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Thursday, May 14, 2009

COMPARITIVE STUDY OF COLLOIDAL DISPERSION IN PHARMACEUTICAL PRODUCTS


 

COMPARITIVE STUDY OF COLLOIDAL DISPERSION IN PHARMACEUTICAL PRODUCTS

Haris Aboobacker Siddiq, K. Sujith Varma

National College of Pharmacy, Manassery, Calicut


 

INTRODUCTION


 

    Colloidal system is a highly dispersed system in which dispersed particles are not molecules but aggregates of many molecules. The size range consume the nanometer (10–9m) to micrometer (10–6m) range. There is no sharp distinction between colloidal and non-colloidal systems. Usually colloidal system is found due to the nature of the substances dissolved in the media and does not depend on aggregation, chemical nature and origin. Colloid science is a part of surface science. The surface interfacial phenomena associated with colloidal systems such as emulsions and forms are often studied by means of experiments on artificially flat surfaces rather than on the colloidal systems themselves.


 

    Colloidal dispersions may be lyophobic (water hating) or lyophilic (water loving). Lyophilic sols are formed spontaneously when the dry coherent material (e.g. gelatin, rubber, soap) is brought in contact with the dispersion medium, hence they are thermodynamically more stable than in the initial state of dry colloid material plus dispersion medium. Lyophobic sols (e.g. gold sol) cannot be formed by spontaneous dispersion in the medium. They are thermodynamically unstable with respect to separation into macroscopic phases, but they may remain for long times in a metastable state. The molecules surface active materials have a strong affinity for interfaces, because they contain both hydrophilic and lipophilic region. These system are of polydispersed in nature that is the molecules of particles in a particular sample varying size7.


 


 


 


 

DEFINITION


 

    A colloidal dispersion is a system in which particles having a size range of
1 nm - 0.5 mm are dispersed in a continuous phase of a different composition.


 

Examples of systems which are colloidal are:

  1. Colloidal solution of metals, ex: sol of platinum, gold, silver
  2. Colloidal solution of silver iodide and arsenic sulphide
  3. Solutions of some organic dyes, soaps, milks and some metal alloys cast irons.


 

Examples of processes which rely heavily on the application of colloid/surface phenomena are:

Adhesion

Ore flotation

Chromatography

Precipitation

Detergency

Road surfacing

Electrophoretic deposition

Sewage disposal

Emulsion polymerization

Soil conditioning

Food processing

Sugar refining

Grinding

Water clarification

Heterogeneous catalysis

Water evaporation control

Ion exchange

Water repellency

Lubrication

Wetting

Oil-well drilling

  


 

PROPERTIES


 

  1. They show opalescing effect
  2. They have slow diffusion
  3. They have low osmotic pressure
  4. They can undergo dialysis
  5. They can be subjected to electrophoresis
  6. They are unstable

Dispersions

Table 1

Dispersed phase

Dispersion medium

Name

Examples

Liquid

Gas

Liquid aerosol

Fog, liquid sprays

Solid

Gas

Solid aerosol

Smoke, dust

Gas

Liquid

Foam

Foam on soap solutions, fire-extinguisher foam

Liquid

Liquid

Emulsion

Milk, mayonnaise

Solid

Liquid

Sol, colloidal suspension; paste (high solid concentration)

Au sol(gold), AgI sol(silver iodide); toothpaste

Gas

Solid

Solid foam

Expanded polystyrene

Liquid

Solid

Solid emulsion

Opal, pearl

Solid

Solid

Solid suspension

Pigmented plastics


 

    Sols and emulsions are by far the most important types of colloidal dispersion. When the dispersion medium is water, the term hydrosol is usually used. If the dispersed phase is polymeric in nature, the dispersion is called a latex (pl. latices or latexes).


 

    Foams are somewhat different is that it is the dispersion medium which has colloidal dimensions.


 

CLASSIFICATION OF COLLOIDAL SYSTEMS


 

Lyophilic colloids

    Systems containing colloidal particles interact to an appreciable extent with the dispersed medium are referred to as lyophilic (solvent loving) colloids. If the solvent is water it is refers to as hydrophilic colloids.


 

Lyophobic colloids

    These are system in which the particles have less force of attraction towards the solvent. If the solvent is water it is called as hydrophobic colloids.


 

Association colloids

    These are the colloidal system with amphiphilic molecules. When present in low concentration it is in subcolloidal state. As the concentration is increased leads to the formation of micelles. The concentration of monomer micelles formed is called as critical micellar concentration6.


 

STRUCTURAL CHARACTERISTICS

Experimental Methods

    The experimental procedures for determining particle size and shape can roughly be categorised, as follows:

  1. Observation of the movement of particles in response to an applied force.
  2. Direct observation of particle images (microscopy and electron microscopy).
  3. Observation of the response of particles to electromagnetic radiation.
  4. Measurements which relate to the total surface area of the particles (gas adsorption and adsorption from solution).

Particle Shape


 

Figure 1: Some model representations for non-spherical particles

    Particle asymmetry is a factor of considerable importance in determining the overall properties (especially those of a mechanical nature) of colloidal systems. Colloidal particles can be classified according to shape as corpuscular, laminar or linear. Colloidal system in emulsions, latexes, liquid aerosols, etc., contain spherical particles. The exact shape may be complex but, to a first approximation, the particles can often be treated theoretically in terms of models which have relatively simple shapes. The crystallite particles in dispersions such as gold and silver iodide sols are sufficiently symmetrical to behave like spheres.


 

    Colloidal particles which deviate from spherical shape can be termed as ellipsoids. Eg. many proteins. An ellipsoid of revolution is characterised by its axial ratio, which is the ratio of the single half-axis a to the radius of revolution b. The axial ratio is greater than unity for a prolate (rugby-football-shaped) ellipsoid, and less than unity for an oblate (discus-shaped) ellipsoid.


 

    Iron(III) oxide and clay suspensions are examples of systems containing plate-like particles.

    The colloidal particles which exists in thread like form are called branched chain molecules. In these most of them are in the chain attracted or cross linked. Such type of colloidal system have increased strength and durability. The main forces involved in it are covalent bonding, hydrogen bonding and van der waal force6.


 

FLEXIBILITY

    In the case of colloidal system with thread like molecules the flexibility is very high when compared with rigid model. Another model is random coil but even in this case we cannot assure the complete flexibility. So in order to predict the flexibility we should consider polymer-polymer and polymer-solvent forces. The case of polymer with sticking nature have less flexibility when compared with non-sticking one.


