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Molecular coatings on powders
Molecular coatings on powders N. Pilpel Coatings a few molecules thick are often applied to the surfaces of powders in order to modify their properties and extend their use in the manufacture of a wide range of products. This article reviews the underlying theory and discusses specific examples from fields as diverse as mineral flotation processes and the formulation of drugs.
Coating the particles in powders can radically alter their properties. The coatings may only be a few molecules thick - less than 0.1 per cent of the weight of the powder. Nevertheless, their effects can be dramatic. An insulating powder such as magnesia becomes electrically conducting when the particles are coated with carbon. Pigments which would not otherwise disperse properly in water or oil do so when coated with a molecular film of a wetting agent. Metallic and nonmetallic powders, which require high pressures for forming them into compacts, can be compressed more easily when the particles have been coated with a lubricant. This article gives an account of the methods used for applying molecular coatings to powders, with an outline of the relevant theory. It then describes the effects the coatings produce on the wettability, flow, compressional and other properties of powders which are of importance in such diverse applications as the extraction of minerals from ores, the storage of cement, the manufacture of paints, and the production of pharmaceutical tablets. Methods
of coating
Several. methods are available for coating powders. During the grinding of cement clinker small amounts of water-repelling (hydrophobic) amines and silicones are added to the contents of the mill. They coat the particles of cement with a layer a few molecules thick which helps to prevent them from absorbing moisture during storage and thus turning to cake. Tungsten carbide may be milled with cobalt to produce
Neiton
Pilpel, Ph.D., D.Sc.
Is Professor of Pharmaceutical Technology at the Chelsea Department of Pharmacy, King’s College, London. He studied at University College and King’s College, London and worked for 12 years in industry before taking an academic appointment in 1964. Endeavour, New Series, Volume 10. No. 3, 1995. 0150-9327186 90.00 + .50. ~i~~~.i~~~~~~s~i~~~ls Ltd.
116
extremely hard surface layers on a product for use in cutting tools. Iron oxide may be similarly coated with nickel or cobalt for the production of magnetic recording materials. Metal coatings can also be deposited on certain powders by sputtering, or by exposing them to vapours of metallic carbonyls which decompose at about 300” to produce a smooth layer of metal on the particles’ surface. 300 Ni t 4co Ni(C0)4 + deposit Nickel carbon monoxide carbonyl . . . (1) Aluminium powder coated with a film of molybdenum using molybdenum carbonyl is claimed to have good compressional and sintering properties. It is generally possible to coat metallic powders in the size range below lpm with molecular films of nitride, oxide, silicide, boride, carbide etc. by heating them respectively in atmospheres of ammonia, oxygen, silane, borane, methane, etc. The reactions proceed from the outsides of the particles inwards and the thickness of the coating can be precisely controlled by stopping heating at the appropriate point. So far, precipitation methods do not seem to have been particularly successful for coating sub-micron sized aluminium powder with other metals like nickel: one possibility is stirring the powder into a solution of nickel chloride, then treating with sodium hydroxide and heating in hydrogen to convert the deposited oxide into metallic nickel. Under the electron microscope these coatings are found to be discontinuous and irregular. But precipitation is used to produce molecular coatings of alumina and silica on the surface. of the white pigment titania (TiOz). The coating reduces its tendency to react with oxygen in sunlight, which would cause discoloration and weathering of the paint. An aqueous slurry of t’itania is treated with sodium polyhexametaphosphate to disperse the particles, then with a mixed solution of aluminium sulphate and sodium silicate at pH3. On raising the pH to 7, a monolayer of alumina and silica de-
posits on the titania (figure 1) and this is stabilised by heating to 200”. The deposition of molecular coatings on powders, whether from the vapour phase or from solution, is usually expressed in terms of an adsorption isotherm. This is a graph relating the amount of material deposited at any particular temperature to its concentration in the vapour or solution. A typical Langmuir isotherm showing the adsorption of cyanine iodide dye on to particles of silver bromide dispersed in an aqueous, 7 per cent gelatin solution at 40” is illustrated schematically in figure 2. The bromide particles become coated with a monolayer of dye when its concentration in the solution is about 50 pmol I-’ (as shown by the plateau on the graph). This increases their sensitivity to red light and dye coatings are widely used in the preparation of photographic film. Effects of coatings
on wettability
In order to measure the effect that a coating has had on the wettability of a powder we form it into a tablet, using a punch and die in a 5 ton press. A drop of water of predetermined volume, which has been saturated with the powder to prevent it dissolving the surface of the tablet, is dropped on to it from a height of 1 cm. The tablet is then covered with a perspex lid to prevent evaporation of the liquid and the height of the drop, h, is measured with a travelling telescope. The more wettable (hydrophilic) the surface the flatter the drop and the smaller the value of h (figure 3). Results are expressed in terms of the contact angle, 0, where ‘vi Kh2 cos 0 = 1 -- f ^ \ \3$(1I$)/ L . .
