http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, 2015; 41(2): 333–341 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.859266
RESEARCH ARTICLE
Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations Drug Dev Ind Pharm Downloaded from informahealthcare.com by Kainan University on 04/13/15 For personal use only.
Naveen K. Bejugam, Shravan K. Mutyam, and Gita N. Shankar SRI International, Menlo Park, CA, USA
Abstract
Keywords
Objective: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching. Methods: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors – roller compaction pressure, intragranular filler percent and filler type – were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors. Results: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index. Conclusion: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.
Direct compression, dry granulation, roller compaction, statistical design, stickiness, tablets
Introduction Tablets are one of the most widely prescribed oral solid dosage forms for drug delivery because of their inherent simplicity in handling and administration. Typically, the ingredients that make up the tablet blend include the active pharmaceutical ingredient (API) and various excipients. Three techniques can be used to prepare a tablet formulation blend before the compression stage: direct compression, dry granulation and wet granulation1. Direct compression involves the fewest steps and is ideal for formulations that can be blended well and that do not require further granulation like for example powders with good flow, powders with high dose and powder blends that do not segregate easily. Dry granulation consists of blending, followed by compaction and size reduction of the blend, to produce a free-flowing granular blend for tableting. In wet granulation, a liquid binder is used to develop granules from the formulation blends; this process entails more steps than do direct compression and dry granulation. Address for correspondence: G. N. Shankar, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. Tel: 1 650 859 5197. Fax: 1 650 859 2889. E-mail: [email protected]
History Received 30 July 2013 Revised 11 October 2013 Accepted 21 October 2013 Published online 27 November 2013
In the work described here, the API was slightly cohesive/ adhesive, had marginal flow properties and had a molecular weight of4300, partition coefficient value of45.00 and a melting point in the 170–180 C range. Preliminary formulation development studies of the API revealed the following issues for tablet formulation, sticking or filming during tablet compression, problems with tablet ejection and poor flow properties of the formulation blend. Chrome-coated tooling was evaluated as one of the formulation factors, in order to determine if it could eliminate the sticking and filming observed in the direct compression of tablet formulations. It is reported in the literature that chrome-coated tooling can eliminate sticking and filming, higher wear resistance and higher corrosion resistance, during tablet compression2–4. As an alternative strategy, tablet formulations of the API were also prepared using dry granulation by the roller compaction technique. The initial dry granulation tablet formulations eliminated the sticking and filming problems. Therefore, to further evaluate and identify optimized levels for the various formulation factors for the dry granulation technique, another full factorial screening design was used. The use of experimental screening designs as part of formulation development is an
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efficient way to study the influence of key formulation factors and to arrive at a tablet formulation with the desired characteristics, as has been documented for the formulation of many pharmaceutical solid dosage forms5–8.
Globe Pharma Mini Press II (New Brunswick, NJ) with 1/2-in. round shaped, scored, concave tooling with either chrome or regular coating on the punch tips. Dry granulation – roller compaction tablet formulation
Materials and methods
Roller compaction blend preparation
Materials
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AvicelÕ PH-102, 200 and 302 (microcrystalline cellulose) were purchased from FMC Corporation (Newark, DE), CAB-O-SILÕ M5P (fumed silica) purchased from Cabot Corporation (Tuscola, IL), magnesium (Mg) stearate purchased from Spectrum Quality Products Inc. (Gardena, CA), Starch 1500Õ purchased from Colorcon (West Point, PA) and talc purchased from Mallinckrodt Baker Inc. (Phillipsburg, NJ). Sodium starch glycolate (PrimojelÕ ) was obtained as a gift sample from DMV-Fonterra Excipients (Goch, Germany). Experimental design Using StatgraphicsÔ Centurion version XV software (Statpoint Technologies Inc., Warrenton, VA), two 23 full factorial designs were created to study how formulation factors affect tablet properties under five response variables. For experimental design 1, the direct compression formulation (Table 1), two continuous factors, drug percentage and filler ratio; and one discontinuous factor, the tooling type (A), either ‘‘regular’’ tooling or ‘‘chromecoated’’ tooling were studied. In experimental design 2, dry granulation using roller compaction (Table 2), three continuous factors at low, medium and high levels: (1) roller compaction pressure, (2) percent of AvicelÕ PH 200/AvicelÕ PH 102 and (3) percent of intragranular (IG) AvicelÕ were studied. For each design, following response variables were analyzed: compressibility index (%), tablet hardness (Kp), disintegration time (s), friability index (%) and stickiness-filming index (SFI; an arbitrary scale of 1–10).
The drug, AvicelÕ PH 102 and PrimojelÕ were weighed and sieved through USP Sieve # 20, followed by blending using a PK V-blender (0.5 quart vessel) for 5 min. At the end of primary blending, a small portion (1 g) of the blend was added to the pre-weighed Mg stearate, mixed and added to the primary blend; the combination was blended for 2 min. Roller compaction, milling and sieving Using a Vector-Freund TF Mini Roller Compactor (Marion, IA), the formulations were roller-compacted from 1000 to 1400 psi, depending on the experimental design. The roll speed was set at 2.4 rpm, and the load was around 1.58 to 1.65 amp. The formulation compacts collected were milled using a mortar and pestle, and the milled compacts were sieved through USP Sieve # 25. Roller compaction tablet blend preparation and compression The predetermined amount of the roller-compacted or IG portion was weighed and blended with the extragranular (EG) portions of the formulations, including AvicelÕ PH 102 and PrimojelÕ . The formulation was blended using a PK V-blender for 10 min. At the end of primary blending, a small portion of the blend was added to pre-weighed Mg stearate, talc and CAB-O-SILÕ M5P, and blended for 3 min. Tablets were compressed using an instrumented Globe Pharma Mini Press II (New Brunswick, NJ) with 0.270 0.560 in. oval-shaped, scored, concave B-tooling. Tablet characterization
Direct compression tablet formulation
Compressibility index
Tablet blend preparation and compression The drug and all the remaining excipients, except Mg stearate, were mixed and sieved through US Pharmacopeia (USP) Sieve # 18, followed by blending using a Patterson Kelly (PK) V-blender (East Stroudsburg, PA) for 5 min. At the end of primary blending, a small portion (4 g) of the blend was added to the pre-weighed Mg stearate, mixed and then added to the primary blend, with the combination blended for 2 min. Tablets were compressed using a
The formulation blend was slowly transferred into a graduated cylinder. The powder was tapped until no further change in volume was observed. The compressibility index was determined by measuring the unsettled apparent volume (Vo) and the final tapped volume (Vf). The percentage compressibility was computed according to Equation (1). Compressibility Index ¼ 100 ½ðVo Vf Þ=Vo
Table 1. Factors evaluated for direct compression tablet formulations by 23 full factorial experimental design. Factors Tooling type Drug % Filler ratio (w/w)
Low
Medium (Center Point)
High
Regular 25.00% AvicelÕ PH 302 (0%)/ AvicelÕ PH 102 (100%)
None 31.25% AvicelÕ PH 302 (50%)/ AvicelÕ PH 102 (50%)
Chrome 37.50% AvicelÕ PH 302 (100%)/ AvicelÕ PH 102 (0%)
Table 2. Factors evaluated for dry granulation tablet formulations by 23 full factorial experimental design. Factors Roller compaction pressure Percent of AvicelÕ PH 200/ AvicelÕ PH 102 (w/w) Percent of IG AvicelÕ (w/w)
Low
Medium (Center Point)
High
1000 psi AvicelÕ PH 200 (0%)/ AvicelÕ PH 102 (100%) 10%
1200 psi AvicelÕ PH 200 (50%)/ AvicelÕ PH 102 (50%) 15%
1400 psi AvicelÕ PH 200 (100%)/ AvicelÕ PH 102 (0%) 30%
ð1Þ
Formulation of an API with sticking and filming problem
DOI: 10.3109/03639045.2013.859266
Hardness and disintegration tests
Drug content analysis and in vitro dissolution
For all the tablet formulations, hardness was measured using a Vanderkemp VK200 hardness tester (Vankel Industries, Inc., Edison, NJ). Disintegration time was determined using a Vanguard LIJ 2 disintegration apparatus (Vanguard Pharmaceutical Machinery, Inc., Spring, TX) in 0.1 N hydrochloric acid (HCl) at 37 0.5 C.
