HK1090549B - Amoxicillin trihydrate - Google Patents

Description

Amoxicillin trihydrate

The invention relates to a product of amoxicillin trihydrate.

The water in the solid form of the beta-lactam antibiotic may be present in different forms. Water may be present, for example, as crystal water. Water of crystallization refers to water incorporated into the molecular structure of the beta-lactam antibiotic. Amoxicillin trihydrate, each molecule of amoxicillin contains three molecules of water of crystallization, wherein the amount of water of crystallization corresponds to about 12.9% water of crystallization. Free water refers to water that is exchangeable with the atmosphere. The amount of free water does not include the amount of water present as crystal water.

The free water content of the β -lactam antibiotic sample and the relative humidity of the air in contact with the sample influence each other. When a sample of a beta-lactam antibiotic is brought into contact with air, a water exchange between the sample and the air usually takes place until an equilibrium state is established. In this equilibrium state, the net exchange of water between the air in contact with the sample and the sample is zero. The free water content of a sample of a beta-lactam antibiotic is usually given for a certain relative humidity value in the above equilibrium state at a given temperature. This relative humidity value is also referred to as equilibrium relative humidity.

The free water content of the sample can be determined by dynamic vapor adsorption (dynamic vapor absorption). The basic principle is as follows: the weight of the sample is monitored when it is in contact with air having a given relative humidity. The sample weight will change due to water absorption or release until an equilibrium state is established. The sample weight at equilibrium is the sample weight corresponding to the equilibrium relative humidity, which is the relative humidity of the given air in contact with the sample. This process is repeated for different values of equilibrium relative humidity and a function of sample weight and equilibrium relative humidity can be determined. The free water content of the sample at temperature T can be determined from ((W)_ERH-W_ref)/W_ref) 100% is given, wherein W_ERHWeight of sample corresponding to equilibrium relative humidity ERH at temperature T, W_refThe weight of the sample corresponding to the reference value of the equilibrium relative humidity at the temperature T, which is chosen so that the free water content at said equilibrium relative humidity is close to zero.

The presence of free water may be a problem in the application of beta-lactam antibiotics. This concern may exist, for example, when amoxicillin trihydrate, is mixed with a second pharmaceutically active agent, for example clavulanic acid. The prior art therefore suggests that amoxicillin trihydrate is dried to a certain extent.

Water activity is defined as the equilibrium relative humidity divided by 100%, which is the method used to determine the extent to which the beta-lactam antibiotic must be dried. Water activity can be measured by the following method: a quantity of the sample is placed in a sealed chamber of small volume and the relative humidity is measured as a function of time until it reaches a constant, the latter being the equilibrium relative humidity of the sample. For applications in which the problems associated with water can have an effect, the water activity of the beta-lactam antibiotic is usually specified to a lower value.

If drying is not carried out to a sufficient extent, the problems associated with water remain. If drying is carried out excessively, physical properties such as color and stability may be impaired. This may be due to, for example, crystal water also being expelled when drying is excessive.

We have surprisingly found a product of amoxicillin trihydrate and a process for the preparation of such a product, having a free water content of less than 0.10 wt.%, measured at an equilibrium relative humidity of 30% and a temperature of 25 ℃.

The present invention thus provides a product of amoxicillin trihydrate which poses no or fewer problems with respect to water than amoxicillin trihydrate having the same water activity according to the prior art. Furthermore, drying may be carried out to a lesser extent, so that properties such as colour and stability are not destroyed or are destroyed to a lesser extent. Due to its low free water content, the amoxicillin trihydrate, may advantageously be mixed with clavulanic acid or salts thereof, which is known to be very sensitive to moisture.

As used herein, the free water content, measured at an equilibrium relative humidity of 30% and a temperature of 25 deg.C, is specifically defined as ((W)₃₀-W₁₀)/W₁₀) 100%, wherein,

W₃₀the weight of the sample corresponding to an equilibrium relative humidity of 30% at a temperature of 25 c,

W₁₀at a temperature of 25 ℃The lower 10% of the equilibrium relative humidity corresponds to the weight of the sample.

