Coupling solubility enhancement and 3D printing

Abstract

The present invention relates to a process for producing a pharmaceutical dosage form by combining hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, in particular hot melt extrusion and selective laser sintering 3-dimensional printing (SLS), and a pharmaceutical dosage form manufactured by that process.

Description

[0001] Coupling solubility enhancement and 3D printing

[0002] Technical Field

[0003] The present invention relates to a process for producing a pharmaceutical dosage form by combining hot melt extrusion and powder bed fusion selective laser 3- dimensional printing, in particular hot melt extrusion and selective laser sintering 3- dimensional printing (SLS), and a pharmaceutical dosage form manufactured by that process.

[0004] Background

[0005] 3D printing (3DP) demonstrated to be a capable set of techniques for the production of individualized solid oral dosage forms (SODFs) in the last years. 3DP or additive manufacturing (AM) is a generic term for the layer-by-layer production of 3D objects from computer-based design. The creation of pharmaceutical SODFs in a layer-by- layer fashion can be done in several ways. There are techniques based on powder and liquid solidification as well as extrusion-based methods. What they have in common is fast adjustability of the 3D tablet design and by that adapting the dose and release properties. 3D printed products are beneficial for the production of personalized medicine and in clinical studies due to flexible dose adjustment and easy scalability.

[0006] Besides the aforementioned, 3DP techniques can also help solving the challenges of poor drug solubility. The majority of newly discovered compounds are poorly soluble and belong to the Biopharmaceutic Classification System (BCS) class II. A common strategy to enhance solubility and bioavailability of these compounds is the formulation of amorphous solid dispersions (ASD), where the amorphous active pharmaceutical ingredient (API) is kinetically stabilized in a polymer matrix. An ASD can be obtained by a variety of techniques among which hot melt extrusion (HME) is widely used. By the means of HME an API-polymer mixture is blended in a heated barrel and the API can become amorphous by either heating to its melting temperature or / and dissolving in the polymer matrix through mixing (Shah et al., 2014). Next to HME, spray-drying and ball-milling are commonly applied techniques for the production of ASDs. HME has been coupled frequently with the 3DP technique Fused Deposition Modeling (FDM), also a melt-extrusion based process, to achieve amorphous drug products. However, the mechanical properties of the filaments often limit the use of a formulation in FDM. Especially high drug loads of API can result in impaired mechanical properties which makes printing almost impossible. Often the addition of plasticizers in the formulation is utilized, which can impair the physical stability of the ASD.

[0007] Another powder-based 3DP technique is selective laser sinter (SLS), where a laser (either CO2 or diode lasers) is used to fuse the powder particles in-situ. Selective Laser Sintering (SLS) is an additive manufacturing processes that creates a three- dimensional (3D) object layer-by-layer. The process applies layers of powder material on top of each other sequentially, where each layer of powder is sintered or coalesced together with a laser according to the computer aided drawing (CAD) geometry of the part.

[0008] SLS is a powder bed based additive manufacturing technique to produce complex three-dimensional parts. In SLS, a rasterized laser is used to scan over a bed of polymer powder, sintering it to form solid shapes in a layer-wise fashion. When the laser beam scans the powder, the powder melts due to the rising temperature, and layer by layer, the final part approaches full density and should result in properties of the bulk material (the polymer). By controlling the energy input it is possible to control the density of the sintered material and to achieve parts ranging from highly porous to almost full dense. Selective laser sintering (SLS) is a subset of powder bed fusion 3D printing which uses a laser beam to create solid objects by heating powder particles, fusing them together at their surfaces. Currently, the majority of commercially available SLS printers employ carbon dioxide (CO2) lasers, which provide higher power at lower cost, permitting the use of a wide array of powdered thermoplastic materials. As such, applications of SLS span many fields, including the aerospace, automotive, military, medical, dentistry, engineering and electronics industries. In the pharmaceutical sector, therapeutic products can be fabricated using SLS printing if the feedstock material is a powder blend of a drug and thermoplastic polymer. This means that, compared with other 3D printing technologies, the feedstock material of SLS printing has the closest resemblance to that of traditional tabletting. As such, it has been anticipated that SLS is more amenable for pharmaceutical use. Whilst other 3D printing technologies, such as binder jetting, are also based on powdered materials, being a solvent-free process makes SLS a faster process, wherein the need for additional drying steps to evaporate any residual binder is avoided.

[0009] Currently described 3D printing concepts for selective laser sintering to create pharmaceutical dosage forms are utilizing a layer by layer approach where a premixed powder is used which usually consists of at least one polymer, an API and potentially a certain absorber material depending on the light / laser source (Awad et al. ,2020; International Journal of Pharmaceutics 586:119594). This concept requires a pre-mix of all components to achieve a homogenous sintering.

[0010] SLS can also be used for the production of ASDs (Davis et al., 2021), requiring low laser speeds and a small particle size (Thakkar et al., 2021a). At high drug loads of 20% - 30% it was reported that API could not be fully amorphized but the crystallinity was reduced. The use of pre-processed material was proposed, e.g., by the means of hot-melt granulation of an API with silica to enhance flowability and reduce crystallinity beforehand to facilitate ASD formation during SLS printing (Thakkar et al., 2021 b).

[0011] However, this process requires adding further pharmaceutical excipients such as an absorber and a polymer and mixing the composition to enable subsequent 3DP. These additional operations are time- and material consuming and also require a high quantity of additional pharmaceutical excipients to enable processing.

[0012] Furthermore, the drug load in amorphous solid dispersions is limited and often less than 40%. Through the addition of further pharmaceutical excipients the drug load is reduced even further. Moreover, physical mixures of different granules or powders are prone to segregation before the 3DP step, resulting in a decreased content uniformity.

[0013] Technologies are required that enable direct processing of amorphous solid dispersions into solid oral dosage forms with a minimum of steps and pharmaceutical excipients.

[0014] Summary of the Invention

[0015] It was surprisingly found that a process for producing a pharmaceutical dosage form by hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, comprising the steps of (a) providing a composition comprising at least one active pharmaceutical ingredient and at least one polymer, wherein said polymer absorbs electromagnetic radiation at a wavelength emitted by the laser, (b) hot melt extruding the composition of step (a) to form a mixture of the active pharmaceutical ingredient and the polymer, (c) milling the solidified mixture of step (b) to provide a sinter powder, and (d) operating a selective laser sintering apparatus that selectively fuses layers of the sinter powder by a laser to produce the pharmaceutical dosage form, leads to an improved manufacturing process and pharmaceutical dosage forms with improved properties.

[0016] In a preferred embodiment of the invention, the hot melt extrusion is a twin-screw hot melt extrusion.

[0017] In a further preferred embodiment of the invention, the powder bed fusion selective laser 3-dimensional printing comprises selective laser sintering 3-dimensional printing, selective laser melting 3-dimensional printing, electron beam melting 3- dimensional printing or multijet fusion or a mixture thereof, preferably selective laser sintering 3-dimensional printing, preferably selective laser sintering 3-dimensional printing.

