http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, 2015; 20(6): 747–754 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2014.920354
RESEARCH ARTICLE
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Compression parameters of hexagonal boron nitride on direct compression mixture of microcrystalline cellulose and modified starch Mekin Dog˘a Halac¸og˘lu and Timuc¸in Ug˘urlu Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpasa, Istanbul, Turkey
Abstract
Keywords
The objective of this study was to investigate the effects of conventional lubricants including a new candidate lubricant ‘‘hexagonal boron nitride (HBN)’’ on direct compression powders. Lubricants such as magnesium stearate (MGST), glyceryl behenate, stearic acid, talc and polyethylene glycol6000 were studied and tablets were manufactured on a single station instrumented tablet press. This study comprised the continuation of our previous one, so mixture of microcrystalline cellulose and modified starch was used as a master formula to evaluate effects of lubricants on pharmaceutical excipients that undergo complete plastic deformation without any fragmentation under compression pressure. Bulk and tapped densities, and Carr’s index parameters were calculated for powders. Tensile strength, cohesion index, lower punch ejection force and lubricant effectiveness values were investigated for tablets. The deformation mechanisms of tablets were studied during compression from the Heckel plots with or without lubricant. MGST was found to be the most effective lubricant and HBN was found very close to it. HBN did not show a significant negative effect on the crushing strength and disintegration time of the tablets when we compared with MGST. Based on the Heckel plots at the level of 1%, formulation prepared with HBN showed the most pronounced plastic character.
Cohesion index, direct compression, hexagonal boron nitride, lubricants, lubricant effectiveness
Introduction Lubricants are pharmaceutical excipients indispensable for improving the quality and manufacturing efficiency of solid preparations, mainly due to their characteristics to improve fluidity, filling properties, as well as to prevent powder adhesion to punch faces, and reduce friction between die wall and granules as the tablet formed and ejected. In a general way, hydrophobic lubricants are more efficient than that of hydrophilic lubricants. On the other hand, hydrophobic lubricants can also alter other physicochemical properties of tablets, such as tensile strength, disintegration time and drug release1,2. The magnitude of these deteriorating effects are explained by the formation of a physical barrier around host particles giving a molecular coverage which makes the interparticle bound formation more difficult. Thus, the lubrication process is a combination of factors involving the nature and properties of the lubricant, the nature and properties of the other tablet ingredients and processing conditions resulting in the final dosage form. Moreover, the concentration of the lubricant in the formulation and the lubrication time should be balanced in terms of the adverse effects of the used lubricant. In general, lubricants are added to the pre-mixed powder mixture as a final step and mixed for only a few minutes. However, even small changes in mixing time and lubricant amount
Address for correspondence: Timuc¸in Ug˘urlu, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668, Haydarpa¸sa, Istanbul, Turkey. Fax: + 90 216 345 29 52. E-mail: [email protected]
History Received 30 January 2014 Revised 15 April 2014 Accepted 17 April 2014 Published online 20 May 2014
can significantly affect the product performance and quality properties3–5. There are different ways to limit the deteriorating effects of lubricants on tablet properties. Undoubtedly, the best method is omitting a lubricant in a tablet formulation. However, without external lubricant addition the modern tableting options could not be carried out. Kara et al.6 investigated possible use of zirconia as a material for the manufacture of punches and dies for use in tablet machines and to study its effect on ejection of tablets made from different formulations. They found that zirconia was an alternative to stainless-steel tooling. The addition of exact amount of suitable lubricant directly on to punch and die surfaces immediately after tablet ejection has also been reported by Yamamura et al.7 and Dawes et al.8. Optimization of lubricant concentration and the choice of alternative lubricants seem an attractive solution of the problem of the deleterious effect of lubricant on the bonding properties of tablet excipients9. One of these alternative lubricant applications has been applied successfully by our laboratory for a while is hexagonal boron nitride (HBN). Its physicochemical and toxicological properties were given in detail in our previous studies10–12. Briefly, HBN is considered as safe when used as a high purity material (99.9%) based on a report issued by the National Toxicology Program13. One of the recent applications of BN is the application of boron nitride nanotubes (BNNTs) in the biomedical area14. Ciofani et al.15 proposed, for the first time, a technique for obtaining BNNT stable dispersions suitable for biological applications based on polyethyleneimine (PEI) water solutions. Results obtained from in vitro testing performed on human neuroblastoma cell line (SH-SY5Y) showed that a satisfactorily
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cell viability up to a concentration of 5.0 mg/ml PEI–BNNTs in the cell culture medium was achieved15. Due to its lubricious and non-toxic properties, we decided to evaluate HBN as a new alternative lubricant in tableting technology. In the first application of HBN, the lubrication properties of HBN on direct compression method were shown previously by Turkoglu et al.10. However, in that study, lower punch ejection force was calculated by comparing the ejection force of control batches with those of lubricant containing ones. It was totally qualitative method. In the second application, the lubrication properties of HBN on wet granulation process were shown quantitatively by Ugurlu et al.11. In our previous study12, which was constituted the first part, and in this study which is the continuation study of our previous one, we reapplied lubricants on direct compression mixture including HBN, and we evaluated the lubricant properties such as lower punch ejection force, cohesion index and lubricant effectiveness quantitatively and in detail. Above as we mentioned, the magnitude of deteriorating effects of lubricants is related to the nature and properties of the other tablet ingredients. In the first part of the study, binary direct compression mixture of spraydried lactose and microcrystalline cellulose was used as our master formula to explore the performance of various lubricant type including HBN and optimum concentration required for compression process. The results were presented in our paper by Ugurlu et al.12. In this study, it is the first time binary direct compression mixture of microcrystalline cellulose and modified starch was used our master formula to show lubrication effects of same studied lubricants of Magnesium stearate, Compritol888-ATO (COMP), Stearic acid (STAC), Talc, PEG6000 and including new lubricant HBN on different direct compression mixtures. The consolidation and compaction characteristics of host particles are known to have considerable influence on their susceptibility to lubrication. The sensitivity of tablet excipients to lubricants depends both on the compression behavior and on the bonding mechanism of the material. The bonding properties of brittle materials like dicalcium phosphate dihydrate and anhydrous b-lactose were hardly influenced by lubrication. The phenomenon was explained by the assumption that clean, lubricant-free surfaces are created by fragmentation of the
particles during consolidation of the particle system. On the other hand, a maximum effect of lubricant was found for excipients that undergo complete plastic deformation without any fragmentation under compression and are bonded by cohesion, such as starch and some starch derivatives as studied in this study16,17. And again we found that HBN was as effective as MGST as a lubricant and did not show a significant negative effect on the crushing strength and disintegration time of the tablets when compared with MGST in binary direct compression mixture of microcrystalline cellulose and modified starch. Tensile strength, cohesion index, LPEF and lubricant effectiveness, which were the important tablet manufacturing parameters, were evaluated in detail. Powder characteristics and their compaction parameters under compression pressure were investigated.
Materials and methods Materials Microcrystalline cellulose (Avicel pH102) was donated by FMC, Brussels, Belgium. Modified starch (Starch 1500) was donated from Colorcon Ltd., Istanbul, Turkey. Magnesium stearate pure (MGST; 0.43 m2/g) was donated from Sigma-Aldrich, St. Louis, MO. Hexagonal boron nitride nanopowder (HBN; 1.13 m2/g; Average particle size 70 nm) was purchased from Lower Mississauga, Ontario, Canada. Glycerol Dibehenate (Compritol888-ATO; COMP; 0.23 m2/g) was donated from Gattefose, Cedex, France. Stearic acide (STAC; 0.03 m2/g) and Polyethylene glycol (PEG6000) were gifts from Deva Research and Development Center (Turkey). Micro Talc (7.60 m2/g) was purchased from Mondo Minerals, Amsterdam, the Netherlands. Powder mixtures A 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) was used as the master powder mixture without a drug. This binary mixture was mixed for 20 min in a laboratory size V-blender. All lubricants were added to previously obtained binary mixture depending on their studied concentrations and mixed further for 5 min. At the end, we obtained 20 batches of lubricated powder mixtures (Table 1).
Table 1. Study design for both lubricated powder mixtures and resulted tablet formulations, and Tests on [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3).
Batches B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 B18 B19 B20
Lubricant type added
Lubricant concentration (%)
Bulk density (g/cm3)
Tapped density (g/cm3)
Carr’s index (%)
MGST MGST MGST MGST HBN HBN HBN HBN COMP COMP COMP TALC TALC TALC STAC STAC STAC PEG PEG PEG
0.5 1 2 4 0.5 1 2 4 1 2 4 1 2 4 1 2 4 1 2 4
0.48 ± 0.01 0.46 ± 0.01 0.52 ± 0,01 0.52 ± 0.01 0.48 ± 0.01 0.49 ± 0.01 0.51 ± 0.01 0.49 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.46 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.49 ± 0.01 0.46 ± 0.01 0.45 ± 0.01 0.46 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.48 ± 0.01
0.61 ± 0.01 0.58 ± 0.01 0.64 ± 0.01 0.65 ± 0.01 0.58 ± 0.01 0.59 ± 0.01 0.60 ± 0.01 0.60 ± 0.01 0.56 ± 0.01 0.57 ± 0.01 0.56 ± 0.01 0.60 ± 0.01 0.60 ± 0.01 0.63 ± 0.02 0.58 ± 0.01 0.57 ± 0.01 0.57 ± 0.01 0.58 ± 0.01 0.59 ± 0.01 0.60 ± 0.01
21.15 ± 0.01 20.25 ± 0.21 18.61 ± 1.87 18.87 ± 1.91 16.77 ± 0.94 16.43 ± 2.11 14.96 ± 0.92 17.76 ± 0.20 15.62 ± 2.09 17.09 ± 0.19 17.24 ± 3.57 21.73 ± 0.85 20.89 ± 0.23 21.52 ± 3.50 20.35 ± 1.48 20.48 ± 0.82 20.11 ± 1.47 18.35 ± 0.90 20.50 ± 0.22 19.86 ± 0.79
Mixing time after the addition of lubticant: 5 min in V-blender.
