A shampoo composition having at least one detersive surfactant, a suspending particulate agent, and a cationic deposition polymer, wherein at least about 5% by weight of the cationic deposition polymer is adsorbed on the suspended particulate agent is described.

This invention relates to washing compositions. More particularly the invention relates to washing compositions which contain a cationic polymer and a suspended particulate agent, and which provide enhanced deposition and delivery of the suspended particulate agent. Such washing compositions include compositions for washing hair or skin, such as hair shampoos and conditioners, body shampoos, shower gels, facial washing compositions and bath foams.
Difficulties arise in achieving effective deposition of suspended particulate agents, such as conditioning agents, onto a surface such as skin or hair when the agent is delivered by means of incorporation into rinse-off compositions, typically hair and body shampoos, conditioners and the like. Frequently, such suspended particulate agents are preferentially rinsed away from the intended site of deposition, rather than being deposited thereat.
Cationic deposition polymers are known to enhance deposition of certain components from shampoos and other personal cleansing compositions. For example, U.S. Pat. Nos. 5,037,818 and 5,085,857 describe the use of cationic guar gum to enhance the deposition of particulate antimicrobials and insoluble silicone respectively. Deposition polymers have also been proposed to enhance the deposition of sunscreen materials from a shampoo composition. In EP 386 898 a cationic polygalactomannan gum derivative is used. WO 95/22311 describes the use of certain cationic polyacrylamide polymers to increase the deposition of conditioning agents which include silicones, fats and oils, waxes, hydrocarbons, fatty acids and fatty alcohols, lipids, vitamins and sunscreens. WO97/48378 is directed to a process for preparing liquid personal cleansing compositions which provide enhanced deposition of a volatile perfume. The process involves forming a premix comprised of a cationic polymer, a volatile perfume and water, and then adding the premix to a personal cleansing base composition containing an anionic surfactant. In this process, it is believed that the volatile perfume becomes physically entrapped within coacervates or ion-pairs formed between the cationic polymer and the anionic surfactant present in the composition.
A problem associated with cationic polymer aided deposition of materials is that although the cationic polymers are effective deposition aids for a wide variety of materials (as can be seen from the art above), they tend to be indiscriminate in what they deposit. It is thought that this indiscriminacy is due to the physical entrapment mechanism postulated in WO97/48378. This reduces the efficiency of deposition of the ingredients it is desired to deposit (e.g. conditioning agents such as silicone) and can also lead to dulling of the hair through excessive build-up.
The present inventors have found that this problem can be solved by preadsorbing the cationic polymer onto the particular suspended particulate agent which it is desired to deposit. Surprisingly, the adsorbates so formed are stable towards the presence of surfactant.
The present invention provides a washing composition comprising, in an aqueous carrier:
a) at least one detersive surfactant selected from the group consisting of anionic surfactants, amphoteric surfactants which have been altered to have a negative charge, and mixtures thereof, and
b) a suspended particulate agent having a cationic deposition polymer adsorbed thereon;
in which the proportion of cationic polymer adsorbed to the suspended particulate agent is at least 5% by weight based on the total weight of cationic polymer present in the composition.
In a second aspect, the present invention provides a process for preparing a washing composition as defined above, which process comprises the steps of;
(i) adsorbing the cationic deposition polymer onto the suspended particulate agent, and
(ii) blending the adsorbate so obtained with a base washing composition comprising, in an aqueous carrier, the at least one detersive surfactant as described above.
The washing compositions of the invention contain at least one detersive surfactant selected from the group consisting of anionic surfactants, amphoteric surfactants which have been altered to have a negative charge, and mixtures thereof.
Anionic Surfactant
Suitable anionic surfactants for washing compositions of the invention include the alkyl sulphates, alkyl ether sulphates, alkaryl sulphonates, alkanoyl isethionates, alkyl succinates, alkyl sulphosuccinates, N-alkoyl sarcosinates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alpha-olefin sulphonates and acyl methyl taurates, especially their sodium, magnesium ammonium and mono-, di- and triethanolamine salts. The alkyl and acyl groups generally contain from 8 to 18 carbon atoms and may be unsaturated. The alkyl ether sulphates, alkyl ether phosphates and alkyl ether carboxylates may contain from one to 10 ethylene oxide or propylene oxide units per molecule, and preferably contain 2 to 3 ethylene oxide units per molecule.
Examples of suitable anionics include sodium lauryl sulphate, sodium lauryl ether sulphate, ammonium lauryl sulphosuccinate, ammonium lauryl sulphate, ammonium lauryl ether sulphate, sodium dodecylbenzene sulphonate, triethanolamine dodecylbenzene sulphonate, sodium cocoyl isethionate, sodium lauroyl isethionate, and sodium N-lauryl sarcosinate.
Amphoteric Surfactant
An amphoteric surfactant which has been altered to have a negative charge can be used in the washing composition of the invention instead of the anionic surfactant or in combination with the anionic surfactant. The charge of the amohoteric surfactant can be altered by conventional means, for example, by adjusting the pH of a surfactant solution containing the amphoteric surfactant.
Amohoteric surfactants suitable for use in compositions of the invention may include alkyl amine oxides, alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines (sultaines), alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkylamphoglycinates and alkyl amidopropyl hydroxysultaines. Examples include lauryl amine oxide, cocodimethyl sulphopropyl betaine and preferably lauryl betaine, cocamidopropyl betaine and sodium cocamphopropionate.
The level of anionic or negatively-charged amphoteric surfactant in washing compositions of the invention is generally from 3 to 50%, preferably from 3 to 30%, more preferably from 5% to 20% by weight of the total composition. The anionic or negatively charged amphoteric surfactant may be used in combination with other natural or synthetic co-surfactants. The optional co-surfactant is typically selected from the group consisting of: nonionic surfactants, amphoteric surfactants, cationic surfactants and mixtures thereof.
Further surfactant may also be present as emulsifier for emulsified components of the washing composition, e.g. emulsified particles of silicone. This may be the same surfactant as the detersive surfactant, or may be different.
Suitable emulsifying surfactants are well known in the art and include anionic and nonionic surfactants. Examples of anionic surfactants used as emulsifiers for materials such as silicone particles are alkylarylsulphonates, e.g., sodium dodecylbenzene sulphonate, alkyl sulphates e.g., sodium lauryl sulphate, alkyl ether sulphates, e.g., sodium lauryl ether sulphate nEO, where n is from 1 to 20 alkylphenol ether sulphates, e.g., octylphenol ether sulphate nEO where n is from 1 to 20, and sulphosuccinates, e.g., sodium dioctylsulphosuccinate.
Examples of nonionic surfactants used as emulsifiers for materials such as silicone particles are alkylphenol ethoxylates, e.g., nonylphenol ethoxylate nEO, where n is from 1 to 50, alcohol ethoxylates, e.g., lauryl alcohol nEO, where n is from 1 to 50, ester ethoxylates, e.g., polyoxyethylene monostearate where the number of oxyethylene units is from 1 to 30.
The total level of surfactant in washing compositions of the invention is generally from 3 to 50%, preferably from 5 to 30%, more preferably from 10% to 25% by weight of the total composition.
The suspended particulate agent may suitably be selected from one or more of the following classes of material:
Conditioning Agents
As used herein, the term xe2x80x9cconditioning agentxe2x80x9d includes any material which is used to give a particular conditioning benefit to hair and/or skin. For example, in washing compositions for use on the skin such as body shampoos materials such as moisturisers, essential oils, sun-protective or after-sun treatment materials, occlusive oils and the like may be used. In washing compositions for use on the hair, such as hair shampoos and conditioners, suitable materials are those which deliver one or more benefits relating to shine, softness, combability, wet-handling, anti-static properties, protection against damage, body, volume, stylability and manageability.
Preferred conditioning agents for use in the present invention include emulsified silicones, used to impart for example wet and dry conditioning benefits to hair such as softness, smooth feel and ease of combability.
Various methods of making emulsions of particles of silicones for use in the invention are available and are well known and documented in the art.
The viscosity of the silicone itself (not the emulsion or the final washing composition) preferably ranges from 10,000 cps to 5 million cps. The viscosity can be measured by means of a glass capillary viscometer as set out further in Dow Corning Corporate Test Method CTMO04 Jul. 20, 1970.
