Use of co-processed excipients in continuous manufacture of solid dosage forms

Abstract

The present invention relates to the use of co-processed excipients in the continuous production of solid dosage forms.

Description

Technical Field

[0001] The present invention relates to the use of co-processed excipients in the continuous manufacture of solid dosage forms. Background Art

[0002] Compared with batch processing, continuous drug manufacturing provides potential flexibility, quality and economic advantages (Sau L.Lee et al., J.Pharm.Innov.2015,10,191-199). However, the number of feeders on the equipment used in continuous manufacturing is typically limited to four to six feeders. Therefore, the continuous manufacture of solid drug dosage forms (such as tablets) is limited to a composition consisting of API and only three to five excipients, unless a premix of multiple excipients is used. However, the use of premixes is economically inefficient, thus offsetting the advantages of continuous manufacturing to a certain extent. Therefore, it is necessary to simplify the pharmaceutical composition so that it is composed of as few excipients as possible. Summary of the invention

[0003] The inventors of the present invention have discovered that an effective way to simplify the composition is to introduce co-processed excipients, which combine the functionality of multiple single excipients.Thus, in one aspect, the present invention relates to the use of co-processed excipients in the continuous manufacture of solid dosage forms. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 A flow chart of the continuous small batch direct compression process according to the present invention described in Example 1 is depicted. DETAILED DESCRIPTION

[0005] definition

[0006] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0007] As used herein, the term "co-processed excipient" refers to any combination of two or more excipients obtained by physical co-processing that does not result in the formation of covalent bonds. Co-processed excipients have functions that cannot be achieved by sample blending. Co-processed excipients can be made by methods that only produce physical interactions between the components, such as co-drying, spray drying, granulation, extrusion, and high shear dispersion. Examples of co-processed excipients include, but are not limited to Sugar Pharmaburst Microcelac SMCC, ProSolv ODT, Comprecel SMCC 90, Pharmacel SMCC 90, SANAQ ML 011 and SANAQ SP205.

[0008] the term Refers to a co-processed excipient consisting of co-crystallized sucrose (97%) and maltodextrin (3%).

[0009] the term Refers to a co-processed excipient consisting of 95% glucose monohydrate and 5% oligosaccharides (produced by enzymatic hydrolysis of starch).

[0010] the term Refers to an excipient consisting of crystalline lactose monohydrate.

[0011] The term "Sugar ” refers to a co-processed excipient consisting of sucrose (90% to 93%) and invert sugar (7% to 10%).

[0012] The term "Pharmaburst ” refers to a co-processed excipient consisting of mannitol (75% to 90%), sorbitol (6% to 20%), crospovidone (7% to 15%), and silicon dioxide (0.1% to 1.5%).

[0013] the term Refers to a co-processed excipient consisting of xanthan gum, locust bean gum and dextrose.

[0014] the term It is composed of 93% lactose monohydrate, 3.5% povidone with a K value of 30 (" 30”) and 3.5% of cross-linked polyvinylpyrrolidone (“ CL”) composed of co-processed excipients.

[0015] the term Refers to a co-processed excipient made from lactose and corn starch.

[0016] the term Refers to an excipient consisting of xylitol.

[0017] the term Refers to a co-processed excipient made from pregelatinized starch and corn starch.

[0018] the term Refers to a co-processed excipient consisting of spray-dried fructose and starch.

[0019] the term Refers to 84.0% to 92.0% D-mannitol, 4.0% to 6.0% The co-processed excipients consist of CL-SF, 3.5% to 6.0% polyvinyl acetate, 0.5% to 2.0% water and 0.25% to 0.60% povidone.

[0020] the term" "CL-SF" refers to an excipient consisting of crospovidone.

[0021] the term Refers to a co-processed excipient obtained by spray drying 75% α-lactose monohydrate and 25% cellulose powder.

[0022] the term Refers to a co-processed excipient consisting of calcium carbonate and sorbitol.

[0023] The term "Microcelac ” refers to a co-processed excipient obtained by spray drying 75% α-lactose monohydrate and 25% microcrystalline cellulose.

