CN1764438A - Methods and apparatuses for the comminution and stabilization of small particles - Google Patents
Methods and apparatuses for the comminution and stabilization of small particles Download PDFInfo
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- CN1764438A CN1764438A CN 200480007793 CN200480007793A CN1764438A CN 1764438 A CN1764438 A CN 1764438A CN 200480007793 CN200480007793 CN 200480007793 CN 200480007793 A CN200480007793 A CN 200480007793A CN 1764438 A CN1764438 A CN 1764438A
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Abstract
The present invention provides a method and apparatuse for comminuting and stabilizing small particles. In one embodiment, an apparatus moves an organic compound dissolved in a solvent to form a suspension of particles in a first fluid stream and moves the suspension in a second fluid stream, wherein the second fluid stream is oriented and positioned with respect to the first stream to cause shearing between the streams and mixing of at least some of the particles in the first and second streams.
Description
The present invention relates to form the granule organic compound, method is that the precipitation organic compound forms preceding suspension in water-bearing media, then adds energy and makes particulate coating stable, or change particulate lattice structure.The present invention further estimates to precipitate when adding energy.These methods are preferred for preparing the short grained suspension of poorly water-soluble, pharmaceutical active compounds, are suitable for by such as parenteral, and are oral, lung, nose, buccal, part, eye, rectum, vagina, route of administration such as percutaneous and transmitting in the body.
Background technology
The indissoluble in aqueous solution or the insoluble organic compounds that have quantity to increase day by day are used for the treatment of or diagnostic effect by preparation.These medicines are provided challenge by above-mentioned route of administration transmission.Insoluble chemical compound has remarkable result in the water when being mixed with the stable suspension of submicron particles.Accurately the control particle diameter is essential to safety and effective these preparations of use.For safety does not cause thromboembolism by capillary tube, particulate diameter must be less than 7 μ m (Allen etc., 1987; Davis and Taube, 1978; Schroeder etc., 1978; Yokel etc., 1981).A scheme of head it off is to produce short grained insoluble drugs material standed for, and generates microparticles or nanoparticle suspension.With this approach, before the medicine that can not prepare in water based systems can be made into and was suitable for intravenous administration.The well-formedness of intravenous administration comprises small particle diameter (＜7 μ m), the bioavailability after hypotoxicity (from toxicity recipe ingredient or residual solvent time) and drug particles are used.
The preparation of granule water-insoluble drug is also applicable to oral, lung, part, eye, nose, buccal, rectum, vagina, percutaneous dosing or other administration route.The granule that size is little has improved the dissolution rate of medicine, thereby has improved its bioavailability and improved its toxicity spectrum potentially.When by these administrations, it is desirable to, the scope of particle diameter is at 5-100 μ m, and this depends on the route of administration of medicine, dosage form, dissolubility, and bioavailability.For example, for oral, it is desirable to, particle diameter is less than about 7 μ m.For the lung administration, particle diameter is preferably less than about 10 μ m.
Summary of the invention
The invention provides the preparation method of the suspension of the compositions of granule organic compound and granule organic compound, described organic compound can mix dissolubility in first solvent greater than the dissolubility in moisture second solvent at water.Described method comprises the following steps: that (i) organifying compound is dissolved in water and can mixes in first solvent and form solution, (ii) mix this solution and second solvent limit particulate before suspension, and (iii) add energy and to preceding suspension, form the particulate suspension of average effective particle diameter less than about 100 μ m.In preferred embodiments, described method further comprises the following steps: to mix one or more surface modifier to the first water miscible solvents or second solvent, perhaps in the first water miscible solvent and second solvent.
In the method that the present invention further provides, first and second steps that form preceding suspension are carried out simultaneously with the step that adds energy.This is applicable to all methods in this discussion.
The present invention also provides the preparation method of the suspension of the compositions of granule pharmaceutical active compounds and granule pharmaceutical active compounds, and described reactive compound can mix dissolubility in first solvent greater than the dissolubility in moisture second solvent at water.Described method comprises the following steps: that (i) is dissolved in water with pharmaceutical active compounds and can mixes formation first solution in first solvent; (ii) make first solution and second solvent limit particulate preceding suspension, and (iii) add the extremely preceding suspension formation of energy average effective particle diameter less than the particulate suspension of the pharmaceutical active compounds of about 100 μ m.Water can mix first solvent or second solvent and can choose wantonly and contain one or more surface modifiers.Described compositions can be by such as parenteral, and is oral, lung, nose, buccal, part, eye, rectum, vagina, route of administration such as percutaneous and transmitting in the body.In preferred embodiments, pharmaceutical active compounds is a poorly water-soluble.In another embodiment preferred, described method comprises compositions disinfectant additional step.
The sterile pharmaceutical composition that the present invention also further is provided for the compositions of granule pharmaceutical active compounds of parenteral and preparation granule pharmaceutical active compounds is used for the method for parenteral.Described chemical compound can mix dissolubility in first solvent greater than the dissolubility in moisture second solvent at water.Described method comprises the following steps: that (i) is dissolved in water with pharmaceutical active compounds and can mixes formation first solution in first solvent; (ii) make first solution and second solvent limit particulate preceding suspension, (iii) add energy to preceding suspension and form the average effective particle diameter less than the particulate suspension of the pharmaceutical active compounds of about 7 μ m; And (iv) compositions is sterilized.Water can mix first solvent or second solvent and can choose wantonly and contain one or more surface modifiers.In preferred embodiments, pharmaceutical active compounds is a poorly water-soluble.
The pharmaceutical composition that the present invention also is provided for the compositions of granule pharmaceutical active compounds of oral delivery and preparation granule pharmaceutical active compounds is used for the method for oral delivery.Described chemical compound can mix dissolubility in first solvent greater than the dissolubility in moisture second solvent at water.Described method comprises the following steps: that (i) is dissolved in water with pharmaceutical active compounds and can mixes formation first solution in first solvent; (ii) make first solution and second solvent limit particulate preceding suspension, and (iii) add the extremely preceding suspension formation of energy average effective particle diameter less than the particulate suspension of the pharmaceutical active compounds of about 100 μ m.Water can mix first solvent or second solvent and can choose wantonly and contain one or more surface modifiers.In preferred embodiments, pharmaceutical active compounds is a poorly water-soluble.
The present invention further compositions by being used for the granule pharmaceutical active compounds that pulmonary transmits and the pharmaceutical composition of preparation granule pharmaceutical active compounds is used for the method that pulmonary transmits.Described chemical compound can mix dissolubility in first solvent greater than the dissolubility in moisture second solvent at water.Described method comprises the following steps: that (i) is dissolved in water with pharmaceutical active compounds and can mixes formation first solution in first solvent; (ii) make first solution and second solvent limit particulate preceding suspension, and (iii) add the extremely preceding suspension formation of energy average effective particle diameter less than the particulate suspension of the pharmaceutical active compounds of about 10 μ m.Water can mix first solvent or second solvent and can choose wantonly and contain one or more surface modifiers.In preferred embodiments, pharmaceutical active compounds is a poorly water-soluble.Described compositions can be by aerosolized and by the aerosol apparatus administration.In addition, described method can comprise the additional step that shifts out liquid phase formation granule dry powder from suspension.Then, dry powder is by the Diskus administration, or dry powder further is suspended in hydrofluorocarbon (hydrofluorocarbon) Compressed Gas to pass through the metered dose inhaler administration.
These and other aspects of the present invention and feature with reference to the accompanying drawings with the description discussion.
The accompanying drawing summary
Fig. 1 is the diagram of a method of the present invention;
Fig. 2 is the diagram of other method of the present invention;
Fig. 3 shows the amorphous granular before the homogenize;
Fig. 4 shows by the granule behind the equal annealing;
Fig. 5 is the x-ray diffraction patterns of homogenize front and back with Polyethylene Glycol-660 12-hydroxy stearic acid ester microdeposit itraconazole;
Fig. 6 shows carbadipimidine (carbamazepine) crystal before the homogenize;
Fig. 7 shows the carbadipimidine microgranule after the homogenize (Avestin C-50);
Fig. 8 illustrates the microdeposit method of prednisolone (prednisolone);
Fig. 9 is the microphotograph of prednisolone suspension before the homogenize;
Figure 10 is the microphotograph of prednisolone suspension after the homogenize;
Figure 11 compares nano suspending liquid (the present invention) and is purchased the size distribution of fats emulsion;
Figure 12 shows the X-ray powder diffraction pattern of raw material itraconazole (last figure) and SMP-2-PRE (figure below).For clarity sake, displacement has been upwards for raw material figure;
Figure 13 a illustrates the DSC trace of raw material itraconazole;
Figure 13 b illustrates the DSC trace of SMP-2-PRE;
Figure 14 illustrates the DSC trace of SMP-2-PRE, and more unsettled polymorphic thawing when being heated to 160 ℃ is shown, the recrystallization incident during cooling, and when reheating to 180 ℃, melt more stable polymorph subsequently;
Figure 15 illustrates the comparison after the SMP-2-PRE sample homogenize.Solid line=the add sample of crystal seed with the raw material itraconazole.Dotted line=unseeded sample.For clarity sake, solid line displacement 1W/g;
Figure 16 illustrates the effect that adds crystal seed in precipitation process.Dotted line=unseeded sample, solid line=the add sample of crystal seed with the raw material itraconazole.For clarity sake, unseeded trace (dotted line) is to top offset 1.5W/g; And
Figure 17 illustrates and adds crystal seed medicine concentrate with aged effect.The top x-ray diffraction pattern for preparation from the crystal of fresh medicine concentrate, and with stable polymorph consistent (referring to Figure 12, last figure).Figure below is the crystal of preparation from the medicine concentrate of aging (adding crystal seed), and with metastable polymorph consistent (referring to Figure 12, figure below).For clarity sake, last figure is to top offset.
Figure 18 is the cross sectional elevation of an embodiment of the present device of solid particle in the comminuted suspension liquid and method.
Figure 19 for the component of hybrid particles suspension to produce suspension and to make solid particle is pulverized in the suspension present device and the cross sectional elevation of an embodiment of method.
Figure 20 utilizes the subtend liquid jet to make the cross sectional elevation of an embodiment of present device that solid particle in the suspension pulverizes and method.
Figure 21 for the component of hybrid particles suspension to produce suspension and to utilize the subtend liquid jet to make the cross sectional elevation of an embodiment of solid particle is pulverized in the suspension present device and method.
Figure 22 makes the mixing of solid particle high energy and the nozzle of the present invention of pulverizing and the cross sectional elevation of an embodiment of the method for using this nozzle in the suspension.
Figure 23 is the perspective view of an embodiment of the turbulence structure of the present invention (turbulatingstructure) in the nozzle that inserts Figure 22.
The form of Figure 24 shows the various dosage forms of the solid drugs of handling via described present device of claim 18 and method.
The result of the known method of solid particle in the medicine processing result of form comparison Figure 24 of Figure 25 and the suspension-treating.
Detailed Description Of The Invention
The present invention allows with multi-form embodiment.Disclosing of the preferred embodiment of the invention is interpreted as, and these disclosures are considered as the illustration of the principle of the invention, is not to be intended to limit extensive aspect of the present invention to described embodiment.
The invention provides the compositions of granule organic compound and the method for formation granule organic compound.The organic compound that is used for the inventive method is any organic compound entity, and its dissolubility reduces to another solvent from a solvent.This organic compound can be pharmaceutical active compounds, is selected from therapeutic agent, diagnostic agent, cosmetics, nutritional supplement and insecticide.
Therapeutic agent can be selected from various known drug, such as, but be not limited to: analgesic, anesthetis, analeptic, the epinephrine agent, adrenergic blocker presses down the epinephrine agent, adrenal corticoid, adrenomimetics, anticholinergic, anticholinergic, anticonvulsant drug, alkylating agent, alkaloid, allosteric inhibitor, anabolic steroid, anorexiants, antacid, anti-diarrhea agents, antidote, antifolics, antipyretic, antirheumatic, psychotherapeutic agent, nerve blocker, antiinflammatory, antihelmintics, anti-arrhythmic agents, antibiotic, anticoagulant, antidepressant, antidiabetic, Anti-epileptics, antifungal, antihistaminic, hypotensive agent, antimuscarinic agent, the Mycobactericidal agent, antimalarial, antiseptic, antitumor agent, protozoacide, immunosuppressant, immunostimulant, antithyroid drug, antiviral agent, the antianxiety drugs tranquilizer, astringent, β-adrenoreceptor blocker, contrast agent, corticosteroid, cough suppressant, diagnostic agent, diagnostic imaging agent, diuretic, the dopaminergic agent, hemorrhage, blood agent, the modified hemoglobin agent, hormone, hypnotic, immunizing agent, anti-high fat agent and other lipid regulators, muscarine, muscle relaxant, Parasympathomimetic, parathyroid gland calcitonin, prostaglandin, radiopharmaceutical, tranquilizer, gonadal hormone, anti-allergy agent, stimulus object, sympathomimetic, thyroid, vasodilation, vaccine, vitamin, and xanthine.Antitumor agent or anticarcinogen include but not limited to paclitaxel and derivative compound, and other are selected from alkaloid, antimetabolite, enzyme inhibitor, alkylating agent and antibiotic antitumor agent.Therapeutic agent also can be biological preparation, includes but not limited to albumen, polypeptide, carbohydrate, polynucleotide, and nucleic acid.Albumen can be antibody, and described antibody is monoclonal antibody or polyclonal antibody.
