Solid dosage forms are obtained by mixing at least one polymeric binder, at least one active ingredient, and, where appropriate, conventional additives to form a plastic mixture, and shaping, using as polymeric binder a copolymer of an N-vinyllactam and a copolymerizable monomer having a hydrophobic radical. Dosage forms which show slow release of the active ingredient are obtained in a simple and low-cost manner.

The invention relates to a process for producing solid dosage forms by mixing at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives to form a plastic mixture, and shaping the mixture. The invention particularly relates to a process for producing solid pharmaceutical dosage forms.
Classical processes for producing solid pharmaceutical forms, especially tablets, are carried out batchwise and comprise a plurality of stages. Pharmaceutical granules represent an important intermediate therefor. Thus, for example, it is evident from Bauer, Frxc3x6mmig and Fuhrer, Pharmazeutische Technologie, Georg-Thieme-Verlag, pages 292 et seq., that drug forms can be obtained from the melt by dry granulation. The possibility of producing solidified melt granules either by melting and shock solidification, by casting and comminuting or by prilling in spray towers is described. One problem with these processes is the accurate shaping which is necessary for producing drugs. Irregular particles or fragments are produced, so that the resulting shape by no means corresponds to customary drug forms, and granules therefore have only little importance as a drug form on their own. Production of desired solid drug forms requires the use of further process steps such as compression in tabletting machines. This is time-consuming and costly. A considerably simpler continuous process for producing solid pharmaceutical forms has been known for some time and entails extruding a solvent-free melt of a polymeric binder containing active ingredients, in shaping the extrudate to the required drug form, for example in a calender with molding rolls, see EP-A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105 (melt extrusion). It is possible in this way to achieve specific shaping. The polymeric binders employed are, in particular, polymers of N-vinylpyrrolidone or copolymers thereof, eg. with vinyl acetate.
Dosage forms based on such polymers have the disadvantage that they release the active ingredient relatively rapidly. It is therefore impossible to produce slow-release dosage forms without taking additional measures, such as applying a coating which controls their release.
It is an object of the present invention to provide dosage forms which can be produced by melt extrusion and are able to release the active ingredient slowly.
We have found that this object is achieved by using as polymeric binder a copolymer of an N-vinyllactam and a copolymerizable monomer having a hydrophobic radical.
The present invention therefore relates to a process for producing solid dosage forms by mixing at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives to form a plastic mixture, and shaping, wherein the polymeric binder used is a copolymer of an N-vinyllactam of the formula I:
where n is 1, 2 or 3, and at least one copolymerizable monomer having a hydrophobic radical.
The process according to the invention makes it possible to produce solid dosage forms with slow release (sustained release) of the active ingredient in a simple and low-cost manner.
Dosage forms mean herein all forms which are suitable for use as drugs, plant treatment compositions, human and animal foods and for delivering fragrances and perfume oils. These include, for example, tablets of any shape, pellets, granules, but also larger forms such as cubes, blocks (bricks) or cylindrical forms, which can be used, in particular, as human or animal foods.
The dosage forms obtainable according to the invention generally comprise:
a) 0.1-90% by weight, in particular 0.1-60% by weight (based on the total weight of the dosage form), of an active ingredient,
b) 10-99.9% by weight, in particular 40-99.9% by weight, of a polymeric binder and
c) where appropriate additives.
The copolymer used as binder comprises as hydrophobic comonomer in particular units of a compound of the formula II:
where R1 is a hydrogen atom or a methyl group, X is O, NH or NR2, R2 is C1-C30-alkyl, and R3 is C8-C30-alkyl, C8-C30-cycloalkyl or C8-C30-alkenyl. The comonomer thus comprises (meth)acrylic esters or (meth)acrylamides having a hydrophobic C8-C30-alkyl, C8-C30-cycloalkyl or C8-C30-alkenyl group. R2 is preferably C1-C18-alkyl and R3 is C8-C18-alkyl or C8-C18-alkenyl.
Examples of suitable acrylic and methacrylic esters are octyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl acrylate, cetyl acrylate, stearyl acrylate, oleyl acrylate, behenyl acrylate, hexyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, lauryl methacrylate, myristyl methacrylate, cetyl methacrylate, stearyl methacrylate, oleyl methacrylate, behenyl methacrylate and tert-butylcyclohexyl acrylate.
Examples of acrylamides and methacrylamides which can be used are N-stearylacrylamide, N-stearylmethacrylamide, N-octylacrylamide, N,N-dioctylacrylamide, N,N-dioctylmethacrylamide, N-cetylacrylamide, N-cetylmethacrylamide, N-dodecylacrylamide, N-dodecylmethacrylamide, N-myristylacrylamide and 2-ethylhexylacrylamide.
Particularly preferred copolymers comprise ethylhexyl, lauryl, myristyl, cetyl, stearyl, oleyl or behenyl acrylate or methacrylate units.
The polymeric binder may also comprise as monomer having a hydrophobic radical a vinyl ester of an aliphatic C8-C30-carboxylic acid, in particular a C8-C18-carboxylic acid. It is possible to use, for example, the vinyl esters of decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and behenic acid.
It is, of course, also possible for the polymeric binder to comprise any desired mixtures of said monomer units.
The polymeric binder contains 50-99 mol %, preferably 70-99 mol %, and particularly preferably 90-99 mol %, of N-vinyllactam units. It contains 1-50 mol %, preferably 1-30 mol %, and in particular 1-10 mol %, of units of monomer having the hydrophobic radical.
In addition, the polymeric binder may contain units of other copolymerizable monomers (other comonomers) in an amount of 0.5 to 48% by weight, preferably 0.5 to 20% by weight, and particularly preferably 0.5 to 10% by weight. Other suitable comonomers are, in particular, monoethylenically unsaturated carboxylic acids having 3 to 8 carbon atoms, such as acrylic acid, methacrylic acid, dimethyl acrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, croton acid, fumaric acid, mesaconic acid and itaconic acid, and the monoesters of said dicarboxylic acids with C1-C18-alkanols. Acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids are preferred. The monoethylenically unsaturated carboxylic acids can be employed in the form of the free acid and, where available, of the anhydrides or in partially or completely neutralized form. The neutralization is preferably carried out with alkali metal or alkaline earth metal bases, ammonia or amines, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, magnesium oxide, calcium hydroxide, calcium oxide, gaseous or aqueous ammonia, triethylamine, ethanolamine, diethanolamine, morpholine, diethylenetriamine or tetraethylenepentamine.
Further examples of suitable comonomers are the esters of the abovementioned carboxylic acids with C1-C6-alkanols, C1-C4-diols, mono- and di-C1-C4-alkylamino-C1-C4-alkanols, and the amides, mono- and di-C1-C4-alkylamides and nitriles of these carboxylic acids, e.g. methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxyisobutyl acrylate, hydroxyisobutyl methacrylate, monomethyl maleate, dimethyl maleate, monoethyl maleate, diethyl maleate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, acrylamide, methacrylamide, N,N-dimethylacrylamide, N-tert-butylacrylamide, acrylonitrile, methacrylonitrile, dimethylaminoethyl acrylate, diethylaminoethyl acrylate, diethylaminoethyl methacrylate and the salts of the last-mentioned monomers with carboxylic acids or mineral acids or the quaternized products.
Also suitable as copolymerizable monomers are acrylamidoglycolic acid, vinylsulfonic acid, allylsulfonic acid, methallylsulfonic acid, styrenesulfonic acid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate and acrylamidomethylpropanesulfonic acid, and phosphono-containing monomers such as vinylphosphonic acid, allylphosphonic acid and acrylamidomethylpropanephosphonic acid.
Further suitable copolymerizable monomers are N-vinylimidazole, N-vinyl-2-methylimidazole, N-vinyl-4-methylimidazole, diallylammonium chloride, vinyl esters such as vinyl acetate and vinyl propionate, and vinylaromatic compounds such as styrene. It is, of course, also possible to employ mixtures of said monomers.
The copolymers are prepared by known processes, e.g. of solution, precipitation, suspension or inverse suspension polymerization, or of emulsion or inverse emulsion polymerization, using compounds which form free radicals under the polymerization conditions.
The polymerizations are normally carried out at from 30 to 200xc2x0 C., preferably 40 to 110xc2x0 C. Examples of suitable initiators are azo and peroxy compounds, and the usual redox initiator systems, such as combinations of hydrogen peroxide and reducing compounds, e.g. sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate and hydrazine.
The copolymers have K values of at least 7, preferably 10 to 100, particularly preferably 10 to 50. The K values are determined by the method of H. Fikentscher, Cellulose-Chemie, 13 (1932) 58-64 and 71-74, in aqueous solution or in an organic solvent at 25xc2x0 C. at concentrations which are from 0.1% to 5% depending on the K value range.
Besides the polymeric binders described above, it is possible to employ in particular up to 30% by weight, based on the total weight of the binder, of other binders. Those suitable are polymers, copolymers, cellulose derivatives, starch and starch derivatives, for example:
Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate or vinyl propionate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, polyacrylamides, polyethylene glycols, polyvinylformamide (partially or completely hydrolyzed where appropriate), cellulose esters, cellulose ethers, especially methyl cellulose and ethyl cellulose, hydroxyalkylcelluloses, especially hydroxypropylcellulose, hydroxyalkylalkylcelluloses, especially hydroxypropylethylcellulose, cellulose phthalates, especially cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and mannans, especially galactomannans. Of these, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses are particularly preferred.
