Process for continuous hot melt granulation of low solubility drugs

Abstract

The present invention relates to a process for loading a polymer with an active pharmaceutical ingredient in a melt granulation process, and the product prepared therefrom. More specifically, the present invention relates to a process for preparing granules containing at least one active pharmaceutical ingredient and polyvinyl alcohol.

Description

[Technical field]

[0001] The present invention relates to a process for loading a polymer with an active pharmaceutical ingredient in a melt granulation process, and the product prepared therefrom. More specifically, the present invention relates to a process for preparing granules containing at least one active pharmaceutical ingredient and polyvinyl alcohol. [Background technology]

[0002] background It is useful for achieving a more consistent administration rate of the active pharmaceutical ingredient of a pharmaceutical formulation when the active pharmaceutical ingredient is present as a uniform dispersion or solution in the carrier. Solubility enhancement, especially of poorly soluble drug substances, is an important application for amorphous solid dispersions.

[0003] Solid dispersions are defined as dispersions of one or more active pharmaceutical ingredients in an inert solid matrix and can be broadly classified as containing drug substances in a crystalline or amorphous state [Chiou WL, Riegelman S. Pharmaceutical applications of Solid dispersion systems; J. Pharm Sci. 1971, 60 (9), 1281 - 1301]. Solid dispersions containing pharmaceutical active ingredients in a crystalline state provide dissolution enhancement simply by reducing surface tension, reducing agglomeration, and improving wettability of the active substance [Sinswat P., et al.; Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution; Int. J. of Pharmaceutics, (2005) 302; 113 - 124]. While crystalline systems are more thermodynamically stable than their amorphous counterparts, the crystalline structure requires energy and must be disrupted during the dissolution process. Solid dispersions containing active pharmaceutical ingredients, which means drugs dissolved at the molecular level, known as amorphous solid solutions, can result in a significant increase in dissolution rate and degree of supersaturation [DiNunzio JC et al. III Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole; Molecular Pharmaceutics (2008);5(6):968-980]. While these systems have some advantages, physical instability can be problematic due to molecular mobility and tendency of the drug to recrystallize. Polymeric carriers with high glass transition temperatures seem to be well suited to stabilizing these systems by limiting molecular mobility. As such, solid dispersions can be made by a number of methods including, but not limited to, spray drying, melt extrusion, or thermodynamic blending.

[0004] Hot melt extrusion (HME) has recently gained acceptance in the pharmaceutical industry for the preparation of formulations containing active pharmaceutical ingredients processed by extrusion. HME has been introduced as a pharmaceutical production technique and has become a well-known process with benefits such as continuous and efficient processing, limited number of process steps, solvent-free process, etc. During hot melt extrusion, a mixture of active pharmaceutical ingredients, thermoplastic excipients, and other functional processing aids is heated and softened or melted inside the extruder and extruded into various forms through a nozzle.

[0005] Solid dispersions can also be made by granulation techniques. Granulation is a well-established pharmaceutical processing technique for agglomerating primary drug and excipient particles into larger secondary particles or granules. A wide variety of both wet- and dry-granulation techniques are already established in the pharmaceutical industry. In the field of continuous granulation, the twin-screw extrusion granulation method is the most promising technology. Continuous twin-screw wet granulation (TSWG) is already frequently used to avoid flow and compaction problems. The drawback here is stability and degradation issues due to proper control of wet processing and associated drying steps.

[0006] Twin-screw melt granulation (TSMG) can offer an interesting alternative to wet granulation. Usually, agglomeration is initiated by a softened or dissolved binder instead of the granulation liquid, making this technique highly suitable for moisture-sensitive drugs. Melt granulation is considered as a size-enlarging process, where the addition of a dissolving or softening binder at a relatively low temperature (usually around 60° C.) is used to achieve agglomeration of solid particles. Various techniques are already established, including spray-congeal and tumbling melt granulation.

[0007] From the technique of (hot) melt extrusion it is known that the polymer should have suitable properties such as thermoplasticity, suitable glass transition temperature or melting point, thermal stability at the required processing temperatures, absence of unexpected chemical interactions with the active pharmaceutical ingredient, etc. Summary of the Invention

[0008] Objective of the invention Common melt granulation techniques require the use of meltable binders. These are usually low melting substances that melt or soften at relatively low temperatures (50°C-90°C), such as low melting waxes or low melting polymers. Meltable binders are used to achieve agglomeration of the solid particles during the granulation process. Typically, the processing temperature is set above the Tm or Tg of the polymeric binder, but below the Tm of the drug substance. This maintains the drug in a crystalline state to minimize any physicochemical changes (Kittikunakorn N, Liu T, Zhang F. Twin-screw melt granulation: Current progress and challenges. International Journal of Pharmaceutics. 2020; 588:119670). Various types of hydrophilic and hydrophobic binders have been described. Usually, the distribution of the dissolved binder on the surface of the solid particles is caused by mixing and compaction during melt granulation.

[0009] Lipids are also frequently used. However, low melting binders run the risk of melting or softening of the binder during handling and storage of the agglomerates. Another problem is the limited number of suitable polymers.

