Advanced Powder Technol., Vol. 15, No. 4, pp. 477 – 493 (2004) © VSP and Society of Powder Technology, Japan 2004. Also available online - www.vsppub.com
Original paper Effects of lubricant mixing on compression properties of various kinds of direct compression excipients and physical properties of the tablets MAKOTO OTSUKA ∗ , IKURO YAMANE and YOSHIHISA MATSUDA Department of Pharmaceutical Technology, Kobe Pharmaceutical University, Motoyama-Kitamachi 4-19-1, Higashi-Nada, Kobe 658-8558, Japan Received 20 June 2003; accepted 9 October 2003 Abstract—The effects of lubricant [magnesium stearate MgSt] mixing time on the characteristics of tablet formulation were investigated by using two types of mixers (twin-shell and high-speed mixers). Three kinds of excipients for the direct compression — spray-dried lactose (SDL), microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA) — were mixed with a lubricant, MgSt, by using a twin-shell or high-speed mixer, respectively. The tablets were compressed from the mixed powders at 98 MPa. The compression parameters of the tablets, such as the tensile strength, compression energy, compression availability and elastic recovery ratio, were evaluated based on the compression proﬁles and the tablet hardness. The tablet hardness of MCC decreased with an increase in mixing time in the high-speed mixer and the related compression properties of MCC changed depending on the hardness, but those of DCPA did not. The order of the effect of mixing was MCC > SDL > DCPA and the high-speed mixer was more effective than the twin-shell mixer. We conclude that the compression properties of DCPA did not ﬂuctuate by mixing with MgSt under any conditions compared with other excipients. Keywords: Mixing; tabetting compression; magnesium stearate; excipients.
In the pharmaceutical industry, large-scale manufacturing of high-quality pharmaceuticals is a very important factor for formulation scientists. Solid dosage forms, such as powders, capsules and tablets, are the most common preparations and the role of an adjuvant in the preparation is an important factor to obtain high-quality pharmaceuticals. In particular, the role of a lubricant in production processes is very sensitive and several production problems occur during tabletting, such as capping, ∗ To
whom correspondence should be addressed. E-mail: [email protected]
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lamination and adhesion due to lubricant-related factors. The negative effects of the lubricant on the physical properties of the tablet are often manifested as defects in the mechanical strength and dissolution properties of the tablets. Therefore, many researchers have investigated [1– 7] whether the interactions between the lubricant and excipient or bulk drug were induced by mixing methods and quality of lubricants. The changes in the physical properties and dissolution behavior are attributed to the quality and/or quantity of magnesium stearate (MgSt) as a lubricant in these formulations. Since MgSt plays an integral part in reducing friction between a die and punches, it is necessary to prepare tablets by mixing for a short time, because prolonged mixing with MgSt induced many tableting problems [1– 7]. Thus, the mixing time and methods used to mix the raw powder with MgSt can modify the intended role of the adjuvant — in some cases altering or diminishing its primary function. These interactions and adverse effects on the physical properties and drug dissolution of the tablets can be avoided by carefully evaluating and selecting excipients. Moreover, in large-scale production, there are many problems. In particular, it is known that it is not easy to make high-quality tablets by using a direct compression method for over-lubrication in the agitating die feeder . It is therefore very important to study the effects of MgSt in drug–excipient interactions. In this study, the mixing effects of MgSt on direct compression formulations and the pharmaceutical properties of tablets were investigated.
2. MATERIALS AND METHODS
2.1. Materials Spray-dried lactose (SDL, DCL 11) was provided by DMV (Veghel, Holland). Microcrystalline cellulose (MCC, PH101) was provided by Asahikasei (Tokyo, Japan). Dibasic calcium phosphate anhydrous (DCPA, Fujicalin) was provided by Fuji Chemical (Kamiichi-Machi, Japan) [9, 10]. MgSt was provided by NOF (Japan). 2.2. Measurement of speciﬁc surface area (Sw ) The Sw of the sample powder was measured 3 times by the BET nitrogen gas adsorption method (micromeritics, Flow Sorb 2300; Shimadzu, Kyoto, Japan). 2.3. Methods of mixing the sample powders The formulation of the tablets was as follows: excipient (SDL, MCC or DCPA) 99.5%; lubricant, MgSt, 0.5%. They were mixed in a twin-shell mixer (Tokujyu, Tokyo, Japan; model V-1, inside volume 2 l) at a mixing speed of 28 r.p.m. or in a high-speed mixer (Tablet mill, model KC-HUK; Konishi Medical, Osaka, Japan, capacity 200 ml) at a rotor speed of 4200 r.p.m. for 5 or 20 min.
