Method for preparing pharmaceutical product

Abstract

To provide an improved method for preparing a pharmaceutical product, involving filling a pharmaceutical carrier with active pharmaceutical ingredient powder using a vacuum assisted metering and a filling device.SOLUTION: A method of filling a pharmaceutical carrier or formulation with pure active pharmaceutical ingredient (API) powder, includes the steps of: dispensing the API powder into a trunk member of the pharmaceutical carrier or formulation using a vacuum assisted metering and a filling device; and covering the trunk member of the pharmaceutical carrier or formulation with a complementary lid member of the pharmaceutical carrier or formulation, thereby producing a filled pharmaceutical carrier or formulation. The filled and sealed pharmaceutical carrier / formulation typically contains only pure API.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to a method for preparing a pharmaceutical product that involves filling an active pharmaceutical ingredient powder into a pharmaceutical carrier using a vacuum assisted measuring and filling device. The method disclosed herein may be used in continuous processes, such as high throughput processes, for manufacturing pharmaceutical products. [Background technology]

[0002] Manufacturing of active pharmaceutical ingredients (APIs) from discovery through early clinical phase to late clinical phase and final commercial product is demanding and resource intensive. Commercial formulations containing APIs and related manufacturing processes generally include blending or granulation of excipients. Geometric dilution, wet granulation, and dry blending are applied especially for manufacturing low dose formulations. Much effort is spent on realizing appropriate blending methods to ensure dose uniformity and homogeneity between excipients and API. Furthermore, much effort is spent on scale-up operations and reformulation when early (or first approach) formulations show unexpected biopharmaceutical profiles or are found not suitable for late processing. To accelerate development, APIs can be delivered in pure form in capsules early on. Pepper pot dosing principle combined with classical weighing (Xcelodose®) is a widely used solution. However, in later stages, classical blending with excipients is still being developed.

[0003] By using pure API in capsules, formulation development time can be reduced by simply assessing compatibility between the capsule shell and API instead of testing excipient compatibility and fully manufacturing the dosage form. Analytical method development time can also be reduced because there is no need to assess specificity due to the absence of interfering excipients. Thus, the analytical method for the drug substance can meet the needs of the drug product. However, achieving consistent fill of pure API into capsules, especially at low fill weights, can be challenging. Summary of the Invention [Means for solving the problem]

[0004] The present invention relates to engineering and manufacturing concepts aimed at the direct encapsulation of pure API (i.e., API with very low amounts of excipients) in a very broad dose range across the entire development pathway of a drug product to commercial manufacturing. The methods of the disclosure are particularly useful in continuous processes, such as high throughput processes for manufacturing pharmaceutical products.

[0005] The disclosed method has the unique ability to accommodate a remarkably wide range of powder characteristics, including powders that cannot be filled in any other facility, allowing users of the platform to address the properties of pure API powders (e.g., excessive cohesion, adhesion, poor flowability, etc.). The disclosed method can address many complex aspects of drug development in a relatively simple combination of technical and organizational solutions that radically simplify the development and manufacturing of oral pharmaceutical forms. The method can be used recursively for any new API (with sufficiently good intrinsic solubility characteristics) that enters the development pathway of pharmaceutical research and development through to commercial manufacturing.

[0006] To achieve the above objectives, the method of the present disclosure applies novel procedures for understanding, predicting, selecting, modifying and controlling powder behavior as well as an unusual combination of equipment and techniques.

[0007] Thus, the present invention provides (a) The following parameters (i) to (viii) were determined using an FT4 powder rheometer: (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) wall friction angle (WFA) up to 40°; providing an active pharmaceutical ingredient (API) that meets at least five of the following criteria: (b) dispensing the API of step (a) into a body member of a pharmaceutical carrier using a vacuum assisted metering and filling device; (c) covering the body member of the pharmaceutical carrier with a complementary cover member of the pharmaceutical carrier, thereby producing a pharmaceutical product; The present invention provides a method for preparing a medicament comprising the steps of:

[0008] In a related aspect, the invention provides a method of loading a pharmaceutical carrier or dosage form with an undiluted active pharmaceutical ingredient (API) powder, comprising the steps of: (a) dispensing an API powder into a body member of a pharmaceutical carrier or dosage form using a vacuum assisted measuring and filling device; (b) covering a body member of said pharmaceutical carrier or dosage form with a complementary cap member of said pharmaceutical carrier or dosage form, thereby producing a filled pharmaceutical carrier or dosage form; Including, The undiluted API was determined using the FT4 powder rheometer with the following parameters (i) to (viii): (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) Compression ratio is up to 47%; (viii) wall friction angle (WFA) up to 40°; Provide a method to meet at least five of the following criteria:

[0009] Thus, the filled and sealed pharmaceutical carrier / dosage form typically contains only the pure API (note that the pure API may contain no more than 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of excipients).

[0010] The present invention also provides pharmaceutical carriers / dosage forms, such as oral dosage forms, comprising only the pure API (note that the pure API may contain not more than 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of additives) obtained or obtainable by the process of the present invention as described in any of the embodiments herein.

[0011] The inventors have developed a method to predict whether an API is suitable for direct incorporation as a pure API into a pharmaceutical product or whether further improvements (particle engineering) are required. Step (a) therefore represents a quality test that defines new minimum standards for certain powder parameters required to incorporate an API into a pharmaceutical product as a pure API.

[0012] Therefore, the present invention also provides a method for predicting whether an API is suitable for direct incorporation as undiluted API into a pharmaceutical product, comprising the steps of: (i) determining the suitability of an API for direct incorporation into a pharmaceutical product as undiluted API by using an FT4 powder rheometer; (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) wall friction angle (WFA) up to 40°; determining whether the at least five of the following are met:

[0013] In the pharmaceutical industry, the use of vacuum-assisted metering and filling devices such as drum filler technology has previously been described in the context of excipient-containing inhalation products (such as lactose blends or engineered particles, e.g. PulmoSpheres™), but its application to dosage forms manufactured with pure API, including oral dosage forms, is believed to be unique. More common in the industry is the delivery of compounded blends or granulated material into capsules using a dosator or tamping pin filling principle.

[0014] In further described embodiments, the vacuum drum dispenser comprises a powder trough equipped with a fluidization device, in particular an acoustic transducer, more particularly an ultrasonic transducer. Additionally, the API may be concentrated in the body member of the pharmaceutical carrier prior to step (c) by vibration, shaking or tapping.

[0015] In certain embodiments, the pharmaceutical agent is in an oral dosage form, an example of which is the injection molded tablet-shaped carrier described in the embodiments below and elsewhere in the specification.

[0016] In one embodiment, the pharmaceutical carrier in step (c) is a tablet-shaped carrier (also referred to herein as Prescido™) as a novel pharmaceutical dosage form. The carrier is designed to have the functionality of a standard pharmaceutical capsule while maintaining the patient appeal of a tablet. The carrier described herein is manufactured by a precision injection molding process with a formulation designed to perform well in thermal processes. The high performance of the formulation in the injection molding process allows for flexible design of the carrier and allows for robust manufacturing of designs with very small dimensional features that have traditionally been challenging in injection molding. The design and manufacturing features, together with their advantages, include, among others, thin walls (fast disintegration time of the carrier in aqueous media), compact snap-on closure features (tight closure prevents opening of the carrier during shipping and limits tampering with the carrier contents), cavity numbering (traceability and part sorting before use), and high weight and dimensional precision (robust handling process).

[0017] The formulation developed, in addition to being easily thermally processable, confers on the carrier a number of advantages compared to conventional capsules, such as low water content (improving compatibility with water-sensitive active substances), low hygroscopicity and low sensitivity to moisture under standard manufacturing conditions, and very relatively fast dissolution (rapid carrier destruction in aqueous media). Thus, Prescido TM The carrier has favorable moisture content and absorbency, which provides advantages with regard to processing and stability of moisture sensitive compounds, and is therefore advantageous compared to conventional capsules. [Brief description of the drawings]

[0018] [Figure 1] 1 shows a simplified measurement technique using a capacitive sensor in a capsule filling machine. [Diagram 2] 1 shows a flow chart of the steps involved in the preparation of a pharmaceutical product. [Diagram 3]1 shows a simplified measurement approach using multiple capacitive sensors in a capsule filling machine. [Figure 4] Various designs of pharmaceutical carriers are shown. [Diagram 5] FIG. 5 shows a cross-sectional view of the cap member (left side) and the body member (right side) of an exemplary embodiment of the pharmaceutical carrier according to FIG. 4, together with a detailed view of the closure mechanism provided on the cap member and the body member. [Figure 6] Fig. 6A is a three-dimensional view of the carrier body member shown on the right side of Fig. 5. Fig. 6B shows a more detailed view of the closure mechanism provided on the lid member and body member of the pharmaceutical carrier according to Fig. 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention, as further defined in the claims, comprises: (a) The following parameters (i) to (viii) were determined using an FT4 powder rheometer: (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) wall friction angle (WFA) up to 40°; providing an active pharmaceutical ingredient (API) that meets at least five of the following criteria: (b) dispensing the API of step (a) into a body member of a pharmaceutical carrier using a vacuum assisted metering and filling device; (c) covering the body member of the pharmaceutical carrier with a complementary cover member of the pharmaceutical carrier, thereby producing a pharmaceutical product; The present invention provides a method for preparing a medicament comprising the steps of:

[0020] A flow chart of the methods disclosed herein that are useful at any scale is provided in FIG.

[0021] Pure API selection and modification The inventors have developed an "8-parameter model" that can identify and predict the packing behavior of powders. The eight parameters are: sBFE: Specific Basic Flow Energy (mJ / g): Obtained by dividing the BFE (obtained from a standard FT4 test platform) by the fractional mass of the sample SI: Stability index, standard variable, dimensionless SE: Specific energy (mJ / g), standard variable MPS@15kPa: Maximum principal stress, standard variable FF@15kPa: Stream function (dimensionless), by shear cell, standard variables CBD@15kPa: Bulk density after compression (g / mL), standard variable (by shear cell) CPS: Compression ratio (%), standard variable WFA: Wall friction angle (deg), standard variable.