[0010] It is therefore an object of the present invention to provide a melt granulation process for obtaining an amorphous solid dispersion of an API in or on a polymer. It is a further object of the present invention to provide a composition that can be used in a melt granulation process without the need for a binder. It is a further object of the present invention to provide a composition where the melt granulation process results in an amorphous solid solution or dispersion of an API in or on a polymer without the need for a binder. It is a further object of the present invention to provide granulation process parameters for the aforementioned archive. Moreover, it is an object of the present invention to provide an extrusion process where the product has beneficial properties, such as degree of amorphization or dissolution.

[0011] BRIEF SUMMARY OF THE INVETION In a typical melt granulation process, a binder is used to form agglomerates of the crystalline drug substance. Usually, a low melting polymer is preferred since the purpose is mostly just agglomeration to increase particle size.

[0012] Surprisingly, it has been found that melt granulation process can be used to load polymer with active pharmaceutical ingredient (API) in its amorphous form.By utilizing polyvinyl alcohol (PVA) as polymer during melt granulation process, the polymer can serve as a base for stabilizing API in its amorphous form.Moreover, it has been surprisingly found that when API is heated above its melting point, certain favorable results are obtained in terms of stabilization of amorphous form and dissolution of API.During the cooling step, liquid drug substance solidifies in or on the surface of polymer and maintains its amorphous state to form amorphous solid solution or dispersion. Furthermore, the resulting particles have been found to have beneficial properties compared to particles prepared by HME. It has further been found that twin-screw melt granulation (TSMG) is particularly suitable as the granulation process.

[0013] Detailed Description of the Invention The present invention refers to a process of loading a polymer with an active pharmaceutical ingredient in a melt granulation process comprising the steps of: a) kneading a mixture comprising at least one active pharmaceutical ingredient and polyvinyl alcohol in a heated screw barrel of an extruder, where the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the decomposition temperature of the polyvinyl alcohol to form a kneaded mixture; and b) Moving the kneaded mixture through an outlet.

[0014] An "active pharmaceutical ingredient" or "API" may be found in the form of one or more pharma- ceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. As used herein, a "pharma-ceutically acceptable salt" is understood to mean a compound formed by the interaction of an acid and a base in which a hydrogen atom of the acid is replaced by a cation of the base.

[0015] The term "polyvinyl alcohol" or "PVA" refers to the compound having the idealized formula [CH 2 CH(OH)] n PVA refers to a synthetic water-soluble polymer having a vinyl alcohol repeating unit, -[CH 2 CH(OH)]- and vinyl acetate repeat units -[CH 2 CH(OOCCH 3)]-, a random copolymer. The polarity of PVA is closely linked to its molecular structure. The degree of hydrolysis and molecular weight determine the molecular properties of PVA. As the degree of hydrolysis of the acetate groups increases, the solubility of the polymer in aqueous media, and also the crystallinity and melting temperature of the polymer, increase. However, at high degrees of hydrolysis, above 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but in some cases is practically insoluble in almost all organic solvents, with the exception of ethanol.

[0016] Typical PVA nomenclature indicates the viscosity of a 4% solution at 20° C. and the degree of hydrolysis of the polymer. For example, PVA 3-83 is a PVA grade that is 83% hydrolyzed, i.e., has 83% vinyl alcohol repeat units and 17% vinyl acetate repeat units, with a viscosity of 3 mPas. Those skilled in the art will recognize that an 83% hydrolysis grade and a viscosity of 3 mPas encompasses calculated hydrolysis grades of 82.50% to 83.49% and calculated viscosities of 2.50 mPas to 3.49 mPas%, according to common rounding methods.

[0017] The viscosity according to the present invention is determined by the method Viscosity-Rotational Method <912> The degree of hydrolysis according to the present invention is measured as described in USP 39 in the monograph "Polyvinyl alcohol" in the monograph "Degree of hydrolysis".

[0018] As the degree of hydrolysis increases, the solubility of the polymer in aqueous media increases, but also the crystallinity of the polymer increases. In addition, the glass transition temperature and melting temperature vary depending on the degree of hydrolysis, molecular weight, and water content. For example, PVA 4-88 with loss on drying of ≦5.0% has a melting temperature of approximately 170° C., a glass transition temperature of approximately 40-45° C., and a decomposition temperature of >250° C. (Technical Information, Parteck® MXP). The heat resistance of a particular PVA or PVA grade can be measured using various methods. In accordance with the present invention, the glass transition temperature, melting temperature, and decomposition temperature are measured using differential scanning calorimetry (DSC).

[0019] Polyvinyl alcohol is soluble in water, but in some cases is nearly insoluble in almost all organic solvents, with the exception of ethanol. This aspect of the polymer makes it extremely difficult to form amorphous and solid dispersions through spray drying when the drug has limited solubility in aqueous media. Polyvinyl alcohol according to the present invention can include any PVA grade. In one embodiment, the polyvinyl alcohol is composed of one or more grades of PVA of different molecular weights and with different grades of hydrolysis.

[0020] In one embodiment, the polyvinyl alcohol has a degree of hydrolysis of 72% to 90%, in particular 74% to 88%, in particular 80% to 90%, and a viscosity of a 4% solution at 20° C. of 2 mPas to 40 mPas, in particular 3 mPas to 18 mPas.

