EP2651397A2 - Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés - Google Patents

Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés

Info

Publication number
EP2651397A2
EP2651397A2 EP11784604.8A EP11784604A EP2651397A2 EP 2651397 A2 EP2651397 A2 EP 2651397A2 EP 11784604 A EP11784604 A EP 11784604A EP 2651397 A2 EP2651397 A2 EP 2651397A2
Authority
EP
European Patent Office
Prior art keywords
mannitol
spray
product
recycled
powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP11784604.8A
Other languages
German (de)
English (en)
Inventor
Martin Erdmann
Walter Hamm
Eugen Schwarz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to PL16001371T priority Critical patent/PL3093011T3/pl
Priority to EP16001371.0A priority patent/EP3093011B1/fr
Priority to EP11784604.8A priority patent/EP2651397A2/fr
Publication of EP2651397A2 publication Critical patent/EP2651397A2/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a process for the preparation of directly tablettable mannitol with a ⁇ -modification content of more than 90%, in particular more than 95%.
  • D-mannitol In the preparation of tablets can be used as a carrier material for a drug D-mannitol.
  • D-mannitol is usually converted into granules in a plurality of process steps, in order to make it manageable for the tableting presses and at the same time to permit the incorporation of active ingredients.
  • Intermediate checks enable controlled process management.
  • US Pat. No. 3,145,146 A discloses a spray-drying process, whereby mannitol is obtained in the form of fine particles having an average diameter of 5 to 50 ⁇ m. A mannitol solution is spray dried by spraying into a hot gas stream. The resulting particles are separated by suitable measures
  • a granular mandite is followed by a process stage through which granules having a uniform particle size distribution are obtained.
  • This process step can both grinding as well as sieving (classifying) the granules.
  • each additional process step in the production poses a potential danger of introducing undesired impurities into the product.
  • D-mannitol can be present in polymorphic crystal forms, in the a, ⁇ and ⁇ forms.
  • the definitions and characterizations used here correspond to those in: Walter Levy, L; A-cad. Sc. Paris, t. 267 Series C, 1779, (1968) classifications of polymorphic forms by X-ray diffraction pattern.
  • the ⁇ -form is the most stable form, although conversions to the other forms are possible depending on the storage time and environmental conditions. For commercial applications, it would therefore be desirable to obtain mannitol directly in the production in the ⁇ -form because of its stability, since in this case the product properties change least as a result of storage. In order to keep a drug evenly distributed in the preparation of pharmaceutical formulations, especially in powdered formulations, it is desirable to firmly bind the active ingredient in the carrier material (excipient).
  • the object is achieved by a process for the preparation of directly tablettable mannitol with a ⁇ -modification content of more than 90%, characterized in that
  • Fluidized bed falls, taken up, fluidized and further transported.
  • a subset of the resulting granular product may be incorporated into the
  • This recycling of product formed is particularly advantageous when it is more than 90% in ⁇ form.
  • the mannitol initially introduced in the process with a ⁇ -modification content of more than 90% can be obtained from a conventional preparation
  • the resulting granules can be sprayed with further liquid medium in one or more granulation step (s), dried and transported further in the fluidized bed or fluidized bed.
  • a granulation step s
  • D-mannitol with a purity of> 90%, preferably> 95% is used.
  • D-mannitol with a purity of> 98% is particularly preferably used.
  • the equilibrium towards the formation of ⁇ -mannitol can be shifted by returning ⁇ -mannitol accumulating as dust fraction from the product discharge zone of the processor to the step a) of the spray-drying.
  • the process is particularly advantageous in that ⁇ -mannitol dust having an average particle size of less than 20 ⁇ m, in particular having an average particle size in the range from about 1 to 20 ⁇ m, preferably in the range from 3 to 15 ⁇ m, is recycled.
  • the return of "dusty" ⁇ -mannitol, which is obtained as a product discharge in the metering in the line (9A) is carried out by controlling the speed of the rotary valve 10A via the fan (E) in the spray drying of the process step a). This means that the granules of the product return in the milling fan are ground to powder.
  • a granulate When we speak here of a granulate, it is a granular, easily pourable solid having a specific structure, as it has the ⁇ -mannitol prepared according to the invention.
  • a granulate thus consists of solid and dry grains, each grain in turn being an agglomerate of particles of sufficient strength to allow for various manipulations.
  • Dust in turn consists of very fine particles that are difficult or impossible to settle in air ( ⁇ 10 ⁇ ), here according to the invention accumulating finest solid from the gas phase (between fluidized bed and filter) of the processor. The particles are so fine that they can not sediment.
  • an aqueous 40-50% D-mannitol solution (based on the weight of the total solution) is used as starting material, which is sprayed at a temperature in the range from 60 to 100.degree.
  • Both as a spray gas and as a carrier and heating gas air or a nertgas selected from the group N 2 and C0 2 can be used.