The polymeric binder must soften or melt in the complete mixture of all the components in the range of from 50 to 180xc2x0 C., preferably 60 to 130xc2x0 C. The glass transition temperature of the mixture must therefore be below 180xc2x0 C., preferably below 130xc2x0 C. If necessary, it is reduced by conventional pharmacologically acceptable plasticizing auxiliaries. The amount of plasticizer does not exceed 30% of the total weight of binder and plasticizer in order to form storage-stable drug forms which show no cold flow. However, the mixture preferably contains no plasticizer.
Examples of such plasticizers are:
Long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, aromatic carboxylic esters (e.g. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacic esters, azelaic esters, citric and tartaric esters), fatty acid esters such as glycerol mono-, di- or triacetate or sodium diethyl sulfosuccinate. The concentration of plasticizer is generally from 0.5 to 15, preferably 0.5 to 5,% of the total weight of the mixture.
Conventional pharmaceutical auxiliaries, whose total amount can be up to 100% of the weight of the polymer, are, for example, extenders and bulking agents such as silicates or diatomaceous earth, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or its salts, e.g. the magnesium or calcium salt, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of from 0.02 to 50, preferably 0.20 to 20,% of the total weight of the mixture.
Lubricants such as aluminum and calcium stearates, talc and silicones, in a concentration of from 0.1 to 5, preferably 0.1 to 3,% of the total weight of the mixture.
Flowability agents such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50xc2x0 C. or above. Triglycerides of C12, C14, C16 and C18 fatty acids are preferred. It is also possible to use waxes such as carnauba wax. These fats and waxes may be admixed advantageously alone or together with mono- and/or diglycerides or phosphatides, especially lecithin. The mono- and diglycerides are preferably derived from the abovementioned fatty acid types. The total amount of fats, waxes, mono-, diglycerides and/or lecithins is from 0.1 to 30, preferably 0.1 to 5,% of the total weight of the composition for each layer.
Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, with preference for inorganic pigments in a concentration of from 0.001 to 10, preferably 0.5 to 3,% of the total weight of the mixture.
Stabilizers such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
It is also possible to add wetting agents, preservatives, disintegrants, adsorbents, release agents and propellants (cf., for example, H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).
Auxiliaries also include for the purpose of the invention substances for producing a solid solution of the active ingredient. Examples of these auxiliaries are pentaerythritol and pentaerythritol tetraacetate, polymers such as polyethylene oxides and polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, in J. L. Ford, Pharm. Acta Helv. 61 (1986) 69-88.
Auxiliaries are also regarded as being bases and acids added to control the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).
The only precondition for the suitability of auxiliaries is adequate thermal stability.
Active ingredients mean for the purpose of the invention all substances with a physiological effect as long as they do not decompose under the processing conditions. These are, in particular, pharmaceutical active ingredients (for humans and animals), active ingredients for plant treatment, insecticides, active ingredients of human and animal foods, fragrances and perfume oils. The amount of active ingredient per dose unit and the concentration may vary within wide limits depending on the activity and the release rate. The only condition is that they suffice to achieve the desired effect. Thus, the concentration of active ingredient can be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70,% by weight. It is also possible to employ combinations of active ingredients. Active ingredients for the purpose of the invention also include vitamins and minerals. The vitamins include the vitamins of the A group, the B group, by which are meant besides B1, B2, B6 and B12 and nicotinic acid and nicotinamide also compounds with vitamin B properties such as adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, and vitamin C, vitamins of the D group, E group, F group, H group, I and J groups, K group and P group. Active ingredients for the purpose of the invention also include therapeutic peptides. Plant treatment agents include, for example, vinclozolin, epoxiconazole and quinmerac.
The novel process is suitable, for example, for processing the following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir, alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazoline, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.
Preferred active ingredients are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
To produce the solid dosage forms, a plastic mixture of the components (melt) is prepared and then subjected to a shaping step. There are various ways of mixing the components and forming the melt. The mixing can take place before, during and/or after the formation of the melt. For example, the components can be mixed first and then melted or be mixed and melted simultaneously. The plastic mixture is often then homogenized in order to disperse the active ingredient thoroughly.
However, it has proven preferable, especially when sensitive active ingredients are used, first to melt the polymeric binder and, where appropriate, make a premix with conventional pharmaceutical additives, and then to mix in (homogenize) the sensitive active ingredient(s) in the plastic phase in intensive mixers with very short residence times. The active ingredient(s) can for this purpose be employed in solid form or in solution or dispersion.
The components are generally employed as such in the production process. However, they can also be used in liquid form, i.e. as solution, suspension or dispersion.
Suitable solvents for the liquid form of the components are primarily water or a water-miscible organic solvent or a mixture thereof with water. However, it is also possible to use organic solvents which are immiscible or miscible with water. Suitable water-miscible solvents are, in particular, C1-C4-alkanols such as ethanol, isopropanol or n-propanol, polyols such as ethylene glycol, glycerol and polyethylene glycols. Suitable water-immiscible solvents are alkanes such as pentane or hexane, esters such as ethyl acetate or butyl acetate, chlorinated hydrocarbons such as methylene chloride, and aromatic hydrocarbons such as toluene and xylene. Another solvent which can be used is liquid CO2.
The solvent used in the individual case depends on the component to be taken up and the properties thereof. For example, pharmaceutical active ingredients are frequently used in the form of a salt which is, in general, soluble in water. Water-soluble active ingredients can therefore be employed as aqueous solution or, preferably, be taken up in the aqueous solution or dispersion of the binder. A corresponding statement applies to active ingredients which are soluble in one of the solvents mentioned, if the liquid form of the components used is based on an organic solvent.
It is possible where appropriate to replace melting by dissolving, suspending, or dispersing in the abovementioned solvents, if desired and/or necessary with the addition of suitable auxiliaries such as emulsifiers. The solvent is then generally removed to form the melt in a suitable apparatus, e.g. an extruder. This will be comprised by the term mixing hereinafter.
The melting and/or mixing takes place in an apparatus customary for this purpose. Particularly suitable ones are extruders or containers which can be heated where appropriate and have an agitator, e.g. kneaders (like those of the type to be mentioned below).
A particularly suitable mixing apparatus is one employed for mixing in plastics technology. Suitable apparatuses are described, for example, in xe2x80x9cMischen beim Herstellen und Verarbeiten von Kunststoffenxe2x80x9d, H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing apparatuses are extruders and dynamic and static mixers, and stirred vessels, single-shaft stirrers with stripper mechanisms, especially paste mixers, multishaft stirrers, especially PDSM mixers, solids mixers and, preferably, mixer/kneader reactors (e.g. ORP, CRP, AP, DTB supplied by List or Reactotherm supplied by Krauss-Maffei or Ko-Kneter supplied by Buss), trough mixers and internal mixers or rotor/stator systems (e.g. Dispax supplied by IKA).
In the case of sensitive active ingredients it is preferable first for the polymeric binder to be melted in an extruder and then for the active ingredient to be admixed in a mixer/kneader reactor. On the other hand, with less sensitive active ingredients, a rotor/stator system can be employed for vigorously dispersing the active ingredient.
The mixing apparatus is charged continuously or batchwise, depending on its design, in a conventional way. Powdered components can be introduced in a free feed, e.g. via a weigh feeder. Plastic compositions can be fed in directly from an extruder or via a gear pump, which is particularly advantageous if the viscosities and pressures are high. Liquid media can be metered in by a suitable pump unit.
The mixture obtained by mixing and/or melting the binder, the active ingredient and, where appropriate, the additive(s) ranges from pasty to viscous (plastic) or fluid and is therefore extrudable. The glass transition temperature of the mixture is below the decomposition temperature of all the components present in the mixture. The binder should preferably be soluble or swellable in a physiological medium.
The steps of mixing and melting in the process can be carried out in the same apparatus or in two or more separately operating apparatuses. The preparation of a premix can take place in one of the conventional mixing apparatuses described above. A premix of this type can then be fed directly, for example, into an extruder and subsequently extruded, where appropriate with the addition of other components.
It is possible in the novel process to employ as extruders single screw machines, intermeshing screw machines or else multiscrew extruders, especially twin screw extruders, corotating or counterrotating and, where appropriate, equipped with kneading disks. If it is necessary in the extrusion to evaporate a solvent, the extruders are generally equipped with an evaporating section. Particularly preferred extruders are those of the ZKS series from Werner and Pfleiderer.
It is also possible according to the invention to produce multilayer pharmaceutical forms by coextrusion, in which case a plurality of mixtures of the components described above is fed together to an extrusion die so as to result in the required layered structure of the multilayer pharmaceutical form. It is preferable to use different binders for different layers.
Multilayer drug forms preferably comprise two or three layers. They may be in open or closed form, in particular as open or closed multilayer tablets.
At least one of the layers contains at least one pharmaceutical active ingredient. It is also possible for another active ingredient to be present in another layer. This has the advantage that two mutually incompatible active ingredients can be processed or that the release characteristics of the active ingredient can be controlled.
The shaping takes place by coextrusion with the mixtures from the individual extruders or other units being fed into a common coextrusion die and extruded. The shape of the coextrusion die depends on the required pharmaceutical form. Examples of suitable dies are those with a flat orifice, called slit dies, and dies with an annular orifice. The design of the die depends on the polymeric binder used and the required pharmaceutical form.
