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Journal of Metals, Materials and Minerals, Vol.22 No.2 pp.13-18, 2012 Cetirizine Dihydrochloride Tablets Comprising Two Different Lubricants with
Highly Loaded Colloidal Silicon Dioxide
Prachya KATEWONGSA1,a, Thawatchai PHAECHAMUD1,b,*
1Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Abstract
Recently, the fast disintegrating tablet (FDT) has started gaining popularity and acceptance as new drug delivery system. Cetirizine dihydrochloride (CD) is the selective histamine (H-1)-receptor antagonist
that is demonstrated to treat the symptoms associated with seasonal and perennial allergic rhinitis which this
drug nowadays was prepared in form of FDT. Lubricant typically influences on tablet disintegration time
(DT) and wetting time (WT). Therefore, it is important for optimizing the lubricant amount in this dosage
form. The purpose of this study was to evaluate the effect of the lubricants (magnesium stearate (Mg-st) and
sodium stearyl fumarate (SSF)) on the CD tablet containing highly loaded colloidal silicon dioxide. Mg-St
was well known as a high hydrophobic lubricant and that sodium stearyl fumarate (SSF) is less hydrophobic
than Mg-St. Therefore, the DT and WT of tablets containing Mg-St increased as the amount of Mg-st
increased. However, the DT and WT of FDT were influenced not only by lubricant properties, but by
hardness. The polarity of the surface tablets was remarkably decreased by increased the amount of Mg-st
which related to the WT of FDT. Therefore, the contact angle of tablets increased and SFE decreased. On
the other hand, the polarity of the surface tablets was remarkably increased by increased the amount of SSF.

Key words: Cetirizine dihydrochloride, Magnesium stearate, Sodium stearyl fumarate, Highly loaded
colloidal silicon dioxide
Introduction
adhesion of compacts to the surface of the punches and dies during compression and ejection from the Cetirizine dihydrochloride (CD) is the selective die cavity. Lubricants can influence on disintegration histamine (H-1)-receptor antagonist that is demonstrated time (DT), hardness and dissolution of prepared to ease the symptoms associated with seasonal and tablets.(10, 11) Too much lubricant, however, will perennial allergic rhinitis.(1, 2) CD is water soluble cause the powder to form globules and to resist the drug (pKa 8.3).(3) Fast disintegrating tablet (FDT) proper cohesion. Magnesium stearate (Mg-st) has of CD can be better alternative to conventional been widely used as the lubricant in tablet tablets for allergic patient. Recent developments in production. Over the years, there have been many the fast disintegrating tablet (FDT) provide a convenient reports that extending this film, through either an solution for patients who have difficulties in increase in the amount of Mg-st or a longer mixing swallowing tablets and other dosage forms.(4, 5, 6) time, has a negative effect on the hardness, friability, The FDT dissolves or disintegrates in the saliva and DT of the tablets. Because the bonds between within a matter of seconds when placed upon the Mg-st particles are weaker than those between tongue and then it is swallowed to the stomach.(7) unlubricated excipient particles, a more extensive The dosage form which can be taken without water coverage of the excipient particles by Mg-st will is useful in the case of the acute onset of a lead to a decrease in tablet hardness. This decrease in hardness may also lead to an increase in tablet friability.(12-14) Along with a decrease in tablet Practically, the basic tablet excipients hardness, most authors report that an increase in include binders, diluents, disintegrants, glidants the amount of Mg-st leads to an increase in tablet and lubricants. Lubricants are added in the final DT.