DESIGN AND DEVELOPMENT OF A STARCH-BASED MULTIFUNCTIONAL EXCIPIENT (STARGELASIL) FOR TABLET FORMULATION

ABSTRACT

The concept of co-processing as a particle engineering technique has been used as a tool to improve the functionality of many existing excipients. This study was designed to improve the functionality of cassava starch as excipient for direct compression by co-processing with gelatin and colloidal silicon dioxide. The Design of Experiment (DoE) approach was employed to optimize the percentage ratios of the primary excipients for the co-processed excipient. Fourteen experimental formulations containing varying proportions of the primary excipients were prepared by the method of co-fusion and twelve tablets each weighing 400 mg each were produced for each formulation using the Hydraulic Carver Press. The compressed tablets were kept for 24 h in the desiccator and evaluated for tensile strength and disintegration time. The data obtained from the tabletswere suitably analysed using the Design Expert software and fittedto a special quartic model that correlated the effect of varying the proportions of the excipients in the different formulations on tablet properties.The composition of the co-processed excipient that produced tablets of desirable characteristics after optimization was found to be cassava starch (90 %), gelatin (7.5 %) and colloidal silicon dioxide (2.5 %). The optimized co-processed excipient subsequently known as “StarGelaSil” (SGS) was prepared in large quantities and stored in an airtight container for further studies. Solid-state  characterization  was  conducted  on  SGS  to  determine  its  particle  size,  shape, distribution, surface morphology, degree of crystallinity, hygroscopicity, compatibility etc  using  established  analytical  techniques.  Powder  properties  of  SGS  were  also determined by measuring its flowability using the angle of repose, bulk and tapped densities, porosity, dilution potential, lubricant sensitivity ratio etc. The compaction behaviour  of  SGS  was  analysed  using  Heckel  and  Kawakita  equations  and  the compressibility, tabletability, compactability (CTC) profile was determined in comparison to the physical mixture of the primary excipients (SGS-PM). Tablets were formulated by direct compression using Ibuprofen as the drug of choice and compared with tablets produced using Prosolv and StarLac as reference standards. The results revealed that co-processed particles of SGS were largelyamorphous and spherical in shape with rough surfaces. There was no incompatibility between the excipients used for co-processing and between drug and co-processed excipient. Flow properties were enhanced as a result of co-processing. A superior CTC profile was obtained for SGS when compared with SGS-PM. The tablets produced by SGS conformed to the specifications of USP (2009) and compared well with those of the reference excipients in terms of tensile strength, disintegration time and drug-release profile. This study concluded that co-processing was able to improve the functionality ofcassava starch as excipient for direct compression. Hence, the excipient can be developed for usein pharmaceutical industry as a choice material for direct compression.

CHAPTER ONE

 INTRODUCTION

1.1  Solid Dosage Forms

Tablets account for more than 80 % of all dosage forms in the market (Khomane and Bansal, 2013)because of the following properties:

• They are easy to dispense,
• Offer dosage accuracy,
• They are amenable to mass production at a relatively cheap cost,
• Tamper resistant compared to capsules, and
• Offer better stability to heat and moisture compared to liquid and semi-solid formulations (Jivraj et al., 2000; Pucelj, 2014).

The European Pharmacopoeia (2002) defines tablets as solid preparations each containing a single dose of one or more active substances and usually obtained by compressing uniform volumes of particles. Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated. Despite the long and continuing history of the development of new technologies for administration of drugs, the tablet form remains the most commonly used dosage form (European Pharmacopoeia, 2002).

1.2         Excipients

The formulation of tabletsusually consists of the active pharmaceutical ingredient (API) and excipients. The International Pharmaceutical Excipient Council (IPEC) has defined excipients as “substances other than the API in finished dosage form, which have been appropriately evaluated for safety and are included in drug delivery systems to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability. They assist in product identification, or enhance any other attributes for the overall safety and effectiveness of the drug delivery system during storage and use” (Daraghmeh, 2012; Pucelj, 2014). They may serve either as diluents, binders, disintegrants, lubricants, glidants, or release control agents (Rashid et al., 2013). They have earlier been labelled as the “functional components” of a formulation (Moreton, 2004). They may be classified as natural (i.e. cellulose, starch, chitosan etc), inorganic (dicalcium phosphate), synthetic (polyvinylpyrrolidone) and semisynthetic (hydroxypropylmethylcellulose) on the basis of their source and chemical nature. More than 70 % of all formulations contain excipients in concentrations higher than that of the API, affirming the contribution of excipients in the design of dosage forms(Nachaegari and Bansal, 2004; Saha and Shahiwala, 2009). It is therefore obvious that excipients contribute in significant terms toward the processing, stability, safety and performance of solid dosage forms.