 

Figure 2: Particle diameter distribution for a polydispersed colloidal dispersion expressed (a) in histogram form, and (b) as a cumulative distribution


 

    Usually average particle size is calculated instead of relative particle size because of some practical problems. Osmotic pressure, which is a colligative property, depends simply on the number of solute molecules present and so yields a number-average relative molecular mass:


 

where ni
is the number of molecules of relative molecular mass Mr,i.

å = sum

M = molecular mass

n = number of molecules

From the above equation even if the number of molecules is less with high molecular mass will have high number average and vice versa.


 


 

For any polydispersed system, Mr (mass average) > Mr (number average), and only when the system is monodispersed will these averages coincide. The ratio Mr (mass average)/Mr (number average) is a measure of the degree of polydispersity1.


 

MANUFACTURING

Formation of Colloids

    There are two basic steps of forming a colloid: reduction of larger particles to colloidal size, and condensation of smaller particles (e.g., molecules) into colloidal particles. Some substances (e.g., gelatin or glue) are easily dispersed (in the proper solvent) to form a colloid; this spontaneous dispersion is called peptization. A metal can be dispersed by evaporating it in an electric arc; if the electrodes are immersed in water, colloidal particles of the metal are form as the metal vapour are cooled. A solid (e.g., paint pigment) can be reduced to colloidal particles in a colloid mill, a mechanical device that uses a shearing force to break apart the larger particles. An emulsion is often prepared by homogenization, usually with the addition of an emulsifying agent. The above methods involves breaking down a larger substance into colloidal particles. Condensation of smaller particles to form a colloid usually involves chemical reactions typically displacement, hydrolysis, or oxidation and reduction.

Colloidal dispersions

    The formation of colloidal material involves either degradation of bulk matter or aggregation of small molecules or ions. Dispersion of bulk material by simple grinding in a colloid mill or by ultrasonics does not, in general, lead to extensive subdivision, owing to the tendency of smaller particles to reunite (a) under the influence of the mechanical forces involved and (b) by virtue of the attractive forces between the particles. After prolonged grinding the distribution of particle sizes reaches an equilibrium. Somewhat finer dispersions can be obtained by incorporating an inert diluent to reduce the chances of particles in question encountering one another during the grinding, or by wet-milling in the presence of surface-active agent. As an example of the first of these techniques, a sulphur sol in the upper colloidal range can be prepared by grinding a mixture of sulphur and glucose, dispersing the resulting powder in water and then removing the dissolved glucose from the sol by dialysis.


 

    A higher degree of dispersion is usually obtainable when a sol is prepared by an aggregation method. Aggregation methods involve the formation of a molecularly dispersed supersaturated solution from which the material in question precipitates in a suitable divided form. A variety of methods, such as the substitution of a poor solvent for a good one, cooling and various chemical reactions, can be utilised to achieve this end.


 

    A coarse sulphur sol can be prepared by pouring a saturated solution of sulphur in alcohol or acetone into water just below boiling point. The alcohol or acetone vaporises, leaving the water-insoluble sulphur colloidally dispersed. This technique is convenient for dispersing wax-like material in an aqueous medium.

Examples of hydrosols which can be prepared by suitably controlled chemical reaction include the following:

  1. Silver iodide sol. Mix equal volumes of aqueous solutions (10-3 to 10-2 mol dm-3) of silver nitrate and potassium iodide. Separate the sol from larger particles by decantation or filtration. By arranging for the silver nitrate or the potassium iodide to be in very slight excess, positively or negatively charged particles, respectively, of silver iodide can be formed.
  2. Gold sol. Add 1 cm3 of 1% HAuC14.3H20 to 100 cm3 of distilled water. Bring to the boil and add 2.5 cm3 of 1 % sodium citrate. Keep the solution just boiling. A ruby red gold sol forms after a few minutes.
  3. Sulphur sol. Mix equal volumes of aqueous solutions (10-3 to 5 x 10-3 mol dm-3) of Na2S2O3 and HCl.
  4. Hydrous iron(111) oxide sol. Add, with stirring, 2 cm3 of 30% FeC13(aq) to 500 cm3 of boiling distilled water. A clear reddish-brown dispersion is formed.

Nucleation and growth

The formation of a new phase during precipitation involves two distinct stages - nucleation (the formation of centres of crystallisation) and crystal growth - and
is the relative rates of these processes which determine the particle size of the precipitate. A high degree of dispersion is obtained when the rate of nucleation is high and the rate of crystal growth is low.


 

    The initial rate of nucleation depends on the degree of supersaturation which can be reached before phase separation occurs, so that colloidal sols are most easily prepared when the substance in question has a very low solubility. For example, calcium carbonate, there is a tendency for the smaller particles to dissolve and recrystallise on the larger particles as the precipitate is allowed to age.


 


 


 


 

The rate of particle growth depends mainly on the following factors:

  1. The amount of material available.
  2. The viscosity of the medium, which controls the rate of diffusion of material to the particle surface.
  3. The ease with which the material is correctly orientated and incorporated into the crystal lattice of the particle.
  4. Adsorption of impurities on the particle surface, which act as growth inhibitors.
  5. Particle-particle aggregation.

    Von Weimarn (1908) investigated the dependence on reagent concentration of the particle sizes of barium sulphate precipitates formed in alcohol-water mixtures by the reaction

Ba(CNS)2 + MgSO4 ->BaSO4 + Mg(CNS)2

At very low concentrations, c.10-4 to 10-3 mol dm-3, the supersaturation is sufficient for extensive nucleation to occur, but crystal growth is limited by the availability of material, as a result sol is formed. At moderate concentrations, c.10-2 to 10-1 mol dm-3, the extent of nucleation is not much greater, so that more material is available for crystal growth and a coarse filterable precipitate is formed. At very high concentrations, c.2 to 3 mol dm-3, the high viscosity of the medium slows down the rate of crystal growth sufficiently to allow time for extensive nucleation and the formation of very small particles. Owing to their closeness, the barium sulphate particles will aggregate and the dispersion will take the form of a translucent, semi-solid gel.