Drug content analysis (n ¼ 3) and dissolution release (n ¼ 6) studies were performed for the optimized dry granulation tablet formulation using a validated high-performance liquid chromatography (HPLC) assay. Dissolution was performed using a USP Type II apparatus Vankel 7000 (Vankel Industries, Inc., Edison, NJ) at 50 rpm in 900 mL of 0.1 N HCl as the dissolution media at 37 0.5 C. Samples were analyzed by HPLC using an Agilent 1100 with diode array detector, C18 column (150 4.6 mm, 4 m) and 0.2% trifluoroacetic acid (TFA) in water:acetonitrile (60:40 ratio) as the mobile phase.
Friability index The friability index was determined using a Vankel 45-1000 friability tester (Vankel Industries, Inc., Edison, NJ) with 10 tablets for 100 revolutions, and the friability index value was calculated from the weight loss after the rotations. Stickiness-filming index
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To determine the stickiness-filming index (SFI), an arbitrary scale was developed based on the amount of drug sticking to the punch tips, the roughness on the tablet surface, the degree of difficulty in ejecting the tablet (characterized by a popping sound and flying away during tablet ejection) and the frequency of punch tip cleaning required to punch tablets smoothly. As mentioned, the arbitrary scale (Table 3) was developed to transform visual observations into a semiquantitative value for use in evaluating the SFI as one of the response variables in the statistical design. Particle size analysis Particle size sieve analysis was determined for the tablet blends by using USP sieve #s 40, 60, 80, 100, 120 and 170. Sieving was performed using the Gilson GA-1 Auto Siever (Gilson Inc., Lewis Center, OH).
Table 3. Stickiness-filming index (SFI: arbitrary scale). Stickiness-filming index (SFI) Scale 1 2 3 4 5 6 7 8 9 10
Characteristics No sticking or filming observed and no tablet ejection problem. Very slight sticking or filming observed but no tablet ejection problem. Stickiness and filming observed but tablets can be punched. Rough tablet surface. Stickiness and filming observed, but tablets can be punched with some level of difficulty at lower speed. Rough tablet surface. Constant cleaning of tips required. Extreme difficulty in punching tablets because of stickiness and failure to eject tablets completely.
Statistical analysis Data obtained from the experimental formulation testing was analyzed by t-test and analysis of variance (ANOVA). StatgraphicsÔ Centurion version XV software (Statpoint Technologies Inc., Warrenton, VA) was used to generate the study design and to perform the statistical analysis
Results and discussion Properties of tablets prepared by direct compression Table 4 lists the formulation factor levels for the 10 formulations encompassed by the full factorial design, along with the percentages of the remaining excipients of the direct compression tablet formulations. All the formulations displayed significant sticking, filming and ejection problems during tablet punching. Moreover, the tablets had to be punched at a lower speed and lower compression pressure to prevent them from flying away during ejection, due to tablet sticking to the lower punch; faulty tablet ejection was also accompanied by a popping sound and the surfaces of the tablets compressed were rough, due to the stickingfilming issue. In an attempt to eliminate the stickiness problem, chrome-coated punch tips were used as an experimental design factor; however, characterization of the tablet formulations and analysis of the data obtained indicated that those tips did not significantly eliminate the stickiness problem. Table 5 lists all the formulation characterization data for the direct compression tablet formulations prepared. Compressibility index Use of the compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of those factors can influence the observed compressibility index9,10. A compressibility index value of less than 25% is considered to be acceptable, and a value of less than 10% is considered to be excellent9,10. For all the direct compression tablet formulations, the compressibility index values exceeded 25%, implying poor
Table 4. Direct Compression tablet formulations based on the factor levels generated by the 23 full factorial design. wt% Formulation Tooling
F1 Regular
F2 Chrome
F3 Chrome
F4 Chrome
F5 Regular
F6 Regular
F7 Chrome
F8 Regular
F9 Regular
F10 Chrome
API AvicelÕ PH 102 AvicelÕ PH 302 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
25.00 66.00 0.00 3.00 4.00 1.00 1.00 100.00
25.00 0.00 66.00 3.00 4.00 1.00 1.00 100.00
37.50 0.00 53.50 3.00 4.00 1.00 1.00 100.00
25.00 66.00 0.00 3.00 4.00 1.00 1.00 100.00
25.00 0.00 66.00 3.00 4.00 1.00 1.00 100.00
37.50 53.50 0.00 3.00 4.00 1.00 1.00 100.00
37.50 53.50 0.00 3.00 4.00 1.00 1.00 100.00
31.25 29.88 29.88 3.00 4.00 1.00 1.00 100.00
37.50 0.00 53.50 3.00 4.00 1.00 1.00 100.00
31.25 29.88 29.88 3.00 4.00 1.00 1.00 100.00
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Table 5. Direct compression tablet formulation average characteristics from the 23 full factorial design.
Formulation
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F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Compressibility index (%)
Hardness (Kp)
Disintegration time (s)
Friability index (%)
SFI
42.26 2.89 35.78 1.41 37.93 0.14 34.25 0.60 31.48 2.62 37.50 0.00 32.50 1.18 41.04 0.71 40.77 0.70 33.02 4.51
2.67 0.54 2.55 0.78 4.12 0.84 2.67 0.79 2.17 0.52 4.55 1.11 3.40 0.75 2.70 0.36 2.68 0.56 2.50 0.36
34 4.84 29 6.35 30 9.07 24 2.34 25 4.46 35 3.66 36 2.66 30 2.43 29 5.06 30 5.16
7.0 6.1 5.5 9.1 7.0 2.3 3.1 7.2 5.6 4.1
8 6 7 6 8 9 7 8 9 7
Figure 1. Standardized Pareto charts and main effects plots for compressibility index and tablet hardness for direct compression tablets.
flow properties of the formulation blends. One of the experimental design factors, the tooling type, was excluded from the analysis because it does not affect the compressibility index of the tablet formulations. The standardized Pareto chart and main effects plot for compressibility index (Figure 1) indicated that none of the factors studied had a significant effect and the compressibility index value increased with an increase in drug percent in the formulation, although the increase was not significant (p ¼ 0.6691). Tablet hardness, friability index and disintegration time Measures of tensile strength or tablet hardness provide basic information for understanding the compaction properties of compressed powders. The tablet hardness values for the 10 formulations ranged from 2.17 to 4.55 Kp. The percent of drug was found to have the maximum effect on tablet hardness, which can be attributed to the cohesive/adhesive nature of the drug material. None of the factors significantly affected hardness, as shown in Figure 1. Due to the stickiness and filming of the
formulations, the compression force could not be increased during tablet manufacturing. Observed friability index values were higher than the generally acceptable range due to the lower hardness and the rough tablet surfaces created due to the sticking and filming nature of the formulations. The friability index values were well correlated with the hardness values. As shown in the Pareto chart and main effects plot for friability index (Figure 2), the percent of drug had a significant effect (p ¼ 0.0469). The disintegration times for all the 10 direct compression tablet formulations were less than 45 s. None of the factors evaluated displayed a significant effect on disintegration time. However, disintegration time increased with an increase in drug concentration as shown in Figure 2. Stickiness-filming index As shown in Table 5, the SFI for the 10 direct compression tablet formulations was assigned. The tooling type factor (chrome tooling versus regular tooling tips) (p ¼ 0.0044) and drug percent (p ¼ 0.0305) resulted in significant effects (p50.05 at the 95%
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Figure 2. Standardized Pareto charts and main effects plots for friability index, disintegration time and SFI for direct compression tablets.
