Field of the invention

The present invention relates to a process for the preparation of crystalline form C of avibactam sodium. The invention also concerns crystalline form C of avibactam sodium prepared by such process as well as a pharmaceutical composition comprising same in combination with one or more antibacterial agents, wherein at least one antibacterial agent is a beta-lactam antibiotic.

Background of the invention

Avibacta m of formula (I) with l UPAC na me [(25,5 ?)-2-carbamoyl-7-oxo-l,6-diazabicylco[3.2.1]octan-6-yl] hydrogen sulfate is a non-beta-lactam beta-lacta mase inhibitor which is reported to have in itself no antibacterial activity at clinically relevant doses.

Formula (I)

However, avibactam protects beta-lactam antibiotics from degradation by beta lactamase enzymes and therefore maintains the antibacterial activity of beta-lactam antibiotics. It is therefore useful in conjunction with beta-lactam antibiotics for the treatment of bacterial infections.

WO 2011/042560 Al refers to crystalline forms of avibactam sodium. For example, WO 2011/042560 Al discloses anhydrous forms B and D as well as hydrated forms A and E. In addition, according to the application (page 3, lines 6 to 7) a fifth form designated "form C" has been observed but only as a mixture with form A. Specifically, WO 2011/042560 Al explicitly

states that "Form C is not isolated as a pure form but is obtained in a mixture with one or more other forms, in particular Form A" (page 12, lines 5-7). However, the application does not provide any teaching as to how to prepare any such mixture or as to how to obtain said form C.

Further, WO 2014/135930 Al discloses a crystalline form of avibactam sodium characterized by powder X-ray diffraction. According to the peak list provided on page 6 and the corresponding powder X-ray diffractogram displayed in figure 1 of said application this solid can be assigned to a mixture comprising at least form B and form D as described in WO 2011/042560 Al, while form C is not present.

PCT/EP2016/068925 relates to crystalline form C of avibactam sodium, especially in polymorphically pure or essentially polymorphically pure form as well as to an industrially applicable, reliable and robust process for its preparation and to pharmaceutical compositions thereof. This document represents the first disclosure for the reliable preparation and isolation of polymorphically pure form C of Avibactam sodium. Anhydrous form C is polymorphically stable, i.e. it does not convert to other crystalline forms, both under ambient conditions as well as under conditions occurring in the manufacturing of pharmaceutical compositions such as solid pharmaceutical dosage forms. In addition, crystalline form C is physically stable against moisture and highly stable against temperature stress.

In addition, EP16185913.7 relates to avibactam in form of its free acid and a method of producing same. Avibactam free acid is highly useful for pharmaceutical purposes, e.g. due to its low hygroscopicity and stability against moisture and temperature stress. This document further establishes that avibactam free acid and the method of producing same are useful for purification of avibactam.

It is well-known by the skilled person that upon temperature stress or under acidic or basic conditions hydrated forms often tend to hydrolyze. Hydrates are also prone to dehydration, for example, they readily release the bound water when subjected to dry conditions and/or increased temperatures. For example, WO 2011/042560 Al mentions that the avibactam sodium dihydrate form E tends to lose water and to hydrolyze during long storage and at higher temperature (page 17, lines 1 to 2). It is further stated in the application that form E is

particularly stable above a relative humidity of about 70% (page 15, line 25), indicating that this hydrated form is only stable in the presence of moisture. In addition, it was found that form E dehydrates to the monohydrate form A at temperatures above about 60 °C and that form A upon further temperature stress dehydrates to the anhydrous form B. Such conversions of physical forms are critical as pharmaceutical processing and milling usually involves the evolution of heat. Hence, for pharmaceutical purposes anhydrous forms of avibactam sodium are preferred over hydrates.