Lubrication properties of HBN on modified starch derivatives
DOI: 10.3109/10837450.2014.920354
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Bulk and tapped densities of powder mixtures Twenty-five grams of powder mixtures with studied concentrations of lubricants were used for powder tests. The lubricated powder mixtures were poured into a 100 ml graduated cylinder (readable to 1 ml). Their bulk volumes were recorded. The cylinder was directly mounted onto a tapping machine which had a tapping speed of 100 taps/min. After 5 min, tapped volumes (V500) were recorded. The differences between V500 and V1250 were smaller than 1 ml. Measurements were carried out in triplicate. By measuring both the untapped volume and the tapped volume, the following factors can be determined. Pour (or Bulk) density ¼ mass/untapped volume Tapped density ¼ mass/tapped volume Carr’s Index (CI) ¼ [(tapped density bulk density) 100]/ tapped density The determination was harmonized with the European Pharmacopoeia 2008. Tablet preparation Tablets were prepared according to the method used in our previous study12. Briefly, for lubricant performance, 20 batches of tablets were manufactured with the same lubricated powder mixtures given in the ‘‘Powder mixtures’’ section using a singlestation instrumented tablet press (Korsch EKO, Berlin, Germany) equipped with a 9 mm flat-faced punch set. Study design was summarized in Table 1. The upper punch compression level, which was responsible for tablet hardness and also the lower punch diving level into die, which was responsible for tablet weight were both kept constant. The final tablet weight for the batch (B1) with 0.5% MGST level was 250 mg. When the tableting operation was changed to the next lubricant, the diving levels of punches into the die were kept constant which meant the tablet weight adjustment of tablet press kept constant, however the tablet weight changed due to powder fluidity. Powder fluidity was independent from tablet press adjustment, it was dependent on lubricant effect and free flowing property of powder from tablet press hopper. If the powder fluidity changes, it will effect the tablet weight. To get rid of this phenomenon, as used for the first time in our previous study12, instead of keeping tablet weight constant, we used the ratio obtained from hardness to upper punch compression force (cohession index), and also the second ratio obtained from upper punch compression forces to lower punch ejection force (lubricant effectiveness). By this way, it was
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possible to compare tablet properties with different lubricants without changing the diving levels of both punches. Instrumentation of tablet press The compaction properties of pharmaceutical formulations can be studied experimentally using a variety of techniques, ranging from instrumented production presses to compaction simulators and methods of analysis. The distribution of compression force being applied on a top of a cylindrical powder mass is given as follows: the force applied by the upper punch, the proportion of force transmitted to the lower punch and the reaction of the die wall due to the friction at this surface. One can evaluate the acting force, mentioned above, by the most basic instrumentation of a tablet press using the compaction force versus time profile. To monitor force–time profile and control, a tablet press certain sensors must be installed at specific locations on the machine and connected to signal conditioner, analog with digital converter board and data acquisition system. Without instrumentation of tablet press measuring, compression force and friction force could be impossible. As compression force increases, so does tablet hardness along with a force required to eject a tablet. Larger friction force leads to larger ejection forces that leads to an increased wear on punches and die surface. Ejection force can also be used to evaluate the lubricant effectiveness. As a result in our study (Figure 1), a single-station tablet press (Korsch EKO, Berlin, Germany) was instrumented for monitoring upper and lower punch forces. Two ring type Dynamic Force Sensors were used to detect compression and ejection force input signals. Sensors converted the forces signals into voltage. Obtained voltages were amplified by signal conditioner from millivolt- to volt-based form, the volt-based voltage signals were converted to a sequence of binary digital numbers, let us answer yes or no, using analog to digital converter board and finally, data acquisition system (National Instruments, Labview 2009, Signalexpress) processed these binary digital numbers and gave continuously time versus force profile from front panel. Finally, upper punch compression and lower punch ejection forces were determined quantitatively with this system as a continuous real time process. To validate the signal readings from the system, the press was run on the automatic mode (3600 tablets/h) to be able to apply an even pressure to each tablet, and at least 50 consecutive tablets were produced for quantitative evaluation of LPEF and upper punch compression force.
Figure 1. Technical diagram of tablet press instrumentation.
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Measurement of tablet properties The weight variations of tablets were determined according to the USP 24. Tablet diameter and thickness were measured using a digital micrometer with a sensitiviy of 0.01 mm (Bestool-Kanon, Japan). The diametrical tablet crushing strength was evaluated using a tablet hardness tester (Model C 50, I-Holland, Ltd., Nottingham, UK). And also the disintegration time of tablets were evaluated according to the USP 24.
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Tensile strength measurement of tablets The tensile strengths of tablets were determined at room temperature by diametral compression using a hardness tester (Model C 50, I-Holland, Ltd., Nottingham, UK) applying the Fell and Newton equation18,19: 2F T¼ dt 2
where T is the tensile strength of the tablet (N/mm ), F is the applied force to cause fracture (N) obtained from crushing strength, d is the tablet diameter (mm) and t is the tablet thickness (mm). Results were taken only from tablets that split cleanly into two halves without any sign of lamination. Cohesion index of tablets Cohesion index of tablets was determined using the same ratio in our previous study12 and briefly, the ratio of tablet hardness (N) on the maximum upper punch force (N) was multiplied by 10. The higher the CohI, the better the compressibility was20. To discriminate Cohession Index and Carr’s Index, the abbreviation was made as CohI for Cohesion Index, and CI for Carr’s Index. Lubricant effectiveness of tablets The quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. A high value indicated good lubrication. The lubricant effectiveness values from each batch were calculated for mean value of compression force and lower punch ejection force21. Compression behavior of tablets The tablets compression characteristics were studied using density measurements and the Heckel equation, which was used in our previous study12,22,23. The equation was written as follows: 1 ¼ KP þ A ln ð1 DÞ where D is the relative density of a powder column at the compression pressure P, K and A are constants obtained from the slope and intercept of the plot ln[1/(1 D)] versus P, respectively22,23. Porosity is a function of the voids in a powder column, including both inter- and intra-particulate voids. For porosity measurement, the dimensions and weight of a powder column (i.e. apparent density) and the particle density of solid material should be known. The porosity, ", can be expressed by the equation: A "¼1 T where A is the apparent density of a powder column, and T is the true density. The value of A/T, also referred as D, is regarded as the relative density24. Usually, the volume of the
entire tablet, VA is calculated from the measured height and the area of the compact. The determination of these dimensions is normally done when the compression is finished and the tablet is ejected. This kind of measurement is called ‘‘zero-pressure’’ determination or ‘‘out of die’’ method. The so-called apparent density A is determined by division of the tablet weight ‘‘m’’ by the apparent volume, VA. The relative density r is obtained by dividing the apparent density by the true density. The following equations written in detail in our previous study12, however these equations constitute the main expression of the Heckel equation that was why they were given briefly: A m m VT ¼ ¼ ¼ D ¼ r VA VT T VA The volume reduction of compact, cylindrical shape, can be calculated as follows: VT r 2 ht ht ¼ 2 ¼ VA r ha ha Since the final compact is a cylindrical shape, the only change occurred in height under pressure. Where ht is minimum thickness of compact under maximum pressure (60 MPa) of hydraulic press, ha is thickness of compact under different compression pressures. To determine compaction properties of lubricated and unlubricated formulations, 500 mg of the corresponding mixtures were compressed at five different compaction pressures in a laboratory type hydraulic press up to 50 MPa (10, 20, 30, 40 and 50 MPa). The punches used were flat and had a diameter of 13 mm. The selected compaction pressures were maintained for 10 s to allow the development of most possible plastic deformation on the powders, to avoid the effect of different dwell times producing different degrees of deformation. The thickness of tablets was measured and volume of tablets was calculated to find volume reduction.
Results and discussion Evaluation of powder properties Carr’s index (CI) measures the flow properties of powders, obtained from bulk and tapped densities. The smaller the CI is, the better the flow properties are. It has a range between 5% and 23% and when CI leans to 5% indicates excellent flow, and when it starts to lean towards 23% indicates poor flow. In our study, all powder mixtures including any of the applied lubricant showed from good to fair flow properties according to their CI, ranged between minimum 14.96% to maximum 21.73%, shown in Table 1. Formulations with MGST, 21.15, 20.25, 18.61 and 18.87% CI values obtained for the lubricant levels of 0.5, 1, 2 and 4%, respectively, and for HBN, 16.77, 16.43, 14.96 and 17.76% CI values obtained for the same lubricant levels. CI values of the other studied lubricants were as follows: 15.62, 17.09 and 17.24% CI for COMP; 21.73, 20.89 and 21.52% CI for TALC; 20.35, 20.48 and 20.11% CI for STAC; and 18.35, 20.50 and 19.86% CI for PEG6000 at 1, 2 and 4% lubricant concentrations, respectively. Suprisingly in the 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102), HBN and COMP had smaller CI values and better flow properties than that of other lubricants including MGST, TALC, STAC and PEG6000. However, in our previous study12, MGST showed smaller CI values. Tablet weight of formulation prepared with MGST, which was 250 mg, choosed as reference and constant for the other lubricated powder mixtures since MGST is the most widely used lubricant in pharmaceutical industry. Under the same conditions, powders with better flow properties, having smaller CI values, filled in the die volume with larger amounts. In contrast, powders
Lubrication properties of HBN on modified starch derivatives
DOI: 10.3109/10837450.2014.920354
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Table 2. Properties of tablets, compression force and lower punch ejection force variation of tablets made with [Modified starch (Starch 1500)/ Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 10).
