Effect of Binder Type and Binder Level on the Properties of Agglomerates Containing Lactose and Dibasic Calcium Phosphate Dihydrate

October 2, 2008
Pharmaceutical Technology, Pharmaceutical Technology-10-02-2008, Volume 32, Issue 10

The authors studied the effect of the combination of binders on the flow and compressibility characteristics of the agglomerates of binary combination of lactose and dibasic calcium phosphate dihydrate.

With the introduction of instrumented single and multistation tablet presses, directly compressible materials have gained increasing importance in tablet formulations. Materials comprising individual unmodified particles are not often suitable as filler–binders because of their lack of flowability (e.g., native starches), lack of binding properties (e.g. α lactose monohydrate 100#), and lubricant sensitivity (e.g., native starches). Although binding properties can be improved with physical modifications such as dehydration, partial pregelatinization, and coating, the flow properties of these products are often still insufficient (1). Coprocessed multicomponent-based excipients help achieve better powder characteristics and tableting properties than when a single substance or a physical mixture is used (2), and several coprocessed filler–binders have appeared in the pharmaceutical market in recent years.


This study evaluated six binders: the traditional binders hydroxypropyl methylcellulose (HPMC), guar gum, acacia, and polyethylene glycol (PEG); colloidal silicon dioxide, which has been reported to increase the hardness of the tablets (3); and starch, which exhibits both binding and disintegrant properties when it is incorporated either as a paste or dry before granulation with other agents. Wet granulation was used because of its simplicity.

Several studies have reported the influence of individual binders on the tensile strength of tablets (4–9). Very few studies have actually combined more than one binder in a single formulation and evaluated their influence on tensile strength (10). In this study, the Plackett-Burman statistical design was used to screen the factors affecting a certain attribute (11–14). These variables were optimized to achieve the desirable response after initial screening (15). Various combinations of the six binders were used according to the Plackett-Burman design to prepare a directly compressible adjuvant.


Materials. Lactose, dibasic calcium phosphate dihydrate (DCP), starch, PEG, and HPMC 15 cps were received as generous gifts from Bombay Tablets (Gandhinagar, India). Acacia, guar gum, magnesium stearate, and colloidal silicon dioxide were received from Torrent Research Centre (Gandhinagar, India).

Table I: Factors in the Plackett-Burman screening design.

Experimental design to prepare agglomerates

Six binders were used to prepare coprocessed directly compressible adjuvant containing lactose and DCP. Table I lists the binders used and the amount used of each. The binders were screened using a 12-run Plackett-Burman design. Table II shows the composition of each batch of agglomerates prepared using various binders as per the Plackett-Burman design. Fifty grams of lactose and 25 g of DCP were mixed. The binders were added according to the Plackett-Burman design. The whole system was mixed, and water was added as an agglomerating agent. PEG when used was dissolved in water before being added to the main bulk. The mass was forced through a 20# sieve and dried in a hot air oven at 80 ° C. The dried agglomerates were sifted through a 40# sieve. The agglomerates of 40–200# were collected and stored in an airtight container until further use.

Table II: Formulation of various batches of agglomerates using a Plackett-Burman design and results of evaluation parameters.

Evaluation of agglomerates

Angle of repose. The angle of repose θ for each powder was determined by placing 30 g of the powder in a funnel. The tip of the orifice of the funnel was fixed and the powder was allowed to flow only under gravity. The angle of repose θ was calculated from the equation tan(θ) = h/r, in which h is the height of the pile of powder and r is the radius of the base of the cone (16).

Carr's index. Thirty grams of each sample were poured through a funnel into a 100-mL tarred graduated cylinder. The cylinder was then lightly tapped twice to collect all the powder sticking on the wall at the bottom of the cylinder. The volume was then read off directly from the cylinder and used to calculate the bulk density. For tap density, the cylinder was tapped from a height of 2.5 cm for 100 times on a wooden bench top before a constant reading was obtained. The percentage compressibility (Carr's index) was calculated as 100 times the ratio of the difference between tapped density and bulk density to the tapped density (17).

Evaluation of compressional characteristics

Preparation of blank tablets. The agglomerates (97%) of each batch of Plackett-Burman design were blended with 2% talc for 5 min and with 1% magnesium stearate for 2 min. Tablets were compressed by using 9-mm diameter flat-faced punches and die on a single–punch tablet machine (Cadmach Machinery Pvt. Ltd., Ahmedabad).

Crushing strength of blank tablets (CSB). The crushing strength of the tablets was determined after 24 h of compression, which allowed time for stress relaxation of the compression, using a tablet tester (Tablet Tester 8M, Dr. Schleuniger Pharmatron, Solothurn, Switzerland).

Preparation of tablets containing acetaminophen. The capacity of a direct-compression tablet diluent is the maximum proportion of other materials that can be mixed with it, while still obtaining tablets of acceptable quality. The capacity will depend on the nature of the materials added because the tableting properties of the drug itself will contribute to the overall tablet strength. Gohel et. al. have used acetaminophen as a model poorly compressible drug (10). Therefore, to test the capacity of the prepared agglomerates, tablets containing 30% acetaminophen were prepared. Tablets (n ≥ 50) containing acetaminophen (150 mg) and agglomerates of each run (350 mg), talc (10 mg), magnesium stearate (5 mg) were prepared on a single-punch tablet machine (Cadmach Machinery Ltd., Ahmedabad). The tablets containing acetaminophen were evaluated for crushing strength (CSP).

