Amorphous cefuroxime axetil and preparation process therefore

This invention relates to a bioavailable amorphous cefuroxime axetil and a preparation process therefore.

Cefuroxime axetil, i.e. (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyimino-acetylamido]-ceph-3-em-4-carboxylic acid 1-acetoxyethyl ester, is 1-acetoxyethyl ester of cefuroxime. A broad spectrum, second generation cephalosporin, cefuroxime axetil is taken by mouth and has good antibiotic activity against both gram-positive and gram-negative microorganisms. The structure of the compound is as follows:

Cefuroxime axetil is present in two forms: crystalline and amorphous. GB 1,571,683 A1 discloses the process for the preparation of crystalline cefuroxime axetil. The crystalline cefuroxime axetil does not possess the necessary bioavailability characteristics associated with the amorphous form. It is known that orally administered cephalosporin (and medicaments in general) must be in a form of highly bioavailability. For this reason, commercially available cefuroxime axetil which is registered throughout the world is in a substantially amorphous form, since cefuroxime axetil in a substantially amorphous form has a higher bioavailability for oral administration than that in a crystalline form, as disclosed in U.S. Pat. No. 4,820,833 (the '833 patent).

The '833 patent describes a process for the preparation of amorphous cefuroxime axetil, in which amorphous cefuroxime axetil is obtained by spray drying a solution of cefuroxime axetil of a crystalline form in an organic solvent. The current process for industrializing amorphous cefuroxime axetil is usually the spray drying techniques as described in the '833 patent. However, the disadvantages associated with those techniques are that, for example, the cost in equipments may be high, recycling the organic solvents may be difficult, and improper temperature control during the drying process may affect the quality of the cefuroxime axetil.

U.S. Pat. No. 5,013,833 discloses a process for preparing amorphous cefuroxime axetil by the spray drying techniques or by solvent precipitation. Neither an amorphous cefuroxime axetil particle with controllable particle size, nor an ultrafine or even nanosized amorphous cefuroxime axetil particle can be produced by the methods described in U.S. Pat. No. 5,013,833. Furthermore, solvent precipitation which is carried out within the conventional stirred vessels does have some disadvantages, e.g. non-uniform mixing and local supersaturation, which may have an influence on the quality of the cefuroxime axetil powder.

Consequently, the present invention is directed to provide a process for the preparation of an ultrafine or nanosized amorphous cefuroxime axetil particle. Specifically, the invention provides a process for the preparation of an cefuroxime axetil particle having both controllable average particle size and narrow particle size distribution.

Based on the techniques in the prior art, it has been found by the present inventors that amorphous cefuroxime axetil can be obtained by, within a high-gravity reactor, mixing a cefuroxime axetil solution with an antisolvent in which cefuroxime axetil is insoluble, or alternatively by, within a stirred reactor, mixing the cefuroxime axetil solution and the antisolvent via two different atomizers for the solution and the antisolvent; then precipitating and crystallizing.

Specifically, the present invention provides a process for the preparation of ultrafine or nanosized amorphous cefuroxime axetil, which comprises the steps of:

(1) providing a cefuroxime axetil solution and an appropriate antisolvent; (2) feeding the cefuroxime axetil solution and the antisolvent substantially simultaneously into a high-gravity reactor via a first inlet for the cefuroxime axetil solution and a second inlet for the antisolvent, respectively; or alternatively by spraying the cefuroxime axetil solution via an atomizer into a stirred reactor in which the antisolvent is contained, thereby precipitating and crystallizing the cefuroxime axetil by means of antisolvent recrystallization; (3) collecting the slurry of the cefuroxime axetil obtained in step (2); and (4) filtering and then drying the slurry to obtain the ultrafine or nanosized cefuroxime axetil powder in an amorphous form.

The invention further provides an amorphous form of cefuroxime axetil powder produced by the process according to the invention, which comprises ultrafine or nanosized cefuroxime axetil particles having a narrow particle size distribution, preferably at least 70% of cefuroxime axetil particles having an average particle size of the same order.

The invention also provides an amorphous cefuroxime axetil particle having X-ray diffraction spectra as disclosed below in the Detailed Description.

During the process of precipitating and crystallizing according to the invention, the solution and the antisolvent are contacted with each other sufficiently and uniformly, thereby achieving ultra-speed molecular micro-mixing, leading to overcome the limitations of non-uniform and insufficient mixing between the solution and the antisolvent, and avoid the typical local supersaturation associated with the known methods. Since the reactants are contacted and mixed sufficiently and uniformly according to the process of the invention, the precipitation time is decreased and the yield ratio is increased compared with those processes in the prior art. Furthermore, less space is required in the invention, hence favoring mass production.

