Description
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The invention relates to a stabilization of fluid oil-based suspensions comprising a hydrophobic silica, and medicaments based on such suspensions.
Formulation of a medicament based on oils may have various advantages, e.g. in the tolerability for the patient or in the stability of the active ingredient. However, oils which can be used pharmaceutically do not always have the necessary viscosity in order for example to reduce or avoid sedimentation of active ingredients. Thus, although most known substances used for increasing the viscosity of oils can be employed in cosmetics, they cannot be employed in pharmacy. Thus, for example, colloidal silicas are used to thicken oils for medicaments (US 2001-0006671, U.S. Pat. No. 4,079,131, WO 03-063877).
In WO 2006/008640, non-ionic emulsifiers are added to colloidal silicon dioxide (a hydrophilic silica) so that the active ingredient is wetted better in oils.
In WO 03/02254, colloidal silica, hydrophilic and hydrophobic silicas are mixed with hydrophilic polymers such as, for example, polyethylene glycol 200 or polyvinyl alcohol in oils. Interaction of the silica with the polymer is intended to reduce the use of the silica, raise the yield point and lower the viscosity on shearing.
FR 2790200 likewise mentions hydrophobic silicas, but explicitly specifically without the addition of stabilizers.
WO 2006/061155 and WO 2006/061156 describe not only hydrophilic but also hydrophobic silicas in oils. Substances which can generally be used in this connection are also for example non-ionic surfactants or else for example polyethylene glycol 200.
Hydrophilic silicas have the disadvantage in oily formulations that they are very sensitive to water or moisture and adsorb moisture even from the ambient air. As a result, the viscosity of the formulation increases and, for example, the removability from the primary packaging is no longer possible to the indicated extent. This is unacceptable in particular for medicaments. If, for example, single-dose containers made of plastics are used for these formulations, the effect of the sensitivity to moisture is particularly evident, because plastic containers are not moisture-tight, and the formulation in the filled container attracts moisture and the viscosity may increase. In addition, the ratio of the surface area of the formulation to the surrounding air in single-dose containers is particularly unfavorable by comparison with multidose containers.
This sensitivity to moisture can be overcome by using hydrophobic silicas for stabilizing suspensions against sedimentation. A distinct disadvantage of hydrophobic silicas is, however, that the long-term stability in relation to sedimentation stabilization is lower than that of hydrophilic silicas. The lower long-term stability is characterized in that the original viscosity of the oily formulations decreases over the course of weeks or months, which is unacceptable for medicaments since this may lead for example to unwanted sedimentations.
It has surprisingly been found that the long-term stability of oily formulations with hydrophobic silicas can be distinctly improved by adding amphiphilic compounds. This effect scarcely occurs on use of hydrophilic silicas. This effect has not yet been described in the state of the art for oily suspensions which specifically comprise hydrophobic silicas.
The Invention Therefore Relates to:
The use of amphiphilic substances for stabilizing fluid oil-based suspensions comprising a hydrophobic silica.
Such fluid suspensions are preferably used in formulations for medicaments.
The Invention Therefore Relates Further to:
Medicaments comprising in an oily base:
“Oil-based” means that the corresponding suspension or the corresponding medicament comprises an oily base. It is possible to use as oily base natural (animal or vegetable), synthetic and semisynthetic oils or fats. Examples thereof are soybean, sunflower, cottonseed, olive, peanut, safflower, palm, rapeseed, coconut, corn or castor oil. Preferably used are medium-chain triglycerides (triglycerides with saturated fatty acids, preferably octanoic and decanoic acid), propylene glycol diesters of caprylic/capric acid, low-viscosity paraffin or sesame oil; of these, the medium-chain triglycerides and propylene glycol diesters of caprylic/capric acid are particularly preferably used.
The oily base is typically employed in a proportion of 99-72% by weight, preferably of 99-88% by weight, particularly preferably of 97-92% by weight, based on the relevant suspension or the finished medicament.
The suspensions may have different viscosities, so that in principle a range from low-viscosity suspensions to pastes is conceivable. Preference is given to fluid systems which include low-viscosity and also higher-viscosity systems as long as they still flow under their own weight. Preferred fluid systems have a yield point, i.e. these systems flow after shearing (e.g. by shaking). In many cases, the active ingredients do not dissolve sufficiently, or at all, in the fluid base, so that the active ingredient must also be suspended. For this reason, hydrophobic silicas are employed as thickeners for stabilizing the suspension against sedimentation.
Hydrophobic silicas are silicas which are not wetted by water; this means that they float on the water surface. Likewise suitable are hydrophobicized mixed oxides of silicon dioxide and aluminum oxide, but hydrophobic pure silicas are preferred. They are produced by mixing hydrophilic silica with silanes (halosilanes, alkoxysilanes, silazanes, siloxanes). This entails silanol groups being alkylated by alkyl groups preferably having up to 18 carbon atoms, particularly preferably having up to 8 carbon atoms, very particularly preferably having up to 4 carbon atoms, especially by methyl groups. Examples of silanes used in the production of hexamethyldisilazane or, preferably, dimethyldichlorosilane. The appropriate hydrophobic silicas may be derived from precipitated, colloidal, precompacted or pyrogenic silicas, with preference for pyrogenic silicas. For example, reaction of a hydrophilic silica with dimethyldichlorosilane results in hydrophobic Aerosil having the proprietary name Aerosil® R 972; this has a degree of methylation of 66%-75% (determined by titration of the remaining silanol groups).
