Process for the production of solid pharmaceutical dosage forms

Abstract

The present invention relates to a process for preparing solid pharmaceutical dosage forms comprising amorphous solid dispersions using a 3D printing process, which allows for a simple and flexible manufacturing of solid pharmaceutical dosage forms comprising amorphous solid dispersions, and the potential for rapid disintegration of dosage forms with high drug loading.

Description

[Technical Field]

[0001] The present invention relates to a process for preparing solid pharmaceutical dosage forms using a powder-based 3D printing process, which allows for the easy and flexible production of solid pharmaceutical dosage forms in which the active ingredient is present as an amorphous solid dispersion within a polymer matrix, in accordance with the high quality standards required for pharmaceutical manufacturing. [Background technology]

[0002] Many recently developed active pharmaceutical ingredients (APIs) have poor water solubility, resulting in incomplete dissolution throughout the gastrointestinal tract and low and variable bioavailability. A significant and growing number of new drug candidates fail during development due to poor bioavailability. Therefore, the advancement of innovative approaches to overcome this important formulation challenge is critically needed, and the development of novel drug delivery systems is highly desirable.

[0003] In this amorphous form, compounds dissolve faster than in the crystalline state, especially when solubility is limited by high lattice energy. This improves oral bioavailability, as shown by Mellaerts et al. (Eur J Pharm Biopharm 69: 223-230, 2008). 3D printing technology offers new possibilities in pharmaceutical development. In contrast to standard manufacturing techniques such as tableting, 3D printing allows for the production of personalized dosage forms, facilitating clinical trials by allowing for easy dosage adjustment.

[0004] The term 3D printing refers to the process of creating a 3D object layer by layer. However, using known 3D printing processes to produce solid pharmaceutical dosage forms in which the active ingredient is present in an amorphous form can be difficult and involve additional problems, as discussed below.

[0005] Fused deposition modeling (FDM) or fused filament fabrication (FFF) is a process that uses continuous filaments of thermoplastic material for 3D printing. In pharmaceutical dosage form production, a filament containing the API is produced by hot melt extrusion (HME), which then feeds into a heated printer nozzle, where the softened material is deposited layer by layer to create the pharmaceutical dosage form. FDM-printed dosage forms consist primarily of a solidified, dense melt that dissolves by erosion. While porous systems are possible, the printer's low resolution limits the degree of porosity. Furthermore, recrystallization of the active ingredient can occur during heating during the printing phase. High drug content poses challenges for FDM because it can impair the mechanical properties of the filament, negatively impacting printability. Furthermore, the second heating step required to soften the filament for printing can cause degradation of the API.

[0006] Direct powder extrusion (DPE) is a 3D printing process that melts a powder mixture and prints it into a tablet in one step, avoiding the dual heating and filament fabrication processes. However, DPE tends to cause powder components within the powder mixture to separate during printing, resulting in poor content uniformity in the resulting dosage form. Furthermore, similar to FDM, printed dosage forms also exhibit poor disintegration due to their dense structure. Furthermore, producing amorphous solids can be more challenging due to the short transition time at the hot end (the heated area above the nozzle of the printhead) and the inability of the attached screw to provide sufficient mechanical energy to amorphize the API. Because the extrusion process is highly sensitive to changes in mass flow rate, altering the printing speed in DPE can significantly alter the properties of the melt or solidified product.

[0007] Another 3D printing technique is selective laser sintering (SLS). This technique produces a 3D printed object by creating a powder layer and then fusing the powder particles within the powder layer with a laser. This technique can be used to produce porous dosage forms. While lasers can amorphize APIs in situ, it is difficult to completely amorphize APIs. Larger-scale tablet production is limited by the technical requirements of laser printers. Furthermore, due to the highly concentrated placement of the laser, SLS can cause certain parts of the printed material to become very hot, which can adversely affect the stability of the API and other printed materials.

[0008] Powder binder jetting, or drop-on powder printing, is an easily scalable 3D printing technique that uses liquid to fuse powder particles. It is used to manufacture high-dose and fast-disintegrating dosage forms. Currently, it is used for highly soluble APIs, where the API is embedded in the powder bed. The production of amorphous solid dispersions of poorly soluble APIs can be achieved by incorporating the API into an ink through rapid solvent evaporation, similar to spray drying. This approach produces amorphous samples but with lower drug loading. Formulation development of high-dose, poorly soluble APIs into fast-disintegrating dosage forms presents challenges. Summary of the Invention [Problem to be solved by the invention]

[0009] As mentioned above, existing 3D printing processes available for producing solid pharmaceutical dosage forms have several drawbacks that limit their widespread applicability. Therefore, there is a strong need for a 3D printing process that enables the production of solid dosage forms without these drawbacks. Such a 3D printing process would result in solid dosage forms in which the active ingredient is present in an amorphous form, and would also enable the production of dosage forms containing active ingredients with low solubility in biorelevant media, as well as dosage forms with high active ingredient content, even when the active ingredient has low solubility in biorelevant media. The present invention provides a process that meets these requirements. [Means for solving the problem]

[0010] The present invention provides a process for producing a solid pharmaceutical dosage form containing an active ingredient, comprising the following steps: (a) preparing a powder comprising particles of an amorphous solid dispersion of an active ingredient in a polymer matrix: (b) spreading the powder prepared in step (a) over the entire production area; (c) jet printing a medium onto the powder, the medium being suitable for providing bonding for the powder; (d) sprinkling a layer of the powder prepared in step (a) onto the surface of the powder obtained after carrying out steps (b) and (c), followed by carrying out steps (b) and (c); (e) repeating step (d) as many times as necessary to construct a solid pharmaceutical dosage form; (f) Separating the solid pharmaceutical dosage form from the powder bed The process relates to the above process, comprising:

[0011] This process can be carried out with a 3D printer consisting of a pair of horizontal XY axes suspended above a vertical piston, allowing control of movement in three directions, and equipped with a jet head known from inkjet printing technology. Suitable jet heads operate, for example, according to the continuous inkjet principle (where the fluid is pressurized and ejected in a continuous stream of droplets) or the drop-on-demand principle (where the fluid is ejected drop by drop from the jet nozzle).