  • the gas is preferably recirculated in the process according to the invention and the circulated gas is freed from particles by filters, dried in the condenser and fed again to the spray nozzles or heated and introduced into the fluidized bed.
  • the recirculated gas is freed by means of dynamic filters of particles.
  • the liquid media used have different compositions at different points in the system.
  • spray pressure, spray quantity, mannitol concentration, recycled quantity of powder, hot air flow and temperature of the hot air particle sizes between 50 and 1000 ⁇ m can be produced in the process according to the invention.
  • the air supplied to the system is preheated to a temperature in the range of 45-110 ° C., and the supplied supply air quantity is controlled in the range of 1000-2000 m 3 / m 2 per hour, whereby the exhaust air temperature is in the region of 30.degree. 50 ° C.
  • the spray pressure of the two-component nozzles is set in the range from 2 to 4 bar, so that about 1.5 to 3 m 3 / (h kg of solution) hot gas is fed to the two-component nozzle, the temperature of the hot gas being in the range from about 80 to 110 ° C is set.
  • Good process results are obtained when the powder and granule recycle is controlled to recycle in the range of 0.5-2.0 kg solids / (h kg solution).
  • a particularly uniform formation of granular powder with a ⁇ -mannitol content of> 95% is carried out by adjusting the parameters, spray pressure, liquid amount, mannitol concentration, recycled powder and granulate amount, hot air flow and temperature of the hot air, whereby the amount of powder in the fluidized bed a bed amount in the range of 50 - 150 kg / m 2 bed is set.
  • a process for the preparation of pure 6- (D) -Mannit was thus developed, can be produced by directly tablettable mannitol (DC mannitol) with a suitable homogeneous particle size distribution.
  • DC mannitol directly tablettable mannitol
  • mannitol with a purity of more than 98% is used, the remainder being sorbitol and other residual sugars.
  • An aqueous solution with a mannitol content of about 40-50% by weight is prepared. This solution is sprayed with a supply air temperature of about 60 - 95 ° C in a spray drying plant and dried.
  • a slightly modified system is used as described in DE 1 99 27 537.
  • the method is carried out in a spray-drying plant which
  • a powder and granule return (9) with fan (E) wherein the measures provided for the powder and granule return lines (9A) and (9B) with rotary valves (10A, 10B) are provided, and not in the powder dosage entering product (8) can be separated by classification into a 0 dusty and a coarse-grained fraction.
  • the ventilator (E) can be supplied with dust-free supply air via the flap (J) or dusty supply air via the flap (H), depending on requirements and the stage of process equilibration (see Fig. 2).
  • liquid medium (5), spray gas (6), powdered material (9) and hot gas (4) are brought together.
  • a particular embodiment is that a spray-drying unit (B) is located vertically above a subsequent fluidized bed in a spray tower.
  • the spray drying unit (B) of the plant may comprise a spraying system consisting of a two-substance spray nozzle heated with hot water with coaxially arranged powder and granulate return and hot gas circulation.
  • a spraying system consisting of a two-substance spray nozzle heated with hot water with coaxially arranged powder and granulate return and hot gas circulation.
  • one or more additional spraying or atomizing nozzles for liquid media (C) may also be provided locally in the fluidized bed.
  • the fluidized bed is followed by a powder dosing system (D) separated by a lock flap (F), which is fed by a product overflow (8).
  • a subset of the product formed may be returned to the spray-drying unit (B) via a flight conveyor in which a fan (E) serves as the conveyor, after comminution (9A.10A) or uncomminuted (9B, 10B) when the balance is established become.
  • the fan (E) acting as a conveyor can at the same time serve as a comminution unit for recirculated powder.
  • the process for the preparation of spray-dried granular 5- (D) -mannitol is carried out by a) in a first step, a liquid medium, spray gas, powdered
  • the resulting granulated product is dropped into a fluidized bed, taken up, fluidized and transported further and optionally c) sprayed in one or more granulation step (s) with further liquid medium, dried d) and in the fluidized bed in the direction of Dosing system is conveyed, from which e) a subset of ground or unground is returned as powder and / or granul-shaped material in the process.
  • the liquid medium is preferably an aqueous solution.
  • a solution in which a water-soluble solvent has been used or a solvent mixture which consists to a certain extent of water is also possible.
  • a particular variant of the method is that the recycled material can be comminuted prior to recycling.
  • carrier and heating gas air or an inert gas selected from the group N 2 and C0 2 can be used.
  • the gas can according to the invention be recycled, whereby it is freed of particles by filters or specifically with the aid of dynamic filters, dried in the condenser and fed again to the spray nozzles or heated and introduced into the fluidized bed.
  • ⁇ -mannitol is initially charged as described above, or such a fluidized bed is prepared from very finely divided ⁇ -mannitol powder.
  • DC-ß-mannitol must be submitted as a bed in the processor.