[0021] In one embodiment, the polyvinyl alcohol is selected from the list consisting of PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA 23-88, PVA 26-80, PVA 26-88, PVA 28-99, PVA 30-98, PVA 30-92, PVA 32-88, and PVA 40-88.

[0022] In further embodiments, the polyvinyl alcohol is selected from the list consisting of PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-88, PVA 4-88, PVA 5-74, PVA 5-88, PVA 8-88, and PVA 18-88.

[0023] In a further embodiment, the polyvinyl alcohol is selected from the list consisting of PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 4-88, and PVA 18-88. In a further embodiment, the polyvinyl alcohol is PVA 4-88. In a further embodiment, the polyvinyl alcohol is PVA 3-82.

[0024] In a further embodiment, the polyvinyl alcohol is freeze-milled. Preferably, the PVA is freeze-milled to a particle size suitable for the melt granulation process. An exemplary commercially available PVA is Parteck® MXP.

[0025] The term "melting temperature" refers to the temperature at which a substance changes state from solid to liquid. At the melting temperature, the solid and liquid phases exist in equilibrium. The melting temperature of a substance depends on the pressure, and in accordance with the present invention, the melting point is specified at a pressure of 1 atmosphere. The melting temperature of PVA grades depends on the degree of hydrolysis and the viscosity of the respective PVA grade. The melting temperature of common PVA ranges from 180 to 220°C.

[0026] The term "glass transition temperature" refers to the gradual and reversible transition in an amorphous material, or in amorphous regions in a semicrystalline material, from a hard and relatively brittle "glassy" state to a sticky or rubbery state as temperature increases. The glass transition temperature of a substance is pressure dependent, and in accordance with the present invention, the glass transition temperature is specified at a pressure of 1 atmosphere. The glass transition temperatures of PVA grades depend on the degree of hydrolysis and the viscosity of the respective PVA grade. In general, the glass transition temperature of PVA ranges from 40 to 80°C.

[0027] The term "decomposition temperature" refers to the temperature at which heat breaks chemical bonds, causing chemical decomposition. The decomposition temperature of a material depends on pressure, and in accordance with the present invention, the decomposition temperature is specified at a pressure of 1 atmosphere. The decomposition temperature of a PVA grade depends on the degree of hydrolysis and the viscosity of the respective PVA grade. Generally, the decomposition temperature of PVA begins at a temperature of 250°C.

[0028] In contrast to conventional hot melt granulation techniques, in which low melting binders are used for agglomeration of solid particles, the process described herein is carried out at a temperature above the melting point of the active pharmaceutical ingredient and above the glass transition temperature of PVA. Experiments have shown that PVA is a highly promising carrier due to its semi-crystalline nature. PVA can stabilize the amorphous phase of the active pharmaceutical ingredient in a solid dispersion.

[0029] In the literature, the use of low melting binders is preferred since high melting point binders require high melting temperatures and can contribute to instability issues, especially for heat labile materials such as heat labile APIs (Melt granulation: An alternative to traditional granulation techniques; March 2013; Indian Drugs 50(3):5-13). According to the present invention, a temperature is selected that causes the API to melt during the granulation process. Surprisingly, it has been found that the molten API itself can be used as a binder, in intimate contact with the mobilized PVA. The intimate interlocking in the granulation system ensures strong interactions between the PVA and the API, leading to a uniform distribution of the API in the polymer.

[0030] According to the present invention, the minimum processing temperature for obtaining an amorphous solid dispersion of an API in a melt granulation process is above the melting temperature of the API in at least one zone along the screw barrel. The maximum processing temperature is the decomposition temperature of PVA. The glass transition temperature of PVA varies between 40°C and 80°C depending on the degree of polymerization and hydrolysis. The decomposition of most PVA grades starts at approximately 250°C. Therefore, the process according to the present invention can be used for APIs with a melting point between 40°C and 250°C. Typical processing temperatures for obtaining an amorphous solid dispersion of an API in a PVA polymer are 140°C to 230°C, preferably 170°C to 210°C, more preferably 180°C to 200°C.

[0031] The twin-screw melt granulation according to the present invention offers a major advantage compared to other processing techniques, such as hot melt extrusion (HME), in which the plasticized melt is forced through a die attached to the end of the extruder barrel. In the process according to the present invention, the mixture is passed not through a die, but through an outlet, which is an opening where the HME connects the PVA granules to the PVA pellets. The active pharmaceutical ingredient in the granules is more stable and / or shows an improved dissolution profile and can be more easily processed into the final dosage form (tablets).

[0032] In one embodiment, the temperature of at least one zone along the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the glass transition temperature and decomposition temperature of the polyvinyl alcohol.

[0033] When the temperature exceeds the melting temperature of PVA, the kneaded mixture conveyed through the outlet is in a molten state. Hence, in step b), the kneaded mixture is conveyed through the outlet to obtain a molten / dissolved mixture.

[0034] In one embodiment, the temperature of at least one zone along the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the melting temperature of the polyvinyl alcohol, preferably above the melting temperature of the at least one active pharmaceutical ingredient and between the glass transition temperature and the melting temperature of the polyvinyl alcohol. In that embodiment, the kneaded mixture conveyed through the outlet is in the form of granules. Thus, in step b), the kneaded mixture is conveyed through the outlet to obtain granules.