Preferably, the free water content, including W, is determined using dynamic vapor adsorption, for example using a VTI-SGA 100 vapor adsorption analyzer₃₀And W₁₀The value of (c). Using this technique, preferably, the adsorption term measurement is performed on a sample weighing 200mg by the following method: adjusting the air in the sample chamber to 10% relative humidity for 90 minutes; the relative humidity was then increased stepwise, 10% per step, and the samples were held at each relative humidity value for 90 minutes; after 90 minutes at each rh value, the sample weight was measured as the sample weight corresponding to the equilibrium rh.

The product of amoxicillin trihydrate according to the invention has a free water content of less than 0.10 wt.%, measured at an equilibrium relative humidity of 30% and a temperature of 25 ℃. Preferably, the product of amoxicillin trihydrate according to the invention has a free water content of less than 0.07 wt.%, more preferably less than 0.05 wt.%, when measured at an equilibrium relative humidity of 30% and a temperature of 25 ℃. There is no particular upper limit for the free water content. The free water content may for example be higher than 0.01 wt.%, measured at an equilibrium relative humidity of 30% and a temperature of 25 ℃.

The product of amoxicillin trihydrate according to the invention may be amoxicillin trihydrate in any suitable form, for example in the form of crystalline powder or granules or a mixture comprising crystalline powder and granules. In a preferred embodiment, the product according to the invention is crystalline amoxicillin trihydrate powder having a free water content of less than 0.1 wt.%, preferably less than 0.07 wt.%, more preferably less than 0.05 wt.%, measured at an equilibrium relative humidity of 30% and a temperature of 25 ℃.

It will be appreciated that the product amoxicillin trihydrate may still contain some impurities. Preferably, the product of amoxicillin trihydrate contains 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 product. Preferably, the product of amoxicillin trihydrate according to the invention is free of auxiliaries.

As used herein, crystalline amoxicillin trihydrate powder refers in particular 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 a binder such as water or starch paste, or with the aid of 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 amoxicillin trihydrate is in particular 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 a 5mg portion of the sample, suspending the sample in 4 drops of paraffin oil on a surface having a surface area of 22 x 40mm, and using a magnification of 140 x.

It is understood that amoxicillin trihydrate powder may still 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 crystalline powder. Preferably, the crystalline amoxicillin trihydrate powder according to the invention is free of auxiliaries.

In a preferred embodiment, the product of amoxicillin trihydrate according to the invention has a water activity of more than 0.05, preferably more than 0.07, preferably more than 0.10, preferably more than 0.15, preferably more than 0.20, preferably more than 0.25, preferably more than 0.30. the increased water content is advantageous in that the properties of amoxicillin trihydrate are not destroyed or are destroyed to a lesser extent in case the amount of free water is still low.

One preferred method of determining the water activity of a sample is: a quantity of the sample is placed in a sealed chamber of small volume and the relative humidity is measured as a function of time until it reaches a 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, into which 3g of sample is loaded.

d₁₀And d₅₀Is a known way of expressing the particle size distribution, d₅₀Refers to a particle size value such that 50 vol.% crystals 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.% crystals have a particle size less than that value. Determination of d₁₀And d₅₀The preferred method of (3) is laser diffraction, preferably using a Malvern apparatus. d₁₀And d₅₀Is a known way of expressing the particle size distribution, d₅₀Refers to a particle size value such that 50 vol.% crystals 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.% crystals 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, employing an objective lens of f-300 mm and a beam length of 14.30 mm. Advantageously, a polydisperse analysis model may be used.

We have found that crystalline amoxicillin trihydrate powder according to the invention preferably has an increased d₅₀. Thus, the present invention also provides d₅₀Preferably higher than 10Crystalline amoxicillin trihydrate powder of μm, preferably above 20 μm, more preferably above 30 μm, more preferably above 35 μm, more preferably above 40 μm. For d₅₀There is no specific upper limit. D of the crystalline powder according to the invention₅₀May be smaller than 150 μm, for example smaller than 100 μm. The crystalline powder according to the invention preferably has an increased d₁₀Preferably higher than 3 μm, preferably higher than 5 μm, more preferably higher than 8 μm, more preferably higher than 10 μm. D for the crystalline powder according to the invention₁₀There is no specific upper limit. D of the crystalline powder according to the invention₁₀And may be less than 50 μm.

Crystalline amoxicillin trihydrate powder may be obtained by the following process: preparing a solution comprising dissolved amoxicillin, crystallizing amoxicillin from the solution to form crystals, separating the crystals from the 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 the present process.

