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Propafenone HCl fast dissolving tablets containing subliming agent prepared by direct compression method

Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half-life, delayed drug dissolution and side effects. Thus, the purpose of this work is to develop orally fast dissolving tablets (OFDTs) containing PPH to provide a rapid drug dissolution and subsequently give rapid onset of action of PPH as an antiarrhythmic drug. Moreover, OFDTs of PPH reduce its side effects and improve its bioavailability. Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half-life, delayed drug dissolution and side effects. Direct compression method was used for the preparation of 15 formulations OFDTs containing PPH using directly compressible excipients, subliming agent and superdisintegrants. The prepared tablets were undergone physical characterization, in vitro dissolution and stability studies. All pre- and post-compression tests met the pharmacopoeia specifications. In vitro dissolution of the prepared PPH OFDTs exhibited high dissolution rate than compared to the marketed tablets. It was found that the tablets prepared by using the higher concentration of crospovidone were found to dissolute the drug at a faster rate when compared to other concentrations. A formula containing croscarmellose sodium showed the higher present of PPH dissolved as compared to the other formulations. It was concluded that PPH OFDTs were formulated successfully with acceptable physical and chemical properties with rapid disintegration in the oral cavity, rapid onset of action, and enhanced patient compliance. It was found that F10 showed good stability upon storage at 25 and 40 °C for 3 months. Formulation of PPH OFDTs can result in a significant improvement in the PPH bioavailability since the first pass metabolism will be avoided.


Introduction
Fast-dissolving tablets (OFDTs) were formulated as a substitute to conventional tablets, especially for pediatric and geriatric patients who suffer from swallowing solid dosage forms (Nagaraju et al., 2013). OFDTs have advantages of rapid onset of action, accurate dosing, fast disintegration and dissolution in the oral cavity without the necessity of water (Heer et al., 2013). Moreover, OFDTs have the benefit of avoidance of first-pass hepatic metabolism that occurs during gastric absorption. Thus, OFDTs can improve bioavailability and safety profiles of drugs that changed in liver to toxic metabolites .
Several approaches were used for the preparation of OFDTs, such as spray drying, molding, direct compression, lyophilization and sublimation (Patel et al., 2007;Suresh et al., 2007). Many OFDTs contain superdisintegrants, such as crospovidone, croscarmellose sodium (Ac-di-sol) and sodium starch glycolate (SSG), to prompt fast disintegration (Al-Khattawi and Mohammed, 2013). Many OFDTs are highly friable due to its porous structure and to avoid these, mechanically hard OFDTs must be prepared using co-processed excipients (Seong et al., 2008).
Propafenone hydrochloride (PPH) (Fig. 1), an antiarrhythmic drug class IC (sodium channel inhibitor), has been broadly used for the management of certain types of life-threatening irregular heartbeat (ventricular and supraventricular arrhythmias) (Funck-Brentano et al. 1990). In certain patients who are complaining of irregular heartbeat (paroxysmal atrial fibrillation/flutter), PPH can be used to help maintain a normal heart rhythm. It works in the heart to stabilize its action and regulate heartbeat. PPH is undergoing high first pass effect with a mean bioavailability about 4.8%. PPH has a short half-life about 3-4 h (Sestito and Molina, 2012). In addition, PPH has weak beta-blocking activity as well as its local anesthetic effect. Because of the side effect of PPH occurs when it reached the peak plasma concentration, small doses of multiple administrations were advised. Thus, PPH was suggested to be taken 4-6 times per day (Ni, 1994).
Bitter undesirable taste is one of the important pharmaceutical formulation problems occurred with most of the drugs. The techniques, which used for achieving taste masking, include various chemical and physical methods that prevent the drug substance from interaction with taste buds in the oral cavity (Venkata et al., 2010). The simplest and economic method involves the use of flavor enhancers as aspartame and menthol.
The aim of this work was to develop OFDTs containing PPH to provide a rapid drug dissolution and subsequently give rapid onset of action of PPH as antiarrhythmic drug. Moreover, OFDTs of PPH would improve its bioavailability.
Rytmonorm Ò 150 mg tablets were purchased from Kahira pharmaceuticals, Egypt. Acetonitrile and methanol (HPLC grade) were purchased from Merck-Schuchardt, Germany. Dipotassium hydrogen orthophosphate was supplied by NICE Chemicals (p) LTD, India. All other materials and solvents were of analytical grade.

