HK1090548A - Crystalline amoxicillin trihydrate powder - Google Patents

Description

Crystalline powder of amoxicillin trihydrate

The invention relates to amoxicillin trihydrate crystalline powder. The invention also relates to a method for preparing the amoxicillin trihydrate crystalline powder.

Crystalline powder of a beta-lactam antibiotic can be obtained by the following method: crystallizing the beta-lactam antibiotic from a solution containing the beta-lactam antibiotic in dissolved form, separating the crystals obtained and drying the crystals. In the art, the beta-lactam antibiotic crystals are also referred to as powder.

The known powders have poor flow properties. The particle size is small and the bulk density is low. This is described, for example, in WO-A-9733564 which discloses amoxicillin trihydrate powder having A grain size of from 10 μm to 30 μm and A bulk density of from 0.15g/m to 0.45g/ml, based on the average volume. Due to the poor flow properties of the known powders, the known powders are not suitable for applications requiring sufficient flow properties, such as filling capsules.

To improve the flow properties, the known powders may be subjected to A process known in the art as granulation, compaction, agglomeration or aggregation to form larger particles with improved flow properties, typically having A grain size of more than 100 μm on average volume basis, see for example WO-A-9733564 and WO-A-9911261. The resulting larger particles have improved flow properties and may be used, for example, as a filling material for capsules or in the preparation of tablets.

These processes require additional process steps, which is disadvantageous. In addition, these processes can compromise the properties of the antibiotic, such as color, stability, if not properly applied. Furthermore, we have found that the dissolution rate of the resulting product is low.

We have surprisingly found crystalline powder of amoxicillin trihydrate having a bulk density higher than 0.45g/ml and a process for its preparation.

The crystalline powder of the invention has improved flow properties and does not have to be subjected to processes such as granulation, compaction, agglomeration or aggregation. If it is desired to subject the crystalline powder to processes such as granulation, compaction, sintering or agglomeration, the application of these processes is facilitated due to the improved flow properties of the crystalline powder of the invention. In addition, more crystalline powder can be packed into a capsule of a given size.

As used herein, amoxicillin trihydrate crystalline powder preferably refers to a product consisting essentially of crystals of amoxicillin trihydrate. It is to be understood that crystals do not refer to aggregates formed by the combination of crystals, for example by means of a binder such as water or starch paste, or mechanical forces such as rolling or extrusion. In typical treatments, such as drying, undesirable aggregate formation may occur. Aggregates were visible using optical microscopy at a magnification of 140 x. As used herein, a product consisting essentially of crystals of a beta-lactam antibiotic preferably refers to a product comprising at least 70 wt.%, preferably at least 80 wt.%, more preferably at least 90 wt.%, more preferably at least 95 wt.%, more preferably at least 98 wt.% crystals of amoxicillin trihydrate. These percentages can be determined using a combination of air jet sieving and optical microscopy. Advantageously, 10g weight of the sample was Air-Jet sieved at 1200Pa using an Alpine Air Jet 200LS-N Air-Jet sieve over 1 minute. Advantageously, optical microscopy is performed by taking 5mg of sample, suspending the sample in 4 drops of paraffin oil on a surface with a surface area of 22 x 40mm, and using a magnification of 140 x.

It will be appreciated that amoxicillin trihydrate may contain certain impurities. The crystalline powder of amoxicillin trihydrate according to the invention may comprise, for example, at least 90 wt.%, preferably at least 95 wt.%, more preferably at least 98 wt.% of amoxicillin trihydrate. These weight percentages are given relative to the weight of the crystalline powder. Preferably, the amoxicillin trihydrate powder is free of adjuvants.

Preferably, the crystalline powder of the invention has a bulk density of greater than 0.46g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml. This further improves the flow properties. Furthermore, an increased bulk density is advantageous, since crystalline powder can be filled into a space, for example a capsule. There is no specific upper limit for the bulk density. The bulk density may be less than 0.8g/ml, for example less than 0.7 g/ml. Bulk density is preferably determined according to method I in USP 24 (page 1913).

Preferably, the crystalline powder of the invention has a bulk density higher than 0.6g/ml, preferably higher than 0.7g/ml, more preferably higher than 0.8 g/ml. The increased bulk density improves flow properties. Furthermore, an increased bulk density is advantageous, since more product can be filled into a space, for example a capsule. There is no specific upper limit for the bulk density. The bulk density may be less than 1.2g/ml, such as less than 1.1g/ml, such as less than 1.0 g/ml. Bulk density is preferably determined according to method II in USP 24 (page 1914).

The invention also relates to crystalline powder of amoxicillin trihydrate, having a bulk density higher than 0.6g/ml, preferably higher than 0.7g/ml, more preferably higher than 0.8 g/ml. The crystalline powder has improved flow properties compared to known powders. The bulk density may be less than 1.2g/ml, such as less than 1.1g/ml, such as less than 1.0 g/ml.

Preferably, the crystalline powder of the invention has a bulk density and a bulk density such that d_t/d_bA ratio of less than 1.7, preferably less than 1.6, preferably less than 1.5, preferably less than 1.45, wherein d_tD is the bulk density_bBulk density. This results in an improved flow capacity. For the ratio d_t/d_bThere is no specific lower limit. d_t/d_bThe ratio may be higher than 1.05, for example higher than 1.1.

The invention also relates to crystalline amoxicillin trihydrate powder having a bulk density and a bulk density such that d_t/d_bThe ratio is below 1.7, preferably below 1.6, preferably below 1.5, preferably below 1.45. The crystalline powder has improved flow properties compared to known powders. For the ratio d_t/d_bThere is no specific lower limit. d_t/d_bThe ratio may be higher than 1.05, for example higher than 1.1.

Preferably, the crystalline powder of the invention has a bulk density and a bulk density such that_t-d_b)/d_t) Compression index defined as 100% is lower than 40%, preferably lower than 35%, more preferably lower than 30%. This results in an improved flow capacity. There is no specific lower limit for the compressibility index. The compressibility index may be, for example, higher than 10%.

The invention also relates to crystalline amoxicillin trihydrate powder having a bulk density and a bulk density such that_t-d_b)/d_t) Compression index defined as 100% is lower than 40%, preferably lower than 35%, more preferably lower than 30%. The crystalline powder has improved flow properties compared to known powders. There is no specific lower limit for the compressibility index. The compressibility index may be, for example, higher than 10%.

d₁₀And d₅₀Is a known way of expressing the particle size distribution, d₅₀Refers to a particle size value such that 50 vol.% of the particles have a particle size less than that value. d₅₀Also referred to as average volume based grain size. Likewise, d₁₀Refers to a particle size value such that 10 vol.% of the particles have a particle size less than that value. Determination of d₁₀And d₅₀The preferred method of (3) is laser diffraction, preferably using a Malvern apparatus. Determination of d₁₀And d₅₀A suitable apparatus is a Malvern particle size instrument 2600C available from Malvern instruments ltd of Malvern UK, for example using an objective lens of f 300mm and a beam length of 14.30 mm. Advantageously, a polydisperse analysis model may be used.

