5. RESULTADOS Y DISCUSIÓN
5.1. RESULTADOS DEL ESTUDIO DE ACTIVIDAD ANTIBACTERIANA
The tensile strength o f all the tablets produced fi-om 650 mg pellet compacted to the same dimensions and 700 mg pellets compacted by the same pressure was relatively low. Some of them could hardly be ejected form the die. Therefore extra care was taken during measuring the dimensions o f the ejected tablets before crushing them diametrically. In the diametrically crushing experiments, not all the tablets failed in tension through their diameter. Especially the tablets containing a higher GMS had a triple cleft feilure. All the feilures were between the
pellets boundaries showing a weaker connection. The dominant presence of MCC could be the main reason for the less intergranular attachments. All the formulations produced tablets o f different tensile strength when 650 mg of pellets were compacted(Table-3.3.8). The magnitude of the influence of each formulation was dependent on the proportions of the excipients’ presence and the type of binding liquids (Fig-3.3.7a- f).
o- 0.3-1 I ' 0.25 D) 0 . 2 - § 0.15 - Lge IGe LGe = 0.05 X average MCCCortert A, I 0.35 n 0.3 £ 0.25 4
lo°,l
I 005 S 0 m M MCC Content - ig E -L g E ---- A - IGE ---- X - -L G E X Average D. a! 0 31 ^0.25- # 02 §0.15- rrgs nrG fe MGfe a! 0.35 ^ 0.05 B. E. o) 0 2 2 0.15 w 0.1 = 0.05 S. 0.35 1 . 0.3 £ 0.25 I 02 £ 0.15%
0.1 M 0.05 S 0 rrJE MIE ml F MLE X Average 9 G GMS Content C. F.Fig-3.3.7:-The effect o f MCC (A and D), lactose (B and E), and GMS (C and F) at their lower (lower case) and higher (upper case) levels on the tensile strength o f the tablets producedfrom 650 mg pellets o f the factorial designed experiment. Pellets mean diameter was 1.09 mm. The letter “e ” stands fo r those formed without ethanol, while “E ” stands fo r those formed with the mixture o f water and ethanol, n=5.
The tensile strength of these compacts of different formulae related to the relative pressure needed to compress the same mass of the pellets to the same volume (Table-3.3.8). This means, those pellets compressed by the relative higher pressure produced stronger tablets.
Tablets Compressed to the same thickness (4.0mm) £ 0.25 n 0-2- ^ g O M5 . .1 0.05 40 -MCC - Lactose -GMS Minimum Maximum Average content
Fig-3.3.8:- The average effect o f each factor (excipients) on the tensile strength o f 650 mg tablets produced from pellets o f the factorial designed experiment. The mean
diameter o f the pellets was 1.09 mm.
Tablets compressed by the same pressure (146 MPa) .c 0.25 -]
I
0.2 ? 0.15 - CO 0_ M5 0.1 - 0.05 - 0 - -MCC ■ Lactose -GMS Minimum Maximum Average ContentFig-3.3.9:- The average effect o f each factor (excipients) on the tensile strength o f 700 mg tablets produced from pellets o f the factorial designed experiment. The mean diameter
o f the pellets was 1.09 mm.
Increase in the MCC content reduced the tensile strength by the highest extent at all levels of the other factors, while increase in the GMS content increased values o f the tensile strength to the highest extent (Fig-3.3.8 and 9). Although to a smaller extent, an increase in the lactose content increased the tensile strength when pellets were formed with water, but reduced slightly when formed with ethanol/water. The statistical analysis of the overall effect o f each factor, revealed that MCC had a significant effect at (P<0.05) when only water was a binding liquid, but at (P< 0.01) when water was mixed with ethanol (Table-3.3.11).
Factor mean change in tensile strength (%) d.f. Mean Square F P MCC -70.1 1 7626 9.90 0.045 Lactose 26.1 1 1128 1.46 - GMS 109.1 1 18721 24.29 0.008 B.