Figure 3. Tablet tooling with filming and sticking observed during and after tablet punching of direct compression tablet formulations.
confidence level) on the SFI of the direct compression tablets as shown in Figure 2. Nonetheless, the effect did not translate into a practical value for eliminating the sticking and filming problem. All the tablets continued to show sticking and filming, and it was concluded that chrome-coated punch tips did not completely eliminate the problem. As the three factors and five
variables evaluated for the 10 direct compression tablet formulations did not eliminate the sticking and filming problem, further optimization was not attempted, instead, dry granulation using roller compaction for tablet preparation was evaluated. As shown in Figure 3, sticking and filming can be observed on the punch tips during tablet punching and also after completion.
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Properties of tablets prepared by dry granulation via roller compaction
formulation characterization data for the dry granulation tablet formulations prepared.
Table 6 lists the formulation factor levels for the 10 formulations encompassed by the full factorial design, along with the percentages and levels of the remaining excipients of the dry granulation tablet formulations. All the dry granulation via roller compaction tablet formulation blends yielded very good compacts (ribbons) without roller sticking problems. Two of the formulation compacts (15681-64-R8 and 15681-64-R9) were relatively brittle but not significantly so. Unlike the direct compression tablet formulations, the roller-compacted formulations experienced no sticking, filming or ejection problems during tablet punching. Moreover, the tablets obtained had smooth and glossy finishes. Accordingly, the chrome-coated punch tips were not needed to eliminate stickiness. The tablet compression data generated during tablet punching for all the dry granulation tablet formulations was observed to make sure a similar compression force was used to compress the tablets. Tables 7 and 8 lists all the
Compressibility index The standardized Pareto chart and main effects plot for compressibility index (Figure 4) show that none of the factors studied had a significant effect. As predicted, the compressibility index value decreased with an increase in AvicelÕ PH 200 percent in the formulation, although the increase was not significant. In accordance with the information provided by FMC Corporation, the manufacturer of AvicelÕ grades, the nominal particle size of AvicelÕ PH 200 grade is approximately 180 mm and that of AvicelÕ PH 102 is 100 mm. It is well documented that increases in particle size can improve blend flow properties, and such increases were effectively implemented in the current study11. Increasing the roller compaction pressure from 1000 psi to 1400 psi also improved the flow properties, although not significantly so.
Table 6. Dry granulation tablet formulations based on the factor levels generated by the 23 full factorial design. wt% Formulation Roller Compaction Pressure (psi) IG Portion API AvicelÕ PH 102 AvicelÕ PH 200 PrimojelÕ Mg Stearate EG Portion AvicelÕ PH 102 AvicelÕ PH 200 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
R1
R2
R2
R4
R5
R6
R7
R8
R9
R10
1000 37.50 0.00 30.00 2.00 0.50 0.00 24.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 0.00 30.00 2.00 0.50 0.00 24.00 3.00 2.00 0.50 0.50 100.00
1200 37.50 10.00 10.00 2.00 0.50 17.00 17.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 0.00 10.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 10.00 0.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1200 37.50 10.00 10.00 2.00 0.50 17.00 17.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 0.00 10.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 30.00 0.00 2.00 0.50 24.00 0.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 30.00 0.00 2.00 0.50 24.00 0.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 10.00 0.00 2.00 0.50 44.00 0.00 3.00 2.00 0.50 0.50 100.00
Table 7. Particle size analysis of dry granulation tablet formulation blends. Cumulative percent retained Formulation Sieve # 40 60 80 100 170 Fines
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
11.88 34.73 50.33 58.15 74.62 98.51
11.00 33.46 49.40 57.13 72.59 99.36
12.45 29.97 41.44 47.77 65.36 98.95
12.15 31.26 46.00 53.70 69.57 96.48
12.14 31.25 45.89 53.50 69.84 99.23
12.36 26.06 37.65 44.33 62.11 98.71
14.11 36.61 52.96 60.32 75.43 99.40
19.25 29.50 35.89 41.20 57.93 98.81
20.01 28.06 34.68 40.02 56.89 97.29
12.47 21.10 28.73 35.41 56.11 98.99
Table 8. Direct compression tablet formulation average characteristics from the 23 full factorial design.
Formulation R1 R2 R3 R4 R5 R6 R7 R8 R9 R10
Compressibility index (%)
Hardness (Kp)
Disintegration time (s)
Friability index (%)
SFI
24.49 0.00 21.51 0.00 25.50 0.71 20.79 0.00 22.06 0.69 25.76 0.71 21.57 0.00 26.06 0.75 27.08 0.00 28.37 0.47
11.25 0.88 11.67 0.78 13.05 0.53 13.90 0.63 11.25 0.88 13.08 0.69 13.75 0.45 10.98 0.75 10.97 0.67 13.45 0.70
126.67 14.61 166.67 21.42 152.80 20.72 121.83 10.15 126.33 14.45 170.00 44.27 157.60 34.85 241.40 46.45 301.00 60.37 182.60 43.43
0.079 0.120 0.081 0.031 0.106 0.107 0.044 0.143 0.137 0.140
1 1 1 1 1 1 1 1 1 1
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Figure 4. Standardized Pareto charts and main effects plots for compressibility index and tablet hardness for dry granulation tablets.
Tablet hardness, friability index and disintegration time The tablet hardness values for the 10 dry granulation formulations ranged between 10.97 and 13.98 Kp. As evident from Figure 4, the percent of IG AvicelÕ was found to have a maximum and statistically significant effect (p ¼ 0.0418) on tablet hardness. Increasing the percent of IG AvicelÕ with a corresponding decrease in the percent of EG AvicelÕ for a formulation decreased tablet hardness, indicating that the percent of EG AvicelÕ plays a greater role than the percent of IG AvicelÕ in determining the tensile strength of the dry granulation tablet formulations. In accordance with the tablet hardness results, two of the three factors studied – percent of IG AvicelÕ and percent of AvicelÕ PH 200 – had the most influence on friability index values. The friability index values for all 10 dry granulation tablet formulations were lower than 0.15%, which is within normally acceptable levels. That outcome can be attributed to the higher hardness values of these tablets compared with the direct compression tablet formulations. The friability index values correlated well with the hardness values. As shown in the Pareto chart and main effects plot for friability index (Figure 5), the percent of IG AvicelÕ and the percent of AvicelÕ PH 200 had statistically significant effects (p ¼ 0.0216 and 0.0059, respectively). Tablet formulations with AvicelÕ PH 200 as the filler had a lower friability index. An increase in the percent of IG Avicel increased the friability index. The disintegration times for the dry granulation tablet formulations (Figure 5) were between 121 and 301 s. Both the percent of IG AvicelÕ and of AvicelÕ PH 200 had the greatest influence on disintegration times. An increase in the percent of IG AvicelÕ resulted in a statistically significant (p ¼ 0.0125) increase in disintegration time, whereas an increase in AvicelÕ PH 200 resulted in a statistically significant decrease (p ¼ 0.0090) in disintegration time as shown in the Pareto chart and main effects plot (Figure 5).