The resulting mixture is preferably solvent-free, i.e. it contains neither water nor an organic solvent.
The plastic mixture is, as a rule, subjected to final shaping. This can result in a large number of shapes depending on the die and mode of shaping. For example, if an extruder is used, the extrudate can be shaped between a belt and a roll, between two belts or between two rolls, as described in EP-A-358 105, or by calendering in a calender with two molding rolls, see, for example, EP-A-240 904. Other shapes can be obtained by extrusion and hot- or cold-cut of the extrudate, for example small-particle and uniformly shaped pellets. Hot-cut pelletization usually results in lenticular dosage forms (tablets) with a diameter of from 1 to 10 mm, while strip pelletization normally results in cylindrical products with a length to diameter ratio of from 1 to 10 and a diameter of from 0.5 to 10 mm. It is thus possible to produce monolayer but also, on use of coextrusion, open or closed multilayer dosage forms, for example oblong tablets, coated tablets, pastilles and pellets. The resulting granules can also be ground to a powder and compressed to tablets in a conventional way. Micropastilles can be produced by the Rotoform-Sandvik process. These dosage forms can be rounded and/or provided with a coating by conventional methods in a subsequent process step. Examples of materials suitable for film coatings are polyacrylates such as the Eudragit types, cellulose esters such as the hydroxypropylcellulose phthalates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose.
In specific cases there may be formation of solid solutions. The term solid solutions is familiar to the skilled worker, for example from the literature cited at the outset. In solid solutions of active ingredients in polymers, the active ingredient is in the form of a molecular dispersion in the polymer.


Methods for monitoring and/or controlling biofouling in membrane separation systems are provided. The present invention utilizes measurable amounts of fluorogenic agent(s) added to a feed stream to monitor and/or control the level of microbial growth during membrane separation and, thus, the purification of such feed stream during membrane separation.

The present invention relates generally to membrane separation and, more particularly, to methods for monitoring and/or controlling biofouling in membrane separation systems.
Membrane separation, which uses a selective membrane, is a fairly recent addition to the industrial separation technology for processing of liquid streams, such as water purification. In membrane separation, constituents of the influent typically pass through the membrane as a result of a driving force(s) in one effluent stream, thus leaving behind some portion of the original constituents in a second stream. Membrane separations commonly used for water purification or other liquid processing include microfiltration (MF), ultrafiltration (UF), nanofiltration (NF), reverse osmosis (RO), electrodialysis, electrodeionization, pervaporation, membrane extraction, membrane distillation, membrane stripping, membrane aeration, and other processes. The driving force of the separation depends on the type of the membrane separation. Pressure-driven membrane filtration, also known as membrane filtration, includes microfiltration, ultrafiltration, nanofiltration and reverse osmosis, and uses pressure as the driving force, whereas the electrical driving force is used in electrodialysis and electrodeionization. Historically, membrane separation processes or systems were not considered cost effective for water treatment due to the adverse impacts that membrane scaling, membrane fouling, membrane degradation and the like had on the efficiency of removing solutes from aqueous water streams. However, advancements in technology have now made membrane separation a more commercially viable technology for treating aqueous feed streams suitable for use in industrial processes.
Furthermore, membrane separation processes have also been made more practical for industrial use, particularly for raw and wastewater purification. This has been achieved through the use of improved diagnostic tools or techniques for evaluating and monitoring membrane separation performance. The performance of membrane separation, such as efficiency (e.g. flux, membrane permeability, permeate recovery, energy efficiency, time between membrane cleanings or time to conduct a cleaning cycle) and effectiveness (e.g. rejection or selectivity) are typically reduced by membrane fouling.
Membrane separation processes are prone to fouling by microbes, i.e. biofouling. The growth of microorganisms during membrane separation is a constant concern particularly in aqueous streams which provide optimum conditions for microbial growth. Biofouling is particularly detrimental to membrane separation systems because once it is started, the growth rate accelerates and biofouling can facilitate other types of fouling as well. For example, the exopolymeric substances (xe2x80x9cEPSxe2x80x9d) or slime layer of the biomass can trap and hold scales and other particulates that might otherwise pass out of the membrane separation system during operation. Furthermore, a thick EPS layer can also decrease turbulent flow within the membrane. This can lead to an increase in the concentration polarization layer which is a known contributor to membrane scaling phenomena.
The immediate and most obvious effect of biofouling is a decrease in membrane permeate output and/or a rise in the pressure drop along the length of a membrane element on the feed and concentrate side of the membrane, referred to herein as xe2x80x9cdifferential pressure.xe2x80x9d Under a constant pressure, this results in a loss in the production of permeate. Pressure can be increased in order to maintain a constant flux, but this increases energy consumption and further accelerates fouling. In addition, continued operation under these conditions (i.e., a loss of permeate flux, an increase in pressure differential and an increase in the pressure driving force) would necessarily require an increased number of cleanings over the life time of the membrane, thereby decreasing the membrane life and potentially increasing water costs if a significant amount of down time is required due to the cleanings. Less obvious effects include reduced solute rejection, contamination of permeate and deterioration of membrane modules, such as biodegradation on membrane glue lines. The review article written by H. F. Ridgway and H. Flemming entitled xe2x80x9cMembrane Biofoulingxe2x80x9d and appearing in Water Treatment Membrane Processes, McGraw Hill, pp. 6.1 to 6.62, 1996, is incorporated herein by reference.
In general, biofouling is controlled through the use of biocides and other biocontrol agents, i.e., chemicals that can inhibit microbial growth by destroying the cell wall or cellular constituents of microorganisms. Mechanical means and radiation means are additional possibilities. Intermittent use of biocides is typically encouraged since biocides can be both expensive and toxic. Thus, to prevent waste, constant monitoring and testing of the water system and of the membrane process parameters are required to determine the proper quantity of biocide for controlling microbial growth.
However, known monitoring techniques may not provide an adequate level of sensitivity, specificity and/or accuracy with respect to monitoring the effects of biofouling on membrane separation. Typical monitoring techniques include pressure and flow measurements and grab sampling to determine microbial population. With respect to pressure measurements, monitoring is generally conducted by evaluating changes in the differential pressure along the length of the membrane. With respect to flow measurement, the flow meters generally employed in such systems are subject to calibration inaccuracies, thus requiring frequent calibration. However, the changes in pressure and flow are not necessarily specific to biofouling, as they can be influenced by any suitable increase in scalants, foulants and/or like constituents that can build-up and remain in the system during membrane separation. As previously discussed, the microbial growth layer can enhance other types of fouling since it can trap or hold scales and other particulates that might otherwise pass out of the system during membrane separation.
For grab samples, water samples are typically taken from the feed stream and/or from the exit stream. Samples from the permeate stream can also be taken to determine if there is any contamination in the permeate. A typical technique involves withdrawing a sample, diluting the sample, and applying the sample to the surface of a nutrient agar medium. After incubation for 24 to 28 hours, the sample is checked for the presence of microorganisms and, where appropriate, the organisms are counted by manual or video means. A variation on this method includes withdrawing a sample and culturing it for a predetermined time, and then observing the culture medium by nephelometry or turbidimetry. In other words, the presence of microorganisms is revealed by the opacity of the culture medium.
A significant problem associated with grab sampling is the time lag between withdrawing the sample and completing the analysis to determine the level of microbiological activity in the sample. In this regard, the time lag can be exacerbated when the samples have to be transported off-site for analysis which can further delay obtaining the results.
Another problem associated with grab sampling is that it can underestimate the overall microbiological activity in the industrial water system because grab sampling is only sufficient to provide an indication of the planktonic microbiological activity, not the sessile activity. Planktonic microbiological populations are alive and exist suspended within the water of a water system. As used herein, the term xe2x80x9csessilexe2x80x9d refers to populations of microorganisms that are alive, but immobile. It is possible to get an industry-acceptable measurement of planktonic populations by grab sampling since planktonic microorganisms are suspended within the water sample that is removed and tested for microorganism concentrations. In contrast, sessile populations are strongly attached to the structures within the system and their presence is not easily measured by removing a sample of water and testing this sample for microorganisms. In this regard, the level of planktonic cells may not directly correlate to the level of sessile cells in the membrane separation system.
Accordingly, a need exists to monitor and/or control biofouling in membrane separation systems in real-time where conventional monitoring techniques are generally complex and/or may lack the sensitivity, specificity and/or accuracy necessary to adequately monitor biofouling such that membrane separation performance can be optimized.
The present invention provides methods for monitoring and/or controlling biofouling in membrane separation systems capable of treating feed streams suitable for use in industrial processes. In this regard, the use of a fluorogenic agent can be utilized to monitor the growth of microorganisms during membrane separation (i.e., monitor biofouling). Applicants have discovered that the fluorescent monitoring technique of the present invention can be performed with a high degree of sensitivity, specificity and/or accuracy with respect to the detection of biofouling, such that membrane separation performance and efficiency can be controllably optimized.