 

Figure 3: The dependence of particle size on reagent concentration for the precipitation of a sparingly soluble material


 


 

Monodispersed sols

    Aggregation methods usually lead to the formation of polydispersed sols, mainly because the formation of new nuclei and the growth of established nuclei occur simultaneously, and so the particles finally formed are grown from nuclei formed at different times. In experiments designed to test the validity of theories, however, there are obvious advantages attached to the use of monodispersed systems. The preparation of such systems requires conditions in which nucleation is restricted to a relatively short period at the start of the sol formation. This situation can sometimes be achieved either by seeding a supersaturated solution with very small particles or under conditions which lead to a short burst of homogeneous nucleation.


 

    An example of the seeding technique is based on Zsigmondy (1906) for preparing approximately monodispersed gold sots. A hot dilute aqueous solution of hydro auric chloride (HAuCl4) is neutralised with potassium carbonate and a part of the solute is reduced with a small amount of white phosphorus to give a highly dispersed gold sol with an average particle radius of c. 1 nm. The remainder of the HAuCl4 is then reduced relatively slowly with formaldehyde in the presence of these small gold particles. Further nucleation is effectively avoided and all of the gold produced in this second stage accumulates on the seed particles. Since the absolute differences in the seed particle sizes are not great, an approximately monodispersed sol is formed. By regulating the amount of HAuCl4 reduced in the second stage and the number of seed particles produced in the first stage, the gold particles can be grown to a desired size.


 

    A similar seeding technique can be used to prepare monodispersed polymer latex dispersions by emulsion polymerisation. A polymerisation method which is of particular interest to the colloid scientist is that of emulsion polymerisation.


 

    In bulk polymerisation, processing difficulties are usually encountered unless the degree of polymerisation is sharply limited. These difficulties arise mainly from the exothermic nature of polymerisation reactions and the necessity for efficient cooling to avoid the undesirable effects associated with a high reaction temperature. Even at moderate degrees of polymerisation the resulting high viscosity of the reaction mixture makes stirring and efficient heat transfer very difficult.


 

    The difficulties associated with heat transfer can be overcome, and higher molecular weight polymers obtained, by the use of an emulsion system. The heat of polymerisation is readily dissipated into the aqueous phase and the viscosity of the system changes only slightly during the reaction.


 

    A typical recipe for the polymerisation of a vinyl monomer would be to form an oil-in-water emulsion from:

Table 2

monomer (e.g. styrene)

25-50 g

emulsifying agent (e.g. fatty acid soap)

2-4 g

initiator (e.g. potassium persulphate)

0.5-1 g

chain transfer agent (e.g. dodecyl mercaptan)

0-0.2 g

water

200 g


 

    Nitrogen is bubbled through the emulsion, which is maintained at c. 50-60°C for c. 4-6 h. The chain transfer agent limits the relative molecular mass of the polymer to c. 104, compared with c. 105-106 without it. The latex so formed is then purified by prolonged dialysis.


 

    The mechanism of emulsion polymerisation is complex. The basic theory is that originally proposed by Harkins21. Monomer is distributed throughout the emulsion system (a) as stabilised emulsion droplets, (b) dissolved to a small extent in the aqueous phase and (c) solubilised in soap micelles. The micellar environment appears to be the most favourable for the initiation of polymerisation. The emulsion droplets of monomer appear to act mainly as reservoirs to supply material to the polymerisation sites by diffusion through the aqueous phase. As the micelles grow, they adsorb free emulsifier from solution, and eventually from the surface of the emulsion droplets. The emulsifier thus serves to stabilise the polymer particles. This theory accounts for the observation that the rate of polymerisation and the number of polymer particles finally produced depend largely on the emulsifier concentration, and that the number of polymer particles may far exceed the number of monomer droplets initially present.


 

    Monodispersed sols containing spherical polymer particles (e.g. polystyrene latexes22-24, 115) can be prepared by emulsion polymerisation, and are particularly useful as model systems for studying various aspects of colloidal behaviour. The seed sol is prepared with the emulsifier concentration well above the critical micelle concentration; then, with the emulsifier concentration below the critical micelle concentration, subsequent growth of the seed particles is achieved without the formation of further new particles.

    Among the monodispersed sols which have been prepared under conditions which lead to a short burst of homogeneous nucleation are (a) sulphur sols132, formed by mixing very dilute aqueous solutions of HCl and Sodium thiosulphate (Na2S2O3); (b) silver bromide so1s, by controlled cooling of hot saturated aqueous solutions of silver bromide; and (c) silver bromide and silver iodide so1s, by diluting aqueous solutions of the complexes formed in the presence of excess silver or halide ions. In each case the concentration of the material of the dispersed phase slowly passes the saturation point and attains a degree of supersaturation at which nucleation becomes appreciable. Since the generation of dispersed phase material is slow, the appearance of nuclei and the accompanying relief of supersaturation is restricted to a relatively short period and few new nuclei are formed after this initial outburst. The nuclei then grow uniformly by a diffusion-controlled process and a sol of monodispersed particles is formed.


 


 

Figure 4: Formation of an approximately monodispersed sulphur sol by the slow reaction between Na2S2O3 and HCl in dilute aqueous solution


 

    Various methods are also available for the preparation of monodispersed hydrous metal oxide sols and silica sols. Monodispersed polystyrene sols are used as calibration standards for electron microscopes, light scattering photometers, Coulter counters, particle sieves, etc. Monodispersed silica is used for antireflection lens coatings. Monodispersity (even at a modest level) can usefully be exploited in photographic film, magnetic devices, pharmaceutical preparations and catalysis.

Macromolecular colloids

    Macromolecular chemistry covers a particularly wide field which includes natural polymeric material, such as proteins, cellulose, gums and natural rubber; industrial derivatives of natural polymers, such as sodium carboxymethyl cellulose, rayon and vulcanised rubber; and the purely synthetic polymers, such as polythene (polyethylene), Teflon (polytetrafluoroethylene), polystyrene, Perspex (poly (methyl methacrylate) ), terylene (poly (ethylene terephthalate) ) and the nylons, e.g. (poly (hexamethylene adipamide) ). Only brief mention of some of the more general aspects of polymerisation will be made. The reader is referred to the various specialised texts for details of preparation, properties and utilisation of these products.


 

    High polymers contain giant molecules which are built up from a large number of similar (but not necessarily identical) units (or monomers) linked by primary valence bonds. Polymerisation reactions can be performed either in the bulk of the monomer material or in solution. A further technique, emulsion polymerisation, which permits far greater control over the reaction, is discussed on.


