Purification of glycerol as excipient in parenteral pharmaceutical applications

Abstract

Disclosed is a method for purifying a bio-based glycerol feedstock, in particular but not limited to bio-based glycerol feedstocks that have not more than 10 parts by weight of aldehydes in total, to provide glycerol suitable for use in parenteral pharmaceutical compositions, the parenteral pharmaceutical composition comprises 5 parts per million or less of glyceraldehyde and 1 part per million or less of formaldehyde, based on the weight of glycerol in the composition, and further comprises at least one active pharmaceutical ingredient, if glyceraldehyde and formaldehyde are present in a higher concentration in the bio-based glycerol component of the composition, the active pharmaceutical ingredient will react with any one or both of glyceraldehyde and formaldehyde.

Description

Field of the Invention

[0001] The present invention relates to a process for purifying glycerol. Background of the Invention

[0003] It is well known that pharmaceutical ingredients have stringent purity requirements.Glycerol is a versatile material obtained from both plant and animal sources, as well as from propylene from petroleum resources, and is used in medical applications, personal care applications, and pharmaceutical applications.

[0004] Milek et al., U.S. Pat. No. 9,097,692, "Method for Quantitatively Determining Impurities in Glycerin," provides an illustration of these stringent purity requirements, relating to the fact that glycerol used in certain pharmaceutical compositions, such as, for example, polypeptides described in EP 1242121B1 (particularly certain insulins), must include less than 10 parts per million of aldehyde impurities according to the European Pharmacopoeia. Unfortunately, according to Milek et al., the method specified in the European Pharmacopoeia for determining compliance with this stringent purity standard is not actually able to reliably determine the true content of aldehydes and ketones in the supplier's glycerol, so that the quality of the finished drug may be negatively affected due to the reactivity of the same substances and the finished drug does not meet the aldehyde standard. Therefore, an alternative analytical method for determining compliance is described, more specifically, a "means that can better quantitatively determine as many and in particular all of the impurities in the form of aldehydes and ketones as possible," column 2, lines 6-8.

[0005] It is noteworthy, however, that Milek et al. do not provide a description of a purification method by which glycerol containing an aldehyde content exceeding the specified maximum permissible content, as determined by means of their analytical method, could then comply with the European Pharmacopoeia standards; nor do they describe how commercially available glycerol obtained from different sources - for example, from the hydrolysis of triglycerides on the one hand and from propylene from petroleum processing on the other hand - may differ in its impurities and therefore require different purification methods in order to be usable for this or that pharmaceutical application.

[0006] Overview

[0007] A simplified summary of the present invention is presented below in order to provide a basic understanding of some aspects thereof. This summary is not an extensive summary of the present invention and is neither intended to identify the key or essential elements of the present invention nor to describe its scope. The sole purpose of this summary is to present some concepts of the present invention in a simplified form as a prelude to a more detailed description presented later.

[0008] Based on this understanding, the present invention in one aspect relates to the purification of glycerol for use as an excipient in parenteral pharmaceutical compositions, and in particular the purification of biologically derived glycerol from the hydrolysis of triglycerides.

[0009] In another more specific aspect, the present invention is directed to the purification of glycerol containing 10 parts per million or less by weight total aldehydes such that the purified glycerol is characterized by a glyceraldehyde content of less than 5 parts per million by weight and a formaldehyde content of less than 1 part per million by weight.

[0010] In another aspect, the present invention is directed to a parenteral pharmaceutical composition comprising a bio-based glycerol component characterized by a glyceraldehyde content of less than 5 parts per million by weight and a formaldehyde content of less than 1 part per million by weight (of the glycerol component); and further comprising at least one active pharmaceutical ingredient that will react with either or both of glyceraldehyde and formaldehyde if these are present in higher concentrations in the bio-based glycerol component.

[0011] Incidentally and for ease of understanding, the singular forms "a", "an", and "the" as used in this application include plural referents unless the context clearly dictates otherwise. As used above and elsewhere herein, the term "comprising" and its derivatives are similarly intended to be open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. This understanding also applies to words with similar meanings, such as "including", "having", and their derivatives. As used herein, the term "consisting of" and its derivatives are intended to be closed terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. As used herein, the term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, as well as the presence of those that do not materially affect the basic and novel characteristics of the stated features, elements, components, groups, integers, and / or steps.

[0012] It should be noted that "biobased" as used herein means and refers to those materials whose carbon content is shown by ASTM D6866 as being derived in significant part (at least 20 percent or more) from or based on bioproducts or renewable agricultural materials (including but not limited to plant materials, animal materials, and marine materials) or forestry materials.