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Lubricant type added MGST MGST MGST MGST HBN HBN HBN HBN COMP COMP COMP TALC TALC TALC STAC STAC STAC PEG PEG PEG
Lubricant concentrations (%)
Weight (mg)
0.5 1 2 4 0.5 1 2 4 1 2 4 1 2 4 1 2 4 1 2 4
250 ± 2.96 253 ± 3.86 268 ± 3.53 263 ± 1.20 251 ± 2.96 260 ± 3.94 254 ± 2.33 248 ± 3.48 238 ± 1.90 237 ± 1.77 240 ± 1.58 238 ± 2.88 244 ± 2.17 245 ± 0.84 240 ± 1.73 237 ± 2.75 238 ± 2.02 242 ± 2.12 240 ± 1.51 240 ± 2.60
Hardness (kg)
Tensile strength (N/mm2)
Cohesion Index
Upper punch ejection force (kN/N)
Lower punch ejection force (N)
Lubricant effectiveness (kN/N)
10.03 ± 0.35 6.90 ± 0.55 4.43 ± 0.37 1.78 ± 0.08 17.41 ± 0.93 16.94 ± 0.72 10.95 ± 0.64 5.43 ± 0.60 13.14 ± 0.48 10.35 ± 0.36 8.96 ± 0.65 14.02 ± 0.94 12.85 ± 0.96 9.78 ± 0.55 12.62 ± 0.63 11.10 ± 0.52 9.66 ± 0.49 12.68 ± 0.39 10.40 ± 0.61 9.30 ± 0,65
2.23 ± 0.07 1.54 ± 0.13 0.93 ± 0.08 0.38 ± 0.01 4.17 ± 0.24 3.89 ± 0.15 2.56 ± 0.15 1.26 ± 0.15 3.12 ± 0.13 2.46 ± 0.12 2.13 ± 0.16 3.31 ± 0.22 2.99 ± 0.23 2.33 ± 0.13 2.93 ± 0.14 2.63 ± 0.13 2.27 ± 0.12 2.97 ± 0.13 2.44 ± 0.14 2.18 ± 0.16
31.08 ± 1.07 21.37 ± 1.71 11.55 ± 0.96 4.36 ± 0.18 59.58 ± 3.19 52.48 ± 2.24 33.75 ± 1.98 26.18 ± 2.91 107.44 ± 3.90 84.59 ± 2.97 69.37 ± 5.04 104.45 ± 7.04 77.98 ± 5.80 65.41 ± 3.69 96.50 ± 4.78 89.46 ± 4.20 75.80 ± 3.85 91.04 ± 2.81 88.73 ± 5.19 91.27 ± 6.36
12.5 ± 0.5 31.7 ± 0.6 37.7 ± 0.58 40.0 ± 2.0 28.7 ± 0.6 31.7 ± 0.6 31.8 ± 0.3 20.3 ± 0.6 12.0 ± 1.0 12.0 ± 1.0 12.7 ± 0.6 13.2 ± 0.3 16.2 ± 0.3 14.7 ± 0.6 12.8 ± 0.3 12.2 ± 0.3 12.5 ± 0.5 13.7 ± 0.3 11.5 ± 0.5 10.0 ± 0,5
342 ± 14 283 ± 29 273 ± 25 275 ± 25 483 ± 29 417 ± 29 383 ± 29 323 ± 25 283 ± 29 183 ± 29 167 ± 29 600 ± 50 550 ± 50 500 ± 1 417 ± 29 367 ± 29 333 ± 29 433 ± 29 417 ± 29 417 ± 29
0.0928 ± 0.0051 0.1127 ± 0.0134 0.1385 ± 0.0108 0.1461 ± 0.0121 0.0594 ± 0.0024 0.0762 ± 0.0046 0.0834 ± 0.0070 0.0632 ± 0.0065 0.0429 ± 0.0081 0.0667 ± 0.0126 0.0778 ± 0.0154 0.0220 ± 0.0019 0.0296 ± 0.0032 0.0293 ± 0.0012 0.0309 ± 0.0027 0.0333 ± 0.0018 0.0378 ± 0.0049 0.0316 ± 0.0019 0.0276 ± 0.0010 0.0240 ± 0.0009
Tablet diameter: 9 mm; kN ¼ 1000 N.
with worse flow properties compared to MGST, having bigger CI values, could not fill the die volume properly, therefore, when we changed the lubricant type tablet weight variations occurred. This phenomenon also explaines the weight variation of tablets, summarized in Table 2. Evaluation of tablet properties Study design is summarized in Table 1. Trials were made with four concentration levels (0.5, 1, 2 and 4%) for MGST and HBN, and three concentration levels (1, 2 and 4%) for COMP, STAC, TALC and PEG6000. Table 2 gives properties of tablets prepared with 1:1 mixture modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) including various lubricant. Evaluation of tensile strength of tablets A maximum surface covering effect of lubricant was found for excipients that undergo complete plastic deformation without any fragmentation under compression such as starch derivatives as studied in this study. Surface covering properties phenomenon leads to the formation of hydrophobic layer around the granule particles and results in decrease in crushing strength and followed by decrease in tensile strength. In Table 2 and Figure 2, fast drops in tensile strength were observed with MGST and HBN curves after 2% lubricant concentration. However, before 2% lubricant concentration, HBN had the biggest tensile strength when compared to that of other lubricant. From the Figure 2, it is clear that even excipients such as starch derivetives that undergo complete plastic deformation HBN has least pronounced effect before level of 2% lubricant concentration. TALC, COMP, PEG6000 and STAC curves were shallow from 1% to 4%. MGST shows the most pronounced effect on lowering tensile strength. It was suprisingly different from our previous study made with 1:1 mixture of spray-dried lactose and microcrystalline cellulose12. At the level of 0.5%, MGST had the minimum tensile strength with 2.23 N/mm2 and HBN had the maximum tensile strength with 4.17 N/mm2. At the level of 1%, the tensile strength of tablets including MGST, HBN, COMP, TALC, STAC and PEG6000 were 1.54, 3.89, 3.12, 3.31, 2.93 and 2.97 N/mm2, respectively. At the level of 2%, the tensile strength of tablets were 0.93, 2.56, 2.46,
Figure 2. Concentration versus tensile strength graph of lubricants.
2.99, 2.63 and 2.44 N/mm2 for MGST, HBN, COMP, TALC, STAC and PEG6000, respectively. At maximum studied level of 4%, MGST shows the minimum tensile strength with 0.38 N/mm2, and HBN shows 1.26 N/mm2. Powders including COMP, TALC, STAC and PEG6000 at the level of 4% gave 2.13, 2.33, 2.27 and 2.18 N/mm2 tensile strength values, respectively. With the increase of the concentration of lubricant, tablet crushing strength decreases. The surface covering property of MGST pronounced more than that of other studied lubricants complied with Nakagawa et al.25. Evaluation of cohesion index of tablets Powders with high Cohesion index (CohI) have better compressibility. It is a combination of crushing strength with upper punch force independant to other factors of tablets. In general, this index decreases as the lubricant amount increases. Effect of lubricant concentration on Cohesion index given in Table 2 and Figure 3. Batches prepared with lubricant concentrations of 1, 2 and 4% gave 107.44, 84.59 and 69.37 CohI values for COMP; 104.45, 77.98 and 65.41 CohI for TALC; 96.50, 89.46 and 75.80 CohI for
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Figure 3. Concentration versus cohesion index graph of lubricants. Figure 4. Concentration versus lower punch ejection force (LPEF) graph of lubricants.
STAC; and 91.04, 88.73 and 91.27 CohI for PEG6000, respectively. Surprisingly, this meant no significant change occurred in CohI with the increase of lubricant concentration when COMP, TALC, STAC and PEG6000 used. The results were complied with our previous study12. On the other hand, both MGST and HBN were reported as the most effective lubricants in our older reports11,12. However, in this study, same with previous one, seen from Figure 3, MGST showsa fast drop and had the minimum CohI values of 31.08, 21.37, 11.55 and 4.36 with the increase of lubricant concentration. HBN shows similar but a little bit better CohI values of 59.58, 52.48, 33.75 and 50.88 than that of MGST, but still much lower than COMP, TALC, STAC and PEG6000. For COMP, TALC, STAC and PEG6000 at the beginning, they had close CohI values in 1% lubricant concentration, however, as the concentration of lubricant increased, CohI values of COMP, TALC, STAC and PEG6000 started to decrease. Low Cohesion index phenomenon for HBN and MGST led to the lowest compressibilty values at the studied level of 2 and 4% lubricant concentrations compared to that of COMP, TALC, STAC and PEG6000. The results were complied with our previous study12. Evaluation of lower punch ejection force (LPEF) of tablets The upper punch compression level, which was responsible for tablet hardness and also the lower punch diving level into die, which was responsible for tablet weight were both kept constant as the same with our previous study12 to prevent any variation resulting from compression procedure. Table 2 and Figure 4 represent the evaluation of LPEF. All studied lubricants depending on their concentration lowered the LPEF, and with the increase in lubricant concentration, LPEF values decreased. At first sight, as shown in Figure 4, suprisingly COMP showed better decline in LPEF than that of MGST and HBN this phenomenon lead to no correlation between powder properties and friction measurements. However, the powder fluidity can be enhanced with lubricant type and lubricant concentration, and any change in the powder fluidity causes to tablet weight variation complied with the literature26,27, with our previous study12, and finally with our results from powder tests. This meant the better powder fluidity led to the heavier tablets and this resulted in higher LPEF needed to eject tablet from the die. As a result, the LPEF was modified with upper punch compression force, and lubricant effectiveness to get ride of mentioned phenomenon. This modification was explained as follows. The quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. If the tablet weight differs due to powder flow property, the upper punch force
Figure 5. Concentration versus lubricant effectiveness graph of lubricants.
will differ simultaneously. Both in this study and our previous one12, the amount of powder in the die and the upper punch force changed in the same direction. If the amount of powder and resulted tablet weight were smaller, upper punch force was smaller. In this point of view, tablet properties discussed with lubricant effectiveness data rather than LPEF alone and using lubricant effectiveness powder properties and friction measurements can be correlated. The punch forces, given in Newton, and lubricant effectiveness values are listed in Table 2 and graphed in Figure 5. Evaluation of lubricant effectiveness of tablets As mentioned above, the quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. We first applied lubricant effectiveness in our previous study in the mixture of spray-dried lactose and microcrystalline cellulose to explain weird results obtained from LPEF alone12. And, in this study, we reapplied lubricant effectiveness in the mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) to evaluate lubricant activity. Table 2 and Figure 5 represent the most reliable evaluation of the lubricant activity apart from flowing properties of powders. The best lubricant effectiveness activity was pronounced with MGST. It showed lubricant effectiveness values of 0.0928, 0.1127, 0.1385 and 0.1461 in
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DOI: 10.3109/10837450.2014.920354
Lubrication properties of HBN on modified starch derivatives
Figure 6. Concentration versus disintegration time graph of lubricants.
the lubricant levels of 0.5, 1, 2 and 4%, respectively. In our previous study depending on its concentartions, MGST shows best lubricant effectiveness when 1:1 mixture of spray-dried lactose and microcrystalline cellulose used as a master formula12. However, the values were lower than that of this study. This meant better surface covering effect of lubricants on excipients that undergo complete plastic deformation without any fragmentation under compression as modified starch leading to better decrease in LPEF and followed by better increase in lubricant effectiveness as in this study. The second lubricant effectivenes activity rank was found with HBN. HBN also showed high lubricant effectiveness values of 0.0594, 0.0762, 0.0834 and 0.0632 in the same lubricants level with MGST. Mentioned phenomenon was also valid for HBN. Lubricant effectiveness values of both MGST and HBN increased with increasing lubricant concentration due to surface covering properties. Surprisingly, lubricant effectiveness value of HBN decreased to 0.0632 at 4% concentration. This phenomenon was thought to be because of segregation of nanosized HBN particles from the master formula during mixing procedure COMP took third turn in the lubricant effectiveness order. Due to bad surface covering properties STAC, TALC and PEG6000 had the lowest lubricant effectiveness values. Obtained values were not changed upon increase in their lubricant concentration. Evaluation of disintegration time of tablets Figure 6 shows the relationship between the lubricant concentration and disintegration time of tablets. The disintegration times were 180, 200, 225 and 670 s for MGST at 0.5, 1, 2 and 4% concentration; 160, 158, 163 and 70 s for HBN at the same lubricant level with MGST; 173, 184 and 247 s for COMP at 1, 2 and 4% concentration; 156, 162 and 165 s for TALC; 174, 170 and 177 s for STAC; and 130, 120 and 163 s for PEG6000. These three lubricants levels were the same as COMP. The higher the lubricant concentration the more pronounced effects of lubricant were observed on disintegration time. In this study, surface covering effect of lubricants on excipients that undergo complete plastic deformation led to higher increase in tablet disintegration times compared with our previous study12 and literature28. The most deteriorating effect on desintegration time was obtained from MGST. Disintegration time over 10 min could be ascribed to the lipophilic tablet surface. HBN was found to be more effective lubricant than MGST, not having a negative effect on tablet disintegration times as much as MGST. Its disintegration time were slightly over water-soluble lubricant PEG6000. However at 4% level, a drastic decline in disintegration time of HBN was observed. It was thought to be because of segregation of
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Figure 7. Heckel plots of lubricated and unlubricated powder mixture. Standard deviations were shown in Table 3.
