WO2021118915A1

WO2021118915A1 - Hydroxypropyl alkyl cellulose acetate succinate heteropolymers

Info

Publication number: WO2021118915A1
Application number: PCT/US2020/063561
Authority: WO
Inventors: Oliver Petermann; Kevin O'donnell
Original assignee: Nutrition & Biosciences Usa 1, Llc
Priority date: 2019-12-09
Filing date: 2020-12-07
Publication date: 2021-06-17

Abstract

A hydroxypropyl alkyl cellulose acetate succinate heteropolymer is produced by esterification of (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 with acetic anhydride and succinic anhydride.

Description

HYDROXYPROPYL ALKYL CELLULOSE ACETATE SUCCINATE HETEROPOLYMERS

FIELD

The present invention relates to novel hydroxypropyl alkyl cellulose acetate succinate (HP AC AS) polymers and their use in hot-melt extrusion.

INTRODUCTION

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is known as enteric polymer for the production of hard capsules, tablet coatings or as a matrix polymer in tablets.

Moreover, HPMCAS is known for improving the solubility of poorly water-soluble drugs. The HPMCAS is aimed at reducing the crystallinity of the drug, thereby minimizing the activation energy necessary for the dissolution of the drug, as well as establishing hydrophilic conditions around the drug molecules, thereby improving the solubility of the drug itself to increase its bioavailability, i.e., its in vivo absorption by an individual upon ingestion. Typically, a solid dispersion comprising the HPMCAS and the drug is prepared. One known method of preparing such solid dispersion includes dissolving the drug together with the HPMCAS in an organic solvent that is optionally blended with water, and to spray- dry the solution. Another method is known as hot-melt extrusion, wherein the drug is blended with the HPMCAS as a powder blend, the powder blend is heated and intensely mixed in the softened or partially or completely melted state and moved towards a die that shapes the melt as strands, films, pellets, tablets or capsules. Hot-melt extrusion is often the preferred method because there is no risk of residual amounts of organic solvents in the solid dispersion. On the other hand, hot-melt extrusion presents challenges when the drug is sensitive to heat. Various suggestions have been made to reduce the temperature required for partially or completely melting the blend of HPMCAS and drug, such as the use of a plasticizer.

EP 2 810 660 A1 suggests the use of a HPMCAS having a hydroxypropoxy molar substitution of 0.40 or more in a composition that is used for hot-melt extrusion. EP 2 810

660 A1 states that such HPMCAS has a lower glass transition temperature and a lower minimum extrusion temperature in comparison to HPMCAS having a hydroxypropoxy molar substitution of less than 0.4. However, HPMCAS having a hydroxypropoxy molar substitution of 0.40 or more is difficult to handle in the purification procedure after production. This type of HPMCAS is very tacky and agglomerates after production in its crude state. Therefore, it is difficult to wash and separate from the by-products in the steps of purifying HPMCAS.

In view of the deficiencies of the HPMCAS disclosed in EP 2 810 660 Al, it would be desirable to provide new hydroxypropyl methyl cellulose acetate succinates which can be melt-extruded at a reasonably low temperature, but which are less difficult to handle in the purification procedure after production.

SUMMARY

Surprisingly, a hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer has been found which can be melt-extruded at a reasonably low temperature and which is not unduly tacky in the purification procedure after production.

One aspect of the present invention is a hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer produced by esterification of (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 with acetic anhydride and succinic anhydride.

Another aspect of the present invention is a process for producing a hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer wherein (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 in combination are esterified with acetic anhydride and succinic anhydride.

Yet another aspect of the present invention is a process for producing a hot-melt extruded HPACAS heteropolymer which comprises the steps of producing a HPACAS heteropolymer according to the above-mentioned process and extruding the HPACAS heteropolymer at a temperature of 180 °C or less.

Yet another aspect of the present invention is a solid dispersion comprising the above-mentioned HPACAS heteropolymer and at least one active ingredient. DESCRIPTION OF EMBODIMENTS

The hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer is produced by esterification of a cellulose ether (a) and a hydroxypropyl methyl cellulose (b).

The cellulose ether (a) and the hydroxypropyl methyl cellulose (b) have a cellulose backbone having b-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. Depending on the type of cellulose ether, 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 methoxyl groups, ethoxyl groups, hydroxypropoxyl groups or a combination of hydroxypropoxyl groups and methoxyl groups. By convention, the weight percent of methoxyl groups, ethoxyl groups and hydroxypropoxyl groups is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents.

When the cellulose ether (a) is a methylcellulose, hydroxyl groups of the cellulose backbone are not substituted with other groups than methoxyl groups. Methylcellulose can be characterized by the weight percent of methoxyl groups. The content of the methoxyl group is reported based on the mass of the methoxyl group (i.e., — OCTb). The determination of the % methoxyl in methylcellulose (MC) polymer is carried out according to the United States Pharmacopeia (USP 37, “Methylcellulose”, pages 3776-3778). The % methoxyl can be converted into degree of substitution (DS) of methoxyl groups, DS(methoxyl). DS(methoxyl) of a methylcellulose is the average number of OH groups substituted with methyl groups per anhydroglucose unit. Preferably, the methylcellulose has a DS(methoxyl) of from 1.0 to 2.7, more preferably of from 1.3 to 2.5, even more preferably of from 1.5 to 2.2, and most preferably of from 1.6 to 2.0. Generally, the methylcellulose has a viscosity of from 1.5 to 100 mPa-s, preferably from 2 to 50 mPa-s, more preferably from 2.5 to 20 mPa-s, and most preferably from 2.5 to 10 mPa-s, measured as a 2.0 weight- % solution in water at 20 °C using an Ubbelohde viscometer.