The hydrophobic silica is employed in the formulations typically in a proportion of 0.1-10% by weight, preferably employed with 0.5-5% by weight, particularly preferably with 1.5-4.0% by weight.
Amphiphilic compounds consist of a polar (hydrophilic) and an apolar (hydrophobic) part. Typical amphiphiles are fatty acids, surfactants and phospholipids. Active ingredients may also be amphiphilic in nature. Thus, for example, quinolones or else fluoroquinolones are amphiphilic. The molecules have an acid group and a basic group. The acid group may be in deprotonated form and then has a negative charge; the basic group may be in protonated form and then has a positive charge. Each charged part of the molecule is highly polar and hydrophilic, while the remainder of the molecule is less polar and thus more hydrophobic.
In the context of this invention, preferred amphiphilic compounds are polyoxyethylated compounds. Polyoxyethylated compounds, also referred to as polyethoxylated compounds, are prepared for example by reaction with ethylene oxide. They have one or more concatenated units of the formula —[O—CH2—CH2]—. Polyoxyethylated compounds which may be mentioned in particular are:
Nonionic amphiphilic polyoxyethylated compounds such as
Fatty acid or fatty alcohol stands in particular for the corresponding compounds having at least 6 carbon atoms and normally not more than 30 carbon atoms.
The amphiphilic, especially the polyoxyethylated, compound is typically employed in the formulation in a proportion of 0.001-0.15% by weight, preferably with 0.005-0.09% by weight and particularly preferably with 0.005-0.08% by weight, especially 0.01-0.07% by weight.
The oil-based suspensions of the invention are preferably employed in medicaments. They then comprise one or more active pharmaceutical ingredients.
Examples which may be mentioned are anti-infective; these are in particular compounds having antibacterial activity, such as penicillins, cephalosporins, aminoglycosides, sulfonamides and, in particular, quinolones.
Quinolones, preferably fluoroquinolones, are inter alia compounds as disclosed in the following documents: U.S. Pat. No. 4,670,444 (Bayer AG), U.S. Pat. No. 4,472,405 (Riker Labs), U.S. Pat. No. 4,730,000 (Abbott), U.S. Pat. No. 4,861,779 (Pfizer), U.S. Pat. No. 4,382,892 (Daiichi), U.S. Pat. No. 4,704,459 (Toyama); specific examples of quinolones which may be mentioned are pipemidic acid and nalidixic acid; examples of fluoroquinolines which may be mentioned are: benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin.
A preferred group of fluoroquinolones are those of the formula (I) or (II):
in which
X is hydrogen, halogen, C1-4-alkyl, C1-4-alkoxy, NH2,
Y is radicals of the structures
The compounds of the formulae (I) and (II) may be in the form of their racemates or in enantiomeric forms.
Preference is given to compounds of the formula (I)
in which
A is ═CH— or ═C—CN,
R1 is optionally halogen-substituted C1-C3-alkyl or cyclopropyl,
R2 is hydrogen or C1-4-alkyl,
Y is radicals of the structures
Particular preference is given to compounds of the formula (I)
in which
A is ═CH— or ═C—CN,
R1 is cyclopropyl,
R2 is hydrogen, methyl or ethyl,
Y is radicals of the structures
Suitable salts are pharmaceutically usable acid addition salts and basic salts.
Pharmaceutically usable salts mean for example the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. The compounds of the invention can also be bound to acidic or basic ion exchangers. Pharmaceutically usable basic salts which may be mentioned are the alkali metal salts, for example the sodium or potassium salts, the alkaline earth metal salts, for example the magnesium or calcium salts; the zinc salts, the silver salts and the guanidinium salts.
Hydrates mean both the hydrates of the fluoroquinolones themselves and the hydrates of salts thereof.
Fluoroquinolones which may be mentioned as particularly preferred are the compounds described in WO 97/31001, in particular 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (pradofloxacin) with the formula
Pradofloxacin is preferably employed in the form of its trihydrate.
Also particularly preferably employed is enrofloxacin:
Besides enrofloxacin and pradofloxacin, further preferred quinolone anti-infectives which may be mentioned are marbofloxacin, orbifloxacin, difloxacin, ofloxacin and ibafloxacin.
Examples of penicillins are benzylpenicillin, ampicillin, amoxicillin, oxacillin, piperacillin, ticarcillin.
Examples of cephalosporins are cefalexin, cefadroxil, cefazolin, cefoxitin, ceftiofur.
Mention may be made for example of erythromycin, spiramycin, tylosin, tilmicosin as macrolide.
Sulfonamides which may be mentioned are for example trimethoprim and sulfadiazine (preferably employed in combination).
Aminoglycosides which may be mentioned are gentamycin, kanamycin, streptomycin, neomycin and spectinomycin.
A further antibiotic which may be mentioned is the lincosamide clindamycin.
Less preferred anti-infectives in the context of this invention are derived from silver, e.g. colloidal silver, silver nitrate or silver sulfadiazine. These may, however, be employed in combination with one of the anti-infectives described hereinabove and/or where appropriate a corticoid.
The anti-infective is typically employed in the proportion of 0.001-6% by weight, preferably 0.01-1.0% by weight, particularly preferably 0.1-0.8% by weight, based on the finished medicament.
Further active pharmaceutical ingredients which may be mentioned are antimycotics such as, for example, an imidazol or a triazol, ketokonazol, enilconazol, econazol, especially for example clotrimazol, miconazol or bifonazol.
