WO2018111459A1

WO2018111459A1 - Method for generating salts of pharmaceutical active ingredients

Info

Publication number: WO2018111459A1
Application number: PCT/US2017/060825
Authority: WO
Inventors: Kevin P. O'donnell; William W. Porter; Michael D. Read
Original assignee: Dow Global Technologies Llc
Priority date: 2016-12-14
Filing date: 2017-11-09
Publication date: 2018-06-21

Abstract

A method for generating salts of pharmaceutical active ingredients. The method comprises feeding into a hot melt extruder: (a) a pharmaceutical active ingredient; (b) a reactant capable of forming a salt with the pharmaceutical active ingredient; and (c) an extrudable polymer.

Description

METHOD FOR GENERATING SALTS

OF PHARMACEUTICAL ACTIVE INGREDIENTS

This invention relates to a method for generating salts of pharmaceutical active ingredients in a hot melt extruder.

Salts of pharmaceutical active ingredients have been prepared in an extruder. For example, U.S. Pat. No. 5,969,181 discloses extrusion of acidic ingredients with a base.

However, generation of salts of pharmaceutical active ingredients in a more usable form would be desirable.

STATEMENT OF INVENTION

The present invention provides a method for generating salts of pharmaceutical active ingredients; said method comprising feeding into a hot melt extruder: (a) a pharmaceutical active ingredient; (b) a reactant capable of forming a salt with the pharmaceutical active ingredient; and (c) an extrudable polymer.

DETAILED DESCRIPTION

Percentages are weight percentages (wt%) and temperatures are in °C, unless specified otherwise. All operations described herein were performed at room temperature (20-25 °C), unless specified otherwise. Weight percentages of monomer units are based on the total weight of monomer units in the polymer. The term "extrusion" includes processes known as injection molding, melt casting and compression molding. All polymer Tg and Tm values are determined by differential scanning calorimetry (DSC) according to ASTM D3418.

Preferably, the extrudable polymer is a polymer accepted for use in pharmaceutical applications and which is crystalline, semi-crystalline, or amorphous. Preferably, the amorphous extrudable polymer possesses a glass transition temperature greater than 0 °C as measured by differential scanning calorimetry, more preferably greater than 25 °C, more preferably greater than 50 °C, preferably less than 210 °C, preferably less than 160 °C, preferably less than 130 °C. Preferably the crystalline extrudable polymer possess a melting point less than 200 °C, preferably less than 150 °C, preferably less than 100 °C. Semi- crystalline polymers may possess a glass transition temperature and melting point that fall within the aforementioned ranges. Furthermore, semicrystalline and amorphous materials may have a glass transition temperature less than 0 °C. Acceptable polymers for use include, preferably a poly(alkylene oxide) (e.g., poly(ethylene oxide) (including materials designated as polyethylene glycols),

poly (propylene oxide), poly(butylene oxide), and mixtures and copolymers thereof), an alkyl (including substituted alkyl) cellulose polymer (e.g., methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and mixtures and copolymers thereof, e.g., hydroxypropyl methyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate), homopolymers and copolymers of N- vinyl lactams and N- Vinyl pyrrolidone (e.g., polyvinylpyrrolidone (PVP), copolymers of N- vinyl pyrrolidone and vinyl acetate or vinyl propionate), polyacrylates and polymethacrylates (e.g., methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, amino methacrylate copolymers), polyvinyl alcohol, and/or ethylene vinyl acetate. Preferred polymers include poly(alkylene oxide) and cellulose polymers.

Techniques for extruding compositions comprising an active ingredient such as a drug are known and described by Joerg Breitenbach, Melt extrusion: from process to drug delivery technology, European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117 or in European Patent Application EP 0 872 233. The above-mentioned components a), b) and optionally c) are preferably mixed in the form of particles, more preferably in powdered form. The components a), b) and optionally c) may also be in the form of a liquid or solution. The components a), c) and optionally b) may be pre-mixed before feeding the blend into a device utilized for extrusion, preferably melt-extrusion, but preferably, the reactant capable of forming a salt is added at a position in the extruder closer to the exit than components a) and c). Useful devices for extrusion, specifically useful extruders, are known in the art.

