< ~~ oS a a + Ss Ss a S a = GD INT NATIONAL APPLICATION PUBL D UNDER THE PATENT COOPERATION TREATY (PCT) World Intellectual Property > era Z AAO A International Burau ional Publication Number 2 (10) Interna 05 March 2020 (05.03.2020) = WIPO| PCT ean (1) International Patent Classificato ABI 9/10 2006.01) AGIK 47726 (2006.01) AOIK 31/167 (2006.01) 21) International Application Number: PCT/EPDOIMOTZNAS International ing Date: 22 August 2019 (22.08.2019) (25) Filing Language: English (26) Publicatio Language: English G0) Priority Data: 62723,561 28 August 2018 (28.08.2018) US (71) Applicant: GSK CONSUMER HEALTHCARE S.A. [CH/CH; Rowe de L'Etaz, 1197 Prangins (CH), (72) Inventors: CAVINATO, Mauro; GSK Consumer Health- care S.A., Route de 'Btraz 2, Case postale 1279, 1260 Ny- on 1 (Cit). GEROLA, Karin; GSK Consumer Healthcare 8.A., Route de Maz 2, Case postale 1279, 1260 Nyon | Ch. (74) Agent: MORRIS, Miriam, Elizabeth; GlaxoSmithKline, Global Patents (CN925.1), 980 Great West Road, Brentford Middlesex TW8 9GS (GB). (81) Designated States (unless otherwise indicated. for every Kind of national protection available): AE, AG. AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY. BZ, CA.CH, CL, CN, CO, CR, CU, CZ, DE, DI, DK, DM, DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, 1S, JO, JP, KE, KG, KH, KN, KP. KR|KW,KZ,LA,LC,LK,LR.LS, LU. LY, MA, MD. ME, MG, MK, MN, MW, MX, MY. MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, 8G, SK, SL, SM, ST, SV, SY, TH, TI, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated. for every ind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST. $Z.1Z, UG, 2M, ZW), Enmasian (AM, AZ, BY, KG, KZ, RU, TI, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, 1S, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BI, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG), Published: — With intemational search report (Art. 21(3) (G8) Title: PARACETAMOL LIQUID SUSPENSIONS, (87) Abstract: The present invention relates o pharmaceutical liquid suspensions suitable for oral administration, More specifically the present invention relates to pharmaceutical liquid suspensions containing paracetamol wherein the suspensions are formulated with ‘paracetamol particles having adS0 of ess than or equal to 1am and a0 of less than or equal to 35jum such that browning discoloration is reduced during prolonged storage10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 PARACETAMOL LIQUID SUSPENSIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical liquid suspensions suitable for oral administration. More specifically, the present invention relates to pharmaceutical liquid suspensions containing N-acetyp-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol). In particular, the invention relates to paracetamol liquid suspensions that are formulated with paracetamol particles having a d50 of less than or equal to 10m and a d90 of less than or equal to 35m such that browning discoloration is reduced during prolonged storage, compared with paracetamol liquid suspensions that are formulated with paracetamol particles having larger average particle sizes. BACKGROUND OF THE INVENTION Paracetamol is a commonly used analgesic and antipyretic drug that has been available in many countries for more than 40 years. A wealth of experience clearly establishes it as the standard antipyretic and analgesic for mild to moderate pain states. Paracetamol is available in many countries for non-prescription over-the-counter sale in conventional orally administered dosage forms, including solid forms, such as, capsules, caplets, gel caps, or tablets, and liquid forms, such as, solutions, e.g., syrups and elixirs, emulsions, or suspensions. Medicaments administered in solid form are usually intended to be swallowed whole. However, children, and some adults, including disabled or incapacitated patients, have trouble swallowing solid dosage forms even if the tablet or capsule is very small. Chewable tablets are an option as well, but are unacceptable if the active pharmaceutical ingredient (API) has a disagreeable taste. For many patients, including pediatric and geriatric patients, a liquid oral dosage form is preferable over chewable dosage form because of the ready swallowability without chewing of the liquid dosage form. Liquid dosage forms can be either syrups or suspensions. Liquid suspensions are a two-phase system having solid, poorly water-soluble API particles, dispersed throughout liquid medium. In a suspension, the API does not dissolve, or dissolves to a limited extent, in the liquid medium and therefore, remains intact in the form of small particles. A suspension does not encompass emulsions, which are meant to describe liquids suspended within liquid carriers. Nor does a suspension encompass syrup formulations, which contain fully dissolved APIs. The preparation of such a suspension is often underestimated and involves more than mixing a solid in a liquid. Knowledge of particles behavior in the liquids, as well as wetting agents, suspending agents, polymers, preservatives, colors and flavors is needed in order to manufacture a product with the targeted quality attributes (David B. Troy, Paul Beringer, The Science and Practice of Pharmacy, p.767-768, Lippincott Williams & Wilkins, 2006).10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 One challenge associated with liquid suspensions is sedimentation, that is the tendency for particles in suspension to settle out of the fluid. Among all the ingredients of a suspension, the suspended phase (i.e., containing API particles, in this case, paracetamol particles) is one of the most critical components since it might tend to sediment over time and under specific conditions. Different factors influence the sedimentation rate of particles in suspension. Stokes’ law is often used to express the sedimentation rate: aS _ (pp ~ pu) dt 1877 ‘ Where dS/dt is the sedimentation rate, d is the diameter of the particles, pp is the density of the particles, pw is the density of the medium, g is the gravitational constant and 11s the viscosity of the medium. According to Stokes’ law, the sedimentation rate of a suspension decreases with decreasing the particle diameter; decreasing the difference between particle density and density of the medium; and increasing the viscosity of the medium. U.S. Pat. Nos. 5,272,137 and 5,409,907 teach the use of suspending agents such as xanthan gum and microcrystalline cellulose to minimize sedimentation. U.S. Pat. No. 5,658,919 discloses the use of xanthan gum, a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, and an auxiliary suspending agent selected from hydroxyethylcellulose and a salt of carboxymethylcellulose to minimize sedimentation of paracetamol suspensions. Color change in pharmaceutical products, which typically ocours during product storage, is