[0012] In the manufacture of solid pharmaceutical dosage forms, powder is spread onto a mounting plate to create a powder bed, and then a jet head is moved over the powder bed or moved under a fixed jet head to precisely distribute the media to a predetermined area of the powder bed. After lowering the mounting plate a certain distance, a layer of powder is spread, and the process is repeated. Instead of lowering the mounting plate, the spreading means can be raised a certain distance.

[0013] The above process of jet printing a suitable medium for binding the powder onto a powder bed is known as drop-on powder (DoP) technology. It belongs to the powder-based 3D printing technology and can be described as in-situ wet granulation, where tiny ink or binder droplets are jet printed onto a thin powder layer, fusing the powder particles together. The iterative process of powder sprinkling and ink application continues until the 3D object is printed.

[0014] The term "solid pharmaceutical dosage form" as used herein means any pharmaceutical formulation that is solid and provides a dosage unit of an active pharmaceutical ingredient that can be administered to a patient by any application method, such as orally, rectally, vaginally, by implant, etc. The solid pharmaceutical dosage form can have any shape that suits the application requirements, such as round, oval, rod-shaped, torpedo-shaped, etc. Examples of solid pharmaceutical dosage forms include tablets, pills, caplets, suppositories, implants, etc. Preferably, the solid pharmaceutical dosage form is a tablet.

[0015] The term "active ingredient," as used herein, refers to an ingredient that produces a pharmacological or biological effect when applied to a biological system. The active ingredient may be a pharmaceutical drug, a virus, or a biological substance of biological origin. Examples of active ingredients that can be used in the process of the present invention include hydrocortisone, prednisone, budesonide, methotrexate, mesalazine, sulfasalazine, amphotericin B, fenofibrate, carbamazepine, ibuprofen, glibenclamide, dipyridamole, itraconazole, celecoxib, haloperidol, indomethacin, posaconazole, and ketoconazole.

[0016] As used herein, the term "solid dispersion" refers to a drug substance dispersed or distributed in a dispersion medium. In the present invention, the dispersion medium is a polymer, forming a polymer matrix. Based on the possible combinations of the physical states of the drug substance and the polymer, the drug substance can be either crystalline or amorphous, and the polymer matrix can also be both crystalline and amorphous, resulting in four possible combinations: crystalline drug substance-crystalline polymer (solid suspension), amorphous drug substance-amorphous polymer, crystalline drug-amorphous polymer, and amorphous drug-crystalline polymer.

[0017] As used herein, the term "amorphous solid dispersion" (ASD) refers to a dispersion in which at least the active ingredient is present in a substantially amorphous form. Preferably, both the active ingredient and the polymer are present in a substantially amorphous form. With respect to the active ingredient, the term "substantially amorphous form" means that at least 80 weight percent, typically at least 85 weight percent, preferably at least 90 weight percent, more preferably at least 95 weight percent, even more preferably at least 96 weight percent, even more preferably at least 97 weight percent, more preferably at least 98 weight percent, more preferably at least 99 weight percent, more preferably at least 99.9 weight percent, and more preferably all of the active ingredient is present in amorphous form.

[0018] The term "amorphous" as used herein refers to the non-crystalline form of a solid. Amorphous solids generally have a crystal-like short-range molecular arrangement, i.e., they lack the long-range molecular packing order found in crystalline solids. The solid form of the solid in a solid dispersion can be determined by polarized light microscopy, X-ray powder diffraction, differential scanning calorimetry, or other techniques known to those skilled in the art. Amorphous forms of active ingredients in solid dispersions can usually be identified by a characteristic broad X-ray powder diffraction pattern, while crystalline solids produce specific, isolated peaks. Amorphous forms can exist in two states: rubbery and glassy, with one state converting to the other at the glass transition temperature (Tg).

[0019] The term "polymer matrix" as used herein refers to a three-dimensional solid formed by one or more polymers. In the powders used in the present invention, the polymer matrix is used to embed the active ingredient. Furthermore, compounds such as one or more active ingredients or other excipients can be incorporated, for example, by dissolving or dispersing them in such a polymer matrix.

[0020] The preparation of the powder in step (a) involves preparing an amorphous solid dispersion of the active ingredient in a polymer matrix and, if necessary, reducing its size to a process-usable particle size, which can be carried out using any suitable process known in the art, such as milling. If the powder contains additional materials, the amorphous solid dispersion particles are mixed with such materials to create the powder used in the further steps. If no additional materials are required, the solid dispersion particles refer to the powder prepared in step (a) that is used in the further steps.

[0021] Powders suitable for carrying out further steps of the process typically have a d50 particle size of about 1 μm to about 200 μm, preferably about 10 μm to about 100 μm, and more preferably about 30 μm to about 70 μm. The d50 value referred to herein relates to the particle size in micrometers that divides the distribution halfway above and halfway below this diameter. The d50 is the median of the volume distribution and is often referred to as Dv50 (or Dv0.5). The d50 value referred to herein can be measured by laser diffraction using a Malvern Mastersizer 2000.

