OLANZAPINE PAMOATE PROCESS AND POLYMORPHS

INTRODUCTION An aspect of the present application provides processes for the preparation of olanzapine pamoate. An aspect provides processes for the purification of pamoic acid. Aspects of the present application also relate to amorphous form of olanzapine pamoate and processes for its preparation.

The drug compound having the adopted name "olanzapine" has a chemical name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. It has the structure of formula (II). Olanzapine is an atypical antipsychotic that belongs to the thienobenzodiazepine class

The salt of olanzapine called "olanzapine pamoate" is the active ingredient in products sold as ZYPREXA® RELPREW™ for injectable suspension, and has a chemical name 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1- piperazinyl)-4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate] (1:1), monohydrate. It has the structure of formula (I).

U.S. Patent No. 6,169,084 discloses olanzapine pamoate, its dimethanolate solvate, its tetrahydrofuran solvate, its monohydrate, bis(olanzapine) pamoate monohydrate, and bis(olanzapine) pamoate acetone solvate. U.S. Patent Application Publication No. 2008/0096871 A1 discloses olanzapine pamoate dihydrate.

There remains a need to provide improved processes for the preparation of olanzapine pamoate, new polymorphic forms of olanzapine pamoate and processes for making the new polymorphic forms.

SUMMARY

In an aspect, the present application provides processes for the preparation of olanzapine pamoate, comprising one or more of the following steps, individually or in the sequence recited:

(a) reacting olanzapine with substantially pure pamoic acid of formula (III); and

(b) isolating olanzapine pamoate.

In an aspect, the present application provides processes for the preparation of substantially pure pamoic acid, comprising:

(a) treating pamoic acid with a solvent; and

(b) isolating substantially pure pamoic acid.

In an aspect, the present application provides a crystalline form of pamoic acid of formula (III), characterized by a powder X-ray diffraction (PXRD) pattern having peak locations substantially as shown in Fig. 1.

In an aspect, the present application provides a crystalline form of pamoic acid of formula (III), characterized by any one or more of: a powder X-ray diffraction (PXRD) pattern substantially as illustrated by Fig. 1; a differential scanning calorimetry (DSC) curve substantially as illustrated by Fig. 2; and a thermogravimetric analysis (TGA) curve substantially as illustrated by Fig. 3.

In an aspect, the present application provides an amorphous form of olanzapine pamoate.

In an aspect, the present application provides a process for the preparation of an amorphous form of olanzapine pamoate, comprising:

a) providing a solution of olanzapine pamoate in a solvent or mixture of solvents; and

b) isolating an amorphous form of olanzapine pamoate.

In an aspect, the present application provides an amorphous form of olanzapine pamoate characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Fig. 4.

In an aspect, the present application also provides a pharmaceutical composition comprising amorphous form of olanzapine pamoate along with one or more pharmaceutically acceptable carriers, excipients, or diluents.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of a PXRD pattern of crystalline pamoic acid, prepared according to Example 1.

Fig. 2 is an illustration of a DSC curve of crystalline pamoic acid, prepared according to Example 1.

Fig. 3 is an illustration of a thermogravimetric analysis (TGA) curve of crystalline pamoic acid, prepared according to Example 1.

Fig. 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of an amorphous form of olanzapine pamoate prepared according to Example 9.

DETAILED DESCRIPTION

In an aspect, the present application provides processes for the preparation of olanzapine pamoate, comprising one or more of the following steps, individually or in the sequence recited:

(a) reacting olanzapine with substantially pure pamoic acid; and

(b) isolating olanzapine pamoate.

Pamoic acid that may be used in a process of the present application may be obtained by any process, including processes described in the art. Optionally, pamoic acid may be purified by recrystallization one or more times from a suitable solvent, prior to use in step (a).

Suitable solvents that may be used for the purification of pamoic acid include, but are not limited to: water; nitrites; polar aprotic solvents; esters; ethers; ketones; halogenated hydrocarbons; aromatic hydrocarbons; aliphatic or acyclic hydrocarbons; and any mixtures of two or more thereof.

Step (a) may be carried out in a suitable solvent. Suitable solvents that may be used in step (a) include, but are not limited to: water; nitriles; polar aprotic solvents; esters; ethers; ketones; halogenated hydrocarbons; aromatic hydrocarbons; aliphatic or acyclic hydrocarbons; and any mixtures of two or more thereof.

