WO2012025624A1 - Procédés pour produire des matériaux de silice microporeux - Google Patents

Procédés pour produire des matériaux de silice microporeux Download PDF

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WO2012025624A1
WO2012025624A1 PCT/EP2011/064755 EP2011064755W WO2012025624A1 WO 2012025624 A1 WO2012025624 A1 WO 2012025624A1 EP 2011064755 W EP2011064755 W EP 2011064755W WO 2012025624 A1 WO2012025624 A1 WO 2012025624A1
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range
surfactant
aqueous solution
silica
process according
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PCT/EP2011/064755
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English (en)
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Johan Martens
Guy Van Den Mooter
Alexander Aerts
Jasper Jammaer
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Formac Pharmaceuticals N.V.
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Publication of WO2012025624A1 publication Critical patent/WO2012025624A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B37/00—Compounds having molecular sieve properties but not having base-exchange properties
    • C01B37/02—Crystalline silica-polymorphs, e.g. silicalites dealuminated aluminosilicate zeolites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • the present invention relates to processes for producing amorphous microporous silica materials by using a triblock copolymer that forms no micelles, to the amorphous microporous silica materials thus prepared and their applications.
  • Porous silica materials have been the subject of intense research, which has resulted in a host of applications. They still are and continue to be the subject of further research efforts that are expected to result in new materials and uses. Porous silica materials are divided into three classes: microporous materials having pore diameters of less than 2 nm, mesoporous materials with pore diameters between 2 nm and 50 nm, and macroporous materials with pore diameters of greater than 50 nm.
  • Zeolites are well-known examples of microporous materials that have found use in a wide range of applications.
  • zeolites are used in the separation and adsorption of ionic species and small molecules, including gases.
  • Synthetic zeolites are widely used as heterogeneous catalysts in the petrochemical industry, for instance in catalytic cracking.
  • the acidified forms of zeolites (prepared by ion-exchange) are powerful solid-state acids, and can facilitate acid-catalyzed reactions, such as isomerisation, alkylation, and cracking.
  • Zeolites are used as ion-exchange beds in water purification, softening, and other applications.
  • a major application of zeolites is their use in detergents.
  • Zeolites also find use in biochemical, medical (in particular in medical diagnosis), and pharmaceutical applications (in particular to trap and release drug molecules). Applications in agriculture include soil treatment by absorbing and releasing mineral nutrients and water. Further applications are in components in electronic devices.
  • Zeolites are usually synthesized under hydrothermal conditions, from solutions of sodium aluminate and/or sodium silicate, using a templating ionic or neutral surfactant or polymer.
  • the precise zeolite formed is determined by the reactants and the particular synthesis conditions used, such as temperature, time, and pH.
  • the templating molecule directs the assembly of the aluminate and/or silicate species by forming the aluminosilicate lattice around the templating molecule. Removal of the latter leaves open pores, whose size is determined by the size of the templating molecule.
  • mesoporous materials are finding their way in similar applications, including in drug delivery. These materials are prepared using surfactants or amphiphilic polymers as structure directing agents (also called “templates”) in an assembly of silica precursors followed by removal of the organic components by calcination or solvent extraction.
  • the synthesis temperature is between 35°C and 80°C and the synthesis procedure takes at least 24h from the start of the self-assembling reaction to the filtration step, with the first 20h after silica-precursor addition at 35°C followed by an at least 4 h aging step at elevated temperatures.
  • Known are MCM-41, synthesized under basic conditions with quaternary alkyl ammonium surfactants, and SBA-15, obtained under strongly acidic conditions in the presence of triblock copolymers.
  • WO 2009/133100 discloses ordered mesoporous silica materials synthesized under mildly acidic or neutral pH conditions using a combination of an amphiphilic block copolymer and a buffer with a pH between 2 and 8 with a synthesis time of 24h.
  • microporous silica materials Although various procedures are available to prepare microporous silica materials, there still is a need for alternative processes that allow their manufacture in a fast, effective, and simple manner.
  • An object of the invention is the provision of such process.
  • a further object is the provision of amorphous silica materials prepared by such process and their application in the various areas where microporous materials find use, in particular as delivery systems for biologically active agents, more in particular such agents for use in cosmetic and pharmaceutical products.
  • a further object of this invention is the provision of a much faster process that preferably can be conducted as a continuous production process.
  • the present invention provides such a process that is fast and wherein no ageing step is required, in particular no ageing step at elevated temperatures, in the process step where the assembled silica material is prepared.
  • the process of the invention in addition enables continuous production of the assembled silica materials.
  • the present invention concerns a process for preparing a self- assembled amorphous microporous silica material by first producing a self-assembled silica precursor material by the reaction between an aqueous solution of a silica precursor and an aqueous solution of a surfactant that forms no micelles under the process conditions, followed by removal of the surfactant from the self-assembled silica precursor material, to provide the amorphous microporous silica material.
  • the reaction between the aqueous solution of the silica precursor and the aqueous solution of said surfactant is conducted without an ageing step, in particular without an ageing step at isothermal elevated temperatures, e.g. at 90°C, in a quick reaction.
  • the reaction time may be in the range of 1 to 100 s, or in the range of 1 to 10 s (e.g. less than 10 s), or in the range of 10 to 50 s. Other reaction times can also be used.
  • the surfactant is removed from the self-assembled silica precursor material using methods described herein such as calcination or solvent extraction.
  • Suitable surfactants that form no micelles under the process conditions include the so-called "reverse Pluronic®” surfactants such as Pluronic® 17R4, in particular when used under mildly acidic or neutral pH conditions.
