The Influence of Storage Conditions on True Density
In order to investigate any changes in true density over storage condition, the true density measurement of matrices containing sodium metabisulphite was carried out for all formulations. The results indicated that there was no significant difference (p > 0.05) on the true densities of PEO polymer formulations in presence of sodium metabisulphite stored over 8 weeks at 40 °C. The results showed that the range of true density for fresh samples was between 1.29 and 1.33 g/cm3. As been claimed that there was no significant change observed in the true density of polymer formulations stored over 8 weeks, the values of the true density remained approximately the same (1.27–1.30 g/cm3) as the fresh samples.
The Influence of Sodium Metabisulphite on Hardness of Various Drug Tablet Matrices
Table 1 shows the effect of sodium metabisulphite at a 1% (w/w) concentration on the hardness of propranolol HCl, theophylline and zonisamide tablet matrices before and after storage time. In general, the hardness of the tablets increases as the molecular weight of the polymer increases. Interestingly, as shown in Table 1, there was no significant difference between the hardness of neither the fresh and aged (up to 4 weeks of storage) propranolol HCl matrices containing the antioxidant nor tablets prepared with different molecular weight PEO. It has only been seen that the hardness of the propranolol tablets was reduced slightly after 8 weeks of storage. This was due to the presence of the antioxidant that was preventing the possible degradation of the PEO matrices resulting in almost similar hardness. For comparison, the manufactured tablets without the SMB exhibited slightly lower values in the hardness of the tablets with PEO 750 (time 0 = ~90.2 N and week 4 = ~88.3 N). In contrast, overall results indicate an increase in tablet hardness over time for semi- and poorly soluble drugs (theophylline and zonisamide). The molecular weights of the polymer matrices seemed to play a pivotal role to the increase in the hardness of the produced tablets. This could be attributed to the fact that the presence of SMB might reduce the bonding strength between particles in the matrices at week 0, which then continues to increase as the storage time increases over 8 weeks.
The Evaluation Effect of Sodium Metabisulphite at Ratio (1% w/w) on Release Rate Behaviour of Propranolol HCl Tablet Matrices
In order to evaluate the effect of sodium metabisulphite on drug release, propranolol was chosen as a model drug due to its high solubility in water (solubility of propranolol HCl is 50.0 mg/ml) and results are shown in Fig. 1. The dissolution profile indicates that there were no significant differences between the release rates of the tablets at different storage time for both molecular weight PEO (compare Fig. 1a with b and c). The results showed that the storage temperature sustained the drug release process from the matrices from 0 week to 8 weeks compared to that of the ‘control’ formulations (without SMB). As can be seen from Fig. 1 b, c drug release was controlled for different storage time (2, 4, 8 weeks) when sodium metabisulphite was incorporated in propranolol HCl polymer formulations. This can be attributed to an increasing in viscosity of gel layer and, the formation of a gel layer with a longer diffusional path with a rise in the concentration of PEO. This means degradation as results of storage did not happen in matrices in presence of this antioxidant. This could be depending on the effect of sodium metabisulphite which dilated penetration of oxygen into the tablet matrices resulting to no degradation, and a loss in molecular weight of PEO did not occur in PEO. These results complement the previous study carried out by Shojaee et al.  who investigated the effect of different concentrations SMB on release rate of diltiazem HCl tablet matrices. The results showed that the drug release was controlled and much slower in the presence of this antioxidant compared to the samples without SMB (compare Fig. 1a with b and c).
On the basis of above information, some of the features in the dissolution rates of PEO can be elaborated particularly by similarity factor (f
2) values. All f
2 values for PEO 750 (low molecular weight) and PEO 303 (high molecular weight) are reported to be greater than 50 when the fresh tablets were compared to aged polyox matrices which is an indication of good similarity between their release profiles (Table 2).
