Katharina M. Picker-Freyer

The first part of this article discussed the latest information regarding carrageenans and tabletting. This article will describe the results and discussion on tabletting, the final formation of the tablets and tablet properties. Finally, general conclusions on the tabletting of carrageenans will be drawn. 

Results and Discussion (continued)Tabletting

The tabletting behaviour was characterized by 3D modelling (Figure 1). Heckel analysis (Figure 2[a]), determination of the parameters of the pressure–time function (Figure 2[b]), and energy calculations from the force–displacement profile (Figures 2[c] and [d]) were 

 in comparison. Figure 1(a) shows different types of carrageenan (κ, ι, and λ) compared with microcrystalline cellulose (MCC). For all three types, pressure plasticity (e) is lower and fast elastic decompression (indicated by ω) is higher compared with MCC. The κ-carrageenan (Gel 911) and the λ-carrageenan (Vis 109) behaved similarly. The ι-carrageenan (Gel 379) showed lower e- and ω-values compared with both Gel 911 and Vis 109. In addition, for all the carrageenans (particularly Gel 379), time plasticity (d) was lower compared with MCC. In conclusion, the carrageenans are less plastic than MCC and exhibit much more elasticity already during tabletting. Brittle fracture can be excluded because the materials do not show the typical decrease in ω-values.

 Figure 1 3D parameter plot in dependence on Ïrel,max (0.72â0.88).			

Because of its anhydrogalactose groups, which are also substituted with sulfate, Gel 379 is the most elastic material. Figure 2(a) shows the slope of the Heckel function for the different types of carrageenan. For five of the six carrageenans the slope of the Heckel function is lower compared with MCC, indicating less deformation. However, the slope of the Heckel function includes plastic and elastic deformation. As known from 3D modelling, the deformation of the carrageenans is mainly elastic deformation. Thus the order of elasticity is the same as by 3D modelling. Figure 2(b) shows the results of the pressure-time 

function in the β–γ diagram. All carrageenans are much more elastic than MCC. Distinguishing the different carrageenans is not as easily possible using this method. However, Gel 379 exhibits the highest β-values and is thus the most elastic material. Finally, Figures 2(c) and (d) illustrate that Gel 379 is the most elastic material. However, the differences between the carrageenans are slight using this method.

Figure 2 (a) Heckel slope, (b) Î²âÎ³ diagram, (c) plastic and (d) elastic energy in dependence on Ïrel,max determined for six different carrageenans and MCC (mean6SD).			

Figure 1(b) shows the tabletting behaviour of Vis 328, a material that consists of both κ- and λ-carrageenan. It was assumed that its behaviour does not differ from Gel 911 and Vis 109. However, the result shows that this composite material is much more plastic in its behaviour; d and e are higher compared with the pure types. Furthermore, fast elastic decompression is lower because ω is higher. The Heckel analysis (Figure 2[a]) underlines this result as the slope of the Heckel function is the highest of all materials. The β–γ diagram (Figure 2[b]) and energy calculations (Figures 2[c] and [d]) show fewer differences. Vis 328 behaves similarly to Vis 109. A reason for this high plasticity might be that in this composite product the texture of the fibres is less homogeneous and thus, the fibres deform more plastic.  

Figure 1(c) shows the deformation behaviour of Gel 812, a κ-carrageenan, which contains more potassium ions than Gel 911.

 d and e are similar to Gel 911. However, this material exhibits a little more elasticity, which is indicated in the lower ω-values. This difference was significant (α=0.05) for all maximum relative densities, ρ

. The Heckel analysis (Figure 2[a]) and energy calculations (Figure 2[c]) show that Gel 812 is less plastic compared with Gel 911; the slope of the Heckel function and plastic energy is lower. Obviously the potassium ions in Gel 812 induce more relaxation during tabletting compared with Gel 911. Again, the β–γ diagram (Figure 2[b]) shows fewer differences compared with the other methods. Gel 812 behaves similar to Gel 911, except for the lowest maximum relative density (0.72).  

