PROCESS OF PREPARING ACTIVE PHARMACEUTICAL INGREDIENT SALTS

Abstract

The invention relates to a process of preparing a salt of an active pharmaceutical ingredient, the process comprising providing a blend of an active pharmaceutical ingredient and a salt forming substance, mixing the blend, optionally in the presence of added water, to react the active pharmaceutical ingredient with the salt forming substance to provide the salt of the active pharmaceutical ingredient; wherein when the active pharmaceutical ingredient is acidic, the salt forming substance is a base and the pKa difference between the acidic active pharmaceutical ingredient and the base is greater than 1, typically greater than 2 or preferably greater than 3; or when the active pharmaceutical ingredient is basic, the salt forming substance is an acid and the pKa difference between the basic active pharmaceutical ingredient and the acid is greater than 1, typically greater than 2 or preferably greater than 3,

Claims

1. A process of preparing a salt of an active pharmaceutical ingredient, the process comprising providing a blend of an active pharmaceutical ingredient and a salt forming substance, mixing the blend, optionally in the presence of added water, to react the active pharmaceutical ingredient with the salt forming substance to provide the salt of the active pharmaceutical ingredient; wherein when the active pharmaceutical ingredient is acidic, the salt forming substance is a base and the pKa difference between the acidic active pharmaceutical ingredient and the base is greater than 1, typically greater than 2 or preferably greater than 3; or when the active pharmaceutical ingredient is basic, the salt forming substance is an acid and the pKa difference between the basic active pharmaceutical ingredient and the acid is greater than 1, typically greater than 2 or preferably greater than 3.

2. The process of claim 1, wherein the mixing is carried out in a twin screw extruder, a single screw extruder or a granulator.

3. The process of claim 1, wherein the process does not comprise adding additional water or solvent.

4. The process of claim 1, wherein the process does not comprise a drying step.

5. The process of claim 1, wherein the process does not comprise a further granulation or micronization step.

6. The process of claim 1, wherein the mixing step provides the salt of the active pharmaceutical ingredient in powder form.

7. The process of claim 1, wherein the mixing is carried out in a twin screw extruder with a modified screw configuration to facilitate dispersive and distributive mixing via the generated shear force and stress inside the heated barrel.

8. The process of claim 1, wherein the process is a continuous process.

9. The process of claim 1, wherein the process further comprises manufacturing tablets or capsules with the salt of the active pharmaceutical ingredient with or without the addition of pharmaceutically acceptable excipients.

10. The process of claim 9 wherein the process comprises manufacturing tablets or capsules with the salt of the active pharmaceutical ingredient with or without the addition of a hydrophilic polymer, super disintegrant, glidant, filler or lubricant.

11. The process of claim 9, wherein a powder of the salt of the active pharmaceutical ingredient is directly compressed to provide a tablet.

12. The process of claim 9, wherein a powder of the salt of the active pharmaceutical ingredient is blended with a lubricant and then directly compressed to provide a tablet.

13. The process of claim 9, wherein the tablet is an orally disintegrating tablet.

14. The process of claim 9, wherein a powder of the salt of the active pharmaceutical ingredient is directly processed via a capsule machine to provide a capsule.

15. The process of claim 9, wherein a powder of the salt of the active pharmaceutical ingredient is blended with a lubricant and then directly processed to provide a capsule.

16. The process of claim 1, wherein a powder form of the salt of the active pharmaceutical ingredient is mixed with one or more pharmaceutically acceptable excipient to provide a sachet formulation.

17. The process of claim 16 wherein the one or more pharmaceutically acceptable excipient is a sugar polyol, sucrose, lactose, PEG 2000-4000, sodium alginate, MCC, citric acid, a carbomer, a poloxamer, methyl p hydroxybenzoate, propyl p hydroxybenzoate, aspartame, saccharin, sodium hydroxide, sodium benzoate, a flavourant, a colouring agent, or a combination thereof.

18.-21. (canceled)

22. A method of treatment of a human or animal body by therapy, the method comprising reconstitution of the sachet formulation of claim 16 in 5-10 ml of water prior to administration to the human or animal.