  • the process for producing a self-assembled silica precursor material is conducted under mildly acidic or neutral pH conditions, in particular at a pH that is in the range of 2 to 8.
  • the pH may be brought and kept in the range of 2 to 8 by using a buffer of the same pH.
  • the aqueous solution of the silica precursor may be acidic or respectively basic, while the aqueous solution of a surfactant is basic respectively acidic, wherein the basicity or acidity are selected such that that upon mixture of both solutions a solution with pH 2-8 is obtained.
  • the process is exclusive of an ageing step, in particular of an ageing step at elevated temperatures.
  • the process of the present invention in the first step for preparing a self-assembled silica precursor material is a continuous process conducted such that first a self-assembled amorphous microporous silica precursor material is produced, wherein an elongated mixing receptacle (conduit, tube) receives a first aqueous solution of the surfactant from a first reservoir member and a second aqueous solution of the silica precursor from a second reservoir member and both are fed/delivered to the elongated mixing receptacle and the self-assembled amorphous microporous silica material emerges from the elongated mixing receptacle even after short residence times.
  • an elongated mixing receptacle (conduit, tube) receives a first aqueous solution of the surfactant from a first reservoir member and a second aqueous solution of the silica precursor from a second reservoir member and both are fed/delivered to the elongated mixing re
  • Such short residence times can be realized by adjusting the linear velocity of the reaction mixture in the elongated mixing receptacle.
  • the linear velocity of the reaction mixture may be adjusted by the velocities of the aqueous solution of the surfactant from the first reservoir member and of the second aqueous solution of the silica precursor from the second reservoir member.
  • the linear velocity of the reaction mixture in the elongated mixing receptacle is in the range of 1000 to 3000 m/h.
  • the self-assembled amorphous microporous silica precursor material in this further aspect may be produced under mildly acidic or neutral pH conditions such as the conditions described herein.
  • the short residence times may be in the range of 0.1 to 100 s, or of 1 to 100 s, or of 1 to 10 s, e.g. residence times of less than 10 s.
  • the surfactant is removed from the self-assembled silica precursor material using methods described herein.
  • the present invention also concerns a process for preparing amorphous microporous precursor silica materials by applying the first step of the processes described herein, and further concerns the amorphous microporous precursor silica materials obtained, obtainable, or prepared by such process.
  • the amorphous microporous precursor silica materials of the invention have a substantially uniform pore size.
  • One embodiment of the present invention concerns a process for preparing an amorphous microporous silica material with a substantially uniform pore size, said process comprising in a first step preparing an aqueous solution 1 comprising a silica precursor; preparing an aqueous solution 2 comprising a surfactant and an acid with a pKa in the range of 3 to 9; adding said aqueous solution 1 to said aqueous solution 2, while keeping the pH of the mixture in the range of 2 to 8, allowing the reaction between the components to take place at a temperature in the range of 10 to 100°C, wherein said surfactant is used at a concentration and temperature at which
  • the acid with a pKa in the range of 3 to 9 may be replaced by an acid with a pKa in the range of 2 to 8, or by a buffer with a pH in the range of 2 to 8.
  • the H of the reaction mixture may be kept in the range of 2 to 8 by adding a buffer with a pH in the range of 2 to 8 to aqueous solution 1, or to aqueous solution 2, or to both.
  • the invention concerns a continuous process for preparing an amorphous microporous silica material with a substantially uniform pore size, wherein in a first step said solution 1 and said solution 2 are fed as liquid streams into an elongated mixing receptacle having a first and a second opening such that the liquid streams of solution 1 and solution 2 are each discharged independently into said first opening of said elongated mixing receptacle such that they directly impinge, thereby giving a pH in the resulting mixture in the range of 2 to 8 and producing an amorphous microporous silica precursor material at a temperature in the range of 10 to 100°C in said elongated mixing receptacle, wherein said surfactant is used at a concentration and temperature at which substantially no micelles are formed.
  • the surfactant is removed from the self-assembled silica precursor material using methods described herein.
  • solution 2 in the processes using solutions 1 and 2 does not contain a strong base such as an alkali or alkaline earth hydroxide (e.g. NaOH, KOH), or a tertraalkylammonium hydroxide (e.g. tetrabutylammonium hydroxide).
  • a strong base such as an alkali or alkaline earth hydroxide (e.g. NaOH, KOH), or a tertraalkylammonium hydroxide (e.g. tetrabutylammonium hydroxide).
  • the processes of the invention may include a filtration step after producing the self-assembled silica precursor material to isolate the latter material.
  • the thus obtained material may be further purified by washing, in particular with water, to remove water- soluble ingredients.
  • the washing step may be followed by a drying step.
  • the present invention concerns an amorphous
  • microporous silica material with a substantial uniform pore size obtained or prepared by a process as specified herein.
  • This invention also relates to a drug-loaded amorphous microporous silica material with a substantial uniform pore size, obtained, obtainable, or prepared by a process as specified herein, and a cosmeceutically or pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a cosmeceutical or pharmaceutical composition
  • a cosmeceutical or pharmaceutical composition comprising a drug loaded into an amorphous microporous silica material with a substantial uniform pore size, obtained, obtainable, or prepared by a process as specified herein, and a cosmeceutically or pharmaceutically acceptable carrier.
  • the drug loaded into said amorphous microporous silica material may be present in an effective amount, which amount can readily be determined by the skilled person from patent and scientific literature.
  • Fig. 1A dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 1.
  • Fig. IB desorption isotherm, Alpha-S-plot, for the amorphous microporous silica of Example 1.
  • Fig. 2 dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 2.