Suitable temperatures that may be used in step (a) may be less than about 55°C, less than about 45°C, less than about 40°C, less than about 35°C, less than about 30°C, less than about 25°C, less than about 20°C, less than about 15°C, less than about 10°C, and any other suitable temperature.

Step b) involves isolating olanzapine pamoate. The isolation in step (b) may be effected by any methods, including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, adding seed crystals, and the like. Suitable temperatures for isolation may be less than about 55°C, less than about 50°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, and any other suitable temperatures. Suitable times for the isolation may be less than about 5 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or longer times may be used. The exact temperatures and times required for complete isolation may be readily determined by a person skilled in the art and will also depend on parameters, such as, for example, concentration and temperature of the solution or slurry. Stirring or other alternate methods, such as, for example, shaking, agitation, andr the like that mix the mass may also be employed for isolation.

The isolated compound may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. The olanzapine pamoate thus isolated may carry some amount of occluded mother liquor and have higher than desired levels of impurities. The solid may be washed with a suitable solvent or a mixture of solvents, such as, for example, those used in step (a), to remove the impurities.

The recovered solid may optionally be further dried. Drying may be carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, less than about 50°C, less than about 50°C, less than about 45°C, less than about 40°C, less than about 35°C, less than about 30°C, and any other suitable temperatures, as long as the olanzapine pamoate is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 20 hours, or longer.

The dried product may be optionally milled to produce the required particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, sifting, milling using mills, such as, for example, ball, roller and hammer mills, and jet mills, including, for example, air jet mills, and any other conventional techniques. The desired particle sizes may also be achieved directly from the reaction mixture by the choice of equipment that is able to provide olanzapine pamoate with the desired particle sizes.

In embodiments, the temperatures that are used in various operations in the preparation of olanzapine pamoate of the present application can affect the formation of an impurity at RRT (relative retention time) of 1.96 by the high performance liquid chromatography (HPLC) analysis method described below, the impurity having a mass number of m/z 330 as characterized by liquid chromatography-mass spectroscopy (LC-MS) analysis. The structure of the impurity at RRT 1.96 is believed to be formula (V).

The temperatures that may be suitably used for various operations in the preparation of olanzapine pamoate of the present application may be less than about 55°C, less than about 50°C, less than about 45°C, less than about 40°C, less than about 35°C, less than about 30°C, in order to control the amounts of the impurity at RRT 1.96 to concentrations less than about 0.05% by weight, as measured by HPLC.

The "various operations" as used herein include, but are not limited to, dissolution, stirring, distillation, evaporation, filtration, drying, milling, and storing.

It has been observed that the temperatures used for dying or storing olanzapine pamoate of the present application affect the formation of the impurity at RRT 1.96.

Olanzapine pamoate prepared according to the present application may be substantially free of one or more of the corresponding impurities as measured by HPLC.

"Substantially free" of one or more of the corresponding impurities as used herein, unless otherwise defined, refers to containing: less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.1%, less than about 0.05%, or less than about 0.03%, by weight, of each individual drug-related impurity including, without limitation, a compound of formula (V), a compound of formula (IV), and any other drug compound-related impurity; and that contains a total amount of drug compound-related impurities in amounts less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.1%, less than about 0.05%, or less than about 0.03%, by weight; as measured by HPLC.

A high performance liquid chromatography method for the analysis of olanzapine pamoate of formula (I) utilizes a Symmetry Shield or equivalent column. Additional parameters are as shown in Table 1.

In an aspect, the present application provides processes for the preparation of substantially pure pamoic acid, comprising:

(a) treating pamoic acid with a solvent; and

(b) isolating substantially pure pamoic acid.

Suitable solvents that may be used in step (a) include, but are not limited to: water; nitriles; polar aprotic solvents; esters; ethers; ketones; halogenated hydrocarbons; aromatic hydrocarbons; aliphatic or acyclic hydrocarbons; and any mixtures of two or more thereof.

Suitable temperatures that may be used in step (a) may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, and any other suitable temperatures.

The isolation in step (b) may be effected by any methods, including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, adding seed crystals, or the like. Suitable temperatures for isolation may be less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, and any other suitable temperatures.
Stirring or other alternate methods, such as, for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.

The isolated compound may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids. The pamoic acid thus isolated may carry some amount of occluded mother liquor and have higher than desired levels of impurities. The solid may be washed with a suitable solvent or a mixture of solvents, such as, for example, those used in step (a), to remove the impurities.

The recovered solid may be optionally further dried. Drying may be carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, and any other suitable temperatures.

