Process for manufacturing a block copolymer of polyether and bioresorbable polyester

Abstract

The invention pertains to a process for manufacturing a block copolymer comprising a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester, comprising the steps of - providing a poly-(C2-C4)-alkylether having a total alkali content, calculated as the total of Na and K, of at most 50 ppm, - reacting said poly-(C2-C4)-alkylether with monomers of bioresorbable polyester, under polymerisation conditions in the presence of a polymerisation catalyst, to form a block copolymer. Objects of the invention include providing a process for manufacturing said block copolymers giving reproducible results and / or showing an attractive reaction rate at an acceptable amount of catalyst, and / or resulting in a block copolymer polymer with low residual monomer content, and / or providing a block copolymer requiring less purification. The block copolymer, its use in pharmaceutical applications, and a pharmaceutical composition comprising it are also claimed.

Description

[0001] PROCESS FOR MANUFACTURING A BLOCK COPOLYMER OF POLYETHER AND BIORESORBABLE POLYESTER

[0002] The present invention relates to a process for manufacturing a block copolymer of polyether, in particular poly-(C2-C4)-alkylether, and bioresorbable polyester. The invention also relates to block copolymer of polyether and bioresorbable polyester. The invention further relates to the use of the polymer in medical, biomedical and pharmaceutical applications. The invention also relates to a pharmaceutical composition comprising the copolymer in combination with a pharmaceutically active ingredient.

[0003] Block copolymers comprising a polyether and a bioresorbable polymer are known in the art. These copolymers in which different polymer blocks have different properties are attractive for a wide range of medical, biomedical, and pharmaceutical applications, e.g., in drug delivery, such as for use in long acting injectables. It has been found, however, that the manufacture of such copolymers on a commercial scale is associated with problems. In particular, it has been found that the manufacturing process is not always reproducible. Further, it has been found that the residual monomer content of the product may be relatively high, requiring extensive post-purification steps. It has also been found that to obtain an acceptable reaction rate during the manufacture of the polyester blocks the addition of substantial amounts of catalyst is required. This is not attractive from a costs point of view. It is also not attractive because, depending on the future use of the polymer, removal of catalyst may be required for regulatory reasons.

[0004] The object of the present invention is to overcome the above mentioned problems. An object of the present invention is to provide a process for manufacturing block copolymers of polyether and bioresorbable polyester which gives reproducible results. Another object of the present invention is to provide a process which has an attractive reaction rate at an acceptable amount of catalyst. A further object of the present invention is to provide a process which results in a block copolymer polymer which has less residual monomer than comparable polymers obtained through different processes. A still further object of the present invention is to provide a block copolymer polymer which requires less purification than comparable polymers obtained through different processes.

[0005] The object of the present invention is achieved in that a process is provided for manufacturing a block copolymer comprising a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester, comprising the steps of

[0006] - providing a poly-(C2-C4)-alkylether having a total alkali content, calculated as the total of Na and K, of at most 50 ppm, - reacting said poly-(C2-C4)-alkylether with monomers of bioresorbable polyester, under polymerisation conditions in the presence of a polymerisation catalyst, to form a block copolymer comprising a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester.

[0007] Surprisingly it has been found that the use of a poly-(C2-C4)-alkylether having a total alkali content, calculated as the total of Na and K, of at most 50 ppm as a starting material in the manufacturing of the block copolymer results in a polymerisation process which gives reproducible results, which has an attractive reaction rate at an acceptable amount of catalyst, and which results in a polymer with a reduced monomer content, and which requires less purification than comparable polymers obtained through different processes. For example, catalyst removal and carbon filtration may not be required. Further, the polymers of the present invention show good color characteristics. Additionally, it has been found that the block copolymers according to the invention, may have an advantageous homogeneous microstructure, which is believed to be related to a homogeneous behaviour in vivo.

[0008] Further advantages of the present process and other aspects of the invention will become apparent from the further specification.

[0009] The invention will be discussed in more detail below.

[0010] In the process of the present invention, a poly-(C2-C4)-alkylether, also indicated herein as “the polyether”, is provided which has a total alkali content, calculated as the total of Na and K, of at most 50 ppm. It is noted that alkali metal contents of commercially available poly-(C2-C4)-alkylethers vary within wide ranges, and often differ from batch to batch. Surprisingly it has been found that a lower total alkali content of the polyether leads to an improved reaction rate, lower catalyst requirements, and improved block copolymer product properties. Improvements include at least one of an increased conversion rate, increased molecular weight, reduced residual monomer content, and improved product color.

[0011] The polyether blocks preferably have a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 25 ppm, still more in particular at most 15 ppm, even more in particular at most 10 ppm. It has been found that a lower total alkali content of the polyether leads to an improved reaction and improved product properties. The alkali metal content is determined through Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) according USP <232>.

[0012] Polyethers are a class of polymers characterized by the presence of multiple ether (- O-) linkages within their molecular structure. These polymers are typically formed through the polymerization of monomers containing ether functional groups, resulting in long chains or networks of repeating ether units. An ether is a class of organic compounds characterized by an oxygen atom bonded to two alkyl or aryl groups. The general formula for ethers is R-O-R', where R and R' represent alkyl or aryl groups. As will be clear to the skilled person, the wording poly-(C2-C4)-alkylether refers to a polyether built up from alkyl monomers having 2 to 4 carbon atoms. The monomers may be linear or branched, and may or may not be substituted with functional groups. Combinations of different types of monomers may be used. Examples of suitable alkylether monomers are ethylene glycol, propylene glycol, isopropylene glycol, and tert-butylene glycol. Preferably the poly-(C2-C4)-alkylether is selected from the group consisting of polyethylene glycol, polypropylene glycol, and polyisopropylene glycol. More preferably the poly-(C2-C4)-alkylether is polyethylene glycol (PEG).