  • Fig. 3 dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 3.
  • Fig. 4 particle size distributions of the amorphous microporous silica particles of
  • Example 2 not stirred over the weekend (bimodal size distribution) and of the amorphous silica particles of Example 3 with stirring over the weekend (monomodal size distribution).
  • Fig. 5 Scheme of experimental setup in which A is the aqueous solution A; AT is the tube transporting the aqueous solution A; B is the aqueous solution B; BT is the tube transporting the aqueous solution B; M is the mixing tube; C is the collector; S is the separator; and D is the drier/calcinating oven.
  • Fig. 6A dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 4.
  • Fig. 6B Desorption isotherm, Alpha-S-plot, for the amorphous microporous silica of Example 4.
  • Fig. 7 X-ray diffraction pattern of the microporous silica material of Example 4.
  • Fig. 8 dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 5.
  • Fig. 9 dependence of the quantity of nitrogen adsorbed (cm /g) versus the relative pressure P/Po for the amorphous microporous silica of Example 6.
  • the term "about” when used in relation to a numerical value has the meaning generally known in the relevant art. In certain embodiments the term “about” may be left out or may be interpreted to mean the numerical value +10%; or +5%; or +2%; or +1%.
  • substantially uniform pore size refers to a pore size distribution curve showing the derivative of pore volume (dV) as a function of pore diameter such that at a point in the curve that is half the height thereof, the ratio of the width of the curve (the difference between the maximum pore diameter and the minimum pore diameter at the half height) to the pore diameter at the maximum height of the plot (as hereinabove described) is no greater than 0.75.
  • the pore size distribution of materials prepared by the present invention may be determined by nitrogen adsorption and desorption and producing from the acquired data a plot of the derivative of pore volume as a function of pore diameter.
  • the nitrogen adsorption and desorption data may be obtained by using instruments available in the art, which instruments are also capable of producing a plot of the derivative of pore volume as a function of the pore diameter. In the micropore range, such a plot may be generated by using the slit pore geometry of the Horvath-Kawazoe model, as described in, J. Chem. Eng. Japan, 16(6), (1983), 470.
  • silicon precursor refers to a silicon compound from which microporous silica can be produced in the process of the present invention.
  • the term "self-assembled microporous silica precursor material” refers to the material obtained by assembling the silica precursor with the surfactant.
  • the reaction between the surfactant and silica precursor components is a self-assembling reaction forming a silica- surfactant composite.
  • room temperature refers to a temperature between 12 to 30°C, or between 18 and 28°C, or between 19 and 27°C, or between 20 and 26°C, e.g. about 23°C.
  • the term “low temperature” refers to a temperature between 15 and 40°C, preferably between 18 and 23°C, more preferably between 20 and 30°C and most preferably it is taken to be roughly between 22 and 28 °C.
  • surfactant removal means a process step in which surfactant is removed, such process step including calcination, e.g. by heating to or above 200°C, or to or above 400°C, to or above 500°C; or extraction with a suitable solvent, e.g. with super-critical carbon dioxide or with ethanol.
  • substantially no micelles are formed means that the number of micelles formed does not interfere with the self-assembly reaction. In one embodiment less than 5%, or less than 3%, or less than 2%, or less than 1% of the surfactant forms micelles.
  • aging step means any step in which the product of the reaction of the silica precursor and the surfactant, e.g. when allowing to react solutions 1 and 2, has to be further treated to complete the process of producing an amorphous silica material with a substantially uniform pore size e.g. by holding it under isothermal conditions for a period of time.
  • elongated mixing receptacle refers to any form of receptacle with two openings e.g. a tube, a pipe, a conduit, etc.
  • drug-loaded refers to microporous silica materials on whose surface an active ingredient, in particular a drug has been adsorbed.
  • the surface may be in the pores but may also be at the outer walls of the porous silica material.
  • low solubility applies to active ingredients, in particular to drugs, that are practically insoluble or poorly water-soluble.
  • this term may be applied to any drug that has a dose (mg) to aqueous solubility (mg/ml) ratio greater than 100 ml, where the drug solubility is that of the neutral (for example, free base or free acid) form in unbuffered water.
  • This term is to include, but is not to be limited to, drugs that have essentially no aqueous solubility (such as less than 1.0 mg/mL, or less than 0.1 mg/mL).
  • any solvent solubility is generally defined as the amount of a solvent (g) required to dissolve 1 g of a compound, whereby the following solubility qualifications are defined: 10-30 g ("soluble”); 30-100 g (“sparingly soluble”); 100-1000 g ("slightly soluble”); 1000- 10000 g ("very slightly soluble” or “poorly soluble”) and more than 10000 (practically insoluble).
  • the biologically active species is poorly soluble or practically insoluble in accordance with the definitions known in the art, or in accordance with the definitions in this paragraph.
  • active ingredient or compound, species, or molecule
  • biologically active compound or ingredient, species, or molecule
  • active ingredient or compound, species, or molecule
  • biologically active compound or ingredient, species, or molecule
  • drug refers to those bioactive compounds or molecules that have prophylactic and/or therapeutic properties, when administered to warm-blooded animals, in particular to mammals, including humans.
  • pharmaceutically acceptable refers to an ingredient that is acceptable for use on or in the human or animal body.
  • cosmetically acceptable may also be limited to topical use.
  • cosmetic refers to non-pharmaceutical applications to improve the general well-being of humans and in particular relate to topical applications, such as, for example, in skin and hair care, cleansing, shampooing, and the like.