  • the DC- ⁇ -mannitol has very similar mechanical properties to the DC- ⁇ -mannitol to be prepared, the start-up process is thus more stable than starting with crystalline ⁇ -mannitol (see FIG. 3).
  • the following parameters must be set in the process:
  • Temperature in the processor max. about 35 - 45 ° C
  • Powder recycling approx. 3 times the amount, based on the
  • the recycled powder is not ground!
  • the powder takes the path 9B / 10B (the way over 9A / 0A is closed!)
  • the flap (H) is closed in the system and the flap (J) is open.
  • the air is taken from the exhaust air of the processor after the filters (G).
  • the formation of the ⁇ -mannitol starts and takes the course as shown in Fig. 3.
  • the formation of ⁇ -mannitol takes place in small quantities.
  • the concentration increases continuously until it is about 95% by weight after an operating time of about 70 hours. Following this, the concentration of ⁇ -mannitol increases only slightly and may be greater than 98% by weight.
  • Flap (J) is closed. Only under these conditions can the content of ⁇ -mannitol be increased to more than 90% by weight in the product.
  • the system is initially charged with pul verförmigem starter material through the filler neck (3).
  • an air flow is generated in the spray drying room.
  • the introduced starter material is fluidized by this airflow and moves in the direction of the discharge caps (F).
  • the product stream receives this direction of movement when generating the air flow through a corresponding perforation of the Conidur convinceds.
  • the fluidized product can be discharged by simply opening the lock flaps (F).
  • the system devices are provided, which make it possible to return the product in a metering and a flight promotion to the spray-drying unit.
  • the fan (E) of the spray-drying unit serves as a conveying means both for product recycling and as a comminuting unit for powder material to be recycled.
  • the supply air is supplied to the fan (E) either dust-laden via the flap (H) or dust-free via the flap (J).
  • Recycled powder and granular material of the return line (9A, 9B) is due to the special design of the spray-drying nozzle with the appropriate media liquid (5), spray air (6) and hot air (4) brought together.
  • the corresponding powder or granules are taken up by the fluidized bed and, as already described above, further transported.
  • granulation nozzles instead of the granulation nozzles (C), as shown in Fig. 2, one or more spray nozzles or spray-drying nozzles or even one, two or more than three granulating nozzles may be attached to the corresponding location of the plant. These additional nozzles may be located directly at the beginning of the fluidized bed or further backward.
  • the choice of the place where the originally formed product is sprayed once or more times is discussed i.a. also dependent on what residual moisture the desired product should have. It goes without saying that a product with particularly low residual moisture after the last spraying requires a longer residence time in the fluidized bed than one with a higher one.
  • compositions can be applied to the already formed particle surfaces by the various nozzles, so that particles having a layered structure can be obtained. But it can also serve to achieve a more uniform particle size distribution.
  • the system can not be operated only with air as the carrier medium. It is also possible to circulate the entire plant with an inert gas such as e.g. Nitrogen or carbon dioxide to drive.
  • an inert gas such as e.g. Nitrogen or carbon dioxide to drive.
  • the system is designed so that the parameters amount of liquid, spray pressure, recycled amount of powder and granules, hot gas, hot gas, hot air, hot air, etc. are individually controlled. Therefore, the recycled amount of powder and granules, the specifically set the amount of liquid fed in and the spray pressure depending on the desired properties with regard to the moisture, the grain size and the particle size distribution of the end product. As desired, products can be produced in the described plant with particle sizes between 50 and 1000pm. Depending on the mode of operation and selected process parameters, the particles may have a layered (onion structure) structure or an agglomerate structure.
  • the formation of the particles can be controlled in particular by means of a spray nozzle integrated in the system, which is suitable for producing spray-dried granules.
  • a spray nozzle integrated in the system, which is suitable for producing spray-dried granules.
  • this spray nozzle is a spray system (B), which consists of a heated with hot water two-component spray nozzle [(1), (2), (3)], which in turn arranged with a two-component spray nozzle powder and Granule return (4) and a H hindergasum- flow (5) is equipped.
  • the powder and granule return (4) may be arranged coaxially around the two-component spray nozzle.
  • the advantage of this spraying system is that recirculated solids come into contact with the liquid droplets generated via the atomizing air directly at the outlet of the two-substance spray nozzle. So that the particles do not stick together and the surface moisture can be removed, the spray nozzle and the powder and granule return are enclosed in a hot gas stream. The drying to the desired residual moisture takes place in a fluidized bed.