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2.4. Scanning electron microscopy Scanning electron microphotographs (SEM) of samples were taken with a model JSM-5200LV (Jeol, Tokyo, Japan) microscope at a magniﬁcation of ×100–1000. 2.5. Tablet preparation and instrument used for the compression process A compression/tension tester (Autograph, model IS-5000; Shimadzu) with two load cells (upper and lower punches) and a displacement transducer were used to measure the upper and lower pressure and distance between the punches at 25◦ C. An 8-mm diameter punch and die with ﬂat surfaces was used to compress 200 mg of a sample at 98 MPa (maximum upper punch pressure) and at a speed of 25 mm/min. Sample tablets were ejected from the punch and die at 30 mm/min. The pressure and thickness data of the tablets during compression were converted digitally and stored directly on a computer system using Super Scope software (Somerville, Boston, MA). The thickness and diameter of each tablet were measured with a micrometer. The hardness of the tablet was measured 4 times using a tablet hardness tester (Toyama Tablet Hardness Tester; Toyama, Osaka, Japan). 2.6. Micropore volume distribution measurement The micropore volume distribution of a tablet was measured by mercury porosimetry (type 2000; Carlo Erba, Strumentazione, Italy). The contact angle and surface tension of mercury were 141.3◦ and 480 dyne/cm, respectively. The pore radius ranged from 6 × 10−3 to 300 μm. 2.7. Elastic recovery of the tablet after compression The elastic recovery ratio  was evaluated by: E=
100 × (He − Hc ) , Hc
where He and Hc are the heights of the compacts under pressure and after ejection (12 h). 2.8. Measurement of surface energy of the powder by an inverse gas chromatography method (iGC) [12– 14] Details of the iGC rig and experimental procedure with modiﬁcations were previously reported by Ticehurst et al. . The powder sample materials were placed in a U-shaped glass column about 300 mm long and 3 mm in diameter. A commercial gas chromatographic apparatus (gas chromatograph GC-8A; Shimadzu) equipped with a highly sensitive ﬂame ionization detector was used for this study. Nitrogen was selected as carrier gas at a ﬂow rate of 10 ml/min. The column temperature was set at 30◦ C for measurement of the retention probes. The probes employed were
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n-heptane (Tokyo Kasei, Tokyo, Japan), octane (Aldrich), n-nonane (Tokyo Kasei) and decane (Aldrich), all of which were >99% pure. In order to achieve inﬁnite dilution conditions, vapors of the probes (equivalent to 10−4 to 10−7 μl of liquid) were introduced into the injection port of the column using a 5 μl syringe. The retention times for a homologous series of alkane probes were used to calculate the dispersive surface energy of the surface under investigation. The equations for this analysis have been ﬁrmly established . The measured parameter is the retention time of the probes, tR . However, the equations deal with the net retention volume, Vn0 , which eliminates any difference in ﬂow rate and temperature of the experiments. These net retention volumes were calculated using: T , (2) Vn0 = jF(tR − t0 ) 273.15 where T is the column temperature, j is the James–Martin pressure drop correction factor, F is the exit ﬂow rate measured at 1 atm and 273.15 K, tR is the retention time of the interacting probe, and t0 is the mobile phase hold up, commonly referred to as the ‘dead time’. The dispersive component of surface free energy (γSD ) was calculated according to the approach of Shultz and Lavielle , who derived (3): 1/2 D1/2 a γL + C, (3) RT ln VN0 = 2NA γSD where N is Avogadro’s number, R is the gas constant, a is the surface area of the probe molecule, γLD is the dispersive component of surface free energy of the liquid probe and C is a constant. By plotting a graph of RT ln VN0 versus a(γLD )1/2 , which are both properties of the adsorbate, for a homologous series of hydrocarbons, a straight line is obtained. The gradient yields the dispersive surface energy, γSD . 3. RESULTS
