Purification of glycerin as an excipient in parenteral pharmaceutical applications

Abstract

Disclosed is a method for purifying a bio-based glycerin feedstock, particularly, but not limited to, a bio-based glycerin feedstock already containing 10 ppm or less by weight of total aldehydes, to provide glycerin suitable for use in parenteral pharmaceutical compositions containing 5 ppm or less of glyceraldehyde and 1 ppm or less of formaldehyde based on the weight of glycerin in the composition, and further containing at least one active ingredient that may react with either or both of glyceraldehyde and formaldehyde when they are present at higher concentrations in the bio-based glycerin component of the composition.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a method for purifying glycerin. [Background technology]

[0002] Background of the Invention It is well known that pharmaceutical ingredients have stringent purity requirements. Glycerin is a versatile material obtained from both plant and animal sources, as well as from petroleum-derived propylene, and is used in medical, personal care, and pharmaceutical applications.

[0003] U.S. Patent No. 9,097,692, Milek et al., "Method for Quantitatively Determining Impurities in Glycerin," explains these stringent purity requirements, explaining that glycerin used in certain pharmaceutical compositions, such as polypeptides (particularly certain insulins) described in EP 1242121 B1, must contain less than 10 ppm of aldehyde impurities in accordance with the European Pharmacopoeia. Unfortunately, Milek et al. argue that the method prescribed in the European Pharmacopoeia for verifying compliance with this stringent purity standard cannot reliably measure the true aldehyde and ketone content of the source glycerin, which could adversely affect the final drug product due to the reactivity of these same chemical species, rendering the final drug product non-compliant with the aldehyde standard. Therefore, an alternative analytical method for verifying compliance is described in column 2, lines 6-8, specifically to provide "a more accurate means of quantitatively determining as many impurities in the form of aldehydes and ketones as possible, particularly in total."

[0004] Notably, however, Milek et al. do not describe methods for purifying glycerin, whose aldehyde content, as determined by their analytical method, exceeds the specified maximum allowable value, to conform to European Pharmacopoeia standards, nor do they describe the possibility that commercially available glycerin obtained from different sources (e.g., that obtained from the hydrolysis of triglycerides and that obtained from propylene obtained from petroleum processing) may differ in impurities and therefore require different purification methods to be useful for various pharmaceutical applications. Summary of the Invention [Means for solving the problem]

[0005] overview The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention and is not intended to identify key or critical elements of the invention or to delineate its scope. Its sole purpose is to present some concepts of the invention in a simplified form as a prelude to the more detailed description that is presented later.

[0006] With this understanding, the present invention relates in one aspect to the purification of glycerin, particularly biologically derived glycerin from the hydrolysis of triglycerides, for use as an excipient in parenteral pharmaceutical compositions.

[0007] In another, more particular aspect, the present invention relates to the purification of glycerin containing 10 ppm or less by weight of total aldehydes, whereby the purified glycerin is characterized by a glyceraldehyde content of less than 5 ppm by weight and a formaldehyde content of less than 1 ppm by weight.

[0008] In another aspect, the present invention relates to a parenteral pharmaceutical composition comprising a bio-based glycerin component characterized by a glyceraldehyde content of less than 5 ppm by weight (of the glycerin component) and a formaldehyde content of less than 1 ppm by weight, and further comprising at least one active ingredient that would react with either or both of glyceraldehyde and formaldehyde if they were present at higher concentrations in the bio-based glycerin component.

[0009] For completeness and ease of understanding, when used in this application, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. The terms "comprising," and their derivatives, as used above and elsewhere herein, 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 of similar meaning, such as "including," "having," and their derivatives. The term "consisting," and its derivatives, as used herein, 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. The term "consisting essentially of," as used herein, is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, as well as the presence of things that do not materially affect the basic and novel characteristics of the stated features, elements, components, groups, integers, and / or steps.

[0010] It should be noted that "bio-based" as used herein means and refers to materials whose carbon content is derived in significant part (at least 20% or more) from or based on biological products or renewable agricultural materials (including but not limited to plants, animals, and marine materials) or forestry materials as indicated by ASTM D6866.