[0022] The following table gives the ranges and preferred ranges for each parameter that forms part of the model. The preferred and most preferred ranges for each parameter can be individually combined with the preferred and most preferred ranges for any other parameter.

[0023] [Table 1]

[0024] In a preferred embodiment, the powder parameters in step (a) satisfy the following requirements, preferably at least five of the following requirements: (i) sBFE is at most 25 mJ / g, in particular at most 6 mJ / g, and / or (ii) SI is between 0.83 and 1.18, in particular between 0.9 and 1.1, and / or (iii) SE is at most 8 mJ / g, in particular at most 6 mJ / g, and / or (iv) MPS-15 is at most 33, in particular at most 25, and / or (v) FF-15 is at least 3, in particular at least 10, and / or (vi) CBD-15 is at least 0.45 g / mL, in particular at least 0.6 g / mL; and / or (vii) a compression ratio of at most 35%, in particular 3% to 15%, and / or (viii) WFA up to 34°, specifically, up to 28°.

[0025] The standard FT4 Powder Rheometer offers at least six powder characterization methods (per measurement cylinder diameter). The ones selected for analysis are: 25mm_1C_Split_Rep+VFR_R01, 25mm_Shear_15kPa, 25mm_Compressibility_1-15kPa, 25mm_Wall Friction_30kPa.

[0026] The parameters can be divided into four groups based on the four characterization methods chosen. Group 1-(i) sBFE, (ii) SI, (iii) SE Group 2 - (iv) MPS-15, (v) FF-15, (vi) CBD-15 Group 3-(vii) CPS Group 4-(viii) WFA.

[0027] The FT4 Powder Rheometer is commercially available from Freeman Technology.

[0028] If four of the parameters are outside the indicated ranges, the powder is expected to be borderline in terms of manufacturability. If more than four of the parameters are outside the indicated ranges, the powder described here as pure API is probably and practically not processable in any automated machine. Furthermore, it has been found that if the MPS is very high and, to a lesser extent, the WFA is also high, the powder is prone to accumulate in the filling and feeding device. This is a negative property of the sonic / ultrasonic filling technique. On the other hand, if the SI is too high, the powder changes its properties over time and the powder becomes more sensitive to shear forces. Such powders are less processable in standard vacuum drum filling techniques using stirrers.

[0029] In a preferred embodiment, at least one of the parameters is selected from parameters (i)-(iii) and at least one of the parameters is selected from parameters (iv)-(vi), i.e. at least one from group 1 and at least one from group 2. Preferably, at least one of the parameters in group 1 is parameter (i) or parameter (iii), and at least one of the parameters in group 2 is parameter (iv) or parameter (v).

[0030] In another embodiment, which may be combined with the previous embodiment, at least one of the parameters is parameter (vii) or parameter (viii), i.e., group 3 or group 4.

[0031] When the vacuum assisted measuring and filling device comprises an ultrasonic device to assist in measuring and dispensing the API, it may be advantageous for the sBFE to be equal to or less than 29, such as equal to or less than 25. The CPS in this situation may be up to 65%.

[0032] In one embodiment, the WFA is 34 or less and / or the CPS is 35 or less.

[0033] Where the vacuum assisted measuring and filling device is equipped with a stirrer to assist in measuring and dispensing the API, it may be advantageous for the SI to be between 0.83 and 1.18, e.g., between 0.9 and 1.1, and for the CPS to be less than or equal to 35%.

[0034] Therefore, the present invention also provides a method (in all its embodiments) for predicting whether an API is suitable for direct incorporation as a pure API into a pharmaceutical product using the above-mentioned eight-parameter model.

[0035] In many cases, step (a) of the process includes a wetting step (leftmost portion of FIG. 2) where the pure API is produced. Generally, such a wetting step includes a crystallization step, which can be controlled in situ to obtain crystals of the desired particle size of the pure API. The parameters and means for controlling particle size in a crystallization process are well known in the art and include temperature, humidity, pH, agitation settings, and the selection of appropriate salts, buffers, and organic solvents. The selection of these parameters depends on the API of interest, and their determination forms part of the production process of the API. Following crystallization, the API is usually filtered and dried.

[0036] However, in a further embodiment, step (a) of the process may further comprise wet-milling the API to further reduce the particle size.

[0037] Particle size may also be controlled by the addition of additives during the wetting stage. Appropriate additives are typically used as suspensions, solutions, or solids. The properties of the additives and the point in the process at which they are added are specific to the API under process development. Alternatively or additionally, additives may also be added to the API during the wetting stage to improve process performance or surface property benefits such as better wettability.

[0038] The additives may be added at one or more points during the manufacturing process, for example, during the crystallization step, the filtration step, and / or the drying step. For example, the API base particles may be coated with the polymer during the crystallization in the wet stage or in suspension after crystallization or after milling.

[0039] The proportion of additives used is always low enough so as not to affect API content uniformity or mass sensor measurement accuracy. This is a concept in contrast to conventional formulations where API is always diluted in a significant amount of excipients, especially at low doses. Therefore, the amount of additives added is very small. For example, during or after the crystallization, filtration, or drying steps, one or more additives may be added in an amount of up to 2% (w / w), preferably up to 1.5% (w / w), more preferably up to 1% (w / w), even more preferably up to 0.5% (w / w), and most preferably up to 0.1% (w / w). The one or more additives may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, acrylic polymers, sodium lauryl sulfate, gelatin, sugar esters such as sucrose monostearate and sucrose monopalmitate, and any combination thereof.

[0040] Following the wetting step, the API may optionally be further conditioned in a drying step. For example, step (a) of the process may further comprise dry milling and / or sieving of the API. Sieving may be selected from sieving through a conical sieving machine, vibratory sieving, or screen sieving assisted by ultrasonic vibration.

[0041] Also during the drying step, the API particles may be treated and even coated with finely divided additives in the context of improving physical properties to obtain process performance advantages (processing aids and surface property aids, see center left of FIG. 2). Thus, in some embodiments, step (a) of the method further comprises a drying step, during which one or more additives are added in an amount of up to 5% (w / w), preferably up to 4% (w / w), more preferably up to 3% (w / w), even more preferably up to 2% (w / w), and most preferably up to 1% (w / w).

[0042] Additives may typically be added after isolation of the API in the wet stage, thereby adding just before or as part of the dry stage API conditioning process. Established techniques available in a commercial environment may be used. For example, one or more additives are added by (i) low shear mixing, especially in a tumbler mixer, (ii) high shear mixing, especially in a rotary mixer, or (iii) ultra-high shear mixing, especially in Mechanofusion. Mixing is typically performed for a duration of at least 3 minutes and up to 3 hours.

[0043] During the drying step, the additives are typically used as solids. In some embodiments, the one or more additives are selected from the group consisting of hydrophobic colloidal silicon dioxide, hydrophilic colloidal silicon dioxide, magnesium stearate, stearic acid, sodium stearyl fumarate, poloxamer 188, hydrogenated vegetable oil, or any combination thereof.

[0044] The purpose of the additive additions in step (a) of the process invention and their different processing methods is first to achieve a sufficient level of powder rheological properties.

[0045] In any case, the final pure API resulting from step (a) comprises at most 5% (w / w), preferably at most 4% (w / w), more preferably at most 3% (w / w), even more preferably at most 2% (w / w), and most preferably at most 1% (w / w) of additives.

[0046] As mentioned above, a person skilled in the art knows how to adapt the powder parameters to comply with the requirements described in step (a). In a similar example, additives may also be added within the indicated ranges to achieve improvements in the biopharmaceutical profile of the API in term or. In addition, scanning electron microscopy (SEM) provides a qualitative impression of particle size and shape. This may only be used as a visual guide, since the small sample size may not be representative of the batch.

[0047] Filling capsules with pure API In step (b) of the method, the API of step (a) is dispensed into a pharmaceutical carrier body member using a vacuum-assisted measuring and filling device. Such devices allow for the delivery of less than 0.25 mg up to 0.5 grams, with very precise delivery over this range. Thus, the disclosed method allows for a total fill mass that can be as low as 0.25 mg to be delivered with high precision without any classical compounding steps. The vacuum-assisted measuring and filling device allows for the filling of poorly flowing and cohesive powders. During dose formation, low mechanical stress is applied to the powder, reducing the risk of adhesion to equipment surfaces in terms of other filling principles. These advantages result in a wider range of powder characteristics that can be processed compared to conventional techniques traditionally used in large-scale encapsulation of solid oral products, and a higher process robustness for the encapsulation of pure drug substances.

[0048] Step (b) only functions if the requirements of step (a) are met. Thus, steps (a) and (b) are interrelated. Thus, the present disclosure makes it possible to determine whether a powder can be dispensed and fed using a vacuum-assisted measuring and filling device. At the same time, the present disclosure provides a person skilled in the art with valuable guidance on how an API must be (re)constituted to be suitable for dispensing by a vacuum-assisted measuring and filling device.

[0049] The use of vacuum-assisted metering and filling devices such as drum filler technology for inhalation products is well known in the pharmaceutical industry, but its application to the manufacture of oral dosage forms with pure API is believed to be unique. Thus, in a preferred embodiment, the pharmaceutical product is an oral dosage form. More common in the industry is to feed compounded blends or granulated materials into capsules using a dosator or tamping pin filling principle.

[0050] The use of a vacuum-assisted measuring and filling device is particularly advantageous since it allows the method of the present disclosure to be applied in a continuous process. As a result, the method of the present invention can be used in a high throughput process for manufacturing a pharmaceutical product, allowing production of 70,000 units / hour or even more. As a result, the method allows the preparation of a pharmaceutical product with a pure API, i.e., an API containing up to 5% (w / w) of excipients, throughout all stages of the development of the pharmaceutical product, including its final commercial production. Prior art methods that do not include steps (a) and (b) of the present method only exhibit low throughput. To implement high throughput production, the API had to be (re)formulated into a pharmaceutical composition during the various development stages.