[0013] The polyether generally has a molecular weight in the range of 100-20.000 g / mole, in particular 100-10.000 g / mol, more in particular 200-8.000 g / mol. The desired molecular weight is dependent on the desired balance between the hydrophobic polyester and the hydrophilic polyether. If the molecular weight of the polyether is too high, the degradation rate of the polymer will be too high. On the other hand, if the molecular weight of the polyether is too low, the desired interaction with, e.g., a hydrophilic pharmaceutical compound will ne be achieved.

[0014] In a first embodiment the polyether is a linear polyether. Within the context of the present specification a linear polyether is a polyether having ether linkages in the main chain and one or two reactive end groups, typically hydroxyl groups. In a further embodiment the polyether is a non-linear polyether. Within the context of the present specification a nonlinear polyether is a polyether having ether linkages in the main chains and having three or more reactive end groups, typically hydroxyl groups. These embodiments will be discussed in more detail below.

[0015] The polyether used as starting material in the process according to the invention, i.e. , the polyether with an alkali metal content of at most 50 ppm, generally has a water content of at most 0.5 wt.%, preferably at most 0.2 wt.%. In some embodiments, the water content is lower, e.g., at most 0.1 wt.%. This is because the presence of water may interfere with polyester formation through ring opening polymerisation.

[0016] The polyether used as starting material in the process according to the invention generally has a total organic acid content (formic acid, lactic acid and acetic acid) of less than 50 mg / kg, in particular less than 30 mg / kg. The presence of organic acid may impact polymerisation kinetics.

[0017] The polyether used as starting material in the process according to the present invention may be obtained by methods known in the art. The starting polyether with an alkali metal content in the range stipulated above may be obtained by subjecting commercially obtained polyethers to a purification step, e.g., by providing a solution of the starting polyether to an ion exchange column to remove excess alkali metal contaminants. Other purification methods may also be used. Accordingly, the present invention also pertains to a process as described herein wherein the poly-(C2-C4)-alkylether used in the polymerisation reaction is obtained by subjecting by a poly-(C2-C4)-alkylether to a step of reducing the total alkali content. This encompasses subjecting a poly-(C2-C4)-alkylether with an alkali metal content above 50 ppm to a purification step to reduce the alkali metal content to a value below 50 ppm. Depending on the desired alkali metal content of the material to be provided to the polymerisation process, it is also possible to subject a poly-(C2-C4)-alkylether with an alkali metal content of above, e.g., 10 ppm to a step of reducing the alkali metal content to below said value. In general, the step encompasses subjecting a poly-(C2-C4)-alkylether with an alkali metal content above a desired value to a step of reducing the alkali metal content to a desired value.

[0018] In the process according to the invention, the poly-(C2-C4)-alkylether is combined with monomers of a bioresorbable polyester, under polymerisation conditions in the presence of a polymerisation catalyst, to form a block copolymer comprising a block of a poly-(C2-C4)- alkylether and at least one block of a bioresorbable polyester. Bioresorbable polymers are well known in the art. A bioresorbable polymer, also known as resorbable or absorbable polymer, is a type of polymer that can be gradually broken down and metabolized by the body over time. These polymers are designed to degrade into non-toxic byproducts, which can be absorbed or eliminated from the body through natural metabolic processes. Resorbable polymers are commonly used in medical applications such as sutures, implants, drug delivery systems, and tissue engineering scaffolds.'

[0019] In one embodiment, the monomers of bioresorbable polyester are selected from the group of lactide, glycolide, caprolactone, trimethylene carbonate, dioxanone, and combinations thereof, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide. In one embodiment, monomers are used selected from the group of DL-lactide, LL-lactide, and DD-lactide, and meso-lactide. The use of DL-lactide may be preferred because it results in amorphous polymers with attractive degradation characteristics.

[0020] The polyether and the monomers are reacted under polymerisation conditions in the presence of a polymerisation catalyst.

[0021] Polymerisation conditions include temperature and pressure conditions suitable for achieving reaction of the polyester monomers with the endgroups of the polyether, and further polymerisations of the polyester monomers to form a polyester chain. Suitable polymerisation conditions generally include a temperature T of at least 100°C, in particular at least 120°C. The polymerisation temperature is generally at most 240°C, more in particular at most 210°C, more in particular at most 180 °C. The reaction is generally carried out at a pressure in the range of 0.5-3 bar, e.g., at atmospheric pressure. The reaction is generally carried out in an inert atmosphere.

[0022] It has been found, advantageously, that the use of the specified polyether leads to an increased reaction rate. This makes it possible to reduce the reaction temperature while maintaining reaction time. A reduced reaction temperature is attractive for economic reasons, and also because it leads to less side product formation. Alternatively or additionally, it is also possible to shorten the reaction time, which is attractive for economic reasons. It is preferred for the process according to the invention to be completed in less than 24 hours, in particular less than 12 hours, in some embodiments less than 10 hours, calculated from the combining of the reactants to removal of the reaction product from the reactor. As a minimum reaction time 0.5 hours may be mentioned, depending on the desired degree of conversion. A relatively short reaction time is attractive to prevent the formation of side products, which may occur when keeping the reactants under reaction conditions for prolonged periods of time.

[0023] Suitable catalysts for the polymerisation of polyester monomers are known in the art. It is within the scope of the skilled person to select a suitable catalyst. In general, a polymerisation catalyst will be used based on tin, zinc, aluminium, or titanium, with tin and zinc being preferred, and with tin-based catalysts being particularly preferred. Examples of suitable tin-based catalysts include Sn-octoate, (also known as Sn(ll)bis 2-ethyl hexanoate), Sn-stearate, dibutyltin diacetate, butyltin tris(2-ethyl hexanoate), and tetraphenyltin. Suitable zinc-based catalysts include zinc alkoxides and zinc stearate. The use of Sn(ll)-bis (2- ethylhexanoate), also indicated as tin octoate, may be preferred, since this material is commercially available. Further, the compound has FDA approval.