[0018] In a further preferred embodiment of the invention, the polymer is selected from the group consisting of acrylic-derived polymers, cellulose-derived polymers and polyvinyl-derived polymers and mixtures thereof.

[0019] In another aspect, the invention provides a pharmaceutical dosage form produced by the process as described above.

[0020] Detailed Description of the Invention

[0021] An embodiment of the invention is a process for producing a pharmaceutical dosage form by hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, comprising the steps of

[0022] (a) providing a composition comprising at least one active pharmaceutical ingredient and at least one polymer, wherein said polymer absorbs electromagnetic radiation at a wavelength emitted by the laser, (b) hot melt extruding the composition of step (a) to form a mixture of the active pharmaceutical ingredient and the polymer,

[0023] (c) milling the solidified mixture of step (b) to provide a sinter powder, and

[0024] (d) operating a selective laser sintering apparatus that selectively fuses layers of the sinter powder by a laser to produce the pharmaceutical dosage form.

[0025] Hot melt extrusion (HME) is a manufacturing process used to produce various forms of products by continuously forcing a molten material through a shaping orifice, then solidifying it. HME involves pumping polymeric materials with a rotating screw through a barrel at temperatures above their glass transition temperature (Tg) and sometimes above the melting temperature (Tm) to achieve molecular level mixing of the active compounds and thermoplastic binders, polymers, or both (Patil et al., 2016). This molecular mixing usually converts the components into an amorphous product with a uniform shape and density, thereby increasing the dissolution profile of the poorly water-soluble drug. HME has emerged as an alternative platform technology to other traditional techniques for manufacturing pharmaceutical dosage forms such as tablets, capsules, films, and implants for drug delivery via oral, transdermal, and transmucosal routes. The introduction of HME to pharmaceutical formulation development has made sophisticated equipment such as the extruder, customized downstream auxiliary equipment, and monitoring tools available for application in evaluating the performance and product quality. This enhanced availability has supported the growth of this innovative technique in pharmaceutical manufacturing processes utilizing both single and twin-screw extruders.

[0026] The extrusion equipment is classified into three main categories: ram, radial screen, and roll and screw extruders. Among these, the screw extruders are the most important in the pharmaceutical industry because they continuously convert feed material to the finished form such as a rod, tube, or film. The rotating screws force the feed material forward in the heated barrel leading to softening of the material. The feed reaches the end of the screw in a viscous state that can then be forced through an orifice (or die) and molded into the desired shape.

[0027] Pharmaceutical screw extruders are designed based on the desired extrudate and are required to meet the current regulatory standards for the manufacture of dosage forms. They are classified as single-screw extruders (SSEs), twin-screw extruders (TSEs) and multi-screw extruders (MSEs).

[0028] According to one embodiment of the invention, the hot melt extrusion in step (b) is a twin-screw hot melt extrusion.

[0029] According to the invention, the minimum working temperature for obtaining an amorphous solid dispersion of the API in the HME process is either a temperature above the melting temperature of the API or a temperature above the glass transition temperature (Tg) or melting temperature (Tm) of the polymer in at least one zone along the length of the screw barrel. The maximum working temperature is the decomposition temperature of the API or the decomposition temperature of the polymer.

[0030] According to one embodiment of the invention, the temperature in at least one zone along the length of the screw barrel is above glass transition temperature (Tg) or above the melting temperature (Tm) of the polymer and below the decomposition temperature of theas polymer.

[0031] According to another embodiment of the invention, the hot melt extrusion in step (b) comprises the steps of

[0032] (1) kneading the composition of step (a) 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 API or above the melting temperature or glass transition temperature and below the decomposition temperature of the polymer to form a kneaded mixture and

[0033] (2) transporting the kneaded mixture through an outlet.

[0034] According to another embodiment of the invention, the hot melt extrusion in step (b) comprises the steps of

[0035] (1) kneading the composition of step (a) 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 or glass transition temperature and below the decomposition temperature of the polymer to form a kneaded mixture and

[0036] (2) transporting the kneaded mixture through an outlet. According to another embodiment of the invention, the hot melt extrusion in step (b) comprises the steps of

[0037] (1) kneading the composition of step (a) 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 API and below the decomposition temperature of the polymer to form a kneaded mixture and

[0038] (2) transporting the kneaded mixture through an outlet.

[0039] Typical HME working temperature depent on the nature of the polymer and API. Polymers typically used in HME can be amorphous or semicrystalline. In one embodiment, the barrel temperature profile is set at least 30 °C above the glass transition temperature (Tg) of the polymer or above its melting point, in the case of a semicrystalline polymer (Shah et. al). In one embodiment, working temperatures are between 50 °C to 250 °C.

[0040] In one embodiment, the polymer is the semi-crystalline polymer polyvinyl alcohol (PVA), which has a glass transition temperature of between 40 °C and 80 °C depending on the degree of polymerization and hydrolysis. The melting point of PVA varies between 150 °C to 230 °C. Decomposition of most PVA grades start at approximately 250 °C. Therefore, in case PVA is used as polymer, the HME temperature according to the invention can be between 100 °C and 250 °C. Typical working temperatures for obtaining an amorphous solid dispersion of an API in a PVA polymer are 120 °C to 250 °C, 140 °C to 230 °C, preferably 170 °C to 210 °C, more preferably 180 °C to 200 °C.

[0041] According to the invention, the term “polymer” refers to an extrudable polymer or low-melting-point wax that function as thermal binder in the molten state during the HME process and act as drug depots, drug-release retardants, or both following cooling and solidification.

[0042] According to one embodiment of the invention, the polymer is a thermoplastic polymer.

[0043] Commonly used polymers include, for example, acrylic-derived polymers, cellulosederived polymers, poloxamers and polyvinyl-derived polymers and mixtures thereof. Examples of suitable polymers are methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, cellulose-esters, cellulose-ethers and cellulose-acrylates, such as cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxypropylmethylcellulose acetate succinate (HPMC-AS), polyethylene oxides (PEOs) of varying molecular weights, poly-methacrylate derivatives, and poloxamers, , polyvinyl acetate phthalate (PVAP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, shellac, various grades of polyethylene glycol (PEG), zein, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) or its copolymers such as polyvinylpyrrolidone-vinyl acetate (PVP-VA), poly (ethylene-co-vinyl acetate), polysaccharides, polylactic acid (PLA), poly(glycolide) (PGA), poly(lactide-co-glycolide) (PLGA), the copolymer of lactide and glycolide, and mixtures thereof.

[0044] In one embodiment of the invention, the polymer is polyvinyl alcohol (PVA).