It has been discovered that the pamoic acid having a content of the compound of formula (IV) greater than about 0.01% leads to a content of the compound of formula (IV) in olanzapine pamoate in undesired amounts. In a large-scale operation, it is very difficult to purify olanzapine pamoate having such an undesired level of the compound of formula
(IV), using conventional techniques.

"Substantially pure" pamoic acid as used herein, unless otherwise defined refers to the compound that contains less than about 2%, or less than about 1.5%, or less than about 1.0%, or less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or less than about 0.05%, or less than about 0.04%, or less than about 0.03%, or less than about 0.02%, or less than about 0.01%, by weight of each individual drug compound-related impurity including, without limitation, the compound of Formula (IV) at RRT 0.89 in the HPLC method described below, and having a mass number 344; the impurity at RRT 0.79 having a mass number 432; the impurity at RRT 1.33 having a mass number 387; and any other drug-related or process-related impurity. The term also refers to pamoic acid having total amounts of drug compound-related or process-related impurities less than about 2%, or less than about 1.5%, or less than about 1%, or less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or less than about 0.05%, or less than about 0.04%, or less than about 0.03%, or less than about 0.02%, or less than about 0.01% by weight.

A HPLC method for the analysis of pamoic acid utilizes a Symmetry Shield or equivalent column. Additional parameters are as shown in Table 2.

In an aspect, the present application provides crystalline pamoic acid of Formula (III), characterized by any one or more of: a powder X-ray diffraction (PXRD) pattern substantially as illustrated by Fig. 1; a differential scanning calorimetry (DSC) curve substantially as illustrated by Fig. 2; and a thermogravimetric analysis (TGA) curve substantially as illustrated by Fig. 3.

All PXRD data reported herein were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer with copper Ka radiation. Differential scanning calorimetric analyses reported herein were carried out using a DSC Q1000 model from TA Instruments with a ramp of 10°C/minute, a starting temperature of 30°C, and an ending temperature of 350°C. Thermogravimetric analyses reported herein were carried out using a TGA Q500 V6.7 Build 203 from TA Instruments, with a ramp of 10°C/minute up to 250°C.

In an aspect, the present application provides an amorphous form of olanzapine pamoate.

In an aspect, the present application provides a process for the preparation of an amorphous form of olanzapine pamoate, comprising:

a) providing a solution of olanzapine pamoate in a solvent or mixture of solvents; and

b) isolating an amorphous form of olanzapine pamoate.

Step a) involves providing a solution of olanzapine pamoate in a solvent or mixture of solvents. Providing a solution in step a) includes:

i) direct use of a reaction mixture containing olanzapine pamoate that is obtained in the course of its synthesis; or

ii) dissolving olanzapine pamoate in a suitable solvent or mixture of solvents.

Any physical form of olanzapine pamoate may be utilized for providing the solution of olanzapine pamoate in step a). Olanzapine pamoate that may be used as the input for the process of the present application may be obtained by any process including the processes described in the art. For example olanzapine pamoate may be prepared by the processes described in US 6,169,084.

Suitable solvents that may be used in step a) include, but are not limited to, polar aprotic solvents such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole or the like; or mixtures thereof. The dissolution temperatures may range from about -20°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of olanzapine pamoate is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.

Optionally, the solution obtained above may be filtered to remove any insoluble particles.
The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step b) involves isolation of an amorphous form of olanzapine pamoate from the solution of step a).

In one embodiment, the isolation may be effected by removing solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), ball milling, and the like, or any other suitable technique.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 200°C, less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80X, or any other suitable temperatures.

Freeze drying (lyophilization) may be carried out by freezing a solution of olanzapine pamoate at low temperatures and reducing the pressure as required to remove the solvent from the frozen solution of olanzapine pamoate. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of olanzapine pamoate, may range from about -80°C to about 0°C, or up to about 20°C. Temperatures that may be required to remove the solvent from the frozen solution may be less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In another embodiment, isolation may also be effected by combining the solution of step a) with a suitable anti-solvent. Adding the solution obtained in step a) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a), to effect the crystallization process are both within the scope of the present application. Optionally, the addition may be carried out after concentrating the solution obtained in step a). Suitable anti-solvents that may be used include, but are not limited to, alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole or the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetralin or the like; or mixtures thereof.

The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The product thus isolated may be optionally further dried to afford an amorphous form of olanzapine pamoate.

Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 200°C, less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

The dried product may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.