[0051] In a preferred embodiment, the vacuum assisted measuring and filling device is a rotatable drum. For example, a vacuum is applied in the drum cavity at -100 to -800 mBar, such as -200 to -800 mBar, preferably -300 to -800 mBar, more preferably -400 to -800 mBar, such as -500 to -800 mBar, or even -600 to -800 mBar. In some embodiments, the vacuum may also be higher than -800 mBar. Independent of the applied vacuum, the API may be dispensed at a discharge pressure of 100-1500mBar, preferably 200-1500mBar, more preferably 300-1500mBar, such as 400-1500mBar, in particular 500-1500mBar, more preferably 600-1500mBar, such as 700-1500mBar, even more preferably 800-1500mBar, in particular 900-1500mBar, or even 1000-1500mBar. In some embodiments, it may be advantageous to dispense the API at a discharge pressure above 1500mBar.

[0052] When the vacuum assisted measuring and filling device is a rotatable drum, the rotatable drum may be assisted by some specific additional features that expand the range of powder properties that can be filled. These include fluidization of the powder using an ultrasonic transducer (sonicator) in a trough near the drum cavity, which fluidizes the powder adjacent to the probe to overcome the poor flow characteristics of some powders, allowing the API to flow more freely into the drum cavity. For example, the vacuum assisted measuring and filling device may include a stirrer, which is set at 1 to 4 revolutions per cycle, for example, about 2 to about 4 revolutions per cycle, or about 1 to about 3 revolutions per cycle, or about 2 to about 3 revolutions per cycle. Alternatively, the vacuum assisted measuring and filling device may include a sonic / ultrasonic device, in particular a pogo or pole, which pushes and breaks micro-bridging of the powder entering the cavity of the rotatable drum. For example, the pogo or pole may have a frequency of 10,000Hz to 180,000Hz, preferably 11,000Hz to 170,000Hz, more preferably 12,000Hz to 160,000Hz, more preferably 13,000Hz to 150,000Hz, more preferably 14,000Hz to 140,000Hz, more preferably 15,000Hz to 130,000Hz, more preferably 16,000Hz to 120,000Hz, more preferably 17,000Hz to 110,000Hz, more preferably 18, More preferably, frequencies of 20,000 Hz to 100,000 Hz, more preferably 19,000 Hz to 90,000 Hz, more preferably 20,000 Hz to 80,000 Hz, more preferably 21,000 Hz to 70,000 Hz, more preferably 21,500 Hz to 60,000 Hz, more preferably 22,000 Hz to 50,000 Hz, more preferably 22,000 Hz to 40,000 Hz, more preferably 22,000 Hz to 30,000 Hz, and most preferably a frequency of about 22,000 Hz is applied.

[0053] Those skilled in the art may choose between stirrer or sonic / ultrasonic device depending on the powder rheology of API. In particular, when MPS-15 is 28 or less and / or WFA is 31° or less, API is suitable for use with vacuum-assisted measuring and filling device with sonic / ultrasonic device to assist in measuring and dispensing API. On the other hand, when SI is more than 1.1, API is not suitable for use with vacuum-assisted measuring and filling device with stirrer to assist in measuring and dispensing API. Please also refer to the following examples herein.

[0054] Other embodiments involve the use of an acoustic device and housing to level the API in the trough and ensure a uniform powder bed. Similar acoustic systems are also used to condition the powder in the hopper and ensure flow from the hopper to the trough. Thus, in further embodiments, the vacuum-assisted measuring and filling device may include a powder trough equipped with a fluidizing device. An example of such a device is an acoustic speaker, which may or may not be supported by an ultrasonic transducer. In particular, embodiments are contemplated in which the feed is from a vibrating hopper to the powder trough, the hopper being preferably actuated by a sensor. In a preferred embodiment, the sensor is a capacitance sensor. In an embodiment, the feed is from the hopper to the powder trough, each equipped with an acoustic device, using a vibration frequency of 100-1000 Hz, and the hopper towards the powder trough is preferably actuated by a sensor, in particular a capacitance sensor. Also, vibration frequencies of 200-900 Hz, 300-800 Hz, 400-700 Hz, or 500-600 Hz may be used.

[0055] It may be suitable that the dose of API in step (b) is selected in the range of 0.1 mg to 550 mg, preferably 0.2 mg to 500 mg, and most preferably 0.25 mg to 450 mg. Preferably, the dose of API in step (b) has a relative standard deviation (RSD) of less than 5%, preferably less than 4%, more preferably less than 3%. Usually, the dose of API in step (b) is gravimetrically checked using a fill mass measurement technique. For example, the dose of API may be gravimetrically checked offline using brutto-tara weighing. However, in a preferred embodiment, the dose of API is gravimetrically checked in real time using a capacitance sensor and / or a microwave sensor, in particular by using a capacitance sensor, allowing the achievement of 100% fill weight control. This kind of in-line fill mass verification is available from low to high throughput facilities. The sensor works on the principle of microwave and / or capacitive non-contact measurement of a powder falling between two capacitor plates in a cavity. During the measurement, the change in the electric field is acquired and correlated to the powder fill weight.

[0056] Recent capacitive sensors are integrated into capsule filling machines and are generally used for powders with doses of a few milligrams. It is also known to theoretically set the sensor in the sub-milligram range, which requires a reduced capacitor distance to the sensor, resulting in a higher electric field. However, this reduces the diameter of the sensor channel through which the powder pack falls and is measured. In non-optimized powders, this often leads to the powder pack colliding with the wall of the channel, or even falling onto the top edge of the sensor or outside the capsule body. Furthermore, typical powder distribution often leads to the formation of a rolling pack, resulting in poor sensor readings during dynamic measurements of such falling entities. In order to use such capacitive sensors in the sub-milligram range, the formulation must produce a stable powder pack or a unique air-borne mass that can pass through the narrow diameter of the sensor channel without fragmenting or rolling, as is sought and achieved by the method of the present invention.

[0057] FIG. 1 shows a simplified measurement approach using such a sensor in a capsule filling machine. The capsule filling machine includes a vacuum drum 10 rotatable about an axis R and equipped with a cavity 12. At least a lower part of the cavity 12 is made of a pressure-permeable material, for example a filter material, which allows the desired pressure to build up in the cavity 12. To fill the cavity 12 with powder, the vacuum drum 10 is rotated so that the cavity 12 is located below a powder reservoir (not shown). Furthermore, a pressure below atmospheric pressure is established in the cavity 12. As a result, powder is fed from the powder reservoir to the cavity 12, and the dosage of the powder can be controlled with high precision. The vacuum drum 10 is then rotated to the position shown in FIG. 1, and a pressure above atmospheric pressure is established in the cavity 12. As a result, the powder pack 14 formed in the cavity 12 is ejected from the cavity 12. The powder puck 14 formed in the cavity 12 falls past a capacitive sensor 16 into the capsule body 18, allowing in-line measurement of the powder fill weight.

[0058] Measurements on-the-fly are almost instantaneous, are not affected by machine operating vibrations, and in particular determine the net fill weight directly in real time. In addition, these measurement principles are independent of capsule shell weight variations. These sensors are typically used to monitor 100% sorting, preferably of conventional carriers such as capsules or special carriers with tablet form, most preferably real-time release testing. These sensors are typically used to determine the fill weight of the carrier. Procedures have been developed to analytically validate these sensors. These validation procedures are adapted from near-infrared spectroscopy used for tablets, with parallel one-to-one testing of NIR vs. HPLC (high-performance liquid chromatography) using the root mean square error of prediction being a common technique. As a result, when using real-time weight control with capacitive and / or microwave sensors, the sensors have a root mean square error of prediction (RSMP) of less than 5%, preferably less than 4.5%, more preferably less than 4%, and most preferably less than 3.5% against analytical control tools such as HPLC or balances.

[0059] The pure or modified API is then placed into a conventional pharmaceutical carrier having at least two members, such as a cap and a body member, In embodiments, the API is concentrated in the body member of the pharmaceutical carrier by vibration, shaking, or tapping prior to step (c).

[0060] The carrier components, body and lid, are loaded separately into the machine, which can handle, orient and transport the parts through two independent channels to the powder filling station. After filling, the body and top members are engaged and pressed together to form the final carrier unit.

[0061] Scaling up of the technology can be easily implemented by parallelization of the supply lines, which allows representative and transferable results throughout all stages of the filling test in the development process. The sensor system used between the devices is always the same. This overall combination results in a highly flexible filling system that allows for quick response to various clinical and market demands, accommodates a wide range of drug products based on different APIs, uses a small footprint in the manufacturing area, and potentially reduces the cost of drug development and processing. Thus, the present disclosure contemplates the use of the above method in a continuous and / or high throughput process for manufacturing pharmaceutical products. In this context, high throughput means at least 25,000 units / hour, preferably more than 30,000 units / hour, more preferably more than 40,000 units / hour, more preferably more than 50,000 units / hour, more preferably more than 60,000 units / hour, and most preferably at least 70,000 units / hour.

[0062] Figure 3 shows a simplified measurement approach using multiple sensors 16 in a capsule filling machine (e.g., three tracks). Powder packs 14 produced in a drum 10 with several cavities 12 as detailed above with reference to Figure 1 drop past the sensors 16 into capsules 18, allowing in-line measurement of powder mass at multiple feeding stations, yielding individual fill weight values.

[0063] Pharmaceutical Carriers Pharmaceutical carriers include mono-dose forms of dry powder inhalers as well as oral dosage forms. Pharmaceutical carriers include conventional capsules, such as two-part capsules made of materials such as gelatin or hypromellose. As an alternative to filling the pure or modified API into a conventional capsule, the API can also be filled into an injection molded container, such as the Prescido™ container described herein. The Prescido™ container is a capsule that is filled like a capsule, but has the appearance of a film-coated tablet. This creates an additional presentation option for sale to choose from when a dosage presentation other than a traditional capsule is desired. Figure 4 (top row) shows various designs of the Prescido™ platform.

