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the system. Thus, the modification of the starch was designed so that it can dissolve at temperatures below 100 °C and form stable solutions (in terms of rheological properties and functionality) at high concentrations (20–30%).
1.3 Objectives of the study
The objectives of this study are:
1. Investigation on effects of carrageenan on dually modified cassava starch flow properties.
2. Investigation on effects of carrageenan on dually modified cassava starch sol-gel transition.
3. Investigation on effects of carrageenan on dually modified cassava starch gel properties.
1.4 Research Flowchart
This research was designed as the following research flowchart.
Figure 1.1: Research flowchart
CHAPTER 2: LITERATURE REVIEW
2.1 PHARMACEUTICAL CAPSULES
The capsules, also called caps (from the Latin word meaning capsulatus container), are solid preparations consisting of a hard or soft shell, shape and capacity variables, usually containing a unit dose of active ingredient. The contents of capsules can be solid, liquid or pasty. The soft capsules mean capsule consists of a single party whose shape can be cylindrical, spherical, ovoid, etc. It usually contains a plasticizer which gives the properties of flexibility where the adjective that means. The hard capsules are made up of two parts (head and body) of cylindrical shape with a diameter slightly different for their engagement. The hard capsules contain very little plasticizer which makes them rigid.
The first patent on the use of gelatin capsules for therapeutic use has been filed in 1834 by MM. J.G.A. Dublanc and fob Moths. Many attempts were undertaken to mask the unpleasant taste of certain drugs in vogue at that time (turpentine, Copaiba). The solution that met the most success was the invention of a cap based on a gelatin film containing the drug.
MM. Dublanc and Moths then develop a process for manufacturing capsule; which is to dip a brass cylindrical object in an aqueous solution of gelatin flavored and sweetened, then remove and place it vertically for drying. After evaporation of water, gelatin is in the form of a solid film covering the walls of the cylinder, forming a capsule. The capsules, which can be regarded as soft capsules are then filled and sealed with a drop of gelatin solution. Moths has only continued to work on improving the process of development and the use of gelatin capsules. The incredible success of his capsules in the following years led to their use worldwide. For more details, you can refer to a book on history of pharmaceutical capsules, their method of manufacture and their characteristic (Podczeck & Jones, 2004). We limit ourselves in the following sections describe the characteristics of pharmaceutical hard capsules, because main part of this thesis focused on hard capsules.
2.1.1 Pharmaceutical hard capsules
In the mid-nineteenth century, the remarkable growth of Mothes pharmaceutical soft capsules, leads the development of many alternative procedures. In 1846, slightly more than ten years after the invention of the first capsule-based gelatin, MJC Lehuby published a patent under the heading “My drug envelopes”. It is the first to suggest a capsule consisting of two parts which are produced by dipping the fingers of casting metal in a gelatin solution and then drying them. The capsules are cylindrical and consist of two half cylinder with a diameter slightly different for easy assembly. It is important to note that this process has been improved by the inventor over the years, was originally intended to produce hard capsules based on cassava starch, and then based on a mixture of carrageenan and gelatin then called lichen capsules. However, these formulations have been abandoned due to their fragility in comparison with gelatin.
Unlike the early success experienced by the Mothes soft gelatin capsules, development of hard capsules has been delayed by technical difficulties posed by the manufacture of the head and body of the capsule. It was not until the early twentieth century to emerge in the U.S. the first industrial production of hard capsules made from gelatin. From 1931, the Parke, Davis & Co., managed to develop a machine capable at the same time to produce the head and body of the capsule and assembling them. The production of hard capsules is still based on this process. Some minor changes have been made over the years, mainly to automate and optimize the various stages of production. The largest producers of pharmaceutical capsules are now Capsugel (USA) and Shionogi Qualicaps (Japan) companies.
2.1.2 Manufacture of gelatin capsules
The manufacturing process of a hard capsule uses a very old process that is casting by dipping. The parameters of molding capsules are based on characteristics specific to gelatin. Each step of the production of capsules should be carefully controlled to ensure continuous operation of production machines at very high speed. The materials used are gelatin, colorants, preservatives, and surfactants. The various stages of manufacture of hard capsules are placed in solution, casting by dipping also called dipping or dip-molding, drying, and assembly.
Dissolution. Gelatin powder form, is dissolved in deionized water at a concentration of 30-40% is then heated to about 60 °C. The mixture is homogenized under vacuum to limit the presence of air bubbles may be trapped in the viscous solution of gelatin and then create appearance defects on the capsule. At this temperature, the gelatin solution can undergo hydrolysis reactions over time, can significantly alter its physical properties such as viscosity in solution or gel strength. For this reason, the production cycle of the capsules must be planned and monitored rigorously. The gelatin is then transferred into tanks regulated to about 55 °C lower volume that will feed into each production line. In those tanks, additives such as dyes, preservatives, and surfactants will be added. Preliminary measurements of viscosity are generally made directly into the tank using a rotational viscometer. Both concentration and viscosity solution are very important parameters because it determines the thickness and mass of the capsule.
