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

CHAPTER ONE

Objectives Of Study

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.

Objectives Of Study

To optimize the composition of the co-processed excipient using the Design of Experiment (DoE) approach.
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).
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.
To characterize the deformation behaviour of the excipient using compaction models like Heckel and Kawakita equations.
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^®).

CHAPTER TWO

LITERATURE REVIEW

Development of novel excipients

More recently, few new excipients have been introduced into the market. The development of novel excipients so far has been market driven (i.e. excipients are developed in response to market demand) rather than marketing driven (i.e. excipients are developed first and market demand created through marketing strategies). One reason for this lack of new excipients is the relatively high cost involved in excipient development, including the toxicity profile. However, with the increasing number of new drug molecules with varying physicochemical, pharmacokinetic, permeation and stability properties, there is a growing interest among formulators to search for new excipients that have minimal scale-up problems, low manufacturing costs, and little environmental impact (Marwaha et al., 2010).

Other factors driving the search for new excipients as reported by Nachaegari and Bansal (2004) include the following:

The growing popularity of the direct compression process and demands for an ideal filler-binder that can replace two or more excipients, avoiding the need for multiple excipients in a formulation (i.e. disintegrant, binder, lubricant etc).
The increasing speed capabilities of tablet presses, which require excipients to maintain good compressibility and low weight variation even at short dwell times.
Shortcomings of existing excipients, such as loss of compaction upon wet granulation, high moisture sensitivity and poor die filling as a result of agglomeration.
The lack of excipients that addresses the needs of a patient, with a specific disease state such as those with diabetes, hypertension, and lactose and/or sorbitol sensitivity.
The ability to modulate the solubility, permeability, or stability of drug molecules.

Sources of novel excipients

Excipients with improved functionality can be obtained by developing a new chemical entity, new grades of existing materials or their combinations(Moreton, 2004). An excipient is only considered novel when it is a new chemical entity, a new route of administration is created by its use, a physical/chemical modification of an existing excipient is formed, a co-processed mixture of existing excipients is developed or a food additive is used for the first time for oral drug administration (Larner et al., 2006). In the last three decades, new grades of existing excipients have been developed, but only a few novel excipients have been introduced into the market (Chang and Chang, 2007).

New grades of existing excipients can be obtained by modifying fundamental properties, leading to improved derived (functional) properties (Odekuet al., 2008; Block et al., 2009). Fundamental characteristics, such as morphology, particle size, shape, surface area, porosity and density all determine excipient functional properties such as flowability, compressibility, compactibility, dilution potential, disintegration, and lubrication potential (Camargo, 2011).

Any new chemical entity being developed as an excipient must undergo various stages of regulatory approval aimed at addressing issues of safety and toxicity, which is a lengthy and costly process. The requirements of purity, safety, and functionality of the excipients are established and harmonized by the International Pharmaceutical Excipients Council (IPEC). In addition, similar to active ingredients, the excipient must undergo a phase of development, which shortens the market exclusivity period making the investment less attractive.

One of the solutions to the above problem was to develop drug products jointly, in which a new excipient becomes part of the new drug application. Thus, the combined expertise of pharmaceutical and excipient companies can lead to the development of tailor made innovative excipients. For example, Cydex Pharmaceuticals (Lenexa, KS) and Pfizer (New York, NY) worked collaboratively to obtain the approval of Captisol, a solubilizer for intravenous (IV) applications (Marwaha et al., 2010).

CHAPTER THREE

MATERIALS AND METHODS

Materials

Chemicals

The following chemicals as listed in Table 3.1 were used for the entire study.

Methods

Selection and optimization of the composition of the co-processed excipient using Design of Experiments (DoE)

A simple centroid (mixture) experimental design was used to select a desirable combination of the three excipients comprising the co-processed mixture. The content of cassava starch (factor A) was varied from 90 – 98 % while the limits for gelatin (factor B) and colloidal silicon dioxide (factor C) were kept at 1 – 9 %. The effect of these independent variables (factors A – C) on dependent variables (Y₁: tensile strength of tablet and Y₂: disintegration time of tablet) was studied using Design Expert^® software version 9 (Stat-Ease Inc., USA). A total of 14 experimental formulations were designed by the software with 4 centre points. Experiments were run in random order to increase the predictability of the model. A batch size of 30 g was prepared for each experimental formulation.