[0045] Polyvinyl alcohol (PVA) is a synthetic water-soluble polymer that has the idealized formula [CH2CH(OH)]n. It possesses good film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the functional acetate groups are either partially or completely hydrolysed to alcohol functional groups. If not completely hydrolysed, PVA is a random copolymer consisting of vinyl alcohol repeat units -[CH2CH(OH)]- and vinyl acetate repeat units -[CH2CH(OOCCH3)]-. The polarity of PVA is closely linked to its molecular structure. The hydrolysis degree and the molecular weight determine the molecular properties of PVA. As the degree of hydrolysis of acetate groups increases, the solubility of the polymer in aqueous media and also crystallinity and melting temperature of the polymer increase. However, at high hydrolysis degrees over 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but almost insoluble in almost all organic solvents, excluding, in some cases, ethanol.

[0046] The typical PVA nomenclature indicates the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA 4-88 is a PVA grade with a viscosity of 4 mPas that is 88% hydrolysed, i.e. having 88% of vinyl alcohol repeat units and 12% of vinyl acetate repeat units. A skilled person is aware that a hydrolysis grade of 88% and a viscosity of 4 mPas encompasses calculated hydrolysis grades of 87,50% to 88,49% and calculated viscosities of 3,50 mPas to 4,49 mPas% according to common rounding methods. Viscosity according to the invention is measured as stated in USP 39 under Monograph “Polyvinyl Alcohol” with the method Viscosity-Rotational Method (912).

[0047] The degree of hydrolysis according to the invention is measured by determining the saponification value of the Polyvinyl Alcohol, e.g. as stated in USP 39 under Monograph “Polyvinyl Alcohol” under “Degree of Hydrolysis”:

[0048] Sample: 1 g of Polyvinyl Alcohol, previously dried at 110° to constant weight Analysis:

[0049] Transfer the Sample to a wide-mouth, 250-ml conical flask fitted by means of a suitable glass joint to a reflux condenser. Add 35 ml of dilute methanol (3 in 5), and mix gently to ensure complete wetting of the solid. Add 3 drops of phenolphthalein TS, and add 0.2 N hydrochloric acid or 0.2 N sodium hydroxide if necessary, to neutralize. Add 25.0 ml of 0.2 N sodium hydroxide VS, and reflux gently on a hot plate for 1 h. Wash the condenser with 10 ml of water, collecting the washings in the flask, cool, and titrate with 0.2 N hydrochloric acid VS. Concomitantly perform a blank determination in the same manner, using the same quantity of 0.2 N sodium hydroxide VS.

[0050] Calculate the saponification value:

[0051] Result = [(VB- Vs) x N x Mr] / W

[0052] VB = volume of 0.2 N hydrochloric acid VS consumed in the titration of the blank (ml) Vs = volume of 0.2 N hydrochloric acid VS consumed in the titration of the Sample solution (ml)

[0053] N = actual normality of hydrochloric acid VS

[0054] Mr= molecular weight of potassium hydroxide, 56.11

[0055] W = weight of the portion of Polyvinyl Alcohol taken (g)

[0056] Calculation of degree of hydrolysis:

[0057] Calculate the degree of hydrolysis, expressed as a percentage of hydrolysis of polyvinyl acetate:

[0058] Result = 100 - [7.84 x S / (100 - 0.075 x S)) S = saponification value of the Polyvinyl Alcohol

[0059] The use of PVA grades according to the invention is of interest for the formulation of solid oral pharmaceutical dosage forms with an instant, immediate or prolonged API release.

[0060] Preferred PVAs have a hydrolysis degree of 70% to 90%, and a viscosity of a 4% solution at 20°C of 3 mPas to 8 mPas, more preferably a viscosity of a 4% solution at 20°C of 3 mPas to 5 mPas, most preferably a viscosity of a 4% solution at 20°C of 3 mPas to 4 mPas.

[0061] In a further embodiment of the invention, the polyvinyl alcohol has a hydrolysis degree of 70% to 90%, preferably 80% to 90% and a viscosity as mentioned above.

[0062] In a further embodiment of the invention, the polyvinyl alcohol has a hydrolysis degree of 80% to 90% and a viscosity of a 4% solution at 20°C of 3 mPas or a hydrolysis degree of 80% to 90% and a viscosity of a 4% solution at20°C of 4 mPas.

[0063] In a further embodiment of the invention, the polyvinyl alcohol is PVA 3-80, PVA 3- 82, PVA 4-88, PVA 5-88, PVA 8-88 or PVA 5-74, preferably PVA 3-80, PVA 3-82 or PVA 4-88, more preferably PVA 4-88.

[0064] In a further embodiment of the invention, the polyvinyl alcohol is PVA 3-82, PVA 4- 88 or PVA 5-74, preferably PVA 3-82 or PVA 4-88, more preferably PVA 3-82.

[0065] In one further embodiment of the invention, the polymer is a poloxamer (PLX).

[0066] Poloxamers are amphiphilic polymers, with two hydrophilic blocks and a hydrophobic block in the middle. A poloxamer is a polyethylene glycol (PEG) / polypropylene glycol (PPG) tri-block copolymer whereby one PPG block is flanked on both sides with a PEG block. The polyethylene glycol (PEG) part is often also called polyethylene oxide (PEG) part. The polypropylene glycol (PPG) part is often also called the polypropylene oxide (PPO) part. Poloxamer grades are commonly named with the letter P (for poloxamer) followed by three digits that is officially used by USP and EP. It describes the composition of the polymer as follows: the first two digits multiplied by 100 represents the molecular weight of the PO block and the last digit multiplied by 10 provides the percentage of EO in %.

[0067] Poloxamer P188 in average is composed of 80% EO, while the remaining 20% PO make up for 1800 g / mol. Poloxamer P407 is a poloxamer with an average polyoxypropylene molecular mass of 4000 g / mol and a 70% polyoxyethylene content.

[0068] Poloxamers have the general formula (I)

[0069] For different poloxamers numbers of x (PEO), y (PPO chain) and z (PEO) are varying over a broad range, depending on the type of poloxamer. For poloxamer P188 the PPO chain contains in the average a unit number ranging from 25 to 30, and each PEO is composed of 75 to 85 EO units in average, with a molecular weight ranging from 7680 to 9510 Da. For poloxamer P407 the PPO chain contains in the average a unit number of 56, and each PEO is composed of approximately 101 EO units in average, with an molecular weight ranging from 9840 to 14600 Da.

[0070] Poloxamer 407 (a=101 , b=56) with molecular weight ranging from 9840 to 14600 Da.

[0071] Table 1 is showing types of poloxamers monographed in the European Pharmacopoeia (Ph. Eur.) and United States Pharmacopeia (USP).

[0072] Table 1

[0073] Preferred poloxamers are P188 and P407.