3.1. Effects of mixer and mixing time on the speciﬁc surface area of the mixed powders Table 1 shows the Sw of excipients before and after mixing with 0.5% of MgSt. Sw of MCC and DCPA did not signiﬁcantly change after mixing in a twin-shell and high-speed mixer, respectively. In contrast, the Sw of SDL did not increase after mixing in the twin-shell mixer, but increased signiﬁcantly in the high-speed mixer. This result indicates that the particle size of SDL was decreased, because the high-speed mixer imparted more mechanical energy to the powder particles than the twin-shell mixer. 3.2. Effects of mixing on the particle size and the surface morphology Figure 1 shows the SEM of the powder samples mixed with twin-shell and highspeed mixers. The surfaces of all sample particles mixed in the twin-shell mixer
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Table 1. Speciﬁc surface area of sample powders before and after mixing (n = 4) Sample
Speciﬁc surface area (m2 /g)
SDL SDL (twin-shell 20 min) SDL (high-speed 20 min) SDL + MgSt 0.5% (calculated)
0.25 ± 0.01 0.23 ± 0.02 0.63 ± 0.01 0.29
MCC MCC (twin-shell 20 min) MCC (high-speed 20 min) MCC + MgSt 0.5% (calculated)
0.98 ± 0.01 0.98 ± 0.01 1.02 ± 0.01 1.02
DCPA DCPA (twin-shell 20 min) DCPA (high-speed 20 min) DCPA + MgSt 0.5% (calculated) MgSt
24.25 ± 0.16 24.01 ± 0.10 24.23 ± 0.04 24.17 8.6 ± 0.09
Table 2. Changes of ejection energy (EE) and tensile strength (TS) of tablets prepared by mixing of DCPA and MgSt using the high-speed mixer for 20 min Sample
Ejection energy (SD) (J/g)
Tensile strength (SD) (MPa)
7.56 (1.05) 1.05 (0.70)
3.65 (0.25) 3.15 (0.11)
Table 3. Surface free energy of powder on mixing condition (n = 3) Sample
Surface free energy (mJ/m2 )
MCC MCC (twin-shell 5 min) MCC (twin-shell 20 min) MCC (high-speed 5 min) MCC (high-speed 20 min)
47.49 ± 0.01 44.75 ± 2.07 42.77 ± 2.31 37.85 ± 0.25 35.09 ± 0.19
DCPA DCPA (high-speed 20 min)
40.88 ± 1.85 37.10 ± 0.43
SDL SDL (high-speed 20 min)
41.31 ± 0.80 36.02 ± 0.85
31.98 ± 1.00
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(2) Figure 1. Morphological change in SDL, MCC and DCPA after mixing with lubricant: (1) SDL, (2) MCC, (3) DCPA.
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were covered by numerous ﬁne particles, indicating that those were forming an ordered mixture with MgSt. In particular, SDL mixed samples showed typical ordered mixture structures. The surfaces of SDL particles (Fig. 1-1) mixed in the high-speed mixer were smooth, which may be due to the adhesive MgSt ﬁne particles reacting mechanochemically and forming a coated layer. However, there were smaller particles in the system (Fig. 1-1) and the mean particle size was slightly reduced. The surfaces of MCC particles (Fig. 1-2) mixed in the twin-shell mixer were adhesive ﬁne particles, but when mixed in the high-speed mixer they showed a smooth particle surface. The particle sizes of both samples were not signiﬁcantly visibly different after treatments. In contrast, the surfaces of DCPA particles (Fig. 13) mixed in the twin-shell mixer showed adhesive ﬁne particles, but in the highspeed mixer they showed smaller particles. The SEM result suggested that DCPA was granules of 50–60 μm in diameter consisting of ﬁne particles a few micrometers in diameter. However, although it had a large Sw , this did not increase after highspeed mixer treatment (Table 1) even when the apparent particle size decreased (Fig. 1-3) by deaggregation during mixing.
(3) Figure 1. (Continued).