We have found that crystalline powders having improved flow ability, bulk density and/or bulk density preferably have an increased d₅₀. The invention also provides₅₀Crystalline powder of amoxicillin trihydrate having a particle size of more than 10 μm, preferably more than 20 μm, more preferably more than 30 μm, more preferably more than 35 μm, more preferably more than 40 μm. For d₅₀There is no specific upper limit. D of crystalline powder of the invention₅₀May be smaller than 150 μm, for example smaller than 100 μm. The crystalline powder of the invention preferably has an increased d₁₀，d₁₀Preferably more than 3 μm, preferably more than 5 μm, more preferably more than 8 μm, more preferably more than 10 μm. D for the crystalline powder of the invention₁₀There is no specific upper limit. D of crystalline powder of the invention₁₀And may be less than 50 μm.

The present invention also provides a method comprising sieving the crystalline powder of the present invention. This leads to a further improvement in the physical properties of the crystalline powder. Preferably, air jet sieving is applied.

The crystalline powder of the invention can be advantageously used for the preparation of pharmaceutical compositions.

The crystalline powder of the invention may advantageously be mixed with pharmaceutically acceptable adjuvants and/or a second pharmaceutically active agent. For example, the crystalline powder of the invention may be mixed with, for example, between 0 and 50 wt%, preferably between 0 and 40 wt%, preferably between 0 and 30 wt%, more preferably between 0 and 20 wt%, preferably more than 1 wt% of the adjuvant, relative to the total weight of the crystalline powder and the adjuvant. For example, the crystalline powder according to the invention may be mixed with clavulanic acid in the form of a salt, preferably a potassium salt, preferably in a weight ratio between amoxicillin and clavulanic acid of between 1: 1 and 15: 1, preferably between 2: 1 and 10: 1, preferably between 4: 1 and 8: 1. These weight ratios are calculated for anhydrous amoxicillin and clavulanate in acid form. The invention therefore also relates to mixtures obtainable by a process comprising mixing the crystalline powder of the invention with auxiliaries and/or a second pharmaceutically active agent. The invention also provides a mixture comprising (i) a crystalline powder of the invention and (ii) an adjuvant and/or a second pharmaceutically active agent.

As second pharmaceutically active agent clavulanic acid is preferably used in the form of a salt, preferably clavulanic acid in the form of a potassium salt.

As auxiliaries, it is possible to use, for example, fillers, dry binders, disintegrants, wetting agents, wet binders, lubricants, flow agents, etc. Examples of adjuvants are lactose, starch, bentonite, calcium carbonate, mannitol, microcrystalline cellulose, polysorbate, sodium lauryl sulfate, carboxymethylcellulose Na, sodium alginate, magnesium stearate, silicon dioxide, talc.

Preferably, the mixture contains between 0 and 50 wt%, preferably between 0 and 40 wt%, preferably between 0 and 30 wt%, more preferably between 0 and 20 wt%, preferably more than 1 wt% of the adjuvant. These weight percentages are given relative to the total weight of amoxicillin trihydrate and the auxiliary agents.

The weight ratio of amoxicillin to clavulanic acid is preferably between 1: 1 and 15: 1, preferably between 2: 1 and 10: 1, preferably between 4: 1 and 8: 1. These weight ratios are calculated as anhydrous amoxicillin and clavulanate in acid form.

The crystalline powder of the invention can be advantageously used for filling pharmaceutical capsules, such as gelatin capsules. The invention therefore also relates to capsules containing the crystalline powder according to the invention or capsules containing the mixture according to the invention. The crystalline powder of the invention or the mixture of the invention may be filled into capsules in any suitable manner. The skilled person will appreciate that filling the material into the capsule may comprise forming a plug (plug) of the material, the plug being loosely composed of the material. The skilled person will appreciate that capsules containing the crystalline powder or mixture of the invention also include capsules containing an embolus of the crystalline powder or mixture of the invention. The invention also relates to the use of the crystalline powder according to the invention or the mixture according to the invention for filling capsules or for producing tablets.

The invention also relates to a method of filling capsules comprising filling a crystalline powder of the invention, optionally in combination with an adjuvant and/or a second pharmaceutically active agent, into capsules. The invention also relates to a process comprising mixing the crystalline powder of the invention with pharmaceutically acceptable adjuvants, and optionally a second pharmaceutically active agent, and filling the resulting mixture into capsules.

We have found that the improved flow properties of the crystalline powder of amoxicillin trihydrate according to the invention facilitate processes such as dry and wet granulation, agglomeration, tablet formation and the like. Accordingly, the present invention also provides a method comprising compressing the crystalline powder of the present invention or compressing the mixture of the present invention to produce a compressed product. The compressed product may be, for example, granules or tablets. The invention also relates to granules or tablets comprising the crystalline powder in compressed form or the mixture of the invention in compressed form.

The invention also relates to a process for the preparation of granules, which comprises filling a roller compactor with the crystalline powder according to the invention or the mixture according to the invention, optionally in combination with auxiliaries and/or a second pharmaceutically active agent, to prepare compacts; and grinding the compact to produce granules. The granules produced may advantageously be sieved to obtain the desired particle size distribution. The invention also relates to granules obtainable by this process.

The invention also relates to a process for the preparation of granules, which comprises mixing the crystalline powder according to the invention or the mixture according to the invention with a binder, which is, for example, dissolved in a wetting fluid; compacting the crystals while wet or dry; the resulting compact was granulated through a sieve. The invention also relates to granules obtainable by this process.

The invention also relates to a process comprising forming a paste from the crystalline powder of the invention or from the mixture of the invention; kneading the paste at a temperature of 10 ℃ to 80 ℃; the paste is extruded in a twin-screw extruder and the resulting granules are dried, if desired. The invention also relates to granules obtainable by this process.

The invention also relates to a process comprising compressing a mixture of granules of the invention, optionally with an adjuvant and/or a second pharmaceutically active agent, to make a tablet. The invention also relates to tablets obtainable by this process.

The invention also provides a process comprising the step of bringing the amoxicillin trihydrate crystalline powder of the invention into association with amoxicillin in another physical form, preferably comprising amoxicillin trihydrateMixing ampicillin granules. The invention also provides a mixture comprising (i) amoxicillin trihydrate powder according to the invention and (ii) amoxicillin trihydrate in another physical form, preferably granules comprising amoxicillin trihydrate. In one embodiment, the mixture is free of adjuvants. In one embodiment, the mixture comprises an adjuvant and/or a second pharmaceutically active agent. The granules containing amoxicillin trihydrate in the mixture (to be mixed) may be any suitable granules, e.g. d₅₀Between 100 and 1000 μm. Granule d₅₀Preferably by performing a sieve analysis. The granules may for example comprise at least 90 wt% amoxicillin trihydrate, preferably at least 95 wt%, more preferably at least 98 wt% amoxicillin trihydrate. Preferably, the granules are free of adjuvants. Granules may be obtained by any suitable process in which powders are mixed, for example by roller compaction, agglomeration, extrusion, aggregation, wet or dry granulation, to form granules.

