WO2024237986A1

WO2024237986A1 - Spray dried excipient blends

Info

Publication number: WO2024237986A1
Application number: PCT/US2024/014633
Authority: WO
Inventors: Luqing QI; Yifan Wang; Xue CHEN; Thomas H. Kalantar; Kathryn A. GRZESIAK; Stephanie A. Hayes
Original assignee: Dow Global Technologies LLC
Current assignee: Dow Global Technologies LLC
Priority date: 2023-05-15
Filing date: 2024-02-06
Publication date: 2024-11-21
Anticipated expiration: 2025-11-15
Also published as: CN121057578A; TW202446361A

Abstract

A granular composition containing blended excipients is made by spray-drying microcrystalline cellulose with a minor amount of polyalkylene oxide. The spray-dried granular composition may have superior flowability compared with physically blended compositions. Tablets made from the spray-dried composition may have superior crush-resistance.

Description

SPRAY DRIED EXCIPIENT BLENDS FIELD This application relates to the field of excipients useful for oral pharmaceuticals. INTRODUCTION Oral pharmaceutical tablets typically contain a small quantity of active ingredient in a larger quantity of excipient. The excipients dilute the active ingredient and may perform a large number of other functions, such as controlling the rate at which the active ingredient is released, helping the active ingredient to be absorbed, moderating side effects, extending shelf life, providing a durable tablet, providing lubrication during tablet pressing, modifying flavor, and providing a distinctive appearance to the tablet. Excipients must also be safe for use in oral medications and must generally be able to meet regulatory and/or approval criteria. Many materials are approved and used as excipients. Some common examples include cellulose and its derivatives, such as microcrystalline cellulose and cellulose ethers; calcium phosphates, calcium carbonates, calcium sulfates, halites, metal oxides such as titanium dioxide, silicates and their derivatives such as fumed silica and colloidal silica, carbohydrates such as sugars or other sweeteners, starches, fatty alcohols, fatty acid salts, waxes, polyethylene glycol polymers, acrylic polymers and proteins. It is desirable to identify combinations of approved excipients that can provide improved processability or properties, such as one or more of the following: better flowability, easier mixing to provide homogeneous blends, or better crush resistance for the resulting tablet, without compromising other properties of the excipient. SUMMARY One aspect of this invention is a process to make a granular excipient composition, comprising the steps of 1. making a slurry that contains the following dry components: a. From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and b. From 75 to 97 weight percent of microcrystalline cellulose, in a solvent that dissolves the polyalkylene glycol but not the microcrystalline cellulose, wherein the weight percentages are based on the total weight dry ingredients, excluding the solvent; and 2. Spray-drying the slurry to form a dry granular composition. The MCC, the polyalkylene glycol and other excipients and/or active ingredients of the granular composition that are solid at room temperature are commonly referred to as “dry” components, even if they dissolve in the water. The solvent in the slurry is described as a “solvent” even though the MCC and optionally other dry components do not dissolve in the water but are suspended. A second aspect of the present invention is a dry granular composition that is made by the process of this invention and that contains: a. From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and b. From 75 to 97 weight percent of microcrystalline cellulose. A third aspect of this invention is a granular composition comprising: a. From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and b. From 75 to 97 weight percent of microcrystalline cellulose, wherein the granules comprise particles of microcrystalline cellulose encapsulated wholly or in part by polyalkylene glycol. A fourth aspect of this invention is the