(15) This is due to the hydrophobic nature of the steps of mixing formulation components prior Mg-st molecule and, by extension, of the lubricant to compression. Lubricants practically prevent film, which hinders the penetration of water in the  *corresponding author E-mail: [email protected]; E-mail: [email protected]  KATEWONGSA, P. and PHAECHAMUD, T.  tablet. Sodium stearyl fumarate (SSF, Alubra®) is the (SSF, Alubra®) was donated from Onimax Co., Ltd., fatty acid esters. Compared to Mg-st, this lubricant Bangkok, Thailand. Ludiflash® was gifted from shows less interference with tablet strength and has BASF, Bangkok, Thailand. Na2HPO4, KH2PO4, a less negative effect on tablet disintegration and NaCl, formamide were purchased from Ajax Finechem, dissolution because of its hydrophilic nature.(16) Auckland, New Zealand. Ethylene glycol was Structures of Mg-st and SSF are depicted in Figure 1. Figure 1. Structure of magnesium stearate (Mg-st)(left) and sodium stearyl fumarate (SSF, Alubra®)(right)
Colloidal silicon dioxide such as Aerosil Methods
200 is hydrophilic glidant incorporated into solid dosage forms to improve the flow properties of Preparation of cetirizine dihydrochloride fast cohesive powders. It decreases the weight variation and minimizes the tendency of powder components to separate or segregate from excessive vibrations.(17) Aerosil 200 can be employed as gelling agent for shown in Table 1. The 5% CD FDT formulation hydrophobic dispersed medium(18). The high loaded was used in this study. Tablet ingredients were Aerosil 200 in tablet was employed in this study accurately weighed as mentioned in Table 1. Direct since the tablet prepared with direct compression compression method was used to prepare the tablet technique had the possibility of particle segregation. because of its ease manufacture and low cost. Drug and all the excipients except Mg-st and SSF were Glidant and lubricant can greatly increase mixed in mortar and pastle by geometric dilution. hydrophobicity (the resistance of a particle to Finally, magnesium stearate and SSF were added absorb water). When a tablet does not allow the into this blend and mixed properly again for 3 min. solvents to penetrate, it will have a slow disintegration, The blend was compressed using hydraulic press or dissolution rate. Tablets exhibiting this dilemma (SPECAC 15011, A Cambridge Electronic Industries will have a high activation delay-time and their Company, Kent England) to produce tablets weighing 200 mg each with a diameter of 9.53 mm with the compression force of 1 ton/cm2. It is important to optimize the concentration of lubricants in formulation. It is mainly important Table 1. Composition of CD FDTs
to maintain the fast disintegration properties of tablets with a sufficient hardness. Therefore, the purpose of this study was to evaluate the effect of Ludiflash ®
the type and amount of lubricant on the tablet Avicel PH 101
characteristics of FDT prepared by direct compression. Aerosil 200
The lubricants used in this study were magnesium stearate (Mg-st) and sodium stearyl fumarate (SSF, weight/tab
Evaluation
Materials and Experimental Procedures

Weight Variation
Materials
on 20 randomly collected tablets from a batch. The CD and Avicel PH 101, magnesium stearate were donated from Pharmanueva Co., Ltd., Bangkok, followed for this test(19). Weight variation test was Thailand. Aerosil 200 was purchased from Wacker- done by weighing 20 tablets individually. Chemie GmBH, Germany. Sodium stearyl fumarate Cetirizine Dihydrochloride Tablets Comprising Two Different Lubricants with Highly angle measurements, using two liquids (water and formamide were used as the solvent in this study) with known polarities. They can be assessed by tablets were measured using a hardness tester solving an equation (1) with two unknowns: (Erweka® TBH 225 Heusenstamm, German) and the data reported was the mean of ten individual
determinations.