We have found that the preparation of a crystalline powder having a reduced free water content for a given equilibrium relative humidity preferably comprises: in order to provide dried crystals with increased particle size, in particular increased d₅₀And/or d₁₀Under the conditions of (1) performing a process, in particular crystallization, separation and drying.

Preferred crystallization conditions include crystallization conditions such that amoxicillin trihydrate that crystallizes out of solution has an increased particle size. This may be obtained, for example, by applying a longer residence time, a lower concentration of amoxicillin aqueous solution, or using a high purity aqueous solution. Other preferred conditions are also described below.

The degree of mechanical impact, for example during separation and/or drying, may affect the particle size. 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. An excessively high degree of mechanical impact may undesirably cause a decrease in particle size. With this insight proposed by the present invention and by varying the mechanical forces, the skilled person will be able to find out how conditions can be avoided in which an undesired reduction of the particle size occurs.

Thus, the present invention also provides a process for the preparation of crystalline amoxicillin trihydrate powder, comprising: crystallizing amoxicillin trihydrate from the solution; separating the crystals from the solution; drying the separated crystals; wherein the process, preferably crystallization, isolation and/or drying, is carried out in such a way that the resulting crystalline powder has d₅₀More 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, in such a way that the resulting crystalline powder has d₅₀Less than 150 μm, for example less than 100 μm. Preferably, the process, preferably crystallization, isolation and/or drying, is carried out such that the crystals are dried₁₀More 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 such that the resulting crystalline powder has d₁₀Less than 50 μm.

We have found that preferably crystals of amoxicillin trihydrate having a reduced free water content can be obtained by applying the preferred process conditions described hereinafter.

Preferably, the process for the preparation of crystalline amoxicillin trihydrate powder according to the invention comprises: preparing amoxicillin by reacting 6-amino-penicillic 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, the aqueous solution comprising hydrochloric acid; and crystallizing amoxicillin trihydrate from said aqueous solution.

Preferably, the solution from which the 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 0.3mol/l.

The aqueous solution from which the 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 ℃.

In a process for the preparation of amoxicillin, the process preferably comprises preparing an aqueous solution comprising dissolved amoxicillin, the 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 0.3mol/l, the process preferably comprises preparing an aqueous solution comprising dissolved amoxicillin, the aqueous solution has a pH value between 0 and 1.5, preferably between 0.5 and 1.2 the dissolution of amoxicillin may be performed in any suitable manner, e.g. by adding acid, preferably by adding hydrochloric acid to an aqueous suspension containing crystals of amoxicillin trihydrate, the amount of acid which may be added, preferably hydrochloric acid, 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 per mol of amoxicillin hydrochloric acid is added, in a preferred embodiment the process comprises keeping the pH value of the (aqueous) solution or the (aqueous) suspension below 1.5, preferably below 1.2, in less than 60 minutes, preferably below 30 minutes, more preferably below 15 minutes, more preferably below 10 minutes, more preferably below 8 minutes, as this may improve the purity of amoxicillin, preferably, the method includes mixing the aqueous solution or suspension with the acid using a rapid mixer, such as a static mixer, which may reduce the time the aqueous solution or suspension remains at a low pH. E.g. above-5 deg.c, e.g. above 10 deg.c, e.g. above 15 deg.c, e.g. below 50 deg.c, e.g. below 40 deg.c, preferably, preferably, the process comprises filtering an aqueous solution containing dissolved amoxicillin, preferably, a filter with a pore size of less than 40 μm, preferably less than 20 μm, preferably less than 10 μm and more preferably less than 5 μm is 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. Amides that are unsubstituted in the-CONH 2 group may be used.

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 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. An advantage of this embodiment is that the finally obtained amoxicillin trihydrate comprises 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. 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 amoxicillin trihydrate powder obtainable by the process of the invention.

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

The product of amoxicillin trihydrate according to the invention may advantageously be mixed with pharmaceutically acceptable auxiliaries and/or a second pharmaceutically active agent. The product of amoxicillin trihydrate according to the invention may for example be mixed with 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 auxiliary agents, relative to the total weight of the crystalline powder and auxiliary agents. For example, the product amoxicillin trihydrate may be mixed with clavulanic acid in the form of a salt, preferably a potassium salt, preferably in a weight ratio amoxicillin to 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 a mixture obtainable by a process comprising mixing the product of amoxicillin trihydrate according to the invention with auxiliaries and/or a second pharmaceutically active agent. The invention also provides a mixture comprising (i) a product of amoxicillin trihydrate according to the invention and (ii) a second pharmaceutically active agent, with or without adjuvants.