FIG. 1 shows a schematic representation of the high-gravity reactor for preparation of the amorphous cefuroxime axetil according to one embodiment of the present invention.

FIG. 2 shows X-ray diffractive spectrum of the crystalline cefuroxime axetil prepared by a conventional method.

FIG. 3 shows X-ray diffractive spectrum of the amorphous cefuroxime axetil prepared by the chloroform-isopropyl ether system according to the present invention.

FIG. 4 shows an SEM (Scanning Electron Microscope) image of the cefuroxime axetil prepared by the conventional method.

FIG. 5 shows an SEM image of the cefuroxime axetil prepared by a conventional method.

FIG. 6 shows an SEM image of the amorphous cefuroxime axetil prepared by the chloroform-isopropyl ether system according to the present invention.

FIG. 7 shows an SEM image of the amorphous cefuroxime axetil prepared by the acetone-isopropyl ether system according to the present invention.

FIG. 8 shows an SEM image of the amorphous cefuroxime axetil prepared by the ethyl acetate-isopropyl ether system according to the present invention.

The first aspect of the invention provides a process for the preparation of ultrafine cefuroxime axetil in an amorphous form, which comprises the steps of:

(1) providing a cefuroxime axetil solution and an appropriate antisolvent; (2) feeding the cefuroxime axetil solution and the antisolvent into a high-gravity reactor via a first inlet for the cefuroxime axetil solution and a second inlet for the antisolvent, respectively; or alternatively by spraying the solution via an atomizer into a stirred reactor in which the antisolvent is contained, thereby precipitating and crystallizing the cefuroxime axetil by means of antisolvent recrystallization; (3) collecting the slurry of cefuroxime axetil obtained in step (2); and (4) filtering and then drying the slurry to obtain the ultrafine or nanosized cefuroxime axetil powder in an amorphous form.

The term “crystallization” herein refers to the general “crystallization” and “recrystallization” processes, and it means the recovery of cefuroxime axetil particles by means of crystallization or recrystallization from any solution which contains cefuroxime axetil, including, for example, a solution of cefuroxime axetil in ethyl acetate, a solution of cefuroxime axetil in acetone, a solution of cefuroxime axetil in chloroform, or a mixed solution of cefuroxime axetil in the above-mentioned solvents.

According to the invention, the antisolvent can be any solvent which is able to be mutually or partially miscible with the solution of cefuroxime axetil, and has solubility as low as possible to the cefuroxime axetil. Preferably, the antisolvent comprises methyl tert-butyl ether, ethyl ether, isopropyl ether, n-hexane, water and the like.

The “high-gravity rotary bed” in this invention comprises the high-gravity rotary packed beds which are well-known and generally used in this art. Hence, the two terms of “high-gravity rotary packed bed” and “high-gravity rotary bed” can be used interchangeably. The high-gravity rotary packed beds include, for example, those described and claimed in Chinese patent ZL 95107423.7, Chinese patent ZL 92100093.6, Chinese patent ZL 91109255.2, Chinese patent ZL 95105343.4, Chinese patent application 00100355.0, and Chinese patent application 00129696.5, which are incorporated herein by reference in their entirety.

The high-gravity reactor used in this invention includes the usual rotary packed bed and the unpacked porthole high-gravity reactor having a porthole, such as screwed porthole and flat porthole inside its rotor. The high-gravity reactor comprises a reactant outlet 1 , a rotor 2 , a packing layer 3 , a liquid inlet 4 , a reactor casing, a liquid distributor, and a gas inlet 5 , as illustrated in FIG. 1 . The reactant feed is fed into the high-gravity reactor via the liquid distributor, and is sprayed into tiny droplets within the packing layer, and is uniformly mixed rapidly there.

The packing which is used in the high-gravity reactor of the present invention can include, but is not limited to, metal or non-metal materials, such as screen, perforated plate, corrugated plate, foam material, and structured packing.

The high-gravity reactor of the present invention has a rotor which usually rotates at a speed of at least between about 100 rpm to about 10,000 rpm, preferably between about 500 rpm to about 5000 rpm, and more preferably between about 1000 rpm to about 3000 rpm. According to the invention, the average particle size of the resultant cefuroxime axetil can be adjusted by regulating the rotating speed of the rotor in the reactor. Although not bound to any theory, those skilled in the art should understand that the higher the rotating speed of the high-gravity reactor is, the smaller the average particle size of the resultant powder is, and vice versa. However, the reaction is usually carried out in the preferred range of rotating speed of the rotor, due to economic reasons, such as the cost of energy consumption.

