Olanzapine, compositions thereof and methods of use thereof

Abstract

The present disclosure is directed to olanzapine, compositions thereof and methods of use, which exhibit good flowability and syringeability.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 301,202, filed January 20, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] Field Provided herein is an olanzapine drug substance and pharmaceutical products containing same that have favorable flow properties. [Background technology]

[0003] Olanzapine is a well-characterized and widely prescribed atypical antipsychotic that is available in oral and parenteral (intramuscular, IM) formulations. Olanzapine belongs to the thienobenzodiazepine class and its chemical name is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

[0004] [ka]

[0005] US Patent Nos. 5,229,382 and 5,736,541 describe olanzapine forms I and II, respectively. US Patent No. 7,323,459 describes olanzapine H, G, Y, X, K, S, Q, Z, and J in crystalline form. As a free base or a salt, e.g., hydrochloride or pamoate, olanzapine is an active pharmaceutical ingredient (API) of medicines used to treat schizophrenia and other neuropsychiatric diseases and disorders. An oral formulation of olanzapine (Zyprexa) and a long-acting intramuscular (IM) depot formulation containing olanzapine pamoate (ZYPREXA RELPREVV®, Eli Lilly & Co.) are approved in the United States for the treatment of adults and adolescents with schizophrenia. An oral formulation of olanzapine is also approved in the United States for the treatment of bipolar disorder type I. An IM formulation of olanzapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I mania in adults.

[0006] Olanzapine exhibits poor water solubility, solubility and flow properties. Methods to improve these characteristics include, for example, particle size reduction, salt screening, spray drying and encapsulation in microspheres. However, not all known methods are practical for all forms of API. Particle size reduction of API can increase solubility, but may adversely affect flow and filling properties. For example, for olanzapine present in pharmaceutical containers, i.e., vials, syringes, capsules, bottles, sachets or ampoules with excipients for parenteral administration, flow properties of API are critical for dose accuracy and container filling (e.g., vial filling). Furthermore, when combined with excipients, one or more of favorable solubility or suspension and successful syringeability properties are required.

[0007] Thus, a need exists for a flowable formulation of olanzapine that exhibits these properties. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 5,229,382 [Patent Document 2] U.S. Patent No. 5,736,541 [Patent Document 3] U.S. Patent No. 7,323,459 [Non-patent literature]

[0009] [Non-Patent Document 1] Sun et al. Modeling Olanzapine Solution Growth Morphologies. Cryst. Growth Des. 2018, 18, pp. 905-911 Summary of the Invention

[0010] Olanzapine is difficult to fill into vials due to its inherent cohesive nature. An unexpected correlation has been identified between the flow function of olanzapine drug substance, low relative standard deviation (RSD) of fill weight and good fill rate with a specific range of D(90) particle size distribution (PSD), D(3,2) PSD, tap density, or any combination thereof. The inventors of the present disclosure have identified characteristics of olanzapine drug substance with favorable flow properties that provide vial filling with dose accuracy and good suspension and syringeability characteristics for olanzapine parenteral formulations. Disclosed herein are olanzapine drug substance and containers or kits containing olanzapine with desirable characteristics, as well as pharmaceutical compositions and methods of use thereof.

[0011] In one aspect, provided herein is olanzapine or a pharma- ceutically acceptable salt thereof having at least one of the following characteristics: a particle size distribution characterized by a D(90) of about 20 to about 37 μm, or a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, or a tap density of about 0.35 to 0.44 g / ml, or any combination thereof. The olanzapine or pharma- ceutically acceptable salt thereof exhibits a flow function of about 2.0 or less and / or an RSD(%) of fill weight of about 1.5% or less and / or a fill rate of 14% or more. In some embodiments, the olanzapine or pharma- ceutically acceptable salt thereof exhibits a flow function of about 2.0 or less, or about 1.0 to about 2.0, or 1.4 to about 2.0. In some embodiments, the olanzapine or pharma- ceutically acceptable salt thereof exhibits an RSD(%) of fill weight of about 1.5% or less, or about 1.0% to about 1.5%. In some embodiments, olanzapine or a pharma- ceutically acceptable salt thereof exhibits a fill rate of about 14% or greater, or about 14% to about 20%. In some embodiments, the olanzapine is olanzapine base. In some embodiments, the olanzapine is an olanzapine salt. In some embodiments, the olanzapine is an olanzapine polymorph. In some embodiments, the olanzapine is olanzapine Form II.

[0012] Further provided is a container comprising Olanzapine Form II having a particle size distribution characterized by a D(90) of about 20 to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, a tap density of about 0.35 to 0.44 g / ml, or any combination thereof. The Olanzapine exhibits a flow function of about 2.0 or less and / or an RSD(%) of fill weight of about 1.5% or less and / or a fill rate of 14% or more. In some embodiments, the Olanzapine is Olanzapine base. In some embodiments, the Olanzapine is an Olanzapine salt. In some embodiments, the Olanzapine is an Olanzapine polymorph. In some embodiments, the Olanzapine is Olanzapine Form II. In some embodiments, the container comprises Olanzapine Form II that is sterile or aseptic. The container may be a vial or other pharma- ceutically acceptable container.