To this end, in an embodiment of the present invention, a method of monitoring biofouling in a membrane separation system including a membrane capable of separating a feed stream into at least a first stream and a second stream is provided. The method includes the steps of providing a fluorogenic agent; adding the fluorogenic agent to the feed stream; providing a fluorometer to detect the fluorescent signal of the fluorogenic agent in at least one of the feed stream, the first stream and the second stream; reacting the fluorogenic agent with one or more microorganisms within the membrane separation system; forming a reacted fluorogenic agent; using the fluorometer to measure the fluorescent signal of at least one of the fluorogenic agent and the reacted fluorogenic agent in at least one of the first stream and the second stream and optionally the feed stream; and monitoring biofouling in the membrane separation system based on the change in the signal of the fluorogenic agent, or the reacted fluorogenic agent or a combination of both signals measured.
It is, therefore, an advantage of the present invention to provide methods that utilize a fluorogenic agent to monitor and/or control biofouling in membrane separation systems.
Another advantage of the present invention is to provide methods that utilize the monitoring of fluorogenic agents to improve the performance of membrane separation.
A further advantage of the present invention is to provide methods for monitoring microbial growth with selectivity, specificity and/or accuracy based on the monitoring of the fluorogenic agent added to the membrane separation system.
Yet another advantage of the present invention is to provide a control signal to add biocides or biocontrol agents to reduce the biofouling in membrane separation systems.
Still further an advantage of the present invention is to provide methods for monitoring the effectiveness of cleaning agents, biocides and biocontrol agents to reduce cleaning time and increase time between cleanings.
Additional features and advantages of the present invention are described in, and will be apparent in, the detailed description of the presently preferred embodiments.
The present invention provides methods for monitoring and/or controlling biofouling in membrane separation systems that are capable of removing solutes and/or other impurities from feed streams, such as aqueous feed streams, which are suitable for use in a number of different industrial applications. More specifically, the methods of the present invention can monitor and/or control biofouling in membrane separation systems based on monitoring the activity of a fluorogenic agent(s) which has been added to the feed stream. In this regard, biofouling due to microbial growth during membrane separation can be evaluated with a high degree of selectivity, specificity and accuracy such that the performance of the membrane separation system can be effectively optimized.
The methods of the present invention can include a variety of different and suitable components, process steps, operating conditions and the like, for monitoring and/or controlling biofouling in membrane separation systems. In an embodiment, the membrane separation system of the present invention includes cross-flow and dead-end flow systems. During cross-flow membrane separation systems, the feed stream can be treated in a flow direction that is substantially parallel to the membrane of the separation system. With respect to dead-end flow systems, the feed stream can be treated in a flow direction that is substantially perpendicular to the membrane of the separation system.
In general, the membrane separation systems of the present invention are capable of treating or purifying feed streams by dividing the feed stream into separate streams. In an embodiment, the feed stream is separated into at least a first and second stream, such as a permeate stream and a concentrate stream. The feed stream can contain various solutes, such as dissolved organics, dissolved inorganics, dissolved solids, suspended solids, the like or combinations thereof. Upon separation of the feed stream into the permeate and the concentrate, in membrane filters for example, the permeate stream essentially contains a substantially lower concentration of dissolved and/or suspended solutes as compared to the aqueous feed stream. On the other hand, the concentrate stream has a higher concentration of dissolved and/or suspended solutes as compared to the aqueous stream. In this regard, the permeate represents a purified feed stream, such as a purified aqueous feed stream.
It should be appreciated that the present invention can be utilized with respect to a number of different types of membrane separation systems including, for example, cross-flow systems, dead-end flow systems, reverse osmosis, nanofiltration, ultrafiltration, microfiltration, electrodialysis, electrodeionization, pervaporation, membrane extraction, membrane distillation, membrane stripping, membrane aeration and the like or combinations thereof. Reverse osmosis, nanofiltration, ultrafiltration and microfiltration are the preferred membrane separation systems.
In reverse osmosis, the feed stream is typically processed under cross-flow conditions. In this regard, the feed stream flows substantially parallel to the membrane surface such that only a portion of the feed stream diffuses through the membrane as permeate. The cross-flow rate is routinely high in order to provide a scouring action that lessens membrane surface fouling. This can also decrease concentration polarization effects (e.g., concentration of solutes in the reduced-turbulence boundary layer at the membrane surface, which can increase the osmotic pressure at the membrane and thus can reduce permeate flow). The concentration polarization effects can inhibit the feed stream water from passing through the membrane as permeate, thus decreasing the recovery ratio, e.g., the ratio of permeate to applied feed stream.
Reverse osmosis systems can employ a variety of different types of membranes. Such commercial membrane element types include, without limitation, hollow fiber membrane elements, tubular membrane elements, spiral-wound membrane elements, plate and frame membrane elements, and the like, some of which are described in more detail in xe2x80x9cThe Nalco Water Handbook,xe2x80x9d Second Edition, Frank N. Kemmer ed., McGraw-Hill Book Company, New York, N.Y., 1988, incorporated hereinto, particularly Chapter 15 entitled xe2x80x9cMembrane Separationxe2x80x9d. It should be appreciated that a single membrane element may be used in a given membrane filtration system, but a number of membrane elements can also be used depending on the industrial application.
A typical reverse osmosis system is described as an example of membrane filtration and more generally membrane separation. Reverse osmosis uses mainly spiral wound elements or modules, which are constructed by winding layers of semi-permeable membranes with feed spacers and permeate water carriers around a central perforated permeate collection tube. Typically, the modules are sealed with tape and/or fiberglass over-wrap. The resulting construction has one channel which can receive an inlet flow. The inlet stream flows longitudinally along the membrane module and exits the other end as a concentrate stream. Within the module, water passes through the semi-porous membrane and is trapped in a permeate channel which flows to a central collection tube. From this tube it flows out of a designated channel and is collected.
In practice, membrane modules are stacked together, end to end, with inter-connectors joining the permeate tubes of the first module to the permeate tube of the second module, and so on. These membrane module stacks are housed in pressure vessels. Within the pressure vessel feed water passes into the first module in the stack, which removes a portion of the water as permeate water. The concentrate stream from the first membrane becomes the feed stream of the second membrane and so on down the stack. The permeate streams from all of the membranes in the stack are collected in the joined permeate tubes.
Within most reverse osmosis systems, pressure vessels are arranged in either xe2x80x9cstagesxe2x80x9d or xe2x80x9cpasses.xe2x80x9d In a staged membrane system, the combined concentrate streams from a bank of pressure vessels are directed to a second bank of pressure vessels where they become the feed stream for the second stage. Commonly systems have 2 to 3 stages with successively fewer pressure vessels in each stage. For example, a system may contain 4 pressure vessels in a first stage, the concentrate streams of which feed 2 pressure vessels in a second stage, the concentrate streams of which in turn feed 1 pressure vessel in the third stage. This is designated as a xe2x80x9c4:2:1xe2x80x9d array. In a staged membrane configuration, the combined permeate streams from all pressure vessels in all stages are collected and used without further membrane treatment. Multi-stage systems are used when large volumes of purified water are required, for example for boiler feed water. The permeate streams from the membrane system may be further purified by ion exchange or other means.
In a multi-pass system, the permeate streams from each bank of pressure vessels are collected and used as the feed to the subsequent banks of pressure vessels. The concentrate streams from all pressure vessels are combined without further membrane treatment of each individual stream. Multi-pass systems are used when very high purity water is required, for example in the microelectronics or pharmaceutical industries.
It should be clear from the above examples that the concentrate stream of one stage of an RO system can be the feed stream of another stage. Likewise the permeate stream of a single pass of a multi-pass system may be the feed stream of a subsequent pass. A challenge in monitoring systems such as the reverse osmosis examples cited above is that there are a limited number of places where sampling and monitoring can occur, namely the feed, permeate and concentrate streams. In some, but not all, systems xe2x80x9cinter-stagexe2x80x9d sampling points allow sampling/monitoring of the first stage concentrate/second stage feed stream. Similar inter-pass sample points may be available on multi-pass systems as well.
In contrast to cross-flow filtration membrane separation systems, conventional filtration of suspended solids can be conducted by passing a feed fluid through a filter media or membrane in a substantially perpendicular direction. This effectively creates one exit stream during the service cycle. Periodically, the filter is backwashed by passing a clean fluid in a direction opposite to the feed, generating a backwash effluent containing species that have been retained by the filter. Thus conventional filtration produces a feed stream, a purified stream and a backwash stream. This type of membrane separation is typically referred to as dead-end flow separation and is typically limited to the separation of suspended particles greater than about one micron in size.
Cross-flow filtration techniques, on the other hand, can be used for removing smaller particles (generally about one micron in size or less), colloids and dissolved solutes. Such types of cross-flow membrane separation systems can include, for example, reverse osmosis, nanofiltration, ultrafiltration, microfiltration, electrodialysis or the like. Reverse osmosis can remove even low molecular weight dissolved species that are at least about 0.0001 to about 0.001 microns in minimum diameter, including, for example, ionic and nonionic species, low molecular weight molecules, water-soluble macromolecules or polymers, suspended solids, colloids, and such substances as bacteria and viruses.