[0074] According to the invention, the term “powder bed fusion selective laser 3- dimensional printing” denotes a subset of four technologies: selective laser sintering (SLS), selective laser melting (SLM), electron beam melting (EBM) and multijet fusion (MJF). The technologies differ by the type of materials they employ and by the type and amount of light or radiation utilised to transmit energy to the powder bed. In all cases, objects are built layer-by-layer through the use of thermal energy resulting from the combination of increased temperature and the use of a light source and all use powders as their feedstock materials. One immediate benefit of this is that it permits fabrication of overhanging and / or intricate structures, without the need for a secondary support material, because the loose powder particles inside the bed act as a support, maintaining the integrity of the object during printing. Thermoplastic polymers are used as the main feedstock material in SLS printing. The laser beam melts the surface of the powder particles, fusing them together, a process termed ‘sintering’. Because a relatively low-power laser is used, the printer itself heats the feedstock powder, so the laser needs only to provide a small increase in surface temperature of the powder to induce sintering. When the feed materials are metals or alloyed powders, the technology is normally called SLM or direct metal laser sintering (DMLS).

[0075] EBM also uses metal and alloyed powders as its main feed material, although the energy required to sinter the particles is provided with an electron beam instead of a laser beam. The high intensity of the electron beam renders the powdered materials completely melted during the printing process.

[0076] MJF utilizes only one feedstock, nylon (for instance, PA 12), and it employs an infrared (IR) lamp as the energy source. Two additional components are needed in MJF: (i) a fusion agent, which is pre- cisely deposited by an ink-jet head onto the printing regions, and (ii) a detailing agent, which is responsible for absorbing heat from the edges of the object. As such, only the regions coated with the fusion agent will melt, enhancing the printing efficiency and speed. The addition of the detailing agent decreases thermal bleeding (e.g. the spreading of heat across neighbouring regions) and enhances the printing resolution and accuracy.

[0077] In a preferred embodiment, the powder bed fusion selective laser 3-dimensional printing comprises selective laser sintering 3-dimensional printing, selective laser melting 3-dimensional printing, electron beam melting 3-dimensional printing or multijet fusion or a mixture thereof, preferably selective laser sintering 3-dimensional printing, more preferably embodiment, the powder bed fusion selective laser 3- dimensional printing is selective laser sintering 3-dimensional printing (SLS).

[0078] According to the invention, the term “selective laser sintering”, “SLS”, “selective laser sintering 3D printing” or “SLS 3DP” is a process in which a laser beam is used to sinter a powder bed filled with a sinter powder by scanning the laser according to the cross-section of a digital model. A version of the digital model is produced in a layer-by-layer fashion by laser scanning successive layers of powder.

[0079] The process will require a selective laser sintering printer equipped with a laser source and a galvanometric system for scanning the laser on the powder bed surface or, alternatively, a xy motion system where the actual laser source is moved to scan the powder bed or a mirror reflecting the laser source to achieve a xy motion of the laser spot within the powder bed. The printer must also provide, two reservoir platforms, a first reservoir platform with a first sinter powder and a second reservoir platform with a second sinter powder, a building platform and a powder application system to spread the powder in layers on the building platform (Spreader) as well as some heating capabilities to heat the build chamber and the surface of the powder bed. Parameters that can be varied in SLS typically include the type of laser and thus its wavelength, as well as the laser power, scan speed, print resolution (layer height), beam spot size, surface temperature, chamber temperature, and the initial position of the build platform and its lowering speed. Also the powder dispenser may vary and the design of the scraper or other toolings, like a roller device. A laser is a device that emits light through a process of optical amplification based on the stimulated emission of electromagnetic radiation. The term "laser" originated as an acronym for "light amplification by stimulated emission of radiation". Lasers emit light coherently.

[0080] Types of lasers used in SLS include, for example, CO2 lasers, infrared lasers, and diode lasers such as blue diode lasers. In a preferred embodiment, the laser is a CO2 laser.

[0081] The wavelength of electromagnetic radiation emitted by lasers suitable for SLS is typically within the range of 200 nm to 11 pm, typically in the near ultra-violet through to the mid-infrared part of the electromagnetic spectrum. For example, suitable lasers may emit electromagnetic radiation in the range of 315 nm to 1.4 pm, such as 400-610 nm, preferably 400-500 nm, more preferably 430-470 nm. Another suitable laser emits electromagnetic radiation in the range of 9.4 to 11 pm, such as 10.2-10.8 pm, preferably around 10.6 pm. Another suitable laser emits electromagnetic radiation in the range of 750-850 nm, such as approximately 800 nm.

[0082] The power of a laser is measured in Watts. This is referring to the optical power output of the laser beam, which is the continuous power output of continuous wave (CW) lasers, or the average power of a pulsed or modulated laser. Typically, SLS 3D printers use continuous wave lasers. Lasers suitable for SLS according to this invention typically have a power in the range of 0.5 W to 140 W. In all aspects and embodiments of this invention it is preferred if the laser has a power in the range of at least 1 W to less than 80 W, for example, 1.5-75 W. More preferably the laser power may be in the range of 1-30 W, such as 2-20 W, for example 3-15 W.

[0083] Suitable SLS 3D printers may use more than one laser. For example, printers may use two lasers, or more than two lasers. The scan speed for SLS is the rate at which the laser moves over the powder bed. Suitable scan speeds for the current invention range from about 5 mm / s to about 50000 mm / s. The scan speed correlates directly with the laser beam interaction time. A slower scan speed results in a longer laser beam interaction time. In a preferred embodiment, applicable to all aspects of the invention, the scan speed may be in the range from 10 mm / s to 10000 mm / s, preferably 20-7000 mm / s, more preferably from 50-6000 mm / s.

[0084] According to the present invention it is preferred to use a layer height in the range of 0.001 mm to 10 mm, preferably 0.025 mm to 0.5 mm, more preferably 0.05 to 0.25 mm, such as 0.1 mm. It is believed that reduction in the layer thickness provides better i.e. increased print resolution of the object printed.

[0085] Suitable beam spot size for the present invention is typically in the range of from 0.0025 mm to 1 mm, for example 0.05-0.5 mm, preferably 0.1-0.3 mm, for example 0.2 mm. Increasing the spot size can be used to increase the laser beam interaction time. Typically, this is influenced by adjusting the scan speed, however.

[0086] The surface temperature is the temperature of the powder that is being sintered. Typically the surface temperature will be in the range of 0-200 degrees centigrade, preferably 40-180 degrees centigrade, most preferably 70-170 degrees centigrade The chamber temperature is the temperature within the chamber in which printing is taking place. Typically this is in the range of 20-200 degrees centigrade, preferably 20-50 degrees centigrade for low-melting polymers, e.g. poloxamers or PEGs or preferably 50-200 degrees centigrade, more preferably 60-150 degrees centigrade for high-melting polymers, e.g. PVAs.

[0087] The first and second sinter powder are loaded into the printer and and the printing process is initiated. In the printing process, parameters such as chamber and print bed temperature are set to appropriate values obtained via experimental studies to provide printed pharmaceutical dosage forms with desirable properties with respect to mechanical and morphological properties. Other parameters influencing the process are laser energy input and layer height of each applied layer. The laser energy input can be controlled in a number of ways depending on which type of printer is used and usually via adjusting laser scanning speed, hatching space (distance between scanned laser lines) or by adjusting the energy output by the laser.

[0088] Once the printing process is finalized the printed pharmaceutical dosage forms are allowed to slowly cool down in the printer before being removed and cleaned from surrounding, unsintered powder.

