Metales Pesados: Cd y Pb

points and HLB values (Baykara and Yüksel, 1991).

On the other hand, 050/13 has a melting point high enough for controlled release and will not soften at the body temperature of 37°C. Some retardation o f sodium salicylate in the urinary excretion of human volunteers was found when aspirin mixed with 050/13 in hard gelatin capsules was administered (Djimbo et al, 1984). As mentioned previously, even though 050/13 has the nominal melting point o f 50°C, it would be more accurate to describe it as a melting range due to the existence of the various components. The melting points of just the main fatty acids that make this gelucire up are given below (Table 1.4). In addition, PEO 1500 which is the PEO incorporated into 050/13 has a melting point between 42-45°C (Ford et al, 1984).

Table 1.4: The melting and boiling points of the main 050/13 fatty acids (Ounstone, 1994). Chain length

( C „ )

Systematic name

Trivial name Acid melting point (°C) Acid boiling point (°C) 12 dodecanoic lauric 44.8 130 14 tetradecanoic myristic 54.4 149 16 hexadecanoic palmitic 62.9 167 18 octadecanoic stearic 70.1 184

050/13 exhibited a gelling ability which meant that even at high temperatures, which were close to its melting range, its matrices were still pliable and able to maintain their integrity which was important for sustaining its controlled-release properties (Kopcha et al, 1991). In an aqueous medium, 050/13 showed a degree o f solubilization and disintegration but stayed intact which allowed salbutamol to be completely released in 8 to 10 hours thus achieving a sustained release profile (Esquisabel et al, 1996). This capacity to alter its dimensions whilst still retaining appropriate release behaviour was also demonstrated by its ability to swell about twice more than that shown by 0 3 5 /1 0 but without significantly altering the release rates (Prapaitrakul et al, 1991).

Incorporation into a variety of gelucires o f a basic drug which existed in two different polymorphic forms showed that the best profile for a prolonged release was demonstrated

Chapter 1: Introduction....38

by G50/13. The drug which was soluble in G50/13 was also converted to its most stable form in the carrier (Mouricout et al, 1990). Drugs which are normally difficult to formulate such as those which are oily liquids, sensitive to air and light, hygroscopic or deliquescent were found to give the most favourable release profiles when incorporated into G50/13 matrices (Doelker et al, 1986).

1.1.6 M anufacturing factors that affect gelucire behaviour

The properties of gelucires can be affected by the preparation conditions used to manufacture the matrices. Cooling rates appeared not to only affect the structure of the carrier as elucidated from thermal analysis but also the dissolution behaviour (Sutananta et al, 1995b). Theophylline release from G55/18 was shown to be markedly different in samples which were slow-cooled or rapidly-cooled during matrix setting, not only in terms of release rates but also release mechanisms. G50/13 also exhibited a dependence on the cooling rate with the slow-cooled samples giving a greater release than the fast-cooled samples. However, the difference in the G55/18 system was attributed to the variation in the crystal structure of the samples whilst the difference in the G50/13 was associated with the redistribution of constituents within the sample. This demonstrates the need to remove all thermal history from such glyceridic bases by heating them above their melting points so that the performance of new formulations are not affected by previous manufacturing processes.

The melt-fusion process for the fabrication of matrices is the method frequently used for gelucires. One of the first sets of investigators advocating this method was Sekiguchi and Obi (1961) who dispersed the poorly soluble sulphathiazole in the soluble carrier, urea, which resulted in the rapid release o f the drug. The dispersion o f finer drug crystallites within the matrix could also be achieved by quenching a supersaturated drug/carrier mixture from a high temperature (Chiou and Riegelman, 1971). This type of dispersion would be superior to the fine drug particles produced by grinding, milling, etc. because the latter could exhibit agglomeration and poor wettability in water. One o f the drawbacks of this technique is that heating is necessary and for drugs which are volatile or those which readily decompose, fusion at high temperatures is not viable. It is important therefore, to

Chapter 1: Introduction....39

select a gelucire with a melting range low enough if such drugs are to be incorporated. One advantage that gelucire offers is that it is thixotropic and can remain fluid at low temperatures with constant stirring (Gattefossé, 1983).

1.2 Controlled-release formulations and their mechanisms of drug release

In general terms, controlled release formulations can be divided into three broad categories which reflect the mechanisms that are responsible for their actions; diffusion, osmosis and polymer erosion (Heller, 1984). However, these categories are not exclusive as each formulation can be governed by more than one mechanism. For example, rate of drug release from erosional devices is usually modulated by both diffusion and erosion processes whilst rate of release from osmotic devices is controlled by the diffusion of water across a semi-permeable membrane combined with osmotic forces.