  • a particular advantage of this spray-drying method is therefore that in a single system without further process steps for the aftertreatment of the product depending on the set process parameters and the liquid media to be sprayed 6- (D) -Mannit with very different properties in terms of moisture, the grain size and the particle size distribution in the powder can be produced.
  • DC directly tablettable
  • a spray tower (B) is located vertically above the fluidized bed.
  • the hot aqueous mannitol solution is sprayed via one or more two-substance nozzle (s) (5) (6), which is heated with hot water (7).
  • the generated spray is flowed around by a nozzle arranged around this nozzle mannitol powder and granules return (9) and hot gas (4).
  • the solid crystallizes in the spray forms agglomerates and is collected by the fluidized bed.
  • Hot air from the air inlet chambers (1) flows through the fluidized bed and fluidizes it.
  • the bottom of the fluidized bed is a Conidurêt, which provides for the targeted transport of the solid for discharge, and also gives a defined residence time of the solid in the fluidized bed.
  • the bed height, spray and recirculation amount can be used to control the residence time of the product in the processor.
  • the solid is transported via several series-connected air inlet chambers (1) and dried to a residual moisture content ⁇ 0.3%. The drying process takes place over the length of the fluidized bed in a specific temperature profile, in order to avoid overheating of the product.
  • the water-laden and dust-laden fluidized air is cleaned via dynamic filter (G) and discharged through the exhaust air chambers (2).
  • the dynamic filters are regularly cleaned with compressed air surges. The cleaned dust binds the sprays out of the spray zone and prevents caking on the walls.
  • the dried solid falls into a dosing system of the recycle (D) via double shuttle valves (F) or other discharge systems. If necessary, the discharged product can be worked up further by means of a classification system.
  • the resulting oversize (- and undersize) can be ground on the powder return (9) in the fan (E) and recycled together with the undersize (dust-like mannitol powder with particle sizes less than 75 ⁇ , especially less than 40 ⁇ ) in the spray dryer.
  • a partial flow is discharged at the discharge as a finished product (8).
  • the product can be classified via a sieve, whereby the oversize (remanence, or coarse powder portion) over the suction side of the grinding fan (9A) can be recycled, ground and returned to the process. This minimizes product losses, among other things.
  • the fan (E) of the spray-drying unit serves both as a conveyor for product to be returned (solid feed on the pressure side (9B)) and as a crushing unit for recycled powder material (solids feed on the suction side (9A)).
  • the two particulate streams are e.g. controlled by the speed of the rotary valves (10A, 10B).
  • the fan (E) is supplied from the product discharge zone of the processor supply air when the flap (H) is opened and the flap (J) is closed. In this way the fine dust ( ⁇ 15pm) is removed from the product at the same time (pneumatic classification). At the same time, the removal of this particulate matter has the effect that higher tablet hardness can be achieved using this exempted from particulate product.
  • the quality of the agglomerates and thus of the product can be controlled via the system parameters such as concentration, spray pressure, temperature, spray quantity, powder and granular recirculation amount, main air quantity, dust extraction, bed height, etc.
  • concentration concentration, spray pressure, temperature, spray quantity, powder and granular recirculation amount, main air quantity, dust extraction, bed height, etc.
  • the powder return (9) via the filler neck (3) take place.
  • both the grain structures, but also modification, grain size distribution, water content, density, etc. must be monitored. It was found that the best tablettable product is obtained when mannitol crystallizes out in a fine needle structure.
  • FIG. 1 shows an SEM image of a product with a proportion of ⁇ modification of more than 98% in a 500-fold magnification.
  • the starting material used is preferably D-mannitol with a purity of> 90%, particularly preferably with a purity of> 95% and very particularly preferably with a purity of> 98%.
  • This educt is used as an aqueous 40-50% solution and sprayed into the system at a temperature in the range of 60 to 95 ° C.
  • the solution is heated prior to spraying to a temperature in the range of 70 to 85 ° C, in particular from 75 to 80 ° C.
  • solutions with different mannitol concentrations can be used at different points in the system.
  • it has proven to be useful to feed spray nozzles above the fluidized bed in the direction of the product discharge with solutions with higher mannitol concentrations than spray nozzles, which are located at the beginning of the fluidized bed.
  • a solution having a mannitol concentration of about 60% by weight, based on the total solution, towards the end of the fluidized bed whereas the two-fluid nozzle with powder recycling is preferably operated with an approximately 40-50% aqueous solution.
  • the product properties can be further improved in the desired way. be influenced with this driving the plant parameters are to be considered exactly.
  • particle sizes between 50 and 1000 ⁇ m can be set in a targeted manner.
  • the spray pressure of the two-component nozzles is to be set in the range from 2 to 4 bar, preferably in the range from 2.5 to 3.5 bar.
  • the supply of hot gas at the top of the plant can assist in the process of forming ⁇ -mannitol.