[0013] In this respect, ASTM method D6866, similar to radiocarbon dating, compares how much decay carbon isotopes are retained in a sample with how much would be retained in the same sample if the sample is made entirely of newly grown materials. This percentage is called the bio-based content of the product. The sample is burned in a quartz sample tube and the gaseous combustion products are transferred to a borosilicate rupture tube. In one method, liquid scintillation is used to calculate the relative amount of carbon isotopes in the carbon dioxide in these gaseous combustion products. In a second method, accelerator mass spectrometry is used to calculate (14C) and measure (13C / 12C)13C / 12C and 14C / 12C isotope ratios. Zero percent of 14C indicates that there is no 14C atom in the material, so the indication is a fossil (e.g., petroleum-based) carbon source. After correction for the explosive injection of 14C into the atmosphere after 1950, 100 percent of 14C indicates a modern carbon source. ASTM D6866 effectively distinguishes between bio-based materials and petroleum-derived materials, in part because isotope fractionation due to physiological processes (such as carbon dioxide transport within plants during photosynthesis) produces specific isotope ratios in natural or bio-based compounds. In contrast, the 13C / 12C carbon isotope ratios of petroleum and petroleum-derived products are different from the isotope ratios in natural or bio-derived compounds, due to the different chemical processes and isotope fractionation during the production of petroleum. In addition, the radioactive decay of the unstable 14C carbon radioisotope produces different isotope ratios in bio-based products compared to petroleum products.

[0014] A particular bio-based glycerol feedstock of interest is one that is currently obtained commercially by hydrolyzing triglycerides to separate the fatty acids from the glycerol backbone.

[0015] The aforementioned and other aspects, embodiments and associated advantages will become apparent from the following detailed description.

[0016] Detailed description of implementation plan

[0017] In a first aspect, the present invention relates to the purification of glycerol, and in particular bio-based glycerol from oilseed processing, to provide a material of the necessary purity for inclusion in a parenteral pharmaceutical composition together with one or more active pharmaceutical ingredients.

[0018] In certain embodiments, bio-based, commercially available glycerol, including but not limited to bio-based, commercially available glycerol that has met the purity requirements for total aldehydes according to the European Pharmacopoeia - that is, bio-based glycerol that has been determined as containing no more than 10 parts per million of aldehydes according to the provisions of the European Pharmacopoeia (according to the EP monograph that existed as of the time of filing of this application), is purified by the means described and exemplified below, such that the glyceraldehyde content of the pharmaceutical grade bio-based glycerol is reduced to less than 5 parts per million by weight, and the formaldehyde content of the glycerol is reduced to less than 1 part per million by weight.

[0019] In other more specific embodiments, bio-based glycerol determined according to the various analytical methods described by Milek et al. or by another analytical method or combination of methods to contain no more than the maximum specified amount of total aldehydes according to any relevant regulatory monograph is purified such that the glyceraldehyde content after the purification method is less than 5 parts per million by weight and the formaldehyde content is less than 1 part per million by weight. In this regard, as of the time of filing this application, only the European Pharmacopoeia contains a specification for aldehydes at 10 parts per million by weight or less of total aldehydes.

[0020] In one embodiment, a chemical alkali treatment is used to reduce the amount of glyceraldehyde and formaldehyde present in bio-based glycerol, even including (but not limited to) bio-based glycerol that already contains 10 parts per million by weight or less of total aldehydes, to below the specified limits of 5 parts per million by weight and 1 part per million by weight. Examples of suitable alkalis include sodium hydroxide, potassium hydroxide, and sodium borohydride, with sodium hydroxide being preferred. An exemplary process would involve mixing 1 percent by weight of sodium hydroxide with the glycerol to be treated and stirring with stirring, such as in a stirred tank reactor at 60 degrees Celsius and under reduced oxygen conditions (e.g., by applying a vacuum or purging with nitrogen to inhibit oxidation of absorbed water and aldehydes from ambient air) for from one to eight hours.

[0021] In another embodiment, molecular distillation or short path distillation is used, for example using wiped film evaporation. In a simple apparatus and method, glycerol is processed for further purification using a wiped film evaporator at 120 degrees Celsius and at a vacuum of 3 torr, using a recycle loop as needed to further reduce the aldehyde. In another apparatus and related method, the glycerol to be purified is fed to a packed column operated at 120 degrees Celsius and at a vacuum of 3 torr, where the aldehyde and some glycerol are taken off at the top of the column, and the bottom glycerol from the column containing the reduced aldehyde is processed in a finishing wiped film evaporator to provide the desired purified glycerol product.

