FORMULATION AND EVALUATION OF QUETIAPINE FUMARATE SUSTAINED RELEASE MATRIX TABLET

ABOUT AUTHORS:
Pranita T. Gaikwad*, Reshma R.Patil, Mr M.M.Nitalikar, Dr.S.S.Patil, Dr.S.K.Mohite
Rajarambapu college of pharmacy,
kasegaon-415404. MH
*pranitatgaikwad@gmail.com

ABSTRACT:
The main objective of the present work was to formulate sustained release matrix tablets of Quetiapine fumarate using different polymers viz. Hydroxy propyl methyl cellulose (HPMC) and Locust Bean Gum (LBG). Varying ratios of drug and polymer like were selected for the study. After fixing the ratio of drug and polymer for Sustain the release of drug up to desired time, the release rates were modulated by combination of two different rates controlling material and triple mixture of two different rate controlling material. After evaluation of physical properties of tablet, the in vitro release study was performed in 0.1 N HCl  pH 1.2 for 2 hrs and in phosphate buffer pH 6.8 up to 24 hrs. The effect of polymer concentration and polymer blend concentration were studied. Dissolution data was analyzed by Higuchi expression. It was observed that matrix tablets contained polymer blend of HPMC and LBG were successfully sustained the release of drug up to 24 hrs. Among all the formulations, formulation  P3 which contains 15 % HPMC K4M  and % 25 of LBG  release the drug which follow Higuchi kinetics via, diffusion and erosion and the release profile of formulation P3 was comparable with the prepared batch products. Stability studies (40±2ºC/75±5%RH) for 3 months indicated that Quetiapine fumarate was stable in the matrix tablets. The DSC and FTIR study revealed that there was no chemical interaction between drug and excipients.

REFERENCE ID: PHARMATUTOR-ART-2032

Introduction:
Quetiapine fumarate (QF) (bis [2-(2-[4-(dibenzo[ b,f][1,4]thiazepin-11-yl)]ethoxy)ethanol] fumarate, a dibenzothiazepine derivative, is a recent antipsychotic drug with an atypical neuropharmacological profile. Quetiapine is the antipsychotic that has the highest serotonin/dopamine binding ratio, being the serotonin type 2 (5-HT2)-receptor blocking effect about twice as strong as the dopamine D2-receptor blocking effect [1]. Due to this binding pattern, quetiapine causes minimal extrapyramidal side effects. It is readily absorbed from the gastrointestinal track with oral bioavailability of about 83% and a plasma elimination half life ranging from 6-7hours. Administration of QF in the sustain release dosage form as once daily would be more desirable as this formulation is intended to be given to schizophrenic patients. The sustain release form would also control the mood for longer period of time by maintaining the plasma concentration of drug well above the therapeutic concentration. It appears as effective as the older antipsychotics producing side effects no worse than those encountered with standard antipsychotics. This characteristic makes quetiapine well tolerated and effective in patients who are particularly susceptible to these severe side effects, including the elderly and adolescents and those with preexisting dopaminergic pathologies, such as Alzheimer’s disease and Parkinson’s disease.

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An effort was therefore made to develop simple and effective sustain release tablets of Quetiapine fumarate using a polymer matrix system. Hydroxypropyl methyl cellulose (HPMC) is the most commonly and successfully used hydrophilic retarding agent for the preparation of oral sustain release drug delivery system [2]. The transport phenomena involved in the drug release from hydrophilic matrices are complex because the microstructure and macrostructure of HPMC exposed to water is strongly time dependent. Upon contact with the gastrointestinal fluid, HPMC swells, gels and finally dissolves slowly [3]. The gel becomes viscous acting as a protective barrier to both, the influx of water and the efflux of drug in solution [4, 5]. As reported by Ford et al, [6]the proportion of polymer in the formulation increases the gel formed is more likely to diminish the diffusion of the drug and delay the erosion of the matrix. Narasimhan and Peppas [7]. showed that the dissolution can be either disentanglement or diffusion controlled depending on the molecular weight and thickness of the diffusion boundary layer. The rate of polymer swelling and dissolution as well as the corresponding rate of the drug release are found to increase with use of lower viscosity grades of polymers. The rate of drug release form HPMC matrix is dependent on various factors such as type of polymers, drug, drug polymer ratio, particle size of drug and polymer, and the type and amount of fillers used in the formulation.