When the cellulose ether (a) is an ethylcellulose, hydroxyl groups of the cellulose backbone are not substituted with other groups than ethoxyl groups. Ethylcellulose can be characterized by the weight percent of ethoxyl groups. The content of the ethoxyl group is reported based on the mass of the ethoxyl group (i.e., — OCH2CH3). The % ethoxyl can be converted into degree of substitution (DS) of ethoxyl groups. Generally, the ethylcellulose has a degree of substitution of ethoxyl groups, DS(ethoxyl), of from 0.5 to 3, preferably from 1.0 to 2.9, more preferably from 2.0 to 2.8, and most preferably from 2.42 to 2.70.

The % ethoxyl in ethylcellulose can be carried out according to Zeisel gas chromatographic technique as described in ASTM D4794-94(2003). The % ethoxyl can be converted into degree of substitution (DS) of ethoxyl groups.

In typical embodiments the ethylcellulose, including ethylcellulose having the preferred DS(ethoxyl) described before, has a 5 % solution viscosity of from 3 to 110 mPa-s, preferably from 15 to 75 mPa-s, and more preferably from 18 to 50 mPa s. The term "5 % solution viscosity" refers to the viscosity of a 5 % by weight solution of the ethylcellulose in a mixture of toluene/ethanol in a weight ratio of 80/20. The viscosity is determined at 25 °C in an Ubbelohde viscometer. Exemplary ethylcelluloses that can be used for producing the HPMCAS of the present invention include ETHOCEL™ Std. 4, 7, 10, 20, 45 or 100 Premium, commercially available from DuPont Nutrition & Biosciences. ETHOCEL™ Std. 4, 7, 10, 20, 45 or 100 Premium ethylcelluloses have a 5 % solution viscosity of 3 - 3.5 mPa s (Std 4), 6 - 8 mPa s (Std 7), 9 - 11 mPa s (Std 10), 41 - 49 mPa s (Std 45) and 90 - 110 mPa s (Std 100) and aDS of 2.46 to 2.57.

When the cellulose ether (a) is a hydroxypropyl methyl cellulose (HPMC), hydroxyl groups of the cellulose backbone are not substituted with any groups other than methoxyl groups, hydroxypropoxyl groups or a combination of hydroxypropoxyl groups and methoxyl groups. 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 by weight. These are subsequently converted into degree of substitution (DS) for methoxyl substituents and molar substitution (MS) for hydroxypropoxyl substituents. The average number of methoxyl groups per anhydroglucose unit is designated as the degree of substitution of methoxyl groups, DS(methoxyl). In hydroxypropyl methyl cellulose the degree of substitution of methoxyl groups, DS(methoxyl), includes not only methylated hydroxyl groups directly bound to the carbon atoms of the cellulose backbone, but also methylated hydroxyl groups of hydroxypropoxyl substituents bound to the cellulose backbone. The HPMC (a) generally has a DS(methoxyl) in the range of 1.0 to 2.7, preferably from 1.1 to 2.5, more preferably from 1.1 to 2.3 and most preferably from 1.6 to 2.1. The degree of the substitution of hydroxyl groups by hydroxypropoxyl groups is expressed by the molar substitution of hydroxypropoxyl groups, the MS(hydroxypropoxyl). The MS(hydroxypropoxyl) is the average number of moles of hydroxypropoxyl groups per anhydroglucose unit in the hydroxypropyl methyl cellulose (HPMC). It is to be understood that during the hydroxypropoxylation reaction the hydroxyl group of a hydroxypropoxyl group bound to the cellulose backbone can be further etherified by a methylation agent and/or a hydroxypropoxylation agent. Multiple subsequent hydroxypropoxylation etherification reactions with respect to the same carbon atom position of an anhydroglucose unit yields a side chain, wherein multiple hydroxypropoxyl groups are covalently bound to each other by ether bonds, each side chain as a whole forming a hydroxypropoxyl substituent to the cellulose backbone. The term “hydroxypropoxyl groups” thus has to be interpreted in the context of the MS as referring to the hydroxypropoxyl groups as the constituting units of hydroxypropoxyl substituents, which either comprise a single hydroxypropoxyl group or a side chain as outlined above, wherein two or more hydroxypropoxyl units are covalently bound to each other by ether bonding. Within this definition it is not important whether the terminal hydroxyl group of a hydroxypropoxyl substituent is further methylated or not; both methylated and non-methylated hydroxypropoxyl substituents are included for the determination of MS. The HPMC (a) has a MS(hydroxypropoxyl) of up to 0.35, preferably from 0.05 to 0.35, more preferably from 0.10 to 0.30, and most preferably from 0.15 to 0.30. In HPMC (a) any preferred range for DS(methoxyl) can be combined with any preferred range for MS(hydroxypropoxyl). The HPMC (a) generally has a viscosity of from 1.2 to 20 mPa-s, preferably from 1.5 to 10 mPa-s, more preferably from 1.5 to 5 mPa-s, and most preferably from 1.5 to 2.4 mPa-s, measured as a 2.0 weight-% solution in water at 20 °C using an Ubbelohde viscometer.