considered an important quality attribute and is often monitored as an indication of non-adequate product manufacture or formulation instability. Color is therefore monitored during pharmaceutical product development. Color change in pharmaceutical products can occur under specific conditions. The color of a paracetamol-containing liquid formulation can change more easily than a paracetamol-containing solid formulation, since color change might be caused by several reactions such as paracetamol degradation through hydrolysis reactions or oxidation reactions; and other chemical reactions of active ingredients and other additives, e.g., Maillard reactions Color change in a paracetamol suspension usually ocours as discoloration from white to off-white or brown. For this reason, color change is often described with the terms discoloration or browning. Dyes are often added to pharmaceutical suspensions for improved appearance and patient acceptability, and to mask discoloration. However, it has been found that some patients develop or have allergies to or are sensitive to dyed suspension or that such suspensions stain clothing, furniture, carpeting, and the like when spilled. Therefore, dye-free suspensions are very desirable. Coloring agents are often added to pharmaceutical liquid products to produce pharmaceutically acceptable characteristics, to provide an identifying factor and also to provide consistency among the batches of a product. Often the color of the excipients that are used to manufacture product contribute an off-color to the product. This color is often dependent on the lots of excipients 210 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 and they can change on storage with no adverse effect on the product. The consumer would however, perceive the color change as having an adverse effect on the effectiveness of the product, potentially resulting in rejection of the product. EP 2.229 937 B1 relates to a dye-free paracetamol liquid suspension comprising by gram per 100 mL of the suspension 1 to 15 APAP having an average particle size of between 10 and 100 microns; 0.1 to 0.25 xanthan gum; 0.4 to 1 microcrystalline cellulose; 20 to 65 sorbitol solution; 1 to 20 glycerin; 0.01 to 1 flavoring; 20 to 50 water; 0.001 to 0.10 of an antimicrobial preservative selected from the group consisting of butylparaben, methylparaben, propylparaben, and combinations thereof; 0.003 to 0.20 citric acid; and 0.1 to 0.5 propylene glycol; wherein the dye-free APAP suspension has a pH of from 5 to 6 and is substantially free of a reducing sugar. The formulation contains sucrose. According to EP 2 229 937 B1, the unique combination of APAP having sorbitol and sucrose at a pH from about 5.1 to 5.9 produces advantageously storage stable and homogeneously dispersed suspensions of APAP. U.S. Patent No. 7,300,670 teaches a suspension containing one particulate drug with a density of from about 0.9 to about 1.6g/ml, an average particle size (X50) of less than about 20 microns, a polymer exhibiting plastic flow selected from but not limited to xanthan gum, carbomer, microcrystalline cellulose, _carboxymethyl-cellulose, sodium carboxymethylcellulose, and combinations thereof, and wherein the suspension has a final yield value of less than about 15 Pa, to ensure that the product is pourable without shaking, and which does not cake on storage and which is able to maintain its homogeneity on prolonged storage without shaking. The Examples in the ‘670 patent teach from 0.02 to 15 Percent by weight acetaminophen liquid suspensions containing invert sugars, sucrose and colorants or dyes. Despite the challenges associated with formulating suspensions many attempts have been made to formulate paracetamol as a liquid suspension. Indeed, there are numerous products currently on the market, including Panadol® Children’s 1-6 Years (sold by GlaxoSmithKline Consumer Healthcare), Children's Tylenol Pain and Fever Reliever (sold by Johnson & Johnson Consumer Inc.) and Panodil Jr. suspension. The present invention is an improvement over these commercial products and relates to the discovery of a dye-free, optionally sugar-free, storage stable paracetamol liquid suspension that provides an organoleptically pleasing mouth feel, low sedimentation and a surprisingly advantageous reduction in browning over a prolonged time period, SUMMARY OF THE INVENTION The present invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 10pm and a d90 of less than or equal to 35m, which composition is substantially dye-free, In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 104m and a d90 of less than or equal to 30ym, which composition is substantially dye-free. 310 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 10um and a d90 of less than or equal to 25ym, which composition is substantially dye-free. In still another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 10um and a 490 of less than or equal to 20m, which composition is substantially dye-free. In yet another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 104m and a d90 of less than or equal to 16m, which composition is substantially dye-free. In still yet another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 8um and a d90 of less than or equal to 354m, which composition is substantially dye-free. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a 450 of less than or equal to 8um and a d90 of less than or equal to 30m, which composition is substantially dye-free. In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 8um and a d90 of less than or equal to 25ym, which composition is substantially dye-free. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 8um and a d90 of less than or equal to 20m, which composition is substantially dye-free. In yet another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to um and a 490 of less than or equal to 16m, which composition is substantially dye-free. In one embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 104m and a d90 of less than or equal to 35m, which composition is substantially dye-free and is substantially free of invert sugars. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 104m and a d90 of less than or equal to 30pm, which composition is substantially dye-free and is substantially free of invert sugars. in a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 104m and a d90 of less than or equal to 25m, which composition is substantially dye-free and is substantially free of invert sugars. In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 10um and a d90 of less than or equal to 20um, which composition is substantially dye-free and is substantially free of invert sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 10m 410 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 and a d90 of less than or equal to 16m, which composition is substantially dye-free and is substantially free of invert sugars. In one embodiment, the invention is directed to @ pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 8um and a d90 of less than or equal to 354m, which composition is substantially dye-free and is substantially free of invert sugars. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a 50 of less than or equal to 8m and a d90 of less than or equal to 30pm, which composition is substantially dye-free and is substantially free of invert sugars. In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a 50 of less than or equal to 8um and a d90 of less than or equal to 25m, which composition is substantially dye-free and is substantially free of invert sugars. In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to um and a d90 of less than or equal to 20um, which composition is substantially dye-free and is substantially free of invert sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles having a d50 of less than or equal to 8um and a d90 of less than or equal to 16m, which composition is substantially dye-free and is substantially free of invert sugars. In one embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10pm and a d90 of less than or equal to 35m, which composition is substantially dye-free and is substantially free of reducing sugars In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10pm and a d90 of less than or equal to 30um, which composition is substantially dye-free and is substantially free of reducing sugars In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10m and a d90 of less than or equal to 25ym, which composition is substantially dye-free and is substantially free of reducing sugars In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10um and a 490 of less than or equal to 20m, which composition is substantially dye-free and is substantially free of reducing sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10um and a 490 of less than or equal to 164m, which composition is substantially dye-free and is substantially free of reducing sugars.10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 In one embodiment, the invention is directed to @ pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 8m and a 90 of less than or equal to 354m, which composition is substantially dye-free and is substantially free of reducing sugars. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 84m and a 90 of less than or equal to 304m, which composition is substantially dye-free and is substantially free of reducing sugars In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 84m and a d90 of less than or equal to 25ym, which composition is substantially dye-free and is substantially free of reducing sugars In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a 450 of less than or equal to 8ym and a 490 of less than or equal to 20m, which composition is substantially dye-free and is substantially free of reducing sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 8um and a 490 of less than or equal to 161m, which composition is substantially dye-free and is substantially free of reducing sugars. In one embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10pm and a 490 of less than or equal to 35m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10m and a 490 of less than or equal to 30m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10um and a 490 of less than or equal to 25ym, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10m and 490 of less than or equal to 20um, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 10um and a 490 of less than or equal to 161m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In one embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 84m and a d90 of less 610 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 than or equal to 35m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In another embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 8m and a 90 of less than or equal to 30m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 84m and a d90 of less than or equal to 254m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a 450 of less than or equal to 8ym and a d90 of less than or equal to 20m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In still yet a further embodiment, the invention is directed to a pharmaceutical composition comprising paracetamol particles with a d50 of less than or equal to 8um and a 490 of less than or equal to 164m, which composition is substantially dye-free and is substantially free of reducing sugars and substantially free of invert sugars. In one embodiment a composition according to the invention is substantially free of a non-reducing sugar which is sucrose. DETAILED DESCRIPTION OF THE INVENTION Definitions ‘As used herein, the term ‘invert sugar’ is a mixture of glucose and fructose obtained by the hydrolysis of sucrose. In sucrose, the enzyme invertase, yields “invert sugar’ (so called because the hydrolysis results in an inversion of the rotation of plane polarized light), a 50:50 mixture of fructose and glucose, its two constituent monosaccharides. It will be understood that the terms “substantially free of an invert sugar” or “substantially free of invert sugars” means that an invert sugar is not added as a separate component to the formulations described herein at any point during their manufacture and therefore, is not a separate component of the end-product liquid suspension. It will be understood that trace amounts of invert sugars may be found in one or more of the excipients used in the formulation, e.g., as may be found in polyols such as maltitol and sorbitol. As used herein, a “particle” may be a crystal, a granule, an agglomerate, or any undissolved solid material. As used herein, the term “prolonged period of time” means a time frame that is greater than about 12 months. In one embodiment, the prolonged period of time is up to and including about 18 months. In another embodiment, the prolonged period of time is up to and including about 24 months. In a further embodiment, the prolonged period of time is up to and including about 36 months.10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 As used herein, the term “reducing sugar’ is any sugar that can act as a reducing agent (and thus can be oxidized) because it has a free aldehyde group or a free ketone group. All monosaccharides are reducing sugars, along with some disaccharides, oligosaccharides, and polysaccharides. The monosaccharides can be divided into two groups: the aldoses, which have an aldehyde group, and the ketoses, which have a ketone group. Ketoses must first tautomerize to aldoses before they can act as reducing sugars. The common dietary monosaccharides galactose, glucose and fructose are all reducing sugars. It will be understood that