixime trihydrate	200	200	200	200	200	200	200	200	200
HPMC K100M	30	40	50	30	40	50	30	40	50
Sodium CMC	10	10	10	20	20	20	30	30	30
MCC	144	134	124	134	124	114	124	114	104
Magnesium Stearate	8	8	8	8	8	8	8	8	8
Talc	8	8	8	8	8	8	8	8	8
Total weight	400	400	400	400	400	400	400	400	400

 

Evaluation of powder characteristics^3-5:

Angle of repose: Angle of repose is defined as the maximum angle possible between the surface of pile of powder and horizontal plane. The angle for the powder of each formulation was determined by the funnel method suggested by Neumann. The powder mixture was allowed to flow out of the funnel orifice on a plane paper kept on the horizontal surface. This forms a pile of powder on the paper by substituting the values of the base radius ‘R’ and pile height ‘H’ in the following equation, the angle of repose was calculated as follows and result of evaluation of powder characteristics of mixture given in the table no.6.

tan =H/R                                           (Eq.1)

Therefore,  = tan^-1 (H / R)  .                            (Eq.2)

 

Bulk density:

Powder mixture was poured gently through a glass funnel into a graduated cylinder cut exactly to 10 ml mark. Excess powder was removed using a spatula and the weight of the cylinder with powder required for filling the cylinder volume was calculated. The bulk density is obtained by dividing the weight of the sample in grams by final volume in cm³.

 

pb = M / V_ρ                                                                                          (Eq.3)

 

Where, pb = bulk density

M = weight of sample in grams, V_ρ = bulk volumes of sample in cm3

 

Tapped density:

The cylinder was then tapped from a height of 2.0 cm until the time when there was no more decrease in the volume. The tapped density was obtained by dividing the weight of sample powder taken by final tapped volume.

 

Pt = M / Vf                                                             (Eq.4)

Where,

 

Pt = tapped density

M = weight of sample in grams

Vf = tapped volume

 

Carr’s index:

An indirect method of measuring powder flow from bulk densities was developed by Carr’s. The percentage compressibility of a powder was a direct measure of the potential powder arch or bridge strength and stability. Carr’s index of each formulation was calculated according to equation given below:

                                       Pt - Pb

% Compressibility = --------------- x   100            (Eq.5)

                                          Pt                    

Where, Pt = Tapped density, Pb = Bulk density.  

 

Hausner’s ratio:

Tapped density and bulk density were measured and Hausners ratio was calculated using following formula.

                                  Pt

Hausner’s ratio =---------                                     (Eq.6)

                               Pb 

Where,

      Pb = Bulk Density, Pt = Tapped density     

 

 

Evaluation of tablet⁵:

Tablet Thickness, Hardness and Diameter:

The uniformity of tablet size depends upon thickness and diameter of tablets. Thickness and diameter were measured using Vernier caliper. The resistance of tablets to shipping or breakage, under conditions of storage, transportation and handling before usage depends on their hardness. The hardness of tablet of each formulation was measured by Monsanto hardness tester. The hardness was measured in terms of kg/cm². Result of the evaluation parameter as thickness, hardness, diameter, drug content, average weight, friability is given in table no.7.

 

Friability of Tablets:

The strength of tablets is measured in terms of friability. Roche Friabilator was used for testing the friability. Twenty tablets were weighed accurately and placed in the drum that revolves at 25 rpm dropping the tablets through a distance of six inches with each revolution. After 4 min the tablets were weighed and the percentage loss in tablet weight was determined by the equation 7.

 

	Initial weight of tablets	-	Final weight of tablets
% Loss = -------------------------------------------------x100     (Eq.7)
	Initial wt. of tablets

 

Table 6: Bulk density, Tapped density, Carr’s index, angle of repose, Hausners ratio of powder Mixture of all batches.

Results are mean of triplicate observations ± SD

 

 

Table 7:  Average weight, Thickness, Diameter of Expandable Cefixime Trihydrate Tablet

Results are mean of triplicate observations ± SD

 

 

 

 

Table 8:  Expansion Properties of the Cefixime Trihydrate Tablet.

Results are mean of triplicate observations ± SD

 

 

 

 

 

Table 9:  Swelling index of Batch F1 to F3:

Time (hour)	% Swelling index
	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	98.53± 0.08	94.68± 0.04	96.92± 0.04	95.23± 0.04	98.20± 0.12	96.23± 0.02	96.24± 0.02	95.45± 0.04	93.24± 0.02
2	141.40± 0.04	130.32± 0.02	120.43± 0.02	135.32± 0.08	141.30± 0.01	130.24± 0.04	120.34± 0.01	130.68± 0.01	130.20± 0.04
3	173.48± 0.20	164.46± 0.04	140.45± 0.01	170.42± 0.12	172.48± 0.14	164.23± 0.02	148.53± 0.04	143.45± 0.02	145.20± 0.02
4	181.72± 0.12	180.12± 0.06	468.32± 0.05	180.48± 0.08	185.20± 0.02	174.48± 0.02	169.24± 0.06	167.85± 0.04	158.90± 0.06
5	191.30± 0.10	190.60± 0.08	182.46± 0.04	190.24± ± 0.06	196.23± 0.05	180.32± 0.01	180.23± 0.08	191.24± 0.06	178.30± 0.08
6	186.10± 0.04	208.60± 0.12	175.16± 0.08	210.24± 0.04	228.24± 0.06	204.16± 0.02	204.21± 0.12	206.34± 0.12	198.30± 0.01
7	180.20± 0.02	190.20± 0.16	195.23± 0.03	180.26± 0.03	210.16± 0.08	190.48± 0.01	190.24± 0.03	192.83± 0.10	180.30± 0.12
8	172.10± 0.06	180.36± 0.08	180.28± 0.08	172.80± 0.01	200.14± 0.10	181.23± 0.12	185.26± 0.06	172.84± 0.08	172.80± 0.14
9	168.15± 0.07	175.48± 0.06	172.72± 0.07	162.10± 0.02	190.12± 0.08	171.23± 0.14	170.20± 0.05	162.30± 0.04	168.30± 0.10
10	158.10± 0.05	163.43± 0.08	162.60± 0.06	142.20± 0.04	182.16± 0.06	159.21± 0.10	158.10± 0.03	154.20± 0.02	154.20± 0.02
11	142.10± 0.04	146.48± 0.04	153.20± 0.12	130.24± 0.08	174.20± 0.02	151.21± 0.08	143.26± 0.04	146.30± 0.01	141.30± 0.01
12	130.20± 0.03	132.46± 0.02	156.42± 0.14	124.62± 0.12	150.10± 0.01	140.23± 0.04	130.21± 0.02	140.20± 0.10	145.10± 0.02

Results are mean of triplicate observations ± SD

 

 

Uniformity of weight:

Twenty tablets were selected at random and average weight was calculated. Not more than two of the individual weights deviate from the average weight by more than the percentage given in the table 7 and none tablet deviates by more than twice that percentage. The IP standards of uniformity of weight are given in table 7.

Drug content:

The values of drug content are given in Table 7. Drug content was in range of 95.65 ± 0.04 to 99.37 ± 0.14 indicating good content uniformity of the prepared formulations.

 

In vitro swelling study:

Expansion Properties of the Cefixime Trihydrate Tablet:

The integrity and swelling duration properties are given in table 7. The water molecules enter the matrix and cause hydration of polymer to form gel. The water is trapped within the gel thus increasing the size (diameter) of the tablet. The density of the tablet increases and tablet remains in stomach and does not pass through the pylorus. The results presented in table revealed that HPMC K100M and Sodium CMC produced tablets with good gel strength, showing stable and persistent swelling. Result of expansion and swelling properties of tablet was given in the table no.8

 

Swelling Index (water uptake study):

All the batches showed satisfactory swelling index values due to incorporation of hydrophilic polymers such as HPMC and sodium CMC in the  tablet which get swollen upon contact with gastric fluids or in vitro dissolution medium, and  form gelly  like appearance and get expanded .The liquid diffuses through the polymer matrix at a constant velocity, and the rate of diffusion of the liquid and macromolecular relaxation of the polymers is almost of the same magnitude or the rate of diffusion of the liquid is relatively higher than that of relaxation of the polymer segment. Result of swelling index was shown in table no.9.

 

The study revealed that initially swelling of polymers leads to increase in the size (diameter) of tablet matrices causing erosion and drug release leading to decrease in tablet size. Swelling or expansion of tablet is critical parameter for gastroretention. Swelling measurement was performed separately in order to collect on the basis of weight increase over time. Swelling allows water uptake leading to increase in tablet weight. The relationship between swelling index and time of all batches is shown in figure and The optimized batch ( F5)showed 98.20 ± 0.12 % and 164.10 ± 0.01 % swelling at 1 and 12 hours respectively.upto First six hrs swelling index is increased rapidly and after that swelling index goes on decreasing gradually as per shown in figure no.3 of relationship between swelling index and time.

 

Relationship between swelling index and time:

 

Figure3:   Relationship between Swelling Index & Time of batch F1 to F9

 

In vitro dissolution study:

The release pattern of cefixime trihydrate from expandable tablets was determined using United State Pharmacopoeia (USP) dissolution testing apparatus type II (Paddle method). The dissolution test was performed using 900ml of 0.1N HCl at 37 ± 0.5⁰C and 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus hourly for 12 hours and the sample were replaced with fresh dissolution medium.

Table 10: Dissolution data of batch F1 to F3

Results are mean of triplicate observations ± SD

 

Figure 4: Relationship between drug release v/s time of batch F1 to F9 :

 

The sample were filtered through a 0.45µ membrane filter and diluted to a suitable concentration with 0.1N HCl. Absorbance of these solutions was measured at 237nm wavelength using Shimadzu spectrophotometer. Cumulative percentage drug release was calculated using an equation obtained from a standard curve. Analysis of data was done by using ‘PCP Disso V-3’ software, India. The graphs of % cumulative release v/s time were plotted shown in figure no. 4 and Result of in vitro drug release of all the 9 batches F1 to F9 given in the table no.10.