  • Cosemeutical active ingredients include, for example, emollients, anti-pruritics, antifungals, disinfectants, scabicides, pediculicides, tar products, vitamins and vitamin derivatives, such as vitamin A, B, and C, vitamin A derivatives, vitamin D analogues, keratolytics, abrasives, systemic antibiotics, topical antibiotics, hormones, desloughing agents, exudate absorbents, fibrinolytics, proteolytics, sunscreens, antiperspirants, corticosteroids.
  • These ingredients can be formulated into formulations suitable for topical application such as lotions, creams, gels, sprays, and the like. Depending on the ingredient and its application, they may also be formulated into oral dosage forms such as capsules or tablets.
  • the silica precursor being a silicon compound from which microporous silica can be produced, includes alkali metal silicates such as sodium silicate, silicic acids, and tetraalkyl orthosilicates, e.g. tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS) and tetrapropyl orthosilicate (TPOS).
  • alkali metal silicates such as sodium silicate, silicic acids, and tetraalkyl orthosilicates, e.g. tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS) and tetrapropyl orthosilicate (TPOS).
  • TEOS tetraethyl orthosilicate
  • TMOS tetramethyl orthosilicate
  • TPOS tetrapropyl orthosilicate
  • Sodium silicates may be composed of at least 10% by weight of sodium
  • alkali metal hydroxide and of silicon dioxide in other alkali metal silicates may be calculated based on the ratio of the atomic weights between the metal and sodium.
  • Aqueous alkali metal silicates are basic and can be used in combination with the surfactant in the presence of an acidic component, either an acid or acid buffer.
  • solution 1 may be an alkali metal silicate solution in water.
  • 3 to 9 in solution 2 may be sufficient to produce a pH upon mixing solutions 1 and 2 of greater than 2 and less than 8, without an alkali salt of an acid with a pKa in the range 3 to 9 being necessary.
  • an acid with a pKa in the range of 3 to 9 in solution 2 may be insufficient to produce a pH upon mixing solutions 1 and 2 of greater than 2 and less than 8 without the addition of an alkali salt of an acid with a pKa in the range 3 to 9.
  • the acid in the pKa range 3 to 9 may be present in a buffer with a pH in the range of 3 to 8 upon mixing solutions 1 and 2 or solution 2 may itself contain a buffer.
  • the acid with a pKa range of 3 to 9 is present in a buffer with a pH in the range of 2 to 8, or of 4 to 8, or of 5 to 8, or of 5 to 7, or of 5.5 to 7.
  • the acid in the pKa range 3 to 9 is largely removed during the washing step associated with the filtration step with any acid left being removed in the surfactant removal process.
  • variation in the reaction mixture pH within the ranges of the present invention may be used together with reaction time or reaction temperature to fine tune the pore size of the final microporous silica materials.
  • the pH at which the reaction is conducted is in the range of 2.2 to 7.8, or in the range of 2.4 to 7.6, or in the range of 2.6 to 7.4, or in the range of 2.8 to 7.2.
  • the pH at which the reaction is performed may be in the range of 3 to 7.2, or in the range of 4 to 7, or in the range of 5 to 6.5.
  • the reaction time of the processes of the present invention may be in the range of 1 s to 10 minutes, or in the range of 5 s to 1200 s, or in the range of 5 s to 600 s, or in the range of 1 to 100 s, or in the range of 1 to 10 s, or in particular in the range of 5 to 300 s, or in the range of 10 s to 120 s, or in the range of 20 s to 100 s.
  • a preferred reaction time is 1 to 100 seconds, 1 to 10 s, or 10 to 50 s.
  • the processes of the present invention may be conducted at temperatures that are in the range of about 10 to 100°C, or in the range of about 10 to 50°C, or in the range of about 20 to 50°C, or in the range of about 20 to 30°C, in particular at room temperature.
  • the amorphous microporous silica material with a substantially uniform pore size of the invention may be produced in the absence of microwave radiation, although microwave radiation may be used in loading said amorphous microporous silica material with a bioactive species.
  • substantially uniform pore size is itself produced in the absence of microwave radiation, although microwave radiation may be used in loading said amorphous microporous silica material with a bioactive species.
  • aqueous solution 1 and aqueous solution 2 may be discharged from the first and second reservoir members via pumps or by pressurizing the reservoir members.
  • the reservoir members can also be linked to the elongated mixing receptacle via appropriate linking conduits or tubes. The latter may come together in a T-shaped member, which in turn is connected to the elongated mixing receptacle.
  • the elongated mixing receptacle and, if present, the linking conduits or tubes preferably are cylindrical, the length and width (inner diameter) of which can vary, for example between the process being conducted on laboratory scale and large scale production.
  • the widths of the elongated mixing receptacle and of the linking elongated receptacles can be different, but are selected such that the desired linear velocities are obtained.
  • the length of the elongated mixing receptacle is directly linked to the residence time, and is preferably selected such that the desired residence time is obtained.
  • the linear velocity in the elongated mixing receptacle may be in the range of 10 m/h to 1000 m/h, or greater than 30 m/h, or greater than 100 m/h, or greater than 500 m/h, such as in the range of 30 m/h to 1000 m/h, or 100 m/h to 1000 m/h, or 500 m/h to 1000 m/h, or in particular 1 m/h to 200 m/h, or 5 m/h to 100 m/h, or 10 m/h to 50 m/h, or 10 m/h to 20 m/h.
  • the upper limit of 1000 m/h in these ranges can be higher such as 10,000 m/h, or 5,000 m/h, or 2500 m/h.