In one aspect of the invention, the crystalline powder of the invention has a high dissolution rate. Preferably, T of the crystalline powder of the invention_85％Less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes, preferably less than 20 minutes. T is_85％For example, it may be greater than 5 minutes. As used herein, T_85％Means the time required for dissolving a predetermined amount of amoxicillin trihydrate of 85 wt% (based on 500mg of anhydrous amoxicillin) in 900ml water at 37 ℃. T is_85％Preferably under conditions as defined in USP 27, chapter "amoxicillin capsules", comprising using the apparatus 1, applying a stirring rate of 100rpm (USP 27, paragraph 711). Preferably, samples are taken periodically, e.g. every 5 minutes, to determine the amount of dissolved amoxicillin by uv absorption. It was not found that the known amoxicillin trihydrate products having a bulk density of more than 0.45g/ml, such as amoxicillin trihydrate granules having a bulk density of more than 0.45g/ml, have such a high dissolution rate.

Accordingly, the present invention also relates to a product of amoxicillin trihydrate, said product having:

(i) t of less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes_85％(ii) a And

(ii) a bulk density of greater than 0.45g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml. There is no specific upper limit for the bulk density. The bulk density may be less than 0.8g/ml, for example less than 0.7 g/ml. T is_85％For example, it may be greater than 5 minutes.

The invention also relates to a product of amoxicillin trihydrate, said product having

(i) T of less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes_85％(ii) a And

(ii) bulk density of greater than 0.6g/ml, preferably greater than 0.7g/ml, more preferably greater than 0.8 g/ml. There is no specific upper limit for the bulk density. The bulk density may be less than 1.2g/ml, such as less than 1.1g/ml, such as less than 1.0 g/ml.

The invention also relates to a product of amoxicillin trihydrate, said product having:

(i) t of less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes_85％(ii) a And

(ii) bulk density and bulk density are such that d_t/d_bA ratio of less than 1.7, preferably less than 1.6, preferably less than 1.5, preferably less than 1.45, wherein d_tD is the bulk density_bBulk density. This results in an improved flow capacity. For the ratio d_t/d_bThere is no specific lower limit. Ratio d_t/d_bMay be higher than 1.05, for example higher than 1.1.

The invention also relates to a product of amoxicillin trihydrate, said product having

(i) Less than 55 minutes, preferably less than 50 minutes,Preferably T of less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes_85％(ii) a And

(ii) the bulk and bulk densities are such as_t-d_b)/d_t) Compression index defined as 100% is lower than 40%, preferably lower than 35%, more preferably lower than 30%. This results in an improved flow capacity. There is no specific lower limit for the compressibility index. The compressibility index may be, for example, higher than 10%.

In a preferred embodiment, the product of amoxicillin trihydrate according to the invention has the above preferred values of bulk density, d mentioned in connection with above_t/d_bRatio and compression index.

The product of amoxicillin trihydrate according to the invention may be amoxicillin trihydrate in any suitable form. It will be appreciated that the product amoxicillin trihydrate may also contain certain impurities. Preferably, the product of amoxicillin trihydrate comprises at least 90 wt.%, preferably at least 95 wt.%, more preferably at least 98 wt.% amoxicillin trihydrate. These weight percentages are given relative to the weight of the product. Preferably, the product of amoxicillin trihydrate according to the invention is free of auxiliaries.

In one embodiment the product according to the invention is amoxicillin trihydrate crystalline powder according to the invention. In another embodiment, the product of the invention is a mixture comprising (i) amoxicillin trihydrate powder, preferably crystalline amoxicillin trihydrate powder according to the invention, and (ii) amoxicillin trihydrate in another physical form, preferably granules comprising amoxicillin trihydrate.

The invention also provides a process comprising mixing amoxicillin trihydrate powder, preferably crystalline amoxicillin trihydrate powder according to the invention, with amoxicillin in another physical form, preferably granules comprising amoxicillin trihydrate, to obtain a product according to the invention. The amounts of amoxicillin trihydrate and granules to be mixed are selected to achieve a preferred combination of T_85％And volumeDensity, bulk density, d_t/d_bRatio and/or compressibility index. The amoxicillin trihydrate powder in the mixture (to be mixed) may be, for example, d₅₀Between 1 μm and 100 μm. The amoxicillin trihydrate crystalline powder of the present invention is preferred.

The granules containing amoxicillin trihydrate in the mixture (to be mixed) may be any suitable granules, e.g. d₅₀Granules between 100 and 1000 μm. Granule d₅₀Preferably by performing a sieve analysis. Granules may comprise for example at least 90 wt% amoxicillin trihydrate, preferably at least 95 wt%, more preferably at least 98 wt% amoxicillin trihydrate. Preferably, the granules are free of adjuvants. Granules may be obtained by any suitable process in which powders are mixed to form granules, for example by roller compaction, agglomeration, extrusion, aggregation, wet or dry granulation.

The products of the invention can advantageously be used for the preparation of pharmaceutical compositions.

The product of the invention may advantageously be mixed with pharmaceutically acceptable adjuvants and/or a second pharmaceutically active agent. The product of the invention may be mixed with an adjuvant, for example between 0 and 50 wt%, preferably between 0 and 40 wt%, preferably between 0 and 30 wt%, more preferably between 0 and 20 wt%, preferably more than 1 wt%, relative to the total weight of the product and the adjuvant. The product of the invention may be mixed with clavulanic acid, for example in the form of a salt, preferably a potassium salt, preferably in a weight ratio between amoxicillin and clavulanic acid of between 1: 1 and 15: 1, preferably between 2: 1 and 10: 1, preferably between 4: 1 and 8: 1. These weight ratios are calculated as anhydrous amoxicillin and clavulanate in acid form. The invention therefore also relates to mixtures obtainable by a process comprising mixing a product of the invention with auxiliaries and/or a second pharmaceutically active agent. The invention also provides a mixture comprising (i) a product of the invention and (ii) an adjuvant and/or a second pharmaceutically active agent.

As second pharmaceutically active agent clavulanic acid is preferably used in the form of a salt, preferably clavulanic acid in the form of a potassium salt.

As auxiliaries, it is possible to use, for example, fillers, dry binders, disintegrants, wetting agents, wet binders, lubricants, flow agents, etc. Examples of adjuvants are lactose, starch, bentonite, calcium carbonate, mannitol, microcrystalline cellulose, polysorbate, sodium lauryl sulfate, carboxymethylcellulose Na, sodium alginate, magnesium stearate, silicon dioxide, talc.