sucrose is made up of two monosaccharides - glucose and fructose. Since the reducing groups of glucose and fructose (i.e., the free aldehyde/ketone groups) are involved in glycosidic bond formation and are not available, sucrose is a non-reducing sugar As used herein, the term “substantially dye-free" means that at a dye is not added as a separate component to the formulations described herein at any point during their manufacture and therefore, is not a separate component of the end-product pharmaceutical liquid suspension It will be understood that the terms “substantially free of a reducing sugar” or “substantially free of reducing sugars” means that a reducing sugar is not added as a separate component to the formulations described herein at any point during their manufacture and therefore, is not a separate component of the end-product pharmaceutical liquid suspension. It will be further understood that trace amounts of reducing sugars may be found in one or more of the excipients used in the formulation, e.g., in the maltitol syrup or the sorbitol solution. Based on a certificate of analysis for maltitol syrup, there is less than 0.10% of reducing sugars, on a dry basis (commercially available from Roquette Freres, France). Based on a certificate of analysis for sorbitol 70% solution, there is for example 0.08% of reducing sugars, on a dry basis; for a maximum of 0.14% of reducing sugars (commercially available from Roquette Freres, France). It will be understood that the term “substantially free of a non-reducing sugar which is sucrose” means that sucrose is not added as a separate component to the formulations described herein at any point during their manufacture and therefore, is not a separate component of the end-product pharmaceutical liquid suspension, The active agent or ingredient is present in a "unit dose volume” of the aqueous suspension in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the active agent being administered, the bioavailability characteristics of the active agent, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art. As used herein a “unit dose volume" of the aqueous suspension is a convenient volume for dosing the product to a patient. The dosing directions instruct the patient to take amounts that are multiples of the unit dose volume depending on, e.g., the age or weight of the patient Typically, the unit dose volume of the suspension will contain an amount of active agent that is therapeutically effective for the smallest patient. For example, suitable unit dose10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 volumes may include one teaspoonful (about 5 mL), one tablespoonful (about 15 mL), one dropperful, or one milliliter. Brief Description of the Fiqures Fig. 1 depicts degradation products of paracetamol in solution. Koshy K.T., Lach L. (1961). Stability of aqueous solutions of N-acetykpaminophenol. J Pharm Sci 50:113- 18. Imaizumi H, Nagai K (1978). Stability of non-pyrine antipyretic analgesic. J.Pract.Pharm. 29:1161-6. Fig. 2 depicts a CIELAB Color Space Diagram (CIE L’a*b* (CIELAB) is a color space specified by the International Commission on Illumination (French Commission internationale de l'éclairage, hence its CIE initialism). It describes all the colors visible to the human eye and was created to serve as a device-independent model to be used as a reference). Fig. 3 is a graphical depiction of a color change comparison, defined by AE* values, for the analyzed samples including Formulation A, Formulation B and Formulation C. Fig. 4A is a graphical depiction of the total color difference AE* for Formulation A and Formulation B at a paracetamol concentration of 48mg/mL. The Formulation A sample just after manufacturing is taken as reference. Fig. 4B is a graphical depiction of the total color difference AE* for Formulation A, Formulation B and Formulation C at a paracetamol concentration of 24mgiml. The Formulation A sample just after manufacturing is taken as reference. Fig. 5 depicts the impact of paracetamol particle size and storage temperature on color measurements in terms of lightness L* for samples taken at 9 months. Fig. 6 is a graphical depiction of the total color difference AE* for Formulation A and Formulation B at a paracetamol concentration of 48mg/ml. The Formulation A sample just after manufacturing is taken as reference. Fig. 7 is a graphical depiction of the total color difference AE” for Formulation A and Formulation B and Formulation C at a paracetamol concentration of 24mgiml. The Formulation A sample just after manufacturing is taken as reference. Paracetamol can be affected by multiple degradation reactions. This is a particular concern when formulating paracetamol as a pharmaceutical liquid suspension. Fig. 1 shows the degradation products of paracetamol in solution. According to the reaction mechanisms in Fig 1, paracetamol hydrolyzes in aqueous solution to form p-aminophenol which then oxidizes further to form pink-colored quinine imines. The influence of oxygen on discoloration of a paracetamol solution is a consequence of both oxygen in the bottle head space of the container and oxygen dissolved in the liquid. Recommendations given to limit discoloration are to: (a) manage the amount of oxygen in the container by controlling filling volume and headspace; (b) ensure appropriate packaging selection to minimize oxygen transfer through the packaging: (c) use a de-aeration method under reduced pressure or replace oxygen with an inactive gas (e.g.. nitrogen) during manufacturing and/or filling; (4) consider the use of antioxidants in the formulation in order to minimize oxidation; 910 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 and (e) remove or replace excipients or primary packaging components that could promote oxidation, such as trace metal ions, hydroperoxides or residual initiators in polymers. (Mochizuchi, K et al., Prediction of color changes in acetaminophen solution using the time- temperature superposition principle, Drug Development and Industrial Pharmacy, Vol.42, No.7, 1050-1057, (2015)). There is no recognition in the literature that reducing the particle size of the paracetamol particles could be a factor in limiting discoloration in a paracetamol-containing pharmaceutical liquid suspension. Furthermore, there is no recognition that a paracetamol pharmaceutical liquid suspension formulated with paracetamol particles having a 450 of less than or equal to 10pm and a d90 of less than or equal to 354m would significantly limit discoloration such that the formulation can be substantially dye-free, and still present a commercially acceptable product. It has also been found that temperature has an important impact on the hydrolysis reaction rate of paracetamol and therefore browning, since a temperature increase translates into an increase of paracetamol