  • the residence time in the elongated mixing receptacle is in the range of 1 s to 10 minutes, or in the range of 5 s to 1200 s, or in the range of 5 s to 600 s, or in the range of 1 to 100 s, or in the range of 1 to 10 s, or in particular in the range of 5 to 300 s, or in the range of 10 s to 120 s, or in the range of 20 s to 100 s.
  • a preferred residence time in the elongated mixing receptacle is 1 to 100 seconds, or 1 to 10 s.
  • the temperature in said elongated mixing receptacle may be in the range of about 10 to 100°C, or in the range of about 10 to 50°C, or in the range of about 20 to 50°C, or in the range of about 20 to 30°C, in particular at room temperature.
  • the linear velocity in the continuous process of this invention may also be in the range of 1000 m/h to 3000 m/h.
  • the receptacle is equipped with an in-line mixing device such as a static mixer.
  • the mixture resulting from the liquid streams of solution 1 and solution 2 impinging may be stirred, for example with a stirring speed in the range of 100 to 700 rpm.
  • the liquid streams of aqueous solution 1 and 2 are each discharged independently into said elongated mixing receptacle at a linear velocity greater than 10 m/h, with a linear velocity greater than 30 m/h being preferred, a linear velocity of 100 m/h being particularly preferred and a linear velocity greater than 1000 m/h being especially preferred.
  • liquid streams of aqueous solution A and B are each discharged independently into said elongated mixing receptacle at a linear velocity of less than 10,000 m/h, or less than 5,000 m/h, or less than 2500 m/h .
  • a particular embodiment of the continuous process of the present invention is a process for producing an amorphous microporous silica material with a substantially uniform pore size using a self-assembling method, wherein the liquid streams of aqueous solution 1 and aqueous solution 2 are each discharged independently into the first opening of said elongated mixing receptacle (e.g. conduit or tube) such that they directly impinge giving a pH in the resulting mixture between 2 and 8 and produce a reaction product at a temperature in the range of 10 to 100°C in said elongated mixing receptacle which upon emergence from the second opening is filtered off, dried and the surfactant removed to produce the amorphous microporous silica material with a substantially uniform pore size.
  • said elongated mixing receptacle e.g. conduit or tube
  • the surfactant for use in the process of the present invention is a (polyalkylene oxide)-(polyethylene oxide)-(polyalkylene oxide) triblock copolymer, which can be represented by formula (A) n (B) m( A) n , wherein each A represents polyalkylene oxide and B represents polyethylene oxide and each n is a number between 5 and 200, and m is a number between 5 and 200.
  • A preferably is polypropylene oxide.
  • Each number n preferably is between 5 and 100, or between 5 and 50, or between 5 and 30.
  • the number m preferably is between 5 and 160, or between 5 and 150, or between 5 and 100, between 5 and 100, or between 5 and 50.
  • Such surfactants are often referred to as "reverse Pluronic® surfactants", a number of which are listed in Table 1 below.
  • the alkylene oxide moiety has at least 3 carbon atoms, in particular 3 or 4 carbon atoms, for instance a propylene oxide or butylene oxide moiety.
  • Of interest are those triblock copolymers wherein the number of ethylene oxide moieties is at least 5 and /or wherein the number of alkylene oxide moieties in each block is at least 15.
  • One such triblock copolymer has the formula ( ⁇ ) ⁇ 4 ( ⁇ ) 24 ( ⁇ ) ⁇ 4 , wherein EO stands for ethylene oxide -CH 2 CH 2 0-, and PO stands for propylene oxide
  • copolymers associate in a different manner from poly(ethylene oxide)-poly(alkylene oxide) -poly (ethylene oxide) triblock copolymers.
  • Mortensen et al. in Macromolecules, volume 27(2), pages 5654-5666 (1994) reports that at low concentrations and low temperatures PPO-PEO-PPO copolymers are dissolved as independent macromolecules and that Pluronic® 25R8 forms an interconnected network of micelles at high concentrations. Alexandridis et al.
  • the entropy penalty associated with the looping geometry of the middle block does not preclude the possibility of micelle formation, but largely reduces the tendency toward self-assembly. This compares with poly(ethylene oxide)-poly(alkylene oxide)- poly(ethylene oxide) triblock copolymers such as Pluronic® PI 23 or Pluronic® L64 with the same ethylene content by weight as Pluronic® 17R4, which form micelles over a large temperature range and a broad concentration range.
  • silicates are used as silica precursors, e.g. alkali metal silicates such as sodium silicate
  • the w/w ratio between Si0 2 and the surfactant can be in the range of 50 to 75, or 60 to 70, e.g. about 65.
  • buffer or “buffer solution” refers to an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid.
  • buffer zone means a zone of pH in the range of about 1.5 pH units above and about 1.5 pH units below the pH numerically equal to the pKa of the acid component of the buffer.
  • the pH range of pH 2 to pH 8 is preferably in the pH zone for the acid
  • Suitable acids with a pKa value in the range of 3 to 9 include those listed in Table 3.
  • succinic (-CH 2 COOH) 2 4.16 succinic acid HOOC-CH 2 CH 2 - 5.61 acid COO
  • Buffers that can be used include a mixture of a weak acid and a salt of the weak acid, or a mixture of salts of weak acids. Buffers can be based on polyacids/salts of salts of polyacids that have mutiple pKa' s within the range of 2 to 8 such as citric acid/citrate salt buffers with buffer zones around each pKa, which overlap to cover the whole range between 2.0 and 7.9: 3.14 ⁇ 1,5, 4.77 ⁇ 1.5 and 6.39 ⁇ 1.5 respectively;
  • succinic acid/succinic acid salt buffers with buffer zones round each pKa which overlap to cover the whole range between 2.66 and 7.1: 4.16 ⁇ 1.5 and 5.61 ⁇ 1.5 respectively
  • the buffer with a pH between 2 and 8 is selected from the citrate/citric acid buffers with a pH range of 2.5 to 7.9, acetate/acetic acid buffers with a pH range of 3.2 to 6.2, and hydrogen
  • phosphate/dihydrogen phosphate buffers HP0 4 2- 7H 2 P0 4 " ) buffers with a pH range of 6 to 9.