(4)
K = pgl2y p is the density of the liquid g cmm3, pa is the bulk density of the solid g cmF3, pp is the true density of the particles g cm-3, g is the acceleration due to gravity, 981
OH I OH-Si-OH I 0 I OH-Al-OH t 0 I 5??zwl ’ ; Ti
OH I OH-Si-OH 9 OH-Al-OH I 0 Ti
/
Figure 1 Surface of titania coated with a monolayer of hydrated silica and alumina.
cm secY’, and y is the surface tension of the liquid (mN m-‘) which is measured with a torsion balance. We find [l] that the contact angle of water on lactose tablets with a packing fraction, pelf+, of 0.85 is about 30”. After coating the powder with 0.003 g of paraffin wax per g of lactose, which produces a surface layer of wax 3 molecules thick, the contact angle on the tablets increased to 67”: when the layer of wax was 10 molecules thick the contact angle was 75”. This is less than the contact angle of water on a perfectly smooth paraffin surface (110’) and is probably due to the roughness of the tablet’s surface. For our purposes comparative values of 0 were sufficient, but to avoid the problem of roughness and obtain absolute values of 0 many authors prefer to derive
Concentrotlon c p mot 1-l Figure 2 Langmuir isotherm* for adsorption of cyanine iodide dye on silver bromide at 40°C (Schematic)
*The Langmuir isotherm is one of several different types of isotherm that describe the adsorption of molecular coatings on solids. It can be written -= (x/“m,
1 ab
C +
7
of the powder.
When -&+
is plotted against c a straight line is obtained whose slop is I/a and whose intercept on the ordinate is Ilab: a and b are constants related to the powder and the coating.
the coating layers. Although it cannot be calculated precisely (because of uncertainty about some of the constants contained in it), provide the overall Brownian energy of the particles (about 15 kT, where k is Boltzmann’s constant and T is the temperature in OK) is less than the peak value of AG total, the dispersion remains stable figure 4. But if the Brownian energy is above this peak the particles collide, grow in size, and eventually settle out as a sediment. This produces an unstable paint and is to be avoided. Many other examples can be cited of particles dispersed in liquids where the stability and performance of the product depend on the presence of an adsorbed coating. They include the use
Air
Drop of water
Tablet surface ( b ) Hydrophkic surface
(a 1 Hydrophobic surface
Figure 3 Drop of water on the surface of a solid. y = surface tension. Subscripts A, W and S denote air, water and solid (tablet) respectively. At equilibrium YSA = cw + YWA cos o... (3)
increase in the contact angle of water and a decrease in the contact angle of oil: they are, therefore. used for oil-based paints. Hydrophilic coatings for example surfactants, polyols. and carboxymethyl cellulose - produce the reverse effect and are, therefore, used in water based paints. The physical stability of the paint, its tendency to form a sediment or to flocculate, is determined by the interplay between Van der Waal’s forces of attraction between the particles, electrostatic forces of repulsion associated with any electric charge on their surfaces, and other (steric) repulsion forces arising from solvation and from the presence of the coating. The total interaction energy, Ac; ,oli,lr between the dispersed pigment particles can be written as
(2)
where c is the concentration of the material being adsorbed, as mol I ‘, and x is the amount adsorbed in mol by m grammes
them from measurements of the heats of immersion of the powders in liquids. By contrast, deposition on the particles of three molecular layers of Tween 40, a typical non-ionic wetting agent, caused the contact angle to decrease to less than 20”. Coatings can produce considerable changes in the wetting of powders and this is of importance in many areas of technology. In the manufacture of paints, the wetting of pigments like iron oxide and carbon black either by water or by an oil is controlled by the use of appropriate additives which become adsorbed as coatings on the surfaces of the particles. Hydrophobic coatings - for example soaps of heavy metals, silicones, and resins - cause an
The first two terms on the right hand side of equation 5 can, in principle, be evaluated numerically by making use of the DLVO theory [2]. The term A G ateric? which often predominates over the other two, is controlled by the compressional characteristics and by interactions between the molecules of
of fillers such as limestone and cement powder, which are treated with cationic surfactants for the manufacture of bituminous road materials; pigments and extenders for printing inks; resincoated silica powder for electrical insulators.
Foam flotation The process of foam flotation, which is applied on a very large scale for the recovery of valuable minerals from unwanted rock, involves treating finely ground ore with chemical ‘collectors’ which attach themselves to the surfaces of selected species making them hydrophobic. A typical collector for sulphide minerals is potassium ethyl xanthate, C2HSO-C-SK. II S When it is added to an aqueous slurry containing particles of, say, silica, calcium fluoride, and lead sulphide (which is generally in an oxidised state) a reaction occurs between the sulphide and the xanthate, thus: PbS,O,
+
2(CZH,0ESK)
+
S GHsO:jS)d’b S
+ K&O, . (6)
(n and m are integers with m > n) 117
Interaction energy GotaL Erownion energy 15kT
particles x 10s cm Stable system - - - - Unstable system Figure 4 Potential energy diagram (schematic) showing interaction between neighbouring particles.
This leads to the formation of a hydrophobic layer of xanthate one molecule thick on the surface of each particle of lead sulphide. One then adds a foaming agent such as pine oil or nonylphenyl,polyoxyethylene alcohol CHs (CH&
10 O(CH&H&OH c and bubbles air into the mixture in a flotation machine (figure 5). The hydrophobic particles of lead sulphide become attached to air bubbles (figure 6), if the contact angle 0 is greater than about 20” and, provided they are sufficiently small and light, rise with them to form a froth on the surface of the slurry. Because the fluoride and silica are hydrophilic and have not become coated by xanthate, they remain in the bulk of the liquid: the valuable sulphide separates from them in the froth which runs off along the overflow gutter of the machine and is recovered.
Figure 5
118
Foam flotation
machine.