[0013] In another aspect, the pharmaceutical composition comprises olanzapine having at least one of the following characteristics: a particle size distribution characterized by a D(90) of about 20 to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, a tap density of about 0.35 to 0.44 g / ml, or any combination thereof, and one or more pharma- ceutically acceptable excipients. In some embodiments, the olanzapine is olanzapine Form II. In some embodiments, the particle size distribution of the olanzapine is characterized by a D(90) of 20 to about 37 μm. The olanzapine exhibits a flow function of about 2.0 or less and / or an RSD(%) of fill weight of about 1.5% or less and / or a fill rate of 14% or more. In some embodiments, the olanzapine or a pharma- ceutically acceptable salt thereof exhibits a flow function of about 2.0 or less, or about 1.0 to about 2.0, or 1.4 to about 2.0. In some embodiments, olanzapine or a pharma- ceutically acceptable salt thereof exhibits an RSD (%) of fill weight of about 1.5% or less, or about 1.0% to about 1.5%. In some embodiments, olanzapine or a pharma- ceutically acceptable salt thereof exhibits a fill rate of 14% or more, or about 15% to about 20%. In some embodiments, olanzapine is olanzapine base. In some embodiments, olanzapine is an olanzapine salt. In some embodiments, olanzapine is an olanzapine polymorph. In some embodiments, olanzapine is olanzapine Form II. In some embodiments, the pharmaceutical composition is in the form of a suspension or solution for parenteral administration, e.g., including one or more polymeric or non-polymeric excipients. The pharmaceutical composition may be in the form of, e.g., a formulation for subcutaneous or intramuscular injection, e.g., contained in a syringe. The syringe may contain from about 100 to about 1,000 mg of olanzapine, or from about 300 to about 800 mg of olanzapine in a polymeric or non-polymeric excipient.

[0014] Further provided are kits comprising olanzapine having at least one of the following characteristics: a particle size distribution characterized by a D(90) of about 20 to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, a tap density of about 0.35 to 0.44 g / ml, or any combination thereof; and optionally further comprising a pharma- ceutically acceptable excipient, a syringe, and / or instructions for use. The olanzapine exhibits a flow function of about 2.0 or less and / or an RSD(%) of fill weight of about 1.5% or less and / or a fill rate of 14% or more. In some embodiments, the olanzapine is olanzapine base. In some embodiments, the olanzapine is an olanzapine salt. In some embodiments, the olanzapine is an olanzapine polymorph. In some embodiments, the olanzapine is olanzapine Form II. The olanzapine may be in a container, such as a vial, capsule, bottle, sachet, syringe, or ampoule.

[0015] Further provided is a method of treating a subject suffering from a neuropsychiatric or other disorder in need of treatment, comprising administering to the subject olanzapine having at least one of the following characteristics: a particle size distribution characterized by a D(90) of about 20 to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, a tap density of about 0.35 to 0.44 g / ml, or any combination thereof; and optionally further comprising a pharma- ceutically acceptable excipient, a syringe, and / or instructions for use. The olanzapine exhibits a flow function of about 2.0 or less and / or an RSD(%) of fill weight of about 1.5% or less and / or a fill rate of 14% or greater. In some embodiments, the olanzapine is olanzapine base. In some embodiments, the olanzapine is an olanzapine salt. In some embodiments, the olanzapine is an olanzapine polymorph. In some embodiments, the olanzapine is olanzapine Form II. Preferably, the olanzapine provides a therapeutically effective plasma concentration of olanzapine for a period of at least about 21 days after administration to a subject. [Brief description of the drawings]

[0016] [Figure 1]FIG. 2 is an X-ray diffraction analysis (XRD) profile of Olanzapine Form II. [Diagram 2] FIG. 2 is an electron micrograph (×1,000) showing the particle morphology of micronized olanzapine Form II. [Figure 3A] FIG. 1 shows a bivariate plot showing the correlation between flow function and D(90). [Figure 3B] FIG. 13 shows a bivariate plot showing the correlation between flow function and D(3,2). [Figure 3C] FIG. 1 shows a bivariate plot showing the correlation between flow function and TD. [Figure 3D] FIG. 1 shows a bivariate plot showing the correlation between RSD and D(90) of fill weight. [Figure 3E] FIG. 1 shows a bivariate plot showing the correlation between RSD of fill weight and D(3,2). [Figure 3F] FIG. 1 shows a bivariate plot showing the correlation between RSD and TD of fill weight. [Figure 3G] FIG. 1 shows a bivariate plot showing the correlation between the RSD of fill weight and flow function. [Figure 3H] FIG. 1 shows a bivariate plot showing the correlation between filling rate (%) and D(90). [Figure 3J] FIG. 1 shows a bivariate plot showing the correlation between filling rate (%) and D(3,2). [Figure 3K] FIG. 1 shows a bivariate plot showing the correlation between filling rate (%) and TD. [Figure 3L] FIG. 1 shows a bivariate plot showing the correlation between filling rate (%) and flow function. [Figure 4A] 1 is a graph depicting the PSD of bulk API compared to the PSD of the API in a vial after sterilization. The Y-axis represents volume density (%, linear scale) and the X-axis represents size in micrometers (μ, logarithmic scale). [Figure 4B]1 is a graph depicting the PSD of bulk API compared to the PSD of the API in a vial after sterilization. The Y-axis represents volume density (%, linear scale) and the X-axis represents size in micrometers (μ, logarithmic scale). [Figure 4C] 1 is a graph depicting the PSD of bulk API compared to the PSD of the API in a vial after sterilization. The Y-axis represents volume density (%, linear scale) and the X-axis represents size in micrometers (μ, logarithmic scale). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Reference will now be made to exemplary embodiments, and specific terms will be used herein to describe them. It will nevertheless be understood that no limitation of the scope of the invention is intended thereby. Alterations and further modifications of the features of the invention exemplified herein, and further applications of the principles of the invention as exemplified herein, which may occur to those skilled in the art having this disclosure in hand, are deemed to be within the scope of the invention.

[0018] The present disclosure provides olanzapine, or a pharma- ceutically acceptable salt thereof, having a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof. In some embodiments, the particle size distribution is characterized by a D(90) of 20 μm to about 37 μm. In some embodiments, the particle size distribution is characterized by a D(90) of 24 μm to about 35 μm. The particle size distribution of the olanzapine may be characterized by a D(3,2) of about 5.5 μm to about 7.5 μm. In some embodiments, the particle size distribution is characterized by a D(3,2) of about 5.8 μm to about 7.0 μm. The tap density of the olanzapine is about 0.35 to about 0.44 g / ml.

[0019] In some embodiments, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a D(3,2) of about 5.5 μm to about 7.5 μm.