1.2.1    Types of excipients

In tablet formulation, a range of excipient materials is normally required along with the active ingredient in order to furnish the tablet with the desired properties. For example, the reproducibility and dose homogeneity of the tablets are dependent on the properties of the powder mass. The tablet should also be sufficiently strong to withstand handling, but should disintegrate after intake to facilitate drug release. The choice of excipient will affect all these properties. Based on their function, excipients have been grouped into the following classes:

1.2.1.1 Diluents/Fillers/Bulking agents

A diluent is any material that is added to a tablet formulation to fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use by increasing the bulk volume of the formulation. Hence, the final product has the proper volume for patient handling. A good filler must be inert, compatible with the other components of the formulation, non-hygroscopic, soluble, relatively cheap, compactable, and preferablytasteless or pleasant tasting (as in chewable tablet). Examples of diluents are lactose, dicalcium phosphate dihydrate, sucrose, glucose, mannitol, sorbitol, calcium sulphate, starch etc.

1.2.1.2 Binders

Bindersareoften added to the granulation liquid during wet granulation to improve the cohesiveness and compactability of the powder particles, which assists in the formation of agglomerates or granules.Materials with high bonding ability can be used as binders to increase the mechanical strength of the tablet. A binder is usually a ductile material prone to undergo plastic (irreversible) deformation (Klevan, 2011). They act by reducing interparticulate distances within the tablet, thereby improving bond formation. If the entire bulk of the binder particles undergo extensive plastic deformation during compression, the interparticulate voids will, at least partly, be filled and the tablet porosity will decrease. This increases the contact area between the particles, which promotes the creation of interparticulate bonds and subsequently increases the tablet strength (Sun, 2011) It is commonly accepted that binders added in dissolved form, during a granulation process, is more effective than incorporating as a dry powder during direct compression. Typical examples of binders include starches, gelatin, acacia, sucrose, sodium alginate, polyvinylpyrrolidone (PVP), carboxymethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose etc. Water and alcohol have been usedasmoisteningagents.

1.2.1.3 Disintegrating agents

Disintegrants are normally added to facilitate the rupture of bonds and subsequent disintegration of the tablets (Daraghmehet al., 2015). Disintegrants are usually added for the purpose of causing the compressed tablet to break up into smaller fragmentswhen placed in an aqueous medium, thereby facilitating dissolution and making the active ingredients ready for absorption in the digestive tract. The most conventionally used disintegrants are: corn starch, potato starch, and alginic acid. Other substances which swell in water can be used as disintegrants such as gelatin, sodium carboxymethylcellulose, microcrystalline cellulose, and bentonite. Superdisintegrants are rapid acting disintegrants which are effective at low concentration and have greater disintegrating efficiency than the conventional disintegrants. They act by swelling and due to swelling pressure exerted in the outer direction or radial direction, they cause tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration. Commercially available superdisintegrants includes sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

.2.1.4 Glidants, antiadherents and lubricants

Glidants are added to increase the flowability of the powder mass, reduce interparticulate friction and improve powderflow in the hopper shoe and die of the tableting machine. Antiadherents can be added to decrease sticking of the powder to the faces of the punches and the die walls during compaction, and lubricants are added to decrease friction between powder and die, facilitating ejection of the tablet from the die. However, addition of lubricants (also including glidants and antiadherents) can exert negative effects on tablet strength, since the lubricant often reduces the creation of interparticulate bonds. Further, lubricants can also slow the drug dissolution process by introducing hydrophobic films around drug and excipient particles(Patelet al., 2006). These negative effects are especially pronounced when long mixing times are required. Therefore, the amount of lubricants should be kept relatively low and the mixing procedure kept short, to avoid a homogenous distribution of lubricant throughout the powder mass.Lubricants such as magnesium stearate, calcium stearate, stearic acid, talc and colloidal silicon dioxide are the most frequently used lubricants in tablets or hard gelatin capsules.