method to use a granular composition of this invention, comprising the step of compressing the granular composition into a solid tablet. A fifth aspect of this invention is a solid tablet comprising: (1) a pharmaceutically effective amount of an oral pharmaceutical dispersed in (2) a compressed granular composition of this invention. The granular compositions of this invention are useful as excipients for oral pharmaceuticals and other tableted supplements, vitamins, actives, etc. In some embodiments, the granular compositions of this invention may have high flowability, and tablets made using the granular composition may have high crush resistance. The granular compositions may also be useful to modify the dissolution speed of the resulting tablets. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the particle size distribution of the granular compositions in Inventive Examples 2 and 3 and in Comparative Examples 2 and 3. DETAILED DESCRIPTION Granular compositions of this invention contain microcrystalline cellulose and polyalkylene glycol. Both ingredients are common excipients that are approved for use in oral pharmaceuticals and are widely available. Microcrystalline cellulose (MCC) is described in Rowe et al, Handbook of Pharmaceutical Excipients, 5^th Ed at 132-135 (2006). MCC is commonly made by partially depolymerizing natural cellulose. In many embodiments, the MCC used in the present invention is pharmaceutical grade. In some embodiments, the MCC meets the standards of United States Pharmacopeia for excipients. In some embodiments, the MCC meets standards in EU Commission Regulation 231/2012 (Specification E460). In some embodiments, the MCC meets both standards. Like ordinary cellulose, MCC contains repeating cyclic glucose units connected by 1-4 beta glycosidic bonds. In some embodiments, the average degree of polymerization of the MCC is less than 400 or less than 350 or no more than 300 or no more than 250. In some embodiments, the average degree of polymerization of the MCC is at least 120 or at least 150 or at least 180 or at least 200. In some embodiments, the MCC contains at least 95 weight percent cellulose, or at least 97 weight percent or at most 98 weight percent. In some embodiments, the MCC contains essentially 100 weight percent cellulose or at most 99.9 weight percent or at most 99.7 weight percent or at most 99.5 weight percent. In some embodiments, the MCC contains no more than 0.5 weight percent water-soluble material at 20℃, or no more than 0.3 weight percent or no more than 0.24 weight percent. There is no minimum desired level of water soluble material; in some embodiments, the MCC contains as little as no measurable quantity of water soluble material (essentially 0.0 weight percent). In some embodiments, the MCC contains no more than 0.7 weight percent ash, or no more than 0.5 weight percent or no more than 0.4 weight percent. There is no minimum desired level of ash; in some embodiments, the MCC contains as little as no measurable quantity of ash (essentially 0.0 weight percent). In some embodiments, the MCC has a D10 particle size of at least 5 micron or at least 6 micron. In some embodiments, the MCC has a D50 particle size at least 10 micron or at least 15 micron or at least 20 micron or at least 40 micron or at least 60 micron or at least 80 micron or at least 90 micron. In some embodiments, the MCC has a D50 particle size of at most 300 micron or at most 250 micron or at most 200 micron or at most 150 micron or at most 120 micron or at most 100 micron or at most 80 micron or at most 60 micron or at most 40 micron. Suitable MCC is commercially available from multiple sources, such as DuPont de Nemours, Inc.; Roquette Freres; JRS Pharma GmbH; FMC Corp. and Sigma-Aldrich.. It can also be made by known processes, such as those described in the Background and Description of US Patent Publication 2006/0020126 A1. Polyalkylene glycols contain repeating units that meet Formula 1: wherein each of R¹ and R² is hydrogen or an alkyl group. In some embodiments, each of R¹ and R² R¹ R² -

