CN100539998C - Preparation method of multi-type superfine naproxen medcine granule - Google Patents
Preparation method of multi-type superfine naproxen medcine granule Download PDFInfo
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- CN100539998C CN100539998C CNB2005101167135A CN200510116713A CN100539998C CN 100539998 C CN100539998 C CN 100539998C CN B2005101167135 A CNB2005101167135 A CN B2005101167135A CN 200510116713 A CN200510116713 A CN 200510116713A CN 100539998 C CN100539998 C CN 100539998C
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Abstract
Preparation method of multi-type superfine naproxen medcine granule of the present invention, adopt reaction-crystallization method, its technical characterictic is: (1) adds or does not add surfactant in sodium hydrate aqueous solution, and then adding naproxen medicine, be mixed with the naproxen drug solution that contains 0.15～0.9g/100ml, surfactant is polyvinyl pyrrolidone or polyoxyethylene 20 sorbitan monooleate, and the concentration of surfactant in solution is 0.5～6.0g/100mL; (2) with the speed dropping of 0.5mL/min or the hydrochloric acid solution of disposable adding; (3) crystallization temperature is at 5 ℃～25 ℃; (4) obtain nanoscale or micron-sized naproxen drug particles, pattern is hexagon lamellar, bar-shaped, spherical, petal-shaped, needle-like, cube or cotton-shaped.
Description
Technical field
The present invention relates to the preparation method of naproxen drug particles, particularly adopt reaction-crystallization method to prepare the method for multi-type superfine naproxen medcine granule.
Background technology
Naproxen (Naproxen) belongs to arylprop acids medicine.Because the existence of carboxyl makes it be faintly acid in the molecular structure.Arylprop acids medicine is the reversible inhibitor of Cycloxygenase, works by the arachidonic acid that suppresses Cycloxygenase mediation conversion plain to thromboxane and various prostaglandins.The main dosage form of arylprop acids medicine comprises in the market: tablet, suspensoid, injection, granule, suppository, gel, slow releasing agent, capsule etc.
Work before the prescription design is to being related to the mensuration and the evaluation of stable, the effective and safe physicochemical property of dosage form, making a kind of medicine reach the process of optimum condition.Wherein, medicine crystal formation, crystalline size and shape are one of key factors that influences its bioavailability and physical and chemical stability, are the important parameters of selecting the required consideration of most preferred dosage form in the product development process.
When the internal structure of medicine was identical, crystalline profile was because of being subjected to the influence of factors such as recrystallization solvent, surfactant, concentration, temperature, and it is widely different.The character that crystal shape may influence has: granule strength, adhesion property, flowability, compressibility, wettability, suspension stability, syringeability, dissolution rate etc.Different dosage forms has different requirements to the character of drug particles.Therefore stability after tablet is wanted press forming and guaranteed shaping have certain requirement to character such as adhesion and intensity, and tablet and powder should possess good flowability in addition, so granule should approach sphere.Sheet-like particle can better pass through the syringe pin hole than elongated piece in addition.Different granule-morphologies also has different dissolution rates according to their surface area difference, also can exert an influence to the dissolution rate of medicine.For example spherical, cube granule dissolution velocity all directions all keep identical, and the granule of other pattern difference owing to the pattern factor when dissolving has also changed dissolution rate.