[0011] In this respect, ASTM Method D6866 is similar to radiocarbon dating, comparing the amount of decaying carbon isotope remnants in a sample to the amount of carbon isotopes that would be present in the same sample if it were made entirely from recently grown material. This ratio is called the product's biobased content. The sample is combusted in a quartz sample tube, and the gaseous combustion products are transferred to a borosilicate break-seal tube. In one method, liquid scintillation is used to count the relative amounts of carbon isotopes in the carbon dioxide in the gaseous combustion products. In a second method, an accelerator mass spectrometer is used to count (14C) and measure (13C / 12C) the isotope ratios of 13C / 12C and 14C / 12C. Zero percent 14C indicates the complete absence of 14C atoms in the material and thus indicates a fossil (e.g., petroleum-based) carbon source. After correcting for the injection of 14C into the atmosphere by bombs since 1950, 0% 14C indicates a modern carbon source. ASTM D6866 effectively distinguishes between biobased and petroleum-derived materials, in part because isotopic fractionation due to physiological processes, such as carbon dioxide transport in plants during photosynthesis, results in specific isotopic ratios in natural or biobased compounds. In contrast, the 13C / 12C carbon isotope ratios of petroleum and petroleum-derived products differ from those of natural or biologically derived compounds due to differences in the chemical processes and isotopic fractionation involved in petroleum production. Furthermore, the isotopic ratios of biobased products differ from those of petroleum-derived products due to the radioactive decay of the unstable 14C carbon radioisotope.

[0012] Bio-based glycerin feedstocks of particular interest are those currently commercially obtained by hydrolyzing triglycerides to separate the fatty acids from the glycerin backbone.

[0013] These and other aspects, embodiments, and associated advantages will become apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of the Embodiments In a first aspect, the present invention relates to the purification of glycerin, particularly bio-based glycerin from oil seed processing, to provide material of the necessary purity for inclusion in parenteral pharmaceutical compositions with one or more active ingredients.

[0015] In certain embodiments, commercially available bio-based glycerin that already meets purity requirements for total aldehydes according to the European Pharmacopoeia, i.e., including but not limited to bio-based glycerin determined as defined in the European Pharmacopoeia to contain 10 ppm or less aldehydes (based on the EP monographs in effect at the time of filing of the immediate application), is purified by the means described and exemplified below such that the glyceraldehyde content of the pharmaceutical-grade bio-based glycerin is reduced to less than 5 ppm by weight and the formaldehyde content of the glycerin is reduced to less than 1 ppm by weight.

[0016] In other more specific embodiments, bio-based glycerin determined to be at or below the maximum specified content of total aldehydes according to any relevant regulatory monograph, according to the different analytical methods described by Milek et al., or by another analytical method or combination of methods, is purified such that after the purification method it contains less than 5 ppm glyceraldehyde and less than 1 ppm formaldehyde. In this regard, as of the filing date of the immediate application, only the European Pharmacopoeia specifies a total aldehyde content of 10 ppm or less by weight.

[0017] In one embodiment, a chemical base treatment is used to reduce the amount of glyceraldehyde and formaldehyde present in bio-based glycerin, including but not limited to bio-based glycerin already containing 10 ppm or less total aldehydes by weight, to below the specified limits of 5 ppm and 1 ppm by weight. Examples of suitable bases include sodium hydroxide, potassium hydroxide, and sodium borohydride, with sodium hydroxide being preferred. An exemplary process may include combining 1% by weight of sodium hydroxide with the glycerin to be treated and stirring, for example, in a stirred-tank reactor for 1-8 hours at 60°C under reduced oxygen conditions (e.g., by applying a vacuum or with a nitrogen purge to suppress water uptake from ambient air and oxidation of aldehydes).

[0018] In another embodiment, molecular distillation or short-path distillation, for example, using wiped film evaporation, is used. In one simple apparatus and process, a wiped film evaporator is used to treat the further purified glycerin at 120° C. and 3 Torr vacuum, with an optional recycle loop to further reduce aldehydes. In another apparatus and associated process, the purified glycerin is fed to a packed column operating at 120° C. and 3 Torr vacuum, with the aldehydes and some of the glycerin taken overhead, while the bottoms glycerin from the column containing the reduced aldehydes is treated in a polishing wiped film evaporator to provide the desired purified glycerin product.