[0035] In a further embodiment, the temperature of at least one zone along the screw barrel is between 40°C and 250°C, preferably between 140°C and 230°C, more preferably between 170°C and 210°C, and most preferably between 180°C and 200°C. In a further embodiment, the temperature is the same in all zones along the screw barrel, as described above.

[0036] The term "melt granulation process" or "HMG" generally refers to a size enlargement process in which the addition of a melting or softening binder is used to achieve the agglomeration of solid particles in the formulation. The process utilizes materials that are effective as granulating agents when they are in a softened or dissolved state. In the pharmaceutical industry, this process can be used for the preparation of immediate or sustained release dosage forms. Binders or meltable binders are usually low melting substances that melt or soften at relatively low temperatures (50°C to 90°C), such as low melting waxes or low melting polymers. Melting binders are used to achieve the agglomeration of solid particles during the granulation process. In contrast to HME, the mixture in the melt granulation process is conveyed through an outlet that is an opening but not a nozzle or die. This means that the outlet is sized in such a way that it does not exert pressure on the kneaded mixture. This is in contrast to a die, which leads to an increase in fluid velocity at the expense of pressure energy.

[0037] The resulting product from HMG is different from that prepared by HME. HME granules have an angular shape and a relatively flat surface as seen from SEM measurements, whereas HMG granules have a more circular shape with less flat surface. HMG granules have a smaller specific surface area. Unexpectedly, with comparable particle size distributions (HME3-750 μm and HMG4-350 rpm as examples), granules prepared by HMG show faster API dissolution even though they have a smaller specific surface area. Surprisingly, the dissolution of granules prepared by HMG is faster with increasing particle size, as seen in FIG. 13. This is not the case with granules prepared by HME (FIG. 12).

[0038] According to the present invention, no additional binder is required. The degree of agglomeration depends on the temperature of the screw barrel. In the temperature range of the above described process ("above the melting point of at least one active pharmaceutical ingredient and between the glass transition temperature and the decomposition temperature of polyvinyl alcohol"), the degree of agglomeration during the granulation process can be controlled by the selection of a specific temperature. At temperatures below the melting temperature of PVA, a low degree of agglomeration can be detected. With increasing temperature, the degree of agglomeration increases. Surprisingly, it has been found that in addition, the dissolved and liquefied API can act as a binder to increase agglomeration.

[0039] Independent of particle size and degree of agglomeration, it has surprisingly been found that under the above conditions, the API is loaded onto the PVA particles in amorphous form and is stabilized in that form. The amorphous solid dispersion may optionally contain further pharma- ceutically acceptable ingredients.

[0040] As used herein, the phrase "pharmaceutically acceptable" generally refers to any compound, such as a solvent, dispersion medium, excipient, carrier, coating, active agent, isotonicity and absorption delaying agent, and the like, that does not produce an allergic or similar untoward reaction when administered to a human. The use of such media and agents in pharmaceutical compositions is well known in the art. In one embodiment, the active pharmaceutical ingredient of the granules is dispersed in amorphous form within and / or on the surface of the polyvinyl alcohol.

[0041] The term "dispersed in amorphous form" refers to the dispersion of an amorphous API in a polymer or on the surface of a polymer. Preferably, the amorphous API is distributed in a molecularly dispersed state on the polymer surface. Upon dissolution, a formulation comprising an amorphous solid dispersion can reach a higher solubility in an aqueous medium than a crystalline API.

[0042] In one embodiment, the API included in the pharmaceutical composition of the present invention has a sufficient amount to be therapeutically effective. For a given API, the therapeutically effective amount is generally known or readily accessible by those skilled in the art. Typically, the API may be present in the pharmaceutical composition in a weight ratio of API to PVA ranging from 1:99 to 90:10, preferably 5:95 to 60:40, and most preferably 10:90 to 30:70.

[0043] The term "extruder" refers to a barrel containing one or more rotating screws that convey the material down the barrel. These extruders include (i) an opening where the material enters the barrel, which may have a hopper filled with the material(s) to be extruded or continuously fed by one or more external feeder(s) in a controlled manner; (ii) a conveying (process) section, which includes the barrel and screw(s) that convey and, if applicable, mix the material; and (iii) optionally downstream auxiliary equipment for cooling, cutting, classifying, and / or collecting the final product. According to the present invention, suitable extruders are single-screw extruders, twin-screw extruders or planetary roller extruders. Twin-screw extruders are preferred. In one embodiment, the melt granulation process is a twin-screw melt granulation process.

[0044] The term "twin-screw melt granulation" (TSMG) refers to a specific form of melt granulation process. In twin-screw melt granulation, a twin screw is used, consisting of two intermeshing, co-rotating screws mounted on a splined shaft of a closed barrel. Due to the wide range of screw and barrel designs, various screw profiles and process functions can be set according to the process requirements. Twin screws are capable of conveying, compressing, mixing, cooking, shearing, heating, cooling, pumping, forming with a high level of flexibility.

[0045] As used herein, the term "hot melt extrusion" or "HME" refers to a process in which active pharmaceutical ingredients, thermoplastic excipients, and other functional processing aids are heated and softened or melted inside an extruder and forced through at least one nozzle or die into various forms.

