Novel amorphous active pharmaceutical ingredients comprising substantially amorphous mesoporous magnesium carbonate

Abstract

The present invention relates to a solid and substantially amorphous active pharmaceutical ingredient, to an oral pharmaceutical preparation comprising the substantially amorphous active pharmaceutical ingredient, and to a method for preparing the substantially amorphous active pharmaceutical ingredient. The present invention also relates to a granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), to a method for preparing the mesoporous magnesium carbonate, and to the use of the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) to stabilize an active pharmaceutical ingredient (API).

Description

Technical Field

[0001] The present invention relates to a solid and substantially amorphous active pharmaceutical ingredient, to an oral pharmaceutical preparation comprising the substantially amorphous active pharmaceutical ingredient, and to a method for preparing the substantially amorphous active pharmaceutical ingredient. The present invention also relates to a granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), to a method for preparing the mesoporous magnesium carbonate, and to the use of the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) in stabilizing an active pharmaceutical ingredient (API). Background Art

[0002] In pharmaceutical drug development, one of the biggest challenges is that drug substances (active pharmaceutical ingredients, API) are often insoluble or poorly soluble in aqueous media. Insufficient or poor API solubility (drug solubility) provides insufficient or poor bioavailability, which in turn generally means that when administered to subjects such as humans or animals, the plasma exposure of the drug is poor. And fasting or feeding conditions may lead to significant differences in drug exposure between patients and differences in drug exposure within a single patient.

[0003] Drug substances are mainly used in their crystalline form when formulated into drug products (drugs). Crystalline forms of poorly soluble drugs have solubility-limited absorption, while amorphous forms of drug substances provide better solubility and dissolution rate than the corresponding crystalline forms. However, the problem with amorphous forms of drugs is that they almost always lack storage stability.

[0004] Currently, as defined by the Biopharmaceutics Classification System (BCS), approximately 40% of APIs on the market and 70% of all APIs in development have poor water solubility. Therefore, the problem is significant in poorly soluble APIs that have been commercialized and in the research and development pipeline. However, the exact numbers vary slightly from one reference to another. Due to their challenging solubility limitations, APIs in drug development may never enter the market for this reason.

[0005] There are a variety of formulation technologies for improving drug solubility, such as particle size reduction, the formation of cyclodextrin complexes and amorphous formulations. The purpose of these technologies is to increase the bioavailability of oral drugs with poor drug solubility. However, improving the water solubility of orally administered drugs is a challenge in drug development because most of these technologies are expensive and / or still provide insufficient solubility improvements. In addition, in the case of API with only a small amount or no crystalline form, the long-term stability of the amorphous phase remains a problem with the current existing technologies for drug formulation development.

[0006] Gupte et al. (British Journal of Pharmaceutical Research 16(6), 2017, 1-9) disclosed mesoporous silica and loaded silica with APIs such as ibuprofen, itraconazole and telmisartan. Gupte cited a study reporting that silica stabilized itraconazole at a loading of more than 32 wt%.

[0007] WO2017 / 174458 discloses a mesoporous magnesium carbonate material, which states that it allows API loading up to 60 wt% of itraconazole by soaking. Itraconazole remains amorphous at up to 30 wt% API loading.

[0008] Yang et al. (International Journal of Pharmaceutics 525, 2017, 183-190) disclosed a mesoporous magnesium carbonate material (particle size <50 μm) containing the API tolfenamic acid and rimonabant. Summary of the invention

[0009] The problem underlying the present invention is to provide a solid, substantially amorphous active pharmaceutical ingredient which remains in substantially amorphous form during storage.

[0010] Yet another problem underlying the present invention is to provide an oral pharmaceutical formulation (drug) that allows for therapeutically adequate API loading without increasing the size of the capsule and / or tablet, which is often a concern for patients when swallowing capsules or tablets that are too large. Patient compliance is therefore another aspect of the present invention. Typically, API loading combined with tablet or capsule size is a limiting factor.

[0011] One aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20% by weight, mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0012] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0013] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0014] (iii) 0.5-1.2 cm 3 The average pore volume in the range of / g; and

[0015] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0016] Yet another aspect of the invention is a heat-treated, solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20 wt. % admixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0017] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0018] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0019] (iii) 0.5-1.2 cm 3 The average pore volume in the range of / g; and

[0020] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0021] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20% by weight, the API being mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0022] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0023] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0024] (iii) 0.5-1.0 cm 3 The average pore volume in the range of / g; and

[0025] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0026] Yet another aspect of the invention is a heat-treated, solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20 wt. % admixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0027] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0028] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0029] (iii) 0.5-1.0 cm 3 The average pore volume in the range of / g; and

[0030] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0031] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20% by weight, the API being mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0032] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0033] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0034] (iii) 0.5-0.8 cm 3 The average pore volume in the range of / g; and

[0035] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0036] Yet another aspect of the invention is a heat-treated, solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20 wt. % admixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC has:

[0037] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0038] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0039] (iii) 0.5-0.8 cm3 The average pore volume in the range of / g; and

[0040] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0041] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient as disclosed and claimed herein, wherein said granular anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) further comprises magnesium oxide (MgO).

[0042] Yet another aspect of the present invention is a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having pores with an average pore size in the range of 3 nm to 8 nm.

[0043] Yet another aspect of the present invention is a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having pores with an average pore size in the range of 4 nm to 7 nm.

[0044] In another aspect of the present invention, a granular anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having a particle size in the range of 270-550 m 2 The average BET surface area is in the range of 1.

[0045] In another aspect of the present invention, a granular anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having a particle diameter in the range of 290-500 m 2 The average BET surface area is in the range of 1.

[0046] In another aspect of the present invention, a granular, substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having a particle diameter in the range of 300-450 m 2 The average BET surface area is in the range of 1.

[0047] In another aspect of the present invention, a granular anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having a particle diameter in the range of 0.5-1.0 cm 3 The average pore volume in the range of / g.

[0048] In another aspect of the present invention, a granular anhydrous and substantially amorphous mesoporous magnesium carbonate particle (MMC) as described and claimed herein, the MMC having a particle diameter in the range of 0.5-0.8 cm 3 The average pore volume in the range of / g.

[0049] In yet another aspect of the invention, there is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, wherein the amount of API is at least 25 wt%.

[0050] In yet another aspect of the present invention, a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 30 wt%.

[0051] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 35 wt%.

[0052] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 40 wt%.

[0053] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 45 wt%.

[0054] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 50 wt%.

[0055] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 55 wt%.

[0056] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 60 wt%.

[0057] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the amount of API is at least 65% by weight.

[0058] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, comprising API in an amount of 20-60 wt%.

[0059] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, comprising API in an amount of 30-50 wt%.

[0060] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, comprising API in an amount of 35-50 wt%.

[0061] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the API is selected from any one of the following: azithromycin, fenofibrate, gefitinib, ibuprofen, ketoprofen, lopinavir, paclitaxel, prednisolone, ritonavir, sulfamethoxazole, telmisartan and tolfenamic acid.

[0062] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the API is selected from any one of the following: afatinib, axitinib, crizotinib, erlotinib, nilotinib, nintedanib, osimertinib, panobinostat, regorafenib, rivaroxaban, selexipag and sorafenib.

[0063] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the API is selected from any one of the following: abiraterone, aprepitant, aripiprazole, bosutinib, dapagliflozin, dasatinib, eltrombopag, ibrutinib, lesinurad, luliconazole, macitentan, palbociclib, posaconazole, rilpivirine, riociguat, trametinib, vemurafenib and vilazodone.

[0064] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a compressibility index of 15 or less.

[0065] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a compressibility index of 12 or less.

[0066] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a compressibility index of 10 or less.

[0067] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a compressibility index of 9 or less.

[0068] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a compressibility index of 8 or less.

[0069] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a Hausner ratio of 1.18 or less.

[0070] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the substantially amorphous active ingredient (MMC-API) has a Hausner Ratio of 1.15 or less.

[0071] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the Hausner Ratio is 1.14 or less.

[0072] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the Hausner Ratio is 1.13 or less.

[0073] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the Hausner Ratio is 1.12 or less.

[0074] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the Hausner Ratio is 1.11 or less.

[0075] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, wherein the Hausner Ratio is 1.10 or less.

[0076] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 10 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution with a value of 80 μm or more.

[0077] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 10 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution with a value of 90 μm or more.

[0078] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 10 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 70-110 μm.

[0079] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 10 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 30-170 μm or 20-40 μm.

[0080] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 75-500 μm.

[0081] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 75-250 μm.

[0082] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 100-250 μm.

[0083] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 150-250 μm.

[0084] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 170-210 μm.

[0085] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 95-125 μm.

[0086] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 140-230 μm.

[0087] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 50 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 95-130 μm.

[0088] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 90 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 260-350 μm.

[0089] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 90 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 280-350 μm.

[0090] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 90 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 305-350 μm.

[0091] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 90Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 180-230 μm.

[0092] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, the MMC-API comprising a 90 Granular anhydrous mesoporous magnesium carbonate particles (MMC) having an average particle size distribution of 180-360 μm.

[0093] Another aspect of the present invention is an oral pharmaceutical formulation comprising a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) mixed with pharmaceutically and pharmacologically acceptable excipients, carriers and / or diluents.

[0094] Yet another aspect of the present invention is an oral pharmaceutical formulation as disclosed and claimed herein, which is bioequivalent to said formulation.