  • the amount of hot gas supplied to the two-fluid nozzle is to be regulated in such a way that about 1.5 to 3 m 3 / (h kg of solution) at a temperature of about 80 to 110 ° C are conveyed. It has been found that with a higher hot gas supply amount, better product quality is obtained when operating at a lower temperature.
  • the recycling of the solid is adjusted according to the invention so that a recirculation in the range of 0.2 to 2.0 kg solids / (h kg solution) takes place. It is preferable to work in the range from 0.5 to 1.5 kg solids / (h kg solution). The process is particularly favorable if the solids recycling is in the range from 0.5 to 1.0 kg solids / (h kg solution).
  • preheated air must be fed into the system. Good results are achieved if the air supplied to the system is preheated to a temperature in the range of 45-120 ° C. It is favorable for the process according to the invention when the supply air has a temperature in the range of 65 to 110 ° C. It is particularly advantageous for the formation of a ⁇ -mannitol granulate with good tableting properties if the temperature of the feed air fed in is in the range of 70 to 100 ° C.
  • the supplied supply air amount is inventively to regulate so that 1000 - 2000 m 3 / m 2 per hour, in particular 1200 to 1700 m 3 / m 2 per hour, are fed into the system.
  • favorable operating conditions are present when the air flow is performed in the system so that the exhaust air temperature is in the range of 30 -50 ° C.
  • the amount of solids present in the fluidized bed or fluidized bed is adjusted to a bed quantity of 50-150 kg / m 2 bed. It is particularly favorable if the bed quantity is in the range of 80-120 kg / m 2 bed.
  • the supply air of the milling fan must be switched from dust-free to dust-laden from the processor.
  • the flap (H) is open and the flap (J) is closed.
  • the ⁇ -mannitol content continues to rise above 90%, with a longer process duration; d. H.
  • the salary even rises to over 95% and even reaches values of over 98%.
  • a solids recirculation can be achieved both by solids removal from the fluidized bed and by recycling a very finely divided solids fraction which, during the preparation, ie. H. Homogenization of the particle size by screening and filling of the product obtained is carried out.
  • the powder flow can be controlled by adjusting the speed of the rotary valves (10A, 10B). Accordingly, in order to pre-grind the solids to be returned prior to recycling to the desired particle size, the rotational speed of the rotary valve 10A (B) must be adjusted so that recycling takes place via the fan with grinding.
  • the equilibrium can be shifted toward the formation of ⁇ -mannitol, if the average particle size of the recirculated, in the fan (E) milled powder is less than 75 ⁇ .
  • the formation of ⁇ -mannitol preferably occurs when the average particle size of the recycled powder is less than 40 ⁇ m.
  • mannitol powder with a proportion of ⁇ fraction of more than 90% is obtained by recycling a powder having particle sizes of less than 20 ⁇ m.
  • the recycling of the so-called dust fraction which is obtained in the product discharge zone of the processor and is usually removed from the product, leads to a uniform product with a particularly high proportion of ⁇ fraction.
  • the average particle size of the dust content is in the range of about 1 to 20 ⁇ , in particular in the range of 3 to 15 ⁇ . It has also been found that the dust from the recirculation leads to a stable driving in the spray zone of the processor.
  • Table 1 Tablet curing using mannitol from various manufacturing processes as support material
  • the granular mannitol with ⁇ modification content greater than 90% can be readily used to prepare a pharmaceutical active in the presence of moisture or a suitable solvent during the conversion of the ⁇ -form crystal structure to firmly bind to the grain in the ⁇ -form or to incorporate it into the granule grain.
  • it is very easy to produce pulverulent active substance formulations by subjecting the product according to the invention to controlled spraying at a suitable temperature in a fluidized bed with a solution or suspension containing active ingredient.
  • ⁇ -mannitol can be converted into ⁇ -mannitol, with the sprayed-on active ingredient being enclosed in the granules and the crystals that form the granulate.
  • FIG. 2 shows a generalized flow diagram of a possible embodiment of a spray-drying plant used for carrying out the process, in which the given numbers and letters have the following meanings: 1 air inlet chambers
  • a fluidized bed apparatus A fluidized bed apparatus
  • Fig. 1 SEM image of a product with a proportion of ⁇ -modification of more than 98% in a 500-fold magnification.
  • Fig. 2 Generalized flow diagram of a possible embodiment of a spray-drying plant used for carrying out the process
  • the spray-drying plant is filled to prepare with about 70 kg / m 2 ⁇ -mannitol as a bed. (This bed should have the desired product characteristics if possible.) If the available bedding material has other properties, it is necessary to start the installation gently until the balance is in the desired direction As turbulence and supply air, the system is operated with 1200 m 3 / m 2 h at a temperature of about 70 ° C.
  • Dust can be generated and blown into the system through powder dosing (D) by forming the product from the suction-side recirculation (9A) and dosing (10 A) over which with the fan (E) is guided and milled.)
  • the supply air of the fan (E) is introduced via the flap (H).