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3.3. Effects of mixer and mixing time on the tableting compression process Figure 2 shows the effect of mixer and mixing time of the lubricant on tensile strength of the tablets. The tensile strength (TS) of the tablets was evaluated by : TS =
2F , π DL
where F is the tablet hardness, and D and L are diameter and thickness of the tablet, respectively. The TS of all samples slightly increased after mixing in the twin-shell mixer for 5 min, which indicated that lubricant mixing reduced friction during compression. It seemed that the mixing of the lubricant decreased the stress resistance during compression and the compression energy was available for powder bonding. However, the TS of SDL and MCC decreased after mixing in the twin-shell mixer for 20 min. On the other hand, the TS of SDL and DCPA was not signiﬁcantly decreased after mixing in the high-speed mixer for 5 and 20 min, but the TS of MCC decreased signiﬁcantly with an increase in mixing time in the high-speed mixer. These results suggested that the order of the mixing effect of lubricant in the excipients was MCC > SDL > DCPA. To evaluate the work of compression (compression energy, CE) for the tableting process, we followed integration from zero to a maximum pressure, as shown in (5). The results are summarized in Fig. 3. hm W h Fup dh = 0 . (5) CE = m m
Figure 2. Effect of mixing conditions on tensile strength of various kinds of tablets. I0, intact sample; T5, T20, mixing in the twin-shell mixer for 5 and 20 min, respectively; M5, M20, mixing in the highspeed mixer for 5 and 20 min, respectively. Each bar represents the mean ± SD (n = 4) (∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.005).
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In this equation, CE is the work of compression per gram, W is the work of compression, m is mass of the sample powder, Fup is the compression pressure by the upper punch, hm is the powder bed thickness at maximum pressure, h0 is the powder bed thickness at pressure zero and h is the thickness of the powder bed. The CE of SDL decreased with an increase in mixing time by both the twinshell and high-speed mixers. The CE of MCC increased after mixing in the twinshell mixer for 5 min, with no change at 20 min; however, in the high-speed mixer it decreased with an increase in mixing time. The CE of DCPA increased with an increase in mixing time in the twin-shell mixer, but it slightly decreased in the high-speed mixer. These results were different depending on the mixing conditions and the sample powders. It seemed that mixing the drug powder with MgSt powder improved the powder ﬂowability and reduced die friction, thereby decreasing the work of compression. However, the mixture with lubricant inhibited particle binding and the tablet mechanical strength decreased, as reported previously [1– 5]. Therefore, we used (6) to evaluate the work efﬁciency of tablet compression. Equation (6)  determines the compression availability of a tablet, CA: CA =
TS , CE
where TS is the tensile strength of tablet and CE is the work of compression per gram. Figure 4 shows the effect of mixing condition on the CA of a tablet. The CA of SDL decreased after mixing time in the twin-shell mixer for 20 min, but in the
Figure 3. Effect of mixing conditions on compression energy of various kinds of tablets. I0, intact sample; T5, T20, mixing in the twin-shell mixer for 5 and 20 min, respectively; M5, M20, mixing in the high-speed mixer for 5 and 20 min, respectively. Each bar represents the mean ± SD (n = 4) (∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.005).
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Figure 4. Effect of mixing conditions on compression availability of various kinds of tablets. I0, intact sample; T5, T20, mixing in the twin-shell mixer for 5 and 20 min, respectively; M5, M20, mixing in the high-speed mixer for 5 and 20 min, respectively. Each bar represents the mean ± SD (n = 4) (∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.005).