Diagnostic agent comprises agent of X-radial imaging and contrast agent.The example of X-radial imaging agent comprises WIN-8883 (ethyl 3,5-diacetylamino-2,4,6-phenyl triiodide formic acid esters), be also referred to as the ethyl ester (EEDA) of diatrazoic acid, WIN 67722, that is, (6-ethyoxyl-6-oxo-hexyl-3, two (acetylamino)-2 of 5-, 4,6-phenyl triiodide formic acid esters); Ethyl-2 (3,5-two (acetylamino)-2,4,6-three iodos-benzoyloxy) butyrate (WIN 16318); Ethyl diatrizoxyacetate (WIN 12901); Ethyl 2-(3, two (acetylamino)-2,4 of 5-, 6-phenyl triiodide formyloxy) propionic ester (WIN 16923); N-ethyl 2-(3, two (acetylamino)-2,4 of 5-, 6-phenyl triiodide formyloxy acetamide (WIN 65312); Isopropyl 2-(3, two (acetylamino)-2,4 of 5-, 6-phenyl triiodide formyloxy) acetamide (WIN 12855); Diethyl 2-(3, two (acetylamino)-2,4 of 5-, 6-phenyl triiodide formyloxy) malonate (WIN 67721); Ethyl 2-(3, two (acetylamino)-2,4 of 5-, 6-phenyl triiodide formyloxy) phenylacetic acid ester (WIN67585); Malonic acid, [[3, two (acetylamino)-2,4 of 5-, 5-three sulphurs are for benzoyl] the oxygen base] two (1-methyl) ester (WIN 68165); And benzoic acid, 3, two (acetylamino)-2,4 of 5-, 6-three iodos-4-(ethyl-3-ethyoxyl-2-butylene acid) ester (WIN 68209).Preferred contrast agent comprises those expectations quickly disintegrated relatively contrast agent under physiological condition, thereby any inflammatory reaction relevant with granule minimized.Disintegrate can be from enzyme hydrolysis, the dissolving of carboxylic acid under the physiological pH condition, or other mechanism.Therefore, poorly soluble iodate carboxylic acid, such as iodipamide, diatrizoic acid and metrizoic acid, in company with the iodate material of facile hydrolysis, such as WIN 67721, WIN12901, WIN 68165 and WIN 68209 or other are preferred.
Other contrast agent include but not limited to the nuclear magnetic resonance auxiliary agent, such as the microparticle formulation of gadolinium chelate compound or other paramagnetic contrast mediums.The example of this compounds is gadopentetatedimeglumine (Magnevist ) and gadoteridol (Prohance ).
The therapeutic agent of these types and diagnostic agent and all types of in the description of chemical compound lists referring to Martindale, The Extra Pharmacopoeia, the 29th edition, The PharmaceuticalPress, London, 1989, be hereby incorporated by reference and become a part of the present invention.Therapeutic agent and diagnostic agent are commercially available, and/or prepare by techniques well known.
Enamel is any active component that can have cosmetic activity.The example of these active component has emollient, wetting agent, free radical inhibitors, antiinflammatory, vitamin, decolourant, anti-acne agent, antiseborrhoeics, keratolytic agent, anoretic, dye agent and sunscreen etc. especially have linoleic acid, retinol, tretinoin, ascorbic acid Arrcostab, poly-unsaturated fatty acid, nicotine acid esters, tocopherol nicotine acid esters, unsaponified rice, Semen sojae atricolor or Adeps Bovis seu Bubali, ceramide, hydroxy acid is such as glycolic, the selenium derivant, antioxidant, solatene, γ-orizanol and stearoyl monoglyceride.Cosmetics are commercially available, and/or prepare by techniques well known.
The example that expectation is used for the nutritional supplement of the invention process includes but not limited to albumen, carbohydrate, water soluble vitamins (for example, vitamin C, B-compound vitamin, Deng), fatsoluble vitamin (for example, vitamin A, D, E, K, etc.), and the medicinal herbs extract.The nutritional supplement is commercially available, and/or prepares by techniques well known.
The understanding of term insecticide comprises herbicide, insecticide, acaricide, nematicide, outer anthelmintic and antifungal.The example that belongs to the chemical compound of insecticide of the present invention comprises carbamide, triazine, triazole, carbamate, phosphate ester, dinitroaniline, morpholine, acyl group alanine, pyrethroid, benzilic acid ester, diphenyl ether and multi-ring halogenated hydrocarbon.The object lesson of these classification insecticides is listed in insecticide handbook (Pesticide Mannual) respectively, and the 9th edition, British Crop Protection Council.Insecticide is commercially available, and/or prepares by techniques well known.
Preferably, the poorly water-soluble of organic compound or pharmaceutical active compounds.The dissolubility of " poorly water-soluble " expression chemical compound in water is less than about 10mg/ml, preferably less than 1mg/ml.The reagent of these poorly water-solubles is best suited for the aqueous suspension preparation, and these are because these reagent of preparation are subjected to limited substituting in water-bearing media.
By (for example in solid phase carrier substrate, polylactic acid-polyglycolic acid copolymer, albumin, starch) in hold back these chemical compounds, or by wrap up these chemical compounds in the insaccation outside impermeable to medical compounds, the present invention also can implement by the water soluble drug reactive compound.This parcel capsule can be a polymer coating, such as polyacrylate.Further, preparation can be modified to improve chemical stability and to control the pharmacokinetics attribute of medicament by controlling the release of medicament from granule from the granule of these water soluble medicaments.The example of water soluble medicament includes but not limited to simple organic compound, albumen, peptide, nucleotide, oligonucleotide, and carbohydrate.
By the dynamic light scattering method, for example, light is proofreaied and correct spectrum, laser diffraction, low angle laser light scattering (LALLS), middle angle laser light scattering (MALLS), the dim method of light (for example, the Coulter method), rheology, or microscopic method (light or electronics), the particulate average effective particle diameter of the present invention is generally less than about 100 μ m.Yet, the magnitude range of preparation of granules, all 20 μ m according to appointment are to about 10nm, and about 10 μ m are to about 10nm, and about 2 μ m are to about 10nm, and about 1 μ m is to about 10nm, and about 400nm is to about 50nm, and about 200nm is to about 50nm, or any scope, or the combination of above-mentioned scope.Preferred average effective particle diameter depends on such as following factors: the route of administration that chemical compound is wanted, dosage form, dissolubility, toxicity and bioavailability.
In order to be suitable for parenteral, particulate average effective particle diameter is preferably less than about 7 μ m, and is more preferably less than about 2 μ m, or the combination of any scope or above-mentioned scope.Parenteral comprises intravenous, intra-arterial, and in the sheath, intraperitoneal, ophthalmic, intraarticular, in the cerebral dura mater, in the ventricle, in the pericardium, intramuscular, Intradermal or subcutaneous injection.
The particle diameter of peroral dosage form can surpass 2 μ m.Particulate magnitude range is up to about 100 μ m, and condition is other features that granule has enough bioavailability and peroral dosage form.Peroral dosage form comprises tablet, capsule, and the capsule sheet, flexible glue and hard-gelatin capsules, or other transmission vehicles are used to transmit oral drugs.
The present invention further provides the organic compound composition granule that is suitable for the pulmonary administration form.The particle diameter of pulmonary's dosage form can surpass 500nm, and is generally less than about 10 μ m.Granule in the suspension can be by aerosolized, and be used for pulmonary administration by aerosol apparatus.In addition, remove liquid phase from suspension after, granule passes through the Diskus administration with dry powder form, or dry powder is resuspended in non-moisture propellant by the metered dose inhaler administration.The example of suitable propellant is a hydrogen fluorine carbon (HFC), such as HFC-134a (1,1,1, the 2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3, the 3-heptafluoro-propane).(CFC) is different with Chlorofluorocarbons, and HFC shows the potentiality of ozone depletion little or that do not have.
To other pipelines, such as nose, the part, eye, nose, buccal, rectum, vagina, the dosage form of percutaneous etc. also can be prepared from the granule of the present invention's preparation.
Prepare particulate technology and can be divided into four kinds of general categories.Each classification technology is enjoyed the following step: (1) is dissolved with organic compounds can mix generation first solution in first solvent in water, (2) with second solvent of water of this first solution and precipitation organic compound to generate preceding suspension, and (3) are with the form of high shear mixing or heating or both combinations, add energy to preceding suspension, thereby the organic compound of the above-mentioned required size scope of having of stable form is provided.Blend step and add the energy step can consecutive steps or carry out simultaneously.
The differentiation of technology category is based on the physical attribute of organic compound, and as before energy adds step and after the energy adding step, by X-ray diffraction research, differential scanning calorimetry (DSC) research or other suitable researchs are determined.In first technology category, energy adds before the step, and the organic compound in the preceding suspension is taked amorphous form, and semi-crystal form or supercool be liquid form but, and has the average effective particle diameter.After energy added step, the average effective particle diameter that the crystal form of organic compound has was substantially the same or less than preceding suspension.
In second technology category, before energy added step, organic compound was crystal form and has the average effective particle diameter.After energy added step, the crystal form of organic compound and energy had essentially identical average effective particle diameter before adding step, but after energy added step, the probability of crystal accumulation was less.
The accumulative tendentiousness of organic compound is crossed dynamic laser light scattering experimental and observation by light microscope than low pass.
In the 3rd technology category, before energy added step, organic compound was a crystal form, and this form is frangible and have an average effective particle diameter.The implication of term " frangible " is that granule is frangible and easier to be resolved into than granule.After energy added step, the average effective particle diameter that the crystal form of organic compound has was less than the crystal in the preceding suspension.By taking the necessary steps organic compound is placed frangible crystal form, when comparing with the non-friable organic compound of crystal habit, energy subsequently adds step can faster and more effectively enforcement.
In technology category 4, first solution and second solvent carry out energy simultaneously and add step.Therefore, the physical attribute of organic compound is before energy adds step and not measured afterwards.
Energy adds step can be implemented by any way, wherein before suspension, or first solution and second solvent be contacted with cavitation, shears or impulsive force.In one preferred form of the invention, it is annealing steps that energy adds step.Annealing is defined as following method in the present invention: by single or apply energy (direct heat or mechanical stress) repeatedly, follow hot relaxation, the unsettled material of heat power is changed into more stable form.The reduction of this energy is by being converted into solid form in order more orderly lattice structure and realizing from less.In addition, by the rearrangement of surface molecular on solid-liquid interface this static stabilization can appear.
These four kinds of technology categories are discussed below respectively.Yet, it should be understood that such as surfactant, or the combination of surfactant, the amount of used surfactant, reaction temperature, solution mixing rate, the treatment conditions of settling rate etc. select to make all medicines in any technology under kind as discussed below.
First technology category, and the second, the third and fourth technology category can further be divided into two subclasses, and method A and B are shown in Fig. 1 and 2.
First solvent of the present invention is that relatively dissolving is wherein and the solvent that can mix with second solvent or the mixture of solvent for the purpose organic compound.Such solvent includes but not limited to that water can mix proton compound, and wherein the hydrogen atom in the molecule is incorporated into the negative electricity atom, such as oxygen, and the VA in nitrogen or other periodic table of elements, VIA and VII A family atom.The example of this solvent includes but not limited to alcohol, amine (primary amine or secondary amine), oxime, hydroxamic acid, carboxylic acid, sulfonic acid, phosphonic acids, phosphoric acid, amide and urea.
Other examples of first solvent comprise aprotic organic solvent.The some of them aprotic solvent can form hydrogen bond with water, but only serves as proton acceptor, supplies with group because they lack effective proton.One class aprotic solvent is the bipolarity aprotic solvent, defines as the International Unionof Pure and Applied Chemistry (IUPAC Compendium of ChemicalTerminology, the 2nd edition, 1997):
Dielectric constant is high relatively, and greater than about 15 and the sizable solvent of permanent dipole moment, the hydrogen atom that can not supply with suitable mutability is to form strong hydrogen bonding, for example dimethyl sulfoxide.
Dipolar aprotic solvent can be selected from: amide (replace fully, nitrogen lacks the hydrogen atom that connects), urea (replace fully, do not have hydrogen atom to be connected in nitrogen), ether, cyclic ethers, nitrile, ketone, sulfone, sulfoxide, the phosphoric acid of Qu Daiing fully, phosphonate ester, phosphamide, nitro compound etc.Dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolinone (NMP), 2-pyrrolinone, 1,3-dimethyl-imidazolinone (DMI), dimethyl acetylamide (DMA), dimethyl formamide (DMF) diox, acetone, oxolane (THF), tetramethylene sulfone (sulfolane), acetonitrile, and hexamethyl phosphoramide (HMPA), Nitrocarbol. etc. are this class members.