[0064] As is evident from FIG. 4, Prescido™ containers may have different designs and different filling capacities. In particular, the containers may have various diameters and heights, for example, so that the appropriate container can be selected based on the amount of powder to be filled in the container. The containers are typically selected to have a tablet shape, such as a disk shape, as opposed to a capsule shape. Considering the lid and lower part of the pharmaceutical carrier, the capsule shape is elongated along a central axis extending from the center of the body member to the center of the lid member. Thus, in conventional capsules, the ratio of the lateral extension range, particularly the diameter of the lid and body member, to the height of the lid and body member after assembly along the central axis is less than 1:1, for example 0.5:1 or less. For example, a Type 000 capsule has a diameter of 5.32 mm and a height of 14.3 mm (a ratio of 0.37:1), and a Type 4 capsule has a diameter of 9.55 mm and a height of 26.1 mm (also a ratio of 0.37:1). In contrast, tablet-shaped carriers have a flatter shape and have a ratio of greater than 1 (1:1 is essentially a sphere). Thus, pharmaceutical carriers are preferably designed such that the lateral extension range, in particular the ratio of the diameter of the cap and body members to the height of the cap and body members after assembly, is >1, preferably ≧1.4, more preferably ≧1.5, even more preferably ≧2, most preferably ≧2.4, and especially ≧2.5.

[0065] Preferably, the cap member and the body member of the pharmaceutical carrier have a complementary closure mechanism. More preferably, the complementary closure mechanism is an interlocking snap mechanism. This handling principle is unique and is the first to be realized in the world for a pharmaceutical powder filling machine.

[0066] Commercially available capsules are manufactured by a dip-coating method, which involves preparing a reservoir of a polymer / water mixture and dipping a pin into the mixture so that it is coated with the mixture. The pin is then withdrawn from the mixture and the polymer mixture on the pin is allowed to dry, forming a hard capsule, which is then removed. On the other hand, Prescido TM The carriers are manufactured by injection molding, which involves melting the material in a screw, using which the melt is then injected at high pressure into a mold where it is rapidly cooled and then ejected. This method has many advantages over dip coating. It can be performed very precisely, as an electrical drive precisely controls the machine movements. In addition, the process parameters such as temperature, pressure and mold precision are very tightly controlled, resulting in highly uniform parts.

[0067] Additionally, injection molding allows greater freedom in accommodating complex part geometries: whereas in dip molding, both the exterior and interior shapes of the capsule are restricted by the pin shape, the shape of the injection molded part is defined by the mold shape, allowing for a wide variety of features on each side of the carrier.

[0068] Conventional capsule compositions are limited to polymers that exhibit the right rheological and film-forming properties when dispersed in water. Injection molding, on the other hand, is a hot melt process that requires materials with completely different properties. This presents both an opportunity to transition from conventional capsule materials such as gelatin (animal origin, mechanical properties change depending on environmental conditions) and HPMC (dissolution lag time) and a challenge (the injection molding process is very demanding in terms of the required material properties). The material must be thermally stable during the process, have good melt flow properties, especially under high shear conditions, be flexible enough to be ejected from the equipment after cooling, have sufficient mechanical strength to allow formulation processing when used in the disclosed applications, and dissolve quickly in water. Furthermore, the material must be suitable for human consumption and approved for pharmaceutical use.

[0069] The inventors have found that polyethylene oxide (PEO) based formulations can be suitable for injection molding. Different molecular weight PEO ratios have been tested to obtain formulations with the right physicochemical properties.

[0070] In this context, the present disclosure further provides a formulation for injection molding of a pharmaceutical carrier, the formulation having a weight average molecular weight M W 94,000-188,000), 3-7% (w / w) of an anti-adherent agent, and optionally one or more excipients.

[0071] The weight average molecular weight of the compound suitable for injection molding of the pharmaceutical carrier is M W In a preferred embodiment, the weight average molecular weight of the polyethylene oxide polymer is M W 95,000 to 185,500, more preferably M W 97,500 to 183,000, more preferably M W 100,000 to 175,000, more preferably M W 102,000 to 165,000, more preferably MW 105,000 to 150,000, more preferably 107,500 to 130,000, most preferably M W 110,000~115,000.

[0072] The polyethylene oxide polymer has a weight average molecular weight of about M W 100,000 polyethylene oxide, with a weight average molecular weight of approximately M W 200,000 polyethylene oxide, with a weight average molecular weight of approximately M W Polyethylene oxide with a weight average molecular weight of about M W 600,000 and a weight average molecular weight of M W It may comprise, and preferably consist of, one or more polyethylene oxides of No. 8,000. Polyethylene oxides of this type are commercially available.

[0073] In certain preferred embodiments, the polyethylene oxide polymer has a weight average molecular weight of M W 35 to 80% (w / w) of a first polyethylene oxide having a weight average molecular weight of M 100,000; W and 4-28.5% (w / w) of the second polyethylene oxide having a molecular weight of 200,000. In other preferred embodiments, the formulation may comprise 41-77.5% (w / w), preferably 42-76% (w / w), more preferably 43-75% (w / w), more preferably 45-74% (w / w), more preferably 50-74% (w / w), and most preferably about 73.5% (w / w). In certain preferred embodiments, the formulation may comprise 4-27.5% (w / w), preferably 5-25% (w / w), more preferably 6-22% (w / w), more preferably 10-21% (w / w), more preferably 11-20.5% (w / w), and most preferably about 20% (w / w).

[0074] In a further embodiment, the injection molding formulation of the pharmaceutical carrier comprises 3.5-6.5%, preferably 4-6% (w / w), more preferably 4.5-5.5% (ww), and most preferably about 5% of an anti-blocking agent. A particularly preferred anti-blocking agent is talc.

[0075] In one embodiment, the formulation comprises 0-6% (w / w) of one or more colouring agents and / or opacifying agents, preferably 0.01-5% (w / w) of one or more colouring agents and / or opacifying agents, more preferably 0.25-4% (w / w) of one or more colouring agents and / or opacifying agents, more preferably 0.5-3% (w / w) of one or more colouring agents and / or opacifying agents, more preferably 0.75-2.5% (w / w) of one or more colouring agents and / or opacifying agents, more preferably 1-2% (w / w) of one or more colouring agents and / or opacifying agents, more preferably 1-1.5% (w / w) of one or more colouring agents and / or opacifying agents, and most preferably about 1% (w / w) of one or more colouring agents and / or opacifying agents.

[0076] More preferably, the formulation comprises 0.01-1% (w / w) antioxidant, preferably 0.05-0.8% (w / w) antioxidant, more preferably 0.1-0.75% (w / w) antioxidant, more preferably 0.2-0.7% (w / w) antioxidant, more preferably 0.3-0.6% (w / w) antioxidant, more preferably 0.4-0.5% (w / w) antioxidant, and most preferably about 0.5% (w / w) antioxidant.

[0077] In a particular embodiment, the formulation comprises 30-38% (w / w) of a filler, preferably 32-38% (w / w), more preferably 34-36% (w / w); in particular the filler is talc.

[0078] At least one of the cover member and the body member has a first wall portion having a thickness of 180 to 250 μm, preferably 185 to 225 μm, and more preferably 190 to 220 μm, and a second wall portion having a thickness of 350 to 450 μm, preferably 375 to 425 μm, more preferably 390 to 410 μm, and most preferably about 400 μm.

[0079] The thickness of the first wall is optimized to 190-220 μm. This is thick enough to ensure that during the manufacture of the pharmaceutical carrier by injection molding, the material can flow through the thin first wall and still fill the thicker walled region of the second wall, while being thin enough to achieve the rapid carrier disintegration required to achieve an immediate release dissolution profile of the loaded compound. The second wall can be optimized to a thickness of 400 μm. This balances the larger internal volume available for loading with the required mechanical strength for loading and handling, including resistance to opening after loading.

[0080] The first wall of the capping member can define at least a portion of the top of the capping member, and preferably defines the entire top of the capping member, such that the compound loaded in the pharmaceutical carrier is rapidly and reliably released via the collapse of the top of the capping member upon collapse of the thin-walled first wall.

[0081] The second wall of the closure member can define at least a portion of the side wall portion of the closure member. For example, the second wall of the closure member can define a shoulder or corner of the closure member that is disposed adjacent to the top of the closure member. In particular, the second wall of the closure member can extend from the first wall, i.e., in particular from the top of the closure member, along its periphery towards the body member. This design provides the closure member with the mechanical stability required for handling the closure member and, if desired, for coupling it with the body member to form a pharmaceutical carrier.

[0082] In a preferred embodiment of the pharmaceutical carrier, the first wall of the body member defines at least a portion of the bottom of the body member, and preferably defines the entire bottom of the body member such that when the thin-walled first wall collapses, the compound loaded in the pharmaceutical carrier is rapidly and reliably released through the collapse of the bottom of the body member.

[0083] The second wall of the body member may define at least a portion of the side wall portion of the body member. In particular, the second wall of the body member may extend from the first wall, i.e. in particular from the bottom of the body member, along its periphery in the direction of the lid member. Preferably, the height of the second wall of the body member is greater than the height of the second wall of the lid member. In other words, in a preferred embodiment of the pharmaceutical carrier, the body member has a hollow, generally cylindrical shape, thus defining a "vessel" that can be filled with the pharmaceutical compound. On the other hand, the lid member may comprise a second wall that defines a mere shoulder or corner surrounding the top of the lid member, which may have a generally "flat" shape. The wall thickness of the second wall is greater than that of the first wall, which gives the body member mechanical strength and stability, thereby allowing the body member to be filled without constraint with the pharmaceutical compound.

[0084] In a preferred embodiment, the closure member and the body member are connected to one another by complementary closure mechanisms that provide a secure and easy to establish connection between the closure member and the body member.

[0085] More specifically, the closure mechanism may include a first snap portion protruding from the second wall of the body member for face-to-face interaction with a second snap portion protruding from the second wall of the cover member. When closing the pharmaceutical carrier, i.e., when connecting the cover member to the body member, at least one of the first and second snap portions may be elastically deformed. When the cover member and the body member reach their final relative positions, i.e., when the cover member is placed on top of the body member to seal the interior of the body member as desired, the elastic deformation of at least one of the first and second snap portions may be released such that the snap portions are intact with each other so that the cover member and the body member are securely connected.