[0020] In some embodiments, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0021] In some embodiments, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0022] In an alternative embodiment, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a D(3,2) of about 5.5 μm to about 7.5 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0023] The olanzapine drug substance disclosed herein has a flow function of about 2.0 or less as measured by a powder rheometer FT4. In some embodiments, the flow function as measured by a powder rheometer FT4 is about 1.0 to about 2.0.

[0024] The olanzapine drug substance disclosed herein results in a RSD % of fill weight of 1.5% or less, or between 1.0% and 1.5%. In some embodiments, the fill rate is 14% or more, or between 14% and 20%.

[0025] Further provided is a container comprising an olanzapine as disclosed herein, e.g., olanzapine or a pharma- ceutically acceptable salt thereof, having a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof. In some embodiments, the container is a vial, syringe, or ampoule. In certain embodiments, the container is a vial. The container may contain about 100 mg to about 1,000 mg of olanzapine, or about 300 mg to about 700 mg of olanzapine. In some embodiments, the olanzapine is terminally sterilized in the container. In other embodiments, the olanzapine is sterile.

[0026] Further provided is a pharmaceutical composition comprising the olanzapine disclosed herein and one or more pharma- ceutically acceptable excipients. The olanzapine or a pharma- ceutically acceptable salt thereof has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof. The pharmaceutical composition may be in the form of a solution or suspension for parenteral administration. In some embodiments, the pharmaceutical composition is an aqueous suspension or a non-aqueous suspension. The pharmaceutical composition may include a pharma- ceutically acceptable excipient, including a polymer or a non-polymer. In some embodiments, the excipient comprises a polymer, which may be a biodegradable polymer, including poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly-1-lactic acid, poly-d-lactic acid, polyethylene glycol, or copolymers of the above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactones), polyorthoesters, poly(glycolic acid-caprolactones), poly(amino acids), polyesteramides, polyanhydrides, polyphosphazines, poly(alkylene alkylates), biodegradable polyurethanes, polyvinylpyrrolidones, polyalkanoates, albumin, chitosan, casein, waxes, or blends or copolymers thereof. In some embodiments, the pharmaceutical composition further comprises a solvent.

[0027] In some embodiments, the pharmaceutical composition is in the form of an injectable formulation, for example in a vial or syringe. The pharmaceutical composition comprises about 100 mg to about 1,000 mg of olanzapine, about 300 mg to 700 mg of olanzapine, or about 300 mg to about 600 mg of olanzapine, or a pharma- ceutically acceptable salt thereof. The pharmaceutical composition provides a therapeutically effective plasma concentration of olanzapine for the treatment of a neuropsychiatric disorder for at least 14 days, or at least 21 days, after administration to a patient. In some embodiments, the pharmaceutical composition provides a therapeutically effective plasma concentration of olanzapine for about 14 days, 21 days, about 28 days, about 30 days, about 42 days, or about 56 days. Olanzapine or a pharma- ceutically acceptable salt thereof may be provided in a kit comprising a container, and optionally further comprising a pharma- ceutically acceptable excipient, a syringe, and / or instructions for use.

[0028] Further provided is a method of treating a subject suffering from a neuropsychiatric or other disorder in need of treatment, comprising administering to the subject olanzapine or a pharmaceutical composition disclosed herein, wherein the olanzapine or pharmaceutical composition provides a therapeutically effective plasma concentration of olanzapine for a period of at least about 14 days or at least 21 days, or for about 14 days, about 21 days, about 28 days, about 30 days, about 42 days, or about 56 days after administration to the subject. The pharmaceutical composition is administered to the subject parenterally, for example intramuscularly or subcutaneously, particularly subcutaneously. In some embodiments, the neuropsychiatric disorder is schizophrenia or bipolar disorder.

[0029] Further provided is a method of filling a container with olanzapine or a pharma- ceutically acceptable salt thereof, comprising the steps of providing olanzapine having a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof, and filling the container using a semi-automatic or fully automatic filling machine, thereby filling the container with olanzapine or a pharma-ceutically acceptable salt thereof.

[0030] Further provided is a method of filling a container with olanzapine or a pharma- ceutically acceptable salt thereof, wherein the RSD% of the fill weight is 1.5% or less, or the fill rate is 14% or more, thereby filling the container with olanzapine or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments of the method, the RSD % of the fill weight is less than or equal to 1.5%, or between 1.0% and 1.5%. In some embodiments of the method, the fill rate is greater than or equal to 14%, or between 14% and 20%. In some embodiments of the method, the container is a vial, syringe, capsule, bottle, sachet or ampoule, in particular a vial.

[0032] The relative standard deviation (RSD) is the ratio of the standard deviation to the mean of the samples. It is the coefficient of variation that describes the precision of the filling method.

[0033] The terms D(90), D(99) and D(100) are well understood in the art. For example, a D(90) (or d(90)) of 25 μm means that 90% of the particles (by volume) have a diameter of 25 μm or less. For example, a D(99) (or d(99)) of 50 μm means that 99% of the particles (by volume) have a diameter of 50 μm or less. For example, a D(100) of 300 μm means that 100% of the particles (by volume) have a diameter of 300 μm or less. D(3,2) refers to the surface area moment average (Sauter Mean Diameter, SMD) and reflects the amount of particulates in the sample, which may be relevant when surface area is important, such as dissolution. D(4,3) refers to the volume / mass moment average (De Brouckere Mean Diameter) and reflects the particle size that constitutes the bulk of the sample. Particle size can be determined by means of laser diffraction techniques. In some embodiments, particle size can be determined using a Mastersizer device from Malvern Instruments.

[0034] Tapped density (TD) refers to the ability of a powder sample to pack when tapped, and gives a measure of the cohesiveness of the powder that can be related to its flow and packing performance. Tapped density can be determined using a tapped density meter, as described in the examples below.