Selectable solvent generally is that water is immiscible, but has enough water solubilities when low volume (less than 10%), can mix first solvent thereby take on water with the volume of these minimizings.Example comprises aromatic hydrocarbons, alkene, alkane, and halogenated aromatic compound, halogenated olefins and halogenation alkane.Aromatic compounds includes but not limited to benzene (replacement or unsubstituted), monocycle or polycyclic aromatic hydrocarbon.The example of substituted benzene includes but not limited to dimethylbenzene (neighbour, or to), and toluene.The example of alkane includes but not limited to hexane, neopentane, heptane, isobutyltrimethylmethane., and cyclohexane extraction.The example of halogenated aromatic compound includes but not limited to chlorobenzene, bromobenzene, and chlorotoluene.The example of halogenation alkane and alkene includes but not limited to trichloroethane, dichloromethane, and dichloroethylene (EDC), etc.
All other examples of above-mentioned solvent based include but not limited to: N-methyl-2-pyrrolinone (being also referred to as the N-N-methyl-2-2-pyrrolidone N-), 2-pyrrolinone (being also referred to as 2-Pyrrolidone), 1; 3-dimethyl-2-imidazolone (DMI), dimethyl sulfoxide, dimethyl acetylamide; acetic acid, lactic acid, methanol; ethanol, isopropyl alcohol, 3-amylalcohol; just-and propanol, benzyl alcohol, glycerol; butanediol, ethylene glycol, propylene glycol; single-and the monoglyceride (such as the glyceryl caprylate) of diacetylation, dimethyl isosorbide, acetone; dimethyl sulfone, dimethyl formamide, 1; the 4-diox, tetramethylene sulfone (sulfolane), acetonitrile; Nitrocarbol., tetramethylurea, hexamethyl phosphoramide (HMPA); oxolane (THF) ， diox, Anaesthetie Ether; t-butyl methyl ether (TBME), aromatic hydrocarbons, alkene; alkane, halogenated aromatic compounds, halogenated olefins; halogenation alkane, dimethylbenzene, toluene; benzene, substituted benzene, ethyl acetate; methyl acetate, butyl acetate, chlorobenzene; bromobenzene; chlorotoluene, trichloroethane, dichloromethane; dichloroethylene (EDC); hexane, neopentane, heptane; isobutyltrimethylmethane.; cyclohexane extraction, Polyethylene Glycol (PEG, for example PEG-4; PEG-8; PEG-9, PEG-12, PEG-14; PEG-16; PEG-120, PEG-75, PEG-150); macrogol ester (example; as the PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate; the PEG-8 palmitostearate; the PEG-150 palmitostearate), the Polyethylene Glycol sorbitan (such as, PEG-20 sorbitan isostearate); polyalkylene glycol monoalkyl ether (example; as the PEG-3 dimethyl ether, the PEG-4 dimethyl ether), polypropylene glycol (PPG); the polypropylene alginate esters; the PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether; PPG-15 stearoyl ether; propylene glycol dicaprylate/two certain herbaceous plants with big flowers acid esters, propylene glycol laurate, and sugared furfural (tetrahydrofurfuryl alcohol polyglycol ether).Preferred first solvent is N-methyl-2-pyrrolinone.Another preferred first solvent is a lactic acid.
Second solvent is an aqueous solvent.This aqueous solvent can be water itself.This solvent also can contain buffer, salt, surfactant, water-soluble polymer, and the combination of these excipient.
Method A
In method A (referring to Fig. 1), organic compound (" medicine ") at first is dissolved in and generates first solution in first solvent.Add organic compound with about 0.1% (w/v) to about 50% (w/v), this depends on the dissolubility of organic compound in first solvent.Concentrate from about 30 ℃ be heated to about 100 ℃ to guaranteeing that the whole strippings of chemical compound first solvent are essential.
Second aqueous solvent provides one or more optional surface modifiers, such as to the radiolucent table surface-active agent that wherein adds, positive surfactant, non-ionic surface active agent, or Bio-surface active molecule.Suitable anion surfactant includes but not limited to alkyl sulfonic ester, alkyl phosphate, phosphonate ester; potassium laurate, triethanolamine stearate, sodium lauryl sulfate; sodium lauryl sulphate, alkyl polyoxyethylene sulfuric ester, sodium alginate; dioctyl sulfo-sodium succinate, phosphatidylcholine, phosphatidyl glycerol; the phosphatidyl inosine, Phosphatidylserine, phosphatidic acid and salt thereof; glyceride; sodium carboxymethyl cellulose, cholic acid and other bile acids (for example, cholic acid; deoxycholic acid; glycocholic acid, cholyltaurine, sweet deoxycholic acid) and (for example reach salt; NaTDC, etc.).Suitable cationic surfactants includes but not limited to quaternary ammonium compound, such as the zephiran chloride, and cetyl trimethyl ammonium bromide, chitosan, lauryl dimethyl hexadecyldimethyl benzyl ammonium chloride, fatty acyl carnitine hydrochloride, or alkyl pyridine halogenide.As anion surfactant, can use phospholipid.Suitable phospholipid comprises, for example, and phosphatidylcholine; PHOSPHATIDYL ETHANOLAMINE, and diacyl-glycerol-3-phosphate ethanolamine (such as two myristoyls-glycerol-3-phosphate ethanolamine (DMPE), two palmityls-glycerol-3-phosphate ethanolamine (DPPE); distearyl-glycerol-3-phosphate ethanolamine (DSPE), and two oleoyls-glycerol-3-phosphate ethanolamine (DOPE)), Phosphatidylserine; phosphatidylinositols; phosphatidyl glycerol, phosphatidic acid, lysophosphatide; lecithin or soybean phospholipid, or its combination.Phospholipid can be by salify or desalination, hydrogenation or partial hydrogenation or natural semisynthetic or synthetic.Phospholipid also can combine with water-soluble polymer or close aqueous polymers.Preferred polymer is Polyethylene Glycol (PEG), and it is also referred to as mono methoxy polyethylene glycol (mPEG).The molecular weight of PEG can change, and for example from 200 to 5,000.Some PEG commonly used are commercially available, comprise PEG 350, and PEG 550, and PEG 750, and PEG 1000, and PEG 2000, and PEG 3000, and PEG 5000.Phospholipid or PEG phospholipids incorporate thing also can mix functional group, and this functional group can be covalently bonded in part, and described part includes but not limited to albumen, peptide, carbohydrate, glycoprotein, antibody, or pharmaceutically active agents.These functional groups for example pass through, and amido link forms, and disulphide or thioether form, or biotin/streptavidin combination, combine with part.Part-include but not limited to caproamide in conjunction with the example of functional group, the dodecane amide, 1,12-dodecanedicarboxylic acid ester, sulfo-ethanol, 4-(p-dimaleoyl imino phenyl) butyramide (MPB), 4-(p-maleimide ylmethyl) cyclohexane extraction-Methanamide (MCC), 3-(2-pyridylthio) propionic ester (PDP), succinate, glutarate, dodecylate, and biotin.
Suitable ionic surfactant pack is drawn together: polyoxyethylene aliphatic alcohol ether (Macrogol and Brij), polyoxyethylene sorbitan aliphatic ester (polysorbate), polyoxyethylene fatty acid ester (Myrj), sorbitan ester (Span), glyceryl monostearate, Polyethylene Glycol, polypropylene glycol, spermol, cetostearyl alcohol, stearyl alcohol, the aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer (poloxamers) is protected beautiful look bright (poloxamines), methylcellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, the amorphous fibres element, polysaccharide comprises starch and starch derivatives, such as hetastarch (HES), polyvinyl alcohol, and polyvinylpyrrolidone.In a preferred form of the invention, non-ionic surface active agent is polyoxyethylene and polyoxypropylene copolymer, and the block copolymer of propylene glycol and ethylene glycol preferably.Such polymer is also referred to as PLURONIC sometimes and sells with trade (brand) name POLOXAMER, and comprises that by some suppliers Spectrum Chemical and Ruger sell.Comprise that in polyoxyethylene fatty acid ester those have the chemical compound of short-chain alkyl.An example of such surfactant is SOLUTOL HS 15, and polyethylene-660-hydroxy stearic acid ester is made by BASF Aktiengesellschaft.
The surface activity biomolecule comprises such as albumin, casein, hirudin or other suitable albumen equimoleculars.The polysaccharide biological preparation also can include, but are not limited to starch, heparin and chitosan.
Ideal pH regulator agent to the second solvent that also can add, such as sodium hydroxide, hydrochloric acid, tris buffer, or citric acid, acetic acid, lactic acid, meglumine, etc.The pH of second solvent should be about 3 to about 11 scope.
For peroral dosage form, can use one or more following excipient: gelatin, casein, lecithin (phospholipid), Radix Acaciae senegalis, cholesterol, tragacanth, stearic acid, the zephiran chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, the cetomacrogol emulsifing wax, sorbitan ester, polyoxyethylene alkyl ether, for example, macrogol ether is such as cetomacrogol 1000, castor oil derivatives, the polyoxyethylene sorbitan aliphatic ester, for example commercially available Tweens
TM, Polyethylene Glycol, Myrj 45, silica sol, phosphate ester, sodium lauryl sulphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, the amorphous fibres element, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP).These excipient of great majority are described in detail in handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), publish by The American Pharmaceutical Association and The PharmaceuticalSociety of Great Britain jointly, the Pharmaceutical Press, 1986.Surface modifier is commercially available, and/or prepares by techniques well known.The use capable of being combined of two or more surface modifiers.
In a preferred form of the invention, the preparation method of granule organic compound comprises the step that adds first solution to the second solvent.Adding speed depends on the precipitation kinetics of batch size and organic compound.Generally speaking, for small scale experiments chamber method (preparing 1 liter), adding speed is that about 0.05cc/min is to about 10cc/min.In the adition process, solution should be under the constant agitation.Utilize optical microscope to observe, amorphous granular, the semi-crystal solid, or super refrigerative liquid forms preceding suspension.Described method comprises the following steps: that further preceding suspension is carried out energy adds step, thereby with amorphous granular, it is solid-state that super refrigerative liquid or hypocrystalline solid change into more stable crystal.The particulate average effective particle diameter of gained is in above-mentioned scope, as (for example passing through the dynamic light scattering method, light is proofreaied and correct spectroscopy, laser diffraction, low angle laser light scattering (LALLS), middle angle laser light scattering (MALLS), the dim method of light (Coulter method, for example), rheology, or microscope (light or electronics)) measure.In the 4th technology category, carry out energy in the time of first solution and the combination of second solvent and add step.
Energy adds step and comprises by ultrasonic, homogenize, and the counter-current flow homogenize, Micro Fluid, or other bodies provide impulsive force, shearing force or cavitation power adding energy.In this stage, sample can be cooled or heat.In one preferred form of the invention, energy adds step by piston crack homogenizer, such as by Avestin Inc. with name of product EmulsiFlex-C160 sell and realize.In another preferred form of the present invention, energy adds step and utilizes ultrasonic processor, and such as by Sonics and Materials, the Viabra-Cell Ultrasonic Processor (600W) that Inc. makes realizes by ultrasonic.In another preferred form of the present invention, energy adds step by using as U.S. patent No.5, the emulsifier unit described in 720,551 and realizing, and described patent is hereby incorporated by reference and becomes a part of the present invention.
Depend on energy and add speed, the temperature that it is desirable to regulate the technology sample near-30 ℃ to 30 ℃ scope.In addition, in order in process solids, to realize required phase transformation, also be necessary energy add in the step process before the heating suspension to from about 30 ℃ to about 100 ℃ scope.
Method B
The difference of method B and method A is aspect following.First difference adds to first solution for the combination of surfactant or surfactant.The optional anion from as mentioned above of surfactant, nonionic, cationic surfactant, and the agent of surface activity bio-modification.The comparing embodiment of method A and method B and USPN 5,780,062
U.S. Patent No. 5,780,062 discloses by at first mixing at suitable water and has been dissolved with the method that organic compounds prepares the granule organic compound in first solvent.The preparation method of second solution is dissolve polymer and an amphiphatic molecule in aqueous solvent.First solution adds second solution and forms by organic compound and precipitate that polymer-the amphiphatic molecule complex is formed then.' 062 patent is unexposed utilizes that energy of the present invention adds step among method A and the B.The stability shortage is usually expressed as quick gathering and germination.Under some situation, the amorphous granular recrystallization becomes megacryst.Add energy to preceding suspension in above-mentioned disclosed mode and generally give granule and demonstrate particle aggregation and growth rate and reduce, and when product stock, lack recrystallization.
The method of ' 062 patent that method A and B further distinguish is to lack the step that forms polymer-amphiphatic molecule complex before precipitation.In method A, such complex can not form, because there is not polymer to add in the dilution (water) mutually.In method B, also can serve as amphiphilic surfactant, perhaps polymer is dissolved in first solvent with organic compound.This has got rid of formed amphiphatic molecule-polymer complex before precipitation.In the patent of ' 062, successfully precipitate granule and depend on and before precipitation, form amphiphatic molecule-polymer complex.' 062 patent disclosure amphiphatic molecule-polymer complex forms aggregation in moisture second solution.' 062 patent has explained that thin water-containing organic compound and amphiphatic molecule-polymer complex interact, and reduces the dissolubility of these aggregations thus, and causes precipitation.In the present invention, proved in first solvent, to comprise surfactant or polymer (method B), in the time of in adding to second solvent subsequently, caused forming the more tiny microgranule of more homogeneous that provides than by ' the 062 described method of patent.