Factor mean change in tensile strength (%)
d.f. Mean Square F P
MCC -74.00 1 22684 152.9 0.001
Lactose -18.75 1 1458 9.8 0.051
GMS 88.20 1 32258 217.4 0.001
Table-3.3.12:- Yates Analysis o f the factorial designed experiment fo r the determination o f the mean effect o f each factor on the properties o f the tablets. Where (A) are pellets form ed with water and (B) form ed with water/ethanol The error mean square was
determined from MLg, and MLG in both cases with 2 d .f
The effect of lactose was not significant on either case, while GMS had a significant effect in increasing the strength o f the compacts (P<0.01 ) fi)r both solvent compositions. The relatively small force needed to compress MCC-rich pellets to the same pre-determined volume could be assumed insufiBcient to force the surface of the pellets to closer proximity to allow interaction at a molecular level. This assumption was, however, disproved when MCC pellets were tableted by using higher pressure, and yet they were very weak. This observation agrees with the findings in the previous sections. Similarly, Maganti and Celik (1993) showed insensitivity o f the strength of MCC pellet conq)acts to compaction pressure compared to MCC powder contacts. On their compaction, the pellets required lower pressure than the powder to obtain the same porosities. However, the tensile strength o f the ejected powder compacts was significantly higher than that o f pellets. Therefore, they concluded that the ability o f the material to reduce in volume when compressed even to a higher extent did not ensure the formation o f strong compacts. Thus, the main reason could be the change in surface nature o f the pellets during their formation, which resulted in poor inter-granular coherence.
Even at its lowest content, since MCC constituents about 6 6.6%w/w o f the dry mass, its effect dominated the addition o f only 10%w/w o f the dry mass o f any other factor. However, addition o f 10%w/w o f lactose was at least able to reduce the tensile strength reduction effect o f MCC in the presence o f ethanol (Table-3.3.11 b). Moreover, its average effect in the absence o f ethanol was observed to increase the tensile strength o f the pellet compacts. Schwartz et al. (1994) made a similar observation. With the addition o f more lactose they observed more fracture o f the MCC pellets during compression which resulted to a stronger compact.
The average increase in GMS content in the factorial designed experiment increased the tensile strength o f the compacts to the highest extent (109%). The smoothness o f the surfece o f the compact, and the change in shape o f the de-aggregated pellets indicated that the compaction process was by plastic deformation. Such compacts were compressed to the greatest extent. This may have helped the surfaces to come closer which enabled the formation o f rigid structures. The increase in temperature due to the inter-particular friction, as these pellets were compressed by a higher force, could also be the reason for the formation o f “fusion welding” as the melting point o f GMS is relatively lower.
There was no any interaction between the factors when the pellets were formed with water and ethanol mixture. In the absence o f ethanol, however, interaction was observed when lactose and GMS were at their higher levels. This could be due to the brittle nature o f lactose was counteracted by the deformable nature o f GMS.
This work revealed that the strength o f the tablets from the eight different excipient compositions increased when the ethanol was incorporated into the liquid binders. This effect was minimal when lactose was at its higher level. The increase in porosity o f the pellets, hence deformability, enhanced the compressibility which intum formed strong compacts as also reported by Millili and Schwartz ( 1990) and Johansson and Alderbom (1996). The smoother surfaces with indistinct pellet boundaries supports this assumption.
Seven hundred-milligram pellets from each o f the formulations were also compacted to tablets by approximately the same pressures (146 MPa and 130MPa). In both cases, the relative effect o f each formula, and the average effect o f each factor on the tensile strength o f the
tablets were of the same order. Thus, the analysis of the results o f those tablets compressed by 146 MPa would be sufficient (Fig-3.3.10),
5 0.25- % 0.2- 2 0.15- 0 0.05 - M m MOCoontert Ige -^IQe LGB Average g 0 .3 - e 0 .2 5 - — igE % 0 .2 - ■ LgE 5 0 .1 5 - R 0.1 - — A— K3E — X— LGE M 0 .0 5 - c n - Average m M MCC content A. D. % 0.25- g> 0.2 " 0.15 — «— mge —1— Mge — A— mGe _ .H--MGe - -X- Average g 0.05- Lactoseoorteft S 0.15 J 0.05 B. E. I 0.15- co Q i- 0) =^0.05- c ' 0.2 5 0.15 OVBœnknt C. F.
Fig-3.3.10:-The effect o f MCC (A and D), lactose (B and E), and GMS) (C and F)at their lower (lower case) and higher (upper case) levels on the tensile strength o f the tablets produced when 700 mg pellets o f the factorial designed experiment were compressed by a constant 146 MPa. Pellets mean diameter was 1.09 mm. The letter “e ” stands fo r those form ed without ethanol, while “E ” stands fo r those form ed with the mixture o f water and
ethanol. n^5.
This work showed that the difference in the strength o f the tablets compacted by 130 MPa and 146 MPa was very small specially for the GMS-rich pellets. This could be due to the ease o f their deformability, which reduced their porosity as a result o f lower pressure to form compacts o f reasonable strength. Conversely, it could be due to the excessive volumetric elastic recovery as a result o f a higher elastic deformation caused by a higher pressure.