The antimycotic is typically employed in a proportion of 0.01-10% by weight, preferably 0.1-5% by weight, particularly preferably 0.5-2% by weight, based on the finished medicament.
Further suitable active pharmaceutical ingredients are for example corticoids. Examples which may be mentioned are hydrocortisone, prednisolone, betamethasone, mometasone, clobetasone, flumethasone; preferably betamethasone, triamcinolone and in particular dexamethasone.
The corticoid is typically employed in a proportion of 0.001-2.0% by weight, preferably 0.005-0.5% by weight, particularly preferably 0.05-0.2% by weight, based on the finished medicament.
Further suitable active pharmaceutical ingredients are triazines, in particular the compounds of the formulae (I) or (II):
in which
R1 is R3—SO2— or R3—S—,
R2 is alkyl, alkoxy, halogen or SO2N(CH3)2, and
R3 is haloalkyl,
R4 and R5 are independently of one another hydrogen or Cl, and
R6 is fluorine or chlorine,
and the physiologically tolerated salts thereof.
The triazines are well known as active ingredients for coccidial infections per se, and mention may be made of the triazinetriones such as, for example, toltrazuril and ponazuril, and the triazinediones such as, for example, clazuril, diclazuril and letrazuril.
The triazinediones are represented by formula (II):
clazuril (R4=Cl, R5═H, R6=Cl in formula (II))
letrazuril (R4=Cl, R5=Cl, R6═F in formula (II)) and
diclazuril (R4=Cl, R5=Cl, R6=Cl in formula (II))).
The most preferred of these 1,2,4-triazinediones is diclazuril.
Particularly preferred as active ingredients according to the invention are the triazinetriones of the formula (I):
Example of particularly preferred triazinetriones of the formula (I) are:
toltrazuril (R1═R3—S—, R2═CH3, R3═CF3)
ponazuril (R1═R3—SO2—, R2═CH3, R3═CF3)
Of these, toltrazuril is most preferred.
It is possible with all the pharmaceutically active ingredients—as explained in detail above for the quinolones—to use the corresponding pharmaceutically acceptable salts, hydrates, solvates and where appropriate various modifications.
Optically active substances can be used in the form of their stereoisomers or as mixture of stereoisomers, e.g. as pure or enriched enantiomers or as racemates.
In the suspensions or medicaments of the invention it is possible for the active ingredients to be present singly in each case or to be employed in combination with further active ingredients.
In a preferred embodiment, the formulation of the invention can be adjusted so that it has thixotropic properties, meaning that it becomes less viscous on shaking, and the viscosity increases again at rest. This leads to satisfactory removability from the primary packaging, and to rapid reconstitution; this is advantageous for example on applications in the auditory canal, so that the applied formulation remains in the ear and cannot be ejected for example by shaking the head. Thixotropic formulations are produced by adding an appropriate additive to the formulation base (fluid, oily base) if the fluid base is not itself thixotropic. Such an additive is normally a suspension stabilizer or thickener such as, for example, colloidal silicon dioxides. The extent of the thixotropy can be specifically adjusted by varying the concentration.
The formulations may comprise further conventional pharmaceutically suitable additives and excipients. Examples which may be mentioned are
The formulations are produced by the active ingredients or excipients which are to be dissolved or suspended being dispersed in the base. A homogenizer or high-pressure homogenizer is employed where appropriate for the dispersing. The sequence of addition of individual ingredients may be varied according to the formulation. After all the formulation ingredients have been dispersed, the finished formulation is put into interim storage or put directly into the primary packaging.
In principle, all possible primary packagings are suitable for the suspensions or medicaments of the invention. In a preferred embodiment, single-dose containers are used as primary packaging. These are charged with a volume of 0.1-0.5 ml, preferably 0.2-0.4 ml, particularly preferably 0.3-2.0 ml, as removable content of formulation.
The medicaments of the invention are generally suitable for use in humans and animals. They are preferably employed in animal management and animal breeding for productive and breeding livestock, zoo, laboratory, experimental and companion animals, especially for mammals.
The productive and breeding livestock include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as, for example, mink, chinchilla, raccoon, and birds such as, for example, chickens, geese, turkeys, ducks, pigeons and ostriches. Examples of preferred productive livestock are cattle, sheep, pigs and chickens.
The laboratory and experimental animals include dogs, cats, rabbits and rodents such as mice, rats, guinea pigs and golden hamsters.
Companion animals include dogs, cats, horses, rabbits, rodents such as golden hamsters, guinea pigs, mice, also reptiles, amphibians and birds for keeping at home and in zoos.
The medicaments of the invention are preferably employed for companion animals, specifically in particular for dogs and cats.
Both prophylactic and therapeutic use are possible.
The medicaments described herein are suitable in principle for all possible modes of administration such as, for example, dermal, oral, rectal, vaginal or nasal administration. They are particularly suitable for example for local administration into the auditory canals.
The described formulations are therefore particularly suitable for hygienic treatment of disorders of the auditory canal such as otitis externa in dogs and cats. For this purpose they are preferably put into single-dose containers as primary packaging. It should be particularly emphasized that the formulation can be removed very reproducibly. If thickeners are employed in suspension formulations it is usually possible to prevent sedimentation of the suspended ingredients. Thixotropic formulations are particularly advantageous because, after shaking the single-dose containers, the formulation can—even if the active ingredient concentrations are low—be removed particularly reproducibly, the formulation can, owing to the thixotropy and the single-dose container, be administered simply and hygienically into the animal ear and nevertheless cannot for example be ejected by the usual shaking of the head. It is likewise desirable that the formulation have good spreading behavior because the formulation is to be satisfactorily distributed in the auditory canal after administration.