For this purpose, prepare and analyze two kinds of preparations.Various preparations have two kinds of solution, and concentrated solution and water diluent carry out ultrasonic again after it mixes.Concentrate in each preparation has organic compound (itraconazole), water miscible solvent (N-methyl-2-pyrrolinone or NMP) and possible polymer (poloxamer 188).Contain water diluent and have water, tris buffer and possible polymer (poloxamer 188) and/or surfactant (NaTDC).The mean diameter of organic granular is measured in ultrasonic front and back.
The first preparation A has dense itraconazole and NMP.Contain water diluent and comprise water, poloxamer 188, tris buffer and NaTDC.Therefore, contain water diluent and comprise polymer (poloxamer 188) and amphiphatic molecule (NaTDC), this can form polymer/amphiphatic molecule complex, so consistent with the disclosure of ' 062 patent.Yet (, once more, patent unexposed energy in ' 062 adds step.)
The second preparation B has dense itraconazole, NMP and poloxamer 188.Contain water diluent and comprise water, tris buffer, and NaTDC.Said preparation produced according to the present invention.Owing to contain the combination that water diluent does not contain polymer (poloxamer) and amphiphatic molecule (NaTDC), polymer/amphiphatic molecule complex can not form before blend step.
Table 1 demonstration repeats the mean diameter that suspension preparation is measured by laser diffraction to three times.Initial size is determined ultrasonic thereafter sample 1 minute.Then, repeating size determines.To reduce be the indication of particle aggregation to large scale during method A ultrasonic.
Table 1:
| Method | Concentrated solution | Contain water diluent | Mean diameter (μ m) | Ultrasonic back (1 minute) |
| A | Itraconazole (18%), N-methyl-2-pyrrolinone (6ml) | Poloxamer 188 (2.3%), NaTDC (0.3%), tris buffer (5mM, pH 8), water (amount is mended to 94ml) | 18.7 10.7 12.1 | 2.36 2.46 1.93 |
| B | Itraconazole (18%), poloxamer 188 (37%), N-methyl-2-pyrrolinone (6ml) | NaTDC (0.3%), tris buffer (5mM, pH 8) water (amount is mended to 94ml) | 0.194 0.178 0.181 | 0.198 0.179 0.177 |
Directly as the Injectable solution administration, condition is that water for injection is used for preparation by the drug suspension of using the method for the invention generation, and uses the solution disinfection suitable manner.Method well-known in the art is adopted in sterilization, such as steam or heat sterilization, gamma-radiation etc.Other sterilization methods, especially for greater than 99% granule less than 200nm, also will comprise at first and filtering, then filter, carry out steam or heat sterilization or aseptic filtration by two 0.2 unnecessary μ m film filters again by 0.45 μ m particulate filter by 3.0 μ m filters are preceding.Another disinfection way is that the aseptic filtration preparation contains water diluent from the concentrated solution and the aseptic filtration of first solvent, and described first solvent contains medicine and one or more optional surfactants.Then, preferably in isolating gnotobasis, make up at aseptic mixer.Under aseptic condition, suspension is mixed homogenize and further technology.
Consisting of before homogenization step of another disinfectant program, in or the back at intravital heat sterilization of homogenizer or autoclaving.Technology behind the heat treatment is carried out under aseptic condition.
Randomly, solvent-free suspension can be at post precipitation by removing solvent production.The method that realizes this has centrifugal, dialysis, saturating filter, field of force fraction, high-pressure filteration, reverse osmosis, or other isolation technics well-known in the art.Shifting out N-methyl-2-pyrrolinone is fully generally undertaken by 1-3 continuous centrifugal round; After centrifugal at every turn (18,000rpm 30 minutes), topple over and abandon supernatant.There is not the suspension media of the fresh volume of organic solvent to add in the remaining solid, by the homogenize dispersed mixture.One skilled in the art will recognize that other high shear mixing technology also can be applicable in this regeneration step.In addition, solvent-free granule optionally can be formulated into various dosage form, is used for various route of administration, such as oral, and pulmonary, nose, part, intramuscular etc.
In addition, any excipient of not expecting, can be replaced by better excipient by using the separation method described in the epimere such as surfactant.Centrifugal or filter after, the solvent and first excipient are dropped with supernatant.Then, the suspension media that adds the fresh volume that does not have the solvent and first excipient.Perhaps, add new surface active agents.For example, by medicine, N-methyl-2-pyrrolinone (solvent), poloxamer 188 (first excipient), NaTDC, the suspension that G ﹠ W is formed can be by phospholipid (new surface active agents) behind centrifugal and removal supernatant, and G ﹠ W is replaced.
I. first technology category
The method of first technology category generally comprises and is dissolved with organic compounds can mix first solvent in water step, the step of suspension before then mixing this solution and aqueous solvent and forming, wherein organic compound is studied by X-ray diffraction, DSC, optical microscope or other analytical technologies are defined as amorphous, semi-crystal form or supercool be liquid form but, and has the average effective particle diameter within above-mentioned a kind of effective grain size scope.Add step for energy after the blend step.
II. second technology category
The method of second technology category comprises and the essentially identical step of first technology category, but aspect following difference.X-ray diffraction, DSC or other suitable analytical technologies show that to preceding suspension analysis organic compound is a crystal form, and have the average effective particle diameter.Organic compound and energy adding step that energy adds after the step have essentially identical average effective particle diameter before, but compare with the granule of preceding suspension, and the tendency that is gathered into larger particles is less.Need not bound by theoryly, it is believed that the difference of granule stability may be owing to the rearrangement of solid-liquid interface surfactant molecule.
III. the 3rd technology category
The 3rd class method for distinguishing has been revised the first two steps in the first and second technology category methods, is frangible form with the preceding suspension of guaranteeing organic compound, has average effective particle diameter (for example, elongated needle and thin plate).The formation method of friable particle is to select suitable solvent, the combination of surfactant or surfactant, the temperature of single solution, mixing rate and settling rate etc.Also can improve fragility by in the step process of mixing first solution and aqueous solvent, importing lattice defect (for example, crystalline parting plane).Rapid crystallization that is provided such as in the settling step will be provided for this.In energy added step, these frangible crystal were converted on the kinetics stable and its average effective particle diameter less than the crystal of preceding suspension.The average grain of dynamic stabilization accumulative tendency when comparing with the unsettled granule of kinetics reduces.In this case, energy adds step and causes breaking of friable particle.Granule by suspension before guaranteeing is in frangible state, when not handling organic compound with frangible form relatively the time with taking steps to give organic compound, the organic compound among the former can be by the easier granule that is prepared into more quickly within the required size scope.
IV. the 4th technology category
The method of the 4th technology category comprises the step of first technology category, except blend step and energy add step carries out simultaneously.
Short grained pulverizing and stable
As mentioned above, utilize U.S. patent No.5, the equipment described in 720,551 (" ' 551 patents ") can be finished a preferred annealing process.' 551 patent has been described the method and apparatus of the emulsion that is used to generate two unmixing liquid phases.One is oil phase mutually, and wherein droplet or solid particle are dissolved in insoluble fluid in oil or the some other water.Other liquid phases in the patent of ' 551 are described as and contain water.Oil phase and aqueous liquid phase are mixed the back by the charging of emulsifying pond.The emulsifying pond generates relative liquid stream.Relative liquid stream produces shearing force, impulsive force and cavitation power.These power help to pulverize oil phase, and provide essential mixing with bag by by pulverizing any new not bag of generating by the product surface.
Emulsifying process described in ' 551 patents comprises that oil phase resolves into the droplet of little more homogeneous, and wherein emulsifying agent and droplet interact and form emulsion.' 551 patent has been described liquid in the intravital decomposition of liquid, i.e. the decomposition of oil phase in containing water.This patent is not instructed the particulate decomposition of relative or complete water-insoluble solid.
There are many methods decomposition solids or crystal structure to become granule.A step of pulverized particles is described in U.S. patent No.5, and in 314,506, its instruction is hereby incorporated by reference, and constitutes part of the present invention.This patent disclosure fluid jet be orientated each other to generate high impact forces.This patent relates in particular to utilizes high impact forces to be used for little mixing that chemical reaction does not have the situation of participation.
The present inventor has been found that the drug particles that relies on impulsive force generation micron of the present invention and sub-micron fully causes problems.For example, that has determined has, for realizing that mean diameter is lower than 1 micron, need at least 20 times with 20,000 pounds per square inch (" psig ") by piston crack homogenizer.Use piston crack homogenizer to cause the bearing of homogenizer and the wearing and tearing of sealing so repeatedly, need often to change these parts.
It is believed that instruction of the present invention has solved and pass through to use high shear counter-current flow form in aqueous medium, to decompose and the relevant problem of stable granule organic compound.As mentioned above, this form causes a plurality of different power that act on the granule, makes solid particle cut or split into granule.Particularly, shear pattern causes shearing force, impulsive force and cavitation.One or more optional surfactants can be provided at and carry in particulate a large amount of fluid, make to take place when cutting or division, stay when not wrapping quilt surperficial, and surfactant wraps immediately by such surface, generates less stable particle.
Unexpected acceleration appears in the described device of Figure 18-22, conform to unexpected pressure decline, cause when local pressure in the fluid (water and surfactant) around the granule is reduced to the vapour pressure of this surrounding fluid down at once, in these install, cavitation just takes place.Vapour pressure descends and forms minute bubbles.A theory is thought, when these bubbles subside, generates shock wave in fluid, decomposes or the pyrolysis solid organic granular.
Relatively the differential of liquid stream causes shearing and appears at the indoor of Figure 18-21 shown device.Generally speaking, chamber core flow and particulate speed are more much higher with the speed (this speed is tending towards 0) of negative line feed basically at the inner surface near the chamber than fluid.Shearing causes aforesaid shearing force, impulsive force and cavitation power.
Generally speaking, the equipment of Figure 18-21 makes the solid particle in the fluid suspension advance with first direction in first liquid stream, until arriving at the barrier that places first-class the place ahead.It is mobile with second direction in second stream that this barrier makes suspension change direction.Second stream and direction are located and orientation with respect to first-class and direction, thereby cause shearing and cavitation between first liquid stream and second liquid stream.In one embodiment, first and second directions each other directly on the contrary or opposite substantially.
Referring now to Figure 18, decompose solid or crystal grain and become a short grained embodiment to illustrate by equipment 100.At equipment 100, solid particle in the suspensions such as all water as described herein and surfactant is forced through at least one and sprays generation hole 102, and enter hole 110, and wherein the kinetic energy of fluid jet 104 is absorbed by liquid stream 106, and described liquid stream 106 is to spray 104 oppositely flow around spraying 104.The liquid stream 104 of reverse flow and 106 impact and cavitation generation brute force, thereby further decomposition and hybrid solid granule generates stable micron, the granule of submicron or nanometer size owing to shearing.Thereby the granule that surfactant described herein is configured to easily flow with the contact pulverizing is stablized them.
When the hole 108 of fluid jet 104 inflow equipment 100, its maintenance is constant relatively.Spray 104 from the hole 108 inflow holes 110.Hole 110 is formed by cylindricality ring wall and hemispherical shock surface 112.In an alternative embodiment, semispherical surface 112 is flat or other shapes.When liquid stream 104 shock surfaces 112, reverse fluid flow also forms the second relevant annular adverse current stream 106.
Because 110 unique channels of coming out are to make direction opposite from the hole, thereby form annular adverse current stream 106.Adverse current stream 106 is forced to interact with the injection 104 that enters.For this reason, adverse current flows 106 absorption fluids and sprays 104 kinetic energy, generates strong reciprocal force.
The exchange of kinetic energy makes the fluid temperature (F.T.) around the granule rise.Temperature rises harmful to some component in the suspension liquid stream 104 potentially.So, it is desirable to after granule is pulverized and stablized, cool off the stable particle of effusive fluid and pulverizing immediately.Therefore, after withdrawing from hole 110, stable product flows between surface 114 and 116 and flows through outlet opening 118.Provide cooling fluid 120 by hole 122.The stable product in hole 118 is withdrawed from cooling fluid 120 contacts.Cooling fluid 120 interacts with warm product, cooled product and further mix products.
The main adverse current character of cooling fluid 120 and the stable product that withdraws from is very effective heat change method.In one embodiment, cooling fluid 120 is a cold water.In another embodiment, use cool air or gasification nitrogen or carbon dioxide.Contain and pulverize and the stable particulate cooling fluid looping pit 124 by equipment 100 withdraws from.