Optimization design. Based on the results of the screening experiment, three potential binders were identified to affect the properties of the agglomerates. These were further studied for optimization using a 23 factorial design, consisting of 3 binders at 2 levels. The design experiment was set up to investigate the effect of significant variables and their interactions on the agglomerates' characteristics. Table III shows the batch composition of the experimental design. The procedure followed for the preparation of the agglomerates was same as that used in the Plackett-Burman design. The agglomerates were evaluated for angle of repose and compressibility index. Blank tablets were prepared using agglomerates and evaluated for crushing strength (CSB). Tablets containing acetaminophen were prepared using 30% acetaminophen and 70% agglomerates, which were then evaluated for crushing strength (CSP).

Table III: Composition of batches of agglomerates using a 23 factorial design, showing level of factors and their measured responses.

Friability. Friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (model EF2, Electrolab, India) for 4 min at 25 rpm. The tablets were dedusted, the loss in weight caused by fracture or abrasion was recorded, and the percentage friability was calculated (18).

Disintegration time. A disintegration test was performed using standard disintegration test apparatus (model ED2, Electrolab, India) at 37 °C in 900 mL of distilled water for six tablets in accordance with USP 24 (19).

In vitro dissolution study. An in vitro dissolution study of the tablets was carried out in phosphate buffer (pH 5.8, 900 mL, 37 ± 0.5 °C) using USP 23 paddle apparatus (50 rpm). Samples (5 mL) were withdrawn at predetermined time intervals, filtered through 0.45 αm filter, and assayed at 246 nm using a UV–vis spectrophotometer (Jasco V530, Japan) to determine the percentage of drug released. The same volume (5 mL) of fresh dissolution medium (37 ± 0.5 °C) was replenished immediately after the sample was withdrawn (20).

Results and discussion

Analysis of the data. The response parameters were fitted to a first-order polynomial model Y = B0 + B1X1 + B2X2 + B3X3+ B4X4 + B5X5 + B6X6 by performing multiple linear regression analysis using Design Expert 7.13 trial (Statease stastical software package). ANOVA was performed on the response parameters to identify the statistically significant factors (see Table IV).

Table IV: Regression analysis data for the parameters evaluated as per Plackett-Burman experimental design.

Evaluation of agglomerates. Angle of repose (Y1). Regression analysis showed that acacia has the highest effect on angle of repose, but the value of its coefficient is positive, which indicates that as the amount of acacia increases, the value of angle of repose increases, resulting in poor flow. Starch was the best in improving the flow properties. Although the remaining four excipients had similar effect in improving the flow properties, the effect was less pronounced than when starch was used.

Carr's index (Y2). HPMC, starch, and silicon dioxide, when used for granulation, had significant effects (p < 0.01) on the compressibility index. The negative sign of their coefficients indicates that they reduce the compressibility index values and thus yield agglomerates with better flow. Guar gum and PEG also improved flow but to a lesser extent. Acacia had a significant effect on compressibility index, but the positive sign of its coefficient indicated that it resulted in poor flow. These findings are similar to those of Chukwu et. al., who reported the poor flow properties of granules prepared using acacia (21).

Evaluation of crushing strength of blank tablets (Y3). PEG has the most significant effect (p < 0.005) on the blank tablets' crushing strength. All the batches exhibiting hardness >100 N showed the presence of PEG. PEG alone, however, may not be a very good binder. The binder may have occupied the voids between the particles, decreasing the porosity of the tablet. Thus the addition of binder with a low yield-pressure value and a relatively small elastic-recovery value (e.g., PEG and PVP) results in tablets of low porosity and high tensile strength (22). The other excipients also tended to increase the hardness of the blank tablet, except acacia.

Evaluation of tablets containing acetaminophen (Y4). Table IV shows that guar gum had the most significant effect on the crushing strength of the tablets containing acetaminophen. HPMC, acacia, and silicon dioxide increased the hardness of acetaminophen-containing tablets, and PEG and starch decreased the hardness of the tablets. Acetaminophen is a poorly compressible drug; therefore, the filler–binder must be robust enough to take up this poorly compressible material and still retain its compressibility. The interaction with the other components of the system might have caused the lower values of coefficients of PEG and starch in the equation for the calculation of CSP. The directly compressible diluent thus behaves in a different manner in presence of acetaminophen. Many researchers have emphasized the fact that the directly compressible diluent behaves differently in presence of drugs; therefore, it is necessary to choose a right directly compressible diluent for a particular drug (23).