  • the salts in these buffers originate from strong bases such as alkali metal or tetraalkylammonium salts such as tetrabutylammonium salts, in particular the sodium or potassium salts, e.g. sodium citrate/citric acid buffers, sodium acetate/acetic acid buffers, or Na 2 HP0 4 /NaH 2 P0 4 buffers, or the corresponding potassium salts.
  • buffers having a pH in the range of 5 - 8, or in the range of 5.5 - 7, or in the range of 6 - 7.5, or in the range of 6 - 7.
  • buffers of which the acid component has a PKA equal to these pH ranges, or a buffer zone within these pH ranges can be used.
  • the buffer is selected from a citrate Vmonohydrogen citrate buffer, an acetate/acetic acid buffer, a hydrogen phosphate/dihydrogen phosphate buffers ( ⁇ 0 4 2- 7H 2 P0 4 ⁇ ) buffers with a pH range of 6 to 9.
  • the citrate/citric acid buffers in particular the sodium citrate/citric acid buffers such as the citrate Vmonohydrogen citrate buffer, may have a citrate : citric acid weight ratio, or respectively a sodium citrate : citric acid weight ratio, that is in the range of 0.1: 1 to 3.3: 1, or in the range of 0.5: 1 to 3: 1, in the range of 0.5: 1 to 2: 1 .
  • the surfactant is removed from the self-assembled silica precursor material using methods such as, for example, calcination by a calcination step at inceased temperature, or by solvent extraction with a suitable solvent such as a lower alkanol, in particular ethanol. Calcination can be done at various temperatures such as above 250°C, or above 300°C, or above 400°C, or above 500°C, e.g. at about 350°C.
  • amorphous microporous silica materials of the invention may have a nitrogen adsorption isotherm of type I, in accordance with the definition of IUPAC (See Pure and Applied Chemistry, Vol. 57, No.
  • Type I isotherms are characteristic for microporous solids having relatively small external surfaces.
  • the specific surface areas of the amorphous microporous silica materials of the invention may be in the range of about 300 to about 900 m /g, or in the range of about 400 to about 800 m 2 /g, or in the range of about 500 to about 700 m 2 /g.
  • the Alpha S micropore volume of the microporous silica materials of the invention, determined from the desorption characteristic of the silica powder, may be in the range of about
  • the amorphous microporous silicas may have a mean pore size in the range of about 0.3 to about 1.5 nm, or of about 0.4 to about 1.2 nm, or of about 0.4 to about 1.0 nm.
  • the amorphous microporous silica materials obtained or obtainable by the process of the present invention may be applied in the various areas where microporous materials find use, in particular, they may be used as delivery systems for biologically active agents, more in particular such agents for use in cosmetic and pharmaceutical products.
  • the amorphous microporous silica materials of the present invention can be loaded with biologically active ingredients. These include synthetic molecules, biomolecules, antibodies, and the like.
  • biologically active ingredients have a partition coefficient (XlogP) in the range from 4 to 9, or in the range from 5 to 8, or in the range from 6 to 7.
  • the active ingredient has a molecular weight in the range of about 200 to about 1,000 (daltons), in particular in the range of about 200 to about 800.
  • the biologically active ingredients are poorly water-soluble having a water-solubility below about 1 g/L, or below about 0.1 g/L, or below about 0.1 g/L.
  • the pharmaceutically active ingredients belong to the so- called BCS classes II and IV and microporous silicas of the present invention loaded with Class II and IV drugs may provide better bioavailability.
  • the Biopharmaceutical Classification System (BCS) classifies drug substances based on their aqueous solubility and gastro-intestinal (GI) permeability into four classes:
  • the solubility class boundary is based on the solubility of the highest dose strength in 250 ml or less of an immediate release ("IR") formulation of a drug in aqueous media over a pH range of 1.2 to 7.5 at 37°C.
  • IR immediate release
  • a drug substance has high solubility when the highest dose strength is soluble under these conditions, and has low solubility when this is not the case.
  • a drug is considered highly soluble when 90% or more of an administered dose, based on a mass determination or in comparison to an intravenous reference dose, is dissolved.
  • An immediate release drug product is considered rapidly dissolving when no less than 85% of the drug substance dissolves within 30 minutes in a volume of 900 ml or less in media of varying pH.
  • a drug substance is considered highly permeable when the extent of absorption in humans is determined to be greater than 90% of an administered dose.
  • the permeability class boundary is based, directly, on measurements of the rate of mass transfer across human intestinal membrane, and, indirectly, on the extent of absorption (fraction of dose absorbed, not systemic bioavailability) of a drug substance.
  • a drug substance is considered highly permeable when the extent of absorption in humans is greater than 90% of an administered dose.
  • An IR (immediate release) drug substance is considered to have low permeability when the extent of absorption in humans is determined to be less than 90% of an administered dose.