Preferably components a) and c) are pre-blended in an extruder feeder and fed from there into the extruder. The composition or the component(s) that has or have been fed into an extruder are passed through a heated area of the extruder at a temperature which will melt or soften the composition or at least one or more components thereof to form a blend throughout which the active ingredient is dispersed. Preferably, the extruder has several independently heated zones. Preferably, the reactant capable of forming a salt is added to a zone after

(downstream) of the zone(s) where other components are added. The blend is subjected to extrusion and caused to exit the extruder. Preferably, the temperature of each heated zone of the hot melt extruder is from 20 to 250 °C; preferably at least 30 °C, preferably at least 35 °C; preferably no more than 225 °C, preferably no more than 200 °C. In a preferred embodiment, the extrudable polymers include hydroxyalkyl methylcellulose having a DS of from 1.0 to 2.7 and an MS of from 0.40 to 1.30, wherein DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxy alkoxyl groups.

Hydroxyalkyl methylcellulose is a polymer having a cellulose backbone having β-1,4 glycosidically bound D-glucopyranose repeating units, designated as anhydroglucose units in the context of this invention, which are represented for unsubstituted cellulose by the formula

illustrating the numbering of the carbon atoms in the anhydroglucose units. The numbering of the carbon atoms in the anhydroglucose units is referred to in order to designate the position of substituents covalently bound to the respective carbon atom. At least a part of the hydroxyl groups of the cellulose backbone at the 2-, 3- and 6-positions of the anhydroglucose units are substituted by a combination of methoxyl and hydroxyalkoxyl groups. The hydroxyalkoxyl groups are typically hydroxymethoxyl, hydroxyethoxyl and/or hydroxypropoxyl groups. Hydroxyethoxyl and/or hydroxypropoxyl groups are preferred. Typically one or two kinds of hydroxyalkoxyl groups are present in the hydroxyalkyl methylcellulose. Preferably a single kind of hydroxyalkoxyl group, more preferably hydroxypropoxyl, is present. Illustrative of the hydroxyalkyl methylcelluloses are hydroxyethyl methylcelluloses, hydroxypropyl methylcelluloses, and hydroxybutyl methylcellulose. Most preferably, the hydroxyalkyl methylcellulose is a hydroxypropyl methylcellulose. The hydroxyl groups of the cellulose backbone at the 2-, 3- and 6-positions of the anhydroglucose units are not substituted by any groups other than methoxyl and hydroxyalkoxyl groups.

The degree of the substitution of hydroxyl groups at the 2-, 3- and 6-positions of the anhydroglucose units by methoxyl groups and hydroxyalkoxyl groups is essential in the present invention.

The average number of methoxyl groups per anhydroglucose unit is designated as the degree of substitution of methoxyl groups, DS. In the definition of DS, the term "hydroxyl groups substituted by methoxyl groups" is to be construed within the present invention to include not only methylated hydroxyl groups directly bound to the carbon atoms of the cellulose backbone, but also methylated hydroxyl groups of hydroxyalkoxyl substituents bound to the cellulose backbone.

The degree of the substitution of hydroxyl groups at the 2-, 3- and 6-positions of the anhydroglucose units by hydroxyalkoxyl groups is expressed by the molar substitution of hydroxyalkoxyl groups, the MS. The MS is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit in the hydroxyalkyl methylcellulose. It is to be understood that during the hydroxyalkylation reaction the hydroxyl group of a hydroxyalkoxyl group bound to the cellulose backbone can be further etherified by a methylation agent and/or a hydroxyalkylation agent. Multiple subsequent hydroxyalkylation etherification reactions with respect to the same carbon atom position of an anhydroglucose unit yields a side chain, wherein multiple hydroxyalkoxyl groups are covalently bound to each other by ether bonds, each side chain as a whole forming a hydroxyalkoxyl substituent to the cellulose backbone. The term "hydroxyalkoxyl groups" thus has to be interpreted in the context of the MS as referring to the hydroxyalkoxyl groups as the constituting units of hydroxyalkoxyl substituents, which either comprise a single hydroxyalkoxyl group or a side chain as outlined above, wherein two or more hydroxyalkoxyl units are covalently bound to each other by ether bonding. Within this definition it is not important whether the terminal hydroxyl group of a hydroxyalkoxyl substituent is further methylated or not; both methylated and non-methylated hydroxyalkoxyl substituents are included for the determination of MS.