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.

In one embodiment, 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 or mixture according to the invention can advantageously be used for filling pharmaceutical capsules, such as gelatin capsules, the invention thus also relates to a capsule containing the product according to the invention or a capsule containing the mixture according to the invention.

The invention also provides a method comprising: compressing a product according to the invention or compressing a mixture according to the invention to produce a compressed product. The compressed product may for example be a granulate or a tablet. The invention also relates to granules or tablets comprising the product according to the invention in compressed form or comprising the mixture according to 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 particles. The manufactured particles may advantageously be sieved to obtain a desired particle size distribution. The invention also relates to particles obtainable by this process.

The invention also relates to a process for the preparation of particles, which process comprises mixing the crystals of the invention or the mixture of the invention with a binder, which binder 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 particles 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, if desired, the resulting granules are dried. The invention also relates to particles obtainable by this process.

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

We have also found that the physical properties of crystalline amoxicillin trihydrate powder can be improved with respect to flowability.

In a preferred embodiment, the amoxicillin trihydrate powder according to the invention has a bulk density above 0.45 g/ml. The crystalline powder according to this aspect of the invention has improved flow properties without having to be subjected to processes such as granulation, compaction, agglomeration or aggregation, the powder also having good colour properties, good stability and a high dissolution rate. If it is still desired to subject the crystalline powder to processes such as granulation, compaction, agglomeration or aggregation, these processes are facilitated since the flow properties of the crystalline powder according to this aspect of the invention have been improved. In addition, a greater amount of crystalline powder can be loaded into a capsule of a given size. Preferably, bulk density is determined according to USP 24, method I (page 1913). Preferably, the bulk density of the crystalline powder is higher than 0.46g/ml, preferably higher than 0.5g/ml, more preferably higher than 0.55 g/ml. This further improves the flow properties. Furthermore, an increased bulk density is advantageous, since crystalline powders can be packed into a given volume, for example a capsule. There is no particular upper limit for the bulk density. The bulk density may be less than 0.8g/ml, for example less than 0.7 mg/l.

In a preferred embodiment, the crystalline powder according to the invention has a bulk density (tapped density) higher than 0.6g/ml, preferably higher than 0.7, more preferably higher than 0.8 g/ml. Increased bulk density improves flow properties. Furthermore, an increased bulk density is advantageous, since more product can be packed into a given volume, e.g. a capsule. There is no particular 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 USP 24, method II (page 1914).

In a preferred embodiment, the crystalline powder according to the invention has a bulk density and a bulk density such that d_t/d_bLess 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. This results in an improved flow capacity. For d_t/d_bThere is no specific lower limit. D is_t/d_bThe ratio may be higher than 1.05, for example higher than 1.1.

In a preferred embodiment, the crystalline powder according to the invention has a bulk density and a bulk density such that d_t/d_bLess than 1.7, preferably less than 1.6, preferably less than 1.5, preferably less than 1.45. The crystalline powder has improved flow properties compared to known powders. For d_t/d_bThan, noneThere is a specific upper limit. D is_t/d_bThe ratio may be higher than 1.05, for example higher than 1.1.

In a preferred embodiment, the crystalline powder according to the invention has a bulk density and a bulk density such that_t-d_b)/d_t) 100% defines a compressibility index of less than 40%, preferably less than 35%, more preferably less than 30%. This results in an improved flow capacity. There is no particular lower limit for the compressibility index. The compressibility index may be, for example, higher than 10%.

We have found that crystalline powders having improved flowability, bulk density and/or bulk density preferably have an increased d₅₀。

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

We have found that the preparation of crystalline powders having improved flowability, in particular having high bulk density and/or high bulk density, preferably comprises: in order to obtain crystals with increased particle size, in particular increased d₅₀And/or d₁₀Under conditions of (3) and in particular to carry out processes of crystallization, separation and drying.

We have also found that, particularly for crystals with increased size, the extent of mechanical impact, for example during crystallization, separation and/or drying, affects the bulk and bulk densities. 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.