Table 3 shows the results of fitting the dissolution data with the dissolution criteria carried out by calculation DE and MDT as described by Khan . As can be seen from Table 3, dissolution efficiency values are reliable with dissolution profiles and these data showed that there was no significant difference between DE data from both PEO 750 and 303. The results obtained for MDT confirmed the same trend (with DE) for both low- and high-molecular-weight PEO, and no major difference was obtained for MDT during the storage of the samples (Table 3).This again verified a stable release rate for both molecular weights PEO in the presence of the antioxidant. For illustration, the dissolution efficiency value of PEO 750 at time 0 was 84.0% whereas this value decreased to 82.0% for tablet matrices stored for 8 weeks at 40 °C. Slightly different pattern was obtained for PEO 303 with DE of 57% at 0 and the same value at week 8 (Table 3).
The Evaluation Effect of Sodium Metabisulphite at Ratio (1% w/w) on Release Rate Behaviour of Zonisamide and Theophylline Tablet Matrices
In order to cover a wide range of drug solubility, zonisamide, a very poorly water soluble drug (0.8 mg/ml) and theophylline, a semi-soluble drug (8 mg/ml) were chosen. The dissolution results of zonisamide and theophylline from the PEO matrix tablets in presence of 1% (w/w) SMB are depicted in Figs. 2 and 3. SMB readily reacts with dissolved oxygen and is converted into sodium hydrogen sulphate . The formulations containing SMB with both PEO 750 and 303 showed entirely different release profiles compared to the matrices without any antioxidant. For fresh tablets, within the first 2 h, about 90 and 75% of the drug released from PEO 750 and PEO 303 matrices, respectively, higher than matrices without SMB (compare Figs. 2a with b and c). At 8 weeks, drug release was further stalled, with approximately 90% being released after 12 h in a formulation including PEO 303; however, with time, instead of increasing, the dissolution decreased slightly. A deceleration of drug release at longer storage time is evident in Fig. 2b, c for preparations containing sodium metabisulphite; however, no major fluctuations can be seen with the antioxidant, proposing that sodium metabisulphite addition has stabilised the oxidation of the polymer. However, as the release profile was getting slower with time, there may be problems with a reproducible in vivo profile.
The difference in the effect of antioxidant is visible in Figs. 2 and 3 compared to that of Fig. 1, with whereby SMB dramatically increases dissolution at week 0 to almost 90 and 75% within 2 h for PEO 750 and 303, respectively. In contrast, a sustained release was achieved by SMB incorporation in propranolol HCl polymer formulations. The probable reason for this increased drug release could be the ionic property and solubility of SMB. The presence of sodium ions in the dosage form itself was reported to cause a rapid disintegration of extended release HPMC matrix tablets . Sodium metabisulphite is readily soluble in water, and in the presence of water, the compound dissociates and forms sodium ion (Na+) and hydrogen sulphite (HSO3
−) . Higher affinity between sodium ion and water molecules may have facilitated the swelling of matrix quickly. It is suggested that the possible enhanced drug release exhibited with sodium metabisulphite is as a result of its high ionic strength, implicating the cloud point (gelation temperature) of gel layers and affecting their formation. The higher the ionic strength, the greater the number of counter-ions available for ion exchange, increasing drug release through enhanced drug unloading . Regardless of the small quantity of sodium metabisulphite present within the batches, the interacting ions may be enough to affect gel layer function, inducing an insufficient barrier and drug release to considerably differ from SMB and the control batch (Fig. 2b, c). It is interesting to note that a good similar pattern release rate was obtained in a formulation containing semi-soluble drug theophylline with both PEO 750 and 303, and the results are shown in Fig. 3b, c. The reason for this drug release was driven for zonisamide tablet matrices earlier in this study. Although, decreasing in release rate with progressive storage time was not noteworthy in theophylline matrices with PEO 303 (Fig. 3c).
To confirm the dissolution profiles, f
2 test was employed to observe the effect of the antioxidants and results presented in Table 2 shows that all f
2 values (except for PEO 303 at week 2, f
2 = 69.5) are less than 50, which is determined that there were no similarity between fresh and aged samples, indicating slower drug release at longer storage time in samples containing sodium metabisulphite (Table 2). As can be seen from Table 2, f
2 values for PEO 750 and theophylline were in the same line, although all f
2 values were obtained for theophylline and PEO 303 are bigger than 50, which demonstrated similar release rate for fresh and aged samples.