  • the dosage (10 A) of the recycle can be reduced and the spraying of mannitol solution is started.
  • the sprayed solution has a concentration of about 40% and a temperature of about 75 ° C. At a spray pressure of about 3 bar (spray medium is air.) About 45 kg / m 2 h solution sprayed in the system.
  • the system Due to the evaporation of the water, the system forms an equilibrium with a bed temperature of approx. 35-40 ° C.
  • the exhaust air temperature is approx. 30-33 ° C. (It must be ensured that the exhaust air is as saturated as possible (approx. 80 90% relative humidity), which is beneficial for the efficiency of the process as well as for the crystallization process of mannitol.) In this way one obtains the best crystal structure and the purest ⁇ -modification of mannitol.
  • the fan (E) fetches its supply air from the product discharge zone in front of the lock flaps (F) of the system (A), and thus the discharged product is low in dust by the pneumatic classification, the ⁇ -mannitol with excellent properties is obtained at the product discharge (8) for direct tableting.
  • DC ⁇ -mannitol with the desired particle size distribution it can be sieved after the discharge sluice (F), ie before the product discharge (8) and the powder dosing (D). It is advantageous for the process also to screen out the oversize particles from the product to be recycled (9 B. 0B), since this otherwise accumulates further in the spray zone and can cause problems in the fluidized bed.
  • the sieved undersize and oversize particles can be fed to the suction side of the fan (E), ground, and fed back into the process together with the other recycled solids streams (9A, 10A, 9B, 10B). In this way and W
  • the spray-drying plant is filled to prepare with about 100 kg / m 2 ⁇ -mannitol as a bed and started.
  • the plant with 1500 m 3 / m 2 h at a temperature ⁇ of about 85 ° C is operated.
  • the mannitol solution to be sprayed has a concentration of about 45% at a temperature of about 80 ° C.
  • At a spray pressure of about 3 bar is a solution amount of about 65 kg / m 2 h in sprayed the plant.
  • the cell wheels (10 A, 10 B) are controlled in such a way that always a sufficient amount of product (9A, 10A) is ground in the fan (E) and returned to the system with the unmilled product (9B, 0B).
  • the supply air of the fan (E) is introduced via the flap (H).
  • the evaporation of the water creates a balance in the system with a bed temperature of approx. 40 ° C.
  • the exhaust air temperature is approx. 35-40 ° C. It is important to ensure that the exhaust air is as saturated as possible (approx. 90% relative humidity).
  • the supernatant from the product to be recycled (9B, 0B) is screened, as this otherwise accumulates in the spray zone and causes problems in the fluidized bed.
  • the segregated bottom and top grain is fed to the fan (E) on the suction side and ground. It is returned to the process together with the other recycled solid streams (9 A, 10 A, 9 B, 10 B).
  • the spray-drying plant is filled to prepare with about 20 kg / m 2 ⁇ -mannitol as a bed.
  • the system is operated at 1700 m 3 / m 2 h at a temperature of about 100 ° C.
  • Pas hot gas is in the order of about 1, 6 m 3 / (h kg solution) at
  • the solution has a concentration of about 50% at a temperature of about 90 ° C.
  • a spray pressure of about 3.5 bar (spraying medium is air.) Is a solution amount of about 100 kg / mh in the Plant sprayed.
  • bed / product of about 0.8-, 0 kg solids / (h kg solution) is recycled via the return (9, 10) into the spray zone.
  • the cell wheels (0A, 10B) are controlled so that always a sufficient amount of product (9A, 10A) is ground in the fan (E) and returned to the plant with the unmilled product (9B, 10B).
  • the evaporation of the water creates a balance in the system with a bed temperature of approx. 40-45 ° C.
  • the exhaust air temperature is approx. 40 ° C. It is important to ensure that the exhaust air is as saturated as possible (approx. 80 ° C). 90% relative humidity).
  • the oversize from the product to be recycled (9 B.10B) is screened out, as this otherwise accumulates in the spray zone and causes problems in the fluidized bed.
  • the sieved undersize and oversize are fed to the suction side of the fan (E) and ground.
  • the supply air of the fan (E) is supplied via the flap (H). It is returned to the process along with the other recycled particulate streams (9A, 10A / 9B, 10B).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L'invention concerne un procédé de préparation de mannitol pouvant être directement transformé en comprimés, qui présente un taux de modification δ supérieur à 90 %.
EP11784604.8A 2010-12-17 2011-11-17 Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés Ceased EP2651397A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PL16001371T PL3093011T3 (pl) 2010-12-17 2011-11-17 Sposób otrzymywania bezpośrednio tabletkowalnego delta-mannitolu
EP16001371.0A EP3093011B1 (fr) 2010-12-17 2011-11-17 Procede de fabrication de mannitol a monter directement sur tablette
EP11784604.8A EP2651397A2 (fr) 2010-12-17 2011-11-17 Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10015770 2010-12-17
PCT/EP2011/005801 WO2012079671A2 (fr) 2010-12-17 2011-11-17 Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés
EP11784604.8A EP2651397A2 (fr) 2010-12-17 2011-11-17 Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP16001371.0A Division EP3093011B1 (fr) 2010-12-17 2011-11-17 Procede de fabrication de mannitol a monter directement sur tablette

