List of Tables. vi
List of Figures. vii
Abstract 1
Chapter 1: Introduction. 2
1.1 Background. 3
1.2 Rational of study. 5
1.3 Objectives of the study. 5
1.4 Research Flowchart 6
Chapter 2: Literature Review.. 8
2.1 PHARMACEUTICAL CAPSULES. 9
2.1.1 Pharmaceutical hard capsules. 10
2.1.2 Manufacture of gelatin capsules. 11
2.1.3 Properties of gelatin capsules. 15
2.1.4 Alternatives to Gelatin. 17
2.2. POLYSACCHARIDES STUDY.. 20
2.2.1 Starch. 20
2.2.1.1 Composition and primary structure of starch. 21
2.2.1.2 Morphology and ultra-structure of starch grains. 24
2.2.1.3 Semi-crystalline structure of starch grains. 27
2.2.1.4 Thermal transitions. 30
2.2.1.5 Starch modification. 35
2.2.1.6 Cassava. 41
2.2.2 Carrageenan. 53
2.2.2.1 Chemical Structure. 53
2.2.2.2 Conformation of κ-carrageenan. 54
2.2.2.3 Gelation of κ-carrageenan. 60
2.2.2.4 Thermoreversibility of gels and rheological properties. 61
2.3 POLYSACCHARIDE MIXTURES. 65
2.3.1 Phase Behavior 65
2.3.2 Thermodynamic Incompatibility. 66
2.3.3 Gels based on mixtures polysaccharides. 68
2.3.3.1 Rheological properties. 69
2.3.3.2 Rheology of blends of starch. 70
Chapter 3: Materials and Methods. 72
3.1 Materials. 73
3.1.1 Gelatin. 73
3.1.2 κ-carrageenan. 73
3.1.3 Acid hydrolyzed hydroxypropylated cassava starch. 73
3.2 Methods. 74
3.2.1 Preparation of solutions. 74
3.2.1.1 Gelatin solutions. 74
3.2.1.2 Starch and κ-carrageenan solutions. 74
3.2.2 Rheological properties. 77
3.2.2.1 Flow properties. 77
3.2.2.2 Viscoelastic properties. 78
Chapter 4: Results and Discussions. 79
4.1 Rheological behavior of gelatin. 80
4.1.1 Gelatin solution at 50 °C.. 80
4.1.2 Sol-gel transitions. 82
4.1.3 Viscoelastic properties of gelatin gels at 20 °C.. 86
4.2 Rheological behavior of starch-κ-carrageenan blends. 90
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4.2.1 Rheological behavior at 50 °C.. 90
4.2.1.1 Dually modified cassava starch (HHSS) 90
4.2.1.2 κ-carrageenan. 95
4.2.1.3 Dually modified cassava starch/κ-carrageenan blends. 96
4.2.2 Rheological behavior in sol-gel transitions (from 50 °C to 20 °C) 102
4.2.2.1 Influence of κ-carrageenan content 104
4.2.2.2 Influence of the different extents of starch hydrolysis. 106
4.2.3 Rheological properties of gels at 20 °C.. 107
4.2.3.1 κ-Carrageenan gels. 107
4.2.3.2 Composite gels. 108
Chapter 5: Discussion and Conclusion. 113
5.1 Synergy and gel state. 114
5.1.1 Dually modified cassava starch and κ-carrageenan. 114
5.1.2 Mixtures. 115
5.2 Comparison with gelatin. 120
5.2.1 Solution properties. 120
5.2.2 Jellification. 121
5.3 Conclusion and recommendation for future research. 123
References. 126
List of Tables
Table 2. 1: Properties and applications of modified starches. 35
Table 2. 2: Performance of starch slurry dewatering by a conventional centrifuge from a typical cassava starch factory. 51
Table 3.1: Compositions of the starch- κ-carrageenan solution. 76
Table 4.1: Changes in viscosity of gelatin as a function of concentration. Experiments were performed at 50 °C 81
Table 4.2: Gelation temperatures, TGEL and melting temperature TM (G’= G”) during cooling from 50 to 25 °C and heating from 25 to 50 °C. The rate of heating or cooling was 1°C/min. Frequency: 1 rad/s. Strain amplitude: 1%. 86
Table 4.3: Viscosity of κ-carrageenan in different concentrations. 95