The hydroxyalkyl methylcellulose utilized in the solid dispersion of the present invention has a DS of from 1.0 to 2.7 and an MS of from 0.40 to 1.30. Preferably the hydroxyalkyl methylcellulose has a DS of from 1.0 to 2.3, more preferably from 1.0 to 2.1, most preferably of 1.1 to 2.1 and particularly from 1.6 to 2.1. Preferably the hydroxyalkyl methylcellulose has an MS of from 0.50 to 1.20, more preferably from 0.60 to 1.10. Any preferred range for DS can be combined with any preferred range for MS. Most preferably the hydroxyalkyl methylcellulose has a DS of from 1.6 to 2.1 and an MS of from 0.60 to 1.10. The sum of the DS and MS preferably is at least 1.8, more preferably at least 1.9, most preferable at least 2.5 and preferably up to 3.2, more preferably up to 3.0, most preferably up to 2.9.

The degree of substitution of methoxyl groups (DS) and the molar substitution of hydroxyalkoxyl groups (MS) can be determined by Zeisel cleavage of the hydroxyalkyl methylcellulose with hydrogen iodide and subsequent quantitative gas chromatographic analysis (G. Bartelmus and R. Ketterer, Z. Anal. Chem., 286 (1977) 161-190). When the hydroxyalkyl methylcellulose is hydroxypropyl methylcellulose, the determination of the % methoxyl and % hydroxypropoxyl is carried out according to the United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469). The values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyoxyl substituents and molar substitution (MS) for hydroxypropoxyl substituents.

Residual amounts of salt have been taken into account in the conversion.

The hydroxyalkyl methylcellulose utilized in the present invention can be in a wide viscosity range. Typically it is in a range from 1.2 to 200,000 mPa-s, measured as a 2 weight- % solution in water at 20 °C according to USP 35, "Hypromellose", pages 3467-3469. It has been found that the method of the present invention can be prepared by extrusion, typically melt-extrusion, over a wide viscosity range of the hydroxyalkyl methylcellulose. Preferably the viscosity of the hydroxyalkyl methylcellulose utilized in a solid dispersion prepared by extrusion is from 2.4 to 200,000 mPa-s, measured as a 2 weight-% solution in water at 20 °C.

Pharmaceutical active ingredients (also referred to as "drugs") are pharmacologically active substances used to treat humans, animals or plants. Preferably, drugs are approved by the relevant regulatory agency for treatment of conditions occurring in humans or animals. Especially preferred drugs include, e.g., antifungals, antibiotics, anti-inflammatory, antimigraine, antihistamines, analgesics, antioxidants, nicotine, antipsychotics and life-style drugs (e.g. erectile dysfunction). More than one drug may be added to the extruder.

Preferably, the drug is in its free base form if it is basic or in its acid form if it is acidic. Preferably, the drug is a "low-solubility drug", meaning that the drug has an aqueous solubility at physiologically relevant pH (e.g., pH 1-8) of about 0.5 mg/mL or less. Thus, compositions of the present invention are preferred for low-solubility drugs having an aqueous solubility of less than 0.1 mg/mL or less than 0.05 mg/mL or less than 0.02 mg/mL, or even less than 0.01 mg/mL where the aqueous solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values between 1 and 8) including USP simulated gastric and intestinal buffers.

In a preferred embodiment, the extrudable polymer is a poly(alkylene oxide) having weight average molecular weight (M_w) from 40,000 to 7,000,000; preferably at least 50,000, preferably at least 80,000, preferably at least 120,000; preferably no greater than 2,000,000, preferably no greater than 1,000,000, preferably no greater than 700,000, preferably no greater than 400,000, preferably no greater than 300,000. Preferably, the poly(alkylene oxide) is poly (ethylene oxide).

The reactant capable of forming a salt with the pharmaceutical active ingredient is a base when the active ingredient is acidic and an acid when the active ingredient is basic. Active ingredients that are acidic or basic are those having pKa values (measured at 20°C) below 7 or above 7, respectively, preferably below 6 or above 8. Preferred bases include hydroxides or oxides of alkali metals or alkaline earth metals, a-amino carboxylic acids having an additional amino group, carbonates or bicarbonates of alkali metals or alkaline earth metals, acetates or formates of alkali metals and alkaline earth metals, and mixtures thereof. Especially preferred bases include sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Preferably, the drug is acidic and has acidic functional groups, e.g., carboxyl groups, phenolic hydroxyl groups; preferably carboxyl groups.

