Formulation and in vitro evaluation of fast dissolving tablets of metoprolol tartrate

The demand for fast dissolving tablets has been growing during the last decade, especially for elderly and children who have swallowing difficulties. In the present work, fast dissolving tablets of metoprolol tartrate, were prepared using sodium starch glycolate, sodium croscarmellose and crospovidone as superdisintegrants, by the direct compression method. The tablets prepared were evaluated for various parameters including weight variation, hardness, friability, in vitro dispersion time, drug-polymer interaction, drug content water absorption ratio, wetting time, in vitro drug release, FTIR and DSC studies. The tablets prepared by the direct compression method had a weight variation in the range of 145 mg to 152 mg, which is below ± 7.5%, a hardness of 3.6 kg/cm2 to 4.5 kg/cm2, percentage friability of 0.46% to 0.73%, in vitro dispersion time of 18 s to 125 s, drug content uniformity of between 98.12% and 100.03%, a water absorption ratio of 67% to 87%, wetting time of 32 sec. to 64 sec., and an in vitro drug release of 53.92% 98.82% within 15 min. The IR spectral analysis and DSC study showed no drug interaction with formulation additives of the tablet, and the formulations indicated no significant changes in hardness, friability, drug content or in vitro drug release. Fast dissolving tablets of metoprolol tartrate have enhanced dissolution and will lead to improved bioavailability and more effective therapy.


INTRODUCTION
Elderly people, children and patients sometimes have difficulties swallowing tablets or hard gelatin capsules.In addition, such difficulties apply not only to patients but also to active working people who have no access to water.These problems can be resolved by means of tablets which disintegrate rapidly in the mouth (Sugimoto et al., 2006).
Recently, fast dissolving tablets (FDTs) have become increasingly popular around the world.On the basis of requests from patients to enhance their quality of life (QOL), new types of FDTs have been developed and then released globally by many pharmaceutical companies (Okuda et al., 2011).These tablets display a fast and spontaneous de-aggregation in the mouth, soon after coming into contact with saliva, dissolving the active ingredient and allowing absorption through all possible membranes it comes into contact with during deglutition (Puttewar et al., 2010).
Fast dissolving tablets are useful for patients with difficulties swallowing conventional tablets, for example pediatric patients and patients under chemotherapy treatment.Patients on chemotherapy treatment may have nausea which is so intense that it complicates the administration of conventional tablets; typically this has been done with water, especially in those with tumors of the mouth and esophagus.Nausea and emesis continue to cause significant problems for patients with cancer receiving highly or moderately emetogenic chemotherapy (Armando et al., 2009).Direct absorption through the oral mucosa allows drugs to achieve systemic circulation, bypassing the gastrointestinal tract and the first-pass metabolism of the liver.To allow fast dissolving of dosage forms in the mouth, these delivery systems comprise either very porous and soft-moulded matrices or compression into tablets with very low compression force (Lai et al., 2011).
However, as a result of rapid FDT disintegration, the active substance comes into contact with the taste buds and the need for a pleasant taste becomes a key aspect for patient palatability.Thus, the taste-masking of bitter active substances is a critical hurdle to overcome for the successful development of FDT formulations.In general, oral administration of bitter active substances through FDT formulations should provide an improved degree of palatability and increased patient compliance with dissolving/disintegrating tablets that include sweeteners and flavors.Nevertheless, these additives were not a sufficient means for complete taste-masking.Recent advances in technology have presented viable dosage alternatives to taste-mask bitter drugs.Several approaches have been reported which involve complexation, freezedrying, microencapsulation, fluidized-bed coating and supercritical fluids for taste-masking purposes (Gryczkc et al., 2011).

MATERIAL AND METHODS
Metoprolol tartrate was obtained from Cipla Pharma, Mumbai, India.Crospovidone, sodium starch glycolate and sodium croscarmellose were also obtained from Cipla Pharma Mumbai, India.Microcrystalline cellulose and mannitol were obtained from Ajantha Pharma, Aurangabad.All other chemicals of analytical grade were purchased from commercial sources.

Preparation of fast dissolving tablets by direct compression method
Fast dissolving tablets of metoprolol tartrate were prepared by direct compression.All the ingredients (except granular directly compressible excipients) were passed through # 60-mesh separately.The ingredients were then weighed and mixed in geometrical order and compressed into tablets of 150 mg using 6 mm round concave punches on an 8-station rotary tablet machine (Karnavati) (Shirsand et al., 2010) (Table I).