 

    There are two distinct types of polymerisation: addition polymerisation and condensation polymerisation. Addition polymerisation does not involve a change of chemical composition. In general, it proceeds by a chain mechanism, a typical series of reactions being:


 

  1. Formation of free radicals from a catalyst (initiator), such as a peroxide.
  2. Initiation: for example,


 

  1. Propagation:


 

  1. Termination. This can take place in several ways, such as reaction of the activated chain with an impurity, an additive or other activated chains, or by disproportionation between two activated chains.


 

    A rise in temperature increases the rates of initiation and termination, so that the rate of polymerisation is increased but the average chain length of the polymer is reduced. The chain length is also reduced by increasing the catalyst concentration, since this cause chain initiation to take place at many mores points throughout the reaction mixture.

Condensation polymerisation involves chemical reactions between functional groups with the elimination of a small molecule, usually, water. For example,


 


 


 

    If the monomers are bifunctional, as in the above example, then a linear polymer is formed. Terminating monofunctional groups will reduce the average degree of polymerisation. Polyfunctional monomers, such as glycerol and phthalic acid, are able to form branching points, which readily leads to irreversible network formation. Bakelite, a condensation product of phenol and formaldehyde, is an example of such a space-network polymer. Linear polymers are usually soluble in suitable solvents and are thermoplastic-i.e. they can be softened by heat without decomposition. In contrast, highly condensed network polymers are usually hard, are almost completely insoluble and thermoset-i.e. they cannot be softened by heat without decomposition.

Dialysis and gel filtration

    Conventional filter papers retain only particles with diameters in excess of at least ìm and are, therefore, permeable to colloidal particles. The use of membranes for separating particles of colloidal dimensions is termed dialysis. The most commonly used membranes are prepared from regenerated cellulose products such as collodion (a partially evaporated solution of cellulose nitrate in alcohol plus ether), Cellophane and Visking. Membranes with various, approximately known, pore sizes can be obtained commercially (usually in the form of ´sausage skins' or ´thimbles'). However, particle size and pore size cannot be properly correlated, since the permeability of a membrane is also affected by factors such as electrical repulsion when .the membrane and particles are of like charge, and particle adsorption on the filter which can lead to a blocking of the pores.


 

Figure 5: A simple dialysis set-up


 

    Dialysis is particularly useful for removing small dissolved molecules from colloidal solutions or dispersions-e.g. extraneous electrolyte such as KNO3 from AgI sol. The process is hastened by stirring so as to maintain a high concentration gradient of diffusible molecules across the membrane and by renewing the outer liquid from time to time.


 

    Ultrafiltration is the application of pressure or suction to force the solvent and small particles across a membrane while the larger particles are retained. The membrane is normally supported between fine wire screens or deposited in a highly porous support such as a sintered glass disc. An important application of ultrafiltration is the so-called reverse osmosis method of water desalination.


 

    Another most valuable development of the ultrafiltration principle is the technique of gel permeation chromatography for the separation of the components of a polymeric sample and determination of the relative molecular mass distribution. The usual experimental arrangement involves the application of a pressure to force polymer solution through a chromatographic column filled with porous beads. The larger polymer molecules tend not to enter the pores of the beads and so pass through the column relatively quickly, whereas the smaller polymer molecules tend to diffuse through the pore structure of the beads and so take longer to pass through the column. The eluted polymer can be detected and estimated by measuring the refractive index of the emerging solution, and the relationship between retention time and relative molecular mass is determined by calibrating the apparatus with polymer fractions which have been characterised by other methods, such as osmotic pressure, light scattering or viscosity.


 

Figure 6: Electrodialysis


 

    A further modification of dialysis is the technique of electrodialysis, as illustrated. The applied potential between the metal screens supporting the membranes speeds up the migration of small ions to the membrane surface prior to their diffusion to the outer liquid. The accompanying concentration of charged colloidal particles at one side and, if they sediment significantly, at the bottom of the middle compartment is termed electrodecantation1.


 

COLLOIDAL STABILITY


 

    A stable colloidal system is one in which the particles resist flocculation or aggregation and exhibits a long shelf-life. This will depend upon the balance of the repulsive and attractive forces that exist between particles as they approach one another. If all the particles have a mutual repulsion then the dispersion will remain stable. In certain circumstances, the particles in a colloidal disperson may adhere to one another and form aggregates of successively increasing size that may settle out under the influence of gravity. An initially formed aggregate is called a floc and the process of its formation flocculation.


 


 


 

The importance of the interface

    A characteristic feature of colloidal dispersions is the large area-to-volume ratio for the particles involved. Surface properties evident at the interface of the dispersed and dispersion medium is adsorption and electric double layer effect. It is the material within a molecular layer or so of the interface which exerts by far the greatest influence on particle-particle and particle-dispersion medium interactions.


 

    Despite the large area-to-volume ratio, the bulk properties of a colloidal dispersion can often be effected by small quantities of suitable additives. For example, pronounced changes in the consistency of certain clay suspensions (such as those used in oil-well drilling) can be effected by the addition of small amounts of calcium ions (thickening) or phosphate ions (thinning).

Solvation

    This is the attraction between dispersed face and dispersion medium and this solvated layer is considered as a part of the particle.


 

    Sometimes much greater amounts of solvent can be immobilised by mechanical entrapment within particle aggregates. This occurs when voluminous flocculent hydroxide precipitates are formed. In solutions of long thread-like molecules the polymer chains may cross-link, chemically or physically, and/or become mechanically entangled to such an extent that a continuous three-dimensional network is formed. If all of the solvent becomes mechanically trapped and immobilised within this network, the system as a whole takes on a solid appearance and is called a gel.


 

Polydispersity and the averages

    The terms relative molecular mass and particle size can only have well-defined meanings when the system under consideration is monodispersed - i.e. when the molecules or particles are all alike.


 

Surface Active Agents

    A surface active agent (surfactant) is a substance which lowers the surface tension of the medium in which it is dissolved, and/or the interfacial tension with other phases, and, accordingly, it is positively adsorbed at the liquid/vapour and/or at other interfaces. The term surfactant is also applied correctly to sparingly soluble substances, which lower the surface tension of a liquid by spreading spontaneously over its surface.


