Modification of Starch

#### **Chapter 1**

## Chemically Modified Starches as Excipients in Pharmaceutical Dosage Forms

*Oladapo Adewale Adetunji*

#### **Abstract**

Excipients play a great role in ensuring that pharmaceutical dosage form meets the required specifications of quality approved by the relevant authorities. Starches are the most widely used excipients in dosage form development, but their use is enhanced by several modification methods (such as chemical degradation, physical alteration, enzymatic modifications or crystalline-genetic transformation), all aimed at restructuring the starch granules, thus ensuring that the reactive polymers are accessible to reactants. Chemical modification of starch usually follows the pathway of substitution, degradation or cross-linking. The most common approaches to chemical modification of starches for pharmaceutical use include oxidation, esterification and etherification, which are employed to optimize the structural and nutritional properties for targeted applications. The oxidant type, botanical origin of starch, and process conditions are all determinants of how effective the oxidation is. Esterification improves the hydrophobicity of starch usually via acetylation and phosphorylation, while etherification is a derivatization technique that involves the use of various alkylation agents such as dimethyl sulphate, diethyl sulphate, alkylene oxides (epoxides) and alkyl halides. Chemically modified starch enhances thermoplasticity, solubility and flow properties. In conclusion, chemically modified starches have shown excellent potentials and are, thus, incorporated as core excipients in several pharmaceutical drug formulations.

**Keywords:** excipients, modified starches, chemical modification, formulations, polymers

#### **1. Introduction**

The goal of an ideal oral solid-dosage drug delivery system is to achieve a situation where the desired therapeutic effect is obtained in conformity with official standards. Excipients play a great role in ensuring that the dosage form meets the required specifications of quality by modifying the release, absorption, distribution and elimination profiles of the drug. This assures product efficacy, safety, patient compliance and acceptance. Compressed tablets still account for the most widely used oral solid dosage form due to their compactness, precision of doses and ease of administration and production. The process of tableting requires that all the ingredients are fairly dried, powdered (or granulated) to form uniform particle sizes, with good content uniformity to ensure delivery of the right dose of the active

#### *Chemical Properties of Starch*

pharmaceutical ingredient. Excipients form a larger bulk of the constituent of tablets and the presence of the excipients ensures, amongst other goals, that acceptable physical and mechanical properties of tablets are achieved.

Based on their primary functions, excipients are classified into two categories as follows:


Ideally, pharmaceutical excipients are expected to be non-toxic, physically and chemically stable, commercially available, pleasant organoleptic properties and economically feasible [1].

This chapter will discuss the different chemical modifications of starch and give documented examples of starches that have been modified and used as excipients in pharmaceutical dosage forms.

#### **2. Starch**

Starch is one of the most abundant organic chemicals on earth and it is synthesized in the amyloplasts of seeds, grain, roots and tubers of many plants where it serves as the chemical storage form of energy from the sun [2]. It is a carbohydrate consisting of a large number of glucose units joined by glycosidic bonds. It is the most common carbohydrate in the human diet and is contained in large amounts in such staple foods as potatoes, wheat, maize (corn), rice, and cassava [3]. Pure starch is a white, tasteless and odourless powder that is, insoluble in cold water or alcohol. It consists of two types of molecules: the linear helical amylose and the branched amylopectin. Depending on the plant, starch generally contains 20–25% amylose and 75–80% amylopectin by weight [4]. The amylose portion is a macromolecule that is, linear in nature, while the amylopectin is the highly branched portion of the starch. Glycogen, the glucose store of animals, is a more branched version of amylopectin.

Starch is the most commonly used excipient in the pharmaceutical industry and this wide application is premised on its availability, low cost, high caloric value, inherent excellent physicochemical properties and the ease of its modification to other derivatives. The versatility of starch in industrial applications is clearly defined by its physicochemical properties; therefore a thorough evaluation of the necessary parameter is important in elucidating its industrial use. The morphology and physicochemical characteristics of starch are typical of its biological origin; hence starch from each plant source will vary somewhat in appearance, composition and properties [2].

The preclusion of the application of starch in its native form in the pharmaceutical industry is based on certain setbacks that have necessitated the need to modify starches to achieve the objective of the formulation scientist in ensuring the production of standard tablets, thereby circumventing the limitations inherent in the use of native starch as pharmaceutical ingredients. Such setbacks that have been linked to the unfavourable properties of native starch include poor solubility, poor flow properties and high hydrophilicity.

Starch has been extensively modified to stabilize the granules during processing. This involves restructuring the starch granules and dispersion of the amylopectin

#### *Chemically Modified Starches as Excipients in Pharmaceutical Dosage Forms DOI: http://dx.doi.org/10.5772/intechopen.88210*

polymers within the granules, thus ensuring that the reactive polymers are accessible to the reactants. Consequently, the profile of starch (after modification) is enhanced as an excipient in the drug manufacturing industry. Starch can be modified through chemical degradation, physical alteration, enzymatic modifications or genetic transformation.

#### **3. Degradation of starch**

Starch degradation proceeds under basic conditions and the extent of degradation depends on the several factors such as the presence or absence of oxygen, concentration of the base used, duration of the reaction and the temperature at which it occurs. Matsunaga and Seib reported the liberation of the proteins and lipids present in wheat starch when exposed to 0.4%w/w dilute aqueous alkali solution at 25°C. It was documented that the process of degradation was slowed down by the presence of hydroxyl ions [5]. In the presence of oxygen, starch degradation is a slow process that has a direct relationship with the concentration of alkali. However, it is not all parts of starch that undergoes degradation when exposed to alkali conditions. Those parts that are alkali resistant to degradation are sensitive to the presence of acids, thus suggesting that starch has selective degradation, depending on the chemical used.

The reducing end of the macromolecular chain of starch has been suggested to be the point where starch degradation progresses from; hence, the reducing-terminal glucose units, even in branched structures, are split off, indicating that, not only amylose but also amylopectin is alkali labile [6].

Starch can be degraded by pregelatinization. Gelatinization involves the disruption of the crystalline and granular structures of starch when heat and water are applied. The presence of excess water (not less than 90%w/w) causes the starch granules to swell due to preferential solubility of the amylose molecules in water. When heat is applied and the gelatinization temperature is exceeded, the crystalline region of the starch becomes irreversibly disoriented, eventually leading to lattice disruption. Alabi et al. pregelatinized millet, sorghum and cocoyam starches and the process resulted in better flowability and compressibility than the natural starches. Tramadol tablets prepared with freeze-dried pregelatinized starches generally exhibited higher crushing strength but lower friability than those prepared with the natural starches [7].