solubility i.e., concentration in solution (Koshy KT. et al., (1961), Stability of aqueous solutions of N-acetyl-paminophenol, J Pharm Sci 50:113-18 and Imaizumi H et al., (1978). Stability of non-pyrine antipyretic analgesic, J Pract. Pharm, 29:1161-6). Sedimentation is also a challenge when formulating liquid suspensions. The viscosity of the suspension is known to have an impact on sedimentation. In general, as the viscosity increases, the sedimentation rate decreases. The particle size of the API is also generally thought to affect the sedimentation rate of a suspension. The larger the particle size, one would expect the sedimentation rate to increase. As the particle size decreases, one would expect the sedimentation rate to decrease. However, as the particle size decreases, one would also expect the color of the suspension to be negatively affected, i.e, an increase in browning is expected because the surface area of the particles is larger and therefore there is more surface exposure to degradation reactions. Surprisingly, the opposite was found by the inventors herein. The invention relates to a paracetamol pharmaceutical liquid suspension wherein the particle size distribution (450 and d90) and the particle size span is significantly smaller than that found in commercial products. Despite the smaller particle size distribution, the invention provides a storage stable suspension that does not brown over a prolonged time period and, therefore, does not require a dye to mask discoloration or browning. One of the most widely used methods of describing particle size distributions are percentiles or “d” values. The d10, d50 and 490 values are particle size values corresponding to the cumulative distribution at 10%, 50% and 90%. Based on a mass distribution, a d-value can be thought of as a “mass division diameter’. It is the diameter which, when all particles in a sample are arranged in order of ascending mass, divides the sample's mass into specified percentages. The percentage mass below the diameter of interest is the number expressed after the “d". For example, the d10 diameter is the diameter at which 10% of a sample's mass is comprised of smaller particles, and the 450 1010 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 is the diameter at which 50% of a sample's mass is comprised of smaller particles. The 50 is also known as the "mass median diameter" as it divides the sample equally by mass. Median values are defined as the value where half of the population of particles of a specified size resides above the median point, and half of the population of particles of a specified size resides below the median point. For particle size distributions, the median is called the 50 (or x50 when following certain International Organization of Standardization guidelines). The d50 is the size in microns that splits the particle population distribution with half above and half below a certain diameter size. For example, according to this invention, a paracetamol particle size distribution defined as a 50 of 10m means that 50% of the paracetamol particles are smaller than 10um and 50% of the paracetamol particles are larger than = 10m. For further details see, page 4, httpsi/wmw.horiba.comffileadmin/uploads/ScientificleMag/PSA/Guidebook/pdt/PSA_Guid ebook.paf. As defined herein, the span or width of the particle size distribution is defined as follows: 490-10 SPAN = {twill be understood that the lower the span, the narrower a particle size distribution is. Suitably the paracetamol particles of use in the invention have a span that is less than 4.5, for example from about 0.1 to about 4 or from about 0.5 to about 3.5. In one ‘embodiment the span is from about 1 to about 3. In one embodiment the span is from about 2 to about 3. In the present invention a good approximation of the span equation above is the d90 /d50 value, given that the d10 value is much smaller than d90. Clearly with d50 values so low, and 410, by definition, even lower, the d10 parameter will not materially affect the span. Suitably in one aspect according to the invention, the paracetamol particles have a d10 value that is less than about 5um for example less than about 4 um or less than about 3.um. In one embodiment the paracetamol particles have a d10 value that is about 2 ym. The typical percentile values for paracetamol particle size distribution as used herein, was measured by a laser diffraction particle size analyzer (Malvern, Mastersizer 2000) and d values are based on a volume distribution. The present invention is related to the discovery that when the particle size distribution of paracetamol in a pharmaceutical liquid suspension and the span of the Particle size distribution of paracetamol in a pharmaceutical liquid suspension is specifically defined, the browning of the suspension is significantly reduced over a prolonged period of time. Suitably, the paracetamol particles have a d50 of less than or equal to 10um. In one embodiment, the paracetamol particles have a d50 from 5pm to 10um. In another embodiment, the paracetamol particles have a d50 from 8um to 10um. In a further embodiment, the paracetamol particles have a d50 less than or equal to 8um. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of "10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 10m and the 490 is less than or equal to 35m. In another embodiment, the paracetamol particles have a distribution range wherein the 450 is less than or equal to 10um and the d90 is less than or equal to 30um. In a further embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 10ym and the 90 is less than or equal to 25m. In yet another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 10um and the d90 is less than or equal to 20m. In still yet another embodiment, the paracetamol particles have a distribution range wherein the 450 is less than or equal to 10m and the d90 is less than or equal to 16m. Suitably, for any of these embodiments, the formulation is substantially dye- free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the d50 is from 5um to 10um and the d90 is less than or equal to 35ym. In one embodiment, the paracetamol particles have a distribution range wherein the d50 is from 8m to 10um and the d90 is less than or equal to 35um. In another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 8um and the d90 is less than or equal to 35ym. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the d50 is from 5um to 10um and the d90 is less than or equal to 30ym. In one embodiment, the paracetamol particles have a distribution range wherein the d50 is from 8m to 10um and the d90 is less than or equal to 304m. In another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to or equal to 8um and the 490 is less than or equal to 30m. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these ‘embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the d50 is from 5um to 10um and the d90 is less than or equal to 25um. In one embodiment, the paracetamol particles have a distribution range wherein the d50 is from 8m to 10um and the d90 is less than or equal to 25m. In another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 8um and the d90 is less than or equal to 25ym. Suitably, for any of these embodiments, the formulation is 1210 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the 450 is from Sum to 10um and the d90 is less than or equal to 20um. In one embodiment, the paracetamol particles have a distribution range wherein the d50 is from 8m to 10um and the d90 is less than or equal to 204m. In another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 8um and the 490 is less than or equal to 20um. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Suitably, the paracetamol particles have a distribution range wherein the 50 is from 5um to 10um and the d90 is less than or equal to 16um. In one embodiment, the paracetamol particles have a distribution range wherein the d50 is from 84m to 10um and the d90 is less than or equal to 16um. In another embodiment, the paracetamol particles have a distribution range wherein the d50 is less than or equal to 8um and the 490 is less than or equal to 16um. Suitably, for any of these embodiments, the formulation is substantially dye-free. Suitably, for any of these embodiments, the formulation is substantially dye-free and substantially free of reducing sugars. Suitably, for any of these embodiments, the formulation is substantially dye-free, substantially free of reducing sugars and substantially free of invert sugars. Paracetamol is present in the instant pharmaceutical liquid suspension in a concentration of from about 2.0 to about 5.0% weight/volume (t will be understood by the skilled artisan that 2.0% weight/volume is equivalent to 2.0 grams/100mL of suspension which is equivalent to 20 milligrams/mL of suspension). In one embodiment of the invention, paracetamol is present in an amount of 2.4 grams/100mL suspension. In another embodiment of the invention, paracetamol is present in an amount of 3.2 grams/100mL of suspension. In a further embodiment of the invention, paracetamol is present in an amount of 4.8 grams/100mL of suspension. Water is present in the pharmaceutical liquid suspension according to the invention Suitably water is present in an amount of from about 30 to about 70% weight/volume (it will be understood that 70% is equivalent to 70 grams per 100mL of suspension. In one embodiment of the invention, water is present in an amount of about 40 to about 60% weightivolume such as about 50% i.e. about 50 grams per 100mL. It will be understood that the amount of water includes both free water added and water added with other materials such as with sorbitol and/or maltitol solutions. The pharmaceutical liquid suspension of the invention may contain additional ingredients known to one of skill in the art, generally referred to as additives. Additives can include, but are not limited to, known components such as flavoring agents, sweeteners, antioxidants, 13,10 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 chelating agents, thickeners, preservatives, pH modifiers, surfactants, antifoaming agents, co-solvents, humectants, and mixtures thereof. Water-soluble high intensity sweeteners also may be employed in this invention, Examples of suitable high intensity sweeteners include, but are not limited to, sucralose, aspartame, saccharin, acesulfame, cyclamate, and pharmaceutically acceptable salts and combinations thereof. The amount of high intensity sweetener used in the suspension will vary depending on the degree of sweetening desired for the particular suspension. Generally, the amount of high intensity sweeteners used in the suspension may vary from about 0 to about 2.0 grams per 100 mL of suspension. In embodiments employing a high intensity sweetener, such as sucralose, aspartame, acesulfame, saccharin, and pharmaceutically acceptable salts thereof, the level of high intensity sweetener is from about 0 to about 1 gram per 100 mL of suspension. In one embodiment the high intensity sweetener is sucralose. In one embodiment of the invention, the suspension comprises a high intensity sweetener at about 0 to about 0.5 gram per 100 mL of suspension for example from about 0.1 to about .4 grams per 100 mL. of suspension. Suitably, polyhydric alcohols for use as sweeteners in the present invention include, but are not limited to, sorbitol, mannitol, xylitol, erythritol, maltitol, and the like, and combinations thereof. The amount of polyhydric alcohol sweetener used in the suspension will vary depending on the degree of sweetening desired for the particular suspension. Generally, the amount of polyhydric alcohol sweetener may be in the range of from about 0 to about 90 grams per 100 mL of the suspension. In the present invention, the suspension comprises maltitol solution at about 20 to about 70 grams per 100mL of the suspension. In one embodiment, the suspension comprises maltitol solution at about 50 to about 70 grams per 100mL of the suspension. In another embodiment, the suspension comprises maltitol solution at about 50 to about 60 grams per 100mL of the suspension. In one embodiment, the suspension comprises sorbitol solution (as a 70% aqueous solution) at about 0 to about 20 grams per 100mL of the suspension. In another embodiment, the suspension comprises sorbitol solution (as a 70% aqueous solution) at about 5 to about 15 grams per 100mL of the suspension. In another embodiment, the suspension comprises sorbitol solution (as a 70% aqueous solution) at about 10 to about 15 grams per 100ml of the suspension. In one embodiment the suspension comprises a sorbitol solution (as a 70% aqueous solution) at about 10 to about 20 grams per 100mL of the suspension and a maltitol solution at about 50 to about 60 grams per 100mL of the suspension. Suitably the sorbitol solution is a non- crystallizing sorbitol solution. Suitable flavoring agents include natural and/or artificial flavors such as mint (i.e., Peppermint, spearmint, etc.), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate, both natural and/or artificial fruit flavors (e.g., cherry, grape, orange, strawberry, and the like) and combinations of two or more thereof. Flavoring agents are often complex mixtures of chemical compounds dissolved or dispersed in an inert medium, such as, propylene glycol. These solutions or dispersions are generally provided as a minor component of the suspension in amounts effective to provide a palatable flavor to the suspension. In one embodiment, flavoring agents are present in the suspension in amounts 1410 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 in the range of from 0.01 to 1 grams