Naproxen be widely used, one of arylprop acids anti-inflammatory analgesic that market sale has a extensive future.(Gordon M.S. such as Gordon M.S., Chowhan Z.T.Drug Development andIndustrial Pharmacy.1990 (16): 1279-1290) adopt the spheroidal crystal technology to prepare the naproxen drug particles, concrete steps are as follows: earlier naproxen is dissolved in 25～30 ℃ the acetone, be mixed with the drug solution that concentration is 12g/100mL, under stirring condition with this drug solution and 5 times of aqueous solution under the room temperature of its volume, stir " coalescence the solution " (hexanol that adds after 1 minute under the room temperature, capryl alcohol or toluene), mixed solution is stirred 5～10 minutes after-filtration, dry, sieve, obtaining particle diameter is the bulk naproxen granule of 200 μ m, and proves that it has good mobility and compressibility.(G.A.Pozarnsky, E. such as Pozarnsky
Journal of Colloid andInterface Science.1997 (125): 47-52) utilize naproxen solvable and character that under acid condition, separate out under alkali condition, adopt reaction-crystallization method to prepare single dispersion naproxen drug particles.Concrete steps are as follows: (0.2～1.0g/100mL) is dissolved in the 0.04mol/L sodium hydroxide solution, and the naproxen of certain mass is dissolved in this sodium hydroxide solution, is mixed with the drug solution of 0.02mol/L, gets 20cm with the surfactant polyvinylpyrrolidone
3This drug solution, under stirring condition, drip the hydrochloric acid solution (3～10mL) of 0.08mol/L with the speed of 1mL/min, obtain the suspension of medicine, with the ageing two days or 60 ℃ of heating 12 hours down in the airtight container of room temperature of this suspension, with suspension filtered, washing, drying obtain the naproxen drug particles then.The result proves, the drug particles pattern that finally obtains through the suspension of ageing or heating is the irregular bulk granules of 10 μ m, obtains the naproxen rod-shpaed particle of major diameter 1 μ m, minor axis 0.3～0.4 μ m after heating or the ageing.The naproxen rod-shpaed particle that is obtained below the 1 μ m by this method needs long ageing or high temperature heating, is unfavorable for keeping the stable and drug effect of pharmaceutical properties; Residual surfactant also might influence drug effect.
Summary of the invention
The present invention's part same as the prior art is it all is to adopt reaction-crystallization method, the sodium hydrate aqueous solution that will contain the naproxen medicine, mix with hydrochloric acid solution, drug crystallization is separated out, obtain containing the suspension of naproxen drug microparticles, drying finally obtains the naproxen drug particles, and technical characterictic of the present invention is:
(1) in sodium hydrate aqueous solution, adds or do not add surfactant, and then adding naproxen medicine, be mixed with the naproxen drug solution that contains 0.15～0.9g/100mL, surfactant is polyvinyl pyrrolidone or polyoxyethylene 20 sorbitan monooleate, and the concentration of surfactant in solution is 0.5～6.0g/100mL;
(2) in above-mentioned solution, with speed dropping or the disposable adding hydrochloric acid solution of 0.5mL/min;
(3) crystallization temperature is at 5 ℃～25 ℃;
(4) obtain nanoscale or micron-sized naproxen drug particles, pattern is hexagon lamellar, bar-shaped, spherical, petal-shaped, needle-like, cube or cotton-shaped.
The inventive method, the concentration of sodium hydrate aqueous solution are 0.04mol/L, and the concentration of hydrochloric acid solution is 0.08mol/L, and the volume ratio of sodium hydrate aqueous solution and hydrochloric acid solution is 2: 1.
The inventive method, the mixing speed during mixing are 100～2100r/min.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.15～0.9g/100mL, does not add surfactant; Speed dripping hydrochloric acid solution with 0.5mL/min; Crystallization temperature is at 15 ℃; Obtaining one dimension is nano level hexagon lamellar naproxen drug particles.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.6g/100mL, adds the polyvinyl pyrrolidone surfactant of molecular weight 10000, and the concentration of surfactant in solution is 0.5g/100mL; Speed dripping hydrochloric acid solution with 0.5mL/min; Crystallization temperature is at 15 ℃; Obtain two dimension and be the bar-shaped naproxen drug particles of sodium meter level.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.6g/100mL, adds the polyvinyl pyrrolidone surfactant of molecular weight 10000, and the concentration of surfactant in solution is 0.5g/100mL; Disposable adding hydrochloric acid solution; Crystallization temperature is at 25 ℃; Obtain micron order petal-shaped naproxen drug particles.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.6g/100mL, adds the polyvinyl pyrrolidone surfactant of molecular weight 10000, and the concentration of surfactant in solution is 0.5g/100mL; Disposable adding hydrochloric acid solution; Crystallization temperature is at 5 ℃; Obtain micron level spherical naproxen drug particles.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.6g/100mL, adds the polyvinyl pyrrolidone surfactant of molecular weight 30000, and the concentration of surfactant in solution is 0.5g/100mL; Disposable adding hydrochloric acid solution; Crystallization temperature is at 15～25 ℃; It is cotton-shaped obtaining naproxen medicine pattern.
