Tài liệu Pharmaceutical Coating Technology (Part 4) pdf

Page 64 4 Solution properties and atomization in film coating Michael E.Aulton and Andrew M.Twitchell SUMMARY A little-considered stage of the film-coating process is the atomization of the coating solution by the spray gun. This chapter will show how formulation and process factors can cause marked changes in the characteristics of the spray, which may have important consequences for film formation and film properties. The chapter begins by describing how film-coating solution or suspension properties, such as density, surface tension and viscosity, alter with changing formulation and then continues by presenting predictions of how these properties could influence spray droplet size. The chapter then discusses various techniques for measuring and representing mean droplet size and size distribution. The influence of formulation and atomization conditions on spray characteristics is discussed and data are presented for aqueous HPMC droplets produced under a wide range of conditions. Parameters examined include concentration of polymer in solution, atomizing air pressure, liquid flow rate (spray rate), gun-to-substrate distance, spray-gun design, spray shape, liquid nozzle diameter and atomizing air velocity. 4.1 INTRODUCTION The overall process of film coating comprises a number of important stages: • Solution or suspension preparation. • Droplet generation. Page 65 All the above are important stages that need to be understood and, where possible, controlled. These stages are outlined schematically in Fig. 4.1 . Atomization has been found to be a particularly important stage in the overall process of film coating. This chapter will discuss the factors which influence the atomization stage—i.e. formulation variables and process variables. The ways in which these factors affect the quality of the film coat in terms of visual examination (both macroscopically and by scanning electron microscopy), film thickness (by light-section microscopy) and surface roughness (by profilimetry) are discussed in Chapter 13 . 4.2 SOLUTION PROPERTIES 4.2.1 Introduction The physical properties of film-coating solutions or suspensions can potentially Fig. 4.1 Schematic representation of the stages in spray film coating. • Droplet travel from the spray gun to the substrate bed. The substrate in question will usually be either a tumbling bed of tablets or a fluidized bed of multiparticulates, i.e. beadlets or pellets. • Impingement, wetting, spreading and coalescence of the droplets at the surface of the tablet or multiparticulate. • Subsequent drying, gelation and adhesion of the film. Page 66 exert an influence at many stages during the film-coating process. These stages include delivery to and droplet production at the atomizing device, travel to the tablet or multiparticulate surface and the wetting, spreading, penetration, evaporation and adhesion of the atomized formulation at the substrate surface. It is important, therefore, to quantify the physical properties of the coating solutions and suspensions that are to be used in the film-coating process in order that their influence on the appearance and properties of the final film coat can be appreciated. The following discussion reviews the areas where the physical properties of the coating solution or suspension may be of importance during the atomization of the droplets and their travel to the tablet or multiparticulate bed. The way in which solution properties influence the wetting, spreading and adhesion of these droplets is discussed in Chapter 5 . How, in turn, these properties influence the quality of the resulting coat is described in Chapter 13 . Little work has been published to date on the effect of solution physical properties on the droplet size distribution or spray shape produced during atomization of film-coating solutions. Schæfer and Wørts (1977), when studying the fluidized-bed granulation process, found with aqueous granulating fluids based on gelatin, methylcellulose, carboxymethylcellulose and polyvinylpyrollidone (PVP), that the higher the solution viscosity, the larger were the droplets formed on atomization. Banks (1981), however, found that with aqueous solutions of PVP K30, increasing the concentration from 5 %w/v to 10 %w/v did not produce a significant change in droplet size, the effect of the viscosity increase being overridden by other factors. The same author also demonstrated that the addition of sodium lauryl sulphate in increasing quantities to PVP- based granulating fluids caused both an increase in the diameter of the spray cone produced on atomization and a reduction in the distance from the spray gun at which the spray maintained its integrity in terms of general shape and pattern. These effects were attributed to the lower surface tension produced by the addition of the surfactant. Work carried out with a variety of other (i.e. non-film-coating) materials and processes has yielded various predictive equations describing how changes in viscosity, surface tension and density affect the quality of the spray. These equations illustrate a wide divergence of findings on the relative importance of these variables. This is due presumably to the wide range of atomizer designs used in the experiments, probably indicating that each equation is valid for the test conditions studied but fails when extrapolated to other systems. The process of airless (hydraulic) atomization (which is used for organic coating systems) is not complicated by the volume, velocity and density of the atomizing gas, as is airborne (pneumatic) atomization. For airless atomization, Fair (1974) suggested the use of equation (4.1) as a guide to the effect of solution properties on the average droplet diameter produced during atomization. (4.1) Page 67 In this equation D VM is the volume mean droplet diameter (see section 4.3.2) and γ, µ and ρ the surface tension, viscosity and density, respectively. More complex equations have been developed for predicting droplet sizes produced by pneumatic atomization. An often-quoted example is that of Nukiyama & Tanasawa (1939), an adapted form of which is: (4.2) Here D s is the surface mean diameter of the droplets (µm), v is the velocity of air relative to liquid at the atomizer nozzle exit (m/s), γ is the liquid surface tension (N/m), ρ is the liquid density (kg/m 3 ), µ is the liquid viscosity (Pa s) and J is the air/liquid volume ratio at the air and liquid orifices. Both these equations indicate that the solution physical properties of viscosity, surface tension and density will influence the atomization process and therefore potentially could affect the quality of