Tablet Manufacturing - Over-Lubrication Effect in the Force Feeder of a Rotary Tablet Press
Lubricants play a vital role in solid dose manufacturing, preventing materials from sticking to punch faces, decreasing friction at the interface between the tablet surface and the die wall during ejection, and reducing wear on punches and dies. However, over-lubrication of the powder blend is a well-recognized issue, adversely affecting many of the properties of the finished tablets (1, 2).
Traditionally, over-lubrication has been associated with overmixing in the blender, but new evidence suggests that other parts of the manufacturing process may contribute to the overall effect. This study confirms that the force feeder of the rotary tablet press may play an important role in the over-lubrication effect.
This study was prompted by earlier work by Feng Li and John C. Cunningham (5), which looked at the mixing/shearing effect of the force feeder. They concluded that, by acting as a second ‘paddle blender’, the feeder could cause over-lubrication of a blend prior to compression.
The Patheon team set out to further investigate the potential of the feeder to cause over-lubrication and its effects on the physical properties and dissolution performance of the tablets produced. Folic acid was selected as several reports suggested that it was very sensitive to a number of formulation and processing factors (3, 4). The lubricant magnesium stearate was also selected as its potential for over-lubrication is well recognized. Finally, two filler materials were selected: microcrystalline cellulose (MCC), which undergoes plastic deformation during compaction, and anhydrous dibasic calcium phosphate (DCP), where the primary consolidation mechanism is fragmentation.
Two direct compression blends were prepared for each model formulation consisting of 0.4 % folic acid (400 µg/tablet), 2.0% croscarmellose sodium, 1.0% magnesium stearate and 96.6% of filler (MCC or DCP respectively). Folic acid was de-lumped and geometrically blended with either MCC or DCP and with croscarmellose for 20 minutes; afterwards, it was lubricated with magnesium stearate for 3 minutes. Each blend was split into twelve portions for separate compression runs during which the powder was compressed into 100 mg tablets. An instrumented 16 station Manesty Betapress equipped with a variable speed paddle feed frame was used for compression.
Twelve runs were performed for each formulation according to the experimental design detailed in Table I. Three key factors were monitored – blend residence time (the time spent inside the feeder), paddle speed and compression force.
All other factors that could affect the responses were kept at a fixed level: compression dwell time was kept invariable by maintaining constant the tablet press turret speed (St). As dictated by equation No.1 which estimates the residence time of powders in the feed frame of a tablet press (5), if the turret speed (St) is fixed and since both the feed frame volume (Vff) and die fill volume (Vd) are constants the only possible way to vary residence time is by varying the number of active stations; therefore, ten and two active stations were used for the low and high residence time respectively. The non-active stations were blocked with blank dies.
A dissolution profile was obtained for each run by determining the dissolution at 5, 10, 15, 30, 45 and 60 minutes according to the USP dissolution method for folic acid tablets (7). Tablet hardness was determined on a sample of 10 tablets from each run, while disintegration testing was performed on a sample of 6 tablets from each run.
Tablet weight was carefully monitored during compression to minimize the impact of tablet weight variability on the dissolution results. For MCC runs, individual tablet weight maintained within range 97-103 mg, and for DCP between 96-104 mg.
Figure 1 (a and b) presents the dissolution profiles of folic acid tablets obtained from the twelve runs using MCC and DCP formulations respectively. For clarity only a subset of dissolution profiles is presented. The 60 minute time point is not included in the graphs.
For the formulation containing MCC there is a pattern in the dissolution profiles (Figure 1, a), noticeable especially at the early dissolution time points. The material subjected to longer residence time in the feed frame resulted in tablets that presented a slower dissolution of folic acid while the tablets from the low residence time had faster dissolution. This observation was confirmed using a least squares multiple regression analysis (6), which showed that increased residence time negatively affected the dissolution of the active. In addition, this factor consistently showed statistical significance (p < 0.05) for all the dissolution time points from 5 to 45 minutes. Compression force seemed to be also important; although, not consistently significant for all the dissolution time points. The paddle speed factor and the two factor interactions of the experimental variables were rather small and non-significant (except for the early time points).