DE and MDT as described by Khan  for zonisamide and theophylline matrices were carried out to match up to the dissolution data and results are given in Table 3. Dissolution efficiency values confirmed that the drug release rate from various PEO was slower when storage time increased, and a smaller DE was obtained at longer storage time. For instance, the dissolution efficiency value of PEO 750 with theophylline and zonisamide and at time 0 was 88.0 and 89.0% while this value declined to 83 and 84.1%, respectively, for aged matrices stored for 8 weeks at 40 °C. Similar patterns were observed for the other molecular weight PEO 303 (Table 3). The results obtained for MDT showed a similar trend for theophylline and zonisamide with fresh PEO 750 tablets being 1.06 and 1.11 h while this value increased to 1.36 and 1.25 h, respectively, at 8-week storage time which is an indication of slower drug release for the tablets stored at 40 °C for 8 weeks (Table 3).
In order to evaluate the effect of sodium metabisulphite on the mechanism of drug release from the formulations at different storage times, all release data were plotted in Korsmeyer and Peppas equation (power law model) which is the best equation to study the in vitro drug release in such polymeric matrices [28, 29]. Although the sample preparations may follow zero-order kinetic, first-order or Higuchi’s model, the results of kinetic release obtained from the matrices with and without SMB are given in Tables 4 and 5. The results showed that the n value for both PEO750 and 303 are between 0.68 and 1.49 which is indicated of anomalous release kinetics and indicates a super case II for all different formulations shown in Tables 4 and 5.
The thermal transitions of the formulations containing SMB before and after storage were investigated by DSC, and results are shown in Figs. 4 and 5 and Tables 6 and 7. For propranolol, the DSC traces of polyox matrices (PEO 750 and 303) with and without SMB clearly showed that there is a significant shift towards higher temperature when metabisulphite was present in the PEO 750 and 303 samples. This means that using the antioxidant could prevent degradation of PEO during a longer storage time with increased temperature. These results obtained via the DSC are summarised in Table 6 including the enthalpy, onset and melting peak. It appears from the table that for samples containing both PEO 750 and 303, the enthalpy values and temperature of melting peak did not decrease as the storage time progressed, maintaining almost similar enthalpies and melting peaks (Table 6).
The DSC traces for zonisamide matrices are presented in Fig. 5 and Table 7. DSC thermograms (Fig. 5) showed that presence of the SMB in PEO 750 and 303 polymer matrices resulted in moving towards higher temperature at longer storage time and an increase in enthalpies as the storage duration increased. This means the fast release rate resultant of using sodium metabisulphite in both PEO 750/303 at week 0 was controlled at longer storage conditions. It is also evident from Table 7 that there was an increase in the melting peak of matrices containing sodium metabisulphite, and then, it was controlled as storage time increased. A quite similar trend for thermal behaviour for theophylline matrices was observed (data not shown).
To cover a good range of drug solubility in presence of SMB, three model soluble drugs, namely, zonisamide, propranolol HCl and theophylline, with water solubility of 0.8, 60 and 8 mg/ml, respectively, were chosen. The results showed that the solubility of the drug by itself directly impacted on the release rate of different types of drugs. Moreover, results clearly demonstrated that sodium metabisulphite is a good candidate to prevent degradation in different molecular weight PEO in highly soluble drugs such as propranolol HCl (60 mg/ml). The observed results may be deemed expected, according to previous reports by Shojaee et al. , and our data for both PEO 750 and 303 containing propranolol HCl showed faster release for aged tablets without sodium metabisulphite; on the other hand, drug release was controlled in the presence of this antioxidant. It is interesting to note that there is no any other previous research that studied the effect of SMB in sustained release matrices. The results of the current study also illustrated that using SMB in the semi- and poorly water-soluble drugs, such as theophylline and zonisamide, had completely different effect in the beginning of drug release in terms of stability in comparison with the fresh samples without this antioxidant, although drug release decreased as storage time increased. These results particularly are not correlated with the previous data published by Shojaee et al. [32, 36], who studied the role of sodium metabisulphite on the release rate of diltiazem hydrochloride from polyethylene oxide. This was also a disagreement with earlier data observed in the beginning of this study with propranolol HCl and the reason is given earlier.