Capsule formation. The gelatin solution is placed in a tank with overflow at a temperature of about 55 °C. At this temperature, continuous evaporation takes place so requiring control the viscosity and readjusts if necessary. The concentration of the solution was kept between 25% and 30%. The container used is fitted in the center of a rectangular plate below which is a Archimedes screw. This device allows one hand to obtain a constant height of bath and, secondly, to homogenize the solution with a constant motion of the liquid. It also helps to filter the gelatin solution and thus eliminate any residues. The fingers of casting steel (coated with a thin layer of lubricant: soy lecithin based solution) with a temperature of about 25 °C, are dipped in a gelatin bath with a temperature of about 50-55 °C (Figure 2.1). The gelatin solution gelled instantly on the surface of the fingers. The fingers are then withdrawn slowly from the solution to ensure uniform thickness. The gel helps to set the gelatin over the finger. The viscosity of the solution determines the amount of material removed and then the final thickness of the capsule. Different velocity profiles fingers molding are also programmed to control the thickness. To avoid the formation of drops or streams of material formed during the ascent, fingers molding undergo several rotations to even thickness of material on the surface of the capsule. A gentle stream of cold air is then blown to permanently set the surface of gelatin film. The molding fingers have a diameter greater for the upper (head) which fits into the bottom of the capsule (body).
Figure 2. 1: Formation of hard gelatin capsules by dip molding
Drying of capsules. The gelatin films are formed successively in the past
drying tunnels, inside which the temperature and relative humidity (RH) are,
controlled very precisely (Figure 2-2). The temperature is between 22 and 28 ° C
relative humidity between 38% and 43% depending on the drying compartment. The
temperature cannot be too high because of the thermo reversibility gelatin gels.
Figure 2. 2: Position fingers dipping during passage through the drying ovens
The drying cycle takes about 30 to 40 minutes. The drying conditions are adjusted to
obtain a slow drying rate at the beginning of the cycle, then reaching a peak
mid-cycle and then decreasing at the end of the cycle. These velocity profiles are needed to
make uniform drying. Indeed, if the drying rate is too high, a “hard skin”
material can be formed on the surface so acts as the insulating film and inside the capsule that remains in gel form. When the capsules out of the drying tunnel, they are not totally
dried. They still contain a residual amount of water between 15% and 18%. (Standard water content at equilibrium is 13-16% under standard temperature and relative humidity: 25 °C, 60% RH). Water is an integral part of the capsules and plays a role of plasticizer.
The higher the water content leads the higher the ductility and flexibility of gelatin film. Instead, for low water contents (<10%), they become fragile and brittle. The capsules are then extracted from the furnace with a water content of 15-18% for them to resist mechanical steps of removing and trimming. Removing, trimming, assembly. The solid gelatin films are removed from the molds using metal jaws around the casting fingers, which allow release capsules molding fingers (Figure 2.3 (a)). The capsules formed are deliberately too long because thickness defects usually appear at the base of the head and body. A trimming step can remove the defective part and thus get a good capsule dimension (Figure 2.3 (b)). The scrap which represents 20% of the capsule mass will be reused later. Indeed, these pieces of film will be dissolved in order to be recycled in the production chain. The head and body of the capsule are then assembled and formed the capsule is stored at 25 ° C and 40% RH to complete the drying (Figure 2.3 (c)). a b c Figure 2. 3: Steps removing (a) trimming (b), and assembly of capsules (c). The castings fingers are then cleaned and lubricated to facilitate the stripping capsules are then transferred to the top of the chain of production for the next round. The produced capsules are controlled so that there is no default in appearance on the surface. Moreover, the dimensions of the capsules are very precisely controlled. The capsules are then sent to pharmaceutical companies that provide open capsules, their filling and final closure in filling machines operating at very high speed. Any default of appearance or wrong size may cause cycle arrest filling. The molding fingers allow current to obtain capsules which both parties have many improvements to forms (ribs, grooves, etc ...) to ensure strength and kept at optimum storage and filling. 