In the conventional flow method of monitoring biofouling, the actual permeate flow rate is a direct reading from a flowmeter. However, the actual permeate flow rate can vary with respect to the feed stream temperature, the pressure driving force, feedstream solutes and suspended solids and, of course, the various fouling factors including biofouling. The normalized permeate flow is typically considered a more sensitive forecaster of trouble in a membrane separation system. Normalized permeate flow is determined through a simple calculation which eliminates the effect of actual system temperature and driving force variations and converts the actual permeate flow readings to what they would be if the system were operating at a standard (xe2x80x9cnormalxe2x80x9d) and constant pressure and temperature conditions, which are routinely the start-up driving force and a specified temperature such as 25xc2x0 C. The calculation thus includes a temperature conversion factor and a pressure conversion factor for a given membrane, which are typically determined empirically with a new membrane or are provided by the membrane manufacturer. Another method, called the xe2x80x9cclean water flux methodxe2x80x9d is used to measure the actual permeate flow using clean water at the standard pressure and temperature conditions. This method requires shutting down the operation and passing clean water through the system to determine fouling and is thus extremely inconvenient and time-consuming.
In the conventional differential pressure method of monitoring biofouling, the difference between two pressure measurements at two locations in the feed/concentrate stream is taken. Typical differential pressure will be the difference between the feed pressure and the concentrate pressure. It is a measure of the hydraulic pressure losses through the membrane-filtration membrane elements on the feed and concentrate side of the membrane and the associated manifold piping. In reverse osmosis, for example, another conventional preferred method is to measure the pressure differential on a single pressure vessel where biofouling is most likely to occur, i.e., the front membrane where the feed water enters. When the feed/concentrate flow channels become clogged, the driving force increases. The differential pressure also depends upon the feedstream flow rate and the percent recovery. An accurate comparison between differential pressure readings taken at different times requires that the membrane filtration system is operating at the same percent recovery and feed flow rate in each instance. In practice, the differential pressure reading is taken at some constant production parameter, such as constant permeate flow or constant pressure.
Another biofouling detection method is the destructive method of membrane autopsy. This includes, after cutting open a membrane removed from service, visual inspection of its surface, a membrane-surface microbiological analysis by swabbing the membrane surface, and surface analysis for deposits by SEM/EDS, IR, electron microscopy, ICP and like surface analysis techniques. By comparing the nature and relative quantities of the various compounds, elements and living organisms, a qualitative determination of biofouling versus other types of fouling and scaling can be determined.
Membrane separation systems and the monitoring thereof are unique because of the following considerations.
1. Systems are constructed with limited flexibility in terms of where monitoring may be done and/or where samples may be collected. Moreover, different types of fouling are usually located in specific segments of the membrane. For example, biofouling is usually predominant at the front end of the membrane system.
2. Membrane separation systems include a concentration polarization layer that forms as water is permeated through the barrier. This is not present in other water treatment systems, such as cooling water systems.
3. Because it is essential that the surface of the membrane remain clean, a relatively small amount of biofouling or fine precipitate can cause a significant performance loss. The performance loss in a membrane is, thus, more sensitive as compared to cooling water treatment. In this regard, performance loss in a membrane can occur at a film thickness appreciably lower than that required for heat transfer loss to occur in a cooling water system. Moreover, due to the small flow channels, the fouling, when not controlled or removed earlier, will continue to accelerate and it will be more difficult, if not impossible, to clean the membrane back to its original performance capability. A shortened membrane life is typically caused by this delay in detection of fouling.
4. The thin, semi-permeable films (polymeric, organic or inorganic) are sensitive to degradation by chemical species, including the chemicals secreted from the cell growth process and the cleaning chemicals. Products which contact membrane surfaces must be compatible with the membrane chemistry to avoid damaging the surface and thereby degrading performance.
5. Chemical treatments used in membrane systems must be demonstrated to be compatible with the membrane material prior to use. Damage from incompatible chemicals can result in immediate loss of performance and perhaps degradation of the membrane surface. Such immediate, irreversible damage from a chemical treatment is highly uncommon in cooling water systems.
6. In membrane separation systems, there is a continuous feed stream and at least one continuous discharge stream. The holding time of a membrane separation system is very short, i.e., on the order of a few seconds to a few minutes.
Based on these differences, a number of different factors and considerations must necessarily be taken into account when developing and/or implementing monitoring and controlling programs for biofouling as compared to other water treatment processes, such as cooling water treatment processes. For example, for effective use in membrane systems, it is believed that the fluorogenic agent must be able to respond to a much lower concentration of organisms than in other industrial water systems, including cooling water systems. In this regard, detection limits as low as about 104 colony forming units per square centimeter (cfu/cm2) are required when applied to membrane separation systems. At such low detection limits, the accuracy and reproducibility of the method are usually very poor.
The short holding time necessarily requires a fluorogenic agent that can react with speed and sensitivity to the microbial growth process under the limited holding time associated with membrane separation as compared to other industrial water systems, such as cooling water systems which have holding times typically of hours.
Due to the nature of a continuous feed stream with short residence time in the membrane separation system, the introduction of the fluorogenic agent is restricted to the feed stream and the measurement of the fluorogenic agent is restricted to the exit stream as the fluorogenic agent exits the system within minutes after its introduction. Thus, the membrane separation system provides an almost immediate measurement of biofouling after the introduction of the fluorogenic agent. The fluorogenic agent does not need to be further introduced until at a later time when the measurement is again deemed necessary.
As previously discussed, the methods of the present invention employ fluorogenic agents to monitor biofouling caused by microbial growth with a high degree of selectivity, sensitivity and/or accuracy such that the performance of membrane separation can be optimized. Microbiological organisms commonly found within industrial water systems which thus far have been detectable by and respond to the detection methods of the present process include, but are not limited to, Pseudomonas, Bacillus, Klebsiella, Enterobacter, Escherichia, Sphaerotilus and Haliscomenobacter.
It should be appreciated that the level of microbial activity during membrane separation is a function of different factors including the population of microbiological organisms in the feed stream, the amount of dissolved oxygen, temperature, water flow, the presence of microbial nutrients and the removal of microbial waste. Even in a single section of biofilm, the sessile microbial activity, for example, can vary across and down the cross-section depending upon these factors. It is believed that the measured fluorogenic agent response can provide a sum total of the response of planktonic and sessile microbiological organisms in the entire system which are in contact with the membrane separation feed stream that contains the fluorogenic agent. Therefore, even if the level of microbial activity is unusually high in a small section of the membrane separation system, but low everywhere else, the fluorogenic agent response may be low. In this regard, it is believed that the method of the present invention can detect the average microbiological organism activity of the system.
In general, the fluorogenic agent added to the membrane system must be a molecule or species that undergoes a change in its fluorescent signal upon interaction with a broad population of microbiological organisms. It should be appreciated by those skilled in the art that environmental factors, such as pH and temperature, may affect the fluorescent signal and should be accounted for and corrected accordingly. Suitable fluorogenic agents, include, but are not limited to,
acetic acid ester of pyrene 3,6,8-trisulfonic acid;
carboxyfluorescein diacetate,
3-carboxyumbelliferyl xcex2-D-galactopyranoside;
3-carboxyumbelliferyl xcex2-D-glucuronide;
9H-(1,3-dichloro-9,0-dimethylacridine-2-one-7-yl), D-glucuronide;
9H-(1,3-dichloro-9,9-dimethylacridin-2-one-7-yl);
resorufin xcex2-D-galactopyranoside;
fluorescein di- xcex2-D-galactopyranoside;
fluorescein di- xcex2-D-glucuronide;
resorufin xcex2-D-glucuronide;
fluorescein diphosphate;
7-hydroxy-3H-phenoxazin-3-one 10-oxide (hereinafter xe2x80x9cresazurinxe2x80x9d);
7-hydroxy-3H-phenoxazin-3-one 10-oxide, sodium salt (hereinafter xe2x80x9cresazurin, sodium saltxe2x80x9d);
4-methylumbelliferyl phosphate (xe2x80x9c4MUPxe2x80x9d);
4-methylumbelliferyl xcex2-D-glucuronide;
pyranine phosphate;
pyrene 3,6,8-trisulfonic acid 1-phosphate; and
all like fluorogenic agents, derivatives and combinations thereof.
The preferred fluorogenic agents include resazurin, 4MUP, pyranine phosphate and combinations thereof. Resazurin is the most preferred fluorogenic agent.
It should be appreciated by those skilled in the art that the fluorogenic agents are either commercially available (for example, resazurin, sodium salt is available from ALDRICH(copyright) of Milwaukee, Wis.) or capable of being synthesized using procedures reported in the literature (for example, as is the case with pyranine phosphate).
The fluorogenic agent is added to the feed stream in an amount which is capable of determining microbial activity. In an embodiment, an effective amount of fluorogenic agent ranges from about 5 ppt to about 500 ppm, preferably from about 0.5 ppb to about 5 ppm, and more preferably from about 5 ppb to about 500 ppb. When the salt form of the agent (e.g., resazurin, sodium salt) is added to the industrial water system, the calculation of ppm is based on the active amount of the fluorogenic agent present.
The cost of the fluorogenic agent also places a practical upper limit on the amount of fluorogenic agent added to the system. Additional factors influencing fluorogenic agent addition to the system include the type of fluorogenic agent, the amount of liquid continuously lost and replenished within the membrane separation system and the type of fluids contained within the membrane separation system.