nanosized HBN particles from the master formula during mixing procedure led to decrease in desentagration time at this level. The least pronounced effect was observed with water soluble lubricant PEG6000. Surprisingly, TALC and STAC showed closer disintegration effect in tablet formulations like HBN. Evaluation of compression behavior of tablets To evaluate the compression properties of 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) with different lubricants, Heckel equation was used. The constants of the Heckel equation22,23 were determined by the linear regression analysis using the least-squares method. Compaction characteristics (Figure 7 and Table 3) revealed that lubricated and unlubricated powder mixtures were easily deformed under compression without subsequent fragmentation. In Table 4, constants and linear regression coefficients of granule formulations were given. For correct calculation of r2 five pressure values were used (10, 20, 30, 40 and 50 MPa). r2 Values of powder without lubricant, HBN, TALC and PEG6000 were found to be 40.95, and r2 values of MGST, COMP and STAC were found to be 50.95. By the addition of 1% lubricants, slopes of Heckel equation were decreased. The K values give the slope and plastic character of the powder mixtures. High slope is indicative of plastic deformation and low slope is indicative of elastic deformation23,29. As shown in Figure 7, upon including any lubricant plastic deformation started to lean towards elastic deformation. In our study, the unlubricated powder mixture had the slope of 0.1000 as summarized in Table 4. Surprisingly different from our previous study12, the most pronounced effect was found with the slope of 0.0944 for TALC at 1% lubricant concentration when studied with a mixture of modified starch (Starch 1500). The obtained K values were as follows: 0.0889 for HBN; 0.0944 for TALC; 0.0584 for STAC; 0.0423 for MGST; 0.0770 for PEG6000; and 0.0744 for COMP, respectively. Therefore, with the studied powder mixture, which underwent complete plastic deformation MGST had the highest elastic deformation property. HBN had slight negative effect on the tablet compaction behavior, but not as much as MGST and still showed plastic character when compared to that of other lubricants such as MGST, COMP, STAC and PEG6000.
Conclusion In general, all tested lubricants in this study were somehow effective and used at different ratio in tablet manufacturing. HBN was found as effective as MGST at low concentrations 0.5–1%
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Table 3. Ln(1/porosity) data of unlubricated and 1% lubricant containing [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3). ln 1/porosity Pressure (MPa)
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10 20 30 40 50
No-lubricant
MGST
HBN
COMP
TALC
STACz
PEG
1.69 ± 0.04 2.86 ± 0.15 3.76 ± 0.10 5.08 ± 0.23 5.58 ± 0.40
1.90 ± 0.08 2.89 ± 0.08 3.23 ± 0.08 3.56 ± 0.64 3.68 ± 0.18
1.92 ± 0.02 3.09 ± 0.28 3.86 ± 0.01 4.66 ± 0.01 5.58 ± 0.80
2.04 ± 0.08 3.55 ± 0.27 4.09 ± 0.45 4.97 ± 0.92 5.05 ± 0.87
2.09 ± 0.10 3.22 ± 0.26 4.73 ± 1.27 5.22 ± 0.90 5.81 ± 0.40
2.07 ± 0.11 3.11 ± 0.08 4.04 ± 0.26 4.49 ± 0.40 4.30 ± 0.34
1.96 ± 0.04 3.09 ± 0.19 4.02 ± 0.37 4.09 ± 0.29 5.31 ± 0.63
Table 4. Constants and linear regression coefficients of Heckel equations of unlubricated and 1% lubricant containing [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3).
10. 11.
A
K
r2
0.794 1.783 1.155 1.708 1.382 1.850 1.384
0.1000 0.0423 0.0889 0.0744 0.0944 0.0584 0.0770
0.986 0.878 0.994 0.881 0.956 0.840 0.949
Powder mixture No lubricant %1 MGST %1 HBN %1 COMP %1 TALC %1 STAC %1 PEG
12.
13.
14. 15.
based on lubricant effectiveness values. Comparing other parameters such disintegration time and Heckel analysis, HBN was found to better than MGST. This study complied with our previous work with binary mixture of spray-dried lactose and microcrystalline cellulose12. HBN can also be used as a new lubricant in direct compression as effective as wet granulation.
16.
17. 18.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. This research was supported by Scientific Research Project Unit of Marmara University (BAPKO; SAG-A-080410-0066).
References 1. Wang J, Wen H, Desai D. Lubrication in tablet formulations. Eur J Pharm Biopharm 2010;75:1–15. 2. Pingali K, Mendez R, Lewis D, et al. Mixing order of glidant and lubricant-influence on powder and tablet properties. Int J Pharm 2011;409:269–277. 3. Bolhuis GK, Ho¨lzer AW. Lubricant sensitivity. In: Alderborn G, Nystro¨m C, eds. Pharmaceutical powder compaction technology. New York: Marcel Dekker Inc.; 1996:517–560. 4. Sheth BB, Bandelin FJ, Shangraw RF. Compressed tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical dosage forms: tablets. Vol. 1. New York: Marcel Dekker Inc.; 1980:109–184. 5. Bastos MO, Friedrich RB, Beck RCR. Effects of filler-binders and lubricants on physicochemical properties of tablets obtained by direct compression: a 22 factorial design. Lat Am J Pharm 2008;27: 578–583. 6. Kara A, Tobyn MJ, Stevens R. An application for zirconia as a pharmaceutical die set. J Eur Ceram Soc 2004;24:3091–3101. 7. Yamamura T, Ohta T, Ogawa Y, et al. Effects of automated external lubrication on tablet properties and the stability of eprazinone hydrochloride. Int J Pharm 2009;370:1–7. 8. Dawes J, Allenspach C, Gamble JF, et al. Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. Pharm Dev Technol 2013;18:246–256. 9. Turkoglu M, Sakr A. Tablet dosage forms. In: Florence AT, Siepmann J, eds. Modern pharmaceutics: basic principles and
19.
20.
21.
22. 23. 24. 25.
26.
27.
28.
29.
systems. Vol. 1. Pinehurst (NC): PharmaceuTech, Inc.; 2009:481–497. Turkoglu M, Sahin I, San T. Evaluation of hexagonal boron nitride as a new tablet lubricant. Pharm Dev Technol 2005;10:381–388. Ugurlu T, Turkoglu M. Hexagonal boron nitride as a tablet lubricant and a comparison with conventional lubricants. Int J Pharm 2008; 353:45–51. Ugurlu T, Halacoglu MD. Effects of some lubricants and evaluation of compression parameters on directly compressible powders. Pharm Dev Technol 2014;19:347–354. Baraton MI, Merle T, Quintard P, Lorenzelli V. Surface activity of a boron nitride powder: a vibrational study. Langmuir 1993;9: 1486–1491. Golberg D, Bando Y, Huang Y, et al. Boron nitride nanotubes and nanosheets. ACS Nano 2010;4:2979–2993. Ciofani G, Raffa V, Menciassi A, Cuschieri A. Boron nitride nanotubes: an innovative tool for nanomedicine. Nano Today 2009; 4:8–10. De Boer AH, Bolhuis GK, Lerk CF. Bonding characteristics by scanning electron microscopy of powders mixed with magnesium stearate. Powder Technol 1978;20:75–82. Bolhuis GK, Armstrong NA. Excipients for direct compaction—an update. Pharm Dev Technol 2006;11:111–124. Fell JT, Newton JM. Determination of tablet strength by the diametrical compression test. J Pharm Sci 1970;59:688–691. Davies PN, Worthington HEC, Podczeck F, Newton JM. The determination of the mechanical strength of tablets of different shapes. Int J Pharm 2003;258:153–163. Ro¨scheisen G, Schmidt PC. The combination of factorial design and simplex method in the optimization of lubricants for effervescent tablets. Eur J Biopharm 1995;41:302–308. Delacourte A, Predella P, Leterme P, et al. A method for quantitative evaluation of the effectiveness of the lubricants used in tablet tecnology. Drug Dev Ind Pharm 1993;19:1047–1060. Heckel RW. Density pressure relationship in powder compaction. Transect Metal Soc AIME 1961;221:671–675. Heckel RW. An analysis of powder compaction phenomena. Transect Metal Soc AIME 1961;221:1001–1008. Kuny TJ. Compression behavior of the enzyme b-galactosidase. Ph.D. Thesis. University of Bassel, Switzerland; 2004. Nakagawa H, Kano M, Hasebe S, et al. Real-time monitoring of lubrication properties of magnesium stearate using NIR spectrometer and thermal effusivity sensor. Int J Pharm 2013;441:402–413. Shah AC, Mlodozeniec AR. Mechanism of surface lubrication: influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets. J Pharm Sci 1977;66:1377–1382. Rashid I, Daraghmeh N, Al-Remawi M, et al. Characterization of the impact of magnesium stearate lubrication on the tableting properties of chitin-Mg silicate as a supersisintegrating binder when compared to AvicelÕ 200. Powder Technol 2010;203:609–619. Late SG, Yu YY, Banga AK. Effects of disintegration-promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets. Int J Pharm 2009;365:4–11. Wade JB, Martin GP, Long DF. A methodological approach for determining the effects of moisture content on the compaction properties of powders: granular hydroxyapaptite. Powder Technol 2013;246:511–519.
