HK1151743A

HK1151743A - Process for recovering flunixin from pharmaceutical compositions

Info

Publication number: HK1151743A
Application number: HK11106016.4A
Authority: HK
Inventors: J‧C‧陶森; D‧科韦内
Original assignee: 英特威国际有限公司
Priority date: 2007-12-14
Filing date: 2008-12-12
Publication date: 2012-02-10

Description

Process for recovering flunixin from pharmaceutical compositions

Technical Field

The present invention relates generally to a novel process for recovering flunixin and flunixin analogs from pharmaceutical compositions.

Background

Flunixin is a nonsteroidal anti-inflammatory drug (NSAID) and a cyclooxygenase inhibitor.

Formula I

Flunixin is an effective analgesic, antipyretic and anti-inflammatory agent for veterinary use. Flunixin is 2- (2-methyl-3-trifluoromethylanilino) nicotinic acid or 2- [ [ 2-methyl-3- (trifluoromethyl) phenyl ] amino ] pyridine-3-carboxylic acid.

FlunixinMeglumine is the active pharmaceutical ingredient in a number of pharmaceutical products. Pharmaceutical products containing flunixin are, for exampleSolution, Banamine paste, Banamine granules,(both from Intervet/Schering Plough animal health).

Because flunixin is an expensive active pharmaceutical ingredient, there is a need for a method of recovering flunixin from a pharmaceutical product that is a manufacturing tail, an unacceptable or expired batch, or a pharmaceutical product that is otherwise unavailable for technical, quality, manufacturing, or other reasons. In some embodiments, the recovered flunixin is reused to prepare a new pharmaceutical product. This reduces the need for (and thus the costs associated with) destruction of unused flunixin-containing pharmaceutical products, while enabling the otherwise unused flunixin to be utilized.

In addition to the economic benefits provided by the present invention, there are also environmental benefits. Pharmaceutical waste (e.g., human or veterinary drug waste) containing unacceptable, expired or unutilized batches of flunixin or flunixin analogs may, after treatment, enter water supplies such as streams, oceans and groundwater contaminated with drainage systems. The present invention provides a method of reusing flunixin or a flunixin analog, which is generally disposed as a pharmaceutical waste, whereby it is possible to reduce contamination of a water supply.

In some embodiments, the present invention provides an efficient and economical process for recovering flunixin or flunixin analogs from pharmaceutical products.

Summary of The Invention

The present invention aims to provide a process for recovering flunixin or flunixin analogs from unused pharmaceutical compositions.

In some embodiments, the present invention relates to a method of recovering flunixin or a flunixin analog from a pharmaceutical composition, the method comprising:

obtaining a pharmaceutical composition comprising flunixin or a flunixin analog and at least one auxiliary substance; and

the flunixin or flunixin analog is recovered from the pharmaceutical composition by preferential dissolution.

In some embodiments, the present invention relates to a method of making a pharmaceutical dosage form comprising:

obtaining a pharmaceutical composition comprising flunixin or a flunixin analog and at least one auxiliary substance;

recovering flunixin or a flunixin analog from the pharmaceutical composition by preferential dissolution; and

the recovered flunixin or flunixin analog is formulated into a pharmaceutical dosage form comprising flunixin or a flunixin analog and at least one auxiliary substance.

In some embodiments, the present invention relates to a method of purifying flunixin or a flunixin analog, the method comprising:

the flunixin or flunixin analog is purified to a purity of at least about 90%, at least about 95%, at least about 97%, or at least about 99%.

In some embodiments, the purified recovered flunixin or flunixin analog is reformulated into a new dosage form.

recovering the flunixin or flunixin analog from the pharmaceutical composition by chromatography.

recovering flunixin or a flunixin analog from the pharmaceutical composition by chromatography; and

In some embodiments, recovering the flunixin or flunixin analog comprises preferentially dissolving the flunixin or flunixin analog relative to dissolving the at least one auxiliary substance.

In some embodiments, recovering the flunixin or flunixin analog comprises preferentially dissolving the at least one auxiliary substance relative to the flunixin or flunixin analog.

In some embodiments, recovering the flunixin or flunixin analog comprises partitioning the at least one auxiliary substance in a first solvent and the flunixin or flunixin analog in a second solvent.

In some embodiments, the present invention relates to a method of conducting a pharmaceutical business comprising providing a stimulus to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form.

In other embodiments, the invention relates to a method of conducting a pharmaceutical business, the method comprising:

obtaining an unused portion of the pharmaceutical dosage form from a patient or healthcare provider; and

recovering the active pharmaceutical ingredient from the unused portion of the pharmaceutical dosage form.

In some embodiments, the present invention relates to a method of conducting a pharmaceutical business, the method comprising:

preparing a pharmaceutical dosage form comprising an active pharmaceutical ingredient and at least one auxiliary substance;

dispensing the pharmaceutical dosage form to a patient or healthcare provider;

In some embodiments of the methods relating to conducting the pharmaceutical business disclosed above, if not otherwise disclosed, an incentive (e.g., payment or discount) is provided (e.g., to the patient or healthcare provider) to obtain the unused portion of the pharmaceutical dosage form.

In some embodiments, the present invention relates to a method of preventing contamination of an environment (e.g., water supplies and landfills), the method comprising:

providing a stimulus to the patient or healthcare provider to return the unused portion of the pharmaceutical dosage form; and

the unused portion of the pharmaceutical dosage form is obtained from the patient or healthcare provider.

In this way, the pharmaceutical dosage form is generally disposed of in this manner: the active pharmaceutical ingredient may eventually contaminate the water supply or else the environment (e.g. in a landfill).

In some embodiments, the present invention relates to a method of recovering a compound of formula II (or a pharmaceutically acceptable salt thereof) from a pharmaceutical composition by preferentially dissolving an auxiliary substance (e.g., a pharmaceutically acceptable excipient or an active pharmaceutical ingredient other than a compound of formula II) relative to the active pharmaceutical ingredient.

The compound of formula II has the following structure:

formula II

Wherein:

R₁is carbon, nitrogen, oxygen, sulfur or phosphorus;

R₂is hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, benzyl, phenyl or phenylalkyl, wherein the phenyl ring may be substituted by one or two halogens, C_1-6Alkyl or C_1-6Alkoxy substitution;

R₃and R₄Is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Dihaloalkyl radical, C_1-6Trihaloalkyl, CH₂Cl、CHCl₂、CCl₃、CH₂Br、CHBr₂、CBr₃、CH₂F、CHF₂、CF₃、C_3-8Cycloalkyl radical, C_3-8Cyclo haloalkyl group, C_3-8Cyclodihaloalkyl group, C_3-8Cyclotrihaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Aralkyl radical, C_2-6Aralkenyl, C_3-6Heterocyclic, benzyl, phenyl or phenylalkyl, wherein the phenyl ring may be substituted by one or two halogens, C_1-6Alkyl or C_1-6Alkoxy substitution; c_1-6Alkyl carboxyl, C_1-6Halogenoalkylcarboxyl, C_3-8Cycloalkyl carboxyl group, C_2-6Alkenyl carboxyl group, C_2-6Alkenyl carboxyl group, C_2-6Alkynyl carboxyl group, C_1-6Alkoxycarboxyl group, C_3-6Heterocyclic carboxyl, benzylcarboxyl, phenylcarboxyl, phenylalkylcarboxyl, wherein the phenyl ring may be substituted by one or two halogens, C_1-6Alkyl or C_1-6Alkoxy substitution.