[0086] For example, the first snap portion may include a protrusion configured to engage with a corresponding protrusion on the second snap portion to resist separation of the first snap portion and the second snap portion, and thus separation of the lid member and the body member. In particular, the protrusion of the first snap portion may include a first abutment surface facing the body member, the first abutment surface being configured to abut against a second abutment surface formed on the second snap portion and to face the lid member when the body member and the lid member are connected to each other. The first abutment surface formed on the first snap portion may extend at an angle of 90 to 150° relative to a sidewall portion of the body member. The second abutment surface formed on the second snap portion may extend at an angle of 90 to 150° relative to a sidewall portion of the lid member.

[0087] The protrusion on the first snap part can be tapered toward the free end of the first snap part to form a first inclined engagement surface. The first inclined engagement surface can be configured to engage with a second inclined engagement surface of the second snap part, tapered toward the free end, formed on the protrusion on the second snap part. When the cap of the pharmaceutical carrier is connected to the body member, the second inclined engagement surface can slide along the first inclined engagement surface, thus guiding the protrusion on the first snap part to engage with the corresponding protrusion on the second snap part. This simplifies the connection of the cap to the body member.

[0088] One of the first and second snap parts can protrude from the second wall part of the lid part or the body part into the inner peripheral region of the second wall part, and in that case the other of the first and second snap parts can protrude from the second wall part of the lid part or the body part into the outer peripheral region of the second wall part of the body part. Preferably, the first snap part provided on the body part of the pharmaceutical carrier extends from the second wall part of the body part into the inner peripheral region of the second wall part. The first snap part designed in this way is particularly suitable for interacting with a second snap part protruding from the second wall part of the lid part, in particular a shoulder or corner shaped second wall part, into the outer peripheral region of the second wall part of the lid part.

[0089] The closure mechanism may further comprise an internal rib protruding from the second wall of the cap or body member into an inner peripheral region of the second wall, the internal rib being spaced apart from a first or second snap portion protruding from the second wall of the cap or body member into an outer peripheral region of the second wall. In particular, the closure mechanism may comprise an internal rib protruding from the second wall of the cap into an inner peripheral region thereof, and thus spaced apart from a second snap portion protruding from the second wall of the cap, in particular a shoulder or corner-shaped second wall of the cap, into an outer peripheral region thereof. As a result, the internal rib and the second snap portion define a gap therebetween that is configured to receive the first snap portion when the cap and body members of the pharmaceutical carrier are coupled to each other. When the cover member and the body member are connected, the first snap portion is positioned at a predetermined position in the gap between the internal rib and the second snap portion by interacting with the second snap portion, i.e., in particular by interacting between the first mating surface formed on the first snap portion and the second mating surface formed on the second snap portion, and at the same time, the internal rib provides further mechanical stability and rigidity to the closure mechanism.

[0090] However, it is also envisaged that the body member of the pharmaceutical carrier may be provided with an internal rib, in particular when the first snap portion provided on the body member projects from the second wall of the body member to its outer circumferential region and is adapted to interact with the second snap portion projecting from the second wall of the cover member to its inner circumferential region, in which case the internal rib and the first snap portion may define a gap therebetween adapted to receive the second snap portion when the cover member and the body member of the pharmaceutical carrier are connected to one another.

[0091] Preferably, the internal rib is shorter than the snap portion arranged on the opposite side of the internal rib. In other words, preferably, the snap portion, together with the internal rib, defines a gap for accommodating the other snap portion protruding from the second wall portion of the cover member or the body member farther than the internal rib. Furthermore, the internal rib may be tapered toward the free end of the internal rib to form a third inclined engagement surface, which protrudes from the second wall portion of the cover member or the body member to the outer peripheral region of the second wall portion and thus faces the first or second snap portion arranged to face the internal rib. Preferably, the third inclined engagement surface provided on the internal rib extends substantially parallel to the abutting surface provided on the protruding portion of the snap portion arranged on the opposite side of the internal rib. In this way, when the cover member and the body member of the pharmaceutical carrier are connected, the snap portion configured to be accommodated in the gap defined between the internal rib and the snap portion arranged on the opposite side of the internal rib is guided to engage with the snap portion arranged on the opposite side of the internal rib. Additionally, the internal ribs stabilize the snap closure and prevent it from opening.

[0092] In a preferred embodiment of the pharmaceutical carrier, the first wall of the closure is provided with a recess, particularly in the area defined by the point where the material is injected into the mold during the closure's manufacture. The wall thickness of this recess may be greater than the wall thickness of the remaining part of the first wall, but less than the wall thickness of the second wall of the closure. For example, the recess may be located in the central area of ​​the top of the closure. During the injection molding process in a multi-cavity mold, a symbol indicating the cavity in which the closure is molded may be engraved on the surface, particularly on the inner surface of the recess. This allows automatic sorting of the closures by cavity for applications requiring strict weight uniformity.

[0093] Alternatively or additionally, a recess is provided in the first wall of the body member, in particular in the area defined by the point where material is injected into the mould during manufacture of the body member. The wall thickness of this recess may be greater than the wall thickness of the remaining part of the first wall, but less than the wall thickness of the second wall of the closure member. For example, the recess may be located in the central area of ​​the bottom of the body member. During the injection moulding process in a multi-cavity mould, a symbol indicating the cavity in which the body member is moulded may be engraved on the surface, in particular on the inner surface of the recess. This allows automatic sorting of the body members by cavity for applications where strict weight uniformity is required.

[0094] At least one of the lid member and the body member may be provided with a plurality of internal protrusions in its inner surface region, which protrude radially inwards from the inner surface of the second wall and / or from the inner surface of the internal rib. If the lid member or body member provided with the internal protrusions is also provided with an internal rib, the internal protrusions may extend from the top of the lid member or from the bottom of the body member in the direction of the central axis of the lid member or body member, along the second wall of the lid member of the body member, and finally along the internal rib protruding from the second wall to its inner peripheral region. If the lid member of the body member provided with the internal protrusions does not include an internal rib, the internal protrusions may extend from the top of the lid member or from the bottom of the body member in the direction of the central axis of the lid member or body member, along the second wall of the lid member or body member. At least one of the internal protrusions, in particular each, may include a protruding nose protruding beyond the second wall and / or the internal rib.

[0095] The internal protrusions, especially when provided with protruding noses, reduce the phenomenon known as "nesting", i.e., the sticking together of stacked members and / or body members, thereby eliminating problems during manual or automated handling that can be caused by "nesting" of stacked members that are difficult to separate.

[0096] In a preferred embodiment of the pharmaceutical carrier, the body member is provided with an angled overhang. The angled overhang can be formed on an outer surface area of ​​the second wall of the body member, particularly in an area adjacent to the first snap portion. The angled overhang can be inclined radially outward from the outer periphery of the first snap portion to the outer surface of the second wall. When filling or closing the pharmaceutical carrier, powdered compound to be filled in the pharmaceutical carrier that unintentionally falls onto the overhang of the body member can be easily removed.

[0097] An exemplary pharmaceutical carrier 20 is shown in Figures 5, 6A, and 6B. The carrier 20 includes a cap member 22 and a body member 24. The cap member 22 shown on the left side of Figure 5 and in Figure 6A includes a first wall portion 26 that defines the top of the cap member 22 and a second wall portion 28 that defines a side wall portion of the cap member 22. In particular, the second wall portion 28 of the cap member 22 defines a shoulder or corner of the cap member 22 that is disposed adjacent to the top of the cap member 22. Specifically, the second wall portion 28 of the cap member 22 extends from the top of the cap member 22 along its periphery toward the body member 24. The wall thickness of the first wall portion 26 is thinner than the wall thickness of the second wall portion 28. In a preferred embodiment of the carrier 20 shown in Figure 5, the wall thickness of the first wall portion 26 is 190-220 μm, while the wall thickness of the second wall portion 28 is about 400 μm.

[0098] Similarly, the body member 24 shown on the right side of Fig. 5 includes a first wall portion 30 that defines the bottom of the body member 24 and a second wall portion 32 that defines a side wall portion of the body member 24. The second wall portion 32 of the body member 24 extends from the bottom of the body member 24 along its outer periphery toward the cover member 22. The wall thickness of the first wall portion 30 is thinner than the wall thickness of the second wall portion 32. In a preferred embodiment of the carrier 20 shown in Fig. 5, the wall thickness of the first wall portion 30 is 190 to 220 µm, while the wall thickness of the second wall portion 32 is about 400 µm.

[0099] The closure member 22 and the body member 24 are connected to each other by a complementary closure mechanism 34, which is illustrated in detail in the detailed views of Figures 5 and 6B. The closure mechanism 34 comprises a first hook-shaped snap portion 36 projecting from the second wall 32 of the body member 24 into the inner peripheral region of the second wall 32. The first hook-shaped snap portion 36 interacts face-to-face with a correspondingly shaped second hook-shaped snap portion 38 projecting from the second wall 28 of the closure member 22 into the outer peripheral region of the second wall 28. However, it would also be conceivable for the closure mechanism 34 to have a first snap portion 36 projecting from the second wall 32 of the body member 24 into the outer peripheral region of the second wall 32 and a second snap portion 38 projecting from the second wall 28 of the closure member 22 into the inner peripheral region of the second wall 28.

[0100] As can be seen from the detailed views shown in Figures 5 and 6B, the first snap portion 36 includes a protrusion 37 that is configured to engage with a corresponding protrusion 39 provided on the second snap portion 38 when the lid member 22 and the body member 24 are connected. The protrusion 37 of the first snap portion 36 includes a first abutment surface 41 that faces the body member 24. Similarly, the protrusion 39 of the lid member 22 includes a second abutment surface 43 that faces the lid member 22. The first abutment surface 41 formed on the protrusion 37 of the first snap portion 36 extends at an angle of approximately 135° to the side wall portion of the body member 24. The second abutment surface 43 formed on the protrusion 39 of the second snap portion 38 extends at an angle of approximately 135° to the side wall portion of the lid member 22. Furthermore, the protrusion 37 provided on the first snap part 36 tapers toward the free end of the first snap part 36 so as to form a first inclined engagement surface 45. Similarly, the protrusion 39 provided on the second snap part 38 tapers toward the free end of the first snap part 36 so as to form a second inclined engagement surface 47.