[0022] The term "spreading" as used herein refers to the process of applying a planar layer of powder to a planar surface. Spreading of powder can be achieved by using a means suitable for creating a planar layer of powder. Examples of such means include a doctor blade or roller, which can move parallel to a planar surface, such as a mounting area or an existing powder layer, to spread powder from a reservoir across the planar surface. The use of a roller can provide a level of compaction, which can be advantageous in the production of solid pharmaceutical dosage forms.

[0023] As used herein, "a" or "an" means one or more. As used herein, "a" or "an" when used in conjunction with the word "comprising" means one or more. As used herein, "other" means at least two or more. Further, unless otherwise required by context, singular terms include the plural and plural terms include the singular.

[0024] As used herein, "about" refers to numerical values, including, for example, integers, fractions, and percentages, whether or not explicitly stated. The term "about" typically refers to a range of numbers (e.g., + / - 1-3% of the stated value) that one of ordinary skill in the art would consider equivalent to the stated value (e.g., having the same function or result). In some cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0025] As used herein, "jet printing" refers to a process in which a medium is dispensed into a powder bed by ejecting droplets of the medium at high velocity toward the powder bed. The ejection of the droplets can be performed with utmost precision at predefined target locations. By controlling the size and volume of the droplets and the specific target location, precise placement and depth of penetration on the substrate can be precisely controlled. Jet printing is better known as an inkjet printing technique; in contrast to this technique, the medium printed in the process of the present invention is not an ink for printing images, but rather a medium containing a material that can be used to print solid pharmaceutical dosage forms.

[0026] The amorphous solid dispersion of an active ingredient in a polymer matrix, present as particles in the powder prepared according to step (a) of the process, can be prepared using any method known in the art that is feasible for preparing an amorphous solid dispersion of an active ingredient in a polymer matrix. According to a suitable embodiment, the amorphous solid dispersion is prepared using hot-melt extrusion, co-precipitation or spray-drying. Thus, the present invention also relates to a process for preparing a solid pharmaceutical dosage form, wherein the amorphous solid dispersion of an active ingredient in a polymer matrix, present as particles in the powder prepared in step (a), is prepared using hot-melt extrusion, co-precipitation or spray-drying. Preparation of the powder by hot-melt extrusion is particularly preferred.

[0027] As used herein, the term "hot melt extrusion" refers to a process in which two or more ingredients are mixed using high shear mixing at a controlled temperature. When used to produce a powder according to step (a) of the process, hot melt extrusion involves mixing an active ingredient with at least one polymer to produce a soft mass. Mixing of the active ingredient and polymer can occur before, during, or after the formation of the soft mass. For example, the ingredients required to produce the soft mass can be mixed first and then extruded, or mixed simultaneously and melt extruded. Finally, the hot melt is homogenized to disperse or embed the active ingredient in the polymer.

[0028] The hot-melt extrusion process can be carried out using conventional extruders known in the art. Suitable extruders include, but are not limited to, single-screw, intermeshing-screw, or multi-screw extruders, preferably twin-screw extruders, which can be co-rotating or counter-rotating and optionally equipped with kneading mixing and / or conveying elements. The operating temperature for preparation of the hot-melt extrusion typically depends on the properties of the API and polymer, as well as the type and screw configuration of the extruder. The extrudate obtained by hot-melt extrusion is further processed, such as by grinding, to obtain a powder of a size and shape suitable for processing.

[0029] As used herein, the term "coprecipitation" refers to the process of dissolving two or more solid ingredients in a common solvent and rapidly mixing them with a common antisolvent, which is miscible with the common solvent. The rapid coprecipitation of the active ingredient and polymer results in a suspension of amorphous particles, which can be further washed and dried to form a powder.

[0030] The term "spray drying" as used herein generally refers to a solvent extraction process. The components of the resulting product are dissolved / dispersed in a liquid, which is then fed to the atomizer of the spray dryer, for example, using a peristaltic pump. Suitable atomizers that can be used to atomize the liquid include nozzles or rotating disks. In the case of nozzles, atomization occurs through the action of compressed gas or pressurized liquid, while in the case of rotating disks, atomization occurs through the rapid rotation of the disk. In both cases, atomization breaks the liquid into small droplets that enter the drying chamber, where the solvent is extracted from the aerosol droplets and discharged, for example, through an exhaust pipe into a solvent trap.

[0031] The medium used in jet printing is a liquid. As used herein, the term "liquid" refers to a solvent that is fluid at ambient temperature (approximately 25°C). Examples of liquids include water, organic solvents such as ethanol, or a mixture of both, which may or may not be soluble in each other. Thus, the present invention is also directed to a process for producing a solid pharmaceutical dosage form, in which the medium used in jet printing in step (c) is a liquid.

[0032] The liquid may further contain an adjuvant dissolved, suspended, or emulsified in the liquid. Examples of adjuvants include surfactants that improve the spreading or wetting of particles in the powder bed. Further examples of adjuvants include viscosity modifiers, such as glycerol, which enable jet printing by preventing excessive wetting of the nozzle plate or by controlling the flow of liquid through the channels and nozzles of the jet head; agents for controlling the hydrophilicity or hydrophobicity of the ink, such as cosolvents such as ethanol, butanol, diethylene glycol, polyethylene glycol, dimethyl sulfoxide, and hexane, which improve the spreading or wetting of particles in the powder bed; humectants such as glycerol and propylene glycol, which prevent nozzle clogging due to ink evaporation; film formers, sometimes called binders or resins, which control the spreading of the ink on the substrate and prevent the ink from bleeding or smearing on the substrate; dyes or pigments; and defoamers.

[0033] The presence of a binder, as known in binder jet printing processes, is not required, since the liquid jet printed onto the powder in step (c) itself provides the powder with a bond. However, in some cases, it may be advantageous for the powder dispersed throughout the production area to contain a binder material that, when activated by the medium jet printed onto the powder, provides additional bonding. Therefore, the present invention is also directed to processes in which the powder contains a binder material. When the powder contains a binder, the binder material is present within the powder, physically mixed with other powder particles.

