Surface tension

The surface tension of coating solutions is likely to have a profound effect on the process of film coating. It will influence droplet generation from bulk solution, behaviour during travel to the substrate and the fate of the droplets once they hit the tablet or multiparticulate substrate. The latter will also be influenced by the interfacial tension between the atomized droplet and either the naked tablet or pellet core or the partially coated substrate. Changes in surface tension will influence wetting, spreading, coalescence and thus the adhesion of the dried film, and these points are discussed in Chapter 5. The specific case of the surface tension of aqueous HPMC solutions is discussed below.

The surface tension of HPMC solutions

HPMC is itself surface active and reduces the surface tension of water; this reduction occurs at very low concentrations. Fig. 4.2 illustrates the surface tension/ concentration profile exhibited by very dilute HPMC E5 solutions at equilibrium.

There is a linear decrease in equilibrium surface tension with increasing concentration from 72.8 mN/m (at 20°C) for water alone up to a concentration of approximately 2×10⁻⁵ %w/w. After this point there is an abrupt change in the gradient of the line and the surface tension falls far less steeply with increasing concentration. The point of intersection between the extrapolated straight lines on either side of the break in the curve is analogous to the critical micelle concentration commonly shown by surface-active materials.

Table 4.1 The density of a range of aqueous film-coating formulations based on HPMC E5 HPMC E5 concentration (%

w/w) Additive Additive concentration (%

w/w) Temperature (°

Fig. 4.2 The relationship between HPMC E5 concentration and equilibrium solution surface tension at low HPMC concentrations.

Table 4.2 shows the surface tension of much more concentrated HPMC E5 solutions at various temperatures.

It illustrates that with HPMC E5 solutions of concentrations between 1 and 12 %w/w (i.e.

encompassing those likely to be used in practice for aqueous film coating) there is very little variation in surface tension, its value reducing with increasing concentration from 46.8 to 44.5 mN/m at 20°C. Thus, although a considerable reduction in surface tension occurs up to 1 %w/w HPMC E5, minimal further reduction occurs between 1 and 12 %w/w HPMC E5.

Table 4.2 also shows that increasing solution temperature has minimal effect on its surface tension.

Increasing the temperature of a 9 %w/w solution of HPMC E5 from 20 to 40°C was found to result in a reduction in surface tension of only about

1 mN/m. Water over the same temperature range would be expected to exhibit a reduction in surface tension of about 4 mN/m (Bikerman, 1970), this being due to the gradual reduction in intermolecular cohesive forces as the temperature increases (surface tension will be zero at some finite temperature).

The difference in behaviour between HPMC E5 solutions and water probably results from the non-volatile nature of HPMC, with the situation being complicated by the differing levels of solvation of HPMC at different temperatures.

Any reduction in surface tension, in the absence of other changes in physical properties, would be expected to favour droplet formation and influence solution spreading on a tablet or multiparticulate surface. The data in Table 4.2 would appear, however, to indicate that any effects caused by the reduction in surface tension with increasing concentration or temperature are likely to be minimal.

Surface ageing

The data presented above are for equilibrium situations in which migration of the surface-active HPMC molecules to the surface of the liquid is complete and a dynamic equilibrium has been reached.

However, in practical situations enormous areas of fresh liquid surface are produced during

atomization. The large HPMC molecules will take a finite time to migrate to the surface, and thus there will be a time-dependent reduction in the observed surface tension (see section 5.2.2). This phenomenon is known as surface ageing. It is quite possible that the actual surface tension of HPMC droplets is far higher than the values measured in an equilibrium situation. The consequences of this are discussed in Chapter 5.

Table 4.2 The effect of polymer concentration and solution temperature on the surface tension of a range of aqueous HPMC E5 solutions

HPMC E5 concentration (%w/w) Temperature (°C) Surface tension (mN/m)

1 20 46.8

The effect of formulation additives on the surface tension of HPMC E5 solutions at different temperatures

The inclusion of additives (such as plasticizers, opacifiers, etc.) also has little effect on surface tension over a range of concentrations and temperatures (Table 4.3). The surfactants sodium lauryl sulphate and polysorbate 20 caused the largest decrease in surface tension although this reduction was relatively small, being approximately 5 mN/m.

The minimal effect that the addition of plasticizers has on the surface tension of 9 %w/w HPMC E5 solutions is perhaps not surprising since the surface tension of 2 %w/w solutions of these plasticizers is above 66 mN/m in each case.