Pre compression characterization parameters
The bulk density, Carr's index and Hausner's ratio of the powder blend were calculated according to USP pharmacopeia.

Preparation of PPH OFDTs
Direct compression method was used for preparation of PPH FDTs (Madgulkar et al., 2009;El-Shenawy et al., 2017). The composition of the prepared tablets formulae is presented in Table 1.
Weighed amount of aspartame and menthol were incorporated for masking the undesirable taste (using digital sensitive electric balance, RADWAG, Poland). Using the bottle method, the amount equal to 150 mg of PPH was mixed with all amount of the excipients for 20 min. The obtained mixture (350 mg) was compressed into a round tablet punch 10 mm (Single punch tableting machine manufactured by Royal artist, India). The compression force was adjusted to attain a tablet hardness of 3-5 kg/cm 2 . The prepared PPH FDTs were subjected to sublimation at 60°C for 12 h in a vacuum oven to ensure full sublimation of camphor, which confirmed by constant weights of the FDTs and hence the porosity and disintegration of the obtained formulae were increased (vacuum oven dryer, SPT-200 Zeamil Horzont co., Poland)

Differential scanning calorimetric analysis
Drug-excipient interaction was evaluated using differential scanning calorimetry (DSC) (DSC-50, Shimadzu Company. Japan). Weighed samples (3-8 mg) of PPH alone and physical mixture of the drug and excipients (1:1) were poured in aluminum pans and then sealed with lid. The temperature rate was adjusted at 10°C.

Fourier transform infrared spectroscopy (FTIR)
Fourier Transform Infrared spectrophotometer (FTIR, Nicolet 6700 FT-IT, Thermo Fisher, Madison, USA) is another tool for drug-excipients interaction. FTIR spectra of PPH alone and physical mixture of the drug-excipients were obtained by scanning the prepared disc with KBr in the range of 500-4000 cm À1 .

. Uniformity of weight
This test was being done to verify that the tablets are uniform in weight. Twenty tablets were randomly taken, weighed and then the average weight was calculated (Thahera et al., 2012).

Drug content
One tablet was powdered and sonicated with 100 ml phosphate buffer pH 6.8 for 10 min and the solution was then filtered. The drug content was calculated by analyzing the filtrate spectrophotometrically (Double beam spectrophotometer, UV-1601 Shimadzu Co., Japan) at 305 nm (Krishna et al., 2013).

In-vitro disintegration time
The disintegration time was determined in phosphate buffer pH 6.8 using tablet disintegration test apparatus (Electrolab, ED-21, Mumbai, India) on six tablets according to the USP30-NF25 requirements for immediate release tablets. The tablet was put in 500 ml phosphate buffer pH 6.8 and the time taken for the tablet to disintegrate into fine particles was calculated (Mahrous et al., 2016).

Wetting time
The tablet was placed on folded tissue paper wetted by phosphate buffer pH 6.8 and eosin solution (water soluble dye). The time required to develop a red color on the upper surface of the tablet was recorded as the wetting time (Shailendra et al., 2015).

In-vitro dissolution study
Drug dissolution rate from the prepared OFDTs was performed according to USP specification using USP paddle type apparatus (Model 85T, Caleva Ltd., Dorset, United Kingdom), at 50 RPM using a continuous automated monitoring system. This system consists of an IBM computer PK8620 series and PU 8605/60 dissolution test software, Philips VIS/UV/NIR single beam eight cell spectrophotometer Model PU 8620 (Caleva), Epson FX 850 printer, and Watson-Marlow peristaltic pump using in each flask 500 ml phosphate buffer, pH 6.8. The temperature was maintained at 37°C ± 1°C. At scheduled time intervals, absorbances were recorded automatically at 305 nm, and the percentage of PPH dissolved was determined as a function of time in triplicate (Shazly et al., 2012).