[0034] In some cases, when the binder material is a polymer, the binder material present in the powder may be the same material used as the matrix material of the solid amorphous dispersion.

[0035] When the vehicle is jet printed onto the powder, bonding of the powder is achieved by partial dissolution and fusion of the polymer matrix and activation of the binding material present within the powder. Accordingly, the present invention also relates to a process for producing a solid pharmaceutical dosage form in which the vehicle is a fluid liquid that partially dissolves the polymer matrix and / or the binding material present therein.

[0036] Partial dissolution of the polymer matrix means that a portion of the polymer matrix of the particles melts and softens to some extent, thereby inducing adhesion and / or partial fusion of particles that are in intimate contact with each other, and building a porous structure of the adhered and / or fused particles.

[0037] Advantageously, the medium jet-printed onto the powder used to cause particle sticking and adhesion contains at least one volatile solvent. Volatile solvents are liquids that readily become gaseous at room temperature (about 25°C) and atmospheric pressure (about 76 mmHg), such as organic solvents such as methanol and ethanol. When the volatile solvent comes into contact with the powder containing a polymer matrix and causes partial dissolution and / or fusion of the polymer matrix of adjacent powder particles, it evaporates, thereby causing resolidification of the polymer matrix present in the powder and sticking of the powder.

[0038] The physicochemical properties of the medium necessary to cause adhesion and / or partial fusion of the matrix polymer present in the powder, such as its ability to dissolve the polymer matrix polymer and / or its volatility, can be easily adapted to the specific requirements of a particular polymer and the implementation requirements of the printing process by using different volatile solvents and / or mixing volatile solvents alone or with non-volatile solvents. Therefore, the present invention also relates to processes in which the medium comprises or consists of one or more volatile solvents, alone or mixed with one or more non-volatile solvents. A non-volatile solvent is a liquid that does not readily vaporize at room temperature (approximately 25°C) and atmospheric pressure (approximately 76 mmHg) and has a vapor pressure equal to or less than that of water.

[0039] Suitable volatile solvents that can be used as a medium in the process of the present invention are methanol, ethanol, propanol, 2-propanol, and acetone, and suitable non-volatile solvents are water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. Therefore, the present invention also relates to a process for producing a solid pharmaceutical dosage form, in which the volatile solvent is selected from the group consisting of methanol, ethanol, propanol, and 2-propanol, and the non-volatile solvent is selected from the group consisting of water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. Methanol and ethanol are particularly preferred.

[0040] In some cases, the medium to be jet printed onto the powder can further comprise a binder material. Accordingly, the present invention is further directed to a process for producing a solid pharmaceutical dosage form, wherein the medium is a liquid and comprises a binder material. When the medium comprises a binder material, such binder material is present in dissolved or dispersed form. Preferably, it is present in dissolved form.

[0041] As used herein, the term "binder" refers to a material that bonds or adheres particles together. When applied to a powder bed, particles that come into contact with the binder adhere to one another, thereby producing a solid comprised of particles adhered to one another. In the present invention, the binder provides cohesion and strength to the solid formulation.

[0042] Binders that can be used in the present invention include, for example, lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (e.g., sucrose stearate, sucrose palmitate), sorbitan esters (e.g., Span®), glycerol fatty acid esters (e.g., glycerol monostearate), fatty acids, fatty alcohols (solid at room temperature), esters of fatty acids with fatty alcohols, and polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose acetate succinate or microcrystalline cellulose, copolymers of acrylic acid or methacrylic acid with acrylic acid or methacrylic acid esters, preferably copolymers of methacrylic acid, and poly(methacrylic acid-methyl methacrylate copolymer) (1 copolymers of methacrylates or acrylates, ethyl acrylate, methyl methacrylate, such as poly(methacrylic acid-methyl methacrylate copolymer) (1:1) (e.g., Eudragit® L100), poly(methacrylic acid-ethyl acrylate copolymer) (1:2) (e.g., Eudragit® S100), or poly(methacrylic acid-ethyl acrylate copolymer) (1:1) (e.g., Eudragit® L100-55), and copolymers of ethyl acrylate, methyl methacrylate, and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit® RL) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS), methacrylic acid esters with a low content of quaternary ammonium groups, such as dimethylaminoethyl methacrylate, butyl methacrylate, and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (2:1:1) (e.g., Eudragit® E PO),Preferably, the binder comprises or consists of methyl methacrylates such as hydroxypropyl methylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropyl methylcellulose acetate succinate. Thus, the present invention also provides binders comprising lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (e.g., sucrose stearate, sucrose palmitate), sorbitan esters (e.g., Span®), glycerol fatty acid esters (e.g., glycerol monostearate), fatty acids, fatty alcohols (solid at room temperature), esters of fatty acids with fatty alcohols, and polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate or microcrystalline cellulose, acrylic acid or methacrylic acid with acrylic acid or methacrylic acid. Copolymers with methacrylic acid esters, preferably copolymers of methacrylic acid and methacrylates or acrylates, such as poly(methacrylic acid-methyl methacrylate copolymer) (1:1) (e.g., Eudragit® L100), poly(methacrylic acid-methyl methacrylate copolymer) (1:2) (e.g., Eudragit® S100), or poly(methacrylic acid-ethyl acrylate copolymer) (1:1) (e.g., Eudragit® L100-55). copolymers of ethyl acrylate, ethyl acrylate, and methyl methacrylate, and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit® RL) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS), dimethylaminoethyl methacrylate,The present invention relates to a process for producing a solid pharmaceutical dosage form containing an active ingredient, the solid pharmaceutical dosage form comprising or consisting of a methacrylic acid ester having a low content of quaternary ammonium groups, such as butyl methacrylate, and a methyl methacrylate, such as poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (2:1:1) (e.g., Eudragit® E PO), preferably hydroxypropyl methylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropyl methylcellulose acetate succinate.