In an aspect, the present application provides an amorphous form of olanzapine pamoate characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Fig. 4.

All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation.
In an aspect, the present application provides pharmaceutical compositions comprising olanzapine pamoate and one or more pharmaceutically acceptable excipients.
Compositions may be formulated as liquid dosage forms, such as, for example, syrups, suspensions, dispersions, and emulsions; and injectable preparations like intravenous, intradermal, intrathecal, and intramuscular depot forms, including freeze-dried compositions for reconstitution with a diluent. Pharmaceutical compositions according to the present application comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, suitable surface modifiers. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants, examples including nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearoyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene allcyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tween™ products, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropyl methylcellulose phthalates, noncrystalline cellulose, magnesium aluminate silicate, triethanolamine, polyvinyl alcohols (PVA), poloxamers, tyloxapol, and polyvinylpyrrolidones (PVP).

DEFINITIONS

The following definitions are used in connection with the present application, unless the context indicates otherwise. Celite® is a flux-calcined diatomaceous earth and is a registered trademark of World Minerals Inc. Hyflow is a flux-calcined diatomaceous earth, treated with sodium carbonate. Hyflo Super Cel® is a registered trademark of the Manville Corp.

A "polar aprotic" solvent has a dielectric constant greater than 15, including: amide-based organic compounds, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic compounds, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic compounds, such as pyridine and picoline; sulfone-based compounds, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethysulfolane, 3-sulfolene, and sulfolane; sulfoxide-based compounds such as dimethylsulfoxide (DMSO); and the like.

A "halogenated hydrocarbon" solvent is an organic compound containing a carbon bound to a halogen, including, but not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, and the like.

An "aromatic hydrocarbon" solvent is a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings and having at least one 6-carbon ring that contains three double bonds. Examples of aromatic hydrocarbons include, but are not limited to, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, and the like.

An "ether" solvent is an organic compound containing an oxygen atom -O-bonded to two other carbon atoms, such as, but not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, and the like.

An "ester" solvent is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms, such as, but not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3.6 esters, and the like.

A "nitrile" solvent is an organic compoundt containing a cyano -(C=N) bonded to another carbon atom, including, but not limited to, acetonitrile, propionitrile, C2-6 nitriles, and the like.

An "alcohol" solvent is an organic compound containing a carbon bound to a hydroxyl group, including, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6 alcohols, and the like.

A "ketone" solvent is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms, including, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, and the like.

An "aliphatic or alicyclic hydrocarbon" solvent is a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. Examples include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, and the like.

Unless specified otherwise, the word "pure" as used herein means that the material has at least about 98% purity. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, degradation products, and unreacted starting materials. "Substantially pure" as used herein means that the material has greater than about 98%, or greater than about 98.5%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.6%, or greater than about 99.7%, or greater than about 99.8%, or greater than about 99.9%, or greater than about 99.95% purity.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

Example 1: Purification of pamoic acid. Pamoic acid (200.0 g) is charged into a round-bottom flask at 25-35°C and N,N-dimethylformamide (2400 mL) is added slowly. The mixture is stirred for 5-10 minutes, then is heated to 55°C and stirred for 45-60 minutes.
The mixture is cooled to 25-35°C and maintained for 16-17 hours. The formed solid is collected by filtration, washed with N,N-dimethylformamide (200 mL) and dried at 60°C to afford 170 g of purified pamoic acid.

Purity by HPLC: 99.7%; PXRD pattern in accordance with Fig. 1; DSC curve in accordance with Fig. 2; TGA curve in accordance with Fig. 3.

Example 2: Purification of pamoic acid. Pamoic acid (5.0 g) is charged into a round-bottom flask at 25-35X and N,N-dimethylformamide (105 mL) is added slowly. The mixture is stirred for 5-10 minutes, then is heated to 55°C and stirred for 30-45 minutes.
The mixture is cooled to 25-35°C and maintained for 15-16 hours. The formed solid is collected by filtration, washed with N,N-dimethylformamide (5 mL), and dried at 55°C to afford 3.9 g of purified pamoic acid.

Purity by HPLC: 99.7%.

Example 3: Purification of pamoic acid. Pamoic acid (2 g) is charged into a round-bottom flask at 25-35°C and N,N-dimethylacetamide (8.5 mL) is added slowly. The mixture is stirred for 5-10 minutes, then is heated to 55°C and stirred for 45-60 minutes. The mixture is cooled to 25-35°C and maintained for 16 hours. The formed solid is collected by filtration, washed with N,N-dimethylacetamide (2 mL) and suction dried for 15 minutes to afford 1.1 g of purified pamoic acid.
Purity by HPLC: 99.7%.