#### **4. Chemical modification of starch in drug formulations**

The biodegradable nature of starch, presence of certain functional groups and the granular structure (macroscopic) have contributed significantly to the chemical modifications that starch is susceptible to. Moreover, the presence and location of hydroxyl groups at C2, C3 and C6 increases this susceptibility to substitution reactions [8]. **Figure 1** shows a representation of the different methods of chemical modifications of starch in the pharmaceutical industry.

Chemical modification of starch usually follows the pathway of substitution, degradation or cross-linking, and these methods are employed to optimize the structural and nutritional properties for targeted applications. Enhancement of the thermoplasticity of starch is achieved by chemical modification of starch, thus causing a disorientation of the hydrogen bonds between the hydroxyl groups of the native starch, and disruption of the crystalline nature. Subsequently, the starch is becomes *more fluid* and the temperature at which it melts become lowered.

**Figure 1.** *Methods of chemical modification of starch.*

Moreover, the reduction in the number of hydroxyl groups due to the chemical modification increases the hydrophobicity of the starch. The most common approaches to chemical modification of starches for pharmaceutical use include oxidation, hydrolysis, esterification and etherification. However, several approaches that involve a combination of the aforementioned chemical modification methods are also applicable.

Starches can be chemically modified following different pathways:


Generally, the biodegradable nature of starch due to its macroscopic granular structure and presence of several functional groups makes it easily susceptible to modification. The glucose residues of starch are responsible for its chemical reactivity, and as mentioned earlier, the presence of the hydroxyl on the amylose and amylopectin are prone to the oxidation, reduction and hydrogen bond formation that starch undergoes in the process of chemical modification. The occurrence of large-sized grains in the granular structure exposes starch to external factors, thereby enhancing modification. The penetrating ability of the chemical involved in the modification process, into the starch granular surface or the interior also influences the chemical modification of starch.

#### **5. Starch modification by oxidation**

Starch modification by oxidation, which is one of the most common modification methods, involves oxidation of primary or secondary hydroxyl groups of the glucose units with formation of aldehyde or carboxyl groups. The oxidized starch has better water solubility and lower viscosity tendency in comparison to the native one [9]. The type of oxidant used, the botanical origin of starch, and the process conditions are all determinants of how effective the oxidation is. Moreover, the oxidation reaction may cause loosening of intermolecular bonds and/or partial depolymerization of the polymer chains [10]. It is worthy of mention that not all methods of oxidation are applicable for use in the pharmaceutical industry. Aerobic oxidation methods are not applicable for use in the pharmaceutical industry, simply due to the unique category of reactions that simply cannot be performed in batches as applicable in most starch oxidation techniques.

Oxidation with hydrogen peroxide appears very promising, especially because of the production of non-toxic residues such as water. However, a limitation of the use of hydrogen peroxide is its low reactivity towards most organic functional groups and the fact that in the presence of the compounds with electrophilic character it behaves as a nucleophile, not exhibiting oxidizing properties [11]. This limitation of hydrogen peroxide can be improved by the use of metal ions as catalysts, subsequently leading to heavy metal contamination of the modified starch.

Oxidation of starch with sodium hypochlorite involves the oxidation of the primary hydroxyl groups to either aldehyde or carboxyl groups. High concentration of the oxidant in an acidic medium has a direct relationship with the progression of oxidation as more of starch is oxidized in the aforementioned conditions. The modification of the hydroxyl group is affected by the protein content of the starting material considering the fact that any reaction on the starch is preceded by oxidation of the proteins. The starch oxidized by sodium hypochlorite is characterized by higher resistance to amylase activity and better stability at higher temperature and is capable of complexing calcium ions while exhibiting the polyelectrolyte properties [8]. Chemical oxidation of starch can also be carried out using sodium periodate. The bonds of the carbon atoms on the second and third positions are cleaved and dialdehyde groups are formed within the starch structure.

Garrido et al. successfully demonstrated the increase in the crystallinity, better water solubility and lower viscosity of cassava starch when modified by oxidation using sodium hypochlorite [12].

#### **6. Starch modification by esterification**

The hydrophobicity of starch is improved by the process of esterification, subsequently leading to improved thermoplasticity of the starch. Starch forms esters with reagents (organic and inorganic acids, and their derivatives such as chlorides, oxychlorides and acid anhydrides) due to the presence of the hydroxyl groups on each glucose residue, been converted to hydrophobic ester groups.

#### **6.1 Esterification by acetylation**

This is carried out with the aid of acetic acid or acetic anhydride. The esterification can be carried out in the presence of acetic acid as an activator or with acetic anhydride in the presence of sodium hydroxide as the activator [13]. A high degree of substitution was obtained when potassium carbonate was applied as the activator in the reaction of starch with acetic anhydride [14]. Starch acetates have been

used extensively in the pharmaceutical industry as binders. In 2011, Singh and Nath demonstrated the potential of acetylated moth bean starch as a carrier for controlled drug delivery of lamivudine tablets [15]. On a micro scale, starches can be acetylated without the presence of a catalyst. The process involves heating the native starch with acetic acid at a temperature between 179 and 181°C for a period of 2–4 min, resulting in a homogenous mixture. Tuovinen et al. documented the potential of natural sensitive starch acetate as an excipient in the retinal delivery of calcein; the *in-vivo* studies revealed that starch acetate nanoparticles, when compared with native starch, were taken up faster by reticuloendothelial cells without significant toxicity [16]. Akin-Ajani et al. also demonstrated the increase in crushing strength and disintegration time but lower friability of acid modified white fonio (*Digitaria exilis*) and sweet potatoe (*Ipomea batatas*) starches when incorporated as exo-disintegrants in paracetamol tablet formulations [17].

#### **6.2 Esterification by phosphorylation**

Phosphorylation of starch enhances the rheological and pasting properties of starch, which improves the flowability of starch when used in tablet formulation as documented by Adetunji and Kolawole [18]. This is as a result of addition of phosphate groups to the C6 position of the glucose residue [19].

Starch phosphate esters containing magnesium, calcium, or aluminum ions are used extensively as disintegrants in the pharmaceutical industry. Monostarch phosphate is obtained by treating starch with potassium or sodium phosphates, while distarch phosphates can be obtained by treating starch with phosphorus oxychloride or sodium trimetaphosphate. The degree of cross-linking of phosphorylated starch determines the swelling ability of the modified starch. At a low degree of cross-linking, starch has high swelling ability but with increasing degree of crosslinking; swelling ability in water decreases, until complete loss of this ability [20].