Tablets were prepared using Hydraulic Carver Press by compressing 400 mg powder at 2000 PSI (53.28 MN/m²) with a dwell time of 30 s using a flat-faced 13 mm punch and die set. The tablets were kept for 24 h to allow for elastic recovery before evaluation of physical properties.

CHAPTER FOUR

RESULTS

Selection of an optimized composition using DoE

The Design of Experiment (DoE) approach was used to optimize and select the best possible combination of the three excipients in preparing a co-processed excipient that will deliver the desired response of tensile strength and disintegration in the final formulation using the simple centroid (SC) experimental design. A summary of the tablet responses obtained for each experimental formulation is presented in Table 4.1. The responses obtained ranged from 2.34 – 4.34 MN/m2 for tensile strength and 0.16 – 4.08 min for disintegration time for all the experimental batches. Formulations having a higher concentration of gelatin in the co-processed mixture produced tablets with higher tensile strength and longer disintegration time.

CHAPTER FIVE

DISCUSSION

Selection of an optimized composition using DoE

The concept of quality by design (QbD) (Yu, 2008; Pawar et al., 2012; Larsen et al., 2014) was applied in this study to optimize the composition of the co-processed excipient, StarGelaSil (SGS). The mixture design model (Simple Centroid) of DoE was chosen as the experimental design because the product under investigation (co-processed excipient) is made up of several components/ingredients. Mixture design experiments accounts for the dependence of response on proportionality of ingredients (Cornell, 1990; Anderson and Whitcomb, 2002). This implies therefore that the functionality of the co-processed excipient under investigation is derivable directly from the relative proportions of the individual components that constitute the co-processed excipient.

Summary

Co-processing was employed as a particle engineering technique to improve the functionality of cassava starch in the formulation of ibuprofen tablets by direct compression. This was achieved by co-processing cassava starch with gelatin and colloidal silicon dioxide in optimized ratios to develop a robust excipient with a multifunctional profile.

Design of Experiment (DoE) was applied to optimize the composition of the co-processed excipient by determining the proportion by percentage weight of each of the ingredients used in co-processing. The optimized formula for preparing the coprocessed excipient, StarGelaSil (SGS) with a multifunctional profile was found to be Cassava starch (90 %), Gelatin (7.5 %) and Colloidal silicon dioxide (2.5 %) respectively.

Solid-state characterization of StarGelaSil revealed an increase in size of spherically-shaped particles with a rough surface. The birefringent property of cassava starch was not lost as a result of co-processing. The material was found to be largely amorphous in nature, moderately hygroscopic and compatible with the drug of choice for the study.

Flow and compression properties of StarGelaSil were enhanced when compared to cassava starch and the physical mixture of the constituent excipients. There was an improvement in the compressibility, tabletability and compactibility (CTC) profile of StarGelaSil when compared to the physical mixture of the constituent excipients.

Tablets produced by StarGelaSil met the USP/NF (2009) specifications for desirable tablets and compared well with tablets produced by Prosolv^® and StarLac^®.

Contribution to Knowledge

The application of a scientific approach (DoE) to optimize the composition of the co-processed excipient, SGS.
The study was able to show the distribution of gelatin in the matrix of the co-processed excipient using confocal laser scanning microscopy.
The development of a three-component multifunctional co-processed excipient containing cassava starch as the parent excipient.

Conclusion

The aim of this study was to improve the functionality of cassava starch for tablet formulation by direct compression. This was achieved by co-processing cassava starch with optimized quantities of gelatin and colloidal silicon dioxide as determined by Design of Experiment (DoE). The resulting excipient coded “StarGelaSil” exhibite superior characteristics required for tableting when compared to its parent excipient (Cassava starch) and the physical mixture, StarGelaSil-PM (SGS-PM). Ibuprofen tablets produced using StarGelaSil as the sole excipient were found to have met the USP specifications for desirable tablets and compared well with commercially available co-processed excipients (Prosolv® and StarLac®) in terms of performance. StarGelaSilcan therefore be put forward as a suitable excipient for tablet formulation by direct compression.

Recommendations for further study

Design of Experiment (DoE) can be applied to optimize the co-processing technique.
Further characterization studies at molecular level can be done to gain more insights into the basis for improved functionality as a result of co-processing.
Other compaction models like Walker, Rhyskewitch and Modified Heckel analysis can be employed to characterize the compaction behaviour of SGS.
Formulation studies can be carried out using other poorly compressible drug models.

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