2.1.3 Properties of gelatin capsules The hard gelatin capsules have water content between 13 and 16% (db). Depending on storage conditions, temperature and relative humidity, the water content can be significantly altered. The sorption/desorption isotherm of gelatin were been widely studied and show the influence of water activity on the water content of hard gelatin capsules (Sobral & Habitante, 2001). For moisture content below 10%, films based on gelatin become brittle. They are deformed and tear at water contents above 18%. The change in water content causes not only changes the physical properties of the capsules but also dimensional changes. For moisture contents between 13 and 16%, a 1% change in water content causes a dimensional change of 0.5%. The relationship between relative humidity during storage, moisture, and mechanical properties of hard gelatin capsules has been established and is shown in Figure 2.4 (Bond, Lees & Packington, 1970). For optimum performance, the capsules should be stored in conditions of relative humidity between 35% and 55%. Conventional methods to assess the fragility of the capsules are based on measurements of impact resistance. The capsules can withstand the impact or rupture thereby defines a criterion of fragility based on storage conditions. However this method empirical remains limited to determine accurately the influence of formulation on rigidity of the capsule. Compression and bending measurements on the capsules were also been conducted to determine the mechanical properties of the capsules (Kuentz & Röthlisberger, 2002; Missaghi & Fassihi, 2006). These studies showed that the rigidity of gelatin capsules is changed over time, depending on the moisture and also according to the excipient. Measurements of traction are also relevant to evaluate the mechanical properties of films based on gelatin. 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(Bond, Lees & Packington, 1970). An important feature of gelatin which explains its use in pharmaceutical capsules since their invention is its ability to dissolve in aqueous media at a temperature close to that of the human body. The study of disintegration of the capsules and their solubility in different biological environments recreating gastric conditions has been the subject of numerous studies (Podczeck & Jones, 2004). The gelatin capsules are insoluble at temperatures below 30 ° C. Microscopic techniques allowed to observe the rupture of the capsules and also view heterogeneities on the thick wall of the capsule. It has been shown in a solution 0.1M HCl as the capsule begins to wrinkle after 40s submersion. Finally, by scanning electron microscopy (SEM), dissemination of biological environment within the wall of the capsule could be visualized. After only 30 s, 75% of the surface of the capsule was achieved. 2.1.4 Alternatives to Gelatin Gelatin is widely used, particularly in the pharmaceutical industry and to be the material most suitable for the manufacture of capsules. It is soluble in water at high levels around 60 °C, it forms gels with cooling temperature at temperatures close to room temperature, it offers excellent film-forming qualities and it dissolves easily at a temperature close human body. Fish gelatin capsules have been marketed recently by some manufacturers (of Roxlor AquaCap ®, OceanCapsTM Capsugel). The gelatin is produced from the skin of certain species of fish in warm water with a proline and hydroxyproline composition (amino acids play an important role in gelation) similar to mammalian gelatin. These capsules have equivalent chemical and physical properties to mammalian gelatin, facilitating their implementation in standard machines. However the cost of these capsules is high. The hydroxypropyl methylcellulose (HPMC) or hypromellose is modified cellulose polysaccharide-based which has been very popular when marketed as vegetarian capsule in the field of herbal medicine. The first hypromellose capsules, for the American market to satisfy consumer demand vegetarians have been marketed by the company A. P. Scherer West Inc. (GS Technologies Inc., 1998; (Grosswald, Andrew & Anderson, 2002; Inc, 1998). However, as the material offered in the mechanical properties lower than those of gelatin, the HPMC based capsules (Vegicaps ®) were twice thick. Shionogi Qualicaps Japan Society has made a point of HPMC capsules in which carrageenan as a gelling agent is added in small quantities, (Yamamoto, Matsuura & Kazukiyo, 1998). These capsules (Quali-V®) have properties similar to gelatin. They have same size and fit into the filling machines used for gelatin capsules. Subsequently, many companies have also developed cellulose-based capsules: Capsugel Division of Pfizer Inc. (Vcaps ® capsules) Natural Capsules Ltd.(Cellulose capsules). The HPMC capsules offer film-forming properties comparable to those of gelatin. In addition, under identical storage conditions, the water content of HPMC (2-5%) is much lower than that of gelatin (13-15%) (Figure 2.5) This allows using these capsules to contain hygroscopic substances. Moreover, the capsules retain their properties despite low water content (Figure 2.6). Figure 2. 5: Isothermal sorption-desorption capsules hard gelatin and HPMC at equilibrium at 25°C(Nagata, 2002). 