In an embodiment, it is preferred that the fluorogenic agent of the present invention meet the following criteria:
1. Not be adsorbed by the membrane in any appreciable amount;
2. Not degrade the membrane or otherwise hinder its performance or alter its composition;
3. Be detectable on a continuous or semi-continuous basis and susceptible to concentration measurements that are accurate, repeatable and capable of being performed on feedwater, concentrate water, permeate water or other suitable media or combinations thereof;
4. Be substantially foreign to the chemical species that are normally present in the water of the membrane separation systems in which inert tracers may be used;
5. Be substantially impervious to interference from, or biasing by, the chemical species that are normally present in the water of membrane separation systems in which inert tracers may be used;
6. Be substantially impervious to any of its own potential specific or selective losses from the water of membrane separation systems, including selective permeation of the membrane;
7. Be compatible with all treatment agents employed in the water of the membrane separation systems in which inert tracers may be used, and thus in no way reduce the efficacy thereof;
8. Be compatible with all components of its formulation; and
9. Be relatively nontoxic and environmentally safe, not only within the environs of the water or the membrane separation system in which it may be used, but also upon discharge therefrom.
It should be appreciated that the present invention only requires a single fluorogenic species to exist with the introduction of the fluorogenic agent as long as that species is reacted and can be measured between the point of introduction and the point of measurement.
In an embodiment, the fluorogenic agents suitable for use in the instant claimed process must have a detectable fluorescent signal prior to their reacting with the microorganisms and also must have a different fluorescent signal after they have reacted with the microorganisms.
It is believed, without intending to be bound thereby, that enzymes synthesized by the living microbiological organisms in the membrane separation can act upon the fluorogenic agents. This activity causes a change in the fluorescent signal of the fluorogenic agent. By monitoring the fluorescent signal, microbiological activity during membrane separation can be monitored. As previously discussed, the methods of the present invention are capable of monitoring microbiological activity from both planktonic and sessile populations, in contrast to methods known in the art.
In an embodiment, the fluorogenic agent can be fed either by itself or in combination with another membrane separation agent, such as an inert fluorescent tracer, a treatment agent, such as scale and corrosion inhibitors, like agents and combinations thereof. By xe2x80x9ctreatment chemicals and/or agentsxe2x80x9d is meant without limitation treatment chemicals that enhance membrane separation process performance, antiscalants that retard/prevent membrane scale deposition, antifoulants that retard/prevent membrane fouling, biodispersants and microbial-growth inhibiting agents, such as biocides and cleaning chemicals that remove membrane deposits.
The fluorescent signals of the fluorogenic agent, the reacted fluorogenic agent and the inert fluorescent tracer material can be measured in a variety of different and suitable ways, such as by commercially available fluorometers. Fluorometers with suitable filters may be used to measure the fluorescent signal or signals derived from the fluorogenic agent, the reacted fluorogenic agent and/or the inert fluorescent tracer.
Measuring the fluorescent signal of both the fluorogenic agent and the reacted fluorogenic agent is a known procedure to someone skilled in the art of fluorometry. For example, the fluorescent properties of the fluorogenic agent resazurin are well known both in its unreacted state and in its reacted xe2x80x9cresorufinxe2x80x9d state. In a preferred embodiment, the membrane separation system is sampled at locations such that grab samples do not have to be taken for measurements via the fluorometers. When the sampling components for the fluorometers are located within the membrane separation system, this type of sampling is typically referred to as an in-line measurement.
An in-line measurement is one that is taken without interrupting the flow of the system being measured. Because the sample components for the fluorometer(s) are positioned in-line when conducting an in-line measurement, the sample they are monitoring accurately reflects the entire membrane separation system and, as such, the information gleaned from conducting this method accurately reflects both the planktonic and sessile microbiological organism populations. In-line measurement overcomes the problems associated with grab sampling and the need to remove a sample from the aqueous stream for later testing. Also, the reacted and unreacted forms of the fluorogenic agents are tested on a real-time basis, wherein an almost instantaneous fluorescence reading of the two fluorogenic agents will provide an indication of microbial activity.
Notwithstanding the fact that in-line measurement is the preferred way of conducting the method of the instant claimed invention, it is possible to conduct the method of the instant claimed invention using a grab sampling technique suitable to secure samples of the industrial water system. If a grab sampling technique is used, a mechanism should necessarily be provided to convey the grab sample to the fluorometer in a reasonable length of time such that the data received from the fluorometer accurately reflects the current microbial growth status of the membrane separation system.
Examples of fluorometers that may be used in the practice of this invention include the TRASAR(copyright) 350 and TRASAR(copyright) 8000 fluorometers (available from Ondeo Nalco Company of Naperville, Ill.); the Hitachi F-4500 fluorometer (available from Hitachi through Hitachi Instruments Inc. of San Jose, Calif.); the JOBIN YVON FluoroMax-3 xe2x80x9cSPEXxe2x80x9d fluorometer (available from JOBIN YVON Inc. of Edison, N.J.); and the Gilford Fluoro-IV spectrophotometer or the SFM 25 (available from Bio-tech Kontron through Research Instruments International of San Diego, Calif.). It should be appreciated by those skilled in the art that the fluorometer list is not comprehensive and is intended only to show examples of fluorometers. Other commercially available fluorometers and modifications thereof can also be used in this invention.
In an embodiment, a fluorescent signal ratio is used as an indication of microbial activity and thus an indication of biofouling during membrane separation. By calculating the ratio as opposed to simply measuring an absolute value of fluorescent signals, information is obtained that is independent of fluorogenic agent concentration. In another embodiment, the ratio can increase the sensitivity due to the fact that the microbiological organisms convert fluorogenic reagent to reacted fluorogenic agent with the ratio increase being due to both the decrease in the fluorescent signal of the unreacted fluorogenic agent and increase in the fluorescent signal of the reacted fluorogenic agent (e.g., the product).
The ratio of the fluorescent signal of the fluorogenic agent to the fluorescent signal of the reacted fluorogenic agent is:   ratio  =            fluorescent                              xe2x80x83                                  xe2x80x83                          signal                    xe2x80x83                  of                    xe2x80x83                  reacted                    xe2x80x83                  fluorogenic                    xe2x80x83                  agent              fluorescent                              xe2x80x83                                  xe2x80x83                          signal                    xe2x80x83                  of                    xe2x80x83                  fluorogenic                              xe2x80x83                                  xe2x80x83                          agent
The ratio is a unitless number. The ratio can be calculated manually or with a calculator or with a computer program. For ease of use, it is preferable that the ratio be calculated using an appropriate computer program such that a record of the ratio can be continuously calculated at set intervals. The rate of change of the ratio can then be used to determine the rate of increase of biofouling.
In an embodiment, the inert fluorescent tracer material is used to determine the concentration of fluorogenic agent present and by knowing that concentration it is possible to operate the system so that a desired level of fluorogenic agent is fed accurately. See U.S. Pat. Nos. 4,783,314; 4,992,380 and 5,041,386, which are incorporated herein by reference.
The meaning of the term xe2x80x9cinertxe2x80x9d, as used herein, is that an inert fluorescent tracer is not appreciably or significantly affected by any other chemistry in the system, or by the other system parameters such as microbiological activity, biocide concentration and scale inhibitor concentration. To quantify what is meant by xe2x80x9cnot appreciably or significantly affectedxe2x80x9d, this statement means that an inert fluorescent compound has no more than a 10% change in its fluorescent signal, under conditions normally encountered in industrial water systems. Conditions normally encountered in industrial water systems are known to people of ordinary skill in the art of industrial water systems.
Inert fluorescent tracer materials suitable for use with the fluorogenic agents that are used in the instant claimed invention must have the property of having their unique fluorescent signal be detectably different than the fluorescent signals of the fluorogenic agent. This means that the fluorescent signal of the fluorogenic agent and the fluorescent signal of the reacted fluorogenic agent must both be detectably different than that of the inert fluorescent tracer material.
Suitable inert fluorescent tracer materials are the mono-, di- and tri-sulfonated naphthalenes, including their known water-soluble salts; and the known sulfonated derivatives of pyrene, such as 1,3,6,8-pyrenetetrasulfonic acid, along with the known water-soluble salts of all of these materials, and Acid Yellow 7 (Chemical Abstract Service Registry Number 2391-30-2, for 1H-Benz(de) isoquinoline-5-sulfonic acid, 6-amino-2,3-dihydro-1,3-dioxo-2-p-tolyl-, monosodium salt (8CI)).
In an embodiment, the present invention includes a controller (not shown) to monitor and/or control the operating condition or performance of the membrane separation system based on the measurable fluorescence of the fluorogenic agent, reacted fluorogenic agent, and/or the inert fluorescent tracer. In this regard, biofouling is monitored in the membrane separation system by measuring the change in the signal of the fluorogenic agent or the reacted fluorogenic agent with respect to the signal of the inert fluorescent tracer and then comparing the resultant ratio to the corresponding ratio in the feed stream or the corresponding ratio at time zero, i.e., right after the membrane has been cleaned. The controller can be configured and/or adjusted in a variety of different and suitable ways.
For example, the controller can be in contact with the detection device (not shown) to process the detection signal (e.g., filter noise from the signal) in order to enhance the detection of the fluorescent signal(s) derived from the fluorogenic agent, reacted fluorogenic agent and/or the inert fluorescent tracer. Further, the controller can be adjusted to communicate with other components of the membrane separation system. The communication can be either hard wired (e.g., electrical communication cable), a wireless communication (e.g., wireless RF interface), a pneumatic interface or the like.