In embodiment shown in Figure 180, if not too many, some solid particle takes place to decompose and pulverize in the process that generates fluid jet by opening 102 at least.The shearing forces that generated by adverse current stream 104 and 106 are further used for decomposition components and the component of pulverizing are mixed with the surfactant coating material, perhaps make the surface-stable between surfactant and the drug particles.Figure 18 shows, sprays or the suspension of liquid stream 104 for forming by said method A or method B.That is, flow through opening 102 generations at suspension and sprayed before 104, appeared as the chemical reaction that generates suspension and take place at some some place.
Referring now to Figure 19, alternate equipment 130 can be mixed with machine solvent and medicine and aqueous solution to precipitate drug particles and to implement above-mentioned and equipment 100 function associated Figure 18 with water.Equipment 130 comprises many aforesaid same assemblies, such as the opening 102 of the injection that produces fluid 204.Fluid jet 204 is with the difference of spraying 104, before component is mixed, spray 204 and comprise the component that can be mixed with the machine solvent by disclosed medicine of the method A of Fig. 1 and water, perhaps relevant, aforesaid medicine, the component of solvent or one or more surfactants with the method B of Fig. 2.
The granule of pulverizing may not have time enough fully to be stabilized in the nozzle 102.So, in case aqueous medium and optional surfactant solution 206 are drawn to medicine via venturi pump, water can be mixed with machine solvent and optional surfactant stream 204 when taking place to mix, solids precipitation, and in nozzle 112 or adjacent nozzles 112 places pulverized, injection stream 104 flows through hole 108, enters hole 110 and shock surface 112.Second liquid stream, 106 relative liquid stream 104 flow, and generate shearing force, impulsive force and the cavitation of suspension.This shearing is further decomposed granule and granule is mixed with fluid, to wrap by granule or the bag on the granule is stabilized.The same, stabilized fluid withdraws from hole 118, runs into the cooling fluid that enters via hole 122 or the adverse current of gas 120 at this.Cooling and stable suspension withdraw from equipment 130 via looping pit 124.
Figure 19 is open fire and optional surfactant 206 for example, is drawn in the stream that contains medicine and solvent 204 via pipe 126.It should be understood that reversing also is possible, its Chinese medicine and solvent 204 are drawn to water and surfactant stream 206 via pipe 126.
Figure 18 and 19 illustrational embodiments have single fluid inlet (Wen's embodiment of Figure 19 finally comprises the single stream 104 that flows through opening 102).Referring now to Figure 20 and 21, illustrational various embodiments comprise a plurality of imports.That is, the component to premixed suspension 104 or its formation has two entrances.The equipment 140 of illustrational Figure 20 is presented at injected suspension 104a in separated point place and the 104b (being referred to as suspension 104) in the equipment 140.Figure 21 illustrates, and water and optional surfactant 206 are injected into an end of equipment 170, and medicine and solvent 204 are injected into the another side of equipment 170.
The fluid form that it should be understood that Figure 20 and 21 is not subject to illustrational import structure, alternately comprises the structure of other equipment or different import structures together.For example, in equipment 140 or 170, suspension 104 can be by import injection, is injected at other imports for mixing suspension or for the custom-designed separate fluid of cooling suspension simultaneously.
The equipment 140 of Figure 20 comprises inner shell 142 and shell 144.Inner shell 142 comprises end cap 146 and 148.Nozzle 150 is soldered to end cap 146, and nozzle 152 is soldered to end cap 148.
What settled in the somewhere in the inner shell 142 is nozzle 154 and striking face 156.In one embodiment, nozzle 154 and striking face 156 are soldered to one or more thin (for example, metal) plates 158, and thin plate welds again or is fixed in the inner shell 142.Nozzle 154 and striking face 156 make double-jet aeration 104a and 104b aligned with each other, and with cut mode but not interact in direct bump mode.As mentioned above, it is believed that to shear to cause various power, further decompose the SOLID ORGANIC granule in the fluid suspension 104.The surfactant that provides in the surface that shearing force also will be sheared and the suspension mixes, with bag quilt and the stable new granule that forms.For this reason, the elongated character of relative liquid stream is also for mixing and wrap the longer time of contact that provides of quilt.
Utilization enters the liquid stream of the suspension fluid 104a of system from nozzle 150, and path 160 generates shearing force, impulsive force and cavitation power.With respect to Figure 18 and 19, equipment 140 can increase particle breakdown and blended level, and this is because the difference that the speed difference of the vector of 104a and 160 generates greater than high interior velocity flow and low outer velocity flow by Figure 18 and 19.
The annular shape of end cap 146 is similar to sugar and receives the cross section of sub-shell bag quilt, and annular stream 160 in being configured to outwards guide again along the inner surface of inner shell 142, to form outer ring stream 162.Outer ring stream 162 is sheared with interior annular stream 160 conversely, generates other power, further decomposes granule and mixing.Outer ring path 162 finally is forced to leave by what inner shell 142 formed and is withdrawed from opening 164.
In the zone that space between inside and outside shell 142 and 144 generates, above-mentioned cooling fluid 120 is injected via inlet ports 166, and mixes with granule stable and that pulverize.Cooling fluid 120 is any above-mentioned cooling fluid.Then, cooling and steady suspension withdraw from shell 144 via port one 68.
The equipment 170 of Figure 21 is similar to the equipment 140 of Figure 20.Equipment 170 comprises inside and outside shell 172 and 174.Inner shell 172 is equipped with end cap 176 and 178.End cap 176 has the above-mentioned annular relevant with end cap 146 or sugar and receives sub-shell shape of cross section.Equipment 170 further comprises the nozzle 180 and 182 that is soldered to end cap 176 and 178 separately.
Another difference is, the component of suspension, but not the component of premixed suspension are injected by nozzle 180 and 182.In illustrational embodiment, water and surfactant liquid stream 206 are injected by nozzle 180.The concave surface of liquid stream 206 shock surfaces 186.Thus, surface 186 flowing often with reverse deflection liquid stream 206.Medicine and solvent streams 204 are injected by nozzle 182, generate the injection stream of the convex surface of impact surface 186.
Annular stream 190 in end cap 176 outwards turns to generates outer ring stream 192.Outer ring stream 192 is sheared with interior annular stream 190, provides required in addition product size to reduce, and mixes and stablizing effect.By in nozzle 180 and 182 and the transfer of the kinetic energy in the shell 172 product of heating leave shell 172 via withdrawing from opening 194.Coolant 120 enters shell 174 by inlet ports 196, and moves forward into the chamber that generates between inside and outside shell 172 and 174.The suspension of shell 172 is left in coolant 120 coolings.Then, refrigerative pulverizing and steady suspension withdraw from shell 172 via port one 98.
It should be understood that equipment 140 and 170 has utilized a large amount of particle breakdown that occur owing to the nozzle effect of nozzle 150,152,180 and 182.Although two nozzles are provided in the illustrational embodiment, can consider the nozzle of any suitable number.In another embodiment, flow and to open arbitrary end from single-nozzle, or be divided into many (that is, more than two) import via manifold and flow to equipment 140 and 170.
Referring now to Figure 22 and 23, illustrate nozzle 200 of the present invention.From above-mentioned discussion, should be realized that, because the cavitation nozzle effect generates instant the acceleration and increase power.The reason that cavitation occurs is the speed difference between the high relatively speed in speed that the nozzle wall place is low relatively and nozzle center place.Nozzle 200 comprises turbulence structure 210.Turbulence structure 210 also is shown among Figure 23.
Turbulence structure 210 is carried out two functions.At first, it generates turbulent flow, increases the mixing and the decomposition of solid particle of the present invention.Further, it increases surface area and is used to generate shearing force between the baffle surface place zero velocity stream and high-speed the flowing between the surface.
Turbulence structure 210 comprises centering bar 212 and is connected, and for example welds the baffle plate 214-220 on it.As shown in the figure, be generally semicircular baffle plate 214-220 radius and reduce, make structure 210 be adapted in the nozzle 200.In one embodiment, baffle plate 214-220 is with the welded corner joint of 212 90 ° on relative centering bar or fixing.In an alternative embodiment, baffle plate is with than more precipitous or more shallow angular orientation shown in Figure 22, or perpendicular to centering bar 212.Figure 23 illustrates, and plate washer 214-220 also is fixed on diverse location around bar 212.In this way, baffle plate generates and progressively clashes into continuously to flow through nozzle 200.
Should be realized that for the given flow velocity of nozzle 200, the open area of the port of export 222 defines the muzzle velocity of suspension fluid 104 for suspension fluid 104.This speed is independent of nozzle 200 and whether comprises turbulence structure 210.Therefore, device 210 does not reduce the speed of outlet suspension fluid, owing to be positioned at the stream of nozzle downstream, opposite orientation, should not reduce the effect of above-mentioned shearing force.Yet, turbulence structure 210 should increase from the pump of the component that drives suspension or suspension by high pressure (for example, 10,000-40,000psig) amount of the energy of Xi Shouing.
Referring now to Figure 24 and 25, understand that for example apparatus and method according to the invention prepares a kind of result of suspension fluid.Utilization is very similar to equipment shown in Figure 180, and obtains the result.The for example clear test suspension liquid stream body of Figure 24 contains the antifungal itraconazole with 1% amount.The result who pulverizes the suspension of Figure 24 via device of the present invention compares in Figure 25 with the result who pulverizes same suspension fluid via above-mentioned piston crack method.
Figure 25 understands that for example adverse current of the present invention (" CF ") system generates littler mean diameter than piston crack method.Further, contracurrent system of the present invention has produced narrower distribution of particles, shown in the small size of 99% above accumulated size distribution.Equipment of the present invention and method with concrete granule disclosed herein and combinations-of surfactants, generate less with the more consistent granule of size than piston crack method.
Polymorph control
Thereby the present invention further provides the suspension that crystal structure final production that additional step is used to control organic compound is provided the chemical compound of required size range and required crystal structure.Term " crystal structure " expression atom is in the intracell arrangement of crystal unit.The chemical compound that can be crystallized into the different crystal structure be it is said polymorphic.Polymorph identifies that be important step in the medicine preparation, this be because the different polymorph of same medicine in dissolubility, therapeutic activity, bioavailability and stability of suspension aspect there are differences.Therefore, importantly control the polymorph of chemical compound, with guarantee product purity and batch between repeatability.
The step of polymorph of control chemical compound comprises and adds crystal seed in first solution that second solvent or preceding suspension are to guarantee to form required polymorph.Adding crystal seed comprises and utilizes the crystal seed chemical compound or add energy.In the preferred form of the present invention, the crystal seed chemical compound is the required polymorph of pharmaceutical active compounds.In addition, the crystal seed chemical compound also can be inert impurities, structurally but chemical compound with nucleus imitation feature, perhaps structure to required polymorph similar organic compound uncorrelated with required polymorph.
The crystal seed chemical compound can precipitate from first solution.This method comprises with capacity and adds organic compound, surpass this organic compound in first solvent dissolubility and generate the step of supersaturated solution.Handle supersaturated solution and be settled out organic compound with required polymorph.Handle supersaturated solution and comprise that one time period of aged solution is crystal formation to produce the crystal seed mixture until observing.Also might in supersaturated solution, add energy from solution so that organic compound is precipitated out with required polymorph.Energy adding mode is varied, comprises that above-mentioned energy adds step.By heating, or suspension is exposed to electromagnetic energy before making, and particle beam or electronic beam current source can add more multipotency.Electromagnetic energy comprises luminous energy (ultraviolet, visible or infrared light) or such as the coherent radiation that is provided by laser instrument, by the microwave energy that maser (microwave by radiating stimulated emission amplifies) provides, dynamically electromagnetic energy, or other radiation sources.Further can estimate, utilize ultrasonic, static electric field or static magnetic field, or its combination adds the source as energy.
In the preferred form of the present invention, the method of producing seeding crystals from aging supersaturated solution comprises the following steps: that (i) adds some organic compound to the first organic solvents and generate supersaturated solution, make (ii) that supersaturated solution is aging to form detectable crystal producing the crystal seed mixture, and (iii) mix crystal seed mixture and the second solvent deposition organic compound to produce preceding suspension.Then, preceding suspension can be further processed as mentioned above, thereby provides the aqueous suspension of organic compounds with required polymorph and required size scope.
Adding crystal seed also can be by adding energy to the first solution, second solvent or preceding suspension and finish, and condition is that the liquid of exposure contains organic compound or crystal seed material.Energy also can add by above-mentioned the same manner to supersaturated solution.
Therefore, the invention provides the compositions that has required polymorph, is substantially free of non-special polymorphic organic compound material.In the preferred form of the present invention, organic compound is a pharmaceutically active substance.A kind of such example is set forth in hereinafter embodiment 16, and wherein adding crystal seed in the microdeposit process provides the polymorph that is substantially free of the raw-material itraconazole of polymorph.Method of the present invention estimates that can be used for selectivity produces required polymorphic numerous pharmaceutical active compounds.