[0019] In another embodiment, ion exchange chromatography is used. Preferred resins are generally weakly basic anion exchange resins with styrenic, phenolic, and macroporous structures. Particularly preferred commercially available examples include Thermax Tulsion A-2X MP macroporous weakly basic anion exchange resin with a polystyrene copolymer matrix structure and tertiary amine functional groups (Thermax Inc., Houston TX), Lewatit VP OC 1065 macroporous, spherical beaded, divinylbenzene crosslinked polymer with primary amine groups (Lanxess AG, Cologne, Germany), and Purolite A133S microporous polystyrene crosslinked with divinylbenzene with tertiary amine functional groups, weakly basic anion resin (Purolite Corporation, King of Prussia, PA). We have also had success with non-functionalized resins, such as non-ionic, macroporous cross-linked divinylbenzene polymers, such as those sold by DuPont de Nemours, Inc. as Amberlite XAD-16N polymeric adsorption resin.

[0020] In another embodiment, purification is accomplished by contacting the glycerin with activated carbon. Preferred carbons are specifically exemplified below. The contacting procedure may preferably simply involve combining powdered or granular activated carbon with the glycerin feedstock to be purified under reduced oxygen conditions at an elevated temperature with continuous mixing for a period of time, preferably, for example, about 24 hours, followed by cooling and filtering the glycerin / treated carbon mixture to recover the desired reduced-aldehyde glycerin product. Alternatively, the glycerin feedstock may be continuously processed through one or more carbon beds or columns in series containing / using one or more treated carbons.

[0021] In another embodiment, steam stripping or deodorization is used to effect purification. The application of 1.8% to 5.8% by weight of steam, based on the weight of the glycerin feedstock being treated therewith, under vacuum for a period of time, e.g., a contact time of 2 to 4 hours, would be an example of a suitable deodorization process.

[0022] In another embodiment, the bio-based glycerin is subjected to treatment with hydrogen in the presence of a catalyst to provide a purified glycerin having at least a reduced content of at least one aldehyde compared to the starting bio-based glycerin. Specifically contemplated is a purified bio-based glycerin having a reduced content of one or both of glyceraldehyde and formaldehyde.

[0023] In still other embodiments, a combination of two or more of these methods is employed, for example, a combination of deodorization followed by a carbon treatment.

[0024] The following examples are presented as representative of the present invention, and are intended to be illustrative and are not to be construed as limiting the scope of the invention, which is defined in the appended claims. [Example]

[0025] Examples 1 to 5 Ten gram samples of glycerin containing 18.4 ppm by weight of glyceraldehyde were placed in vials with various amounts of 1% by weight sodium hydroxide solution, capped, and allowed to react at 60°C for the specified times, after which time the glyceraldehyde content was measured in the same way as the starting concentration was originally measured, and the results are reported below in Table 1:

[0026] [Table 1]

[0027] Examples 6 to 10 A 1-liter glass round-bottom flask equipped with a heating mantle was connected to a pressure-boosting flask containing water for steam generation. A vacuum pump was connected to evacuate the 1-liter glass flask, and a condenser containing dry ice was used to collect the removed aldehydes. For each deodorization experiment, 200 g of glycerin, initially containing 13.7 ppm glyceraldehyde and 1.04 ppm formaldehyde by weight, was placed in a 1-liter glass flask and heated to 120°C or 130°C, as shown in Table 2 below. A vacuum of 3 Torr (absolute) was applied, and steam was sparged into the flask. After the designated time, the heating, vacuum, and steam application were discontinued, and the contents of the flask were allowed to return to ambient temperature and pressure. The remaining glyceraldehyde and formaldehyde in the deodorized glycerin were quantified and compared to the initial concentrations. The results are shown in Table 2 below, where "GA" is glyceraldehyde and "FA" is formaldehyde:

[0028] [Table 2]