independently contains no or no more than 4 carbon atoms or no more than 2 carbon atoms or no more than 1 carbon atom. In some embodiments, R¹ and R² together contain on average no more than 8 carbon atoms or no more than 6 carbon atoms or no more than 4 carbon atoms or no more than 2 carbon atoms or no more than 1 carbon atom or no more than 0.5 carbon atoms or no more than 0.25 carbon atoms. In some embodiments, R¹ and R² are both hydrogen in at least 80 percent of repeating units, or at least 90 percent or essentially 100 percent. In some embodiments, the polyoxyalkylene chains contain, as desired, ethylene oxide [—CH₂—CH₂—O—] units, propylene oxide [—CH₂(CH₃)—CH₂--O—] units or both types of units in any desired ratio in the same molecular chain. In some embodiments, the polyalkylene glycol is polyethylene glycol. In some embodiments, the polyalkylene glycol is a polyethylene glycol/polypropylene glycol copolymer. In some embodiments, the polyalkylene glycol is a poloxamer, which is a triblock copolymer composed of a central chain of polypropylene glycol flanked by two chains of polyethylene glycol. In many poloxamers, the polypropylene glycol chain is hydrophobic, and the polyethylene glycol chains are hydrophilic. Examples of polyethylene glycols used as excipients are described in Rowe et al, Handbook of Pharmaceutical Excipients, 5^th Ed at 545-550 (2006). The polyalkylene glycol should be water soluble. In some embodiments, it is soluble in water at 20℃ up to at least 20 weight percent, or at least 40 weight percent or at least 50 weight percent or at least 60 weight percent. No maximum solubility is desired, but solubility over 100 weight percent or 80 weight percent may be unnecessary for some uses. The polyalkylene glycol should be solid up to 35℃. In some embodiments, it has a melting temperature of at least 40℃ or at least 45℃ or at least 50℃ or at least 54℃. In some embodiments, it has a melting temperature of no more than 100℃ or no more than 80℃ or no more than 70℃ or no more than 65℃. In some embodiments, the polyalkylene glycol has a number average molecular weight of at least 2000 Da or at least 3000 Da or at least 4000 Da or at least 5000 Da or at least 6000 Da or at least 7000 Da or at least 7500 Da or at least 8000 Da. In some embodiments, the polyalkylene glycol has a number average molecular weight of at most 25,000 Da or at most 20,000 Da or at most 15,000 Da or at most 12,000 Da or at most 10,000 Da. In some embodiments, the polyalkylene glycol has a viscosity at 100℃ of at least 200 cSt or at least 400 cSt or at least 450 cSt or at least 500 cSt. In some embodiments, the polyalkylene glycol has a viscosity at 100℃ of at most 5000 cSt or at most 3000 cSt or at most 2000 cSt or at most 1000 cSt. Suitable polyalkylene glycols are commercially available under the CARBOWAX SENTRY™ trademark and the Kollisolv trademark. Others can be made by known processes, such as polymerization of corresponding alkylene oxide monomers in the presence of an acid or base initiator. See for example, US Patent Publication US 2007/0179199 A1 and “Introduction of Polyethylene Glycol (PEG)”, made available by BOC Sciences at https://peg.bocsci.com/resources/technical-information/introduction-of- polyethylene-glycol-peg.