Preferably, the cellulose ether (a) is a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of up to 0.35 or a methylcellulose and the produced HPACAS heteropolymer is a hydroxypropyl methyl cellulose acetate succinate (HPMCAS) heteropolymer. More preferably, cellulose ether (a) is a hydroxypropyl methyl cellulose (HPMC), hereafter designated as hydroxypropyl methyl cellulose (a) or HPMC (a). Preferred HPMC (a) and methylcelluloses are described above.

In addition to cellulose ether (a), a hydroxypropyl methyl cellulose (b), also designated as HPMC (b), is used for producing the HPACAS of the present invention.

When cellulose ether (a) is a HPMC (a) as described above, it is essential for the present invention that the MS(hydroxypropoxyl) in the HPMC (a) is different from the MS(hydroxypropoxyl) in HPMC (b). The HPMC (b) has a MS(hydroxypropoxyl) of from 0.40 to 1.90, generally from 0.40 to 1.50, preferably from 0.45 to 1.30, more preferably from 0.50 to 1.20, and most preferably from 0.60 to 1.10. The HPMC (b) generally has a DS(methoxyl) in the range of 1.0 to 2.7, preferably from 1.1 to 2.5, more preferably from 1.1 to 2.3 and most preferably from 1.6 to 2.1. In HPMC (b) any preferred range for DS(methoxyl) can be combined with any preferred range for MS(hydroxypropoxyl). The determination of the % methoxyl and % hydroxypropoxyl and the subsequent conversion into DS(methoxyl) and MS(hydroxypropoxyl) are carried out in the same manner as described above for HPMC (a). The HPMC (b) generally has a viscosity of from 1.2 to 20 mPa-s, preferably from 1.5 to 10 mPa-s, more preferably from 1.5 to 5 mPa-s, and most preferably from 1.5 to 2.4 mPa-s, measured as a 2.0 weight-% solution in water at 20 °C using an Ubbelohde viscometer.

The HPACAS of the present invention is a heteropolymer that has preferably been produced by esterification of a cellulose ether (a) at an amount of from 30 to 95 weight percent, preferably from 45 to 95 weight percent, more preferably from 55 to 90 weight percent, and most preferably from 65 to 85 weight percent, and of a hydroxypropyl methyl cellulose (b) at an amount of from 5 to 70 weight percent, preferably from 5 to 55 weight percent, more preferably from 10 to 45 weight percent, and most preferably from 15 to 35 weight percent, based on the total weight of (a) and (b).

In the HPACAS heteropolymer of the present invention the molar substitution of hydroxypropoxyl groups, MS(hydroxypropoxyl), generally is in the range of from 0.1 to 1.2, preferably from 0.13 to 0.9, more preferably from 0.15 to 0.7, and most preferably from 0.25 - 0.55.

When the cellulose ether (a) used for producing the HPACAS heteropolymer is methylcellulose or hydroxypropyl methylcellulose, a hydroxypropyl methyl cellulose acetate succinate (HPMCAS) heteropolymer results which generally has a DS(methoxyl) in the range of 1.0 to 2.7, preferably from 1.1 to 2.5, more preferably from 1.1 to 2.2 and most from 1.6 to 2.1.

When the cellulose ether (a) used for producing the HPACAS heteropolymer is ethylcellulose, a HPACAS heteropolymer results which generally has a degree of substitution of ethoxyl groups, DS(ethoxyl), of from 0.1 to 2.5, preferably from 0.5 to 2.3, more preferably from 0.8 to 2.0, and most preferably from 0.9 to 1.6 and a DS(methoxyl) in the range of 0.3 to 2.4, preferably from 0.5 to 2.3, more preferably from 0.8 to 2.2 and most from 1.0 to 2.1.

In the HPACAS heteropolymer of the present invention the content of hydroxypropoxyl groups and methoxyl groups is determined in the same manner as described for “Hypromellose”, United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469. If the HPACAS heteropolymer of the present invention additionally comprises ethoxyl groups, the DS(ethoxyl) can be determined in the same manner as for ethylcellulose according to Zeisel gas chromatographic technique as described in ASTM D4794-94(2003).

The HPACAS heteropolymer of the present invention generally has a degree of substitution of acetyl groups of from 0.05 to 1.75, preferably from 0.10 to 1.30, more preferably from 0.15 to 1.25, and most preferably from 0.20 to 0.90. The HPACAS of the present invention generally has a degree of substitution of succinoyl groups of 0.02 to 1.6, preferably of 0.05 to 1.30, more preferably of 0.05 to 1.00, and most preferably of 0.10 to 0.70 or even 0.10 to 0.60. The sum of i) the degree of substitution of acetyl groups and ii) the degree of substitution of succinoyl groups is generally from 0.07 to 2.0, preferably from 0.10 to 1.4, more preferably from 0.30 to 1.55 and most preferably from 0.40 to 1.00.

The content of the acetate and succinate ester groups is determined according to “Hypromellose Acetate Succinate, United States Pharmacopia and National Formulary, NF 29, pp. 1548-1550”. Reported values are corrected for volatiles (determined as described in section “loss on drying” in the above HPMCAS monograph).