Preferred acids include l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (- L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (- L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L), thiocyanic acid, toluenesulfonic acid (p) and undecylenic acid. Water, carbon dioxide or any other volatile byproducts of the

neutralization reaction are removed via standard extruder devolatilization equipment.

Preferably, the reactant capable of forming a salt with the pharmaceutical active ingredient is added in an equivalents ratio to the pharmaceutical active ingredient from 1 : 1 to 1.4:1; preferably at least 1.01:1, preferably at least 1.05:1; preferably no more than 1.3: 1, preferably no more than 1.2:1, preferably no more than 1.1:1. Examples

Example 1

Raw materials

The list of raw materials is contained in the section listed below. All materials were commercially available.

AFFINISOL HPMC HME, hypromellose from The Dow Chemical Company

Naproxen, CAS 22204-53-1, from Spectrum Chemical

20% sodium hydroxide, aqueous solution from Ricca Chemical

Acid Neutralization Reaction

The acid neutralization of the naproxen in the excipient polymer took place in a Krupp Werner & Pfleiderer twin-screw co-rotating extruder system (ZSK-30). Figure 1 shows the layout of such a system. Briefly, the system is comprised of an extruder with 12 barrel sections, 11 of which are independently controlled with electric heating and water cooling, two twin-screw loss-in-weight powder feeders (K-Tron, model KT-20), a high-performance positive displacement pump (Teledyne ISCO, model D-1000) to inject the sodium hydroxide solution, a vacuum system to remove water and any volatile residuals, and a TEFLON conveyor belt for sample collection. The length to diameter ratio of the extruder is 37.

Process Description and Conditions

Acid Neutralization Process conditions

In all the samples, a K-Tron feeder fed the excipient powder under a nitrogen purge into the extruder feed throat (barrel 1). The API (naproxen) was fed with a second K-Tron loss in weight powder feeder to independently control the amount of API relative to the polymer excipient mass flow rate. The ISCO pump injected the aqueous sodium hydroxide solution in the 8^th barrel section. The vacuum system (comprised of 3 knock-out pots) connected to the devolatilization port in barrel 10 removed the water, and any by-products of the acid-base neutralization reaction. The vacuum system operated at 0.68 bar vacuum. Finally, the resulting hot melt extruded blend was pumped by the extruder through a two-hole die onto a moving cooling belt. The total feed rate (4.54 kg/h) and screw speed (250 rpm) was held constant for all samples. The extruder torque load varied from 15-25 %. Table 1 shows examples of a typical trial run and summarizes other process variables such as the temperature profile of the extruder, die pressure, specific feed rates of the components, etc.

Table 1 - Set Point Values for Process

The process conditions were chosen to insure that the excipient polymer and API were in the molten state. The injection of the aqueous base was located downstream of the primary dynamic melt seal to insure that the water did not flash off into steam upon injection to the heated process stream. The flow rate of the sodium hydroxide solution was calculated based on the mass flow rate of the naproxen into the system. The flow rate was varied to provide a range of theoretical percent neutralization values corresponding to 0, 25%, 50%, 75%, and 100% of the available acid groups on the naproxen feed material.

Results

Infrared spectra were acquired with a Thermo Scientific Nicolet iS50 FT-IR and its built-in ATR accessory at a resolution of 4 cm ¹. Forty-eight scans (71 -second acquisition time) were collected for each spectrum. The ATR accessory was equipped with a single bounce diamond ATR crystal. The spectra of the starting materials and a naproxen sodium control showed that naproxen was successfully converted to naproxen- sodium by the process. Example 2

Raw Materials

POLYOX WSR N80 from The Dow Chemical Company

Naproxen, CAS 22204-53-1, from Spectrum Chemical

20% sodium hydroxide, aqueous solution from Ricca Chemical

Acid Neutralization Reaction

The acid neutralization of the naproxen in the excipient polymer took place in a Krupp Werner & Pfleiderer twin-screw co-rotating extruder system (ZSK-30). The system is comprised of an extruder with 12 barrel sections, 11 of which are independently controlled with electric heating and water cooling, two twin-screw loss-in-weight powder feeders (K- Tron, model KT-20), a high-performance positive displacement pump (Teledyne ISCO, model D-1000) to inject the sodium hydroxide solution, a vacuum system to remove water and any volatile residuals, and a TEFLON conveyor belt for sample collection. The length to diameter ratio of the extruder is 37.