The micro-mixing and micro-mass-transfer of the fluids within the high-gravity reactor is greatly enhanced by the use of the reactor, and thus a uniform concentration distribution is obtained, thereby producing unexpected effects which otherwise can not be obtained in the field of normal earth gravity. For instance, the reaction time is reduced by 4 to 100 times, depending on the intrinsic reaction speed of the reaction system, hence dramatically improving the production efficiency; the production capacity of a unit volume of the reactor in a unit time is enhanced by a times of from tens to hundreds, hence greatly reducing energy consumption; and the particle size of the ultrafine powder is also improved. In addition, due to the uniform mixing, the compositions within the particles tends to be easily homogenized, thus improving the quality and grade of the powder.

The atomizer used in the invention generally can be any atomizer used in the art. For example, an atomizer comprising a stationary spray nozzle with a small orifice can be used, in which the spray nozzle is placed at the center of a high-speed packed rotor. Ultrafine atomized liquid droplets can be obtained by spraying the liquid feed out of the orifice of the spray nozzle with a certain speed, and then shearing and atomizing by the high-speed rotary packing layer.

The disadvantages associated with the conventional stirred vessel reactors are that the quality of the product is affected by local supersaturation, which is due to liquid feed can not be uniformly and rapidly mixed at each part of the reactor, upon entering into the reactor. In the present invention, the liquid feed can be atomized into ultrafine droplets immediately after the liquid is fed via the atomizer, and upon entering into the reactor the liquid can be more rapidly and uniformly mixed with the solution (or the solvent) in the reactor, thereby avoiding any local supersaturation and thus improving the quality of the desired product. In addition, since the reactants are contacted and mixed sufficiently and uniformly, the precipitation time is decreased and the yield ratio is increased compared with other processes in the prior art. Furthermore, particles having a smaller and more uniform particle size can be obtained due to the reaction (precipitating and crystallizing) of the atomized droplets in the reactor. Consequently, the size of the particles can be controlled by adjusting the size of the orifice of the nozzle.

Alternatively, the solution of cefuroxime axetil and the antisolvent can be sprayed into the stirred reactor via different atomizers. In addition, it is possible to obtain ultrafine cefuroxime axetil particles with a controllable and uniform average particle size, particularly ultrafine cefuroxime axetil particles with a controllable average particle size and a narrow particle size distribution, by appropriately adjusting the operating parameters of the stirred vessel reactor or high-gravity reactor, such as the rotating speed of the stirred vessel or the rotating speed of the rotor in the high-gravity reactor, and the size of the nozzle. Typically the stirred reactor operates at a stirred speed ranging from between about 50 rpm to about 10,000 rpm. The particles prepared according to the process of the present invention can be used in the forms of tablet and capsule in the pharmaceutical field, since the particles have a uniform particle size, unlike prior art particles having non-uniform size due to the non-uniform stirring associated with the techniques of the prior art. Furthermore, the particles, due to their small and uniform particle size, can be easily formulated into tablet and capsule and have a higher bioavailability.

In the method described above, the solution of cefuroxime axetil and the antisolvent simultaneously are fed into the high-gravity reactor or sprayed into the stirred reactor via different atomizers.

The cefuroxime axetil solution used in the present invention includes any solution of cefuroxime axetil formed by dissolving the crystalline cefuroxime axetil as obtained in any appropriate solvent.

Commonly used solvents in the cefuroxime axetil solution can include, as a non-limiting example, methanol, dichloromethane, chloroform, ethyl acetate, N,N-dimethyl formamide, formic acid, acetic acid, dioxane, acetone, dimethyl sulfoxide or mixtures thereof. Those skilled in the art may choose any other solvents which can be used to dissolve cefuroxime axetil. As used herein, the term “dissolve” means that a clear solution is obtained by dissolving cefuroxime axetil in a solvent. The concentration of the cefuroxime axetil solution is not specially limited, as long as it can meet the requirement of dissolution.

The antisolvent used in the invention typically comprises methyl tert-butyl ether, isopropyl ether, ethyl ether, n-hexane, water and the like, preferably methyl tert-butyl ether, isopropyl ether, ethyl ether, and n-hexane.