Table 4.3 The effect of various formulation additives on the surface tension of 9%w/w HPMC E5 solutions over a range of temperatures

Formulation additive Additive concentration (%w/w) Temperature (°C) Surface tension (mN/m)

PEG 200 3 20 45.6

If the addition of a surfactant to HPMC E5 solutions was required, it may be preferable to use polysorbate 20 rather than sodium lauryl sulphate since the latter may cause significant increases in solution viscosity (see section 4.2.4, Fig. 4.7).

4.2.4 Viscosity

The rheological properties of a polymer solution depend mainly on the following parameters:

It is beneficial to assess how these factors influence the rheological profiles of filmcoating polymer formulations in order to gain an understanding of how formulations may behave during the film-coating process.

Commercial grades of coating polymers are not monodisperse, but are known to contain polymer molecules covering a wide range of degrees of polymerization and hence chain lengths (Rowe, 1980;

Tufnell et al., 1983; Davies, 1985). Molecular weight fractions between 10³ and 10⁶ Da (Rowe, 1980) and 10² and 10⁶ Da (Davies, 1985) have been found to exist for HPMC.

The molecular weight distribution of a polymer can be described by characteristic molecular weight averages. These include number-average molecular weights, M_N, and weight-average molecular weights, M_W where:

(4.3)

(4.4)

and there are n_i molecules of molecular weight M_i.

Examination of these equations indicates that the value of M_N is particularly influenced by the presence of small amounts of low molecular weight fractions of the polymer and M_W by small amounts of high molecular weight fractions. It can also be calculated that, always, M_W≥M_N.

The degree of polydispersity of a polymer can be defined by the polydispersity index (Q) where

(4.5)

1. polymer size and shape;

2. polymer-polymer and polymer-dispersion medium molecular interactions;

3. polymer concentration;

4. solution or suspension temperature;

5. viscosity of the solvent or dispersion medium.

The average molecular weight and molecular weight distribution of polymers are important factors in the coating process since they will influence not only solution

viscosity, but also the mechanical properties of the final film coat (Rowe, 1976, see also Chapter 12).

Several authors have attempted to characterize the molecular weight of HPMC (Rowe, 1980; Tufnell et al., 1983; Davies, 1985). Absolute methods of analysis, such as light scattering, which allow

molecular weights to be determined directly from experimental data, have been found to be unsuitable for HPMC (Tufnell et al., 1983; Davies, 1985). The technique that has been used successfully is gel permeation chromatography (GPC) which allows the determination of M_N, M_W and the degree of polydispersity (Q) for polymers having a wide range of molecular weights. GPC, however, suffers from the disadvantage that since no monodisperse fractionated samples of HPMC are available, the gel bed has to be calibrated with other standards, such as dextrans. The molecular weight values derived for HPMC must therefore be expressed as values equivalent to the standard molecule used. Since the hydrodynamic volume of an HPMC molecule may be different to that of the standard molecule and will vary depending on the solvent used, the molar mass expressed as an equivalent to a standard molecule is likely to be different to the absolute molecular weight. In practice, different GPC systems have been shown to produce different molecular weight values for the same HPMC sample (Davies, 1985).

The rheological properties of HPMC solutions

Dilute aqueous solutions of HPMC E5 consist of randomly orientated and randomly extended coils of hydrated molecules of a wide range of sizes, with their configuration and degree of solvation changing continuously due to random bombardment by solvent molecules. Each molecule will tend to act as a single entity with little or no intra- or intermolecular interactions (Davies, 1985). This would explain why dilute aqueous solutions of HPMC grades with low nominal viscosities exhibit Newtonian behaviour.

Polymer concentration

HPMC solution viscosity was found (Twitchell, 1990) to vary more than any other solution property for a range of coating formulations. Data for two commercial batches of HPMC E5 are shown in Table 4.4 as an indication of the interbatch variation that is typical of most polymeric coating materals. The concentration of HPMC in solution has a profound effect on solution viscosity, with this effect

increasing with increasing concentration. For example, a doubling in concentration from 6 to 12 %w/w causes a greater than ten-fold increase in viscosity. The data in Table 4.4 are shown graphically in Figure 4.3.

Fig. 4.3 illustrates how the viscosity of HPMC solutions increases markedly with HPMC concentration. Note particularly how the gradient of the viscosity-concen-tration plot becomes

extremely steep after solution concentrations above 10 %w/w. It is tempting when preparing a coating solution to have the concentration of dissolved polymer as high as possible (i.e. a ‘high solids loading’) in order to reduce the application time and the amount of solvent that needs to be evaporated. This is particularly so in the case of water, due to its high latent heat of vaporization.

However, these solutions will be very viscous. The consequences of using high viscosity polymer solutions are discussed fully in Chapter 13.