[0024] In general, the catalyst concentration is generally at least 2 ppm, calculated as metal weight on the weight of the total polymer (polyether and polyester). The catalyst concentration is generally at most 1300 ppm, preferably at most 500 ppm. It is an advantage of the claimed invention that the use of a polyether with a limited amount of alkali metal makes it possible to reduce the amount of polymerisation catalyst as compared to the situation where the starting polyether has a higher content of alkali metal while achieving the same degree of polymerisation within the same time frame. The use of a limited amount of catalyst results in less catalysts having to be removed from the final block copolymer. This is highly preferred as it simplifies the downstream processing. In some embodiments it may be possible to dispense with catalyst removal altogether. Additionally, the use of less catalyst will result in less side product formation, makes it possible dispense with a catalyst removal step at the end of the manufacturing process. Accordingly, in one embodiment, the catalyst concentration is at most 300 ppm, in particular at most 180 ppm. In some embodiments it may be possible to apply less than 150 ppm, or less than 100 ppm, or even less than 50 ppm, in some embodiments less than 25 ppm, or even less than 10 ppm.

[0025] The reaction is stopped when the desired degree of conversion has been achieved. It is preferred to continue the reaction until a degree of conversion of at least 80% has been achieved, calculated on the amount of monomer provided, more preferably at least 90%, more in particular at least 95%.

[0026] The block copolymer resulting from the process may be processed as desired. It can, e.g., be applied in medical, biomedical, and pharmaceutical applications. Depending on the polymer properties and intended use it may be desirable to subject the block copolymer as it is obtained from the polymerisation process to a purification step to reduce the content of undesirable contaminants, e.g., catalyst and / or monomers. Suitable purification processes are known in the art and require no further elucidation. They include, e.g., washing steps., treatment with active carbon, or ion exchange etc. As indicated above, it is an advantage of the process of the invention that the block copolymer as obtained from the polymerisation step in the process of the invention generally has a lower residual monomer content and often a lower catalyst content than comparable polymers obtained through other processes, which means that less downstream purification of the resulting block copolymers is required.

[0027] The block copolymer in general

[0028] The invention also pertains to a block copolymer comprising a block of a poly-(C2- C4)-alkylether and at least one block of a bioresorbable polyester, wherein the poly-(C2-C4)- alkylether block has a total alkali content, calculated as the total of Na and K, of at most 50 ppm. This block copolymer can be obtained using the process of the present invention. It is advantageous because it can be obtained efficiently in a reproducible manner, at a higher reaction rate and / or lower reaction temperature than comparable polymers which do not meet the stipulated requirement as the amount of alkali metal in the polyether block. The block copolymer generally has a lower residual monomer content, and often a lower catalyst content than comparable polymers which do not meet the stipulated requirement as regards the amount of alkali metal in the polyether block. This means that less downstream purification of the resulting block copolymers is required, making the purification process less costly, and resulting in a higher yield. In one embodiment, the block copolymer comprises a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester, wherein the block copolymer has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, more in particular at most 25 ppm, still more in particular at most 15 ppm, even more in particular at most 10 ppm. The polyether block preferably has a total alkali content, calculated as the total of Na and K, of at most 75 ppm, in particular at most 50 ppm, more in particular at most 25 ppm, still more in particular at most 15 ppm, even more in particular at most 10 ppm. For the composition and further properties of the polyether block reference is made to what is stated above in the context of the process. Preferably the poly-(C2-C4)-alkylether is selected from the group consisting of polyethylene glycol, polypropylene glycol, and polyisopropylene glycol. More preferably the poly-(C2-C4)-alkylether is polyethylene glycol (PEG).

[0029] The block copolymer comprises at least one block of a bioresorbable polyester. The number of polyester blocks is dependent on the number of reactive end groups in the polyether block on which the block copolymer is based. Accordingly, in one embodiment the block copolymer has an A-B structure, in which A is the polyester block and B is the polyether block. A copolymer with this structure is obtained from a, generally linear, polyether block with a single reactive endgroup. In another embodiment the block copolymer has an A- B-A structure, in which the A-blocks are polyester blocks and B is the polyether block. A copolymer with this structure is obtained from a, generally linear, polyether block with two reactive endgroups, for example two hydroxyl groups. In a further embodiment the block copolymer has an B(A)n structure, wherein B is the polyether block to which n polyester blocks are connected. Such a polymer can be derived from a non-linear polyether block with n reactive groups.

[0030] In one embodiment the polyester blocks are derived from monomers selected from the group of lactide, glycolide, caprolactone, trimethylene carbonate, dioxanone, and combinations thereof, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide. Preferably the monomers are derived from monomers selected from the group of DL-lactide, LL-lactide, and DD-lactide, and meso-lactide. The use of DL-lactide may be preferred because it results in amorphous polymers with attractive degradation characteristics.

[0031] It is preferred for the polyether block to make up 2-75 wt.% of the total block copolymer.

[0032] The block copolymer of the present invention has a molecular weight, as expressed as IV, in the range of 0.05 to 1.1 d L / g , in particular 0.05 to 1.0 dL / g. I of the block copolymer is determined as indicated in the examples.