Palatability test
One group, three healthy human volunteers aged from 23 to 43. The study was approved by the Human ethics committee of Assuit University, Assuit, Egypt (IRB Nr. IRB00009982) that ensured the investigations of Human Volunteers followed the Declaration of Helsinki guidelines 1964. The selected tablet F3 was kept in the mouth until complete disintegration occurred, and then disgorged. The test was repeated for three days and the resulted data were collected and evaluated. The acceptability scale was divided into 5 levels (level 1 is the lowest degree of taste masking and level 5 is the highest degree of taste masking).

Effect of storage on characterization parameters of PPH OFDTs at 25 and 40°C
Three PPH OFDTs formulations (F3, F10, and F14) were stored at 25 and 40°C for three months. These formulae were selected because they showed low disintegration time, low% friability, and the highest percent amount dissolved in 10 min. About 110 OFDTs of each formula each containing 150 mg of PPH were stored in a tightly closed, light protected bottles and wrapped within aluminum foil and stored at 25 and 40°C + RH 75% ± 5 in thermostatically controlled hot air ovens (India). Samples of 18 tablets of each formula from each temperature were taken at zero time and after 1, 2, 3, 4, 8 and 12 weeks and were evaluated for weight variation, drug content, in-vitro disintegration time, wetting time, the% amount dissolved in 10 min,% friability and hardness (Sahitya et al., 2014).

Results and discussion
PPH OFDTs were prepared by direct compression method using CP, CCS as superdisintegrants and camphor as a subliming agent in different ratios. Fifteen formulae were designed and evaluated (Table 1).

DSC
DSC thermogram of untreated drug shows an endothermic peak at 173°C, which is related to its melting point (Fig. 3A). The physical mixture of excipient used (Placebo) has endothermic peak at 194°C (Fig. 3B). Physical mixture of excipients and the drug showed endothermic peaks at 164.71°C and 193.44°C (Fig. 2C). It was found that there are no new peaks appeared in the thermogram of the drug and excipients. Thus, there is no interaction between the drug and the tablet excipients, was observed. However, there is a very slight shift in the drug peak and this might be due to a reduction of the purity of components by mixing (Tayel, 2013).

FTIR
FTIR spectroscopy for pure PPH, physical mixture of excipients and physical mixture of excipients and drug was shown in Fig. 4. The spectrum of PPH showed characteristic bands, at wave number 1662 cm À1 corresponding to the carbonyl group (C@O), 3421 cm À1 corresponding to the tertiary amine group (NAH), 3312 cm À1 corresponding to the hydroxyl group (OAH) and another peak at 2940 cm À1 refer to methyl group. From the FTIR spectra, it was found that all the characteristic peaks of PPH were also found in the spectrum of formulations. The results suggest that the drug is intact in the formulations and there is no interaction found between the drug and the contents (Manju et al., 2016).

Pre-compression characterization parameters
The values of pre-compression parameters evaluated (angle of repose, bulk density, Carr's index and Hausner ' s ratio) were investigated. The results indicated, all the examined formulae showed a poor flowability (Carr's index ranged from 21.36 to 28.47) except formulae F4 exhibit a good powder flow. While the values of Hausner's ratio were ranging between 1.27 and 1.44 indicated poor flowing properties (Table 2).

Post-compression characterization of PPH OFDTs
Uniformity of weight, drug content, and in vitro disintegration time, wetting time, hardness, thickness and friability met the pharmacopeia requirements (Table 3). The results indicated that disintegration time ranged between 25.4 s (F 8 ) and 53.4 s (F 6 ). The calculated wetting time values were between 20.46 s and 34.93 s for F 10 and F 12 respectively. According to the noticed results formulae F 8 , F10, and F3 gave the lowest disintegration and wetting time. The hardness of FDTs was between 3.443 and 4.609 kg/cm 2 (Shailendra et al., 2015;El-Shenawy et al., 2017).