In some embodiments, recovering flunixin or a flunixin analog from a pharmaceutical composition comprises:

adding a solvent to the pharmaceutical composition that preferentially dissolves the auxiliary substances relative to the flunixin or flunixin analog to form a mixture;

facilitating the dissolution of the auxiliary substance relative to the flunixin or flunixin analog in the mixture by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

isolating the flunixin or flunixin analog from the mixture;

optionally drying the flunixin or flunixin analog isolated from the mixture; and

optionally purifying flunixin or a flunixin analog.

adding a solvent to the pharmaceutical composition, the solvent preferentially dissolving the auxiliary substance over the flunixin or flunixin analog to form a mixture (the solvent may, for example, be selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, acetone, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, N-dimethylformamide, trifluoroethanol, and combinations thereof);

the mixture is heated up to and including the boiling point of the solvent or solvent combination,

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

adjusting the pH of the mixture to a pH of from about 1 to about 12, or alternatively to a pH of greater than about 10 or less than about 4,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

separating the flunixin or flunixin analog from the mixture by centrifugation or filtration (including optionally washing the flunixin or flunixin analog with one or more solvents to further remove soluble auxiliary substances);

optionally drying the flunixin or flunixin analog isolated from the mixture at a temperature of about 50 ℃ to about 100 ℃; and

the flunixin or flunixin analog is optionally purified by recrystallization or chromatography.

In some embodiments, the present invention relates to methods of recovering a compound of formula II from a pharmaceutical composition by preferentially dissolving the compound of formula II over a dissolution aid.

adding a solvent to the pharmaceutical composition (which is also meant to include adding the pharmaceutical composition to a solvent in all embodiments herein) that preferentially dissolves the flunixin or flunixin analog relative to the auxiliary substance to form a mixture;

facilitating the dissolution of the flunixin or flunixin analog relative to the auxiliary substance in the mixture by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

removing undissolved auxiliary substances from the mixture;

precipitating or crystallizing flunixin or a flunixin analog from the mixture (by, e.g., reducing the solvent volume of the mixture);

isolating the flunixin or flunixin analog from the mixture;

optionally purifying flunixin or a flunixin analog.

adding a solvent to the pharmaceutical composition that preferentially dissolves flunixin or a flunixin analog relative to the auxiliary substance to form a mixture (the solvent may, for example, be selected from the group consisting of water, methanol, acetone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, trifluoroethanol, and combinations thereof);

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

removing undissolved auxiliary substances from the mixture by centrifugation or filtration (including optionally washing the auxiliary substances with one or more solvents to further remove the flunixin or flunixin analog);

reducing the solvent volume by evaporation or distillation to precipitate or crystallize flunixin or a flunixin analog;

In some embodiments, the invention includes methods of recovering a compound of formula II from a pharmaceutical composition by partitioning the auxiliary substance in one solvent or solvent system and the compound of formula II in a different solvent or solvent system.

dissolving the pharmaceutical composition in at least two solvents to form a mixture such that the flunixin or flunixin analog partitions preferentially in at least one solvent relative to the auxiliary substance;

facilitating the dissolution of the flunixin or flunixin analog in the at least one solvent by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

separating at least one solvent comprising the preferentially dissolved flunixin from the mixture;

optionally repeating steps b-d above one or more times on the solvent comprising flunixin or a flunixin analog to further remove auxiliary substances;

optionally repeating steps b-d one or more times on the residual mixture containing auxiliary substances to further remove flunixin or a flunixin analog;

precipitating or crystallizing flunixin or a flunixin analog from at least one solvent by, for example, reducing the solvent volume;

separating the flunixin or flunixin analog from the at least one solvent (including optionally washing the flunixin or flunixin analog with one or more solvents to further remove soluble auxiliary substances);

optionally drying the flunixin or flunixin analog isolated from the at least one solvent; and

optionally purifying flunixin or a flunixin analog.

dissolving the pharmaceutical composition in at least two solvents to form a mixture such that the flunixin or flunixin analog partitions preferentially in at least one solvent relative to the auxiliary substance (the solvent in which the flunixin is dissolved may be, for example, selected from the group consisting of water, methanol, acetone, dimethyl sulfoxide, dimethylformamide, trifluoroethanol, and combinations thereof);

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

adjusting the volume of the mixture, and

stirring the mixture;

optionally repeating steps b-d above one or more times with a solvent comprising flunixin or a flunixin analog to further remove auxiliary substances;

optionally repeating steps b-d one or more times on the remaining mixture comprising auxiliary substances to further remove flunixin or a flunixin analog;

In some embodiments disclosed herein, recovering flunixin or a flunixin analog comprises dissolving the pharmaceutical composition in a suitable solvent or solvent system, injecting the dissolved pharmaceutical composition onto a chromatographic column, separating flunixin and/or a flunixin analog (if more than one is present) and at least one auxiliary substance from each other by elution through the chromatographic column with a suitable mobile phase, and collecting and separating the separated flunixin or flunixin analog.

After chromatographic recovery, the flunixin or flunixin analog is optionally dried and/or purified. In some embodiments, the flunixin or flunixin analog is dried at a temperature of about 50 ℃ to about 100 ℃ and optionally purified by recrystallization or again by chromatography.

By the present invention, applicants provide significant processing advantages by recovering the compound of formula II from a pharmaceutical composition.

In some preferred embodiments, flunixin is recovered from the pharmaceutical composition.

Recovery of the compounds of formula I-II from the pharmaceutical composition eliminates the expense associated with disrupting unusable compositions. In some embodiments, the recovered compound of formula I-II is reused to prepare a new pharmaceutical dosage form, thereby saving additional expense by eliminating the need to prepare such a compound (e.g., flunixin). In addition, recovery of the compounds of formula I-II eliminates the need to dispose of pharmaceutical waste. This can thereby reduce pollution to the environment.

The present invention generally has the advantage of an efficient and economical process for recovering and reusing flunixin from pharmaceutical compositions.

The present invention includes situations where one auxiliary substance is present and situations where more than one auxiliary substance is present, and it is necessary to repeat the process disclosed herein (in part or in whole) to separate flunixin or a flunixin analog from the auxiliary substance. For example, the disclosed methods may preferentially dissolve one auxiliary substance (e.g., excipient) over another auxiliary substance, such as another active pharmaceutical ingredient. This may result in the precipitation of flunixin or a flunixin analog in addition to other auxiliary substances such as additional active pharmaceutical ingredients. In some embodiments, the resulting precipitate is then subjected to the same or different recovery methods disclosed herein one or more times to recover the flunixin or flunixin analog.

In addition, some embodiments of the invention include an additional step of determining the solubility of some or all of the ingredients in the pharmaceutical composition. By determining the solubility of the ingredients in the composition, the solvent or solvent system necessary to preferentially dissolve, preferentially not dissolve, or partition a particular ingredient can be selected.

In some embodiments of the methods disclosed herein, flunixin or a flunixin analog is recovered from a pharmaceutical composition and used to prepare the same or a different pharmaceutical composition. For example, in some such embodiments, flunixin or a flunixin analog is recovered from a transdermal dosage form and then incorporated into a transdermal or solid oral dosage form. In some embodiments, the unusable and newly manufactured pharmaceutical composition is independently selected from the group consisting of parenteral dosage forms, topical dosage forms, oral solid dosage forms, liquid dosage forms, granular dosage forms, suspension dosage forms, aerosol dosage forms, transdermal dosage forms, sustained or controlled release dosage forms, implant dosage forms, and powder dosage forms.

Other benefits of the invention will become apparent to those skilled in the art upon reading this specification.

Description of The Preferred Embodiment

This detailed description of the preferred embodiments is merely intended to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may utilize and apply the invention in its various forms, as they are most suited to the requirements of a particular application. This detailed description and its specific examples are intended for purposes of illustration only and are indicative of preferred embodiments of the invention. Therefore, the present invention is not limited to the above-described embodiments and may be modified in various ways.

In this patent, including the claims, the following terms are to be read as defined below, unless otherwise indicated. These definitions (and other definitions found in the context of this patent) apply to all forms of defined terms, including singular, plural, active and past forms, to the extent that multiple forms exist.

The term "flunixin analog" means a compound of formula II that is a non-flunixin compound. The term "flunixin analog" also includes salts of compounds of formula II, including salts of flunixin. In general, such salts are preferably pharmaceutically acceptable. Flunixin meglumine is particularly preferred.