EXPERIMENTAL SECTION

Materials:

All other chemicals and reagents were of analytical grades.

PREPARATION OF MATRIX TABLET BY DIRECT COMPRESSION

METHOD:
Different tablet formulations were prepared bydirect compressionmethod .The formulations are composed of various concentrations of HPMC K4M and Locust Bean Gum in the ratios as drug and polymers  in various percentages. All powders were passed through 100- mesh sieve. The lactose and the polymer were mixed uniformly. Drug was added to the lactose and the polymer mixture and the blended for 20 min.  Blend  were then passed through sieve no.12 .The resulting mass were mixed with magnesium stearate and talc.  The lubricated mass  were compressed using 13mm die  punch (  KBr Press ) in to tablets. Compression pressure was adjusted during tabletting of each formula to get the tablet hardness in the range of 5 to 7 kg/cm3.The total weight of tablet was kept at 500 mg

Table no.1: Formulation table

All ingredients are weigh in mg.

Evaluation of tablets
As mentioned in the preparation of tablet section, to study the effect of polymer concentration of drug release, 9 different formulas, having different concentrations of polymers HPMC and LBG were developed. Figure 1 shows the drug release profiles of the 9formulations studied.

The prepared tablets were tested as per standard procedure [17] for weight variation (n=20), hardness (n=6), thickness (n=6), drug content and friability. Hardness of the tablets was determined by using Monsanto tablet hardness tester, Friability test (n=10) was conducted using Roche friabilator (F. Hoffman-La Roche Ltd, Basel, Switzerland). Thickness of the tablets was measured by digital Vernier calipers (Aerospace). Drug content of QF was analyzed by measuring the absorbance of standard and samples at l=289 nm using the UV/Visible spectrophotometer (Schimatzu 1800) and comparing the content from a standard calibration curve.

Further the similarity factor f2 for the release of QF between the test product and that of the marketed formulation, Quel SR (IPCA Pharmaceuticals), was performed.

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Dissolution testing
Dissolution studies were performed using the USP XXVIII, paddle-rotating method (Electrolab dissolution tester, TDT-08, India) at 37 °C ± 0.5 °C and 50 rpm using 0.1 N HCl in the initial 2 hours and phosphate buffered solution, pH 6.8 (PBS) till the end of the study , as the dissolution media. Dissolution studies were carried out in triplicate. A 5ml aliquot of sample was withdrawn at regular time intervals, filtered and then these samples were diluted 10 folds with dissolution medium and then assayed spectrophotometrically at 289 nm. The cumulative % drug release was calculated for the formulations and the drug release data were curve fitted using PCP Disso v3.00 software to study the possible mechanism of drug release from hydrophilic swollen matrices.

Mechanisms of drug release.
To analyze the mechanism of drug release from the matrix tablets, the release data were fitted to the following equations [13-14]:

Zero- order equation: Q = k0t

Where, Q is the amount of drug released at time t, and k0 is the release rate;

First- order equation: log (100-Q) = log100 - k1t

Where, Q is the percentage of drug release at time t, and k1 is the release rate constant;

Higuchi's equation:
Q = k2 t1/2

Where, Q is the percent of drug released at time t, and k2 is the diffusion rate constant

Korsmeyer Peppas equation: Mt/ M¥= ktn

Where, Mt/ M¥is the fractional solute release,

t is the release time, k is the kinetic constant and n is an  exponential value.

IR Spectroscopy:
IR spectroscopy is one of the analytical techniques useful in detecting chemical interactions. The IR spectra of Quetiapine fumarate and formulation were determined by Fourier Transform Infrared Spectrophotometer using KBr dispersion method. The base line correction was done using dried potassium bromide. Then the spectrum of dried mixture of drug and potassium bromide was run on FT-IR JASCO(MODEL No.410) and Brucker.The spectra were scanned over wavelength region of 4000 to 400 cm^-1.