[0035] Flow function (FF) is a parameter commonly used to rate the flowability of powders, with higher values ​​indicating better flow properties of the sample. FF was obtained as described in the Examples below. The olanzapine described herein is in the form of a cohesive powder and has favorable flow properties, e.g., a flow function value of about 2.0 or less, e.g., a flow function of 1.4 to 2.0, as measured, e.g., using a powder rheometer FT4. In some embodiments, the flow function of olanzapine is about 2.0 or less, or about 1.4 to 2.0, as measured by a powder rheometer FT4.

[0036] The relative standard deviation of the fill weights is calculated as follows: RSD(%)=(SD(mg)) / (MEAN(mg)) (where RSD is the relative standard deviation, SD is the standard deviation of the fill weight distribution in milligrams, and MEAN is the mean fill weight in milligrams).

[0037] In some embodiments, the %RSD of the fill weight is 1.5% or less.

[0038] As used herein, fill rate refers to the number of units per minute in percent (%) of the machine's maximum capacity as stated in its technical specifications. In some embodiments, the fill rate is 14% or more. In some embodiments, the fill rate is 14%-20%. In some embodiments, the fill rate is 20% or more.

[0039] The particle morphology can be obtained, for example, by examining the particles with a scanning electron microscope (SEM). The particle morphology of the olanzapine disclosed herein is irregular and is substantially as shown in FIG.

[0040] The singular forms "a," "an," and "the" may refer to plural items unless specifically stated otherwise.

[0041] As used herein, the term "about" is intended to qualify the numerical value it modifies and indicate that such value may vary within a difference of ±10 wt%. The endpoints of all ranges directed to the same component or property are included in the range and are independently combinable (e.g., the range "up to 25 wt%, or from 5 wt% to 20 wt%" includes the endpoints of the range "5 wt% to 25 wt%" and all intermediate values, etc.).

[0042] As used herein, the term "pharmacologically acceptable" refers to compounds, substances, compositions, and / or excipients that are within the scope of sound medical judgment, suitable for contact with human tissue, without excessive toxicity, irritation, allergic response, or other problematic complications, and commensurate with a reasonable benefit / risk ratio.

[0043] As used herein, a vial refers to a container suitable for use in packaging, distributing, and using a composition. A vial may be a single-dose vial (i.e., a vial containing an amount of API equivalent to a single dose, e.g., a single human dose). Alternatively, a vial may contain multiple doses (multi-dose vial). As used herein, vial filling refers to placing an amount of an API, e.g., olanzapine, into a single vial or other container. Vial filling can be performed manually, semi-automatically, or automatically.

[0044] The pharmaceutical composition of the present disclosure comprises an active pharmaceutical ingredient, or a salt form thereof, and at least one pharma- ceutically acceptable carrier or excipient. The pharmaceutical composition can be formulated using methods known in the art using polymers and / or other suitable materials. The pharmaceutical composition can be aqueous or non-aqueous. In some embodiments, the API, e.g., olanzapine, and the excipient, e.g., a polymer, form a depot in situ from which the API is released over time, e.g., following intramuscular or subcutaneous administration.

[0045] Examples of excipients useful for preparing pharmaceutical compositions of the present disclosure include biodegradable polymers, including poly(lactides) (polylactic acid, PLA), poly(glycolides) (polyglycolic acid, PGA), poly(lactide-co-glycolide) (PLGA), poly-1-lactic acid (PLLA), poly-d-lactic acid (PDLA), polyethylene glycol, or copolymers of the above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), poly(amino acids), polyesteramides, polyanhydrides, polyphosphazines, poly(alkylene alkylates), biodegradable polyurethanes, polyvinylpyrrolidones, polyalkanoates; albumin, chitosan, casein, gelatin, waxes, or blends or copolymers thereof. Non-polymeric excipients include sucrose acetate isobutyrate (SAIB).

[0046] Those of skill in the art will know how to formulate active ingredients into pharmaceutical compositions suitable for use in the method at hand.

[0047] The olanzapine used in the method of the present disclosure may be present in the pharmaceutical composition as either olanzapine or a pharma- ceutically acceptable salt of olanzapine. Examples of pharma-ceutically acceptable salts include tartrate, such as (D)(-) tartrate or (L)(+) tartrate, hydrochloride, citrate, malate, particularly D-malate, fumarate, succinate, benzoate, benzenesulfonate, pamoate, formate, malonate, 1,5-naphthalenedisulfonate, salicylate, cyclohexanesulfamate, lactate, mandelate, particularly (R)(-) mandelate, glutarate, adipate, squarate, vanillate, oxaloacetate, ascorbate, particularly (L)-ascorbate, and sulfate. In some embodiments, the form of olanzapine is olanzapine base Form II, which has an XRD profile as shown in FIG. 1.

[0048] Parenteral administration refers to administration other than oral administration. As used herein, "subcutaneous administration" refers to administration to the layer of skin directly below the dermis and epidermis. This term specifically excludes intramuscular and intravenous methods of administration. In some embodiments, subcutaneous administration methods include subcutaneous injection.

[0049] As used herein, a "therapeutically effective amount" refers to an amount of olanzapine sufficient to alleviate the positive and / or negative symptoms of schizophrenia and / or bipolar disorder in a patient.

[0050] Each container contains about 100 mg to about 1,000 mg of olanzapine or a pharma- ceutically acceptable salt of olanzapine. In some embodiments, each container contains about 150 mg to about 800 mg of olanzapine or a pharma- ceutically acceptable salt of olanzapine, or about 300 mg to 700 mg of olanzapine or a pharma- ceutically acceptable salt of olanzapine. In some embodiments, the container is a vial, particularly a glass vial. In some embodiments, the container contains olanzapine Form II as disclosed herein.

[0051] As used herein, reference to a particular amount or range of amounts of "olanzapine or a pharma- ceutically acceptable salt thereof" means that the amount of any pharma- ceutically acceptable salt of olanzapine is equivalent to the particular amount or range of amounts of olanzapine.