23. The method of treatment of the human or animal body by therapy of claim 22, wherein the sachet formulation comprises a dose of 5-200 mg, based on the salt of the active pharmaceutical ingredient.

24. A sachet comprising a formulation as defined in claim 16.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0051] FIG. 1 illustrates screw configurations used in the process of the present invention.

[0052] FIG. 2 is a scheme showing how the process of the invention can be useful in directly manufacturing tablets/capsules without any intermediate steps (e.g. blending with lubricants).

[0053] FIG. 3 is a scheme showing how the process of the invention can be useful in directly manufacturing orally disintegrating tablets/capsules with intermediate step (e.g. blending with lubricants).

[0054] FIG. 4 shows Residence Time Distribution (RTD) and Mean Residence Time (MRT) for certain Examples. The examples shown in FIG. 4 are, in order of increasing peak absorbance, Examples 2, 4 and 29.

[0055] FIG. 5(a) shows XPRD diffractograms of, from top to bottom, a commercially-available ibuprofen salt, pure ibuprofen, and Example 2.

[0056] FIG. 5(b) shows XPRD diffractograms of, from top to bottom, Example 8 and commercially available ibuprofen lysine

[0057] FIG. 5(c) shows XPRD diffractograms of, from top to bottom, Example 18 and commercially available diclofenac sodium.

[0058] FIG. 5(d) shows XPRD diffractograms of, from top to bottom, pure tranilast, the composition of Example 27 and a physical blend of the components of Example 27

[0059] FIG. 6(a) shows DSC thermal transitions of commercially available ibuprofen, a physical mixture of the components of Example 2, and Example 2.

[0060] FIG. 6(b) shows thermal transitions of Example 2 for melting and recrystallization.

[0061] FIG. 6(c) shows thermal transitions of ibuprofen in bulk form.

[0062] FIG. 6(d) shows thermal transitions of Example 8.

[0063] FIG. 6(e) shows thermal transitions of commercially available diclofenac sodium salt and Example 17.

[0064] FIG. 7 shows particle size analysis of Examples 2, 8 and 28.

[0065] FIG. 8 shows SEM images of Example 2 FIG. 9 shows NMR results for, from left to right, Example 2 and commercially available ibuprofen.

[0066] FIG. 10 shows results of in vitro dissolution studies (pH 1.2) for, from top to bottom at t=5s, Examples 3, 8, 7 and 2, and pure ibuprofen.

[0067] FIG. 11 shows results of in vitro dissolution studies (pH 1.2) for, from top to bottom at t=5s, Examples 22 and 23 and pure phenytoin.

[0068] FIG. 12 shows thermal transitions of ketoconazole (KTZ), oxalic acid (OXA) and ketoconazole oxalate salt (KTZ/OXA) prepared according to the process of the present invention.

[0069] FIG. 13 shows XRD diffractograms of ketoconazole (KTZ), oxalic acid (OXA) and ketoconazole oxalate salt (KTZ/OXA) prepared according to the process of the present invention.

[0070] FIG. 14 identifies 2-theta positions of peaks in XRD diffractograms of ketoconazole (KTZ), oxalic acid (OXA) and ketoconazole oxalate salt (KTZ/OXA) prepared according to the process of the present invention.

EXAMPLES

[0071] The following substances are used:

TABLE-US-00001 Ingredients Chemical Name Ibuprofen (RS)-2-(4-(2-methylpropyl)phenyl) propanoic acid Diclofenac 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid Phenytoin 5,5-diphenylimidazolidine-2,4-dione Tranilast 2-{[(2E)-3-(3,4-dimethoxyphenyl)prop-2- enoyl]amino}benzoic acid Ketoconazole 1-[4-(4-{[(2R,4S)-rel-2-(2,4-dichlorophenyl)-2- (1H-imidazol-1-ylmethyl)-1,3-dioxolan-4- yl]methoxyl}phenyl)piperazin-1-yl]ethan-1-one Lamotrigine 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine Lactose -D-galactopyranosyl-(1.fwdarw.4)-D-glucose Sorbitol (2S,3R,4R,5R)-Hexane-1,2,3,4,5,6-hexol Pearlitol Mannitol MCC Microcrystalline cellulose Xl 10 Polyplasdone crossprovidone superdisintegrants Xl Polyplasdone crossprovidone superdisintegrants Vivasol Croscarmellose sodium Kollidon Cl-SF Crospovidone CL-SF Kollidon Cl-MF Crospovidone CL-MF PRUV Sodium Stearyl Fumarate MgSt Magnesium stearate SiO2 Silica dioxide