The SFI was not analyzed using the statistical design for the dry granulation formulations because none of the dry granulation tablet formulations showed any signs of stickiness, filming or tablet ejection problems. Our studies thus demonstrated that the dry granulation method eliminated the stickiness, filming and tablet ejection problems of the tablet formulations with the API investigated. Once all the responses were analyzed separately, to determine the experimental factor settings to achieve the desired characteristics for more than one response, the multiple-response optimization feature of StatgraphicsÔ Centurion version XV software was used. Multiple response optimization was performed to determine the roller compaction pressure, and the percent of AvicelÕ PH 200 with IG AvicelÕ at 10% to optimize the tablet formulation with the desired characteristics like decreased compressibility index, friability index and disintegration time, while simultaneously increasing the tablet hardness. Figure 6 shows the multiple response optimization plot for the three factors and five variables evaluated for the dry granulation tablet formulation experimental design. Given the statistical design analysis, a dry granulation tablet formulation of the API using AvicelÕ PH 200 at the 10% IG level with a roller compaction pressure of 1330 psi and following all the process parameters discussed above was prepared without sticking or filming (Table 9). Table 10 presents the predicted response values, based on the surface plot and the experimental design, along with the observed or experimental response values for the optimized dry granulation tablet formulation. The observed values of the responses for the optimized formulation were in close agreement with the predicted values. These results demonstrate the reliability of the statistical design used to predict the effect of formulation factors on the characteristics of tablet dosage forms. The optimized dry granulation tablet formulation was further evaluated for drug content and dissolution. The average drug content weight (n ¼ 3 tablets) was 155.8 9.5 mg, equivalent to
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Figure 5. Standardized Pareto charts and main effects plots for friability index and disintegration time for dry granulation tablets.
Table 9. Optimized dry granulation tablet formulation (RCO1). Formulation RCO1 RC Pressure: 1330 psi Ingredients IGI Portion
EG Portion
Figure 6. Estimated response surface plot for desired tablet characteristic features by the dry granulation technique showing the levels of roller compaction pressure and AvicelÕ PH 200 level with IG AvicelÕ at 10%.
38.8% 1.96 wt% of the API or 103.5% of the target of 37.5 wt%. The dissolution release (n ¼ 6 tablets) study was conducted in 0.1 N HCl as the dissolution medium and the HPLC analysis indicated that more than 85% of the drug was released within the first 30 min of the dissolution study in accordance with typical immediate release dosage forms.
wt% API AvicelÕ PH 200 PrimojelÕ Mg Stearate AvicelÕ PH 200 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
37.50 10.00 2.00 0.50 44.00 3.00 2.00 0.50 0.50 100.00
Table 10. Predicted response values derived from the multiple response optimization for the dry granulation formulation experimental design and the corresponding observed values. Response Compressibility index Disintegration time Friability index Tablet hardness
Predicted value
Observed value
20.48% 121.50 s 0.03% 13.9 Kp
19.38% 157.67 43.14 s 0.08% 12.59 0.44 Kp
Conclusion The main objective of this study was to evaluate direct compression as a tablet formulation technique to improve formulation flow properties and eliminate sticking, filming and tablet ejection problems during tablet punching. Direct compression was evaluated by preparing preliminary tablet formulations
and by modifying some formulation factors; however, none of the modifications completely eliminated the problems. Accordingly, using a more robust and comprehensive approach that included experimental design, additional direct compression
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DOI: 10.3109/03639045.2013.859266
tablet formulation factors were evaluated, including chromecoated punch tips, filler type and the percent of API in tablet formulation, as well as their effects on flow properties, sticking and filming problems and other tablet characteristics. By following the experimental design, 10 direct compression tablet formulations were prepared and characterized them in regard to compressibility index, tablet thickness, hardness, disintegration time, friability index and SFI. None of the direct compression tablet formulations, in spite of the use of chrome-coated tips, completely eliminated sticking and filming; moreover, other formulation characteristics such as compressibility index, hardness and friability index were not in the desired range. Therefore, as an alternative strategy, dry granulation and roller compaction was evaluated as tablet formulations technique. After preparing and evaluating preliminary formulations, it was determined that dry granulation tablet formulations eliminated sticking and filming. To further optimize the dry granulation tablet formulations, using a full factorial screening design, effect of formulation factors like roller compaction pressure, percent of IG filler and filler type on several tablet response variables were studied. All 10 dry granulation tablet formulations prepared were eliminating the sticking, filming and tablet ejection problems observed during tablet punching. The flow properties as measured by compressibility index were also in the desired range for most of the formulations. All other tablet characteristics such as hardness, disintegration and friability index were in the desired range. By optimizing the multiple responses, a surface plot was generated for the dry granulation to lower the compressibility index (thus improving flow properties), the friability index and disintegration time, while simultaneously increasing the tablet hardness value. As the surface plot (Figure 6) indicates, when a tablet formulation prepared by dry granulation technique using AvicelÕ PH 200 at the 10% IG level and roller compaction pressure at 1330 psi and following all the process parameters discussed above, a tablet formulation was generated that can eliminate sticking and filming issues. The optimized tablet formulation prepared had a compressibility index of 19.38%, a hardness of 13 Kp, a disintegration time of about 159 s, and a friability index of about 0.08%; all these observed responses for the optimized formulation were in close agreement with the predicted values. Experimental design thus helped in identifying both the optimum levels of formulation factors and the method to use to eliminate sticking and filming. Unlike direct compression even with the use of chrome-coated tooling, the dry granulation
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method yielded tablets for which sticking and filming were eliminated.
Acknowledgements The authors wish to thank Baek-Ki Kim and Paul Wortel for formulation work; Elaine Struble and Honghui Zhou for the HPLC analysis of the assay and dissolution samples.
Declaration of interest This project has been funded in whole or in part by the US National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the US Department of Health and Human Services under Contract HHSN266200600011C/N01-AI-60011. The authors report no declarations of interest.
References 1. Remington: the science and practice of pharmacy. Vol. 21. New Delhi: Wolters Kluwer (India) Pvt. Ltd; 2005:889–928. 2. Roberts M, Ford JL, MacLeod GS, et al. Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations. J Pharm Pharmacol 2003;55:1223–8. 3. Deutchman AH, Natoli DC. Tableting punch performance can be improved with precision coatings. Beamalloy Technologies LLC [Online]. Available from: http://www.beamalloy.net/client_images/ catalog19951/pages/files/Pharmproc902B.pdf [last accessed 12 Nov 2013]. 4. Deutchman AH. Choosing coatings to improve the performance of tablet tooling. Tablets Capsules 2004;2:1–7. 5. Chopra S, Patil GV, Motwani SK. Release modulating hydrophilic matrix systems of losartan potassium: optimization of formulation using statistical experimental design. Eur J Pharm Biopharm 2007; 66:73–82. 6. Bejugam NK, Parish HJ, Shankar GN. Influence of formulation factors on tablet formulations with liquid permeation enhancer using factorial design. AAPS PharmSciTech 2009;10:1437–43. 7. Singh B, Kapil R, Nandi M, Ahuja N. Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects. Expert Opin Drug Deliv 2011;8:1341–60. 8. Landin M, Rowe RC, York P. Advantages of neurofuzzy logic against conventional experimental design and statistical analysis in studying and developing direct compression formulations. Eur J Pharm Sci 2009;38:325–31. 9. Carr RL. Evaluating flow properties of solids. Chem Eng 1965;72: 163–8. 10. USP36–NF31. Chapter 1174: Powder flow. Rockville (MD): USP36NF31 ed.; 2013:891. 11. Yu W, Muteki K, Zhang L, Kim G. Prediction of bulk powder flow performance using comprehensive particle size and particle shape distributions. J Pharm Sci 2011;100:284–93.