Preferably, the mixture contains between 0 and 50 wt%, preferably between 0 and 40 wt%, preferably between 0 and 30 wt%, more preferably between 0 and 20 wt%, preferably more than 1 wt% of the adjuvant. These weight percentages are given relative to the total weight of amoxicillin trihydrate and the auxiliary agents.

The weight ratio of amoxicillin to clavulanic acid is preferably between 1: 1 and 15: 1, preferably between 2: 1 and 10: 1, preferably between 4: 1 and 8: 1. These weight ratios are calculated as anhydrous amoxicillin and clavulanate in acid form.

The product of the invention can advantageously be used for filling pharmaceutical capsules, such as gelatin capsules. The invention therefore also relates to capsules containing the product according to the invention or to capsules containing the mixture according to the invention. The product of the invention or the mixture of the invention can be filled into capsules in any suitable manner. The skilled person will appreciate that filling the material into the capsule may comprise forming a plug of the material, said plug consisting loosely of the material. The skilled person will appreciate that capsules containing a product or mixture of the invention also include capsules containing an embolus of a product or mixture of the invention. The invention also relates to the use of the product according to the invention or the mixture according to the invention for filling capsules or for producing tablets.

The invention also relates to a method of filling capsules comprising filling capsules with a product of the invention, optionally in combination with an adjuvant and/or a second pharmaceutically active agent. The invention also relates to a process comprising mixing a product of the invention with pharmaceutically acceptable adjuvants, and optionally a second pharmaceutically active agent, and filling the resulting mixture into capsules.

We have found that the improved flow properties of the product of the invention facilitate processes such as dry and wet granulation, agglomeration, tablet formation and the like. The invention therefore also provides a process comprising compressing a product of the invention or compressing a mixture of the invention to produce a compressed product. The compressed product may be, for example, granules or tablets. The invention also relates to granules or tablets comprising the product according to the invention in compressed form or the mixture according to the invention in compressed form.

The invention also relates to a process for the preparation of granules, which process comprises filling a roller compactor with the product of the invention or the mixture of the invention, optionally in combination with adjuvants and/or a second pharmaceutically active agent, to prepare compacts; and grinding the compact to produce granules. The granules produced may advantageously be sieved to obtain the desired particle size distribution. The invention also relates to granules obtainable by this process.

The invention also relates to a process for the preparation of granules, which comprises mixing the product of the invention or the mixture of the invention with a binder, for example dissolved in a wetting fluid; compacting the crystals while wet or dry; the resulting compact was granulated through a sieve. The invention also relates to granules obtainable by this process.

The invention also relates to a process comprising forming a paste from the product of the invention or from the mixture of the invention; kneading the paste at a temperature of 10 ℃ to 80 ℃; extruding the paste in a twin screw extruder; and, if necessary, drying the resulting granules. The invention also relates to granules obtainable by this process.

The invention also relates to a process comprising compressing a mixture of granules of the invention and optionally with adjuvants and/or a second pharmaceutically active agent to make a tablet. The invention also relates to tablets obtainable by this process.

The amoxicillin trihydrate crystalline powder can be obtained by the following method: preparing a solution containing dissolved amoxicillin, crystallizing amoxicillin trihydrate from said solution to form crystals, separating the crystals from said solution, and drying the separated crystals. As used herein, the term crystalline powder includes, but is not limited to, the dried product obtained and/or obtainable by this process.

It has surprisingly been found that crystalline powders having improved flow properties, in particular a high bulk density and/or a high bulk density, can be obtained by selecting the conditions of crystallization, separation and/or drying.

It has been found that the preparation of crystalline powders having improved flow properties, in particular a high bulk density and/or a high bulk density, preferably involves providing dried crystals having an increased particle size, in particular an increased d₅₀And/or d₁₀In particular crystallization, separation and drying.

Preferred crystallization conditions may include longer residence times, lower concentrations of amoxicillin aqueous solution, lower concentrations of protein aqueous solution, and/or the use of high purity aqueous solution. More preferred conditions are described below.

It has also been found that, especially for crystals with increased size, the degree of mechanical impact, e.g. during crystallization, separation and/or drying, affects the bulk density and the bulk density. If the crystals are subjected to mechanical forces, for example during drying and/or separation or transport of the crystals, it has surprisingly been found that both the bulk density and the bulk density are increased compared to the case without mechanical impact. However, if the mechanical force is too great, the bulk density and the bulk density are found to decrease. Mechanical impact in the separation process can be obtained, for example, during centrifugation. The mechanical impact during drying can be obtained, for example, by using a contact dryer, such as a Vrieco-Nauta contact dryer or a flash dryer. Mechanical impact may also be obtained by using gas transport, for example by gas transport of amoxicillin trihydrate from the separation step to the drying step. While not wishing to be bound by any scientific theory, it is believed that a limited degree of mechanical impact has the effect of breaking up the larger needle crystals, thus leading to an increase in bulk density and/or packing density. However, it is believed that excessive mechanical forces may produce excessively fine crystals, thereby reducing bulk and/or bulk density. With this insight proposed by the present invention and by varying the mechanical forces, the skilled person is able to find out the conditions under which the optimal bulk density and/or tapped density is achieved.

Accordingly, the present invention provides a process for the preparation of crystalline amoxicillin trihydrate powder, said process comprising: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin; separating the crystals from the solution; drying the separated crystals; wherein the process, preferably crystallization, isolation and/or drying, is carried out under conditions such that the bulk density of the resulting crystalline powder is greater than 0.45g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml. There is no specific upper limit for the bulk density. The process, preferably crystallization, isolation and/or drying, may for example be carried out at a bulk density of less than 0.8g/ml, for example less than 0.7 g/ml.

The invention also provides a method for preparing amoxicillin trihydrate crystalline powder, comprising the following steps: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin; separating the crystals from the solution; drying the separated crystals; wherein the process, preferably crystallization, isolation and/or drying, is carried out under conditions such that the bulk density of the crystalline powder obtained is greater than 0.6g/ml, preferably greater than 0.7g/ml, more preferably greater than 0.8 g/ml. There is no specific upper limit for the bulk density. The process, preferably crystallization, isolation and/or drying, may for example be carried out at a bulk density of less than 1.2g/ml, such as less than 1.1g/ml, such as less than 1.0 g/ml.

The invention also provides a method for preparing amoxicillin trihydrate crystalline powder, comprising the following steps: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin; separating the crystals from the solution; drying the separated crystals; among these, the method is preferably one in which the crystalline powder obtained is crystallized, isolated and/or driedd_t/d_bAt a ratio of less than 1.7, preferably less than 1.6, preferably less than 1.5, preferably less than 1.45, where d_tD is the bulk density_bBulk density. There is no specific lower limit for this ratio. The process, preferably crystallization, isolation and/or drying, may be carried out, for example, in d_t/d_bAt a ratio higher than 1.05, for example higher than 1.1.