The contents of ether and ester groups obtained by the above analyses are converted to DS and MS values of individual substituents according to the formulas below. The formulas may be used in analogue manner to determine the DS and MS of substituents of other cellulose ether groups, such as ethyl. % cellulose backbone

M(OCH₃) - M(OH)\

= 100 - %MeO *

M(OCH₃)

%MeO %HPO

M(0CH₃)

DS(Me) = MS(HP) = _ _

%cellulose backbone ^ ' %cellulose backbone

M(AGU) M(AGU)

%Acetyl %Succinoyl M (Acetyl) M(Succinoyl)

DS(Acetyl) = DS(Succinoyl) =

%cellulose backbone %cellulose backbone

M(AGU) M(AGU)

M(MeO) = M(OCH₃) = 31.03 Da M(HPO) = M(OCH₂CH(OH)CH₃) = 75.09 Da M (Acetyl) = M(COCH₃) = 43.04 Da M(Succinoyl) = M(C0C₂H₄C00H) = 101.08 Da M(AGU) = 162.14 Da M(OH) = 17.008 Da M(H) = 1.008 Da

By convention, the weight percent is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents. The content of the methoxyl group is reported based on the mass of the methoxyl group (i.e., -OCH3). The content of the hydroxypropoxyl group is reported based on the mass of the hydroxypropoxyl group (i.e., -0-CH2CH(CH3)-0H). The content of the acetyl groups is reported based on the mass of acetyl (-C(0)-CH₃). The content of the succinoyl group is reported based on the mass of succinoyl groups (i.e., - C(O) - CTb - CH2 - COOH). The content of the ethoxyl group, if present, is reported based on the mass of the ethoxyl group (i.e., -OCH2CH3). The HP AC AS, preferably the HPMCAS polymers, of the present invention generally have a weight average molecular weight M_w of from 10,000 to 350,000 Dalton, preferably from 20,000 to 300,000 Dalton, more preferably from 30,000 to 250,000 Dalton, and most preferably from 40,000 to 200,000 Dalton. The HPACAS, preferably the HPMCAS polymers, of the present invention generally have a number average molecular weight M_nof from 5000 to 150,000 Dalton, preferably from 10,000 to 80,000 Dalton, more preferably from 15,000 to 70,000 Dalton, and most preferably from 20,000 to 60,000 Dalton. M_wand M_nare measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 using a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH2PC>4 and 0.1 M NaNCb as mobile phase. The mobile phase is adjusted to a pH of 8.0. The measurement of M_w and M_nis described in more details in the Examples.

Most preferably, the hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer of the present invention is a hydroxypropyl methyl cellulose acetate succinate (HPMCAS) heteropolymer. The HPMCAS heteropolymers of the present invention have the general, preferred, more preferred and most preferred molar substitution of hydroxypropoxyl groups (MS(hydroxypropoxyl)), the general, preferred, more preferred and most preferred degree of substitution (DS) of methoxyl groups (DS(methoxyl)), the general, preferred, more preferred and most preferred degree of substitution of acetyl groups and the general, preferred, more preferred and most preferred degree of substitution of succinoyl group, the general, preferred, more preferred and most preferred weight average molecular weights Mw and the general, preferred, more preferred and most preferred number average molecular weights Mn that are described above for the HPACAS heteropolymer.

The present invention further relates to a process for producing a hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymer wherein (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 are esterified with acetic anhydride and succinic anhydride. The cellulose ether (a) and the hydroxypropyl methyl cellulose (b) are esterified in combination, i.e., in the same reactor. Preferred cellulose ethers (a), preferred hydroxypropyl methyl celluloses (b), and the preferred produced hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymers are described above. Most preferably, the cellulose ether (a) is a hydroxypropyl methyl cellulose (a) and both hydroxypropyl methyl celluloses (a) and (b), each independently, have a viscosity of from 1.2 to 20 mPa-s, preferably from 1.5 to 10 mPa-s, and more preferably from 1.5 to 5 mPa-s, measured as a 2.0 weight-% solution in water at 20 °C using an Ubbelohde viscometer. Most preferably at least one of the hydroxypropyl methyl celluloses (a) and (b) have a viscosity of from 1.5 to 2.4 mPa-s, measured as a 2.0 weight-% solution in water at 20 °C using an Ubbelohde viscometer. The amounts of cellulose ether (a) and hydroxypropyl methyl cellulose (b) are from 30 to 95 weight percent, preferably from 45 to 95 weight percent, more preferably from 55 to 90 weight percent, and most preferably from 65 to 85 weight percent of cellulose ether (a) and from 5 to 70 weight percent, preferably from 5 to 55 weight percent, more preferably from 10 to 45 weight percent, and most preferably from 15 to 35 weight percent of hydroxypropyl methyl cellulose (b), based on the total weight of (a) and (b).

The cellulose ether (a) and hydroxypropyl methyl cellulose (b) are typically mixed with an aliphatic carboxylic acid as a reaction medium, such as acetic acid, propionic acid, or butyric acid. The reaction medium can comprise minor amounts of other solvents or diluents which are liquid at room temperature and do not react with the cellulose ether, such as halogenated C1-C3 derivatives like dichloro methane or dichloro methyl ether, but the amount of the aliphatic carboxylic acid should generally be more than 50 percent, preferably at least 75 percent, and more preferably at least 90 percent, based on the total weight of the reaction medium. Most preferably the reaction medium consists of an aliphatic carboxylic acid. The amount of the aliphatic carboxylic acid is generally 100 to 2,000 parts by weight per 100 parts by total weight of the cellulose ether (a) and hydroxypropyl methyl cellulose (b). The order of addition of the cellulose ether (a) and the hydroxypropyl methyl cellulose (b) to the aliphatic carboxylic acid is not critical, but both should generally be added to the reaction vessel before the reaction mixture is heated to a temperature at which the esterification takes place. The esterification reaction is generally conducted in the presence of an esterification catalyst, preferably in the presence of an alkali metal carboxylate, such as sodium acetate or potassium acetate. The amount of the alkali metal carboxylate is preferably 20 to 200 parts by weight of the alkali metal carboxylate per 100 parts by total weight of the cellulose ether (a) and hydroxypropyl methyl cellulose (b). Acetic anhydride and succinic anhydride may be introduced into the reaction vessel at the same time or separately one after the other. The amount of each anhydride to be introduced into the reaction vessel is determined depending on the desired degree of esterification to be obtained in the final product, usually being 1 to 10 times the stoichiometric amounts of the desired molar degree of substitution of the anhydroglucose units by esterification.