[0089] In a further embodiment of the invention, only one reservoir is filled with the solidified and milled mixture of the HME step (b) and the second reservoir is filled with a second sinter powder, wherein the second sinter powder absorbs electromagnetic radiation at a wavelength emitted by the laser.

[0090] The second sinter powder can comprise at least one selective laser 3D printable material or at leat one selective laser 3D printable material and at least one API. The API can be identical or different compared to the API of the first sinter powder. The material can be identical or different compared to the polymer used in the HME step (a).

[0091] Accordingly, one embodiment of the invention is a process for producing a pharmaceutical dosage form by hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, comprising the steps of

[0092] (a) providing a composition comprising an active pharmaceutical ingredient and an first polymer, wherein said polymer absorbs electromagnetic radiation at a wavelength emitted by the laser,

[0093] (b) hot melt extruding the composition of step (a) to form a mixture of the active pharmaceutical ingredient and the polymer,

[0094] (c) milling the solidified mixture of step (b) to provide a first sinter powder in a first reservoir platform,

[0095] (d) providing a second sinter powder, wherein said second sinter powder absorbs electromagnetic radiation at a wavelength emitted by the laser, and

[0096] (e) operating a selective laser sintering apparatus that fuses layers of the first and second sinter powder to produce the pharmaceutical dosage form. In one embodiment, the second sinter powder can comprise at least one selective laser 3D printable material or at leat one selective laser 3D printable material and at least one API. According to the invention, the term “selective laser 3D printable material” refers to at least one component that absorbs electromagnetic radiation at a wavelength emitted by the laser and is suitable to be used in powder bed fusion selective laser 3-dimensional printing processes, e.g suitable to be melted at the surface of the powder particles, fusing them together, during a powder bed fusion selective laser 3-dimensional printing process.

[0097] In one embodiment of the invention, the selective laser 3D printable material comprises or consists of at least one polymer or polyol.

[0098] Commonly used selective laser 3D printable materials include, for example, acrylic- derived polymers, cellulose-derived polymers and polyvinyl-derived polymers and mixtures thereof. Examples of suitable polymers are methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, cellulose-esters, cellulose-ethers and cellulose-acrylates, such as cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxypropylmethylcellulose acetate succinate (HPMC-AS), polyethylene oxides (PEOs) of varying molecular weights, poly-methacrylate derivatives, and poloxamers, , polyvinyl acetate phthalate (PVAP), shellac, various grades of polyethylene glycol (PEG), zein, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) or its copolymers such as polyvinylpyrrolidone-vinyl acetate (PVP-VA), poly (ethylene-co-vinyl acetate), polysaccharides, polylactic acid (PLA), poly(glycolide) (PGA), poly(lactide-co-glycolide) (PLGA), the copolymer of lactide and glycolide, and mixtures thereof.

[0099] Further commonly used selective laser 3D printable materials include, for example, sorbitol, mannitol, xylitol, erythritol, maltitol or isomalt.

[0100] I n a preferred embodiment the particle size of the sinter powder or first sinter powder and the second sinter powder has a D50 of 200 pm or lower. Preferably, the particle size (D50) of the sinter powder is between 20 pm and 200 pm, 20 pm and 150 pm or 20 pm and 100 pm.

[0101] In a preferred embodiment the particle size of the PVA has a D50 of 200 pm or lower. Preferably, the particle size (D50) of the PVA is between 20 pm and 200 pm, 20 pm and 150 pm or 20 pm and 100 pm.

[0102] In a further preferred embodiment the particle size of the PVA has a D90 of 250 pm or lower. Preferably, the particle size (D90) of the PVA is between 100 pm and 250 pm, more preferably between 140 pm and 220 pm.

[0103] In a further embodiment of the invention, the sinter powder or first sinter powder of step (c) and / or second sinter powder may comprise further pharmaceutically acceptable additives. Pharmaceutically acceptable additives comprise flow control agents, such as silicon dioxide, fillers, plasticizers, surfactants, light-absorbing material, such as ruby red or Candurin pigments and other suitable components that are well known to those skilled in the art.

[0104] In one embodiment of the invention, the composition in step (a) further comprises at least one pharmaceutically acceptable additive. In a further embodiment, the composition in step (a) further comprises the second sinter powder further comprises a light-absorbing material, gliding agent or plasticizer, preferably a lightabsorbing material.

[0105] Depending on the wavelength of the light emitted by the laser, a light-absorbing material (pigment) which absorbs light at the wavelength emitted may be required. These light-absorbing materials can contain transition metals for absorption at around 450 nm or carbon for a wider range covering the visible- and near IR range. Light absorption is a process by which light is absorbed and converted into energy. When light is absorbed heat is generated. So the selective absorption of light by a particular material occurs because the frequency of the light wave matches the frequency at which electrons in the atoms of that material vibrate.

[0106] Light-absorbing materials are all materials suitable for the SLS method as described above and known to the skilled person in the art. Preferably light-absorbing materials which have been demonstrated to work at 455 nm laser irradiation are used, e.g. Candurin NXT, Ruby Red, Candurin Gold Sheen, Aluminum Lake, activated carbon (also works at 808 nm) or iron oxide (Fe2Oa) . More preferably ruby red is used.

[0107] Carbon dioxide laser emitting at around 9-10 microns will usually not require addition of light-absorbing materials as C-H bonds absorb energy will at this wavelength and this type of bonds can be found in most polymers.

[0108] For the avoidance of doubt, further pharmaceutically acceptable additives as defined above are not needed for the beneficial properties according to the invention. Yet those additives can be used for other purposes, e.g. to optimize the process of manufacturing of the pharmaceutical composition or oral dosage form according to the invention.

[0109] Furthermore, the pharmaceutical composition according to the invention may comprise additional pharmaceutically acceptable hydrophilic or lipophilic polymers.

[0110] As used herein, the phrase "pharmaceutically acceptable" refers to all addtives, polymers, compounds, solvents, dispersion media, flow control agents, carriers, coatings, active agents, isotonic and absorption delaying agents, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general. The use of such material in pharmaceutical compositions is well known in the art.

[0111] According to the invention, the term “active pharmaceutical ingredient” refers to any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals.

[0112] The API included in the pharmaceutical dosage form of the present invention has a sufficient amount to be therapeutically effective. For a given API, therapeutically effective amounts are generally known or readily accessible by persons skilled in the art. Typically, the API may be present in the pharmaceutical dosage form in a weight ratio of API to pharmaceutical excipient of 0.1 :99.1 to 60:40, preferably 1 :99 to 50:50, more preferably 5:95 to 40:60 and most preferably 10:90 to 30:70. The sinter powder or first sinter powder of step (c) and the second sinter powder may comprise more than one API.

[0113] The API may be a small molecule in form of a weak base, a weak acid or a neutral molecule and may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogues, prodrugs, and solvates thereof. The first sinter powder may comprise more than one API. In one embodiment the API is a poorly soluble API, poorly water-soluble API, lipophilic API or belongs to the Biopharmaceutics Classification System (BCS) classes 2 and / or 4.