[0095] Yet another aspect of the present invention is a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein for use in stabilizing an active pharmaceutical ingredient (API).

[0096] One aspect of the present invention is a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate having:

[0097] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0098] (ii) 250-600m 2 Average BET surface area in the range of / g;

[0099] (iii) 0.5-1.2 cm 3 The average pore volume in the range of / g; and

[0100] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0101] In another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate as disclosed and claimed herein may further comprise magnesium oxide (MgO).

[0102] In yet another aspect of the invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate as disclosed and claimed herein has been heat treated to provide a heat-treated particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as described and claimed herein.

[0103] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a compressibility index of 15 or less.

[0104] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a compressibility index of 12 or less.

[0105] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a compressibility index of 10 or less.

[0106] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a compressibility index of 9 or less.

[0107] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a compressibility index of 8 or less.

[0108] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner ratio of 1.18 or less.

[0109] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner ratio of 1.15 or less.

[0110] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner ratio of 1.14 or less.

[0111] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner ratio of 1.13 or less.

[0112] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner Ratio of 1.12 or less.

[0113] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner ratio of 1.11 or less.

[0114] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a Hausner Ratio of 1.10 or less.

[0115] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution has a value of 80 μm or more.

[0116] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution has a value of 90 μm or more.

[0117] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution has a value of 100 μm or more.

[0118] In yet a further aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution has a value of 70-110 μm.

[0119] In yet a further aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution is 30-170 μm.

[0120] In yet a further aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 10 The average particle size distribution is 20-40 μm.

[0121] In yet a further aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution is 70-500 μm.

[0122] In yet a further aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50The average particle size distribution is 70-250 μm.

[0123] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution is 100-250 μm.

[0124] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution is 150-250 μm.

[0125] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution has a value of 170-210 μm.

[0126] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution is 95-125 μm.

[0127] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution has a value of 140-230 μm.

[0128] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 50 The average particle size distribution is 95-230 μm.

[0129] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 90 The average particle size distribution has a value of 260-350 μm.

[0130] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 90 The average particle size distribution has a value of 280-350 μm.

[0131] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 90 The average particle size distribution has a value of 305-350 μm.

[0132] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 90 The average particle size distribution is 180-360 μm.

[0133] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC) as disclosed and claimed herein have a 90 The average particle size distribution has a value of 180-230 μm.

[0134] One aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20 wt. %, mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein the mixture of MMC and API (MMC-API) has:

[0135] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0136] (ii) 150-600m 2 Average BET surface area in the range of / g;

[0137] (iii) 0.1-1.2 cm 3 The average pore volume in the range of / g; and

[0138] (iv) Display d 10 The average particle size distribution is 70-430 μm.

[0139] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having pores with a mean pore size in the range of 3 nm to 9 nm.

[0140] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having pores with a mean pore size in the range of 3 nm to 8 nm.

[0141] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having pores with a mean pore size in the range of 3 nm to 7 nm.

[0142] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a molecular weight of 150-500 m / s. 2 The average BET surface area is in the range of 1.

[0143] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a molecular weight of 170-430 m / s. 2 The average BET surface area is in the range of 1.

[0144] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a particle size in the range of 0.1 to 0.9 cm 3 The average pore volume in the range of / g.

[0145] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a particle size in the range of 0.15-0.8 cm 3 The average pore volume in the range of / g.

[0146] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 10 The average particle size distribution is 80-180 μm.

[0147] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 10 The average particle size distribution is 90-170 μm.

[0148] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 50 The average particle size distribution is 100-300 μm.

[0149] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 50 The average particle size distribution is 130-300 μm.

[0150] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 50 The average particle size distribution is 150-290 μm.

[0151] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 50 The average particle size distribution has a value of 160-280 μm.

[0152] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 90 The average particle size distribution is 150-450 μm.

[0153] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 90 The average particle size distribution is 200-450 μm.

[0154] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 90 The average particle size distribution has a value of 220-440 μm.

[0155] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, the MMC-API having a 90 The average particle size distribution is 250-430 μm.

[0156] One aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient, comprising an API in an amount of at least 20 wt. %, mixed with particulate anhydrous substantially amorphous mesoporous magnesium carbonate (MMC), wherein the MMC-API (MMC-API) mixture has:

[0157] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0158] (ii) 150-600m 2 Average BET surface area in the range of / g;

[0159] (iii) 0.1-1.2 cm 3 The average pore volume in the range of / g; and

[0160] (iv) Display d 10 An average particle size distribution of 70-200 μm; and

[0161] (v) Display d 50 The average particle size distribution is 100-300 μm.

[0162] Yet another aspect of the present invention is a solid, substantially amorphous active pharmaceutical ingredient, the active pharmaceutical ingredient comprising an API in an amount of at least 20 wt. %, the API being mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), and wherein the mixture of MMC and API (MMC-API) has:

[0163] (i) pores with an average pore diameter in the range of 2 nm to 10 nm;

[0164] (ii) 150-600m 2 Average BET surface area in the range of / g;

[0165] (iii) 0.1-1.2 cm 3 The average pore volume in the range of / g; and

[0166] (iv) Display d 10 The average particle size distribution is 70-200 μm;

[0167] (v) Display d 50 An average particle size distribution of 100-300 μm; and

[0168] (vi) Display d 90 The average particle size distribution is 150-450 μm.

[0169] High material loading (i.e., API loading) may often lead to crystallization, especially for materials (API) with a high tendency to crystallize. The inventors have shown that a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein is useful even at high API loading of an active pharmaceutical ingredient (API) to provide a material that remains XRPD amorphous and DSC amorphous during storage.

[0170] Yet another aspect of the present invention is a method for preparing particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein, the method comprising the steps of:

[0171] (i) stirring magnesium oxide (MgO) and methanol at a pressure of 0.5-5 bar or 0.5-8 bar and at a temperature of 10-70° C. or 15-60° C. for 12-36 hours, or up to 1 week, to provide a reaction mixture;

[0172] (ii) heating the reaction mixture at a pressure of 100 mbar to 1013 mbar and at a temperature of -10 to 70° C. to provide a gel;

[0173] (iii) drying the gel of step (ii) at 50-70° C. or 70-120° C. to provide particles;

[0174] (iv) finally heat treating the particles obtained in step (iii) at a temperature of 240-300° C. or 160-300° C.; and

[0175] (v) grinding and size classifying the particles obtained in step (iv).

[0176] In one aspect of the present invention, the solid MMC material obtained in step (iv) is milled or ground to convert the material into a particulate material, which may be performed by grinding or milling (eg jet milling).

[0177] In one aspect of the invention, the particles obtained in step (iv) are classified, for example, by wet sieving or dry sieving. The particles of the desired size are then size-fractionated to provide a particle size showing d 10 The particle size distribution has a value of 70-430 μm.

[0178] Another aspect of the present invention is a method for preparing a solid, substantially amorphous active pharmaceutical ingredient (API-MMC), the method comprising the following steps:

[0179] a. dissolving the API in a solvent such as an organic solvent;

[0180] b. adding a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein to the API solution of step (a);

[0181] c. evaporating the solvent; and

[0182] d. Optionally dry the final product.

[0183] definition

[0184] As used herein, the terms "poorly soluble API," "poorly soluble drug," and "inadequate drug solubility" refer to an API that requires more than 250 ml of aqueous medium to dissolve at a pH of about 1 to about 8, based on the highest dosage strength of an immediate release product as defined by the BCS II drug definition.

[0185] As used herein, the terms "amorphous API" and "substantially amorphous API" are defined as a solid active pharmaceutical ingredient that is maintained in its amorphous form and is substantially free of crystalline material as determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Thus, an amorphous API, or substantially amorphous API, is substantially free of crystalline material and has no sharp peaks in the XRPD diffraction pattern and no melting point as measured by DSC.

[0186] As used herein, the term "stable API" refers to an API that is physically stable and persists in a substantially amorphous form for at least 1 month, or at least 3 months, or at least 6 months, 9 months, or up to a year or longer under storage conditions, such as room temperature (18-25° C.) and 25% relative humidity, or room temperature (18-25° C.) and 75% relative humidity. During storage under these conditions, no crystals or substantially no crystals are present as determined by XRPD and DSC.

[0187] As used herein, the term "crystalline API" is defined as an API whose structural units are arranged in a fixed geometric pattern or lattice, so that the crystalline solid has a rigid long-range order. The structural units that make up the crystal can be atoms, molecules or ions. Crystalline solid materials show a definite melting point and display sharp characteristic crystalline peaks in an XRPD diffraction pattern (XRPD pattern).

[0188] As used herein, the term "MMC" refers to a particulate, anhydrous and substantially amorphous mesoporous magnesium carbonate which may or may not contain residual magnesium oxide and / or methanol.

[0189] As used herein, the term "MMC-API" refers to a solid, substantially amorphous active pharmaceutical ingredient comprising an API in an amount of at least 20% by weight, which is mixed with the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) claimed and described herein. Throughout this specification and claims, whenever the term "solid, substantially amorphous active pharmaceutical ingredient" and / or "MMC-API" is used, it means the API mixed with the granular and substantially amorphous mesoporous magnesium carbonate (MMC). When the API and the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) of the present invention are put together as a mixture, it provides a solid, substantially amorphous active pharmaceutical ingredient (MMC-API).