Finally, Figure 1(d) shows Vis 209, the particles of which are bigger than those of Vis 109. This was proven by laser diffractometry (Figure 4, Part I). For Vis 209, d and e are slightly lower compared with Vis 109. Moreover, this material exhibits lower ω-values and shows thus higher fast elastic decompression. Obviously the bigger particles deform less plastically and exhibit more elasticity. The decrease of e at low densification indicates crushing of the particles as for brittle materials.

This result is underlined by a lower Heckel slope for Vis 209, higher β-values (in the β–γ diagram) and slightly higher elastic energy (Figure 2[d]). The powder shows more resistance to pressure. 

Because the carrageenans contain much more water than MCC and show sorption with increasing humidity, tabletting was analysed exemplarily for Gel 911 at different relative humidities (RHs). Figure 3(a) shows the results for tabletting at different RHs by 3D modelling. With increasing humidity and increasing water content, d and e increase, and fast elastic decompression decreases. This result is similar as for MCC (Figure 3[b]), although much more pronounced compared with MCC.

Figure 3 3D parameter plot in dependence on Ïrel,max (0.72â0.88) of (a) Gelcarin GP-911 and (b) Avicel PH 102 at four different RHs.			

Figure 4 shows the elastic recovery of tablets made of carrageenan compared with MCC. For all carrageenan tablets, elastic recovery is higher compared with those made of MCC. Relaxation, which already started during tabletting, continues. Elastic recovery is different for the different types of carrageenan. Tablets made of κ-carrageenans (Gel 911 and Gel 812) showed higher elastic recovery than those made of the ι-type (Gel 379). The order was inverse for fast elastic decompression. Tablets made of the λ-carrageenan (Vis 109) and of Vis 328 exhibit less elastic recovery. This behaviour conforms with the behaviour during tabletting. The λ-carrageenan tablets (Vis 209) demonstrated higher elastic recovery after tabletting. For this type, particle size is the reason, as its bigger carrageenan particles relax more. 

Figure 4 Elastic recovery in dependence on rrel,max of six different carrageenans and MCC (mean6SD); (a) directly after tabletting and (b) 10 days after tabletting.			

In summary, for a great deal the process of tablet formation continues  after tabletting. Thus, to fully illustrate tablet formation, elastic recovery after tabletting was determined in dependence on time.  

Figure 5 shows the results for elastic recovery obtained by thermomechanical analysis at constant temperature. To rule out the influence of the applied slight force during thermomechanical analysis, experiments were also performed with the automatic micrometer screw.

measurement. Figure 6 shows similar results as they were obtained with thermomechanical analysis. 

Figure 5 Elastic recovery in dependence on time determined by thermomechanical analysis at constant temperature for (a) Gelcarin GP-379 NF; (b) Gelcarin GP-911 NF; (c) Gelcarin GP-812 NF; (d) Viscarin GP-328 NF; (e) Viscarin GP-109 NF; and (f) Viscarin GP-209 NF.			

For tablets of all three types of carrageenan, in the beginning an increase in elastic recovery followed by a decrease in elastic recovery was observed. Most probably parallel to the relaxation of the tablets after tabletting a shrinking of the tablets occurred.

This process is most pronounced for tablets made with 

κ- and ι-carrageenan (Figure 6 [a–d]). Tablets made of λ-carrageenan exhibit less shrinking (Figure 6 [e and f]). Thus, a shrinking (S) order can be established: S(κ-carrageenan)>S(ι-carrageenan) >S(λ-carrageenan). During all experiments tablet mass remained constant and thus, the tablets did not dry.

Figure 6 Elastic recovery in dependence on time determined by analysis with the automatic micrometer screw for34 (a) Gelcarin GP-379 N; (b) Gelcarin GP-911 NF; (c) Gelcarin GP-812 NF; (d) Viscarin GP-328 NF; (e) Viscarin GP-109 NF; and (f) Viscarin GP-209 NF.			

How can this shrinking be proven? What is the reason? Density measurements with carrageenan tablets after tabletting showed that the apparent density of the tablets, as determined by helium pycnometry, increased with storage time (0.052 g/cm

 (repetitions n=10). This density increase could be caused by a reorganization in the fibre structure caused by the force applied during tabletting.