[0114] As used herein, the terms “poorly soluble API”, “poorly water-soluble API” and “lipophilic API” refer to an API having 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 media ranging in pH from 1 to 8 following the definition of low solubility according to the Biopharmaceutics Classification System (BCS) classes 2 and 4. Poorly soluble APIs with weakly basic or weakly acidic characteristics have a pH-dependent solubility profile and can have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs falling under BCS classes 2 or 4, respectively, are well known to persons skilled in the art.

[0115] In one embodiment the API is a weakly basic API. As used herein, the term “weakly basic API” refers to a basic API wherein the basic API does not completely ionize in water.

[0116] In one embodiment of the invention, the at least one active pharmaceutical ingredient (API) according to the invention may be dispersed in the mixture in step (b) forming an amorphous dispersion of the active pharmaceutical ingredient in the polymer.

[0117] Accordingly, the solidified mixture in step (c) is an amorphous solid dispersion of the active pharmaceutical ingredient in the polymer.

[0118] As used herein, the term "amorphous solid dispersion" is a dispersion of at least one amorphous API in the polymer. Preferably, the amorphous API is distributed in a molecularly dispersed state within the pharmaceutical dosage form. In this case, the solid dispersion is a solid solution. Upon dissolution, formulations comprising an amorphous solid dispersion can reach higher solubilities in aqueous media than the crystalline API.

[0119] Differential scanning calorimetry (DSC) and powder diffractometry (XRPD) measurements are used to test whether an API is a non-crystalline state in the solid dispersions. DSC works by measuring the difference in heat flow to or from a sample and a reference material as a function of temperature or time. When a material is crystalline, it will exhibit characteristic endothermic due to melting, while amorphous materials lack these distinct thermal transitions. XRPD works by exposing a powdered sample to X-rays, which diffract according to the crystal planes present in the material, generating a diffraction pattern. The absence of diffraction peaks indicates an amorphous material.

[0120] A further embodiment of the invention is a pharmaceutical dosage form obtainable by the process as described above.

[0121] According to the invention, a “pharmaceutical dosage form” means a dosage form or unit dose containing a drug for pharmaceutical application. Typically the dosage forms may be cylindrical, spherical, prismatic, oval, capsule-shape, or elongate, or diamond shaped. The pharmaceutical dosage forms may be prepared with a variety of physical forms, including tablets, caplets, orally-disintegrating tablets, films, masks and patches, preferably a tablet. The pharmaceutical dosage forms may be prepared with a range of release-behaviour. The pharmaceutical dosage forms according to the invention may provide at least one of modified release, immediate release, colonic delivery, enteric delivery, or gastroretentive drug delivery performance. Preferably, immediate release or controlled-release is provided. In one embodiment the pharmaceutical dosage form is an immediate release tablet.

[0122] The pharmaceutical dosage forms, may be suitable for administration via oral, buccal, topical, transdermal, sublingual, enteral, dental, rectal, urethral or vaginal routes. Preferably oral, buccal, topical or transdermal administration may be used, more preferable oral administration is used.

[0123] It was surprisingly found that the pharmaceutical dosage forms printed with the process according to the invention have at least one of the following features: • An improved high drug loading,

[0124] • less demixing during the printing process,

[0125] • an improved structure consistency,

[0126] • a more accurante geometry,

[0127] • no need fo additional component, e.g. solvents for agglomeration,

[0128] • an improved surface quality as measured by SEM, BET or pCT,

[0129] • a faster and / or higher API release, in particular when compared to a 3D- printed pharmaceutical dosage form without the HME step, as measured by dissolution experiments and / or

[0130] • an improved amorphization of the API, in particular when compared to a 3D- printed pharmaceutical dosage form without the HME step as measured by PXRD and / or DSC.

[0131] Examples:

[0132] 1. Extrusion process

[0133] 1. 1 Extrusion of 1.5 kg Pellets (PVA 4-88 80% / Indometaci n (IND) 20%)

[0134] All components were blended in a vessel for 5 min at 37 rpm using a drum hoop mixer (Engelsmann). After the heating zones reached their Set Point 1 temperature, dosing and screw speed were gradually adjusted to the target parameters of 400 g / h and 350 rpm. After all process parameters were set to the target values, the first yellowish transparent extrudate started to emerge from the nozzle after a few minutes (~ 5-7 min), which was initially discarded for ~20 minutes. Subsequently, at 13:55, the extrudate was crushed into small 1.5 mm-long pellets using a conveyor belt and pelletizer and collected. After about 25 minutes, it was observed that dosed powder was clogging and clumping in the material inlet, which could only be prevented by using a wooden spatula. As a result, the temperature in HZ 2 and 3 was lowered to 60 and 120°C, as it was suspected that the escape of steam towards the material inlet was responsible for the clumping. After both heating zones reached the respective temperature, with HZ2 not tempering to 60°C but staying in the lower 80°C range, it was observed that the problem with the powder blockage disappeared. The process could now be run with the mentioned parameters until nearly all of the physical mixture had been consumed. The process was then terminated.

[0135] A degassing block was placed in the third barrel slot starting from the nozzle.

[0136] Extrusion Parameters:

[0137] Nozzle diameter: 2,0 mm

[0138] 7.2 Extrusion of 1.5 kg Pellets (PVA 4-88 80% / Ketoconazole (KTZ) 20%)

[0139] All components were blended in a vessel for 5 min at 37 rpm using a drum hoop mixer (Engelsmann). After the heating zones reached their Set Point 1 temperature, the dosing and screw speed were gradually adjusted to the target parameters of 400 g / h and 350 rpm. Once all the target parameters were achieved, the first transparent, slightly yellowish melt began to extrude from the nozzle as a filament strand after approximately 2 minutes. The extrudate that emerged was discarded for about 10 minutes. Afterward, the process of converting the filament strand into granules using a pelletizer began at 11 :46. During this process, it was observed that the powder mixture at the material inlet tended to continuously clump and block the entry. Attempts were made to improve the powder feed by further lowering the temperature of the first two heating zones. Lowering the dosing rate to 0.4 kg / h did not bring any improvement either. Since the problems with the powder feed persisted, the extrusion was briefly stopped at 12:18 to install a second vent port after the material inlet area on the first barrel port. After the vent port was installed and extrusion resumed, no further issues with clumping powder at the inlet were observed. Extrusion could continue without major problems from the moment the second vent port was introduced, except for occasional dosing fluctuations and powder bridging in the dosing hopper. The use of a wooden spatula occasionally loosened the bridging, although a part of the wooden spatula broke off and was pulled into the doser mixing wheel at 15:15. Since the wooden piece could neither be removed from the hopper nor was pulled into the dosing screws, it was decided to continue dosing and extrusion until the powder mixture was consumed. No further problems occurred. The extrusion was carried out until almost the entire powder mixture was used / extruded / granulated.