RESEARCH ARTICLE
Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations Drug Dev Ind Pharm Downloaded from informahealthcare.com by Kainan University on 04/13/15 For personal use only.
Naveen K. Bejugam, Shravan K. Mutyam, and Gita N. Shankar SRI International, Menlo Park, CA, USA
Abstract
Keywords
Objective: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching. Methods: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors – roller compaction pressure, intragranular filler percent and filler type – were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors. Results: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index. Conclusion: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.
Direct compression, dry granulation, roller compaction, statistical design, stickiness, tablets
Introduction Tablets are one of the most widely prescribed oral solid dosage forms for drug delivery because of their inherent simplicity in handling and administration. Typically, the ingredients that make up the tablet blend include the active pharmaceutical ingredient (API) and various excipients. Three techniques can be used to prepare a tablet formulation blend before the compression stage: direct compression, dry granulation and wet granulation1. Direct compression involves the fewest steps and is ideal for formulations that can be blended well and that do not require further granulation like for example powders with good flow, powders with high dose and powder blends that do not segregate easily. Dry granulation consists of blending, followed by compaction and size reduction of the blend, to produce a free-flowing granular blend for tableting. In wet granulation, a liquid binder is used to develop granules from the formulation blends; this process entails more steps than do direct compression and dry granulation. Address for correspondence: G. N. Shankar, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. Tel: 1 650 859 5197. Fax: 1 650 859 2889. E-mail: [email protected]
History Received 30 July 2013 Revised 11 October 2013 Accepted 21 October 2013 Published online 27 November 2013
In the work described here, the API was slightly cohesive/ adhesive, had marginal flow properties and had a molecular weight of4300, partition coefficient value of45.00 and a melting point in the 170–180 C range. Preliminary formulation development studies of the API revealed the following issues for tablet formulation, sticking or filming during tablet compression, problems with tablet ejection and poor flow properties of the formulation blend. Chrome-coated tooling was evaluated as one of the formulation factors, in order to determine if it could eliminate the sticking and filming observed in the direct compression of tablet formulations. It is reported in the literature that chrome-coated tooling can eliminate sticking and filming, higher wear resistance and higher corrosion resistance, during tablet compression2–4. As an alternative strategy, tablet formulations of the API were also prepared using dry granulation by the roller compaction technique. The initial dry granulation tablet formulations eliminated the sticking and filming problems. Therefore, to further evaluate and identify optimized levels for the various formulation factors for the dry granulation technique, another full factorial screening design was used. The use of experimental screening designs as part of formulation development is an
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efficient way to study the influence of key formulation factors and to arrive at a tablet formulation with the desired characteristics, as has been documented for the formulation of many pharmaceutical solid dosage forms5–8.
Globe Pharma Mini Press II (New Brunswick, NJ) with 1/2-in. round shaped, scored, concave tooling with either chrome or regular coating on the punch tips. Dry granulation – roller compaction tablet formulation
Materials and methods
Roller compaction blend preparation
Materials
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AvicelÕ PH-102, 200 and 302 (microcrystalline cellulose) were purchased from FMC Corporation (Newark, DE), CAB-O-SILÕ M5P (fumed silica) purchased from Cabot Corporation (Tuscola, IL), magnesium (Mg) stearate purchased from Spectrum Quality Products Inc. (Gardena, CA), Starch 1500Õ purchased from Colorcon (West Point, PA) and talc purchased from Mallinckrodt Baker Inc. (Phillipsburg, NJ). Sodium starch glycolate (PrimojelÕ ) was obtained as a gift sample from DMV-Fonterra Excipients (Goch, Germany). Experimental design Using StatgraphicsÔ Centurion version XV software (Statpoint Technologies Inc., Warrenton, VA), two 23 full factorial designs were created to study how formulation factors affect tablet properties under five response variables. For experimental design 1, the direct compression formulation (Table 1), two continuous factors, drug percentage and filler ratio; and one discontinuous factor, the tooling type (A), either ‘‘regular’’ tooling or ‘‘chromecoated’’ tooling were studied. In experimental design 2, dry granulation using roller compaction (Table 2), three continuous factors at low, medium and high levels: (1) roller compaction pressure, (2) percent of AvicelÕ PH 200/AvicelÕ PH 102 and (3) percent of intragranular (IG) AvicelÕ were studied. For each design, following response variables were analyzed: compressibility index (%), tablet hardness (Kp), disintegration time (s), friability index (%) and stickiness-filming index (SFI; an arbitrary scale of 1–10).
The drug, AvicelÕ PH 102 and PrimojelÕ were weighed and sieved through USP Sieve # 20, followed by blending using a PK V-blender (0.5 quart vessel) for 5 min. At the end of primary blending, a small portion (1 g) of the blend was added to the pre-weighed Mg stearate, mixed and added to the primary blend; the combination was blended for 2 min. Roller compaction, milling and sieving Using a Vector-Freund TF Mini Roller Compactor (Marion, IA), the formulations were roller-compacted from 1000 to 1400 psi, depending on the experimental design. The roll speed was set at 2.4 rpm, and the load was around 1.58 to 1.65 amp. The formulation compacts collected were milled using a mortar and pestle, and the milled compacts were sieved through USP Sieve # 25. Roller compaction tablet blend preparation and compression The predetermined amount of the roller-compacted or IG portion was weighed and blended with the extragranular (EG) portions of the formulations, including AvicelÕ PH 102 and PrimojelÕ . The formulation was blended using a PK V-blender for 10 min. At the end of primary blending, a small portion of the blend was added to pre-weighed Mg stearate, talc and CAB-O-SILÕ M5P, and blended for 3 min. Tablets were compressed using an instrumented Globe Pharma Mini Press II (New Brunswick, NJ) with 0.270 0.560 in. oval-shaped, scored, concave B-tooling. Tablet characterization
Direct compression tablet formulation
Compressibility index
Tablet blend preparation and compression The drug and all the remaining excipients, except Mg stearate, were mixed and sieved through US Pharmacopeia (USP) Sieve # 18, followed by blending using a Patterson Kelly (PK) V-blender (East Stroudsburg, PA) for 5 min. At the end of primary blending, a small portion (4 g) of the blend was added to the pre-weighed Mg stearate, mixed and then added to the primary blend, with the combination blended for 2 min. Tablets were compressed using a
The formulation blend was slowly transferred into a graduated cylinder. The powder was tapped until no further change in volume was observed. The compressibility index was determined by measuring the unsettled apparent volume (Vo) and the final tapped volume (Vf). The percentage compressibility was computed according to Equation (1). Compressibility Index ¼ 100 ½ðVo Vf Þ=Vo
Table 1. Factors evaluated for direct compression tablet formulations by 23 full factorial experimental design. Factors Tooling type Drug % Filler ratio (w/w)
Low
Medium (Center Point)
High
Regular 25.00% AvicelÕ PH 302 (0%)/ AvicelÕ PH 102 (100%)
None 31.25% AvicelÕ PH 302 (50%)/ AvicelÕ PH 102 (50%)
Chrome 37.50% AvicelÕ PH 302 (100%)/ AvicelÕ PH 102 (0%)
Table 2. Factors evaluated for dry granulation tablet formulations by 23 full factorial experimental design. Factors Roller compaction pressure Percent of AvicelÕ PH 200/ AvicelÕ PH 102 (w/w) Percent of IG AvicelÕ (w/w)
Low
Medium (Center Point)
High
1000 psi AvicelÕ PH 200 (0%)/ AvicelÕ PH 102 (100%) 10%
1200 psi AvicelÕ PH 200 (50%)/ AvicelÕ PH 102 (50%) 15%
1400 psi AvicelÕ PH 200 (100%)/ AvicelÕ PH 102 (0%) 30%
ð1Þ
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Hardness and disintegration tests
Drug content analysis and in vitro dissolution
For all the tablet formulations, hardness was measured using a Vanderkemp VK200 hardness tester (Vankel Industries, Inc., Edison, NJ). Disintegration time was determined using a Vanguard LIJ 2 disintegration apparatus (Vanguard Pharmaceutical Machinery, Inc., Spring, TX) in 0.1 N hydrochloric acid (HCl) at 37 0.5 C.