Blending

[0072] The active pharmaceutical ingredient/salt forming substance (base or acid) powder blends in various concentrations (% w/w) were mixed thoroughly for 10 min using a turbula TF2 mixer (Basel, Switzerland) to form a homogeneous powder prior to the hot-melt extrusion (HME) processing.

Process

[0073] Extrusion was carried out using a 16 mm co-rotating twin screw extruder (Eurolab, Thermo Scientific, UK) having length-to-diameter ratio of 40:1, with two different extruder screw configurations for ensuring distributive and dispersive mixing of the active pharmaceutical ingredient and salt forming substance in order to facilitate the interactions. The extruder was operated without a die. Feeding material was fed into the extruder at a rate of 0.5-7 kg/h using a gravimetric twin screw feeder (Brabender, Germany) at three different extruder barrel temperature profiles (120 C. for ibuprofen, 180 C. for diclofenac) at screw speeds of 50-100 rpm. Extruder screw configurations were selected to achieve a range of shearing intensities (Table 1 and FIG. 1).

TABLE-US-00002 TABLE 1 Screw configurations for the manufacture of salts Screw Configuration I Screw Configuration II Element/Blocks Element/Blocks Length (D) type Length (D) type 11 Forward conveying 19 Forward conveying 1 30 forward mixing 1 30 forward mixing 1 60 forward mixing 1 60 forward mixing 1 90 mixing 1 90 mixing 6 Forward conveying 2 Forward conveying 1.5 60 forward mixing 0.5 0 mixing 8 Forward conveying 1 Forward conveying 1 60 forward mixing 0.5 0 mixing 2 90 forward mixing 2 Forward conveying 6 Forward conveying 0.5 0 mixing 1.5 Discharge 1 Forward conveying 0.5 0 mixing 2 90 6.5 Forward conveying 1.5 Discharge D = 16 mm conveying block

[0074] The process a) involves the processing of the active ingredients (either acidic or basic) with a wide range of acids/bases with a pKa difference of more than 3 in the active pharmaceutical ingredient/salt forming substance (base or acid) in a binary blend with an option for tarnary mixture, b) does not require the use of water or organic solvents (e.g lower alcohols) to facilitate the exothermic reaction, c) does not require a drying process for the obtained granules of the salts, d) the shear force and mechanical energy produced inside the barrel aided by the temperature get the drug to react with base to form salts and d) it does not require further granule micronization.

[0075] Typically the granules are produced by forming solid bridges through the following mechanisms: a) partial melting (or complete) of the drug substance when drug/inorganic excipient blends are used due to the high temperature and torque applied during the process. The drug then interacts with the inorganic excipient through a proton exchange and when the temperature is relieved (late barrel zones) crystallization will take place and bind the particles together.

[0076] Inorganic excipients are mainly the base or weak acids and are referred as salt forming substances herein. For an example, for weak acidic drug (e.g. ibuprofen of phenytoin) inorganic excipients are mainly referred to those bases having pKa values more than 7 or above. These bases are selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium glycinate, sodium lysinate, L-arginine, sodium glycinate monohydrate, N-methylglucosamine, potassium glycinate and tribasic sodium and potassium phosphates. For weak basic drug (e.g. propranolol, cetirizine or diphenhydramine), inorganic excipients are mainly referred to acids having lower pKa values than the drugs (the pKa difference is more than 3).

[0077] In this process the extrusion die is removed and the granules are obtained as a free flowing powder. All trials were conducted using a EuroLab 16 twin screw extruder (ThermoFisher, Germany) and all as extruded free flowing powders were suitable to incorporate into final tablet formulations (FIGS. 2 and 3).