Differential Scanning Calorimetry (DSC):
The Thermal analysis of pure drug was carried out using a DSC, Mettler Toledo 823e and SDT Q600 V20.9 Build20.The analysis was performed at a rate 10ºC min-1 from 50ºC to 300ºC temperature ranges under Nitrogen. The DSC profiles thus obtained were compared for possible drug polymer interaction.

Stability studies: DSC scans of about 5mg; using an automatic thermal analyser system performed accurately weighed Quetiapine Fumarate and tablet containing the same amount of drug. (DSC 60, Shimadzu, Japan) Sealed and perforated aluminium pans were used in the experiments for all the samples. Temperature calibrations were performed using indium as standard. An empty pan sealed in the same way as the sample was used as a reference. The entire samples were run at a scanning rate of 10°C/min from 50-300°C. stabilitystudies were carried out on optimized formulation. Tablets were stored at 40 ± 20 C/75 ± 5 % RH for duration of 1 and 3month. After completion of one month sample was withdrawn and tested for different tests such as thickness, hardness, drug content andin-vitro drug release.

RESULT AND DISCUSSION:
Precompressional parameters of granules shows (Table 2), angle of repose (28.363 to 29.68), % compressibility (18.91 to 22.73%), and Hausner's ratio (1.25 to 1.29) are in the range given in official standards. Table No.3 shows post compressional parameters i. e. hardness (5.14 to 5.53 kg/cm2), friability (0.44 to 0.66  %), weight variation (498 to 509 ) and thickness (5.31 to 5.42 mm). Drug content was (97.20t o 99.60%) within the acceptable official limits.

Table No.2: Precompressinoal parameters of grannules

Table No.3:Post compressinal parameters

Similarity factor (f2) Analysis
In- vitro release profile of the marketed QF sustain release tablets (SR) tablets, (Quel SR, IPCA) was performed under similarity conditions as used for in- vitro release testing of the test product for the release of QF. The similarity factor between the two formulations was determined using the data obtained from the drug release pattern. The data was analyzed by the following formula shown in equation 1. [15].

Where,

n= number of pull points,            

Wt=Optional weight factor,

Rt=Reference profile at time point t and

Tt= Test profile at same time point.

In- Vitro release studies :
As the drug in study had a slight solubility in water moderate molecular weight HPMC and LBG  are used as a rate controlling polymers (K4M  and LBG) to retard the release of drug from a matrix at levels of 15 to 25% w/w in tablets prepared. The effect of polymer level on the release of the drug from matrix tablets was studied for tablets containing 15%, 20% and 25% of the polymer(Formulations P1 to P9). Figure 1 shows that the amount of HPMC and as well as LBG used affects the release rate of the drug. This may be due to the erosion of the polymer as it is of a very low viscosity.Thus, indicating that higher the percentage of the polymer more is the drug releaseretardation

Figure No.1: Dissolution profile for all formulated batches

Drug release mechanism :
The obtained release data from the in-vitro dissolution study from various formulations was fitted to the mathematical models. The kinetic models included First order, Higuchi equation (matrix system) and Korsmeyer-

Peppas model. Table No.4 shows the data obtained from the model fitting, for all the 9 formulations studied (P1-P7) along with their R values, K constant and n exponential value. The overall curve fitting showed that the drug release from the sustained release matrix tablets followed either Higuchi equation or the Korsmeyer- Peppas model.

The values of the exponential factor 'n' were found to be in between 0.4299- 0.5034 indicating the Fickian diffusion- controlled drug release. The correlation co-efficient R was same time best fitting to the Matrix system. and some time to the Korsmeyer-Peppas equation which was adequate from the sustain release systems. However, looking at the negligible variation in the R values for the release of the drug QF, the release data analysis applying these mathematical models can be purely empirical.

Table No.4: Drug Release Mechanism