high-speed mixer it increased slightly. The CA of MCC slightly decreased with an increase in mixing time in the twin-shell mixer, but dramatically decreased in the high-speed mixer. In contrast, the CA of DCPA did not change in all mixing conditions. These results indicated that the CAs of SDL and MCC were affected by mixing conditions, but that of DCPA was independent of the mixing conditions. The effect of mixing conditions on the tablet ejection process was investigated. The ejection force (Fe ) was related to the surface friction coefﬁcient between the tablet and die wall. The ejection energy (EE) was calculated by integrating Fe and range of movement distance into tablet ejection: Fe =
U ×P , m le l0
. (8) m The term Fe in (7) and (8) is ejection force, U is the friction coefﬁcient between the die wall and tablet, P is residual stress in the tablet, EE is the ejection energy, l is movement distance for tablet ejection, l0 is initial displacement, le is displacement at tablet ejection, and m is mass of the sample powder. Figure 5 shows the effect of mixing condition on the EE of the tablet compressed at 98 MPa. The EE of three kinds of excipients was decreased with mixing lubricant. The order of EE was DCPA > SDL > MCC. The EE of SDL was not changed under any mixing conditions, but that of MCC decreased in the twin-shell mixer for 20 min. The EE of DCPA mixed in the twin-shell and high-speed mixers decreased EE =
Effects of lubricant mixing
Figure 5. Effect of mixing conditions on ejection energy of various kinds of tablets. I0, intact sample; T5, T20, mixing in the twin-shell mixer for 5 and 20 min, respectively; M5, M20, mixing in the highspeed mixer for 5 and 20 min, respectively. Each bar represents the mean ± SD (n = 4) (∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.005).
Figure 6. Effect of mixing conditions on pore size distribution of various kinds of tablets: (!), intact sample; (F) twin-shell mixer and (E) high-speed mixer.
to 60 and 34% that of intact samples, respectively. The high EE was a disadvantage as a direct compression excipient. However, suitable lubricant addition reduced the EE and improved the tableting conditions. Figure 6 shows the effects of mixing conditions on the cumulative pore size distribution of tablets. The total pore volume of intact excipients was DCPA > SDL > MCC. The total pore volume of SDL mixed with the high-speed mixer was smaller than that of the intact and twin-shell mixer samples, respectively. The total pore volume of MCC was affected by mixing method and the order was
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Figure 7. Effect of mixing conditions on relative pore volume of various kinds of tablets. The solid line is the intact sample, the long dashed line in the twin-shell mixer for 20 min and the dotted line is the high-speed mixer for 20 min.
high − speed > twin − shell > intact. In contrast, the total pore volume of DCPA had no effect on the mixing method. Figure 7 shows the effects of mixing conditions on the relative pore distribution of the tablets. In SDL, the intact tablet had large pores between 1 and 10 μm in radius, but those of the twin-shell and high-speed mixers did not. The pores of the intact sample at 1 μm in radius decreased by addition of lubricant. In MCC, pores of 8–30 and 0.5–0.7 μm in radius when mixed with the high-speed mixer and twin-shell mixer were larger than those of the intact sample. In contrast, the relative pore distribution of DCPA showed no change due to mixing conditions. These geometrical structures of the tablets correspond to the mechanical strength, because the structure of MCC changed signiﬁcantly by mixing with lubricant and then the TS decreased signiﬁcantly as shown in Fig. 2. In contrast, the TS of DCPA was almost the same after mixing, since the structure was not changed. Figure 8 shows the effects of mixing conditions on the elastic recovery ratio (ER) of the tablets. The ER of MCC showed a signiﬁcant difference between intact and high-speed mixing samples. However, DCPA and SDL did not change. The elastic characteristics of SDL or DCPA and MCC were signiﬁcantly different. Since particle bonding has some relationship with the surface free energy of powder, the relationship between the tablet mechanical strength and surface free energy of powder was investigated. Figure 9 shows the effects of mixing conditions on the surface energy of various kinds of excipients by iGC. The surface energy of MCC mixed with the high-speed mixer was signiﬁcantly lower than that of the intact sample. This is because particles were coated with MgSt by a mechanochemical effect. The order for surface free energy decreasing after the mixing was MCC > SDL > DCPA.
Effects of lubricant mixing
Figure 8. Effect of mixing conditions on elastic recovery of various kinds of tablets. I0, intact sample; T20, mixing in the twin-shell mixer for 20 min, M20, mixing in the high-speed mixer for 20 min. Each bar represents the mean ± SD (n = 4) (∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.005).
Figure 9. Effect of mixing with lubricant on surface energy of various kinds of excipients. The samples where mixed in the high-speed mixer for 20 min. Open and closed bars represent intact and mixed samples.