Besides proper physical properties, the manufacturability of a solid form determines whether it is a feasible candidate for the preparation of a drug product. According to WO 2011/042560 Al (page 16, lines 30 to 31) anhydrous form D was only obtained as very small crystals, making filtration difficult and slow and hence making it difficult to prepare form D. Thus, due to its limitations with regard to isolation, form D cannot be produced on an industrial scale. In addition, the robustness and reliability of a manufacturing process is a key criterion for physical form selection. WO 2011/042560 Al (page 17, lines 8 to 14) for example mentions that anhydrous form B is difficult to prepare in the absence of seed crystals and only obtained in a very narrow range of water activity. The seed crystal preparation disclosed in the application (page 16, lines 22 to 26) seems not to be straightforward, let alone industrially applicable. Therefore, a reliable industrial production of anhydrous form B seems to be very challenging.

Since anhydrous forms of Avibactam sodium are preferred for pharmaceutical purposes, anhydrous form C, which does not convert to any other physical form of Avibactam sodium during formulation and storage of a pharmaceutical composition and which is physically stable against moisture and highly stable against temperature stress, is particularly qualified for the preparation of pharmaceutical products.

In view of the above, there is a need for an efficient process which can provide polymorphically pure crystalline form C of Avibactam sodium. One objective of the present invention is therefore the provision of an improved process for the preparation of crystalline form C of avibactam sodium, in particular a process which can be employed on an industrial scale in an efficient manner, i.e. which is cost-effective and does not involve the use of large quantities of organic solvents and/or hazardous reagents.

A further objective of the present invention is the provision of an improved process for the preparation of crystalline form C of avibactam sodium which shows a high tolerance with regard to the starting material employed, i.e. a process which allows for the use of different starting materials such as different crystalline forms and that consistently and reliably provides crystalline form C of Avibactam sodium.

Summary of the invention

It was surprisingly found that the process provided by the present invention fulfills all the above-mentioned requirements and represents an industrially-applicable method with which crystalline form C of avibactam sodium can be prepared in an efficient and cost-effective manner.

In particular, the process provided by the present invention allows for the use of different starting materials including the free acid of avibactam and various salts thereof, e.g. its tetrabutylammonium or sodium salt.

Furthermore, the process of the present invention can be employed to obtain crystalline form C of avibactam sodium, which is polymorphically pure or essentially polymorphically pure.

Hence, the present invention relates to a process for the preparation of avibactam sodium in polymorphic form C having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.5 ± 0.2)°, (14.4 ± 0.2)°, (15.5 ± 0.2)°, (18.0 ± 0.2)° and (19.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, comprising

(i) providing a mixture comprising avibactam or a salt thereof and a solvent, wherein the mixture has a water content of less than 2 % by weight based on the weight of the mixture,

(ii) increasing the temperature of the mixture provided in (i) to at least 55 °C and providing a positive pressure,

adding a sodium source to the mixture in step (i) and/or (ii) if the form of avibactam provided in (i) is not avibactam sodium,

thereby obtaining avibactam sodium in polymorphic form C.

Detailed description of the invention

Different aspects of the invention are described below in further detail by embodiments, without being limited thereto. Each aspect of the invention may be described by one embodiment or by combining two or more embodiments.

The present invention relates to a process for the preparation of avibactam sodium in polymorphic form C having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.5 ± 0.2)°, (14.4 ± 0.2)°, (15.5 ± 0.2)°, (18.0 ± 0.2)° and (19.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, comprising

(i) providing a mixture comprising avibactam or a salt thereof and a solvent, wherein the mixture has a water content of less than 2 % by weight based on the weight of the mixture,

(ii) increasing the temperature of the mixture provided in (i) to at least 55 °C and providing a positive pressure,

adding a sodium source to the mixture in step (i) and/or (ii) if the form of avibactam provided in (i) is not avibactam sodium,

thereby obtaining avibactam sodium in polymorphic form C.

At least step (ii) of this process is carried out in a closed system, e.g. in a sea lable vessel having a defined reaction volume. In a preferred embodiment step (ii) is conducted in a sea led reaction vessel . As used herein, the term "sealed reaction vessel" refers to any vessel suitable for carrying out the sequence of steps of the present invention. Specifically, the sealed reaction vessel allows one to tightly control the reaction conditions, in particular temperature and pressure during step (ii). Nevertheless, the

sea led reaction vessel may comprise additional inlets and/or outlets for adding or removing material in a controlled manner, e.g. by adding an inert gas in step (ii) in order to obtain the desired positive pressure and/or by adding a sodium source, if necessary. The reaction vessel may also be sealed with a septum which can be punctured to add or remove material.