[0190] The phrase "API mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC)" is defined as an API starting material that has been mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) to provide an API loaded into MMC according to the present invention (referred to herein as "MMC-API").

[0191] As used herein, the phrase "API loaded into MMC" refers to the API (ie, particulate anhydrous and substantially amorphous mesoporous magnesium carbonate) mixed with MMC.

[0192] As used herein, the term "API loading" refers to the amount of API raw material that can be contained in a solid substantially amorphous active pharmaceutical ingredient (MMC-API) described and claimed herein or formulated into a pharmaceutical preparation (ie, drug product).

[0193] As used herein, the term "high API loading" is defined as an amount of at least 20 weight % of API used as a raw material, which can be mixed with the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein to provide a solid and substantially amorphous active pharmaceutical ingredient (API) (MMC-API).

[0194] As used herein, the abbreviation "wt %" means weight %, which is the weight fraction expressed as a percentage of a component relative to the total weight of the mixture as described and required herein.

[0195] As used herein, the term "stable" is defined as the use of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as described and claimed herein, which, when mixed with an active pharmaceutical ingredient as a raw material, provides a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) that remains in an amorphous form during storage at room temperature and 75% relative humidity for at least 1 month.

[0196] As used herein, the term "peak pore width" corresponds to a pore width value on the x-axis extracted from the maximum value (peak value) of the incremental pore volume on the y-axis in a pore size distribution curve obtained from nitrogen adsorption.

[0197] As used herein, the term "room temperature" or "RT" is defined as a temperature of 18-25°C.

[0198] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition in which a pharmaceutically active ingredient has been formulated into a drug product.

[0199] As used herein, the term "drug product" is defined as a pharmaceutical composition comprising a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as described and claimed herein, and a pharmaceutically and pharmacologically acceptable excipient, carrier and / or diluent.

[0200] As used herein, the term "active pharmaceutical ingredient (API)" refers to a substance that is a therapeutically active ingredient in a pharmaceutical substance that is administered to humans and / or animals in need of medical treatment.

[0201] When preparing a substantially amorphous active pharmaceutical ingredient according to the present invention, the API as starting material may be the API in its free base form, acid form or neutral form, or in salt form, crystalline or polymorphic form or as a solvate.

[0202] As used herein, the term "pharmaceutically and pharmacologically acceptable excipient, carrier and / or diluent" refers to any non-therapeutic agent that may be included in a pharmaceutical composition when the API is formulated into, for example, a drug product.

[0203] The terms "compressibility index" (also called "Carr index") and "Hausner ratio" are used to predict the flowability of a powder. As used herein, the term "flowability" refers to the ability of a powder to flow. Flowability is an important factor in the process of preparing tablets or capsules.

[0204] The term "compressibility index" (Carr's index) used throughout the specification and claims is a measure of bulk density, size and shape, surface area, moisture content and cohesiveness in the case of the solid, substantially amorphous active pharmaceutical ingredient (MMC-API) disclosed and claimed herein, and in the case of the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) disclosed and claimed herein, and is also the ratio (percentage) of the difference between the tapped density and the bulk density to the tapped density. A lower Carr's index value means higher flowability, and a higher Carr's index value means lower flowability.

[0205] The inventors of the present invention have recognized that the particle size distribution of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (with and without API) affects the flow properties of the particles (ie, with and without API).

[0206] Particles that are too small may provide good release properties but may also exhibit poor flow properties, acting like dust. On the other hand, particles that are too large tend to break during API loading, resulting in the formation of small particles and uneven size distribution, which in turn leads to low dosing accuracy and reduced flow properties of small particles.

[0207] As used throughout the specification and claims, the term "Hausner ratio" refers to the flowability of the solid, substantially amorphous active pharmaceutical ingredient (MMC-API) disclosed and claimed herein, and the flowability of the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) disclosed and claimed herein, and is the ratio between the bulk density and the volume density. A lower Hausner value means a higher flowability, while a higher Hausner ratio means a lower flowability.

[0208] The flow properties were classified according to European Pharmacopoeia 9.0 and expressed as excellent, good, fair, acceptable, poor, very poor and very poor.

[0209] The bulk density of a powder is the ratio of the mass of an unpacked sample of powder to its volume (including the contribution of inter-particle void volume). The bulk density therefore depends on the density of the powder particles and the spatial arrangement of the particles in the powder bed. Bulk density is expressed in grams per milliliter (g / ml), although the international unit is kilograms per cubic meter (1 g / ml = 1000 kg / m 3 ) because the measurement is made using a cylinder. Bulk density can also be expressed in grams per cubic centimeter (g / cm 3 )express.

[0210] By reducing the number of small particles, flowability is improved.

[0211] As used herein, the term "average particle size distribution" shows a particle size distribution of 70 μm or more. 10 The value means that at most 10% by volume of the particles have a particle size of less than 70 μm.

[0212] As used herein, the term "average particle size distribution" shows a particle size distribution of 80 μm or more. 10 The value means that at most 10% by volume of the largest particles have a particle size of less than 80 μm.

[0213] As used herein, the term "average particle size distribution" shows a particle size distribution of 90 μm or more. 10 The value means that at most 10% by volume of the largest particles have a particle size of less than 90 μm.

[0214] As used herein, the term "average particle size distribution" shows a d of 70-430 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 70-430 μm.

[0215] As used herein, the term "average particle size distribution" shows a d of 70-110 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 70-110 μm.

[0216] As used herein, the term "average particle size distribution" shows a d of 30-170 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 30-170 μm.

[0217] As used herein, the term "average particle size distribution" shows a d of 20-40 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 20-40 μm.

[0218] As used herein, the term "average particle size distribution" shows a d of 75-500 μm. 50 The value means that 50% by volume of the particles have a particle size of 75-500 μm.

[0219] As used herein, the term "average particle size distribution" shows a d of 75-250 μm. 50 The value means that 50% by volume of the particles have a particle size of 75-250 μm.

[0220] As used herein, the term "average particle size distribution" indicates a particle size distribution of 100-250 μm. 50 The value means that 50% by volume of the particles have a particle size of 100-250 μm.

[0221] As used herein, the term "average particle size distribution" shows a d of 150-250 μm. 50 The value means that 50% by volume of the particles have a particle size of 150-250 μm.

[0222] As used herein, the term "average particle size distribution" shows a d of 170-210 μm. 50 The value means that 50% by volume of the particles have a particle size of 170-210 μm.

[0223] As used herein, the term "average particle size distribution" shows a d of 95-125 μm. 50 The value means that 50% by volume of the particles have a particle size of 95-125 μm.

[0224] As used herein, the term "average particle size distribution" shows a d of 140-230 μm. 50 The value of d means that 50% by volume of the particles have a particle size of 140-230 μm. As used herein, the term "average particle size distribution" shows a d of 95-130 μm. 50 The value means that 50% by volume of the particles have a particle size of 95-130 μm.

[0225] As used herein, the term "mean particle size distribution" shows a d of 260-350 μm. 90 The value means that 90% by volume of the particles have a particle size less than 260-350 μm.

[0226] As used herein, the term "mean particle size distribution" shows a d of 280-350 μm. 90 The value means that 90% by volume of the particles have a particle size less than 280-350 μm.

[0227] As used herein, the term "mean particle size distribution" shows a d of 305-350 μm. 90 The value means that 90% by volume of the particles have a particle size smaller than 305-350 μm.

[0228] As used herein, the term "mean particle size distribution" shows a d of 180-360 μm. 90 The value means that 90% by volume of the particles have a particle size less than 180-360 μm.

[0229] As used herein, the term "average particle size distribution" shows a d of 70-200 μm. 10 The value means that 10% by volume of the particles have a particle size of less than 70-200 μm.

[0230] As used herein, the term "average particle size distribution" shows a d of 80-180 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 80-180 μm.

[0231] As used herein, the term "average particle size distribution" shows a d of 90-170 μm. 10 The value means that 10% by volume of the particles have a particle size smaller than 90-170 μm.

[0232] As used herein, the term "average particle size distribution" indicates a particle size distribution of 100-300 μm. 50 The value means that 50% by volume of the particles have a particle size of 100-300 μm.

[0233] As used herein, the term "average particle size distribution" shows a d of 130-300 μm. 50 The value means that 50% by volume of the particles have a particle size of 130-300 μm.

[0234] As used herein, the term "mean particle size distribution" shows a d of 150-290 μm. 50 The value means that 50% by volume of the particles have a particle size of 150-290 μm.

[0235] As used herein, the term "mean particle size distribution" shows a d of 160-280 μm. 50 The value means that 50% by volume of the particles have a particle size of 160-280 μm.

[0236] As used herein, the term "average particle size distribution" shows a d of 150-450 μm. 90 The value means that 90% by volume of the particles have a particle size less than 150-450 μm.

[0237] As used herein, the term "average particle size distribution" shows a d of 200-450 μm. 90 The value means that 90% by volume of the particles have a particle size of less than 200-450 μm.

[0238] As used herein, the term "mean particle size distribution" shows a d of 220-440 μm. 90 The value means that 90% by volume of the particles have a particle size smaller than 220-440 μm.

[0239] As used herein, the term "mean particle size distribution" shows a d of 250-430 μm. 90 The value means that 90% by volume of the particles have a particle size less than 250-430 μm.