23 factorial design. The Placket-Burman design indicated that starch, silicon dioxide, and HPMC had pronounced effect on the compressibility index. Starch was a common ingredient affecting the angle of repose and compressibility index. The results of crushing strength indicate that guar gum and polyethylene glycol had predominant effects on the crushing strength of the blank tablets. Guar gum was a common factor affecting the crushing strength of the blank tablets and that of acetaminophen-containing tablets. Hence the 23 factorial design was applied, with starch and guar gum as constant excipients along with the lactose and DCP and hydroxypropyl methylcellulose (A), silicon dioxide (B), and polyethylene glycol (C) were varied at two levels in accordance with the data shown in Table III.

Results from the analysis of data obtained for each response parameter were fitted into a linear polynomial equation of the form

Y = b0 + aA + bB + cC + abAB + bcBC + caCA + abcABC

in which Y is the level of response parameter, b0 is the arithmetic average of eight response and a, b, c, ab, bc, ca, and abc are the estimated coefficients for the factors A, B, C and the interaction terms AB, BC, CA and ABC, respectively. ANOVA was performed to eliminate the non-significant terms from the equation.

Table V: Regression analysis data for the parameters evaluated as per 23 factorial design indicating the values of coefficients for the factors and their interactive terms

The results of regression analysis (see Table V) indicate that silicon dioxide had a significant effect on the angle of repose (Y1) and compressibility index (Y2) of the agglomerates. Silicon dioxide had the lowest values of the coefficients in the regressed equations for the angle of repose and Carr's index. The high-value coefficients for silicon dioxide in equations for CSB (Y3) and CSP (Y4) indicate that using silicon dioxide increases the hardness of the tablets more than using both HPMC and PEG. The role of silicon dioxide in increasing the hardness of tablets also been has appreciated by Linden et. al (3). The combination of starch, guar gum and silicon dioxide was thus vital to achieving the desirable attributes for the tablets.

Figure 1, (All figures are courtesy of the authors.)

Figure 1 indicates that for obtaining the lower values of angle of repose, the amount of all three components should be kept low. At higher amounts of HPMC and silicon dioxide, the interaction between the two components becomes more prominent, and the graph loses its linearity. Nevertheless the angle of repose values are <25 for all combinations of HPMC and silicon dioxide when PEG is absent.

Figure 2, (All figures are courtesy of the authors.)

Figure 2 indicates that a high level of HPMC and a low level of silicon dioxide gives lower values of Carr's index and vice versa. The interaction between the three components plays a major role in determining the value of compressibility index, as indicated by the high value of the coefficient of interaction term in the equation for determining Carr's index. Similarly, Figure 3 indicates higher levels of HPMC and silicon dioxide are required for obtaining higher values of CSB; and Figure 4 indicates that a higher level of silicon dioxide is required to achieve the higher value of CSP.

Figure 3, (All figures are courtesy of the authors.)

For a material to be a good filler–binder, it should be free flowing and at the same time have good compaction properties (24). The lower values of angle of repose and compressibility index and higher values of crushing strength are indicative of the same. It was therefore decided that the angle of repose values <25, compressibility index <15, CSB >50 N, and CSP >50 N would be constraints for the selection of the best batch.

Figure 4, (All figures are courtesy of the authors.)

Figure 5 shows the overlay plot. Superimposing the contour of individual responses to achieve a region that satisfies the constraints for all the attributes generated the overlay plot. All combinations falling in the yellow region satisfy the selected constraints. Batch F3 falls is this region and therefore was selected as the best of the batches prepared according to the 23 factorial design. Tablets containing 30% acetaminophen and 70% agglomerates of batch F3 had friability values <1% and disintegration time <15 min. The in vitro dissolution study indicated that more than 90% of the drug released in 30 min, indicating the noninterference of the filler–binder with drug release.

Figure 5, (All figures are courtesy of the authors.)

Validation of the evolved mathematical models. To validate the evolved mathematical models, two check points were selected. Two batches CH1 and CH2 were prepared and evaluated (see Table VI). To further validate the model an optimum batch OPT was located using grid analysis where angle of repose was 23°, Carr's index was 12, crushing strength of blank tablet was 110 N, and crushing strength of acetaminophen containing tablets was 51 N. Close agreement was found between observed and predicted values, thus strengthening the predictability of the mathematical model.

Table VI: Validation of the evolved mathematical models.


Various binders were screened for their effect on agglomerates of lactose and dibasic calcium phosphate diydrate. Each binder shows marked effect on various aspects of the agglomerate. If HPMC, starch, and silicon dioxide enhance the flow properties, acacia has a negative effect on these properties. PEG increases the crushing strength of blank tablets. Guar gum increased the hardness of tablets containing acetaminophen. Combination of binders for agglomeration of lactose and DCP to yield a directly compressible product with desirable attributes could be isolated using the 23 factorial design.

Anita Lalwani* is an assistant professor in the Department of Pharmaceutics at the K.B. Institute of Pharmaceutical Education and Research, Sector-23, Gh-6 Road, Gandhinagar-382023, Gujarat, India, tel. 91 98983 20018, anitanlalwani@yahoo.co.inJolly Parikh is an assistant professor in the Department of Pharmaceutics at A.R. College of Pharmacy and G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar-388 120, Gujarat, India.

*To whom all correspondence should be addressed.

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