Zuo et al. documented the use of maleic anhydride in the esterification of corn starch. The esterification led to roughness on the surface of the starch particle with a subsequent increase in particles size. Crystal lattice destruction of the starch during the maleic anhydride esterification also led to improved thermoplasticity and reduction in gelatinization temperature [21]. Phosphorylated starch yielded a better result than native starch when Prosanthi and Rama incorporated it a disintegrant in Ziprasidone tablet formulations [22], while starches from various botanical sources with different amylose contents (way corn, common corn, Hylon V, Hylon VII and potatoe) were phosphorylated at pH 9.0 and 11.0 using reactive extrusion method prior to their use in the formulation of sustained release metoprolol tartrate tablets; these phosphorylated starches produced stronger hydrogels than the corresponding native starch [23]. Chowdary et al. used phosphorylated potatoe starch prepared by the reaction of the native starch with di-sodium hydrogen orthophosphate anhydrous at elevated temperatures as a carrier in solid dispersions for enhancing the dissolution rate of aceclofenac; better results were achieved from the formulations containing the phosphorylated starches [24].

#### **7. Starch modification by etherification**

Etherification of starch is a derivatization technique that involves the use of various alkylation agents such as dimethyl sulphate, diethyl sulphate, alkylene oxides (epoxides) and alkyl halides. The use of diethyl (or dimethyl) sulphates in starch etherification was documented to have taken place in dimethyl sulfoxide with the addition of aqueous sodium chloride [25]. Starch ethers with branched chains are usually produced through reactions with alkyl halides.

*Chemically Modified Starches as Excipients in Pharmaceutical Dosage Forms DOI: http://dx.doi.org/10.5772/intechopen.88210*

The use of epoxides in starch etherification can proceed in the absence of sodium hydroxide. According to Cui, the high reactivity of the asymmetrical epoxide group is due to the highly strained three-membered ring with bond angles of 60° [25]. Etherification of macrogranular starch (containing ≤10%w/w moisture) by pressurized hot air can also be carried out using ethylene oxide [26].

Starch etherification involving the introduction of ammonium, amino or imino group yields important industrial derivatives. The use of different amino-alkyl agents, such as 2-diethylaminoethyl chloride, 2,3-(epoxypropyl), trimethylammonuim chloride, (4-chlorobutene-2)-trimethylammonium chloride, etc., in etherification is a major way of producing cationic starches with enhanced gelatinization behavior, pasting properties and solubility [6].

Carboxymethylated starches are derivatives of etherification of starch that are formed when hydrogen atoms are replaced by carboxymethyl functional groups. Carboxymethylated starches have been documented to show low gelatinization temperature and swelling properties and, solubility in cold water than most interesting native starches [27]. Synthesis of carboxymethyled starch involves initial activation of the native starch with aqueous sodium hydroxide in an organic slurry, followed by the reaction with monochloroacetic acid or its sodium salt. The tablet film-coating potential of carboxymethylated mungbean starch was reported by Kittipongpatana et al. as due to the formation of clear, thin film with greater flexibility and strength than that of the native starch [28]. Drug release was better sustained when high amylose sodium carboxymethylated starch matrices were used in the formulation of oral acetaminophen tablets [29].

#### **8. Conclusion**

The modification of starch using different approaches such as oxidation, esterification and esterification is well documented in literature. While small scale researches have substantiated the usefulness of modified starches as excellent excipients in the manufacture of different dosage forms due to enhancement of characters such as flow properties of starch, favorable particle size, robust crystallinity etc., it is pertinent to develop more methods of chemically modifying starch that can be scaled-up in the pharmaceutical industry to increase the options that drug formulation scientists can exploit when choosing excipients for drug dosage form designs.

#### **Author details**

Oladapo Adewale Adetunji Department of Pharmaceutics and Industrial Pharmacy and Centre for Drug Discovery, Development and Production, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria

\*Address all correspondence to: adetunjioladapo@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### Chapter 2

## Physical and Chemical Modifications in Starch Structure and Reactivity

Haq Nawaz, Rashem Waheed, Mubashir Nawaz and Dure Shahwar

#### Abstract

Starch is a naturally occurring glucose homo-polysaccharide of nutritional, pharmaceutical, and industrial importance. The complex polymeric structure and poor solubility of native starch in water limits their importance at pharmaceutical and industrial level. The structure, reactivity, and functionality of the native starch can be modified by physical, chemical, enzymatic, and biotechnological methods. Various physical modifications techniques, including the thermal, radio-thermal, freezing and thawing, annealing, high-pressure, ultrasonic, and pulsed electric field treatment, and chemical modifications, including oxidation, etherification, esterification, cationization, cross-linking, and graft polymerization, have been found to change the surface properties, polarity and linearity of the molecular chains, the degree of substitution, the polymeric, granular, and crystalline structure, amylose to amylopectin ratio, solubility, viscosity, pasting, gelatinization, swelling, water absorption, and emulsifying properties of starch. The structural changes have resulted in the improvement of thermal and freeze-thaw stability, viscosity, solubility, water binding capacity, swelling power, gelling ability, and enzymatic digestibility of starch. The exposure of reactive functional groups after physical or chemical modification modifies the reactivity of starch toward water, oil, acids, enzymes, and other chemical species. These modification techniques have led to some revolutionary changes in reactivity, functionality, and application of starch in various fields.

Keywords: starch structure, starch reactivity, functional properties, chemical modifications, physical modification

#### 1. Introduction

Starch is the most important polysaccharide as well as storage polymer of plants abundantly found in leaves, stem, fruit, seed, tubers, and roots of various plants. Starch is produced in chloroplast and amyloplast of plant cells by photosynthesis, stored as a source of food and energy. It is stored in plant cell during tubers sprouting, germination of seeds and fruit maturation [1, 2]. Major sources of starch included cereals grains such as wheat, barley, rice and corn, the seeds of the legumes such as beans, garden peas, chickpeas, and pulses, the

tubers such as potato, sweet potato, ginger, turmeric and groundnut and immature fruits and vegetables [3–5].

Starch has great nutritional, pharmaceutical and industrial significance due to its unique physical, chemical and functional and nutritional properties. Starch is a good source of nutrition as it is hydrolyzed into glucose on digestion by α-amylase. The metabolic oxidation of glucose provides instant energy which is utilized in various metabolic and other cellular activities [6–8]. Due to the higher concentration of amylose, starch is used as an excipient to activate drugs and act as an encapsulating agent facilitating the deliver the drug to its target organ [9–11]. As a natural polymer, starch is used to replace plastic in the coating of food materials and production edible films in the food industry. It is usually mixed with food components to protect them from mechanical damage, to extend their half-life and to improve their appearance. It is also used as a recyclable component for molds production in the food industry. It is added as a bulking agent in food and pharmaceutical formulations to enhance handling and stability as well as preservation of components texture and to enhance their viscosity [12–14]. Moreover, due to water-resistant nature of amylose, it can form excellent films due to which it has great importance at industrial level [15].

