THE METHOD OF RANDOM BALANCE FOR STUDYING THE INFLUENCE OF EXCIPIENTSʼ QUANTITIES ON TECHNOLOGICAL PARAMETERS OF METFORMIN ORODISPERSIBLE TABLETS

Methods: The tablets were prepared by using direct compression method. The formulations were designed according to the method of random balance. The technological parameters of metformin orodispersible tablets have been studied as a function of quantitative factors: crospovidone (Polyplasdone XL-10®), magnesium aluminometasilicate (Neusilin US2®), microcrystalline cellulose (MCC Sanaq®burst), lactose monohydrate, magnesium stearate (Tablube®MgSt micronized vegetable) and talc.


INTRODUCTION
Diabetes is an important public health problem, one of the major causes of morbidity and mortality in the world [1,2]. According to the data International Diabetes Federation (IDF) Diabetes Atlas, [3] there are 425 million people with diabetes in the world. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, which has increased alongside cultural and societal changes. Around 90 % of patients with diabetes have T2DM. There is an increasing tendency in the number of patients with T2DM. The most common objectives of T2DM are overweight and obesity rates, lifestyle and dietary changes, and an aging population. Managing T2DM is complex and time-intensive. There are many clinical practice guidelines to manage T2DM. Now all the guidelines recommend metformin as the first choice for initiating pharmacological treatment of people with T2DM [4][5][6].
The pharmaceutical technologists have developed a new oral dosage form known as orodispersible tablets (ODT). They disperse rapidly in saliva before being swallowed, without the taking water (disintegrate within 3 min) [7,8].
In the previous study, the effects of 16 different excipients on technological characteristics of metformin ODT were evaluated. Based on the obtained results related to the choice of excipients, the best excipients were chosen for the development of metformin ODT [9].
The aim of our study was to analyze the influence of the amount of excipients on the technological parameters of metformin ODT using the method of random balance.
In our investigation, we used the method of random balance, which is based on the fact that the significance of certain factor effects depends on their contribution to the response variance [10].
Primarily, the matrix of design of experiments was defined, the experiment took place and based on its results scatter diagrams were constructed. Significant factors are taken from scatter diagrams, and their selection is proved by calculations. The design construction of experiments matrix is preceded by coding the factors, selection of variation levels and by determining the experiment center [11].
The formulations were designed according to the method of random balance. In this design, technological parameters of metformin ODT have been studied as a function of 6 quantitative factors. The names of factors, with their variation levels, are shown in table 1.
We studied Polyplasdone XL-10 ® crospovidone as a superdisintegrant in the metformin ODT. During tablets compression, crospovidone particles become highly deformed. After water penetration into the tablets, the deformed particles of Polyplasdone ® recover their normal structure, then swell and cause hydrostatic pressures necessary to provide rapid disintegration in the mouth [12,13].
MCC Sanaq ® burst can be used as a disintegrant and filler in tableting. It has excellent compressibility. The outstanding plasticity enables to produce tablets with high strength. Furthermore, the tablets have very short disintegration time [14].
Neusilin US2 ® is a multifunctional excipient which can be used for direct compression. It has a porous structure which improves flowability of powder mixtures and hardness of obtained tablets. In addition, low concentrations of Neusilin US2 ® can improve the hardness of other filler and binder excipients [15,16].
The sugar-based excipients display high aqueous solubility and sweetness and hence have a taste masking property and provide pleasing mouth feel [17,18]. Lactose was used as the sugar-based excipients. Tablube ® MgSt micronized vegetable was used as a lubricant. Talc was used as a glidant and lubricant.

Preparation of tablets
Fast dissolving tablets of metformin were prepared by direct compression method according to the matrix given in table 2.
All the ingredients were passed through #60 mesh separately, weighed and mixed. MCC 200 was added in the amount of 24 % of tablet's weight. Then lubricant and talc powder (# 200 mesh) were added and mixed for further 5 min. The mixture was directly compressed using 12 mm flat round punches into tablets of 500 mg on a single tooling tablet compression machine. A batch of 60 tablets was prepared for all the designed formulations.

Pre-compression evaluation
Before compression, the powder mixture from each formula was evaluated by several parameters such as flowability, bulk density and tapped density. The results of the pre-compression parameters were shown in table 2.

Flowability
Flowability was determined using the fixed funnel method. The powder mixture (±100 g) was poured through the funnel. The time for the powder mixture to fall down through the funnel was used to calculate flowability of the powder [19].