Medicaments for administration in the auditory canal may preferably comprise antibiotics, corticoids or antimycotics as described hereinabove. A combination of antibiotics and corticoids is preferred, and a triple combination of antibiotics, corticoids and antimycotics is particularly preferred. The statements made above about preferred embodiments for the respective groups of active ingredients also apply to this area of use.
Examples of particularly preferred combinations of active ingredients which may be mentioned are: pradofloxacin, clotrimazole and dexamethasone (preferably in the form of its acetate), and enrofloxacin, bifonazole and dexamethasone (preferably in the form of its acetate).
DETERMINATION OF THE SEDIMENTATION KINETICSFIG. 1 depicts the sedimentation kinetics of formulations with hydrophobic silica. The measurements were carried out with a so-called Lumifuge by measuring the diffraction of light. The sedimentation kinetics depict the sedimentation of the formulation on the y axis (“Interphase Height”) and the duration of exposure to gravity in the centrifugal field on the x axis (indicated in hours). A formulation which has an interface height of 100% does not sediment under the applied gravity, and a formulation with an interface height of for example 80% sediments more than one with for example 90%.
The measured formulations, inter alia that of Example 13, comprise a hydrophobic silica (Aerosil R972, a methylated silica from Degussa) and toltrazuril in low-viscosity paraffin. The lowermost curve contains no addition of polyethoxylated compounds, and the other curves contain polyethoxylatcd compounds as addition, specifically poloxamer from BASF (Pluronic PE8100, Pluronic PE 3100 and Pluronic RPE3110).
It is evident that the formulation with hydrophobic silica without addition of a polyethoxylated compound (poloxamer) shows the lowest curve profile. All the other formulations which, besides the hydrophobic silica, comprise addition of polyethoxylated compounds (various poloxamers as named above) lie distinctly higher. The sedimentation properties (i.e. the prevention of sedimentation) of the formulations with addition of polyethoxylated compounds are thus distinctly improved by comparison with the formulation without addition of polyethoxylated compounds.
EXAMPLESThe percentage data for the formulations described herein are indicated in weight per volume. Medium-chain triglycerides to be used are the triglycerides of caprylic/capric esters, for example Miglyol® 812 from Sasol/Witten (e.g. used in Examples 3 and 6). The methylated silica Aerosil® R972 from Degussa is used as colloidal hydrophobic silicas. (Aerosil R972 is a pyrogenic silica which is hydrophobized with dimethyldichlorosilane and is based on hydrophilic pyrogenic silica with a specific surface area of about 130 m2/g and a degree of methylation of 66%-75%).
Example 10.14% pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of clotrimazole and 0.05 g of dexamethasone acetate are suspended. 0.14 g of pradofloxacin trihydrate are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 20.14% pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95 g of MCT to 60° C. and dissolved. At about 22°, 0.14 g of pradofloxacin trihydrate, 1.0 g of clotrimazole, 0.05 g of dexamethasone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 30.14% pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% glycerol polyethylene glycol ricinoleate (prepared from 1 mol of castor oil and 35 ml of ethylene oxide. The product contains 83% hydrophobic polyoxyethylene glycerol ricinoleate compounds and about 17% hydrophilic polyoxyethylene glycerol and polyethylene glycol)
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of clotrimazole and 0.05 g of dexamethasone acetate are suspended. 0.14 g of pradofloxacin trihydrate are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
0.14% pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% glycerol polyethylene glycol ricinoleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95 g of MCT to 60° C. and dissolved. At about 22°, 0.14 g of pradofloxacin trihydrate, 1.0 g of clotrimazole, 0.05 g of dexamethasone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 50.14% pradofloxacin trihydrate
1.0% bifonazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of bifonazole and 0.05 g of dexamethasone acetate are suspended. 0.14 g of pradofloxacin trihydrate are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
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Example 60.14% pradofloxacin trihydrate
1.0% bifonazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95 g of MCT to 60° C. and dissolved. At about 22°, 0.14 g of pradofloxacin trihydrate, 1.0 g of bifonazole, 0.05 g of dexamethasone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 70.1% enrofloxacin
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of clotrimazole and 0.05 g of dexamethasone acetate are suspended. 0.1 g of enrofloxacin are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 80.1% enrofloxacin
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95 g of MCT to 60° C. and dissolved. At about 22°, 0.1 g of enrofloxacin, 1.0 g of clotrimazole, 0.05 g of dexamethasone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 90.1% enrofloxacin
1.0% bifonazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of bifonazole and 0.05 g of dexamethasone acetate are suspended. 0.1 g of enrofloxacin are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 100.1% enrofloxacin
1.0% bifonazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95 g of MCT to 60° C. and dissolved. At about 22°, 0.1 g of enrofloxacin, 1.0 g of bifonazole, 0.05 g of dexamethasone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 110.1% enrofloxacin
1.0% bifonazole
0.05% triamcinolone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 91 g of MCT to 60° C. and dissolved. At about 22°, 1.0 g of bifonazole and 0.05 g of triamcinolone acetate are suspended. 0.1 g of enrofloxacin are dissolved in 4 g of benzyl alcohol and mixed into the suspension. 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 120.1% enrofloxacin
1.0% bifonazole
0.05% triamcinolone acetate
0.1% sorbic acid
0.05% polyoxyethylene 20 sorbitan monooleate
3.2% colloidal hydrophobic silica
ad 100% medium-chain triglycerides
0.1 g of sorbic acid is heated in 95.5 g of MCT to 60° C. and dissolved. At about 22°, 0.1 g of enrofloxacin, 1.0 g of bifonazole, 0.05 g of triamcinolone acetate, 0.05 g of polyoxyethylene 20 sorbitan monooleate and 3.2 g of colloidal hydrophobic silica are dispersed. The suspension is then homogenized for about 10 min with a homogenizer.