#### 1.1 Starch structure and composition

Chemically starch is a homopolymer of α-Glucopyranose units with the chemical formula (C6H10O5)n. Starch is composed of two types of polymer chains known as amylose and amylopectin. Amylose possesses a linear structure with α1–4 glycosidic linkage while amylopectin possesses a branched structure with α1–4 as well as α1–6 glycosidic linkages (Figure 1) [16, 17]. Normally, starch consists of relatively lower amount of amylose (20–30%) than that of amylopectin (70–80%). The ratio of amylose and amylopectin affects the starch structure in terms of crystallinity, size of the granules and chemical nature and arrangement of polymers within the granule. The studies have shown that the fine structure of amylopectin plays an important role in the functionality of starch. It is the relative concentration of amylose and amylopectin which determines the physical and functional properties of starch. The starches containing low amylopectin have been found to show the quick onset of gelation as compared to low amylose starches. The starches containing relatively high amylose content have been found to form comparatively hard and rigid gels and strong films while high amylopectin starches are dispersed easily in water and form soft gels and weak films [15, 18–21]. The amylose to amylopectin ratio also influences the nutritional quality of starch that is assessed by its rate of digestion and glycemic index (GI) as an indicator to check the quality of carbohydrates [22].

#### 1.2 Functional properties of starch

Based on its compact structure, starch possesses diverse functional properties and applications in biomedical and industrial fields. Due to polymeric and branching nature starch shows relatively less solubility in water and possesses relatively lower ability to absorb water and oil. Starch shows good iodine-binding ability. It also possesses a relatively high viscosity and good swelling power and gelatinization abilities. It also shows good pasting properties with consistency, smoothness, and clarity and can form thin films. Starch shows freeze–thaw and cold storage stabilities which make it a favorable candidate for various food and industrial formulations. Starch is resistant to moderate temperature and pressure but

Figure 1. Structure of amylose and amylopectin in starch.

susceptible to acid and enzyme-catalyzed hydrolysis. However, the native starches show relatively lower values of enzymatic digestibility [18, 23–26]. To increase its nutritional, biomedical and industrial importance, the functional properties of starch can be improved under the influence of various physical and chemical factors.

#### 1.3 Factors affecting the structure and properties of starch

The native starches possess a complex granular and crystalline structures which differ in size in various plants [2, 16]. Several factors have been reported which affect the structural, physical, chemical, and functional properties of starch. Starch is sensitive to very high and very low pH, high temperature, high pressure, and osmotic pressure, light, radiation, mechanical stress, and ultrasound waves. Heating treatment of starch in aqueous medium has been found to cause transition of amorphous form to crystalline starch resulting in gelatinization of starch. The treatment with microwave radiation has been found to affect the crystalline structure and functional properties of starch which is linked with the loss of birefringence and crystallinity due to deformation during modification [27–36]. Interaction of starch with water and oil also affects the properties of starch. The absorption of water results in the breakdown of amylose-amylopectin linkages, loss of

crystallinity and swelling of starch granules. The swelling of starch granules is reversible at the initial stage but irreversible after a certain period [37]. Freezing at low temperature after gelatinization results in recrystallization of starch granules and increases the resistance and hardness of starch [38].

Along with these physical factors, some chemical factors have been also reported to affect the structure and functions of starch. Various oxidizing agents, hydroxy or carboxy derivatives of hydrocarbons, some carboxylic acids, phosphates, different acid, and base cross-linkers and synthetic polymers, and some cationic molecules are the major chemical factors which have been reported to modify the structure and properties of native starches [39–46]. Starch is also susceptible to acids and enzymatic hydrolysis which results in degradation of amylose and amylopectin and alter the morphology and surface properties of granules leading to the change in functional value of starch [47–49]. These physical and chemical factors have helped improve the functional quality of starch to obtain better results while used in various food and industrial formulations.

#### 2. Starch modification

Any changes in the structure of starch molecule caused by various environmental, operational and processing factors are termed as modifications. These modifications may exert either positive or negative effects on the structure and functionality of starch molecules. The native starches obtained from various plants are diverse in their structure and functions. To enhance the structural and functional quality of these starches and achieve better results in various formulations, the researchers suggest some modification in their structure. Several studies have been reported on the improvement of functional quality of starch by physical, chemical or mechanical modifications [23, 43, 45, 48, 50–58]. However, some environmental and processing factors may reduce the functional quality of starch by various modifications during storage and processing [57]. The physical modifications are comparatively safe and preferable over chemical modifications as the later involve the changes in the chemical structure of the molecule which limit its use in most of the formulations.

#### 2.1 Physical modification of starch

Physical modifications involve the changes in the morphology and threedimensional structure of starch under the influence of some physical factors such as milling, moisture, temperature, pressure, pH, radiation, pulse-electric field, ultrasonic waves, etc. Physical modifications result in the variation in particle size, surface properties, solubility index and functional properties such as water absorption, swelling capacity, pasting and gelation ability of starch. These modifications directly influence the functional quality and selectivity and suitability of the modified starch for various nutritional, pharmaceutical and industrial formulations. Several studies have been reported on the physical modification of starch using different techniques. The commonly used methods of physical modification include superheating of starch, thermal inhibition treatment, UV and gamma irradiation, microwave treatment, high pressure, osmotic pressure and instantaneous controlled pressure treatment, mechanical activation by stirring ball mill, treatment by pulsed electric field, micronization in vacuum ball mill, annealing and freeze–thaw treatment [28, 29, 31, 33, 51, 53, 55, 56, 59–68]. The most frequently used and the most effective methods of physical modification are presented in Figure 2 and their effects on the structure and properties of various starches are summarized in Table 1.

#### Figure 2.

Methods of physical and chemical modifications of starch.

#### 2.2 Chemical modification of starch

The chemical modification involves the alteration of physiochemical properties of starch by introducing new chemical or functional groups in starch without any physical alteration in the shape and size of the molecule. Each of the glucose units in amylose and amylopectin has three reactive hydroxyl groups which are the major sites for chemical modification in starch. The chemical modification alters the physical behavior of starch including retrogradation, salting, and gelatinization that work by stabilizing the intermolecular and intramolecular bonding of starch granules. The commonly used methods of chemical modification of starch include oxidation by different oxidizing agents, etherification by addition of some hydroxyethyl, hydroxypropyl or carboxymethyl moieties on hydroxyl groups of starch, esterification by condensation of some fatty acids, other carboxylic acids and phosphates with active hydroxyl groups of starch, cationization by introducing some cationic molecules, cross-linking by addition of various cross-linkers and graft-polymerization of starch with synthetic polymers [40–43, 46, 68–72]. Cationic modifications involve the reaction of starch molecules that contain tertiary and secondary ammonium, imino, amino, sulfuric and phosphate groups which react with hydroxyl groups of starch. It improves the dielectric constant of starch granules. It has great importance in the textile industry as an additive, in paper and cosmetic industry due to low cost, rapid degradation and bioavailability [73].