1.2.1.5 Flavours, sweeteners and colorants

Flavours and sweeteners are primarily used to improve or mask the taste of the drug, with subsequent substantial improvement in patient compliance. Typical examples of flavours commonly used are volatile oils which include clove, fennel, orange and wintergreen oil while sweeteners include sucrose, sorbitol, mannitol, xylitol, saccharin and aspartame. Colorants are added to provide tablets with good aesthetic value, and can improve tablet identification, especially when patients are taking a number of different tablets. The common colorants used in tableting include erythrosine, tartrazine, sunset yellow, brilliant blue, indigotine and fast green.

1.2.2    Functionality of an excipient

The quality of medicines depends not only on the active drug and production processes, but also on the performance of the excipients. The traditional concept of the excipient as any component other than the active substance has undergone a substantial evolution from an “inert” and cheap vehicle to an essential constituent of the formulation(Moreton, 2004). More than a thousand raw materials are available from a wide variety of sources and have been adapted for use in the pharmaceutical industry. Their chemical structures vary from small molecules to complex natural or synthetic polymeric mixtures. Excipients are now incorporated as functional components to perform a wide variety of functions to guarantee the stability and bioavailability of the drug substance from the drug product and its potential for manufacture on a production scale. Beyond the dosage form necessities, excipients are required to perform important and specific technological functions particularly in the domain of solid dosage forms. The functionality of an excipient is best described as its‟ contribution to a dosage form‟s stability, identity, delivery and processability which does not depend solely on the excipient‟s inherent properties but also on its application, formulation and process(Moreton, 2004). A good number of excipients relevant to tableting are multifunctional in nature, i.e. having the ability to combine two or more functions in a formulation. A typical example is microcrystalline cellulose (MCC) which is available in various grades. MCC is highly compactable and can also aid disintegration due to its ability to take up water by wicking action(Rumman, 2009). The use of a multifunctional excipient reduces the number of excipients incorporated in a formulation to the barest minimum thereby simplifying the final formulation and the manufacturing process. The European Pharmacopoeia (2008) has developed a list of functionality-related characteristics (FRC) for some of the excipient monograph. These tests have been described as non-mandatory but highly recommended because of their importance to the excipient‟s performance in many applications. Characterization studies on excipients must go beyond the simple tests for identity, purity and safety as recommended in the Pharmacopoeial monographs and extend to testing the technological functionality of the xcipient, which is usually employed in the solid state. The functionality of an excipient is defined by the physical, physico-mechanical and biopharmaceutical properties. The characterization of the solid state and surface parameters is therefore fundamental first to assess and then guarantee the behaviour of the excipient in the formulation and production phases. Analytical techniques such as infra-red spectroscopy and nuclear magnetic resonance (NMR) can be used to determine molecular structure and possible chemical interactions. Thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC) are often employed to clarify the stability, compatibility, degree of crystallinity and phase transitions occurring in the excipient. The structure of the single crystal or the powder can be examined with absolute certainty by powder x-ray diffraction (PXRD). A thorough understanding of the specific properties of a material gives us insight as to which of them will be crucial to the stability, bioavailability and easy manufacturability of the formulation (Zhou and Qiu, 2010).

1.2.3     Powder compaction and particle bonding process

Excipients for direct compression are required to form solid compacts when mixed with poorly compressible drugs. Mechanical properties of direct compression excipients determine success of the powder compaction and the deformation behaviour of material is a property that mainly affects the tableting ofpowders (Roberts and Rowe, 1986). The compaction process is a series of several events: particle movement into void spaces, partial fracture, elastic deformation, plastic deformation and cohesion between particle surfaces. These events occur simultaneously, but not necessarily to the same degree at any stage of the compression process (Patel et al., 2006; Zhou and Qiu, 2010). During consolidation of a powder bed, a reduction in porosity occurs. This reduction in compact volume brings particles into close proximity to each other. The reduced distance between the particles facilitates creation of bonds and makes the particles adhere together to form a coherent compact. Two different types of interactions are normally considered in direct compression of pharmaceutical materials; intermolecular interactions and mechanical interlocking. Van der Waal forces are probably the most important intermolecular forces responsible for bond formation in tablets. Hydrogen bonding is another example of intermolecular forces that act over a short distance between particles. The nature of these forces depends on the chemical composition of the material(Patel et al., 2006). Bonding by hooking or twisting of particles depends on the surface texture and shape of the particles. The dominant bond type depends on various factors, including the degree of compression and the inherent properties of the material. In the high porosity range, the principal attraction between particles has been suggested to be intermolecular forces; whereas in the low porosity range, solid bridges play a major role (Adolfsson and Nystrom, 1996). Usually, solid bridges connect particles by spanning, sintering, melting and crystallization (Klevan, 2011).

