Design and Development of a Starch-based Multifunctional Excipient (Stargelasil) for Tablet Formulation

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 tablets were suitably analysed using the Design Expert software and fitted to 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 vii

compressibility, tablet ability, compact ability (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 largely amorphous 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 of cassava starch as excipient for direct compression. Hence, the excipient can be developed for use in pharmaceutical industry as a choice material for direct compression.

CHAPTER ONE

1.0 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:

(i) They are easy to dispense,

(ii) Offer dosage accuracy,

(iii) They are amenable to mass production at a relatively cheap cost,

(iv) Tamper resistant compared to capsules, and

(v) 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 excipients 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.

1.2.1.4 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.