Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same

a technology of allosteric hemoglobin and modifier, which is applied in the field of compositions of allosteric hemoglobin modifier compounds, can solve the problems of high exothermicity, inability to easily adapt to the environment, and difficulty in generating pharmaceutical grade compositions, so as to improve the sensitivity, improve the method sensitivity, and maintain precision and accuracy

Inactive Publication Date: 2007-12-20
ALLOS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031] Finally the present invention includes a method for analyzing compositions of allosteric hemoglobin modifying compounds for impurities, particularly polymeric impurities and more particularly PEM. In this embodiment of the invention, the method for analyzing compositions of allosteric hemoglobin modifier compounds is comprised of the steps of a) pyrolyzing (PY) a composition comprised of an allosteric hemoglobin modifier compound and b) analyzing said pyrolyzed composition by gas chromatography / mass spectrometry (GC / MS). In order to improve the sensitivity of the method by the two orders of magnitude needed to measure trace amounts of polymeric impurity an isotopic internal standard is added to the sample prior to analysis. It is believed that this is the first report of the use of an internal standard, particularly an isotopic internal standard prior to analysis by PY / GC / MS for trace level analysis of polymers in drugs. The internal standard is added in an amount so as to produce a concentration approximately the same as that expected for the polymeric impurity in the compound being analyzed, which in the instant application is endogenous PEM. As noted above, the use of an internal standard, particularly an isotopic internal standard greatly improves the sensitivity while maintaining precision and accuracy in the analytical method making quantitative measurements in the 10-100 ppm range possible. Isotopes of any atom can be used including, but not limited to isotopes of hydrogen, carbon, oxygen and nitrogen. Examples of such isotopes include, but are not limited to deuterium (D), carbon 13 (3C), oxygen 18 (18O) and nitrogen (15N). The method described herein can be extended to the identification and quantification of any compound amenable to analysis by PY / GC / MS.

Problems solved by technology

Process A is highly exothermic, not easily amenable to commercial scale manufacture and uses a halogenated hydrocarbon solvent.
The primary drawback of Process B, however, is the unexpected generation of the polymeric impurity poly (ethyl methacrylate) and precursors to this compound, which are referred to herein collectively as PEM, which is formed in Step 2 via the following mechanism.
Despite the general utility and importance of these compounds in treating disease, problems remain in generating pharmaceutical grade compositions.
In the process of testing these compounds, difficulty with the drug product manufacturing (IV solution formation) has been traced to the PEM byproduct generated during their synthesis as outlined above.
Another problem associated with the prior art methods is that there is currently no effective way to measure the low levels of impurities capable of causing failure in the IV solutions prepared from compositions, which are comprised of these compounds.
As noted above, a particularly undesirable impurity is PEM.
Prior art methods for measuring PEM are deficient in several respects, particularly in that they are unable to detect very low levels of PEM.
For analysis of highly pure compositions of allosteric hemoglobin modifiers however, none of the prior art techniques can be used because the limit of detection is not low enough.

Method used

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  • Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same
  • Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same
  • Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 2-[4-((((3 5-dimethylphenyl)amino)carbonyl)methyl)phenoxy]-2-methyl propionic acid

[0094]FIG. 3 illustrates a general five step reaction scheme for the preparation of 2-[4-((((3,5-dimethylphenyl)amino)carbonyl)methyl)phenoxy]-2-methyl propionic acid which is described in detail below.

Synthesis of Amidophenol (3)

[0095] With reference to FIG. 3, 4-hydroxyphenylacetic acid (2001 kg) (2) was added to xylene (760 L) with stirring. To this mixture, 3,5-xylidine (3,5-dimethyl aniline) (178 L) (1) was added. The reaction mixture was heated to reflux and water was removed azeotropically as the reaction proceeded. Upon completion, the reaction mixture was distilled to provide amidophenol (3), which solidified upon cooling. To recrystallize, ethanol (1180 L) and methyl isobutyl ketone (MIBK) (56 L) were added to the solid and the mixture was refluxed until dissolution. Upon dissolution water was added (70° C., 490 L) and mixture was stirred and cooled slowly over 6 hours to ab...

example 2

Purification of Efaproxiral Sodium (5) by Extraction with MIBK

[0098] Purified water (1658 L) was added to the product (5) (325 kg) obtained using the method described in Example 1. The mixture was distilled under vacuum at a maximum temperature of 50° C. until about 423 L of solvent was removed. Another 423 L of purified water was then added and the aqueous solution was extracted with MIBK (390 L, below 30° C.). The organic phase was discarded, the aqueous phase was extracted again with MIBK (228 L, below 30° C.) and the organic phase was discarded.

example 3

Purification of Efaproxiral Sodium (5) by Recrystallization with Acetone / Ethanol

[0099] The sodium salt of efaproxiral (5) synthesized as described in Examples 1 and 2 in the aqueous solution was concentrated under vacuum at a maximum temperature of 50° C. to the maximum extraction of solvent, after which absolute ethanol (406 L) was added to provide a mixture having a water content of between 5 and 5.4%. The mixture was then cooled to about 47° C., acetone (975 L) was added and the mixture was stirred while maintaining the temperature. After crystallization, the mixture was stirred for at least one hour, after which an equal volume of acetone was added. The mixture was then slowly cooled to a temperature of about 15° C. and stirred for at least 5 hours. The crystals were collected on a filter and washed with acetone (146 L).

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Abstract

The present invention provides novel compositions of allosteric hemoglobin modifiers which are substantially free of impurities, specifically polymeric impurities. In one embodiment, the novel compositions contain an allosteric hemoglobin modifier compound and less than 100 ppm of the polymeric impurities generated during the preparation of this compound. Included in the present invention are novel methods for preparing allosteric hemoglobin modifiers that are substantially free of polymeric impurities. Also included in the present invention are improved methods for the purification of the product formed by the method of this invention. The novel methods of purification comprise extracting the crude composition with a water immiscible or partially immiscible solvent such as methylisobutyl ketone (MIBK) to lower amounts of impurities, specifically polymeric impurities. Also included are methods to reduce impurities by recrystallization of the crude synthesized product, followed by filtration of the recrystallized product. The present invention also includes the products made by the processes of the invention and methods for analyzing compositions comprised of these products.

Description

FIELD OF THE INVENTION [0001] The present invention relates to compositions of allosteric hemoglobin modifier compounds having low levels of impurities. The invention also relates to novel methods of preparing such compositions. Included in the present invention are improved methods for the purification of compositions of allosteric hemoglobin modifier compounds. Also included in the present invention is a method for analyzing compositions of allosteric hemoglobin modifier compounds, which enables detection and quantification of impurities. BACKGROUND OF THE INVENTION [0002] Hemoglobin is a tetrameric protein which delivers oxygen via an allosteric mechanism. There are four binding sites for oxygen on the hemoglobin molecule, as each protein chain contains one heme group. Each heme group contains a substituted porphyrin and a central iron atom. The iron atom in heme can be in the ferrous (+2) or ferric (+3) state, but only the ferrous form binds oxygen. The ferrous-oxygen bond is re...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C233/01C07C231/00G01N30/00C07C233/00A61K31/195
CPCA61K31/195
Inventor QUICK, ALSANTOS, ANTONIO M.CARVALHO, ALEXANDRE J.G. G.JOHNSON, DOUGLAS G.ETTER, JEFFREY B.MURRAY, CHRIS
Owner ALLOS THERAPEUTICS
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