The invention also provides a method for preparing amoxicillin trihydrate crystalline powder, comprising the following steps: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin; separating the crystals from the solution; drying the separated crystals; wherein the process, preferably crystallization, isolation and/or drying is carried out in the presence of a catalyst such as ((d)_t-d_b)/d_t) 100% is less than 40%, preferably less than 35%, more preferably less than 30%, wherein d_tD is the bulk density_bBulk density. There is no specific lower limit for the compressibility index. The compressibility index may be, for example, higher than 10%.

The invention also provides a method for preparing amoxicillin trihydrate crystalline powder, comprising the following steps: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin; separating the crystals from the solution; drying the separated crystals; among these, the method preferably crystallizes, separates and/or dries d in the resulting crystalline powder₅₀More than 10 μm, preferably more than 20 μm, more preferably more than 30 μm, in particular more than 35 μm, more preferably more than 40 μm. For d₅₀There is no specific upper limit. The process, preferably crystallization, isolation and/or drying, may be carried out, for example, on d of the crystalline powder obtained₅₀Less than 150 μm, for example less than 100 μm. Preferably, the process, preferably crystallization, isolation and/or drying of the crystals in dry form d₁₀More than 3 μm, preferably more than 5 μm, more preferably more than 8 μm, more preferably more than 10 μm. For d₁₀There is no specific upper limit. The process, preferably crystallization, isolation and/or drying, may be carried out on the crystalline powder obtainedD of₁₀Less than 50 μm.

The water activity that can be used to indicate the dryness of the product can have any suitable value. The drying may be performed such that the resulting crystalline powder of amoxicillin trihydrate has a water activity of, for example, above 0.05, for example above 0.1, for example above 0.15, for example above 0.2, for example above 0.25, for example above 0.3, for example below 0.7, for example below 0.6, for example below 0.5. The crystal powder of amoxicillin trihydrate according to the invention may have a water activity of, for example, above 0.05, for example above 0.1, for example above 0.15, for example above 0.2, for example above 0.25, for example above 0.3. The crystal powder of amoxicillin trihydrate according to the invention may have a water activity of, for example, less than 0.7, such as less than 0.6, such as less than 0.5. These values refer to the water activity measured at 25 ℃. Water activity is known to be defined as equilibrium relative humidity divided by 100%. A preferred method of determining the water activity of a sample is to place a measured amount of the sample in a closed chamber of small volume and measure the relative humidity as a function of time until the relative humidity has become constant (e.g. after 30 minutes), the latter being the equilibrium relative humidity of the sample. Preferably, Novasina TH200 Thermoconstant is used, with a sample holder volume of 12ml and 3g of sample contained therein.

Preferably, according to the invention, the process for the preparation of crystalline powder of amoxicillin trihydrate comprises: preparing amoxicillin by reacting 6-amino penicillic acid or a salt thereof with p-hydroxyphenyl glycine in activated form in the presence of an enzyme immobilized on a carrier; forming an aqueous solution comprising amoxicillin, said aqueous solution comprising hydrochloric acid; and crystallizing amoxicillin trihydrate from said aqueous solution.

Preferably, the solution from which amoxicillin trihydrate is crystallized is an aqueous solution. Any suitable aqueous solution may be used. Suitable aqueous solutions include solutions in which the weight ratio of water to organic solvent is between 100: 0 and 70: 30, preferably between 100: 0 and 80: 20, preferably between 100: 0 and 90: 10, preferably between 100: 0 and 95: 5, preferably between 100: 0 and 99: 1.

Preferably, the solution from which the amoxicillin trihydrate is crystallized contains less than 200 parts by weight of protein per 1,000,000 parts by weight of amoxicillin (total concentration of amoxicillin, whether or not in dissolved form), preferably less than 100 parts by weight of protein, more preferably less than 50 parts by weight of protein, more preferably less than 35 parts by weight of protein.

Preferably, the solution from which the amoxicillin trihydrate is crystallized is an aqueous solution having an amoxicillin concentration (total amoxicillin concentration, whether or not in dissolved form) of less than 0.6mol/l, preferably less than 0.5mol/l, more preferably less than 0.4mol/l, more preferably less than 0.3 mol/l.

The aqueous solution from which amoxicillin trihydrate is crystallized is preferably a solution containing hydrochloric acid or chloride. The aqueous solution from which the amoxicillin trihydrate is crystallized preferably contains between 0.9 and 5mol hydrochloric acid or chloride, preferably between 0.9 and 3mol hydrochloric acid or chloride, more preferably between 0.9 and 1.5mol hydrochloric acid or chloride per mole amoxicillin (total concentration of amoxicillin, whether or not in dissolved form). The aqueous solution from which amoxicillin is crystallized preferably contains more than 1.0mol hydrochloric acid or chloride per mol amoxicillin.

Preferably, amoxicillin trihydrate is crystallized from an aqueous solution at a pH value between 2 and 7, preferably between 3 and 6. Preferably, the process comprises crystallizing amoxicillin trihydrate from an aqueous solution in a first step at a pH value preferably between 2 and 5, preferably between 3 and 4, and in a second step at a pH value higher than the pH value of the first step, preferably between 4 and 7, preferably between 4.5 and 6.

Preferably, amoxicillin trihydrate is crystallized from an aqueous solution at a temperature between 5 ℃ and 40 ℃, preferably between 10 ℃ and 30 ℃, more preferably between 15 ℃ and 25 ℃.

The solution from which amoxicillin trihydrate is crystallized may be prepared in any suitable manner. An aqueous solution containing dissolved amoxicillin may be prepared by dissolving amoxicillin trihydrate. Amoxicillin trihydrate may be added to the solution and the added amoxicillin trihydrate may be dissolved. The suspension may also be prepared by forming amoxicillin trihydrate crystals directly in solution and dissolving the amoxicillin trihydrate crystals in an aqueous suspension. In a process for the preparation of amoxicillin, the process preferably comprises preparing an aqueous solution containing dissolved amoxicillin, said aqueous solution having an amoxicillin concentration of less than 0.6mol/l, preferably less than 0.5mol/l, more preferably less than 0.4mol/l, more preferably less than 0.3 mol/l. The process preferably comprises preparing an aqueous solution containing dissolved amoxicillin, said aqueous solution having a pH between 0 and 1.5, preferably between 0.5 and 1.2. The dissolution of amoxicillin may be performed in any suitable way, e.g. by adding acid, preferably by adding hydrochloric acid to an aqueous suspension containing crystals of amoxicillin trihydrate. The amount of acid, preferably hydrochloric acid, which may be added is between 0.9 and 5mol, preferably between 0.9 and 3mol, more preferably between 0.9 and 1.5mol per mol of amoxicillin. Preferably more than 1.0mol hydrochloric acid is added per mole amoxicillin. In a preferred embodiment the process comprises maintaining the pH of the (aqueous) solution or the (aqueous) suspension at a value of less than 1.5, preferably less than 1.2 in less than 60 minutes, preferably less than 30 minutes, more preferably less than 15 minutes, more preferably less than 10 minutes, more preferably less than 8 minutes, as this may improve the purity of amoxicillin. Preferably, the method comprises mixing the aqueous solution or aqueous suspension with the acid using a rapid mixer, such as a static mixer. This may reduce the time during which the aqueous solution or suspension is kept at a low pH. The mixing of the acid with the aqueous suspension may be carried out at any suitable temperature, for example above-5 ℃, for example above 10 ℃, for example above 15 ℃, for example below 50 ℃, for example below 40 ℃. Preferably, the method comprises filtering the solution prior to said crystallization. Preferably, the process comprises filtering an aqueous solution containing dissolved amoxicillin, said aqueous solution preferably having a pH between 0 and 1.5, preferably between 0.5 and 1.2. The solution may be passed through any suitable filter. Preferably, filters with pore sizes of less than 40 μm, preferably less than 20 μm, preferably less than 10 μm and more preferably less than 5 μm are used.