[0240] The particulate anhydrous and substantially amorphous mesoporous magnesium carbonate material (MMC) as disclosed and claimed herein consists of a plurality of particles, wherein technical parameters such as pore size, BET surface area, pore volume, and particle size distribution between particles may vary. Whenever the term "average" is used, for example but not limited to, the terms "average pore size", "average BET surface area", "average pore volume", and "average particle size", refer to the average pore size, average BET surface area, average pore volume, and average particle size of a particular particle of mesoporous magnesium carbonate (MMC) and / or MMC-API.

[0241] The term "about" as used throughout the specification and claims is intended to indicate a deviation of + / - 2%, or a deviation of + / - 5% or + / - 10% of a given value, as applicable.

[0242] In one aspect of the present invention, a particulate anhydrous and substantially amorphous mesoporous material of magnesium carbonate (MMC) is amorphous as measured by X-ray powder diffraction (XRPD amorphous).

[0243] In another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous material of magnesium carbonate (MMC) according to the present invention is amorphous as measured by differential scanning calorimetry (DSC amorphous).

[0244] In yet another aspect of the present invention, the particulate anhydrous and substantially amorphous mesoporous material of magnesium carbonate (MMC) according to the present invention is XRPD amorphous and DSC amorphous.

[0245] In yet another aspect of the present invention, a particulate anhydrous and substantially amorphous mesoporous material is a particulate composite of an X-ray amorphous and DSC amorphous mesoporous magnesium carbonate (MMC) and magnesium oxide (MgO).

[0246] In one aspect of the invention, magnesium oxide (MgO) is a residue from a process for preparing the particulate anhydrous and substantially amorphous mesoporous material described and claimed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0247] Figure 1 (Example 2) illustrates the peak pore width of azithromycin loaded into MMC (referred to as MMC-azithromycin).

[0248] Figure 2(Example 2) shows the X-ray powder diffraction pattern (XRPD) of a solid, substantially amorphous API after loading the API into a granular, anhydrous, and substantially amorphous mesoporous magnesium carbonate (MMC) (i.e., MMC-API). The 2θ range in this figure is limited to 10-65°. Crystalline API (telmisartan) was measured as a reference.

[0249] Figure 3 (Example 2) shows the X-ray powder diffraction pattern (XRPD) of MMC-API after storage at room temperature and 75% relative humidity. The 2θ range in this figure is limited to 10-65 °. Crystalline API (telmisartan) was measured as a reference. T1, T3, T6, T12, T15 and T17 are the storage time periods of each corresponding MMC-API.

[0250] Figure 4 (Example 4) shows the peak pore width of MMC batch 2 compared to loading dapagliflozin into MMC batch 2 (referred to as MMC-dapagliflozin).

[0251] Figure 5 (Example 4) shows the X-ray powder diffraction pattern (XRPD) of solid, substantially amorphous API (i.e., MMC-API) after loading the API into granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC). The 2θ range in this figure is limited to 10-65°.

[0252] Figure 6 (Example 4) shows the X-ray powder diffraction pattern (XRPD) of a solid, substantially amorphous API (i.e., MMC-API) after storage at room temperature and 75% relative humidity. The 2θ range in this figure is limited to 10-65°. T1, T3, T6, and T9 are the storage time periods for each corresponding MMC-API.

[0253] Figure 7 and Figure 8 The crystalline low melting point ( Figure 7 ) API (dotted line) and crystalline high melting point ( Figure 8 ) Thermogram of the API (dotted line). Neither the MMC-API nor the stability samples showed endothermic signals indicative of the presence of crystalline API. For clarity, the relative heat flow thermogram was separated.

[0254] Fig. 9 (Example 8) shows the pore peak width of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC).

[0255] Fig.10 (Example 8) shows the X-ray powder diffraction pattern (XRPD) of granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) before (T0) and after (T12) storage at 25°C and 65% relative humidity. The 2θ range in this figure is limited to 10-65°. T0 and T12 are storage time periods. DETAILED DESCRIPTION

[0256] General method of preparation

[0257] I. General method for preparing granular anhydrous mesoporous magnesium carbonate (MMC)

[0258] The particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein may be prepared by a process comprising the following steps:

[0259] (i) stirring magnesium oxide (MgO) and methanol at a pressure of 0.5-8 bar and at a temperature of 15-60° C. in a pressure reactor for 12 hours to 1 week to provide a reaction mixture;

[0260] (ii) heating the reaction mixture at a pressure of 100 mbar to 1013 mbar and at a temperature of -10 to 70° C. to provide a gel;

[0261] (iii) drying the gel of step (ii) at 70-120° C. to provide particles;

[0262] (iv) finally heat treating the particles obtained in step (iii) at a temperature up to 300°C; and

[0263] (v) optionally, grinding and size classifying the particles obtained in step (iv).

[0264] The stirring in step (i) may be performed at a rotation speed of 50-500 rpm, and the ratio of MgO [g] / methanol [ml] may be 1:12.5, i.e. 1.0 g MgO / 12.5 ml methanol.

[0265] The final optional heat treatment (iv) of the particles can be carried out by using a furnace with a normal atmosphere. The temperature can be raised from room temperature to 300°C for 5-15 hours, after which the temperature can be subsequently fixed at the elevated temperature for up to 24 hours.

[0266] The material obtained is a solid material or a mass which is then crushed into a granular material. This can be done by grinding or milling (e.g. jet milling). The particles of the desired size are then size graded to provide a granular material. 10The particle size distribution has a value of 70-430 μm.

[0267] The classification step (v) by size can be performed by dry sieving or by wet sieving.During the synthesis, the particle size can also be controlled by using different types of reactors, raw materials or different thermal treatment methods.

[0268] Material characterization

[0269] Particle size was determined using nitrogen adsorption. Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, Georgia, the United States) was measured at 77.3K, providing data for determining the pore size, pore volume and BET surface area of ​​MMC and MMC (MMC-API) loaded with API, respectively. Before analysis, 100-200 mg of sample was added to a sample tube and degassed at 105 ° C for at least 12 hours without vacuum or vacuum. Using the density functional theory (DFT) applied to the adsorption branch of the nitrogen adsorption isotherm, pore size distribution was obtained. The surface area is determined by using the recognized BET equation, and therefore calculated from the nitrogen adsorption isotherm (Brunauer et al., JACS, 60, 1938, 309-319).

[0270] It is noted that the BET surface area measured by nitrogen adsorption analysis as described herein can be higher if measured on MMC that has not been heat treated as described herein. Heat treating the MMC, i.e., exposing the MMC to elevated temperatures for extended periods of time in an oven, e.g., above 200°C for more than 10 hours, can reduce the residual methanol content to typically less than 4 wt%. The residual methanol is largely dispersed in the pores of the MMC, which, depending on the weight, can affect the measurement of the BET surface area by nitrogen adsorption analysis. Thus, the BET surface area of ​​MMC that has not been heat treated can be in the range of 400-900 m 2 / g (e.g. 450-900m 2 / g or 500-850m 2 The BET surface area measured according to the invention is measured on heat-treated MMC.

[0271] Powder XRPD patterns were obtained on a Bruker D8Advance Twin-Twin diffractometer (Bruker Ltd., Coventry, UK) using Cu-Ka radiation (l = 1.54A) and generated by elastic X-ray scattering. Prior to analysis, the samples were ground, dispersed with ethanol and applied as a thin layer to a zero-background silicon sample holder. Prior to analysis, all residual solvent was evaporated under a heating lamp. The analysis settings can be in the range of 20-80°, 5-80° or 5-65° in 2θ.

[0272] The presence or absence of crystals detected by DSC is determined by balancing a weighed sample in a DSC (Differential Scanning Calorimetry) sample holder at a suitable temperature. The temperature is raised to a suitable temperature at a rate of 10°C / min, the sample is kept isothermally at this temperature for 5 minutes, and then the temperature is lowered to the equilibrium temperature. Finally, the temperature is raised to well above the melting point of the sample. The equilibrium temperature can be -35°C and the isothermal temperature can be 80°C.

[0273] Particle size distribution was measured using a dry method using laser diffraction on a Malvern Mastersizer 3000. Non-spherical particles and MMC (MgCO3) were used as materials (i.e., settings for the refractive index, adsorption index, and density of MgCO3) and the light scattering data converted to particle size distribution was analyzed using a Mie-scattering model. Before adding the sample to the instrument, the sample container was thoroughly mixed to ensure good sampling. A few grams of powder were added to the instrument for measurement, and the measurement time was set to 10-30 seconds. The lower limit of the blockage was set to 0.5%, the upper limit was set to 5%, and the air pressure was set to 1.5 barg. During the measurement, the feed rate was constantly adjusted to keep the blockage rate between 0.5% and 5%. All measurements were repeated at least three times, from which the average result was calculated.

[0274] The particle size distribution of MMC-API or MMC can also be measured by laser diffraction using a wet method using a Malvern Mastersizer 3000 with a Hydro MV accessory. Using a non-spherical particle class, the light scattering data converted to a particle size distribution is analyzed using the Mie scattering model. The refractive index is set to 1.72 and the absorption is set to 0.01. In the software, the dispersant is set to water, which has a refractive index of 1.33, and the level sensor threshold is 100.