[0033] While it is possible for the copolymer of the present invention to contain segments which are neither alkylether blocks or blocks of bioresorbable polymer, this is not preferred. It is preferred for at least 80 wt.%, in particular at least 90 wt.%, more in particular at least 95 wt.%, even more in particular at least 98 wt.% of the block copolymer to be the total of alkylether and bioresorbable polymer. The block copolymer resulting from the process of the present invention generally has a residual content of monomer of the bioresorbable polyester, calculated on the total weight of the block copolymer, of at most than 10 wt.%, more in particular at most 5 wt.%, still more in particular at most 2.5 wt.%. This is substantially lower than the residual monomer content of polymers obtained when the polyether block has an alkali metal content which is outside the range specified above. As indicated above, it is an advantage of the present invention that a block polymer can be obtained which has such a low residual content of monomers of the bioresorbable polyester. As indicated above, the monomer content may be quite low, e.g., at most 5 wt.%, in particular at most 2.5 wt.%.

[0034] The block copolymer according to the invention generally has residual content of alkylether monomer of at most 2 wt.%, calculated on the total weight of the block copolymer, in particular below 1 wt.%, and even more in particular below 0.5 wt.%. It is preferred for the block copolymer to have a total content of free ethylene glycol, diethylene glycol of maximum 0.5 wt.%, in particular 0.25 wt.%. It is also preferred for the polymer to have a total free 1 ,4- dioxane content of at most 40 ppm, in particular at most 20 ppm, more in particular at most 10 ppm.

[0035] Preferably the block copolymer meets the requirements as stipulated by the FDA in Q3D(R2) Elemental Impurities. In particular, it is preferred if the polymer has a Sn content of up to or below 60 ppm, preferably below 40 ppm, more preferably below 10 ppm.

[0036] The various types of block copolymer and the preferred embodiments thereof will be discussed in more detail below.

[0037] Linear block copolymers

[0038] In one embodiment, the block copolymer is a linear block copolymer of the structure A-B or of the structure A-B-A, wherein A stands for a block of a biodegradable polyester and B stands for a polyether block of a polyether. As the skilled person will be aware, linear block copolymers of the A-B type are obtained starting out from polyether with one reactive group, while block copolymers of the A-B-A type are obtained starting out from polyether with two reactive groups. Polyether with one reactive group is often indicated as m-polyether, e.g., mPEG. As will be evident to the skilled person, in the present specification the term poly-(C2- C4)-alkylether encompasses all poly-(C2-C4)-alkylether having one or more reactive groups.

[0039] For the chemical composition of the polyether and the bioresorbable polyester and associated preferences, reference is made to what is stated above for the block copolymer in general. The same applies to the alkali metal content, catalyst content, residual monomer content, and other parameters discussed above. For the linear polymer some more specific preferences have been found to apply. They will be discussed below. The linear block copolymer generally has a molecular weight as expressed by way of IV in the range of 0.05 to 1.1 dL / g , in particular 0.05 to 1.0 dL / g. The linear block copolymer generally has a molecular weight Mn in the range of 0.5 to 150 kg / mol, in some embodiments 0.5 to 30 kg / mole.

[0040] The polyether block in the linear copolymer generally has a Mn as measured by DIN EN ISO 4629 titration in the range of 0.05 to 20 kg / mole, in particular in the range of 0.05-10 kg / mole, more in particular 0.1 to 7 kg / mole, still more in particular in the range of 0.2 to 6 kg / mole.

[0041] The block or blocks of bioresorbable polyester generally have a Mn in the range of 0.5 to 150 kg / mole, in particular 1.0 to 130 kg / mole, more in particular 2.0 to 30 kg / mole, e.g. in the range of 3.0-25 kg / mole, more in particular in the range of 4.0-20 kg / mole.

[0042] A particularly preferred polymer within the present invention is the following: A linear block copolymer comprising a polyethylene glycol block and one or two blocks of a bioresorbable polyester, wherein the polyethylene glycol block has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 20 ppm, more in particular at most 10 ppm, and wherein the polyester is a polyester derived from monomers selected from one or more of the group of lactide, glycolide, and caprolactone, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide.

[0043] Non-linear block copolymers

[0044] In one embodiment, the block copolymer is a non-linear block copolymer. In one embodiment, the block copolymer has a B(A)n structure, wherein B is the polyether block to which n polyester blocks are connected, wherein n is at least 3. Such a polymer can be derived from a non-linear polyether block with n reactive endgroups such as hydroxyl groups.

[0045] For the chemical composition of the polyether and the bioresorbable polyester and associated preferences, reference is made to what is stated above for the block copolymer in general. The same applies to the alkali metal content, catalyst content, residual monomer content, and other parameters discussed above. For non-linear copolymers some specific preferences have been found to apply. They will be discussed below.

[0046] In one embodiment, the non-linear block copolymer is a star polymer. The star polymer generally has 3 to 10 arms, in particular 3-8 arms, more in particular 3-6 arms, still more in particular 3-4 arms, wherein the number of arms is the average number of arms. Star block copolymers are attractive because they show a lower solution viscosity at the same molecular weight as compared to their linear analogues. The preferences stated below for non-linear polymers apply in particular to star polymers.

[0047] The non-linear block copolymer generally has a molecular weight as expressed by way of IV in the range of 0.05 to 1.1 dL / g , in particular 0.05 to 1.0 dL / g. The non-linear block copolymer generally has a molecular weight Mn in the range of 0.5 to 150 kg / mol, in some embodiments 0.5 to 30 kg / mole.

[0048] The polyether block in the non-linear copolymer generally has a Mn as measured by DIN EN ISO 4629 titration in the range of 0.05 to 20 kg / mole, in particular in the range of 0.05-10 kg / mole, more in particular 0.1 to 7 kg / mole, still more in particular in the range of 0.2 to 6 kg / mole.

[0049] The blocks of bioresorbable polyester generally have a Mn in the range of 0.5 to 150 kg / mole, in particular 1.0 to 130 kg / mole, more in particular 2.0 to 30 kg / mole, e.g. in the range of 3.0-25 kg / mole, more in particular in the range of 4.0-20 kg / mole.