Suitable silicones include polydiorganosiloxanes, in particular polydimethylsiloxanes which have the CTFA designation dimethicone. An example is dimethicone fluid having a viscosity of up to 100,000 centistokes at 25xc2x0 C., which is available commercially from the General Electric Company as the Viscasil series and from Dow Corning as the DC 200 series.
Aminofunctional silicones which have the CTFA designation amodimethicone, are also suitable for use in the compositions of the invention, as are polydimethyl siloxanes having hydroxyl end groups, which have the CTFA designation dimethiconol.
Also suitable are silicone gums. xe2x80x9cSilicone gumxe2x80x9d denotes polydiorganosiloxanes having a molecular weight of from 200,000 to 1,000,000 and specific examples include dimethicone gums, dimethiconol gums, polydimethyl siloxane/diphenyl/methylvinylsiloxane copolymers, polydimethylsiloxane/methylvinylsiloxane copolymers and mixtures thereof. Examples include those materials described in U.S. Pat. No. 4,152,416 (Spitzer), and on General Electric Silicone Rubber product Data Sheet SE 30, SE 33, SE 54 and SE 76.
Also suitable for use in the present invention are silicone gums having a slight degree of cross-linking, as are described for example in WO 96/31188. These materials can impart body, volume and stylability to hair, as well as good wet and dry conditioning.
Preferred emulsified silicones for use in washing compositions of the invention have an average silicone particle size in the washing composition of less than 30 microns. Particle size may be measured by means of a laser light scattering technique, using a 2600D Particle Sizer from Malvern Instruments.
The average particle size of the silicone material in the washing composition may for example range from 2 to 30 microns, preferably from 2 to 20 microns, more preferably 3 to 10 microns.
Alternatively the silicone material may be present in the washing composition in the form of emulsified particles of small size, for example less than 2 microns. Reducing the particle size may under some circumstances improve conditioning performance.
Silicone emulsions having an average silicone particle size of xe2x89xa60.15 microns are generally termed microemulsions. Typically such microemulsified particles will have a particle size of xe2x89xa60.15 microns, suitably from 0.01 to 0.15 microns. These may be advantageous since they enable the formulation of washing compositions of high stability and excellent optical properties such as translucent or transparent formulations.
Suitable silicone emulsions for use in the invention are commercially available in a pre-emulsified form. This is particularly preferred since the pre-formed emulsion can be incorporated into the washing composition by simple mixing.
Typically, a pre-formed emulsion will contain around 50% of silicone. Pre-formed emulsions are available from suppliers of silicone oils such as Dow Corning, General Electric, Union Carbide, Wacker Chemie, Shin Etsu, Toshiba, Toyo Beauty Co, and Toray Silicone Co. Examples of larger particle size silicone emulsions (around 3 to 20 micron average particle size in the emulsion ) are the material sold as DC-1310 by Dow Corning, and the materials sold as X-52-1086, X-52-2127 and X-52-2112 by Shin-Etsu.
Examples of suitable pre-formed emulsions of smaller particle size (less than about 2 micron average particle size in the emulsion) include emulsions DC2-1766, DC2-1784, and microemulsions DC2-1865 and DC2-1870, all available from Dow Corning. These are all emulsions/microemulsions of dimethiconol. Cross-linked silicone gums are also available in a pre-emulsified form, which is advantageous for ease of formulation. A preferred example is the material available from Dow Corning as DC X2-1787, which is an emulsion of cross-linked dimethiconol gum. A further preferred example is the material available from Dow Corning as DC X2-1391, which is a microemulsion of cross-linked dimethiconol gum.
The amount of silicone incorporated into the washing compositions of the invention depends on the level of conditioning desired and the material used. A preferred amount is from 0.01 to about 10% by weight of the total composition although these limits are not absolute. The lower limit is determined by the minimum level to achieve conditioning and the upper limit by the maximum level to avoid making the hair and/or skin unacceptably greasy. We have found that an amount of silicone of from 0.5 to 1.5% by weight of the total composition, is a particularly suitable level.
When the silicone is incorporated as a pre-formed emulsion as described above, the exact quantity of emulsion will of course depend on the concentration of the emulsion, and should be selected to give the desired quantity of insoluble, non-volatile silicone in the final composition.
A further preferred class of conditioning agents are per-alk(en)yl hydrocarbon materials, used to enhance the body, volume and stylability of hair.
EP 567 326 and EP 498 119 describe suitable peralk(en)yl hydrocarbon materials for imparting stylability and enhanced body to hair. Preferred materials are polyisobutylene materials available from Presperse, Inc. under the PERMETHYL trade name.
The amount of per-alk(en)yl hydrocarbon material incorporated into the washing compositions of the invention depends on the level of body and volume enhancement desired and the specific material used. A preferred amount is from 0.01 to about 10% by weight of the total composition although these limits are not absolute. The lower limit is determined by the minimum level to achieve the body and volume enhancing effect and the upper limit by the maximum level to avoid making the hair unacceptably stiff. We have found that an amount of per-alk(en)yl hydrocarbon material of from 0.5 to 2% by weight of the total composition is a particularly suitable level.
Solid Active Agents
Examples of typical solid active agents include antimicrobials such as the heavy metal salts of pyridinethione, especially zinc pyridinethione, other antimicrobials such as climbazole, piroctone olamine, selenium sulphide and ketoconazole. These substances typically have an average particle diameter of from about 0.2 to about 50 microns, preferably from about 0.4 to about 10 microns.
Where the solid active agent is an antimicrobial agent, such as zinc pyridinethione, this may be suitably be employed in the composition in an amount of from 0.001% to about 1% by weight of the total composition.
Other suitable solid active agents include pigment particles, such as solid dyes or colorants suitable for application to hair, and metal colloids.
Aesthetic Agents
Hair treatment compositions such as shampoos and conditioners are frequently opacified or pearlised to enhance consumer appeal.
Examples of opacifying agents include higher fatty alcohols (e.g. cetyl, stearyl, arachidyl and behenyl), solid esters (e.g. cetyl palmitate, glyceryl laurate, stearamide MEA-stearate), high molecular weight fatty amides and alkanolamides and various fatty acid derivatives such as propylene glycol and polyethylene glycol esters. Inorganic materials used to opacify hair treatment compositions include magnesium aluminium silicate, zinc oxide, and titanium dioxide.
Pearlescing agents typically form thin, platelet-type crystals in the composition, which act like tiny mirrors. This gives the pearl lustre effect. Some of the opacifying agents listed above may also crystallise as pearlescing agents, depending on the media in which they are used and the conditions employed.
Typical pearlescing agents may be selected from C16-C22 fatty acids (e.g. stearic acid, myristic acid, oleic acid and behenic acid), esters of C16-C22 fatty acid with alcohols and esters of C16-C22 fatty acid incorporating such elements as alkylene glycol units. Suitable alkylene glycol units may include ethylene glycol and propylene glycol. However, higher alkylene chain length glycols may be employed. Suitable higher alkylene chain length glycols include polyethylene glycol and polypropylene glycol.
Examples are polyethylene glycol mono or diesters of C16-C22 fatty acids having from 1 to 7 ethylene oxide units, and ethylene glycol esters of C16-C22 fatty acids. Preferred esters include polyethylene glycol distearates and ethylene glycol distearates. Examples of a polyethylene glycol distearate available commercially are EUPERLAN PK900 (ex Henkel) or GENAPOL TS (ex Hoechst). An example of an ethylene glycol distearate is EUPERLAN PK3000 (ex Henkel).
Other pearlescing agents include alkanolamides of fatty acids having from 16 to 22 carbon atoms, (e.g. stearic monoethanolamide, stearic diethanolamide, stearic monoisopropanolamide and stearic monoethanolamide stearate); long chain esters of long chain fatty acids (e.g. stearyl stearate, cetyl palmitate); glyceryl esters (e.g. glyceryl distearate),long chain esters of long chain alkanolamides (e.g. stearamide DEA distearate, stearamide MEA stearate), and alkyl (C18-C22) dimethyl amine oxides (e.g. stearyl dimethyl amine oxide).
Further suitable pearlescing agents include inorganic materials such as nacreous pigments based on the natural mineral mica. An example is titanium dioxide coated mica. Particles of this material may vary in size from 2 to 150 microns in diameter. In general, smaller particles give rise to a pearly appearance, whereas particles having a larger average diameter will result in a glittery composition.