Amoxicillin trihydrate may advantageously be crystallized from said aqueous solution by increasing the pH, for example by adding a base, such as NaOH.

The crystallization may be carried out batchwise or continuously. When the process is carried out batchwise, it is preferred to add seed crystals to the aqueous solution. Preferably, the crystallization is carried out continuously.

Amoxicillin is preferably prepared by reacting 6-amino-penicillic acid or a derivative thereof, such as a salt of 6-amino-penicillic acid, with an acylating agent selected from p-hydroxyphenyl glycine in activated form in the presence of an enzyme in an aqueous reaction medium. The activated form of p-hydroxyphenylglycine is preferably an ester or an amide of p-hydroxyphenylglycine. Suitable esters include, for example, 1 to 4 alkyl esters, such as methyl, ethyl, n-propyl or isopropyl esters. Glycol esters, such as ethylene glycol esters, may also be used. Can be used in-CONH₂Amides unsubstituted in the group.

The enzyme may be any enzyme having hydrolytic activity (hydrolase). The enzyme may for example be an acyltransferase, in particular penicillin G acyltransferase, an amidase or an esterase. The enzymes can be isolated from various natural microorganisms, such as fungi and bacteria. Organisms which have been found to produce penicillin acylases are, for example, Acetobacter, Aeromonas, Alcaligenes (Alcaligenes), Sphingobacterium (aphanocladium), Bacillus sp., Cephalosporium, Escherichia, Flavobacterium, Kluyveromyces, Cladonobacterium, Protaminobacter, Pseudomonas or Xanthomonas.

Processes for the preparation of amoxicillin in the presence of an enzyme are described in WO-A-9201061, WO-A-9417800, WO-A-9704086, WO-A-9820120, EP-A-771357, the contents of which are hereby incorporated by reference.

The reaction may be carried out at any suitable pH, preferably at a pH between 5 and 9, preferably between 5.5 and 8, more preferably between 6 and 7.5. The reaction may be carried out at any suitable temperature, for example at a temperature between 0 ℃ and 40 ℃, preferably between 0 ℃ and 30 ℃, more preferably between 0 ℃ and 15 ℃.

The amoxicillin formed may be crystallized under the conditions under which the reaction is carried out. The crystallization of amoxicillin may for example be carried out at a pH value between 5 and 8, preferably between 5.5 and 7.5.

Preferably, the enzyme is an enzyme immobilized on a carrier. Any suitable carrier may be used. Preferably, the carrier comprises a gelling agent and a polymer containing free amino groups. Preferably, the polymer is selected from alginate amine, chitosan, pectin or polyethyleneimine. Preferably, the gelling agent is gelatin. Such vectors and their preparation are described in EP-A-222462 and WO-A-9704086. The isolated enzyme is preferably purified by ion exchange chromatography prior to immobilization.

Preferably, the enzyme is an enzyme immobilized on a carrier and the process preferably comprises separating the product comprising amoxicillin formed from the immobilized enzyme. The separation of the product from the immobilized enzyme may be carried out by using any suitable method, for example by using gravity or a sieve impermeable to the major part of the immobilized enzyme. Preferably, the product separated from the immobilized enzyme contains less than 200 parts by weight of protein, preferably less than 100 parts by weight of protein, more preferably less than 50 parts by weight of protein, more preferably less than 35 parts by weight of protein per 1,000,000 parts by weight of amoxicillin. This is preferably achieved by using an enzyme sufficiently immobilized on a carrier to avoid separation of small amounts of protein from amoxicillin trihydrate. This has the advantage that the finally obtained amoxicillin trihydrate contains less than 200 parts by weight of protein, preferably less than 100 parts by weight of protein, more preferably less than 50 parts by weight of protein, more preferably less than 35 parts by weight of protein per 1,000,000 parts by weight of amoxicillin. The product separated from the immobilized enzyme may be an aqueous solution containing amoxicillin in dissolved form. The product separated from the immobilized enzyme may also be a wet cake (wetcake). The isolated product is preferably an aqueous suspension comprising crystals of amoxicillin trihydrate. Preferably, the process comprises dissolving the amoxicillin trihydrate crystals to form an aqueous solution containing dissolved amoxicillin.

The invention also relates to crystalline powder of amoxicillin trihydrate obtainable by the process of the invention.

The invention will be further illustrated by the following non-limiting examples.

Examples and comparative experiments

Examples I to V

Preparation of immobilized enzymes

The E.coli penicillin acylase was isolated as described in WO-A-9212782, purified by ion exchange chromatography and immobilized as described in EP-A-222462 and WO-A-9704086.

The following definitions apply for the activity of penicillin G acylase: one unit (U) corresponds to (100 g.l) under standard conditions^-1Penicillin G potassium salt, 0.05M potassium phosphate buffer, pH 8.0, 28 ℃), an amount of enzyme that hydrolyzes 1 micromole of penicillin G per minute.

Production of amoxicillin

162.2g of 6-APA (6-aminopenicillanic acid) and 184.8g of HPGM (D (-) -p-hydroxyphenyl glycine methyl ester) were suspended in 450ml of water. The suspension was cooled to 10 ℃. To this reaction mixture 32850 units of immobilized penicillin acylase were added and water was added to a final volume of 1500 ml. The mixture was stirred for 6 hours. During the reaction, the pH increased to 6.9 and at the end of the reaction the pH had decreased to 6.2. To this mixture was added 750ml of water, and the suspension was filtered over 2 hours with a sieve (mesh opening 100 μm) to separate off the immobilized enzyme. The resulting suspension containing crystals of amoxicillin trihydrate was cooled to 0 ℃. The suspension contains less than 50ppm protein relative to amoxicillin trihydrate (less than 50 parts by weight protein per 1,000,000 parts by weight amoxicillin trihydrate).