Many attempts have been made by scientists to linearize such viscosity-concentration data. Pickard (1979), Delporte (1980) and Prater (1982), in attempting to determine a relationship between viscosity and HPMC E5 solution concentration, found that plots of log viscosity versus solution concentration were not linear. Philippoff (1936), however, had demonstrated for methylcellulose that if the eighth root of viscosity was plotted against concentration (%w/v) a straight line resulted. This latter relationship was also found by Aulton et al. (1986) to be applicable for HPMC E5. The result of a Philippoff plot for aqueous HPMC E5 solutions is shown in Fig. 4.4.

It is apparent from Fig. 4.3 that there is a very large increase in viscosity as increased concentrations of HPMC E5 are dissolved in water, a 12 %w/w solution, for example, being around 500 times more viscous than water alone. One contributing factor to this is the large hydrodynamic volume of the randomly coiled polymer chains and their associated hydrogen-bonded water molecules. These large flow units increase the resistance to flow and thus viscosity. The work of Davies (1985) suggests additionally that a significant amount of water is located within the random coil of the polymer. With HPMC E5 molecules this is thought to be non-draining, the water being mechanically trapped within the polymer coil and dragged along with the macromolecule during flow. This further increases resistance to flow and also decreases the amount of remaining free solvent.

As explained previously, commercial grades of HPMC are polydisperse in nature, consisting of a wide range of molecular weight fractions. Of these, the larger molecular weight fractions contribute to the viscosity to an extent which is disproportion-ate to their concentration on a weight basis. Thus a HPMC molecule with a degree of polymerization of 200 will produce a viscosity far higher than if the 200 individual units were present. This occurs since the cooperative nature of the flow of the 200 unit Table 4.4 The effect of HPMC E5 concentration on aqueous solution viscosity at 20°C for two batches of polymer

HPMC E5 concentration (%w/w) Viscosity (mPa s)

Batch 1 Batch 2

* These solutions are non-Newtonian. The figures quoted are apparent Newtonian viscosities calculated using a power-law equation.

Fig. 4.3 Viscosity versus concentration curves for aqueous solutions of HPMC E5 at 20°C.

Two sets of data are shown, corresponding to the two batches of HPMC E5 referred to in Table 4.4.

chain and its accompanying water molecules, which move together with the polymer, results in a very large flow unit. The work of Davies (1985) appears to support this although the data from Rowe (1980) show there to be no correlation between the viscosity at 2 %w/v and the value of the weight-average molecular weight.

For higher polymer concentrations where pseudoplastic flow is exhibited, the polymer chains, when under conditions of increasing shear, become progressively untangled and the hydrogen bonds may be broken, resulting in a reduction in the dimensions of the polymer and the release of any entrapped solvent, resulting in turn in a reduction in the disturbance to flow and therefore a reduction in viscosity.

Fig. 4.4 Graph of the eighth root of viscosity against concentration for aqueous solutions of HPMC E5 at 20°C.

During the film-coating process it is likely that film coat formulations will encounter a wide range of shear rates. These range from the low values in the tubing delivering solutions to the spray gun, to values of around 300 to 20 000 s⁻¹ as they pass through the liquid spray nozzle (values calculated from equations in Henderson et al., 1961) and to highly variable shear rates produced by the high-velocity atomizing air at the droplet production stage. Once impinged on the substrate, the shear rate encountered will be dependent on the atomization conditions and the tumbling action of tablets occurring in a coating pan or multiparticulates moving vigorously in a fluidized bed. Newtonian solutions are likely to exhibit the same rheological behaviour at all stages of the coating process irrespective of the shear rate

encountered. At temperatures below approximately 45–50°C, dilute HPMC E5 solutions

behave as Newtonian liquids. It is probable, however, that coating solutions or suspensions which exhibit non-Newtonian behaviour may vary in viscosity at various stages during the coating process and when different coating conditions and coating equipment are used.

Fig. 4.3 showed that at the higher HPMC E5 concentrations small changes in concentration result in relatively large increases in viscosity. For example, the viscosity of an 11 %w/w solution is 350 mPa s whereas a 12% w/w solution has a viscosity of 520 mPa s. This concept may be of importance in relation to any evaporation that occurs from atomized droplets before they impinge on the substrate surface. If, for example, 20 % of the water is lost from the droplets during their passage to a tablet bed in a perforated pan coater, as suggested by Yoakam and Campbell (1984), then solutions initially of 6 % w/w and having a viscosity of 45 mPa s would hit the tablet with a concentration of 7.4 %w/w and a viscosity of approximately 80 mPa s. Similarly, droplets from 9 and 12 %w/w solutions may increase in viscosity from 166 to 360 mPa s and from 520 to 1265 mPa s, respectively. In the case of a 12 %w/w solution this is likely to be accompanied by a change in the rheological nature of the solution from Newtonian to pseudoplastic. Large differences may therefore potentially exist between the viscosity of the droplets and that of the bulk solution, with this effect becoming considerably greater as the initial solution concentration increases. The extent to which these changes in viscosity may occur during the coating process will be dependent on a number of factors, such as the temperature and humidity of the drying air, droplet size and the time taken to reach the tablet or multiparticulate surface.

