Each of the levetiracetam effervescent tablets consists of a particular composition of citric acid and effersoda. The results of the FTIR study demonstrates that the excipients used in the present study are compatible with levetiracetam and there is no interaction between levetiracetam drug and other ingredients.
It is always critical and tedious to develop and optimize complex manufacturing processes of any dosage form. Thus, efforts have been made to utilize different statistical designs to overcome these types of problems. Among various experimental designs, RSD is the most common advanced design used for statistical process control and design of pharmaceutical formulations. Based on selected design, a total of 14 formulation combinations (C1–C14) were made and evaluated for micromeritic properties (angle of repose, bulk density, tapped density, Carr’s index, Hausner’s ratio, and water content).
From the preformulation study, it was observed that majority of formulations exhibited fair angle of repose, reflecting excellent or good flow abilities as per USP general chapter . However, the compressibility of blends were coming under fair (16–20) to passable (20–25) category. While there were variations in the bulk density of the formulations, the tapped density of all the formulations were found to be close to each other. It has been observed that as the concentration of citric acid and effersoda increased, the flow property decreased. This is due to very poor rheological properties of both citric acid and effersoda .
The final lubricated powder blends were used for the development of levetiracetam effervescent tablets. The formulated effervescent tablets were evaluated for various parameters, such as weight variations, hardness, friability, effervescent time, amount of carbon dioxide released, drug content analysis, and percentage of drug release.
Weights of tablet layers of all formulations (C1–C14) were in close proximity to the actual value. It has been observed that the percentages of drug release for all formulations were found to be more than 90%. It is due to BCS class I solubility characteristics of levetiracetam which enables higher solubility of levetiracetam across the pH.
The release of carbon dioxide study of the formulations was carried out by using alcalimetric method. In this method, the water is taken by the sulfuric acid and thus, the determination is more accurate and exact . From the study, it has been observed that apparently a lower amount of carbon dioxide is being released for all formulations. This may be due to use of hygroscopic diluents such as sorbitol and anhydrous lactose. The high absorption capacity of these diluents causes beginning of an effervescent reaction slow. A similar type of result was reported in a study while developing the effervescent formulation containing sorbitol as a diluent . It has been also observed that the amount of carbon dioxide released for all formulations were similar and of close proximity to each other.
For the optimization of citric acid and effersoda ratio, the effect of variables on hardness, friability, and effervescent time was investigated through polynomial equation and response curves.
The RSM effect of each response was studied with respect to the independent variable citric acid and effersoda. From the study of RSM effect of citric acid and effersoda on hardness, it has been observed that the hardness vary from 123 to 158 N. The observed tablet hardness was relatively higher. This result is due to the properties of used excipients such as anhydrous lactose, mannitol, and starch. All these excipients are having high-binding capacity, good compressibility which enables to produce quality, robust tablets at lower compression forces. Moreover, anhydrous lactose has a lower lubrication property which enables high elastic modulus and tensile strength. In the formulation, higher amount of anhydrous lactose was used which reduces surface irregularities and increases the tensile strength. A study by Sun et al. also obtained similar results by using lactose and mannitol as a diluent .
There was a clear indication from the results that the ratio of citric acid and effersoda imposes a great impact on the response variable hardness. A trend of increase in hardness of the tablet was observed with increase in concentration of citric acid and effersoda ratio from 187.5 to 640 mg. The increase in tensile strength of the tablets with increase in concentration of citric acid is attributed due to the physical properties of citric acid. The unique coarser particle size properties of citric acid support the bonding between the particle surfaces and resulted in a stronger compact. As a result with increase in concentration of citric acid:effersoda ratio, the hardness also showed an increasing or upward trend. The results obtained were in consonance with the study conducted by Sun et al. reporting a relation of citric acid with hardness .
However, it has been observed that the required hardness was achieved when citric acid:effersoda was used in 640:640 mg (1:1 ratio). Higher amount of both the ingredients decreases the hardness. This could be attributed due to the plasticizer properties of citric acid when used in larger quantity. As the citric acid concentration was increased, the citric acid present in the blend played a role of plasticizer, which decreased the interactions among the macromolecules and resulted in the decrease of the tensile strength . The diminution of hardness may also be endorsed due to the plastic deformation of sodium bicarbonate when compressed. The results obtained were in agreement with the early work with sodium bicarbonate suggesting plastic deformation .
From the RSM effect of citric acid and effersoda on friability, it was observed that all formulations were within the friability limit of not more than 1%. A direct relationship between percentage of friability and tablet hardness was observed. Study has also reported that there is a direct relationship that exists between percentages of friability with the tablet hardness . From the analyzed data, it was inferred that friability was less when the concentration of both the variables are in 640 mg:640 mg (1:1 ratio). However, higher friability was observed when the concentrations of both the variables are less than 640 mg, and same trend was observed with higher concentration of citric acid and effersoda. The full quadratic polynomial equation model used to measure the response friability revealed very negligible and small values of interaction effects, squared effects, and linear effects. The observed values of MLRA studies indicated that the obtained results of friability are mainly influenced by hardness.
There was a clear indication from the results that there was no significant effect of both the independent factors individually on effervescent time. However, ratio of citric acid and effersoda imposes a great impact on the response variable effervescent time. A trend of decrease in effervescent time was observed with increase in concentration of both citric acid and effersoda from 640 to 1092 mg. This may be due to increasing amounts of citric acid and sodium bicarbonate that result in formation of carbon dioxide which helps to break up the tablet and accelerates faster reaction .The high hardness of the tablet also affected the effervescent time. In hardness study, it was observed that there was an increase in hardness of the tablets with increase in concentration of citric acid and effersoda ratio from 187.5 to 640 mg. On the other hand, higher amount of both the ingredients decreases the hardness. The similar trend was observed for effervescent time also. Thus, it was believed that the effervescent time was driven by both hardness and reaction of both citric acid and effersoda. Similar types of results were observed by Sun et al.  while developing fast dispersible fruit tablet made from mango, Chlorella, and cactus powder.
The RSM effect of citric acid and effersoda on effervescent time revealed that higher effervescent time was observed with citric acid:effersoda in 640 mg:640 mg (1:1 ratio). Our observed effervescent time with citric acid:effersoda in 640 mg:640 mg (1:1 ratio) was found to be from 96 to 102 s. A lower effervescent time was reported with other combinations of citric acid and effersoda (68 to 83 s). Moreover, as per EP, the limit for effervescent time should be less than 5 min. All the effervescent tablet formulation had acceptable effervescent time value. However, based on the required responses, i.e., hardness, friability, and effervescent time, the formulation containing citric acid:effersoda in 640 mg:640 mg (1:1 ratio) was considered as optimized formulation.
The standard error of the regression equation (S) which represents the relation between actual and predicted response was found to be 2.36032, 0.02878, and 2.3554 for hardness, friability, and effervescent time respectively. It represents the average distance of the data points from the fitted line and found to be 2.36%, 0.02%, and 2.35% respectively for hardness, friability, and effervescent time. The adjusted regression values (R2) for hardness, friability, and effervescent time were 0.9939, 0.9892, and 0.9808 respectively. The lower S value and higher adjusted regression values (R2) reflected the appropriateness or goodness of the model. Among all the manufactured formulations, C3, C4, C6, C8, C9, and C13 were selected as optimized formulations in view of reduced friability, acceptable hardness, and effervescent time. These 6 trials represent the center point of the studied model.