RESEARCH ARTICLE
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Compression parameters of hexagonal boron nitride on direct compression mixture of microcrystalline cellulose and modified starch Mekin Dog˘a Halac¸og˘lu and Timuc¸in Ug˘urlu Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpasa, Istanbul, Turkey
Abstract
Keywords
The objective of this study was to investigate the effects of conventional lubricants including a new candidate lubricant ‘‘hexagonal boron nitride (HBN)’’ on direct compression powders. Lubricants such as magnesium stearate (MGST), glyceryl behenate, stearic acid, talc and polyethylene glycol6000 were studied and tablets were manufactured on a single station instrumented tablet press. This study comprised the continuation of our previous one, so mixture of microcrystalline cellulose and modified starch was used as a master formula to evaluate effects of lubricants on pharmaceutical excipients that undergo complete plastic deformation without any fragmentation under compression pressure. Bulk and tapped densities, and Carr’s index parameters were calculated for powders. Tensile strength, cohesion index, lower punch ejection force and lubricant effectiveness values were investigated for tablets. The deformation mechanisms of tablets were studied during compression from the Heckel plots with or without lubricant. MGST was found to be the most effective lubricant and HBN was found very close to it. HBN did not show a significant negative effect on the crushing strength and disintegration time of the tablets when we compared with MGST. Based on the Heckel plots at the level of 1%, formulation prepared with HBN showed the most pronounced plastic character.
Cohesion index, direct compression, hexagonal boron nitride, lubricants, lubricant effectiveness
Introduction Lubricants are pharmaceutical excipients indispensable for improving the quality and manufacturing efficiency of solid preparations, mainly due to their characteristics to improve fluidity, filling properties, as well as to prevent powder adhesion to punch faces, and reduce friction between die wall and granules as the tablet formed and ejected. In a general way, hydrophobic lubricants are more efficient than that of hydrophilic lubricants. On the other hand, hydrophobic lubricants can also alter other physicochemical properties of tablets, such as tensile strength, disintegration time and drug release1,2. The magnitude of these deteriorating effects are explained by the formation of a physical barrier around host particles giving a molecular coverage which makes the interparticle bound formation more difficult. Thus, the lubrication process is a combination of factors involving the nature and properties of the lubricant, the nature and properties of the other tablet ingredients and processing conditions resulting in the final dosage form. Moreover, the concentration of the lubricant in the formulation and the lubrication time should be balanced in terms of the adverse effects of the used lubricant. In general, lubricants are added to the pre-mixed powder mixture as a final step and mixed for only a few minutes. However, even small changes in mixing time and lubricant amount
Address for correspondence: Timuc¸in Ug˘urlu, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668, Haydarpa¸sa, Istanbul, Turkey. Fax: + 90 216 345 29 52. E-mail: [email protected]
History Received 30 January 2014 Revised 15 April 2014 Accepted 17 April 2014 Published online 20 May 2014
can significantly affect the product performance and quality properties3–5. There are different ways to limit the deteriorating effects of lubricants on tablet properties. Undoubtedly, the best method is omitting a lubricant in a tablet formulation. However, without external lubricant addition the modern tableting options could not be carried out. Kara et al.6 investigated possible use of zirconia as a material for the manufacture of punches and dies for use in tablet machines and to study its effect on ejection of tablets made from different formulations. They found that zirconia was an alternative to stainless-steel tooling. The addition of exact amount of suitable lubricant directly on to punch and die surfaces immediately after tablet ejection has also been reported by Yamamura et al.7 and Dawes et al.8. Optimization of lubricant concentration and the choice of alternative lubricants seem an attractive solution of the problem of the deleterious effect of lubricant on the bonding properties of tablet excipients9. One of these alternative lubricant applications has been applied successfully by our laboratory for a while is hexagonal boron nitride (HBN). Its physicochemical and toxicological properties were given in detail in our previous studies10–12. Briefly, HBN is considered as safe when used as a high purity material (99.9%) based on a report issued by the National Toxicology Program13. One of the recent applications of BN is the application of boron nitride nanotubes (BNNTs) in the biomedical area14. Ciofani et al.15 proposed, for the first time, a technique for obtaining BNNT stable dispersions suitable for biological applications based on polyethyleneimine (PEI) water solutions. Results obtained from in vitro testing performed on human neuroblastoma cell line (SH-SY5Y) showed that a satisfactorily
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cell viability up to a concentration of 5.0 mg/ml PEI–BNNTs in the cell culture medium was achieved15. Due to its lubricious and non-toxic properties, we decided to evaluate HBN as a new alternative lubricant in tableting technology. In the first application of HBN, the lubrication properties of HBN on direct compression method were shown previously by Turkoglu et al.10. However, in that study, lower punch ejection force was calculated by comparing the ejection force of control batches with those of lubricant containing ones. It was totally qualitative method. In the second application, the lubrication properties of HBN on wet granulation process were shown quantitatively by Ugurlu et al.11. In our previous study12, which was constituted the first part, and in this study which is the continuation study of our previous one, we reapplied lubricants on direct compression mixture including HBN, and we evaluated the lubricant properties such as lower punch ejection force, cohesion index and lubricant effectiveness quantitatively and in detail. Above as we mentioned, the magnitude of deteriorating effects of lubricants is related to the nature and properties of the other tablet ingredients. In the first part of the study, binary direct compression mixture of spraydried lactose and microcrystalline cellulose was used as our master formula to explore the performance of various lubricant type including HBN and optimum concentration required for compression process. The results were presented in our paper by Ugurlu et al.12. In this study, it is the first time binary direct compression mixture of microcrystalline cellulose and modified starch was used our master formula to show lubrication effects of same studied lubricants of Magnesium stearate, Compritol888-ATO (COMP), Stearic acid (STAC), Talc, PEG6000 and including new lubricant HBN on different direct compression mixtures. The consolidation and compaction characteristics of host particles are known to have considerable influence on their susceptibility to lubrication. The sensitivity of tablet excipients to lubricants depends both on the compression behavior and on the bonding mechanism of the material. The bonding properties of brittle materials like dicalcium phosphate dihydrate and anhydrous b-lactose were hardly influenced by lubrication. The phenomenon was explained by the assumption that clean, lubricant-free surfaces are created by fragmentation of the
particles during consolidation of the particle system. On the other hand, a maximum effect of lubricant was found for excipients that undergo complete plastic deformation without any fragmentation under compression and are bonded by cohesion, such as starch and some starch derivatives as studied in this study16,17. And again we found that HBN was as effective as MGST as a lubricant and did not show a significant negative effect on the crushing strength and disintegration time of the tablets when compared with MGST in binary direct compression mixture of microcrystalline cellulose and modified starch. Tensile strength, cohesion index, LPEF and lubricant effectiveness, which were the important tablet manufacturing parameters, were evaluated in detail. Powder characteristics and their compaction parameters under compression pressure were investigated.
Materials and methods Materials Microcrystalline cellulose (Avicel pH102) was donated by FMC, Brussels, Belgium. Modified starch (Starch 1500) was donated from Colorcon Ltd., Istanbul, Turkey. Magnesium stearate pure (MGST; 0.43 m2/g) was donated from Sigma-Aldrich, St. Louis, MO. Hexagonal boron nitride nanopowder (HBN; 1.13 m2/g; Average particle size 70 nm) was purchased from Lower Mississauga, Ontario, Canada. Glycerol Dibehenate (Compritol888-ATO; COMP; 0.23 m2/g) was donated from Gattefose, Cedex, France. Stearic acide (STAC; 0.03 m2/g) and Polyethylene glycol (PEG6000) were gifts from Deva Research and Development Center (Turkey). Micro Talc (7.60 m2/g) was purchased from Mondo Minerals, Amsterdam, the Netherlands. Powder mixtures A 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) was used as the master powder mixture without a drug. This binary mixture was mixed for 20 min in a laboratory size V-blender. All lubricants were added to previously obtained binary mixture depending on their studied concentrations and mixed further for 5 min. At the end, we obtained 20 batches of lubricated powder mixtures (Table 1).
Table 1. Study design for both lubricated powder mixtures and resulted tablet formulations, and Tests on [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3).
Batches B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 B18 B19 B20
Lubricant type added
Lubricant concentration (%)
Bulk density (g/cm3)
Tapped density (g/cm3)
Carr’s index (%)
MGST MGST MGST MGST HBN HBN HBN HBN COMP COMP COMP TALC TALC TALC STAC STAC STAC PEG PEG PEG
0.5 1 2 4 0.5 1 2 4 1 2 4 1 2 4 1 2 4 1 2 4
0.48 ± 0.01 0.46 ± 0.01 0.52 ± 0,01 0.52 ± 0.01 0.48 ± 0.01 0.49 ± 0.01 0.51 ± 0.01 0.49 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.46 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.49 ± 0.01 0.46 ± 0.01 0.45 ± 0.01 0.46 ± 0.01 0.47 ± 0.01 0.47 ± 0.01 0.48 ± 0.01
0.61 ± 0.01 0.58 ± 0.01 0.64 ± 0.01 0.65 ± 0.01 0.58 ± 0.01 0.59 ± 0.01 0.60 ± 0.01 0.60 ± 0.01 0.56 ± 0.01 0.57 ± 0.01 0.56 ± 0.01 0.60 ± 0.01 0.60 ± 0.01 0.63 ± 0.02 0.58 ± 0.01 0.57 ± 0.01 0.57 ± 0.01 0.58 ± 0.01 0.59 ± 0.01 0.60 ± 0.01
21.15 ± 0.01 20.25 ± 0.21 18.61 ± 1.87 18.87 ± 1.91 16.77 ± 0.94 16.43 ± 2.11 14.96 ± 0.92 17.76 ± 0.20 15.62 ± 2.09 17.09 ± 0.19 17.24 ± 3.57 21.73 ± 0.85 20.89 ± 0.23 21.52 ± 3.50 20.35 ± 1.48 20.48 ± 0.82 20.11 ± 1.47 18.35 ± 0.90 20.50 ± 0.22 19.86 ± 0.79
Mixing time after the addition of lubticant: 5 min in V-blender.