  • BCS Class II drugs include anti-fungals, such as intraconazole, fluoconazole, terconazole, ketoconazole, griseofulvin, griseoverdin, and the like; anti-infectives such as sulfasalazine; anti malaria drugs (e.g. atovaquone); immune system modulators (e.g. cyclosporin); cardiovascular drugs (e.g. digoxin and spironolactone); and ibuprofen (analgesic); ritonavir, nevirapine, lopinavir (antiviral); clofazinine (leprostatic);
  • anti-fungals such as intraconazole, fluoconazole, terconazole, ketoconazole, griseofulvin, griseoverdin, and the like
  • anti-infectives such as sulfasalazine
  • anti malaria drugs e.g. atovaquone
  • immune system modulators e.g. cyclospor
  • diloxanide furoate anti-amebic
  • glibenclamide anti-diabetes
  • nifedipine antianginal
  • spironolactone diuretic
  • sterols or steroids such as danazol
  • carbamazepine anti-virals
  • antibiotics such as amoxicillin, tetracycline, or
  • metronidazole acid suppressants
  • H2 blockers include cimetidine, ranitidine, famotidine, and nizatidine
  • proton pump inhibitors including omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprozole
  • mucosal defense enhancing agent bismuth salts; bismuth subsalicylate
  • mucolytic agents megaldrate
  • BCS Class IV drugs are acetazolamide, furosemide, tobramycin, cefuroxmine, allopurinol, dapsone, doxycycline, paracetamol, nalidixic acid, clorothiazide, tobramycin, cyclosporin, tacrolimus, and paclitaxel.
  • prostaglandines e.g. prostaglandine E2, prostaglandine F2 and prostaglandine El
  • cytotoxics e.g.
  • paclitaxel doxorubicine, daunorubicine, epirubicine, idarubicine, zorubicine, mitoxantrone, amsacrine, vinblastine, vincristine, vindesine, dactiomycine, bleomycine; metallocenes, e.g. titanium metallocene dichloride; lipid-drug conjugates, e.g.
  • diminazene stearate and diminazene oleate diminazene stearate and diminazene oleate; anti-infectives such as clindamycine;
  • antiparasitic drugs e.g chloroquine, mefloquine, primaquine, vancomycin, vecuronium, pentamidine, metronidazole, nimorazole, tinidazole, atovaquone, buparvaquone, nifurtimoxe; anti-inflammatory drugs, e.g. cyclosporin, methotrexate, azathioprine.
  • the microporous materials prepared in accordance with the present invention can be used to host small antibody fragments.
  • small antibody fragments are Fv" fragments, single-chain Fv (scFv) antibodies, antibody Fab fragments, antibody Fab' fragments, antibody fragments of heavy or light chain CDRs, or anobodies.
  • the amorphous microporous silica materials of the present invention may also host small oligonucleic acid or peptide molecules for instance such that bind a specific target molecule such as aptamers. (DNA aptamers, RNA aptamers, or peptide aptamers).
  • the microporous materials of present invention hosting the small oligonucleic acid or intended to host such can be used for hybridisation of such oligonucleic acids.
  • the amorphous microporous silica materials are loaded with a biologically active ingredient by treatment with a solution of the active ingredient, particularly a solution in an organic solvent, after which the solvent is removed.
  • the biologically active ingredient is mainly loaded into the pores.
  • a solution of the biologically active ingredient is prepared by dissolution in an appropriate solvent in which the bioactive ingredient has sufficient solubility.
  • Sonication can be used to speed up the dissolution process.
  • Appropriate solvents comprise dichloromethane or ethanol, or mixtures thereof such as 50/50 V/V mixtures, 1,4-dioxane, tetrahydrofuran, 2-propanol, diethyl ether, ethyl acetate , chloroform, hexafluoroisopropanol, acetone; polar aprotic solvents such as, acetonitrile, dimethylformamide N-methyl-pyrrolidinone or dimethyl sulfoxide; non-polar solvents such as hexane, benzene, toluene.
  • Solutions holding up to 50 mg of bioactive species solved in 1 ml can be used.
  • amorphous microporous silica materials of the present invention loaded with an active ingredient can be formulated using cosmeceutically or pharmaceutically acceptable carrier materials, into cosmeceutical or pharmaceutical compositions.
  • the latter may be administered to a warm-blooded animal, including a mammal, such as a domestic animal, or in particular to a human patient, in a variety of forms adapted to the chosen route of administration, i.e., oral, peroral, topical, orally, parenteral, rectal, or other delivery routes.
  • the following examples are meant to illustrate the invention and should not be construed as limiting the scope of the invention thereto.
  • Aqueous surfactant solution 1 was prepared by dissolving 1.7715 g Pluronic®
  • Aqueous (silicate precursor) solution 2 was prepared by diluting 8.42 g of sodium silicate solution (extra pure, 7.5 wt% Na 2 0 and 26.5-28.5 wt% Si0 2 from Merck, Germany) with 24.6082 g of deionized water.
  • Example 1 Preparation of amorphous microporous silica
  • the resulting material was characterized by nitrogen adsorption performed on a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 200°C for lOh (ramp: 5°C/min up to 200°C).
  • the nitrogen adsorption isotherm of the calcined material is shown in Figure 1A. This is a typical type I isotherm (IUPAC).
  • the strong adsorption in the low pressure region relates to micropore adsorption.
  • Micropore volumes are generally adduced from alpha S plot, see Figure IB. The intercept on the n axis, by back-extrapolation of the linear multilayer section, gives the micropore capacity [np(mic)] .
  • v p (mic) n p (mic) x M/p
  • M the molar mass of nitrogen
  • p the average absolute density of the adsorbate, generally assumed equal to the density of the liquid nitrogen.
  • the Alpha S micropore volume was determined from the desorption
  • Example 2 Preparation of amorphous microporous silica
  • the nitrogen adsorption characteristic of the calcined powder is shown in Figure 3. This is a typical type I isotherm (IUP AC). The strong adsorption in the low pressure region is due to the micropore adsorption.