The viscosity of most aqueous solutions is reduced by elevating their temperature. This is also true for HPMC, as is shown in Fig. 4.5.

As might be expected, a rise in temperature decreases solution viscosity, but one must be aware that HPMC solutions undergo thermal gelation at temperatures just above 50°C. The phenomenon of thermal gelation of HPMC solutions is discussed below.

The reduction in viscosity with increasing solution temperature is more pronounced at lower temperatures and higher solution concentrations. For the example data given, a temperature increase from 10 to 20°C results in a viscosity decrease of 17 mPa s for a 6 %w/w solution, 66 mPa s for a 9 % w/w solution and 216 mPa s for 12 %w/w solution. A temperature increase from 20 to 30°C, however, results in falls of only 10, 35 and 115 mPa s respectively.

Thermal gelation

Aqueous HPMC solutions exhibit the property of thermal gelation—that is, if a solution is heated above a certain temperature, a gel network is formed.

The thermal gelation temperature of HPMC E5 is often taken as the temperature at which the trend of decreasing viscosity with increasing temperature is reversed (Prater, 1982). This definition will

generate, however, markedly different values of the gelation temperature depending on the shear rate at which the apparent viscosity is measured. Twitchell (1990) took the thermal gelation temperature as that

Fig. 4.5 The effect of solution temperature on the viscosity of aqueous HPMC E5 solutions of different concentrations.

temperature at which thixotropic behaviour was noted, since this is indicative of the formation of a gel structure and its breakdown on the application of shear forces.

If the temperature of dilute HPMC E5 solutions is raised above 50°C, there is a change in the shape of the rheological profile. Deviation from linearity occurs and there is evidence of pseudoplasticity.

Plots of the logarithm of viscosity versus the reciprocal of absolute temperature for 6, 9 and 12 %w/w aqueous solutions of HPMC E5 appear to be linear up to a temperature of approximately 45°C. At temperatures above 45°C deviation from linearity is observed. These findings are probably associated with the changing of rheological behaviour as the solution temperature approaches 50°C. Around this

temperature, the extent of the desolvation of the polymer is such that polymer-water bonds are replaced by polymer-polymer bonds, resulting in associations between polymer chains and a restriction in the flow of the continuous phase. When the solution is sheared increasingly, the chains become more linearly orientated and any structure formed may be broken, resulting in a decrease in apparent viscosity.

At temperatures above about 52°C, thermal gelation occurs at most HPMC solution concentrations.

This is due to the formation of a structured gel network in which the solvent is entrapped between chains of hydrogen-bonded polymer. For the many HPMC E5 solutions studied, Twitchell (1990) found no detectable differences in the thermal gelation temperature, this being 52±1°C in each case.

Heating the HPMC E5 solutions to temperatures above approximately 60°C results in precipitation of the polymer and a decrease in viscosity. HPMC solutions which undergo thermal gelation will revert to their original rheological behaviour on cooling to 20°C.

A temperature rise from 20 to 40°C results in an approximate halving of the viscosities of the three concentrations studied (Fig. 4.5). It has been suggested that this behaviour could be exploited during the film coating process, since if HPMC E5 solutions were heated prior to use, then a greater solids loading could be achieved for a particular viscosity value, leaving atomization unchanged and the coating process time reduced (Hogan, 1982). Care must be taken, however, in controlling the temperature in industrial coating or employing temperature as a means of viscosity control for HPMC coating

solutions, since heating HPMC solutions above their thermal gelation temperature will result in a semi-solid, unsprayable solution. Secondly, an excessive drying air temperature in a coater may result in atomized droplets gelling before they hit the substrate surface (however, this is unlikely, as a result of evaporative cooling).

It is important also to be aware that the gelation temperatures of the HPMC solutions used in aqueous film coating may be affected by the addition of commonly used formulation additives, so that factors leading to the phenomenon occurring in practice can be avoided. Reduction of the gelation temperature, to 37°C or below for example, has been associated with the reduction in release rate from coated tablets (Schwartz & Alvino, 1976).

In order to avoid changes in rheological behaviour and the problems associated with thermal gelation

In order to avoid changes in rheological behaviour and the problems associated with thermal gelation