Embodiment
A. the embodiment of technology category 1
Embodiment 1: by using technology category 1, method A and homogenize prepare the itraconazole suspension
The water for injection that in the 3L flask, adds 1680ml.Heating liquid slowly adds the Pluronic F-68 (poloxamer 188) of 44g then to 60-65 ℃, and the NaTDC of 12g, stirs after each the adding so that the solid dissolving.Solid add finish after, stir in addition at 60-65 ℃ and to dissolve fully guaranteeing in 15 minutes.6.06g tris is dissolved in preparation 50mM tris (tromethamine) buffer in the water for injection of 800ml.With this solution of 0.1M salt acidometric titration to pH 8.0.With extra injection dilute with water gained solution to 1 liter.The tris buffer that adds 200ml is to poloxamer/ deoxycholic acid saline solution.Fully stir with mixed solution.
In the 150ml beaker, add the itraconazole of 20g and N-methyl-2-pyrrolinone of 120ml.Heating blends is to 50-60 ℃, and stirring makes the solid dissolving.Range estimation is all after the dissolving, continues to stir to dissolve fully guaranteeing in 15 minutes.Cooling itraconazole-nmp solution is to room temperature.
Itraconazole solution filling syringe pump (two 60ml glass syringes) with the 120ml prepared beforehand.Simultaneously all surface activator solution is poured onto the homogenizer funnel that is cooled to 0-5 ℃ (this can by utilize coolant therefrom circulation chuck funnel or by realizing around funnel with ice).Make mechanical agitator place surfactant solution, so that complete submergence blade.Use syringe pump, slowly (1-3ml/ minute) adds all itraconazole solution to stirring refrigerative surfactant solution.Stir speed (S.S.) is recommended 700rpm at least.Adopt optical microscope (Hoffman Modulation Contrast) and laser diffraction (Horiba) to analyze the sample aliquot of gained suspension (suspending liquid A).By the observation by light microscope suspending liquid A, find that it consists of roughly spheric amorphous granular (1 μ m is following), is bonded to each other with aggregation, or moves freely by Brownian movement.Referring to Fig. 3, dynamic light scattering measurement provides the double-peak type distribution pattern usually, and there is aggregation (10-100 μ m size) in expression and has median particle diameter is the single amorphous granular of 200-700nm.
Suspension immediately homogenize (10,000-30,000psi) 10-30 minute.When homogenize finished, the temperature of suspension in funnel was no more than 75 ℃.The suspension of homogenize is collected in the 500ml bottle, cooling in refrigerator (2-8 ℃) immediately.Analyze this suspension (suspension B) by optical microscope, find that it consists of the little lengthy motion picture of long 0.5-2 μ m, wide 0.2-1 μ m.Referring to Fig. 4.Dynamic light scattering measurement shows that generally median diameter is 200-700nm.
The stability of suspending liquid A (" preceding suspension ") (embodiment 1)
In the sample aliquot process of micrography suspending liquid A, observe directly crystalline amorphous solid.Suspending liquid A was stored 12 hours at 2-8 ℃, and passed through light microscopy.Sample is slightly estimated discovery serious flocculation, and some content is settled down to the bottom of container.Microscopy shows the strip sample crystal that exists length 10 μ m above, big.
The stability of suspension B
Opposite with the unstability of suspending liquid A, suspension B is the 2-8 ℃ of persistent period (1 month) that can stablize the precondition Journal of Sex Research.Microscopy to aged samples shows that clearly significant the variation do not taken place for particulate form or size.Also confirm so by light scattering measurement.
Embodiment 2: by utilizing technology category 1, method A and ultrasound wave prepare the itraconazole suspension
The water for injection that adds 252ml to the 500ml rustless steel container.Heating liquid slowly adds the Pluronic F-68 (poloxamer 188) of 6.6g then to 60-65 ℃, and the NaTDC of 0.9g, stirs after each the adding so that the solid dissolving.Solid add finish after, stir in addition at 60-65 ℃ and to dissolve fully guaranteeing in 15 minutes.6.06g tris is dissolved in preparation 50mM tris (tromethamine) buffer in the water for injection of 800ml.With this solution of 0.1M salt acidometric titration to pH 8.0.With extra injection dilute with water gained solution to 1 liter.The tris buffer that adds 30ml is to poloxamer/ deoxycholic acid saline solution.Fully stir with mixed solution.
In the 30ml container, add the itraconazole of 3g and N-methyl-2-pyrrolinone of 18ml.Heating blends is to 50-60 ℃, and stirring makes the solid dissolving.Range estimation is all after the dissolving, continues to stir to dissolve fully guaranteeing in 15 minutes.Cooling itraconazole-nmp solution is to room temperature.
Itraconazole solution filling syringe pump with the preparation of 18ml above-mentioned steps.Mechanical agitator is placed surfactant solution, so that complete submergence blade.Submergence in ice bath is so that container is cooled to 0-5 ℃.Use syringe pump, slowly (1-3ml/ minute) adds all itraconazole solution to stirring refrigerative surfactant solution.Stir speed (S.S.) is recommended 700rpm at least.Submergence Ultrasound Instrument horn is in the gained suspension, so that probe is higher than the nearly 1cm in rustless steel container bottom.Ultrasonic (10,000-25,000Hz, 400W at least) 15-20 minute, be 5 minutes blanking time.First 5 minutes ultrasonic after, shift out ice bath, further ultrasonic.During ultrasonic end, the temperature of suspension in container is no more than 75 ℃.
Suspension is collected in the 500ml I type vial, cooling in refrigerator (2-8 ℃) immediately.Closely similar (referring to the embodiment 1) that the particle shape feature of this suspension is seen before and after the homogenize of ultrasonic front and back and method A.
Embodiment 3: utilize technology category 1, method B and homogenize prepare the itraconazole suspension
6.06g tris is dissolved in preparation 50mM tris (tromethamine) buffer in the water for injection of 800ml.With this solution of 0.1M salt acidometric titration to pH 8.0.With extra injection dilute with water gained solution to 1 liter.The water for injection that in the 3L flask, adds 1680ml.The tris buffer that adds 200ml is to the water of 1680ml.Fully stir with mixed solution.
The NaTDC of the Pluronic F-68 (poloxamer 188) of adding 44g and 12g is to N-methyl-2-pyrrolinone of 120ml in the 150ml beaker.Heating blends is to 50-60 ℃, and stirring makes the solid dissolving.Range estimation is all after the dissolving, continues to stir to dissolve fully guaranteeing in 15 minutes.The itraconazole that adds 20g in this solution stirs until dissolving fully.Cooling itraconazole-surfactant-nmp solution is to room temperature.
Dense itraconazole solution filling syringe pump (two 60ml glass syringes) with the 120ml prepared beforehand.The tris buffer solution of the above-mentioned preparation that will dilute simultaneously be poured onto the homogenizer funnel that is cooled to 0-5 ℃ (this can by utilize coolant therefrom circulation chuck funnel or by realizing around funnel with ice).Mechanical agitator is placed buffer solution, so that complete submergence blade.Use syringe pump, slowly (1-3ml/ minute) adds all itraconazoles-surfactant concentrated solution to stirring refrigerative buffer solution.Stir speed (S.S.) is recommended 700rpm at least.The refrigerative suspension of gained immediately homogenize (10,000-30,000psi) 10-30 minute.When homogenize finished, the temperature of suspension in funnel was no more than 75 ℃.
The suspension of homogenize is collected in the 500ml bottle, cooling in refrigerator (2-8 ℃) immediately.The particle shape feature of suspension is very similar to before and after the homogenize seen in the embodiment 1, and except in technology category 1B, the material of homogenize tends to form still less and littler aggregation in advance, causes much smaller total particle diameter, and is measured as laser diffraction.After the homogenize, the dynamic light scattering result is identical with shown in the embodiment 1 usually.
Embodiment 4: utilize technology category 1, method B and ultrasound wave prepare the itraconazole suspension
The water for injection that adds 252ml to the 500ml flask.6.06g tris is dissolved in preparation 50mM tris (tromethamine) buffer in the water for injection of 800ml.With this solution of 0.1M salt acidometric titration to pH 8.0.With extra injection dilute with water gained solution to 1 liter.The tris buffer that adds 30ml is to water.Fully stir with mixed solution.
The NaTDC of the Pluronic F-68 (poloxamer 188) of adding 6.6g and 0.9g is to N-methyl-2-pyrrolinone of 18ml in the 30ml beaker.Heating blends is to 50-60 ℃, and stirring makes the solid dissolving.Range estimation is all after the dissolving, continues to stir to dissolve fully guaranteeing in 15 minutes.In this solution, add the itraconazole of 3.0g, and stir until dissolving fully.Cooling itraconazole-surfactant-nmp solution is to room temperature.
Dense itraconazole solution filling syringe pump (a 30ml glass syringe) with the preparation of 18ml above-mentioned steps.Mechanical agitator is placed buffer solution, so that complete submergence blade.Submergence in ice bath is so that container is cooled to 0-5 ℃.Use syringe pump, slowly (1-3ml/ minute) adds all itraconazoles-surfactant concentrated solution to stirring refrigerative buffer solution.Stir speed (S.S.) is recommended 700rpm at least.The refrigerative suspension of gained ultrasonic immediately (10,000-25,000Hz, 400W at least) 15-20 minute, be 5 minutes blanking time.First 5 minutes ultrasonic after, shift out ice bath, further ultrasonic.During ultrasonic end, the temperature of suspension in leaking material is no more than 75 ℃.
The gained suspension is collected in the 500ml bottle, cooling in refrigerator (2-8 ℃) immediately.The particle shape feature of this suspension closely similar seen in ultrasonic front and back and embodiment 1, except at technology category 1, among the method B, ultransonic in advance material tends to form still less and littler aggregation, causes much smaller total particle diameter, learns as laser diffraction.After ultrasonic, dynamic light scattering is identical with shown in the embodiment 1 generally.
B. the embodiment of technology category 2
Embodiment 5: utilize 0.75% Solutol HR (PEG-660 12-hydroxy stearic acid ester) technology category 2, method B prepares itraconazole suspension (1%)
Weigh Solutol (2.25g) and itraconazole (3.0g) to beaker, add the filtering N-methyl of 36ml-2-pyrrolinone (NMP).This mixture low heating (up to 40 ℃) down stir about 15 minutes dissolve until solution composition.Solution is cooled to room temperature, and the filter by 0.2 μ m filters under vacuum.Two 60ml syringes load filtering medicine concentrated solution, place syringe pump.This pump is set the water buffer solution that the concentrated solution that makes nearly 1ml/min is passed to quick stirring (400rpm).Buffer solution is the 5mM tris buffer of 22g/L glycerol.In whole concentrated solution adition process, buffer solution remains in 2-3 ℃ the ice bath.When precipitation finished, after concentrated solution all added to buffer solution, centrifugal 1 hour of the suspension of about 100ml abandoned supernatant.Precipitate is resuspended in the water of 20% nmp solution recentrifuge 1 hour.The gained material is 25 ℃ of following dried overnight in vacuum tank.Drying material is transferred in the bottle, utilizes the chromium radiation to learn by X-ray diffraction then and analyzes.
The microdeposit suspension of 100ml sample aliquot is expired amplitude (full amplitude=600W) ultrasonic 30 minute with 80% 20 under the 000Hz in addition.Ultrasonic sample is homogenize in 3 equal samples, each 45 minutes (Avestin C5,2-5 ℃, 15,000-20,000psi).Combination stage was divided centrifugal about 3 hours, shifts out supernatant, and precipitate is resuspended among the 20%NMP.The mixture recentrifuge of resuspension (15,000rpm, 5 ℃).Topple over supernatant, precipitate spends the night at 25 ℃ of vacuum dryings.Precipitate submits to the X-ray diffraction credit to analyse (referring to Fig. 5).As shown in Figure 5, the X-ray diffraction pattern of handling sample is identical before and after homogenize basically, yet more still shows significant difference with the pattern of initiation material.The suspension of homogenize is not unsettled, assembles when storing under the room temperature.As the result of homogenize, stability it is believed that and originates from the rearrangement of surfactant on particle surface.This rearrangement causes the tendency of particle aggregation to reduce.
C. the embodiment of technology category
Embodiment 6: by utilizing technology category 3, method A and homogenize prepare the carbadipimidine suspension
2.08g carbadipimidine be dissolved in the NMP of 10ml.1.0ml this concentrated solution drop to the agitating solution of 20ml 1.2% lecithin and 2.25% glycerol subsequently with 0.1ml/min.The temperature of lecithin system maintains 2-5 ℃ in whole adition process.Then, preceding dispersion is with 15,000psi cold (5-15 ℃) homogenize 35 minutes.Pressure is increased to 23,000pis, and continued homogenize 20 minutes.The particulate average diameter of technology generation is 0.881 μ m thus, and wherein 99% granule is less than 2.44 μ m.
Embodiment 7: by utilizing technology category 3, method B and homogenize preparation contain the 1% carbadipimidine suspension of 0.125% Solutol
The medicine concentrated solution for preparing the N-methyl-2-pyrrolinone of 20% carbadipimidine and 5% sweet deoxycholic acid (Sigma Chemical Co.).The microdeposit step comprises that the speed with 0.1ml/min adds the medicine concentrated solution in acceptable solution (distilled water).Stir acceptable solution, and in precipitation process, maintain nearly 5 ℃.Post precipitation, composition ultimate density are 1% carbadipimidine and 0.125%Solutol .Under optical microscope, utilize positive lining (400 *) to check medicine crystal.Granulometric composition is the fine needle of nearly 2 μ m of diameter and length 50-150 μ m.