Figure 10 shows the effects of mixing time on the surface free energy of the mixed MCC powders and TS of the compressed tablet. The surface free energy of MCC (Fig. 10A) mixed in the twin-shell mixer slightly decreased with an increase in mixing time, but that in the high-speed mixer signiﬁcantly decreased. On the other hand, TS of MCC (Fig. 10B) mixed in the twin-shell mixer was almost a constant value at all mixing times, but that in the mixer signiﬁcantly decreased the same as in the result of surface free energy. In MCC, the relationship between surface free energy and TS had a straight line as shown in Fig. 11.
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Figure 10. Effect of mixing time on surface energy and tensile strength of MCC tablets. ∗ P < 0.05, ∗∗∗ P < 0.005 (surface energy, n = 3; tensile strength, n = 4).
Figure 11. Relationship between surface energy and tensile strength of MCC powder on mixing condition. Surface energy and tensile strength from an average of three and four experiments, respectively.
The effect of mixing with MgSt on the physical properties affected the particle mechanism of excipients, as reported previously [19– 22]. In the present study, the mixing effect of a lubricant in three kinds of typical excipients for direct compression, which had signiﬁcantly different physical characteristics, were investigated. MCC had a single particle, which had the most elastic characteristics. SDL and
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Figure 12. Models of adhesion of lubricant particles to excipient particles.
DCPA had aggregated particles (granules) consisting of ﬁne crystalline and amorphous sections due to spray drying. Since MCC had no fragmentation during the mixing process, it seemed that it formed an ordered mixture after mixing in the twinshell mixer, but formed mechanochemical-coated particles in the high-speed mixer as shown in Fig. 12. The ordered mixture powder did not inhibit particle bonding during tablet compression, but the mechanochemical-coated particles inhibited particle bonding and decreased tablet hardness as shown in Fig. 2. In contrast, DCPA showed fragmentation during the mixing process in the high-speed mixer. Since DCPA granules were deaggregated and decreased in particle size, new surfaces appeared during mixing in the sample powder as shown in Figs 1–3, thus the tablet mechanical strength did not decrease even when partially coated by MgSt. On the other hand, SDL particles are also known to have fragmentation properties; however, SDL used in this work was about 15% amorphous , having elastic characteristics, and therefore it showed characteristics between MCC and DCPA. On the other hand, the results of surface free energy also support this hypothesis — surface free energy of MCC deceased by the mixing and the surface structure might be not change during compression, since MCC had an elastic characteristics, therefore the TS decreased. In contrast, the surface free energy of SDL and DCPA showed a similarly signiﬁcant change after mixing, but TS of their tablets did not change after mixing. This result suggested that TS of SDL and DCPA was not affected by the surface condition (surface free energy) of the sample powder before compression, meaning that SDL and DCPA formed new particle surfaces during
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compression. These results suggested that the tablets based on DCPA had stable characteristics when mixed with a lubricant under any mixing condition.
The effects of mixer and mixing time on the pharmaceutical properties of excipients for direct compression, such as MCC, SDL and DCPA, depended strongly on particle properties. The result also indicated that DCPA had the most stable characteristics during the mixing process with a lubricant among these excipients, since DCPA showed no over-lubrication effect. However, pharmaceutical properties of direct tabletting preparations were affected by many factors in the mixing process. Therefore, when a pharmaceutical preparation is designed, it is necessary to consider which excipients are selected and the effects of addition of a lubricant. Surface free energy evaluation by iGC was useful to predict the potential of pharmaceutical bulk powders for tablet mechanical strength before mixing with lubricants.