Environmental scanning electron micrographs (ESEMs) of a Gel 911 tablet (Figure 7) produced by video analysis show that indeed fibre shrinking occurred after tabletting. Figure 7 shows precisely the same breaking surface of a tablet (a) 30 min and (b) 12 h after tabletting. The tablet remained at constant humidity in the ESEM. The fibre strength decreased and also the gaps between the fibres increased. 

Figure 7 SEMs (first line) and black and white images of the SEMs (second line) of the same location at the breaking surface of a Gelcarin GP-911 NF tablet at 40% RH (ESEM); (a) 30 min and (b) 12 h after tabletting.			

The result proves that following tabletting, changes in the material took place that caused the increase in density. To analyse the fibre structure more precisely, the breaking surface of Gel 911 tablets were analysed by transmission electron microscopy (TEM) after freeze fracturing (Figure 8). After 24 h (Figure 8[b]) stripes were visible that could not be detected 2 h (Figure 8[a]) after tabletting. A mechanical activation occurred that caused changes in the fibre structure and lead to the tablets shrinking. This mechanical activation can contribute to bonding.

Figure 8 TEMs of the replica breaking the surface of a Gelcarin GP-911 NF tablet after freeze fracturing (a) 2 h and (b) 24 h after tabletting (magnification: 66.000x).			

As shown in Figure 5, Part I the tablets were analysed on the upper and breaking surfaces after tabletting and relaxation. Compared with MCC (Figure 5[b(g)], Part I) both surfaces show a high porosity and a loose entanglement of the fibres, even the upper surface of the tablets is not plane. Mechanical interlocking is of importance for bonding. The fibres are less deformed than the MCC fibres, and this could enable their suitability for soft tabletting. A reason for this behaviour might be the low glass transition temperature (Tg) of the carrageenans (Table 1, Part I). The carrageenans are at room temperature in the rubbery state, MCC is in the glassy state. Tablets made with λ-carrageenan (Vis 109, Vis 209 and Vis 328 [Figure 5(b), Part I] seem to be more loose in structure than tablets made of the ι- and κ-carrageenans (Gel 379, Gel 911 and Gel 812 [Figure 5(a), Part I].  

Despite the loose structure of the carrageenan tablets, mechanically stable tablets were obtained for all types of carrageenan (Figure 9). However, the slope in the compactibility plot is much lower compared with MCC; obviously the high elasticity of the carrageenans reduces crushing force. In all cases, the crushing force is satisfying and thus, bonding inside the tablet is sufficient for mechanical stability. 

Figure 9 Compactibility plot of six different carrageenans and MCC (mean6SD).			

Carrageenans form tablets by plastic deformation. Simultaneously, the materials exhibit elastic relaxation of the tablets, particularly for ι- and κ-carrageenans. After tabletting, relaxation continues to different extents for the various types of carrageenan. Overall, elastic recovery is higher compared with most of the usually used tabletting materials

However, mechanically stable tablets are formed. The compaction energy is used for plastic deformation and a reorganization of the fibre structure. Part of the energy is released in the form of elastic recovery. Thus, less energy is transformed into pure plastic deformation.  

In summary, the special tabletting behaviour of the carrageenans described here enables them to be useful for soft tabletting of pressure-sensitive materials.

The author gratefully acknowledges Prof. Dr. C.C. Müller Goymann, Institute of Pharmaceutical Technology, Technical University of Brunswick (Germany) for the use of freeze fracturing and TEM, Dr.-Ing. K. Legenhausen, Institute of Mechanical Engineering, Technical University Clausthal-Zellerfeld (Germany) for the use of laser light diffractometry, and Lehmann & Voss, Hamburg (Germany) for donation of materials. 

 is associate professor (Private Docent) at the Institute of Pharmaceutical Technology and Biopharmacy Martin-Luther-University Halle-Wittenberg, Germany.

5. M. Hariharan, T.A. Wheatley and J.C. Price, 

Articles

The tablet formation of six different carrageenans was analysed by 3D modelling, Heckel analysis, the pressure–time function and energy calculations. It was found that the fibres experienced plastic deformation, which was accompanied by a great deal of elasticity. Measurement of elastic recovery in dependence on maximum relative density and time showed that relaxation is completed a considerable amount of time after tabletting. Shrinking of the fibres occurred in parallel with elastic recovery as a result of the reorganization of the fibre structure. The tabletting behaviour of carrageenans makes them suitable for the soft tabletting of pressure sensitive materials.