The inventive method in the sodium hydrate aqueous solution of the naproxen medicine that contains 0.6g/100mL, adds the polyoxyethylene 20 sorbitan monooleate surfactant, and the concentration of surfactant in solution is 5.0～6.0g/100mL; Disposable adding hydrochloric acid solution; Crystallization temperature is at 25 ℃; Obtain micron order needle-like naproxen drug particles.If needle-like naproxen drug particles suspension was at room temperature left standstill 48 hours, obtaining nanoscale naproxen drug particles is cube.
The present invention utilizes naproxen solvable and character of separating out in alkaline solution in sour environment, adopt reaction-crystallization method, under the condition of surfactant-free or surfactant existence, by to crystallization condition, comprise that surfactant, temperature, mixing speed, soda acid ratio, acid solution add speed, have prepared multi-type superfine naproxen medcine granule.Method of the present invention can reduce following four kinds of operational approach:
(1) sodium hydrate aqueous solution of elder generation's preparation 0.04mol/L, add the naproxen medicine again, be mixed with the drug solution that contains 0.15～0.9g/100mL naproxen, under stirring condition, with the hydrochloric acid solution of the speed Dropwise 5 0mL 0.08mol/L of 0.5mL/min, crystallization temperature is 15 ℃, mixing speed is 100～2100r/min, obtains the drug particles suspension, obtains drug particles through super-dry, with its pattern of scanning electron microscopic observation, be the flaky naproxen drug particles of hexagon.
(2) sodium hydrate aqueous solution of elder generation's preparation 0.04mol/L, add surfactant polyvinyl pyrrolidone and naproxen medicine more successively, be mixed with the naproxen drug solution, wherein: surfactant concentrations is that 0.5g/100mL, drug level are 0.6g/100mL; Mixing speed is 100～2100r/min, and crystallization temperature is 5～25 ℃, adds the hydrochloric acid of 50mL 0.08mol/L again, and the adding mode of hydrochloric acid is pressed speed or the disposable adding of 0.5mL/min, obtains the drug particles suspension, obtains drug particles through super-dry.With its pattern of scanning electron microscopic observation, be bar-shaped, petal-shaped, the spherical or cotton-shaped naproxen drug particles of thorn.
(3) sodium hydrate aqueous solution of elder generation's preparation 0.04mol/L, add surfactant polyoxyethylene sorbitan monooleate and naproxen medicine more successively, be mixed with drug solution, wherein: surfactant concentrations is that 5.0～6.0g/100mL, drug level are 0.6g/100mL; Mixing speed is 100～2100r/min, and crystallization temperature is 25 ℃, adds the hydrochloric acid of 50mL 0.08mol/L again, and the adding mode of hydrochloric acid is disposable adding, obtains the drug particles suspension, obtains drug particles through super-dry.With its pattern of microscopic examination, be needle-like.
(4) sodium hydrate aqueous solution of elder generation's preparation 0.04mol/L, add surfactant polyoxyethylene sorbitan monooleate and naproxen medicine more successively, be mixed with drug solution, wherein: surfactant concentrations is that 5.0～6.0g/100mL, drug level are 0.6g/100mL; Mixing speed is 100～2100r/min, and crystallization temperature is 25 ℃, adds the hydrochloric acid of 50mL 0.08mol/L again, and the adding mode of hydrochloric acid is disposable adding, obtains the drug particles suspension, and room temperature left standstill 48 hours, obtained drug particles through super-dry.With its pattern of scanning electron microscopic observation, be cube shaped drug particles.
In the method for the present invention, but the concentration of sodium hydroxide solution and hydrochloric acid solution and ratio list of references (G.A.Pozarnsky, E.