[0024] the term Refers to a co-processed excipient obtained by spray drying microcrystalline cellulose and sodium carboxymethyl cellulose.

[0025] The term "SMCC90" refers to a co-processed excipient obtained by spray drying 98% microcrystalline cellulose and 2% colloidal silicon dioxide.

[0026] the term" "Easytab" refers to a co-processed excipient consisting of microcrystalline cellulose (96%), sodium starch glycolate (1.2%), colloidal silicon dioxide (2%) and sodium stearyl fumarate (0.8%).

[0027] the term Refers to a co-processed excipient consisting of 70% α-lactose monohydrate, 20% microcrystalline cellulose (MCC) and 10% white native corn starch.

[0028] the term Refers to an excipient composed of starch.

[0029] the term" "ODT" refers to a co-processed excipient consisting of D-mannitol and croscarmellose sodium.

[0030] The term "SANAQ ML 011" refers to a co-processed excipient consisting of lactose monohydrate and microcrystalline cellulose.

[0031] The term "SANAQ SP205" refers to a co-processed excipient consisting of microcrystalline cellulose, colloidal silicon dioxide, crospovidone and povidone.

[0032] As used herein, the term "API" refers to an active pharmaceutical ingredient. Preferably, the API is a small molecule, i.e., an organic compound with a molecular weight of ≤1000 Daltons. Specific but non-limiting examples of APIs are ralmitaront, alogabat, and fenebrutinib.

[0033] As used herein, the term "filler" refers to a substance added to a pharmaceutical composition to increase the weight and / or size of the pharmaceutical composition. Pharmaceutically acceptable fillers are described in Remington's Pharmaceutical Sciences and listed in Sheskey et al., Handbook of Pharmaceutical Excipients, 2017. Non-limiting examples of fillers are starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose) and lactose (e.g., lactose monohydrate). Preferred but non-limiting examples of fillers are cellulose and lactose.

[0034] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) (e.g., after administration) and release the active ingredient (e.g., Form B described herein). Pharmaceutically acceptable disintegrants are described in Remington's Pharmaceutical Sciences and listed in Sheskey et al., Handbook of Pharmaceutical Excipients, 2017. Non-limiting examples of disintegrants are low-substituted hydroxypropyl cellulose (also known as hydroxypropyl methylcellulose (HPMC) or hypromellose) and cross-linked sodium carboxymethylcellulose. A preferred but non-limiting example of a disintegrant is cross-linked sodium carboxymethylcellulose.

[0035] As used herein, the term "acidulant" refers to a pharmaceutically acceptable excipient having a pH of less than 4.0 in a 1% (w / w) aqueous solution. Acidulants are typically added to enhance the taste or to improve the dissolution of a (basic) API. Some examples of acidulants include citric acid, tartaric acid, fumaric acid, lactic acid, malic acid, succinic acid, phosphoric acid and acetic acid. Preferably, the acidulant is selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid and / or malic acid. More preferably, the acidulant is fumaric acid.

[0036] As used herein, the term "lubricant" refers to a substance added to a pharmaceutical composition to help reduce the adhesion of powder particles to equipment surfaces. Pharmaceutically acceptable glidants are described in Remington's Pharmaceutical Sciences and listed in Sheskey et al., Handbook of Pharmaceutical Excipients, 2017. Non-limiting examples of glidants are sodium stearyl fumarate and magnesium stearate. A preferred but non-limiting example of a glidant is sodium stearyl fumarate.

[0037] As used herein, the term "flow agent" refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticle friction. Pharmaceutically acceptable flow agents are described in Remington's Pharmaceutical Sciences and listed in the Handbook of Pharmaceutical Excipients by Sheskey et al., 2017. Non-limiting examples of flow agents include silicon dioxide (colloidal), polyethylene glycol PEG 6000, fumed silica, and polyoxyethylene glycol. 200, talc, etc. A preferred but non-limiting example is anhydrous colloidal silica.

[0038] As used herein, the term "crospovidone" refers to a cross-linked homopolymer of N-vinyl-2-pyrrolidone.

[0039] Specific but non-limiting examples of "sugar alcohol" as used herein include mannitol and isomalt.