Lubrication properties of HBN on modified starch derivatives
DOI: 10.3109/10837450.2014.920354
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Bulk and tapped densities of powder mixtures Twenty-five grams of powder mixtures with studied concentrations of lubricants were used for powder tests. The lubricated powder mixtures were poured into a 100 ml graduated cylinder (readable to 1 ml). Their bulk volumes were recorded. The cylinder was directly mounted onto a tapping machine which had a tapping speed of 100 taps/min. After 5 min, tapped volumes (V500) were recorded. The differences between V500 and V1250 were smaller than 1 ml. Measurements were carried out in triplicate. By measuring both the untapped volume and the tapped volume, the following factors can be determined. Pour (or Bulk) density ¼ mass/untapped volume Tapped density ¼ mass/tapped volume Carr’s Index (CI) ¼ [(tapped density bulk density) 100]/ tapped density The determination was harmonized with the European Pharmacopoeia 2008. Tablet preparation Tablets were prepared according to the method used in our previous study12. Briefly, for lubricant performance, 20 batches of tablets were manufactured with the same lubricated powder mixtures given in the ‘‘Powder mixtures’’ section using a singlestation instrumented tablet press (Korsch EKO, Berlin, Germany) equipped with a 9 mm flat-faced punch set. Study design was summarized in Table 1. The upper punch compression level, which was responsible for tablet hardness and also the lower punch diving level into die, which was responsible for tablet weight were both kept constant. The final tablet weight for the batch (B1) with 0.5% MGST level was 250 mg. When the tableting operation was changed to the next lubricant, the diving levels of punches into the die were kept constant which meant the tablet weight adjustment of tablet press kept constant, however the tablet weight changed due to powder fluidity. Powder fluidity was independent from tablet press adjustment, it was dependent on lubricant effect and free flowing property of powder from tablet press hopper. If the powder fluidity changes, it will effect the tablet weight. To get rid of this phenomenon, as used for the first time in our previous study12, instead of keeping tablet weight constant, we used the ratio obtained from hardness to upper punch compression force (cohession index), and also the second ratio obtained from upper punch compression forces to lower punch ejection force (lubricant effectiveness). By this way, it was
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possible to compare tablet properties with different lubricants without changing the diving levels of both punches. Instrumentation of tablet press The compaction properties of pharmaceutical formulations can be studied experimentally using a variety of techniques, ranging from instrumented production presses to compaction simulators and methods of analysis. The distribution of compression force being applied on a top of a cylindrical powder mass is given as follows: the force applied by the upper punch, the proportion of force transmitted to the lower punch and the reaction of the die wall due to the friction at this surface. One can evaluate the acting force, mentioned above, by the most basic instrumentation of a tablet press using the compaction force versus time profile. To monitor force–time profile and control, a tablet press certain sensors must be installed at specific locations on the machine and connected to signal conditioner, analog with digital converter board and data acquisition system. Without instrumentation of tablet press measuring, compression force and friction force could be impossible. As compression force increases, so does tablet hardness along with a force required to eject a tablet. Larger friction force leads to larger ejection forces that leads to an increased wear on punches and die surface. Ejection force can also be used to evaluate the lubricant effectiveness. As a result in our study (Figure 1), a single-station tablet press (Korsch EKO, Berlin, Germany) was instrumented for monitoring upper and lower punch forces. Two ring type Dynamic Force Sensors were used to detect compression and ejection force input signals. Sensors converted the forces signals into voltage. Obtained voltages were amplified by signal conditioner from millivolt- to volt-based form, the volt-based voltage signals were converted to a sequence of binary digital numbers, let us answer yes or no, using analog to digital converter board and finally, data acquisition system (National Instruments, Labview 2009, Signalexpress) processed these binary digital numbers and gave continuously time versus force profile from front panel. Finally, upper punch compression and lower punch ejection forces were determined quantitatively with this system as a continuous real time process. To validate the signal readings from the system, the press was run on the automatic mode (3600 tablets/h) to be able to apply an even pressure to each tablet, and at least 50 consecutive tablets were produced for quantitative evaluation of LPEF and upper punch compression force.
Figure 1. Technical diagram of tablet press instrumentation.
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M. D. Halac¸og˘lu & T. Ug˘urlu
Pharm Dev Technol, 2015; 20(6): 747–754
Measurement of tablet properties The weight variations of tablets were determined according to the USP 24. Tablet diameter and thickness were measured using a digital micrometer with a sensitiviy of 0.01 mm (Bestool-Kanon, Japan). The diametrical tablet crushing strength was evaluated using a tablet hardness tester (Model C 50, I-Holland, Ltd., Nottingham, UK). And also the disintegration time of tablets were evaluated according to the USP 24.
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Tensile strength measurement of tablets The tensile strengths of tablets were determined at room temperature by diametral compression using a hardness tester (Model C 50, I-Holland, Ltd., Nottingham, UK) applying the Fell and Newton equation18,19: 2F T¼ dt 2
where T is the tensile strength of the tablet (N/mm ), F is the applied force to cause fracture (N) obtained from crushing strength, d is the tablet diameter (mm) and t is the tablet thickness (mm). Results were taken only from tablets that split cleanly into two halves without any sign of lamination. Cohesion index of tablets Cohesion index of tablets was determined using the same ratio in our previous study12 and briefly, the ratio of tablet hardness (N) on the maximum upper punch force (N) was multiplied by 10. The higher the CohI, the better the compressibility was20. To discriminate Cohession Index and Carr’s Index, the abbreviation was made as CohI for Cohesion Index, and CI for Carr’s Index. Lubricant effectiveness of tablets The quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. A high value indicated good lubrication. The lubricant effectiveness values from each batch were calculated for mean value of compression force and lower punch ejection force21. Compression behavior of tablets The tablets compression characteristics were studied using density measurements and the Heckel equation, which was used in our previous study12,22,23. The equation was written as follows: 1 ¼ KP þ A ln ð1 DÞ where D is the relative density of a powder column at the compression pressure P, K and A are constants obtained from the slope and intercept of the plot ln[1/(1 D)] versus P, respectively22,23. Porosity is a function of the voids in a powder column, including both inter- and intra-particulate voids. For porosity measurement, the dimensions and weight of a powder column (i.e. apparent density) and the particle density of solid material should be known. The porosity, ", can be expressed by the equation: A "¼1 T where A is the apparent density of a powder column, and T is the true density. The value of A/T, also referred as D, is regarded as the relative density24. Usually, the volume of the
entire tablet, VA is calculated from the measured height and the area of the compact. The determination of these dimensions is normally done when the compression is finished and the tablet is ejected. This kind of measurement is called ‘‘zero-pressure’’ determination or ‘‘out of die’’ method. The so-called apparent density A is determined by division of the tablet weight ‘‘m’’ by the apparent volume, VA. The relative density r is obtained by dividing the apparent density by the true density. The following equations written in detail in our previous study12, however these equations constitute the main expression of the Heckel equation that was why they were given briefly: A m m VT ¼ ¼ ¼ D ¼ r VA VT T VA The volume reduction of compact, cylindrical shape, can be calculated as follows: VT r 2 ht ht ¼ 2 ¼ VA r ha ha Since the final compact is a cylindrical shape, the only change occurred in height under pressure. Where ht is minimum thickness of compact under maximum pressure (60 MPa) of hydraulic press, ha is thickness of compact under different compression pressures. To determine compaction properties of lubricated and unlubricated formulations, 500 mg of the corresponding mixtures were compressed at five different compaction pressures in a laboratory type hydraulic press up to 50 MPa (10, 20, 30, 40 and 50 MPa). The punches used were flat and had a diameter of 13 mm. The selected compaction pressures were maintained for 10 s to allow the development of most possible plastic deformation on the powders, to avoid the effect of different dwell times producing different degrees of deformation. The thickness of tablets was measured and volume of tablets was calculated to find volume reduction.
Results and discussion Evaluation of powder properties Carr’s index (CI) measures the flow properties of powders, obtained from bulk and tapped densities. The smaller the CI is, the better the flow properties are. It has a range between 5% and 23% and when CI leans to 5% indicates excellent flow, and when it starts to lean towards 23% indicates poor flow. In our study, all powder mixtures including any of the applied lubricant showed from good to fair flow properties according to their CI, ranged between minimum 14.96% to maximum 21.73%, shown in Table 1. Formulations with MGST, 21.15, 20.25, 18.61 and 18.87% CI values obtained for the lubricant levels of 0.5, 1, 2 and 4%, respectively, and for HBN, 16.77, 16.43, 14.96 and 17.76% CI values obtained for the same lubricant levels. CI values of the other studied lubricants were as follows: 15.62, 17.09 and 17.24% CI for COMP; 21.73, 20.89 and 21.52% CI for TALC; 20.35, 20.48 and 20.11% CI for STAC; and 18.35, 20.50 and 19.86% CI for PEG6000 at 1, 2 and 4% lubricant concentrations, respectively. Suprisingly in the 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102), HBN and COMP had smaller CI values and better flow properties than that of other lubricants including MGST, TALC, STAC and PEG6000. However, in our previous study12, MGST showed smaller CI values. Tablet weight of formulation prepared with MGST, which was 250 mg, choosed as reference and constant for the other lubricated powder mixtures since MGST is the most widely used lubricant in pharmaceutical industry. Under the same conditions, powders with better flow properties, having smaller CI values, filled in the die volume with larger amounts. In contrast, powders
Lubrication properties of HBN on modified starch derivatives
DOI: 10.3109/10837450.2014.920354
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Table 2. Properties of tablets, compression force and lower punch ejection force variation of tablets made with [Modified starch (Starch 1500)/ Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 10).