In this regard, the controller can be utilized to control the performance of membrane separation by determining the optimal amount of biocontrol treatment needed. xe2x80x9cBiochemical treatmentxe2x80x9d includes biocides, biocontrol agents, biocontrol methods and combinations thereof. For example, the controller can communicate with a feed device (not shown) in order to control various biofouling control chemicals or biofouling control devices or process parameters. In an embodiment, the controller is capable of adjusting the feed rate of biocontrol agent(s) added to the feed stream during membrane separation based on the fluorescence of the fluorogenic agent and reacted fluorogenic agent that are measured. In another embodiment, the addition of biocontrol agents are controlled based on the determination of the ratio of reacted fluorogenic agent to fluorogenic agent. In another embodiment, the addition of biocides are controlled based on the determination of the rate of change of ratio of reacted fluorogenic agent to fluorogenic agent.
A real-time determination of the fluorescence of the fluorogenic agent(s) enables immediate evaluation of the microbial activity as well as the efficiency of the current biocontrol agent dosage and/or the need for an additional feed of the biocontrol agent. Real-time determination of biological activity enables the process to add biocontrol agents on an as needed basis. Adding excess biocontrol agents, greater than what is needed to control the microbial activity is avoided when the biofouling condition is accessed on a real-time basis. Thus, the use of biocontrol agents can be administered at determined effective levels, which results in the correct amount being used. Additionally, the effectiveness of a biocontrol agent feed can be evaluated on a real-time basis and the dosage can be increased or decreased depending upon the real-time reading.
When the method of the instant claimed invention is conducted in the presence of biocontrol agents, certain adjustments have to be made. People of ordinary skill in the art know what biocides are used in membrane separation systems. In an embodiment, biocides added in response to unacceptable levels of microbial activity include oxidizing biocides, non-oxidizing biocides and combinations thereof.
Suitable oxidizing biocides include, but are not limited to:
BCDMH (92.5%, 93.5%, 98%), which is either 1,3-dichloro-5,5-dimethylhydantoin and 1-bromo-3-chloro-5,5-dimethyl hydantoin (CAS Registry #16079-88-2) or a mixture thereof,
bleaches, including stabilized bleaches;
bromine, including stabilized bromine;
calcium hypochlorite (CAS Registry #7778-54-3) xe2x80x9cCal Hypoxe2x80x9d (68%);
chlorine, including stabilized chlorine (8.34%);
H2O2/PAA (21.7%/5.1%) which is hydrogen peroxide (CAS Registry #7722-84-1)/peracetic acid (CAS Registry #79-21-0);
hypobromite;
hypobromous acid;
iodine;
organobromines;
NaBr (42.8%, 43%, 46%) which is sodium bromide;
NaOCI (10%, 12.5%) which is sodium hypochlorite (CAS Registry #7681-52-9);
and mixtures thereof.
Suitable non-oxidizing biocides include, but are not limited to,
ADBAC Quat (10%, 40%(CAS Registry #68391-0-5), 80%)xe2x80x94alkyl dimethyl benzyl ammonium chloride, also known as xe2x80x9cquatxe2x80x9d;
ADBAC quat(15%)/TBTO (tributyl tin oxide 5%);
ADBAC(12.5%)/TBTO (2.5%), (ADBAC Quat/bis tributyl tin oxide) (CAS Registry #56-35-9);
carbamates (30%), of formula T2NCO2H, where T2 is a C1-C10 alkyl group; copper sulfate (80%);
DBNPA (20%, 40%), which is 2,2-dibromo-3-nitrilopropionamide (CAS Registry #10222-01-2);
DDAC Quat (50%) which is didecyl dimethyl ammonium chloride quat;
DPEEDBAC Quat (1%) which is (2-(2-p-(diisobutyl)phenoxy)ethoxy)ethyl dimethyl, dimethyl benzyl;
glutaraldehyde (15%, 45%), CAS Registry #111-30-8;
glutaraldehyde (14%)/ADBAC quat (2.5%);
HHTHTxe2x80x94hexahydro-1,3,5-tris (2-hydroxyethyl)-5-triazine (78.5%); isothiazolones (1.5%, 5.6%)xe2x80x94a mixture of 5-chloro-2-methyl-4-isothiazoline-3-one (CAS Registry #26172-55-4) and 2-methyl;-4-isothiazoline-3-one (CAS Registry #2682-20-4);
MBT (10%)xe2x80x94methylene bis thiocyanate;
polyquat (20%, 60%), a polymeric quaternary compound; polyamines and salts thereofxe2x80x94polymeric amine compounds;
terbutylazine (4%, 44.7%)xe2x80x942-(tert-butylamino)-4-chloro-6-ethylamino-5-triazine (CAS Registry #5915-41-3);
TMTT (24%)xe2x80x94tetramethylthiuram disulfide;
and mixtures thereof.
Other types of biocontrol agents include bio-dispersants, bio-detergents, chaotropic agents, surfactants, chelating agents, enzymatic cleaners, and other chemicals that kill bacteria or interfere with bacterial and EPS attachment and bacteria colonization processes.
Biocontrol methods, such as mechanical means to disrupt biofilm integrity including ultrasound, electric fields, air backwashes, etc. can also be used.
Since membrane systems have very short holding times, the interference of biocontrol agents with the fluorogenic agent does not pose any problems in most practical applications by simply not applying the biocontrol agent during the introduction of the fluorogenic agent. In practice, the biocontrol agent may only be added intermittently.
Although membrane separation systems are often employed for the purification of water, or the processing of aqueous streams, the systems of the present invention are not limited to the use of an aqueous influent. In an embodiment, the influent may be another fluid, or a combination of water and another fluid. The operational principles of membrane separation systems and processes of the present invention are not so governed by the nature of the influent that the present invention could not be employed with influents otherwise suitable for water purification in a given membrane separation system. The descriptions of the invention above that refer to aqueous systems are applicable also to nonaqueous and mixed aqueous/nonaqueous systems.
The foregoing descriptions of the present invention at times refer specifically to aqueous influents and effluents, and the use of an aqueous system for describing a membrane filtration system and the operation of the present invention therein is exemplitive. A person of ordinary skill in the art, given the disclosures of the present specification, would be aware of how to apply the foregoing descriptions to nonaqueous membrane filtration systems.
It should be appreciated that the present invention is applicable to all industries that can employ membrane separation processes. For example, the different types of industrial processes in which the method of the present invention can be applied generally include raw water processes, waste water processes, industrial water processes, municipal water treatment, food and beverage processes, pharmaceutical processes, electronic manufacturing, utility operations, pulp and paper processes, mining and mineral processes, transportation-related processes, textile processes, plating and metal working processes, laundry and cleaning processes, leather and tanning processes, and paint processes.
In particular, food and beverage processes can include, for example, dairy processes relating to the production of cream, low-fat milk, cheese, specialty milk products, protein isolates, lactose manufacture, whey, casein, fat separation, and brine recovery from salting cheese. Uses relating to the beverage industry including, for example, fruit juice clarification, concentration or deacidification, alcoholic beverage clarification, alcohol removal for low-alcohol content beverages, process water; and uses relating to sugar refining, vegetable protein processing, vegetable oil production/processing, wet milling of grain, animal processing (e.g., red meat, eggs, gelatin, fish and poultry), reclamation of wash waters, food processing waste and the like.
Examples of industrial water uses as applied to the present invention include, for example, boiler water production, process water purification and recycle/reuse, softening of raw water, treatment of cooling water blow-down, reclamation of water from papermaking processes, desalination of sea and brackish water for industrial and municipal use, drinking/raw/surface water purification including, for example, the use of membranes to exclude harmful micro-organisms from drinking water, polishing of softened water, membrane bio-reactors, mining and mineral process waters.
Examples of waste water treatment applications with respect to the inert tracer monitoring methods of the present invention include, for example, industrial waste water treatment, biological waste treatment systems, removal of heavy metal contaminants, polishing of tertiary effluent water, oily waste waters, transportation related processes (e.g., tank car wash water), textile waste (e.g., dye, adhesives, size, oils for wool scouring, fabric finishing oils), plating and metal working waste, laundries, printing, leather and tanning, pulp and paper (e.g., color removal, concentration of dilute spent sulfite liquor, lignon recovery, recovery of paper coatings), chemicals (e.g., emulsions, latex, pigments, paints, chemical reaction by-products), and municipal waste water treatment (e.g., sewage, industrial waste).
Other examples of industrial applications of the present invention include, for example, semiconductor rinse water processes, production of water for injection, pharmaceutical water including water used in enzyme production/recovery and product formulation, and electro-coat paint processing.

Method of monitoring biofouling in membrane separation systems


To reduce random noise caused by address setting in an apparatus that controls a read address of an image sensing device, without causing a significant increase in circuit complexity.

In various applications, to detect a physical quantity distribution, a semiconductor device is widely used which includes a linear array or a matrix array of unit elements (pixels) sensitive to a change in a physical quantity such as a pressure or an electromagnetic wave such as light or radiation incident from the outside.
For example, as shown in FIG. 2B, in video devices, a solid-state image sensor is used which includes an image sensor device (image sensing device) of a CCD (Charge Coupled Device) type, a MOS (Metal Oxide Semiconductor) type, or a CMOS (Complementary Metal-Oxide Semiconductor) type to detect a change in a physical quantity such as light (which is an example of an electromagnetic wave).