The mixture is generally heated at 60 °C to 110 °C, preferably at 70 to 100 °C, for a period of time sufficient to complete the reaction, that is, typically from 2 to 25 hours, more typically from 2 to 8 hours. After completion of the esterification reaction, the reaction product can be precipitated from the reaction mixture in a known manner, for example by contacting the reaction mixture with a large volume of water, such as described in U.S. Patent No. 4,226,981, International Patent Application WO 2005/115330 or European Patent Application EP 0219426. In a preferred embodiment of the invention the reaction product is precipitated from the reaction mixture as described in International Patent Application WO2013/148154 to produce an esterified cellulose ether in the form of a powder.

Another aspect of the present invention is a process for producing a hot-melt extruded HPACAS heteropolymer which comprises the steps of producing a HPACAS heteropolymer according to the above-mentioned process and extruding the HPACAS heteropolymer at a temperature of 180 °C or less, preferably 175 °C or less. In the most preferred embodiments of the invention, the HPACAS heteropolymer of the present invention can even be extruded at a temperature of 170 °C or less, 160 °C or less, or even 155 °C or less. The extrusion temperature of the undiluted HPACAS heteropolymer of the present invention generally is 140 °C or more, typically 150 °C or more. Preferred hydroxypropyl alkyl cellulose acetate succinate (HPACAS) heteropolymers of the present invention, such as preferred hydroxypropyl methyl cellulose acetate succinate (HPMCAS) heteropolymers are described further above.

Typically, the HPACAS heteropolymer is blended with an active ingredient and an optional adjuvant before it is subjected to extrusion.

Preferred active ingredients are as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements and drugs. One or more drugs are the most preferred active ingredients. The term "drug" is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans. 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. The invention finds greater utility as the aqueous solubility of the drug decreases. 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. The active ingredient does not need to be a low-solubility active ingredient in order to benefit from this invention, although low-solubility active ingredients represent a preferred class for use with the invention. An active ingredient that exhibits appreciable aqueous solubility in the desired environment of use may have an aqueous solubility up to 1 to 2 mg/mL, or even as high as 20 to 40 mg/mL. Useful low-solubility drugs are listed in the International Patent Application WO 2005/115330, pages 17 - 22.

Preferred optional adjuvants are coloring agents, pigments, opacifiers, flavor and taste improvers, antioxidants, plasticizers and any combination thereof.

The term “extrusion” as used herein includes processes known as injection molding, melt casting and compression molding. Techniques for extruding, preferably for melt 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 872233. The above-mentioned HPACAS heteropolymer, active ingredient(s) and an optional adjuvant(s) are preferably mixed in the form of particles, more preferably in powdered form. The HPACAS heteropolymer, active ingredient(s) and an optional adjuvant(s) may be pre-mixed before feeding the blend into a device utilized for extrusion. Useful devices for extrusion, specifically useful extruders, are known in the art. Alternatively, the HPACAS heteropolymer, active ingredient(s) and an optional adjuvant(s) may be fed separately into the extruder and blended in the device before or during a heating step. Preferably HPACAS heteropolymer, active ingredient(s) and an optional adjuvant(s) 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. The blend is subjected to melt-extrusion and caused to exit the extruder. Typical extrusion temperatures are from 50 to 190 °C, preferably from 70 to 180°C, more preferably from 90 to 170°C, as determined by the setting for the extruder heating zone(s). The preferred extrusion temperatures depend on the specific HPACAS heteropolymer utilized for extrusion, and the types of active ingredient(s) and an optional adjuvant(s). An operating temperature range should be selected that will minimize the degradation or decomposition of the active ingredient and other components of the composition during processing. Single or multiple screw extruders, preferably twin screw extruders, can be used in the extrusion process. The molten or softened mixture obtained in the extruder is forced through one or more exit openings, such as one or more nozzles or dies. The molten or softened mixture then exits via a die or other such element having one or a plurality of openings, at which time, the extruded blend (now called the extrudate) begins to harden. Since the extrudate is still in a softened state upon exiting the die, the extrudate may be easily shaped, molded, chopped, spheronized into beads, cut into strands, tabletted or otherwise processed to the desired physical form. The extrudate can optionally be cooled to hardening and ground into a powdered form.

Yet another aspect of the present invention is a solid dispersion comprising the above-mentioned HPACAS heteropolymer and at least one active ingredient. The solid dispersion is preferably prepared by hot-melt extrusion as described above. The amount of the active ingredient, preferably a drug, in the solid dispersion is generally is at least 0.1 percent, preferably at least 1 percent, more preferably at least 3 percent, most preferably at least 5 percent and generally up to 70 percent, preferably up to 50 percent, more preferably up to 30 percent, most preferably up to 25 percent, based on the total weight of the solid dispersion.

Some embodiments of the invention will now be described in detail in the following Examples.

EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. In the Examples the following test procedures are used.