The term "auxiliary substance" means any ingredient other than the active pharmaceutical ingredient specified for recovery. Such ingredients may include, for example, excipients or additional active pharmaceutical ingredients. In some embodiments, the methods of the present disclosure are used to recover two or more active pharmaceutical ingredients from a pharmaceutical composition. Such an embodiment may require repetition of some or all of the disclosed steps one or more times.

The term "impurities" means components other than the specified recovered active pharmaceutical ingredient and auxiliary substances. Impurities may include, for example, elemental species or degradation products such as dimers, hydroxylated compounds, ketones, oxides, aldol adducts, semiquinones, radical peroxides, ether-linked adducts, and dehydrogenated compounds.

The term "excipient" means all pharmacologically inactive substances of the inactive pharmaceutical ingredient in the pharmaceutical composition (e.g. solvents, carriers, buffers, fillers, dispersants, colorants, preservatives, antimicrobials, antioxidants and any other substance other than impurities).

The term "active pharmaceutical ingredient" is a pharmacologically active substance that confers pharmacological activity on a pharmaceutical product.

The term "pharmaceutical composition" is synonymous with the term "pharmaceutical product" and means the combination of one or more active pharmaceutical ingredients with one or more excipients. The pharmaceutical composition may be the final pharmaceutical dosage form or an intermediate in the preparation of the pharmaceutical dosage form. The "pharmaceutical dosage form" may be in the form of, for example, a parenteral dosage form, a topical dosage form, an oral solid dosage form, a liquid dosage form, a granular dosage form, a suspension dosage form, an aerosol dosage form, a transdermal dosage form, a sustained or controlled release dosage form, an implant dosage form, or a powder dosage form. The intermediate may be any composition used in the manufacture of dosage forms, such as a free-flowing powder from a tableting machine or a solution of the active pharmaceutical ingredient to be processed into a suitable parenteral dosage form.

The term "patient" is defined as any subject who receives medical or veterinary attention, care, or treatment and includes humans and animals.

The term "healthcare provider" is defined as an organization or individual that delivers healthcare to any patient. A "healthcare provider" can be, for example, a hospital, research laboratory, medical and clinical laboratory, clinician, physician's assistant, assistance person, nurse, pharmacist, therapist, psychologist, dentist, dispenser, psychiatrist, clinicocardiologist, socio-therapist, psychiatrist nurse, friend, family member, veterinarian, animal owner, or animal caregiver.

The term "chromatography" means a technique for separating a mixture of components, carried out by passing a mixture of components dissolved in a suitable mobile phase through a stationary phase which separates the compounds of interest so that they can be separated.

The term "acetyl" means CH₃A CO-group.

The term "alcoholic solvent" includes C_1-10Monohydric alcohols (e.g., methanol, ethanol, and mixtures thereof), C_2-10Glycols (e.g. ethylene glycol) and C_1-10Trihydric alcohols (e.g., glycerol). The term "alcoholic solvent" also includes such alcohols in admixture with any suitable co-solvent (i.e., the second solvent is added to the starting solvent, typically at a lower concentration, to form a mixture that significantly enhances solvency due to synergistic effects). Such co-solvents include solvents miscible with alcoholic solvents such as C_4-10Alkanes, aromatic solvents (e.g., benzene, toluene, and xylene), halobenzenes (e.g., chlorobenzene), ethers (e.g., diethyl ether, t-butyl methyl ether, isopropyl ether, and tetrahydrofuran), and mixtures of any of the foregoing co-solvents.

The term "adding one or more solvents to the pharmaceutical composition" also means adding the pharmaceutical composition to the solvent and vice versa.

The term "purity" means that the active pharmaceutical ingredient is free or substantially free of auxiliary substances and/or free or substantially free of impurities such as degradation products or other non-auxiliary substances. Each purity is independently at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In some embodiments, the purity is at least about 99% relative to the auxiliary substance and at least about 97% relative to the impurity.

The term "obtaining a pharmaceutical composition" means collecting the pharmaceutical dosage forms to subject them to the methods disclosed herein. The collection may come from, for example, production tails or unacceptable or outdated batches.

The term "alkyl" means a saturated straight or branched chain hydrocarbon, such as methyl, ethyl, propyl, or sec-butyl. Alternatively, the number of carbons on the alkyl group may be specified. E.g. "C_1-6Alkyl "means an" alkyl "group containing 1 to 6 carbon atoms.

The term "C_2-6Alkenyl "means an unsaturated branched or unbranched hydrocarbon group having at least one double-bonded carbon-carbon (-C ═ C-) bond and containing 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, isopropylAlkenyl, 2-butenyl, 1, 3-butadienyl, 3-pentenyl, 2-hexenyl and the like.

The term "C_2-6Alkynyl "means an unsaturated branched or unbranched hydrocarbon group having at least one triple-bonded carbon-carbon (-C ≡ C-) bond and containing 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pent-4-ynyl, and the like.

The term "C_1-6Alkoxy "means an alkyl-O-group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), t-butoxy, and the like.

The term "C_1-6Arylalkyl "means C substituted with aryl_1-6An alkyl group, the aryl group being any group derived from an aromatic hydrocarbon by removal of a hydrogen atom. Aryl being optionally substituted by halogen or C_1-6Alkyl substitution.

The term "C_2-6Arylalkenyl "means C substituted with aryl_2-6Alkenyl, said aryl being any radical derived from an aromatic hydrocarbon by removal of a hydrogen atom. Aryl being optionally substituted by halogen or C_1-6Alkyl substitution.

The term "bromine" means the chemical element bromine.

The term "benzyl" means a monovalent group C₆H₅CH₂-, which is formally derived from toluene (i.e., methylbenzene).

The term "chlorine" means the chemical element chlorine.

The term "C_3-8Cycloalkyl "means a saturated cyclic hydrocarbon containing from 3 to 8 carbon atoms (i.e., cyclic alkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "C_3-8Halocycloalkyl "means C substituted by one or more halogens_3-8A cycloalkyl group. When more than one halogen is present, the halogens may be the same or different. In some embodiments，C_3-8Halo-cycloalkyl is "C_3-8Monohalocycloalkyl "i.e. C substituted by one halogen_3-8A cycloalkyl group. In some embodiments, C_3-8Halo-cycloalkyl is "C_3-8Dihalocycloalkyl "i.e. C substituted by two halogens_3-8A cycloalkyl group. In some embodiments, C_3-8Halo-cycloalkyl is "C_3-8Trihalocycloalkyl "i.e. C substituted by three halogens_3-8A cycloalkyl group.

The term "C_2-10By glycol "is meant an alcohol comprising two hydroxyl groups and 2-10 carbon atoms.

The term "fluorine" means the chemical element fluorine.

The term "fluoromethylsulfonyl" means CH₂FSO₂-a group.

The term "fluoromethylsulfinyl (sulfoxy)" means CH₂FSO-group.

The term "fluoromethylthio" means CH₂A FS-group.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "C_1-6Haloalkyl "means C_1-6Alkyl, wherein one or more hydrogens are replaced by a halogen. When more than one halogen is present, the halogens may be the same or different. In some embodiments, C_1-6Haloalkyl is "C_1-6Monohaloalkyl "i.e. C substituted by one halogen_1-6An alkyl group. In some embodiments, C_1-6Haloalkyl is "C_1-6Dihaloalkyl "i.e. C substituted by two halogens_1-6An alkyl group. In some embodiments, C_1-6Haloalkyl is "C_1-6Trihaloalkyl "i.e. C substituted by three halogens_1-6An alkyl group.

The term "halo-substituted phenyl" means a phenyl group substituted with a halo.

The term "C_3-8Heterocyclyl "means a ring systemGroups in which one or more ring-forming carbon atoms are replaced by heteroatoms, such as heteroatoms of oxygen, nitrogen or sulfur atoms, include mono-or polycyclic (i.e., having 2 or more fused rings) ring systems as well as spiro ring systems. The ring system may contain 3 to 8 carbon atoms and may be aromatic or non-aromatic.

The term "iodine" means the chemical element iodine.

The term "methylsulfonyl" means CH₃SO₂-a group.

