Title of Invention

PROCESS FOR PREPARING GRANULES COMPRISING A BETA-LACTAM ANTIBIOTIC

Abstract

The present invention relates to granules comprising a ss-lactam antibiotic, wherein C<SUB>H2S(72h) </SUB>< 50 L OF H<SUB>2</SUB>S gas per kg of ss-lactam antibiotic, wherein C<SUB>H2S(72h) </SUB>is the volume of H<SUB>2</SUB>S gas above said granules per kg of said ss-lactam antibiotic, when a sample of between 3.5 and 4.5 g of said granules is kept in a closed container having a volume of 20 ml at a temperature of 22 DEG C during 72 hours at atmospheric pressure (1 bar). The invention also relates to a process for the preparation of granules comprising a ss-lactam antibiotic, said process comprising feeding said ss-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the temperature of the ss-lactam antibiotic that is fed to the roller compactor is sufficiently low that C<SUB>H2S(72h)</SUB> < 50 L OF H<SUB>2</SUB>S gas per kg of ss-lactam antibiotic, wherein C<SUB>H2S(72h)</SUB> is the volume of H<SUB>2</SUB>S gas above said granules per kg of said ss-lactam antibiotic, when a sample of between 3.5 and 4.5 g of said granules is kept in a closed container having a volume of 20 ml at a temperature of 22 DEG C during 72 hours at atmospheric pressure (1 bar).