Nearly 20,000psi homogenize (Avestin C-50 piston crack homogenizer) caused little granule in about 15 minutes, and size is less than 1 μ m, and major part is not assembled.All the laser diffraction analysis (Horiba) of formed material shows, particulate average-size is 0.4 μ m, and wherein 99% granule is less than 0.8 μ m.The low-yield ultrasonic accumulative granule that is suitable for breaking, but its energy shortage to be causing the pulverizing of individual particle, the low-yield ultrasonic of sample do not influence (have ultrasonic with do not have ultrasonic number the same) to the result before Horiba analyzes.This result lacks consistent with particle aggregation.
Sample by above-mentioned prepared is centrifugal, and supernatant is replaced with the replacement liquid of 0.125% Solutol .After centrifugal and supernatant was replaced, the suspension constituent concentration was 1% carbadipimidine and 0.125% Solutol .Sample is through piston crack homogenizer homogenize again, and is stored in 5 ℃.After storing for 4 weeks, the mean diameter of suspension is 0.751, wherein has 99% less than 1.729.The report number from Horiba to the not analysis of ultrasonic sample.
Embodiment 8: utilize technology category 3, method B and homogenize preparation contain the 1% carbadipimidine suspension of 0.06% Sodium glycodeoxycholate. and 0.06% poloxamer 188
Preparation contains the medicine concentrated solution of the N-methyl-2-pyrrolinone of 20% carbadipimidine and 5% sweet deoxycholic acid.The microdeposit step comprises that the speed with 0.1ml/min adds the medicine concentrated solution in acceptable solution (distilled water).Therefore, the following example proves, adds surfactant in aqueous precipitate solution or other excipient are chosen wantonly in method A and B.Acceptable solution stirs, and maintains nearly 5 ℃ in precipitation process.Post precipitation, composition ultimate density are 1% carbadipimidine and 0.125% Solutol .Under optical microscope, utilize positive lining (400 *) to check medicine crystal.Granulometric composition is the fine needle of nearly 2 μ m of diameter and length 50-150 μ m.Precipitate with the precipitation before raw material comparison shows that the settling step in the presence of surface modifier (sweet deoxycholic acid) causes very tiny crystal, than the raw material that sets out thin many (referring to Fig. 6).
Nearly 20,000psi homogenize (Avestin C-50 piston crack homogenizer) caused little granule in about 15 minutes, and size is less than 1 μ m, and major part is not assembled.Referring to Fig. 7.All the laser diffraction analysis (Horiba) of formed material shows, particulate average-size is 0.4 μ m, and wherein 99% granule is less than 0.8 μ m.Before Horiba analyzes, sample ultrasonic to not influence of result (have ultrasonic with do not have ultrasonic number the same).This result lacks consistent with particle aggregation.
Sample by above-mentioned prepared is centrifugal, and supernatant is replaced with the replacement liquid of 0.06% sweet deoxycholic acid (SigmaChemical Co.) and 0.06% Poloxamer 188.Sample is through piston crack homogenizer homogenize again, and is stored in 5 ℃.After storing for 2 weeks, the mean diameter of suspension is 0.531 μ m, wherein has 99% less than 1.14 μ m.The report number from Horiba to the not analysis of ultrasonic sample.
The set out required power of granule of raw material (carbadipimidine) of mathematical analysis (embodiment 8) and destruction is compared the required power of deposit seed of destroying:
The crystalline width of visible maximum in the carbadipimidine raw material (Fig. 6, left width of cloth figure) is roughly big 10 times than crystalline width in the microdeposit material (Fig. 6, right width of cloth figure).The ratio (1: 10) of supposing crystal thickness is proportional with the ratio of crystal width (1: 10), and the moment required than megacryst should roughly be to destroy 1000 times of the required power of microdeposit material in the raw material that splits, this be because:
e
L=6PL/ (Ewx
2) equation 1
Wherein,
e
LThe required longitudinal strain (" yield value ") of=destruction crystal
Load on the P=beam
L=is from the distance of the fulcrum of loading
The E=modulus of elasticity
W=crystal width
The x=crystal thickness
The L that supposes raw material and deposited material is identical with E.
In addition, suppose w/w
0=x/x
0=10.Then,
(e
L)
0=6P
0L (Ew
0x
0 2), wherein ' 0 ' subscript refers to raw material
e
L=6PL (Ewx
2), for microdeposit
Make (e
L)
0=e
L,
6PL(Ewx
2)＝6P
0L(Ew
0x
0 2)
After the simplification,
P＝P
0(w/w
0)(x/x
0)
2＝P
0(0.1)(0.1)
2＝0.001P
0
Thus, destroy the required yield force P of microdeposit solid for destroying the one thousandth of the required power of crystalline solid of setting out.If because rapid precipitation, introduce lattice defect or amorphous attribute, then modulus (E) should reduce, and makes microdeposit even easier incision.
Embodiment 9: by utilizing technology category 3, method B preparation contains 1.6% (w/v) prednisolone suspension of 0.05% NaTDC and 3%N-methyl-2-pyrrolinone
Total preparation process sketch map as shown in Figure 8.The concentrated solution of the pure and mild NaTDC of preparation dehydrogenation cortex.The 1-methyl 2-pyrrolinone (NMP) that prednisolone (32g) and NaTDC (1g) is added to enough volumes generates final volume 60ml.Gained dehydrogenation cortex determining alcohol is nearly 533.3mg/ml, and the about 16.67mg/ml of deoxycholic acid na concn.The NMP concentrated solution of 60ml is added to 2L with the adding speed of 2.5ml/min and is cooled in 5 ℃ the water, simultaneously with about 400rpm stirring.The gained suspension contains fine needle type crystal, and width is less than 2 μ m (Fig. 9).Contained concentration is 1.6% (w/v) prednisolone in the precipitation suspension, 0.05% NaTDC, and 3%NMP.
The pH of precipitation suspension utilizes sodium hydroxide and saline to be adjusted to 7.5-8.5, then 10, and homogenize under the 000psi (Avestin C-50 piston crack homogenizer) 10 times.Shift out NMP by double centrifugation step, replace supernatant with the unsalted surface activator solution at every turn, described unsalted surface solution contains the surfactant (referring to table 2) of stable suspension desired concn.Suspension is 10, and other homogenize is 10 times under the 000psi.The granule mean diameter that final suspension contains is less than 1 μ m, and wherein 99% granule is less than 2 μ m.Figure 10 is the microphotograph of final prednisolone suspension after the homogenize.
Centrifugal/surfactant replacement step (referring to table 2) that the various surfactants of variable concentrations are used for.Table 2 has been listed particle diameter (average＜1 μ m, 99%＜2 μ m) pH (6-8), drug level (loss is less than 2%) and can resuspended buoyancy the combination of (at 60 seconds or resuspension still less) stabilized surfactant.
Obviously, this technology considers do not having to add reactive compound to containing water diluent in the presence of surfactant or other additives.This is the modification of process B among Fig. 2.
Table 2: the stable prednisolone suspension tabulation (embodiment 9) of the microdeposit prepared by Fig. 8
| 2 weeks | February | ||||||||||
| Initially | 40 | 5 | 25℃ | 40℃ | |||||||
| Prescription | On average | ＞99％ | On average | ＞99％ | On average | ＞99％ | On average | ＞99％ | On average | ＞99％ | The % loss * |
| 1.6% prednisolone, 0.6% phospholipid, 0.5% NaTDC, 5mM TRIS, 2.2% glycerol * | 0.79 | 1.65 | 0.84 | 1.79 | 0.83 | 1.86 | 0.82 | 1.78 | 0.82 | 1.93 | ＜2％ |
| 1.6% prednisolone, 0.6%Solutol , 0.5% NaTDC, 2.2% glycerol | 0.77 | 1.52 | 0.79 | 1.67 | 0.805 | 1.763 | 0.796 | 1.693 | 0.81 | 1.633 | ＜2％ |
| 1.6% prednisolone, 0.1%poloxamer 188,0.5% NaTDC, 2.2% glycerol | 0.64 | 1.16 | 0.82 | 1.78 | 0.696 | 1.385 | 0.758 | 1.698 | 0.719 | 1.473 | ＜2％ |
| 1.6% prednisolone, 5% phospholipid, 5mM TRIS, 2.2% glycerol | 0.824 | 1.77 | 0.87 | 1.93 | 0.88 | 1.95 | 0.869 | 1.778 | 0.909 | 1.993 | ＜2％ |
*Itraconazole concentration at sample in 5 and 25 ℃ of following differences between the storage 2 months.
*At least 6 months stablize.
Particle diameter (passing through determination of laser light scattering), μ m:
5 ℃: 0.80 (on average), 1.7 (99%)
25 ℃: 0.90 (on average), 2.51 (99%)
40 ℃: 0.99 (on average), 2.03 (99%)
Itraconazole concentration at sample in 5 and 25 ℃ of following differences between the storage:＜2%
Embodiment 10: by utilizing technology category 3, method A and homogenize prepare the prednisolone suspension
The prednisolone of 32g is dissolved in the NMP of 40ml.For realizing that dissolving needs 40-50 ℃ of following mild heat.With 2.5ml/min medicine NMP concentrated solution is dropped to the agitating solution of 2L subsequently, agitating solution consist of 0.1.2% lecithin and 2.2% glycerol.Do not add other surface modifiers.Surfactant system cushions at pH=8.0 with 5mM tris buffer, and in whole depositing technology temperature maintenance at 0-5 ℃.Then the dispersion of post precipitation is 10, cold under the 000psi (5-15 ℃) homogenize 20 times.After the homogenize, the centrifugal removal of suspension NMP shifts out supernatant, and replaces supernatant with the unsalted surface activator solution.Suspension after this is centrifugal is 10, other 20 times of cold under the 000psi (5-15 ℃) weight averageization.The particulate average diameter of explained hereafter is 0.927 μ m thus, and wherein 99% granule is less than 2.36 μ m.
Embodiment 11: by technology category 3, method B and homogenize prepare the nabumetone suspension
Surfactant (poloxamer 188 of 2.2g) is dissolved in N-methyl-2-pyrrolinone of 6ml.This solution stirred 15 minutes down at 45 ℃, added the nabumetone of 1.0g thereafter.Medicine dissolves fast.The diluent of preparation consists of 5mM tris buffer and 2.2% glycerol, is adjusted to pH 8.The diluent cooling of 100ml part is in ice bath.Slowly add (near 0.8ml/min) medicine concentrated solution to diluent under the vigorous stirring.This thick suspension is 15, and homogenize is 30 minutes under the 000psi, then 20, and homogenize 30 minutes under the 000pis (temperature=5 ℃).Effective average diameter of final nano suspending liquid is 930nm (passing through laser diffraction analysis).99% granule is less than nearly 2.6 μ m.
Embodiment 12: by utilizing technology category 3, and method B and homogenize and utilize Solutol HS15 to prepare the nabumetone suspension as surfactant
Replace supernatant with the phospholipid medium
Nabumetone (0.987g) is dissolved in N-methyl-2-pyrrolinone of 8ml.The Solutol HS 15 that in this solution, adds 2.2g.Stirring this mixture is dissolved in the medicine concentrated solution fully until surfactant.The diluent of preparation consists of 5mM tris buffer and 2.2% glycerol, is adjusted to pH 8.Diluent is cooling in water-ice is bathed, and slowly adds (near 0.5ml/min) medicine concentrated solution to diluent under the vigorous stirring.This thick suspension is 15, and homogenize is 20 minutes under the 000psi, and 20, homogenize is 30 minutes under the 000pis.
Suspension is with 15, centrifugal 15 minutes of 000rpm, and shift out and abandon supernatant.The remaining solid spherolite is resuspended in the diluent that consists of 1.2% phospholipid.The volume of this medium equates with the amount of the supernatant that the preceding step shifts out.Then, the gained suspension is with nearly 21,000psi homogenize 30 minutes.Final suspension is by laser diffraction analysis, and finds that the average diameter of particles that contains is that 542nm and 99% cumulative distribution of particles size are less than 1 μ m.
Embodiment 13: preparation average diameter of particles about 220nm, contain the 1% itraconazole suspension of poloxamer
Itraconazole by dissolving 10.02g prepares the itraconazole concentrated solution in the N-of 60ml methyl-2-pyrrolinone.For dissolved substance need be heated to 70 ℃.Solution is cooled to room temperature then.The part of preparation 50mM three (methylol) aminomethane buffer solution (tris buffer), pH is adjusted to 8.0 with 5M hydrochloric acid.The preparation method of aqueous surfactant solution is combination 22g/Lpoloxamer 407,3.0g/L lecithin, 22g/L glycerol and 3.0g/L sodium cholate dihydrate.The surfactant solution of 900ml mixes the water diluent that contains that 1000ml is provided with the tris buffer of 100ml.