1.2.3.1 Compaction models

The assessment of powder compressibility can be determined by studying the relationship between compact porosity and compression pressure. If high pressures are applied to a powder bed, low porosities of the resulting compacts can be achieved. When the porosity of the tablet is close to zero, the structure of the tablet should be different from the structure at normal porosities (5-25 %) (Adolfsson and Nystrom, 1996).The final porosity reduction may eventually represent a transformation to a new physical structure, where the solid constitutes the continuous phase. Thus, the bonding structure of the resulting compact may also be altered. Knowledge of the volume reduction ability of a powder makes it possible to predict the compaction behaviour of a pharmaceutical material (Zhou and Qiu, 2010).

A compaction equation shows the relationship between the state of consolidation of a powder such as porosity, volume (or relative volume), density, or void ratio, as a function of the compression pressure. The most widely used equation relating the porosity (Ɛ ) of the powder bed during compaction to the applied pressure (P) is the Heckel equation. This equation is based on the assumption that densification of the powder under pressure follows first-order kinetics. It is given as: whereD is the relative density of the tablet (ratio of tablet density to the true density of the powder) at applied pressure, P and K is the slope of the straight line portion of the Heckel plot. The reciprocal of the slope (K) of the linear portion of the Heckel curve is referred to as the mean yield pressure, P_Y. The P_Y can be used to indicate the mechanism occurring during compression. From the value of A (intercept), the total relative density, D_A (D_A= 1 – e^-A) or powder solid fraction due to die filling and particle rearrangement can be calculated (Roberts and Rowe, 1986). Kuentz and Leuenberger (1977) postulated a modified Heckel equation which allows the description of the transition between the states of a powder to the state of the tablet. The modified Heckel equation is given as follows: whereσ is the pressure, ρ is the relative density, ρ_c is the critical density, and C is a constant. Powders have been classified into three types A, B, and C on the basis of the Heckel plot and the compaction behaviour of the material (Wong and Pilpel, 1990). The graphical illustration of the three plots is given as Figure 1.1.

With type „A‟ materials, a linear relationship is observed, with plots remaining parallel as the applied pressure is increased indicating deformation apparently only by plastic deformation. A typical example of a type „A‟ material is sodium chloride. They are comparatively soft and readily undergo plastic deformation retaining different degrees of porosity depending on the initial packing of the powder in the die. This is usually influenced by the size distribution and shape of the original particles. For type „B‟ materials, there is an initial curved region followed by a straight line. This indicates that the particles are fragmenting at the early stages of the compression process i.e. brittle fracture precedes plastic flow. Type „B‟ Heckel plots are usually seen with harder materials with higher yield pressures which undergo compression by fragmentation to achieve a densely packed arrangement e.g. lactose. In type „C‟ materials, there is an initial steep linear region which become superimposed and flattens out as the applied pressure is increased. Wong and Pilpel (1990) explained this behaviour to be due to the absence of a rearrangement stage and densification is due to plastic deformation and asperity melting.

There are two methods used to obtain density-pressure profiles: the in-die and out-of-die (or ejected tablets) methods. In the out-of-die method, the compact volume is measured after the tablet is ejected from the die having undergone partial elastic recovery. Conversely, the in-die method measures the compact densification in the die by evaluating punch displacement(s) relative to the increase in compression pressure. This method is faster and consumes less material than the out-of-die method, which requires a new compact for each compression pressure. However, the in-die density measurement contains an elastic component leading to falsely low mean yield pressures, which is a limitation when using the information to prepare a tablet formulation (Egart et al., 2014).