Viscosity of Hydroxypropyl Methyl Cellulose (HPMC) samples

The viscosity of the HPMC samples was measured as a 2.0 % by weight solution in water at 20°C ± 0.1 °C. The 2.0 % by weight HPMC solution in water was prepared according to United States Pharmacopeia (USP 35, “Hypromellose”, pages 3467-3469), followed by an Ubbelohde viscosity measurement according to DIN 51562-1:1999-01 (January 1999).

Content of ether and ester groups

The content of methoxyl and hydroxypropoxyl groups in the hydroxypropoxyl methylcellulose (HPMC) and hydroxypropoxyl methylcellulose acetate succinate (HPMCAS) heteropolymer was determined as described for “Hypromellose”, United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469. The ester substitutions with acetyl groups (-CO-CH3) and with succinoyl groups (-CO-CH2-CH2-COOH) were determined according to Hypromellose Acetate Succinate, United States Pharmacopeia and National Formulary, NF 29, pp. 1548-1550. Reported values for ester substitution were corrected for volatiles (determined as described in section “loss on drying” in the above HPMCAS monograph).

Determination of M_w and Mn

Mw and M_n were measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 unless stated otherwise. The mobile phase was a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaFhPCri and 0.1 M NaNCb. The mobile phase was adjusted to a pH of 8.0. Solutions of the HPMCAS heteropolymer were filtered into a HPLC vial through a syringe filter of 0.45 pm pore size. The exact details of measuring M_w and M_n were disclosed in the International Patent Application No. WO 2014/137777 in the section “Examples” under the title “Determination of M_w, M_nand M_z”.

Differential Scanning Calorimetry (DSC)

Dried HPMCAS polymers of all examples and comparative examples were analyzed by DSC according to the DSC temperature program: Isothermal 5.0 min; modulate temperature 0.63 °C for 60 sec.; ramp 2 °C/min to 200 °C, ramp 10 °C/min to 20 °C, equilibrate 20 °C, Isothermal 5.0 min; modulate temperature 0.63 °C for 60 sec.; ramp 2 °C/min to 200 °C; mark end of the cycle. Glass transition temperature Tg was observed as midpoint temperature, which is the point on the thermal curve corresponding to ½ the heat flow difference between the extrapolated onset and extrapolated end. Details on DSC curves and how to determine the Tg midpoint temperature, the extrapolated onset and extrapolated end can be found in ASTM E 1356 - 98.

All Examples only exhibited a single glass transition temperature Tg. None of the Examples showed two glass transition temperatures. This indicates that in all Examples the esterification of a blend of two different types of HPMC resulted in a real HPMCAS heteropolymer instead of in a blend of two different HPMCAS polymers. Determination of extrudabilitv

In each experiment 30 g of the HPMCAS was kneaded in in Brabender™ Plasti- corder™ 2000 kneader. HPMCAS powder was added to the rheometer at 85 °C. Heating from 90 to 210 °C was conducted within 2 hours.

When the HPCAS is still in powder form, the torque is close to zero. A sharp increase of the torque indicates melting of the HPCAS. Experience shows that the HPMCAS is sufficiently softened and/or molten to be well extrudable at a torque of 11 N. Hence, the temperature was determined at which the torque of the softened and/or molten HPMCAS was 11 N.

Hydroxypropyl methyl cellulose (HPMC) utilized as starting material

HPMC (a-1): HPMC (a-1) has a DS(methoxyl) of 1.93, an MS(hydroxypropoxyl) of 0.25 and a viscosity of 2.9 mPa-s as a 2.0 wt. % solution in water at 20°C.

HPMC (a-2): HPMC (a-2) has a DS(methoxyl) of 1.94, an MS(hydroxypropoxyl) of 0.25 and a viscosity of 1.9 mPa-s as a 2.0 wt. % solution in water at 20°C.

HPMC (b-1): HPMC (b-1) has a DS(methoxyl) of 1.97, an MS(hydroxypropoxyl) of 0.94 and a viscosity of 5.1 mPa-s as a 2.0 wt. % solution in water at 20°C.

HPMC (b-2): HPMC (b-1) has a DS(methoxyl) of 1.96, an MS(hydroxypropoxyl) of 0.96 and a viscosity of 2.3 mPa-s as a 2.0 wt. % solution in water at 20°C.

Production of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS) polymers

Comparative Example A and Example 1

The hydroxypropyl methylcellulose (HPMC, water free) used as a starting material consisted either of HPMC (a) alone or a blend of HPMC (a) and HPMC (b). The type of HPMC (a) was designated as HPMC (a-1). The type of HPMC (b) was designated as HPMC (b-1). The properties of HPMC (a-1) and HPMC (b-1) are listed above. The weight ratios of HPMC (a-1) and HPMC (b-1) are listed in Table 1 below.

608.62 g of glacial acetic acid, as listed in Table 1 below, 230 g of HPMC and 49.72 g of sodium acetate (water free) were introduced into a reaction vessel under thorough stirring. The mixture was heated to 85° C. Subsequently 37.15 g of succinic anhydride and 155.69 g of acetic anhydride were added. The mixture was allowed to react for 30 min. Subsequently 149.15 g of sodium acetate was added and the mixture was reacted for 3 hours under stirring at 85° C. After esterification 2 L of water was added to the reactor under stirring to precipitate the HPMCAS.

I. Washing under high shearing: The precipitated HPMCAS heteropolymers of Example 1 and Comparative Example A were removed from the reactor and separately washed three times with 1 - 2 L of water by applying high shear mixing using an Ultra- Turrax stirrer S50-G45 running at 5000 rpm for 1 min., followed by suction filtration.