 

 

4.     Treatment of dissolution data with different kinetic equations:

Models	Regression coefficient value
Zero order	0.928
First order	0.870
Higuchi	0.945
Korsmeyer Peppas	0.986
Hixon crowel	0.808

 

To study the release kinetics, and to determine model fitting of the optimized batch. It is concluded that from the value of regression coefficient the best fitted release kinetic model was found to be Korsmeyer Peppas with regression coefficient of 0.986 highest among all other models.

 

Table: 11 % drug release for stability study of batch F5

Time (hour)	% Drug Release (Initial)	% Drug Release (After 3 months)	Swelling Index (Initial)	Swelling Index (After 3 months)
0	0	0	0	0
1	28.22±0.02	28.20±0.02	98.20±0.12	98.25±0.10
2	33.21±0.04	33.0±0.04	141.30±0.01	141.0±0.02
3	37.39±0.02	36.5±0.06	172.48±0.14	170.6±0.04
4	41.31±0.06	41.2±0.04	185.20±0.02	185.6±0.06
5	47.86±0.02	46.9±0.08	196.23±0.05	196.5±0.08
6	55.22±0.08	55.22±0.04	228.24±0.06	228.5±0.12
7	62.5±0.12	62.24±0.03	210.16±0.08	210.5±0.04
8	75.5±0.10	75.5±0.01	200.14±0.10	200.16±0.02
9	80.67±0.08	80.60±0.04	190.12±0.08	190.12±0.04
10	87.87±0.04	87.87±0.04	182.16±0.06	181.5±0.04
11	91.80±0.02	91.70±0.06	174.20±0.02	174.20±0.02
12	96.30±0.02	96.05±0.02	150.10±0.01	150.6±0.04

Results are mean of triplicate observations ± SD

 

 

Stability study⁵:

Stability study is the essential factor for quality, efficacy and safety of the drug product. The drug product with insufficient stability can result in change of their physical well as chemical characteristics. The stability study was carried out to check the dissolution behaviour and physical appearance of the optimized formulation F5. The stability study was carried out at accelerated conditions of 40^oC / 75% RH. for three months. Result of stability study was given in the table no.11.

 

There was no change in physical appearance in the dosage form of batch F5 over a period of three months in accelerated conditions.

 

The results of stability study after three months are given in table. There was no significant change in the percentage release of drug after three months indicating the stability of the formulation.

 

RESULT AND DISCUSSION:

This study presents an approach for gastro retentive drug delivery system. The direct compression method was used to formulate cefixime trihydrate expandable tablet. The formulation variables, HPMC K100M and Sodium CMC influenced the swelling index and in vitro drug release characteristics of the prepared tablets. The direct compression method is simple and economic and which offers an efficient way for producing the tablets.

 

The obtained tablets exhibited rounded shape, low friability and good drug content. The concentration of polymers significantly affects the drug release from tablets. It is also important parameter which affects swelling index. The swelling index governs the gastric retention of tablets. High levels of HPMC K100M and intermediate levels of Sodium CMC showed optimum swelling index which is required to prevent the passing of tablet through the pylorus. The dissolution study of all batches revealed that increase in the concentration of hydrophilic polymers cause retardation of drug release. Hydrophilic polymers absorb water and swelling or hydration of polymeric matrices occurs. Hydration is directly proportional to the weight gain by tablets. After maximum absorption of water, erosion causes decrease in swelling index. For the sustained release of the drug, optimum levels of concentrations of polymers are required.

 

Expandable gastroretentive drug delivery system can be used as alternative for floating drug delivery system with some advantages. It is concluded that the expandable gastroretentive tablets prepared by direct compression method for specific drug delivery. It releases drug in sustained manner for an extended period of time to reduce frequency of administration and improve patient compliance.

 

REFERENCES:

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2.     Amnon Hoffman, Kiran B Patel, Mohnish S Rokade et al Expandable gastroretentive dosage forms. Journal of Controlled Release, (90);2003:143–162.

3.     Lachman L., Libermann H. A., Kanig J. L., “The theory and practice of industrial  Pharmacy”, 3^rd edition, Lea and Febiger Philadelphi, 1986; 430-431.

4.     Amelia Avachat, Kiran B Patel, Mohnish S Rokade et. al. Formulation and characterization of an expandable, gastroretentive system of carvedilol phosphate by 3² factorial design, PDA Journal of Pharmaceutical Science and Technology  (65); 2011: 12- 19.

5.     Yash Paul, Manoj Kumar and Bhupinder Singh, Formulation and in Vitro evaluation of Gastroretentive drug delivery system of Cefixime Trihydrate. International Journal of Drug Development & Research, 3 (4); 2011:148-161.

6.     Okeke C.C., srinivasan V.S., brittain H.G. Cefixime- analytical profile of drug substance. USA. Academic Press Inc. (25) 1958, 39-83.

7.     Patil U K, Pare A, Yadav S K et. al. Formulation and Evaluation of Effervescent Floating Tablet of Amlodipine besylate, Research Journal of Pharmacy and Technology. 1(4); 2008: 526-530.

 

 

 

Received on 04.06.2013          Modified on 15.06.2013

Accepted on 30.06.2013         © RJPT All right reserved