[0040] As used herein, the term "mini-batches" refers to a variation of the batch blending process whereby the size of each batch is reduced to minimize the mass of the "in-process" material. A series of discrete mini-batches are transferred to a conventional rotary tablet press to achieve continuous tablet manufacturing via a direct compression process.

[0041] As used herein, the term "direct compression" refers to a tablet manufacturing process in which a physically mixed powder blend of the active pharmaceutical ingredient (API) and excipients is compressed directly into tablets without the addition of a wet or dry granulation step.

[0042] As used herein, the term "flowability" refers to the ability of a bulk powder to flow in a piece of equipment. It is quantified by appropriate testing equipment, such as a shear tester. Typically, the ratio of the consolidation stress to the unconfined yield strength is c Used to characterize fluidity numerically.

[0043] As used herein, the term "bulk density" refers to the ratio of the mass of a quantity of bulk solid to its volume. It is typically measured by gently introducing a known mass of sample into a graduated cylinder and carefully leveling the powder without compacting it. The apparent untapped volume is then read to the nearest scale unit.

[0044] As used herein, the term "lamilonide" refers to 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide.

[0045] As used herein, the term "alogabat" refers to 6-[[5-methyl-3-(6-methyl-3-pyridinyl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide.

[0046] As used herein, the term “fenbutinib” refers to 2-[3′-(hydroxymethyl)-1-methyl-5-([5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino)-6-oxo-1,6-dihydro-3,4′-bipyridin-2′-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one.

[0047] New uses for co-processed excipients

[0048] In a first aspect, the present invention provides the use of co-processed excipients in the continuous manufacture of a solid dosage form.

[0049] In a preferred embodiment, the continuous manufacturing is continuous small batch direct pressing.

[0050] In one embodiment, the solid dosage form is a tablet comprising:

[0051] (i) a core; and optionally

[0052] (ii) Coating.

[0053] As mentioned above, the number of feeders on equipment used in continuous manufacturing is limited, typically four to six feeders. Therefore, if a pharmaceutical composition is to be manufactured in a continuous manner, it is important to limit the amount of excipients in the pharmaceutical composition.

[0054] In one embodiment, the kernel consists of:

[0055] (i) API;

[0056] (ii) 1 to 4 co-processed excipients; and

[0057] (iii) 1 to 4 additional excipients selected from fillers, disintegrants, lubricants, flow agents and acidifiers;

[0058] The total number of excipients (ii) and (iii) is ≤5.

[0059] In one embodiment, the kernel consists of:

[0060] (i) API;

[0061] (ii) co-processed excipients;

[0062] (iii) fillers, disintegrants or acidifiers; and

[0063] (iv) Lubricants.

[0064] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0065] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium.

[0066] In one embodiment, the acidulant is fumaric acid.

[0067] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol and magnesium stearate.

[0068] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG 6000, fumed silicon dioxide 200 and talcum powder.

[0069] In one embodiment, the co-processed excipient is selected from Sugar Pharmaburst Microcelac SMCC90, Prosolv ODT, Comprecel SMCC 90, Pharmacel SMCC 90, SANAQ ML 011, and SANAQ SP205.

[0070] In a preferred embodiment, the co-processed excipient is selected from ProSolv ProSolv and

[0071] In a preferred embodiment, the co-processed excipients are selected from Combilac and SMCC90.

[0072] In a particularly preferred embodiment, the co-processed excipient is

[0073] In a particularly preferred embodiment, the co-processed excipient is

[0074] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0075] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0076] In a particularly preferred embodiment, the co-processed excipient is

[0077] In a particularly preferred embodiment, the co-processed excipient is

[0078] In a preferred embodiment, the API is selected from lamivudine, alogabat and fenbutinib.

[0079] In a particularly preferred embodiment, the API is Lamirontide.

[0080] In a particularly preferred embodiment, the API is alogabat.

[0081] In particularly preferred embodiments, the API is fenbutinib.

[0082] New tablet blends

[0083] In another aspect, the present invention provides a blend for continuous direct compression of tablet cores consisting of:

[0084] (i) API;

[0085] (ii) co-processed excipients; and

[0086] (iii) 1 to 4 additional excipients selected from fillers, disintegrants, lubricants and flow agents.