Journal of Colloid and Interface Science.1997 (125): 47-52), but the inventor finds by test, the concentration of sodium hydroxide solution and hydrochloric acid solution and ratio are little to the pattern influence of crystalline particle, but mainly influence crystalline yield.(mixing speed is respectively 300 only to change mixing speed, 900,1200,2100r/min), the granule that obtains has different suspension character, the particles settling for preparing under the slow-speed of revolution is in the solution bottom, and the granule for preparing under high rotating speed floats on the liquid level of solution, shows that rotating speed influences particle surface character.When crystallization temperature was 15 ℃, the gained particle grain size at first reduced along with mixing speed raises, and increases gradually again when mixing speed is higher than 300r/min.When the present invention adopts the polyvinyl pyrrolidone surfactant, its molecular weight is influential to the drug particles pattern, adopt the polyvinyl pyrrolidone of higher molecular weight to obtain cotton-shaped product, adopt lower molecular weight polyethylene base ketopyrrolidine then to obtain the spherical particle that the surface is a thorn shape.
The inventive method adopts polyoxyethylene 20 sorbitan monooleate as surfactant control naproxen drug particles pattern, the trade name of polyoxyethylene 20 sorbitan monooleate: Tween 80, be a kind of non-ionic water-soluble surfactant, this surfactant concentrations just can obtain the needle-like naproxen drug particles of pattern homogeneous in 5.0～6.0g/100mL scope.The concentration of polyoxyethylene 20 sorbitan monooleate is during less than 2.5g/100mL, and crystalline particle is irregular lamellar; The concentration of polyoxyethylene 20 sorbitan monooleate obtains elongated piece when 3.0～4.0g/100mL, but particulate minor axis skewness one; When the concentration of polyoxyethylene 20 sorbitan monooleate reached 10.0g/100mL, induction time was long, and reacting did not have crystalline particle to separate out after 15 minutes yet.
The inventive method also can be prepared hexagon flake micron level naproxen granule under the condition that does not add any surfactant, do not use surfactant can reduce the cost of drug micronization process, and it is residual to reduce surfactant.In addition, method of the present invention does not need ageing or pyroprocess can prepare the drug particles that particle diameter is less than or equal to 2 μ m, and document (G.A.Pozarnsky, E.
Journal of Colloid and Interface Science.1997 (125): the naproxen drug particles of gained is 10 μ m 47-52), method of the present invention can obtain the littler drug particles of granularity, helps further increasing the dissolution rate and the bioavailability of medicine.
Description of drawings
Fig. 1 is the particulate scanning electron microscope of hexagon lamellar naproxen (SEM) photo that embodiment 1 makes.
Fig. 2 is the stereoscan photograph of the crystalline particle that obtains of embodiment 8.
Fig. 3 is the particulate stereoscan photograph of naproxen that embodiment 9 obtains.
Fig. 4 is the particulate stereoscan photograph of naproxen that embodiment 10 obtains.
Fig. 5 is the particulate stereoscan photograph of naproxen that embodiment 11 obtains.
Fig. 6 is the particulate microphotograph of naproxen that embodiment 13 obtains.
Fig. 7 is the particulate stereoscan photograph of naproxen that embodiment 14 obtains.
The specific embodiment
Embodiment 1
Taking by weighing naproxen 0.6g is dissolved in the sodium hydrate aqueous solution that 100mL concentration is 0.04mol/L, and in the adding stirred tank, rotating speed with 1500r/min stirs, under 15 ℃ of temperature, the rate of addition of 50mL0.08mol/L hydrochloric acid solution with 0.5mL/min joined in the stirred tank, obtain the suspension of naproxen drug particles, draw a small amount of suspension and it is dripped on microscope slide with dropper, blot solvent with filter paper, obtain exsiccant drug particles, use the electronics scanning electron microscopic observation, the naproxen drug particles is the hexagon lamellar, and shown in Fig. 1 scanning electron microscope (SEM) photo, the average major diameter of naproxen drug particles is 2.89 μ m, average minor axis is 1.28 μ m, and thickness is at 200～300nm.
Embodiment 2
Operating procedure is identical with embodiment 1, except that speed of agitator is that the consumption of 300r/min, naproxen is the 0.15g, other condition is with embodiment 1, gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, the average major diameter of naproxen drug particles is 1.68 μ m, and average minor axis is 0.78 μ m.