Carrageenans: Analysis of Tablet Formation and Properties (Part II)

Carrageenans are natural polymers that have been successfully applied to different purposes in tabletting technology. They can be used as controlled release agents;

 they can reduce the inactivation of α-amylase during tabletting;

 and they can reduce the recrystallization of amorphous indomethacin during tabletting,

 Therefore, it is important to know the powder technological and tabletting properties in detail.  

Carrageenans are polysaccharides extracted from red algae

 and are similar to alginates (extracted from brown algae) and agar (extracted from red algae). The most important members used for extraction are 

, which originate from Ireland, Brittany, Denmark, the US and the Philippines. The carrageenans are named according to their origin, the Irish coastal village Carragheen, and have been used since 1945. In the 

 Chemically they are galactanes, which consist partially of anhydrogalactose, are substituted by sulfate groups (Figure 1) and are anionic. They were first isolated in 1953;

 and their structure was analysed in 1955.

 Three basic types exist: ι-, κ- and λ-carrageenans (Figure 1), which differ in their sulfate content. The sulfate content increases in the following order: κ-carrageenan (25–30%), ι-carrageenan (28–35%) and λ-carrageenan (32–39%). 

 Figure 1:  Chemical structure of carrageenans.			

For carrageenan production, the algae are washed and dried, and treated with alkali.

 The raw extract is cleaned, concentrated and the carrageenans are precipitated in alcohol. The raw carrageenan is produced by drying. Following this, the product is milled and by mixing fractions with different substitution or different potassium content, a range of commercially available types of carrageenan can be produced. Further particle size can vary.  

To study the process of tablet formation of the carrageenans, the physicochemical properties of these polymers are important. All types of carrageenan show a broad distribution of molecular weight between 100000 and 500000. The crystallinity of these polymers has not been studied until now. The glass transition temperature (Tg) was only determined for lyophilized products. It varies between –10 °C and –80 °C depending on the humidity.

3D modelling is a method that has been successfully applied to study the deformation properties of different materials during tabletting. The utility and validity of this technique has previously been documented.

 In particular, this technique is unique as it allows the simultaneous evaluation of the three most important tabletting process variables (normalized time, pressure and density). To these data a twisted plane is fitted, which is characterized by three parameters, d, e and ω. Time plasticity (d) describes the plastic deformation with respect to time. Increasing time plasticity indicates faster deformation during tabletting. Pressure plasticity (e) describes the relationship between density and pressure. Increasing pressure plasticity indicates greater deformation at lower pressures. The angle of torsion (ω) is a measure of the material's elasticity. With increasing ω, elasticity decreases. Using this method, brittle fracture, plastic deformation and elasticity can be clearly distinguished. 

The aim of this study was to analyse the powder technological and compaction properties completely for six types of carrageenan and to study the process of tablet formation and the properties of the final tablets in detail.  

The excipients used were ι-carrageenan Gelcarin GP-379 NF, Gel 379 (Lot # ZA 502); two κ-carrageenans which differ in their potassium content,

 Gelcarin GP-812 NF, Gel 812 (Lot # ZB 502) and Gelcarin GP-911 NF, Gel 911 (Lot # ZC 502); and two λ-carrageenans, Viscarin GP-109 NF, Vis 109 (Lot # ZH 712) and Viscarin GP-209 NF, Vis 209 (Lot # ZI 502). There was also one carrageenan containing both κ- and λ-carrageenans: Viscarin GP-328 NF, Vis 328 (Lot # ZJ 714). All carrageenans were obtained from FMC Corp., (Princeton, NJ, USA). For comparison MCC, Avicel PH 101 (Lot # 6911C) and Avicel PH 102 (Lot # 7808C, FMC Princeton NJ, USA]) were used. 			

All materials and tablets were equilibrated, produced and stored between 35% and 45% relative humidity (RH). Tabletting was performed in a special climate-controlled room, which was set to 23 ±1 °C and 45% ±2% RH. To study the influence of humidity the substances were equilibrated at 30, 45, 60 or 75 RH; the climate room was set to these conditions at 23 ±1 °C and humidity remained constant after tabletting.  			