The invention also provides a method comprising sieving the crystalline powder according to the invention. This enables the physical properties of the crystalline powder to be further improved. Preferably air jet sieving is applied.

The following examples further illustrate the invention but are not intended to limit it.

Examples and comparative experiments

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-hydroxyphenylglycine methyl ester) are suspended in 450ml of water, the suspension is cooled to 10 ℃ and 32850 units of immobilized penicillin acylase are added to the reaction mixture, and water was added to a final volume of 1500ml the mixture was stirred for 6 hours, during the reaction, the pH was raised to 6.9 and at the end of the reaction the pH had dropped to 6.2, 750ml of water were added to this mixture, the resulting suspension containing crystals of amoxicillin trihydrate, was cooled to 0c, the suspension containing less than 50ppm of protein relative to amoxicillin trihydrate (less than 50 parts by weight of protein per 1,000,000 parts by weight of 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

Use ofMalvern particle sizer 2600C determines particle size distribution (including d)₁₀And d₅₀) The particle size instrument 2600C has an objective lens of f 300mm, a Malvern sample measurement unit PS1 and a Malvern dry powder injector PS 64. The beam length was 14.30 mm. A polydisperse analysis model was used.

Measurement of adsorption isotherms

Adsorption isotherms were determined using dynamic vapor adsorption using a VTI-SGA 100 vapor adsorption analyzer. The weight of the sample used was 200 mg. The air in the sample chamber was conditioned at 10% relative humidity for 90 minutes. Subsequently, the relative humidity was increased by 10% per step while the samples were held at each relative humidity value for 90 minutes. The sample weight after 90 minutes was taken as the sample weight corresponding to this equilibrium relative humidity. The temperature was 25 ℃.

Example I

A batch of amoxicillin trihydrate crystalline powder is prepared by the above method. The adsorption isotherm and the particle size distribution were determined. Figure 1 shows the adsorption isotherm. d₅₀And d₁₀See table.

At 25 ℃, a free water content of 0.05 wt.% was measured at an equilibrium relative humidity of 30%.

Comparative experiment A

In a chemical process for the preparation of amoxicillin, a solution containing amoxicillin in dilute HCl and isopropanol is obtained. The solution was fed to a stirred tank. The pH was maintained at 3.7 at a temperature of 20 ℃. The pH was then raised to 5.0 by the addition of NaOH. The resulting mixture is held in a vessel at 1 to 5 ℃ for 3 to 12 hours. Amoxicillin was isolated by centrifuge and dried in a fluid bed dryer.

The adsorption isotherm and the particle size distribution were determined. Figure 1 shows the adsorption isotherm. d₅₀And d₁₀See table. At 25 ℃ and at an equilibrium relative humidity of 30% free water content was measured as 0.11 wt.%.

	Bulk Density (g/ml)	Bulk Density (g/ml)	d(μm)	d(μm)	Free water content at ERH 30% (in wt.%)
						Example I	0.51	0.73	43.1	11.4	0.05wt.％
Comparative experiment A			8.3	2.7	0.11wt.％

A comparison of example 1 and comparative experiment a shows that the amoxicillin powder of example I contains less free water than the amoxicillin powder of comparative experiment a.

Example II

Amoxicillin trihydrate powder obtained by the process of example I is dried to a water activity of 0.15. This powder was mixed with potassium clavulanate in a weight ratio of 4: 1 (calculated as amoxicillin anhydrate and clavulanic acid). The mixture is stable.

Example III

Amoxicillin powder obtained by the process of example I was dried to a water activity of 0.2. The powder was mixed with potassium clavulanate in a ratio of 4: 1. The mixture is stable.

Example IV

Amoxicillin powder obtained by the process of example I is dried to a water activity of 0.15. The powder was mixed with potassium clavulanate in a ratio of 4: 1. The mixture is stable.

Example V

Example I was repeated, except that the drying was not carried out using a conical vacuum contact dryer (vreiconatua), but using a dryer in which the material was not subjected to mechanical impact (ventilation oven). Drying was carried out at a temperature of 35 ℃ for 16 hours. d₅₀And d₁₀Respectively 66.3 μm and 17.4. mu.m. The bulk density and the bulk density were 0.25g/ml and 0.47g/ml, respectively.