The term "methylsulfinyl" means CH₃A SO-group.

The term "methylthio" means CH₃An S-group.

The term "C_1-10By monohydric alcohol "is meant an alcohol comprising one hydroxyl group and 1-10 carbon atoms.

The term "nitro" means NO₂A group.

The term "phenyl" means a monovalent radical C of benzene₆H₅-, benzene being an aromatic hydrocarbon C₆H₆。

The term "C_1-6Phenylalkyl "means C substituted by phenyl_1-6An alkyl group.

The term "C_1-10Trihydric alcohols "are intended to mean alcohols comprising three hydroxyl groups and 1 to 10 carbon atoms.

The term "pharmaceutically acceptable" when used in an adjective means that the modified noun is appropriate for a pharmaceutical product. When used, e.g., to describe a salt, the salt is characterized as not being deleterious to the intended recipient to the extent that the deleterious effect outweighs the beneficial effect of the salt.

In the context of the present specification and the appended claims, a given chemical formula or name shall include all stereo-and optical isomers and racemates thereof as well as mixtures of individual enantiomers in different proportions, wherein such isomers and enantiomers exist, and pharmaceutically acceptable salts and solvates thereof, such as hydrates. The isomers may be separated using conventional techniques such as chromatography or fractional crystallization. Enantiomers can be separated by separation of the racemic mixture, for example, by fractional crystallization, resolution, or high performance (or High Pressure) Liquid Chromatography (HPLC). Diastereoisomers may be separated by separation of the mixture of isomers, for example by fractional crystallisation, HPLC or flash chromatography. Stereoisomers may also be prepared by chiral synthesis from chiral starting materials or by derivatization using chiral reagents under conditions that do not result in racemization or epimerization. The starting materials and conditions are within the purview of those skilled in the art. All stereoisomers are included within the scope of the present invention.

The indicated chemical formula or name shall include all prodrugs. Prodrugs include, but are not limited to, agents that are converted to the active agent by esterase or DOPA decarboxylase, esters of the active agent, and agents that are demethylated, dephosphorylated, deacetylated, or dehydrated to the active agent.

The specified chemical formula or name shall also include all metabolites such as hydroxylated metabolites.

In some embodiments, there is provided a method of recovering a compound of formula II (or a pharmaceutically acceptable salt thereof) from a pharmaceutical composition by preferentially dissolving an auxiliary substance:

in some preferred embodiments, the compound is flunixin.

Preferential dissolution of auxiliary substances

A preferred process corresponding to the present invention comprises the following steps:

one or more solvents are added to a pharmaceutical composition comprising a compound of formula II such that the auxiliary substances of the pharmaceutical composition are preferentially dissolved, but the compound of formula II is not preferentially dissolved. In some embodiments, the pharmaceutical composition is placed in a reaction vessel and one or more solvents are added. For the purposes of the present invention, the term "reaction vessel" is understood to mean a vessel understood by the person skilled in the art to be capable of being loaded with reactants and of being completely recovered. Of course, the size and type of vessel will depend on the size of the selected batch and the particular reactants. A non-limiting list of solvents for dissolution, depending on the solubility of the auxiliary substances, is water, methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, pentanol, neo-pentanol, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, acetone, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, N-dimethylformamide, trifluoroethanol or combinations thereof. In some embodiments, the solvent that dissolves the auxiliary substance is water, ethanol, isopropanol, propanol, butanol, tert-butanol, pentanol, neo-pentanol, and combinations thereof. In some preferred embodiments, the solvent in which the auxiliary substance is dissolved is water. In some embodiments, the volume ratio of solvent to pharmaceutical composition is from about 1: 1 to about 20: 1. In some embodiments, the volume ratio of solvent (e.g., water) to drug product is from about 5: 1 to about 10: 1. The solvent may be added to the reaction vessel at any suitable time, for example, within about 24 hours, within about 12 hours, or within about 3 hours. In some embodiments, the water is added over about 6 hours.

Heating, cooling, adjusting pH, adjusting volume, adding one or more additional solvents, separating and/or removing different solvent phases, agitating or stirring the mixture to facilitate further dissolution of the auxiliary substance and insolubilization of the compound of formula II. In some embodiments, the mixture is heated to the boiling point of the solvent used (or the boiling point of the mixture). In other embodiments, the mixture is cooled to a temperature of less than about 25 ℃, e.g., from about-25 ℃ to about 25 ℃, from about-15 ℃ to about 15 ℃, or from about-5 ℃ to about 5 ℃. In some embodiments, the temperature of the mixture is maintained at about-15 ℃ to about 30 ℃ or about-20 ℃ to about 25 ℃. In some embodiments, the pH is adjusted with a base, e.g., to a pH greater than about 8, e.g., from about 8 to about 12 or from about 9 to about 11. In other embodiments, the pH is adjusted with an acid to a pH of less than about 5, for example to a pH of about 1. A non-limiting list of agents suitable for alkaline pH adjustment includes inorganic bases such as NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃、KHCO₃Or an organic base such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof. A non-limiting list of agents suitable for acidic pH adjustment includes inorganic acids such as HCl, H₂SO₄、HNO₃、H₃PO₄Organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof. In some embodiments, the pH is adjusted to a neutral pH by the addition of a base, acid, or buffer, which is defined as a pH of from about 6 to about 8. A non-limiting list of buffers includes biological buffers such as tris (hydroxymethyl) methylamine, 2- { [ tris (hydroxymethyl) methyl]A combination of amino } ethanesulfonic acid, piperazine-N, N' -bis (2-ethanesulfonic acid), N- (2-acetamido) -2-aminoethanesulfonic acid, and commercial buffers such as potassium dihydrogen phosphate and disodium hydrogen phosphate. The volume of the mixture can be reduced, for example, by distilling the solvent or by separating the phases which should phase separate. The volume can be increased by adding more solvent or co-solvent which further increases the solubility of the auxiliary substance. Stirring or agitation may also enhance the solubility of the auxiliary substances. In some embodiments, the mixture is stirred or agitated for up to about 24 hours. In other embodiments, the mixture is stirred or agitated for about 1 hour to about 10 hours.

The undissolved compound of formula II is separated from the mixture (by, for example, filtration) and optionally washed with one or more solvents to further remove soluble auxiliary substances. In some embodiments, the undissolved compound of formula II is separated by centrifugation or filtration. In some embodiments, the isolated compound of formula II is then washed with the same or a different solvent that dissolves the auxiliary substances to further remove the soluble auxiliary substances. Non-limiting examples of the washing solvent include water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, acetone, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, N-dimethylformamide, trifluoroethanol, and combinations thereof, depending on the solubility of the auxiliary substances. In some embodiments, the solvent in which the auxiliary substance excipient is dissolved is water, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, or combinations thereof. In some preferred embodiments, the solvent in which the auxiliary substance is dissolved is water. The volume of the washing solvent used depends on the relative solubility of the auxiliary substances and the insolubility of the compound of the formula II. In some embodiments, the volume-to-weight ratio of the washing solvent to the compound of formula II is from about 0.1: 1 to about 10: 1 or from about 0.1: 1 to about 3: 1. In other embodiments, the ratio is from about 1 to about 5: 1 or from about 1 to about 1.5: 1.

The crude recovered compound of formula I I is dried, if necessary. In some embodiments, the crude recovered compound of formula II is used directly. In other embodiments, the recovered compound of formula II is crude at a temperature of, for example, about 50 ℃ to about 100 ℃. In other embodiments, the crude recovered compound of formula II is dried at a temperature of, for example, about 70 ℃ to about 90 ℃. Drying is carried out for a suitable time (e.g., from about 1 to about 24 hours) to obtain the desired moisture content. In preferred embodiments, the moisture content is less than about 5% or less than about 1%.