 

    Certain molecules or ions termed amphiphiles or surface active agents are characterized by having two distinct regions of opposite solution affinities within the same molecule or ion. When present in a liquid medium at low concentration, the amphiphile exists separately and are of a such size as to be subcolloidal. As the concentration is increased, aggregation occurs over a narrow concentration range. These aggregates are called micelles of size 15 Ao. The concentration of monomer at which micelle formed is termed critical micellar concentration (CMC). When a surface active agents are added free agents, surface tension also decreases upto the cmc. This may leads to increasing interfacial adsorption.6


 

Figure 7: The lamelle (L) and the Spherulite (S)


 

Kinetic properties of colloids


 

    Kinetic properties of colloidal systems relate to the motion of particles with respect to the dispersion medium. They are;


 

Brownian Motion


 

    Brownian motion is seen in particular of sizes 6 mm, as a result of the bombardment of the particles by the molecules of the dispersion medium. It is not observable due to small size. The velocity of the particle increases with the decrease in particle size. Brownian movement can be stopped by increasing the viscosity of medium by the addition of glycerine or similar agents.


 


 


 

Diffusion


 

    Diffusion is another kinetic property of colloid which occur as a result of brownian movement. Here particles get diffused spontaneously from a region of higher concentration to one of lower concentration until the concentration of system is uniform throughout.


 

    According to fick's 1st law, the amount dq of a substance diffusing in time dt across an area S is directly proportional to charge of concentration dc with distance dx


 


 


 

D is the diffusion coefficient


 

    Diffusion coefficient may be obtained in colloidal chemistry by diffusion experiments in which the material is allowed to pass through a porous disc and samples are removed and analysed periodically.


 

    If the colloidal particles are assumed to be spherical, the following equation is used to obtain radius of the particle and molecular weight.


 


 

R    =    Molar gas constant

T    =    Absolute temperature

m    =    Visocity of the solvent

N    =    Avagadros number

r    =    radius of the particles


 

Molecular weight of spherical molecules such as egg albumin haemoglobin can be determined by


 


 

M    =    Molecular weight

    =    Partial specific volume


 

OSMOTIC PRESSURE


 

    Van's Hoff equation


 


 

can be used to calculate the molecular weight of a colloid in a dilute solution. Replacing C with Cg/M, in which Cg is the grams of solute per litre of solution and M is the molecular weight, we obtain,

                (2)

then,

                (3)

which applies in very dilute.

Solution: The quantity 5/cg for a polymer having a molecular weight of 50,000 in a linear function of the concentration Cg, and the following equation can be written


 


 


 

    B is a constant for any particular solvent solute system and depends on degree of interaction between the solvent and solute molecules. The form BCg is needed because equation (3) holds only for ideal solutions. With linear lyophillie molecules deviation occur because the solute molecules become solvated, leading to reduction in the concentration of free solvent and our apparent increase in solute concentration.


 


 

    A plot of 5/Cg against Cg results in one of three lines depending on whether the system is ideal (line 1) or real (line 2 and 3). The intercept is RT/M. if the temperature is known molecular weight of the solute can be determined.


 

    In line 1, B equals zero where B is interaction constant and is typical of a dilute colloidal system. In line 2 and 3 slope of the line is B line 3 is typical of a linear colloid in a solvent having high affinity for the dispersed particle. Such a solvent is referenced good solvent for that particular colloid. There is a marked deviation from ideality as the concentration is increased. Line 2 depicts the situation in which the same colloid is present in a relatively poor solvent having relative affinity.


 

SEDIMENTATION


 

    The velocity V of sedimentation of spherical particles having density r in a medium of density ro and a viscosity ho is given by Stoke's law.


 


 

    if the particles are subjected only to force of gravity then the lower size limit of particles obeying stoke's equation is about 0.5 mm. this is because Brownian movement become significant and tends to offset sedimentation due to gravity and promotes mixing. 50 a stronger force must be applied to bring about the sedimentation of colloidal particles. This is accomplished by ultra centrifuge, developed by Svedberg. The instantaneous velocity V = dx/dt of a particle in a unit centrifugal field is expressed in terms of the Svedberg sedimentation coefficient, S


 

= Angular acceleration


 

Molecular weight can be determined by two method,

1) Sedimentation velocity technique

2) Sedimentation equilibrium method


 

Sedimentation velocity technique:


 

    There owing to the centrifugal forces particules having a high molecular weight pass from position x1 at time t1 to position x2 at time t2, sedimentation coefficient is obtained by integrating equation;


 


 


 

    The distances x1 and x2 refer to position of the boundary between the solvent and the high molecular weight components in the centrifuge cell. The bondary is located by the change of refractive index which may be attained at any time during the run of translated into a peal on a photographic plate. Photographs are taken at definite intervals and the pearls of the schlieren pattern as they are called, give the position x of the boundary at each time t. if the sample contains a component of definite molecular weight, schlieren pattern will have a single sharp pearl at any moment during the run. If it contains different compounds several peaks will appear on the schlieren pattern. Thus this method helps to determine molecular weight of the polymers particularly proteins and also degree of homogeneity of the sample.


 

    By obtaining Svedberg sedimentation coefficient it is possible to determine the molecular weight of a polymer,


 


 

R = Molar gas constant

T = Absolute temperature

= Partial specific volume of the protein

= Density of solvent

D = Diffusion coefficient


 

Both S &D must be obtained at, or corrected to, 200C.


 

Sedimentation Equilibrium

    

    Equilibrium is established when the sedimentation force is just balanced by the counteracting diffusional force and the boundary is therefore stationary. In this method diffusion coefficient is not measured however the centrifuge may have to be run for several weeks to attain equilibrium throughout the cell. Newer method of calculation have been developed recently for obtaining molecular weights by the equilibrium method without requiring these long periods of centrifugation.


 

VISCOSITY


 

    Viscosity is an expression of the resistance to flow of a system under an applied stress. The more viscous a liquid, the greater the applied force required to make it flow at particular rate. Viscosity studies also provide information regarding the shape of the particle in solution.


 

    Einstein developed an equation of flow applicable to dilute colloidal dispersion of spherical particles namely,


 

h = h0 (1 + 2.5 q)

h0 = viscosity of the dispersion medium

h = viscosity of the dispersion when the volume fraction of colloidal particles present is q. The volume fraction is defined the volume of particles divided by the total volume of dispersion, it is therefore equivalent to a concentration term.


 

    Several viscosity coefficients may be defined with respect to this equation. These include relative viscosity, specific viscosity, intrinsic viscosity.


 


 

Since volume fraction is directly related to concentration.


 


 


 

    in which C is expressed in grams of colloidal particles per 100 ml of total dispersion. For highly polymeric materials dispersed in the medium at moderate concentration.