[0043] Polymers that can be used as matrix polymers to produce powders containing amorphous solid dispersions of the active ingredient in a polymer matrix are vinylpyrrolidone-vinyl acetate copolymers (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), (Eudragit® L100-55), and poly(methacrylic acid-methyl methacrylate) (Eudragit® L and Eudragit® S), polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), (Soluplus®), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT). Thus, the present invention also relates to a process for producing a solid pharmaceutical dosage form, wherein the polymer matrix comprises vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), (Eudragit® L100-55), and poly(methacrylic acid-methyl methacrylate) (Eudragit® L and Eudragit® S), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), (Soluplus®), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT).

[0044] In some cases, depending on the type and amount of medium to be jet printed onto the powder, in particular the volatility of the liquid, and the physicochemical properties of the powder after the medium has been jet printed onto the powder according to step (c), it may be necessary to wait a period of time for the liquid to evaporate before proceeding to the next step. In such cases, it may be desirable to accelerate the evaporation of the liquid so that the process can be carried out more quickly. In such cases, a drying step can be introduced after performing step (c) and / or step (d). Thus, the present invention further relates to a process for producing a solid pharmaceutical dosage form, in which a drying step is carried out after performing step (c) and / or step (d).

[0045] According to suitable embodiments, the drying step is carried out using heat, reduced air pressure, or convection. Since each of these means alone promotes evaporation, each of these means can be combined with one or more of the others to achieve an additive effect and speed up the drying step. Thus, the present invention also relates to a process for producing solid pharmaceutical dosage forms, wherein the drying step comprises heat, low pressure (air pressure), and / or convection. Suitable low pressures are pressures below atmospheric pressure, for example, in the range of 100-80,000 Pa, preferably in the range of 5,000-50,000 Pa. Convection can be applied, for example, by a blower. An example of an embodiment of a drying step combining heat and convection is to use a blower to blow heated air onto the powder bed.

[0046] Heating can be applied by infrared radiation, a hot gas stream, and / or a heated surface. Accordingly, the present invention also relates to a process for producing solid pharmaceutical dosage forms in which heating is applied by infrared radiation, a hot gas stream, and / or a heated surface. The gas in the hot gas stream is a single element or compound gas, such as nitrogen or carbon dioxide, or a mixture of element and compound gases, such as air. The heated surface can be provided, for example, by heating the mounting plate or by heating part or all of the case of the 3D printer used to carry out the process.

[0047] In principle, solid pharmaceutical dosage forms for any application method, such as oral, rectal, vaginal, implant, etc., can be produced by the process described herein. However, the process is particularly suitable for producing solid pharmaceutical dosage forms for oral use. Therefore, an advantageous embodiment of the invention described herein relates to a process for producing solid pharmaceutical dosage forms for oral administration.

[0048] The active ingredient is present in an amorphous solid state, which enhances its solubility in biologically relevant media. Therefore, the process of the present invention is particularly suitable for producing immediate release formulations. Therefore, a preferred embodiment of the present invention relates to a process for producing a solid pharmaceutical dosage form that provides immediate release of the active ingredient.

[0049] As used herein, the term "immediate release" means that the majority of the active pharmaceutical ingredient is rapidly released from the pharmaceutical dosage form. Preferably, at least 80 percent of the active ingredient is released within 30 minutes after administration, and more preferably within 15 minutes. The release (dissolution) of the active ingredient from the pharmaceutical dosage form is measured in pH 6.8 buffer or 0.1 N HCl using a conventional dissolution test that conforms to the standard dissolution test described in the appropriate pharmacopoeia (e.g., USP Chapter 711).

[0050] In some cases, after separation from the powder bed according to process step (f), the solid pharmaceutical dosage form may still contain residual liquid that has not previously evaporated, which must be removed before further handling, e.g., to avoid physical damage. In such cases, it may be necessary to remove the remaining liquid from the solid pharmaceutical dosage form, followed by a drying step. Thus, the present invention also relates to a process for producing a solid pharmaceutical dosage form, in which a drying step is performed after step (f). Such drying steps include heating, low pressure (air pressure), and / or convection.

[0051] The present invention will be described in detail below with reference to exemplary embodiments thereof, but the present invention is not limited to these embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0052] example printing equipment The following examples were produced using a machine with a powder bed that can move in the x and y directions of the machine and serves as the production area for the described objects. The printhead assembly is located above the powder bed. The assembly consists of a modified HP C6602 inkjet cartridge. The cartridge is connected to electronic circuitry that activates the nozzles to eject liquid droplets in sync with the movement of the powder bed. The cartridge was modified to allow for replacement of the ink contained in the stock cartridge. Additionally, a connector was introduced to connect the cartridge to a pressure regulator. A negative pressure of 20 mmH2O was applied to the cartridge's ink reservoir. To jet print binder-containing media, the cartridge's native nozzle pitch was used. In a separate location, the powder reservoir was mounted above the build plate containing the powder. Material could be deposited in a controlled manner into the production area of the powder bed.

[0053] The printing process is controlled by software commands that are executed in sequence. First, a thin layer of powder is prepared on the powder bed. Then, the powder bed moves under the printing assembly, and liquid material is jet-printed onto the surface of the powder bed. After all printing commands and optional dwell times for a particular layer have been executed, the next layer of particulate material (height: 0.1 mm) is deposited on the already prepared powder bed surface, and liquid material is jet-printed onto the new powder layer. This process is repeated until all layers of the object have been printed.