Suitable titanium dioxide coated mica particles are those sold under the trade names TIMIRON (Merck) or FLAMENCO (Mearl).
The level of opacifying or pearlescing agent employed in compositions of the invention is generally from 0.01 to 20%, preferably 0.01 to 5%, more preferably from 0.02 to 2% by weight of the total composition.
By xe2x80x9cdeposition polymerxe2x80x9d is meant an agent which enhances deposition of the conditioning agent from the washing composition of the invention onto the intended site during use, i.e. the hair and/or the scalp.
The deposition polymer may be a homopolymer or be formed from two or more types of monomers. The molecular weight of the polymer will generally be between 5,000 and 10,000,000, typically at least 10,000 and preferably in the range 100,000 to about 2,000,000. The polymers will have cationic nitrogen containing groups such as quaternary ammonium or protonated amino groups, or a mixture thereof.
The cationic nitrogen-containing group will generally be present as a substituent on a fraction of the total monomer units of the deposition polymer. Thus when the polymer is not a homopolymer it can contain spacer non-cationic monomer units. Such polymers are described in the CTFA Cosmetic Ingredient Directory, 3rd edition. The ratio of the cationic to non-cationic monomer units is selected to give a polymer having a cationic charge density in the required range.
Suitable cationic deposition polymers include, for example, copolymers of vinyl monomers having cationic amine or quaternary ammonium functionalities with water soluble spacer monomers such as (meth)acrylamide, alkyl and dialkyl (meth)acrylamides, alkyl (meth)acrylate, vinyl caprolactone and vinyl pyrrolidine. The alkyl and dialkyl substituted monomers preferably have C1-C7 alkyl groups, more preferably C1-3 alkyl groups. Other suitable spacers include vinyl esters, vinyl alcohol, maleic anhydride, propylene glycol and ethylene glycol.
The cationic amines can be primary, secondary or tertiary amines, depending upon the particular species and the pH of the composition. In general secondary and tertiary amines, especially tertiary, are preferred.
Amine substituted vinyl monomers and amines can be polymerized in the amine form and then converted to ammonium by quaternization.
The cationic deposition polymers can comprise mixtures of monomer units derived from amine- and/or quaternary ammonium-substituted monomer and/or compatible spacer monomers.
Suitable cationic deposition polymers include, for example:
copolymers of 1-vinyl-2-pyrrolidine and 1-vinyl-3-methyl-imidazolium salt (e.g. chloride salt), referred to in the industry by the Cosmetic, Toiletry, and Fragrance Association, (CTFA) as Polyquaternium-16. This material is commercially available from BASF Wyandotte Corp. (Parsippany, N.J. USA) under the LUVIQUAT tradename (e.g. LUVIQUAT FC 370);
copolymers of 1-vinyl-2-pyrrolidine and dimethylaminoethyl methacrylate, referred to in the industry (CTFA) as Polyquaternium-11. This material is available commercially from Gaf Corporation (Wayne, N.J. USA) under the GAFQUAT tradename (e.g., GAFQUAT 755N);
cationic diallyl quaternary ammonium-containing polymers including, for example, dimethyldiallyammonium chloride homopolymer and copolymers of acrylamide and dimethyldiallylammonium chloride, referred to in the industry (CTFA) as Polyquaternium 6 and Polyquaternium 7, respectively;
mineral acid salts of amino-alkyl esters of homo-and co-polymers of unsaturated carboxylic acids having from 3 to 5 carbon atoms, (as described in U.S. Pat. No. 4,009,256);
cationic polyacrylamides(as described in WO95/22311). Other cationic deposition polymers that can be used include cationic polysaccharide polymers, such as cationic cellulose derivatives, cationic starch derivatives, and cationic guar gum derivatives.
Cationic polysaccharide polymers suitable for use in compositions of the invention include those of the formula:
Axe2x80x94Oxe2x80x94[Rxe2x80x94N+(R1)(R2) (R3)Xxe2x88x92],
wherein: A is an anhydroglucose residual group, such as a starch or cellulose anhydroglucose residual. R is an alkylene, oxyalkylene, polyoxyalkylene, or hydroxyalkylene group, or combination thereof. R1, R2 and R3 independently represent alkyl, aryl, alkylaryl, arylalkyl, alkoxyalkyl, or alkoxyaryl groups, each group containing up to about 18 carbon atoms. The total number of carbon atoms for each cationic moiety (i.e., the sum of carbon atoms in R1, R2 and R3) is preferably about 20 or less, and X is an anionic counterion.
Cationic cellulose is available from Amerchol Corp. (Edison, N.J. USA) in their Polymer JR (trade mark) and LR (trade mark) series of polymers, as salts of hydroxyethyl cellulose reacted with trimethyl ammonium substituted epoxide, referred to in the industry (CTFA) as Polyquaternium 10. Another type of cationic cellulose includes the polymeric quaternary ammonium salts of hydroxyethyl cellulose reacted with lauryl dimethyl ammonium-substituted epoxide, referred to in the industry (CTFA) as Polyquaternium 24. These materials are available from Amerchol Corp. (Edison, N.J. USA) under the tradename Polymer LM-200.
Other suitable cationic polysaccharide polymers include quaternary nitrogen-containing cellulose ethers (e.g. as described in U.S. Pat. No. 3,962,418), and copolymers of etherified cellulose and starch (e.g. as described in U.S. Pat. No. 3,958,581).
A particularly suitable type of cationic polysaccharide polymer that can be used is a cationic guar gum derivative, such as guar hydroxypropyltrimonium chloride (Commercially available from Rhone-Poulenc in their JAGUAR trademark series).
Examples are JAGUAR C13S, which has a low degree of substitution of the cationic groups and high viscosity. JAGUAR C15, having a moderate degree of substitution and a low viscosity, JAGUAR C17(high degree of substitution, high viscosity), JAGUAR C16, which is a hydroxypropylated cationic guar derivative containing a low level of substituent groups as well as cationic quaternary ammonium groups, and JAGUAR 162 which is a high transparency, medium viscosity guar having a low degree of substitution.
Preferably the cationic deposition polymer is selected from cationic cellulose and cationic guar derivatives.
Particularly preferred deposition polymers are JAGUAR C13S, JAGUAR C15, JAGUAR C17 and JAGUAR C16 and JAGUAR C162.
The Adsorbate
Key to the present invention is the adsorption of the cationic deposition polymer to the suspended particulate agent. The inventors have found that adsorbates can be formed which are surprisingly stable towards the addition of surfactant and which can facilitate preferential deposition of the suspended particulate agent from the washing composition when it is diluted during use.
One convenient way of preparing the adsorbate of cationic deposition polymer and suspended particulate agent is by:
(i) preparing an aqueous solution of the cationic deposition polymer;
(ii) adding the suspended particulate agent to the resulting solution;
(iii) adjusting the pH of the solution so that the cationic deposition polymer becomes at or near to its isoelectric point, mixing and then readjusting the pH of the mixture so as to recharge the cationic deposition polymer.
By the phrase xe2x80x9cnear its isoelectric pointxe2x80x9d it is generally meant that the cationic polymer is within 1 to 1.5 pH units of its isoelectric point. The isoelectric point will depend on the particular cationic polymer used.
When recharged after step (iii) described above, the cationic charge density of the cationic deposition polymer, which is defined as the moles of cationic charge per gram of polymer, should typically be at least 0.1 meq/g, preferably above 0.8 or higher. The cationic charge density should typically not exceed 4 meq/g. It is preferably less than 3 and more preferably less than 2 meq/g. The charge density can be measured using conductimetric analysis.
For example, a preferred cationic deposition polymer is JAGUAR C13S which will typically have a cationic charge density when recharged of about 0.8meq/g.
Following the method as described above for the material JAGUAR C13S, we have found that particularly durable adsorbates can be formed with silicone droplets as the suspended particulate agent, by:
(i) preparing an aqueous solution (suitably about 1wt %) or the JAGUAR C13S at pH above 8, (preferably about 9);
(ii) adding the silicone droplets;
(iii) adjusting the mixture to pH 4-7, (preferably about 6), mixing for about 20 minutes, and then readjusting the pH of the mixture to above 8, (preferably about 9).