[0050] A particularly preferred block copolymer within the present invention is the following: A non-linear block copolymer, in particular a star block copolymer having 3-8 arms comprising a polyethylene glycol block and blocks of a bioresorbable polyester, wherein the polyethylene glycol block has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 20 ppm, more in particular at most 10 ppm, and wherein the polyester is a polyester derived from one or more monomers selected from the group of lactide, glycolide, and caprolactone, in particular monomers selected from the group of lactide, glycolide, and the combination of lactide and glycolide, The use of lactide, e.g., DL lactide may be particularly preferred.

[0051] Applications

[0052] The block copolymers of the present invention may find use in a variety of applications. In one embodiment, they are used in medical, biomedical, or pharmaceutical applications. In one embodiment the invention pertains to a pharmaceutical composition comprising a block copolymer as discussed above, and a pharmaceutically active ingredient. This composition can, e.g., be used in in drug delivery, such as for use in long acting injectables.

[0053] As will be evident to the skilled person, different embodiments of the present invention can be combined unless they are mutually exclusive. In the present specification headers are only used to improve readability of the text. They should not be construed to change the interpretation. All percentages used herein are weight percentages, unless specified otherwise.

[0054] When amounts, concentrations, dimensions and other parameters are expressed in the form of a range, a preferable range, an upper limit value, a lower limit value or preferable upper and limit values, it should be understood that any ranges obtainable by combining any upper limit or preferable value with any lower limit or preferable value are also specifically disclosed, irrespective of whether the obtained ranges are clearly mentioned in the context.

[0055] The invention is illustrated by the following examples, without being limited thereto or thereby.

[0056] Materials

[0057] Poly(ethylene glycol) materials were purchased from JenKem USA or Clariant. Ion exchange resin (MB 400) for the removal of alkali salts was purchased from Purolite. Purasorb® D,L-lactide and glycolide were purchased as biomedical, GMP-purity grades from PURAC BIOCHEM. Potassium acetate was purchased from Sigma-Aldrich. Solvents used for analytical procedures were purchased from Sigma-Aldrich, Fisher Scientific, Biosolve or VWR. The polymerization catalyst used was SnOct2 (Sigma-Aldrich, minimum 95% purity).

[0058] Characterisation and purification of poly(ethylene glycol)

[0059] The following polyethylene glycol starting materials were obtained:

[0060] - methoxypoly(ethylene glycol) with a molecular weight of 2.0 kg / mol (mPEG 2000) from Clariant

[0061] - poly(ethylene glycol) with a molecular weight of 2.0 kg / mol (PEG 2000) from Clariant

[0062] - 6-arm poly(ethylene glycol) star-shaped polymer with a molecular weight of 2.5 kg / mol (S6- PEG 2500 from JenKem)

[0063] The removal of alkali salts from the different PEG materials proceeded by passage of aqueous (MiliQ) solutions of PEGs over a bed of ion exchange resin (100 g, MB 400, purolite). In this fashion up to 1 kg of each PEG was purified.

[0064] For the linear PEGs (mPEG 2000 and PEG 2000), the desalinated PEG solutions of were then concentrated to dryness using lyophilization.

[0065] The desalinated solution of star shaped 6 arms S6-PEG 2500 was concentrated to dryness using a rotary evaporator (45 oC, Buchi B-490) and an additional chiller (-40 oC) to reach the required final vacuum (10 mbar) after bulk water removal. Table 1 provides the properties of the “as received” polyethylene glycols as well as the purified materials.

[0066] Table 1 Analytical results for as received and I EX purified PEGs.

[0067] *mg / g KOH; ** from OH-number; *** Volumetric Karl Fisher

[0068] Analytical methods

[0069] All (co)polymers were characterized using gas chromatography with programmed temperature vaporization (GC-PTV) for residual monomer content, gel permeation chromatography with refractive index (GPC-RI ) for molecular weight data, differential scanning calorimetry (DSC) for thermal properties, inductively coupled plasma optical emission spectrometry (ICP-OES) for residual tin and alkali content, and inherent viscosity (IV) measurements in chloroform.

[0070] GPC-RI

[0071] GPC-RI analysis of the copolymers was performed using a liquid chromatography system equipped with a refractive index (Rl) detector. The mobile phase consisted of tetrahydrofuran (THF) stabilized with butylated hydroxytoluene (BHT), operated under isocratic conditions. The column oven was maintained at 35 °C, and the flow rate was set to 0.8 mL / min. An injection volume of 30 pL was used for all samples. The system was calibrated using narrow polystyrene standards to generate a log(MW) versus retention time calibration curve. From this, the number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (PDI = Mw / Mn) were calculated.

[0072] The molecular weight of the block copolymer and the polyester blocks can be determined using GPC-RI. The molecular weight of the polyether block can be determined using DIN EN ISO 4629 titration. Instrumentation included a 1260 Agilent Infinity II system comprising an Isopump (G7110B), Degasser (G7122A), Vial sampler (G7129A), Multicolumn Thermostat (G7116A), and Diode Array Detector WR (G7115A). An Agilent Pre-Guard column of 50 x 7.5 mm with 5 pm particle size was used in line with a set of three Agilent PLGel MIXED-D columns (size 300 x 7.5 mm, particle size 5pm).

[0073] Sample preparation:

[0074] Polymer samples were prepared by dissolving 60 mg of material in 15 mL of stabilized tetrahydrofuran (THF) containing 0.025% BHT as an antioxidant. Solutions were gently agitated and allowed to stand at room temperature for a minimum of 12 hours to ensure complete dissolution.