Example VI

Another batch of amoxicillin trihydrate powder (d) was prepared as in example 1₅₀And d₁₀61 μm and 19 μm, respectively, and the bulk density were 0.58g/ml and 0.79g/ml, respectively). Spraying air to the batch of powderSieving (200 LS-N air-jet sieve manufactured by Hosakawa Alpine). Sieving was carried out for 10 minutes using a 75 μm sieve. A few agglomerates formed during the sieving were removed from the screen top part (not passing through the screen) using a vibrating screen (425 μm), and then the bulk density, d of the crystals obtained from the screen top part were measured₅₀、d₁₀。d₅₀And d₁₀Respectively 86 μm and 36 μm. The bulk density and the bulk density were 0.59g/ml and 0.74g/ml, respectively.

Claims (24)

1. Product of amoxicillin trihydrate, having a free water content of less than 0.1 wt.%, measured at a temperature of 25 ℃ and an equilibrium relative humidity of 30%, wherein the free water content is defined as ((W)₃₀-W₁₀)/W₁₀) 100% of W, wherein₃₀Weight of sample corresponding to an equilibrium relative humidity of 30% at a temperature of 25 ℃, W₁₀Weight of sample corresponding to an equilibrium relative humidity of 10% at a temperature of 25 ℃.

2. The product according to claim 1, wherein the free water content of the product is less than 0.07 wt.%, measured at a temperature of 25 ℃ and an equilibrium relative humidity of 30%.

3. Product according to claim 1, having a water activity higher than 0.05 measured at a temperature of 25 ℃.

4. The product according to any one of claims 1 to 3, wherein the product is crystalline amoxicillin trihydrate powder.

5. A product according to claim 4, which is d₅₀Above 10 μm.

6. A product according to claim 4, which is d₁₀Above 3 μm.

7. A product according to claim 5, which is d₁₀Above 3 μm.

8. A product according to claim 4 having a bulk density of greater than 0.45 g/ml.

9. The product according to claim 4, having a bulk density higher than 0.6 g/ml.

10. A mixture, comprising:

(i) a product according to any one of claims 1 to 9; and

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

11. A process for producing the mixture of claim 10, the process comprising: mixing a product according to any one of claims 1 to 9 with a second pharmaceutically active agent and/or adjuvant.

12. The method according to claim 11, wherein the second pharmaceutically active agent is clavulanic acid in salt form.

13. The process according to claim 12, wherein the salt form of clavulanic acid is the potassium salt form of clavulanic acid.

14. The mixture according to claim 10, wherein the second pharmaceutically active agent is clavulanic acid in salt form.

15. The mixture according to claim 14, wherein the salt form of clavulanic acid is the potassium salt form of clavulanic acid.

16. A method for producing a compressed product, the method comprising: compressing a product according to any one of claims 1 to 9 or a mixture according to claim 10 or 14.

17. The method of claim 16, wherein the compressed product is a granule or tablet.

18. Use of a product according to any one of claims 1 to 9 for the preparation of a pharmaceutical composition.

19. Use of a product according to any one of claims 1 to 9 or a mixture according to claim 10 for the preparation of tablets or filled capsules.

20. A method of preparing a product as defined in claim 4, the method comprising:

preparing amoxicillin by reacting 6-amino-penicillic acid or a salt thereof with p-hydroxyphenylglycine in activated form, in the presence of a penicillin acylase immobilized on a carrier, at a pH between 5 and 9;

forming an aqueous solution comprising amoxicillin, said aqueous solution comprising between 0.9 and 5 moles hydrochloric acid per mole amoxicillin; and

amoxicillin trihydrate is crystallized from said aqueous solution at a pH between 2 and 7.

21. Process according to claim 20, wherein the aqueous solution from which amoxicillin is crystallized has an amoxicillin concentration of less than 0.6 mol/l.

22. Process according to claim 20 or 21, wherein the solution from which amoxicillin is crystallized contains less than 200 parts by weight of protein per 1,000,000 parts by weight amoxicillin in the solution.

23. The method of claim 20, wherein the method comprises: separating the crystals from the aqueous solution; and drying the separated crystals to obtain d₅₀Crystalline powder higher than 10 μm.

24. A process according to claim 20, to obtain d₁₀Crystalline powder higher than 3 μm.