[0101] The closure mechanism 34 further includes an internal rib 40 that protrudes from the shoulder or corner-shaped second wall portion 28 of the capping member 22 to an inner peripheral region of the second wall portion 28. The internal rib 40 thus protrudes from the second wall portion 28 of the capping member 22 and is spaced apart from the second snap portion 38 that protrudes from the second wall portion 28 of the capping member 22 to an outer peripheral region of the second wall portion 28. In this manner, the internal rib 40 and the second snap portion 38 define a gap therebetween that is configured to receive the first snap portion 36 when the capping member 22 and the body member 24 of the pharmaceutical carrier 20 are coupled together. However, it is also envisaged that the closure mechanism 34 may include an internal rib 40 protruding from the second wall 32 of the body member 24 to the internal periphery of the second wall 32, if the lid member 22 is provided with a second snap portion 38 arranged in an inner peripheral region of the second wall 28, which second snap portion 38 is adapted to interact with a first snap portion 36 arranged in an outer peripheral region of the second wall 32 of the body member 24. In that case, the first snap portion 36 together with the internal rib 40 defines a gap configured to receive the second snap portion 38 when the lid member 22 and the body member 24 of the pharmaceutical carrier 20 are connected to one another.

[0102] The inner rib 40 is shorter in length than the second snap portion 38 located on the opposite side of the inner rib 40, i.e., the second snap portion 38 protrudes farther from the second wall portion 28 of the cover member 22 than the inner rib 40. Furthermore, the inner rib 40 tapers toward the free end of the inner rib 40 to form a third inclined engagement surface 49, which faces the second snap portion 38 protruding from the second wall portion 28 of the cover member 22 to the outer peripheral region of the second wall portion 28 on the opposite side of the inner rib 40. The third inclined engagement surface 49 extends substantially parallel to the second abutment surface 43 provided on the protruding portion 39 of the second snap portion 38 located on the opposite side of the inner rib 40. When the cover member 22 is provided with a second snap portion 38 arranged in the inner peripheral region of the second wall portion 28, and the second snap portion 38 is configured to interact with the first snap portion 36 arranged in the outer peripheral region of the second wall portion 32 of the body member 24, the third inclined engagement surface 49 formed on the inner rib 40 can face the first snap portion 36, which protrudes from the second wall portion 32 of the body member 24 to the outer peripheral region of the second wall portion 32 so as to face the inner rib 40.

[0103] When the pharmaceutical carrier 20 is closed, i.e., when the cover member 22 is connected to the body member 24, the first inclined engagement surface 45 provided on the protrusion 37 of the first snap portion 36 comes into contact with the second inclined engagement surface 47 provided on the protrusion 39 of the second snap portion 38. When the cover member 22 approaches the body member 24, the second inclined engagement surface 47 slides along the first inclined engagement surface 45, resulting in slight elastic deformation of the first and second snap portions 36, 38. Specifically, the first snap portion 36 bends slightly inward in a radial direction, while the second snap portion 38 bends slightly outward in a radial direction. However, the inward bending of the first snap portion 36 is restricted by the inner rib 40. Furthermore, the third inclined engagement surface 49 provided on the inner rib 40 guides the second snap portion 38 to its final position, which is the gap defined between the second snap portion 38 and the inner rib 40. Please refer to Figure 6B.

[0104] When the lid member 22 and the body member 24 reach their final relative positions, i.e., when the lid member 22 is placed on the top of the body member 24 to seal the inside of the body member 24, the elastic deformation of the first and second snap portions 36, 38 is released, and the first abutting surface 41 provided on the protrusion 37 of the first snap portion 36 abuts against the second abutting surface 43 provided on the protrusion 39 of the second snap portion 38. The interaction of the first and second abutting surfaces 41, 43 results in the separation of the body member 24 and the lid member 22. The internal rib 40 increases the mechanical stability and rigidity of the closure mechanism 34.

[0105] The first wall 26 of the lid member 22 is provided with a recess 42 in a central region defined by a point where material is injected into a mold when the lid member 22 is manufactured, the wall thickness of the recess 42 being thicker than the wall thickness of the remaining part of the first wall 26, but still thinner than the wall thickness of the second wall 28 of the lid member 22. The inner surface of the recess 42 is stamped with a number (the number "1" in the drawing), which indicates a cavity when the lid member 22 is molded in a multi-cavity mold. Similarly, the first wall 30 of the body member 24 is provided with a recess 44 in a central region defined by a point where material is injected into a mold when the body member 24 is manufactured, the wall thickness of the recess 42 being thicker than the wall thickness of the remaining part of the first wall 30, but still thinner than the wall thickness of the second wall 32 of the body member 24. On the inner surface of the recess 44, a number (not shown) is stamped which indicates the cavity when the body member 24 is molded in a multi-cavity molding die.

[0106] As can be seen in FIG. 6A, the lid member 22 is further provided with a plurality of internal protrusions 46 projecting radially inward from the inner surface of the second wall portion 28 and from the inner surface of the inner rib 40, respectively. In the particular embodiment of the lid member 22 shown in the figures, three internal protrusions 46 are provided. However, it is also envisaged to provide the lid member 22 with less than or more than three internal protrusions 46. The internal protrusions 46 serve to prevent jamming of the stacked members 22 during handling. The internal protrusions 46 each include a nose 48 projecting from the inner rib 40, which further reduces the risk of jamming of the stacked members 22. In the embodiment of the carrier 20 illustrated in the figures, only the lid member 22 is provided with the internal protrusions 46. However, it is also envisaged to provide the body member 24 of the carrier 20 with the internal protrusions described herein, alternatively or additionally.

[0107] Finally, as can be seen in Fig. 6B, the body member 24 is provided with an angled overhang 50 formed in the outer surface area of ​​the second wall portion 32 adjacent to the first hook-shaped snap portion 36, the overhang 50 being inclined radially outward from the outer periphery of the hook-shaped snap portion 38 towards the outer surface of the second wall portion 32. Powder that unintentionally falls onto the overhang 50 when closing the carrier 20 can be easily removed.

[0108] Advantageously, the standard deviation of the mass of each component of the pharmaceutical carrier is less than 1 mg, preferably less than 0.8 mg, more preferably less than 0.6 mg, even more preferably less than 0.4 mg, even more preferably less than 0.3 mg, even more preferably less than 0.2 mg, and most preferably less than 0.1 mg.

[0109] The present invention will be further described with reference to the following embodiments.

[0110] 1. (a) The following parameters (i) to (viii) were determined using an FT4 powder rheometer: (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) wall friction angle (WFA) up to 40°; providing an active pharmaceutical ingredient (API) that meets at least five of the following criteria: (b) dispensing the API of step (a) into a body member of a pharmaceutical carrier using a vacuum assisted metering and filling device; (c) covering the body member of the pharmaceutical carrier with a complementary cover member of the pharmaceutical carrier, thereby producing a pharmaceutical product; A method for preparing a pharmaceutical product comprising:

[0111] 2. (i) sBFE is at most 25 mJ / g, in particular at most 6 mJ / g, and / or (ii) SI is between 0.83 and 1.18, in particular between 0.9 and 1.1, and / or (iii) SE is at most 8 mJ / g, in particular at most 6 mJ / g, and / or (iv) MPS-15 is at most 33, in particular at most 25, and / or (v) FF-15 is at least 3, in particular at least 10, and / or (vi) CBD-15 is at least 0.45 g / mL, in particular at least 0.6 g / mL; and / or (vii) a compression ratio of at most 35%, in particular 3% to 15%, and / or (viii) WFA is up to 34°, and in particular up to 28° 2. The method of embodiment 1, wherein

[0112] 3. Parameters (i) to (viii) are determined using the FT4 powder rheometer and the powder characterization method per cylinder diameter measured; (i)25mm_1C_Split_Rep+VFR_R01, (ii) 25mm_Shear_15kPa, (iii) 25mm_Compressibility_1-15kPa, and (iv) 25mm_Wall Friction_30kPa 3. The method of claim 1 or 2, wherein the determination is made by using

[0113] 4. The method according to any one of the preceding claims, wherein the vacuum assisted measuring and filling device is a rotatable drum (10).

[0114] 5. The method of embodiment 4, wherein a vacuum is applied in the drum cavity at -100 to -800 mBar and / or the API is dispensed at a discharge pressure of 100 to 1500 mBar.

[0115] 6. The method of embodiment 4 or 5, wherein the vacuum assisted measuring and filling device is a rotatable drum (10) and is equipped with either a stirrer or a sonic / ultrasonic device to assist in measuring and dispensing the API.

[0116] 7. The method of embodiment 6, wherein the vacuum assisted measuring and filling device is equipped with a stirrer, and the stirrer is set to 1 to 4 revolutions per cycle.

[0117] 8. The method according to embodiment 6, wherein the vacuum assisted measuring and filling device comprises a sonic / ultrasonic device, in particular a pogo or pole, which pushes and breaks micro-bridging of the powder entering the cavity of the rotatable drum, in particular the pogo or pole applies a vibration frequency between 10000 Hz and 180,000 Hz, preferably about 22,000 Hz.

[0118] 9.(i) If the MPS-15 is less than or equal to 28 and / or the WFA is less than or equal to 31, the API is suitable for use in conjunction with a vacuum-assisted measuring and filling device that comprises a sonic / ultrasonic device to assist in measuring and dispensing the API; The method of any one of embodiments 6 to 8, wherein (ii) if the SI is greater than 1.1, the API is not suitable for use with a vacuum-assisted measuring and filling device comprising a stirrer to assist in measuring and dispensing the API.