[0052] In some embodiments, the pharmaceutical compositions, including the compositions and methods disclosed herein, the syringes contain about 100 mg to about 1,000 mg of olanzapine or a pharma- ceutically acceptable salt thereof. For example, the pharmaceutical compositions and methods disclosed herein contain about 150 to about 700 mg, or about 300 to about 600 mg of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions and methods as disclosed herein contain olanzapine form II.

[0053] The pharmaceutical compositions and methods of the present disclosure provide a therapeutically effective amount of olanzapine for at least 14 days or at least 21 days. In some embodiments, the pharmaceutical compositions and methods provide a therapeutically effective amount of olanzapine for at least about 14 days, 21 days, 28 days, 30 days, 45 days, 56 days, 60 days, or 90 days.

[0054] According to the described methods, the pharmaceutical composition can be administered no more than once a month (i.e., no more than once every about 28-30 days). Alternatively, the pharmaceutical composition can be administered no more than once every two months (i.e., no more than once every about 56-60 days). In other methods, the pharmaceutical composition can be administered no more than once every three months (i.e., no more than once every about 84-90 days). Those skilled in the art will understand that references to days herein refer to time periods such that, for example, the phrase "for at least about 28 days" is understood to be equivalent to "for a period of at least about 28 days" and the phrase "for at least about 56 days" is understood to be equivalent to "for a period of at least about 56 days."

[0055] Further provided is a kit comprising olanzapine as disclosed herein. The kit may comprise a container comprising olanzapine. The container may be a vial. The vial may comprise a vial adaptor. The kit may comprise one or more syringes, at least one of which comprises an excipient, which may be used for reconstitution. The syringe may be used with a vial or a vial adaptor. The excipient may comprise, for example, a solvent and / or a polymer. The syringe may additionally or alternatively comprise a drug, for example a drug different from the API contained in the vial. The syringe may alternatively be empty and may be utilized to withdraw fluid from a separate container. The syringe in the kit may contain a solvent used to reconstitute the API. The syringe in the kit may contain a polymer used to reconstitute the API. The syringe may contain both a solvent and a polymer solution used to reconstitute the API. In some embodiments, the solvent is a pharma- ceutically acceptable solvent, which may be an aqueous or non-aqueous solvent. Non-limiting examples of solvents include water, benzyl alcohol (BA), benzyl benzoate (BB), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl ether acetate, N-methyl-2-pyrrolidone (NMP), triacetin, tributyrin, tripropionin, and mixtures thereof. The vial may contain (e.g., only) olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the API is olanzapine having at least one of the following characteristics: a particle size distribution characterized by a D(90) of about 20 to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 to about 7.5 μm, or a tap density of about 0.35 to 0.44 g / ml, or any combination thereof, and optionally further comprising a pharma- ceutically acceptable excipient, a syringe, and / or instructions for use. In some embodiments, the olanzapine is olanzapine Form II. The olanzapine may be provided in a container, such as a vial, capsule, bottle, sachet, syringe or ampoule. The kit may optionally further comprise one or more needles or syringes for performing the injections.The syringe can be used to reconstitute the solution and / or withdraw the reconstituted solution from the vial. As used herein, "reconstituted solution" refers to a reconstituted solution or a reconstituted suspension, in which the API is fully or partially dissolved. The kit may optionally include a syringe adapter configured for use with a vial or vial adapter. The syringe adapter may be configured to connect, for example, to a syringe connection port of a vial adapter. The syringe may allow for fluid mixing. The kit may additionally or alternatively include instructions for the user.

[0056] With respect to the above-mentioned embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other embodiments of the present disclosure, for example elements detailed in method embodiments can be used in the pharmaceutical composition, kit, process and use embodiments described herein, and vice versa.

[0057] The following examples serve to illustrate the invention without limiting it. EXAMPLES

[0058] Example 1: Standard Method 1. Particle size distribution (PSD) For purposes herein, particle size distribution (PSD) was determined as percent volume, i.e., D(90) and D(3,2), and was measured by laser diffraction using a Malvern Mastersizer 2000 equipped with a Hydro 2000S dispersion unit.

[0059] Measurements were performed in saturated aqueous dispersion medium (refractive index = 1.22 (general purpose)). The water was saturated with olanzapine to prevent sample dissolution during the measurement. The dispersion medium was prepared by adding approximately 3 gm of olanzapine to 1 liter of water, sonicating in an ultrasonic bath for 30 minutes and filtering (0.22-0.45 um). The sample was added as a concentrated suspension under stirring until an opacity of 10-20% was reached. Results were derived from 10 measurement cycles with a recirculation time (after sonication) of 30 seconds. The following parameters were used: Dispersion unit: Hydro 2000S Measurement range: 0.02~2000μm Analysis models: General purpose, normal, Mie model Sensitivity: Normal · Particle shape: irregular Refractive index of sample: 1.709 · Absorption: 0.01 Dispersant: Olanzapine saturated aqueous dispersion medium Refractive index of dispersion medium: 1.330 · Opacity: 10~20% Pump / agitation speed: 2500 rpm Level Sensor Threshold: 64% Sample measurement time: 10s Background measurement time: 10s Replicates (per portion): 10 Internal ultrasound: 30s at 90% power Recirculation time (after sonication): 30s Number of measurements (each portion): 1

[0060] Sample preparation: Samples were prepared as concentrated suspensions. Approximately 50-100 mg of olanzapine sample was added to a small glass beaker using a spatula and a few drops of saturated aqueous dispersion medium were added. A paste was obtained by gentle mixing and an additional amount (1 ml) of saturated aqueous dispersion medium was added to obtain a concentrated homogenous suspension.

[0061] The particle size distribution and other powder properties of different batches of olanzapine are shown in Table 1.

[0062] 2. Bulk density / tap density Bulk density / tapped density was determined according to the European Pharmacopoeia 2.9.34. Method 1 (https: / / www.drugfuture.com / Pharmacopoeia / EP7 / DATA / 20934E.PDF, PDF download 14 November 2021).