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 (Nagata, 2002). The main disadvantage of HPMC capsules is their high cost compared to that of gelatin. This material also has the disadvantage of having a taste and odor. In recent years the growing number of patents dealing with substitutes gelatin for the manufacture of pharmaceutical hard capsules, including pullulan (Robert, Cadé, Xiongwei & Cole, 2005) and hydroxypropyl starch, shows how research in this area remain active (Basquin, Darasse, Despre & Messager, 2003; Paris & Viau, 2001). Recently, new capsule containing pullulan (NPCAP ®) have been marketed by the company Capsugel Division of Pfizer Inc(Robert, Cadé, Xiongwei & Cole, 2005). Capsules of starch were manufactured by injection molding (Wittwer, Tomka, Bodenmann, Raible & Gillow, 1998). These capsules had a significant thickness and a different shape compared with capsules containing gelatin and require the use of specific equipment for filling. The manufacture of hydroxypropyl starch capsules has also been described (Christen & Cheng, 1977). Unfortunately, due to the absence of gelation of these solutions of starch, the soaking time is relatively long (20 s compared to 1 to 2 s for gelatin), hindering the marketing of such capsules. Currently, despite the large number of patents on starch, no commercial exploitation is done. 2.2. POLYSACCHARIDES STUDY 2.2.1 Starch Starch is a polysaccharide of plant origin. This is the main carbohydrate reserve substance of most plants. It represents a significant mass fraction of agricultural commodities. It is found in the storage organs of plants such as cereals (30-80% dry matter), tubers (60-90%), and legumes (25-50%). Starch is the main source of energy for food and feed. It is a nutritional compound abundant, renewable, inexpensive, which is in foods multiple functions as a thickener, gelling agent, binder, sweeteners. Starch is also used in many non-food industrial: paper production, pharmaceuticals, cosmetics, textiles, etc. It has also become in recent years an interesting raw material for renewable plastics production and biodegradable and poses as a potential candidate for the manufacture of biofuels. 2.2.1.1 Composition and primary structure of starch Characteristics of composition, morphology and ultra structure depending on the botanical origin of starch have been many literature reviews (Banks & Greenwood, 1975; Buléon, Bizot, Delage & Multno, 1982; Zobel, 1988). Starch is a polymer of glucose C6H10O5, consisting of two homopolymers of different primary structures: amylose, macromolecule almost linear, and amylopectin, heavily branched macromolecule. The amylose content varies according to the botanical origin of starch. It varies between 0% (waxy maize starch or waxy) and 70-80% (wrinkled pea starch and high amylose maize). These extreme values are obtained for the mutated genotypes, whereas the amylose content of wild species such as potato, wheat, smooth pea is between 18 and 35%. Starch consist entities granular semi-crystalline result of an organization of its two constituents. The starch also contains small amounts of non-carbohydrate constituents representing 0.1 to 2% according to botanical origin. These are mainly minor components of lipids, proteins and minerals located both on the surface of starch grains and inside. 2.2.1.1.1 Amylose Amylose is a linear polymer composed of D-glucose units linked by bonds of type α (1,4) (Figure 2.7). The native amylose contains 500 to 6000 glucose units according to botanical origin, divided into several channels including the average degree of polymerization is about 500, corresponding to a average molecular weight Mw between 105 to 106 g/mol(Banks & Greenwood, 1975). Some chains can be branched amylose bonds by α (1,6) (Banks & Greenwood, 1975). However the number of these bonds is low and they seem to be frequently located near the reducing end (Takeda, Hizukuri, Takeda & Suzuki, 1987). Figure 2. 7: Structure of amylose(Carvalho, 2008) Amylose has the specificity of complex power hydrophobic molecules such as iodine, fatty acids, alcohols etc. Its conformation and binding mode enables it to adopt helical forms comprising 6 glucose units per turn, stabilized by intramolecular hydrogen bonds. The hydrophilic groups are directed outwards and the hydrophobic groups inward, forming a hydrophobic cavity which will be accommodated molecules complexed. The binding capacity of iodine is 20 mg to 100 mg of amylose is characterized by maximum wave length absorption (λmax) between 620 and 640 nm. Amylose can be extracted from starch granules dispersed in water by complexation with some alcohols (eg. butanol) (Schoch, 1945). Amylose can also be synthesized in vitro by enzymatic (Ball, van de Wal & Visser, 1998; Pfannemüller, 1987; Potocki-Veronese et al., 2005). 2.2.1.1.2 Amylopectin Unlike the linear chain amylose, amylopectin is a highly branched polymer consisting of hundreds of short chains of glucose units linked together mainly by connections α (1,4) and by 5 to 6% bonds α (1 , 6) responsible ramifications (Figure 2.8). Figure 2. 8: Structure of amylopectin(Carvalho, 2008) Amylopectin is the main constituent of most starches. The first structural models of amylopectin proposed a homogeneous organization ramifications, but it was later determined that amylopectin consisted of a set of clusters of short channels (S chains or A chain) DPW 15-20, linked by longer chains of DPW (L chains or B chain) 40-45 (Robin, Mercier, Charbonniere & Guilbot, 1974). This model was then completed with the presence of chains of DPW> 60 (C strings) bearing the single reducing end on which are grafted B chains (Burchard & Thurn, 1985) . The structural differences, related to the botanical origin, focus on the report of long chains L on short chain S, which would be

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