[0075] Inherent viscosity

[0076] The IV of the block copolymer was performed using an Ubbelohde capillary (DIN, type 0c, SI Analytics) viscometer in a waterbath (AVS-370, SI Analytics) at 25°C. The solvent used was chloroform. Polymer solutions were prepared at concentrations ranging from 0.50 - 2.00 g / dL and filtered through 45 pm filters prior to measurement. The flow times of both the pure solvent and the polymer solutions were recorded using the WinVisco software.

[0077] Differential Scanning Calorimetry (DSC)

[0078] Thermal analysis was performed using differential scanning calorimetry (DSC) on a TA Instruments DSC-250. Approximately 5 ± 1mg of each sample was weighed into Tzero Hermetic aluminum pans and sealed.

[0079] Measurements were carried out under a nitrogen atmosphere with a flow rate of 50 mL / min. The samples were subjected to a heating-cooling-heating cycle from -80 °C to 170 °C at a rate of 10 °C / min. or for the star shaped copolymer from 0 °C to 200 °C. Thermal transitions such as the glass transition temperature (Tg) were determined from the second heating cycle

[0080] Residual monomer (RM)

[0081] Residual monomer content was determined using gas chromatography (GC) on a Thermo Scientific Trace 1300 GC equipped with a flame ionization detector (FID) and an Agilent column (DB17-MS L = 30m, i.d. = 0.25 mm, df = 0.25 pm). An instant connect module Programmable Temperature Vaporizer (PTV) with back flush was used for injection.

[0082] Quantification was performed using external calibration with D,L-lactide, meso-lactide and glycolide as standards in DCM and 2,6-dimethyl-y-pyrone as an internal standard. ICP-OES

[0083] Elemental impurities, including Na and K, were quantified using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) on an AVIO 550 Max ICP-OES from Perkin Elmer. This technique enables the detection of elements in trace amounts by vaporization of aqueous sample solutions and excitation in a high-temperature plasma. Emission intensities were measured at element-specific wavelengths using the optical spectrometer. Calibration was performed using multi-element standards (e.g. Ag, As, Bi, Ca, Cd, Co, Cr, Cu, Fe, K, Mg and Mn), and quantification was based on external calibration curves.

[0084] Melt polymerization procedures

[0085] Reactors used for polymerizations were typical laboratory type set-ups. Reactors were made of stainless steel or glass (1000 mL), and equipped with mechanical overhead stirring in combination with stainless steel shafts and propellor blades. Reactors were submerged in a temperature controlled oil bath. The reactions were monitored using both temperature and Raman spectroscopy probes (0.25”) introduced through appendages on the reactor lids. For Raman spectroscopy, the probes were coupled to an Endress + Hauser Rxn2 station. Raman data was processed using Peaxact software.

[0086] Example 1 - synthesis of a linear mPEG2ooo - PDL1700 diblock copolymer

[0087] 220g (0.11 mol) of purified or non-purified methoxy poly(ethylene glycol) (mPEG 2000) and D,L-lactide (185g, 1.28 mol) were introduced into a nitrogen-purged, closed reactor. To monitor reaction kinetics in situ, a Raman probe was inserted into the reactor. The system was put under vacuum, and the oil bath was heated to 85 °C to dry the reactants overnight. Simultaneously, the Raman spectrophotometer was turned on and stabilized overnight to ensure thermal equilibrium.

[0088] After 16 hours, the reactor was returned to a nitrogen atmosphere, and the oil bath was set to 135 C with stirring initiated at 200 rpm. At a dosing temperature of 130 C, Raman acquisition was started, and the catalyst (tin octoate, 60 ppm Sn by total polymer weight) was added via a syringe, marking time zero (t = 0). After 4 hours, the oil bath temperature was increased, and the reaction was continued for an additional 2 hours at a maintained temperature of 150 C. To support process scale-up, the stirring rate was gradually reduced over the course of the reaction. After a total reaction time of 6 hours the Raman measurement was stopped and the probe was removed. The reactor was cooled to room temperature, and the product was collected and packaged under dry conditions to prevent hydrolysis and oxidation. The analytical results are provided in Table 2 below. Example 1 is derived from purified mPEG (Na < 0.5 ppm; K < 0.14 ppm). Comparative Example A is derived from nonpurified mPEG (Na 223 ppm; K < 0.14 ppm).

[0089] Table 2: Overview of Analytical data for mPEG-PDL

[0090] Figure 1 shows photographs of the polymers obtained using non-purified mPEG (Figure 1a) versus purified mPEG (figure 1 b).

[0091] Figure 2 shows the lactide conversion over time for the polymer synthesis using nonpurified mPEG (continuous line), versus purified PEG (dotted line).

[0092] The results of this example may be summarized as follows:

[0093] As can be seen from the data presented in Table 2, distinct differences in the final properties of the copolymers synthesized from purified versus non-purified mPEG are evident. The most pronounced disparity lies in the residual monomer content: the copolymer derived from non-purified mPEG (Comparative Example A) exhibited a significantly higher total residual monomer content (9.37 wt.%) compared to the 1.80 wt.% observed in the product obtained using purified mPEG (Example 1).

[0094] Molecular weight analysis revealed that both the number-average (Mn) and weightaverage (Mw) molecular weights were higher in the copolymer incorporating purified mPEG (Example 1) relative to its non-purified counterpart (Comparative Example A). In contrast, intrinsic viscosity (IV) and Tg were comparable between the two samples, indicating minimal influence of mPEG purification on these parameters.

[0095] Elemental analysis further demonstrated reduced levels of impurities — particularly sodium (Na) and potassium (K) — in the copolymer synthesized from purified mPEG. Visually, the difference in product appearance was striking. As shown in Figure 1 , the copolymer from non-purified mPEG (Figure 1a) exhibited a noticeably darker coloration than the product from purified mPEG (Figure 1b). Finally, kinetic data presented in Figure 2 indicate a markedly faster monomer conversion rate when purified mPEG was used, suggesting enhanced reaction efficiency and control in the synthesis of the target copolymer.