[0046] According to the present invention, at least one active pharmaceutical ingredient (API) is a biologically active substance, which may be in the form of one or more pharma- ceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. A pharmaceutical composition may contain one or more APIs.

[0047] As used herein, the terms "poorly soluble API", "poorly water soluble API", and "lipophilic API" refer to APIs that have a solubility such that the highest therapeutic dose of the particular API to be administered to an individual cannot be dissolved in 250 ml of aqueous medium at a pH range of 1 to 8, in line with the definition of poor solubility according to Biopharmaceutics Classification System (BCS) classes 2 and 4. APIs that fall into BCS class 2 or 4, respectively, are well known to those skilled in the art. A typical example for a poorly soluble API of BCS class 2 is itraconazole (ITZ).

[0048] In one embodiment, the active pharmaceutical ingredient is a poorly soluble API. After the process is finished, the product is preferably released in the form of granules. These granules can be easily used for further processing steps, such as milling, capsule filling or direct compression, with or without the addition of additional excipients. The particle size of the granules can be adapted by changing the process parameters.

[0049] As used herein, the term "granules" refers to predominantly spherical, angular, nearly spherical, or nearly angular structures of macromolecular size, preferably with an average particle size between 20 and 2500 μm, more preferably between 50 and 2000 μm, and most preferably between 100 and 1500 μm. "Average particle size" is defined as the diameter equivalent to which 50% of the sampled powder or granule mass (of particles) have a smaller diameter. For the measurement of particle size distribution, various methods are available. According to the present invention, particle size distribution is measured by Dynamic Image Analysis (ISO 13322-2).

[0050] In a specific embodiment, the particle size distribution is measured using a Camsizer X2 from Retsch GmbH, preferably with both camera systems CCD-B and CCD-Z activated during the measurement, the air pressure for dispersion set to 50 kPa, and the slit width set to 4 mm.

[0051] The concept of a granulation process carried out by melt granulation here is not limited to twin screw melt granulation only. Other thermal processing techniques carried out in batches are also possible, provided that the API and the polymer(s) can be processed under suitable temperature conditions.

[0052] In the described manner, itraconazole (ITZ) is treated as a model active substance with low solubility and is treated with polyvinyl alcohol using the disclosed melt granulation process, which illustrates the present invention. It is emphasized that the present invention is not limited to ITZ or low solubility APIs. The process can be carried out with all APIs with a melting temperature between 40°C and 250°C, as described above.

[0053] The present invention further refers to a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in PVA by the process as described above.The present invention further refers to a method for dispersing an amorphous active ingredient in PVA by the process as described above.

[0054] The present invention further refers to the granules obtainable by the process described above. The granules obtained by the previously mentioned process can be filled directly into sachets or capsules or can be further processed into tablets, capsules or multiparticulate systems. Typically, the granules comprise at least the API and PVA. They may optionally contain further pharma- ceutically acceptable ingredients.

[0055] At least one API and PVA may be present in the granules in a weight ratio of API to PVA ranging from 1:99 to 90:10, preferably from 5:95 to 60:40, and most preferably from 10:90 to 30:70.

[0056] The granules preferably contain at least 50% (w / w) of the API, more preferably at least 80% of the API in amorphous form, most preferably at least 90%. Optionally, the granules can be further milled to a defined particle size. Preferably, the granules are milled to an average particle size between 50 μm and 300 μm. The present invention further refers to a tablet obtainable by the process described above.

[0057] While making and using various embodiments of the invention are discussed in detail below, it should be understood that the present invention provides inventive concepts that have more applications than are specifically described herein. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

[0058] Terms not defined herein have the meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Terms such as "a," "an," and "the" are not intended to refer to only a single entity, but include a general class of which a specific example may be used for illustration. The terminology herein is used to describe certain aspects of the present invention, but their use does not limit the invention, except as outlined in the claims. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 shows the X-ray diffraction patterns of different hot melt granules obtained at different temperatures. [Diagram 2] FIG. 2 shows the X-ray diffraction pattern of crystalline itraconazole, as used for the twin-screw melt granulation process of Example 1. [Diagram 3] FIG. 3 shows the dissolution profile of itraconazole from the granules obtained in Example 1 compared to the crystalline forms of itraconazole. [Figure 4] Figure 4 shows an SEM image of HMG1-200 rpm at 500x magnification. [Diagram 5] Figure 5 shows an SEM image of HMG2-25 rpm at 500x magnification. [Figure 6] Figure 6 shows an SEM image of HMG3-300 rpm at 500x magnification. [Figure 7] Figure 7 is an SEM image of HMG4-350 rpm at 500x magnification. [Figure 8] Figure 8 is an SEM image of HMG5-400 rpm at 500x magnification. [Figure 9] Figure 9 is an SEM image of HME1-350 μm at 500× magnification. [Figure 10] Figure 10 is an SEM image of HME2-500μm at 500x magnification. [Figure 11] Figure 11 shows an SEM image of HME3-750 μm at 500× magnification. [Figure 12]FIG. 12 shows the dissolution of various batches of PVA4-88 particles in 900 ml SGF, 75 rpm, paddle with 50 mg API. [Figure 13] FIG. 13 shows a comparison of dissolution of batches HME3-750 μm and HMG4-350 rpm in 900 ml SGF, 75 rpm, paddle with 50 mg API. [Figure 14] FIG. 14 shows the process profile for hot melt extrusion (through a nozzle). [Figure 15] FIG. 15 shows the process profile for hot melt granulation.