In computer devices, a fingerprint recognition device is used to acquire fingerprint information by detecting an image of a fingerprint based on a change in an electrical or optical characteristic associated with a pressure. In these apparatus, a physical quantity distribution is converted into an electrical signal by unit elements (pixels in the case of a solid-state image sensor) and the resultant electrical signal is read out.
In some solid-state image sensors, an active pixel sensor (APS) is used in which a driving transistor for amplification is disposed in each image signal generation part that generates an image signal corresponding to a signal charge generated in a charge generation part. This structure is used in many CMOS solid-state image sensors.
In such an active solid-state image sensing apparatus, to read an image signal, unit pixels arranged in a pixel array part are sequentially selected by controlling addressing, and signals are read from the respective unit pixels. That is, the active solid-state image sensing apparatus is a solid-state image sensor of the address control type.
For example, in an active pixel sensor of the X-Y addressing type in which unit pixels are arranged in the form of a matrix array, each pixel is configured to have an amplification capability using an active element having a MOS structure (MOS transistor). In this structure, a signal charge (photoelectrons) accumulated in a photodiode serving as a photoelectric conversion device is amplified by the active element and read out as image information.
In the X-Y addressing solid-state image sensing device of this type, for example, a pixel array part is formed using a large number of pixel transistors arranged in the form of a two-dimensional matrix array. Accumulation of signal charges corresponding to incident light is started on a line-by-line (row-by-row) basis or a pixel-by-pixel basis, and a current or a voltage corresponding to the signal charge accumulated in each pixel is read sequentially from the respective pixels by accessing the pixels by means of addressing.
In solid-state image sensing devices of the MOS type (and of the CMOS type), the addressing is performed, for example, such that pixels are simultaneously accessed on a line-by-line basis and pixel signals are read from the accessed pixels, that is, pixel signals are read on a line-by-line basis from a pixel array part. In some solid-state image sensing devices of this type, to adapt to the reading scheme of accessing the pixel array part on a line-by-line basis and reading pixels signals from the accessed line, analog-to-digital converters and/or other signal processing units are disposed for respective vertical columns. This configuration is called a column parallel arrangement. Of solid-state image sensing devices with a column-parallel arrangement, a solid-state image sensing device in which a CDS processor or a digital converter is disposed in each vertical column such that pixel signals are sequentially read and output is called a column-type solid-state image sensing device.
As a result of reductions in size and cost of solid-state image sensing devices such as CCD or CMOS image sensors, various kinds of video devices using a solid-state image sensing device, such as a digital still camera for taking a still image, a portable telephone with a camera, and a video camera for taking a motion image, have come to be widely used. CMOS image sensors can operate with less consumption power and can be produced at a lower cost than CCD image sensors, and thus CMOS image sensors are expected to be widely used instead of CCD image sensors.
For example, in CMOS image sensors, electrons generated as a result of a photoelectric conversion are accumulated in each pixel, and pixel signals are sequentially read from pixels in pixel columns (vertical columns) specified by address control signals output from a sensor control unit (SCU).
More specifically, an address setting circuit is disposed in a vertical scanning circuit located close to the pixel array part, and an address control signal is supplied from the address setting circuit to sequentially select pixels. In accordance with the address control signal, the vertical scanning circuit supplies various kinds of control signals (generically referred to as control signals) to the respective pixels via driving buffers thereby turning on/off the pixel transistor at the specified horizontal address position. Thus, the address decoder generates data indicating the address of a pixel to be selected.
The solid-state image sensing device of the X-Y addressing type is capable of reading a signal from an arbitrary pixel at a specified address, that is, the solid-state image sensing device of this type has a random access capability. Unlike the CCD (Charge Coupled Device) image sensor that reads signal charges from pixels while sequentially selecting pixels using a shift register, the solid-state image sensing device of the X-Y addressing type is capable of arbitrarily setting the order in which to read signals from pixels.
When pixel signals are read from all pixels, the address setting circuit may be formed using counter circuits (hereinafter, also referred to as address counters). In this case, a vertical address counter and a horizontal address counter are sequentially incremented by "1" to scan all pixels. However, in some cases, it is not necessary to output pixel signals from all pixels.
For example, in the technique of taking a still image using a digital still camera or the like, it is known to use a CMOS-type solid-state image sensing device with a great number of pixels to obtain a high-resolution still image. In an "all-pixel read mode", which is a mode to obtain a high-resolution still image, pixel information is read independently from all pixels. However, when there are a great number of pixels, if pixel information is read from all pixels, it is difficult to achieve a sufficiently high frame rate in displaying a motion image on a monitor screen.
To avoid the above problem, it is known to provide other modes in addition to the "all-pixel read mode". More specifically, in a "decimation read mode", pixel information is read while skipping a particular number of rows or columns. In an "addition read mode", a particular number of rows or columns (pixels are not necessarily adjacent) are selected, and the sum of pixel information is output. In these modes, as a result of decimation or addition, the number of output pixels is reduced, and thus it is possible to increase the frame rate.
The decimation read mode is used to display an image with low resolution (corresponding to the number of a liquid crystal monitor) of a subject on the liquid crystal monitor to check the image of the subject. The decimation read mode is also used when a data size of a motion image is reduced by decimating pixel information, and the resultant motion image data is transmitted. The addition read mode is used not only to increase the frame rate by reducing the number of pixels of an output image but also to expand the dynamic range by adding pixel signals of a plurality of rows (for example, two rows).
In CCD-type image sensors, it is also possible to provide the decimation read mode or the addition read mode. However, because of its structure, the CCD-type image sensor can only read signal charges from pixels while sequentially selecting pixels using a shift register. Therefore, pixel information is first read from all pixels, and then the pixel information is decimated or added by an external signal processing circuit. In contrast, in X-Y addressing image sensors, decimation and addition of image information can be performed on an image sensing part, and an external signal processing circuit for this purpose is not necessary.
To freely select an order in which to read pixel information from pixels, a particular control mechanism to specify addresses is necessary depending on each mode.
For example, to decimate image information by a factor of 2 in both vertical and horizontal directions, the address counter is increased in steps of 2. That is, it is needed to change the steps in which to increase the address counter, depending on the mode.
Typically, address values are represented using a binary code or a Gray code.
When address values are represented in binary code, it is possible to easily realize a circuit for adding an address value with an arbitrary value, and thus it is possible to easily change the steps in which to increase the address value.
However, it is known that noise is generated when the data value inverts, and the noise can propagate via a power supply line or space. That is, the address counter can be a source of noise, whose state randomly changes because the number of inverting bits in data (hereinafter referred to as the number of toggled bits) changes randomly. If noise is generated in a constant state, it may be possible to deal with the generated noise. However, when the number of toggled bits randomly changes, it is difficult to deal with noise.
When the value changed from "0" to "1", only one bit is toggled. This is the smallest case in terms of the number of toggled bits. On the other hand, when a carry occurs from a lowest-order bit to a highest-order bit, all bits are toggled. This is the greatest case in terms of the number of toggled bits.
Because power source noise of the address counter varies depending on the randomly varying number of toggled bits as described above, the power source noise has a bad influence on an image.
FIGS. 23 and 24 show examples of relationships among accessed pixels, the address value, and the number of toggled bits for a case in which the binary code or the Gary code is used. More specifically, FIG. 23 shows an example of a manner in which the address value is increased in steps of 3, and FIG. 24 shows an example of a manner in which the address value is increased in steps of 5.
In both examples shown in FIGS. 23 and 24, the number of toggled bits of the binary code changes in a great range of 2 to 4.
One technique of reducing the number of toggled bits is to use Gray code. In the Gray code, when the address value is increased in steps of 1, a change occurs only in one bit. That is, the Gray code provides the least number of toggled bits and thus provides least noise.
However, even when the Gray code is used to express the address value, if the address value is increased in steps other than "1" as in the examples shown in FIGS. 23 and 24, the number of toggled bits also varies in a range of 1 to 3.
Another problem with the Gray code is that, unlike the binary code, it is difficult to realize a simple circuit capable of increasing the address value in various specified steps, but a complicated circuit is needed. The complexity of the circuit causes an increase in noise.
As described above, in the technique of increasing the address value using the counter based on the binary code or the Gray code, it is difficult to perform addressing in various modes needed, for example, in decimation while maintaining the change in the number of toggled bits within a small range which would make it easy to handle a problem associated with noise arising from the change in the number of toggled bits.
The above-described problem can occur not only in systems using an image sensing device but also in semiconductor systems using a semiconductor device such as a semiconductor memory in which the manner of addressing in the reading operation is allowed to be changed to a certain extent.
In view of the above, it is an object of the present invention to provide a technique of switching the manner of addressing as required depending on the reading mode, while maintaining the change in the number of toggled bits within a small range without needing a complicated circuit for addressing.

Method of controlling read address, physical information acquisition apparatus, and semiconductor device

Abstract: A ring shift register sets a low-order address value depending on a value in steps of which an overall address value is incremented, and a Gray code counter sets a high-order address value. In the ring shift register, a carry from the lowest-order bit to the highest-order bit does not occur, and thus use of the ring shift register makes it possible to reduce the maximum number of toggled bits. The Gray code counter does not need to include a complicated circuit for switching the value in steps of which to increment the high-order address value. Thus, an overall address setting unit can be configured in a simple form without needing any complicated circuit such that addressing can be performed while maintaining the number of toggled bits within a small range and thus random noise generated in the addressing operation can be minimized.