According to the process of the present invention, cefuroxime axetil particles with the desired narrow particle size distribution can be obtained by adjusting the reaction conditions, e.g., the rotating speed of the stirred vessel, stirred reactor or high-gravity reactor, reaction temperature, and the flow rates of the solution and antisolvent. Thus, the present invention provides cefuroxime axetil particles with a uniform particle size distribution, specially ultrafine or even nanosized cefuroxime axetil particles. Specifically, the present invention provides ultrafine cefuroxime axetil particles with an average particle size of usually less than about 100 μm, preferably in the range between about 50 μm and about 20 nm, more preferably in the range between about 10 μm and about 20 nm, and still more preferably in the range between about 5 μm and about 20 nm.

Amorphous cefuroxime axetil particles with a narrow particle size distribution can be obtained by adjusting the reaction conditions (e.g., rotating speed, temperature and flow rate). The particles obtained by the methods described herein differ from those obtained by prior art techniques in that the former has a narrow particle size distribution; that is, at least about 50%, preferably about 70%, and more preferably about 90% of the particles are present in the same order of particle size ranges, such as a particle size distribution of from between about 10 nm to about 100 nm, from between about 200 nm to about 500 nm, from between about 1 μm to about 5 μm, and from between about 5 μm to about 10 μm.

The cefuroxime axetil powders obtained by the method of the present invention have a purity of above 98%, and no less than 75% in terms of dry basis, as determined by HPLC (High Performance Liquid Chromatography).

Unlike the crystalline cefuroxime axetil typically produced by the prior art which has the X-ray diffractive spectrum shown in FIG. 2 , the amorphous cefuroxime axetil particles of the present invention have the X-ray diffractive spectrum shown in FIG. 3 . The data of X-ray diffractive analysis is shown in Table 1.

The process of the present invention and the characteristics, features and advantages of the cefuroxime axetil particles obtained by the present process will be appreciated by those skilled in the art, with reference to the attached drawings and the following specific examples.

The liquid-liquid high-gravity reactor as shown in FIG. 1 was used in one of the examples in the invention. The schematic representation of the rotary bed was disclosed in Chinese patent No. 02127654.4, which is incorporated herein by reference in its entirety.

As illustrated in FIG. 1 , upon starting up the high-gravity rotary packed bed, packing 3 is driven to rotate by rotor 2 . The cefuroxime axetil solution and the antisolvent are contacted with each other instantaneously, and then precipitate and crystallize, upon feeding the cefuroxime axetil solution into the reactor via inlet 4 and spraying into packing 3 via the liquid distributor, and upon feeding the antisolvent into packing 3 via inlet 5 . During the process of precipitating and crystallizing, the precipitated mixture from the packing 3 exits out of high-gravity rotary bed reactor via outlet 1 . The temperature for precipitating can be adjusted within the range of between about −25° C. to about 95° C. by means of recycling water, and the ratio of solution to the antisolvent can be varied from between about 1:2 to about 1:40. Amorphous cefuroxime axetil can be obtained by filtering the slurry exiting from the high-gravity reactor, then washing and drying the filtrate.

According to the process of the invention, the flow rates of the materials involved in the process of precipitating and crystallizing in the high-gravity reactor are such that the reactants of the cefuroxime axetil solution and the antisolvent are able to enter into the reactor in a fashion to provide continuous and sufficient contact between the materials. During the preparation, the flow rates of the solution and the antisolvent are usually determined based on the different solvent systems. Typically the lowest outlet flow rate is above about 5 m/s in the high-gravity reactor. The solution and antisolvent can be separately fed into the high-gravity reactor with a respective flow rate as determined based on the specific high-gravity reaction apparatus.

For example, for the chloroform and isopropyl ether or ethyl ether system, the ratio of flow rates between the solution of cefuroxime axetil in chloroform and isopropyl ether or ethyl ether is within the range from between about 1:4 to about 1:50 (in volume), preferably from between about 1:10 to about 1:30. The flow rate of the solution of cefuroxime axetil in chloroform is within the range from between about 0.01 to about 0.06 m 3 /hour, while that of isopropyl ether or ethyl ether is within the range from between about 0.04 to about 0.18 m 3 /hour. When precipitation is complete, the slurry is filtered, washed, and dried immediately to obtain the desired ultrafine cefuroxime axetil powder in an amorphous form.

The invention will be further illustrated with reference to the following examples; however those examples are only illustrative of the invention and not intended to limit the scope thereof. The raw materials of cefuroxime axetil in its crystalline form are used in the examples, which can be commercially available, or can be prepared by the methods disclosed in GB 1,571,683 A1 or Chinese patent applications No. 01814420.9 (publication number 1447812A), which are all incorporated herein by reference.