Example 135% toltrazuril
0.07% poloxamer (Pluronic PE 3100)
3% colloidal hydrophobic silica
ad 100% paraffin, low-viscosity
5 g of toltrazuril, 0.07 g of poloxamer and 3 g of colloidal hydrophobic silica are dispersed in 92 g of paraffin. The suspension is then homogenized for about 10 min with a homogenizer.
By C. Jim Reader and Maria Nargiello, Evonik Corporation
The field of coatings technology has utilized many forms of silica-based particles in the last 70 years. This large, varied class of fillers is generically broken into two categories of crystalline and amorphous morphology. With ongoing scrutiny and sensitivity in the coatings industry to move towards less hazards in the workplace, greater emphasis is placed on suitable amorphous technology to replace crystalline silica technology. Amorphous silica is highly adaptable and flexible to be modified in both powder and pre-dispersed forms, and numerous engineered types of technologies have been developed to provide functional solutions to many coatings problems.
Amorphous silica technology has been developed to address functionalities including: rheological control, suspension of pigments and fillers, and reinforcement of coatings film; to impart scratch resistance, hydrophobicity / anti-corrosion benefits, and oleophobicity; as a carrier of trace actives into coatings for homogenous distribution; for flow control, charge, and fluidization enhancement of powdered coatings; and gloss reduction of liquid systems. Particle technology and modification will be addressed along with performance attributes highlighted for each of the types of tailor-made modifications. The importance of proper dispersion and homogenous distribution within a coating matrix will be reviewed.
This article will address how amorphous silica technology is differentiated and engineered to create specially tailored solutions to enhance the performance of coatings and will highlight the latest technical developments in this field.
Introduction
Silica, or silicon dioxide, is one of the most abundant minerals present on earth. It is estimated that quartz, the most stable form of this complex family of materials, makes up more than 10% of the earth’s crust and, as a major component of the natural sands widely used in the construction industry, is a key raw material to produce glass and silicon.1
Silica is also an important raw material for the coatings industry, as it can provide a wide range of functionalities and benefits. These include rheological control, enhanced film formation, improved mechanical properties of the final coating film, free flow and fluidization enhancement of powders, and control of gloss. Silica is also an important raw material for the formulation and production of defoamers. The silica grades used in the coatings industry are produced synthetically and typically meet greater quality control standards, often having tighter physical-chemical requirements, such as color and brightness. The enormous variety of performance properties is achieved by adjusting the particle size and morphology during production as well as via surface treatment and densification of the silica particles in downstream processes.
A summary of the main methods for producing synthetic silica is shown in Figure 1. The most common types of silica used in modern coatings are produced either by a liquid phase process of precipitation or gas phase process of flame hydrolysis. Precipitated silica is produced by the controlled reaction of sodium silicate (“water glass”) and sulfuric acid similar to the production of silica gels. The silica is precipitated, filtered, washed, and dried before milling and classification (Figure 1).
The production of fumed silica began with the discovery of the flame hydrolysis of silicon tetrachloride by Harry Klöpfer in 1943. This discovery was part of a wartime effort to produce silica that could act as a white reinforcing filler to modify rubber, which was then much needed for tire production to replace oil used to make carbon black. A simple diagram of the process is shown in Figure 2. The overall chemistry of the process is efficient and versatile. A vaporizable metal precursor is fed into a hydrogen/air flame, and the hydrolysis product, silicic acid for instance, rapidly condenses to the metal oxide. Multiple pathways to particle formation are possible, such as particle growth through deposition, particle evaporation, aggregation, and aggregate coagulation. The elegant efficiency of the overall chemistry makes the process very amenable to variation. A diverse array of metal oxides beyond silica has been produced, including mixed metal systems and surface modified and doped particles that can be used for a wide variety of industries and applications.
Fumed silica consists of three conceptual levels of structure (Figure 3). The primary particle only exists for a short time in the flame. Primary particles fuse together to form an aggregate, which is the secondary particle structure. Isolated primary particles, in this model, are rare. The tertiary structure is an agglomeration of the secondary structures. This collection of particle aggregates can be disrupted by the introduction of shear, and then reform over time after the shear is removed from the system. This mechanism is the means by which fumed silica imparts pseudo-plastic rheological properties to formulations.
A comparison of the different physical properties of synthetic silica is shown in Table 1. It is important to note that all of these synthetic silica types are amorphous and do not contain crystalline silica. This has been confirmed by X-ray diffraction.
The second element of particle design is surface modification to render the hydrophilic particles hydrophobic in character. This is achieved by the reaction of the surface silanol groups with different silanes. These treatments create different grades of fumed silicas that vary in hydrophobicity, tribo-electrostatic charge, and thickening efficiency. A summary of the typical surface treatments with corresponding attributes is shown in Table 2. The level of treatment, which can be measured by carbon content and methanol wettability (Figure 4), indicates the consistency of treatment and the balance of hydrophilic to hydrophobic surface.