the final film coat. Once atomized, the physical properties of the droplets may influence their behaviour during passage to the substrate to be coated. The viscosity of the droplet may affect solvent evaporation rate, with droplets of higher viscosity exhibiting reduced evaporation. Similarly, any surface-active components may form a layer on the surface of the droplets which could retard evaporation. The surface tension and viscosity of the droplet may also affect the tendency of the airborne droplets to coalesce. Thus, of the solution properties which could exert an influence, the following are most likely to have the greatest effect during the atomization of film coat formulations: These properties of solutions have been investigated in some detail for aqueous hydroxypropyl methylcellulose (HPMC E5) (Methocel E5) solutions (Aulton et al., 1986; Twitchell, 1990). The results of some of this work are discussed below. Unless stated otherwise, all data presented are the result of these studies. In examining these data for HPMC E5 it could be considered that many of these relationships will probably also be applicable to other grades and types of polymer. 4.2.2 Density Table 4.1 shows the density values for a range of HPMC E5 formulations at 20°C and 40°C. Density is found to vary little between these formulations and over the temperature range used in practice, and thus is likely to contribute little to any changes in droplet size distribution. Again it is possible that a similar situation occurs with other grades of HPMC and for dispersion systems, although there is little published data to support this. 1. density 2. surface tension 3. viscosity. Page 68 4.2.3 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 (° C) Formulation density (kg/m 3 ) 5 — — 20 1010 9 — — 20 1021 9 — — 40 1014 12 — — 20 1029 12 — — 40 1022 9 Opaspray 15 20 1044 9 Opaspray 15 40 1038 9 PEG 200 3 20 1025 9 PEG 200 3 40 1019 9 Glycerol 3 20 1028 9 Glycerol 3 40 1020 Page 69 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 Page 70 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 1 30 46.3 1 40 46.0 5 20 46.2 5 30 45.8 5 40 45.6 9 20 45.7 9 30 44.8 9 40 44.5 12 20 44.5 12 30 44.1 12 40 43.9 Page 71 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 PEG 200 3 30 45.0 PEG 200 3 40 44.9 PEG 400 3 20 45.6 PEG 400 3 30 45.2 PEG 400 3 40 44.7 PEG 1500 3 20 45.6 PEG 1500 3 30 44.9 PEG 1500 3 40 44.8 Glycerol 3 20 45.7 Glycerol 3 30 45.5 Glycerol 3 40 45.0 Propylene glycol 3 20 45.7 Propylene glycol 3 30 45.0 Propylene glycol 3 40 44.9 Opaspray 15 20 46.9 Opaspray 15 30 45.2 Opaspray 15 40 45.0 Polysorbate 20 0.5 20 42.1 Polysorbate 20 0.5 40 40.8 Polysorbate 20 1.0 20 41.2 Polysorbate 20 1.0 40 40.3 Sodium lauryl sulphate 0.5 20 41.3 Sodium lauryl sulphate 0.5 40 40.5 Sodium lauryl sulphate 1.0 20 39.9 Sodium lauryl sulphate 1.0 40 39.4 Page 72 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 10 3 and 10 6 Da (Rowe, 1980) and 10 2 and 10 6 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. If the polymer is monosize, then M W =M N and Q=1. The average molecular weight and molecular weight distribution of polymers are important factors in the coating process since they will influence not only solution [...]... aqueous film coating, it is important that HPMC E5 solutions are not subjected to temperatures over approximately 45°C at any point in the coating process Similarly, it should be remembered that the viscosity of a coating solution may vary considerably at different points in the coating process if it is subjected to fluctuating temperatures (Fig 4.5) These temperature changes may occur in the coating solution... and film coating In film coating the utilization of atomization techniques enables the coating polymer to be efficiently applied to a granule, pellet, bead or tablet core surface Atomized droplets hitting the substrate during film coating should be in such a state that they spread evenly over the surface and form a Page 92 smooth continuous film of even thickness The atomization stage of the coating. .. viscous coating solutions demand that the flow rates produced are relatively high even with very small orifice diameters This is acceptable with highly volatile organic solvents, but when water is used, as is the preferred practice in pharmaceutical coating, the ability of the coating equipment to evaporate the solvent satisfactorily may be overcome and the product overwetted, resulting in poor-quality coatings... 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,... multiparticulate core and the gloss and roughness of the coat The extent to which the physical properties of the film -coating solutions affect the various stages of the coating process becomes clearer after examination of the actual droplet sizes produced during film coating (see section 4 .4) and the properties of film coats produced in a practical situation (Chapters 12 and 13) Page 86 4.3 DROPLET SIZE... heating film -coating solutions prior to atomization Heating film -coating solutions has been shown to cause a reduction in their viscosity (see section 4.2 .4) It may be considered, therefore, that the heating of formulations prior to atomization may be used as a method of reducing the atomized droplet size Twitchell (1990), with solutions atomized by a Schlick spray-gun, has shown that heating the coating. .. 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 Page 77 behave as Newtonian liquids It is probable, however, that coating solutions or... proved unsatisfactory to date The conditions encountered in aqueous pharmaceutical film coating are also quite unlike most of those in other atomization applications However, a survey of work in other fields yields the following general conclusions about the factors most likely to influence the atomization process during aqueous film coating: 1 The size of droplets produced during atomization will depend... 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,... subjecting the fluid to intense high-frequency vibrations They have not tended to be used for tablet, granule or multiparticulate film coating to date, since those available either have difficulty in coping with the flow rates required for either organic or aqueous film coating, produce droplets which do not possess sufficient momentum or have nozzles which are easily fouled Hydraulic (airless) atomization . in film coating Michael E.Aulton and Andrew M.Twitchell SUMMARY A little-considered stage of the film -coating process is the atomization of the coating. filmcoating polymer formulations in order to gain an understanding of how formulations may behave during the film -coating process. Commercial grades of coating