#### Table 1.

Methods of physical modification of starch and changes in starch structure and properties.





Table 2.

Methods of chemical modification and changes in the structure and properties of modified starches.

Cross-linking is the mechanism of covalent interaction between starch molecules. The reagents used to form copolymer in starch are sodium trimetaphosphate, sodium tripyrophosphate, epichlorohydrin and phosphoryl chloride. It has been reported to modify the starch to form frozen products in the food industry and also used to make plastics due to resistant properties [42, 45, 46]. The mechanism of addition of anhydrous acetyl group or vinyl acetate in the presence of sodium hydroxide and potassium hydroxide to native starch granules is called esterification. Acetylated starch has great importance at the industrial level as a thickener, stabilizer, adherent and encapsulator [39, 74, 75]. The commonly used effective methods of chemical modification of starch are presented in Figure 2 and their effects on the structure and properties of various starches are summarized in Table 2.

### 3. Effect of modification on the reactivity of starch

Both the physical and chemical modifications have been found to result in a change in the granular and molecular structure of starch which leads to the change in its reactivity and functionality. The mechanical, thermal radiolytic, and acidcatalyzed hydrolytic degradation of starch granules result in an increase in its

reactivity due to the exposure of reactive functional groups after the breakdown of amylose and amylopectin chains. Oxidation, acetylation, phosphorylation, carboxymethylation, cationization, and copolymerization also introduce some new functional groups on starch resulting in a change in reactivity of starch towards the water, oil, acids, enzymes, and other chemical species. Cross-linking by the addition of cross-linker molecules also results in the formation of inter and intramolecular bridges among the components of starch which alters its reactivity and specificity for use in industrial and biomedical fields.

#### 4. Conclusion

The physical and chemical modifications have been found to improve the functional quality of starch for its use in certain formulations while such modifications may also limit its use for other purposes. The choice of modification type and treatment method depends on what types of changes in functionality and reactivity of starch are required for a specific application. The modification of starch by various physical methods have been found to affect its structural parameters and physical and functional properties including crystallinity, surface properties, solubility, viscosity, swelling ability, pasting and gelatinization properties, and thermal and freeze–thaw stability. The modifications of starch by the chemical method have been also found to affect the molecular structure and reactivity of starch by addition of new functional groups, degradation of the polymeric structure, oxidation by free radical or cross linking of starch molecules. The change in the polarity due to exposure of reactive functional groups and the increase in the degree of substitution and intermolecular cross-linking results in a change in the reactivity of starch towards water, oil, acids, enzymes, and other chemical species. These modification techniques may lead to some revolutionary changes in reactivity, functionality starch and application of starch in the nutritional, pharmaceutical, biomedical and industrial field. However, the selection of a suitable modification method is much more important for the researchers to make the desired and targeted improvement in the functional quality of starch.

#### Conflict of interest

I confirm that there are no conflicts of interest.

#### Author details

Haq Nawaz\*, Rashem Waheed, Mubashir Nawaz and Dure Shahwar Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan

\*Address all correspondence to: haqnawaz@bzu.edu.pk

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## Starch Source and Its Impact on Pharmaceutical Applications

*Olobayo O. Kunle*

#### **Abstract**

Starch can be obtained from a variety of plant sources. The specific source of starch, the environmental conditions during starch maturation, and the age of the plant affect the physicochemical composition of the starch. This is because of the effect they have on critical factors especially the amylose amylopectin content of the starch as well as their relative quantities. These factors also affect the starch granule size and size distribution and the levels of minor components such as phosphates, lipids, and the nature of these interactions with amylose and amylopectin. In its wide use as a pharmaceutical excipient especially as binder and disintegrant, unmodified starch is affected in its functionality by the physicochemical properties of the starch. These factors especially by their influence on the swelling power and gelatinization as well as granule size and shape determine the properties of dosage forms in which the starches are used. This results in dosage forms that, although meeting compendial standards, differ in specific properties. The source of starches therefore affects the properties of pharmaceutical dosage forms. This should be taken into consideration in the choice of excipients in drug formulation and before the substitution of one starch for another in a formulation.

**Keywords:** starch, source, amylose, amylopectin, swelling, viscosity, pharmaceutical excipients

#### **1. Introduction**

In its native form, pure starch is a white, amorphous relatively tasteless powder which is odorless and is insoluble in water and other common organic solvents. It is one of the most widely distributed chemical substances in nature being the energy storage form of plant materials.

Microscopically, starch consists of colorless, highly refractive particles whose size and shape depend on various factors most important of which is the source of the starch. A starch granule involves alternating regions of amorphous and crystalline lamellae seen as rings which are essentially the crystalline portion.

Starch is chemically a carbohydrate composed of two similar carbohydrate molecules—amylose and amylopectin. Amylose is a straight chain α-1,4-glycosidic bonds, while amylopectin is a branched polymer also made of α-1,4-glycosodic with branched chain linked by α-1,6-glycosidic bonds. This conformational difference confers different properties on each of these polymers. For example the short branching of amylopectin at the α-1,6-glycosidic bonds is responsible for the crystalline region of the granules [1–3]. In the natural state, starch is approximately 20–30% amylose and 70–80% amylopectin.

#### *Chemical Properties of Starch*

Amylose which is rigid due to packing resulting from its straight chain is insoluble in water but soluble in hot water without gel formation. Amylopectin is, however, nonrigid in structure and soluble in water and forms a gel in hot water.

Starch which is largely synthesized in the amyloplast of the storage organs of plants and/or the chloroplast of plant leaves also contains traces of lipids and phosphate groups.

#### **2. Pharmaceutical applications of starch**

Starch is one of the most widely used pharmaceutical excipients because it is one of the few natural products that, with minimal processing, meet most of the requirements for excipients. It is nontoxic, odorless, inexpensive, widely available, and biocompatible.

In its native form, starch is used in the formulation of a number of dosage forms where its particular functions depend on the specific dosage form. This section discusses the most commonly utilized functions of starches as an excipient.

#### **2.1 Binder**

Starch is widely used as a binder in the wet granulation process of massing and screening which is an important step in the production of tablets, capsules, and other solid dosage forms. The granulation process is used to improve the flow of APIs which tend to be very cohesive. Flow is critical to the maintenance of dosage form weight consistency in high-speed manufacturing equipment, to avoid the dose variation that can result from irregular flow and powder segregation. In this process, starch is used as a liquid binder to create agglomerates with good flow properties. The paste produced on heating a suspension of starch is used to cause the "sticking together" of the particles in the formulation to create larger sized agglomerates that will reduce cohesiveness and encourage flow. This is achieved by the creation of bonding between particles in the powder bed which become solid bridges on drying. The more viscous the paste, the stronger the bridges formed, and the larger the size of the particles formed up to a limit [4]. It would therefore imply that any factors that affect the viscosity of the starch paste would affect the functionality of the starch as a binder. Studies have shown that the source and by implication the chemical composition and nature of starches influence their viscosity [5].