Sorption isotherms (Figure 2) were recorded gravimetrically after equilibration over saturated salt solutions for 7 days in triplicate.

 The powder was equilibrated at a specific RH. After equilibration, the powder was weighed and transferred to the next higher RH for equilibration. This procedure started at 32% RH and was performed up to 90% RH. Then the powder was weighed and, after equilibration, moved to the next lower RH up to 0% RH (phosphorous pentoxide).

Figure 2: Sorption isotherms of six different carrageenans compared with MCC.						

The water content was determined by thermogravimetric analysis using TGA 209 (Netzsch Gerätebau GmbH, Germany) in triplicate. The powder was heated with 10 K min

 up to 150 °C and water loss was determined.  			

				Particle size distribution was determined by laser light diffractometry using a dry feeder (Sympatec Rodos 12 SR; Sympatec, Germany). The settings of the feeder were									

The mean volume particle size distribution was calculated and medium particle size determined. 

Both powder and tablets (upper surface and breaking surface) were analysed by scanning electron microscopy (SEM [JSM 6400; JEOL, Tokyo, Japan]) at an accelerating voltage of 5 keV depending on the sample. Previously, they were mounted onto a sample holder and coated with coal/gold/coal.  			

The apparent particle density of all materials was determined by Helium pycnometry (Accupyc 1330; Micromeritics, Norcross, GA, USA) in triplicate. The equilibrated materials were analysed to determine the apparent particle density of the materials containing some moisture (Tables 1 and 2). The method is described by Picker and Mielck.

Bulk and tap density were determined with two repetitions in a weighed 250 mL cylinder using a volumeter (Erweka GmbH, Germany). Determinations were performed according to the 

 was calculated using bulk and tap density (Equation 1 in Figure 3).

The Tg was determined using DSC 200 (Netzsch Gerätebau GmbH) and hermetically closed pans. All determinations were performed for the materials equilibrated at 45% RH. For Gel 911, analysis was also performed at 30% RH. Sample size varied between 5 and 10 mg. Heating rate was 40 K min

. Weak transitions can only be determined with a high heating rate.

 The temperature interval was set to –50 °C to 150 °C. The Tg was determined by calculating the temperature of the half step height during the first heating. To verify the results the maximum of the first derivative was also determined. 			

The crystallinities of the powders were compared using a Roentgen diffractometer (URD 63; Freiberger Präzisionsmechanik, Germany). The radiation was copper and a nickel filter was used. Bragg's angle was analysed between 3 and 50 2θ.  			

Tabletting was performed on an instrumented eccentric tabletting machine (EK0/DMS, No. 1.0083.92; Korsch GmbH, Germany) with 11 mm diameter flat faced punches (Ritter GmbH, Germany). Equal volumes of the substances based on apparent particle density were tabletted to different graded maximum relative densities (ρ 

) of the tablets (precision 0.001) between 0.70 and 0.90. The tablet height at maximum densification under load was held constant at 3 mm.  			

Displacement of the punch faces was measured using an inductive transducer (W20 TK; Hottinger Baldwin Messtechnik, Germany) and corrected for elastic deformation of the punches. The depth of filling was held constant at 13 mm. The production rate was 10 tablets/min. No lubricant was used. The amount of material necessary for each tablet with a given ρ 

 was calculated. The powder was manually filled into the die and one compaction cycle was performed.  

Ten single tablets were produced at each condition. Data acquisition was performed by a DMC-plus system (Hottinger Baldwin Messtechnik) and data were stored by BEAM-Software (AMS-Flöha, Germany). Force, time and displacement of the upper punch were recorded for each compaction cycle.  

For analysing tabletting data, only data >1 MPa were used. For five compaction cycles of each material, normalized time, pressure and 

The aim of this study was to analyse the process of tablet formation and the properties of the final tablets for six different carrageenans. The carrageenans used were based on the basic types of ?-, ?- and ?-carrageenan. Microcrystalline cellulose was used for comparison. Determination of material properties, compression analysis and tablet properties were described. Water content, particle size and morphology, glass transition temperature, and crystallinity were studied. The results show that the carrageenans are predominantly amorphous fibres, which are in the rubbery state during tabletting.