The aqueous suspension containing amoxicillin in water (100g amoxicillin trihydrate per liter of suspension) obtained as above was mixed with a 32 wt.% HCL solution (at a temperature of 25 ℃) using a static mixer, thus obtaining a solution with a pH of 1. The residence time in the static mixer was 1.5 minutes. The resulting acidic solution was pumped through two filters, the first filter having a pore size of 40 μm and the second filter having a pore size of 4.5 μm. The residence time in the filter was about 3 minutes. The acidic filtered solution was fed to a first stirred tank maintained at a pH of 3.7 by the addition of 8M NaOH solution. The temperature in the first tank is between 17 ℃ and 23 ℃. The residence time in the first tank was 45 minutes. The contents of the first tank were fed to a second stirred tank where the pH was maintained at 5.0 by the addition of 8M NaOH solution. The temperature in the second stirred tank was between 17 ℃ and 23 ℃. The residence time in the second stirred tank was 15 minutes. And feeding the materials in the second stirring kettle into a third stirring kettle with the temperature kept between 1 ℃ and 5 ℃, wherein the retention time in the third stirring kettle is more than 4 hours. The contents of the third stirred tank were fed to a reverse filter centrifuge to separate the crystals of amoxicillin, thereby obtaining a wet cake containing 86 wt.% of solid material. The wet cake was washed with water and conveyed with gas to a conical vacuum contact dryer (Vrieco-Nauta) where it was dried for 7 hours at a temperature of 30 ℃ to 40 ℃ and a pressure of 30 mbar.

Measurement of particle size distribution, bulk density and bulk density

Particle size distribution (including d) of samples from the mixer was determined using a Malvern particle sizer 2600C₁₀And d₅₀) The particle size instrument 2600C has an objective lens of f 300mm, a Malvern sample measurement unit PS1 and a Malvern dry powder injectorPS 64. The beam length was 14.30 mm. A polydisperse analysis model was used.

Bulk density was determined according to method I of USP 24 (page 1913).

Bulk density was determined according to method II of USP 24 (page 1914).

Five different batches of material were prepared using the above method. Table 1 shows the bulk density, d of the crystals obtained₅₀And d₁₀。

Example VI

The powder of example V was subjected to air jet sieving (200 LS-N air jet sieve manufactured by Hosakava Alpine). Sieving was carried out for 10 minutes using a 75 μm sieve. A few agglomerates formed during the sieving were removed from the sieve top portion (not passing through the sieve) using a vibrating sieve (425 μm), and then the bulk density, d of the resulting crystals of the sieve top portion were determined₅₀And d₁₀. The results are shown in Table 1. This example shows that the compressibility and Hausner ratio are further reduced. The resulting powder was passed through an 8mm Klein cup.

TABLE 1

	Bulk density (d)b)(g/ml)	Bulk density (d)t)(g/ml)	dt/db	db*(1/db-1/dt)*100％	d50(μm)	d10(μm)
							Example I	0.51	0.73	1.43	30％	43.1	11.4
Example II	0.56	0.78	1.39	28％	42.8	8.8
							Example III	0.56	0.81	1.45	31％	47.8	9.9

Example IV	0.54	0.81	1.50	33％	37.0	7.0
							Example V	0.58	0.79	1.36	26％	61	19
Example VI	0.59	0.74	1.25	20％	86	36
							Comparative experiment A	0.26	0.55	2.12	53％	17	4.0
Reference experiment B	0.26	0.47	1.8	45％	66.3	17.4

Comparative experiment A

In a chemical process for the preparation of amoxicillin, a solution containing amoxicillin in dilute HCl and isopropanol is obtained. This solution was fed to a stirred tank. The pH was maintained at 3.7 at 20 ℃. The pH was then raised to 5.0 by addition of NaOH. The resulting mixture was stored in a container at 1 ℃ to 5 ℃ for 3 to 12 hours. Amoxicillin was isolated with a centrifuge and dried with a fluidized bed dryer. Table 1 shows bulk density, d₅₀、d₁₀。

Reference experiment B

Example I was repeated, except that instead of using a conical vacuum contact dryer (Vrieco-Nauta) for drying, a dryer (ventilated oven) was used in which the material was not mechanically collided. Drying was carried out at 35 ℃ for 16 hours. The results are shown in Table 1. Comparison of examples I-IV with example B shows that the use of mechanical impact during drying results in an increase in bulk density and bulk density.

Example VII

The crystalline powder of amoxicillin trihydrate of example IV was filled by hand into 6 gelatin capsules (size 0) each containing 500mg of anhydrous amoxicillin. No adjuvant is added. Dissolution testing was performed using apparatus 1 under the conditions described in USP 27, paragraph "amoxicillin capsules" (including a stirring rate of 100rpm, at a temperature of 37 ℃). Six beakers were used, each filled with 900ml of water. Samples were taken every 5 minutes and the amount of dissolved amoxicillin was determined using uv absorption with a maximum absorption wavelength of 272 nm.

84 wt% amoxicillin was dissolved within 15 minutes.

Within 20 minutes 90 wt% amoxicillin was dissolved.

Comparative experiment C

Example VII was repeated using commercially available granulated adjuvant-free amoxicillin trihydrate granules obtained by rolling amoxicillin trihydrate powder having the size distribution shown in Table 2. After 60 minutes 82.0 wt% amoxicillin was dissolved.

Comparative experiment D

Example VII was repeated using commercially available granulated amoxicillin trihydrate having no adjuvant, with different particle size distributions as shown in Table 2. The results are shown in FIG. 1. After 60 minutes 84.4 wt% amoxicillin was dissolved.

TABLE 2

	＜125μm	125-250μm	250-500μm	500-850μm	850-1000μm	＞1000μm	Bulk density	Bulk density
									Comparative experiment C	14.5	4.9	20.7	53.7	5.6	0	0.68	0.85
Comparative experiment D	8.6	3.1	24.9	57.1	6.3	0.3	0.69	0.83

Example VIII

20g of the amoxicillin trihydrate crystal powder of the present invention and 2g of microcrystalline cellulose (Avicel) were weighed^*PH102) in a 200ml container and mixed for 5 minutes in a Turbula T2C blender. 0.1g magnesium stearate was added and mixed for an additional 2 minutes.