Full Text

GRANULES COMPRISING A β-LACTAM ANTIBIOTIC The present invention relates to granules comprising a β-lactam antibiotic, to a process for the preparation thereof and to an apparatus for preparing the granules comprising the β-lactam antibiotic. The preparation of a β-lactam antibiotic typically involves obtaining the β-lactam antibiotic as a crystalline powder, e.g. by crystallizing the β-lactam antibiotic from a solution, and drying the resulting crystals resulting in the powder. When improved physical properties are desired, e.g. bulk density or flowability, the powder may be compressed, e.g. by roller compacting to form granules comprising compressed powder. Roller compacting of a β-lactam antibiotic is e.g. described in WO-A-9911261. It was found that the known process for the preparation of granules comprising a β-lactam antibiotic in compressed form results in a product having an unpleasant smell. It is an object of the invention to provide granules comprising having no smell or a smell that is at least less intensive. This object is achieved by providing granules comprising a β-lactam antibiotic, wherein CH2s(72h) Preferably, the granules comprising a β-lactam antibiotic according to the invention, have a CH2s(72h) 1 μl of H2S gas per kg of β-lactam antibiotic. As used herein CH2s(72h) is determined under the following conditions: a sample of between 3.5 and 4.5 gram of said granules is kept in a closed container (volume of 20 ml) at a temperature of 22 °C during 72 hours at atmospheric pressure (1 bar). After said 72 hours a sample of air is taken from the container and analysed by gas chromatography to determine the volume fraction of H2S in said sample of air. Said volume fraction of H2S gas is multiplied by the gas phase volume above the sample (i.e. volume of the container, i.e. 20 ml, minus the volume of the sample) resulting in the volume of H2S gas in the container. The calculated value of said volume of H2S gas in the container is divided by the weight of the sample, resulting in CH2S(72H). The invention also provides granules comprising a β-lactam antibiotic, wherein CH2s(3h) In the latter aspect of the invention, the CH2s(3h) is determined under the following conditions: a sample of between 3.5 and 4.5 gram of said granules is kept in a closed container (volume of 20 ml) at a temperature of 22 °C during 3 hours at atmospheric pressure (1 bar). After said 3 hours a sample of air is taken from the container and analysed by gas chromatography to determine the volume fraction of H2S in said sample of air. Said volume fraction of H2S gas is multiplied by the gas phase volume above the sample (i.e. volume of the container, i.e. 20 ml, minus the volume of the sample) resulting in the volume of H2S gas in the container. The calculated value of said volume of H2S gas in the container is divided by the weight of the sample, resulting in CH2s(3h). In a preferred embodiment, the invention provides granules comprising a β-lactam antibiotic, wherein CH2s(3h) Granules according to the invention may comprise auxiliaries or may be free of auxiliaries. Granules according to the invention may comprise compressed β-lactam antibiotic, for instance β-lactam antibiotic compressed by roller compacting. Granules according to the invention are preferably obtained by roller compacting. The granules according to the invention may for instance have a bulk density of between 0.4 and 1.0 g/ml, for instance between 0.45 and 0.8 g/ml. As used herein, bulk density is preferably determined using USP 24, method I, (page 1913). Preferably, bulk density is determined using method Eur. Ph. 5.0, section 2.9.15. As auxiliaries may for instance be used fillers, dry binders, disintegrants, wetting agents, wet binders, lubricants, flow agents and the like. Examples of auxiliaries are lactose, starches, bentonite, calcium carbonate, mannitol, microcrystalline cellulose, polysorbate, sodium lauryl sulphate, carboxymethylcellulose Na, sodium alginate, magnesium stearate, silicon dioxid, talc. Preferably, the granules according to the invention are free of auxiliaries. The invention also provides a process for preparing granules according to the invention. The invention provides a process for preparing granules comprising a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a roller compactor to form compacts, size-reducing, e.g. milling the compacts to produce granules, where in the temperature of the β-lactam antibiotic that is fed to the roller compactor is sufficiently low that CH2s(72h) In another embodiment, the invention provides a process for preparing granules comprising a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the temperature of the β-lactam antibiotic that is fed to the roller compactor is sufficiently low that CH2S(3h} preferably CH2s(3h) Surprisingly ft was found that by cooling the antibiotic prior to feeding to the roller compactor decreases CH2s(72h) and CH2s(3h). In an embodiment, the invention provides a process for preparing granules comprising a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the said β-lactam antibiotic is cooled prior to said feeding. In another embodiment, the invention provides a process for preparing granules comprising a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the temperature of the (3-lactam antibiotic that is fed to said roller compactor is below 20 °C, preferably below 18 °C, more preferably bilow15°C. The β-lactam antibiotic is preferably fed to the roller compactor as a crystalline powder of the β-lactam antibiotic, preferably without auxiliaries. However, it is also possible to feed a mixture comprising a crystalline powder and auxiliaries to the roller compactor. As auxiliaries may for instance be used fillers, dry binders, disintegrants, wetting agents, wet binders, lubricants, flow agents and the like. Examples of auxiliaries are lactose, starches, bentonite, calcium carbonate, mannitol, microcrystalline cellulose, polysorbate, sodium lauryl sulphate, carboxymethyicellulose Na, sodium alginate, magnesium stearate, silicon dioxid, talc. The roller compactor may be operated at any suitable roller pressure, for instance between 10 and 250 kN, for instance between 50-200 kN. The invention also provides a β-lactam antibiotic in compressed form wherein CH2s(72h) lactam antibiotic, preferably CH2s(72h) The invention also provides a β-lactam antibiotic in compressed form wherein CH2s(3h) 1 μl of H2S gas per kg of β-lactam antibiotic. The invention also provides a process for compressing a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a step in which the β-lactam antibiotic is compressed to form compressed β-lactam antibiotic, wherein the temperature of the β-lactam antibiotic that is fed to said step is sufficiently low that H2S gas per kg of β-lactam antibiotic, preferably CH2S(72h) lactam antibiotic, preferably CH2s(72h) The invention also provides a process for compressing a β-lactam antibiotic, said process comprising feeding said β-lactam antibiotic to a step in which the β-lactam antibiotic is compressed to form compressed β-lactam antibiotic, wherein the temperature of the β-lactam antibiotic that is fed to said step is sufficiently low that CH2s(3h) closed container having a volume of 20 ml at a temperature of 22 °C during 3 hours at atmospheric pressure (1 bar). in an embodiment, the process comprises cooling the β-lactam antibiotic prior to said feeding. In an embodiment, the process comprises feeding said β-lactam antibiotic to a step in which the β-lactam antibiotic is compressed to form compressed β-lactam antibiotic, wherein the β-lactam antibiotic is cooled prior to said feeding. In an embodiment, the temperature of the β-lactam antibiotic that is fed to said step is below 20 °C, preferably below 18 °C, more preferably below 15 °C. The invention also provides an apparatus comprising (I) a cooler for cooling an antibiotic; and (ii) a means for compressing the cooled antibiotic, wherein said (i) cooler is arranged such that the antibiotic can be cooled prior to feeding the antibiotic to (ii) the means for compressing the antibiotic. Preferably said means for compressing the antibiotic is a roller compactor. Preferably, said apparatus further comprises a dryer for drying the β-lactam antibiotic, said dryer arranged such that the dried antibiotic can be fed to the cooler. The β-lactam antibiotic is not limited to a specific type of β-lactam