[0063] Bulk and tapped densities were determined using an ERWEKA tapped density tester SVM122 equipped with a 100 mL glass cylinder. Approximately 30 g of powder was carefully poured into a 100 mL graduated cylinder using a funnel. Bulk density was calculated by dividing the amount of powder (in grams) by the measured volume (in mL). Tapped density was then determined as follows: Tap 10× - reading volume (=V10) Tap 500 x (10 + 490) -> Reading volume (= V500) Tap 1250 x (500 + 750) - reading volume (= V1250) Tap 2500 x (1250 + 1250) - reading volume (= V2500)

[0064] If the difference between V500 and V1250 was greater than 2 mL, the tap was repeated, ie, 1250x more taps, and so on until the difference was less than 2 mL. Bulk density = sample weight / volume before tapping. Tapped density = weight / volume after tapping. Calculation: Bulk density = m(mg) / V0(mL) Tap density = m(mg) / V2500(mL) The tap densities of different batches of olanzapine are shown in Table 1.

[0065] 3. Determining the flow function The flow function (FF) was determined using a Powder Rheometer FT4, Freeman FT4 instrument, and the standard Freeman shear test - 9 kPa (using a small 1 ml cell) according to the procedure below. Compress to 9kPa for 60s Pre-shear 7kPa for 16s, held Shear test at 7kPa (10° shear at 18° / min with auto-detected peak torque) Pre-shear 6kPa for 16s, held Shear test at 6kPa (10° shear at 18° / min with auto-detected peak torque) Pre-shear 5kPa for 16s, held Shear test at 5kPa (10° shear at 18° / min with auto-detected peak torque) Pre-shear 4kPa for 16s, held Shear test at 4kPa (10° shear at 18° / min with auto-detected peak torque) Pre-shear 3kPa for 16s, held Shear test at 3kPa (10° shear at 18° / min with auto-detected peak torque)

[0066] The flow properties of different batches of olanzapine are shown in Table 1.

[0067] 4. SEM (Scanning Electron Microscope) Powder samples were fixed to aluminium stubs using conductive double-sided adhesive tape and coated with gold. Gold was sputtered using an Edwards S150 sputter coater. Samples were imaged under a JEOL JSM-5800 scanning microscope, an Oxford Aztec X-max 20mm 2 The samples were scanned by EDS under the conditions of WD=20 and HT=10 kV (magnifications of 500× and 1,000×).

[0068] 5. Filling API into vials Once the bulk API (i.e., olanzapine Form II as described herein) was obtained, it was filled into glass vials using a semi-automatic powder filling machine using auger technology (SVP100, Bausch & Strebel, Germany). The powder filling machine used an auger and stir bar set to fill the powder into the glass vials. Each vial was subjected to in-process weight control (100%). The vials were closed with rubber caps and aluminum caps and crimped.

[0069] 6. Terminal sterilization by dry heat The API-filled, closed, and crimped vials were terminally sterilized using dry heat in a Kambic (Slovenia) dry heat oven SP-470 at 150-160°C for 2 hours. Additional methods of terminal sterilization include radiation, e.g., gamma radiation, X-ray, electron beam, and others, with similar results. Alternatively, the API can be prepared aseptically.

[0070] 7. JMP Software Analysis Plots for the bivariate fits were prepared and analyzed using JMP® version 13.2.1 software.

[0071] Example 2: Preparation of micronized olanzapine form II Olanzapine form I (4.00 kg) was charged to the dissolver and the reactor was blanketed with nitrogen. The dissolver jacket was heated to 75-80 °C. Toluene (48 kg) was charged to the crystallizer and the reactor was blanketed with nitrogen. In addition to toluene, acetone, ethyl acetate, n-butyl acetate, or methyl isobutyl ketone can be used as the solvent (Sun et al. Modeling Olanzapine Solution Growth Morphologies. Cryst. Growth Des. 2018, 18, 905-911). The solvent in the crystallizer was heated to 75-80 °C. The heated toluene was transferred from the crystallizer to the dissolver using nitrogen pressure. The mixture was stirred at 75-80 °C until complete dissolution was observed (visual inspection). Mechanical filtration of the solution was performed from the dissolver to the crystallizer through a heated transfer line and a filter cartridge. The transfer line between the dissolver and the crystallizer was washed with toluene (0.7 kg). The internal temperature of the crystallizer was adjusted to 75-80°C. The solution was cooled to 61-63°C. Micronized seeds of Olanzapine Form II (20 g) were added to the crystallizer. The solution was cooled to 53-57°C over 50-70 min using a linear cooling gradient. The solution was further cooled to 43-47°C over 50-70 min using a linear cooling gradient. The solution was then further cooled to 2-8°C over 80-100 min using a linear cooling gradient. The suspension was stirred for 80-100 min at 2-8°C and then filtered through a filter drier. The cake was washed with toluene (3.5 kg), cooled to 2-8°C, washed once more with toluene (1.7 kg) and further cooled to 2-8°C.

[0072] The product was dried at a dryer jacket temperature of 75-100° C. and under a vacuum of 100-200 mbar until a limit of detection (LOD) level of less than 0.5% was achieved, after which the dried material was cooled to 20-30° C. and removed from the filter dryer. The dried material was sieved through a screen size of 300 microns using a vibrating sieve. The sieved material was then micronized in an air jet micronizer using nitrogen pressures ranging from 1.5 to 4 bar. The XRD profile of Olanzapine Form II described herein is shown in FIG. 1. The main typical peaks of Olanzapine Form II are determined to be at about 8.7, 12.5, 17.4, 19.9, 21.1, 21.6, 22.4, 24.0, 25.3, and 29.8±0.2 degrees 2θ. The particle morphology of Olanzapine Form II disclosed herein is irregular and is substantially as shown in FIG. 2 (×1,000 magnification).