The results indicate the dominance o f MCC in these experiments compared to the work o f Maganti and Celik (1995) who used MCC content as low as 20%w/w o f the dry mass. Their lactose-rich MCC pellet compacts were relatively stronger when they were compressed by a higher force to 87% solid fraction than by a lower force to 80% solid fraction. In this work, the overall effect o f each fector was the same when a definite mass o f the pellets was compressed to the same volume or compressed by the same force (Fig-3.3.9 and 10). The addition o f 10%w/w GMS in each o f the eight formulae containing a minimum amount of GMS resulted in an average increase o f tensile strength o f the compacts by 135%. The addition o f 10%w/w o f MCC in each o f the eight formulae containing minimum amount o f MCC resulted in an average decrease o f the tensile strength o f the compacts by 50%. Similarly increase of 10% w/w o f lactose to the dry mass had only 15% reduction effect on tensile strength. Moreover, the rank order o f the effect o f these three factors was the same even when the composition o f the binding liquid was altered.
3.3.3.4 CONCLUDING REMARKS
The overall effects o f each o f the formulation factors have been extensively studied at two different set o f factorial designed experiments. This revealed that the stronger MCC-rich pellets needed a relatively lower compressing pressure and produced weaker compacts which have lower tendency o f volumetric elastic recovery. This was attributed to their plastic nature and the effect o f the pelletization process on the surface o f their pellets. The dominance o f MCC in the dry mass o f the formulations in this study, relatively hindered a significant response due to the addition o f the other excipients. However, the low percentage added showed a considerable change in the properties o f the pellets which were moderately reflected on the properties o f their compacts. GMS-rich pellets increased the compression force, and produce compacts o f greater strength and higher volumetric elastic recovery. This was assumed to be due to its greater deformability and lower apparent density. The lactose-rich pellets were observed to have moderately higher compressing pressure due to their relatively
Stronger pellets. The failure of these pellets during compaction was the main reason for the least volumetric elastic recovery of their compacts. Moreover, the exposure of new surfaces enabled the pellets to form inter-granular connection network to produce tablets of greater strength than the MCC-rich pellets.
I
3.1 a 3.1b
r
T2a 3.2b
Plate-3 (la) the surface, (Ib) the cross-section o f pellet compacts having a higher amount o f glyceryl monostrearate; (2a) the surface, (2 b) the cross-section o f pellet compacts having a higher amount o f lactose.
CHAPTER- FOUR
THE EFFECTS OF LIQUID BINDERS
The objective o f this chapter is to observe the effects o f the different liquid binders on the mechanical properties ofMCC pellets, their compaction mechanism and the properties o f their compacts. First, the effect o f moisture content was considered, where MCC was mixed with different amount of water in the production o f pellets. Secondly, MCC pellets were prepared with different water/ethanol mixture (100/0, 80/20,60/40, and 40/60) as liquid binders. Both liquids evaporated during drying process leaving MCC particles to form the skeletal structure o f the dry pellets. Thirdly, a similar water/glycerol proportions were used as liquid binders to produce MCC pellets. Glycerol was retained inside the pellets even after drying process. After a detailed study on the gradual change in the properties o f the pellets with a stepwise change in liquid binders, a 2^ factorial designed experiment was performed to study the effects o f each liquid binder at two different levels o f the others. Moreover, their ternary mixture at different proportions was used to produce 18 different batches o f pellets. The structural (2.2.2) and mechanical (2.2.3) properties o f the pellets were analysed followed by their compaction mechanism (2.2.4.1) and the properties o f the compacts (2.2.4.2).
4.1 THE EFFECTS OF MOISTURE CONTENT
In this section, formulations containing only MCC were tested for their sensitivity to moisture content. Four different MCC : Water ratios (10/11,10/10,10/9, and 10/8) were analysed in terms o f extrusion force, mechanical properties o f pellets, and their conq)action mechanism. The compacted pellets, for all moisture contents, produced very soft tablets which failed immediately after ejection form the die.