Contain the funnel that water diluent adds to homogenizer (APV Gaulin Model 15MR-8TA), this funnel utilizes the cooling of ice tongs cover.Solution stirs (4700rpm) and monitoring temperature fast.Utilize syringe pump, slowly add the itraconazole concentrated solution with the speed of about 2ml/min.Add after about 30 minutes and finish.The gained suspension stirred 30 minutes in addition, and funnel still cools off in the ice tongs cover simultaneously, shifts out sample aliquot and is used for optical microscope and dynamic light scattering analysis.Remaining suspension liquid is with 10 subsequently, 000psi homogenize 15 minutes.When homogenize finished, temperature had risen to 74 ℃.The homogenize suspension is collected in the 1LI type vial, and seals with rubber closure.The bottle that contains suspension is stored in 5 ℃ of refrigerators.
Suspension sample show sample before the homogenize is by free particles, and particulate mass and multilamellar lipid body are formed.Because Brownian movement, free particles can not clearly be seen; As if yet many aggregations are by amorphous, amorphous material is formed.
The homogenize sample contains the dimensional homogeneity excellence, does not have the free submicron particles of visible lipid vesicle.Dynamic light scattering shows single logarithm distribution of sizes, about 220nm of median diameter of disperseing.Accumulated size more than 99% is held back about 500nm.Figure 11 shows distribution of sizes and typical parenteral fats emulsion product (10%Intralipid , comparison Pharmacia) of the nano-particle of preparation.
Embodiment 14: preparation contains the preparation of 1% Itraconazole nanometer suspension solution A of hetastarch:
(1g Ajinomoto) is dissolved in N-methyl-2-pyrrolinone (NMP) of 3ml to hetastarch.This solution is heated to 70-80 ℃ in water-bath, last 1 hour.In another container, add the itraconazole (Wyckoff) of 1g.The NMP that adds 3ml, this mixture heated is dissolved (nearly 30 minutes) to 70-80 ℃ with realization.In this hot solution, add phospholipid (Lipoid S-100).Continue heating 30 minutes down at 70-90 ℃, until all phospholipid dissolvings.Hydroxyethyl starch solution and itraconazole/phospholipid solution combination.This mixture heats 30 minutes in addition with dissolving mixt under 80-95 ℃.
Solution A adds to 50mM three (methylol) the aminomethane buffer solution cooling of Tris buffer: 94ml in ice bath.Along with tris solution stirs fast, hot solution A (as mentioned above) slowly drips (less than 2cc/min).
After adding was finished, gained suspension ultrasonic (Cole-Parmer ultrasonic processor-20,000Hz, 80% amplitude setting) still cooled off in ice bath simultaneously.Utilize 1 inch solid probe.Ultrasonic lasting 5 minutes.Remove ice bath, shift out probe, be immersed in the suspension once more after readjusting.Suspension when not having ice bath ultrasonic 5 minutes in addition.Ultrasonic probe shifts out once more and readjusts, and makes sample ultrasonic 5 minutes in addition behind the submergence probe.At this moment, the temperature of suspension has risen to 82 ℃.Suspension cools off in ice bath once more fast, and impouring I type vial and sealing when being lower than room temperature.The single particle diameter of microscopically visible particle is in 1 μ m or magnitude still less.
Storage was reappraised the particle diameter of suspension after 1 year under the room temperature, found the about 300nm of average diameter.
Embodiment 15: the embodiment in advance that utilizes HES method A
The present invention estimates after the step of embodiment 14, utilizes method A preparation to contain 1% Itraconazole nanometer suspension of hetastarch, adds to the tris buffer except HES but not adds to nmp solution.Aqueous solution might must be heated with dissolving HES.
Embodiment 16: add crystal seed and make polymorphic mixture change into more stable polymorph in homogenization process
Sample preparation.Adopt following microdeposit homogenization process to prepare the Itraconazole nanometer suspension.Itraconazole (3g) and Solutol HR (2.25g) are dissolved in N-methyl-2-pyrrolinone (NMP) of 36ml under low grade fever and stirring, form the medicine concentrated solution.This solution is cooled to room temperature, and filters by 0.2 μ m nylon filter under vacuum, to remove undissolved medicine or particle matter.Under polarized light, observe this solution to guarantee not having crystalline material to exist after the filtration.Then, the medicine concentrated solution adds to the water-containing buffering liquid (the 5mM tris buffer of 22g/L glycerol) of about 264ml with the speed of 1.0ml/min.Aqueous solution remains on 2-3 ℃, and continues to stir nearly 400rpm in adding medicine concentrated solution process.The gained suspension of about 100ml is centrifugal, and solid is resuspended to before the filter of water of 20%NMP in the solution.This suspension is heavy centrifugal, and solid transfer is to vacuum tank, 25 ℃ of following dried overnight.Gained solid sample labelling SMP 2 PRE.
Sample characterization.Utilize the powder x-ray diffraction credit to analyse SMP 2 PRE samples and raw material itraconazole.Measure to adopt the Rigaku MiniFlex+ instrument of being furnished with copper radiation, step-length is that 0.02 ° 22 and scanning speed are 0.25 ° of 22/min.The gained powder diffraction is illustrated among Figure 12.Diffraction pattern shows that SMP-2-PRE significantly is different from raw material, and prompting exists different polymorph or false polymorph.
The differential scanning calorimetry of sample (DSC) trace is shown in Figure 13 a and b.Two samples all are heated to 180 ℃ in hermetic aluminum pan with 2 °/min.
(Figure 13 a) shows that endothermic peak is at about 165 ℃ to the trace of raw material itraconazole.
The trace of SMP 2 PRE (Figure 13 b) shows two heat absorptions of about 159 ℃ and 153 ℃.This result and powder x-ray diffraction figure combination, prompting SMP 2 PRE are made up of polymorphic mixture, and principal mode is polymorph, and are more unstable than the polymorph that exists in the raw material.
The further evidence of this conclusion is provided by the DSC trace among Figure 14, and it shows 2 PRE by the first transformation heating SMP, then cooling and reheating, more unsettled polymorph fusing, and the more stable polymorph of recrystallization formation.
Add crystal seed.Raw material itraconazole by combination solid SMP 2 PRE of 0.2g and 0.2g and distilled water are to final volume 20ml supending (crystal seed sample).Stirred suspension soaks into until all solids.Prepare second suspension with the same manner, but do not add raw material itraconazole (not adding the crystal seed sample).Two suspensions are about 18, and homogenize is 30 minutes under the 000psi.The finishing temperature of homogenize rear suspension liquid is about 30 ℃.Then, centrifugal suspension, and about 16 hours of 30 ℃ of following drying solids.
Figure 15 shows the DSC trace that adds crystal seed and unseeded sample.In hermetic aluminum pan, the rate of heat addition of two samples is that 2 °/min is until 180 ℃.The trace of unseeded sample shows two endothermic peaks, still exists after showing polymorphic mixture homogenization.The trace that adds the sample of crystal seed shows, adds crystal seed and homogenize and causes solid to change into stable polymorph.So as if add crystal seed influences from unstable to the kinetics of stablizing polymorphic transformation.
Embodiment 17: add the stable polymorph of the preferential formation of crystal seed in precipitation process
Sample preparation.The itraconazole of dissolving 1.67g prepares itraconazole-NMP medicine concentrated solution in the NMP of 10ml under stirring and mild heat.Utilize twice of 0.2 μ m injection filter filtering solution.Then, add the water acceptable solution of the medicine concentrated solution of 1.2ml down at about 3 ℃, and under about 500rpm, stir, preparation Itraconazole nanometer suspension to 20ml.The mixture of the distilled water of the raw material itraconazole by adopting about 0.02g prepares the nano suspending liquid that adds crystal seed as acceptable solution.By only preparing unseeded nano suspending liquid as acceptable solution with distilled water.Two suspensions are centrifugal, topple over supernatant, and in vacuum tank about 16 hours of 30 ℃ of following drying solids.
Sample characterization.Figure 16 shows the comparison that adds crystal seed and do not add the solid DSC trace of crystal seed suspension.Sample is heated to 180 ℃ with 2 °/min in hermetic aluminum pan.Dotted line is represented unseeded sample, and it shows two endothermic peaks, shows to have the polymorph mixture.
Solid line representative adds the sample of crystal seed, and it only shows an endothermic peak, near the expectation fusion temperature of raw material, shows that seed crystal material induces the more stable polymorph of unique formation.
Embodiment 18: by adding crystal seed medicine concentrated solution control polymorph
Sample preparation.Room temperature (the about 22 ℃) dissolubility of itraconazole in NMP down is defined as 0.16g/ml by test.Heating and stirring are dissolved among the 10ml NMP itraconazole of 2.0g and 0.2gPoloxamer 188 down, preparation 0.20g/ml medicine concentrated solution.Allow this solution be cooled to room temperature then and generate supersaturated solution.Carry out microdeposit experiment immediately, wherein 1.5ml medicine concentrated solution adds to 30ml and contains 0.1% dexycholate, the aqueous solution of 2.2% glycerol.In adding step process, aqueous solution maintains about 2 ℃, and stir speed (S.S.) is 350rpm.Suspension is with about 13 before the gained, and 000psi was nearly 10 minutes of 50 ℃ of following homogenize.Centrifugal then suspension is toppled over supernatant, solid crystal in vacuum tank 30 ℃ dry 135 hours down.
Subsequently, over-saturation medicine concentrated solution is at room temperature preserved aging with induced crystallization.After 12 days, medicine concentrated solution feculence, demonstration has taken place crystal formation.With with test for the first time identical mode, contain 0.1% dexycholate by adding 1.5-30ml, the aqueous solution of 2.2% glycerol, preparation itraconazole suspension from the medicine concentrated solution.In adding step process, aqueous solution maintains about 5 ℃, and stir speed (S.S.) is 350rpm.Suspension is with about 13 before the gained, and 000psi was nearly 10 minutes of 50 ℃ of homogenize.Then, centrifugal suspension is toppled over supernatant, solid crystal in vacuum tank 30 ℃ dry 135 hours down.
Sample characterization.The analysis of X-ray powder diffraction is used for determining the morphology of dried crystals.The gained diffraction pattern is shown in Figure 17.The crystal (utilizing fresh medicine concentrated solution) of experiment is through determining to consist of more stable polymorph for the first time.In contrast, the crystal (aged medicine concentrated solution) of experiment mainly consists of more unsettled polymorph for the second time, though also there is a spot of more stable polymorph to exist.Therefore, it is believed that wears out induces the formation of more unsettled polymorphic crystals in the medicine concentrated solution, take on seed crystal material then in microdeposit and homogenization step process, thereby more unsettled polymorph forms preferentially.
Although set forth and illustrated specific embodiments, under the situation that does not deviate from essence of the present invention, multiple modification can be arranged, only the enclosed restriction of scope of claims of scope of the present invention.
Claims (8)
1. improving one's methods of particle suspension liquid comprises the following steps:
Fluid suspended solid particle is operated in first liquid stream; And
This fluid is turned round in second liquid stream, and wherein second liquid stream is with respect to first-class orientation and location, cause shearing between stream and at least some granule in first and second liquid stream, mix.
2. improving one's methods of particle suspension liquid comprises the following steps:
To operate at from the fluid suspended solid particle of first inlet point in first liquid stream; And
Fluid from second inlet point is operated in second liquid stream, and wherein second liquid stream is with respect to first liquid stream orientation and location, cause shearing between stream and at least some granule in first and second liquid stream, mix.
3. improving one's methods of particle suspension liquid comprises the following steps:
The solid particle that first fluid is suspended operates in first liquid stream; And
Second fluid is operated in second liquid stream, and wherein second liquid stream is with respect to first liquid stream orientation and location, cause shearing between stream and at least some granule in first liquid stream, mix.
4. the method for claim 3, wherein second fluid comprises solid particle.
5. the preparation method of particle suspension liquid comprises the following steps:
The solution and the solvent that will comprise dissolved organic compound form particulate suspension;
Suspension is operated in first liquid stream; And
Suspension is operated in second liquid stream, and wherein second liquid stream is with respect to first liquid stream orientation and location, cause shearing between stream and at least some granule in first and second liquid stream, mix.
6. the method for claim 5, wherein blend step comprises and utilizes venturi effect with solution and the synthetic single flow process of group of solvents.
7. the preparation method of particle suspension liquid comprises the following steps:
Make and comprise that being dissolved in the solution running that water can be mixed with the organic compound in the organic compounds forms first liquid stream; And
Water is operated in second liquid stream, and wherein first liquid stream is with respect to second liquid stream orientation and location, and the solution of shearing and solvent streams mixes to generate particle suspension liquid between causing flowing.
8. be used for the particulate equipment of comminuted suspension, comprise at solution:
Nozzle; And
The turbulence structure that is provided with in the nozzle, turbulence structure comprise at least one baffle plate.
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| US45742403P | 2003-03-24 | 2003-03-24 | |
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| CN107875407A (en) * | 2017-12-15 | 2018-04-06 | 天津梅花生物医药科技有限公司 | A kind of new bulk drug sterile processing systems |
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2004
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| CN107875407A (en) * | 2017-12-15 | 2018-04-06 | 天津梅花生物医药科技有限公司 | A kind of new bulk drug sterile processing systems |
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