[0073] Example 3 Preparation of Sterile Vials with Olanzapine Each of the batches from Example 1 was filled into vials by auger filling and terminally sterilized according to Example 1, sections 5 and 6. Critical parameters of filling performance were monitored during each filling run, including the relative standard deviation (RSD) (%) of fill weight and the fill rate (% of its maximum capacity as stated in the machine's technical specifications).

[0074] Fill performance was measured by two parameters: RSD of fill weight and fill rate. The RSD of fill weight is a direct measure of the accuracy of the filling operation, with smaller numbers indicating lower variability. The variability of fill weight affects the dose uniformity of the final formulation, which is a critical quality attribute. The fill rate determines the production time, with higher rates being preferred. The results of the fill performance parameters for each API batch are shown in Table 1.

[0075] During initial experiments filling vials with micronized olanzapine, significant differences in filling performance were observed between different batches. Filling was rated as ranging from very poor to good filling.

[0076] result Without limitation, the RSD of the fill weight is about 2.0% or less, specifically 1.5% or less, and more specifically about 1.0% to about 1.5%.

[0077] Without being limiting, in some embodiments, the filling rate is about 14 to about 20%, and may vary depending on the capacity of the filling machine as stated in the technical specifications. In some embodiments, the filling of the container, e.g., vial filling, is performed by auger filling. In some embodiments, the filling of the container, e.g., vial filling, is performed by vacuum filling. The filling method is not limiting, as the filling method may be contemplated. In order to improve the filling characteristics of olanzapine and to quantify the filling performance of different manufacturing batches, the properties of olanzapine, e.g., particle size distribution (PSD) by LALLS, tapped density (TD), and flow function (FF) by Freeman, were analyzed relative to the filling performance: see Table 1 for the relative standard deviation (RSD) of the filling weight, and the filling rate (% of its maximum capacity as stated in the technical specifications of the machine).

[0078] [Table 1]

[0079] The results shown in Table 1 indicate that the parameters most indicative of desirable flow and packing characteristics and subsequent reconstitution and pourability are the D(90) particle size, D(3,2) or tap density.

[0080] Additionally, an analysis was performed in JMP software to correlate API parameters with packing performance, with the parameters that proved to be most meaningful being particle size at D(90), D(3,2) or tap density. This analysis can be visualized in Figures 3A-L. The cluster of black circles in the center of the plot represents the preferred values ​​for each feature. All batches with desirable flow and packing properties are depicted by black circles. All black circles are clustered in a bivariate fit analysis. When all plots are shown with batches that meet the criteria, all black circles fall within the ranges as stated.

[0081] Bivariate fits of the flow function to the variables D(90), D(3,2), and TD are shown in Figures 3A-3C, respectively. In Figure 3A, the collection of filled circles indicates that for D(90) of about 20 to about 37 μm, the flow function is 1.4 or greater, specifically about 1.4 to about 2.0. In Figure 3B, the collection of filled circles indicates that for D(3,2) of about 5.5 to about 7.5 μm, the flow function is 2.0 or less, specifically about 1.4 to about 2.0. In Figure 3C, the collection of filled circles indicates that for TD of about 0.38 g / mL to about 0.44, the flow function is about 1.4 to about 2.0. In some embodiments, the flow function is about 1.5 to about 2.0.

[0082] Bivariate fits of the RSD(%) of the fill weight with variables D(90), D(3,2), TD, and flow function are shown in Figures 3D-3G, respectively. In Figure 3D, the collection of filled circles shows that for D(90) of about 20 to about 37 μm, the RSD(%) of the fill weight is less than 1.5%. In Figure 3E, the collection of filled circles shows that for D(3,2) of about 5.5 to about 7.5 μm, the RSD(%) of the fill weight is less than 1.5%. In Figure 3F, the collection of filled circles shows that for TD of about 0.35 to about 0.44 g / mL, the RSD(%) of the fill weight is less than 1.5%. In Figure 3G, the collection of filled circles shows that for flow functions less than 2.0, the RSD(%) of the fill weight is less than 1.5%.

[0083] Bivariate fits of the fill rate with variables D(90), D(3,2), TD, and flow function are shown in Figures 3H-L, respectively. In Figure 3H, the collection of black circles indicates that for D(90) of about 20 to about 37 μm, the fill rate is 14% or greater. In Figure 3J, the collection of black circles indicates that for D(3,2) of about 5.5 to about 7.5 μm, the fill rate is 14% or greater. In Figure 3K, the collection of black circles indicates that for TD of about 0.35 to about 0.44 g / mL, the fill rate is 14% or greater. In Figure 3L, the collection of black circles indicates that for flow functions less than 2.0, specifically about 1.4 to about 2.0, the fill rate is 14% or greater.

[0084] [Table 2]

[0085] The manufacturing process of the final drug product includes a terminal sterilization step, and the quality of the bulk API in particular should not be affected by the sterilization. Therefore, after dry heat sterilization, API samples in filled vials of two batches (with low PSD) were analyzed for PSD and compared with the starting API material. The results are shown in Table 3.

[0086] [Table 3]

[0087] Table 3 shows that olanzapine drug substance before dry heat sterilization, having a PSD characterized by a D(90) of 20-37 μm, changes slightly after the terminal sterilization process, but the D(90) remains within an acceptable range. Table 3 also shows that olanzapine drug substance before dry heat sterilization, having a PSD characterized by a D(3,2) of 5.5-7.5 μm, changes slightly after the terminal sterilization process, but the D(3,2) remains within an acceptable range.

[0088] For example, if the final product is a solution or suspension for parenteral administration, it may be desirable to control the maximum particle size, D(99) and D(100). In some embodiments, the PSD of olanzapine, characterized by D(99) and D(100), is limited to about 2 / 3, 1 / 2, or about 1 / 3 of the inner diameter (ID) of the administration needle. Without wishing to be bound by theory, values ​​above this value may increase the risk of needle clogging and syringeability problems. For example, a 21 gauge (21 g) needle has an ID of about 490-510 μm. Some typical D(90), D(99), and D(100) values ​​are shown in Table 4.