per 100 mL of the suspension. In one embodiment, flavoring agents are present in the suspension in amounts in the range of from 0.05 to 0.15 grams per 100 mL of the suspension The pH of the suspension should be optimized to minimize the solubility and maximize the chemical stability of the unpleasant tasting and hydrolysis susceptible active agent, APAP. In the present invention, the pH of the suspension is suitably in the range from 4.5 to 6 or from 5.5 to 6.5. In one embodiment of the invention, the pH of the suspension is 4.7-5.5. In one embodiment the pH of the suspension about 6.0. Suitably, in one embodiment the target pH of a suspension according to the invention is about 5. The suspension can be buffered using pH adjusting agents to maintain the pH of the suspension in the desired pH range. Suitable pH-adjusting agents may be present in the suspension in amounts sufficient to provide the desired degree of pH buffering. The pH-adjusting agents are typically used in the range of from about 0 to about 1 gram per 100 mL of the dye-free pharmaceutical suspension. The pH adjusting agent may be selected from weak organic acids, such as, citric acid, malic acid, sodium citrate (dihydrate), glutamic acid, and the like having acceptable taste characteristics for use in taste-masked oral suspensions. In the present invention, citric acid is present at 0.003 to 0.20 grams per 100mL of suspension. Citric acid is added to the suspension to stabilize the pH of the suspension at between 4.5 and 6, e.g., from about 4.7 to about 5.5. Antimicrobial preservatives are selected for their activity within this pH range. In dye-free suspensions of the present invention, there is optionally an antimicrobial preservative. Suitable preservatives include, but are not limited to, methyl paraben, propyl Paraben, sodium methyl paraben, sodium ethyl paraben, sodium propyl paraben and the like and combinations thereof. A combination of sodium methyl, sodium ethyl and sodium propyl parabens may be used, available commercially in one form as Niasept sodium from Clariant. Suitably, the preservatives are present in a percent weight/volume amount of about 0.00 to 0.25 gram per 100mL of suspension. In one embodiment, the methyl paraben is present in an amount of 0.2 grams/100mL of suspension. In one embodiment, the propyl paraben is present in an amount of 0.045 grams/100mL of suspension. In yet another ‘embodiment of the invention, methyl paraben is present in an amount of 0.2 grams/100mL of suspension and propyl paraben is present in an amount of 0.045 grams/100mL of suspension Suitable chelating agents include, but are not limited to ethylenediaminetetraacetic acid including salts thereof such as the disodium salt and the calcium disodium salt Suitably the chelating agents are used in a percent weight/volume amount of about 0.005 to 0.015 gram per 100mL of suspension. The dye+ree pharmaceutical liquid suspension of the present invention is substantially free of coloring agents, such as, dyes, lakes, and the like. However, the dye- free pharmaceutical liquid suspension of the present invention may optionally incorporate certain pigments, e.g., titanium dioxide and the like, as opacifiers. The suspensions of the present invention can employ suspending systems as known in the art that include, but are not limited to, at least one thickening component. In 1510 15 20 25 30 35 40 WO 2020/043587 PCT/EP2019/072445 one embodiment of the invention, the thickening component is present in the pharmaceutical liquid suspension in an amount of about 0.05 to about 1.5 grams per 100mL of suspension for example from about 0.05 to about 0.70 grams per100mL of suspension. In another embodiment of the invention, the thickening component is xanthan gum. In yet another embodiment of the invention, the xanthan gum is present in the pharmaceutical liquid suspension in an amount of about 0.65 grams per100mL of suspension. Another optional component of the pharmaceutical liquid suspensions of the invention a humectant. Suitable humectants for use in the invention include glycerine, sorbitol, polyethylene glycol, propylene glycol, and other edible polyhydric alcohols. Generally, the amount of humectant may be in the range of about 10 to about 20 grams/100mL of the suspension. In one embodiment of the invention, the humectant is glycerine. In another embodiment of the invention, the humectant is glycerine in the amount of about 10 to about 20 grams such as about 15 grams/100mL of the suspension. ‘An exemplary composition according to the invention is a pharmaceutical liquid suspension comprising by grams per 100mL of the suspension: (a) a therapeutically effective amount of paracetamol in particulate form wherein the paracetamol particles have a D0 of less than or equal to 10 of less than or equal to 104m and a D90 of less than or equal to 20m; (b) about 0.20 to about 0.30 of a high intensity sweetener such as sucralose; (c) about 40 to about 80 of a polyhydric alcohol sweetener such as a combination of maltitol and sorbitol; (d) about 0.1 to about 0.3 of a preservative such as a combination of methyl parabens and propyl parabens; (e) about 0.2 to about 0.4 of a buffering agent; (f) about 0.5 to about 1 of a thickening agent such as xanthan gum; (g) about 10 to about 20 of a humectant such as glycerine; (h) about 0.05 to about 0.1 of a flavouring agent; (i) about 40 to 60 of water; and wherein the pH of the composition is about 5.5 to about 6.5. A suitable process for preparing a suspension composition as described herein is a standard process understood by those of skill in the art, and includes the following steps: a) transferring polyhydric alcohol sweeteners into a main mixing vessel and adding purified water, and mixing continuously to produce a uniform mixture; b) dissolving preservatives, if present in the liquid suspension, in purified water in a small pre-mixing vessel while stirring continuously and transferring to the main mixing vessel while stirring continuously; c) dissolving water soluble ingredients in a small pre-mixing vessel and transferring to the main mixing vessel while stirring continuously; d) adding thickeners to the main mixing vessel and mixing continuously until a uniform suspension is obtained; 1610 15 WO 2020/043587 PCT/EP2019/072445 e) adding paracetamol to the main mixing vessel and stirring until a uniform suspension is obtained; ) adding flavour to the main mixing vessel while stirring continuously; and 9) adding and mixing sufficient water to the mixture of step (f) to produce a pharmaceutical suspension in accordance with the invention of 100% desired volume, after which the suspension is transferred to a storage tank before filling, labelling and packaging, EXAMPLES The invention will now be illustrated by examples. The examples are not intended to be limiting of the scope