antibiotic. It may for instance be a penicillin, for instance ampicillin or amoxicillin, or a cephalosporin, for instance cephalexin, cefadroxil, cephradin, or cefalcor. Cephalexin may be in any suitable form, for instance in the form of a hydrate, for instance cephalexin monohydrate. Cefadroxil may be in any suitable form, for instance in the form of a hydrate, for instance cefadroxil monohydrate. Cephradin may be in any suitable form, for instance in the form of a hydrate, for instance cephradin monohydrate. Cefaclor may be in any suitable form, for instance in the form of a hydrate, for instance cefaclor monohydrate. Amoxicillin may be in any suitable form, for instance in the form of a hydrate, for instance amoxicillin trihydrate. Ampicillin may be in any suitable form, for instance in the form of a hydrate, for instance ampicillin trihydrate. The β-lactam antiobiotic may be prepared in any suitable process known in the art, for instance using a chemical process or an enzymatic process. EXAMPLES Materials In comparative experiment A and example 1, cephalexin was prepared and recovered using the process as described in WO-A-9623796. The cephalexin (monohydrate) crystals obtained were washed with water and subsequently with a water-acetone mixture containing 80 vol.% of acetone. The resulting wet cake contained 8 wt.% of free water and 8 wt.% of acetone, In addition one sample of cephalexin granules in comparative experiment A was obtained from company A. In comparative experiment B, a sample of granules of cephradin was obtained from company B. In example 2, cephradine was prepared and recovered according to the method as described in WO 2005/003367, using PenG acylase mutant Phe-24-Ala. The cephradine, hydrate crystals obtained, were washed with water and subsequently with a water-acetone mixture containing 80 vol.% of acetone. The resulting wet cake contained 8 wt.% of free water and 8 wt.% of acetone. Comparative experiment A The cephalexin wet cake was dried using a Vacuum Paddle dryer type SH V-3000 supplied by Bachiller S.A., Spain. The dryer was charged with 600 kg cephalexin wet cake produced as described above, containing 8 wt.% of free water and 8 wt% of acetone. The walls were heated at a temperature of 70 °C (product temperature 40 °C). The final pressure was 20 mbar. During drying the wet cake was stirred at a speed of 7 rpm. After 2 hours and 40 minutes of drying the product was discharged. The water content was 5.2 wt.% (Karl Fisher). The resulting powder, having a temperature between 20-25 °C, was fed to a roller compactor produced by Hosokawa-Bepex, type K200/1 00 operated at a roller speed of 12 rpm and a roller pressure of 1 30 KN. The resulting compacted product was crushed to obtain granules having a bulk density above 0.45 g/ml and a tapped density above 0.75 g/ml. The densities were determined using method Eur. Ph. 5.0, section 2.9.15 (with the difference that a 100 ml cylinder was used). The resulting product was analysed for the H2S content using a HP 6890 gas chromatograph, and a Supelco SPB-1 sulfur, 30 m x 0.32 mm x 4.00 urn column. 3 reference experiments were carried using gases containing known volume concentrations of H2S in N2: (0.5 vol ppm, 1 .5 ppm, and 5.6 ppm). Using these reference experiments, a calibration curve was constructed. A.1. Determination CH2s(3h) After this the CH2s(3h) of the cephalexin granules was determined. A sample (4.04 gram), was introduced into a vial having a volume of 20 ml. The sample was equilibrated at ambient temperature (22 °C) for 3 hours. After said 3 hours a sample of air (300 μl injection volume) from the vial was analysed. The H2S vol ppm in said sample was 3.2 ppm. The volume of the gas phase above the sample was 14.5 ml (i.e. sample volume was 5.5 ml). Hence, CH2s(3h) = 11 μI of H2S gas per kg of β-lactam antibiotic. This experiment was repeated 3 times, resulting in an average value for ) of 1 0 μl of H2S gas per kg of β-lactam antibiotic. A.2. Determination CH2s(72h) of cephalexin granules from company A The CH2s(72h) of cephalexin granules from company A was determined by weighing a sample of 3.5 to 4.5 g of the cephalexin granules into a vial of 20 ml. The H2S content was analysed as described above under § A.1., with the difference that the sample was equilibrated at an ambient temperature for 72 h. The average value for CH2s(72h) of cephalexin granules from company A was 73 μl of H2S gas per kg of β-lactam antibiotic. Example 1 Comparative experiment A was repeated with the difference that the powder was cooled after drying. A cooler (Vertical conical mixer, type MCV-3000-N, produced by Bachiller S.A.) was charged with 550 kg cephalexin powder. The wall temperature of the mixer was kept at a temperature of 5 °C. The cephalexin was cooled in the cooler under mixing during 2 hours until a product temperature of just below 1 5 °C was achieved. 1.1. Determination The resulting powder was roller compacted as described above, and the of the thus pepared cephalexin granules was determined. Due to the cooling the smell of the resulting product was significantly less intensive. 1.2. Determination In addition, the CH2s(72h) of the cephalexin granules as prepared under § 1.1 was determined. A sample of 3.5 to 4.5 g of the cephalexin granules was analysed for the H2S content according to the method as described under comparative experiment A.2., wherein the sample was equilibrated at ambient temperature (22 °C) for 72 h. The average value for CH2s(72h) was 21 μl of H2S gas per kg of β-lactam antibiotic. Comparative experiment B The CH2s(72h) of cephradine granules from competitor B was determined. A sample of 3.5 to 4.5 g of cephradine granules from competitor B was analysed for the H2S content according to the method as described under comparative experiment A, wherein the sample was equilibrated at ambient temperature for 72 h. The average value for CH2s(72h) of cephradine granules from competitor B was 28 μl of H2S gas per kg of β-lactam antibiotic. Examples The cephradine wet cake was dried and compacted according to the method as described under comparative experiment A with the difference that after drying the product was cooled as described in Example 1 . Subsequently, the CH2s(72h) was determined as described under comparative experiment A.2. The average value for was 1 8 μl of H2S gas per kg of β-lactam antibiotic. The results in Examples 1 to 2 show that cooling before compacting results in reduced concentrations of H2S. We claim: 1. Process for preparing granules comprising a p-lactam antibiotic, said process comprising feeding said p-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the temperature of the p-lactam antibiotic that is fed to said roller compactor is below 20 OC and wherein CHZS(7 H2S gas above said granules per kg of said p-lactam antibiotic, when a sample of between 3.5 and 4.5 g of said granules is kept in a closed container having a volume of 20 ml at a temperature of 22 OC during 72 hours at atmospheric pressure (1 bar). 2. Process for preparing granules comprising a P-lactam antibiotic, said process comprising feeding said P-lactam antibiotic to a roller compactor to form compacts, size reducing, e.g. milling the compacts to produce granules, wherein the temperature of the p-lactam antibiotic that is fed to said roller compactor is below 20 OC and wherein and wherein CHZS@ between 3.5 and 4.5 g of said granules is kept in a closed container having a volume of 20 ml at a temperature of 22 OC during 3 hours at atmospheric pressure (1 bar). 3. Process as claimed in claim 1 or 2, wherein the process comprises cooling the plactam antibiotic prior to said feeding. 4. Process for preparing granules comprising a p-lactam antibiotic as claimed in any one of the claims 1 to 3, said process comprising feeding said P-lactam antibiotic to a roller compactor to form compacts, size reducing, wherein said p-lactam antibiotic is cooled prior to said feeding. 5. Process as claimed in any one of the claims 1 to 4, wherein said p-lactam antibiotic is a cephalosporin. 6. Process as claimed in claim 5, wherein cephalosporin is selected from the group consisting of cephalexin, cefadroxil, cephradin, and cefaclor 7. Process as claimed in any one of the claims 1 to 4, wherein said p-lactam antibiotic is a penicillin. 8. Process as claimed in claim 7, wherein penicillin is selected from the group consisting of amoxicillin and ampicillin.