Publications (1)

Publication Number Publication Date
EP2651397A2 true EP2651397A2 (fr) 2013-10-23

Family

ID=44993528

Family Applications (2)

Application Number Title Priority Date Filing Date
EP11784604.8A Ceased EP2651397A2 (fr) 2010-12-17 2011-11-17 Procédé de préparation de mannitol delta pouvant être directement transformé en comprimés
EP16001371.0A Active EP3093011B1 (fr) 2010-12-17 2011-11-17 Procede de fabrication de mannitol a monter directement sur tablette

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP16001371.0A Active EP3093011B1 (fr) 2010-12-17 2011-11-17 Procede de fabrication de mannitol a monter directement sur tablette

Country Status (7)

Country Link
US (1) US8716536B2 (fr)
EP (2) EP2651397A2 (fr)
JP (2) JP2014501226A (fr)
CN (2) CN103429229A (fr)
HU (1) HUE054747T2 (fr)
PL (1) PL3093011T3 (fr)
WO (1) WO2012079671A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2994569B1 (fr) * 2012-08-17 2016-11-04 Roquette Freres Procede de fabrication de compositions riches en cristaux de mannitol sous forme delta, compositions et cristaux obtenus ainsi que leurs utilisations
CN118558277A (zh) * 2024-07-31 2024-08-30 江苏先卓食品科技股份有限公司 一种异麦芽酮糖醇生产用受热均匀型喷雾结晶装置及其方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3145146A (en) 1961-10-31 1964-08-18 Warner Lambert Pharmaceutical Modified mannitol for pharmaceutical tablets
CZ333698A3 (cs) 1996-04-16 1999-01-13 Bayer Ag D-mannitol a způsob jeho přípravy
DE19615418A1 (de) * 1996-04-22 1997-10-23 Merck Patent Gmbh Polyol-Zusammensetzung
JP2001519378A (ja) * 1997-10-15 2001-10-23 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 直接圧縮可能な錠剤化助剤の製造
DE19927537A1 (de) 1999-06-16 2000-12-21 Merck Patent Gmbh Sprühtrocknungsanlage und Verfahren zu ihrer Verwendung
DE10161402A1 (de) 2001-12-13 2003-06-18 Merck Patent Gmbh Verfahren zur Herstellung von direkt tablettierbarem beta-Mannit
DE10240778A1 (de) * 2002-08-30 2004-03-11 Merck Patent Gmbh Verfahren zur Herstellung von direkt tablettierbarem a-Mannit
EP1623153A1 (fr) 2003-05-15 2006-02-08 Lucea AG Source lumineuse
US20080255193A1 (en) * 2005-09-30 2008-10-16 Jeffrey Brum Pharmaceutical Composition
WO2007074856A1 (fr) * 2005-12-28 2007-07-05 Takeda Pharmaceutical Company Limited Procede de production de preparation solide se desintegrant dans la cavite orale
CA2687813C (fr) * 2007-05-22 2015-07-07 Ssci, Inc. Preparation de modification iii de mannitol
WO2010038695A1 (fr) * 2008-09-30 2010-04-08 大洋薬品工業株式会社 Préparation moulée par compression et son procédé de production