In practice, the flotation process is more complicated than this and special precautions have to be taken, involving the use of ‘activators’, ‘suppressors’, ‘conditioners’, in order to achieve clean separations and economic recovery of the required minerals. Ultimately, however, the process depends on the formation of adsorbed films of hydrophobic or (if it is operated in reverse by discarding the froth) of hydrophilic substances on the surface of the mineral particles. Foam flotation is not confined only to the recovery of minerals: suitably modified it is now also being used for concentrating and purifying biological substances - such as spores and microorganisms - which are required for new processes in biotechnology. Pharmaceutical
water
Figure 6 Attachment of hydrophobic mineral particle to air bubble, which then rises in the froth. At eouilibrium
YSA= Ysw +YWA’ cos 0
(3)
applications
There is a wide range of pharmaceutical applications in which adsorbed films on particles and the subsequent wetting of their surfaces play a crucial role. Suspensions of barium sulphate are used to line the gastro-intestinal tract in suspected cancer patients in order to make it opaque for X-ray examination. Careful control has to be exercised over the state of dispersion of the particles by employing monomolecular coatings of polymers to ensure that the preparation has satisfactory flow properties, penetrates folds in the gut, and adheres to the mucosal surface of the stomach without causing misleading artifacts to appear on the X-ray photographs [Z]. One consequence of the change in wettability produced by a monomolecular/multimolecular coating on the particles in a pharmaceutical
tablet is the rate at which this subsequently dissolves in the gastrointestinal tract releasing the active drug into the patient’s blood stream. Many commercial tablets are also coated on the outside with films of sugar or polymers to improve their taste and appearance. Special enteric coatings, eg cellulose acetate phthalate, which is insoluble in acid but soluble in alkali, are used when the tablet is required to pass intact through the stomach (for example because the drug would be decomposed by acid) and not disintegrate until it has reached the alkaline environment of the intestines. Disintegration and dissolution tests are carried out in vitro as a first step towards evaluating the likely performance of tableted drugs in patients [4, 51. Their disintegration is measured by timing how long it takes for tablets to break up when they are repeatedly dunked in water, using a standard disintegration tester. Dissolution is followed by suspending the tablets in 1 litre of stirred water at 37” or in artificial gastric juice (water containing pepsin, sodium chloride, and hydrochloric acid at pH 1 to 2) or in artificial intestinal fluid (water containing pancreatin, ox bile, potassium biphosphate, and sodium hydroxide at pH 7.5) using a chemical or spectroscopic method to measure how much drug has dissolved in the liquid over a period of time. Typical results (figure 7) show the effect produced on the dissolution of some formulated oxytetracycline/ lactose tablets when they had been coated firstly with three molecular layers of Tween 40 and secondly with six molecular layers of silicone DC 550. The latter caused the rate of dissolution to slow down to about one-third of its original value.
0
b
5
IO
C
25
15
Time
Imir?
Figure 7 Dissolution profiles at 26°C of tablets made from oxytetracycline + 50% lactose at pr - h 0.8 (schematic) (- P,) a = untreated b = particles coated with 3 molecular layers of Tween 40 c = particles coated with 6 molecular layers of silicone DC 550
lose - to coat the formulated drug particles. Correlations have also been found between these parameters and the levels of different drugs in the blood of laboratory animals after they have been fed with tablets. The levels, expressed as pg of drug per mil of blood, are plotted against the time elapsed since administration of the dose (figure 9). The peaks shift to longer times as 0 increases: that is, as the surfaces of the particles are made more hydrophobic by the coating. From this type of investigation it is now becoming possible literally to tailor pharmaceutical tablets (as well as encapsulated drug powders) to release the active medicament at different times and at different sites - oesophagus, stomach, small intestine, large intestine - thereby producing the optimum therapeutic effect in patients. Other effects of coatings
The results are expressed [6] in the form of the equation In (&)
=
Kt
(7)
where C, is the concentration of drug which saturates the liquid, C its concentration at any time t after the start of the experiment, and k is the dissolution rate constant. For certain drugs - such as metronidazole, which is used for treating infections of the genito-urinary tract it has been possible to establish good correlations between the contact angle of water on the tablets and their disintegration and dissolution times (as expressed by tgg, the time taken for 90 per cent of the drug to dissolve.). Typical correlations are shown in (figure 8) [7] where the changes in contact angle were achieved by using different binding agents - polyvinyl pyrrolidone, gelatin, and methyl cellu-
TABLE 1
EFFECTS OF COATING
We have recently shown that in addition to affecting the wetting and dissolution behaviour of pharmaceutical powders, coatings also produce changes in some of their mechanical properties - flow, tensile strength, compressibility, and so on. These properties are important not only in the manufacture of pharmaceutical capsules and tablets, but also in the production of other powders for foodstuffs, detergents, fertilisers, pesticides. One of the problems encountered in the storage of powders is that many of them absorb moisture from the atmosphere and thus cake. Hoppers become blocked; difficulties are encountered in transporting the powders through pipes; pesticides and insecticides may fail to form a satisfactory cloud of dust when puffed from a container. Molecular coatings of dimethyl dichlorosilane, quaternary ammonium compounds, amines, and so on have proved effective in overcoming some of these difficulties. They are applied either directly as a vapour or in the form of