Evaluation of pre-compression parameters of powder •
Preformulation study • Angle of repose (q) The angle of repose was determined by using the funnel method.The accurately weighed blend was taken in a funnel.The height of the funnel was adjusted in such a way that the tip of funnel just touched the apex of the heap and the drug-excipient blend was allowed to flow through the funnel freely to the surface.The diameter of the powder cone was measured and angle of repose calculated using the following equation.
Tan θ = h/r Different ranges of flowability in terms of angle of repose (Table II) are given below (Bikshapathi et al., 2011).

•
Bulk density (Pb) Apparent bulk density (Pb) was determined by pouring the blend into a graduated cylinder.The bulk  Very poor volume (Vb) and weight of powder (M) was determined.
The bulk density was calculated using the formula (ShahV et al., 2011).
The measuring cylinder containing a known mass of blend was tapped for a fixed time.The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was measured.The tapped density (pt) was calculated using the formula (Suresh et al., 2011).

• Hausner's ratio
Hausners's ratio is the ratio of tapped density to bulk density.The lower the value of Hausner's ratio the better the flow property.The ratio is calculated by the following formula Lower Hausner ratios (<1.25) indicate better flow properties than higher ratios (>1.25) (Sayeed et al., 2011).

•
Carr's compressibility index The percentage compressibility (Carr's index) was calculated as 100 times the ratio of the difference between tapped density and bulk density to tapped density (Sayeed et al., 2011).(Table III).
It is expressed in percentage and calculated by the following formula The study was carried out to determine the molecular structure, serving as an identification test to ascertain the purity of the molecule.IR spectroscopy was obtained by a FTIR spectrophotometer (H400-84100, Shimadzu, Japan) using KBr pellets.The scanning range used was 4400 to 400 cm -1 at a scan period of 1min.Spectra of pure drug and the blend are shown in Figures 1  and 2. There is no change in the shape of the peak or shift of the peak, hence the drug and excipients are compatible ( Prameela et al., 2010).

•
Differential scanning calorimetry (DSC) Study DSC analysis of pure drug, and of the optimized formulation was performed on a Shimadzu DSC 60 thermal analyser at the heating flow rates of 5 °C per min between 50-300 °C under static air using aluminium pans (Nayak et al., 2011).

Hardness test
The hardness of a tablet is indicative of its tensile strength and is measured in terms of load/pressure required to crush it when placed on its edge.A number of handy hardness testers such as the Mosanto type or Pfizer type are currently in use.Hardness of about 5 kg is considered to be a minimum for uncoated tablets for mechanical stability.The hardness is a function of physical properties of granules such as hardness and deformation under load, binders and above all the compressional force.The hardness has an influence on disintegration and dissolution times and is, as such, a factor that may affect bioavailabilities (Puttewar et al., 2010).

•
Friability test Friability of the tablets was determined using a Roche friabilator.This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm, dropping the tablets from a height of 6 inches on each revolution.A preweighed sample of tablets was placed in the friabilator and subjected to 100 revolutions.Tablets were de-dusted using a soft muslin cloth and reweighed.
The friability (F%) is given by the formula Where, W 0 is weight of the tablets before the test and W is the weight of the tablets after the test (Mehta et al., 2009).

•
Weight variation test Twenty tablets were selected randomly and average weight was determined.Subsequently, individual tablets were weighed and compared with average weight.If the comparison variation lies within the I.P limits, it passes the weight variation test (Chandira et al., 2010).

•
Water absorption A piece of tissue paper folded twice was placed in  a small Petri dish containing 6 ml of water.A tablet was placed on the paper and the time required for complete wetting was measured.The wetted tablet was then weighed.Water absorption ratio is indicated by R, which is calculated by using the equation below (Chandira et al., 2010).
• Uniformity of thickness Thickness can be measured using a simple procedure.A total of 5 tablets were taken and their thicknesses measured using Vernier calipers.The thickness was measured by placing the tablet between the two arms of the Vernier calipers (Parmar et al., 2009).

Drug content uniformity
The formulated tablets were also analyzed for the drug uniformity contents as per the Indian Pharmacopoeia.A total of 20 tablets were taken, weighed and ground.An amount of this powder equivalent to 5 mg of the drug was accurately weighed, suitably diluted and analyzed on a double-beam UV spectrophotometer (Jasco-630V) at 221.70 nm.(Bagul et al., 2010).