The total amount of cationic deposition polymer in the washing composition generally ranges from 0.005 to 2%, preferably from 0.01 to 1.0%, optimally from 0.03 to 0.8% by weight of the total composition.
By xe2x80x9ctotal amountxe2x80x9d is meant that which is adsorbed to the suspended particulate agent and in addition any free cationic deposition polymer, if this is present.
By xe2x80x9cfree cationic deposition polymerxe2x80x9d is meant cationic deposition polymer which is not adsorbed to the suspended particulate agent in the washing composition.
In washing compositions according to the invention, it is required that the proportion of cationic polymer adsorbed to the suspended particulate agent is at least 5% by weight based on the total weight of cationic polymer present in the composition. Preferably this proportion is at least 30%, more preferably at least 40% and optimally at least 50%.
The washing compositions of the present invention contain an aqueous carrier. The carrier of the composition of the invention is predominantly water, but non-aqueous solvents also can be used in order to help solubilise ingredients that are not sufficiently soluble in water. Suitable non-aqueous solvents include the lower alcohols like ethyl alcohol and propyl alcohol; polyols like glycerol; glycols or glycol ethers, like 2-butoxyethanol, ethylene glycol, ethylene glycol monoethyl ether, propylene glycol and diethylene glycol monoethyl ether or monomethyl ether and mixtures thereof.
The total level of water in the final washing composition ranges in general from 20% to 99%, preferably from 40 to 90%, more preferably from 60% to 90%, ideally from 70% to 90%, by weight of the total composition.
Depending on the type of composition employed, one or more additional ingredients conventionally incorporated into personal care formulations may be included in the compositions of the invention. Such additional ingredients include opacifiers such as polyethylene glycol distearate and ethylene glycol stearates, polymer lazices, additional antimicrobial agents such as ZnPTO and Octopirox, foam boosters, perfumes, colouring agents, preservatives, viscosity modifiers, proteins, polymers, buffering or pH adjusting agents, moisturising agents, herb or other plant extracts and other natural ingredients.
Each of these ingredients will be present in an amount effective to accomplish its purpose. Generally these optional ingredients are included individually at a level of up to about 5% by weight of the total composition.
Preferably, compositions of this invention intended for hair treatment also contain adjuvants suitable for hair care. Generally such ingredients are included individually at a level of up to 2%, preferably up to 1%, by weight of the total composition.
Among suitable hair care adjuvants, are:
(i) natural hair root nutrients, such as amino acids and sugars. Examples of suitable amino acids include arginine, cysteine, glutamine, glutamic acid, isoleucine, leucine, methionine, serine and valine, and/or precursors and derivatives thereof. The amino acids may be added singly, in mixtures, or in the form of peptides, e.g. di- and tripeptides. The amino acids may also be added in the form of a protein hydrolysate, such as a keratin or collagen hydrolysate. Suitable sugars are glucose, dextrose and fructose. These may be added singly or in the form of, e.g. fruit extracts. A particularly preferred combination of natural hair root nutrients for inclusion in compositions of the invention is isoleucine and glucose. A particularly preferred amino acid nutrient is arginine.
(ii) hair fibre benefit agents. Examples are: ceramides, for moisturising the fibre and maintaining cuticle integrity. Ceramides are available by extraction from natural sources, or as synthetic ceramides and pseudoceramides. A preferred ceramide is Ceramide II, ex Quest. Mixtures of ceramides may also be suitable, such as Ceramides LS, ex Laboratoires Serobiologiques.
Fatty acids, for cuticle repair and damage prevention. Examples are branched chain fatty acids such as 18-methyleicosanoic acid and other homologues of this series, straight chain fatty acids such as stearic, myristic and palmitic acids, and unsaturated fatty acids such as oleic acid, linoleic acid, linolenic acid and arachidonic acid. A preferred fatty acid is oleic acid. The fatty acids may be added singly, as mixtures, or in the form of blends derived from extracts of, e.g. lanolin.
Mixtures of any of the above active ingredients may also be used.
The washing compositions of the invention may take any suitable form appropriate to the suspended particulate agent which they contain and are intended to deposit. By suitable selection of essential and non-essential ingredients and relative amounts thereof, the washing compositions of the invention may be in the form of, for example, hair shampoos and conditioners and other rinse-off hair treatment compositions, body shampoos, shower gels, facial washing compositions, bath foams and the like.
Preferred compositions in the form of body or hair shampoos may be applied to the skin or hair, as appropriate, and worked to create a lather. The lather may be retained at the applied site for a short time, e.g. one or several minutes, before rinsing, or may be immediately rinsed. The procedure may be repeated if desired.
Retention of the lather at the site of application and repetition of the application regime may be of additional benefit in enhancing even further the amount or rate of deposition of the suspended particulate agent on the skin or hair surface, and/or its delivery to the hair follicle.


A combustion gas furnace includes a plurality of primary heat exchangers for passage of combustion gases therethrough. A plurality of secondary heat exchangers receive the combustion gases from the primary heat exchanger. Each of the secondary heat exchangers includes a heat conductive element defining a plurality of elongate passageways for the flow of combustion gas therethrough. The passageways include aligned ports at either end thereof. The passageways are generally aligned and separated by longitudinal walls extending between the ends. The walls are positioned for heat conductive contact with the combustion gases flowing through passageways.

Heat exchangers are commonly used in gas fired hot air furnaces in both residential and commercial settings. Heat exchangers are generally divided into two types. The first includes tubular heat exchangers where a tube is formed in a serpentine configuration and hot combustion gases are allowed to propagate through the tube. The second type of heat exchanger includes a compact design which may have a clam shell construction.
In typical use in a furnace, a series of heat exchangers are provided in which hot combustion gases pass through the exchangers transferring heat to the surfaces of the heat exchanger. Forced air passed externally over the heated surfaces of heat exchangers is warmed and circulated into a room which is to be heated. The efficiency of the heat exchanger is dictated by the effectiveness of the transfer of heat from the hot combustion gases within a heat exchanger to the external surfaces of the heat exchanger itself.
Also, many furnaces employ secondary heat exchangers which are used to extract added heat from the combustion gas exiting the primary heat exchangers.
As may be appreciated, it is desirable to increase the heat transfer between the combustion gases and the walls of the primary and secondary heat exchangers.
One such example is shown in U.S. Pat. No. 6,938,688 which employs a clam shell design for primary heat exchangers where turbulent flow of the combustion gases is caused. This results in more efficient heat transfer.
However, as may be appreciated, such techniques may increase the size of the heat exchanger. Thus, additionally employing such a design for secondary heat exchangers would increase both the size and cost of the furnace.
It is, therefore, desirable to provide an increase in the heat transfer surface area of a heat exchanger that is exposed to the combustion gases without increasing the external size of the heat exchanger itself.


Apparatus is disclosed for an improved hydraulic piston and cylinder design wherein grooves in the piston surface create a dashpot effect at the respective ends of piston stroke and assist hydraulic oil porting into the cylinder for improved response during stroke reversal, where the piston at least partially covers the cylinder oil flow port.

The present invention is related in some respects to the invention disclosed in my U.S. patent application No. 659,127, filed Feb. 18, 1976, now U.S. Pat. No. 4,086,844 and entitled "Hydraulic Cylinder Utilizing Corrugated Running Surfaces." Reference also is made to my U.S. Pat. No. 4,072,434, issued Jan. 24, 1977, and entitled "Hydraulic Cylinder With Concentrically Maintained Piston and Rod," as it applies to pistons "bottomed" at either terminal end of the cylinder stroke.