[0060] example: I. Melt Granulation Process 1. Twin screw melt granulation process 700 g of a 10% mixture of crystalline itraconazole and PVA 4-88 (Parteck® MXP) was fed into the barrel of a twin-screw extruder equipped with a granulation kit. The rotation speed and dosing rate were adapted until the target parameters were reached. After all heating zones had reached their target temperatures, the granulation process was started.

[0061] The screw rotation speed was set at 300 rpm. The injection rate was kept constant at 150 grams / hour. The temperature profile of the individual heating zones is presented in Table 1.

[0062] [Table 1]

[0063] 2. Powder Diffraction (PXRD) The crystalline itraconazole and granules obtained in Example 1 were measured by powder diffractometry. The granules of Example 1 were milled in an IKA Tubemill 100 with a 40 ml vessel at 25000 rpm for 20 seconds and sieved through a 250 μl sieve. PXRD was measured on a Rigaku Miniflex 600 with the following settings: The X-ray beam was generated at 40 kV and 15 mA. An AD / teX Ultra2 detector was used. The scan speed / duration was set at 5 degrees / min with a step width of 0.02 degrees. The scan range was set from 3.0 to 50.0 degrees. FIG. 1 shows the X-ray diffraction patterns of the different hot melt granules obtained at different temperatures, as shown in Table 1. FIG. 2 shows the X-ray diffraction pattern of crystalline itraconazole, as used for the twin-screw melt granulation process of Example 1.

[0064] As can be seen in Figure 1, the physical mixture of crystalline itraconazole and PVA still contains crystalline patterns, e.g. peaks at diffraction angles of approximately 14 and 21, which can be clearly associated with crystalline itraconazole (see Figure 2). The same pattern can also be observed in samples up to a processing temperature of about 170°C. At temperatures higher than 170°C, all of the drug substance appears to be converted to its amorphous form. Itraconazole has a melting temperature of 166.2°C. Therefore, the experiment shows that temperatures above the melting point are necessary to obtain PVA particles loaded with amorphous itraconazole.

[0065] 3. Dissolution measurement To measure dissolution, the granules obtained in Example 1 were used directly without further treatment. Three samples were used per temperature setup. 500 mg of 10% ITZ granules were weighed (Mettler Toledo Delta Range XP105), which is equivalent to 50 mg ITZ API.

[0066] Dissolution was carried out with an online photoelectric spectrometer Specord 200+ from Analytik Jena using a Sotax AT7 smart. As medium 900 ml of SGF.sp (10.0 L VE-water with 20 g NaCl, 800 ml 0.1 M HCl) was used at 37°C ± 0.5. The following settings were used: rotation speed 75 rpm; paddle method; prefilter: Glass Microfiber Filters GE Whatmann GF / D Diameter 25 mm, 5 mm HELMA flow-through cuvette, sampling points: 5, 20, 35, 50, 60, 120 min. FIG. 3 shows the dissolution profile of itraconazole from the granules obtained in Example 1 compared to the crystalline forms of itraconazole.

[0067] Figure 3 demonstrates that crystalline itraconazole (line 1) exhibits very little solubility in the release agent. Granulation with polyvinyl alcohol at temperatures between 140°C and 170°C increases the solubility of the compound (lines 2-6).

[0068] At 175°C, the solubility increases sharply. With higher temperatures, the solubility is further enhanced. Immediate release can be observed for temperatures of 180°C to 190°C (lines 8-10). With further increase in temperature above the melting temperature of PCA, the drug release rate is delayed (line 11; 200°C).

[0069] 4. Particle size measurement To measure the particle size distribution, 1-3 g of the granules obtained in Example 1 were used directly without further treatment. The particle size was measured using a Camsizer X2 from Retsch GmbH. Both camera systems CCD-B and CCD-Z were activated during the measurement. The air pressure for the dispersion was set at 50 kPa. The slit width was set at 4 mm. The cumulative distribution of the volume percentage is given in Table 2.

[0070] [Table 2]

[0071] II. Comparison Hot Melt Extrusion vs. Hot Melt Granulation 1. Hot Melt Extrusion (HME) 540.15 g of Parteck MXP and 60.0 g of itraconazole were weighed into a mixing vessel and mixed in a tubular mixer for 5 minutes. The polymer / API mixture (ratio: 90 / 10) was then filled into a pycnometer twin screw feeder (Thermo Fisher scientific, Karlsruhe, Germany) and the maximum injection rate was measured. Maximum injection rate: 0.885 kg / h

[0072] Extrusion was performed with a Pharma 11 twin screw extruder (Thermo Fisher scientific, Karlsruhe, Germany) with a screw speed of 250 rpm and a feed rate of 0.15 kg / h. The torque was 12% of the maximum possible torque (maximum torque = 12 Nm). A circular hole nozzle with a diameter of 2.0 mm was installed, and a vent port was also installed.