Table 4. 4: Gelling temperatures (TGEL) and melting temperatures ™ of κ-carrageenan alone and the mixture HHSS12-κ-carrageenan determined from cooling and heating ramps at 1 °C/min and 1 rad/s. 104
Table 4.5: Storage and loss moduli G’ and G” of κ-carrageenan alone and HHSS12-κC0.5 mixture determined from temperature ramps during cooling and heating at 1 °C/min by rheological measurements. Frequency: 1 rad/s. 111
List of Figures
Figure 1.1: Research flowchart 7
Figure 2. 1: Formation of hard gelatin capsules by dip molding. 12
Figure 2. 2: Position fingers dipping during passage through the drying ovens. 13
Figure 2. 3: Steps removing (a) trimming (b), and assembly of capsules ©. 14
Figure 2. 4: Water content at equilibrium of pharmaceutical hard empty gelatin capsules in relationship with the mechanical behavior. The capsules are stored at different relative humidities for two weeks at 20 ° C. 16
Figure 2. 5: Isothermal sorption-desorption capsules hard gelatin and HPMC at equilibrium at 25°C. 19
Figure 2. 6: Test for fragility of the capsules: the percentage of broken capsules according to their water content. a: resistance to pressure with capsules filled with corn starch. b: impact resistance with empty capsules. 19
Figure 2. 7: Structure of amylose. 22
Figure 2. 8: Structure of amylopectin. 23
Figure 2. 9: Grains of different starches observed in scanning electron microscopy SEM (magnification × 280) 24
Figure 2. 10: The different levels of grain starch. 25
Figure 2. 11: Organization of starch grains in “blocklets”. 27
Figure 2. 12: X-ray diffraction diagram for crystalline starch type A, B and C. 28
Figure 2. 13: Crystallinity of potato starch: influence of water content on the resolution of the diffraction pattern of X-rays. 29
Figure 2. 14: Crystalline arrangement of double helices of amylose type A and B.. 30
Figure 2. 15: Variation of classical transitions of the potato starch as a function of water content 33
Figure 2. 16: Hydroxypropylation reaction. 38
Figure 2. 17: Mass balance of cassava starch manufacturing process in a starch factory with a decanter. 47
Figure 2. 18: Mass balance of cassava starch manufacturing process in a starch factory without a decanter. 48
Figure 2. 19: Starch granules trapped in discharged pulp of cassava starch process. 49
Figure 2. 17: Ideal repeating units of λ-carrageenan (a) (R = H or SO3–), and (b) for ι- carrageenan (R1 = R2 = SO3–) and κ- carrageenan (R1 = H ; R2 = SO3–). 54
Figure 2. 18: Percentage of order of κ-carrageenan solution by polarimetry (0) and conductivity measurements (D) 55
Figure 2. 19: Change in transition temperature Tm at cooling κ-carrageenan based on the total concentration of CT different monovalent cations (1) Rb+, (2) Cs+, (3) K+ ,(4) NH4+, (7) N(CH3)4+ (8) Na+, (9) Li+ and divalent cations (5-6) Ba2+, Ca2+, Sr2+, Mg2+, Zn2+, Co2+. 57
Figure 2. 20: Phase diagram of κ-carrageenan representing the variation of transition temperature on cooling and heating according to the total concentration of potassium (Rochas, 1982; Rochas & Rinaudo, 1980). 59
Figure 2. 21: κ -Carrageenan gelation model, cation to promote gelation. (Morris et al., 1980) 60
Figure 2. 22: Variations of G’ and G” as a function of temperature for a concentration of 1% κ-carrageenan, Frequency 1 Hz, Tg: temperature of gelation, Tm: melting temperature. Cooling G’ (■), G” (¨). Heating G’ (□), G” (◊). (Fernandes, Gonçalves & Doublier, 1992). 63