[0275] The maximum pump speed (3500rpm) is used to prevent the MMC-API or MMC sedimentation of dispersion. All measurements including MMC-API or MMC are carried out in 10mM NaOH. Background is obtained by the trough (cell) full of 10mM NaOH and 3500rpm pumping. Common analysis includes by 2 minutes bath ultrasonic treatment, 20mg MMC-API or MMC is dispersed in the 2.5ml 10mM sodium hydroxide in the 5ml glass bottle. After ultrasonic treatment MMC-API or MMC, sample is transferred in the measuring cell. Bottle is rinsed several times to ensure that all specific materials have been transferred. The measurement duration is 10 seconds background and 10 seconds sampling. Six sub-operations are carried out, and then average results are calculated on this basis.

[0276] Study on powder flowability

[0277] Bulk and bulk density measurements

[0278] A mechanically tapping device (Pharma Test PT-TD, Hamburg, Germany) was used to assess the tendency of the powder to densely pack. A glass measuring cylinder with a diameter of 12 mm (n=3) was filled with 10 mL of powder and weighed to obtain the initial bulk density, pBulk. Thereafter, the measuring cylinder was mechanically tapped at a constant speed until the most stable arrangement was obtained and the volume no longer decreased. pBulk was compared with the final bulk density (ptapped). The apparent volume of the undeployed V0 and the apparent volume of the final pile V0 were measured. f , the compressibility index and the Hausner ratio can be calculated using formulas 1 and 2. The compressibility index and the Hausner ratio are used as measures of powder flowability (European Pharmacopeia 9.0).

[0279] Formula 1: Compressibility index (%) = 100X (V0-V f / V0,)

[0280] Formula 2: Hausner ratio = V0 / V f

[0281] II. Preparation of Solid, Substantially Amorphous API (MMC-API)

[0282] A solid, substantially amorphous active pharmaceutical ingredient comprising an API mixed with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), the active pharmaceutical ingredient being prepared by the following process:

[0283] a. dissolving the API in a solvent such as an organic solvent;

[0284] b. adding particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein to the API solution of step (a);

[0285] c. evaporating the solvent; and

[0286] d. Optionally dry the final product.

[0287] The API raw materials fenofibrate, ibuprofen, ketoprofen, prednisolone, ritonavir, and telmisartan were purchased from Sigma-Aldrich. The API raw materials gefitinib, paclitaxel, sulfamethoxazole, tolfenamic acid, and afatinib, bosutinib, crizotinib, dapagliflozin, gefitinib, ibrutinib, lesinad, luliconazole, macitentan, nintedanib, osimertinib, panobinostat, posaconazole, regorafenib, rilpivirine, riociguat, rivaroxaban, selexipag, sorafenib, and vilazodone were purchased from Chemtronica.

[0288] The ratio of API [g] / anhydrous and particulate substantially amorphous mesoporous magnesium carbonate (MMC) [g] depends on the target API loading: for example, 3 / 7 at an API loading of 30 wt % and 1 / 1 at an API loading of 50 wt %.

[0289] Examples of solvents useful for dissolving the API in step a) are lower alcohols, such as methanol or ethanol, and acetone or mixtures thereof. Also useful in dissolving the API are 1-butanol, 2-butanol, acidified ethanol (0.1% 1M HCl), butyl acetate, tert-butyl methyl ether, dichloromethane, dimethyl sulfoxide, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and triethylamine, which may be useful in dissolving the API.

[0290] The evaporation of the solvent in step c) may be carried out under reduced pressure and at a temperature ranging from room temperature up to 70°C, such as 50-70°C.

[0291] The optional drying in step d) may be carried out at a temperature of 70-100°C.

[0292] When formulating an amorphous API into a drug product, a high API loading may help to reduce the amount of mesoporous material and in order to reduce the size of the capsule or tablet, but the API content cannot be too high due to the risk of crystallization.

[0293] The inventors of the present invention have developed a novel particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) and provided a novel technique for stable amorphous active pharmaceutical ingredients (MMC-API).

[0294] In order to obtain a substantially amorphous active pharmaceutical ingredient (MMC-API) according to the present invention, the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) obtained after sieving is mixed with a solution of the API in a container such as an evaporating bottle or a round flask, or in a reactor such as glass / glass-lined / stainless steel / Hastello alloy. The loading step depends on the nature of the active pharmaceutical ingredient. The mixing can be carried out by stirring, swirling or shaking, and can be carried out at room temperature (18-25°C). The mixing can be carried out for 20-120 minutes or 30-60 minutes, and then the solvent is evaporated under reduced pressure. The evaporation is completed during stirring, shaking or rotation of the container. The reduced pressure can be 900mbar or less, such as 500mbar or less, or 200mbar or less, or 100mbar or less. The complete loading step, or at least the evaporation of the solvent, can be carried out in a rotary evaporator. The MMC-API (ie MMC loaded with API) is isolated and optionally dried, for example at 60-80°C, such as about 70°C.

[0295] The solid, essentially amorphous solid pharmaceutical active ingredient (MMC-API) according to the present invention can also be obtained by first preparing a solution of the API in a suitable solvent and then wet impregnating it onto MMC, by spray drying the dissolved API with dispersed MMC particles, by spraying the API onto MMC material suspended by a gas stream (fluidized bed setting), by low shear or high shear wet granulation, the dissolved API can be applied by spraying or any other pharmaceutical processing method.

[0296] If the mixture of MMC and API (i.e. the substantially amorphous active pharmaceutical ingredient according to the present invention, i.e. MMC-API) is prepared on MMC that has not been heat-treated, i.e. MMC having a residual methanol content of typically above 7 wt. %, it is worth noting that on such MMC-API, the BET surface area may be higher. Thus, in this case, the BET surface area of ​​the MMC-API prepared on MMC that has not been heat-treated may be in the range of 300-600 m 2 / g (e.g. 310-550m 2 / g or 320-500m 2 The BET surface area described and claimed in accordance with the present invention is measured on MMC-API prepared on MMC that was heat treated prior to loading the API into the MMC material.

[0297] Stability test

[0298] A solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein is stored in a desiccator at room temperature comprising a saturated NaCl mixture such that the relative humidity is substantially 75%. The stability of the amorphous form is measured at different time points (such as 1 month, 1 year or longer) using XRPD and DSC.

[0299] Powder XRPD patterns were obtained on a Bruker D8Advance Gemini diffractometer (Bruker Corporation, Coventry, UK) using Cu-Ka radiation (λ=1.54A), and the XRPD patterns were generated by elastic X-ray scattering. Prior to analysis, the sample may be ground, dispersed with ethanol, and then applied as a thin layer to a zero-background silicon sample holder, or as a dry powder. Prior to analysis, any residual solvent is evaporated, such as under a heat lamp or infrared lamp. The analysis settings may be in the range of 2θ of 20-80°, 5-80°, or 5-65°.

[0300] DSC analysis is determined by balancing a weighed sample in a DSC (Differential Scanning Calorimetry) sample holder at a suitable temperature. The temperature is raised at a rate of 10°C / min to a suitable temperature, at which the sample is kept isothermal for 5 minutes, and then the temperature is lowered to the equilibrium temperature. Finally, the temperature is raised to a temperature well above the melting point of the API. The equilibrium temperature may be -35°C and the isothermal temperature may be 80°C.

[0301] To assess the chemical integrity of the API and excipients, in the case of ease excipients, a High Performance Liquid Chromatography (HPLC) system with appropriate software and equipped with a suitable pump, autosampler, chromatographic column, column oven, and UV-VIS detector can be used. The analytical column for separation is selected taking into account the type of system used and the chemical entity being analyzed. The analysis is typically (but not limited to) performed at a constant column temperature of 25 ± 2 ° C, and the separation is typically (but not limited to) performed in isocratic mode with acetonitrile as the mobile phase. Prior to use, the mobile phase can be filtered using a millipore 0.45 μm filter and degassed on an ultrasonic bath. After optimization, the ideal flow rate is determined and the sample of the appropriate volume and concentration is injected into the HPLC system to start the analysis. The analytical goal is to determine the absence or presence of the parent chemical entity and / or any chemical degradation products.

[0302] Pharmaceutical preparations

[0303] The solid, substantially amorphous active pharmaceutical ingredients (MMC-API) described and claimed herein can be formulated into oral pharmaceutical preparations in admixture with pharmaceutically and pharmacologically acceptable excipients, carriers and / or diluents. Examples of useful oral pharmaceutical preparations (drugs) can be selected from tablets, powders, capsules with solid, substantially amorphous API, granules or cachets, each of which includes a predetermined amount of the amorphous API described and claimed herein.

[0304] When formulating the solid, substantially amorphous active pharmaceutical ingredients (MMC-API) described and claimed herein, examples of pharmaceutically acceptable excipients, carriers and / or diluents are thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, carrier materials, lubricants or adhesives. Common pharmaceutical carriers include, but are not limited to, adhesives (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose, etc.), fillers (e.g., lactose, glucose, sucrose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.), lubricants (e.g., magnesium stearate, talc, silicon dioxide, colloidal silicon dioxide, stearic acid, metal stearates (esters), hydrogenated vegetable oils, corn starch, polyethylene glycol, sodium benzoate, sodium acetate, etc.), disintegrants (e.g., starch and sodium starch glycolate), wetting agents, diluents, coloring agents, emulsifiers, pH buffers, preservatives, and mixtures thereof.