#### **2.2 Disintegrant**

A disintegrant is an excipient included in a pharmaceutical formulation to achieve the breakup of solid dosage forms such as tablets or granules into smaller discrete particles. Disintegration is a critical step in the process of drug release and absorption as it exposes a larger surface area for the drug to more easily and quickly go into solution. This accelerates the dissolution process, drug release, and absorption to achieve the desired therapeutic activity of the drug. Starch is a cheap and convenient disintegrant which is thought to exert this action as a result of the swelling properties of its particles in the presence of water leading to the disruption of the solid bridges and other binding forces in the dosage form. The extent of swelling is a function of the source or type of the starch which is reflective of the relative proportion and conformation of the amylose and amylopectin in the particular starch [6, 7]. Weak associative forces in a starch could be an indication of its potential as a disintegrant [1]. Disintegrant action could also be due to the formation of channels through which fluids are able to penetrate the solid dosage form allowing the dissolution of the drug.

#### **2.3 Diluent**

Some drugs are used at very low doses thus making it very difficult to process them and eventually compress them into tablets and other required dosage forms. In such cases, inert materials that do not exert the pharmacological effect of the drug can be included in the formulation to bulk it up to allow for the normal formulation processes. Because it is bland, odorless, and digestible, starch is used for this purpose.

#### **2.4 Absorbents**

Starch is hygroscopic and can absorb moisture up to 10–17% when equilibrated at normal atmospheric conditions [8]. It therefore finds use as an absorbent in drug formulations to keep powders dry and ensure the stability of drugs that are liable to deteriorate by hydrolysis and other similar chemical reactions.

#### **2.5 Glidant/lubricant**

Starches have been studied for use as lubricants and glidants [9] because of their slippery nature and ability to adhere to surfaces.

#### **2.6 Modified starches**

In its native form, the uses of starch are limited by its inability to withstand some processing conditions such as high temperatures, varying pH, freeze-thaw cycles, its tendency for retrogradation and decomposition, and brittleness.

When modified, starch becomes even more versatile in its pharmaceutical applications. For example, acetylation results in improved paste clarity and flow, as well as increased swelling capacity [10, 11], while with carboxylmethylation there is increased water solubility, lowered gelatinization temperature, and paste stability [12, 13]. An important factor in the modification processes and the specific properties of the modified products is the physicochemical characteristics of the particular starch used. Modifications could be physical using heat and moisture, gelatinization, extrusion, spray drying, granulation, or agglomeration. Starch can also be modified chemically by the introduction of functional groups using derivatization techniques such as esterification, cationization, cross-linking, or hydrolysis and oxidation which are usually achieved by the replacement of all or some of the hydroxyl groups.

### **3. Starch source and its pharmaceutically relevant properties**

Starch is one of the most widely distributed substances in nature and can therefore be obtained from several different plant sources. Starch for use as an excipient is one that meets the official compendial standards of quality in the relevant official books (pharmacopeias) and is generally referred to as official starch. Examples of such are potato, corn, rice, and tapioca starches. Pharmaceutical grade starch can be obtained from several plant sources but generally meet the standards shown in **Table 1**.

In addition to the compendial starches, several other plant sources have been investigated by various workers and reported as suitable sources of pharmaceutical grade starch in studies using the pharmacopeial starches as standards [9, 14, 15].


#### **Table 1.**

*Pharmacopoeial requirements of pharmaceutical grade starch [14].*

These reports show that although starches from a variety of sources can be used as excipients, the specific effects (especially quantitative) on the formulation properties are dependent on the source. For example, the disintegrant effect of yam starch was higher than that of cocoyam starch. This is attributed to the difference in the fundamental properties of the starches such as particle size and the amylose/ amylopectin ratio which affect functional properties such as swelling, water sorption, and viscosity [16].

Pharmaceutical grade starches can come from either underground plant storage organs such as tubers, rhizomes, or roots or from grains and cereals. The choice of starch source is largely dependent on the availability, ease of extraction, and the yield. The underground storage organs tend to be more easily processed as they are less associated extraneous materials.

While the general physical and chemical properties of starches are the same, their specific functional properties are dependent on the particular plant source which determines their physicochemical properties. The biological origin of starch serves as a determining factor in the granule shape, size, and morphology [17]. This section will examine the effect that the specific plant sources have on some physicochemical properties of starch that are relevant to their use in pharmaceutical formulations.

#### **3.1 Swelling and gelatinization properties**

#### *3.1.1 Gelatinization*

The most common use of starch as a pharmaceutical excipient is as binder and disintegrant in the formulation of tablets and other solid dosage forms. Its behavior in the presence of water is therefore its most important property from the perspective of the pharmaceutical industry. While the disintegrant action of starch is substantially determined by the response of the starch particle to water uptake leading to a ballooning before the leakage of its contents and complete rupture, its use as a binder will depend on the cohesiveness resulting from the series of events that result in increased viscosity of the starch paste. The extent of changes induced

#### *Starch Source and Its Impact on Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.89811*

in the starch particle by heating depends on the temperature and duration [18] and has been reported to be greatly influenced by the starch species [1].

Gelatinization is the disruption of the granular structure of starch by heating with an excess of water. This is because as the suspension is heated gradually, the starch particles begin to swell tangentially [19], and particle content begins to leak with the leakage of amylose, until the eventual rupture of the granule which results in further increase in viscosity and solubility. Initially some amylose is retained in the interior cavity, but rupture and collapse and dissolution of the swollen granule occur during prolonged heating. This process results in a gradual increase in viscosity of the suspension until the complete rupture of the starch granules until the peak viscosity is attained [20].

It essentially involves the weakening of the micellar network within the particle subjected to heat in a suspension by disrupting the hydrogen bonds which permits further hydration and irreversible starch particle swelling. This conversion has been related to various irreversible changes such as granule swelling, loss of birefringence, leaching of amylose, and increased viscosity and solubility and tangential swelling of the particle [19]. From a thermodynamic standpoint, gelatinization refers to the enthalpic transitions involving the starch granule treated as a semicrystalline entity (spherulite). Collapse of the crystalline structure leads to a gain in entropy. This tends to dislodge the hydrogen bonding network occurring in the spherulite.

The apparent viscosity of a starch paste is essentially the result of properties of the individual swollen entities, their fragments, presence of starch soluble, and the interaction or cohesiveness between swollen particles.

