Fundamentos del Sistema Nacional de Orientación

There are three general taste masking strategies, namely; the use of physical barriers, chemical or solubility modification and solid dispersions. Table 1.6 gives a list of the different techniques currently used for taste masking. Physical barrier methods are described in brief because they are the most common method. Solid dispersion strategies are discussed in further detail as one of these strategies is going to be used in this thesis.

TABLE 1.6 SUMMARY OF CLASSIFICATION AND EXAMPLES OF TASTE MASKING STRATEGIES

Taste Masking Strategies

Physical Barriers Chemical modification Solid dispersion Fluidised bed coating Chemical derivitisation Melt granulation

Micro-encapsulation Complexation Spray congealing

Supercritical fluids Melt extrusion

57

1.4.1 P

The simplest and most common method to taste mask a bitter API, especially chewable and liquid formulation is via physical barriers. A barrier coated onto the API could successfully provide a palatable oral dosage form, as sometimes such barriers prevent early dissolution of API in the oral cavity.

FLUIDISED BED COATING

This technology is commonly used to apply a continuous coat around the core particle.

Generally coating can be achieved using polymeric solutions or molten material. The atomisation of polymeric systems dispersed as solutions/suspensions in volatile organic solvent(s) and/ or aqueous vehicles are used to apply the film coat. While the use of organic solvents is generally fast with simplified film formation processes due to the dissolved nature of the polymer, the use of aqueous systems remains the preferred option. Aqueous systems are advantageous because of the absence of solvent toxicity, increase process safety and lower production costs. Despite these benefits, cases still remain where aqueous systems are inappropriate namely: API sensitivity to water resulting in degradation and migration of water leading to compromised quality of product (Bose et al. 2007). Alternatively, a solvent free process i.e. the atomisation of molten materials commonly known as melt coating has been adopted. This process requires application of low melting point materials maintained at temperature of about 40 – 60^oC above the melting point of the wax or polymeric component. When fatty acids or glycerol ester or low melting polymers such as polyethylene glycols are applied; the melt coating is performed in fluid bed coater with the aid of heating systems for atomised air to provide a molten spray plume (Cerea et al. 2008). A study has reported the preparation of diclofenac sodium granules with Eudragit L30 D-55®

by fluidised bed system. The subsequent dissolution studies confirmed the effectiveness of fluidised bed for applying enteric coated on diclofenac granules (Silva et al. 2006).

CHAPTER 1 INTRODUCTION

58

MICROENCAPSULATION

Microencapsulation is defined as a process by which small discrete solid materials, liquid droplets or gases are completely enveloped within an intact membrane. Taste masking is often achieved by applying an encapsulating barrier around an API. The barrier remains intact while the dosage form in administered. Following administration, the barrier allows API release either immediately or in a modified fashion. Ethyl cellulose microcapsules containing theophylline exhibited modified release performance. It was reported that the microcapsules demonstrated excellent taste masking properties (Golzi et al. 2004). This is because the API was released slowly.

Therefore an insufficient amount was release into the mouth to trigger a taste response prior to swallowing. There are several methods to achieve microencapsulation. The most common include: temperature-induced phase separation, emulsion solvent evaporation, solvent evaporation, film coating, non-solvent addition and spray drying. A very comprehensive review is described by Rogers et al (2011). The authors describe microencapsulation in terms of background and materials used (Rogers et al. 2011a), techniques used to make microcapsules (Rogers et al. 2011b) and applications (Rogers et al. 2011c).

SUPERCRITICAL FLUIDS

This is a rather limited approach which involves the use of supercritical fluids (SCFs). It is a one step process. The supercritical state is defined as a state where both the pressure and temperature of a substance are greater than its critical pressure (P_c) and critical temperature (T_c). The thermal and physical properties of SCFs fall in between pure liquids and pure gases. In a critical isotherm (between T_c and 1.2T_c), the density, viscosity, diffusivity and other physical properties, such as solvent strength and dielectric constant, can be varied in a range from gas like to liquid like with small changes around the critical pressure (0.9 – 2.0Pc) (Subramaniam et al. 1997). Carbon dioxide is one of the most commonly used supercritical solvents because of its relatively low critical temperature and pressure (Tc = 31.1^oC, Pc= 78.3bar)

59

(Bose et al. 2007). In this technique, essentially, the drug and polymer are dissolved in an organic solvent and then sprayed into a high pressure chamber filled with supercritical carbon dioxide (scCO₂). Rapid expansion supercritical solution (RESS) is the most common supercritical fluid process in pharmaceutical applications. The coating agent is solubilised in scCO₂ in a high pressure vessel. The API is dispersed in the SCF. The suspension is rapidly expanded by passing through a heated nozzle at supersonic speed. By so doing, the solvent power of carbon dioxide is reduced. This results in the coating material precipitating onto the particle of drug dispersed in the medium (Thies et al. 2003, Moribe et al. 2008). SCFs offer considerable promise for taste masking through the formation of micro-particles. However, this technique is not widely used because of its expensive running costs, limited polymer /drug solubility in carbon dioxide and insufficient drug loading in some cases.

1.4.2 S

MELT GRANULATION

This process involves the dispersion of the API into a molten mixture of highly water soluble sugars e.g. mannitol and xylitol. The mixture is heated above the eutectic temperature and then rapidly cooled to form a glassy solid. In some cases, solvents such as methanol, ethanol and polyethylene glycol are used to facilitate lower melting temperatures. The solvents are removed via cooling and solidification. In cases where the API is heat sensitive, a low melting point polymer can be used.

SPRAY CONGEALING

This method is used to change the structure of a material with the aim of obtaining free flowing powders. Generally, the API is allowed to melt, disperse or dissolve in a hot melt of an inert polymer and other additives. This molten mixture is sprayed into an air chamber where the temperature is below the melting point of the formulation components, the product of which are spherical congealed pellets which usually range from 0.25 to 2.0mm in size (Yajima et al. 2003). Spray congealing presents noticeable

CHAPTER 1 INTRODUCTION

60

advantages including the absence of solvent evaporation which makes the pellets non-porous, strong and remain intact on agitation. It is also a single step continuous process. However, the high temperature exposure of the API presents a problem for APIs that are thermally labile. If amorphous / anhydrous forms of the API are generated this alters the dissolution behaviour and by extension the release profile. Furthermore, coated particles maybe perceived as gritty in the mouth due to the fact that water-insoluble polymers remain intact in the mouth after all the other excipients have disintegrated or dissolved.

PRECIPITATION AND DRYING

This is a method of preparing stable dispersions of poorly soluble APIs in the presence of one or more stabilisers free of any toxic solvents. Initially, the poorly water soluble API is dissolved in a suitable solvent. This solution is added to another solution containing at least one surface stabiliser to form a second solution. The formulation is precipitated by adding an appropriate non solvent usually a polymer. The API is entrapped within the polymer matrix by in-situ complexation which eliminates the bitter taste and provides a good mouth feel. Any salt formed is removed by dialysis or filtration and concentrations of the dispersion by conventional means. Although precipitation can be applied to several APIs, in some cases, it is necessary to use harmful solvents. In addition, increased polymer-drug ratios are necessary to mask the bitter taste, resulting in a slow release profile.

MELT EXTRUSION

Melt extrusion is a well-known, solvent free approach which is generally accepted as a method to enhance the dissolution characteristics of poorly water soluble drugs. In taste masking, melt extrusion is performed by mixing API with an extrudable material e.g. Eudragit®. The process and pharmaceutical application of melt extrusion are described in detail in section 1.5

61