The Kawakita linear model is another porosity-pressure function used to characterize powder compressibility. It is based on the assumption that the particles are subjected to compressive load in equilibrium at all stages of compression, so that the product of pressure term and volume term is constant. It is expressed as: whereP is the applied pressure and C is the degree of volume reduction, ρ₀ is the bulk density, ρ_a is the compact apparent density, „a‟ is indicative of powder compressibility and „b‟ is a constant that is inversely related to the yield strength of particles. The plot of P/C vs P gives a straight line. The constants „a‟ and „b‟ can be determined from the slope and intercept, respectively. This equation is applicable for soft fluffy powders, and is best used for low pressures and high porosity situations.

1.3         Tableting Methods

Tablets have been produced by three main methods namely wet granulation, dry granulation and direct compression.

1.3.1    Wet granulation

Wet granulation typically involves wet massing a blend of active pharmaceutical ingredients (API) and excipients in a wet granulator followed by subsequent wet screening and finally drying(Martinelloet al., 2006). The most commonly used liquid for wet granulation is water although non-aqueous solvents such as ethanol and isopropyl alcohol may be used when water is unsuitable. While water is extremely economical and environmentally friendly, wet-granulation techniques are labour intensive and process times are inherently long due to wetting and drying stages.

Wet granulation, encompassing low- and high-shear mixing, fluid-bed mixing (spraying) and wet-mass extrusion, is an extremely versatile technique that has several advantages over dry methods, including improved control of drug content, better uniformity for highly potent drugs (low-dose APIs) and production of granules with superior bulk density and compactibility (high- and low-dose APIs).

1.3.2     Dry granulation

Dry granulation typically involves the compaction of powder blends through slugging or roller compaction. Slugging involves the manufacture of a large compressed tablet whereas roller compaction pushes powder blends through two counter-rotating rolls, producing a sheet of agglomerated material. In both cases, the formed solid compact is milled to produce granules of the desired particle size range for compression or filling.Dry granulation is a suitable alternative to wet granulation particularly when the API or excipients are sensitive to water/moisture and non-ambient temperatures, conditions that are typical for wet granulation. Interestingly, dry granulation processes produce granules with an extremely high bulk density and low intra-granular porosity in comparison with granules produced using alternative techniques(Patelet al., 2008). Furthermore, dry-granulated materials exhibit better gravimetric flowability; however, the high-density granules produced using this process have been shown to suffer from loss of tabletability, due to the significant number of particle defects and loss of plasticity introduced during processing. This is extremely important, as the quality of the final dosage form is significantly influenced by the compaction properties of the granular material(Joiriset al., 1998). In addition to loss of tabletability and possible phase transformation during compression, dry granulation may alsoresult in high levels of dust (problematic for potent API), poor compaction homogeneity and high levels of adhesion to the production equipment.

The significant lack of process understanding of dry granulation has limited its use in tableting though it is conceptually very simple and relatively cost effective. These disadvantages combined with a willingness to accept static agglomeration processes have led to wet granulation remaining the preferred and most widely accepted method for size enlargement within the pharmaceutical industry.

1.3.3     Direct compression

Direct compression is by far the simplest means of production of tablet dosage forms. It only requires that the drug is properly blended with appropriate excipients before compression (Rashid et al., 2013). This procedure involves fewer processing steps, less time and energy thereby reducing cost of production. It is also suitable to formulate heat and/or moisture sensitive drugs (Avachat and Ahire, 2007). Changes in dissolution profiles and the possibility of microbial growth on storage are also less likely to occur in tablets made by DC compared to those prepared by wet granulation due to the absence of moisture during processing. Compacts made by DC disintegrate into primary particles, rather than granules, and hence, can provide faster API release (Saha and Shahiwala, 2009).

A recent report states that around 80 % of new drug application (NDA) projects utilize wet granulation. The decision is driven by timelines rather than costs, since this is the most likely process to succeed. Employing direct compression which might appear as a rapid formulation procedure may have a higher chance of failure since it might not work for poorly compressible drugs with challenging physicochemical properties (McCormick, 2005). Less than 20 % of actives can be compressed directly into tablets (Harden et al., 2004). For some APIs, the doses are too small to be compressed into a tablet directly without needing a bulking agent, i.e. folic acid (5 mg).