Figure 2. 23: Kinetics of evolution of κ-carrageenan at a concentration of 1%. Temperature is 25 ° C. Frequency 1Hz. G’ (■), G” (¨). 64
Figure 2. 24: Phase diagram at 25 °C mixture of waxy hydroxypropyl starch/κ-carrageenan. 67
Figure 3.1: Phase diagram of κ-carrageenan representing the variation of transition temperature on cooling and heating according to the total concentration of potassium.. 75
Figure 4.1: Newtonian behavior of gelatin at 50 °C and 20% concentration. 80
Figure 4.2: Mechanical spectrum of 25% gelatin solution. G’: filled symbols, G”: empty symbols. Experiments were performed at 50 °C, strain amplitude was 1%.. 82
Figure 4.3: Storage and loss moduli G¢, G² for a 25% gelatin sample during a cooling ramp. Temperature was ramped from 50 to 20 °C at 1°C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 84
Figure 4.4: Storage and loss moduli G¢, G² as a function of temperature during a heating ramp of a 25% gelatin sample. Temperature was ramped from 25 °C to 50 °C at 1 °C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 85
Figure 4.5: Mechanical spectrum of 25% gelatin. G’: filled symbols, G”: empty symbols. The temperature was 20 °C. Strain amplitude: 1%. 87
Figure 4.6: Changes in modulus G’ and G” as a function of time for a 27% gelatin gel. Measurement temperature was 20 ° C. Frequency: 1 rad / s. Strain amplitude: 1%. 88
Figure 4.7: Changes in G’ as function of gelatin concentration. Data obtained after 6 h of time sweep measurement at 20 °C. Frequency: 1 rad/s. Strain amplitude: 1%. 89
Figure 4.8: Flow curves of hydrolyzed hydroxypropylated cassava starch dispersions at a concentration of 25% (g/g): HHSS6 (●), HHSS12 (■), HHSS18 (o), HHSS24 (). Measurements were performed at 50 °C.. 91
Figure 4.9: Flow curves for dually modified cassava starch (HHSS12) dispersions at a concentration of 25% (g/g). Measurement was performed at 50 °C.. 92
Figure 4.10: Flow curves of dispersions of hydroxypropyl cassava starch HHSS12 at concentrations of 20% (■), 23% (●) and 25% (▲). Temperature was 50°C.. 93
Figure 4.11: Mechanical spectra of different dually modified cassava starches at concentrations of 25%: a) HHSS6, b) HHSS12, c) HHSS18, d) HHSS24. G’: filled symbols, G”: empty symbols. Measurement temperature was 50 °C and strain amplitude was 1%.. 94
Figure 4.12: Newtonian behavior of κ-carrageenan in the concentration range of 0.25% to 1% at 50 °C 96
Figure 4.13: Flow curves of the mixture HHSS12-κC0.5 (¨), 20%HHSS12 and 0.5% κ-carrageenan, κC0, 5 (×), and starch dispersions HHSS12 20% (□), 23% (○) and 25% (Δ). The temperature was 50 °C 97
Figure 4. 14: Flow curve of the HHSS12-κC0.5. Shear rate up 0 to 100 s-1 empty symbols, and down 100 to 0 s-1 filled symbols. 98
Figure 4.15: Flow curves of mixtures of 25% starch HHSS12 with κ-carrageenan at different concentrations. Measurements were taken at 50 °C.. 99
Figure 4.16: Flow curves for 0.5% κ-carrageenan and mixtures of 25% dually modified cassava starches/κC0.5. Measurement temperature was 50 °C. 100
Figure 4.17: Mechanical spectrum of κC0.5 (solid lines ■, □), HHSS12 (solid lines ●, ○), and the mixture κC0.5-HHSS12 (■, □). Concentration of HHSS12 alone was 25% and in combination total concentration was 25%. G’: filled symbols, G”: empty symbols. Measurement temperature: 50 ° C. Strain amplitude: 1%.. 101