The crude recovered compound of formula II is purified, if necessary, by, for example, recrystallization or chromatography to produce a purified compound of formula II. In some embodiments, purifying the compound of formula II comprises using an alcoholic solvent such as C_1-10Alkyl monoalcohol, C_1-10Alkyl diols or C_1-10An alkyltriol, each optionally mixed with water, to form a purified compound of formula II. C_1-10A non-limiting list of monohydric alcohols includes methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, pentanol, and mixtures thereof. C_1-10A non-limiting list of glycols includes ethylene glycol, propylene glycol, butylene glycol, and mixtures thereof. C_1-10A non-limiting example of a triol is glycerol. In some embodiments of the methods of the invention, C is used for purification_1-10The monohydric alcohol comprises isopropanol. In some embodiments of the methods of the invention, C is used for purification_1-10The glycol comprises propylene glycol. In some embodiments of the methods of the invention, C is used for purification_1-10The trihydric alcohols include glycerol. In the method of the inventionIn some embodiments, the purification comprises using a mixture of alcohol and water. In some embodiments, the mixture comprises methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, pentanol, ethylene glycol, propylene glycol, butylene glycol, glycerol, or mixtures thereof. In some embodiments, the alcohol, e.g., isopropanol, and water are present in a ratio of about 1: 5 to about 5: 1 (e.g., about 1: 1). In some embodiments, the alcohol comprises isopropanol, and the ratio of the mixture of isopropanol and water is about 1: 1. In some embodiments, the compound of formula II has a weight-to-volume ratio with a mixture of isopropanol and water of about 1: 1 to about 10: 1. In some embodiments, the weight-to-volume ratio of the compound of formula II to the isopropanol/water mixture is about 1: 4.6.

In some embodiments of purification, the compound of formula II is dissolved in an about 1: 1 mixture of isopropanol and water such that the volume ratio of the compound of formula II to the isopropanol/water mixture is about 1: 4.6. The resulting mixture was heated to reflux. The resulting solution is purified by filtration over activated carbon and a filter and then cooled to a temperature of about 10 ℃ to about 30 ℃ to yield pure crystalline compound of formula II. The term "pure" or "purified" as used in this patent means a reduced level of impurities and improved color compared to the unpurified compound. In some embodiments, the resulting compound of formula II achieves a purity level of at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In some embodiments, the solution is cooled to a temperature of about 20 ℃ to about 25 ℃ to crystallize the purified compound of formula II from the solution. The purified compound of formula II was isolated by filtration, washed with 1: 1 isopropanol and water. In some embodiments, the volume-to-weight wash ratio of the isopropanol/water mixture to the compound of formula II is about 0.25 to about 1.5: 1. In some embodiments, the wash ratio is about 0.5 to about 0.7: 1. The purified compound of formula II is then dried at a temperature of about 60 to about 90 ℃. In some embodiments, the purified compound of formula II is dried at a temperature of about 75 to about 85 ℃. Drying was continued for about 24 hours. In some embodiments, drying is continued until the moisture content of the purified compound of formula II is less than about 2%. In some embodiments, drying is continued until the moisture content is less than about 0.5%. In a preferred embodiment, the purified compound of formula II crystallized from solution is flunixin.

B. Preferential dissolution of flunixin or flunixin analogs

Another preferred process corresponding to the present invention comprises the following steps:

one or more solvents are added to the pharmaceutical composition comprising the compound of formula II such that the compound of formula II is preferentially dissolved and the auxiliary substances are not preferentially dissolved. In some embodiments, the pharmaceutical composition is placed in a reaction vessel as described above in part a, and a solvent or solvents are added. Non-limiting examples of dissolution solvents for the compound of formula II include water, methanol, acetone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, trifluoroethanol, and combinations thereof. In some embodiments, the dissolution solvent for the compound of formula II is water, methanol, acetone, and combinations thereof. In some preferred embodiments, the dissolution solvent for the compound of formula II is methanol. In some embodiments, the volume ratio of solvent to pharmaceutical composition is from about 1: 1 to about 20: 1. In some embodiments, the volume ratio of methanol to drug product is from about 2: 1 to about 8: 1. The solvent may be added to the reaction vessel at any suitable time, for example, within about 24 hours, within about 12 hours, or within about 3 hours. In some embodiments, methanol is added over about 6 hours.

Heating, cooling, adjusting pH, adjusting volume, adding one or more additional solvents, separating and/or removing different solvent phases, agitating or stirring the mixture to promote further dissolution of the compound of formula II and insolubilization of the auxiliary substance. In some embodiments, the mixture is heated to the boiling point of the solvent used (or the boiling point of the mixture). In some embodiments, the mixture is cooled to a temperature of less than about 25 ℃, e.g., from about-25 ℃ to about 25 ℃, from about-15 ℃ to about 15 ℃, or from about-5 ℃ to about 5 ℃. In some embodiments, the mixing is carried outThe temperature of the material is maintained at about-15 ℃ to about 30 ℃ or about-20 ℃ to about 25 ℃. In some embodiments, the pH is adjusted with a base, e.g., to a pH greater than about 8, e.g., from about 8 to about 12 or from about 9 to about 11. In some embodiments, the pH is adjusted with an acid to a pH of less than about 5, for example to a pH of about 1. A non-limiting list of agents suitable for alkaline pH adjustment includes inorganic bases such as NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃、KHCO₃Or an organic base such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof. A non-limiting list of agents suitable for acidic pH adjustment includes inorganic acids such as HCl, H₂SO₄、HNO₃、H₃PO₄Organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof. In some embodiments, the pH is adjusted to a neutral pH by the addition of a base, acid, or buffer, which is defined as a pH of from about 6 to about 8. A non-limiting list of buffers includes biological buffers such as tris (hydroxymethyl) methylamine, 2- { [ tris (hydroxymethyl) methyl]A combination of amino } ethanesulfonic acid, piperazine-N, N' -bis (2-ethanesulfonic acid), N- (2-acetamido) -2-aminoethanesulfonic acid, and commercial buffers such as potassium dihydrogen phosphate and disodium hydrogen phosphate. The volume of the mixture can be reduced, for example, by distilling the solvent or by separating the phases which should phase separate. The volume may be increased by adding more solvent or co-solvent which further increases the solubility of the compound of formula II. Stirring or agitation may also increase the solubility of the compound of formula II. In some embodiments, the mixture is stirred or agitated for up to about 24 hours. In other embodiments, the mixture is stirred or agitated for about 1 hour to about 10 hours.

Undissolved solids of the auxiliary substance are removed from the mixture, for example by filtration. In some embodiments, undissolved auxiliary substances are separated by centrifugation or filtration. In some embodiments, the isolated adjunct material is then washed with a solvent that dissolves the compound of formula II or other solvent that further removes the soluble compound of formula II. In some embodiments, the solvent of dissolved formula II is selected from the list disclosed above. The volume of washing solvent used depends on the relative solubility of the compound of formula II and the insolubility of the auxiliary substances. In some embodiments, the volume-to-weight ratio of the wash solvent to the adjunct materials is about 0.1: 1 to about 10: 1. In some embodiments, the ratio is about 1 to about 3: 1.

The compound of formula II is precipitated or crystallized, for example, by reducing the volume of the solvent while cooling to a temperature of about-25 ℃ to about 10 ℃ or by cooling to a temperature of about-25 ℃ to about 10 ℃. In some embodiments, cooling is to a temperature of about-5 ℃ to about 5 ℃.

The compound of formula II is isolated from the mixture using the techniques discussed in section a above.

If necessary, the crude recovered compound of formula II is dried and/or purified as described above in section A.

By dispensing preferential dissolution of flunixin or flunixin analogs and auxiliary substances

at least two solvents are added to the pharmaceutical composition comprising the compound of formula II such that the auxiliary substances of the pharmaceutical composition are preferentially distributed in one solvent (or solvent system) and the compound of formula II is preferentially distributed in the other solvent (or solvent system). In some embodiments, the pharmaceutical composition is placed into a reaction vessel as described in section a above. A non-limiting list of solvents that dissolve the auxiliary substances may include, for example, those disclosed in section a above, depending on the solubility of the auxiliary substance. Furthermore, the solvent used for partitioning the compound of formula II may for example be selected from those disclosed in section B above. In some embodiments, the solvent is added to the pharmaceutical composition in the proportions and for the time period discussed in sections a and B above.