[0096] Example 2 - synthesis of a linear PDLGGTOO -PEG2000 -PDLGGTOO triblock copolymer

[0097] 52g (0.03 mol) of purified or non-purified poly(ethylene glycol) (PEG 2000) and D,L- lactide (275g, 1.91 mol) and glycolide ( 73g, 0.63 mol) (DL:G ratio of 75:25)were introduced into a nitrogen-purged, closed reactor. To monitor reaction kinetics in situ, a Raman probe was inserted into the reactor. The system was put under vacuum, and the oil bath was heated to 85 °C to dry the reactants overnight. Simultaneously, the Raman spectrophotometer was turned on and stabilized overnight to ensure thermal equilibrium.

[0098] After 16 hours, the reactor was returned to a nitrogen atmosphere, and the oil bath was set to 133 C with stirring initiated at 200 rpm. When the internal temperature had reached the dosing temperature of 130 C, Raman acquisition was started, and the tin catalyst (tin octoate, 50 ppm of Sn based on total polymer weight) was added via a syringe, marking time zero (t = 0). After 4 hours, the oil bath temperature was increased, and the reaction was continued for an additional 2 hours at a maintained temperature of 150 C. To support process scale-up, the stirring rate was gradually reduced over the course of the reaction.

[0099] After a total reaction time of 6 hours, the Raman measurement was stopped and the probe was removed. The reactor was cooled to room temperature, and the product was collected and packaged under dry conditions to prevent hydrolysis and oxidation.

[0100] The analytical results are provided in Table 3 below. Example 2 is derived from purified PEG (Na < 0.18 ppm; K < 0.6 ppm). Comparative Example B is derived from nonpurified mPEG (Na 85 ppm; K < 0.6 ppm).

[0101] Table 3: Overview of Analytical data for from PDLG-PEG-PDLG product did not dissolve in THF, making molecular weight determination not possible.

[0102] Figure 3 shows photographs of the polymers obtained using non-purified PEG (Figure 3a) versus purified PEG (figure 3b).

[0103] Figures 4a and 4b shows the lactide (figure 4a) and glycolide (figure 4b) conversion over time for the polymer synthesis using non-purified PEG (continuous line), versus purified PEG (dotted line).

[0104] Based on the physicochemical data presented in Table 3, it is evident that the purification of PEG prior to copolymerization exerts a significant influence on the final polymer properties. Notably, the residual monomer content differs markedly between the two samples. The copolymer synthesized using non-purified PEG exhibited a residual lactide content exceeding 30 wt%, whereas the corresponding value for the purified PEG-based copolymer was substantially lower at 1 .02 wt%. A similar trend was observed for residual glycolide. In the purified sample (Example 2), the concentration was below the limit of quantification (LOQ), while in the non-purified counterpart (Comparative Example B), it reached 0.31 wt%.

[0105] Differences in inherent viscosity (IV) were also observed, with the purified PEG-based copolymer displaying a higher IV (0.34 dL / g) compared to the non-purified sample (0.22 dL / g), suggesting a higher molecular weight. These findings were corroborated by the Mw and Mn data obtained though GPC-RI analysis. The purified sample (Example 2) was readily soluble in THF and yielded a measurable molecular weight distribution, whereas the nonpurified sample (Comparative Example B) was insoluble under the same conditions, precluding GPC analysis. This insolubility may indicate a more heterogeneous microstructure, potentially due to phase-separated microdomains, in contrast to a more random copolymer architecture inferred for the purified sample. Thermal analysis further supported these observations. The glass transition temperature (Tg) of the non-purified sample was significantly lower, which can be attributed to the plasticizing effect of unreacted monomers present in higher concentrations.

[0106] Elemental analysis revealed reduced levels of inorganic impurities — specifically sodium (Na) and potassium (K) — in the copolymer derived from purified PEG. Visually, the difference in product appearance was also pronounced: the copolymer from non-purified PEG (Comparative Example B, figure 3a) exhibited a darker coloration relative to the lighter appearance of the purified counterpart (Example 2, Figure 3b). Finally, kinetic data (Figures 4a and 4b) demonstrated a markedly accelerated monomer conversion rate in the presence of purified PEG for both lactide and glycolide, suggesting enhanced reaction efficiency and improved control over the polymerization process.

[0107] Example 3 - synthesis of a PEG25oo(PDLi7oo)e 6-arm star copolymer

[0108] Two reactors were each charged with 59g (0.024 mol) of the purified 6-arm poly(ethylene glycol) star shaped polymer with a molecular weight of 2.5 kg / mol (Na < 0.16 ppm, K < 0.14 ppm). To investigate the impact of alkali, potassium acetate was added to one reaction (38 mg, 638 ppm; equaling 254 ppm K). The D,L-lactide (241g, 1.67 mol) was then added to each of the two PEG containing reactors. The system was put under vacuum (< 10 mbar) and placed in a pre-heated oil bath (85 °C) for two hours to dry the reactants whilst increasing the temperature to 100 oC.

[0109] After drying, the vacuum was released using nitrogen and the reactor vessels were kept under a nitrogen blanket. The oil bath was heated to 133 oC. Stirring was initiated (200 rpm) when the reactor had reached an internal temperature of 122 oC. At the dosing temperature of 130 °C a solution of a Sn-based catalyst was added via a 500 pL syringe (tin octoate, 50 ppm Sn by weight of polymer), marking time zero (t = 0). The stirring was adjusted to 150 rpm, the oil bath ramped to 143 oC and the reaction was allowed to proceed for an additional 4 hours. The stirring blades were then removed and both the polymer melts were collected by pouring them in appropriate plastic containers in which they were stored dry and cool (-20 oC) until further analysis.