where θ is the contact angle, γs is the solid surface The 10 mL simulated saliva fluid was added free energy and γl is the liquid surface free energy.(22) to the petri dish with the diameter of 10 cm. A The result of wettability and surface free energy tablet was carefully placed in petri dish. The time studies were to understand the formation of the required for the simulated saliva fluid to appear on surface tablets which related to the disintegration the upper surface of tablet was noted as wetting and wetting time of FDT containing various
Results and Discussion
Ludiflash® (containing mannitol, polyvinyl The time required for disintegration of six alcohol and crospovidone) is a new direct tablets, placed in each tube of disintegration apparatus, compressible excipient designed for FDT. It was was measured at 37±2°C using 900 ml simulated utilized in the formulation as diluents with saliva fluid. The time for the tablet to completely disintegrating property.(23) Avicel PH 101 was also disintegrate into fine particles was noted. included in the formulation as diluent. Colloidal silicon dioxide (Aerosil 200) acted as a glidant. It Contact Angle and Surface Free Energy (SFE) is known that Mg-St is hydrophobic and SSF is Knowledge of the wettability and surface tablets exhibited low weight variation that varies free energy of pharmaceutical solids is very important between 0.1948 g to 0.2004 g from different in the design of pharmaceutical formulation. Since batches (Table 2). Thickness and diameter also lubricants form a hydrophobic membrane on the showed low variation. The hardness of tablets surface of the powder particle, the wettability and containing Mg-st (A2-A5) seems to decrease as the surface free energy of tablets are assessed by amount of lubricant increased (Table 2) because contact angle measurement. The method of the lubricant created a waxy covering and assessing the surface free energy indirectly from prohibited inter-particulate forces from bonding. wettability measurement is widely used. The The incorporation of 0.25-5% Mg-st decreased in wettability and SFE of tablets were determined by the hardness of the tablets. This can be attributed to contact angle measurement which was carried out negation of the enhanced volume reduction and by the liquid drop on the tablet surface using the ability to consolidation by greater particle surface drop shape analysis method on the goniometer coating and subsequence interference in the (FTA 1000, First Ten Angstroms, USA) with the bonding. Hardness of the tablets increased when pump out rate of 2.5757 ul/s. A stainless tube concentration of Mg-st increased (A6, A7 packed with the mixture was lowered into liquid compared with A2-A5). The increased hardness and the recording of the contact angle was started with increased levels of Mg-st can partially be when the liquid contacted with the tablet at 1 explained on the basis of improved volume second (n=6). Distilled water, formamide, ethylene reduction and consolidation behavior. It may also glycol were used as test solvents which had the be assisted by formation of new surface and denser different polarities. The SFE of tablets was compacts by bringing the particle surface areas into calculated by Wu harmonic method(21). In the closer proximity and an increased ability to method of Wu, the surface free energy is taken as transmit the compression force resulting in more the sum of the dispersive (γd) and the polar (γp)
cohesive compacts. On the other hand, the components. The surface free energies of solid hardness of tablets containing SSF did not depend materials can be determined by means of contact KATEWONGSA, P. and PHAECHAMUD, T. ble 2. Physical properties of CD FDT
higher the concentration of Mg-st, the poorer the Formula weight (mg) thickness (mm)diameter (m
m) hardness (N)
DT (second)
WT (second)
9.59±0.01 135.33±6.31 288.32±11.36 180.33±15.98 wettability of the surface, as expected. It can be increased as the amount of Mg-st increased. A supported by the poor wetting of magnesium possible explanation for this behavior was the stearate (contact angle with water). The contact formation of the hydrophobic membrane of Mg-st angle of tablets containing Mg-St increased as the on the surface of the powder particles. Moreover, amount of Mg-st increased (Table 3)(22) whereas the the DT and WT of tablets containing SSF seems to contact angle of tablets containing SSF decreased as decrease as the amount of SSF increased owing to the amount of SSF increased (Figures 2 a and b). hydrophilic property of SSF. In addition, this is due In addition, the SFE of tablets