Embodiment 3
Operating procedure is identical with embodiment 1, and except that speed of agitator was 300r/min, other condition was with embodiment 1, and gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, and average major diameter is 2.02 μ m, and average minor axis is 1.15 μ m.
Embodiment 4
Operating procedure is identical with embodiment 1, except that speed of agitator is that the amount of rotating speed 300r/min, naproxen is the 0.9g, other condition is with embodiment 1, and gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, average major diameter is 2.67 μ m, and average minor axis is 1.20 μ m.
Embodiment 5
Operating procedure is identical with embodiment 1, and except that speed of agitator was rotating speed 100r/min, other condition was with embodiment 1, and gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, and average major diameter is 5.62 μ m, and average minor axis is 2.32 μ m.
Embodiment 6
Operating procedure is identical with embodiment 1, and except that speed of agitator was rotating speed 900r/min, other condition was with embodiment 1, and gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, and average major diameter is 2.82 μ m, and average minor axis is 1.20 μ m.
Embodiment 7
Operating procedure is identical with embodiment 1, and except that speed of agitator was rotating speed 2100r/min, other condition was with embodiment 1, and gained drug particles pattern is all the hexagon lamellar mutually with embodiment 1, and average major diameter is 3.23 μ m, and average minor axis is 1.21 μ m.
Embodiment 8
Take by weighing 0.5g polyvinyl pyrrolidone and 0.6g naproxen, be dissolved in successively in the sodium hydrate aqueous solution that 100mL concentration is 0.04mol/L, and with in this solution adding stirred tank, rotating speed with 1500r/min stirs, under 15 ℃ of temperature, the rate of addition of 50mL 0.08mol/L hydrochloric acid solution with 0.5mL/min joined in the stirred tank, solution begins to become muddiness and obtains suspension when the hydrochloric acid solution dripping quantity reaches 17mL, the hanging drop that takes a morsel is added on the microscope slide, blot solvent with filter paper, obtain the naproxen drug particles, use the electronics scanning electron microscopic observation, the naproxen drug particles is an irregular polyhedrons, particle diameter is at 200～500nm, when hydrochloric acid dropwises the reaction end,, use the electronics scanning electron microscopic observation with the suspension filtered drying, the naproxen drug particles is the at one end accumulative aggregates of a plurality of rod-shpaed particles, shown in Fig. 2 stereoscan photograph, the minor axis of rod-shpaed particle is about 200nm, and major diameter is about 2 μ m.
Embodiment 9
Operating procedure is identical with embodiment 8, take by weighing 0.5g polyvinyl pyrrolidone (molecular weight is 10000) and 0.6g naproxen, be dissolved in successively in the sodium hydrate aqueous solution that 100mL concentration is 0.04mol/L, and with in this solution adding stirred tank, rotating speed with 1500r/min stirs, under 25 ℃ of temperature, join in the stirred tank 50mL 0.08mol/L hydrochloric acid solution is disposable, obtain the suspension of naproxen drug particles, with the suspension filtered drying, use the electronics scanning electron microscopic observation, shown in Fig. 3 stereoscan photograph, the naproxen drug particles is a petal-shaped, and mean diameter is 2 μ m.
Embodiment 10
Operating procedure is identical with embodiment 9, and except that the crystallization temperature is 5 ℃, other condition obtains the naproxen drug particles with embodiment 9, with the electronics scanning electron microscopic observation as, shown in Fig. 4 stereoscan photograph, the naproxen drug particles is spherical for thorn, mean diameter is 2 μ m.
Embodiment 11
Operating procedure is identical with embodiment 9, with the polyvinyl pyrrolidone in the polyvinyl pyrrolidone alternate embodiment 9 of high molecular (molecular weight is 30000), crystallization temperature is 15 ℃, other condition is with embodiment 9, obtain the naproxen drug particles, use the electronics scanning electron microscopic observation, shown in Fig. 5 stereoscan photograph, the naproxen drug particles is cotton-shaped.