 

If is plotted against C, the line which is polated to infinite dilution, the intercept is K1 known as intrinsic viscosity (h) is used to calculate the approximate molecular weight of polymers.


 

According to the Mark-Houwink equation,


 

[h] = KMa


 

K & a are constants, characteristics of the particular polymer-solvent system.

M=molecular weight

    The characteristics of polymers used as substitutes for blood plasma depend in part on molecular weight of the material. These characteristics include the size and shape of macromolecules and the ability of the polymers to impart the proper viscosity and osmotic pressure to the blood. These methods are used to determine the average molecular weight of hydroxyl ethyl starch and gelatine preparation used as plasma extenders.5,6


 

ELECTRIC PROPERTIES OF COLLOIDS


 

    The presence of a charge on the surface of a particle may effect the properties of colloids. They are:


 

Electro kinetic phenomena

    It includes electrophoresis, electro osmosis, sedimentation potential and streaming potential.


 

    Electrophoresis involves the movement of a charged partied through a liquid under the influence of an applied potential difference. An electrophoresis cell fitted with two electrodes, contains the dispersion. When a potential is applied across the electrodes, the particles migrate to the oppositively charged electrode. The rate can be determined by the ultramicroscope and is a function of the charge on the particle. As the shear plane of the particle is located at the periphery of the tightly bound layer, the rate determining potential is the zeta potential.


 


 

    z = Zeta potential in volts

    h = Viscosity of medium in poise

    Î = Dielectric constant of the medium

    E = Potential gradient in volts/cm

    V/E = Mobility


 

    The above equation can be coritten as;


 


 


 

    It is expressed in stat volts.

For colloidal system at 200C in which the dispersion medium is water, equation is reduced to


 


 


 

    electro osmosis is opposite in principle to that of electrophoresis. Here the solid is rendered in mobile phase and the liquid moves relative to the charged surface. This is electroosmosis, so called because the liquid moves through a plug or membrane across which a potential is applied. It also helps to determine zeta potential by determining the rate of flow of liquid through the plug under standard condition.


 

    Sedimentation potential, the reverse of electrophoresis is the creation of potential when particles undergo sedimentation.


 

    Streaming potential differs from electro osmosis in that potential is created by forcing a liquid to flow through a plug or bed of particles.


 

Example


 

    From the association studies the electrophoretic properties of microcapsules of sulfamethoxazole in droplets of a gelatine-acacia coacervate as the part of a study to stabilize such drugs in microcapsules.


 

DONNAN MEMBRANE EQUILIBRIUM


 

    If sodium chloride is placed in solution on one side of a semi permeable membrane and negatively charged colloid together with its counter ion R Na+, is placed on other side, the sodium and chloride ions can pass freely across the barrier but not the colloidal anionic particles.


 

    At equilibrium, it can be represented as,

Outside (o)            inside (i)

Na+                H+

Cl–                Na+

                Cl


 

The volume of solution on the two sides of the membrane are considered to be equal. After equilibrium has been established the concentration in dilute solution of sodium chloride must be same on both sides of the membrane. Therefore,


 

[Na+]o
[Cl]o = [Na+]i
[Cl]i                    (1)


 

The condition of electro neutrality must also applied. Here concentration of positively charged ions in the solution on either side of the membrane must balance the concentration of negatively charged ions. Therefore, on the outside,


 

[Na+]o
= [Cl]o

    and inside,

[Na+]i = [R]i
+ [Cl]i


 

This can be substituted in equation (1) to give,


 


 


 

    This equation gives the ratio of concentration of the diffusible anion outside and inside the membrane equilibrium. This shows that a negatively charged polyelectrolyte inside a semi permeable Sac would influence the equilibrium concentration ratio of a diffusible anion. When [R]I is large compared to [Cl]i, the ratio roughly equals . If, on the other hand the [Cl]i is quite large with respect to [R]I, the ratio in the equation becomes equal to unity and the concentration of the salt is thus equals on both sides of the membrane.


 

    The unequal distribution of diffusible electrolyte ion on the two sides of the membrane will result in erroneous values for osmotic pressure of polyelectrolyte solution. If however, the concentration of salt in the solution is made large, the donnan equilibrium effect can be practically eliminated in the determination of molecular weights of protein involving the osmotic pressure method. This equation can be used to demonstrate the use of polyelectrolyte, sodium carboxy methyl cellulose, for enhancing the absorption of drugs such as sodium salicylate and potassium benzyl pencillin. If [Cl] in the equation is replaced by the concentration of the diffusible drug, anion [D] at equilibrium and [R] is used to represent the concentration of sodium carboxy methyl cellulose at equilibrium, we have


 


 


 

    Therefore, the addition of an anionic polyelectrolyte to a diffusible drug anion should enhance the diffusion of the drug out of the chamber.


 

Electric double layer


 

    Consider a solid surface contact with a polar solution containing ions. Eg: Aqueous solution of an electrolyte. At first the solid surface will be adsorbed with cations. Later the counter ions actually the anions are added to the surface. In addition to these an equilibrium is set up in which some of the excess anion approach the surface while the remainder are distributed in decreasing amounts as one proceeds away from the charge of surface. The system as a whole electrically neutral.


 

    The adsorbed ion that gave positive charge to surface is called as potential determining ions. aa' surface of the solid with positive ions. The region between aa' and bb' are filled with counter ions or gegenions. The region between bb' and cc' excess of anions are present. The region between cc' and dd' is the electrically neutral region and the system as a whole electrically neutral.


 

    The first layer (extending from aa' to bb') tightly bound and second layer (from bb' to cc') that is more diffuse and these layers combinedly called diffuse double layer.


 


 


 

Figure 8: Electric double layer


 

ZETA POTENTIAL


 

    The zeta potential is defined as the difference in potential between surface of the tightly bound layer and the electro neutral region of the solution.


 

    Zeta potential has practical application in the stability of system containing dispersed particles. Since this potential, rather than the charge potential, governs the degree of repulsion between adjacent, similarly charged dispersed particle. If the zeta potential is reduced below certain values the attractive force exceeds the repulsive force and the particles come together and this process is known as flocculation.6


 


 

Figure 9: Principle of Zeta potential measurement


 

KINETICS OF COAGULATION


 

    The coagulation of colloidal particles proceeds by three different mechanisms,


 


 

Von smoluchowski derived the following expression for diffusion – controlled coagulation


 


 

    where is the rate of disappearance of N primary particles

    N0 – the initial number of particles/unit volume

    k0 – the rate constant

    D – the diffusion coefficient

    R – the collision radius

    W – the stability ratio


 

    The stability ratio W represents the retardation factor of the slow coagulation compared with rapid coagulation. The stability ratio is related to the height of the maximum of the potential energy curve.