Although simple in terms of unit processes involved, the direct compression process is greatly influenced by the characteristics of the powder blend (Rojaset al., 2013). The physico-mechanical properties of excipients required for a smooth DC process include good flowability, low or no moisture sensitivity, low lubricant sensitivity, good compressibility, optimum dilution potential, and good adaptability to high-speed tableting machines ( Saha and Shahiwala, 2009).

The choice of the excipient grade can be a challenge in DC. Selecting an improper grade of an excipient could lead to segregation and greater lubricant sensitivity (Almaya and Aburub,  2008).  For  example,  Avicel^® PH-200  (180  µm)  is  more  sensitive  to  the addition of magnesium stearate than Avicel^® PH-101 (50 µm) and Avicel^® PH-102 (100 µm) because it has more regularly-shaped particles which are easily covered by magnesium stearate leading to less particle bonding (Camargo, 2011). In addition, wide variations between the excipients and APIs particle shape and size may lead to inconsistent die filling, preferred orientations in particle bonding, non-homogeneous particle slippage and differences in pressure transmission within the powder bed, all resulting in tablet lamination and capping. Lamination occurs when there is separation of a compact into two or more distinct horizontal layers, whereas capping occurs when the upper or lower segment of the compact separates horizontally from the main body (Chow et al., 2008).

1.3.3.1 Characteristics of an ideal direct compression excipient

The manufacture of a tablet dosage form usually involves a diluent, disintegrant, binder, lubricant and glidant (flow enhancer). Functionality describes the activity of an excipient. A multifunctional excipient is defined as a material that has more than one functional property (Camargo, 2011). A glidant improves flowability of the powder mixture; while a lubricant is added to reduce the friction between the powder and tablet tooling. The latter also enhances tablet efficiency and reduces punch – and – die wear. The filler (diluent) is used to increase the bulk of the tablet or capsule to the desired size/volume, easy compact handling and administration. A binder allows the formation of granules or tablets of adequate tensile strength, whereas the use of a disintegrant allows the tablet break into particles when it comes in contact with water. Compressibility is expressed as the relative volume reduction of the powder bed in response to the applied pressure, and compactibility is the ability to form a compact with sufficient strength when a compression force is applied (Khomaneet al., 2013; Upadhyayet al.,2013). Carrying capacity or dilution potential is defined as the minimum amount of the excipient that when mixed with a drug shows no change in its compressibility, flow rate and ability to form hard compacts at low pressures (Flores et al., 2000; Camargo, 2011; Rojas et al., 2013) In order to ensure a robust and successful manufacture of tablets, an ideal direct compression (DC) excipient should possess the following characteristics: excellent compressibility, adequate powder flow, resistance to segregation during handling and storage, fast compact disintegration, a broad range of bulk densities, low sensitivity to lubricants, should be easily scaled up and allow higher drug loading even at low usage levels and should be easily prepared (Zeleznik and Renak, 2005; Jacob et al., 2007). In addition to the above requirements, characterized by the following properties 2008): a DC multifunctional excipient should be (Chang and Chang, 2007; Thoorens et al.,

1. Physiologically safe and not affect drug bioavailability.
2. Be physically and chemically stable to heat, moisture and air.

• It should not interfere with the functional properties of other excipients and API.

1. Be compatible with the packaging material.
2. It should have comparable particle size distribution with the API.
3. Good compactibility even in high speed tableting machines (low dwell times).

• Ability to be reworked without loss of flow or compactibility.
• Be cost effective and available preferably from multiple suppliers.

1. Have pleasant organoleptic properties, be well characterized and accepted by the industry and regulatory agencies.
2. Not contribute to microbiological load of the formulation.
3. Preferably white.

There is no single excipient currently available that meets all the requirements listed for an ideal direct compression excipient (Patel and Patel, 2007). Hence, it has become necessary to develop novel excipients with a wider spectrum of functionality via co-processing.

1.4         Co-processing

Co-processing was introduced as an intervention strategy to develop excipients that will supply the functionality required in direct compression. It is a particle engineering technique that combines two or more excipients at the sub-particle level with the aim of improving the functionality of the final product while minimising the short-comings of the individual excipients (Nachaegari and Bansal, 2004). This procedure has shown promise in providing improved performance of the co-processed excipient over and above its physical mixture(Kittipongpatana and Kittipongpatana, 2012). This study aims to develop a co-processed excipient with multifunctional application by combining three excipients in optimum proportions.