[0073] The resulting white, opaque filaments were transported through a conveyor belt (Brabender GmbH & Co.KG., Duisburg, Germany). The conveyor belt speed was set at 1.49. Colling of the filaments was performed at room temperature. The filaments were then cut by a pelletizer (Brabender GmbH & Co.KG., Duisburg, Germany) and the white granules were collected. The process profile for hot melt extrusion (through a nozzle) is shown in FIG.

[0074] Shattering: Three batches of granules from the experiment, each with 60 g, were frozen with liquid nitrogen. The frozen granules were then milled with a ZM200 ultracentrifugal mill (RETSCH GmbH, Haan, Germany) under the following conditions: 18000 rpm 12-tooth rotor First batch with 350μm sieve spacing (Batch HME1-350μm) Second batch with 500μm spacing sieve (Batch HME1-500μm) Third batch with 750μm sieve spacing (Batch HME1-750μm) Cyclone Cassette

[0075] 2. Hot Melt Granulation (HMG) 450.0 g of Parteck MXP and 50.1 g of itraconazole were weighed into a mixing vessel and mixed in a tubular mixer for 5 minutes. The polymer / API mixture (ratio: 90 / 10) was then filled into a pycnometer twin screw feeder (Thermo Fisher scientific, Karlsruhe, Germany) and the maximum injection rate was measured. Maximum injection rate: 0.705 kg / h

[0076] Hot melt granulation was performed with a Pharma11 twin screw extruder (Thermo Fisher scientific, Karlsruhe, Germany) equipped with a twin screw granulation kit.

[0077] Granulation was carried out at screw speeds of 200 rpm, 250 rpm, 300 rpm, 350 rpm, and 400 rpm at 190° C. At a given rpm, granules were collected for 15 minutes. After each new set point, granules were discarded for an additional 10 minutes before a new batch was collected. The process profile for hot melt granulation is shown in FIG.

[0078] 3. SEM measurements Sample preparation: A small amount of powder is prepared on an aluminum sample holder that is covered with conductive double-sided adhesive tape. To prevent loose particles from contaminating the high vacuum chamber of the SEM, unattached particles are removed by compressed air or a blower. To avoid static charging, the sample is coated with ~10 nm platinum before measurement (if the particles are slightly wet, drying at 10~2 bar in the sputtering system prior to sputtering is recommended). The prepared sample is then transferred to the SEM and measured under high vacuum.

[0079] SEM Metrology: ZEISS Supra 35 / LEO 1530, field emission cathode, up to 2 nm resolution, high vacuum, magnification 20x-500,000x, voltage 0.1 kV-30 kV, in-lens detector, Everhart-Thornley detector, 4-Quadrant BSE detector. Figures 4-11 show SEM images of particles from the batches as described above. Figure 4: SEM image of HMG1-200 rpm at 500x magnification. Figure 5: SEM image of HMG2-250rpm at 500x magnification Figure 6: SEM image of HMG3-300rpm at 500x magnification. Figure 7: SEM image of HMG4-350 rpm at 500x magnification Figure 8: SEM image of HMG5-400 rpm at 500x magnification Figure 9: SEM image of HME1-350μm at 500x magnification Figure 10: SEM image of HME2-500μm at 500x magnification Figure 11: SEM image of HME3-750μm at 500x magnification

[0080] 4. Dissolution measurement Sample preparation: Unground sample was used: n=3 (per granule) The weighing of 500 mg of 10% ITZ granules is equivalent to 50 mg ITZ API (balance: Mettler Toledo Delta Range XP105 was used). The dissolution was carried out using a Sotax AT7 smart with an online photometer Specord 200+ from Analytik Jena: Media: 900 ml of SGF.sp (10.0 L VE-water supplemented with 20 g NaCl, 800 ml 0.1 M HCl) at 37°C ± 0.5. Rotation speed 75 rpm; paddle method; pre-filter: Glass Microfiber Filters GE Whatmann GF / D diameter 25 mm 5mm HELMA Flow-Through Cuvettes Sampling points: 5, 20, 35, 50, 60, 120 minutes

[0081] Figure 12 shows the dissolution of various batches of PVA4-88 particles in 900 ml SGF, 75 rpm, paddle with 50 mg API. Figure 13 shows a comparison of the dissolution of batches HME3-750 μm and HMG4-350 rpm in 900 ml SGF, 75 rpm, paddle with 50 mg API.

[0082] It can be seen that HMG4-350rpm has faster dissolution compared to HME3-750μm. Both batches have comparable particle size distribution (see Example II 8). In general, HMG granules with higher particle size show faster dissolution, where this is the opposite to HME granules.