In vitro dissolution studies of PPH OFDTs
Figs. 5 and 6 exhibited in vitro dissolution of the prepared HPP OFDTs. These studies indicated that all the tablet formulations prepared by using various superdisintegrants were found to exhibit high dissolution rate than compared to the marketed tablets. All the prepared tablets formulae showed a rapid drug dissolution (more than 70% of PPH dissolved within the first 10 min) this attributed to the porosity and capillary action (wicking) of the superdisintegrant and the subliming agent (Vineet et al., 2010). The results illustrated that F 7 and F 11 gave the highest drug dissolution after 10 min while F 12 gave the lowest.
Crospovidone is a cross-linked polyvinylpyrolidone. It is insoluble but highly hydrophilic. It was noticed that the tablets prepared by using the higher concentration of crospovidone found to dissolute the drug at a faster rate than those prepared by higher concentrations of croscramellose as superdisintegrant. These results agreed with that obtained by Shailesh et al., 2010, who found that increasing the concentration of Crospovidone during the formulation and optimization of promethazine theoclate FDTs led to increase the amount of drug dissolved after 10 min. Crospovidone facilitates penetration of liquid into the tablet and particles because its particles are porous leading to rapid disintegration (Raymond, 2006). In addition, crospovidone swells rapidly in water without gelling due to its high Crosslink density than other superdisintegrants (Shrivastava and Sethi, 2013). Moreover, Crospovidone displays effectively no affinity toward gel formation, even at high use levels in contrast to other superdisintegrants (Mohanachandran et al., 2011). A pronounced effect of the combination of different ratios of both crospovidone and crosscarmellose sodium as a superdisintegrants on the cumulative amount of drug  dissolved after 10 min was obtained (Patil and Das, 2011). These findings were in a good accordance with Jagdale et al., 2010. Lactose is an example of water soluble diluents used in these formulations. It was used as a sweetening agent and to enhance the tablets wettability and disintegration (Chandrasekhar et al., 2009).

Rank order of prepared PPH OFDTs
After characterization of the prepared OFDTs of postcompression parameters, the optimized formula which has the best properties (e.g. the lowest % variability, the shorter in vitro disintegration time, the fastest wetting time and the maximum % cumulative amount dissolved in 10 min) were selected for further investigation by conduction of rank order. The final rank order showed that F3 was the optimum formula. F10 and F14 were in the next order in OFDTs properties to F3 . The total and final rank orders are listed in Table 4. Table 5 exhibited the evaluation parameters, e.g. degree of the selected fast dissolving tablets F3. The results showed the effectiveness of PPH bitter taste masking as the final rank in the case of the tested formulation. The used amounts of aspartame (3%) with menthol (1%) were powerful in taste masking (Jae-Il and Hoo-Kyun, 2010). The results of the taste evaluation show that the formula was acceptable by more than half of the volunteers, while other volunteers showed good response and acceptable mouth feel with few show gritty mouth feel. The volunteers have no complain of numbness.    Table 6 shows the evaluation parameters (e.g. Weight variation, drug content, in-vitro disintegration time, wetting time, the% amount dissolved in 10 min,% friability and hardness) of the selected formulations F3, F10 and F14 that subjected to storage at 25 and 40°C. From this table, it is clear that weight variation and drug content showed non-significant variation (p values < 0.05).

Palatability test
For the disintegration time, there is a small decrease in the values for all formulations. The wetting time of F3 and F10 was decreased significantly, but it was not significantly changed in case of F14.
Regarding% amount dissolved in 10 min for all formulations after twelve weeks of storage under the mentioned conditions was markedly increased. The% friability for all formulations was slightly increased. F3, F10, and F14 showed significant decrease in their hardness values.

Conclusion
OFDTs containing PPH has been successfully developed and manufactured by direct compression method using different quantities of superdisintegrants and camphor as subliming agent. The tablets have acceptable physical and chemical properties. The use of two superdisintegrants in combination with subliming agent in the formulation resulted in tablet accepted properties. All tablets that were manufactured met the specification limits for all pre-and post-compression characterization parameters. Formulation of PPH as fast dissolving tablets resulted in a significant improvement in the dissolution, which could be reflected in PPH bioavailability enhancement.