The least squares multiple regression analysis for the dissolution profiles from the folic acid DCP formulation revealed a statistically significant interaction between residence time and compression force at each dissolution time point, which indicates that the compression force has a different effect on a blend with a low residence time than it does on a blend with high residence time. Since it is generally accepted that DCP is not normally affected by over-lubrication because of its tendency to fragment during compression, this result is surprising and warrants further confirmation. Residence time and compression force alone did not show statistical significance except for the first dissolution time point. It was also observed that tablets from most of the experimental runs failed the USP dissolution standard for folic acid (in contrast to those that used MCC in the formula which all pass the USP test). This is not surprising since it has been reported that DCP can impede dissolution (4). This phenomenon possibly masked or influence the effects under evaluation.
Looking at tablet hardness, the MCC formulation was affected by residence time, paddle speed and compression force, while compression force was the most important factor for the DCP formulation. Figure 2 (a and b) shows the compression profiles for the 12 runs of the MCC and DCP based formulations respectively.
All tablets from both MCC and DCP formulations and from all the runs presented a very rapid disintegration time (less that 2 minutes); therefore, this response was not analysed.
Results from the study allowed the team at Patheon to make several conclusions. Firstly, that over-lubrication does occur in the force feeder of a rotary tablet press. Secondly, that the residence time of a powder blend in the feeder is an important parameter influencing the dissolution and mechanical properties of a pharmaceutical tablet, where formulations are sensitive to magnesium stearate. Finally, that the impact of residence time is both drug and excipient-dependent.
Moving forwards, it is clear that pharmaceutical scientists need to look beyond the blender when considering the impact of over-lubrication and seeking to optimize the blend process. They must look to minimize both the time a blend is kept in the feeder and the speed of rotation of the paddles (to avoid overblending).
While folic acid was known to be sensitive to processing factors, the extent to which the force feeder may affect the properties of other active ingredients is currently unknown, yet worthy of further investigation. It is also possible that the feeder may not be the only part of the manufacturing process that contributes to the over-lubrication effect.
The author thanks the following team members for their contributions to this research: Anush Mehta, Jasmine Ramsuran, Akaash Singh, Radu Balint, and Austin Freedman.
1. B.B. Sheth, F.J. Bandelin and R.F. Shangraw, “Compressed Tablets,” in Pharmaceutical Dosage Forms: Tablets Volume 1, H.A. Lieberman and L. Lachman, Eds. (Marcel Dekker, Inc. New York, 1980), p. 164.
2. G.K. Bolhuis and A.W. Hölzer, “Lubricant Sensitivity,” in Pharmaceutical Powder Compaction Technology (Drugs and the Pharmaceutical Sciences, Vol. 71), G. Alderborn and C. Nyström, Eds. (Marcel Dekker, Inc. New York, 1996), pp. 517-560.
3. S.W. Hoag, H. Ramachandruni, and R.F. Shangraw, “Failure of Prescription Prenatal Vitamin Products to Meet USP Standards for Folic Acid Dissolution,” J. Am. Pharm. Assoc. NS37 (4), 397-400 (1997).
4. J. Du, and S.W. Hoag, “Characterization of Excipient and Tableting Factors That Influence Folic Acid Dissolution, Friability, and Breaking Strength of Oil- and Water-Soluble Multivitamin with Minerals Tablets,” Drug Dev. Ind. Pharm. 29 (10), 1137-1147 (2003).
5. F. Li, and J.C. Cunningham, “Effect of Feed Frame Paddle Speed, Powder Residence Time Inside the Feed Frame, Pre-compression and Strain Rate on Tablet Strength,” poster presented at the 2003 AAPS Annual Meeting and Exposition, Salt Lake City, UT, October 26-30, 2003.
6. JMP, Version 5.1. SAS Institute Inc., Cary, NC, 2002.
7.Folic Acid Tablets, Official Monograph in USP 29-NF 24 (United States Pharmacopeial Convention, Rockville, MD, 2006).
Manuel Hervas, Senior Technical Project Leader
Anush Mehta, Technical Project Leader
Jasmine Ramsuran, Project Manager
Akaash Singh, Technical Project Leader
Radu Balint, Senior Research Chemist
Austin Freedman, Former Director at Patheon
Patheon Inc., Pharmaceutical Development Services
Toronto Region Operations, 2100 Syntex Court,
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