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Lubricant type added MGST MGST MGST MGST HBN HBN HBN HBN COMP COMP COMP TALC TALC TALC STAC STAC STAC PEG PEG PEG
Lubricant concentrations (%)
Weight (mg)
0.5 1 2 4 0.5 1 2 4 1 2 4 1 2 4 1 2 4 1 2 4
250 ± 2.96 253 ± 3.86 268 ± 3.53 263 ± 1.20 251 ± 2.96 260 ± 3.94 254 ± 2.33 248 ± 3.48 238 ± 1.90 237 ± 1.77 240 ± 1.58 238 ± 2.88 244 ± 2.17 245 ± 0.84 240 ± 1.73 237 ± 2.75 238 ± 2.02 242 ± 2.12 240 ± 1.51 240 ± 2.60
Hardness (kg)
Tensile strength (N/mm2)
Cohesion Index
Upper punch ejection force (kN/N)
Lower punch ejection force (N)
Lubricant effectiveness (kN/N)
10.03 ± 0.35 6.90 ± 0.55 4.43 ± 0.37 1.78 ± 0.08 17.41 ± 0.93 16.94 ± 0.72 10.95 ± 0.64 5.43 ± 0.60 13.14 ± 0.48 10.35 ± 0.36 8.96 ± 0.65 14.02 ± 0.94 12.85 ± 0.96 9.78 ± 0.55 12.62 ± 0.63 11.10 ± 0.52 9.66 ± 0.49 12.68 ± 0.39 10.40 ± 0.61 9.30 ± 0,65
2.23 ± 0.07 1.54 ± 0.13 0.93 ± 0.08 0.38 ± 0.01 4.17 ± 0.24 3.89 ± 0.15 2.56 ± 0.15 1.26 ± 0.15 3.12 ± 0.13 2.46 ± 0.12 2.13 ± 0.16 3.31 ± 0.22 2.99 ± 0.23 2.33 ± 0.13 2.93 ± 0.14 2.63 ± 0.13 2.27 ± 0.12 2.97 ± 0.13 2.44 ± 0.14 2.18 ± 0.16
31.08 ± 1.07 21.37 ± 1.71 11.55 ± 0.96 4.36 ± 0.18 59.58 ± 3.19 52.48 ± 2.24 33.75 ± 1.98 26.18 ± 2.91 107.44 ± 3.90 84.59 ± 2.97 69.37 ± 5.04 104.45 ± 7.04 77.98 ± 5.80 65.41 ± 3.69 96.50 ± 4.78 89.46 ± 4.20 75.80 ± 3.85 91.04 ± 2.81 88.73 ± 5.19 91.27 ± 6.36
12.5 ± 0.5 31.7 ± 0.6 37.7 ± 0.58 40.0 ± 2.0 28.7 ± 0.6 31.7 ± 0.6 31.8 ± 0.3 20.3 ± 0.6 12.0 ± 1.0 12.0 ± 1.0 12.7 ± 0.6 13.2 ± 0.3 16.2 ± 0.3 14.7 ± 0.6 12.8 ± 0.3 12.2 ± 0.3 12.5 ± 0.5 13.7 ± 0.3 11.5 ± 0.5 10.0 ± 0,5
342 ± 14 283 ± 29 273 ± 25 275 ± 25 483 ± 29 417 ± 29 383 ± 29 323 ± 25 283 ± 29 183 ± 29 167 ± 29 600 ± 50 550 ± 50 500 ± 1 417 ± 29 367 ± 29 333 ± 29 433 ± 29 417 ± 29 417 ± 29
0.0928 ± 0.0051 0.1127 ± 0.0134 0.1385 ± 0.0108 0.1461 ± 0.0121 0.0594 ± 0.0024 0.0762 ± 0.0046 0.0834 ± 0.0070 0.0632 ± 0.0065 0.0429 ± 0.0081 0.0667 ± 0.0126 0.0778 ± 0.0154 0.0220 ± 0.0019 0.0296 ± 0.0032 0.0293 ± 0.0012 0.0309 ± 0.0027 0.0333 ± 0.0018 0.0378 ± 0.0049 0.0316 ± 0.0019 0.0276 ± 0.0010 0.0240 ± 0.0009
Tablet diameter: 9 mm; kN ¼ 1000 N.
with worse flow properties compared to MGST, having bigger CI values, could not fill the die volume properly, therefore, when we changed the lubricant type tablet weight variations occurred. This phenomenon also explaines the weight variation of tablets, summarized in Table 2. Evaluation of tablet properties Study design is summarized in Table 1. Trials were made with four concentration levels (0.5, 1, 2 and 4%) for MGST and HBN, and three concentration levels (1, 2 and 4%) for COMP, STAC, TALC and PEG6000. Table 2 gives properties of tablets prepared with 1:1 mixture modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) including various lubricant. Evaluation of tensile strength of tablets A maximum surface covering effect of lubricant was found for excipients that undergo complete plastic deformation without any fragmentation under compression such as starch derivatives as studied in this study. Surface covering properties phenomenon leads to the formation of hydrophobic layer around the granule particles and results in decrease in crushing strength and followed by decrease in tensile strength. In Table 2 and Figure 2, fast drops in tensile strength were observed with MGST and HBN curves after 2% lubricant concentration. However, before 2% lubricant concentration, HBN had the biggest tensile strength when compared to that of other lubricant. From the Figure 2, it is clear that even excipients such as starch derivetives that undergo complete plastic deformation HBN has least pronounced effect before level of 2% lubricant concentration. TALC, COMP, PEG6000 and STAC curves were shallow from 1% to 4%. MGST shows the most pronounced effect on lowering tensile strength. It was suprisingly different from our previous study made with 1:1 mixture of spray-dried lactose and microcrystalline cellulose12. At the level of 0.5%, MGST had the minimum tensile strength with 2.23 N/mm2 and HBN had the maximum tensile strength with 4.17 N/mm2. At the level of 1%, the tensile strength of tablets including MGST, HBN, COMP, TALC, STAC and PEG6000 were 1.54, 3.89, 3.12, 3.31, 2.93 and 2.97 N/mm2, respectively. At the level of 2%, the tensile strength of tablets were 0.93, 2.56, 2.46,
Figure 2. Concentration versus tensile strength graph of lubricants.
2.99, 2.63 and 2.44 N/mm2 for MGST, HBN, COMP, TALC, STAC and PEG6000, respectively. At maximum studied level of 4%, MGST shows the minimum tensile strength with 0.38 N/mm2, and HBN shows 1.26 N/mm2. Powders including COMP, TALC, STAC and PEG6000 at the level of 4% gave 2.13, 2.33, 2.27 and 2.18 N/mm2 tensile strength values, respectively. With the increase of the concentration of lubricant, tablet crushing strength decreases. The surface covering property of MGST pronounced more than that of other studied lubricants complied with Nakagawa et al.25. Evaluation of cohesion index of tablets Powders with high Cohesion index (CohI) have better compressibility. It is a combination of crushing strength with upper punch force independant to other factors of tablets. In general, this index decreases as the lubricant amount increases. Effect of lubricant concentration on Cohesion index given in Table 2 and Figure 3. Batches prepared with lubricant concentrations of 1, 2 and 4% gave 107.44, 84.59 and 69.37 CohI values for COMP; 104.45, 77.98 and 65.41 CohI for TALC; 96.50, 89.46 and 75.80 CohI for
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M. D. Halac¸og˘lu & T. Ug˘urlu
Pharm Dev Technol, 2015; 20(6): 747–754
Figure 3. Concentration versus cohesion index graph of lubricants. Figure 4. Concentration versus lower punch ejection force (LPEF) graph of lubricants.
STAC; and 91.04, 88.73 and 91.27 CohI for PEG6000, respectively. Surprisingly, this meant no significant change occurred in CohI with the increase of lubricant concentration when COMP, TALC, STAC and PEG6000 used. The results were complied with our previous study12. On the other hand, both MGST and HBN were reported as the most effective lubricants in our older reports11,12. However, in this study, same with previous one, seen from Figure 3, MGST showsa fast drop and had the minimum CohI values of 31.08, 21.37, 11.55 and 4.36 with the increase of lubricant concentration. HBN shows similar but a little bit better CohI values of 59.58, 52.48, 33.75 and 50.88 than that of MGST, but still much lower than COMP, TALC, STAC and PEG6000. For COMP, TALC, STAC and PEG6000 at the beginning, they had close CohI values in 1% lubricant concentration, however, as the concentration of lubricant increased, CohI values of COMP, TALC, STAC and PEG6000 started to decrease. Low Cohesion index phenomenon for HBN and MGST led to the lowest compressibilty values at the studied level of 2 and 4% lubricant concentrations compared to that of COMP, TALC, STAC and PEG6000. The results were complied with our previous study12. Evaluation of lower punch ejection force (LPEF) of tablets The upper punch compression level, which was responsible for tablet hardness and also the lower punch diving level into die, which was responsible for tablet weight were both kept constant as the same with our previous study12 to prevent any variation resulting from compression procedure. Table 2 and Figure 4 represent the evaluation of LPEF. All studied lubricants depending on their concentration lowered the LPEF, and with the increase in lubricant concentration, LPEF values decreased. At first sight, as shown in Figure 4, suprisingly COMP showed better decline in LPEF than that of MGST and HBN this phenomenon lead to no correlation between powder properties and friction measurements. However, the powder fluidity can be enhanced with lubricant type and lubricant concentration, and any change in the powder fluidity causes to tablet weight variation complied with the literature26,27, with our previous study12, and finally with our results from powder tests. This meant the better powder fluidity led to the heavier tablets and this resulted in higher LPEF needed to eject tablet from the die. As a result, the LPEF was modified with upper punch compression force, and lubricant effectiveness to get ride of mentioned phenomenon. This modification was explained as follows. The quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. If the tablet weight differs due to powder flow property, the upper punch force
Figure 5. Concentration versus lubricant effectiveness graph of lubricants.
will differ simultaneously. Both in this study and our previous one12, the amount of powder in the die and the upper punch force changed in the same direction. If the amount of powder and resulted tablet weight were smaller, upper punch force was smaller. In this point of view, tablet properties discussed with lubricant effectiveness data rather than LPEF alone and using lubricant effectiveness powder properties and friction measurements can be correlated. The punch forces, given in Newton, and lubricant effectiveness values are listed in Table 2 and graphed in Figure 5. Evaluation of lubricant effectiveness of tablets As mentioned above, the quotient of upper punch compression force and lower punch ejection force (kN/N) was calculated as a parameter of lubricant effectiveness. We first applied lubricant effectiveness in our previous study in the mixture of spray-dried lactose and microcrystalline cellulose to explain weird results obtained from LPEF alone12. And, in this study, we reapplied lubricant effectiveness in the mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) to evaluate lubricant activity. Table 2 and Figure 5 represent the most reliable evaluation of the lubricant activity apart from flowing properties of powders. The best lubricant effectiveness activity was pronounced with MGST. It showed lubricant effectiveness values of 0.0928, 0.1127, 0.1385 and 0.1461 in
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DOI: 10.3109/10837450.2014.920354
Lubrication properties of HBN on modified starch derivatives
Figure 6. Concentration versus disintegration time graph of lubricants.
the lubricant levels of 0.5, 1, 2 and 4%, respectively. In our previous study depending on its concentartions, MGST shows best lubricant effectiveness when 1:1 mixture of spray-dried lactose and microcrystalline cellulose used as a master formula12. However, the values were lower than that of this study. This meant better surface covering effect of lubricants on excipients that undergo complete plastic deformation without any fragmentation under compression as modified starch leading to better decrease in LPEF and followed by better increase in lubricant effectiveness as in this study. The second lubricant effectivenes activity rank was found with HBN. HBN also showed high lubricant effectiveness values of 0.0594, 0.0762, 0.0834 and 0.0632 in the same lubricants level with MGST. Mentioned phenomenon was also valid for HBN. Lubricant effectiveness values of both MGST and HBN increased with increasing lubricant concentration due to surface covering properties. Surprisingly, lubricant effectiveness value of HBN decreased to 0.0632 at 4% concentration. This phenomenon was thought to be because of segregation of nanosized HBN particles from the master formula during mixing procedure COMP took third turn in the lubricant effectiveness order. Due to bad surface covering properties STAC, TALC and PEG6000 had the lowest lubricant effectiveness values. Obtained values were not changed upon increase in their lubricant concentration. Evaluation of disintegration time of tablets Figure 6 shows the relationship between the lubricant concentration and disintegration time of tablets. The disintegration times were 180, 200, 225 and 670 s for MGST at 0.5, 1, 2 and 4% concentration; 160, 158, 163 and 70 s for HBN at the same lubricant level with MGST; 173, 184 and 247 s for COMP at 1, 2 and 4% concentration; 156, 162 and 165 s for TALC; 174, 170 and 177 s for STAC; and 130, 120 and 163 s for PEG6000. These three lubricants levels were the same as COMP. The higher the lubricant concentration the more pronounced effects of lubricant were observed on disintegration time. In this study, surface covering effect of lubricants on excipients that undergo complete plastic deformation led to higher increase in tablet disintegration times compared with our previous study12 and literature28. The most deteriorating effect on desintegration time was obtained from MGST. Disintegration time over 10 min could be ascribed to the lipophilic tablet surface. HBN was found to be more effective lubricant than MGST, not having a negative effect on tablet disintegration times as much as MGST. Its disintegration time were slightly over water-soluble lubricant PEG6000. However at 4% level, a drastic decline in disintegration time of HBN was observed. It was thought to be because of segregation of
753
Figure 7. Heckel plots of lubricated and unlubricated powder mixture. Standard deviations were shown in Table 3.