Example 4: Preparation of olanzapine pamoate monohydrate. Pamoic acid (3.733 g) and olanzapine (3.0 g) are charged into a round-bottom flask at 25°C and stirred for 5-10 minutes. The mixture is heated to 55°C and N,N-dimethylformamide (15 mL) is added. The obtained solution is added to water (144 ml_) at 40°C and the formed slurry is stirred for 15-20 minutes at 40°C. The mixture is cooled to 25-35°C and the obtained solid is collected by filtration, washed with water (37.8 mL), and dried under reduced pressure to afford 4 g of olanzapine pamoate monohydrate.

Purity by HPLC: 99.7%; moisture content by a Karl Fischer (KF) method: 3.53% w/w; TGA weight loss: 3.10% w/w.

Example 5: Preparation of olanzapine pamoate monohydrate. Olanzapine (3.0 g) and pamoic acid (3.733 g) are charged into a round-bottom flask at 25-35°C and stirred for 5-10 minutes. The mixture is heated to 55°C and N,N-dimethylacetamide (12 mL) is added. The obtained solution is added to water (144 mL) at 40°C. The formed slurry is stirred for 20-35 minutes at 40°C and cooled to 25-35°C, and the obtained solid is collected by filtration, washed with water (37.8 mL) and dried under reduced pressure to afford 4.6 g of olanzapine pamoate monohydrate.

Purity by HPLC: 99.7%; moisture content by a KF method: 3.63% w/w; TGA weight loss: 3.06% w/w.

Example 6: Preparation of olanzapine pamoate dihydrate. Olanzapine (5.0 g) and pamoic acid (6.22 g) are charged into a round-bottom flak at 25°C and stirred for 5-10 minutes. A mixture of dimethylsulfoxide (12.5 mL) and acetonitrile (12.5 mL) is added and the mass is stirred for 5 minutes. The mass is filtered and the filtrate is transferred to another round-bottom flask. Water (30 mL) is added to the filtrate at 25°C and the mixture is stirred for 1-2 hours. The formed solid is collected by filtration, washed with water (5 mL) and acetonitrile (5 mL), and dried at 25°C to afford 10.3 g of olanzapine pamoate monohydrate.

Moisture content by a KF method: 4.85% w/w.

Example 7: Purification of pamoic acid. Pamoic acid (25.0 g) and N,N-dimethylformamdie (150 mL) are charged into a round-bottom flask at 25-35°C and stirred for 5-10 minutes. The mixture is heated to 80-85X and stirred for 30-45 minutes.
The mixture is cooled to 25-35°C and further cooled to -5°C, then is stirred at -5°C for 4-5 hours. The formed solid is collected by filtration, washed with chilled N,N-dimethylformamide (25 mL), and suction dried for 10-20 minutes.

The wet solid (34.0 g) and N, N-dimethyl formamide (138 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to 80-85°C and stirred for 20-30 minutes. The mixture is cooled to 25-35°C, further cooled to -5°C, and maintained for 4-5 hours. The obtained solid is collected by filtration, washed with N,N-dimethylformamide (23 mL) and suction dried for 10-20 minutes.

The wet solid (25.0 g) and water (250 mL) are charged into a round bottom flask at 25-35°C and stirred for 30-40 minutes. The solid is collected by filtration, washed with water (25 mL), and dried at 55-60°C under reduced pressure to afford 14.0 g of pamoic acid.

Purity by HPLC: 99.88%; compound of formula (IV): 0.01%; impurity at RRT 0.79: 0.03%; impurity at RRT 1.33: 0.03%.

Example 8: Preparation of olanzapine pamoate monohydrate.

Dimethylsulphoxide (30 mL) and olanzapine (5.0 g) are charged into a round bottom flask and stirred for 10-15 minutes at 27°C. Pamoic acid (6.22 g) is added at 27°C and the mixture is stirred for 15-20 minutes. The mixture is added to water (120 mL) at 40°C and the formed slurry is stirred for 50-60 minutes at 40°C. The mixture is cooled to 25-35°C and the solid is collected by filtration and washed with water (2x30 mL). The solid is dried at 27°C for 2-3 hours and further dried at 38°C under reduced pressure to afford 10.9 g of olanzapine pamoate monohydrate.