Aside from advantages previously described in application of a corrugated running surface on the circumference of hydraulic cylinder pistons in general, it is of particular importance here that the cross-sectional profile of the surface show a unique combination of three characteristics:
(a) Little, if any reduction of total piston bearing surface. While the corrugated surface valleys result in a unit area bearing surface reduction of approximately 20%, a greater total circumferential piston surface is made available in the preferred surface-seal embodiment of the present invention over that of typical piston circumferential bearing surfaces. PA1 (b) A substantial sub-surface hydro-dynamic fluid flow capability that approaches full port flow requirements in the terminal piston positions. PA1 (c) A surface interruption so minimal as to still provide adequate anti-extrusion support for elastomeric or relatively soft piston-bore seals in circumferential grooves adjacent to or intermediately located in the corrugated piston surface. PA1 (a) a general reduction in cylinder costs through base end plate and cylinder head simplification by elimination of porting dashpot consideration in these components; PA1 (b) a much wider range of "standard" base end plate-piston-head applications in short, medium and long length cylinders; PA1 (c) a substantial reduction of cylinder "dead length;" PA1 (d) a more universal use of simple "side wall" porting; and PA1 (e) greatly expanded potential use and improved performance of typical side wall cushions at the stroke terminal ends and elimination of the need for secondary "out of cushion" circuits, in such cushions or stroke dampening designs; the latter elimination becoming even more of an advantage by incorporation of a "single directional sealing piston ring" as explained herein, but which is not integral to the present invention. PA1 (a) typical dashpot functions are of relatively short time-length consideration, relevant only to the ends of cylinder strokes, and intended simply to prevent piston-port orifice flow interference, in the terminal piston positions; PA1 (b) hydraulic cylinder pistons generally are of somewhat greater length or thickness than the combined axial length of their typical two port orifice diameters; this provides the possibility of complete piston-side-wall port orifice overlap at both ends of the cylinder with enough residual axial piston length to accommodate a single, centrally located, double acting, elastomeric seal member, the combined axial length of the two port diameters representing the approximate minimum potential length savings; PA1 (c) while common cylinder case ovality, local portcase weld distortion and high cylinder side loadings, etc., would drastically affect the already severely restricted flow of the proposed piston covered orifice, absent the inventive surface, these have little effect on average circumferential clearance between the piston bearing surface and the cylinder bore; PA1 (d) there is a "conveniently" close relationship between the cross sectional area, hydro-dynamic flow potential of average piston-bore clearances and their associated port flow requirements in the terminal piston position; it is also conveniently true that the larger the cylinder bore, the larger the port orifices and the greater the piston bore clearances which the inventive surface greatly supplements in added fluid flow capacity. PA1 (1) Basic single seal, the seal located in a piston circumferential groove relatively central to the two piston faces and flanked on one or both sides by the corrugated surface configuration. PA1 (2) Universal or multiple seal, a variation of the basic in which the central seal must be elastomeric and is supplemented by a metallic seal in a groove near either or both piston faces, with the corrugated surface configuration located intermediate the seals, on one or both sides of the central seal. PA1 (1) can accommodate the cylinder porting dashpot purposes at either or both cylinder ends within the axial length of the piston circumference; PA1 (2) allows the same surface configuration to satisfy all performance requirements of a cylinder cushion at either or both cylinder ends; PA1 (3) allows both dashpot and cushion functions to be simultaneously accomplished within the same piston surface configuration; and PA1 (4) results in either or both dashpot and cushion functions accomplishment in a simpler more economical form and in less cylinder axial length than any prior art design of equal bearing span.
The design significance of this unique combination of characteristics is that it affords the opportunity to eliminate the typical, axial length wasting, cylinder port dashpot provisions at both cylinder stroke ends, thereby to accommodate their fluid flow purposes tangent to and within the axial length of the piston itself, by utilizing the hydro-dynamic flow capability of normal piston-bore clearances as supplemented by the corrugated surface applied to the piston circumference, in conjunction with a basic sidewall cylinder porting approach.
The prior art term "dashpot" as herein used means "protected area adjacent to a cylinder port orifice, whose purpose is to provide an open fluid flow path between a port orifice and its associated piston pressure face when the piston is in a terminal or stroke end position." The typical "dashpot" results from prevention of piston surface interference with the port orifice by means of counterbores, step diameter hubs, piston stroke stops, etc. This is in direct contrast to application of the present inventive surface of the piston circumference whereby the piston bearing surface is deliberately allowed to contact, cover, or overlap side wall port orifices at either terminal end of the cylinder stroke, with the following advantages:
Hydraulic cylinders typically have two "dashpotted" ports to affect cylinder extension and retraction. These ports are located at the approximate terminal ends of the cylinder or piston strokes. Each port alternately affects a fluid input orifice for energizing one stroke direction and acts as an exhaust orifice for fluid being expelled by the piston in the opposite stroke direction. It then follows that the "base end" port affects cylinder extension and retraction exhaust, with the "rod end" port affecting cylinder retraction and extension exhaust. Base end porting has been affected through the base end plate in countless variations, which have limited application in space critical instances. In any case, base end plate porting involves a more complex end plate configuration than the simple circular disc end plate adequate for use with the invention. This is particularly true if the end plate also houses a "plunger" type base end hydraulic cushion and/or a secondary "out of cushion" full velocity circuit, which is unnecessary with the invention. Most generally, base end porting has been affected simply by welding a port or port tube over an orifice in the cylinder case. This orifice is located immediately forward from the cylinder internal face of the base end plate, and thereby utilizes a typical axial length wasting dashpot area created by a typical, projecting, piston retaining nut on the base end plate side of the piston; the nut projection prevents piston-orifice overlap, since the nut thickness is normally, approximately the same thickness as the port orifice diameter. For space conservation purposes, a nut recessing counterbore has at times been provided in the base end plate, with porting then accomplished through the end plate. While this may allow the piston itself to bottom against the end plate, as a space savings, it also results in loss of space through a thicker than otherwise required end plate, with more material, weight and end plate complexity over that required by the present invention. In other instances, the piston retaining nut has been recessed by a counterbore into the "backside" of the piston. Welded and threaded piston-rod unions have been used that eliminate the piston nut and its recessing counterbores, and in which the piston can also either bottom or approximate that position. The invention described in my U.S. Pat. No. 4,072,434 is one of these. In many cases, where the piston approximates contact with the base end plate, either end plate porting is used or the piston diameter may be machined back as a reduced diameter hub (dashpot) for a sufficient distance to prevent the piston surface or piston seal contact with a sidewall port orifice, but this obviously reduces both potential piston bearing area and overall cylinder bearing span and makes pointless the nut counterbore. Another choice has been to retain full piston bearing length in conjunction with a positive, centrally located, soft piston seal and to deliberately piston surface block a sidewall port orifice in the terminal piston position, while ignoring its flow performance effect. The basic difference between this concept and the present invention is that, absent the inventive piston surface, performance is unacceptable as a universal design approach and should be restricted to known low performance instances primarily because of excessive heat generation and slow initial reverse stroke response, until the piston moves clear of the orifice.
Rod end porting has also had many variations. Typical cylinders have a removable end cap that is in some manner attached to the cylinder case. The end cap provides a sliding bearing journal for rod support in stroke reciprocation, houses seals to prevent outboard fluid leakage between the rod and its journal, contains outside diameter (O.D.) seals to prevent fluid leakage through the capcase junction, and incorporates some means to retain the end cap to the cylinder case. Historically this end cap has been called a cylinder "gland" or "head gland," perhaps because in many instances retract cycle hydraulic fluid has been fed into the cylinder directly through this member, thereby also creating a more complex head because of the internal porting and flow patterns required. At times this has also involved a dashpot counterbore in the piston contact face of the head or gland; this obviously reduces otherwise available rod journal bearing area. Another approach has been to port through the case in a head-case overlapped dashpot area formed by a reduced diameter hub of the head. This has limited application in that it limits the available length to accommodate a case-head seal and to retain the head-case union; this is especially critical if internal case threads are used to retain the head. Such threads obviously consuming more axial length than a lighter duty snap ring which is limited to relatively low hydraulic system pressure ranges. Another approach has been to create a dashpot in the rod side of the piston circumferential surface, by affecting a reduced diameter hub of a length approximately the axial length of the rod end port orifice diameter. This generally does not critically limit piston bearing area in relatively short cylinders and has no effect on overall cylinder bearing span. In medium to long length cylinders, some form of piston stop, stop tubes, etc. are generally used to further axially separate the head and piston bearing surfaces, thereby maintaining a reasonable bearing span to extended length relationships for adequate minimum bearing loads. The stop tubes also provide a "natural," otherwise wasted, potential dashpot length that can be utilized by the retract port orifice without affecting head or piston configurations. No claim is made here that the present invention eliminates stop tubes or the need of increased bearing span in medium to long stroke cylinders, but its incorporation into the piston bearing surface accomplishes an adequate dashpot function within the piston bearing surface itself while full length piston-cylinder bore bearing contact is accomplished. Porting and dashpot provisions therefore have no part in base end plate or head end cap design consideration; these components are then reduced to simpler basic forms and minimum possible "dead length" or "no stroke" combinations. The piston, therefore, with its greater possible bearing length and relatively full flow surface is capable of application over a much wider range of stroke length situations in "standard " piston forms and fewer stop tube required instances. A greater range of standards application, in itself, represents great overall cost savings.