[0029] Examples 11 to 24 Two quantities of activated carbon were dried overnight in an oven at 110-120°C and then cooled to ambient temperature. The first carbon investigated was a low-ash (less than 5% by weight), coconut-based carbon with an iodine value of 900 mg / g minimum—OLC 12x30 ("OLC" in the tables below) from Calgon Carbon Corporation (Pittsburgh, PA), while the second carbon, PICACTIF Medicinal EP 40 ("EP 40" in the tables below) from Jacobi Carbons AB (Kalmar, Sweden), is also a low-ash, coconut-based steam-activated carbon characterized by a particle size of 8-35 micrometers and further characterized by the manufacturer as conforming to the United States Pharmacopoeia and the European Pharmacopoeia. Varying amounts of each dried carbon were combined with 30 g of untreated glycerin characterized for starting glyceraldehyde and formaldehyde content and placed into a series of 50 mL centrifuge tubes, which were sealed and incubated at 40° C. for 24 hours with mixing on a rotating rack. The carbon was then recovered from each centrifuge tube by filtration, and the recovered treated glycerin was analyzed for residual glyceraldehyde and formaldehyde content. The results are shown in Table 3 below:

[0030] [Table 3]

[0031] Examples 25 and 26 A 30 cubic centimeter stainless steel tubular reactor with an internal diameter of 0.61 inches was used to evaluate catalytic hydrogenation as a means to reduce at least certain aldehyde content in commercially available bio-based glycerin. The reactor was jacketed and heated with circulating oil. The reactor temperature was monitored with an internal thermocouple. The reactor inlet was attached to an Isco dual piston pump and mass flow controller for gas supply. The reactor outlet was attached to a condenser maintained at 5°C by a chiller unit.

[0032] A catalyst containing 2 wt. % ruthenium on activated carbon powder and a catalyst containing 1 wt. % palladium on activated carbon powder were evaluated for their effectiveness in reducing the observed content of various impurities in glycerin using a hydrogen flow rate of 0.4 mL / min, a pressure of 1800 psig (unless otherwise noted in Table 4 below), an LHSV of 1, and reactor temperatures and reaction times as follows:

[0033] [Table 4]

[0034] Examples 27 to 34 A 1-liter glass round-bottom flask equipped with a heating mantle was connected to a pressure-boosting flask containing water for steam generation, and a vacuum pump was connected to draw a vacuum on the 1-liter glass flask. A condenser filled with dry ice was also used to collect impurities removed from various lots of bio-based glycerin containing different concentrations of both aldehydes and ketones (which interact in a similar manner to aldehydes in parenteral-grade glycerin products).

[0035] In these examples, 900 to 1,000 grams of bio-based glycerin 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 initially placed in a 1-liter glass flask for each deodorization experiment, heated to 130°C as shown in Table 5 below, a vacuum of 3 Torr (absolute) was applied, and steam was sparged into the flask. After the designated time, the heating, vacuum, and steam application were discontinued, and the flask contents were allowed to return to ambient temperature and pressure. The remaining glyceraldehyde, formaldehyde, hydroxyacetone, and dihydroxyacetone in the deodorized glycerin were then quantified and compared to the initial concentrations. The results are shown in Table 5 below, where "GA" is glyceraldehyde, "FA" is formaldehyde, "HA" is hydroxyacetone, and "DHA" is dihydroxyacetone:

[0036]

Table 5

Claims

1. providing a bio-based glycerin feedstock; and applying one or more purification methods selected from the group consisting of chemical base treatment, catalytic hydrogenation, molecular distillation, ion exchange chromatography, deodorization, and treatment with activated carbon to the glycerin feedstock to produce a purified glycerin product containing 5 ppm or less of glyceraldehyde and 1 ppm or less of formaldehyde; 1. A process for providing a bio-based glycerin suitable for use in a parenteral pharmaceutical composition containing one or more active ingredients, comprising:

2. 10. The process of claim 1, wherein the bio-based glycerin feedstock is characterized by a total aldehyde content of 10 ppm by weight or less.

3. 3. The process of claim 1 or 2, which employs a combination of deodorization and treatment with activated carbon.

4. 1. A parenteral pharmaceutical composition comprising a bio-based glycerin component characterized by a glyceraldehyde content of less than 5 ppm by weight of the glycerin component and a formaldehyde content of less than 1 ppm by weight on the same basis, and further comprising at least one active ingredient that may react with either or both of glyceraldehyde and formaldehyde when they are present at higher concentrations in the bio-based glycerin component.

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