Bulk density
Bulk density of the powder mixture was determined by pouring the powder into the graduated cylinder. The bulk volume and weight of the blend were also determined. The bulk density is the ratio of the total mass of the powder to the bulk volume of the powder [20].

Tapped density
Tapped density is the ratio of the total mass of the powder to the tapped volume of the powder. The volume was measured by tapping the powder for 500 times. The volume was read every 100 intervals [20]. Tapped volume was noted if the volume did not show a difference between two tapping intervals.

Evaluation of tablets
The results of the technological parameters of obtained metformin ODT were shown in table 3. All the prepared tablets were evaluated for the following parameters:

Uniformity of weight
Twenty tablets were weighed individually, and the average weight was compared with the individual tablet weights. As per the specifications, for tablets weighing 250 mg and more, the allowed weight variation deviation is 5 %. The tablets meet the test if not more than two tablets are outside the limit and no tablet differs the limit by more than twice [21].
The tabletʼs hardness is used to test the breaking point. The resistance of tablets to shipping, breakage, under conditions of storage, transportation, and handling before usage depends on their hardness. The hardness of each batch of tablets was measured in Newton, where five tablets from each formula were tested through tablet's hardness tester (Tianjin Guoming Medicinal Equipment Co., LTD), and then the average value was documented [21].
The friability test was conducted by placing pre-weighed tablets in the friabilator (Tianjin Guoming Medicinal Equipment Co., LTD); the latter was operated at 25 rpm for 4 min. The tablets were deducted and the weight loss caused by fracture or abrasion was recorded as the percentage weight loss. Tablets should lose not more than 1 % of their weight to be acceptable [19,21].
The disintegration time for all formulations was carried out using tablet disintegration test apparatus. Six tablets were placed individually in each tube of the disintegration test apparatus and discs were placed. The water was maintained at the temperature of 37±2 °C and the time taken for the entire tablet to disintegrate completely was noted [19,21].

Wetting time
A piece of circular tissue paper (8 cm) folded twice was placed in a Petri dish containing 10 ml of buffer solution simulating saliva pH 6.8. A tablet was placed on the paper and the time taken for complete wetting was noted. Three tablets from each formulation were randomly selected and the average wetting time was noted [20,22].

RESULTS AND DISCUSSION
Scatter diagrams were constructed based on the results from table 2 and  table 3. Determination of significant factors was carried out using scatter diagram. The difference between the average values of the factor for the upper and lower levels determines the influence of the factor on the technological parameter. The difference between the average values of the parameter is shown through the median on scatter diagram. The value of the median indicates the significance of the factor. Then, the significance check of the obtained effects is done by the Students tcriterion.
Based on the results of the pre-compression parameter, it can be concluded that all formulas have good flowability. The flow velocity of the powder blend has the predictive power for its ability to fulfill the dies during the compression stage. The homogeneity of powder flow will decrease the variation in the tablet weight.
The analysis of the scatter diagram of flowability results shows the significance of the effects of factors х3 and х1 ( fig. 1). Increasing the quantity of Neusilin US2 ® (х3) from 2 to 4 % in powder mixtures leads to the reduction of the flow time of powder from the funnel. Better flowability results are obtained when Polyplasdone XL-10 ® crospovidone is introduced in an amount of 3 % in powder mixtures. Although the statistical significance of other factors within the studied intervals has not been confirmed, the medians of the factors x2 and x4 are visually distinguished on the scatter diagram of flowability results. The flow rate of the investigated powders is better in those formulations, which contain less quantity of MCC Sanaq ® burst (2 %) and lactose (8 %).  . .

Fig. 1: Scatter diagram of flowability results
The influence of quantitative factors on the bulk density (y2) is depicted in fig. 2. The analysis of the scatter diagram of bulk density results and significance check of obtained effects show the statistically significant effects of factors х3 and х6. The smaller the content of Neusilin US2 ® is in the powder mixtures for pressing, the larger the value of bulk density becomes. The introduction of the talk on the lower level (factor x6) into the composition of the powder mixtures reduces the value of the studied parameter.
The influence of the investigated factors on the tapped density is shown in fig. 3. The impact of the factors x3 and x6 on the tapped density is significant at the level α=0.05 and α=0.10, respectively (table 4). Adding the factor x3 at the upper level in the powder mixtures decreases the value of tapped density. The median of the effect of the factor x6 shows that the decrease in the amount of talk causes the reduction in the value of the tapped density.    .