Normal and Orally Disintegrating Tablet (ODT) Preparation

[0078] Batches were prepared using batch sizes of 100 g. All materials (see Tables 2-4) were passed through a mesh sieve with an aperture of 500 m before use. Where included, the batches were blended with sodium stearyl fumarate (1%) in a Turbula TF2 mixer (Basel, Switzerland) for 10 minutes. Blends were directly compressed on a Flexitab trilayer tablet press (Oystar-Manesty, Germany) using 13 mm normal flat punches. Dwell time was set at 30 ms and the compaction force varied from 8-12 kN to obtain tablets of about 3 mm thickness (average weight 250-400 mg). All prepared ODTs were further evaluated to characterise the properties of the manufactured dosage forms (Table 5).

Formulations Processing Parameters

[0079] Temperature profiles for Ibuprofen Temperature profiles (40 C.-80 C.-80 C.-100 C.-120 C.-120 C.-120 C.-120 C.-25 C. (5 C., feeder.fwdarw.die); Screw speed 50-100 rpm; feed rate 1-7 kg/h.

[0080] Temperature for Diclofenac/Phenytoin/Ketoconazole-Temperature profiles (50 C.-170 C.-170 C.-180 C.-180 C.-180 C.-180 C.-180 C.-25 C. (5 C., feeder.fwdarw.die); Screw speed 50-100 rpm; feed rate 0.5-7 kg/h.

[0081] Temperature for Lamotrigine-Temperature profiles (50 C.-170 C.-180 C.-200 C.-200 C.-200 C.-200 C.-200 C.-25 C. (5 C., feeder.fwdarw.die); Screw speed 50-100 rpm; feed rate 0.5-5 kg/h.

TABLE-US-00003 TABLE 2 Extrusion compositions comprising pharmaceutical ingredient & salt forming substance Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- E ple ple 1 ple 2 ple 3 ple 4 ple 5 ple 6 ple 7 ple 8 ple 9 ple 10 ple 11 ple 12 ple 13 Ingredients Molar Ratio Ibuprofen 1 1 1 2 1 1 1 1 1 2 1 1 1 Diclofenac Phenytoin Tranilast NaOH 1 2 3 3 KOH 2 3 Ca(OH).sub.2 1 3 Na.sub.2CO.sub.3 K.sub.2CO.sub.3 Sodium 2 3 Lysinate Pottasium 1 3 Lysinate Tribasic 1 sodium Potassium 2 phospahte Tartaric Acid Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- ple 15 ple 16 ple 17 ple 18 ple 19 ple 20 ple 21 ple 22 ple 23 ple 24 ple 25 ple 26 ple 27 ple 28 Ingredients Molar Ratio Diclofenac 1 2 1 1 Phenytoin 1 1 2 1 1 1 Tranilast 1 2 1 1 NaOH 2 3 2 3 2 2 2 KOH Ca(OH).sub.2 Na.sub.2CO.sub.3 2 3 1 2 K.sub.2CO3 1 Sodium Lysinate Pottasium Lysinate Tribasic 2 3 5 sodium Potassium phospahte Tartaric 1 1 2 Acid Exam- Exam- Exam- Exam- Exam- Exam- ple 29 ple 30 ple 31 ple 32 ple 33 ple 34 Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam Ingredients Molar ratio ple 35 ple 36 ple 37 ple 38 ple 39 ple 40 ple 41 42 Ibuprofen 1 1 1 1 1 1 Diclofenac Ketoconazole 0.9 1 1 0.45 1 1 Lamotrigine 1 1 Tranilast NaOH KOH Ca(OH).sub.2 Na.sub.2CO.sub.3 K.sub.2CO3 Sodium Lysinate L-Arginine 0.8 0.9 1 1.1 1.2 2 Oxalic acid 1 1 1.1 0.55 1.5 2 Saccharin 1 2 Pottasium Lysinate Tribasic sodium Potassium phospahte Tartaric Acid indicates data missing or illegible when filed