Gelatinization begins from portions of the granule where bonding is weakest, and so since the degree of association in individual particles differs and is influenced by factors such as plant source and some environmental conditions of growth, gelatinization temperature and pattern would differ from one starch source to another [14].

#### *3.1.2 Retrogradation*

Retrogradation is a slow recrystallization of starch components (amylose and amylopectin) upon cooling or dehydration [21]. It is as a result of the long molecular chains and the numerous hydroxyl groups present causing a great tendency for bonding between chains, thus producing bundles of amylase molecules which are rigid resulting in rigid gels and insoluble precipitates. The rate of retrogradation in a starch paste depends on the amount of amylose, the size of the amylose molecule, and the method of preparation of the paste [22, 23].

#### *3.1.3 Factors that affect gelatinization/swelling properties*

The strength of the starch granular structure would depend on the specific nature of the component molecules, their association, and spatial arrangement as well as their interaction with water molecules. Since the crystalline region of starch is largely composed of amylose, the exact amount will have a bearing on the gelatinization process. There is significant correlation between apparent amylose content and viscosity parameters such as peak viscosity (PV), minimum viscosity (MV), final viscosity (FV), breakdown (BD), total setback viscosity (TSV), and setback viscosity (SV) [24]. Phosphate monoester derivatives increase the paste viscosity; potato starch which contains a large amount of phosphate monoesters is more resistant to heat and shearing than cereal starches, but hot paste stability is lost when potassium bound to phosphate monoester is displaced by other cations [25].

#### *Chemical Properties of Starch*

Amylopectin is primarily responsible for granule swelling and viscosity [26], and starch pasting properties are affected by amylose and lipid contents [27, 28]. Increased gelatinization temperatures have been associated with higher levels of amylopectin double helices resulting in enhanced rigidity of the amorphous region [29].

The lipids contained in starches in the form of phospholipids and free fatty acids [30] tend to form complexes with amylose and the long branches of amylopectin resulting in starch granules with limited solubility [28]. They result in opaque and low-viscosity pastes [31] significantly reducing the swelling capacity of starch particles [32]. The phosphorylation level, which appears to be confined to the amylopectin fraction and is enriched in the amorphous regions, is lower in cereal than in tuber starches [33]. It is associated with increased granular hydration and lowered crystallinity, yielding pastes with higher transparency, viscosity, and freeze-thaw stability [34].

The swelling power of starch is associated more with granule structure and chemical composition especially amylose and lipid component than with granule size. Higher amounts of lipid-complexed amylose would inhibit swelling and gelatinization [26].

#### *3.1.4 Moisture sorption*

Moisture sorption by starch which leads to particle swelling has been attributed to the interaction between the hydroxyl groups of the hexose moiety and water molecules. Although water molecules form hydrogen bonds with both amylose and amylopectin, the amylopectin structure has been shown to physically trap water molecules. Based on this, it has been hypothesized that starch particles high in amylopectin would have a higher moisture sorption potential. Crystalline polymers have been proposed to have extensive secondary intermolecular bonding. This secondary bonding causes the hydroxyl groups on adjacent glucose units to interact with each other and hence reduces the available sites for absorption of water molecules. As a result, the higher degree of crystallinity could reduce the moisture sorption [1].

#### *3.1.5 Effect of growth conditions*

The conditions of growth of starch-containing plants especially during starch maturation affect the content and gelatinization behavior of the starch [35]. Gelatinization peak temperature has been reported to be lower for barley cultivar grown at low temperatures [36].

Higher growing temperature and abundant moisture during the development of starch granules could cause annealing of starch and result in higher onset and narrower gelatinization temperatures of the starch [37]. The swelling properties of starch particles are significantly affected by the growing temperatures of the plant during its development.

#### **3.2 Amylose/amylopectin content**

Amylose/amylopectin ratio, molecular weight, and molecular fine structure influence the physicochemical properties of starch and are therefore major determinants of its functional properties such as flow and swelling properties [38]. This is especially because of its swelling and pasting characteristics which have been earlier mentioned and are critical to the pharmaceutical uses of starch. Physicochemical properties of starch in solution are likely direct functions of the molecular constitution of the polymer including the molecular size, unit chain length distribution, branching pattern, degree of phosphate substitution, and granule size and

#### *Starch Source and Its Impact on Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.89811*

distribution [39]. Thermal properties are largely influenced by the branch chain length of amylopectin [40, 41].

A number of factors including environmental and genetic [42] factors influence the amylose amylopectin content and their relative content in a particular starch.

It can occur within the range 65–85:15–20. This difference in composition has been reported to result in some of the peculiar physical and functional properties seen in some starches, such as a difference in crystallinity, starch granule size, gelling, pasting, and flow properties. The membranous structures and physical characteristics of plastids can affect the arrangement and association of the amylose and the amylopectin molecules within the granules [43] with amylose content increasing with granule maturity [44].

The effect of growth conditions on the gelatinization behavior of starches is essentially through their effects on their amylose content. For example, studies have shown that matured at 15 degrees had higher peak viscosity temperatures. FV, TSV, and shorter time maintained at greater than 80% of peak viscosity than starch from plants grown at ambient temperature in the field due to the difference in amylose content [35].

The elevation of growth temperature increases the gelatinization temperature of wheat starch due primarily to the enhanced presence of amylopectin double helices and probably enhanced rigidity of the amorphous region [29]. The effect of environmental temperature on amylose content is dependent on the specific plant with the possibility of both increase and decrease.

The amylose content of rice and maize were reduced at elevated growth temperatures [38, 45], while with wheat the amylose content increased slightly as a function of temperature [29] indicating that the specific plant is also important. Further illustrating the effect of temperature on the amylose content, it was found to differ significantly in plants grown at 15° from those grown at 20° and that the longer rice plants were exposed to cool temperatures, the greater the accumulation of amylose [46]. Additionally, starch granule size is a factor in amylose content of a starch, with the level increasing with granule size [40, 41].

#### **3.3 Starch granule size**

Granule size influences the physicochemical characteristics of starch, and since starches from different botanical origins differ in morphology [47], it is one of the important physicochemical parameters that could affect the functional properties of different starches. Characteristics affected include starch composition, gelatinization and pasting properties, enzyme susceptibility, crystallinity, swelling, and solubility. The membranous structures and physical characteristics of plastids can impart a particular shape or morphology to the starch granules [43]. Granules of tuber and root starches, for example, are generally oval [17] while granules from fruits and nuts vary in shape. Granules of small granule starches are characterized by their very irregular, polygonal shape [43].