[0305] The substantially amorphous active pharmaceutical ingredient (MMC-API) disclosed and claimed herein may be formulated as tablets, powders, capsules or cachets using any suitable formulation techniques known to the skilled artisan. Alternatively, the substantially amorphous active pharmaceutical ingredient (MMC-API) may be filled into capsules, such as hard gelatin capsules or soft gelatin capsules.

[0306] Medical Uses

[0307] One aspect of the invention is the use of a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein in therapy.

[0308] Yet another aspect of the invention is a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein, for use in treating cancer such as breast cancer, prostate cancer, lung cancer, or any disease that can be treated with an anti-tumor agent; infections such as bacterial infections; human immunodeficiency virus (HIV) infections; cardiovascular diseases such as hypertension; pain; migraines; inflammation; asthma; allergic reactions; diabetes such as type 2 diabetes; nausea; thrombocytopenia; hyperuricemia; fungal infections; pulmonary hypertension; depression; thrombosis; or rheumatoid arthritis.

[0309] Yet another aspect of the invention is the use of a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein in the preparation of a medicament for treating cancer such as breast cancer, prostate cancer, lung cancer, or any disease that can be treated with an anti-tumor agent; infections such as bacterial infections; human immunodeficiency virus (HIV) infections; cardiovascular diseases such as hypertension; pain; migraines; inflammation; asthma; allergic reactions; diabetes such as type 2 diabetes; nausea; thrombocytopenia; hyperuricemia; fungal infections; pulmonary hypertension; depression; thrombosis or rheumatoid arthritis.

[0310] Yet another aspect of the invention is a method for treating cancer such as breast cancer, prostate cancer, lung cancer, or any disease that can be treated with an anti-tumor agent; infection such as bacterial infection; HIV infection; cardiovascular disease such as hypertension; pain; migraine; inflammation; asthma; allergic reaction; diabetes such as type 2 diabetes; nausea; thrombocytopenia; hyperuricemia; fungal infection; pulmonary hypertension; depression; thrombosis or rheumatoid arthritis; wherein a solid, substantially amorphous active pharmaceutical ingredient (MMC-API) as disclosed and claimed herein is administered to a subject in need of such treatment.

[0311] The use or treatment of the medical indications disclosed herein may be as a monotherapy or in combination therapy.

[0312] Example

[0313] Example 1 - Preparation and flow properties of granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC)

[0314] The particulate anhydrous and substantially amorphous mesoporous magnesium carbonate is prepared by the following steps:

[0315] (i) 160 g of magnesium oxide (MgO) (Magnesia 295, purchased from Brenntag Nordic AB Taby, Sweden) and 2 L of methanol (purchased from Solveco AB, Rosersberg, Sweden) were stirred in a stainless steel pressure reactor;

[0316] (ii) applying 4 bar of CO2 pressure and stirring the solution in (i) at room temperature (500 rpm) for 8 days;

[0317] (iii) transferring the reaction liquid formed in (ii) into an evaporating flask connected to a rotary evaporator;

[0318] (iv) heating the reaction solution using a rotary evaporator at 60-80° C., 950 mbar and 60 rpm for 4 hours to provide a gel;

[0319] (v) drying the gel using a rotary evaporator at 80-100° C., 950 mbar and 60 rpm for 1 hour to form particles;

[0320] (vi) Finally, the particles of step (v) are heat treated at 250°C using a furnace under standard atmospheric pressure. The temperature is gradually increased from room temperature to 250°C so as to:

[0321] - Raise the oven from room temperature to 80°C over 1 hour and 15 minutes;

[0322] - During 2 hours, the furnace was raised from 80°C to 120°C;

[0323] - During 2 hours, the furnace was raised from 120°C to 150°C;

[0324] - During 2 hours, the furnace was raised from 150° C. to 250° C. After a total of 14 hours of heating, the furnace was turned off and the powder was left in the furnace to cool.

[0325] (vii) The anhydrous and substantially amorphous mesoporous particulate magnesium carbonate obtained was ground with a mortar and pestle and sieved (dry) using a vibratory sieve shaker AS 200 basic (Retsch GmbH, Hahn, Germany) with sieves having mesh sizes of 710 μm, 500 μm, 250 μm, 150 μm, 100 μm, 75 μm and 50 μm (30 minutes, amplitude 100%).

[0326] The obtained MMC was subjected to nitrogen adsorption analysis, XRPD and powder flowability studies, including measurements of bulk and bulk density, as described elsewhere herein.

[0327] result

[0328] A set of six different fractions were obtained, with average particle sizes (D50) of 630.0 μm, 203.4 μm, 112.1 μm, 60.3 μm, 45.8 μm and 24.0 μm, respectively.

[0329] The obtained granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) has a 2 / g and a BET surface area of ​​0.71 cm 3 / g of pore volume, of which about 100% of the pore volume comes from pores with a diameter of <10 nm.

[0330] The bulk density and tap density of the different size fractions are shown in Table 1. By using the values ​​obtained, the Carr's index and the Hausner ratio for each size fraction and the flow properties classified according to Ph. Eur. 9.0 were calculated, and fractions 1 and 2 were classified as excellent, fraction 3 as good, fractions 4 and 5 as poor, and fraction 6 as very very poor, and the results are summarized in Table 1 below.

[0331] Table 1. Flow properties of six different fractions of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (abbreviated in the table below as MMC) obtained in Example 1. Values ​​are given as mean and (sd).

[0332]

[0333] *According to European Pharmacopoeia 9.0 (2016), Chapter 2 9.26. Flowability of Powders

[0334] Example 2 - Preparation and stability of MMC-API

[0335] Three batches of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) were prepared and analyzed as described above, except that only 100 and 250 μm mesh sizes were used for sieving. The average BET surface area of ​​the particulate mesoporous MMC material used was between about 340 and 590 m 2 / g range, with an average pore volume of about 0.56-1.05cm 3 / g, wherein about 100% of the pore volume comes from pores with a diameter of <10 nm. The magnesium oxide (MgO) used was purchased from Lehmann & Voss & Co.

[0336] The API-loaded MMC materials, i.e., mixtures of MMC and API (MMC-API), showed average BET surface areas of 100-286 m2 / g, total pore volumes of 0.17-0.8 cm3 / g, depending on the type and amount of API, and peak pore diameters reduced by about 1 nm compared to the unloaded materials.

[0337] Each API raw material (i.e. azithromycin, fenofibrate, gefitinib, ibuprofen, ketoprofen, lopinavir, paclitaxel, prednisolone, ritonavir, sulfamethoxazole, telmisartan and tolfenamic acid) is dissolved in ethanol (pH 6-10) respectively and mesoporous particles (MMC) are added to the solution. The target API load is 30 wt % and / or 50 wt %. A magnetic stirrer is used to mix the mesoporous particles with the API solution at room temperature for 20-60 minutes. After mixing, a rotary evaporator (Büchi with heating bath B-305, heating bath B-300 base, vacuum pump V-300 and interface 1-300 or interface 1-300Pro) is used. or Biichi, Flawil, Switzerland) was used to remove ethanol under reduced pressure (500-100 mbar) at 60° C. The solid, essentially amorphous API obtained was finally dried in an oven at 70° C. All API starting materials were used in their respective free forms, except for gefitinib, which was used as the hydrochloride salt.

[0338] The solid, substantially amorphous active pharmaceutical ingredient (MMC-API) obtained was analyzed by nitrogen adsorption to determine the pore size, pore volume and BET surface area. XRPD and DSC were performed to determine whether the API was present in its amorphous form.

[0339] In Gemini VII 2390 or Nitrogen adsorption was performed on a Micromeritics II Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, GA, USA) operating at 77.3 K. Prior to analysis, 100-200 mg of MMC-API was added to the sample tube and degassed at 105 °C for at least 12 h.

[0340] XRPD was measured using a Bruker D8 Gemini X-ray diffractometer (Bruker Ltd., Coventry, UK) with Cu-Ka radiation (l = 1.54A). Ethanol was added to the sample to prepare a suspension, which was applied to a zero-background silicon sample holder. Prior to analysis, the solvent was evaporated under light. The analysis was set in the range of 2θ 20-80°, 5-80° or 5-65°.

[0341] DSC analysis was performed by adding 2-3 mg of sample into an aluminum pan, an aluminum lid was placed on the pan and closed securely using a crimper. To allow the water in the sample to evaporate during analysis, a pinhole was made in the middle of the pan using a needle.

[0342] Run the DSC analysis accordingly:

[0343] Cycle 1:

[0344] Equilibrium was reached at -35°C.

[0345] Cycle 2:

[0346] Ramp up to 80.00°C at 10°C / min.

[0347] Wait for 5 minutes.

[0348] Ramp down to -35°C at 10°C / min.

[0349] Cycle 3:

[0350] The temperature was ramped up at 10°C / min to well above the melting temperature of each corresponding API.

[0351] The solid, substantially amorphous API samples (i.e., MMC-API) azithromycin, fenofibrate, ibuprofen, ketoprofen, lopinavir, prednisolone, ritonavir 30 wt%, sulfamethoxazole, telmisartan 30 wt% and tolfenamic acid 30 and 50 wt% were stored at room temperature in a desiccator containing a saturated NaCl solution to create a 75% relative humidity atmosphere. After 1 month of storage and after 1 year of storage, the samples were analyzed using XRPD and DSC as described above to determine whether they were still amorphous or whether they had crystallized.