Drug content analysis (n ¼ 3) and dissolution release (n ¼ 6) studies were performed for the optimized dry granulation tablet formulation using a validated high-performance liquid chromatography (HPLC) assay. Dissolution was performed using a USP Type II apparatus Vankel 7000 (Vankel Industries, Inc., Edison, NJ) at 50 rpm in 900 mL of 0.1 N HCl as the dissolution media at 37 0.5 C. Samples were analyzed by HPLC using an Agilent 1100 with diode array detector, C18 column (150 4.6 mm, 4 m) and 0.2% trifluoroacetic acid (TFA) in water:acetonitrile (60:40 ratio) as the mobile phase.
Friability index The friability index was determined using a Vankel 45-1000 friability tester (Vankel Industries, Inc., Edison, NJ) with 10 tablets for 100 revolutions, and the friability index value was calculated from the weight loss after the rotations. Stickiness-filming index
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To determine the stickiness-filming index (SFI), an arbitrary scale was developed based on the amount of drug sticking to the punch tips, the roughness on the tablet surface, the degree of difficulty in ejecting the tablet (characterized by a popping sound and flying away during tablet ejection) and the frequency of punch tip cleaning required to punch tablets smoothly. As mentioned, the arbitrary scale (Table 3) was developed to transform visual observations into a semiquantitative value for use in evaluating the SFI as one of the response variables in the statistical design. Particle size analysis Particle size sieve analysis was determined for the tablet blends by using USP sieve #s 40, 60, 80, 100, 120 and 170. Sieving was performed using the Gilson GA-1 Auto Siever (Gilson Inc., Lewis Center, OH).
Table 3. Stickiness-filming index (SFI: arbitrary scale). Stickiness-filming index (SFI) Scale 1 2 3 4 5 6 7 8 9 10
Characteristics No sticking or filming observed and no tablet ejection problem. Very slight sticking or filming observed but no tablet ejection problem. Stickiness and filming observed but tablets can be punched. Rough tablet surface. Stickiness and filming observed, but tablets can be punched with some level of difficulty at lower speed. Rough tablet surface. Constant cleaning of tips required. Extreme difficulty in punching tablets because of stickiness and failure to eject tablets completely.
Statistical analysis Data obtained from the experimental formulation testing was analyzed by t-test and analysis of variance (ANOVA). StatgraphicsÔ Centurion version XV software (Statpoint Technologies Inc., Warrenton, VA) was used to generate the study design and to perform the statistical analysis
Results and discussion Properties of tablets prepared by direct compression Table 4 lists the formulation factor levels for the 10 formulations encompassed by the full factorial design, along with the percentages of the remaining excipients of the direct compression tablet formulations. All the formulations displayed significant sticking, filming and ejection problems during tablet punching. Moreover, the tablets had to be punched at a lower speed and lower compression pressure to prevent them from flying away during ejection, due to tablet sticking to the lower punch; faulty tablet ejection was also accompanied by a popping sound and the surfaces of the tablets compressed were rough, due to the stickingfilming issue. In an attempt to eliminate the stickiness problem, chrome-coated punch tips were used as an experimental design factor; however, characterization of the tablet formulations and analysis of the data obtained indicated that those tips did not significantly eliminate the stickiness problem. Table 5 lists all the formulation characterization data for the direct compression tablet formulations prepared. Compressibility index Use of the compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of those factors can influence the observed compressibility index9,10. A compressibility index value of less than 25% is considered to be acceptable, and a value of less than 10% is considered to be excellent9,10. For all the direct compression tablet formulations, the compressibility index values exceeded 25%, implying poor
Table 4. Direct Compression tablet formulations based on the factor levels generated by the 23 full factorial design. wt% Formulation Tooling
F1 Regular
F2 Chrome
F3 Chrome
F4 Chrome
F5 Regular
F6 Regular
F7 Chrome
F8 Regular
F9 Regular
F10 Chrome
API AvicelÕ PH 102 AvicelÕ PH 302 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
25.00 66.00 0.00 3.00 4.00 1.00 1.00 100.00
25.00 0.00 66.00 3.00 4.00 1.00 1.00 100.00
37.50 0.00 53.50 3.00 4.00 1.00 1.00 100.00
25.00 66.00 0.00 3.00 4.00 1.00 1.00 100.00
25.00 0.00 66.00 3.00 4.00 1.00 1.00 100.00
37.50 53.50 0.00 3.00 4.00 1.00 1.00 100.00
37.50 53.50 0.00 3.00 4.00 1.00 1.00 100.00
31.25 29.88 29.88 3.00 4.00 1.00 1.00 100.00
37.50 0.00 53.50 3.00 4.00 1.00 1.00 100.00
31.25 29.88 29.88 3.00 4.00 1.00 1.00 100.00
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Table 5. Direct compression tablet formulation average characteristics from the 23 full factorial design.