The Multipoint Methanol Wettability method is a quantitative test method to measure the level and consistency of hydrophobic treatment. The 0.2 g of the treated silica is added to a series of graduated test tubes containing 8 ml of dilutions of methanol in water made in 5% increments, starting with 100% water, 95% water, and 5% methanol up to 100% methanol. The silica/solutions mixtures are shaken and then centrifuged under controlled and defined conditions. Depending on the level of hydrophobicity and consistency of surface treatment, the silica will wet differently into each water. Methanol mixtures and the amount of wetted silica in each solution mixture is recorded and plotted to a curve known as the methanol wettability fingerprint. Silicas requiring higher methanol amounts for wetting are more hydrophobic. Consistently treated silica shows a steep rise in wet-in, whereas a more gradual curve indicates a wider range in the consistency of treatment. Precipitated silicas can also be surface treated, typically with waxes and reactive oligomers, to improve product and formulation stability and reduce viscosity impact.
The third element of particle design is structure modification via one of several proprietary processes. Granulation results in larger, individual spherical particles in the range of 20–30 μm that are porous; their main function is to act as free-flowing carriers of liquid-based actives and oils. Other chemical and mechanical post-processes reduce structure (i.e., the level of aggregation or agglomeration). Products resulting from post-processing can have significantly higher bulk densities and dramatically reduced thickening efficiency due to reduced levels of aggregation at the primary aggregate level. The functional benefit resulting from such grades are enhanced scratch and abrasion resistance, as higher loading can be achieved with minimal impact to formulation viscosity. This higher loading results in reinforced domains, which drives the scratch and abrasion resistance.
Rheology and Film Formation
Fumed silica, in various grades and modifications, has been used for decades in coating formulations to impart thixotropy, anti-settling, and anti-sag properties. The main requirements for good performance are proper selection and adequate dispersion to homogenously distribute aggregates throughout the coating matrix. Proper grade selection can be loosely correlated to dosage, particle size, structure, and surface treatment. Untreated, hydrophilic fumed silica grades give the best performance in non-polar environments, whereas hydrophobically modified grades, such as those treated with DDS, TMOS, and HMDS (Table 2) are more efficient as polarity increases. This trend is shown in Figure 5.
Grades treated with TMOS and HMDS are highly effective for high solids and radiation-cure systems. Polydimethylsiloxane-treated grades are the most hydrophobic. This technology can also be considered in high solids and 100% solids systems, where it is very effective. However, care must be taken, as this surface modification is not fully reacted to the surface, and migration of the free PDMS may cause surface defects or adhesion problems.
Proper dispersion of the fumed silica is critical to good performance. When optimizing a dispersion for thickening efficiency and rheological enhancement, several parameters should be considered including shear rate. Dispersion time, temperature control, and sequence of addition are all important. High-speed dispersion using a saw-type blade at a shear rate > 10 m/s is recommended. Longer dispersion time will not compensate for inadequate shear rate. The consequences of poor dispersion are typically larger agglomerates that remain visible in the final coating, reduced thickening efficiency, poor thixotropic stability over time, lower gloss and transparency, and possibly film defects.
Fumed silica has excellent thermal stability, but as the temperature of the coating environment increases, particularly upon shear, the wetting properties of the coating typically improve. This can lead to over-dispersion, whereby the aggregates are reduced past their optimum association level. Once this occurs, reduced thickening efficiency results, sometimes to the point where it appears as if no thickener was added. Fumed silica is one of the smallest particle size materials added to a coating formulation. This component should be added early in the formulation, preferably to the resin or binder, rather than into non-film-forming components like solvents for optimal effect. Caution should be used when post-adjusting batches with powder, as only minimal shear that is inadequate for homogeneous incorporation can often be used at this stage. Post addition with low shear may bring formulations to their desired rheology, but this can deteriorate over time, as larger agglomerates slowly wet-out.
Lab evaluations have demonstrated that multiple performance attributes can also be enhanced using fumed silica dispersions. These include improved suspension of pigments, fillers and matting agents, reduced tack, improved dirt pick-up resistance, enhanced film strength, and even improved film formation. These features are achieved without compromising gloss and other appearance attributes. An example is shown in Figure 6, where a pre-made aqueous fumed silica dispersion improves the film formation in combination with reduced coalescent solvent levels. These improvements have been seen with many different film-forming resins and using less or no coalescing solvents. This can help reduce the overall volatile organic compounds of the formulation, in addition to providing the other properties referenced above. This enhanced film formation is a result of reduced stress propagation due to the reinforcing effects of the very finely dispersed fumed silica.9
Anti-Corrosion/Water Repellency
Hydrophobically modified grades of fumed silica have also been used together with anticorrosive pigments to improve corrosion performance and water repellency of coatings. These grades are not considered to be anti-corrosion pigments, but they work effectively with many classes of anti-corrosive pigments such as modified barium metaborate, calcium phosphosilicate, and zinc dust. Loadings between 1.0% and 3.0% by weight of total formulation are used to ensure that there are enough particles in the coating matrix to support a hydrophobic barrier, improve the mechanical properties of the film, and increase hydrophobicity. Water repellency measured by improved blister resistance can be improved at lower loading levels starting at 0.5% by total formulation weight. Two examples of this effect are shown in Figure 7.