While the corrugated surface, applied to the piston circumference, can eliminate otherwise-provided dashpot areas, its incorporation for that purpose is also a result of some directly associated observations:
For purposes of describing the present invention the term "sidewall cushioning" is intended to mean: a method of cylinder stroke velocity deceleration accomplished by by the piston O.D. surface being allowed to cover-restrict its fluid exhausting sidewall port orifice at and near the terminal end of the stroke. It two primary advantages over "plunger" type cushion forms, are in conservation of cylinder axial length and potential elimination of secondary "out of cushion" circuits typically required, since its purpose is accomplished by mere piston-port orifice overlap, as with the aforementioned inventive piston surface dashpot. Its normal piston seal configuration also includes a single bi-directional resilient sealing member in a piston circumferential groove located central to the piston O.D. surface or far enough inboard from the leading piston edge to prevent its extrusion into the port orifice, at the terminal piston position. The differentiation here between general dashpot and specific sidewall cushion purposes may be fine line, dependent on the extent of piston-orifice overlap length and more particularly on the exclusion or inclusion of a fluid metering piston ring, as described below. The effect of the corrugated surface in this is to greatly increase piston blocked orifice fluid flow, to the advantage of both dashpot and cushion purposes. For more positive sidewall cushion results, the central piston seal is often supplemented by a "non-extrudable," overlap jointed metallic ring in a piston circumferential groove near the leading edge of the piston; the ring becoming the primary orifice flow closing medium. The metallic ring has more positive fluid metering characteristics than the piston surface itself, allowing a more controlled stroke deceleration by better control of by-passing cushion area fluid flow to the exhausting orifice being blocked. The term "fluid metering" ring, used above, refers to the characteristic fluid by-pass of common available metallic rings, here adequate to the desired fluid metering cushion flow effect, not to any special fluid metering types. While a cylinder cushion's primary function of stroke velocity deceleration is accomplished by exhaust flow restriction, this is also a process of heat generation, more effectively dissipated by the sidewall type, over that of the plunger, simply by its greater total cooling surface exposure, and here aided by the inventive surface valleys. A secondary, but critical, requirement of cylinder cushions, of either type, is that stroke deceleration be accompanied by a reasonably instant "out of cushion" full, reverse stroke velocity, in which the "plunger" virtually requires a secondary "starter circuit" a space and cost consuming, typical check valve arrangement incorporated into either or both the base end plate or the cylinder head. While the previously described fluid metering ring obviously also retards reverse stroke velocity, the corrugated surface performs as an intermediately located dashpot and assures a greater volume of instant reverse or free fluid to the circumferential inner face of the metallic ring; the combination providing adequate reverse stroke velocity under many circumstances that otherwise would have required secondary circuits for adequate requirements. Maximum "in and out" of cushion performance can be realized without resort to secondary circuits and within the described piston configuration, by simple substitution of the previously described metallic piston ring for a "single directional sealing ring," also in conjunction with a corrugated piston surface. The single sealing ring performs in conventional manner in one piston direction and permits virtual free fluid flow in the opposite direction, as a one directional flow metering check valve, but is not part of the present invention.
In summary of the foregoing discussion, there are two general corrugated piston surface preferred embodiment forms to accomplish the dashpot cushion purposes:
No claims are made here on the individual seals involved or in their combinations, but rather in their compatible combinations with the corrugated surface for the space saving and fluid flow improvements within the piston circumferential surface, for cylinder porting dashpot and cushion purposes.
It is of unique cylinder design significance that the present invention:
The herein accomplished objective of the corrugated surface has been to affect a piston surface configuration adequate to cylinder dashpot, cushion flow requirements, without significant reduction of cylinder bearing or antiextrusion support for intermediately located piston seals. The emphasis here is utilizing the hydro-dynamic fluid flow capabilities of the corrugated surface rather than the surface hydro-static advantages of the prior art.
While the basic angled, parallel valley, corrugated surface will greatly improve fluid flow between the blocked port orifice and the piston surface, in any case, the full here described "circumferential-cross flow" effect is realized simply by adding one or more auxiliary piston circumferential grooves intermediate or adjacent the surface pattern, as part of the pattern. The auxiliary grooves are spaced so as to accomplish and maintain "double ended" intersection with the port orifice during the terminal, piston-orifice blocking portion of the stroke. The "grooves" here perform as "collector rings" circumferentially joining the corrugated surface valleys, thereby affecting a more positive piston circumferential flow union between the "blocked" port orifice and the pressure face of the piston, regardless of and in addition to piston-bore clearances, and in addition to the lesser flow "joining" effect provided by the adjacent seal ring grooves themselves. It is preferred that any added auxiliary grooves be of rectangular cross section-relatively narrow and deep, so as to cause minimum reduction of piston bearing surface. Considering the double flow ends of the groove affected by intersection with the port orifice, total flow groove end exposure should equal or exceed the cross sectional area of the corrugated surface valleys. For example:
A 6" diameter corrugated piston surface of typical parallel "V" shaped valleys with the "V" shaped valleys spaced at preferred 12 to 14 per piston circumferential inch, and approximately 0.015 deep, the total valley cross sectional area roughly equals 0.035 in..sup.2.
This is approximately equal to a single, port orifice intersecting, auxiliary groove 1/16" wide.times.5/16" deep. The resulting blocked orifice piston circumferential crossflow is approximately 30 gallons per minute (GPM) at 1,000 pounds per square inch (psi), or half normal system pressure, which is adequate for normal dashpot-cushion requirements even if no actual piston bore or piston orifice clearance existed.
As a rule of thumb, the prescribed corrugated surface valleys create an added piston surface cross flow capability roughly equivalent to 50% of average piston-bore clearances or to an equivalent 3/32" diameter orifice per inch of piston diameter. If desired or as required, this flow can be circumferentially joined and orifice intersected by a single auxiliary groove of 1/2 the surface valley total cross sectional area, since such intersection doubles the auxiliary or collector groove flow exposure. Correspondingly, the corrugated surface cross flow of a 12" bore cylinder piston can be circumferentially joined and orifice intersected by a single 1/16" wide.times.5/8" deep groove. Ignoring all positive variable piston bore clearances, seal ring groove collections and local orifice area diffusion flow, the resultant circumferential cross flow of the "surface" alone should be adequate to any dashpot-cushion flow requirements. Beyond suggested variation, no attempt is made here to include or define auxiliary circumferential flow grooves. The purpose has been to illustrate that in conjunction with previously prescribed combinations of piston-bore seals, the present corrugated surface invention offers a unique basic means to a positive "fluid flow" system between a piston blocked sidewall port orifice and the pressure face of the piston, by way of a simple, expanded circumferential-cross flow in the parent piston bearing surface itself, regardless of orifice overlapped length and local piston-orifice, and piston-bore clearances. This is not to say that clearance variations will not vary flow, only that adequate hydro-dynamic flow capability is assured in the overlapped piston-port orifice position by incorporation of the invention surface. Whatever resulting flow restriction, from overlap, is of short time duration and any resultant heat generation is effectively dissipated over the "flute cooled" piston circumference, rather than concentrated at the piston-orifice junction. In this regard, when using the "surface" for piston dashpot purposes, if severe full stroke cycling might be experienced and particularly if the more positive fluid restrictive sidewall cushioning is to be used. . . it is advantageous to select a piston material with high heat conduction properties, such as aluminum. Aluminum is particularly compatible with "the surface," since it also easily accepts application of the surface by a variety of optional high speed rolling or maching processes... and the surface eliminates the objectionable stroke cycling "screech harmonic" tendency commonly associated with sliding journal applications of direct bearing aluminum.

Hydraulic cylinder with improved dashpot and porting


The present invention provides a process for the synthesis of Midazolam I

The present invention relates to a process for the preparation of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (Midazolam) from 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (tricyclic acid).