Documents:

313-delnp-2007-Abstract-(08-10-2012).pdf

313-delnp-2007-abstract.pdf

313-delnp-2007-Assignment-(06-08-2012).pdf

313-delnp-2007-Claims-(08-10-2012).pdf

313-delnp-2007-Claims-(18-07-2013).pdf

313-delnp-2007-claims.pdf

313-delnp-2007-Correspondence Others-(05-07-2012).pdf

313-delnp-2007-Correspondence Others-(06-08-2012).pdf

313-delnp-2007-Correspondence Others-(17-06-2008).pdf

313-delnp-2007-Correspondence Others-(27-12-2012).pdf

313-delnp-2007-Correspondence-Others-(08-10-2012).pdf

313-DELNP-2007-Correspondence-Others.pdf

313-delnp-2007-description (complete).pdf

313-delnp-2007-form-1.pdf

313-delnp-2007-Form-18-(17-06-2008).pdf

313-delnp-2007-Form-2-(06-08-2012).pdf

313-delnp-2007-form-2.pdf

313-delnp-2007-Form-3-(05-07-2012).pdf

313-DELNP-2007-Form-3.pdf

313-delnp-2007-form-5.pdf

313-delnp-2007-GPA-(18-07-2013).pdf

313-delnp-2007-gpa.pdf

313-delnp-2007-pct-304.pdf

313-delnp-2007-pct-search report.pdf

313-delnp-2007-Petition-137-(27-12-2012).pdf