[0087] In one embodiment, the blend consists of:

[0088] (i) API;

[0089] (ii) co-processed excipients;

[0090] (iii) a filler or disintegrant; and

[0091] (iv) Lubricants.

[0092] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0093] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium.

[0094] In one embodiment, the acidulant is fumaric acid.

[0095] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol and magnesium stearate.

[0096] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG 6000, fumed silicon dioxide 200 and talcum powder.

[0097] In one embodiment, the co-processed excipient is selected from Sugar Pharmaburst Microcelac SMCC90, Prosolv ODT, Comprecel SMCC 90, Pharmacel SMCC 90, SANAQ ML 011, and SANAQ SP205.

[0098] In a preferred embodiment, the co-processed excipient is selected from ProSolv ProSolv and

[0099] In a preferred embodiment, the co-processed excipients are selected from Combilac and SMCC90.

[0100] In a particularly preferred embodiment, the co-processed excipient is

[0101] In a particularly preferred embodiment, the co-processed excipient is

[0102] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0103] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0104] In a particularly preferred embodiment, the co-processed excipient is

[0105] In a particularly preferred embodiment, the co-processed excipient is

[0106] In a preferred embodiment, the API is selected from lamivudine, alogabat and fenbutinib.

[0107] In a particularly preferred embodiment, the API is Lamirontide.

[0108] In a particularly preferred embodiment, the API is alogabat.

[0109] In particularly preferred embodiments, the API is fenbutinib.

[0110] It has been found that in order to facilitate free flowing material that can be gravity fed onto the tablet press and ensure a robust tablet compression process, it is very important that the flowability of the tablet blend is >FFc 4-5. Therefore, in a preferred embodiment, the blend according to the present invention has a flowability of >FFc 4-5.

[0111] Furthermore, it was found that blends with a bulk density > 0.4 g / mL improve the reliability of the tablet compression process.Thus, in a preferred embodiment, the blend according to the present invention has a bulk density > 0.4 g / mL.

[0112] It has been found that even with high drug loading, the blends according to the present invention can be reliably compressed into tablets in a continuous manner. In one embodiment, the blends according to the present invention have a drug loading of 1% wt / wt to 30% wt / wt, preferably 2% wt / wt to 25% wt / wt, more preferably 2% wt / wt to 20% wt / wt.

[0113] In a particularly preferred embodiment, the API (i) is lamironide; the co-processed excipient (ii) is ProSolv SMCC 90; the additional excipient (iii) is a disintegrant which is croscarmellose sodium; and the lubricant (iv) is sodium stearyl fumarate (see Example 2).

[0114] In a particularly preferred embodiment, the API (i) is alogabat; the co-processed excipient (ii) is ProSolv SMCC 90; the additional excipient (iii) is a disintegrant which is croscarmellose sodium; and the lubricant (iv) is sodium stearyl fumarate (see Example 3).

[0115] In a particularly preferred embodiment, the API (i) is fenbutinib; the co-processed excipient (ii) is compilac; the additional excipient (iii) is the acidifier, which is fumaric acid; and the lubricant (iv) is magnesium stearate (see Example 4).

[0116] New tableting method

[0117] In another aspect, the present invention provides a continuous process for manufacturing tablets in a small batch mode, comprising the steps of:

[0118] (i) feeding the API, co-processed excipients and 1 to 4 additional excipients each from separate screw feeders into a small batch mixer;

[0119] (ii) blending the components of step (i) in a small batch blender;

[0120] (iii) discharging the small batch prepared in steps (i) and (ii) into a tablet press;

[0121] (iv) compressing the blend from step (iii) into tablet cores;

[0122] (v) repeating steps (i) to (iv) as necessary to produce the desired batch size; and

[0123] (vi) Optionally spraying the film coating suspension onto the tablet cores from step (iv).

[0124] In one embodiment, the 1 to 4 additional excipients are selected from fillers, disintegrants, lubricants and flow agents.

[0125] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0126] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium.

[0127] In one embodiment, the acidulant is fumaric acid.

[0128] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol and magnesium stearate.