The extrusion force/time profiles o f the MCC wet mass containing four different moisture contents indicated that there was an increase in ram extrusion force, at the steady state stage, with the decrease o f moisture content (Fig-4.1.1). This was similar to the results o f Harrison et al. (1985), Pinto, (1992) and Bains et al.(1991) even though the first two authors had added lactose while the latter had added barium sulphate to the MCC formulations. This could presumably be due to the decrease in die wall shear stress o f MCC extrudate with the increase in moisture content o f the formulation. During the process, water could have moved towards the die wall and formed a thin layer upon which the shearing took place, hence reduction in
the extrusion force resulted (Benbow and Bridgwater, 1993). Thus water seems to have served as a lubricant.
110%
80% 90% 100%
water content
Fig-4.1.1:- The effect o f the water expressed as % o f the mass o f MCC on extrusion force at ram speed o f 200 mm/min.
The pellet size and size distribution was affected by the original water content of the wet mass. With the increase o f water content the mean pellet diameter and size distribution of the pellets increased (Table-4.1.1). The extradâtes produced from the formulation having 110% water content compared to the MCC mass, agglomerated during spheronization to form very large “balls”, hence no further analysis was made on them. In the 1.0-1.4 mm size fraction, 13.3 %, 39.4%, and 45.8% of the pellets were retained form those formulations produced with 80%, 90%, and 100% water compared to the dry mass. The increase in modal proportion was also observed to be in reverse order to the water content o f the formulations (Table-4.1.1). Fielden et al. ( 1993) made a similar observation. They reported a subsequently shift o f the number and weight distribution curves to the right (larger size) at 37.5%w/w moisture content of their MCC and coarse lactose formulation, which indicates an increase in pellet size and distribution of sizes as spheronization progressed. For 33.3%w/w moisture content of the same formulation, however, they observed a shift towards the left. Otsuka et al. (1994) reported a similar findings. They obtained a larger mean particle size of granules from those produced by extrusion/spheronization process having 250ml/kg water than those having 150ml/kg water content. This shows that the extrudate with lower water content had insuffrcient plasticity, as a result they shattered on the spheroniser plate generating a large quantity of fines.
Structural and Mechanical Properties o f Pellets
Amount o f water to the mass o f MCC (%)
80% 90% 100%
Mode (0.71-1.0mm size fraction) in(%) 85.9 59.3 47.3
Median pellet diameter (mm) 0.60 0.75 0.85
Interquartile range (mm) 0.25 0.40 0.45
Porosity (sealed) (%) 11.93±0.15 11.38±0.16 9.11±0.14
Table-4.1.1:- The size and size distribution o f MCC pellets produced with different water content and the porosity o f pellets in the 1.0-1.18mm size fraction.
The porosity o f the pellets, as measured by helium pycnometer, was also dependent on the original moisture content o f the wet mass. The ‘sealed’ porosity o f pellets decreased with the increase o f water content (Table-4.1.1). Otsuka et al. (1994) also observed a decrease in porosity with increase in water content. Their result from mercury porosimetry showed that the amount o f water affected the internal porosity o f the spherical granules. It decreased with increased in water proportion. The higher water content may have helped the MCC fibres to slip along each other and be rearranged in a more packed way to produce pellets o f less porosity.
Extrudates from 80% water content to the dry mass could not produced spherical pellets. They were very dry and rigid and could not be rounded, thus, no more further analysis was performed. Pellets from 90% and 100% water content, however, were relatively spherical (0.53 shape fector) and the effect o f the moisture content on the mechanical properties o f the pellets o f 1.0-1.18 mm size fraction was assess and compared. Pellets from the higher water content were stronger (Fig-4.1.2a), less deformable (Fig-4.1.2b), with higher linear strain (Fig-4.1.2c) and ‘elastic modulus’ (Fig-4.1.2d). Moreover, the shear strength o f pellets produced with 100% water content to the dry mass(2.44 MPa) was 24% higher than those produced with 90% water (1.97 MPa). The overall shear strength was, however, about a third o f the tensile strength. In their work to determine the effect o f water added on the mechanical property o f spherical pharmaceutical granules produced by extrusion/ spheronization process, Otsuka et al. (1994) found a decrease in fiiability o f the granules with the increase o f added water. The magnitude o f interaction between the different MCC fibres Millili et al. (1990)
could have been enhanced by increase in moisture content. In addition a decrease in internal porosity with increase o f water content (Table-4.1.1) could have reduced the propagation of the crack, hence resisted failure.
CO 0_ 100% w ater content (%) (a) w ater content (%) water content (%) (b) 100% Water content (%)
Fig-4.1.2:- Tensile strength (a), Deformability (b), Linear strain (c), and 'Elastic modulus’(d) o f pellets o f 1.0-1.18 mm size fraction produced by different water