[0054] The print pattern and the movements required to produce a specific object are defined by software using a digital 3D model and a configuration file. The shape of the print object can be defined via the digital 3D model. Each nozzle in the printhead fires up to 500 droplets per second.

[0055] Droplet volume The printhead droplet volume is measured by printing a defined number of droplets into the cavities of an acrylic 96-well plate. The deposited material is diluted and the concentration of incorporated dye is measured by UV / VIS spectroscopy. The droplet volume is calculated using the following formula:

number

[0056] Powder bed preparation The powder used in the printing process was prepared by hot-melt extrusion. Ketoconazole, copovidone, and fumed silica were mixed in a tumbler mixer in ratios of 20:79:1 and 40:59:1. Ketoconazole was used as a poorly soluble model compound. Extrusion was carried out in a co-rotating twin-screw extruder with an 11 mm screw. Extrusion was carried out above the melting point of ketoconazole. The powder mixture was gravimetrically fed at 0.2 kg / h. The screw speed was set at 300 rpm. The extrudate strand was drawn using a conveyor belt. The collected extrudate strand was milled using an ultracentrifugal mill equipped with a sieve (mesh size 200 μm). Milling was carried out at 10,000 rpm.

[0057] Glossary Copovidone: Copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (Ph.Eur.11.0 monograph "Copovidone") Fumed silica: Colloidal silicon dioxide according to Ph.Eur.11.0 monograph "Silica, colloidal anhydrous" Methylene Blue: IUPAC name 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride

[0058] Non-settling dissolution 1.2 ml of FaSSIF was prepared from FaSSIF powder (Biorelevant.com Ltd, London, UK) according to the instructions (L. Klumpp, "Dissolution behavior of various drugs in different FaSSIF versions", European Journal of Pharmaceutical Sciences, 2020) and heated to 37°C in an Eppendorf cap.

[0059] The drug content of the object was determined by diluting the medium after the dissolution experiment with an organic solvent to comprehensively dissolve ketocoanol and measuring the concentration of ketocoanol by UPLC. The mass of API in the printed object was calculated from all the drawn samples and the final value.

[0060] Sink Dissolution The formulation prototypes were analyzed in a dissolution apparatus equipped with paddles conforming to USP Apparatus Type 2. The dissolution medium (0.1 N hydrochloric acid) was heated to 37°C. The paddle speed was set at 100 rpm. Samples were taken at various time points, mixed with an equal volume of organic solvent, and analyzed for concentration by UPLC.

[0061] tensile strength Tablet crush resistance was measured according to Ph. Eur. 11.0, 2.9.8 "Resistance to crushing of tablets." Tensile strength was calculated according to the planar compression equation of Pitt, KG and MG Heasley (2013). "Determination of the tensile strength of elongated tablets." Powder Technology 238: 169-175.

[0062] Storage conditions The formulation prototypes were stored in a desiccator at 40°C for 4 weeks.

[0063] Differential Scanning Calorimetry (DSC) The samples were weighed into aluminum containers and sealed. The containers were punctured before analysis. The samples were heated from 0°C to 180°C (physical mixtures) or from 0°C to 200°C (formulation prototypes) and cooled to 0°C at a rate of 10 K / min.

[0064] Powder X-ray diffraction (pXRD) Powder X-ray diffraction was performed in the Bragg-Brentano configuration. X-rays were generated by a copper anode at 30 kV and 10 mA. Sample preparation was performed in a zero-background holder over a range of 6° to 35°. The step size was 0.02 mm. The measurement time per step was set to 6 seconds for the formulation prototypes and 1 second for the physical mixtures. The present invention will be further described below with reference to exemplary embodiments thereof, but the present invention is not limited to these embodiments.

[0065] Example A The medium is prepared by mixing ethanol and purified water in a volume ratio of 7:3. A powder bed containing 20% (w / w) ketoconazole, prepared by hot melt extrusion and milling, is used. The medium is jet-printed onto the surface of the powder bed at 30 drops per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed, and the printing process is repeated for a total of 24 layers.

[0066] The described process results in the production of objects (shape: cylinders with diameter = 10 mm and height = 2.4 mm) with a mass of 150.6 mg ± 6.2 mg (mean ± standard deviation, n = 75), a drug content of 19.85% ± 0.09% (mean ± standard deviation, n = 3), and a tensile strength of 0.9 MPa ± 0.3 MPa (mean ± standard deviation, n = 10).

[0067] Example B The medium is prepared by mixing ethanol and purified water in a volume ratio of 7:3. A powder bed containing 40% (w / w) ketoconazole is prepared by hot-melt extrusion and milling. The medium is jet-printed onto the surface of the powder bed at 30 drops per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed, and the printing process is repeated for a total of 24 layers. The described process results in the production of objects (shape: cylinders with diameter = 10 mm and height = 2.4 mm) with a mass of 157.6 mg ± 69.7 mg (mean ± standard deviation, n = 24) and a tensile strength of 1.1 MPa ± 0.2 MPa (mean ± standard deviation, n = 3).

[0068] Example C The media was pure methanol. A powder bed containing 20% (w / w) ketoconazole was used, prepared by hot-melt extrusion and milling. The media was jet-printed onto the surface of the powder bed at 30 drops per mm in the printing direction. A new layer of powder (0.1 mm) was applied to the surface of the powder bed, and the printing process was repeated for a total of 24 layers.