[0083] 5. PXRD measurements The granules were milled in an IKA Tubemill 100 equipped with a 40 ml vessel at 25000 rpm for 20 seconds. Sieved through a 250 μl sieve SI-Low Background Sample Holder PXRD method: Rigaku Miniflex 600 ·X-ray 40kV, 15mA Goniometer MiniFlex 600 Attachment ASC-8 Filter K-beta (x1.5) Detector D / teX Ultra2 Scan mode CONTINUOUS Scan speed / duration 5.0000 degrees / min Step width 0.0200 degrees ·Scan axis Theta / 2-Theta Scan range 3.0000 - 50.0000 degrees Incident slit 0.625 degrees Limited length slit 10.0mm Receiving slit #1 13.0mm (open) Receiving slit #213.0mm (open)

[0084] 6. Description Camsizer: The sample (1-3g) was placed in the groove. Create or assign a method to the specimen Start measurement Camsizer method: ·Funnel position [mm]:5 Groove width [mm]: 60 Slit width [mm]: 4 Dispersion pressure [kPa]: 50 ·Speed ​​adjustment · Size definition: xc_min Sieve size: Pharm.Eur Parameters: Cumulative distribution, sphericity, width / length, symmetry Camera: CCD-Basic / CCD-Zoom Frame rate: 100% (1:1) Measurement completed after 5000 images

[0085] 7. Specific surface area measurements The specific surface area was determined by the gas adsorption-BET method. The measurements were carried out in accordance with DIN ISO 9277:2014-01 and ISO 9277:2010(E).

[0086] The degassing and measurement of the specimens is carried out by an "ASAP2420" instrument from Micromeritics Instrument Cooperation, which uses the static volume measurement principle.

[0087] Sample amounts ranging from 1.6 g to 4.5 g were used. The specimens were degassed by drying under reduced pressure at 40° C. for 20 hours. Krypton (molecular cross-sectional area: 0.2100 nm 2 ) was used as the adsorbate. To achieve good correlation, the specific surface area was determined using multipoint determinations (7 or 8 points) over the pressure range p / p 0 Based on the adsorption isotherm, the correlation coefficients were calculated to be greater than 0.9999 and the BET parameters C ranged from 13 to 18 for all measurements.

[0088] For the monitoring of the inspection equipment, two reference materials were used: alumina (specific surface area: 0.22 m 2 / g, batch 152624, product 004-16816-00) and silica-alumina (specific surface area: 199 m 2 / g, Batch A-501-71, Item 004 / 16821 / 00) both distributed by Micromeritics Instrument Cooperation.

[0089] [Table 3]

[0090] 8. PSD (laser) method: The particle size distribution was measured by laser diffraction spectroscopy according to ISO 13320:2020(E). A laser diffraction spectrometer "Mastersizer 2000" with a dry dispersion unit "Scirocco 2000" from Malvern Panalytical Ltd. was used.

[0091] A sample amount of approximately 1.5 g was analyzed. The sample was dispersed in air (refractive index of 1) using a feed rate of 75%, a gap size of 6 mm, and an air pressure of 3 bar. The range of the obscuration rate is set from 0.1% to 10%. A sieve (diameter 2 mm) with 10 balls was used.

[0092] The light diffraction patterns were evaluated by the Fraunhofer model with a multi-objective analytical model. Table 6 shows the particle size distribution of the batches listed. HME3-750 μm and HMG4-350 rpm have comparable particle size distributions.

[0093] [Table 4]

Claims

1. A process for loading a polymer together with an active pharmaceutical ingredient in a melt granulation process, comprising the following steps: a) kneading a mixture containing at least one active pharmaceutical ingredient and polyvinyl alcohol in a heated screw barrel of an extruder, wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below 250°C, which is the decomposition temperature of polyvinyl alcohol, in order to form a kneaded mixture, and b) Moving the mixed mixture through the discharge port. In this process, the outlet does not exert pressure on the mixture.

2. The process according to claim 1, wherein the active pharmaceutical ingredient in the granules is dispersed in an amorphous form in polyvinyl alcohol.

3. The process according to claim 1 or 2, wherein the temperature in at least one zone along the screw barrel is above the melting temperature of at least one active pharmaceutical ingredient and below 220°C, which is the melting temperature of polyvinyl alcohol, and thereafter the kneaded mixture is moved through an outlet to obtain granules.

4. The process according to any one of claims 1 to 3, wherein the granulation process is a twin-screw melt granulation process.

5. The process according to any one of claims 1 to 4, wherein the polyvinyl alcohol is a 4% solution with a degree of hydrolysis of 72% to 90% and a viscosity of 2 mPas to 40 mPas at 20°C.

6. Polyvinyl alcohol is PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA 23-88, PVA 26-80, PVA 26-88, PVA 28-99, PVA 30-98, PVA The process according to any one of claims 1 to 5, selected from the list consisting of 30-92, PVA 32-88, and PVA 40-88.

7. The process according to any one of claims 1 to 6, wherein the polyvinyl alcohol is PVA 4-88.

8. The process according to any one of claims 1 to 7, wherein polyvinyl alcohol is freeze-dried.

9. The process according to any one of claims 1 to 8, wherein the active pharmaceutical ingredient is present in the mixture in a weight ratio of the active pharmaceutical ingredient to polyvinyl alcohol in the range of 1:99 to 90:

10.

10. The process according to any one of claims 1 to 9, wherein the active pharmaceutical ingredient has low solubility in water.

11. The process according to any one of claims 1 to 10, wherein the granules are further ground to an average particle size of 50 μm to 300 μm.

12. The process according to any one of claims 1 to 11, wherein the granules are further processed into tablets.

13. Granules obtainable by the process described in any one of claims 1 to 11.

14. A tablet comprising the granules described in claim 13.

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