Polymer erosion can be further subdivided according to the mechanisms that change the polymer properties. Type 1 erosion involves the hydrolytic cleavage of water soluble polymers that are made insoluble by covalent cross-links. This cleavage can take place at the cross-links themselves or at the backbone of the chain, thus releasing the water-soluble polymers. Type 2 erosion occurs through the hydrolysis, ionization or protonation o f a pendant group which would make the polymer soluble in water. Type 3 erosion is like Type I except it occurs not in polymers with covalent cross-links but simple insoluble chains made soluble by backbone cleavages which release small molecules. Again, these classifications are not exclusive and an erosional process can be a combination of the above categories. Erosional processes are designed to give a zero-order rate o f release, so that release is constant over a period o f time. However, a completely zero-order release is difficult to obtain because frequently, the diffusional process also play a part in drug release in a particular controlled-release matrix.

Diffusional release follows a square-root of time profile, as described by Higuchi (1963). A matrix with a drug dissolved or dispersed in it, when placed in a dissolution medium which is thermodynamically compatible with the polymer, will swell with the formation of a polymeric gel phase (Peppas et al, 1980). Even though such a process is frequently quoted

Chapter 1: Introduction....40

for hydrophilic polymers such as HPMC, it could also be applied to a certain extent to hydrophilic gelucires like G50/13 because those gelucires are also composed of long repetitive hydrocarbon chains, moreover esterified with PEG chains which give them the hydrophilic character. In addition, many studies concerning gelucires have reported the swelling o f matrices incorporated with the carriers. Diffusion can be diagrammatically represented as below (Figure 1.4) if the process is taken to come from a single surface of the matrix, for simplicity.

A is an inert substrate, B is the solvent-free polymer, C is the swollen polymeric gel and D is the surrounding swelling medium. X*(t) is the position o f the polymer/gel interface, is the initial thickness of the matrix tablet and L(t) is the position of gel/medium interface.

Figure 1.4: Diagrammatic representation of drug diffusion in a swellable polymer.

A ' / ' B

X*(t)

D

0

If Dj and Dj are the drug diffusion coefficients in the dry polymer and in the gel-like phase respectively, then 6 is the diffusitivity ratio D^/Dg. P is a dimensionless constant described by MgSg/p where M, is the molecular weight of the medium, Sg is the initial concentration of the medium and p is the density o f the medium. is the dimensionless position described by X*/Lg (see Figure 1.4). C* is the concentration of the drug at the polymer/gel interface. The relationship between all these parameters is evident in the equation describing the position of the polymer/gel interface (Equation 1.1) (Peppas et al, 1980).

Chapter 1: Introduction....41

~ X I ....Equation 1.1

2 e ( i - C * ) exp(-7T ^ /2^ )

When a matrix is placed in a liquid medium, the drug within it will diffuse outwards while a countercurrent diffusion of the medium, D, into the matrix occurs. This relaxes the polymer and a gel-like swollen layer is formed. The interface between the dry polymer and the gel phase is a constantly moving front. As dissolution progresses, the interface recedes and the gel layer thickens. The drug now has a longer distance to travel with the added tortuosity and therefore, the release is slightly retarded, giving the square-root o f time kinetics. More details of these erosional and diffusional processes will be given in Section

1 o f Chapters 4 and 5.

1.3 Fatty acids and glycerides

Although gelucires have already been used for a variety of purposes, comparatively little is known regarding their physical and performance characteristics. This is partly due to the wide range of different components making up the gelucires, as exemplified by G50/13 (Table 1.3), resulting in physical and chemical complexity. Even small concentrations of the minor constituents can influence the solidification and melting characteristics o f a fat which is made up of several components (Dimick, 1991).

The different components can exert individual effects or interact between each other to influence the characteristics o f the gelucire matrix. Moreover, the glyceride and fatty acid components may show polymorphism which can have additional effects on the matrix behaviour. The occurrence o f polymorphism in lipids will be discussed in the following section.

1,3,1 Polymorphism in fa tty acids and glycerides

Polymorphism is a phenomenon that has long been established to occur in fatty acids. It is defined as “the ability to reveal different unit cell structures in crystal, originating from a variety o f molecular conformations and molecular packings” (Sato and Garti, 1988) or in other words, the ability of a substance to exist in more than one crystalline form. The