[0352] According to the results of Example 2

[0353] All APIs were loaded into the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate to provide MMC-APIs as shown by the changes in pore volume, BET surface area and pore size. The results of nitrogen adsorption are shown in Table 2a below.

[0354] Table 2a. Pore volume, BET surface area, and pore peak width of MMC-API after loading API into granular anhydrous and substantially amorphous magnesium carbonate (MMC). The pore peak width of azithromycin loaded into MMC (referred to as MMC-azithromycin) is also shown in Table 2a. Figure 1 Shown in.

[0355]

[0356] As shown in Table 2b and Figure 2 As shown, the corresponding API loaded into MMC is amorphous according to XRPD and DSC.

[0357] Table 2b. Physical state of API after loading into particulate anhydrous and substantially amorphous magnesium carbonate (MMC) to provide MMC-API.

[0358]

[0359] After storage at 75% relative humidity and room temperature for 1 month, the samples (MMC-API) were analyzed again by XRPD and DSC. Samples were also analyzed after storage for 3 months or more (3 months, 6 months, 12 months (1 year), 15 months and / or 17 months). Table 2c and Figure 3 The results are shown in .

[0360] Table 2c. Physical state of solid, substantially amorphous API (ie, MMC-API) after storage at room temperature and 75% relative humidity.

[0361]

[0362] Example 3 - General Methods for Preparation and Stability Testing of MMC-API

[0363] An appropriate amount of API is added to the container, followed by a sufficient amount of a suitable organic solvent to dissolve the API. The API solvent mixture is sonicated in the range of room temperature to 55°C or as needed until the API is completely dissolved (usually 1-150 minutes). In addition, the MMC according to the present invention is added to the API solution. The target API loading is 20-30% by weight. The mesoporous particles (MMC) are mixed with the API solution by manually shaking the flask for 10 seconds at room temperature (20-25°C), and then the container is connected to a rotary evaporator (with a heating bath B-305, a heating bath B-300 base, a vacuum pump V-300 and an interface 1-300 or an interface 1-300Pro). Büchi, Flawil, Switzerland). The solvent is evaporated from the mixture at a temperature ranging from room temperature to 60°C, at a rotation speed of 60 rpm or 100 rpm, at a pressure of 50-990 mbar. The solid, substantially amorphous active pharmaceutical ingredient (herein referred to as MMC-API) obtained from the solvent evaporation is then placed in an oven for final drying, typically at 80°C for 16-92 hours. The final dried intermediate is removed from the container and analyzed by nitrogen adsorption to determine the pore size, pore volume and BET surface area, as well as by XRPD and DSC to determine whether the API is present in its amorphous state.

[0364] Nitrogen adsorption is The analysis was performed on a Micromeritics Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, GA, USA) operating at 7.3 K. 100-200 mg of MMC-API was added to the sample tube and degassed at 105°C under vacuum for at least 12 hours prior to analysis.

[0365] X-ray diffractometer (Bruker UK Ltd., Coventry, UK) was used to irradiate Cu-Ka. XRPD was measured. Prior to analysis, the MMC-API was ground, dispersed in a solvent such as ethanol, and then applied as a thin layer to a zero-background silicon sample holder, or ground as dry material and applied to a zero-background silicon sample holder. Prior to analysis, any remaining solvent was evaporated under a heating lamp. The analysis was set up in the range of 2θ of 20-80°, 5-80°, or 5-65°.

[0366] DSC analysis was performed using a DSC Q2000 (TA Instruments, Newcastle, Delaware, USA). 2-3 mg of MMC-API was applied to an aluminum pan, an aluminum cover was placed on the pan, and a crimper was used to securely close the pan. In order to allow the moisture in the sample to evaporate during the analysis, a pinhole was made in the middle of the pan using a needle.

[0367] Run the DSC analysis accordingly:

[0368] Cycle 1:

[0369] Equilibrium was reached at -35°C.

[0370] Cycle 2:

[0371] Ramp up to 80.00°C at 10°C / min.

[0372] Wait for 5 minutes.

[0373] Ramp down to -35°C at 10°C / min.

[0374] Cycle 3:

[0375] The temperature was ramped up at 10°C / min to well above the melting temperature of each corresponding API.

[0376] Solid, substantially amorphous active pharmaceutical ingredients (MMC-API) were stored at room temperature in a desiccator containing a saturated NaCl solution to provide a 75% relative humidity atmosphere. After storage for 1 month and n months, respectively, the MMC-APIs were analyzed using XRPD and DSC as described above to determine whether they were still amorphous or had crystallized.

[0377] Example 4 - Preparation and stability testing of solid, substantially amorphous dapagliflozin (i.e., MMC-dapagliflozin) try

[0378] 1499.8mg dapagliflozin is added to an evaporating bottle. 250ml ethyl acetate is added to dissolve dapagliflozin. The mixture is ultrasonicated at 20°C for 5 minutes, then ultrasonicated at 50°C for 20 minutes, until dapagliflozin is dissolved. 3499.2mg mesoporous particles (MMC) are added to the dapagliflozin solution. The target API load of dapagliflozin is 30% by weight. The mesoporous particles (MMC) are mixed with the dapagliflozin solution by shaking the flask by hand for 10 seconds at room temperature (20-25°C), and then the evaporating bottle is connected to a rotary evaporator (with interface 1-300Pro). At 250mbar, a temperature of 40°C and a rotation speed of 60rpm, the solvent is evaporated from the mixture. After 15 minutes, the pressure is reduced to 200bar, and then the evaporation continues for an additional 35 minutes. The pressure is further reduced to 190mbar, and the evaporation continues for an additional 60 minutes. Finally, the pressure was reduced to 150 mbar for 1 minute until the ethyl acetate evaporated and solid, substantially amorphous dapagliflozin, referred to herein as MMC-dapagliflozin, was obtained. MMC-dapagliflozin was placed in an oven and finally dried at 80°C for 24 hours. The final dried MMC-dapagliflozin was removed from the evaporating flask and analyzed by nitrogen adsorption to determine the pore size, pore volume and BET surface area, as well as by XRPD and DSC to determine whether dapagliflozin is present in its amorphous state.

[0379] Nitrogen adsorbed on II Plus 3030 Surface Area and Porosity Analyzer (Micromeritics, Norcross, GA, USA) operated at 77.3 K. 100-200 mg of MMC-dapagliflozin was added to the sample tube and degassed at 105°C for at least 12 hours prior to analysis.

[0380] X-ray diffractometer (Bruker UK Ltd., Coventry, UK) was used to irradiate Cu-Ka. XRPD was measured. MMC-dapagliflozin was ground, dispersed in ethanol to make a suspension, and then applied to a zero-background silicon sample holder. The solvent was evaporated under light before analysis. The analysis was set in the range of 2θ 5-80°.

[0381] DSC analysis was performed using a DSC Q2000 (TA Instruments, Newcastle, Delaware, USA). 3.0 mg of MMC-dapagliflozin was added to an aluminum pan for DSC analysis, and an aluminum cover was placed on the pan and securely closed using a crimper. In order to allow the moisture in the sample to evaporate during the analysis, a pinhole was made in the middle of the pan using a needle.

[0382] Run the DSC analysis accordingly:

[0383] Cycle 1:

[0384] Equilibrium was reached at -35°C.

[0385] Cycle 2:

[0386] Ramp up to 80.00°C at 10°C / min.

[0387] Wait for 5 minutes.

[0388] Ramp down to -35°C at 10°C / min.

[0389] Cycle 3:

[0390] Ramp up to 300°C at 10°C / min.

[0391] MMC-dapagliflozin was stored at room temperature in a desiccator containing a saturated NaCl solution to provide a 75% relative humidity atmosphere. After 1 month and 3 months of storage, MMC-dapagliflozin was analyzed by XRPD and DSC according to the methods described herein to determine whether it was still amorphous or had crystallized.

[0392] Table 3a and Table 3b summarize the specific conditions for loading dapagliflozin into granular anhydrous and substantially amorphous mesoporous magnesium carbonate given in this embodiment. According to the general API loading procedure previously described in Example 3, API afatinib, bosutinib, crizotinib, gefitinib, ibrutinib, lesinad, luliconazole, macitentan, nintedanib, osimertinib, panobinostat, posaconazole, regorafenib, rilpivirine, riociguat, rivaroxaban, selexipag, sorafenib and vilazodone are also shown in Table 3a and Table 3b. As described above, all MMC-APIs were analyzed by nitrogen adsorption, XRPD and / or DSC.

[0393] Table 3a. Selected APIs loaded into MMC, quantities and parameters used to generate the corresponding amorphous MMC-APIs.

[0394]

[0395] Table 3b. Specific conditions for loading API into MMC by solvent evaporation according to the general loading instructions for the preparation of the corresponding amorphous MMC-API.

[0396]

[0397] result

[0398] All APIs were loaded into the granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as shown by the changes in pore volume, BET surface area and pore size. The following table lists the nitrogen adsorption results of the unloaded mesoporous particulate magnesium carbonate (MMC) (Table 3c) and the loaded material (MMC) (Table 3d). Figure 4 Illustrated are the pore peak widths of MMC batch 2 compared to dapagliflozin loaded into MMC batch 2 (referred to as MMC-dapagliflozin).

[0399] Table 3c Pore volume, BET surface area and pore peak width of MMC.