[0089] [Table 4]

[0090] Additionally, results of the PSD parameter D(100) of the batch obtained by stratifying samples using a sample sieve indicate that the particles have a PSD characterized by a D(99) of less than about 100 μm and / or a PSD characterized by a D(100) of less than about 250 μm, less than about 210 μm, or between about 60 and about 210 μm.

[0091] The upper limit of the preferred D(90) range may also be limited with respect to the presence of the largest particles as measured by D(100). Specifically, as described herein, Olanzapine Form II is characterized by a D(100) that is less than the inner diameter (ID) of the administration needle. For example, a standard 21 g, 16 mm long needle is approximately 0.49-0.51 mm.

[0092] Figures 4A-C show the PSD of the bulk API compared to the PSD of the API in the vial after sterilization. Figure 4A: Olanzapine API S1-920 (curve slightly to the left), API in the vial after sterilization (curve on the right). Figure 4B: Olanzapine API S3-020 before (lower curve) and after sterilization (upper curve) show that the curves are very similar. Figure 4C: Olanzapine API S1-220 (curve slightly to the left), API in the vial after sterilization (curve on the right and slightly above).

[0093] All patent documents and publications are incorporated herein by reference to the same extent as if each separate publication was specifically and individually incorporated by reference. The invention illustratively described herein can be suitably practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each instance herein, either of the terms "comprising" and "consisting of" can be replaced with the other of the two terms. With respect to the above-mentioned embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other embodiments disclosed. For example, elements detailed in API embodiments can be used in pharmaceutical composition embodiments, kit embodiments and method embodiments described herein, and vice versa. The terms and expressions used are used as terms of description rather than limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it is to be understood that modifications and variations of the concepts disclosed herein may be contemplated by those skilled in the art, and such modifications and variations are deemed to be within the scope of this invention as defined by the appended claims.

Claims

1. 1. A method of filling a container with olanzapine or a pharmaceutically acceptable salt thereof, comprising: Providing olanzapine having a particle size distribution characterized by a D(90) of 20 μm to 37 μm, a particle size distribution characterized by a D(3,2) of 5.5 μm to 7.5 μm, or a tap density of 0.35 g / ml to 0.44 g / ml, or any combination thereof; filling the containers using a semi-automatic or fully automatic filling machine, thereby filling the containers with olanzapine or a pharmaceutically acceptable salt thereof. A method comprising: D(90) means that 90% of the particles (by volume) have a diameter less than or equal to that value as measured by laser diffraction; D(3,2) is the moment mean of the surface area (Sauter mean diameter, SMD) measured by laser diffraction; Tap density is measured by the method described in Example 1 herein.

2. The method of claim 1, wherein the RSD% of the fill weight is less than 1.5% or the fill rate is 14% or more, thereby filling the container with olanzapine or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 or 2, wherein the RSD% of the fill weight is 1.5% or less or 1.0% to 1.5%, and / or the fill rate is 14% or more or 14% to 20%.

4. The method according to any one of claims 1 to 3, wherein the container is a vial, syringe, capsule, bottle, sachet or ampoule, preferably the container is a vial.

5. A method according to any one of claims 1 to 4, wherein the filled container contains 100 mg to 1,000 mg of olanzapine, or 300 mg to 700 mg of olanzapine.

6. The method according to any one of claims 1 to 5, wherein the olanzapine in the container is terminally sterilized.

7. The method of any one of claims 1 to 6, wherein the olanzapine in the container is sterile.

8. 1. Olanzapine or a pharmaceutically acceptable salt thereof, having a particle size distribution characterized by a D(90) of 20 μm to 37 μm, a particle size distribution characterized by a D(3,2) of 5.5 μm to 7.5 μm, or a tap density of 0.35 g / ml to 0.44 g / ml, or any combination thereof; D(90) means that 90% of the particles (by volume) have a diameter less than or equal to that value as measured by laser diffraction; D(3,2) is the moment mean of the surface area (Sauter mean diameter, SMD) measured by laser diffraction; Tap density is measured by the method described in Example 1 herein. Olanzapine or a pharmaceutically acceptable salt thereof.

9. A particle size distribution of olanzapine or a pharmaceutically acceptable salt thereof D(90) of 20 μm to 37 μm, preferably D(90) of 24 μm to 35 μm, or D(3,2) of 5.5 μm to 7.5 μm, preferably D(3,2) of 5.8 μm to 7.0 μm The method according to any one of claims 1 to 7, or olanzapine according to claim 8, characterized in that

10. A method according to any one of claims 1 to 7 or 9, or olanzapine according to claim 8 or 9, wherein the tap density of olanzapine or a pharmaceutically acceptable salt thereof is 0.35 g / ml to 0.44 g / ml.

11. A particle size distribution of olanzapine or a pharmaceutically acceptable salt thereof D(90) between 20 μm and 37 μm, and D(3,2) between 5.5 μm and 7.5 μm; D(90) of 20 μm to 37 μm and a tap density of 0.35 g / ml to 0.44 g / ml; D(3,2) between 5.5 μm and 7.5 μm and a tap density between 0.35 g / ml and 0.44 g / ml, or D(90) from 20μm to 37μm, D(3,2) from 5.5μm to 7.5μm, and tap density from 0.35g / ml to 0.44g / ml The method according to any one of claims 1 to 7, 9 or 10, or the olanzapine according to any one of claims 8 to 10, characterized in that

12. A method according to any one of claims 1 to 7 or 9 to 11, or olanzapine according to any one of claims 8 to 11, wherein the flow function of olanzapine or a pharmaceutically acceptable salt thereof measured by a powder rheometer FT4 is 2.0 or less, preferably 1.0 to 2.

0.

13. The method of any one of claims 1 to 7 or 9 to 12, or the olanzapine of any one of claims 8 to 12, wherein the olanzapine is olanzapine form II.

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