[0069] The described process results in the production of objects (shape: cylinders with diameter = 10 mm and height = 2.4 mm) with a mass of 148.5 mg ± 3.7 mg (mean ± standard deviation, n = 27), a drug content of 16.1% ± 0.8% (mean ± standard deviation, n = 3), and a tensile strength of 0.6 MPa ± 0.2 MPa (mean ± standard deviation, n = 3).

[0070] Example D The media is pure methanol. A powder bed containing 40% (w / w) ketoconazole, prepared by hot melt extrusion and milling, is used. The media is jet printed onto the surface of the powder bed at 30 drops per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed, and the printing process is repeated for a total of 24 layers.

[0071] The described process results in the production of objects (shape: cylinders with diameter = 10 mm and height = 2.4 mm) with a mass of 151.9 mg ± 6.9 mg (mean ± standard deviation, n = 36), a drug content of 35.7% ± 1.3% (mean ± standard deviation, n = 3), and a tensile strength of 0.5 MPa ± 0.1 MPa (mean ± standard deviation, n = 4).

[0072] Example E The medium was prepared by mixing ethanol and purified water in a volume ratio of 7:3. A powder bed containing 40% (w / w) ketoconazole, prepared by hot-melt extrusion and milling, was used. The medium was jet-printed onto the surface of the powder bed at 40 drops per mm in the printing direction. The process described produces a single layer of objects.

[0073] Example F The medium was pure methanol containing methylene blue at a concentration of 0.15 mg / mL. A powder bed containing 40% (w / w) ketoconazole, prepared by hot-melt extrusion and milling, was used. The medium was jet-printed onto the surface of the powder bed at 40 drops per mm in the printing direction. The process described produces a single layer of objects.

[0074] Example G The medium was pure methanol containing 0.15 mg / mL methylene blue. A powder bed prepared by hot-melt extrusion and milling containing 40% (w / w) ketoconazole was used. The medium was jet-printed onto the surface of the powder bed at 50 drops per mm in the printing direction. The process described produces a single layer object.

[0075] Example H The media was prepared by mixing isopropyl alcohol and purified water in a 9:1 volume ratio and adding methylene blue at a concentration of 0.16 mg / mL. A powder bed containing 40% ketoconazole prepared by hot melt extrusion and milling was used. The media was jet printed onto the surface of the powder bed at 40 drops per mm in the printing direction. The process described produces a single layer object.

[0076] Example I The medium was prepared by mixing isopropyl alcohol and purified water in a 9:1 volume ratio and adding methylene blue at a concentration of 0.16 mg / mL. A powder bed containing 40% (w / w) ketoconazole was used, prepared by hot melt extrusion and milling. The medium was jet-printed onto the surface of the powder bed at 50 drops per mm in the printing direction. The process described produces a single layer object. The present invention is illustrated in the figures. [Brief explanation of the drawings]

[0077] [Figure 1] Figure 1 shows the non-sinking dissolution curves of the formulation prototypes (mean ± SD, n=3). Solid line: Example A. Dashed line: Example A after 4 weeks of storage. Dotted line: Crystalline ketoconazole physically mixed with copovidone. The example shows a higher degree of supersaturation of ketoconazole in the dissolution medium compared to the physical mixture of ketoconazole and polymer. The supersaturation profile remains similar after 4 weeks of storage at accelerated storage conditions, indicating that the sample is physically stable. [Figure 2] Figure 2 shows the non-sinking dissolution curves of the formulation prototypes (mean ± SD, n=3). Solid line: Example B. Dotted line: Crystalline ketoconazole in a physical mixture with copovidone. The example showed a higher degree of supersaturation of ketoconazole in the dissolution medium than in a physical mixture of ketoconazole and polymer. [Figure 3] Figure 3 shows the non-sinking dissolution curves of the formulation prototypes (mean ± SD, n=3). Solid line: Example C. Dashed line: Example C after 4 weeks of storage. Dotted line: Crystalline ketoconazole physically mixed with copovidone. The example shows a higher degree of supersaturation of ketoconazole in the dissolution medium compared to the physical mixture of ketoconazole and polymer. The supersaturation profile remains similar after 4 weeks of storage at accelerated storage conditions, indicating that the sample is physically stable. [Figure 4]Figure 4 shows the non-sinking dissolution curves of the formulation prototypes (mean ± SD, n=3). Solid line: Example D. Dashed line: Example D after 4 weeks of storage. Dotted line: Crystalline ketoconazole physically mixed with copovidone. The example shows a higher degree of supersaturation of ketoconazole in the dissolution medium compared to the physical mixture of ketoconazole and polymer. The supersaturation profile remains similar after 4 weeks of storage at accelerated storage conditions, indicating that the sample is physically stable. [Figure 5] Figure 5 shows the sedimentation dissolution curves of the formulation prototype of Example A (mean ± SD, n = 3). Solid line: Example A immediately after preparation. Dashed line: Example A after 12 weeks of storage. Example A: This formulation released 80% of the ketoconazole within 30 minutes, meeting the criteria for an immediate-release solid oral dosage form. [Figure 6] Figure 6 shows the pXRD measurements of Examples A and C before and after storage compared to a physical mixture containing the polymer and 20% ketoconazole. The graph shows that the formulation prototypes were amorphous after preparation and storage. [Figure 7] Figure 7 compares the pXRD results of Example B after preparation and Example D before and after storage with a physical mixture containing polymer and 40% (w / w) ketoconazole. The graph shows that the formulation prototype of Example D was amorphous after preparation and storage. The formulation prototype of Example B shows evidence of crystallinity. [Figure 8] Figure 8 shows the DSC thermograms of Examples E-I compared to a physical mixture of polymer and ketoconazole. Shown is the first heating cycle. No melting events were observed in the formulation types prepared, indicating that they were amorphous after preparation. [Figure 9]Figure 9 is a schematic diagram of the printing device. The build plate (E) is connected to a control system. Using axes, the build plate can be moved to various positions to align with additional parts of the printing device. For single-layer production, the build plate is moved to the powder feed (C), where powder is applied to the surface of the build plate or the surface of the powder bed. A blade (D) is used to spread a thin layer of powder (J) while linearly moving the build plate below the blade. A jet printing assembly (A) can be used to apply fluid droplets (H) to the surface of the powder layer in a spatially controlled manner. A halogen lamp (K) can be used to illuminate the powder bed. [Figure 10] Figure 10 shows the spreading step (a) of the process. Powder supplied from the powder reservoir (3a) is spread onto the mounting plate (1) by moving the doctor blade (4) in the direction of the arrow to form a powder layer. A portion of the powder layer that has already been spread is indicated by (3). Additional powder layers are formed by repeatedly spreading powder on the existing powder layer as needed. [Figure 11] FIG. 11 shows a powder layer (2) being built up step by step (a) on a mounting plate (1). [Figure 12] Figure 12 shows jet printing according to process steps (b) or (c). The jet head (7) moves along the x- and / or y-axis, thereby jet printing fluid (6) (fine droplets) onto the powder bed (2). This jet printing produces powder immersed in the fluid (5) created by adjacent voxels. [Figure 13] Figure 13 shows a jet printing step similar to Figure 9, in which a layer of powder is used sprinkled on the intermediate product shown in Figure 9. In contrast to Figure 9, the fluid is not jet printed in a continuous area, but rather in defined areas of powder separated from one another, creating layers of powder voxels immersed in fluid (8) and powder voxels without fluid (8a).