At similar amylose contents, small granule starches tend to have a lower pasting temperature and more amylose leakage out of the intact granule than do their larger granules at 55 degrees and above [48]; they (small granules) are associated with a higher rate of water absorption, earlier hydration, and more swelling than larger granules [49]. This is due to the less crystallized arrangement of the polysaccharide chains in the smaller starch particles thus providing a higher proportion of amorphous zones which are more accessible to water. Other factors such as amylose/amylopectin ratio and molecular weight and molecular fine structure also contribute [47] with amylose content increasing with granule size [44]. The branch chain length of amylopectin is also correlated with granule size and granule size

#### *Chemical Properties of Starch*

distribution. Decreasing granule size has been associated with reduced degree of polymerization of amylopectin, and smaller less branched amylose polymers are seen in large size starch granules [49, 50].

However the dissociation enthalpy of the amylose-lipid complexes of small granules is higher than that of large granules [51, 52]. The pattern is similar for acid or enzyme hydrolysis with small granules hydrolyzing faster than do large granules [53, 54]. The pattern of enzyme digestion also differs between small and large granules [55].

Starch particle size distribution is affected by the environment with the elevation of growth temperature tending to decrease the number and size of starch granules [41].

#### **4. Effect of source on the pharmaceutical applications of starch**

Starches that have been investigated for their potential as pharmaceutical excipients differ in their granule morphology, amylose/amylopectin ratios, water sorption, swelling power, and gelatinization characteristics. A number of workers have found that the physicochemical properties of starches affect the pharmaceutico-technical properties of the dosage forms produced using the various starches [9, 14, 15]. This is the case irrespective of the particular use to which the starch was put in the formulation.

While, in most cases, formulations containing novel starches meet the compendial quality standards, they differed from those containing the official starches. These differences can be attributed to the differences in the physicochemical properties of the starches.

As earlier stated the pharmaceutical uses of starch, especially in drug formulation, are largely based on its water sorption, swelling, and gelatinization properties. While these properties are generally applicable and qualitatively similar whatever the source of the starch, the previous section has shown that the specific or quantitative values of these properties differ from one starch source to another and even among starches from the same source if growth conditions differ. A few cases are mentioned below to illustrate the effect of these differing properties on dosage form characteristics.

A comparative study indicated that cocoyam starch has a higher viscosity than yam and cassava starches, when used as binder resulted in more fragile tablets relative to the other starches as indicated by the high tablet friability values obtained for such tablets [16].

Tablets produced by dry granulation with yam (a large granule) starch as disintegrant were more friable than those formulated with cocoyam (a small granule) starch which also had the highest hardness. There was also an inverse relationship between the starch swelling power and the rate and extent of disintegration and dissolution of the tablets. This is an indication that one of the mechanisms of tablet disintegration by starches is by swell rupture [56].

Starch size and shape affect the compaction characteristics of granulations for tableting. Yam starch which is ovoid in shape with a high mean diameter has high densification as a result of die filling and less densification from subsequent rearrangement of particles at low pressures, while potato and cassava starches with smaller diameters and more rounded shape were the reverse. While yam starch had the highest yield pressure, it had the lowest tensile strength and brittle fracture index [57].

The gelatinization characteristics of *Tacca* starch as determined by onset, peak, and conclusion temperatures of gelatinization, crystallinity, and enthalpy of gelatinization were lower than for maize starch. This implies that it has more crystalline

*Starch Source and Its Impact on Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.89811*

regions that are thermally and structurally less stable than maize starch [1]. These differences in properties resulted in the starches having different compaction properties. While they both underwent plastic deformation, the deformation for maize was more extensive than for *Tacca* which was more resistant to deformation. Maize starch also produced harder compacts. There was a correlation between these formulation characteristics and the starch properties [58].

Other workers have reported similar co relationship between fundamental properties and formulation properties [59, 60].

The functionality of the modified starches used in modified drug formulations has also been reported to be dependent on the source of the native starch. Studies using starches obtained from diverse sources have shown that the source of a starch will affect its function as a sustained release excipient [61–63].

#### **5. Conclusion**

Starch is a widely available natural material. It is versatile and has found use in many industries due to its different physical and functional properties. A number of modifications or derivatives can be produced because of the presence of a high number of hydroxyl groups on the surface. In the pharmaceutical industry, it finds extensive use as an excipient especially as a disintegrant and binder in the formulation of solid dosage forms. This use is dependent on its behavior in the presence of moisture, essentially the way it interacts and behaves in the presence of water.

Its use as a disintegrant is largely dependent on its insolubility which creates channels in the compact that allow for water to penetrate the compact to dissolve the active drug component. It also depends on the swelling of starch particles which results in the disruption of the solid bridges formed in the compact. The swelling behavior of any particular starch is dependent on a number of factors which are closely related to the exact chemical composition (amylose, amylopectin, lipids, and phosphates) of the starch. The relative quantities of the two carbohydrate moieties—the straight chained amylose and the branched chained amylopectin—is critical to the pattern and extent of interaction between starch and water since it determines the extent of interaction as well as the speed of interaction between water and the OH group on the chain. The conformation and the extent of branching of the molecules also determine the speed with which water can access and eventually disrupt the bonds within the molecule.

The use of starch as binder is dependent on its behavior when a suspension of starch powder is subjected to increased temperatures which cause the gradual weakening of the intermolecular bonding in the starch granule. The continued supply of energy in the form of heat eventually results in the breakdown of the granules, the outflow of the amylose, and eventually the breakdown of amylopectin. All these processes result in increased viscosity. It is the viscous gel produced that provides the gluing property exploited for the binding of powder particles to obtain granules in drug formulation. On drying, the wet bridges formed dry into solid stable bridges that create the granules for improved flow. This process is also dependent on the amylose amylopectin ratio as well as the moisture content of the starch and the conditions during the production of the starch in the plants.

The relative quantities of amylose and amylopectin, the extent of branching, the conformation of the moieties, the presence of phospholipids, the interaction between the carbohydrates and lipid, the particle size, and the extent of phosphorylation, all of which are affected by environmental and genetic factors, influence starch fundamental (physicochemical) properties that relate to its functional properties as a pharmaceutical excipient.

#### *Chemical Properties of Starch*

In general it can be concluded that although starches from different sources can be used as pharmaceutical excipients, as long as they meet compendial standards, consideration should always be given to the fact that their performance in formulation is dependent on their source. Since they affect functional properties especially the key properties of swelling and pasting, it is necessary to collect as much information on the growth conditions and physicochemical properties of starches to be used as pharmaceutical excipients to ensure batch-to-batch consistency in drug production. These considerations are particularly important when considering changing from one type of starch to another as excipients and in formulary development.

### **Author details**

Olobayo O. Kunle National Institute for Pharmaceutical Research and Development (NIPRD), Abuja, Nigeria

\*Address all correspondence to: kunleoo@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Starch Source and Its Impact on Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.89811*

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