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazopine (Midazolam), a pre-operative anesthetic, belongs to a class of imidazobenzodiazepine compounds which are useful as anticonvulsants, sedatives, and muscle relaxants.
The last step in the synthesis of Midazolam is thermal decarboxylation of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazopine-3-carboxylic acid (tricyclic acid). Also produced in this step is 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazopine (Isomidazolam) and decomposition biproducts resulting from high temperature dehalogenation and dimerization of tricyclic acid. Removal of the decomposition biproducts and purification of Midazolam and Isomidazolam are accomplished by column chromatography (GB Patent 1,549,836 and U.S. Pat. Nos. 4,280,957, 4,440,685 and 4,377,523), a method which is impractical for large scale preparation of Midazolam because of the costly chromatography equipment required.
Attempts at improving the overall yield of Midazolam have focused on isomerizing purified Isomidazolam to Midazolam by treatment of the former with potassiun tert-butoxide in N,N-dimethylformamide (DMF) under kinetically controlled conditions (U.S. Pat. Nos. 4,377,523 and 4,440,685). This method is also impractical for large scale syntheses of Midazolam because of the amount of thermal energy required for removal of the DMF.
Thus, there is a continuing need in the pharmaceutical manufacturing industry for a large scale conversion of tricyclic acid to Midazolam which minimizes Isomidazolam formation and provides for non-chromatographic removal of biproducts.
The process of the present invention provides a large scale conversion of tricyclic acid to Midazolam which minimizes Isomidazolam formation and provides for non-chromatographic removal of biproducts.
In one embodiment of the present invention is provided a process for the synthesis of a compound of formula I (Midazolam)
or a pharmaceutically acceptable salt or prodrug thereof, comprising:
(a) forming a first reaction medium comprising from about 1 to about 20 parts by
weight of a first solvent system per 1 part by weight of tricyclic acid II,
wherein said tricyclic acid exhibits a first critical solution temperature behavior in said first solvent system;
(b) maintaining said first reaction medium at a second temperature of between about 190xc2x0 C. and about 260xc2x0 C. such that said compound of formula II decarboxylates to substantially form said compound of formula I; and
(c) isolating said compound of formula I from said first solvent system.
In another embodiment of the present invention is disclosed a method of decarboxylating tricyclic acid to form a Midazolam/Isomidazolam product ratio of about 6:1.
In yet another embodiment of the present invention is disclosed a method of converting the Midazolam/Isomidazolam product ratio from about 6:1 to about 50:1 using thermodynamic, basic workup conditions.
In still yet another embodiment of the present invention is disclosed a method of isolating and purifying Midazolam without using column chromatography.
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
Percentages obtained by HPLC analysis are defined by peak area calculations.
As used in the specification and the claims, the following terms have the meanings specified:
The term xe2x80x9calkali metal alkoxide,xe2x80x9d as used herein, refers to Mxe2x80x94OR1, wherein M is a cation selected from the group consisting of lithium, sodium, and potassium, and R1 is an is an alkyl group, as defined herein.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms. Alkyl groups of this invention include methyl, ethyl, n-propyl, iso-propyl, 2-methylpropyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.
The term xe2x80x9cbase,xe2x80x9d as used herein, refers to a species capable of abstracting a proton in either a polar or nonpolar solvent. Examples of bases include alkali metal alkoxides as defined herein, alkali metal hydrides such as lithium, sodium, or potassium hydride, and nitrogen-containing bases such as lithium diisopropyl amide (LDA), lithium, sodium, or potassium bis(trimethylsilyl)amide, and the like. It will be obvious to those skilled in the art that individual base and solvent combinations may be preferred for specific reaction conditions depending upon such factors as the solubility of reagents, reactivity of reagents with Isomidazolam or the solvent, and preferred temperature ranges.
The term xe2x80x9cfirst organic extraction solvent,xe2x80x9d as used herein, refers to a polar solvent, as defined herein.
The term xe2x80x9cfirst solvent system,xe2x80x9d as used herein, refers to a solvent with a boiling range high enough to promote decarboxylation of tricyclic acid, typically between about 190xc2x0 C. and about 260xc2x0 C. First solvent systems of the present invention include. but are not limited to, N,N-dimethylacetamide, phenyl ether, ethylene glycol, propylene glycol, mineral oil, tetrahydronaphthalene, Decalin(trademark) (decahydronaphthalene), and mixtures thereof.
The term xe2x80x9cnonpolar solventxe2x80x9d as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton donor. Examples include, but are not limited to, hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, and isomers thereof, aromatic solvents such as benzene, toluene, and o-, m-, and p-xylenes 5 halogenated hydrocarbons, such as, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether and bis(methoxymethyl) ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick, et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, NY, 1986.
The term xe2x80x9cpharmaceutically acceptable prodrugs,xe2x80x9d as used herein, refers to those prodrugs of Midazolam which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The term xe2x80x9cpolar solvent,xe2x80x9d as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or a solvent polarized due to the presence of an electron withdrawing group, such as acetonitrile or tetrahydrofuran, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Method of Purification. 4th ea., edited by John A. Riddick, et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, New York, 1986.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, refers to compounds which are rapidly transformed in vivo to Midazolam, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-Drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ea., Bioreversible Carriers in Drug Design, American Pharmaceutical Association Press, 1987.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as used herein, refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared in situ during the final isolation of Midazolam, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammoniumn, and tetraethylammonium. Preferred pharmaceutically acceptable salts of Midazolam are hydrochloride and maleate.
The term xe2x80x9csecond organic extraction solvent,xe2x80x9d as used herein, refers to a nonpolar solvent, as defined herein.
The compounds and processes of the present invention will be better understood in connection with Scheme 1 and Example 1, each of which is intended as an illustration of, and not a limitation upon, the scope of the invention as defined in the appended claims.
A preferred embodiment is shown as Scheme 1. Tricyclic acid, in a first solvent system such as mineral oil or N,N-dimethylacetamide, was heated to a temperature of between 160xc2x0 C. and 230xc2x0 C., until it substantially decarboxylated to form Midazolam, Isomidazolam, and biproducts. In an improvement over preexisting syntheses, adjusting the weight ratio of the first solvent system to tricyclic acid from about 4:1 to about 10:1 increased the Midazolam/Isomidazolam product ratio from about 3:1 to about 6:1. After cooling, the crude first reaction medium was treated with a nonpolar solvent, such as heptane, which was miscible with the first solvent system, but in which the crude Midazolam/Isomidazolam mixture is insoluble. In a preferred embodiment, the reaction mixture is extracted with a polar organic solvent, such as methanol, such that the product mixture substantially dissolved into the methanol to form a first extraction medium. The first solvent system, insoluble in the polar solvent, was separated and discarded. For the preferred thermodynamic, basic workup conditions, treatment of the first extraction medium with a strong base, such as potassium tert-butoxide, to form a second reaction medium and heating the resulting second reaction medium to reflux increased the the Midazolam/Isomidazolam product ratio to about 50:1. After cooling, the methanol insoluble Midazolam dimer which precipitated was removed from the reaction mixture by filtration. The second reaction medium was again heated to reflux, treated with water, and cooled to precipitate Midazolam which was of about 98% purity. Two recrystallizations from ethyl acetate/heptane or isopropyl acetate/heptane provided Midazolam of greater than 99.8% purity as determined by HPLC analysis.

Process for the preparation of Midazolam

Abstract: from a compound of formula II,

Abstract: using thermodynamic, basic workup conditions. Additional steps to isolate the pure bulk product follow.


A cutting line intended to trim and cut vegetation which can be used in rotary-head implements such as brush cutters and edge trimmers. The cutting line consists of a core of the monofilament type, which is coated with a granular coating, especially in the form of inorganic particles. The line thus has an uneven and/or rough surface appearance. The composite cutting line of this kind has a lower operating noise, a better cutting effect, and eliminates the problems of sticking and breaking at the eyelet in the rotary head.

The present invention relates to cutting lines intended for trimming and cutting vegetation, which can be used in motorized rotary-head cultivation implements commonly known as brush cutters and edge trimmers.