[0022] In another embodiment, ion exchange chromatography is used.Preferred resins are generally weak base anion exchange resins with styrene structure, phenolic structure and macroporous structure.Particularly preferred commercially available examples include the Thermax Tulsion A-2X MP macroporous weak base anion exchange resin (Thermax Inc, Houston TX) with polystyrene copolymer matrix structure and tertiary amine functional groups, Lewatit VP OC 1065 macroporous divinylbenzene crosslinked polymers (Lanxess AG, Cologne, Germany) in the form of spherical beads with primary amine groups, and Purolite A133S macroporous polystyrene weak base anion resin (Purolite Corporation, King of Prussia, PA) crosslinked with divinylbenzene with tertiary amine functional groups The resin sold.We have also achieved success in non-functionalized resins, such as nonionic macroporous crosslinked divinylbenzene polymers, such as sold as Amberlite XAD-16N polymer adsorption resins by DuPont de Nemours, Inc.

[0023] In another embodiment, purification is achieved by contacting glycerol with activated carbon. Preferred carbon is those specifically exemplified below. The contact mode may involve preferably simply mixing powdered or granular activated carbon with the glycerol raw material to be purified, and continuously mixing for a period of time, and preferably mixing for example about 24 hours at an elevated temperature under reduced oxygen conditions, then cooling and filtering the glycerol / treatment carbon mixture to reclaim the desired reduced aldehyde glycerol product. Alternatively, the glycerol raw material can be processed continuously by one or more carbon beds or carbon towers in series, and the carbon bed or carbon tower contains / uses one or more treatment carbons.

[0024] In another embodiment, steam stripping or deodorization is used for purification. Applying from 1.8 to 5.8 percent by weight steam based on the weight of the glycerol feedstock thus treated under vacuum for a period of time, such as from two to four hours of contact time, would be an example of a suitable deodorization process.

[0025] In another embodiment, the bio-based glycerol is subjected to treatment with hydrogen in the presence of a catalyst to provide a purified glycerol having at least a reduced content of at least one aldehyde compared to the starting bio-based glycerol. In particular, it is contemplated that the purified bio-based glycerol has a reduced content of one or both of glyceraldehyde and formaldehyde.

[0026] In still other embodiments, a combination of two or more of these methods is employed, such as a combination of deodorization followed by carbon treatment.

[0027] The following examples are set forth as representative of the present invention. These examples are illustrative and are not to be construed as limiting the scope of the invention as defined in the appended claims.

[0028] Example 1-Example 5

[0029] A 10 g sample of glycerin containing 18.4 parts per million by weight of glyceraldehyde was placed in vials with varying amounts of 1 weight percent sodium hydroxide solution, and the vials were then capped and allowed to react at 60 degrees Celsius for the specified time, wherein the glyceraldehyde content after such time was measured in the same manner as the initial determination of the starting concentration, and wherein the results are reported in Table 1 below:

[0030] Table 1

[0031] Amount added Reaction time GA,ppm 20 μl 1 hour 16.4 20 μl 4.5 hours 12.7 20 μl 8 hours 12.2 12.5 μl 1 hour 18.2 12.5 μl 4.5 hours 15.2

[0032] Example 6-Example 10

[0033] 1 liter of glass round-bottom flask with heating mantle is provided with the overhead flask that comprises the connection of the water for steam generation and the vacuum pump for the connection that 1 liter of glass flask is evacuated, and is also provided with the condenser that is filled with dry ice to collect the aldehyde removed.200 grams of glycerine that initially contains the glyceraldehyde of 13.7ppm by weight and the formaldehyde of 1.04ppm by weight are placed in 1 liter of glass flask for each deodorization experiment, and are heated to 120 degrees Celsius or 130 degrees Celsius as indicated in table 2 below, and 3 tor absolute vacuums are applied, and by flask jet steam.After the specified time, stop applying of heating, vacuum and steam, and allow the content of flask to return to environment (room temperature) temperature and ambient pressure.Then remaining glyceraldehyde and formaldehyde in the glycerine of quantitative deodorization are compared with its initial concentration, and wherein result is shown in table 2 below, wherein " GA " is glyceraldehyde and " FA " is formaldehyde:

[0034] Table 2

[0035]

[0036]