Figure 4.18: Variation of viscoelastic modulus G’ and G” as a function of temperature for κC0.5 and for the mixture of κC0.5 and HHSS12. a) Cooling from 50 °C to 20 °C. b) Heating from 20 °C to 50 °C. Heating/cooling rate: 1 °C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 103
Figure 4.19: Variations of modulus G’ and G” as a function of temperature during cooling from 50 °C to 20 °C for 25% HHSS24 alone and in combination with κ-carrageenan. G”: filled symbols; G’: empty symbols. Cooling rate: 1 °C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 105
Figure 4.20: Variations of modulus G’ and G” as a function of temperature during cooling from 50 °C to 20 °C for 1% κ-carrageenan and 25% starch mixtures. G’: empty symbols; G”: filled symbols. Cooling rate: 1 °C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 106
Figure 4.21: Variations of modulus G’ and G” as a function of temperature during heating from 20 °C to 60 °C for 1% κ-carrageenan and 25% starch mixtures. G’: empty symbols; G”: filled symbols. Cooling rate: 1 °C/min. Frequency: 1 rad/s. Strain amplitude: 1%.. 107
Figure 4.22: Mechanical spectra of κC1 (■, □), κC0.75 (●, ○) and κC0.5 (▲, Δ). G’: filled symbols, G”: empty symbols. Temperature: 20 ° C. Strain amplitude: 1%. 108
Figure 4. 23: Mechanical spectrum of κC0.5 (●, ○), 25% HHSS12 (dashed line with ▲, Δ) and the mixture of κC0.5-HHSS12 (■, □) at 20°C. G’: filled symbols, G”: empty symbols. Strain amplitude: 0.1% for mixtures and 1% for constituents. 109
Figure 4.24: Mechanical spectrum of mixtures HHSS12-κC1(▲, Δ), HHSS12-κC0.5 (dashed line with ●, ○) and HHSS12-κC0.25 (■, □) at 20 °C. G’: filled symbols, G”: empty symbols. Strain amplitude: 0.1% 110
Abstract
With the goal of finding an alternative to gelatin in the processing of pharmaceutical capsules, the effects of k-carrageenans on dually modified cassava starch were investigated. While film forming and mechanical properties are important in all pharmaceutical capsules, solubility at high solid concentration and thermo-reversibility are important factors for hard capsule processing. Casava starches were modified first by hydrochloric acid (0.14 N for 6, 12, 18, and 24 h at 50 °C) and secondly by propylene oxide (10, 20, and 30% of solid for 24 h at 40°C).
To improve the gel setting property of the dually modified starch, dually modified cassava starches were combined with k-carrageenan (0.25, 0.5, 0.75, and, 1%). The concentration of the K+ ion in the composite mixture was adjusted appropriately to achieve the same sol-gel transition temperature. The rheological properties of the mixtures were measured and compared, with gelatin as the reference material. The solution viscosity, sol-gel transition, and mechanical properties of the films made from the mixtures at 50 °C were comparable to those of gelatin. The viscoelastic moduli (G’ and G”) for the gel mixtures were lower than those of gelatin. The composite gels had temperatures of gelation similar to that of gelatin. Both viscosity in solution and stiffness in gels could be adjusted using high levels of κ-carrageenan and was relatively independent of the molecular weight of the starch. These results illustrate that dually modified cassava starch in combination with k-carrageenan has properties similar to those of gelatin, thus these starches can be used in dip-molding processes, such as those used to make pharmaceutical hard capsules.
Chapter 1: Introduction