II. Intermediate washing step in Comparative Example A: In Comparative Example A the above-mentioned repeated washing by applying high shear was not sufficient. The HPMCAS of Comparative Example A was washed in portions on a suction filter with 10 L of water in total. As still lumps were visible, the HPMCAS of Comparative Example A was again washed with 1.5 L of water by applying high shear mixing using an Ultra-Turrax stirrer S50-G45 running at 5000 rpm for 1 min., followed by suction filtration. In Example 1 this intermediate washing step was not needed.

III. Washing to reach a pH of 6-7: After the washing step I. under high shearing and the intermediate washing step II, the HPMCAS of Comparative Example A was washed with 15 L of water to reach a pH of 6-7. The HPMCAS of Example 1 was washed with 17 L of water to reach a pH of 6-7 directly after the washing step I, without conduction an intermediate washing step II.

In Comparative Example A the total amount of water needed for washing in steps I, II and III was 30.5 L. In Example 1 the total amount of water needed for washing in steps I and III was and 23 L. The HPMCAS polymers of Example 1 and Comparative Example A were isolated by filtration and dried at 55°C overnight.

Comparative Example B

788 g of glacial acetic acid, 230 g of HPMC (b-1) and 57.5 g of sodium acetate (water free) were introduced into a reaction vessel under thorough stirring. The mixture was heated to 85° C. Subsequently 69 g of succinic anhydride and 230 g of acetic anhydride were added. The mixture was allowed to react for 30 min. Subsequently 172.5 g of sodium acetate was added and the mixture was reacted for 3 hours under stirring at 85° C. After esterification 2.3 L of water was added to the reactor under stirring to precipitate the HPMCAS.

The precipitated product was very sticky and agglomerated like chewing gum. The precipitated product was much stickier than the precipitated products of Examples 2 - 13 according to the present invention. Due to the small, laboratory scale of Comparative Example B, the sticky precipitated product could be removed and washed as described below, but on larger scale such a sticky material is nearly not processable.

The precipitated product was removed from the reactor and washed three times with 3 L of water by applying high shear mixing using an Ultra-Turrax stirrer S50-G45 running at 5000 rpm for 3, 2 and 2 min. The product was then washed with 12 L of water to reach a pH of 6-7. The total amount of water used for washing was about 21 L of water. The product was isolated by filtration and dried at 55°C overnight.

Examples 2 - 4

The hydroxypropyl methylcellulose (HPMC, water free) used as a starting material consisted of a blend of HPMC (a) and HPMC (b). Two different types of HPMC (a) were used, designated as HPMC (a-1) and HPMC (a-2). Also two different types of HPMC (b) were used, designated as HPMC (b-1) and HPMC (b-2). The properties of HPMC (a-1), HPMC (a-2), HPMC (b-1) and HPMC (b-2) are listed above. The weight ratios of HPMC (a) and HPMC (b) are listed in Table 1 below.

608.62 g of glacial acetic acid, as listed in Table 1 below, 230 g of HPMC, 230 g of sodium acetate (water free), 37.15 g of succinic anhydride and 155.69 g of acetic anhydride were introduced into a reaction vessel under thorough stirring. The mixture was heated to 85° C and allowed to react for 3.5 hours. After esterification 2 L of water was added to the reactor under stirring to precipitate the HPMC AS.

The precipitated product was removed from the reactor and washed twice with 3 L of water by applying high shear mixing using an Ultra-Turrax stirrer S50-G45 running at 5000 rpm for 60 sec. After filtration the product was washed 3 times with 4L of water to reach a pH of 6-7. The product was isolated by filtration and dried at 55°C overnight.

Examples 5 - 13

The hydroxypropyl methylcellulose (HPMC, water free) used as a starting material consisted of a blend of HPMC (a) and HPMC (b). Two different types of HPMC (a) were used, designated as HPMC (a-1) and HPMC (a-2). Also two different types of HPMC (b) were used, designated as HPMC (b-1) and HPMC (b-2). The properties of HPMC (a-1), HPMC (a-2), HPMC (b-1) and HPMC (b-2) are listed above. The weight ratios of HPMC (a) and HPMC (b) are listed in Table 1 below. 538.62 g of glacial acetic acid, as listed in Table 1 below, 230 g of HPMC and 49.72 g of sodium acetate (water free) were introduced into a reaction vessel under thorough stirring. The mixture was heated to 85° C. Subsequently 37.15 g of succinic anhydride and 155.69 g of acetic anhydride were added. The mixture was allowed to react for 30 min. Subsequently 149.15 g of sodium acetate was added and the mixture was reacted for 3 hours under stirring at 85° C. After esterification 2 L of water was added to the reactor under stirring to precipitate the HPMC AS.

The precipitated product was removed from the reactor and washed three times with 3 L of water by applying high shear mixing using an Ultra-Turrax stirrer S50-G45 running at 5000 rpm for 1 min. The product was then washed with 13 - 20 L of water to reach a pH of

6-7. The total amount of water used for washing was 22 - 29 L of water. In none of the examples an intermediate washing step II was needed that had been carried out in Comparative Example A. The product was isolated by filtration and dried at 55°C overnight.