Heating, cooling, adjusting pH, adjusting volume, adding one or more additional solvents, agitating or stirring the mixture to facilitate further partitioning of the auxiliary substances and the compound of formula II in their respective solvents or solvent systems. In some casesIn embodiments, the mixture is heated to the boiling point of the mixture. In other embodiments, the mixture is cooled to a temperature of less than about 25 ℃, e.g., from about-25 ℃ to about 25 ℃, from about-15 ℃ to about 15 ℃, or from about-5 ℃ to about 5 ℃. In some embodiments, the temperature of the mixture is maintained at about-15 ℃ to about 30 ℃ or about-20 ℃ to about 25 ℃. In some embodiments, the pH is adjusted with a base, e.g., to a pH greater than about 8, e.g., from about 8 to about 12 or from about 9 to about 11. In some embodiments, the pH is adjusted with an acid to a pH of less than about 5, for example to a pH of about 1. A non-limiting list of agents suitable for alkaline pH adjustment includes inorganic bases such as NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃、KHCO₃Or an organic base such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and combinations thereof. A non-limiting list of agents suitable for acidic pH adjustment includes inorganic acids such as HCl, H₂SO₄、HNO₃、H₃PO₄Organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, and combinations thereof. In some embodiments, the pH is adjusted to a neutral pH by the addition of a base, acid, or buffer, which is defined as a pH of from about 6 to about 8. A non-limiting list of buffers includes biological buffers such as tris (hydroxymethyl) methylamine, 2- { [ tris (hydroxymethyl) methyl]A combination of amino } ethanesulfonic acid, piperazine-N, N' -bis (2-ethanesulfonic acid), N- (2-acetamido) -2-aminoethanesulfonic acid, and commercial buffers such as potassium dihydrogen phosphate and disodium hydrogen phosphate. The volume of the mixture can be reduced, for example, by distilling the solvent or by separating the phases which should phase separate. The volume may be increased by adding more solvent or co-solvent which further facilitates the partitioning of the auxiliary substance and the compound of formula II. Stirring or agitation may also facilitate the distribution of the auxiliary substances and the compound of formula II. In some embodiments, the mixture is stirred or agitated for up to about 24 hours. In some embodiments, the mixture is stirred or agitated for about 1 hour to about 10 hours.

Further dispensing the auxiliary substance and the compound of formula II, if necessary, by repeating one or more of the steps disclosed above one or more times;

separating the at least one solvent comprising the preferentially dissolved compound of formula II from the mixture;

optionally repeating the above steps one or more times with the solvent comprising the dispensed compound of formula II to further remove auxiliary substances;

optionally repeating the above steps one or more times on the remaining mixture comprising the partitioned auxiliary substances to further remove the compound of formula II;

collecting the solvent or solvent system comprising the partitioned compound of formula II and precipitating or crystallizing the compound as disclosed in section a above;

separating undissolved solid compound of formula II from the mixture as disclosed in section a above, including any further washing to remove additional auxiliary substances; and

if necessary, the crude recovered compound of formula II is dried and/or purified as disclosed in section A above.

D. Recovery of flunixin or flunixin analogs and/or auxiliary substances by chromatography

In some embodiments, flunixin analogs, or auxiliary substances can be recovered using chromatography. The term "chromatography" is as described in IUPAC Nomenclature for chromatography, Pure & Appl. chem., Vol.65, No.4, pp.819-872, 1993, the disclosure of which is incorporated herein by reference, which term means a separation process wherein the component to be separated is partitioned between two phases, one of which is stationary (stationary phase) and the other phase (mobile phase) is moving in a defined direction. Chromatography methods that may be used in the present invention include: such as first-line chromatography, displacement chromatography, elution chromatography, column chromatography (e.g., packed column and open column chromatography), planar chromatography (e.g., Paper Chromatography (PC), Thin Layer Chromatography (TLC)), gas-liquid chromatography (GLC), gas-fixation chromatography (GSC), liquid-liquid chromatography (LLC), liquid-fixation chromatography (LSC), Gas Chromatography (GC), Liquid Chromatography (LC) (e.g., high performance or High Pressure Liquid Chromatography (HPLC)), simulated moving bed chromatography (SMB), Supercritical Fluid Chromatography (SFC), adsorption chromatography, partition chromatography, ion exchange chromatography (IC), exclusion chromatography, affinity chromatography, reverse phase chromatography, Simulated Moving Bed Chromatography (SMBC), normal phase chromatography, isocratic analysis, gradient elution, stepwise elution, two-dimensional chromatography, multidimensional chromatography, Isothermal chromatography, temperature programmed chromatography, flow programmed chromatography, pressure programmed chromatography, reaction chromatography, pyrolysis gas chromatography, post-column derivatization, and any combinations thereof.

dissolving the pharmaceutical composition in a suitable solvent or solvent system;

introducing (e.g., injecting) the dissolved pharmaceutical composition onto a chromatographic column;

separating the auxiliary substance from the flunixin or flunixin analog by elution through a chromatographic column with a suitable mobile phase;

collecting and combining the fraction or fractions comprising the isolated flunixin or flunixin analog;

if necessary, further isolating the flunixin or flunixin analog, subjecting the combined fractions or fractions containing the isolated flunixin or flunixin analog to steps b-e above;

isolating flunixin or a flunixin analog by precipitation or crystallization as described in section a above;

optionally drying the isolated flunixin or flunixin analog; and

optionally purifying flunixin or a flunixin analog.

dissolving the pharmaceutical composition in a suitable solvent or solvent system (the solvent or solvent system may, for example, be selected from the group consisting of water, methanol, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, trifluoroethanol, and combinations thereof);

separating the flunixin or flunixin analogs from each other (if more than one is present) and auxiliary substances by elution through a chromatography column comprising a positive or reverse stationary phase such as silica, cyano silica, amino silica, octyl silane, butyl silane, octadecyl silane, diisopropyloctadecyl silane or diisobutyl octadecyl silane and a suitable mobile phase such as an organic solvent, water, buffered aqueous solution or a combination thereof;

optionally drying the isolated flunixin or flunixin analog as described in section a above; and

flunixin or a flunixin analog is optionally purified as described in section a above.

E. Method for conducting pharmaceutical business

In some embodiments of the methods relating to conducting the pharmaceutical business disclosed herein, the manufacturer obtains an unused portion of the pharmaceutical dosage form from a patient or healthcare provider and conducts a recovery of the active pharmaceutical ingredient contained therein. In some embodiments, the recovered active pharmaceutical ingredient is then recycled into a new dosage form.

The unused portion of the pharmaceutical dosage form may be due to any number of reasons such as expiration of the drug or discontinuation of therapy by the patient due to intolerance, recovery from disease, or dose intensity or change in drug therapy.

In a preferred embodiment, the patient or healthcare provider is given a stimulus to promote the return of the dosage form. In some embodiments, the incentive is, for example, a payment, discount, coupon, commercial transaction, or commercial transaction voucher.

In some embodiments, the original manufacturer obtains the pharmaceutical dosage form in the unutilized portion or a third party obtains the pharmaceutical dosage form in the unutilized portion. In some such embodiments, the third party then recovers the active pharmaceutical ingredient from the dosage form and uses the recovered active agent for resale or application in its manufacturing process. In some embodiments, a Ticket military clearinghouse (clearinghouse) is established that receives the unutilized portion of the pharmaceutically active agent from multiple manufacturers and sources.

In some embodiments, the original manufacturer or third party who obtained the unused portion of the active pharmaceutical ingredient outsources the recovery of the active pharmaceutical ingredient contained therein.

In some embodiments, the above disclosed methods are also used to reduce the treatment of unused portions of the active pharmaceutical ingredient to reduce its disposal, for example in drainage systems or landfill sites. This may potentially reduce contamination of water sources (e.g., streams, oceans, and groundwater) with pharmaceutically active agents.