of the present invention but read in conjunction with the detailed and general description above, provide further understanding of the present invention and an outline of a preferred composition of the invention. The examples were conducted using three paracetamol pharmaceutical liquid suspensions with the compositions shown in Table 1, below. It will be understood that the units below are in percent weight/volume, which is grams/100mL solution. Table 4 Ingredient Formulation A | Formulation B Formulation C Paracetamol, 2.0-5.0%wtlv 2.0-5.0%wtiv (2.0 | 2.0-5.0%wtlv (2.0 to Pheur(*) — | (20t0 to.5.0mg/i00mL; | 5.0mgit00mt; 5.0mg/100mL; | 20mgimL to 2omgimL to 20mg/mL to: ‘50mg/mL) ‘50mg/mL) S0mgitmL) ‘Carbomer, Ph. 0.20-0.70 - Eur Xanthan gum, | 050-7.00 TOTOOE 0507.00 Ph. Eur Nipasept 5 0.10020 : Sodium Methyl Paraben _| 0.01 to 0.20 5 : Propyl Paraben | 0.01 t0 0.065 | - : ‘Sodium Methy! |= = 0.07-0.15 Paraben ‘Sodium Ethyl |= = 0.01-0.03, Paraben ‘Sodium Propyl | = ~ 0.07-0.03, Paraben Glycerine: 10-20 EDTA, Ph.Eur._| 0.005-0.015 0,005-0.075 Non- 10-20 10-20 10-20 Crystallizing Sorbitol (70% solution), Ph. Eur, ‘Sorbitol 20-25 Maltitol Solution, | 50-60 50-60 65-75 Ph. Eur. Malic Acid, Ph. | ~ 0.05-0.15 0.0T-0.07 Eur. 710 15 20 25 WO 2020/043587 PCT/EP2019/072445 “Anhydrous citric | 0.020-0.030 = 0.02 acid ‘Sodium Citrate | 0.20-.030 = > (dihydrate) ‘Sodium ~ 0:10-0.20 - Hydroxide, Ph. Eur. ‘Sucralose, Ph. | 0.20-0.30 0.05-0.10 - Eur, ‘Acesulfame K, | = 0.07-0.05 - Ph. Eur. ‘Strawberry 0.05-0.10 0.010-0.075 0.05-0.15, Flavor ‘Orange Flavor | 0.05-0.15 0.05-0.15, Purified Water | qs. to 100 qs. fo 100 qs. t6 100 pH. 6.0 6.0 5.0 A fine grade of paracetamol (commercially available from Granules India, Ltd. or Farmson Ltd.) was used for Formulation A. A coarser powder grade of paracetamol (commercially available from Granules India, Ltd. or Farmson Ltd.) was used for Formulations B and C. Therefore, Formulation A falls within the scope of the invention. Formulations B and C fall outside the scope of the invention. The particle size distribution of the formulations is found in Table 2, below. The particle size is measured by the laser diffraction method using a Malvern Mastersizer 2000. Table 2 Formulation A Formulation B/C Oxidation NHCOCH, NHCOCHs NCOCH, (a) acetaminophen (b) p-aminophenol (©) p-benzoquinone imine (d) 2,2'-dihydroxy-5,5'- diacetylaminobipheny! (©) n-acetyl-p-benzoquinone imine OH oH ° @ ©) SUBSTITUTE SHEET (RULE 26)WO 2020/043587 PCT/EP2019/072445 216 FIG. 2 L 100 Delta E SUBSTITUTE SHEET (RULE 26)WO 2020/043587 PCT/EP2019/072445 316 FIG, 3 de* ‘ 4s areing with ‘Sesiorsdon | | | | | 2» 10 o pr mine ating sn TT S77 eT er 7 C.2kme/m, 6 2Ama/ah G 2emg/e, 8 2h, BABI, REFERENCE: A, Bgl, A, Amal A, mg/h A, AImg/m WSC me ST We WC Ime ATK Imo AO Imo Aamg/m SC AO Imo. OT Ine 0G Imo AT ee (tine First color measurements to compare Formulation A samples (48mag/ml) with Formulation B samples (24 and 48mgiml) and Formulation C samples (24mg/ml) over a storage time of maximum 6 months (6M) at different temperature conditions SUBSTITUTE SHEET (RULE 26)WO 2020/043587 FIG. 4A . : : : : : o = oe FIG. 4B . : : : : M1 oe 2amg/el aimed ‘amg /ml at 3M, 258C _24mg/ml at 3M, 408C PCT/EP2019/072445 46 AE* 32.62 16.42 A B B 48mg/ml,at3M —48mg/ml at timeo —A8m¢/ml at 3M 40% ‘40% AE* 3354 3007 2 A c e 2amg/ml at 3M, at 24mg /el 383M, st sore ore SUBSTITUTE SHEET (RULE 26)WO 2020/043587 PCT/EP2019/072445 516 FIG. 5 0 j J ‘A: PSD (90) (micron) : Temperature (deg) FIG. 6 AE* i es a Sos : 4 48me/ml at 48mg/ml,at 48mg/ml,at 48mg/ml at 48mg/ml, at 48mg/ml at SUBSTITUTE SHEET (RULE 26)WO 2020/043587 616 FIG. 7 3s 2 20 5 20 AE* 2078 8.00 nnn 9 69-—— G 786 2 i a a 8 8 a 8 1959 c PCT/EP2019/072445 awn 1956 c c 2emgfnl at 2Amg/int at 24mg/ml at 24mg/el at 2Amg/ml at 2émg/ml at_2Amgnl at 2Amg/ml at 24g/el at timed 3M,258C 3M, 402C—timeO—3M, at 250C 3M, at 408 timed SUBSTITUTE SHEET (RULE 26) 3M, at 258.30, at 408INTERNATIONAL SEARCH REPORT Teterational aplication No PCT/EP2019/072445 TN REIS Te "ReTK1/167 —A61K47/26 ADD. According to Intemational Patent Cassfeaton (PC) or tobothnatona elatttoaton and IPC ‘imum documentation aearsved lasefcaon system flowed by danaioabon a7 baR) AGIK Dosurrenaton searched Sher an ranrum docurentaion othe Hert Wal auahGasumnlsSre waded ithe hails Seana Testor database coneuTed dung he Wlematonal earch (name oT dala base ard, where pasioabe search Te ed) EP0-Internal, BIOSIS, EMBASE, WPI Data {DOCUMENTS CONSIDERED TO BE RELEVANT Catgon7 | Ctaton ot docureet, wth heaton, where eppepta, of te eon peeagen aerate, Y US 2006/093629 Al (BUEHLER GAIL K [US]) 1-15 4 May 2006 (2006-05-04) example 1 claims 18-37 y WO 03/082243 A1 (VENUS DANILO R [PH]; 1-15 SINGH EULOGIO C [PH] ET AL.) 9 October 2003 (2003-10-09) examples 1-3 claims 20-26 Y WO 2004/012708 Al (GRUENENTHAL GMBH [DE]; 1-15 KUGELMANN HEINRICH [DE] ET AL.) 12 February 2004 (2004-02-12) example 1 Y US2006/292214 Al (JENKINS SCOTT [US] ET 1-15 AL) 28 December 2006 (2006-12-28) claims 1-13 Further documents are listed in the continuation af Box ©, X_| See patent family annex. peceleategores of ched ooumen lator document published ater he intmatonal ling date or pry aes eee “his and aie sor oan he span chasers A" eooumart fing te gee sche a wich ee ‘Repo or teary underiing be mvenson “© ager pinion read onorstertnons! dna prs eet aid neon sma “L eequmort wish may tom dts on pry, info) o wich i ep when ie cosument taken peo reason (or speed) Being obvious toa parson “P dgeumentpubahed pr to the stem! ng date bt ater han ‘he peony date Samed "8 document member ofthe eame patent amy ‘Date of te satel conploton ofthe lamatonal aoaoh ‘Date of maling of he wieranal seek Topo 23 October 2019 31/10/2019 European Pte’ foe, P5818 Patertuan2 fees Fae (31-1) 9009018 Sindel, Ulrike Fa POTTSAaIO exons hon) Roa DHINTERNATIONAL SEARCH REPORT Teterational aplication No Information on patent family members PCT/EP2619/672445 Patent dooument Publestion Patent ami Publeation citedin search report date members) ‘ste US 2006093629 Al 04-05-2006 AR 051944 Al 21-02-2007 cA 2585855 Al 11-05-2006 CN = 101065111 A 31-10-2007 ep 1809250 AL 25-07-2007 ep 2229937 Al 22-09-2010 US 2006093629 Al 04-05-2006 US 2010226945 AL 09-09-2010 WO 2006050101 Al 11-05-2006 wo 03082243 09-10-2003 2003225444 AL 13-10-2003, US 2003191192 Al 09-10-2003 WO 03082243 AL 09-10-2003 WO 2004012708 Al 12-02-2004 AU 2003251671 AL 23-02-2004 DE 10234784 Al 19-02-2004 ep 1526838 AL 04-05-2005 ES 2389837 13 02-11-2012 WO 2004012708 AL 12-02-2004 US 2006292214 Al 28-12-2006 AU BR cA cN EA ep oP KR US WO ZA 2006309295 Al 10-05-2007 PIO611075 AZ 03-08-2010 2610480 Al 10-05-2007 101262860 A 10-09-2008 200702638 Al 28-04-2008 1901728 A2 26-03-2008 2008542396 A 27-11-2008 20080017065 A 25-02-2008 2006292214 AL 28-12-2006 2007053197 A2 10-05-2007 200710764 B 26-08-2009