Claims

1. 1. A process for producing a solid pharmaceutical dosage form containing an active ingredient, comprising the steps of: (a) preparing a powder comprising particles of an amorphous solid dispersion of an active ingredient in a polymer matrix; (b) spreading the powder prepared in step (a) over the production area; (c) jet printing a medium onto the powder, the medium being suitable for providing bonding of the powder; (d) sprinkling a layer of the powder prepared in step (a) onto the surface of the powder obtained after carrying out steps (b) and (c), followed by carrying out steps (b) and (c); (e) repeating step (d) as many times as necessary to construct a solid pharmaceutical dosage form; (f) Separating the solid pharmaceutical dosage form from the powder bed The process comprising:

2. 10. The process for producing a solid pharmaceutical dosage form according to claim 1, wherein the amorphous solid dispersion of the active ingredient in the polymer matrix present as particles in the powder prepared in step (a) is prepared using hot melt extrusion, co-precipitation or spray drying.

3. 3. The process for producing a solid pharmaceutical dosage form according to claim 1 or 2, wherein the medium used for jet printing in step (c) is a liquid.

4. A process for producing a solid pharmaceutical dosage form according to any one of claims 1 to 3, wherein the powder comprises a binder material.

5. A process for producing a solid pharmaceutical dosage form according to any one of claims 1 to 4, wherein the vehicle is a liquid that partially dissolves the polymer matrix and / or binder material present therein.

6. 6. A process for producing a solid pharmaceutical dosage form according to claim 5, wherein the vehicle comprises or consists of one or more volatile solvents, alone or in admixture with one or more non-volatile solvents.

7. 7. The process for producing a solid pharmaceutical dosage form of claim 6, wherein the volatile solvent is selected from the group consisting of methanol, ethanol, propanol, 2-propanol, and acetone, and the non-volatile solvent is selected from the group consisting of water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, and dimethylsulfoxide.

8. A process for producing a solid pharmaceutical dosage form according to any one of claims 1 to 7, wherein the vehicle is fluid and comprises a binder material.

9. The binder may be selected from the group consisting of lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (e.g., sucrose stearate, sucrose palmitate), sorbitan esters (e.g., Span®), glycerol fatty acid esters (e.g., glycerol monostearate), fatty acids, fatty alcohols (solid at room temperature), esters of fatty acids with fatty alcohols, and polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate or microcrystalline cellulose, copolymers of acrylic acid or methacrylic acid with acrylic acid or methacrylic acid esters, preferably copolymers of methacrylic acid, and poly(methacrylic acid-methyl methacrylate copolymer) (1:1) (e.g., E copolymers of methacrylates or acrylates, ethyl acrylate, methyl methacrylate, such as poly(methacrylic acid-methyl methacrylate copolymer) (1:2) (e.g., Eudragit® L100), poly(methacrylic acid-ethyl acrylate copolymer) (1:1) (e.g., Eudragit® L100-55), and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit® L100); methacrylates with a low content of quaternary ammonium groups, such as dimethylaminoethyl methacrylate, butyl methacrylate, and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (2:1:1) (e.g., Eudragit® E); or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS);9. A process for producing a solid pharmaceutical dosage form according to any one of claims 4 to 8, comprising or consisting of a methyl methacrylate such as hydroxypropyl methylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropyl methylcellulose acetate succinate.

10. The polymer matrix may be vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), (Eudragit® L100-55), and poly(methacrylic acid-methyl methacrylate) (Eudragit® L and Eudragit® S), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft 10. A process for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 9, comprising or consisting of copolymer (PVAc-PVCap-PEG), (Soluplus®), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT).

11. A process for producing a solid pharmaceutical dosage form according to any one of claims 1 to 10, wherein after carrying out step (c) and / or step (d) a drying step is carried out.

12. A process for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 11, wherein the pharmaceutical dosage form is for oral administration.

13. 13. The process for producing a solid pharmaceutical dosage form of claim 12, wherein the pharmaceutical dosage form provides immediate release of the active pharmaceutical ingredient.

14. A process for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 13, wherein step (f) is followed by a drying step.

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