It is essential that the mixture provided in (i) has a water content of less than 2 % by weight, based on the weight of the mixture, when increasing the temperature of the mixture in (ii) to at least 55 °C and providing a positive pressure. Preferably, the mixture provided in (i) has a water content of less than 1.8 % by weight, more preferably less than 1.6 % by weight, more preferably less than 1.5 % by weight, more preferably less than 1.4 % by weight, more preferably less than 1.3 % by weight, more preferably less than 1.2 % by weight, more preferably less than 1.1 % by weight, more preferably less than 1.0 % by weight, more preferably less than 0.9 % by weight, more preferably less than 0.8 % by weight, more preferably less than 0.7 % by weight, more preferably less than 0.6 % by weight, more preferably less than 0.55 % by weight based on the weight of the mixture. In various embodiments the mixture provided in (i) may have a water content in a range of from 0.01 % by weight to less than 2.0 % by weight, preferably of from 0.1 % by weight to 1.5 % by weight, more preferably of from 0.2 % by weight to 0.9 % by weight, still more preferably of from 0.3 % by weight to 0.6 % by weight based on the weight of the mixture. Typically, the mixture is provided by mixing a solid form of avibactam or a salt thereof and a solvent. Thus, the water content of the mixture is usually provided by choosing a solvent having a corresponding water content.

It is also essential that in step (ii) a positive pressure is provided in the mixture provided in step (i). As used herein, "providing a positive pressure" relates to increasing the pressure in step (ii) by any suitable means in the art relative to the pressure at which the mixture in step (i) is provided. There are several ways to provide said positive pressure, which may be used alone or in combination. For example, the positive pressure can be provided by the vapor pressure of the solvent as a result of increasing the temperature of the mixture provided in step (i), e.g. when the temperature is increased above the boiling point of the solvent. The positive pressure

can also be provided by pressurization using an inert gas. Also the addition of a sodium source, if necessary, to a sealed reaction vessel may contribute to the positive pressure. The positive pressure can also be provided by a combination of the previously mentioned methods.

Thus, in a preferred embodiment, an inert gas is added in step (ii). Preferably, the inert gas is added to the reaction volume, e.g. to the sealed reaction vessel. In a more preferred embodiment, the inert gas is in a sufficient amount to provide a positive pressure in step (ii), e.g. in the sealed reaction vessel. As detailed above, this may be achieved via an additional inlet of the sealed reaction vessel. Any suitable inert gas can be used, e.g. an inert gas selected from the group consisting of nitrogen and noble gases.

In general, the mixture may be provided in step (i) at any pressure, e.g. at a pressure in the range of from 0.1 bar to 5 bar. In one embodiment the pressure at which the mixture in step (i) is provided may be standard atmospheric pressure of about 1.00 bar. However, in other embodiments the pressure may be lower or higher, e.g. about 0.70, 0.80, 0.90, 0.95, 1.00, 1.05, 1.10, 1.20 or 1.30 bar. As regards said positive pressure provided in step (ii), it is positive, i.e. higher, in relation to the pressure at which the mixture in step (i) is provided.

In a preferred embodiment the positive pressure in (ii) is a positive pressure of at least 5 mbar, preferably at least 8 mbar, more preferably at least 10 mbar, still more preferably at least 15 mbar, still more preferably at least 20 mbar. The positive pressure in (ii) may also be a positive pressure of at least 50 mbar, 60 mbar, 70 mbar, 80 mbar, 90 mbar, 100 mbar, 200 mbar, 300 mbar, 400 mbar or 500 mbar.