Proper dispersion is again needed to homogeneously distribute the silica throughout the coating matrix for maximum effect. It is suggested that the treated fumed silica be dispersed together with the anti-corrosion pigments to ensure optimal dispersion. The best results have been obtained using DDS, TMOS, and HMDS treatments, although the impact on formulation rheology must also be considered.
Scratch Resistance
The development of silica particles for the specific purpose of improving scratch resistance came from the creation of particles for high reinforcement of elastomers and composites. The critical factor needed to achieve high reinforcement is to be able to fill the polymer matrices with significantly higher levels of fumed silica without increasing the viscosity to unworkable levels. This is achieved by structure modification through a proprietary post-processing to achieve a highly reduced structure and a low level of aggregation. This results in a material that can be used as a reinforcing filler to increase the mechanical strength of the coating and impart scratch resistance. The corresponding physical property observed is a significant increase in the bulk density (Figure 8) and a dramatic reduction in the ability of silica to increase viscosity. When compared to other reinforcing fillers, such as alumina, silica has the advantage of a lower refractive index of 1.46, more closely aligned with many polymer systems, which results in improved transparency and clarity. These materials can also be hydrophobically modified with DDS, HMDS, and TMOS for improved water resistance.
The main consideration for successful use of surface-treated, structure-modified fumed silica particles is adequate loading level. Optimum loading levels start at 5% by weight on total formulation and can approach 15%. Inorganic particle load must be high enough to attain a homogenous density through the polymer to achieve a consistent, reinforced matrix. This can be seen in the scanning electron microscopy (SEM) analysis of a cross-section of a high-solids coating (Figure 9), which shows a homogenous distribution through the film with no surface enrichment resulting from higher particle density.
Five percent loading of an easy-to-disperse (E2D) structured modified silica particle treated with DDS achieved improved scratch resistance in a high-solids system, tested by a dry scratch method using a Crock meter (abrasive paper) and wet scratching using an Elcometer (40 double strokes, bristle brush, and 0.15% quartz in water slurry). Improved scratch resistance and higher gloss retention of the coating was observed after using both scratching methods, and reduced haze was observed after the panels were subjected to Elcometer testing (Figure 10). The addition of 5% silica did slightly reduce gloss, but the silica significantly improved scratch resistance.
Results in Figure 10 show three variants of DDS-treated structure-modified silica. Variant 1 is the original that requires milling, variant 2 the same DDS structure modified silica pre-dispersed in methoxypropyl acetate (MPA), and variant 3 is the newest version, which is easy-to-disperse.
Free Flow, Fluidization, Transfer Efficiency
Powder coatings, whether conventional, fine, thermosetting, thermoplastic, tribo, or UV-cured, all require good flow, reduced moisture pick-up, good package stability (no caking), efficient fluidization, and high-transfer efficiency as well as reduced Faraday cage effects for even film thickness and optimized appearance during application. Hydrophilic- and hydrophobic-treated fumed silica and alumina can be used to improve flow, storage stability with reduced moisture pick-up, and improved fluidization and transfer efficiency.
In practice, flow additives used in powder coatings can be added in one of three places during the powder coating manufacturing process: 1) directly in the hopper, 2) dosed into the powder during chipping, or 3) post-added after pulverization. Flow additives can be dry blended into problematic powdered components before they are charged into the hopper to help them feed more consistently and homogeneously into the extruder. The typical loading of flow additives used in this step is 0.1–0.3%. Flow additives used to pre-treat ingredients are extruded into the powder matrix and do not influence the bulk flow properties after compounding and pulverization.
When additives are used to influence the final powder coating properties, they must be added after extrusion and be oriented on the outside of the powder coating particles. There are typically two places where silica or alumina (or a combination of the two) can be added into the process to achieve this: 1) prior to chipping where the additive is cut into the powder coating particle or 2) after pulverization and classification. Care should be taken when dosing the additive before pulverization, as classification systems can remove the additive out of the powder and reduce the final dose remaining in the powder coating. The typical dosage level used in the chipping or as post add is also 0.1–0.3% by weight.
A study was organized with the University of Western Ontario to assess specific performance attributes associated with four classes of additives in different powder coatings. The first two powder coatings were corona applied. The first was a conventional polyester with d50 of 31.5 μm and the second was a finer particle size, polyester with d50 of 21.5 μm. The additive dosage level was adjusted based on the particle size of the powder. A 0.3% dosage level was used for the coarse powder and a 0.5% dosage level for the fine powder. A third powder was a tribo-applied polyester powder coating. The attributes tested were angle of repose (flowability), bed expansion (flowability and fluidity), transfer efficiency, Faraday cage effects, gloss, and gel time. Four types of silica were tested: untreated hydrophilic silica with a surface area of 200 m2/g, HDMS- and aminosilane-treated silica with a surface area of 200 m2/g, DDS-treated silica with a surface area of 130 m2/g, and HDMS-treated silica with a surface area of 300 m2/g.
Surface-treated alumina was most effective at improving transfer efficiency and reducing Faraday cage effects due to its neutral to slightly positive electrostatic charge character. This is shown in Figure 11 where a disk applied with coarse powder containing 0.3% high surface area alumina (130 m2/g) has a more consistent level of jetness than the disk applied with powder containing no additive. This test measures how much powder is transferred and the consistency of coverage of the disk (by weight) under controlled application conditions.