TABLE-US-00004 TABLE 3 Conventional Tablet Compositions without any other excipients Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- ple 2 ple 3 ple 7 ple 8 ple 15 ple 18 ple 21 ple 22 ple 23 ple 25 ple 26 ple 28 ple 29 ple 32 Ingre- (% (% (% (% (% (% (% (% (% (% (% (% (% (% dients w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) Salts 98 100 98 98 99 98 99.5 99 98 98 95 99 99 99 MgSt 1 1 1 0.8 1.5 0.5 0.5 1 0.5 1 0.5 0.5 0.5 SiO2 1 1 1 0.2 0.5 0.5 1 1.5 4 0.5 0.5 0.5

TABLE-US-00005 TABLE 4 ODTs compositions Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- Exam- ple 2 ple 3 ple 7 ple 8 ple 15 ple 18 ple 21 ple 22 ple 23 ple 25 ple 26 ple 28 ple 29 ple 32 Ingre- (% (% (% (% (% (% (% (% (% (% (% (% (% (% dients w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) w/w) Salts 71.4 71.4 71.4 71.4 71.4 83.33 66.67 66.67 83.33 83.33 79.11 79.11 83.33 79.11 Pearlitol/ 6.1 7 7.6 12.6 sorbitol Xl 10 15 20 20 15.67 19.88 19.88 Xl Vivasol 20 20 15.67 Kollidon 10 15.67 Cl- SF Kollidon 15 15.67 19.88 Cl- MF PRUV 1 1 1 1 1 1 1 1 1 1 1 1 MgSt 0.8 SiO2 0.2 indicates data missing or illegible when filed

Evaluation of Tablets: Protocols

[0082] All prepared tablets were evaluated for the uniformity of thickness, hardness (Erweka TBH 28, Frankfurt, Germany), friability (Erweka friabilator, model A3R, Frankfurt, Germany), and disintegration time (Erweka, model ZT4, Heusenstamm, Germany) according to USP22 tests. The results are shown in Table 5.

In Vivo Drug Disintegration

[0083] In vivo disintegration and taste masking evaluation was performed by a panel of 6 healthy human volunteers from whom written consent was first obtained (approved by the Ethics Committee of the University of Greenwich). The study is also in accordance to the Code of Ethics of the World Medical Association (Declaration of Helsinki). The healthy volunteers of either sex (age 18-25) were selected, trained and the one tablet was held in the mouth after rinsing and the time required for complete disintegration of the tablet was recorded. The time when the tablet placed on the tongue disintegrated without leaving any lumps was taken as the end point. The disintegrated material was held in the mouth for another 60 seconds, and then spat out. The mouth was rinsed with water without swallowing the disintegrated material and, finally, the roughness levels were recorded on a numerical scale ranging from 1 to 5 where 1, 2, 3, 4 and 5 indicate no, slight, threshold, moderate, and high roughness, respectively. The results are shown in Table 5.

In Vitro Dissolution Tests

[0084] Results obtained from in vitro dissolution studies (pH 1.2) were obtained. All manufactured salts showed faster release compared to that of pure active ingredients. The dissolution rate of the poorly water soluble ibuprofen was increased 30 folds in Example 1 or 2 compared to that of pure ibuprofen.

TABLE-US-00006 TABLE 5 Properties of prepared ODTs from Table 4 Disintegration Time (s) Formulations Hardness (Kp) Friability (%) In vitro In vivo Example 2 9.6 0.5 0.9 5 0.2 9 0.2 Example 3 10.6 0.5 0.8 6 0.2 11 0.2 Example 7 11.6 0.5 0.7 4 0.2 9 0.2 Example 8 10.6 0.5 0.9 3 0.2 10 0.2 Example 15 8.6 0.5 1.0 6 0.2 12 0.2 Example 18 10.6 0.5 0.9 5 0.2 12 0.2 Example 21 8.6 0.5 0.6 5 0.2 9 0.2 Example 22 8.9 0.5 0.8 6 0.2 13 0.2 Example 23 9.6 0.5 0.8 4 0.2 8 0.2 Example 25 10.6 0.5 0.7 7 0.2 13 0.2 Example 26 9.6 0.5 0.8 6 0.2 13 0.2 Example 28 11.0 0.5 0.6 5 0.2 11 0.2 Example 29 10.10 0.5 0.6 5 0.2 12 0.2 Example 35 9.7 0.5 0.8 9 0.2 17 0.2