THICKNESS
ON PLASTICITY,
ELASTICITY,
2 E 8 .e IC
Thickness (molecular layers)
Silicone DC 200/50 Tween
END 10:3-c
40
Plasticity %
E/P
45’
0
Figure 8 Correlations between cos Q and dissolution, tsO, and disintegration times for formulated metronidazole tablets at pr 0.9 (schematic)
an aerosol spray. Dusting the surface of the particles with ultrafine (< 0.2 pm diameter) aerosil (a form of silica) and talc can produce similarly beneficial results. The effects of coatings on the tensile strengths, TS, elasticity, E, plasticity, P, and compressional properties of two representative powders - sodium salicylate and calcium carbonate (both in the size range l-20 pm) are shown in Table 1 [8]. The tensile strengths were measured by forming the powders into tablets, then compressing them across their diameter until they broke cleanly into two halves. The plasticity and elasticity were deduced from the deformation and subsequent partial recovery in shape of tablets when subjected first to compression of up to 20 kN and then to decompression over a period of one minute. We find that irrespective of whether the coating is hydrophilic (Tween) or hydrophobic (silicone) the thicker the coating the less plastic the particles become and the greater the ratio, E/P, of their elasticity to plasticity. The
TENSILE STRENGTH,
Sodium salicylate (I to 20 pm) Coating material
I
I 66”
I 84’
AND YIELD STRENGTH
Calcium carbonate (I to 20 pm) Tensile strength at pr 0.9 MN rn~-’
Yield strength
Thickness molecular layers
Plasticity %
E/P
MN mm2
Tensile strength at PF 0.8 MN mm2
Yield strength MN me2
0 4 16
1.8 1.4 1.2
6.6 8.7 9.6
3.8 2.1 1.7
390 340 300
0 7 28
1.5 1.4 1.1
8.1 8.6 10.9
1.5 0.8 0.6
610 580 550
1 4 10
1.6 1.4 1.3
7.2 8.2 8.8
3.0 2.4 1.9
370 320 300
2 8 20
1.4 1.3 1.2
8.9 9.9 10.8
1.0 0.8 0.6
580 560 560
119
tensile strengths of the tablets also decrease with coating thickness. Both findings indicate that the coating is acting as a lubricant, making it easier for particles to slide past each other during compression and inhibiting the formation
of welded
bonds between
their surfaces (figure 10). Such ‘bonds form when, as a result of friction and high pressures at actual points of contact, the temperature
of the surface
rises above its melting point and then cools by conduction or convection and re-sets. One interesting observation is that at very high pressures some coatings which would normally be expected to be ‘solid’ at the temperature concerned begin to act as though they had turned to ‘liquid’ (assuming that one can apply the terms ‘solid’ and ‘liquid’ to molecular layers). This behaviour appears to contradict the Clapeyron-Clausius equation dM dP=
+
(v, - V,)
. . . (8)
where M = melting point of coating “C; P = pressure in atmospheres; L = latent heat of fusion of coating in cal g -l; VL = volume of 1 g liquid; Vs =
volume 1 g solid, both in ml. This predicts that the melting point of a solid coating should increase with pressure, because in most cases VL > Vs (ice is an exception). However, in powders the applied pressure is not uniformly distributed as in other solids, but is localised at the relatively few points of real contact between the particles. Any liquid formed from the
Time
coating could escape into the pore spaces between particles and in these circumstances the applied pressure appears to reduce its melting point, equation 8 becoming [9] dM dP
M Vs =-L
.‘..
(9)
[3] Thomas A. and Winkler M. A. in ‘Topics in Enzyme and Fermentation Bio-Technology’ (Wiseman A. ed) Vol. 1. Chap. 3. Ellis Horwood Wiley, London, 1977. [4] Carstensen J. T. ‘Theory of Pharmaceutical Svstems’ Vol. 2. Chao. 4. Academic Press, New York, 1973. [5] Chapman D. G. Crisafio R. and Campbell J. A. J. Pharm. Sci.. 45. 374. 1956. (61 Kitazawa S. Johno I. Ito Y. Teramura S. and Okada J. J. Pharm. Pharmacol., 27, 765, 1975. [7] Itiola 0. A. and Pilpel N. J. Pharm. Pharmacol.. 38, 81, 1986. [S] Ejiofor 0. Esezobo S. and Pilpel N. J. Pharm. Pharmacol.. 38. 1. 1986.
A calculation, admittedly rather approximate, leads one to think that at the pressures employed during commercial tableting, the ‘melting point’ of any coating at the actual points of contact between the particles could be lowered by as much as 30°C and this would account for the above observa[9] Skotnicky J. Czech. J. Phys.; 3, 225, tion. 1953. Work is currently in progress to elucidate in more detail how the densities and strengths of compacts made from such diverse powders as metals, mineral oxides, charcoal, polymers, and pharmaceutical drugs can Bibliography be altered by changing the applied Society of Chemical Industry Monograph pressure and temperature and the No. 14. ‘Powders in Industry’. 1961. nature and thickness of any coating Parfitt G. D. and Sing K. S. W. (eds) ‘Characterisation of Powder Surfaces’. that may have been applied to the Academic Press, London, 1976. particles.
(hr)
Figure 9 Blood level versus time (schematic). a = 300 mg untreated tablet administered orally, 0 = 30 b = 300 mg particle coated tablet administered orally, 0 = 65” c = Same quantity of untreated drug administered intravenously
120
Figure 10 Surface of amylose tablets x 200 (after C. F. Lerk et a/., courtesy Elsevier). (a) Untreated particles exhibiting extensive welding. (b) Particles coated with 0.05% w/w magnesium stearate exhibiting less welding.
References [l] Igwilo C. I. and Pilpel N. Znt. J. Pharamaceutics, 15, 73, 1983. [2] Florence A. T. and Attwood D. ‘Physiochemical Principles of Pharmacy. Chap 7. Macmillan Press, London, 1981.
Parfitt G. D. ‘Dispersion of Powders in Liquids’. Elsevie;, London, 1973. Kuhn W. E. fed) ‘Ultraline Particles’. John Wiley. London, 1963. Gregg S. J. ‘The Surface Chemistry of Solids’. Chapman & Hall, London, 1961. Carstensen J. T. ‘Solid Pharmaceutics: Mechanical Properties and Rate Phenomena’. Academic Press, London, 1980. Taggart A. F. ‘Elements of Ore Dressing’. Chapman & Hall, London, 1951.