[0129] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG 6000, fumed silicon dioxide 200 and talcum powder.

[0130] In one embodiment, the co-processed excipient is selected from Sugar Pharmaburst Microcelac SMCC90, Prosolv ODT, Comprecel SMCC 90, Pharmacel SMCC 90, SANAQ ML 011, and SANAQ SP205.

[0131] In a preferred embodiment, the co-processed excipient is selected from ProSolv ProSolv and

[0132] In a preferred embodiment, the co-processed excipients are selected from Combilac and SMCC90.

[0133] In a particularly preferred embodiment, the co-processed excipient is

[0134] In a particularly preferred embodiment, the co-processed excipient is

[0135] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0136] In a particularly preferred embodiment, the co-processed excipient is ProSolv

[0137] In a particularly preferred embodiment, the co-processed excipient is

[0138] In a particularly preferred embodiment, the co-processed excipient is

[0139] In a preferred embodiment, the API is selected from lamivudine, alogabat and fenbutinib.

[0140] In a particularly preferred embodiment, the API is Lamirontide.

[0141] In a particularly preferred embodiment, the API is alogabat.

[0142] In particularly preferred embodiments, the API is fenbutinib.

[0143] In one embodiment, the rate of the process according to the invention is ≤ 30 kg, preferably ≤ 25 kg, more preferably ≤ 20 kg, more preferably ≤ 15 kg, most preferably ≤ 10 kg tablet cores per hour.

[0144] In one embodiment of the method according to the invention the small batch mixer is a high shear mixer.

[0145] In one embodiment of the method according to the invention, the pressing in step (iv) is direct pressing.

[0146] In one aspect, the present invention provides a tablet having an inner core consisting of a blend as described herein above (when obtained from a process according to the invention).

[0147] In one aspect, the present invention provides the use of a blend as described herein above in a method according to the present invention.

[0148] Examples

[0149] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the present invention, but merely as representative thereof.

[0150] Example 1 – Continuous small batch direct compression method

[0151] equipment

[0152]

[0153] deal with

[0154] 1. Feed excipient (i) from a large feeder; and API, excipient (ii) and excipient (iii) from three small feeders into a small batch mixer.

[0155] 2. Mix small batches in a small batch blender.

[0156] 3. Discharge the small batch prepared in steps 1 and 2 into the tablet press.

[0157] 4. Compress the tablet cores and conduct IPC on the single tablet weight, hardness, thickness, friability and disintegration time of the tablet cores.

[0158] 5. Repeat steps 1 through 4 as necessary to make the desired batch size.

[0159] 6. Optionally prepare a film coating suspension and spray the film coating onto the tablet cores obtained from step 4.

[0160] IPC was performed on the average weight, thickness and disintegration time of the film-coated tablets.

[0161] A schematic diagram of this method is provided in Figure 1 middle.

[0162] Example 2 - Lamiront 150 mg Tablet Formulation

[0163]

[0164] a) SMCC90 is a commercially available excipient composed of silicified microcrystalline cellulose.

[0165] All excipients used in the formulations were of pharmacopoeial (Ph. European and / or USP / NF) grade.

[0166] Tablets can be manufactured according to the continuous process described in Example 1.

[0167] Example 3 - alogabat 20 mg tablet formulation

[0168]

[0169] a) ProSolv SMCC 90 is a commercially available excipient consisting of silicified microcrystalline cellulose.

[0170] All excipients used in the formulations were of pharmacopoeial (Ph. European and / or USP / NF) grade.

[0171] Tablets can be manufactured according to the continuous process described in Example 1.

[0172] Example 4 - Fenbutinib 200 mg Tablet Formulation I

[0173]

[0174]

[0175] a)Combilac is a commercially available excipient consisting of microcrystalline cellulose, corn starch, and lactose monohydrate.

[0176] All excipients used in the formulations were of pharmacopoeial (Ph. European and / or USP / NF) grade.

[0177] Tablets can be manufactured according to the continuous process described in Example 1.

Claims

1. Use of co-processed excipients in the continuous manufacture of solid dosage forms.

2. The use according to claim 1, wherein the solid dosage form is a tablet, comprising: (i) kernel; and optionally (ii) Coating.