A portion of the mixture was transferred into a press mold having a diameter of 7mm and a height of 2.3cm so that the press mold was sufficiently filled. The punch was placed on top of the die and 5kg of pressure was applied within 5 seconds. The resulting empty space in the die was filled and a pressure of 5kg was again applied. This process was repeated until no further reduction in volume was found. Finally, the formed plug was released from the die and filled into the nr.0 Star-lock of empty gelatin capsule bodies, Capsugel^*In (1). The formulation consisted of:

amoxicillin trihydrate crystal powder 570.1mg (500mg amoxicillin)

Microcrystalline cellulose 57.1mg

Magnesium stearate2.8mg

630.0mg in total

This example shows that the crystalline powder according to the invention can be used directly for filling capsules in the indicated amount of 500mg amoxicillin (calculated as anhydrous amoxicillin), without the need for a compaction or granulation step.

Example IX

297.5g of amoxicillin trihydrate crystal powder according to the invention and 88.5g of microcrystalline cellulose (Avicel) were weighed^*PH200), 10g croscarmellose sodium (Ac-Di-Sol)^*) And 1g of colloidal silica (Aerosil)^*200) In a 1000ml container and mixed in a Turbula TC2 blender for 10 minutes, 3g of magnesium stearate was added and mixed for an additional 2 minutes.

The mixture was transferred to Korsch^*Feeder of EKO eccentric tablet press and press out tablets with the following properties:

the formulation consisted of:

amoxicillin trihydrate crystal powder 581.7mg (500mg amoxicillin)

Microcrystalline cellulose 190.3mg

Croscarmellose sodium 20

Silica gel 2

Magnesium stearate6mg

800mg

Claims (28)

1. Crystalline powder of amoxicillin trihydrate, having a bulk density of more than 0.45g/ml, preferably more than 0.5g/ml, more preferably more than 0.55 g/ml.

2. Crystalline powder according to claim 1, having a bulk density of more than 0.6g/ml, preferably more than 0.7g/ml, more preferably more than 0.8 g/ml.

3. Crystalline powder according to claim 1 or 2, having a grain size of more than 10 μm, preferably more than 20 μm,More preferably a d of more than 30 μm, more preferably more than 35 μm, more preferably more than 40 μm, preferably less than 150 μm₅₀。

4. Crystalline powder according to any one of claims 1 to 3, having a d of greater than 3 μm, preferably greater than 5 μm, more preferably greater than 8 μm, more preferably greater than 10 μm₁₀。

5. Crystalline powder according to any one of claims 1 to 4, having a T of less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes₈₅%, wherein T₈₅% is the time required to dissolve a predetermined amount of amoxicillin trihydrate of 85 wt% (based on 500mg of anhydrous amoxicillin) in 900ml water at 37 ℃.

6. A mixture comprising

(i) A crystalline powder according to any one of claims 1 to 5; and

(ii) (a) granules comprising amoxicillin trihydrate; and/or

(b) A second pharmaceutically active agent; and/or

(c) Adjuvant

7. A product of amoxicillin trihydrate, has

(i) T of less than 55 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes₈₅Percent; and

(ii) a bulk density of greater than 0.45g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml.

8. A product according to claim 7, comprising (i) amoxicillin trihydrate powder and (ii) granules comprising amoxicillin.

9. Product according to claim 8, wherein the amoxicillin trihydrate powder is amoxicillin trihydrate crystalline powder according to any one of claims 1 to 5.

10. Product according to claim 8 or 9, wherein the granules have a d between 100 and 1000 μm₅₀。

11. A product according to any one of claims 8 to 10 or a mixture according to claim 6 wherein the granules are free of adjuvants.

12. A product according to any one of claims 7 to 11, wherein the product is free of adjuvants.

13. A mixture comprising

(i) A product according to any one of claims 7 to 12 and

(ii) an adjuvant and/or a second pharmaceutically active agent.

14. A mixture according to claim 13, said mixture having:

(i) t of less than 60 minutes, preferably less than 50 minutes, preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes₈₅Percent; and

(ii) a bulk density of greater than 0.45g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml.

15. The mixture according to claim 6 or 13 or 14, wherein the second pharmaceutically active agent is clavulanic acid in the form of a salt, preferably clavulanic acid in the form of a potassium salt.

16. Use of the crystalline powder according to any one of claims 1 to 5 or the product according to any one of claims 7 to 12 or the mixture according to any one of claims 6 or 13 to 15 for filling capsules or for preparing tablets.

17. A capsule containing a crystalline powder according to any one of claims 1 to 5 or a product according to any one of claims 7 to 12 or a mixture according to any one of claims 6 or 14 to 15.

18. A process comprising compressing a crystalline powder according to any one of claims 1 to 5 or a product according to any one of claims 7 to 12 or a mixture according to any one of claims 6 or 13 to 15 to produce a compressed product.

19. A granulate or tablet comprising a crystalline powder according to any one of claims 1 to 5 or a product according to any one of claims 7 to 12 or a mixture according to any one of claims 6 or 13 to 15 in compressed form.

20. Use of a crystalline powder according to any one of claims 1 to 5 or a product according to any one of claims 7 to 12 for the preparation of a pharmaceutical composition.

21. A process for the preparation of crystalline powder of amoxicillin trihydrate, comprising: crystallizing amoxicillin trihydrate from a solution containing dissolved amoxicillin;

separating the crystals from the solution; and

drying the separated crystals;

to obtain a crystalline powder having a bulk density greater than 0.45g/ml, preferably greater than 0.5g/ml, more preferably greater than 0.55 g/ml.

22. Process according to claim 21, resulting in a crystalline powder having a bulk density of more than 0.6g/ml, preferably more than 0.7g/ml, more preferably more than 0.8 g/ml.

23. A process according to claim 21 or 22, to obtain d₅₀Crystalline powder of more than 10 μm, preferably more than 20 μm, more preferably more than 30 μm, more preferably more than 35 μm, more preferably more than 40 μm.

24. A process according to any one of claims 21 to 23, to obtain d₁₀Crystalline powder of more than 3 μm, preferably more than 5 μm, more preferably more than 8 μm, more preferably more than 10 μm.

25. A method according to any one of claims 21 to 24, wherein the method comprises mechanically stamping the crystals during said drying.

26. A method according to any one of claims 21 to 25, wherein the method comprises: preparing amoxicillin by reacting 6-aminopenicilytic acid or a salt thereof with p-hydroxyphenylglycine in activated form in the presence of an enzyme immobilized on a carrier;

forming an aqueous solution comprising amoxicillin, said aqueous solution comprising hydrochloric acid; and

crystallizing amoxicillin trihydrate from said aqueous solution.

27. Process according to any one of claims 21 to 26, wherein the aqueous solution from which amoxicillin is crystallized has an amoxicillin concentration of less than 0.6mol/l, preferably less than 0.5mol/l, more preferably less than 0.4mol/l, more preferably less than 0.3 mol/l.

28. Process according to any one of claims 21 to 27, wherein the solution from which amoxicillin is crystallized contains less than 200 parts by weight protein, preferably less than 100 parts by weight protein, more preferably less than 50 parts by weight protein, more preferably less than 35 parts by weight protein per 1,000,000 parts by weight amoxicillin antibiotic in said solution.