containing Mg-St to overriding influence of the strength of the decreased as the amount of Mg-st increased; interparticle bonds on the disintegration time of the nevertheless, the SFE of tablets containing SSF tablets as well as on their hardness. We previously increased as the amount of SSF increased(22,25). hypothesized that the DT and WT of the tablets These result described that the polarity of the surface containing Mg-st and SSF depended on only the tablets was remarkably decreased by increasing the properties of two lubricants. However, the DT and amount of Mg-st which related to the WT of FDT. WT of tablets were influenced not only by lubricants Therefore, the contact angle of tablets increased properties, but by hardness. In the same amount of and SFE decreased. On the other hand, the polarity two lubricants (A2 and A8), the hardness of A2 of the surface tablets was remarkably increased by was 148.83 N and that of A8 was 144.33 N. DT of A2 and A8 was 196s and 252.83s respectively. Moreover, the mechanical stress is applied, hardness or tensile strength of tablets is influenced by different factors such as, the elastic and plastic characteristics of the material. Furthermore, Mg-st and Aerosil® is enhance the hardness of tablets containing plastic deformation of the materials (Avicel®)(24) than that of A1 (without lubricant) because formulation of A1 comprised of water soluble diluent, glidant, disintegrant and water soluble drug, the DT of A1 tend to dissolve rather than disintegrate. When the tablet dissolved, it formed the layer film that Typically, the wettability of surface tablets could be described from the contact angle and SFE Figure 2. Effect of type and amount of lubricants on
values. The hydrophilicity of the surface tablets characteristics (a) contact angle (θwater) and was changed with increasing amount of Mg-st. The Cetirizine Dihydrochloride Tablets Comprising Two Different Lubricants with Highly Based on this study, SSF was chosen as a 4. Seager, H. (1998). Drug-delivery products and lubricant at 2.25% concentration as it gave optimum the Zydis fast dissolving dosage form. J. hardness value with low disintegration time and Pharm. Pharmacol. 50 : 375 –82.
wetting time. Owing to the low disintegrating property of Aerosil 200 it high loading did not 5. Dobetti, L. (2001). Fast-melting tablets: Developments promote the disintegration and wetting time(26-28) and technologies. Pharm. Technol. Drug Conclusion
6. Fu, Y., Yang, S., Jeong, S.H., Kimura, K. and Park, K. (2004). Orally for fast disintegrating tablets: and DT, we evaluated the effect of the type of developments, technologies, taste-masking lubricant on the characteristics. The FDT were and clinical studies. Crit. Rev. Ther. Drug produced by direct compression method. The type Carr Syst. 21: 433–75.
and amount of lubricant had an influence on characteristics of FDT especially WT, DT, contact 7. Wilson, C.G., Washington, N., Peach, J., Murray, G.R. angle, SFE. Mg-St was well known as a high and Kennerly, J. (1987). The behaviour of hydrophobic lubricant and that sodium stearyl a fast dissolving dosage form (expidet) followed fumarate (SSF) is less hydrophobic than Mg-St. by g-scintigraphy. Int. J. Pharm. 40 :119-23.
Therefore, the DT and WT of tablets containing Mg-St increased as the amount of Mg-st increased. 8. Sunada, H., Bi, Y. (2002). Preparation, evaluation However, the DT and WT of FDT were influenced and optimization of rapidly disintegrating not only by lubricant properties, but by hardness. tablets. Powder. Technol. 122:188–98.
The polarity of the surface tablets was remarkably decreased by increasing the amount of Mg-st 9. Fukami, J., Yonemochi, E., Yoshihashi, Y., and which related to the WT of FDT. Therefore, the Terada, K. (2006). Evaluation of rapidly contact angle of tablets increased and SFE decreased. disintegrating tablets containing glycine ad On the other hand, the polarity of the surface carboxymethylcellulose. Int. J. Pharm. 310
tablets was remarkably increased by increasing the 10. Joshi, A.A. and Duriez, X. (2004). Added functionality Acknowledgement
excipients: An answer to challenging formulations. Pharm. Technol. Suppl. 19 :12–19.
Royal Golden Jubilee Ph.D and Pharmanueva Co., 11. Lyad, R., Nidal, D., Mayyas, A.R. and Stephen, A.L. Ltd. Scholarship Student Association and also was (2010). Characterization of the impact of kindly supported by the Faculty of Pharmacy, tableting properties of chitin-Mg silicate as a superdisintegrating binder when compared to Avicel® 200. Powder. Technol. 203 : 609-19.
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