[0140] A degassing block was placed in the third barrel slot starting from the nozzle.

[0141] Extrusion Parameters:

[0142] Nozzle diameter: 2,0 mm

[0143] 2. Preparation of sinter powder

[0144] 2. 1 Milling of PVA 4-88 80% / IND 20% Pellets The pellets (1464 g) were ground using a Retsch ZM200 Ultra Centrifugal Mill. For this purpose, the pellets were frozen in a 1 L Dewar vessel using liquid nitrogen and then ground with the following parameters.

[0145] Rotation Speed (rpm): 18,000

[0146] Rotor Type: 12-Tooth Rotor

[0147] Sieve (mm): 0.35mm Distance Sieve, Trapezoidal Perforation

[0148] Cyclone: Cyclone + Fabric Bag

[0149] Sample Temperature: -196°C

[0150] Powder Dosing: Manual addition by hand

[0151] Yield of light yellowish fine powder: 1428.4 g

[0152] Yield in %: 97.6

[0153] 2.2 Milling of PV A 4-88 80% / KTZ 20% Pellets

[0154] The pellets (1464 g) were ground using a Retsch ZM200 Ultra Centrifugal Mill. For this purpose, the pellets were frozen in a 1 L Dewar vessel using liquid nitrogen and then ground with the following parameters.

[0155] Rotation Speed (rpm): 18,000

[0156] Rotor Type: 12-Tooth Rotor

[0157] Sieve (mm): 0.35mm Distance Sieve, Trapezoidal Perforation

[0158] Cyclone: Cyclone + Fabric Bag

[0159] Sample Temperature: -196°C

[0160] Powder Dosing: Manual addition by hand

[0161] Yield of light yellowish fine powder: 1228.4 g

[0162] Yield in %: 81.89

[0163] 2.3 Preparation of physical mixture (PVA 4-88 80% / Indometaci n (IND) 20%)

[0164] All components were blended in a vessel for 5 min at 37 rpm using a drum hoop mixer (Engelsmann). The blend was used for printing.

[0165] 3. 3D Printing

[0166] 3. 1 CAD-Data

[0167] To design the tablets, the following steps were taken: 1. The 3D structure is initially designed using Autodesk Fusion 360 software (Version 2.0.16007).

[0168] 2. The designed structure is saved as an STL file.

[0169] 3. The STL file is then loaded into the slicing software Cura (Version 4.10.0).

[0170] 4. For the tablet geometry, a cylindrical shape is employed with a diameter of 10 mm and a height of 4 mm

[0171] 5. The Geode was then transferred to the 3D Printer

[0172] 3.2 SLS process

[0173] To produce the tablets the 3D printer (SLS) SnowWhite2 (Sharebot, Nibionno, Italy) was used.

[0174] The powder was scooped onto the build platform and into the powder reservoirs. Afterwards, the powder in the reservoirs was stirred to ensure even distribution and prevent unevenness. Subsequently, the powder was evenly spread using a leveling tool, creating a powder bed. Following this, the camera and F Theta Lens were cleaned with ethanol. Then, the parameters were set, and the process was initiated. After production, the build chamber was allowed to cool to room temperature. Following this, the tablets were taken out of the building chamber and were sieved using a 1mm sieve. Two sets of 30 tablets were printed.

[0175] Parameters for all Examples:

[0176] Three different oral solide dosage forms have been prepared:

[0177] Example 1 : Example 1 was prepared by combining processes 1.1, 2.1 and 3.

[0178] Example 2: Example 2 was prepared by combining processes 1.2, 2.2 and 3.

[0179] Example 3: Example 3 was prepared by combining processes 2.3 and 3.

[0180] 4. Analytical methods

[0181] 4.1 Dissolution Indometacin (Online)

[0182] Description:

[0183] • Samples n=6

[0184] • All samples were weighed on an analytic balance (Mettler Toledo Delta Range XP105)

[0185] • Dissolution performance was measured on a Sotax AT7 smart • Paddle method

[0186] • 37°C

[0187] • Time points [min]: 2,5,10,15,30,45,60,90,120,180,240

[0188] • SGF_sp, 900ml

[0189] • 75 rpm

[0190] • 10mm cuvettes

[0191] • 318 nm

[0192] Fig. 1 shows the IND release [%] of Example 1 in comparison with Example 3 (named 3DPT_Phys_Mix in the Figure), extrudate, physical mixture and crystalline IND during the dissolution test. The AUG is shown in the following table.

[0193] 4.2 Dissolution Ketoconazole (Offline)

[0194] Description:

[0195] • Samples n=6

[0196] • All samples were weighed on an analytic balance (Mettler Toledo Delta Range XP105)

[0197] • Dissolution performance was measured on a Sotax AT7 smart with fraction collector

[0198] • Paddle method

[0199] • 37°C

[0200] • Time points [min]: 5,10,15,30,60,90,120,240

[0201] • FaSSiF 500ml

[0202] • 75 rpm Fig. 2 shows the KTZ release [%] of Example 2 in comparison with the physical mixture and crystalline KTZ during the dissolution test. The AUC is shown in the following table.

[0203] 4.3 HPLC method for Ketoconazole

[0204] • Equipment: Agilent 1260 infinity II

[0205] • Lamp: UV Wavelength: 225nm

[0206] • Column: Supelcosil LC-18 (30cm x 4 mm, 5 pm (Lot: 176153-02)

[0207] • Temp. Column: 40°C

[0208] • Flow rate: 2 mL / min

[0209] • Run time: 8 min

[0210] • Injection volume: 5 pl

[0211] • Mobile Phase: 70% Eluent A: 10mL Diisopropylamin 15L MeoH; 30% Eluent B: 5g Ammoniumacetat in 1 L Milli Q water

[0212] 4.4 HPLC method for Indometacin

[0213] • Equipment: Agilent 1260 infinity II

[0214] • Lamp: UV Wavelength: 254nm

[0215] • Column: Supelcosil LC-18, 30cm x 4mm, 5pm (Lot: 176153-02)

[0216] • Temp. Column: 40°C

[0217] • Flow rate: 1 mL / min

[0218] • Run time: 5 min

[0219] • Injection volume: 10 pl

[0220] • Mobile Phase: 1000 ml CAN, 1000ml IND buffer (0,01 M NaH2PO*H2O 1 ,38g / L+ 0,01M Na2HPO41 ,41g / L) (1 :1)

[0221] 4.5 Assay method Ketoconazole Sample preparation (n=3)

[0222] Each sample were injected twice.