Coating the particles in powders can radically alter their properties. The coatings may only be a few molecules thick - less than 0.1 per cent of the weight of the powder. Nevertheless, their effects can be dramatic. An insulating powder such as magnesia becomes electrically conducting when the particles are coated with carbon. Pigments which would not otherwise disperse properly in water or oil do so when coated with a molecular film of a wetting agent. Metallic and nonmetallic powders, which require high pressures for forming them into compacts, can be compressed more easily when the particles have been coated with a lubricant. This article gives an account of the methods used for applying molecular coatings to powders, with an outline of the relevant theory. It then describes the effects the coatings produce on the wettability, flow, compressional and other properties of powders which are of importance in such diverse applications as the extraction of minerals from ores, the storage of cement, the manufacture of paints, and the production of pharmaceutical tablets. Methods
of coating
Several. methods are available for coating powders. During the grinding of cement clinker small amounts of water-repelling (hydrophobic) amines and silicones are added to the contents of the mill. They coat the particles of cement with a layer a few molecules thick which helps to prevent them from absorbing moisture during storage and thus turning to cake. Tungsten carbide may be milled with cobalt to produce
Neiton
Pilpel, Ph.D., D.Sc.
Is Professor of Pharmaceutical Technology at the Chelsea Department of Pharmacy, King’s College, London. He studied at University College and King’s College, London and worked for 12 years in industry before taking an academic appointment in 1964. Endeavour, New Series, Volume 10. No. 3, 1995. 0150-9327186 90.00 + .50. ~i~~~.i~~~~~~s~i~~~ls Ltd.
116
extremely hard surface layers on a product for use in cutting tools. Iron oxide may be similarly coated with nickel or cobalt for the production of magnetic recording materials. Metal coatings can also be deposited on certain powders by sputtering, or by exposing them to vapours of metallic carbonyls which decompose at about 300” to produce a smooth layer of metal on the particles’ surface. 300 Ni t 4co Ni(C0)4 + deposit Nickel carbon monoxide carbonyl . . . (1) Aluminium powder coated with a film of molybdenum using molybdenum carbonyl is claimed to have good compressional and sintering properties. It is generally possible to coat metallic powders in the size range below lpm with molecular films of nitride, oxide, silicide, boride, carbide etc. by heating them respectively in atmospheres of ammonia, oxygen, silane, borane, methane, etc. The reactions proceed from the outsides of the particles inwards and the thickness of the coating can be precisely controlled by stopping heating at the appropriate point. So far, precipitation methods do not seem to have been particularly successful for coating sub-micron sized aluminium powder with other metals like nickel: one possibility is stirring the powder into a solution of nickel chloride, then treating with sodium hydroxide and heating in hydrogen to convert the deposited oxide into metallic nickel. Under the electron microscope these coatings are found to be discontinuous and irregular. But precipitation is used to produce molecular coatings of alumina and silica on the surface. of the white pigment titania (TiOz). The coating reduces its tendency to react with oxygen in sunlight, which would cause discoloration and weathering of the paint. An aqueous slurry of t’itania is treated with sodium polyhexametaphosphate to disperse the particles, then with a mixed solution of aluminium sulphate and sodium silicate at pH3. On raising the pH to 7, a monolayer of alumina and silica de-
posits on the titania (figure 1) and this is stabilised by heating to 200”. The deposition of molecular coatings on powders, whether from the vapour phase or from solution, is usually expressed in terms of an adsorption isotherm. This is a graph relating the amount of material deposited at any particular temperature to its concentration in the vapour or solution. A typical Langmuir isotherm showing the adsorption of cyanine iodide dye on to particles of silver bromide dispersed in an aqueous, 7 per cent gelatin solution at 40” is illustrated schematically in figure 2. The bromide particles become coated with a monolayer of dye when its concentration in the solution is about 50 pmol I-’ (as shown by the plateau on the graph). This increases their sensitivity to red light and dye coatings are widely used in the preparation of photographic film. Effects of coatings
on wettability
In order to measure the effect that a coating has had on the wettability of a powder we form it into a tablet, using a punch and die in a 5 ton press. A drop of water of predetermined volume, which has been saturated with the powder to prevent it dissolving the surface of the tablet, is dropped on to it from a height of 1 cm. The tablet is then covered with a perspex lid to prevent evaporation of the liquid and the height of the drop, h, is measured with a travelling telescope. The more wettable (hydrophilic) the surface the flatter the drop and the smaller the value of h (figure 3). Results are expressed in terms of the contact angle, 0, where ‘vi Kh2 cos 0 = 1 -- f ^ \ \3$(1I$)/ L . .
(4)
K = pgl2y p is the density of the liquid g cmm3, pa is the bulk density of the solid g cmF3, pp is the true density of the particles g cm-3, g is the acceleration due to gravity, 981
OH I OH-Si-OH I 0 I OH-Al-OH t 0 I 5??zwl ’ ; Ti
OH I OH-Si-OH 9 OH-Al-OH I 0 Ti
/
Figure 1 Surface of titania coated with a monolayer of hydrated silica and alumina.
cm secY’, and y is the surface tension of the liquid (mN m-‘) which is measured with a torsion balance. We find [l] that the contact angle of water on lactose tablets with a packing fraction, pelf+, of 0.85 is about 30”. After coating the powder with 0.003 g of paraffin wax per g of lactose, which produces a surface layer of wax 3 molecules thick, the contact angle on the tablets increased to 67”: when the layer of wax was 10 molecules thick the contact angle was 75”. This is less than the contact angle of water on a perfectly smooth paraffin surface (110’) and is probably due to the roughness of the tablet’s surface. For our purposes comparative values of 0 were sufficient, but to avoid the problem of roughness and obtain absolute values of 0 many authors prefer to derive
Concentrotlon c p mot 1-l Figure 2 Langmuir isotherm* for adsorption of cyanine iodide dye on silver bromide at 40°C (Schematic)
*The Langmuir isotherm is one of several different types of isotherm that describe the adsorption of molecular coatings on solids. It can be written -= (x/“m,
1 ab
C +
7
of the powder.