Embodiment 12
Operating procedure is identical with embodiment 9, with the polyvinyl pyrrolidone in the polyvinyl pyrrolidone alternate embodiment 9 of high molecular (30000), crystallization temperature is 25 ℃, other condition is with embodiment 9, obtain the naproxen drug particles, use the electronics scanning electron microscopic observation, the naproxen drug particles is cotton-shaped same Fig. 5.
Embodiment 13
Operating procedure is identical with embodiment 9, sodium hydrate aqueous solution with 0.5g/100mL polyvinyl pyrrolidone in the sodium hydrate aqueous solution alternate embodiment 9 that contains the 5.0g/100mL polyoxyethylene 20 sorbitan monooleate, other condition is with embodiment 9, obtain naproxen drug particles suspension, the hanging drop that takes a morsel is added on the microscope slide, blot solvent with filter paper, obtain the naproxen drug particles, use microscopic examination, shown in Fig. 6 microphotograph, the naproxen drug particles is a needle-like, and average major diameter is that 30 μ m, minor axis are 1 μ m.
Embodiment 14
The needle-like naproxen drug particles suspension that the embodiment 13 that takes a morsel obtains, drip on microscope slide, and cover drop with coverslip, after 24 hours, coverslip is removed, used the electronics scanning electron microscopic observation through 24 hours again, shown in Fig. 7 stereoscan photograph, the naproxen drug particles is a cube, and mean diameter is 500nm.
Embodiment 15
Operating procedure is identical with embodiment 13, and except that the concentration with polyoxyethylene 20 sorbitan monooleate is the 6.0g/100mL, other condition obtains the naproxen drug particles with embodiment 13, uses microscopic examination, and the naproxen drug particles is a needle-like.
Claims (3)
1. the preparation method of a multi-type superfine naproxen medcine granule, adopt reaction-crystallization method, the sodium hydrate aqueous solution and the hydrochloric acid solution that will contain the naproxen medicine mix, drug crystallization is separated out, obtain containing the suspension of naproxen drug particles, drying finally obtains the naproxen drug particles, it is characterized in that:
In the sodium hydrate aqueous solution that contains 0.15～0.9g/100mL naproxen medicine, do not add surfactant; Speed dripping hydrochloric acid solution with 0.5mL/min; Crystallization temperature is at 15 ℃; Obtaining one dimension is nano level hexagon lamellar naproxen drug particles.
2. method according to claim 1 is characterized in that: the concentration of sodium hydrate aqueous solution is 0.04mol/L, and the concentration of hydrochloric acid solution is 0.08mol/L, and the volume ratio of sodium hydrate aqueous solution and hydrochloric acid solution is 2: 1.
3. method according to claim 1 is characterized in that: the mixing speed during mixing is 100～2100r/min.
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Non-Patent Citations (7)
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| Engineered microcrystals for direct surface modificationwithlayer-by-layer technique for optimized dissolution. Dinesh B. Shenoy,等.European Journal of Pharmaceutics and Biopharmaceutics,Vol.58 No.3. 2004 |
| Engineered microcrystals for direct surface modificationwithlayer-by-layer technique for optimized dissolution. Dinesh B. Shenoy,等.European Journal of Pharmaceutics and Biopharmaceutics,Vol.58 No.3. 2004 * |
| Precipitation of Barium and Calcium Naproxenate ParticlesofDifferent Morphologies. Corina Goia,等.JOURNAL OF COLLOID AND INTERFACE SCIENCE,Vol.206 No.2. 1998 |
| Precipitation of Barium and Calcium Naproxenate ParticlesofDifferent Morphologies. Corina Goia,等.JOURNAL OF COLLOID AND INTERFACE SCIENCE,Vol.206 No.2. 1998 * |
| Preparation of monodisperse colloids of biologically activecompounds 1.Naproxen. G.A.Pozarnsky，等.Journal of Colloids and Surfaces,Vol.125 No.1. 1997 |
| Preparation of monodisperse colloids of biologically activecompounds 1.Naproxen. G.A.Pozarnsky,等.Journal of Colloids and Surfaces,Vol.125 No.1. 1997 * |
| Properties of Ibuprofen Crystallized Under VariousConditions:A Comparative Study. N. Rasenack,等.DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY,Vol.28 No.9. 2002 |
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