Formulation
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F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Compressibility index (%)
Hardness (Kp)
Disintegration time (s)
Friability index (%)
SFI
42.26 2.89 35.78 1.41 37.93 0.14 34.25 0.60 31.48 2.62 37.50 0.00 32.50 1.18 41.04 0.71 40.77 0.70 33.02 4.51
2.67 0.54 2.55 0.78 4.12 0.84 2.67 0.79 2.17 0.52 4.55 1.11 3.40 0.75 2.70 0.36 2.68 0.56 2.50 0.36
34 4.84 29 6.35 30 9.07 24 2.34 25 4.46 35 3.66 36 2.66 30 2.43 29 5.06 30 5.16
7.0 6.1 5.5 9.1 7.0 2.3 3.1 7.2 5.6 4.1
8 6 7 6 8 9 7 8 9 7
Figure 1. Standardized Pareto charts and main effects plots for compressibility index and tablet hardness for direct compression tablets.
flow properties of the formulation blends. One of the experimental design factors, the tooling type, was excluded from the analysis because it does not affect the compressibility index of the tablet formulations. The standardized Pareto chart and main effects plot for compressibility index (Figure 1) indicated that none of the factors studied had a significant effect and the compressibility index value increased with an increase in drug percent in the formulation, although the increase was not significant (p ¼ 0.6691). Tablet hardness, friability index and disintegration time Measures of tensile strength or tablet hardness provide basic information for understanding the compaction properties of compressed powders. The tablet hardness values for the 10 formulations ranged from 2.17 to 4.55 Kp. The percent of drug was found to have the maximum effect on tablet hardness, which can be attributed to the cohesive/adhesive nature of the drug material. None of the factors significantly affected hardness, as shown in Figure 1. Due to the stickiness and filming of the
formulations, the compression force could not be increased during tablet manufacturing. Observed friability index values were higher than the generally acceptable range due to the lower hardness and the rough tablet surfaces created due to the sticking and filming nature of the formulations. The friability index values were well correlated with the hardness values. As shown in the Pareto chart and main effects plot for friability index (Figure 2), the percent of drug had a significant effect (p ¼ 0.0469). The disintegration times for all the 10 direct compression tablet formulations were less than 45 s. None of the factors evaluated displayed a significant effect on disintegration time. However, disintegration time increased with an increase in drug concentration as shown in Figure 2. Stickiness-filming index As shown in Table 5, the SFI for the 10 direct compression tablet formulations was assigned. The tooling type factor (chrome tooling versus regular tooling tips) (p ¼ 0.0044) and drug percent (p ¼ 0.0305) resulted in significant effects (p50.05 at the 95%
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Figure 2. Standardized Pareto charts and main effects plots for friability index, disintegration time and SFI for direct compression tablets.
Figure 3. Tablet tooling with filming and sticking observed during and after tablet punching of direct compression tablet formulations.
confidence level) on the SFI of the direct compression tablets as shown in Figure 2. Nonetheless, the effect did not translate into a practical value for eliminating the sticking and filming problem. All the tablets continued to show sticking and filming, and it was concluded that chrome-coated punch tips did not completely eliminate the problem. As the three factors and five
variables evaluated for the 10 direct compression tablet formulations did not eliminate the sticking and filming problem, further optimization was not attempted, instead, dry granulation using roller compaction for tablet preparation was evaluated. As shown in Figure 3, sticking and filming can be observed on the punch tips during tablet punching and also after completion.
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Properties of tablets prepared by dry granulation via roller compaction
formulation characterization data for the dry granulation tablet formulations prepared.
Table 6 lists the formulation factor levels for the 10 formulations encompassed by the full factorial design, along with the percentages and levels of the remaining excipients of the dry granulation tablet formulations. All the dry granulation via roller compaction tablet formulation blends yielded very good compacts (ribbons) without roller sticking problems. Two of the formulation compacts (15681-64-R8 and 15681-64-R9) were relatively brittle but not significantly so. Unlike the direct compression tablet formulations, the roller-compacted formulations experienced no sticking, filming or ejection problems during tablet punching. Moreover, the tablets obtained had smooth and glossy finishes. Accordingly, the chrome-coated punch tips were not needed to eliminate stickiness. The tablet compression data generated during tablet punching for all the dry granulation tablet formulations was observed to make sure a similar compression force was used to compress the tablets. Tables 7 and 8 lists all the
Compressibility index The standardized Pareto chart and main effects plot for compressibility index (Figure 4) show that none of the factors studied had a significant effect. As predicted, the compressibility index value decreased with an increase in AvicelÕ PH 200 percent in the formulation, although the increase was not significant. In accordance with the information provided by FMC Corporation, the manufacturer of AvicelÕ grades, the nominal particle size of AvicelÕ PH 200 grade is approximately 180 mm and that of AvicelÕ PH 102 is 100 mm. It is well documented that increases in particle size can improve blend flow properties, and such increases were effectively implemented in the current study11. Increasing the roller compaction pressure from 1000 psi to 1400 psi also improved the flow properties, although not significantly so.
Table 6. Dry granulation tablet formulations based on the factor levels generated by the 23 full factorial design. wt% Formulation Roller Compaction Pressure (psi) IG Portion API AvicelÕ PH 102 AvicelÕ PH 200 PrimojelÕ Mg Stearate EG Portion AvicelÕ PH 102 AvicelÕ PH 200 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
R1
R2
R2
R4
R5
R6
R7
R8
R9
R10
1000 37.50 0.00 30.00 2.00 0.50 0.00 24.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 0.00 30.00 2.00 0.50 0.00 24.00 3.00 2.00 0.50 0.50 100.00
1200 37.50 10.00 10.00 2.00 0.50 17.00 17.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 0.00 10.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 10.00 0.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1200 37.50 10.00 10.00 2.00 0.50 17.00 17.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 0.00 10.00 2.00 0.50 0.00 44.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 30.00 0.00 2.00 0.50 24.00 0.00 3.00 2.00 0.50 0.50 100.00
1400 37.50 30.00 0.00 2.00 0.50 24.00 0.00 3.00 2.00 0.50 0.50 100.00
1000 37.50 10.00 0.00 2.00 0.50 44.00 0.00 3.00 2.00 0.50 0.50 100.00
Table 7. Particle size analysis of dry granulation tablet formulation blends. Cumulative percent retained Formulation Sieve # 40 60 80 100 170 Fines
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
11.88 34.73 50.33 58.15 74.62 98.51
11.00 33.46 49.40 57.13 72.59 99.36
12.45 29.97 41.44 47.77 65.36 98.95
12.15 31.26 46.00 53.70 69.57 96.48
12.14 31.25 45.89 53.50 69.84 99.23
12.36 26.06 37.65 44.33 62.11 98.71
14.11 36.61 52.96 60.32 75.43 99.40
19.25 29.50 35.89 41.20 57.93 98.81
20.01 28.06 34.68 40.02 56.89 97.29
12.47 21.10 28.73 35.41 56.11 98.99
Table 8. Direct compression tablet formulation average characteristics from the 23 full factorial design.
Formulation R1 R2 R3 R4 R5 R6 R7 R8 R9 R10
Compressibility index (%)
Hardness (Kp)
Disintegration time (s)
Friability index (%)
SFI
24.49 0.00 21.51 0.00 25.50 0.71 20.79 0.00 22.06 0.69 25.76 0.71 21.57 0.00 26.06 0.75 27.08 0.00 28.37 0.47
11.25 0.88 11.67 0.78 13.05 0.53 13.90 0.63 11.25 0.88 13.08 0.69 13.75 0.45 10.98 0.75 10.97 0.67 13.45 0.70
126.67 14.61 166.67 21.42 152.80 20.72 121.83 10.15 126.33 14.45 170.00 44.27 157.60 34.85 241.40 46.45 301.00 60.37 182.60 43.43
0.079 0.120 0.081 0.031 0.106 0.107 0.044 0.143 0.137 0.140
1 1 1 1 1 1 1 1 1 1
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Figure 4. Standardized Pareto charts and main effects plots for compressibility index and tablet hardness for dry granulation tablets.