When -&+
is plotted against c a straight line is obtained whose slop is I/a and whose intercept on the ordinate is Ilab: a and b are constants related to the powder and the coating.
the coating layers. Although it cannot be calculated precisely (because of uncertainty about some of the constants contained in it), provide the overall Brownian energy of the particles (about 15 kT, where k is Boltzmann’s constant and T is the temperature in OK) is less than the peak value of AG total, the dispersion remains stable figure 4. But if the Brownian energy is above this peak the particles collide, grow in size, and eventually settle out as a sediment. This produces an unstable paint and is to be avoided. Many other examples can be cited of particles dispersed in liquids where the stability and performance of the product depend on the presence of an adsorbed coating. They include the use
Air
Drop of water
Tablet surface ( b ) Hydrophkic surface
(a 1 Hydrophobic surface
Figure 3 Drop of water on the surface of a solid. y = surface tension. Subscripts A, W and S denote air, water and solid (tablet) respectively. At equilibrium YSA = cw + YWA cos o... (3)
increase in the contact angle of water and a decrease in the contact angle of oil: they are, therefore. used for oil-based paints. Hydrophilic coatings for example surfactants, polyols. and carboxymethyl cellulose - produce the reverse effect and are, therefore, used in water based paints. The physical stability of the paint, its tendency to form a sediment or to flocculate, is determined by the interplay between Van der Waal’s forces of attraction between the particles, electrostatic forces of repulsion associated with any electric charge on their surfaces, and other (steric) repulsion forces arising from solvation and from the presence of the coating. The total interaction energy, Ac; ,oli,lr between the dispersed pigment particles can be written as
(2)
where c is the concentration of the material being adsorbed, as mol I ‘, and x is the amount adsorbed in mol by m grammes
them from measurements of the heats of immersion of the powders in liquids. By contrast, deposition on the particles of three molecular layers of Tween 40, a typical non-ionic wetting agent, caused the contact angle to decrease to less than 20”. Coatings can produce considerable changes in the wetting of powders and this is of importance in many areas of technology. In the manufacture of paints, the wetting of pigments like iron oxide and carbon black either by water or by an oil is controlled by the use of appropriate additives which become adsorbed as coatings on the surfaces of the particles. Hydrophobic coatings - for example soaps of heavy metals, silicones, and resins - cause an
The first two terms on the right hand side of equation 5 can, in principle, be evaluated numerically by making use of the DLVO theory [2]. The term A G ateric? which often predominates over the other two, is controlled by the compressional characteristics and by interactions between the molecules of
of fillers such as limestone and cement powder, which are treated with cationic surfactants for the manufacture of bituminous road materials; pigments and extenders for printing inks; resincoated silica powder for electrical insulators.
Foam flotation The process of foam flotation, which is applied on a very large scale for the recovery of valuable minerals from unwanted rock, involves treating finely ground ore with chemical ‘collectors’ which attach themselves to the surfaces of selected species making them hydrophobic. A typical collector for sulphide minerals is potassium ethyl xanthate, C2HSO-C-SK. II S When it is added to an aqueous slurry containing particles of, say, silica, calcium fluoride, and lead sulphide (which is generally in an oxidised state) a reaction occurs between the sulphide and the xanthate, thus: PbS,O,
+
2(CZH,0ESK)
+
S GHsO:jS)d’b S
+ K&O, . (6)
(n and m are integers with m > n) 117
Interaction energy GotaL Erownion energy 15kT
particles x 10s cm Stable system - - - - Unstable system Figure 4 Potential energy diagram (schematic) showing interaction between neighbouring particles.
This leads to the formation of a hydrophobic layer of xanthate one molecule thick on the surface of each particle of lead sulphide. One then adds a foaming agent such as pine oil or nonylphenyl,polyoxyethylene alcohol CHs (CH&
10 O(CH&H&OH c and bubbles air into the mixture in a flotation machine (figure 5). The hydrophobic particles of lead sulphide become attached to air bubbles (figure 6), if the contact angle 0 is greater than about 20” and, provided they are sufficiently small and light, rise with them to form a froth on the surface of the slurry. Because the fluoride and silica are hydrophilic and have not become coated by xanthate, they remain in the bulk of the liquid: the valuable sulphide separates from them in the froth which runs off along the overflow gutter of the machine and is recovered.
Figure 5
118
Foam flotation
machine.