[0119] 10. The method according to any one of embodiments 4 to 8, wherein the vacuum-assisted measuring and filling device comprises a powder trough equipped with a fluidization device, in particular an acoustic speaker, and furthermore an ultrasonic transducer.

[0120] 11. The method according to embodiment 10, wherein the feeding is from a vibrating hopper to the powder trough, the hopper being actuated towards the powder trough, preferably by a sensor, in particular a capacitive sensor.

[0121] 12. The method according to embodiment 11, wherein the feeding is carried out from a hopper to the powder trough, each equipped with an acoustic device, using a vibration frequency of 100 to 1000 Hz, the hopper being actuated towards the powder trough preferably by a sensor, in particular a capacitive sensor.

[0122] 13. The method of any one of the preceding embodiments, wherein the dose of API is gravimetrically checked using fill weight measurement technology.

[0123] 14. The method according to embodiment 13, wherein the dose of API is gravimetrically checked in real time using a capacitance sensor and / or a microwave sensor (16), in particular by using a capacitance sensor.

[0124] 15. The method of embodiment 14, wherein the sensor (16) has a root mean square error of prediction (RMSP) relative to an analytical control tool such as an HPLC or balance of less than 5%, preferably less than 4.5%, more preferably less than 4%, and most preferably less than 3.5%.

[0125] 16. The method of embodiment 13, wherein the dose of API is gravimetrically checked offline using a Brut-Tara balance.

[0126] 17. The method according to any one of the preceding embodiments, wherein the API comprises at most 5% (w / w), preferably at most 4% (w / w), more preferably at most 3% (w / w), even more preferably at most 2% (w / w), and most preferably at most 1% (w / w) of an additive.

[0127] 18. The method of embodiment 17, wherein the one or more additives are selected from the group of hydrophobic colloidal silicon dioxide, hydrophilic colloidal silicon dioxide, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer 188, hydrogenated vegetable oil, or any combination thereof.

[0128] 19. The method of any one of the preceding embodiments, wherein step (a) further comprises sieving the API, the sieving being selected from sieving through a conical sieving device, vibratory sieving, or screen sieving assisted by ultrasonic vibration.

[0129] 20. The method according to any one of the preceding embodiments, wherein the dosage of API in step (b) is in the range of 0.1 mg to 550 mg, preferably 0.2 mg to 500 mg, and most preferably 0.25 mg to 450 mg.

[0130] 21. The method according to any one of the preceding embodiments, wherein the dosage of API in step (b) has a relative standard deviation (RSD) of less than 5%, preferably less than 4%, more preferably less than 3%.

[0131] 22. The method according to any one of the preceding embodiments, wherein the API is concentrated within the body member of the pharmaceutical carrier prior to step (c) by vibration, shaking, or tapping.

[0132] 23. The method according to any one of embodiments 1 to 22, wherein at least one of the cover member (22) and the body member (24) of the pharmaceutical carrier (20) has a first wall portion (26, 30) having a thickness of 180 to 250 μm, preferably 185 to 225 μm, and even more preferably 190 to 220 μm, and a second wall portion (28, 32) having a thickness of 350 to 450 μm, preferably 375 to 425 μm, more preferably 390 to 410 μm, and most preferably about 400 μm.

[0133] 24. The cover member (22) and the body member (24) are connected to each other by a complementary closure mechanism (34); In particular, the closure mechanism (34) includes a first snap portion (36) protruding from the second wall portion (32) of the body member (24) to face and interact with a second snap portion (38) protruding from the second wall portion (28) of the lid member (22); In particular, the first snap portion (36) includes a protrusion (37) adapted to engage a corresponding protrusion (39) provided on the second snap portion (38) to prevent separation of the first snap portion (36) and the second snap portion (38), and thus separation of the lid member (22) and the body member (24); More particularly, the protrusion (37) provided on the first snap part (36) tapers towards the free end of the first snap part (36) to form a first inclined engagement surface (45) adapted to engage with a second inclined engagement surface (47) formed on a protrusion (39) provided on the second snap part (38) which tapers towards the free end of the second snap part (36); Most preferably, one of the first snap portion and the second snap portion (36, 38) protrudes from the second wall portion (28, 32) of the cover member (22) or the body member (24) within an inner peripheral region of the second wall portion (28, 32), and the other of the first snap portion and the second snap portion (36, 38) protrudes from the second wall portion (28, 32) of the cover member (22) or the body member (24) within an outer peripheral region of the second wall portion (28, 32). The method according to any one of embodiments 1 to 23.

[0134] 25. The closure mechanism (34) further includes an internal rib (40) protruding from the second wall portion (28) of the lid member (22) or the body member (24) to an inner peripheral region of the second wall portion (28, 32), the internal rib (40) being spaced apart from the first or second snap portion (36, 38) protruding from the second wall portion (28, 32) of the lid member (22) or the body member (24) to an outer peripheral region of the second wall portion (28, 32); In particular, the inner rib (40) tapers toward the free end of the inner rib (40) to form a third inclined engagement surface (49), which faces a first or second snap portion (36, 38) protruding from the second wall portion (28, 32) of the cover member (22) or body member (24) to an outer peripheral region of the second wall portion (28, 32).

[0135] 26. The method according to any one of embodiments 1 to 25, wherein the body member (24) is provided with an angled overhang (50) formed on an outer surface region of the second wall portion (32) of the body member (24), particularly adjacent to the first snap portion (36), and the overhang (50) slopes outwardly radially, particularly from the outer periphery of the first snap portion (36) toward the outer surface of the second wall portion (32).

[0136] 27. Use of the method according to any one of embodiments 1 to 26 in a continuous process.

[0137] 28. Use of the method according to any one of embodiments 1 to 26 in a high throughput process for the manufacture of a pharmaceutical product.

[0138] The present invention as defined in the following embodiments will be further illustrated by the following examples, which are not intended to limit the scope of the present invention. All references cited herein are expressly incorporated by reference herein as part of this specification. EXAMPLES

[0139] The standard FT4 Powder Rheometer offers at least six powder characterization methods (per measurement cylinder diameter). The ones selected for analysis are: 25mm_1C_Split_Rep+VFR_R01, 25mm_Shear_15kPa, 25mm_Compressibility_1-15kPa, 25mm_Wall Friction_30kPa.

[0140] Each characterization method produces several response parameters (default or manually selectable). A complete set of powder characterizations (at least 22 response parameters per row) was measured for over 350 different powders and over 60 different compounds using a standard FT4 powder rheometer and compiled into a database. Various parameters were correlated to each packing behavior in order to determine a set of parameters and parameter ranges that can identify and predict the packing behavior of the powders. The following 8-parameter model was obtained:

[0141] [Table 2]

[0142] The parameters are as follows. sBFE: Specific Basic Flow Energy (mJ / g): Obtained by dividing the BFE (obtained from a standard FT4 testing platform) by the fractional mass of the sample. SI: Stability index, standard variable, dimensionless. SE: Specific energy (mJ / g), standard variable MPS@15kPa: Maximum principal stress, standard variable FF@15kPa: Stream function (dimensionless), by shear cell, standard variables CBD@15kPa: Bulk density after compression (g / mL), standard variable (by shear cell) CPS: Compression ratio (%), standard variable WFA: Wall friction angle (deg), standard variable.

[0143] If four of the parameters are outside the indicated ranges, the powder is expected to be borderline in terms of manufacturability. If more than four of the parameters are outside the indicated ranges, the powder described here as pure API is probably and practically not processable in any automated machine. Furthermore, it has been found that if the MPS is very high and, to a lesser extent, the WFA is also high, the powder is prone to accumulate in the filling and feeding device. This is a negative property of the sonic / ultrasonic filling technique. On the other hand, if the SI is too high, the powder changes its properties over time and the powder becomes more sensitive to shear forces. Such powders are less processable in standard vacuum drum filling techniques using stirrers.

[0144] The "8-parameter model" found is able to identify and predict the filling behavior of powders in the database and at least 40% of the powders have reported experimental responses / scores in a capsule filling facility. The following cases demonstrate the ability of the 8-parameter model to predict and drive the development of powders suitable for supply as pure API. Numbers in bold are outside the desired range.

[0145] [Table 3]

[0146] Most of these powders are described in the Examples below.

[0147] Example 1 Mass production of pharmaceutical products containing LEE011 was required from the early stages of the development life cycle of such compound. Several batches of API were crystallized, sieved and filled into capsules by equipment platforms using both types of vacuum drum equipment described here, namely standard and sonic filling machines. Although the filling performance of most of the powder types used was quite good, especially in terms of dose uniformity (dose range 10-250 mg), the powder behavior / flowability in the machine hopper and the occurrence of friction between the moving parts were challenging aspects that, on average, caused some challenges and process downtimes during very long runs. While the standard filling technique was able to address such inherent challenges associated with LEE011 powder, especially after some optimization (several million capsule units were successfully filled), the sonic filling technique showed important manifestations of process downtimes and parts breakages due to the accumulation of powder in the powder trough, especially when the MPS parameters were measured to be particularly high. The "8-parameter model" could advise against choosing sonic filling of powders with simultaneously high MPS and WF. However, in one example (6.) it was possible to fill despite these values.

[0148] Example 2 Filling of pure API at a specific throughput suitable for manufacturing large batches is not generally established in the industry. For API LXS196, particle characteristics and filling process have been developed in an integrated manner. The method described allowed the production of LXS196 capsules for clinical supply with a throughput of more than 40,000 capsules within 6 hours. The percentage of good capsules out of the total number of capsules produced was 98.8%. A simplified manufacturing process was realized by only performing sieving and encapsulation of the pure API (including 100% weight control by capacitive sensor, dust removal and metal inspection). Similarly, doses up to 400 mg were filled into capsule size 0. Furthermore, doses above 450 mg were encapsulated in an automated drum filling facility by applying an in-house developed high dose technology (tapping mechanism).