•
Wetting time A piece of double-folded tissue paper was placed in a petri plate (internal diameter 6.5 cm) containing 6ml of water.The tablet was placed on the paper and the time for complete wetting of the tablet was measured in seconds.The method was slightly modified by maintaining water at 37 ο C (Figure 3) (Margret et al., 2010).

•
In vitro disintegration time The disintegration time was measured using disintegration test apparatus.One tablet was placed in each tube of the basket.This basket was immersed in a water bath at 37+ 20 o C. The time required for complete disintegration was recorded with standard deviation (Chacko et al., 2010)

(Table VI)
• In vitro dissolution studies The in vitro dissolution study was performed using an USP dissolution apparatus Type 2 (Paddle type) at 100 rpm using 900 ml phosphate buffer pH 6.8 as the dissolution medium at 37±0.5 ºC.Aliquots of dissolution medium were withdrawn and the absorbances of filtered solutions determined by a UV Spectrophotometer at 221.70 nm.Six trials were performed for each batch and average percentage drug release with standard deviation was calculated and recorded (Chacko et al., 2010).

RESULTS AND DISCUSSION
Fast dissolving tablets of metoprolol tartrate were prepared by a method employing crospovidone, sodium starch glycolate and sodium croscarmellose as super-disintegrants at different ratios.A total of nine formulations were designed.The flow properties of the powder mixture are important for the uniformity of mass of the tablets; the flow of the powder mixture was analyzed before compression to tablets.Low Hausner`s ratio (≤1.14), compressibility index (≤15) and angle of repose (≤ 28.04) values indicated fairly good flowability of the powder mixture (Table IV).
As the tablet powder mixture was free flowing, tablets produced were of uniform weight with acceptable weight variation in the range from 145 mg to 152 mg due to uniform die fill.Hardness (3.6 kg/cm 2 -4.5 kg/cm 2 ) and friability loss (0.46% -0.73%) indicated that tablets had good mechanical resistance.Drug content was found to be high (≥ 98.12 %) in all the tablet formulations.Water absorption ratio and wetting time, which are important criteria for understanding the capacity of disintegrants to swell in the presence of a small amount of water, were found to be in the range of 67.32% -87.91% and 28 sec -57 sec, respectively (Tables V and VI).
The most important parameter that needs to be optimized in the development of fast disintegrating tablets is the disintegration time of tablets.In the present study, it was observed that the disintegration time of the tablets had no effect with increasing level of crospovidone.The faster disintegration of crospovidone tablets may be attributed to its rapid capillary activity and pronounced hydration with low capacity for gel formation.Thus, these results suggest that disintegration times can be reduced by using a wicking type disintegrant (crospovidone).Thus, wetting times of tablets with crospovidone were found to be less than those with  sodium starch glycolate or sodium croscarmellose.These results are consistent with disintegration test results.IR shows the drug interaction study, indicating that the drug is compatible with all the excipients (Figures 4 and 5).
The DSC shows that when the drug metoprolol tartrate was taken to study its properties at higher temperature, it exhibited a melting peak at 126.69 o C with very little variation compared with the literature-reported temperature.This is probably due to error in experimental determination.The DSC of the optimized formulation showed a melting peak at 120.19 o C. DSC studies of all formulations indicated that no chemical constituent produced any reaction products (Figure 6 and 7).
. The drug release from the optimized batch (MT5) was 98.82% at 15 min.

FIGURE 6 -
FIGURE 6 -DSC analysis of metoprolol tartrate.FIGURE 7 -DSC analysis of metoprolol tartrate with optimized FDT formulation.

FIGURE 7 -
FIGURE 6 -DSC analysis of metoprolol tartrate.FIGURE 7 -DSC analysis of metoprolol tartrate with optimized FDT formulation.

FIGURE 8 -
FIGURE 8 -In vitro release of metoprolol tartrate from tablets of MT1 to MT3.

FIGURE 9 -
FIGURE 9 -In vitro release of metoprolol tartrate from tablets of MT4 to MT6.

TABLE II -
Relationship between angle of repose (q) and flow properties

TABLE III -
Grading of the powders for their flow properties according to Carr's index

TABLE IV -
Pre-compression results of direct compression method

TABLE V -
Post-compressional parameters for direct compression method

TABLE VI -
Post-compressional parameters for direct compression method

TABLE VII -
Dissolution of metoprolol tartrate in phosphate buffer pH 6.8 from tablets of MT1 to MT9