In practice, the flotation process is more complicated than this and special precautions have to be taken, involving the use of ‘activators’, ‘suppressors’, ‘conditioners’, in order to achieve clean separations and economic recovery of the required minerals. Ultimately, however, the process depends on the formation of adsorbed films of hydrophobic or (if it is operated in reverse by discarding the froth) of hydrophilic substances on the surface of the mineral particles. Foam flotation is not confined only to the recovery of minerals: suitably modified it is now also being used for concentrating and purifying biological substances - such as spores and microorganisms - which are required for new processes in biotechnology. Pharmaceutical
water
Figure 6 Attachment of hydrophobic mineral particle to air bubble, which then rises in the froth. At eouilibrium
YSA= Ysw +YWA’ cos 0
(3)
applications
There is a wide range of pharmaceutical applications in which adsorbed films on particles and the subsequent wetting of their surfaces play a crucial role. Suspensions of barium sulphate are used to line the gastro-intestinal tract in suspected cancer patients in order to make it opaque for X-ray examination. Careful control has to be exercised over the state of dispersion of the particles by employing monomolecular coatings of polymers to ensure that the preparation has satisfactory flow properties, penetrates folds in the gut, and adheres to the mucosal surface of the stomach without causing misleading artifacts to appear on the X-ray photographs [Z]. One consequence of the change in wettability produced by a monomolecular/multimolecular coating on the particles in a pharmaceutical
tablet is the rate at which this subsequently dissolves in the gastrointestinal tract releasing the active drug into the patient’s blood stream. Many commercial tablets are also coated on the outside with films of sugar or polymers to improve their taste and appearance. Special enteric coatings, eg cellulose acetate phthalate, which is insoluble in acid but soluble in alkali, are used when the tablet is required to pass intact through the stomach (for example because the drug would be decomposed by acid) and not disintegrate until it has reached the alkaline environment of the intestines. Disintegration and dissolution tests are carried out in vitro as a first step towards evaluating the likely performance of tableted drugs in patients [4, 51. Their disintegration is measured by timing how long it takes for tablets to break up when they are repeatedly dunked in water, using a standard disintegration tester. Dissolution is followed by suspending the tablets in 1 litre of stirred water at 37” or in artificial gastric juice (water containing pepsin, sodium chloride, and hydrochloric acid at pH 1 to 2) or in artificial intestinal fluid (water containing pancreatin, ox bile, potassium biphosphate, and sodium hydroxide at pH 7.5) using a chemical or spectroscopic method to measure how much drug has dissolved in the liquid over a period of time. Typical results (figure 7) show the effect produced on the dissolution of some formulated oxytetracycline/ lactose tablets when they had been coated firstly with three molecular layers of Tween 40 and secondly with six molecular layers of silicone DC 550. The latter caused the rate of dissolution to slow down to about one-third of its original value.
0
b
5
IO
C
25
15
Time
Imir?
Figure 7 Dissolution profiles at 26°C of tablets made from oxytetracycline + 50% lactose at pr - h 0.8 (schematic) (- P,) a = untreated b = particles coated with 3 molecular layers of Tween 40 c = particles coated with 6 molecular layers of silicone DC 550
lose - to coat the formulated drug particles. Correlations have also been found between these parameters and the levels of different drugs in the blood of laboratory animals after they have been fed with tablets. The levels, expressed as pg of drug per mil of blood, are plotted against the time elapsed since administration of the dose (figure 9). The peaks shift to longer times as 0 increases: that is, as the surfaces of the particles are made more hydrophobic by the coating. From this type of investigation it is now becoming possible literally to tailor pharmaceutical tablets (as well as encapsulated drug powders) to release the active medicament at different times and at different sites - oesophagus, stomach, small intestine, large intestine - thereby producing the optimum therapeutic effect in patients. Other effects of coatings
The results are expressed [6] in the form of the equation In (&)
=
Kt
(7)
where C, is the concentration of drug which saturates the liquid, C its concentration at any time t after the start of the experiment, and k is the dissolution rate constant. For certain drugs - such as metronidazole, which is used for treating infections of the genito-urinary tract it has been possible to establish good correlations between the contact angle of water on the tablets and their disintegration and dissolution times (as expressed by tgg, the time taken for 90 per cent of the drug to dissolve.). Typical correlations are shown in (figure 8) [7] where the changes in contact angle were achieved by using different binding agents - polyvinyl pyrrolidone, gelatin, and methyl cellu-
TABLE 1
EFFECTS OF COATING
We have recently shown that in addition to affecting the wetting and dissolution behaviour of pharmaceutical powders, coatings also produce changes in some of their mechanical properties - flow, tensile strength, compressibility, and so on. These properties are important not only in the manufacture of pharmaceutical capsules and tablets, but also in the production of other powders for foodstuffs, detergents, fertilisers, pesticides. One of the problems encountered in the storage of powders is that many of them absorb moisture from the atmosphere and thus cake. Hoppers become blocked; difficulties are encountered in transporting the powders through pipes; pesticides and insecticides may fail to form a satisfactory cloud of dust when puffed from a container. Molecular coatings of dimethyl dichlorosilane, quaternary ammonium compounds, amines, and so on have proved effective in overcoming some of these difficulties. They are applied either directly as a vapour or in the form of