 


 


 


 


 

For VT = 0, W = 1, which is the condition for rapid coagulation. The rate constant K for slow coagulation is given by .


 

    The rate of coagulation is measured at different electrolyte concentrations by turbidimetry or light-scattering measurements. The date are unusually given as the variation of log W with log electrolyte concentration Ce.


 

    The following information can be obtained from the log W – log Ce plots.


 

Figure 10: Variation of log stability factor with log electrolyte concentration


 

DLVO Theory


 


 

    DLVO theory states that when two droplets approach each other, the counter ions forming the diffuse part of the electric double layer beg into overlap. This overlap means that the electrical potential (the work done to bring one electric charge from a long distance to the point observed) between the droplets is increased. Which in turn means that more energy must be added with reduced distance between the droplets. An increase in energy with reduced distance means a repulse force between the droplets. The force is equal to the negative value of the slope of the curve. It the same time, there is always an attractive force between emulsion droplets and this force becomes stronger with reduced distance between them.


 

    The interaction between droplets is decided by the total potential (the sum with signs of the two potentials). In this energy from the electric double layer is numerically greater than the Van der waals potential for a certain distance range and the sum of the two energies becomes positive. This means the resulting force is repulsive. On the other hand, for small distances, the resulting energy is always negative and the particles will spontaneously move towards each other.


 

    The relative value of the two potentials also explains why the electric stabilization disappears entirely for an added electrolyte because the concentration of the electric double layer counter ions exceeds a certain value. Addition of an electrolyte to the continuous phase causes a reduction of the electric double layer repulsion potential whereas Van der waals potential remains essentially exchanged. Hence, a maximum in the total potential is reduced more with increased electrolyte concentration and at a certain value, the maximum barrier height is reduced to a level at which the stability is lost.6

SURFACE ACTIVE AGENTS


 

A surface active agent (surfactant) is a substance which lowers the surface tension of the medium in which it is dissolved, and/or the interfacial tension with other phases, and, accordingly, is positively adsorbed at the liquid/vapour and/or at other interfaces. The term surfactant is also applied correctly to sparingly soluble substances, which lower the surface tension of a liquid by spreading spontaneously over its surface.


 

Certain molecules or ions termed amphiphiles or surface active agents are characterized by having two distinct regions of opposite solution affinities within the same molecule or ion when present in a liquid medium at low concentration, the amphiphiles exist separately and are of such a size as to be sub colloidal. As the concentration is increased, aggregation occurs over a narrow concentration range. These aggregates are called micelles of size 50A0. The concentration of monomer at which micelle formed is termed Critical Micellar Concentration (CMC). When a surface active agent is added free energy of a system is reduced, surface tension also decreases up to the CMC. This may leads to increasing interfacial adsorption.6


 

Advantages of colloidal system

    

    Colloidal formulations have increased therapeutic activity.


 

    Colloidal silver chloride (AgCl2), silver iodide (Ag2) and silver protein are effective germicides and do not cause the irritation that is characteristics of ionic silver salt.

    

    Colloidal copper has been used in the treatment of cancer, colloidal fold has a diagnostic agent for paresis, and colloidal mercury for syphilis.


 

    The plasma proteins are responsible for binding certain drug molecule to such an extend that the pharmacological activity of the drug is effected.


 

    Colloidal electrolytes are sometimes used to increase the solubility, stability and taste of certain compounds in aqueous and oily pharmaceutical preparations.9


 

General advantages

Colloidal drug carriers offer a number of potential advantages as delivery systems for, for example, poorly soluble compounds. The first generation of colloidal carriers, in particular liposomes and submicron-sized lipid emulsions, are, however, associated with several drawbacks which so far have prevented the extensive use of these carriers in drug delivery. As an alternative colloidal delivery system melt-emulsified nanoparticles based on solid lipids have been proposed. Careful physicochemical characterization has demonstrated that these lipid-based nanosuspensions (solid lipid nanoparticles) are not just emulsions with solidified droplets. During the development process of these systems interesting phenomena have been observed, such as gel formation on solidification and upon storage, unexpected dynamics of polymorphic transitions, extensive annealing of nanocrystals over significant periods of time, stepwise melting of particle fractions in the lower-nanometer-size range, drug expulsion from the carrier particles on crystallization and upon storage, and extensive supercooling. These phenomena can be related to the crystalline nature of the carrier matrix in combination with its colloidal state. Observation of the supercooling effect has led to the development of a second new type of carrier system: nanospheres of supercooled melts. This novel type of colloidal lipidic carrier represents an intermediate state between emulsions and suspensions. Moreover, these dispersions are particularly suited to the study of the basic differences between colloidal triglyceride emulsions and suspensions. For many decades drug carriers have represented the only group of colloidal drug administration systems. Nowadays a fundamentally different group of dispersions is also under investigation: drug nanodispersions. They overcome a number of carrier-related drawbacks, such as limitations in drug load as well as side effects due to the matrix material of the carrier particles. Utilizing this concept virtually insoluble drugs can be formulated as colloidal particles, of solid or supercooled nature. For example, coenzyme Q[10] (Q[10]) has been successfully processed into a dispersion of a supercooled melt. Droplet sizes in the lower nanometer range and shelf lives of more than 3 years can easily be achieved for Q[10] dispersions. The drug load of the emulsion particles reaches nearly 100%.


 

Advantages of colloidal bismuth subcitrate


 

The effect of colloidal bismuth subcitrate (De-Nol) on symptoms, Helicobacter pylori status and histological features was studied in 35 patients with non-ulcer dyspepsia. Pain (34 cases) and gas bloat (18) were the predominant symptoms. H pylori was present in 26 (74.3%) patients. Gastritis and duodenitis were present in 29 of 32 and 22 of 31 cases respectively in whom biopsies were available. Relief in symptoms after treatment was seen in 29 (82.8%) cases. Improvement in gastritis and duodenitis was noted in 60.8% and 58.8% respectively; over 70% of H pylori positive patients cleared the organism. These changes did not correlate with the relief in symptoms. We conclude that colloidal bismuth subcitrate is effective in the short term treatment of non-ulcer dyspepsia. It also clears H pylori infection and results in improvement of histological features.