[0110] The analytical results are provided in Table 4 below. Example 3 is derived from purified 6-arm star PEG (Na 0.16 ppm; K < 0.14 ppm). Comparative Example C is derived from purified 6-arm star PEG to which potassium acetate has been added (Na 0.16 ppm; K 254 ppm).

[0111] Table 4: Overview of Analytical data for from the PEG2500(PDL1700)66-arm star shaped PEG-PDL copolymers

[0112] Figure 5 shows photographs of the polymers obtained using purified stars-PEG to which potassium acetate had been added (Figure 5a) versus purified stars-PEG to which no potassium acetate had been added.

[0113] Figure 6 shows the lactide conversion over time for the polymer synthesis using purified star-PEG to which potassium acetate had been added (continuous line) to purified star-PEG to which no potassium lactate had been added (dotted line).

[0114] Based on the physicochemical data presented in Table 4, it is evident that the absence of alkali metal in the stars-PEG prior to copolymerization exerts a significant influence on the final polymer properties. Notably, the residual lactide monomer content differs markedly between the two samples. The residual lactide monomer content of the copolymer synthesized using stars-PEG containing potassium acetate exceeded 30 wt%, whereas the corresponding value for the copolymer based on purified stars-PEG was substantially lower at 3.47 wt%.

[0115] Differences in inherent viscosity (IV) were also observed, with the purified PEG-based copolymer displaying a higher IV (0.16 dL / g) compared to the sample based on stars-PEG to which potassium acetate had been added (0.0.08 dL / g), suggesting a higher molecular weight. These findings were corroborated by the Mn and Mw data obtained though GPC-RI analysis. The Tg is significantly higher in purified materials (61.5°C) than in the non-purified product (40.6°C), likely due to reduced residual monomer, which otherwise acts as a plasticizer.

[0116] Elemental analysis revealed reduced levels of inorganic impurities — specifically sodium (Na) and potassium (K) — in the copolymer derived from purified stars-PEG. Visually, the difference in product appearance was also pronounced: the copolymer from stars-PEG to which potassium acetate had been added (Comparative Example C, figure 5a) exhibited a darker coloration relative to the lighter appearance of the purified counterpart (Example 3, Figure 5b).

[0117] Finally, kinetic data (Figure 6) demonstrated a markedly accelerated monomer conversion rate in the presence of purified star-PEG, in comparison with purified star-PEG to which potassium acetate had been added. This suggests enhanced reaction efficiency and improved control over the polymerization process.

Claims

CLAIMS1. Process for manufacturing a block copolymer comprising a block of a poly- (C2-C4)-alkylether and at least one block of a bioresorbable polyester, comprising the steps of- providing a poly-(C2-C4)-alkylether having a total alkali content, calculated as the total of Na and K, of at most 50 ppm,- reacting said poly-(C2-C4)-alkylether with monomers of bioresorbable polyester, under polymerisation conditions in the presence of a polymerisation catalyst, to form a block copolymer comprising a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester.

2. Process according to any one of claims 1, wherein the poly-(C2-C4)-alkylether has a has a total alkali content, calculated as the total of Na and K, of at most 25 ppm, more in particular at most 15 ppm, even more in particular at most 10 ppm.

3. Process according to claim 1 or 2, wherein the poly-(C2-C4)-alkylether is selected from the group of polyethylene glycol, polypropylene glycol, and polyisopropylene glycol, in particular polyethylene glycol.

4. Process according to any one of claims 1-3, wherein the poly-(C2-C4)- alkylether is a linear polymer.

5. Process according to any one of claims 1-3, wherein the poly-(C2-C4)- alkylether is a non-linear polymer.

6. Process according to any one of claims 1-5, wherein the monomers of bioresorbable polyester are selected from the group of lactide, glycolide, caprolactone, trimethylene carbonate, dioxanone, and combinations thereof, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide.

7. Process according to any one of claims 1-6, wherein the poly-(C2-C4)- alkylether having a total alkali content, calculated as the total of Na and K, of at most 50 ppm, is obtained by subjecting a poly-(C2-C4)-alkylether to a step of reducing its total alkali content .

8. Process according to any one of claims 1-7 wherein the polymerisation catalyst is selected from the group of tin-based catalysts and zinc-based catalysts, in particular tin-based catalysts.

9. Block copolymer comprising a block of a poly-(C2-C4)-alkylether and at least one block of a bioresorbable polyester, wherein the block copolymer has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 25 ppm, still more in particular at most 15 ppm, even more in particular at most 10 ppm.

10. Block copolymer according to claim 9, which is obtainable by the process of any one of claims 1-8.

11. Block copolymer according to claim 9 or 10 which is a linear block copolymer comprising a polyethylene glycol block and one or two blocks of a bioresorbable polyester, wherein the polyethylene glycol block has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 20 ppm, and wherein the polyester is a polyester derived from monomers selected from the group of at least one of lactide, glycolide, and caprolactone, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide.

12. Block copolymer according to claim 9 or 10, which is a non-linearblock copolymer, in particular a star block copolymer having 3- 6 arms comprising a polyethylene glycol block and blocks of a bioresorbable polyester, wherein the polyethylene glycol block has a total alkali content, calculated as the total of Na and K, of at most 50 ppm, in particular at most 20 ppm, and wherein the polyester is a polyester derived from monomers selected from the group of at least one of lactide, glycolide, and caprolactone, in particular from the group of lactide, glycolide, and the combination of lactide and glycolide.

13. Use of the block copolymer according to any one of claims 9-12 in pharmaceutical applications.

14. Pharmaceutical composition comprising the block copolymer according to any one of claims 9-12 and a pharmaceutically active ingredient.

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