In certain embodiments the absolute pressure in (ii) is not more than 210 bar, preferably not more than 12 bar, more preferably not more than 8 bar, still more preferably not more than 5 bar. For example, when the pressure at which the mixture in step (i) is provided is about 1.013 bar or is in the range of from 0.95 bar to 1.05 bar, the absolute pressure in step (ii) may be about 1.1 bar, 1.5 bar, 2.0 bar, 5 bar, 7.0 bar, 11.0 bar.

As will be clear from the explanations hereinbefore, the term "positive pressure" or overpressure does not refer to pressure differences between the reaction mixture and the environment of the system but refers to a pressure difference in the reaction mixture between

step (i) and step (ii), namely wherein the pressure in step (ii) is increased relative to step (i). In other words, the absolute pressure in the mixture is increased in step (ii) relative to step (i). For explanatory purposes, if the absolute pressure in the mixture in step (i) is, e.g., 1.00 bar, providing a positive pressure or overpressure in step (ii) will lead to an absolute pressure in the mixture in step (ii) of any value above 1.00 bar, e.g., 1.005 bar, 1.1 bar, or 2 bar. While said pressure increase can be achieved by pressurization using an inert gas, it can also be achieved by any other suitable means or any combination thereof. For example, said pressure increase can be achieved by increasing the temperature of the mixture in a sealed reaction vessel in step (ii) relative to step (i). This is illustrated in, e.g., example 2. When said pressure increase is achieved by other means than pressurization, e.g. by increasing the temperature of the mixture in a sealed reaction vessel in step (ii) relative to step (i), pressurization using an inert gas is optional.

In various embodiments, in step (ii) the pressure in the mixture is increased relative to the pressure in step (i) by at least 5 mbar, preferably at least 8 mbar, more preferably at least 10 mbar, still more preferably at least 15 mbar, still more preferably at least 20 mbar. In other embodiments, the pressure may also be increased by at least 50 mbar, 60 mbar, 70 mbar, 80 mbar, 90 mbar, 100 mbar, 200 mbar, 300 mbar, 400 mbar or 500 mbar.

In a preferred embodiment the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, carbonates, each having an alkyl chain of at least 4 carbon atoms , and mixtures thereof. All of these compounds can be linear, branched or cyclic. E.g., primary, secondary or tertiary alcohols can be used. As stated hereinabove, the solvent typically has a water content of less than 2 % by weight, or lower, in order to obtain in the mixture a water content as specified hereinabove.
Claims

1. A process for the preparation of avibactam sodium in polymorphic form C having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.5 ± 0.2)°, (14.4 ± 0.2)°, (15.5 ± 0.2)°, (18.0 ± 0.2)° and (19.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, comprising the steps

(i) providing a mixture comprising avibactam or a salt thereof and a solvent, wherein the mixture has a water content of less than 2 % by weight based on the weight of the mixture,

(ii) increasing the temperature of the mixture provided in (i) to at least 55 °C and increasing the pressure relative to step (i),

adding a sodium source to the mixture in step (i) a nd/or (ii) if the form of avibactam provided in (i) is not avibactam sodium,

thereby obtaining avibactam sodium in polymorphic form C.

2. The process according to claim 1, wherein the mixture in (i) has a water content of less than 1.5 % by weight, preferably less than 1.3 % by weight, more preferably less than 0.7 % by weight, most preferably less than 0.6 % by weight based on the weight of the mixture.

3. The process according to any of the preceding claims, wherein the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, carbonates, each having an alkyl chain of at least 4 carbon atoms, and mixtures thereof.

4. The process according to any of the preceding claims, wherein the solvent is selected from the group consisting of a C4-C6 alcohol, a C4-C6 ester, a C4-C6 cyclic ether, a linear or cyclic ketone, a carbonate, and mixtures thereof.

5. The process according to any of the preceding claims, wherein the solvent is selected from the group consisting of isobutanol, n-butanol, 2-butanol, 2-methyl-2-butanol, 1,4-

dioxane, THF, methyl-THF, ethyl acetate, isobutyl acetate, cyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl carbonate.