[0037] Example 11-Example 24

[0038] Amounts of two different activated carbons were dried in an oven at 110-120 degrees Celsius overnight and then cooled to ambient temperature. The first carbon studied was a low ash (<5 wt%), minimum 900 mg / g iodine value coconut-based carbon - OLC 12x30 ("OLC" in the table below) from Calgon Carbon Corporation, Pittsburgh, PA, while the second carbon, PICACTIF Medicinal EP 40 ("EP 40" in the table below) from Jacobi Carbons AB, Kalmar, Sweden, was also a low ash, coconut-based steam activated carbon characterized as having a particle size between 8 and 35 microns and further characterized by its manufacturer as conforming to both the United States Pharmacopoeia and the European Pharmacopoeia. Different amounts of each dried carbon were combined with 30 grams of untreated glycerol characterized for initial glyceraldehyde and formaldehyde content in a series of 50 mL centrifuge tubes, the tubes were sealed and incubated at 40 degrees Celsius with mixing in a rotating rack for 24 hours. The carbon was then recovered from each such centrifuge tube by filtration, and the recovered treated glycerol was then analyzed for the remaining glyceraldehyde and formaldehyde content. The results are shown in Table 3 below.

[0039] Table 3

[0040]

[0041]

[0042] Example 25 and Example 26

[0043] Catalytic hydrogenation was evaluated using a stainless steel, 30 cubic centimeter volume tubular reactor with an inner diameter of 0.61 inches as a means for reducing the content of at least some aldehydes in commercially available bio-based glycerol. The reactor was jacketed and heated with circulating oil. The reactor temperature was monitored via an internal thermocouple. The inlet of the reactor was attached to an Isco double piston pump and a mass flow controller for supply gas. The reactor outlet was attached to a condenser maintained at 5 degrees Celsius by a chiller unit.

[0044] A catalyst comprising 2% by weight ruthenium supported on activated carbon powder and 1% by weight palladium supported on activated carbon powder was evaluated for effectiveness in reducing the levels of various impurities observed in glycerol at the reactor temperatures and reaction times set forth below, using a hydrogen flow rate of 0.4 mL / min and a pressure of 1800 psig (unless otherwise indicated in Table 4 below) and at an LHSV of 1:

[0045] Table 4

[0046]

[0047]

[0048] *Starting glycerol feed

[0049] Example 27 to Example 34

[0050] A 1 liter glass round bottom flask with a heating mantle was provided with a connected overhead flask containing water for steam generation and a connected vacuum pump for evacuating the 1 liter glass flask, and also provided with a condenser filled with dry ice to collect removed impurities from different batches of bio-based glycerol containing different concentrations of both aldehydes and ketones (which interact in a similar manner to aldehydes in the case of parenteral grade glycerol products).

[0051] For these examples, from 900 to 1000 grams of bio-based glycerol initially containing up to 29.0 ppm by weight of glyceraldehyde, up to 0.73 ppm by weight of formaldehyde, up to 4.88 ppm by weight of hydroxyacetone, and up to 21.8 ppm by weight of dihydroxyacetone was placed in a 1-liter glass flask for each deodorization experiment and heated to 130 degrees Celsius as indicated in Table 5 below, and 3 torr absolute vacuum was applied, and steam was sparged through the flask. After the specified time, the application of heating, vacuum, and steam was stopped, and the contents of the flask were allowed to return to ambient (room temperature) temperature and ambient pressure. The remaining glyceraldehyde, formaldehyde, hydroxyacetone, and dihydroxyacetone in the deodorized glycerol were then quantitatively compared with their initial concentrations, wherein the results are shown in Table 5 below, wherein "GA" is glyceraldehyde, "FA" is formaldehyde, "HA" is hydroxyacetone, and "DHA" is dihydroxyacetone:

[0052] Table 5

[0053]

[0054]

Claims

1. A process for providing bio-based glycerol suitable for use in a parenteral pharmaceutical composition comprising one or more active pharmaceutical ingredients, the process comprising: include: Providing bio-based glycerol raw materials; as well as One or more purification methods selected from the group consisting of chemical alkali treatment, catalytic hydrogenation, molecular distillation, ion exchange chromatography, deodorization, and treatment with activated carbon are applied to the glycerol raw material to produce a purified glycerol product containing 5 parts per million or less of glyceraldehyde and 1 part per million or less of formaldehyde.

2. The process of claim 1 wherein the bio-based glycerol feedstock is characterized by a total aldehyde content of no more than 10 parts per million by weight.

3. A process according to claim 1 or claim 2, wherein a combination of deodorization and treatment with activated carbon is employed.

4. A parenteral pharmaceutical composition comprising a bio-based glycerol component characterized by a glyceraldehyde content of less than 5 parts per million by weight and a formaldehyde content of less than 1 part per million by weight on the same basis, and further comprising at least one active pharmaceutical ingredient that will react with either or both of glyceraldehyde and formaldehyde if these are present in higher concentrations in the bio-based glycerol component.

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