REFERENCES 1. M. Otsuka, J. Gao and Y. Matsuda, Effects of mixer and mixing time on the pharmaceutical properties of theophylline tablets containing various kinds of lactose as diluents, Drug. Dev. Ind. Pharm. 19(3), 333–348 (1993). 2. A. C. Shah and A. R. Mlodozeniec, Mechanism of surface lubrication: inﬂuence of duration of lubricant excipient mixing on processing characteristics of powders and propertyes of compressed tablets, J. Pharm. Sci. 66, 1377 (1977). 3. J. Kikuta and N. Kitamori, Effect of mixing time on the lubricating properties of magnesium stearate and the ﬁnal characteristics of the compressed tablet, Drug. Dev. Ind. Pharm. 20, 343– 355 (1994). 4. Z. T. Chowhan and L. H. Chi, Drug-excipient interactions resulting from powder mixing 3: solid state propertyes and their effect on drug dissolution, J. Pharm. Sci. 75, 534 (1986). 5. Z. T. Chowhan and L. H. Chi, Drug-excipient interactions resulting from powder mixing 5: role of lubricants and their effect on in vitro dissolution, J. Pharm. Sci. 75, 542 (1986). 6. K. S. Murthy and J. C. Samyn, Effect on shear mixing on in vitro drug release of capsule formulations containing lubricants, J. Pharm. Sci. 66, 1215 (1977). 7. R. Pezoa, M. I. Morasso, B. Ludwig and A. Arancibia, Effect of mixing on the dissolution kinetics of nitrofurantoin capsules, Drug. Dev. Ind. Pharm. 14, 475 (1988). 8. K. Tanino, Y. Aoki, K. Sato, T. Takeda and T. Mizuta, The cause and preventive method of over-lubrication during tableting, Yakuzaigaku 55, 155–156 (1995). 9. K. Takami, H. Machimura, K. Takado, M. Inagaki and Y. Kawasima, Novel preparation of free ﬂowing spherically granulated dibasic calsium phosphate anhydrous for direct tableting, Chem. Pharm. Bull. 44, 868–870 (1996). 10. H. Schlack, A. Bauer-Brandl, R. Schubert and D. Becker, Properties of fujicalin, a new modiﬁed anhydrous dibasic calsium phosphate for direct compression: comparison with dicalcium phosphate dihydrate, Drug. Dev. Ind. Pharm. 27, 789–801 (2001). 11. I. Krycer, D. G. Pope and J. A. Hersey, The role of intra-granular porosity in powder compaction, Powder Technol. 34, 802 (1982).
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12. M. D. Ticehurst, R. C. Rowe and P. York, Determination of the surface properties of two batches of salbutamol sulphate by inverse gas chromatography, Int. J. Pharm. 111, 241–249 (1994). 13. H. E. Newell, G. Buckton, D. A. Butler, F. Thielmann and D.R. Williams, The use of inverse phase gas chromatography to measure the surface energy of crystalline, amorphous, and recently milled lactose, Pharm. Res. 18, 662–666 (2001). 14. H. E. Newell, G. Buckton, D. A. Butler, F. Thielmann and D. R. Williams, The use of inverse phase gas chromatography to study the change of surface energy of amorphous lactose as a function of relative humidity and the processes of collapse and crystallization, Int. J. Pharm. 217, 45–56 (2001). 15. J. R. Condor and C. L. Young, Physicochemical Measurement by Gas Chromatography. Wiley, Chichester (1979). 16. J. Shultz, L. Lavielle and C. Martin, The role of the interface in carbon ﬁbre-epoxy composites, J. Adhesion 23, 45–60 (1987). 17. J. T. Fell and J. M. Newton, The tensile strength of lactose tablets, J. Pharm. Pharmacol. 20, 657–658 (1968). 18. M. Otsuka, M. Sato and Y. Matsuda, Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: inhibition of enzymatic activity of tripsin preparation by using external lubricant addition during the tableting compression process, AAPS Pharm. Sci. 3, 1–11 (2002). 19. K. Van der Voort Maarshalk and G. K. Bolhuis, Improving properties of materials for direct compaction, Pharm. Tech. 34–46 (1999). 20. K. Zuurmann, K. Van der Voort Maarschalk and G. K. Bolhuis, Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties, Int. J. Pharm. 179, 107–115 (1999). 21. K. Van der Voort Maarshalk, K. Zuurman, M. J. van Steenbergen, W. E. Hennink, H. Vormans, G. K. Bolhuis and C. F. Lerk, Effect of compaction temperature on consolidation of amorphous copolymers with different glass transition temperatures, Pharm. Res. 14, 415–419 (1997). 22. K. Van der Voort Maarshalk, K. Zuurman, H. Vromans, G. K. Bolhuis and C. F. Lerk, Stress relaxation of compacts produced from viscoelastic materials, Int. J. Pharm. 151, 27–34 (1997). 23. H. Vormans, G. K. Bolhuis and C. F. Lerk, Studies on tableting properties of lactose, Acta Pharm. Suec. 23, 231–240 (1986).