3. The use according to claim 2, wherein the core consists of: (i) API; (ii) 1 to 4 co-processed excipients; as well as (iii) 1 to 4 additional excipients selected from fillers, disintegrants, lubricants, flow agents and acidifiers; The total number of excipients (ii) and (iii) is ≤5.

4. The use according to claim 3, wherein the core consists of: (i) API; (ii) co-processed excipients; (iii) fillers, disintegrants or acidifiers; as well as (iv) Lubricants.

5. A blend for continuous direct compression of tablet cores consisting of: (i) API; (ii) co-processed excipients; as well as (iii) 1 to 4 additional excipients selected from fillers, disintegrants, lubricants, flow agents and acidifiers.

6. The blend according to claim 5, consisting of: (i) API; (ii) co-processed excipients; (iii) fillers, disintegrants or acidifiers; as well as (iv) Lubricants.

7. The use according to claim 3 or 4, or the blend according to claim 5 or 6, wherein the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

8. The use according to any one of claims 3, 4 and 7, or the blend according to any one of claims 5, 6 and 7, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium.

9. The use according to any one of claims 3, 4, 7 and 8, or the blend according to any one of claims 5, 6, 7 and 8, wherein the lubricant is selected from sodium stearyl fumarate, polyethylene glycol and magnesium stearate.

10. The use according to any one of claims 3 and 7 to 9, or the blend according to any one of claims 5 and 7 to 9, wherein the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG 6000, fumed silicon dioxide 200 and talcum powder.

11. The use according to any one of claims 3, 4 and 7 to 10, or the blend according to any one of claims 5 to 10, wherein the acidulant is fumaric acid.

12. The use according to any one of claims 1 to 4 and 7 to 11, or the blend according to any one of claims 5 to 11, wherein the co-processed excipient is selected from Sugar Pharmaburst Microcelac SMCC90, Prosolv ODT, Comprecel SMCC 90, Pharmacel SMCC 90, SANAQ ML 011 and SANAQSP205.

13. The use or blend according to claim 12, wherein the co-processed excipient is selected from ProSolv ProSolv and 14. The use or blend according to claim 13, wherein the co-processed excipient is selected from Combilac and SMCC90.

15. The use according to any one of claims 3, 4 and 7 to 14, or the blend according to any one of claims 5 to 14, wherein the API is selected from lamivudine, alogabat and fenbutinib.

16. A small batch continuous process for manufacturing tablets, the process comprising the steps of: (i) feeding the API, co-processed excipients and 1 to 4 additional excipients each from separate screw feeders into a small batch mixer; (ii) blending the components of step (i) in the small batch mixer; (iii) discharging the small batch prepared in steps (i) and (ii) into a tablet press; (iv) compressing the blend from step (iii) into tablet cores; (v) repeating steps (i) to (iv) as necessary to produce the desired batch size; and (vi) optionally spraying a film coating suspension onto the tablet cores from step (iv).

17. A continuous process according to claim 16, wherein the process rate is ≤ 30 kg, preferably ≤ 25 kg, more preferably ≤ 20 kg, more preferably ≤ 15 kg, most preferably ≤ 10 kg tablet cores per hour.

18. A continuous process according to claim 16 or 17, wherein the small batch mixer is a high shear mixer.

19. The continuous process according to any one of claims 16 to 18, wherein the pressing in step (iv) is direct pressing.

20. A tablet having a core consisting of the blend according to any one of claims 5 to 15, said tablet being obtained by the process according to any one of claims 16 to 19.

21. Use of a blend according to any one of claims 5 to 14 in a method according to any one of claims 16 to 19.

22. The blend according to any one of claims 5 to 15 having a flowability of >FFc 4-5.

23. The blend of any one of claims 5 to 15 and 22 having a bulk density > 0.4 g / mL.

24. The blend according to any one of claims 5 to 15, 22 and 23 having a drug loading of 1% wt / wt to 30% wt / wt, preferably 2% wt / wt to 25% wt / wt, more preferably 2% wt / wt to 20% wt / wt.

25. The invention as hereinbefore described.

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