nanosized HBN particles from the master formula during mixing procedure led to decrease in desentagration time at this level. The least pronounced effect was observed with water soluble lubricant PEG6000. Surprisingly, TALC and STAC showed closer disintegration effect in tablet formulations like HBN. Evaluation of compression behavior of tablets To evaluate the compression properties of 1:1 mixture of modified starch (Starch 1500) and microcrystalline cellulose (Avicel pH102) with different lubricants, Heckel equation was used. The constants of the Heckel equation22,23 were determined by the linear regression analysis using the least-squares method. Compaction characteristics (Figure 7 and Table 3) revealed that lubricated and unlubricated powder mixtures were easily deformed under compression without subsequent fragmentation. In Table 4, constants and linear regression coefficients of granule formulations were given. For correct calculation of r2 five pressure values were used (10, 20, 30, 40 and 50 MPa). r2 Values of powder without lubricant, HBN, TALC and PEG6000 were found to be 40.95, and r2 values of MGST, COMP and STAC were found to be 50.95. By the addition of 1% lubricants, slopes of Heckel equation were decreased. The K values give the slope and plastic character of the powder mixtures. High slope is indicative of plastic deformation and low slope is indicative of elastic deformation23,29. As shown in Figure 7, upon including any lubricant plastic deformation started to lean towards elastic deformation. In our study, the unlubricated powder mixture had the slope of 0.1000 as summarized in Table 4. Surprisingly different from our previous study12, the most pronounced effect was found with the slope of 0.0944 for TALC at 1% lubricant concentration when studied with a mixture of modified starch (Starch 1500). The obtained K values were as follows: 0.0889 for HBN; 0.0944 for TALC; 0.0584 for STAC; 0.0423 for MGST; 0.0770 for PEG6000; and 0.0744 for COMP, respectively. Therefore, with the studied powder mixture, which underwent complete plastic deformation MGST had the highest elastic deformation property. HBN had slight negative effect on the tablet compaction behavior, but not as much as MGST and still showed plastic character when compared to that of other lubricants such as MGST, COMP, STAC and PEG6000.
Conclusion In general, all tested lubricants in this study were somehow effective and used at different ratio in tablet manufacturing. HBN was found as effective as MGST at low concentrations 0.5–1%
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M. D. Halac¸og˘lu & T. Ug˘urlu
Pharm Dev Technol, 2015; 20(6): 747–754
Table 3. Ln(1/porosity) data of unlubricated and 1% lubricant containing [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3). ln 1/porosity Pressure (MPa)
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10 20 30 40 50
No-lubricant
MGST
HBN
COMP
TALC
STACz
PEG
1.69 ± 0.04 2.86 ± 0.15 3.76 ± 0.10 5.08 ± 0.23 5.58 ± 0.40
1.90 ± 0.08 2.89 ± 0.08 3.23 ± 0.08 3.56 ± 0.64 3.68 ± 0.18
1.92 ± 0.02 3.09 ± 0.28 3.86 ± 0.01 4.66 ± 0.01 5.58 ± 0.80
2.04 ± 0.08 3.55 ± 0.27 4.09 ± 0.45 4.97 ± 0.92 5.05 ± 0.87
2.09 ± 0.10 3.22 ± 0.26 4.73 ± 1.27 5.22 ± 0.90 5.81 ± 0.40
2.07 ± 0.11 3.11 ± 0.08 4.04 ± 0.26 4.49 ± 0.40 4.30 ± 0.34
1.96 ± 0.04 3.09 ± 0.19 4.02 ± 0.37 4.09 ± 0.29 5.31 ± 0.63
Table 4. Constants and linear regression coefficients of Heckel equations of unlubricated and 1% lubricant containing [Modified starch (Starch 1500)/Microcrystalline cellulose (Avicel pH102) (1:1)] powder mixture (n ¼ 3).
10. 11.
A
K
r2
0.794 1.783 1.155 1.708 1.382 1.850 1.384
0.1000 0.0423 0.0889 0.0744 0.0944 0.0584 0.0770
0.986 0.878 0.994 0.881 0.956 0.840 0.949
Powder mixture No lubricant %1 MGST %1 HBN %1 COMP %1 TALC %1 STAC %1 PEG
12.
13.
14. 15.
based on lubricant effectiveness values. Comparing other parameters such disintegration time and Heckel analysis, HBN was found to better than MGST. This study complied with our previous work with binary mixture of spray-dried lactose and microcrystalline cellulose12. HBN can also be used as a new lubricant in direct compression as effective as wet granulation.
16.
17. 18.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. This research was supported by Scientific Research Project Unit of Marmara University (BAPKO; SAG-A-080410-0066).
References 1. Wang J, Wen H, Desai D. Lubrication in tablet formulations. Eur J Pharm Biopharm 2010;75:1–15. 2. Pingali K, Mendez R, Lewis D, et al. Mixing order of glidant and lubricant-influence on powder and tablet properties. Int J Pharm 2011;409:269–277. 3. Bolhuis GK, Ho¨lzer AW. Lubricant sensitivity. In: Alderborn G, Nystro¨m C, eds. Pharmaceutical powder compaction technology. New York: Marcel Dekker Inc.; 1996:517–560. 4. Sheth BB, Bandelin FJ, Shangraw RF. Compressed tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical dosage forms: tablets. Vol. 1. New York: Marcel Dekker Inc.; 1980:109–184. 5. Bastos MO, Friedrich RB, Beck RCR. Effects of filler-binders and lubricants on physicochemical properties of tablets obtained by direct compression: a 22 factorial design. Lat Am J Pharm 2008;27: 578–583. 6. Kara A, Tobyn MJ, Stevens R. An application for zirconia as a pharmaceutical die set. J Eur Ceram Soc 2004;24:3091–3101. 7. Yamamura T, Ohta T, Ogawa Y, et al. Effects of automated external lubrication on tablet properties and the stability of eprazinone hydrochloride. Int J Pharm 2009;370:1–7. 8. Dawes J, Allenspach C, Gamble JF, et al. Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. Pharm Dev Technol 2013;18:246–256. 9. Turkoglu M, Sakr A. Tablet dosage forms. In: Florence AT, Siepmann J, eds. Modern pharmaceutics: basic principles and
19.
20.
21.
22. 23. 24. 25.
26.
27.
28.
29.
systems. Vol. 1. Pinehurst (NC): PharmaceuTech, Inc.; 2009:481–497. Turkoglu M, Sahin I, San T. Evaluation of hexagonal boron nitride as a new tablet lubricant. Pharm Dev Technol 2005;10:381–388. Ugurlu T, Turkoglu M. Hexagonal boron nitride as a tablet lubricant and a comparison with conventional lubricants. Int J Pharm 2008; 353:45–51. Ugurlu T, Halacoglu MD. Effects of some lubricants and evaluation of compression parameters on directly compressible powders. Pharm Dev Technol 2014;19:347–354. Baraton MI, Merle T, Quintard P, Lorenzelli V. Surface activity of a boron nitride powder: a vibrational study. Langmuir 1993;9: 1486–1491. Golberg D, Bando Y, Huang Y, et al. Boron nitride nanotubes and nanosheets. ACS Nano 2010;4:2979–2993. Ciofani G, Raffa V, Menciassi A, Cuschieri A. Boron nitride nanotubes: an innovative tool for nanomedicine. Nano Today 2009; 4:8–10. De Boer AH, Bolhuis GK, Lerk CF. Bonding characteristics by scanning electron microscopy of powders mixed with magnesium stearate. Powder Technol 1978;20:75–82. Bolhuis GK, Armstrong NA. Excipients for direct compaction—an update. Pharm Dev Technol 2006;11:111–124. Fell JT, Newton JM. Determination of tablet strength by the diametrical compression test. J Pharm Sci 1970;59:688–691. Davies PN, Worthington HEC, Podczeck F, Newton JM. The determination of the mechanical strength of tablets of different shapes. Int J Pharm 2003;258:153–163. Ro¨scheisen G, Schmidt PC. The combination of factorial design and simplex method in the optimization of lubricants for effervescent tablets. Eur J Biopharm 1995;41:302–308. Delacourte A, Predella P, Leterme P, et al. A method for quantitative evaluation of the effectiveness of the lubricants used in tablet tecnology. Drug Dev Ind Pharm 1993;19:1047–1060. Heckel RW. Density pressure relationship in powder compaction. Transect Metal Soc AIME 1961;221:671–675. Heckel RW. An analysis of powder compaction phenomena. Transect Metal Soc AIME 1961;221:1001–1008. Kuny TJ. Compression behavior of the enzyme b-galactosidase. Ph.D. Thesis. University of Bassel, Switzerland; 2004. Nakagawa H, Kano M, Hasebe S, et al. Real-time monitoring of lubrication properties of magnesium stearate using NIR spectrometer and thermal effusivity sensor. Int J Pharm 2013;441:402–413. Shah AC, Mlodozeniec AR. Mechanism of surface lubrication: influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets. J Pharm Sci 1977;66:1377–1382. Rashid I, Daraghmeh N, Al-Remawi M, et al. Characterization of the impact of magnesium stearate lubrication on the tableting properties of chitin-Mg silicate as a supersisintegrating binder when compared to AvicelÕ 200. Powder Technol 2010;203:609–619. Late SG, Yu YY, Banga AK. Effects of disintegration-promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets. Int J Pharm 2009;365:4–11. Wade JB, Martin GP, Long DF. A methodological approach for determining the effects of moisture content on the compaction properties of powders: granular hydroxyapaptite. Powder Technol 2013;246:511–519.