Tablet hardness, friability index and disintegration time The tablet hardness values for the 10 dry granulation formulations ranged between 10.97 and 13.98 Kp. As evident from Figure 4, the percent of IG AvicelÕ was found to have a maximum and statistically significant effect (p ¼ 0.0418) on tablet hardness. Increasing the percent of IG AvicelÕ with a corresponding decrease in the percent of EG AvicelÕ for a formulation decreased tablet hardness, indicating that the percent of EG AvicelÕ plays a greater role than the percent of IG AvicelÕ in determining the tensile strength of the dry granulation tablet formulations. In accordance with the tablet hardness results, two of the three factors studied – percent of IG AvicelÕ and percent of AvicelÕ PH 200 – had the most influence on friability index values. The friability index values for all 10 dry granulation tablet formulations were lower than 0.15%, which is within normally acceptable levels. That outcome can be attributed to the higher hardness values of these tablets compared with the direct compression tablet formulations. The friability index values correlated well with the hardness values. As shown in the Pareto chart and main effects plot for friability index (Figure 5), the percent of IG AvicelÕ and the percent of AvicelÕ PH 200 had statistically significant effects (p ¼ 0.0216 and 0.0059, respectively). Tablet formulations with AvicelÕ PH 200 as the filler had a lower friability index. An increase in the percent of IG Avicel increased the friability index. The disintegration times for the dry granulation tablet formulations (Figure 5) were between 121 and 301 s. Both the percent of IG AvicelÕ and of AvicelÕ PH 200 had the greatest influence on disintegration times. An increase in the percent of IG AvicelÕ resulted in a statistically significant (p ¼ 0.0125) increase in disintegration time, whereas an increase in AvicelÕ PH 200 resulted in a statistically significant decrease (p ¼ 0.0090) in disintegration time as shown in the Pareto chart and main effects plot (Figure 5).
The SFI was not analyzed using the statistical design for the dry granulation formulations because none of the dry granulation tablet formulations showed any signs of stickiness, filming or tablet ejection problems. Our studies thus demonstrated that the dry granulation method eliminated the stickiness, filming and tablet ejection problems of the tablet formulations with the API investigated. Once all the responses were analyzed separately, to determine the experimental factor settings to achieve the desired characteristics for more than one response, the multiple-response optimization feature of StatgraphicsÔ Centurion version XV software was used. Multiple response optimization was performed to determine the roller compaction pressure, and the percent of AvicelÕ PH 200 with IG AvicelÕ at 10% to optimize the tablet formulation with the desired characteristics like decreased compressibility index, friability index and disintegration time, while simultaneously increasing the tablet hardness. Figure 6 shows the multiple response optimization plot for the three factors and five variables evaluated for the dry granulation tablet formulation experimental design. Given the statistical design analysis, a dry granulation tablet formulation of the API using AvicelÕ PH 200 at the 10% IG level with a roller compaction pressure of 1330 psi and following all the process parameters discussed above was prepared without sticking or filming (Table 9). Table 10 presents the predicted response values, based on the surface plot and the experimental design, along with the observed or experimental response values for the optimized dry granulation tablet formulation. The observed values of the responses for the optimized formulation were in close agreement with the predicted values. These results demonstrate the reliability of the statistical design used to predict the effect of formulation factors on the characteristics of tablet dosage forms. The optimized dry granulation tablet formulation was further evaluated for drug content and dissolution. The average drug content weight (n ¼ 3 tablets) was 155.8 9.5 mg, equivalent to
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Figure 5. Standardized Pareto charts and main effects plots for friability index and disintegration time for dry granulation tablets.
Table 9. Optimized dry granulation tablet formulation (RCO1). Formulation RCO1 RC Pressure: 1330 psi Ingredients IGI Portion
EG Portion
Figure 6. Estimated response surface plot for desired tablet characteristic features by the dry granulation technique showing the levels of roller compaction pressure and AvicelÕ PH 200 level with IG AvicelÕ at 10%.
38.8% 1.96 wt% of the API or 103.5% of the target of 37.5 wt%. The dissolution release (n ¼ 6 tablets) study was conducted in 0.1 N HCl as the dissolution medium and the HPLC analysis indicated that more than 85% of the drug was released within the first 30 min of the dissolution study in accordance with typical immediate release dosage forms.
wt% API AvicelÕ PH 200 PrimojelÕ Mg Stearate AvicelÕ PH 200 Talc PrimojelÕ Cab-O-SilÕ M5P Mg Stearate Total
37.50 10.00 2.00 0.50 44.00 3.00 2.00 0.50 0.50 100.00
Table 10. Predicted response values derived from the multiple response optimization for the dry granulation formulation experimental design and the corresponding observed values. Response Compressibility index Disintegration time Friability index Tablet hardness
Predicted value
Observed value
20.48% 121.50 s 0.03% 13.9 Kp
19.38% 157.67 43.14 s 0.08% 12.59 0.44 Kp
Conclusion The main objective of this study was to evaluate direct compression as a tablet formulation technique to improve formulation flow properties and eliminate sticking, filming and tablet ejection problems during tablet punching. Direct compression was evaluated by preparing preliminary tablet formulations
and by modifying some formulation factors; however, none of the modifications completely eliminated the problems. Accordingly, using a more robust and comprehensive approach that included experimental design, additional direct compression
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DOI: 10.3109/03639045.2013.859266
tablet formulation factors were evaluated, including chromecoated punch tips, filler type and the percent of API in tablet formulation, as well as their effects on flow properties, sticking and filming problems and other tablet characteristics. By following the experimental design, 10 direct compression tablet formulations were prepared and characterized them in regard to compressibility index, tablet thickness, hardness, disintegration time, friability index and SFI. None of the direct compression tablet formulations, in spite of the use of chrome-coated tips, completely eliminated sticking and filming; moreover, other formulation characteristics such as compressibility index, hardness and friability index were not in the desired range. Therefore, as an alternative strategy, dry granulation and roller compaction was evaluated as tablet formulations technique. After preparing and evaluating preliminary formulations, it was determined that dry granulation tablet formulations eliminated sticking and filming. To further optimize the dry granulation tablet formulations, using a full factorial screening design, effect of formulation factors like roller compaction pressure, percent of IG filler and filler type on several tablet response variables were studied. All 10 dry granulation tablet formulations prepared were eliminating the sticking, filming and tablet ejection problems observed during tablet punching. The flow properties as measured by compressibility index were also in the desired range for most of the formulations. All other tablet characteristics such as hardness, disintegration and friability index were in the desired range. By optimizing the multiple responses, a surface plot was generated for the dry granulation to lower the compressibility index (thus improving flow properties), the friability index and disintegration time, while simultaneously increasing the tablet hardness value. As the surface plot (Figure 6) indicates, when a tablet formulation prepared by dry granulation technique using AvicelÕ PH 200 at the 10% IG level and roller compaction pressure at 1330 psi and following all the process parameters discussed above, a tablet formulation was generated that can eliminate sticking and filming issues. The optimized tablet formulation prepared had a compressibility index of 19.38%, a hardness of 13 Kp, a disintegration time of about 159 s, and a friability index of about 0.08%; all these observed responses for the optimized formulation were in close agreement with the predicted values. Experimental design thus helped in identifying both the optimum levels of formulation factors and the method to use to eliminate sticking and filming. Unlike direct compression even with the use of chrome-coated tooling, the dry granulation
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method yielded tablets for which sticking and filming were eliminated.
Acknowledgements The authors wish to thank Baek-Ki Kim and Paul Wortel for formulation work; Elaine Struble and Honghui Zhou for the HPLC analysis of the assay and dissolution samples.
Declaration of interest This project has been funded in whole or in part by the US National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the US Department of Health and Human Services under Contract HHSN266200600011C/N01-AI-60011. The authors report no declarations of interest.
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