Purity by HPLC: 99.54%; compound of formula (V): 0.02%; compound of formula (IV); 0.04%; moisture content by a KF method: 3.48% w/w.

Example 9: Preparation of amorphous form of olanzapine pamoate.

Olanzapine pamoate (4.0 g) and N,N-dimethylformamide (80 mL) are charged in to a round-bottom flask at 25-35°C and stirred to dissolve olanzapine pamoate completely.
The resulting solution is filtered and the filtrate is evaporated through spray drying using a Biichi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295 spray-drier, to afford 2.2 g of the title compound. Parameters of the spray drier of the above experiment:

Aspirator-70%
Feedrate-10%
N2 Pressure-5.0 kgf/cm2
Inlet temperature-170°C
PXRD Pattern is shown as Fig.4.
Example 10: Preparation of amorphous form of olanzapine pamoate.
Olanzapine pamoate (4.0 g) and N,N-dimethylsulphoxide (100 ml_) are charged in to
a round-bottom flask at 25-35°C and stirred to dissolve olanzapine pamoate completely. The resulting solution is filtered and the filtrate is evaporated through spray drying to afford, 2.1 g of the title compound.
Parameters of the spray drier of the above experiment:
Aspirator-70%
Feed rate-10%
N2 Pressure-5.0 kgf/cm2
Inlet temperature-190°C
PXRD: Compiles with a reference pattern of amorphous form.

Example 11: Preparation of amorphous form of olanzapine pamoate.

Olanzapine pamoate (1.0 g) and N,N-dimethylsulphoxide (20.0 mL) are charged in to a round-bottom flask at 25-35°C and stirred for 5 minutes to dissolve olanzapine pamoate completely. The resulting solution is filtered and the filtrate is evaporated through freeze drying using VirTis® Advantage™ 2.0 bench top freeze drier, at -40°C to afford, 0.7 g of the title compound. PXRD: Compiles with a reference pattern of amorphous form.

Example 12: Preparation of amorphous form of olanzapine pamoate.

Olanzapine pamoate (1.0 g) and N,N-dimethylformamide (20.0 mL) are charged in to a round bottom flask and stirred at 25-35°C for 10-15 minutes to dissolve olanzapine pamoate completely. The resulting solution is filtered and the filtrate is evaporated completely in Buchi® Rotavapor® at 150-153°C under reduced pressure to afford, 0.95 g of the title compound. PXRD: Compiles with a reference pattern of amorphous form.

Example 13: Preparation of amorphous form of olanzapine pamoate.
Olanzapine pamoate (3.0 g) is milled in Retsch™ PM100 ball mill (bowl) for 3 hours
to afford 2.5 g of the title compound.
Parameters of Retsch PM100 ball mill (bowl):
RPM: 600
Time: 3hours
Interval: 10 minutes
Reverse rotation-Yes
PXRD: Compiles with a reference pattern of amorphous form.

Example 14: Preparation of amorphous form of olanzapine pamoate.

Olanzapine pamoate (1.0 g) and N,N-dimethylformamide (8 ml) are charged in to a round-bottom flask at 28°C and stirred to dissolve olanzapine pamoate completely. The resulting solution is filtered and is charged to a round-bottom flask containing isopropyl alcohol (100 mL) at 30°C and stirred for 2-5 minutes. The obtained solid is filtered, washed with n-heptane (100 mL) and suction dried for 10 minutes to afford 0.75 g of the title compound. PXRD: Compiles with a reference pattern of amorphous form.

We claim:

1. A process for the preparation of olanzapine pamoate, comprising: (a) reacting olanzapine with substantially pure pamoic acid of formula (III);
and

(b) isolating olanzapine pamoate.

2. A process for the preparation of substantially pure pamoic acid, comprising:

(a) treating pamoic acid with a solvent; and

(b) isolating substantially pure pamoic acid.

3. The process of claim 1 or claim 2, wherein the solvent comprises any one or more of water, nitrites, polar aprotic solvents, esters, ethers, ketones, halogenated hydrocarbons, aromatic hydrocarbons and aliphatic or acyclic hydrocarbons.

4. A process for the preparation of an amorphous form of olanzapine pamoate, comprising:

a) providing a solution of olanzapine pamoate in a solvent or mixture of solvents; and

b) isolating an amorphous form of olanzapine pamoate.

5. The process of claim 4, wherein the solvent comprises any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2 dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol and anisole.