Faraday cage effects were measured by determining how much coating is deposited in the inner trough of a test specimen. The interior parts of the trough have three removable panels under controlled applications conditions. After application, these inner panels are removed and weighed. Reduced Faraday cage effects (improvement) are associated with higher, more consistent weights of powder deposited on these inner removable panels. The 0.3% alumina treated with TMOS was effective in reducing Faraday cage effects in the coarse, black powder coating.
Fluidization efficiency was also assessed in this study. The results in coarse and fine powder show that particle size of the powder coating significantly affects the type of additive most effective for improving fluidization. Alumina was more effective in improving fluidization in the coarse powder coating as measured by lower air velocities needed to obtain 20% bed expansion, while silica was more effective in the fine powder coating (Figure 12). This trend suggests that additive packages may need to be adjusted based on their particle sizes.
Gloss Control
Gloss is defined, according to DIN EN ISO 4618, as the human perception of the more-or-less directed reflection of light rays from a surface. Glossy surfaces appear shiny and reflect most light in the specular (mirror-like) direction, while matte surfaces diffuse most of the light in a range of angles. Gloss level can be characterized by the angular distribution of light scattered from a surface, measured with a glossmeter or reflectometer, and it is dependent upon the viewing angle (Figure 13).
There is no common or globally accepted definition of the term “matte.” It is always measured based on a comparative measurement of the gloss against a standard.2-5 For coating surfaces, the term “gloss” means almost complete reflection in the sense that the surface reflects and scatters incident light in a wide-angle cone. The greater the cone angle, the less gloss is generally observed (Figure 14).6
Lin and Biesiada demonstrated that matting is a function of both the silica particle size and degree of coating shrinkage during drying (either through solvent evaporation, chemical reaction, or coalescence).7 Larger particles are more efficient at reducing gloss as a function of silica dosage, but the larger particles can lead to a rough surface and increased dirt pickup over time. Most silica grades used for matting coatings are produced via wet and gas phase processes and are classically larger than the grades used for rheology. Some of these grades can influence thickening to a lesser or greater extent. Surface treatment, either with wax or reactive oligomers, can help reduce viscosity build-up, prevent hard settling, and improve transparency and stability. Recent technology developments have produced silicas with improved haptic effects like soft-feel.
Recent Developments in Silica Technology
While considered a mature technology, the use of silica in coatings continues to benefit through innovation. Romer described a new process for producing precipitated silica that allows greater control of particle morphology during the precipitation process to produce highly spherical particles with narrow-sized distributions (Figure 15).8 The spherical shape imparts high apparent hardness to improve scrub, abrasion, and burnish resistance of the formulated coating, with low binder demand and minimal impact on coating rheology. These spherical silica particles also can provide matting properties, depending on particle size, and they have excellent transparency for use in deep colors and clear coats.
Both hydrophilic (200 m2/g) and some hydrophobically treated grades (e.g., DDS, HDS, HMDS, 130–300 m2/g) of fumed silica can be used in water-based coatings when it is possible to adequately disperse the powder into water dispersible resins and solutions. However, the low viscosity and high dielectric constant makes water a poor grinding medium for fumed silica, and it is difficult to achieve the degree of de-aggregation and dispersion of particles needed to achieve optimum benefits in water-based coatings. Incorporation of hydrophobically treated grades can also be difficult due to the poor wetting properties of water-based formulations, especially when resin solids drop below 35% non-volatile content. Additives, such as acetylenic diols, can help to improve the wetting and dispersion of fumed silica into water, but care must be taken to ensure that the additives do not disrupt the silica network formation, reducing rheology control.
When adding the silica directly into water, or when using a shear-sensitive, film-forming resin, it is recommended to use a pre-dispersed form of fumed silica to overcome these challenges. A new aqueous dispersion of a functionalized fumed silica has been developed using a new production process and carefully selected additives. The silica is already dispersed, so it can be easily stirred into water-based formulations without requiring high shear dispersion.
The new dispersion WF 7620, contains 20% functionalized silica with a high surface area of 300 m2/g and demonstrates outstanding rheological effectiveness in waterborne coatings, especially those applied via spray application where anti-sagging properties are critical while maintaining excellent flow and levelling properties.
This is demonstrated in the jump-curve rheology graph shown in Figure 16. The jump curve simulates a spray application where the coating is sheared at high shear (500s-1) continuously to simulate the spraying process and then the shear is suddenly reduced to 0.1s-1 simulating the coating on the substrate after application. A fast build-up of viscosity is desired to prevent sagging after application onto vertical surfaces. This enables the formulator designing perfect finishes for three-dimensional parts including general industrial coatings, transportation coatings, plastic coatings, and wood coatings. The jump curve demonstrates the new dispersion WF 7620 and gives a significant increase and improvement in rheological efficiency, compared to an existing water-based dispersion of fumed silica based on a fumed silica core of 130 m2/g. This improved performance is due to the use of a higher surface area silica, combined with a novel functionalization in-situ. The use of a higher surface area fumed silica in the dispersion also helps to improve clarity and transparency and helps to reduce haze in the final coating.
Conclusion
Modified grades of silica have been used for many years to improve a variety of performance attributes in many different coating applications. These include rheology, film formation, and mechanical properties as well as surface appearance. The morphology of the silica particles, size distribution, and surface treatment are critical to the broad range of properties that can be attained using these materials. Recent advances in the manufacturing and post-treatment processing of silica have continued to develop new grades of silica that offer new and or improved performance for the coatings industry.
References
CoatingsTech | Vol. 17, No. 6 | June 2020
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