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Parteck - Functional Particle Engineering" *
FRANK R. FRONCZEK ET AL: "THREE POLYMORPHS (ALPHA,BETA AND DELTA) OF D-MANNITOL AT 100 K", ACTA CRYSTALLOGRAPHICA SECTION C CRYSTAL STRUCTURE COMMUNICATIONS, vol. 59, no. 10, 23 September 2003 (2003-09-23), pages O567 - O570, XP055123554, ISSN: 0108-2701, DOI: 10.1107/S0108270103018961 *
See also references of WO2012079671A2 *

Also Published As

Publication number Publication date
JP2014501226A (ja) 2014-01-20
US20130261346A1 (en) 2013-10-03
EP3093011A1 (fr) 2016-11-16
EP3093011B1 (fr) 2021-03-24
WO2012079671A3 (fr) 2012-08-30
PL3093011T3 (pl) 2021-09-06
CN106727355A (zh) 2017-05-31
HUE054747T2 (hu) 2021-09-28
CN103429229A (zh) 2013-12-04
JP6419759B2 (ja) 2018-11-07
WO2012079671A2 (fr) 2012-06-21
US8716536B2 (en) 2014-05-06
JP2017036280A (ja) 2017-02-16

Similar Documents

Publication Publication Date Title
EP1319644B2 (fr) Procédé de préparation de beta-mannitol directement comprimable
EP0809940B2 (fr) Procédé de fabrication d'un additif fourrager pour animaux à base d'un moût de fermentation
DE102008037025C5 (de) Verfahren zur Herstellung kristalliner Wirkstoff-Mikropartikel bzw. einer Wirkstoffpartikel-Festkörperform
EP1915135B1 (fr) Procédé pour produire les particules sphériques à base de substances pharmaceutiques
DE102006007299B4 (de) Tierfuttermittel-Zusatzstoffe auf der Basis von Fermentationsbrühe und deren Herstellungsverfahren durch Granulation
DE2230158A1 (de) Verfahren zur Herstellung von granalienförmigem wasserhaltigem Natriumsilikat
EP1884168A1 (fr) Procédé destiné à la granulation d'un additif fourrager contenant de la L-thréonine
WO2018122017A1 (fr) Procédé de préparation de noir de carbone et procédé de fabrication d'un prémélange pour une installation de mélange de caoutchouc
EP3529225A1 (fr) Granulés contenant du sulfate d'ammonium, procédé et installation pour leur production
DE3804509A1 (de) Kontinuierliches verfahren zur herstellung von natriumperborat-granulaten
EP3093011B1 (fr) Procede de fabrication de mannitol a monter directement sur tablette
EP0433653B1 (fr) Procédé de préparation de granulés d'hydrate de perborate de sodium
WO2004020648A1 (fr) Procede de production d'alpha-mannitol pouvant directement etre agglomere sous forme de comprimes
EP3302777A1 (fr) Granulation de sulfate d'ammonium
EP1413567B1 (fr) Procédé pour la préparation de sorbitol sec par atomisation
EP1609848A1 (fr) Procédé de granulation d'un extrait de malt
DE2643439A1 (de) Alkalimetallsalze von dihalogenisocyanursaeuren in granulatform und verfahren zu ihrer herstellung
WO2009135601A1 (fr) Procédé pour fabriquer de la poudre de gélatine et poudre de gélatine ainsi fabriquée

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130516

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140623

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

APBK Appeal reference recorded

Free format text: ORIGINAL CODE: EPIDOSNREFNE

APBN Date of receipt of notice of appeal recorded

Free format text: ORIGINAL CODE: EPIDOSNNOA2E

APBR Date of receipt of statement of grounds of appeal recorded

Free format text: ORIGINAL CODE: EPIDOSNNOA3E

APAF Appeal reference modified

Free format text: ORIGINAL CODE: EPIDOSCREFNE

APBT Appeal procedure closed

Free format text: ORIGINAL CODE: EPIDOSNNOA9E

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20210606