6. The process according to any of the preceding claims, wherein the pressure in (ii) is increased by at least 5 mbar, preferably at least 8 mbar, more preferably at least 10 mbar, still more preferably at least 15 mbar, still more preferably at least 20 mbar.

7. The process according to any of the preceding claims, wherein in (ii) the temperature is increased to at least 59 °C, preferably at least 63 °C, more preferably at least 66 °C, still more preferably at least 70 °C, most preferably at least 73 °C.

8. The process according to any of the preceding claims, wherein in (ii) the temperature is increased to a temperature in the range of from 55 °C to 180 °C, preferably of from 59 °C to 150 °C, more preferably of from 63 °C to 140 °C, still more preferably of from 66°C to 135 °C, still more preferably of from 70 °C to 130 °C, most preferably of from 73 °C to 126 °C.

9. The process according to any of the preceding claims, wherein the mixture provided in (i) comprises avibactam or a salt thereof in crystalline form, amorphous form or a mixture thereof, preferably in crystalline form.

10. The process according to any of the preceding claims, wherein the mixture provided in (i) is a mixture comprising a solvent and avibactam sodium in crystalline form "A" having a PXRD comprising reflections at 2-Theta angles of (8.5 ± 0.2)°, (16.4 ± 0.2)°, (17.1 ± 0.2)°, crystalline form "B" having a PXRD comprising reflections at 2-Theta angles of (13.0 ± 0.2)°, (16.5 ± 0.2)°, (17.2 ± 0.2)°, crystalline form "D" having a PXRD comprising reflections at 2-Theta angles of (16.2 ± 0.2)°, (17.4 ± 0.2)°, (17.8 ± 0.2)°, or crystalline form "E" having a PXRD comprising reflections at 2-Theta angles of (13.7 ± 0.2)°, (15.0 ± 0.2)° and (15.4 ± 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, or a mixture thereof, preferably in crystalline form "A".

11. The process according to any one of claims 1 to 9, wherein the avibactam or salt thereof provided in (i) is a salt of avibactam, wherein the anion is a compound of formula (X),

and the cation is M+, wherein M+ is N+RR'R"R"', and wherein R, R', R" and R'" are each independently selected from hydrogen and an alkyl group having 1 to 6 carbon atoms, preferably wherein the cation M+ is tetrabutylammonium,.

12. The process according to any of claims 1 to 10, wherein step (i) is

providing a mixture comprising avibactam sodium in crystalline form "B" and/or "D" and a solvent having a water content of at least 2 % by weight, preferably greater than 5 % by weight,

incubating the mixture, and

subsequently reducing the water content of the mixture to less than 0.9 % by weight, preferably less than 0.7 % by weight, based on the weight of the mixture.

13. The process according to any of claims 1 to 9, wherein step (i) is

providing a mixture comprising free acid of avibactam and a solvent having a water content of at least 2 % by weight, preferably greater than 5 % by weight,

adding a suitable sodium source,

optionally incubating the mixture, and

subsequently reducing the water content of the mixture to less than 0.9 % by weight, preferably less than 0.7 % by weight, based on the weight of the mixture.

14. The process according to any of claims 1 to 9, wherein step (i) is

providing a mixture comprising a salt of avibactam, wherein the anion is a compound of formula (X),

and the cation is M+, wherein M+ is N+RR'R"R"', and wherein R, R', R" and R'" are each independently selected from hydrogen and an alkyl group having 1 to 6 carbon atoms, preferably wherein the cation M+ is tetrabutylammonium, and a solvent having a water content of at least 2 % by weight, preferably greater than 5 % by weight,

adding a suitable sodium source,

optionally incubating the mixture, and

subsequently reducing the water content of the mixture to less than 0.9 % by weight, preferably less than 0.7 % by weight, based on the weight of the mixture.

15. The process according to any of the preceding claims, wherein the sodium source comprises one or more alkaline sodium salt(s), preferably sodium 2-ethylhexanoate, more preferably wherein the sodium source is a solution of sodium 2-ethylhexanoate.