 

Formulation aspects 

Biopharmaceutical aspects 

Benefits 

Injectability/size

Solubilisation of poorly soluble drugs

Increased dissolution rate

Controlled/sustained release

Protection for labile agents

High surface area = rapid dissolution/ rapid onset

Targeting

Extravascular/transdermal transport 

drawbacks 

Less drug per mass of dose form

Excipient requirements

Colloidal stability issues

Complex

Complication pharmacokinetic analysis

Less control over drug disposition

Excipients may influenced the drug pharmacokinetics 


 

Advantages of colloidal amphotericin B over amphotericin B deoxycholate suspension

The efficacy and safety of amphotericin B colloidal dispersion (ABCD) were compared with those of amphotericin B deoxycholate suspension (ABDS) (Fungizone) in a murine model of disseminated cryptococcosis. Mice were treated intravenously with either ABDS at 0.2, 0.8, or 3.2 mg/kg of body weight per dose or ABCD at 0.8, 3.2, 6.4, 12.8, or 19.2 mg/kg dose three times per week for 2 weeks. Excluding mice treated with ABDS at 3.2 mg/kg, which was acutely lethal in 100% of mice, and ABCD at 19.2 mg/kg, which also resulted in two early deaths, the survival of ABCD- and ABDS-treated groups was prolonged over survival of controls (P < or = 0.05). Survival of ABCD (3.2 mg/kg)-treated mice was improved over that of ABDS (0.2 mg/kg)-treated mice (P < 0.05); however, comparisons of mice given all other dosages of ABCD with mice given sublethal dosages of ABDS did not demonstrate differences in survival. Comparative fungal burdens in organs showed a decrease in liver (P < 0.05) and spleen (P < 0.05) burdens for ABCD with the 19.2-mg/kg therapy versus those with ABDS with the 0.8-mg/kg therapy and liver burdens for ABCD with the 12.8-mg/kg therapy versus ABDS with the 0.8-mg/kg therapy (P < 0.05). There was no difference in organ burdens between therapy with ABCD at 0.8 mg/kg and ABDS at 0.8 mg/kg. These data show that the efficacy of ABCD is equal to that of ABDS on a milligram-per-kilogram basis for murine disseminated cryptococcosis. Because of its decreased toxicity, greater efficacy with ABCD could be achieved through doses fourfold higher than the 100% lethal dose for ABDS. Thus, ABCD shows promise as an effective but less toxic alternative to ABDS for the treatment of disseminated cryptococcosis.


 

PREPARATIONS OF COLLOIDAL SYSTEM


 

    Various preparations include Bentonite, Aluminum hydroxide gel, Milk of Magnesia etc. Because of high degree of attraction between the dispersed phase and aqueous medium, these preparation remain fairly uniform on standing with little settling of the disperse phase. However on long standing a supernatant layer of the dispersion medium develops, but the uniformity of the preparation is easily re-established by moderate shaking.


 

    In colloidal preparations the particles size of the dispersed phase is larger than true solution. True solutions do not scatter light and therefore appear clear, but colloidal dispersions contain opaque particle that do scatter light and thus appear turbid. This turbidity is easily seen, even with dilute preparations, when the dispersion is observed at right angle to a beam of light pass through the dispersion. The particle size of the dispersed phase in some pharmaceutical preparation may not be uniform and the preparation may contain particles with in and outside of the colloidal range, giving the preparation more of an opaque appearance than if all particles where uniformly colloidal.


 

MILK OF MAGNESIA (USP)


 

    Milk of magnesia is a preparation containing between 7 and 8.5% of magnesium hydroxide. It may be prepared by a reaction between sodium hydroxide and magnesium sulphate to form precipitate of magnesium hydroxide. The precipitate so produced is washed with purified water to remove the sodium sulphate prior to its incorporation with additional purified water to prepare the required volume of product.Another is hydration reaction between magnesium oxide and water form magnesium hydroxide.

    The preparation has a PH of about 10 which may bring about a reaction between the magma of the glass container imparting a bitter taste to the preparation. To minimize the bitter taste 0.1% citric acid and flavouring oils at a concentration not exceeding 0.05% may be added to enhance the palatability of the preparation. It has acid neutrilizing ability and laxative effect.


 

ALUMINIUM HYDROXIDE GEL (USP)


 

    It is an aqueous suspension of a gelatinous precipitate composed of insoluble aluminium hydroxide and hydrated aluminium oxide equivalent to 4% of aluminium oxide. It is prepared by chemical reaction of various reactants. The aluminium source of reaction is aluminium chloride or aluminium alum which yields the insoluble aluminium oxide and aluminium hydroxide precipitate. It is effective in neutralizing a portion of the gastric hydrochloric acid and by virtue of its gelatinous viscous and insoluble character, coats the inflammable and perhaps ulcerated gastric surface and is useful in the treatment of hyper acidity and peptic ulcer.9


 

COLLOIDAL DRUGS

Amphoterion B

Chemical form    :    C47H73NO17

Trade name        :    AMPHOCIL

                AMPHOTEC

FLUCYTOSINE

Chemical form    :    C4H4FN3O

Trade name        :    Ancobon

Paclitaxel (Anticancer)

Chemical form    :    C47H51NI14

Trade name        :    Taxol

Verteporgin

Chemical form    :    C41H42H4O8

Trade name        :    Visudyne

Doxorubucin hydrochloride (Anticancer)

Chemical form    :    C27H29NO11

Trade Name        :    Doxil


 

Colloidal bismuth sulcitrate (Antacid)

Trade name        :    De-NOL10

CONCLUSION


 

    Colloidal dispersion are safe and improves the therapeutic efficacy. The formulation of colloidal dispersion improves the dissolution rate and also enhances the solubility properties of a drug. Colloidal dispersion improves the biopharmaceutical aspects like controlled or sustained release and better drug targeting.


 

    Hence it can be concluded that colloidal dispersion are safe and improves the pharmacological activity and can be formulated as controlled or sustained release for better biopharmaceutical approach.


 


 


 


 


 

BIBLIOGRAPHY


 


 


 


 

3 comments:

kanchan sarviya said...
This comment has been removed by the author.
kanchan sarviya said...

lyophobic (water loving) or lyophilic (water hating).

prabhakar yadav said...

Biopharmaceutical products processing conventional of instruments. Biopharmaceutical systems as well as disposable, single-use systems. Biopharmaceutical products are manufacture and provide to suppliers around the globe.