Fig. 4: Scatter diagram of uniformity of weight results
As the mixture for pressing was characterized by satisfactory flow velocity, the obtained tablets had uniform weight from 0.93 to 2.30 % (table 3). The impact of factors х1 and х6 on the uniformity of tablets' weight was significant on the level of 95 %. The increase in the amount of Polyplasdone XL-10 ® crospovidone improves the uniformity of tablets' weights. The decrease in the amount of talk (х6) in the formulations causes a reduction in the percentage deviation from the average weight of tablets. From fig. 4, we can observe that a median of the effect of x2 on the uniformity of tablets' weight is noticeable. An increase in the amount of MCC Sanaq ® burst in the formulations improves tablets' uniformity.
The metformin ODTs were characterized by satisfied hardness, except the formulations # 5-7, values of which were less than 50 N (table 3). The impact of factors х2 and х3 were significant. The decrease in the amount of MCC Sanaq ® burst in the tablets leads to an increase of hardness. Adding Neusilin US2 ® by 4 % (upper level) to the tablets causes an increase of hardness. From fig. 5, it is observed that the medians of the effect of х1 and х4 on the tablet hardness are noticeable. The decrease in the amount of Polyplasdone XL-10 ® crospovidone and lactose in the formulations causes an increase in this indicator.
The friability of metformin tablets less than 1 % observed in all formulations, meets the requirements of the European Pharmacopoeia and State Pharmacopoeia of Ukraine for tablets. The impact of factors х2 and х3 on the friability of tablets was significant on the level of 95 %. The tablets containing Neusilin US2 ® on the upper level were the most resistant to abrasion. The better results of friability were obtained in formulations, which contain less quantity of MCC Sanaq ® burst (2 %).
From fig. 6, we can observe that the medians of the effect of х5 and х6 on the friability of metformin tablets are noticeable. The percentage deviation from the average weight of tablets after friability is less in formulations, which contain Tablube ® MgSt (1 %) and talc (2 %).

Fig. 8: Scatter diagram of wetting time results
Wetting time test is not a standard test, but it is useful for quality control and provides a correlative evaluation of water absorption. The wetting test uses a minimal quantity of buffer solution simulating saliva pH 6.8, which represents the amount of moisture available in the oral cavity [20]. The wetting time for all formulations of tablets was less than 25 s. The faster wetting time of the tablets produces better disintegration time.
The impact of the investigated factors allowed us to discover the statistical significance of the factors х1 and х5. The decrease in the amount of Tablube ® MgSt grade micronized vegetable and the increase in the amount of Polyplasdone XL-10 ® crospovidone in tablets enable to reduce the absorption time in phosphate buffer (pH 6.8).
As the reduction of the amount of Polyplasdone XL-10 ® crospovidone in the powder mixtures improves flowability and tabletʼs hardness but simultaneously worsens uniformity of weight, disintegration and absorption time in the phosphate buffer (pH 6.8). Hence, the amount of Polyplasdone XL-10 ® crospovidone (x1) was stabilized at a basic level of 4 % in the formulations.
The impact of the amount MCC Sanaq ® burst (x2) on the technological parameters of the metformin ODT is ambiguous. The decrease of its amounts accelerates the flowability of powder mixtures, but increases the uniformity of tablets weight, and improves mechanical strength and disintegration time. Hence, on the next stage of research, we have decided to investigate more detailed the impact of the amount of MCC Sanaq ® burst on the main technological parameters of metformin tablets.
The amount of Neusilin US2 ® in the powder mixtures has the greatest impact on the technological parameters of the tablets. Thus, the reduction of its amount in the powder mixtures improves flowability, bulk density, and tapped density. However, the increase of its amount allows us to obtain tablets with higher hardness and friability. Hence, on the next stage of research, we have decided to investigate the impact of the amount of Neusilin US2 ® on the main indicators of metformin ODT.
We have decided to stabilize the amount of lactose monohydrate at a lower level of 8 % in the powder mixtures. The amount of Tablube ® MgSt grade micronized vegetable has been decided to stabilize at the upper level in the amount of 1 %. As with the increase of its amount we have obtained the better flowing properties of the powder mixtures, tabletʼs hardness and friability. The amount of talc has been decided to stabilize at the upper level of 2 %.

CONCLUSION
Oral disintegrating tablets of metformin were successfully prepared by direct compression method. All the oral disintegrating tablets possessed good physicochemical and dissolution properties. The random balance method enabled us to identify the most significant quantitative factors and stabilize them at optimal values, except the two factors of MCC Sanaq ® burst and Neusilin US2 ® . For these factors, an additional stage of optimization will be conducted at the next stage of the studying.