THICKNESS
ON PLASTICITY,
ELASTICITY,
2 E 8 .e IC
Thickness (molecular layers)
Silicone DC 200/50 Tween
END 10:3-c
40
Plasticity %
E/P
45’
0
Figure 8 Correlations between cos Q and dissolution, tsO, and disintegration times for formulated metronidazole tablets at pr 0.9 (schematic)
an aerosol spray. Dusting the surface of the particles with ultrafine (< 0.2 pm diameter) aerosil (a form of silica) and talc can produce similarly beneficial results. The effects of coatings on the tensile strengths, TS, elasticity, E, plasticity, P, and compressional properties of two representative powders - sodium salicylate and calcium carbonate (both in the size range l-20 pm) are shown in Table 1 [8]. The tensile strengths were measured by forming the powders into tablets, then compressing them across their diameter until they broke cleanly into two halves. The plasticity and elasticity were deduced from the deformation and subsequent partial recovery in shape of tablets when subjected first to compression of up to 20 kN and then to decompression over a period of one minute. We find that irrespective of whether the coating is hydrophilic (Tween) or hydrophobic (silicone) the thicker the coating the less plastic the particles become and the greater the ratio, E/P, of their elasticity to plasticity. The
TENSILE STRENGTH,
Sodium salicylate (I to 20 pm) Coating material
I
I 66”
I 84’
AND YIELD STRENGTH
Calcium carbonate (I to 20 pm) Tensile strength at pr 0.9 MN rn~-’
Yield strength
Thickness molecular layers
Plasticity %
E/P
MN mm2
Tensile strength at PF 0.8 MN mm2
Yield strength MN me2
0 4 16
1.8 1.4 1.2
6.6 8.7 9.6
3.8 2.1 1.7
390 340 300
0 7 28
1.5 1.4 1.1
8.1 8.6 10.9
1.5 0.8 0.6
610 580 550
1 4 10
1.6 1.4 1.3
7.2 8.2 8.8
3.0 2.4 1.9
370 320 300
2 8 20
1.4 1.3 1.2
8.9 9.9 10.8
1.0 0.8 0.6
580 560 560
119
tensile strengths of the tablets also decrease with coating thickness. Both findings indicate that the coating is acting as a lubricant, making it easier for particles to slide past each other during compression and inhibiting the formation
of welded
bonds between
their surfaces (figure 10). Such ‘bonds form when, as a result of friction and high pressures at actual points of contact, the temperature
of the surface
rises above its melting point and then cools by conduction or convection and re-sets. One interesting observation is that at very high pressures some coatings which would normally be expected to be ‘solid’ at the temperature concerned begin to act as though they had turned to ‘liquid’ (assuming that one can apply the terms ‘solid’ and ‘liquid’ to molecular layers). This behaviour appears to contradict the Clapeyron-Clausius equation dM dP=
+
(v, - V,)
. . . (8)
where M = melting point of coating “C; P = pressure in atmospheres; L = latent heat of fusion of coating in cal g -l; VL = volume of 1 g liquid; Vs =
volume 1 g solid, both in ml. This predicts that the melting point of a solid coating should increase with pressure, because in most cases VL > Vs (ice is an exception). However, in powders the applied pressure is not uniformly distributed as in other solids, but is localised at the relatively few points of real contact between the particles. Any liquid formed from the
Time
coating could escape into the pore spaces between particles and in these circumstances the applied pressure appears to reduce its melting point, equation 8 becoming [9] dM dP
M Vs =-L
.‘..
(9)
[3] Thomas A. and Winkler M. A. in ‘Topics in Enzyme and Fermentation Bio-Technology’ (Wiseman A. ed) Vol. 1. Chap. 3. Ellis Horwood Wiley, London, 1977. [4] Carstensen J. T. ‘Theory of Pharmaceutical Svstems’ Vol. 2. Chao. 4. Academic Press, New York, 1973. [5] Chapman D. G. Crisafio R. and Campbell J. A. J. Pharm. Sci.. 45. 374. 1956. (61 Kitazawa S. Johno I. Ito Y. Teramura S. and Okada J. J. Pharm. Pharmacol., 27, 765, 1975. [7] Itiola 0. A. and Pilpel N. J. Pharm. Pharmacol.. 38, 81, 1986. [S] Ejiofor 0. Esezobo S. and Pilpel N. J. Pharm. Pharmacol.. 38. 1. 1986.
A calculation, admittedly rather approximate, leads one to think that at the pressures employed during commercial tableting, the ‘melting point’ of any coating at the actual points of contact between the particles could be lowered by as much as 30°C and this would account for the above observa[9] Skotnicky J. Czech. J. Phys.; 3, 225, tion. 1953. Work is currently in progress to elucidate in more detail how the densities and strengths of compacts made from such diverse powders as metals, mineral oxides, charcoal, polymers, and pharmaceutical drugs can Bibliography be altered by changing the applied Society of Chemical Industry Monograph pressure and temperature and the No. 14. ‘Powders in Industry’. 1961. nature and thickness of any coating Parfitt G. D. and Sing K. S. W. (eds) ‘Characterisation of Powder Surfaces’. that may have been applied to the Academic Press, London, 1976. particles.
(hr)
Figure 9 Blood level versus time (schematic). a = 300 mg untreated tablet administered orally, 0 = 30 b = 300 mg particle coated tablet administered orally, 0 = 65” c = Same quantity of untreated drug administered intravenously
120
Figure 10 Surface of amylose tablets x 200 (after C. F. Lerk et a/., courtesy Elsevier). (a) Untreated particles exhibiting extensive welding. (b) Particles coated with 0.05% w/w magnesium stearate exhibiting less welding.
References [l] Igwilo C. I. and Pilpel N. Znt. J. Pharamaceutics, 15, 73, 1983. [2] Florence A. T. and Attwood D. ‘Physiochemical Principles of Pharmacy. Chap 7. Macmillan Press, London, 1981.
Parfitt G. D. ‘Dispersion of Powders in Liquids’. Elsevie;, London, 1973. Kuhn W. E. fed) ‘Ultraline Particles’. John Wiley. London, 1963. Gregg S. J. ‘The Surface Chemistry of Solids’. Chapman & Hall, London, 1961. Carstensen J. T. ‘Solid Pharmaceutics: Mechanical Properties and Rate Phenomena’. Academic Press, London, 1980. Taggart A. F. ‘Elements of Ore Dressing’. Chapman & Hall, London, 1951.