[0400]

[0401] Table 3d Pore volume, BET surface area and pore peak width of MMC-API (ie after API is loaded into MMC).

[0402]

[0403] According to the results of XRPD and / or DSC, all the APIs loaded were measured to be amorphous, as shown in Tables 3e and Figure 5 shown.

[0404] Table 3e. Physical state of API after loading into MMC (ie, MMC-API).

[0405]

[0406] After storage at 75% relative humidity and room temperature for 1 month, the MMC-APIs (except afatinib (2), rilpivirine, riociguat, selexipag (2), and vilazodone) were analyzed again by XRPD and DSC. The results of XRPD and DSC are shown in Table 3f, and in Figure 6 , Figure 7 and Figure 8 This is explained in .

[0407] Table 3f. Physical state of solid, substantially amorphous API (ie, MMC-API) after storage at room temperature and 75% relative humidity.

[0408]

[0409] Example 5 - Flowability of a solid, substantially amorphous API [MMC-API]

[0410] Granular anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) was prepared as described in Example 1, except that the final heat treatment was performed at 250°C for 10 hours, then maintained at 250°C for 10 hours, and then cooled naturally to room temperature. The MMC was analyzed as described in Material Characterization. The average BET surface area of ​​the mesoporous granular material (MMC) was about 320-445 m 2 / g range, and the average pore volume is about 0.5-0.8cm 3 / g, wherein about 100% of the pore volume comes from pores with a diameter of <10 nm. The magnesium oxide (MgO) used was purchased from Lehmann & Voss & Co.

[0411] MMC material is divided into three batches, and three different APIs (azithromycin, ibuprofen and ritonavir) are loaded respectively. Different batches of different size fractions are loaded with 30wt% azithromycin, 30wt% ritonavir and 30wt% ibuprofen respectively, to provide a solid amorphous API (i.e., MMC-API). As prepared and characterized in Example 2, a solid amorphous API (MMC-API). The flow properties of the solid amorphous API (MMC-API) are as determined in the material characterization.

[0412] The results are summarized in Table 4a, Table 4b and Table 4c below.

[0413] Table 4a. Particle size distribution and physical state of a sample portion (ie, a specific MMC-API) of solid azithromycin loaded into MMC according to Example 1.

[0414]

[0415] *MMC-API is defined as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0416] Table 4b. Particle size distribution and physical state of solid ritonavir (ie specific MMC-API) loaded into MMC of sample fractions according to Example 1.

[0417]

[0418] *MMC-API is classified as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0419] Table 4c. Particle size distribution and physical state of solid ibuprofen (ie specific MMC-API) loaded into MMC of sample fractions according to Example 1.

[0420]

[0421] *MMC-API is classified as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0422] The results of bulk density and tap density measurements are shown in Table 4d, Table 4e and Table 4f below.

[0423] Table 4d. Flow properties of solid azithromycin (ie specific MMC-API) loaded into MMC of sample fractions according to Example 1. Values ​​are given as mean and (sd).

[0424]

[0425] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0426] Table 4e. Flow properties of solid ritonavir (ie specific MMC-API) loaded into MMC of sample fractions according to Example 1. Values ​​are given as mean and (sd).

[0427]

[0428] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0429] Table 4f. Flow properties of solid ibuprofen (ie specific MMC-API) loaded into MMC of sample fractions according to Example 1. Values ​​are given as mean and (sd).

[0430]

[0431] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0432] Example 6 - Flowability of a solid, substantially amorphous API loaded into MMC (ie, MMC-API)

[0433] By following the process described in Example 5 above, the different size fractions of different MMC batches are respectively loaded with 20% by weight of azithromycin, 35% by weight of ibuprofen and 40% by weight of ritonavir, thereby providing solid, substantially amorphous API (i.e., MMC-API). As described in Example 2, each MMC-API is prepared and characterized respectively. The flow properties of each MMC-API are determined as described in Material Characterization. The results are summarized in Table 6a, Table 6b and Table 6c below.

[0434] Table 6a. Particle size distribution and physical state of solid azithromycin (20 wt%) loaded into MMC (ie, MMC-API).

[0435]

[0436] *MMC-API is classified as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0437] Table 6b. Particle size distribution and physical state of solid ibuprofen (35 wt%) loaded into MMC (ie, MMC-API).

[0438]

[0439] *MMC-API is classified as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0440] Table 6c. Particle size distribution and physical state of solid ritonavir (40 wt%) loaded into MMC (ie, MMC-API).

[0441]

[0442] *MMC-API is classified as crystalline if sharp peaks are present in the diffraction pattern and / or if a melting point is detected using DSC

[0443] The results of the bulk density and tap density measurements are shown in Table 6d, Table 6e and Table 6f below.

[0444] Table 6d. Flow properties of solid azithromycin (20 wt%) loaded into MMC (ie, MMC-API). Values ​​are given as mean and (sd).

[0445]

[0446] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0447] Table 6e. Flow properties of solid ibuprofen (35 wt%) loaded into MMC (ie, MMC-API). Values ​​are given as mean and (sd).

[0448]

[0449] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0450] Table 6f. Flow properties of solid ritonavir (40 wt%) loaded into MMC (ie, MMC-API). Values ​​are given as mean and (sd).

[0451]

[0452] *According to European Pharmacopoeia 9.0 (2016) Chapter 2 9.36. Flowability of Powders

[0453] Example 7 - Particle Size Distribution of Solid, Substantially Amorphous API

[0454] Particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) was prepared as described in Example 1, except that the final heat treatment was performed at 250°C for 10 hours, then maintained at 250°C for 10 hours, and then naturally cooled to room temperature. The MMC was analyzed as described in Material Characterization. The MMC material had a relative humidity of about 370-440 m 2 The average BET surface area is in the range of about 0.55-0.7 cm 3 The average pore volume in the range of 100 / g, of which about 100% of the pore volume comes from pores with a diameter of <10 nm. The particle size distribution of MMC materials shows an average d 10 In the range of about 87-102 μm, the average d 50 In the range of about 192-198 μm and with an average d 90 In the range of about 306-319 μm. The magnesium oxide (MgO) used was purchased from Lehmann & Voss & Co.

[0455] Different batches of MMC were loaded with the following APIs: 30 wt% dapagliflozin, 30 wt% lesinad, 30 wt% macitentan, 30 wt% selexipag, 30 wt% ibrutinib, 30 wt% bosutinib, 30 wt% afatinib, 30 wt% osimertinib and 30 wt% luliconazole, respectively, to provide a solid, substantially amorphous API (i.e., a specific MMC-API). A solid, substantially amorphous API (i.e., a specific MMC-API) was prepared and characterized as described in Example 2.

[0456] Use the laser diffraction of the Malvern Mastersizer 3000 with the Hydro MV attachment, use the wet method as described above, measure the particle size distribution of every kind of MMC-API.The measurement duration is 10 seconds background and 10 seconds sample.Carry out six sub-operations, then calculate average result on this basis.The results are summarized in Table 7 below.

[0457] Table 7. Particle size distribution of solid, substantially amorphous API (ie, MMC-API). Values ​​are given as mean and (sd).

[0458]

[0459] *) Since MMC was not subjected to heat treatment as described elsewhere, the MMC used to prepare afatinib MMC-API exhibited an ethanol content >7%

[0460] Example 8 - Preparation and stability of anhydrous and substantially amorphous mesoporous magnesium carbonate particles (MMC)

[0461] Particulate anhydrous and substantially amorphous mesoporous magnesium carbonate was prepared as described and claimed herein. Table 8a shows the pore volume, BET surface area, and pore peak width from nitrogen adsorption analysis. Fig. 9 The pore peak widths obtained from the particle size distribution curve of MMC are illustrated. The XRPD patterns were obtained as described in Materials Characterization and are shown in Tables 8b and Fig.10 The MMC was stored in sealed containers in a climate chamber at 25°C and 65% relative humidity. After 1 year of storage, the samples were analyzed by XRPD as described above to determine whether the samples were still amorphous or had crystallized (Table 2) and Fig.10 .

[0462] Table 8a. Pore volume, BET surface area and pore peak width of MMC.

[0463]

[0464] Table 8b. Physical state of MMC before (T0) and after storage for 12 months (T12) at 25°C and 65% relative humidity.

[0465]

Claims

1. A solid, amorphous active pharmaceutical mixture, comprising an active pharmaceutical ingredient API in an amount of at least 20% by weight, the active pharmaceutical ingredient API being mixed with granular anhydrous and amorphous mesoporous magnesium carbonate MMC, wherein: The solid, amorphous active drug mixture has: i. Pores with peak pore widths in the range of 2 nm to 10 nm; ii. 150-600m 2 Average BET surface area in the range of / g; iii. 0.1-1.2cm 3 Average pore volume in the range of / g; as well as iv. Display d 10 The average particle size distribution is 70-200 μm; The active pharmaceutical ingredient API is sorafenib.

2. An oral pharmaceutical preparation comprising the solid, amorphous active drug mixture according to claim 1.

3. An oral pharmaceutical preparation comprising the solid, amorphous active drug mixture of claim 1 mixed with a pharmaceutically acceptable excipient.

4. The oral pharmaceutical preparation according to claim 2 or claim 3, which is a capsule.

5. The oral pharmaceutical preparation according to claim 2 or claim 3, which is a tablet.

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