These implements are generally fitted with a combustion engine or electric motor which rotates, at a high speed which may be between about 3000 revolutions per minute and 12,000 revolutions per minute, a cutting head which carries one or more cutting lines. As the head rotates, and under the effect of centrifugal force, the cutting line or lines splay out radially and thus sweep a certain circular area, within which they have a cutting effect on the vegetation they encounter.
Cutting lines currently manufactured and marketed, intended for such a use, are smooth monofilaments, usually of the xe2x80x9cone-materialxe2x80x9d type, which therefore have the qualities and weaknesses of the raw material used to make them.
The raw material most often used to make cutting lines are synthetic substances, and more particularly polyamide 6, copolyamide 6/66 and copolyamide 6/12. These substances can be very slightly modified or filled to improve their basic characteristics. These substances are always extruded in the form of monofilaments which can have varying diameters and cross sections, in particular a round cross section, but also polygonal or star-shaped profiles. In all instances, and even if they have edges, these monofilaments maintain a smooth surface appearance, that is to say one without roughness.
The cutting lines currently manufactured are therefore good compromises, but their characteristics and performance are still limited by the raw materials used and by the way in which they are manufactured by extrusion, which inevitably leads to a smooth and uniform surface appearance.
The defects and inadequacies of such cutting lines are, in particular, as follows:
While they are being used, these smooth cutting lines generate a great deal of turbulence in the air, and this causes a great deal of unpleasant noise heard as a strong whistling which adds to the noise of the engine or motor driving the rotary head. These noises cause sound pollution which is all the more troublesome since, by their very nature, brush cutters and edge trimmers are used out of doors. Moreover, legislatory stipulations aimed at limiting the noise of these implements to an acceptable level are being written.
The cutting effect of the current cutting lines is due only to the shock induced on the vegetation by their rotation at high speed. This effect may be inadequate, depending on the type of vegetation encountered.
Another drawback is the phenomenon of sticking. Some powerful implements considerably stress the cutting line inside their rotary head, on account of the vibrations and tension in the line due to the rotation of said head at a very high speed, which may be as much as 12,000 revolutions per minute. This causes a significant rise in temperature to very close to the melting point of conventional smooth cutting lines (from 200 to 222xc2x0 C.), and this rise in temperature may go so far as to cause the turns of line wound on the reel housed in the rotary head to stick.
Another phenomenon observed is xe2x80x9cbreaking off at the eyeletxe2x80x9d: an overly stressed conventional smooth cutting line will end up breaking off at the eyelet via which the line emerges from the rotary head. What happens is that following repeated flexural mechanical loadings, the line heats up where it emerges from the eyelet in the head. The progressive rise in temperature of the line causes it to become greatly distended at this point which rapidly becomes a point of weakness, causing the start of a crack in the line; the smooth line then breaks.
Finally, conventional cutting lines made of polyamide are practically nonbiodegradable after use, and the amount of fragmented or worn away cutting line strewn across the entire earth each year is estimated at 10,000 tonnes. A certain amount of European environmental protection arrangements are aimed at limiting the pollution caused from the breakage, wearing away or fragmentation of synthetic monofilaments during their use, but current filaments are not yet able to meet these legislatory requirements.
The object of the present invention is to eliminate all of the drawbacks explained earlier, by providing an improved cutting line which, in particular, gives reduction in noise disturbance and an improved cutting effect, and eliminates the problems of sticking and breaking off at the eyelet, while favoring degradability.
To this end, the invention provides a cutting line for brush cutters and edge trimmers, the essential feature of which is that it consists of a core of the monofilament type which is coated with a granular coating giving the cutting line an uneven and/or rough surface appearance.
Thus, the invention proposes a cutting line which can be described as a xe2x80x9ccomposite filamentxe2x80x9d, combining a core and a coating, itself composed of one or more ingredients.
The core of this cutting filament can be made, in particular, of an extruded and then drawn synthetic sub-stance, such as polyamide, in the same way as conventional monofilaments which have long proved themselves in this field. This core gives the cutting line the desired characteristics of flexibility and tenacity, which result from its chemical composition, its dimensions and its method of manufacture. The core may have various pro-files; this core may thus have a round cross section, which is the simplest shape, but it may also have a star-shaped or jagged profile, which has the advantage of increasing the area onto which the granular coating can be stuck, and of improving the sticking of this coating to the core. The same results are also obtained, in an alternative form, by providing shapings, such as markings, which are repeated in the direction of the length of the cutting line, on the core.
As regards the granular coating fixed to the core and covering it entirely, this may consist of inorganic, plant-matter, metal or synthetic particles, in each instance giving the final product an uneven and/or rough surface appearance. Inorganic particles, such as particles of silica, glass, fine sand, emery, marble, etc. are more particularly advantageous, in order to increase the abrasive power of the cutting line, and its thermal qualities. The nature and particle size of the particles forming the coating allow the weaknesses of conventional smooth cutting lines to be overcome, in various aspects:
First of all, the surface roughness of the cutting line gives better fluidity of rotation of the line in the air, the roughness on the line breaking up significant turbulence created by a conventional smooth cutting line. The result of this is, on the one hand, a steep drop in the amount of sound generated by the rotation of the line through the air; thus trials carried out by the applicant have recorded, for equal line diameter and equal speed, noise reductions of 8 to 12 decibels depending on the particle size of the coating and, therefore, on the amount of unevenness at the surface of the line. Eliminating the turbulence also, on the other hand, yields a not insignificant reduction in the power needed to keep the line rotating at a given speed; trials carried out by the applicant have thus allowed a saving of 3 to 7% to be measured, for equal line diameters, on the energy consumption needed to keep the cutting line rotating.
Thanks to the roughness of its coating, the cutting line which is the subject of the present invention also creates, as it is used, a xe2x80x9csawxe2x80x9d effect which adds to the cutting effect due to the shock produced by the high-speed rotation of this line, and the combination of this abrasive effect with the shock effect significantly improves the cutting capability of the line. The abrasive power of the cutting line is increased to a greater or lesser extent depending on the nature and particle size of the coating. Inorganic particles such as particles of silica, glass, sand, emery, marble, etc. are particularly advantageous in this respect but attractive results can also be obtained with metal particles such as particles of zinc, of iron, of aluminum, especially in the form of powdered oxides of an appropriate particle size. It is also possible to use, from which to make the coating, particles of synthetic substances chosen from those which have excellent abrasion behavior, such as powdered polyamide 11 and elastomers. The use of a coating made of a synthetic substance also seems advantageous in reducing the noise and increasing the life of the cutting line, the elasticity of such a coating offering a first wearing layer before the core of the filament is attacked. A combination of two or more of the previously-mentioned substances, in the form of particles, may be envisaged.
The nature of the coating, and the granular surface appearance of the cutting line according to the invention also allow the problem of the turns sticking inside the rotary head to be eliminated entirely. In particular, certain particles such as particles of silica or glass are recommended for this because the temperatures reached inside the head, although high, can get nowhere near the point at which these particles stick or melt. Furthermore, the granular surface appearance considerably increases the area for heat exchange and therefore encourages cooling of the cutting line. A combination of these two effects allows the phenomenon of sticking in the rotating head to be eliminated entirely.
The granular surface appearance of the cutting line according to the invention also considerably increases the area for heat exchange where the line emerges from the rotary head, and this also results in an appreciable reduction, or even complete elimination of the phenomenon of breaking off at the eyelet.
Finally, for a cutting line of given diameter and given mass, the design that is the subject of the invention makes it possible to reduce the amount of polyamide, limiting it to just the core of the filament, which core may be of a small diameter, and to choose for the coating natural materials or materials which are in themselves readily degradable or alternatively materials whose presence may accelerate the degradation of the xe2x80x9ccore+coatingxe2x80x9d assembly by restricting the chemical stability of this complex. Thus, the composite cutting line that is the subject of the invention plays a part in protecting the environment.
Furthermore, it will be noted that such a cutting line can be obtained industrially in a rational and economical way, it being possible for the granular coating to be applied around the core by a coextrusion, coating or dipping process employed continuously. In particular, the method of obtaining the cutting line may consist in coating a continuously-traveling core filament with an adhesive agent, then dusting it with the particles intended to form the granular coating, then finally baking it to fix this coating definitively to the core filament.

Composite cutting line for brush cutters and edge trimmers