[0149] Example 3 The delivery of powders containing sub-milligram quantities of API is the state of the art for capsule filling. To overcome the difficulties, in herbal medicine development, the standard process for low-dose formulations explains that the API is mixed and diluted with excipients within a serval mixing step, thus allowing the final delivery of a few milligrams of diluted blend to the capsule. The same applies to machines equipped with capacitive sensors for mass inspection, which are typically used in capsule filling starting from a minimum of a few milligrams and above.

[0150] The method described herein allows to process pure API of FTY720 containing less than 1% excipients (>99% API) with optimal physical properties suitable for precision capsule filling at very low doses such as 0.5 and 0.25 mg using process analytical technology with 100% fill mass confirmation corresponding to 100% content uniformity testing, introduced for the first time in the sub-milligram range. Furthermore, the disclosed method presents a very simple process compared to the current commercial formulations where several process steps (i.e. several sieving-mixing passes to gradually dilute the blend) are used.

[0151] The final drug product also exhibited a longer shelf life than the corresponding commercial formulation because only two components (silicon dioxide and gelatin) are in direct contact with the drug substance.

[0152] Example 4 NBU928 is a fumarate salt with a difficult crystallization process. The resulting particles typically have an elongated aspect ratio, with the crystals being strip-like up to 400 μm long, and with a strong tendency to agglomerate. Such kind of crystal shape makes the resulting powder bulky, which cannot be directly processed in any capsule filling equipment. Therefore, this API powder was subjected to a particle engineering process to selectively grow the shot side of the crystals, and then crushed by pin mill equipment to obtain very regular pieces, with more stable aspect ratio, no agglomeration, and smaller particles with an average diameter (X50) of about 25 μm. The rheological properties of the freshly milled API powder (Lot No. NBU928-metzgch4-001-03) suggest a difficult processability in standard PDP filling technology (expected powder bridging in the hopper under the action of the shear force of the stirrer due to certain instabilities in the bulk aeration level), but perfect processability in sonic filling machine vacuum drum equipment. Indeed, very good capsule filling performance was obtained in the required dose range of 5-50 mg.

[0153] Reference example 5 CDZ173 is a monophosphate compound. It is characterized by needle-like crystals with an aspect ratio of more than 10, aggregated / fused rod-like crystals, and very low bulk density (always less than 0.2 g / mL, frequently less than 0.12 g / mL). CDZ173 is reported here in two different varieties (milled and unmilled). Line 6 is borderline packable (at very low speed / throughput) even though its properties were outside the parameters of our model (4 / 8 of the criteria were met), while line 7 material could not be packed with the processing method of the present disclosure unless a significant change in crystallization was pursued (not described here). It should be noted that the present invention includes the following aspects. [Aspect 1] (a) The following parameters (i) to (viii) were determined using an FT4 powder rheometer: (i) Specific Basic Flow Energy (sBFE) of at most 60 mJ / g; (ii) stability index (SI) between 0.75 and 1.25; (iii) specific energy (SE) up to 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a stream function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) wall friction angle (WFA) up to 40°; providing a pure active pharmaceutical ingredient (API) that meets at least five of the following criteria: (b) dispensing the pure API of step (a) into a pharmaceutical carrier body member using a vacuum assisted measuring and filling device; (c) covering the body member of the pharmaceutical carrier with a complementary cover member of the pharmaceutical carrier, thereby producing a pharmaceutical product; A method for preparing a pharmaceutical product comprising: [Aspect 2] 2. The method of claim 1, wherein at least one of the parameters is selected from parameters (i)-(iii) and at least one of the parameters is selected from parameters (iv)-(vi). [Aspect 3] 3. The method of embodiment 2, wherein at least one of the parameters is parameter (i) or parameter (iii), and at least one of the parameters is parameter (iv) or parameter (v). [Aspect 4] The method of any one of aspects 1 to 3, wherein at least one of the parameters is parameter (vii) or parameter (viii). [Aspect 5] The method of any one of aspects 1 to 4, wherein the pharmaceutical agent is in an oral dosage form. [Aspect 6] 6. The method of any one of aspects 1-5, wherein the vacuum assisted measuring and filling device is a rotatable drum. [Aspect 7] the vacuum assisted measuring and filling device is a rotatable drum and is equipped with either a stirrer or a sonic / ultrasonic device to assist in measuring and dispensing the API; If the vacuum assisted measuring and filling device includes a stirrer, the stirrer is set to 1 to 4 revolutions per cycle; If the vacuum assisted measuring and filling device comprises an ultrasonic device which is a pogo or pole to push and break micro-bridging of the powder entering the cavity of the rotatable drum, the pogo or pole applies a vibration frequency of 10,000 Hz to 180,000 Hz; The method according to embodiment 6. [Aspect 8] 8. The method of claim 6 or 7, wherein the vacuum assisted measuring and filling device comprises a powder trough equipped with a fluidizing device and an ultrasonic transducer. [Aspect 9] 9. The method of embodiment 8, wherein feeding is from a vibrating hopper to a powder trough, the hopper being actuated by a sensor toward the powder trough. [Aspect 10] 9. The method according to claim 8, wherein the feeding is performed using a vibration frequency of 100-1000 Hz from a hopper to a powder trough, each of which is equipped with an acoustic device, and the hopper is preferably actuated by a sensor towards the powder trough. [Aspect 11] 11. The method according to any one of the preceding aspects, wherein the pure API comprises up to 5% (w / w) of an additive. [Aspect 12] 12. The method according to any one of the preceding aspects, wherein the dosage of said pure API in step (b) is in the range of 0.1 mg to 550 mg. [Aspect 13] 13. The method of claim 12, wherein the dose of pure API in step (b) has a root-square deviation (RSD) of less than 5%. [Aspect 14] Aspect 14. The method of any one of aspects 1-13, wherein the pure API is concentrated within the body member of the pharmaceutical carrier prior to step (c) by vibration, shaking, or tapping. [Aspect 15] 15. The method of any one of embodiments 1 to 14, which is a continuous process.

Claims

1. A method for preparing a pharmaceutical product, comprising: (a) The following parameters (i) to (viii) determined by use of an FT4 powder rheometer: (i) a specific basic flow energy (sBFE) of at most 60 mJ / g; (ii) a stability index (SI) of 0.75 to 1.25; (iii) a specific energy (SE) of at most 10 mJ / g; (iv) maximum principal stress at 15 kPa (MPS-15) is up to 40; (v) a flow function at 15 kPa (FF-15) of at least 1.3; (vi) a bulk density after compression at 15 kPa (CBD-15) of at least 0.26 g / mL; (vii) compression ratio of up to 47%; and (viii) Wall Friction Angle (WFA) up to 40°; providing an active pharmaceutical ingredient (API) that meets at least five of the following criteria: (b) dispensing the API of step (a) into a body member of a pharmaceutical carrier using a vacuum assisted metering and filling device; (c) covering the body member of the pharmaceutical carrier with a complementary cap member of the pharmaceutical carrier, thereby producing a pharmaceutical product; Including, the pharmaceutical product is an oral dosage form, and at least one of the parameters is parameter (vii); said API comprising up to 5% (w / w) of additives; 13. A method for preparing a pharmaceutical product, wherein the specific basic flow energy (sBFE) of parameter (i) is less than or equal to 29 mJ / g when dispensing the API in step (b) is performed using a vacuum assisted measuring and filling device equipped with an ultrasonic device to assist in measuring and dispensing the API, and the API complies with parameters (i) and (vii) and at least three of parameters (ii)-(vi) and (viii).

2. The method of claim 1 , wherein at least one of the parameters is selected from parameters (i)-(iii) and at least one of the parameters is selected from parameters (iv)-(vi).

3. The method of claim 2 , wherein at least one of the parameters is parameter (i) or parameter (iii), and at least one of the parameters is parameter (iv) or parameter (v).

4. The method of any one of claims 1 to 3, wherein at least one of said parameters is parameter (viii).

5. The method according to any one of claims 1 to 4, wherein the vacuum assisted measuring and filling device is a rotatable drum.

6. the vacuum assisted measuring and filling device is a rotatable drum and is equipped with either a stirrer or a sonic / ultrasonic device to assist in measuring and dispensing the API; If the vacuum assisted measuring and filling device includes a stirrer, the stirrer is set at 1 to 4 revolutions per cycle; If the vacuum assisted measuring and filling device comprises an ultrasonic device which is a pogo or pole to push and break micro-bridging of the powder entering the cavity of the rotatable drum, the pogo or pole applies a vibration frequency between 10,000 Hz and 180,000 Hz. The method according to claim 5.

7. The method according to claim 5 or 6, wherein the vacuum assisted measuring and filling device comprises a powder trough equipped with a fluidizing device and an ultrasonic transducer.

8. 8. The method of claim 7, wherein feeding is from a vibrating hopper to a powder trough, said hopper being sensor actuated towards said powder trough.

9. 8. The method according to claim 7, wherein the feeding is performed using a vibration frequency of 100-1000 Hz from a hopper to a powder trough, each equipped with an acoustic device, said hopper being actuated towards said powder trough, preferably by a sensor.

10. 10. The method according to any one of claims 1 to 9, wherein the dose of said API in step (b) is in the range of 0.1 mg to 550 mg.

11. 11. The method of claim 10, wherein the dose of API in step (b) has a root-square deviation (RSD) of less than 5%.

12. The method of any one of claims 1 to 11, wherein the API is massed within the body member of the pharmaceutical carrier prior to step (c) by vibration, shaking or tapping.

13. The method according to any one of claims 1 to 12, which is a continuous process.

14. the vacuum assisted measuring and filling device is a rotatable drum and is equipped with either a stirrer or a sonic / ultrasonic device to assist in measuring and dispensing the API; (1) when the vacuum assisted measuring and filling device comprises a stirrer, the API of step (a) meets parameter (ii) and at least four of parameters (i) and (iii)-(viii); (2) The method of any one of claims 1 to 13, wherein when the vacuum assisted measuring and filling device comprises a sonic / ultrasonic device, the API of step (a) complies with parameters (iv) and (viii) and complies with at least three of parameters (i)-(iii) and (v)-(vii).

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