[0223] • 150mg of sample is weighed in a 100 ml volumetric flask and suspended in 50 ml MilliQ water

[0224] • Adding 1 ml of 25% hydrochloric acid

[0225] • Stirring at room temperature on a stirring plate at 500 rpm for 45 min until the solution is clear

[0226] • Fill up to 100 ml with ethanol

[0227] • 20 ml of sample solution are filtered through a PTFE-filter (0,45pm)

[0228] • Diluting sample 10 / 20 with ethanol

[0229] • Filter again through a PTFE-filter (0,45pm)

[0230] Standard preparation

[0231] 50 mg Ketoconazole is weighed in a 100 ml volumetric flask, dissolved in ethanol in an ultrasonic bath for 5 min and filled up to 100 ml (S1)

[0232] A dissolution series with ethanol is made from S1 to S2: 10 / 20 S3: 5 / 20 S4: 1 / 20 S5: 0,5 / 20 S6: 0,25 / 20

[0233] 4.6 Assay method Indometacin

[0234] Sample preparation (n=3)

[0235] Each sample were injected twice.

[0236] • 150mg of sample is weighed in a 100 ml volumetric flask and suspended in 50 ml MilliQ water

[0237] • Stirring at room temperature on a stirring plate at 500 rpm for 45 min until the solution is clear

[0238] • Fill up to 100 ml with ACN

[0239] • sample solution are filtered through a PTFE-filter (0,45pm)

[0240] Standard preparation

[0241] 50 mg Indometacin is weighed in a 100 ml volumetric flask, dissolved in mobile phase in an ultrasonic bath for 5 min and filled up to 100 ml (S1)

[0242] A dissolution series with ethanol is made from S1 to S2: 10 / 20 S3: 5 / 20 S4: 1 / 20 S5: 0,5 / 20 4.7 Mass, dimension and hardness of printed tablets

[0243] All samples were weighed on an analytic balance (Mettler Toledo Delta Range XP105) (Mettler Toledo, Columbus, USA). The dimension of the examples were measured with a caliper S225 (Format, Wuppertal, Germany).

[0244] For hardness determination, the Hardness Tester 8M (Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland) was used in manual mode. The hardness of 10 tablets was determined.

[0245] 4.8 DSC measurement

[0246] To perform the DSC measurement, the physical mixture was weighed in a 40pl alumium crucible (~5 mg, n=3) and got closed with a aluminium lid.

[0247] Fig. 3 shows the DSC curve of Example 1 in comparison with Example 3, extrudate and the physical mixture. Fig. 4 shows the DSC curve of Example 2 in comparison with the extrudate and the physical mixture.

[0248] 4.9 PXRD measurement

[0249] Instrument Name: X-Ray Powder Diffraction XRPD (Rigaku, Japan)

[0250] Measurement Parameters:

[0251] • Range: 3 - 50 degrees

[0252] • Step: 0.02 degrees

[0253] • Speed: 0.8 degrees per minute

[0254] • Voltage: 40 kV

[0255] • Current: 15 mA

[0256] Measurement Duration: 1 hour and 6 minutes

[0257] Fig. 5 shows the XRD patterns of Example 1 in comparison with Example 2, the extrudate, physical mixture, PVA 4-88 (Parteck MXP 4-88) and the crystalline IND. Fig. 6 shows the XRD patterns of Example 3 in comparison with the extrudate, physical mixture, PVA 4-88 (Parteck MXP 4-88) and the crystalline IND.

[0258] References

[0259] • Davis et al., 2021 ; Journal of Pharmaceutical Sciences 110 (2021) 1432-1443

[0260] • Patil et al, 2016; AAPS PharmSciTech. 2016 Feb; 17(1): 20-42

[0261] • Shah, N., Sandhu, Ha., Choi, D.S., Chokshi, H., Malick, A.W. (Eds.), 2014.

[0262] Dissolution of amorphous solid dispersions: Theory and practice. Springer, New York, USA. pp. 185, 201

[0263] • Thakkar et al., 2021a; Pharmaceutics 2021, 13, 1149

[0264] • Thakkar et al., 2021b; European Journal of Pharmaceutics and

[0265] Biopharmaceutics 163 (2021) 141-156

Claims

Claims1 . Process for producing a pharmaceutical dosage form by hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, comprising the steps of(a) providing a composition comprising at least one active pharmaceutical ingredient and at least one polymer, wherein said polymer absorbs electromagnetic radiation at a wavelength emitted by the laser,(b) hot melt extruding the composition of step (a) to form a mixture of the active pharmaceutical ingredient and the polymer,(c) milling the solidified mixture of step (b) to provide a sinter powder, and(d) operating a selective laser sintering apparatus that selectively fuses layers of the sinter powder by a laser to produce the pharmaceutical dosage form.

2. Process for producing a pharmaceutical dosage form by hot melt extrusion and powder bed fusion selective laser 3-dimensional printing, comprising the steps of(a) providing a composition comprising an active pharmaceutical ingredient and an first polymer, wherein said polymer absorbs electromagnetic radiation at a wavelength emitted by the laser,(b) hot melt extruding the composition of step (a) to form a mixture of the active pharmaceutical ingredient and the polymer,(c) milling the solidified mixture of step (b) to provide a first sinter powder in a first reservoir platform,(d) providing a second sinter powder, wherein said second sinter powder absorbs electromagnetic radiation at a wavelength emitted by the laser, and(e) operating a selective laser sintering apparatus that fuses layers of the first and second sinter powder to produce the pharmaceutical dosage form.

3. Process according to Claim 1 or 2, wherein the composition in step (a) further comprises at least one pharmaceutically acceptable additive.

4. Process according to any of Claims 1 to 3, wherein the hot melt extrusion in step (b) is a twin-screw hot melt extrusion.

5. Process according to any of Claims 1 to 4, wherein the hot melt extrusion in step (b) comprises the steps of(1) kneading the composition of step (a) 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 API or above the melting temperature or glass transition temperature of the polymer and below the decomposition temperature of the polymer to form a kneaded mixture, and(2) transporting the kneaded mixture through an outlet.

6. Process according to any of Claims 1 to 5, wherein the hot melt extrusion in step (b) is performed at a temperature between 50 °C to 250 °C.

7. Process according to any of Claims 1 to 6, wherein the solidified mixture in step (c) is an amorphous dispersion of the active pharmaceutical ingredient in the polymer.

8. Process according to any of Claims 1 to 7, wherein the solidified mixture in step (c) is cryo-milled.

9. Process according to any of any of Claims 1 to 8, wherein said powder bed fusion selective laser 3-dimensional printing is selective laser sintering 3- dimensional printing.

10. Process according to any of Claims 1 to 9, wherein the laser is a CO2 laser.11 . Process according to any of Claims 1 to 10, wherein said polymer is selected from the group consisting of acrylic-derived polymers, cellulose-derived polymers, poloxamers and polyvinyl-derived polymers and mixtures thereof.

12. Process according to any of Claims 1 to 11 , wherein said polymer is polyvinyl alcohol.

13. Process according to any of Claims 1 to 12, wherein said polymer is polyvinyl alcohol having a hydrolysis degree of 70% to 90%, and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

14. Pharmaceutical dosage form produced by the process of any of Claims 1 to 13.

15. Pharmaceutical dosage form according to Claim 14, wherein the pharmaceutical dosage form is an oral pharmaceutical dosage form, preferably a tablet.

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