Table 1

DSM = DS(methyloxyl): degree of substitution with methoxyl groups MSHP = MS(hydroxypropoxyl): molar substitution with hydroxypropoxyl groups DOSA_C: degree of substitution of acetyl groups 5 DOS_s: degree of substitution of succinoyl groups

The comparison between Comparative Example A and Example 1 illustrates that the heteropolymers of the present invention, which are produced by esterifying a blend of two different types of HPMC, are extrudable at a considerably lower temperature than the HPMCAS of Comparative Example 1. The HPMCAS heteropolymer of Example 1 is extrudable at a temperature that is 15 °C lower than that of the HPMCAS polymer of Comparative Example A.

The thoroughly purified HPMCAS of Comparative Example B was well extrudable. However, the crude HPMCAS of Comparative Example B was much stickier after precipitation than the crude HPMCAS heteropolymers of the inventive Examples 2 - 13. On production scale such a sticky crude material is extremely difficult to process in the required subsequent purification steps.

Examples 1 and 2 illustrate that extrusion at reduced temperature is achieved at different weight ratios of HPMC (a) to HPMC (b).

Examples 3 and 4 illustrate that the extrusion temperature can be even further reduced when a HPMC having a viscosity of 1.9 mPa-s as a 2.0 wt. % solution in water at 20°C is used for producing the HPMCAS heteropolymer of the present invention.

Examples 5 - 13 illustrate that extrusion at reduced temperature is also achieved at a different amount of acetic acid, at different weight ratios of HPMC (a) to HPMC (b) or when using a different HPMC (b) than in Comparative Example A. Moreover, Examples 10 - 13 illustrate that the extrusion temperature can be even further reduced when a HPMC having a viscosity of 1.9 mPa-s as a 2.0 wt. % solution in water at 20°C is used for producing the HPMCAS heteropolymer of the present invention.

Claims

1. A hydroxypropyl alkyl cellulose acetate succinate heteropolymer produced by esterification of (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 with acetic anhydride and succinic anhydride.

2. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of claim 1 wherein the cellulose ether (a) is selected from i) methylcelluloses having a degree of substitution of methoxyl groups of from 1.0 to 2.7, ii) ethylcelluloses having a degree of substitution of ethoxyl groups of from 0.5 to 3, and iii) hydroxypropyl methyl celluloses having a degree of substitution of methoxyl groups of from 1.0 to 2.7 and a hydroxypropoxy molar substitution of from 0.05 to 0.35.

3. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of claim 1 wherein the cellulose ether (a) is a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of up to 0.35 or a methylcellulose and the hydroxypropyl alkyl cellulose acetate succinate heteropolymer is a hydroxypropyl methyl cellulose acetate succinate heteropolymer.

4. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of any one of claims 1 to 3 wherein the cellulose ether (a) is a hydroxypropyl methyl cellulose having a degree of substitution of methoxyl groups of from 1.1 to 2.5 and a hydroxypropoxy molar substitution of from 0.10 to 0.30.

5. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of any one of claims 1 to 4 wherein the hydroxypropyl methyl cellulose (b) has a degree of substitution of methoxyl groups of 1.0 to 2.7 and a hydroxypropoxy molar substitution of from 0.40 to 1.50.

6. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of claim 5 wherein the hydroxypropyl methyl cellulose (b) has a degree of substitution of methoxyl groups of 1.1 to 2.3 and a hydroxypropoxy molar substitution of from 0.50 to 1 20

7. The hydroxypropyl alkyl cellulose acetate succinate heteropolymer of any one of claims 1 to 6 produced by esterification of from 30 to 95 weight percent of the cellulose ether (a) and from 5 to 70 weight percent of the hydroxypropyl methyl cellulose (b), based on the total weight of (a) and (b).

8. A process for producing a hydroxypropyl alkyl cellulose acetate succinate heteropolymer wherein (a) a cellulose ether selected from methylcelluloses, ethylcelluloses and hydroxypropyl methyl celluloses having a hydroxypropoxy molar substitution of up to 0.35 and (b) a hydroxypropyl methyl cellulose having a hydroxypropoxy molar substitution of from 0.40 to 1.90 in combination are esterified with acetic anhydride and succinic anhydride.

9. The process of claim 8 wherein the cellulose ether (a) and the hydroxypropyl methyl cellulose (b), each independently, have a viscosity of from 1.5 to 10 mPa-s, measured as a 2 weight-% solution in water at 20 °C.

10. The process of claim 8 or claim 9 wherein the cellulose ether (a) is a hydroxypropyl methyl cellulose (a) and at least one of the hydroxypropyl methyl celluloses (a) and (b) has a viscosity of from 1.5 to 2.4 mPa-s, measured as a 2 weight-% solution in water at 20 °C.

11. The process of any one of claims 8 to 10 wherein the hydroxypropyl alkyl cellulose acetate succinate heteropolymer of any one of claims 1 to 6 is produced.

12. A process for producing a hot-melt extruded hydroxypropyl alkyl cellulose acetate succinate heteropolymer which comprises the steps of producing a hydroxypropyl alkyl cellulose acetate succinate heteropolymer according to the process of any one of claims 8 to 11 and extruding the hydroxypropyl alkyl cellulose acetate succinate heteropolymer at a temperature of 180 °C or less.

13. The process of claim 12 wherein the produced hydroxypropyl alkyl cellulose acetate succinate heteropolymer is blended with an active ingredient and an optional adjuvant before it is subjected to extrusion.

14. A solid dispersion comprising the hydroxypropyl alkyl cellulose acetate succinate heteropolymer of any one of claims 1 to 7 and at least one active ingredient.

15. The solid dispersion of claim 14 that has been prepared by hot-melt extrusion.