  • Example 3 Preparation of amorphous microporous silica
  • the nitrogen adsorption characteristic of the calcined powder is shown in Figure 3 and the particle size distributions of the calcined particles of Example 2 not stirred over the weekend (bimodal size distribution) and of the calcined particles of Example 3 with stirring over the weekend (monomodal size distribution) are shown in Figure 4.
  • Example 4 Preparation of silica material in a continuous process.
  • Soln. 2 is the aqueous solution 2 comprising a poly(alkylene oxide) triblock copolymer
  • Soln. 2 T is the tube transporting the aqueous solution B
  • M is the mixing tube
  • C is the collector
  • S is the separator
  • D is the drier/calcining oven.
  • the two syringes of the perfusion pumps were connected to two transporting tubes each 20 cm long, with a 1.6 mm internal diameter and cylindrical ends and were connected by a Swagelok T-coupling piece under a 90° angle to a 30 cm long mixing tube with an internal diameter of 3.2 mm.
  • the two syringes were filled with aqueous solution 1 and aqueous solution 2 respectively and aqueous solution 1 and aqueous solution 2 were jetted into one another at rates of 99.0 mL/hour (49.2 m/h) and 35.0 mL/hr (18.5 m/h) respectively into the 30 cm long mixing tube realizing a pH of ca. 5.2 in the mixture.
  • the linear velocity through the mixing pipe was 16.6 m/h and the residence time of the mixture of aqueous solution 1 and aqueous solution 2 in the mixing tube was 64.78 s.
  • the pumps started simultaneously. Condensation started upon mixing and the particles were collected at the outlet of the mixing tube in a polypropylene beaker. Within 15 minutes, the collected slurry had been filtered under vacuum and washed with three times with deionised water. At room temperature no micelles were formed. The resulting material was first dried at 60°C for 2 h and then calcined in an oven by heating up at a rate of l°C/min to a temperature of 350°C and then holding the temperature at 350°C for 6 hours.
  • the nitrogen adsorption isotherm of the calcined material is shown in Figure 7A. This is a typical type I isotherm (IUPAC).
  • the strong adsorption in the low pressure region relates to micropore adsorption.
  • Micropore volumes are generally adduced from alpha S plot, see Figure 7B. The intercept on the n axis, by back-extrapolation of the linear multilayer section, gives the micropore capacity [np(mic)].
  • the Alpha S micropore volume was determined from the desorption
  • Example 5 Preparation by stirring for 5 minutes and aging at room temperature for 24h 4.5748 g Pluronic 17R4 (BASF), 4.0050 g citric acid monohydrate and 2.7169 g trisodium citrate dihydrate were dissolved in 118.900 g deionised water in a polypropylene beaker. The solution was stirred with a magnetic stirring bar at 23 °C (room temperature). 11.11 g Sodium silicate solution (27% Si0 2 , 10% NaOH from Merck) was diluted with 32.30 g deionised water in a polypropylene beaker. The sodium silicate solution was quickly added to the surfactant solution. The resulting mixture was stirred for 5 minutes and kept at 23 °C (room temperature) overnight. At room temperature no micelles were formed. The resulting slurry was vacuum-filtered and washed with 3 times its volume with deionised water. The resulting powder was dried overnight at 60°C and then calcined at 350°C for 6 hours (6h ramp).
  • polypropylene beaker The solution was stirred with a magnetic stirring bar at 23 °C (room temperature). 11.12 g Sodium silicate solution (27%Si0 2 , 10%NaOH from Merck) was diluted with 32.4211 g deionised water in a polypropylene beaker. The sodium silicate solution was quickly added to the surfactant solution. The resulting mixture was stirred for 5 minutes and kept at 23 °C (room temperature) overnight. At room temperature no micelles were formed. The resulting slurry was vacuum-filtered and washed with 3 times its volume with deionised water. The resulting powder was dried overnight at 60°C and then calcined at 350°C for 6 hours (6h ramp).
  • the nitrogen adsorption characteristic of the calcined powder is shown in Figure 9. This is a typical type I isotherm (IUPAC). The strong adsorption in the low pressure region was due to the micropore adsorption.

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Abstract

La présente invention concerne un procédé pour préparer un matériau de silice microporeux amorphe autoassemblé en produisant dans un premier temps un matériau précurseur de silice autoassemblé par une réaction entre une solution aqueuse d'un précurseur de silice et une solution aqueuse d'un tensioactif qui ne s'assemble pas en micelles dans les conditions de procédé, suivi par l'élimination du tensioactif du matériau précurseur de silice autoassemblé, de manière à produire un matériau de silice microporeux.
PCT/EP2011/064755 2010-08-27 2011-08-26 Procédés pour produire des matériaux de silice microporeux WO2012025624A1 (fr)

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CN115092936A (zh) * 2022-06-24 2022-09-23 华南理工大学 一种利用废旧硅橡胶裂解渣制备有序介孔二氧化硅的方法

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CN109368648A (zh) * 2018-12-14 2019-02-22 深圳元颉新材料科技有限公司 单分散介孔二氧化硅纳米片材料的制备方法
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CN115092936A (zh) * 2022-06-24 2022-09-23 华南理工大学 一种利用废旧硅橡胶裂解渣制备有序介孔二氧化硅的方法
CN115092936B (zh) * 2022-06-24 2023-11-28 华南理工大学 一种利用废旧硅橡胶裂解渣制备有序介孔二氧化硅的方法

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