In addition to flunixin and flunixin analogs, the methods of conducting the pharmaceutical business are also applicable to other active pharmaceutical ingredients such as steroid compounds (e.g., mometasone, betamethasone, or a pharmaceutically acceptable salt thereof), antibiotics (e.g., florfenicol, moxifloxacin, ciprofloxacin, obifloxacin, gentamicin, cephamine, enramycin (enramycin), or a pharmaceutically acceptable salt thereof), anthelmintics (e.g., netobiam, ivermectin, or a pharmaceutically acceptable salt thereof), anticoccidial drugs (e.g., diclazuril, or a pharmaceutically acceptable salt thereof), immunosuppressive agents (e.g., cyclosporine, or a pharmaceutically acceptable salt thereof), anthelmintics (e.g., emamectin, indoxacarb, or a pharmaceutically acceptable salt thereof), anabolic agents (e.g., zeranol, or a pharmaceutically acceptable salt thereof), sterile drugs (e.g., chlorprostol, or a pharmaceutically acceptable salt thereof), Antihistamines (e.g., loratadine, desloratadine, or a pharmaceutically acceptable salt thereof), beta agonists (e.g., salbutamol, formoterol, or a pharmaceutically acceptable salt thereof), antifungal agents (e.g., clotrimazole, posaconazole, or a pharmaceutically acceptable salt thereof), opioid derivatives (e.g., buprenorphine, naloxone, or a pharmaceutically acceptable salt thereof), chemotherapeutic agents (e.g., temozolomide, doxorubicin, amifostine, or a pharmaceutically acceptable salt thereof), antiviral agents (e.g., ribavirin or a pharmaceutically acceptable salt thereof), monoclonal antibodies (e.g., infliximab), antihyperlipidemic agents (e.g., ezetimibe or a pharmaceutically acceptable salt thereof), non-steroidal anti-inflammatory agents (e.g., tepoxacillin, flunixin, or a pharmaceutically acceptable salt thereof), interferons (e.g., peinterferon alpha 2b), anticoagulants (e.g., eptifibatide or a pharmaceutically acceptable salt thereof), and vasodilators (e.g., nitroglycerin ).

The words "comprise", "comprising" and "contain" in this patent, including in the claims, are to be construed in a non-exclusive sense. The meaning of this interpretation is the same as that of the words specified in the U.S. patent law.

The foregoing detailed description of the preferred embodiments is merely intended to acquaint others skilled in the art with the invention, its principles and its practical application so that others skilled in the art may utilize and apply the invention in its various forms, as they are most suited to the requirements of a particular application. Therefore, the present invention is not limited to the above-described embodiments and may be modified in various ways.

Examples

The following preparation examples are representative of the processes and compounds of the invention. Although the present invention has been described with specificity in accordance with some embodiments of the invention, the following examples are intended only to exemplify and illustrate the invention and are not intended to limit or define the effective scope of the invention.

Example 1

FromRecovering flunixin from the solution

Is an Intervet/Schering-Plough Animal Health Corp. drug product comprising 300mg of florfenicol, 27.4mg of flunixin meglumine, 250mg of N-methyl-2-pyrrolidone or 2-pyrrolidone (2-pyrrolidone), 10mg of citric acid, 150mg of propylene glycol and polyethylene glycol in 1 mL.

About 300gTo about 3L of a stirred solution of about 24mL of concentrated aqueous ammonia heated to about 50 c was added over about 1 hour. Stronger ammonia was added to ensure a pH of about 9. The mixture was stirred and cooled to room temperature. The resulting precipitated florfenicol was removed by filtration. With 10% H₂SO₄The filtrate was acidified to about pH 4.5 and then stirred for about 1 hour. The resulting precipitated flunixin was collected by filtration and then dried to a moisture content of less than about 1% to yield about 4g of crude flunixin (100%).

Example 2

FromRecovering flunixin from the solution

The solution was an Intervet/Schering Plough Animal Health pharmaceutical product containing 83mg flunixin meglumine (equivalent to 50mg flunixin), 0.1mg disodium edetate, 2.5mg sodium formaldehyde sulfoxylate, 4.0mg diethanolamine, 207.2mg propylene glycol, 5.0mg phenol, hydrochloric acid and water for injection, diluted to 1 mL.

50% aqueous citric acid was added to about 0.5L of the Banamine solution while maintaining the temperature below 30 ℃. The resulting mixture was stirred for about 1 hour while continuously maintaining the temperature below 30 ℃. The precipitated flunixin was collected by filtration, washed with 0.5L of water, and then dried at about 50-60 ℃ to a moisture content of less than 1% to give about 23.5g of crude flunixin (94%).

Example 3

From Banamine pasteRecovering flunixin from the solution

Banamine pasteIs an Intervet/Schering Plough Animal Health pharmaceutical product comprising 83.0mg flunixin meglumine (equivalent to 50mg flunixin), 12.0mg sodium carboxymethylcellulose, 250.0mg corn starch, 100.0mg propylene glycol and 555.0mg pure water per gram of paste.

5L of water was added to about 500g of the Banamine paste while maintaining the temperature below 30 ℃. The mixture was stirred for about 3 hours while continuously maintaining the temperature below 30 ℃. The resulting precipitate was removed by filtration. The filtered solid was washed with about 1L of water and the pH of the filtrate was adjusted to 4-5 with aqueous citric acid (50%). The precipitated flunixin was collected by filtration, washed with 0.5L of water, and then dried at about 50-60 ℃ to a moisture content of less than 1% to give about 22.4g of crude flunixin (90%).

Example 4

From Banamine particlesRecovering flunixin from the solution

Banamine particlesIs an Intervet/Schering Plough Animal Health pharmaceutical product comprising 41.46mg flunixin meglumine (equivalent to 25.0mg flunixin), 363.54mg corn starch, 320.00mg sucrose 250.00mg calcium phosphate, 20.00mg povidone, and 5.00mg silicon dioxide per gram of particle.

5L of water was added to about 500g of Banamine particles while maintaining the temperature below 30 ℃. The mixture was stirred for about 3 hours while continuously maintaining the temperature below 30 ℃. The solids were removed by filtration. The filtered solid was washed with about 1L of water and the pH of the combined filtrates was adjusted to 4-5 with aqueous citric acid. The precipitated flunixin was collected by filtration, washed with 0.5L of water, and then dried at about 50-60 ℃ to a moisture content of less than 1% to give crude flunixin.

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Claims

1. A method of preparing a pharmaceutical dosage form comprising flunixin or a flunixin analog, wherein the method comprises:

(a) obtaining a pharmaceutical composition comprising flunixin or a flunixin analog and at least one auxiliary substance;

(b) recovering flunixin or a flunixin analog from the pharmaceutical composition by preferential dissolution; and

(c) the flunixin or flunixin analog is formulated into a pharmaceutical dosage form comprising flunixin or a flunixin analog and at least one auxiliary substance.

2. The method of claim 1, wherein:

the flunixin analog is a compound of formula II or a pharmaceutically acceptable salt thereof:

wherein:

R₁is carbon, nitrogen, oxygen, sulfur or phosphorus;

3. A method of preparing a pharmaceutical dosage form comprising flunixin or a flunixin analog, wherein the method comprises:

(b) recovering flunixin or a flunixin analog from the pharmaceutical composition by chromatography; and

4. A method of purifying flunixin or a flunixin analog, wherein the method comprises:

(c) the flunixin or flunixin analog is purified to a purity of at least about 90%.

5. The method of claim 4, wherein:

the active pharmaceutical ingredient comprises a compound of formula II (or a pharmaceutically acceptable salt thereof):

wherein:

R₁is carbon, nitrogen, oxygen, sulfur or phosphorus;

6. A method of purifying flunixin or a flunixin analog, wherein the method comprises:

7. A process for recovering flunixin or a flunixin analog from a pharmaceutical composition, wherein the process comprises:

(a) obtaining a pharmaceutical composition comprising flunixin or a flunixin analog and at least one auxiliary substance; and

(b) the flunixin or flunixin analog is recovered from the pharmaceutical composition by preferential dissolution.