Process Description and Conditions

Acid Neutralization Process conditions

In all the samples, a K-Tron feeder fed the excipient powder under a nitrogen purge into the extruder feed throat (barrel 1). The API (naproxen) was fed with a second K-Tron loss in weight powder feeder to independently control the amount of API relative to the polymer excipient mass flow rate. The ISCO pump injected the aqueous sodium hydroxide solution in the 8^th barrel section. The vacuum system (comprised of 3 knock-out pots) connected to the devolatilization port in barrel 10 removed the water, and any by-products of the acid-base neutralization reaction. The vacuum system operated at 0.68 bar vacuum. Finally, the resulting hot melt extruded blend was pumped by the extruder through a two-hole die onto a moving cooling belt. The total feed rate (4.54 kg/h) and screw speed (150 rpm) was held constant for all samples. The extruder torque load varied from 19-45 %. Table 1 shows examples of a typical trial run and summarizes other process variables such as the temperature profile of the extruder, die pressure, specific feed rates of the components, etc. Table 1 - Set Point Values for Process

The process conditions were chosen to insure that the excipient polymer and API were in the molten state. The injection of the aqueous base was located downstream of the primary dynamic melt seal to insure that the water did not flash off into steam upon injection to the heated process stream. The flow rate of the sodium hydroxide solution was calculated based on the mass flow rate of the naproxen into the system. The flow rate was varied to provide a range of theoretical percent neutralization values corresponding to 0, 25%, 50%, and 100% of the available acid groups on the naproxen feed material.

Results

Infrared spectra were acquired with a Thermo Scientific Nicolet iS50 FT-IR and its built-in ATR accessory at a resolution of 4 cm-1. Thirty-two scans (47-second acquisition time) were collected for each spectrum. The ATR accessory was equipped with a single bounce diamond ATR crystal. The spectra of the starting materials and a naproxen sodium control showed that naproxen was successfully converted to naproxen-sodium by the process.

Claims

1. A method for generating salts of pharmaceutical active ingredients; said method comprising feeding into a hot melt extruder: (a) a pharmaceutical active ingredient; (b) a reactant capable of forming a salt with the pharmaceutical active ingredient; and (c) an extrudable polymer.

2. The method of claim 1 in which the extrudable polymer is: (i) a poly(alkylene oxide) having weight average molecular weight from 40,000 to 7,000,000, (ii) a hydroxyalkyl methylcellulose having a DS of from 1.0 to 2.7 and an MS of from 0.40 to 1.30, wherein DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxy alkoxyl groups, or (iii) a mixture thereof.

3. The method of claim 2 in which the pharmaceutical active ingredient is acidic.

4. The method of claim 3 in which the reactant capable of forming a salt with the pharmaceutical active ingredient is a base selected from the group consisting of hydroxides or oxides of alkali metals or alkaline earth metals, a-amino carboxylic acids having an additional amino group, carbonates or bicarbonates of alkali metals or alkaline earth metals, acetates or formates of alkali metals and alkaline earth metals, and mixtures thereof.

5. The method of claim 4 in which the base is selected from the group consisting of hydroxides or oxides of alkali metals or alkaline earth metals, carbonates or bicarbonates of alkali metals or alkaline earth metals, and mixtures thereof.

6. The method of claim 5 in which the extrudable polymer is a hydroxyalkyl methylcellulose having a DS of from 1.1 to 2.1 and an MS of from 0.50 to 1.20.

7. The method of claim 6 in which the extrudable polymer is hydroxypropyl methylcellulose.

8. The method of claim 7 in which a sum of DS and MS is from 1.9 to 3.0.

9. The method of claim 4 in which the extrudable polymer is poly(ethylene oxide).

10. The method of claim 9 in which poly(ethylene oxide) has weight average molecular weight from 50,000 to 700,000.