1.5         Statement of Research Problem

Native starch from a wide variety of sources have been used in tablet production either as a filler, disintegrant, binder or lubricant (Odeku and Itiola, 2007; Kadajji and Betageri, 2011). This is associated with the fact that starch, in one hand, can provide essential tablet properties for drug release; on the other hand, the nature of starch has made it amenable to modification to serve different functions (Jivraj et al., 2000).

Native starch offers two main benefits to a formulation namely, a rapid disintegrating property and ability to add bulk to the drug formulation (as filler) (Zhang et al., 2003; Rashidet al., 2013). In spite of these properties, starch possesses limited functionalities with regard to powder compression, tensile strength, and flow properties in solid dosage form preparations (Alebiowu and Itiola, 2002; Adedokun and Itiola, 2010). These short-comings have restricted the use of native starch in direct compression formulations and subsequently in high-speed tableting machines. Owing to the limitations above, a number of chemical and physical modifications were applied to transform native starch into a DC excipient with a wider spectrum of functionalities (Atichokudomchai and Varavinit, 2003; Apeji et al., 2011). Again, there was a limit to which modification improved its potential for direct compression coupled with the safety and toxicity issues associated with chemical modification. Hence, it became imperative to seek another route for developing starch-based excipients with improved functionalities. Co-processing is a strategy that has been adopted to improve the functionality of starch for direct compression in combination with other excipients.

1.6         Justification for the Study

This study has become necessary because of the following reasons

1. Starch is readily available in abundant supply from diverse sources. This makes it a good candidate for co-processing.
2. Cassava is grown in industrial quantities in Nigeria. Hence, it can be harnessed to develop home-grown excipients for our pharmaceutical industries.

• Currently, a sizeable proportion of co-processed excipients available to the pharmaceutical industry are either lactose-based or cellulose based (i.e. StarLac®, Prosolv®, Ludipress® etc.) with a limited number of starch-based excipients.

1. The inclusion of gelatin into the structure of cassava starch during co-processing will fuse the starch particles resulting in an increase in particle size. This will enhance flow properties and improve the overall compressibility of the excipient.
2. There is no single-based excipient that can deliver all the performance requirements for a robust direct compression process.
3. Co-processing will limit the number of excipients added to a formulation thereby reducing the incidence of incompatibility.

• Co-processing is a cheaper alternative because it involves existing excipients that do not need to be characterised since their properties are already documented.
• Co-processing involves manipulation of the physical properties excluding any changes in the chemical nature of the excipients.

1.7         Aim and Objectives

1.7.1    Aim

The aim of this research is to improve the functionality of cassava starch as excipient for direct compression by co-processing with gelatin and colloidal silicon dioxide in optimum proportions.

1.7.2    Objectives

1. To optimize the composition of the co-processed excipient using the Design of Experiment (DoE) approach.
2. To prepare the co-processed excipient using the optimized formula.

• To carry out solid-state characterisation using analytical techniques such as Scanning electron microscopy (SEM), Confocal laser scanning microscopy (CLSM), Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and Powder X-ray diffraction (PXRD).

1. To determine the physico-mechanical properties of the co-processed excipient i.e. particle size analysis, flow properties, bulk, tapped and true densities, moisture content, dilution potential, lubricant sensitivity.
2. To characterize the deformation behaviour of the excipient using compaction models like Heckel and Kawakita equations.
3. To formulate and evaluate tablets by direct compression using a poorly compactible drug model i.e. Ibuprofen.

• To evaluate the performance of the co-processed excipient in comparison to two commercially available co-processed excipient (Prosolv^® and StarLac

1.8         Research Hypothesis

1.8.1     Null Hypothesis (H₀)

The co-processing of cassava starch with gelatin and colloidal silicon dioxide in optimized ratios will not improve the functionality of starch as a multifunctional excipient in tablet formulation by direct compression.

1.8.2     Alternate Hypothesis (H_a)

The co-processing of cassava starch with gelatin and colloidal silicon dioxide in optimized ratios will improve the functionality of starch as a multifunctional excipient in tablet formulation by direct compression.