8. The method of any one of claims 1, 4 and 7, wherein the pharmaceutical composition of step (a) constitutes a pharmaceutical dosage form.

9. The method of claim 8, wherein the pharmaceutical composition comprises a pharmaceutical dosage form selected from the group consisting of: parenteral dosage forms, topical dosage forms, oral solid dosage forms, liquid dosage forms, granular dosage forms, suspensions, aerosol dosage forms, transdermal dosage forms, sustained release dosage forms, controlled release dosage forms, implant dosage forms, and powder dosage forms.

10. The process of any one of claims 1, 4 and 7, wherein the pharmaceutical composition of step (a) constitutes an intermediate in the manufacture of a pharmaceutical dosage form.

11. The method of any one of claims 1, 4 and 7, wherein the auxiliary substance of the pharmaceutical composition comprises a substance selected from the group consisting of a pharmaceutically acceptable excipient, an additional active pharmaceutical ingredient, and combinations thereof.

12. The process of any one of claims 1, 4 and 7, wherein recovering the flunixin or flunixin analog comprises preferentially dissolving the flunixin or flunixin analog relative to dissolving the at least one auxiliary substance.

13. The process of any one of claims 1, 4 and 7, wherein recovering the flunixin or flunixin analog comprises preferentially dissolving at least one auxiliary substance relative to the flunixin or flunixin analog.

14. The process of any one of claims 1, 4 and 7, wherein the preferential dissolution of the recovery comprises partitioning at least one auxiliary substance in a first solvent and the flunixin or flunixin analog in a second solvent.

15. A process for recovering flunixin or a flunixin analog from a pharmaceutical composition, wherein the process comprises:

(a) adding a solvent to the pharmaceutical composition that preferentially dissolves the flunixin or flunixin analog relative to the auxiliary substance to form a mixture;

(b) facilitating the dissolution of the flunixin or flunixin analog relative to the auxiliary substance in the mixture by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(c) removing undissolved auxiliary substances from the mixture;

(d) reducing the solvent volume of the mixture to precipitate or crystallize flunixin or a flunixin analog;

(e) isolating the flunixin or flunixin analog from the mixture;

(f) drying the flunixin or flunixin analog separated from the mixture; and

(g) purifying flunixin or a flunixin analog.

16. The process of recovering flunixin or a flunixin analog from a pharmaceutical composition of claim 15, wherein the process comprises:

(b) adding a solvent to the pharmaceutical composition that preferentially dissolves the flunixin or flunixin analog relative to the auxiliary substance to form a mixture, wherein:

the solvent is selected from the group consisting of water, methanol, acetone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, trifluoroethanol, and combinations thereof;

(c) facilitating the dissolution of the flunixin or flunixin analog relative to the auxiliary substance in the mixture by performing at least one operation selected from the group consisting of:

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

adjusting the pH of the mixture to a pH of about 1 to about 12,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(c) removing undissolved auxiliary substances from the mixture by centrifugation or filtration;

(d) reducing the solvent volume of the mixture by evaporation or distillation to precipitate or crystallize flunixin or a flunixin analog;

(d) separating flunixin or a flunixin analog from the mixture by centrifugation or filtration;

(e) drying the flunixin or flunixin analog isolated from the mixture at a temperature of about 50 ℃ to about 100 ℃; and

(f) the flunixin or flunixin analog is purified by recrystallization or chromatography.

17. A process for recovering flunixin or a flunixin analog from a pharmaceutical composition, wherein the process comprises:

(b) adding a solvent to the pharmaceutical composition that preferentially dissolves the auxiliary substances relative to the flunixin or flunixin analog to form a mixture;

(c) facilitating the dissolution of the auxiliary substance relative to the flunixin or flunixin analog in the mixture by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(d) isolating the flunixin or flunixin analog from the mixture;

(e) drying the flunixin or flunixin analog separated from the mixture; and

(f) purifying flunixin or a flunixin analog.

18. The process of recovering flunixin or a flunixin analog from a pharmaceutical composition of claim 17, wherein the process comprises:

(b) adding a solvent to the pharmaceutical composition that preferentially dissolves the auxiliary substances relative to the flunixin or flunixin analog to form a mixture, wherein:

the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, t-butanol, pentanol, neo-pentanol, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, acetone, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, N-dimethylformamide, trifluoroethanol, and combinations thereof;

the mixture is heated to the boil and,

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

adjusting the pH of the mixture to a pH greater than about 10 or less than about 4,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

19. The method of claim 14, wherein partitioning the auxiliary substances in a first solvent and the flunixin or flunixin analog in a second solvent comprises:

(i) dissolving the pharmaceutical composition in at least two solvents to form a mixture such that the flunixin or flunixin analog is preferentially soluble in at least one solvent relative to the auxiliary substance;

(ii) facilitating the dissolution of the flunixin or flunixin analog in the at least one solvent by performing at least one operation selected from the group consisting of:

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(iii) separating at least one solvent comprising the preferentially dissolved flunixin from the mixture;

(iv) reducing the solvent volume of the at least one solvent to precipitate or crystallize flunixin or a flunixin analog; and

(v) isolating the flunixin or flunixin analog from the at least one solvent.

20. The process for recovering flunixin or a flunixin analog from a pharmaceutical composition of claim 19, wherein the process comprises:

(b) adding a solvent to the pharmaceutical composition that preferentially partitions the flunixin or flunixin analog relative to the auxiliary substance to form a mixture, wherein:

cooling the mixture to a temperature of about-25 ℃ to about 25 ℃,

adjusting the pH of the mixture to a pH of about 1 to about 12,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(c) separating at least one solvent comprising the preferentially dissolved flunixin from the mixture;

21. A process for recovering flunixin or a flunixin analog from a pharmaceutical composition, wherein the process comprises:

(i) dissolving the pharmaceutical composition in at least two solvents to form a mixture such that the flunixin or flunixin analog partitions preferentially in at least one solvent relative to the auxiliary substance;

the mixture is heated to a temperature at which,

the mixture is cooled down and the mixture is cooled down,

the pH of the mixture is adjusted to provide,

the volume of the mixture is adjusted so that,

the solvent phase in the mixture is separated,

removing the solvent phase from the mixture, and

stirring the mixture;

(iv) reducing the solvent volume of the at least one solvent to precipitate or crystallize flunixin or a flunixin analog;

(v) separating the flunixin or flunixin analog from the at least one solvent;

(vi) drying the flunixin or flunixin analog separated from the at least one solvent; and

(vii) purifying flunixin or a flunixin analog.

22. A process for recovering flunixin or a flunixin analog from a pharmaceutical composition, wherein the process comprises:

(b) recovering the flunixin or flunixin analog from the pharmaceutical composition by chromatography.

23. A method of conducting a pharmaceutical business, wherein the method comprises providing a stimulus to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form comprising an active pharmaceutical ingredient.

24. A method of conducting a pharmaceutical business, wherein the method comprises:

(a) preparing a pharmaceutical dosage form comprising an active pharmaceutical ingredient and at least one auxiliary substance;

(b) dispensing a pharmaceutical dosage form to a patient;

(c) providing a stimulus to the patient to return the unused portion of the pharmaceutical dosage form;

(d) obtaining an unused portion of the pharmaceutical dosage form;

(e) recovering the active pharmaceutical ingredient from the unused portion of the pharmaceutical dosage form; and

(f) a second dosage form is prepared comprising the recovered active pharmaceutical ingredient.

25. A method of reducing contamination of a water supply by a pharmaceutical product, wherein the method comprises providing a stimulus to a patient or healthcare provider to return an unused portion of a pharmaceutical dosage form comprising an active pharmaceutical ingredient, such that the amount of active ingredient disposed of in a drainage system is reduced.

26. The method of any one of claims 23, 24 and 25, wherein the active pharmaceutical ingredient comprises flunixin or a flunixin analog.