contains 3 to 25 weight percent polyalkylene glycol. In some embodiments, the granular composition contains at least 4 weight percent polyalkylene glycol or at least 5 weight percent or at least 6 weight percent or at least 7 weight percent or at least 8 weight percent or at least 9 weight percent or at least 10 weight percent. In some embodiments, the granular composition contains at most 23 weight percent polyalkylene glycol or at most 20 weight percent or at most 18 weight percent or at most 16 weight percent or at most 14 weight percent or at most 12 weight percent or at most 10 weight percent or at most 8 weight percent or at most 6 weight percent. The granular composition contains from 75 to 97 weight percent microcrystalline cellulose. In some embodiments, the granular composition contains at least 77 weight percent microcrystalline cellulose or at least 80 weight percent or at least 82 weight percent or at least 84 weight percent or at least 86 weight percent or at least 88 weight percent or at least 90 weight percent. In some embodiments, the granular composition contains at most 95 weight percent microcrystalline cellulose, or at most 93 weight percent or at most 92 weight percent or at most 91 weight percent or at most 90 weight percent. The granular composition optionally contains from 0 to 22 weight percent of other excipients useful for oral pharmaceuticals and tablets. A wide range of excipients are available that serve a number of different purposes, such as • Fillers & Diluents, • Binders, • Anti-Caking Agents • Suspension & Viscosity Agents, • Coatings, • Flavoring Agents and Sweeteners, • Disintegrants, • Colorants, • Lubricants & Glidants, • Preservatives, • Surfactants, • Controlled release agents, • Blending and Mixing Aids; and • Compression Aids. Examples of useful excipients include dibasic phosphates such as calcium phosphates, calcium carbonates, calcium sulfates, halites, metal oxides such as titanium dioxide, colloidal silica, carbohydrates such as sugars or other sweeteners, starches, cellulose ethers, fatty alcohols, fatty acid salts, waxes, acrylic polymers and proteins. More common examples include magnesium stearate, starch, silicone/titanium dioxide, colloidal silicon dioxide, stearic acid, sodium starch glycolate, gelatin, talc, sucrose, calcium stearate, edible dyes, croscarmellose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, povidone and crospovidone. Some excipients are further described in Kibbe, Handbook of Pharmaceutical Excipients, Third Ed. (2000); PCT Publication WO 2011/024028 from Paragraphs [9] to [19], inclusive and PCT Publication WO 2021/231946 A1, Paragraphs [0073] to [0084] inclusive. In addition, fumed silica can be added to improve spray-drying performance. In some embodiments, the concentration of other excipients is at least 1 weight percent or at least 2 weight percent or at least 3 weight percent or at least 4 weight percent or at least 5 weight percent. In some embodiments, the concentration of other excipients is at most 20 weight percent or at most 18 weight percent or at most 16 weight percent or at most 14 weight percent or at most 12 weight percent or at most 10 weight percent or at most 8 weight percent or at most 6 weight percent. In some embodiments, a surface modifying agent is included among the other excipients to improve the flowability of the spray-dried granular composition. We hypothesize, without intending to be bound, that the surface modifying agent improves mixability by roughening the surface of the spray- dried particle. Examples of surface modifying agents include inorganic salts such as dibasic calcium phosphate and other dibasic phosphates. In some embodiments, the granular composition further contains one or more active ingredients. Active ingredients can include any pharmaceutical, probiotic or nutrient that is solid at room temperature and is suitable for oral administration. Examples of active ingredients are described in numerous sources such as PCT Publication WO 2021/231946 A1, Paragraphs [0065] to [0072] inclusive. Examples of potential active ingredients include vitamins such as Vitamins A, B, C, D and/or E; probiotics such as bacteria; pain relievers such as aspirin, acetaminophen or ibuprofen; decongestants; antibiotics; antacids; and other nutrition supplements. In some embodiments, the granular composition contains a single active ingredient. In some embodiments, such as multivitamins, the composition may contain multiple active ingredients. The active ingredient may be present in a pharmaceutically-effective concentration, which may vary depending on the active ingredients. Some pharmaceutical tablets may contain active doses as low as 5 mg or lower. On the other hand, some vitamin tablets may contain 1000 mg of active vitamins or more. In the process of this invention, the MCC and polyalkylene glycol and optionally other excipients and/or active ingredients (the dry components) are mixed in solvent that dissolves the polyalkylene glycol but not the MCC to form a well-dispersed slurry. Then the slurry is spray-dried to make the granular composition of the invention. For clarity, the MCC and the polyalkylene glycol must be mixed into the slurry. However, any other excipients and active ingredients may be added to the granular composition in one or more stages of its production and use. The other excipients and/or active ingredients may be added to the slurry before the granular composition is spray dried. They may be introduced into the spray-drying chamber when the granular compositions are dried. They may be physically mixed with the granular composition after it is recovered from the spray-drying and/or before it is compressed into tablets. To form the slurry, the MCC and the polyalkylene glycol and optionally other dry components are mixed in solvent that dissolves the polyalkylene glycol but not the MCC until a homogeneous slurry is formed. The quantity of solvent should be sufficient to dissolve the water-soluble ingredients, including the polyalkylene glycol, and to suspend or disperse the water-insoluble ingredients, including the microcrystalline cellulose. In some embodiments, the solvent comprises water or comprises at least 50 weight percent water. In some embodiments, the solvent comprises lower alkanol, dichloromethane, chloroform or acetonitrile. In some embodiments, the solvent consists essentially of water. In some embodiments, excess solvent is kept low, in order to minimize the need for drying in the spray drying step. In some embodiments, the slurry contains at least 1 weight percent dry components or at least 5 weight percent or at least 10 weight percent. In some embodiments, the slurry contains at most 60 weight percent dry components or at most 50 weight percent. In some embodiments, the slurry contains at least 40 weight percent solvent, or at least 50 weight percent. In some embodiments, the slurry contains at most 99 weight percent solvent, or at most 95 weight percent or at most 90 weight percent. In some embodiments, one or more of the dry components may already be dissolved or suspended in solvent, and this solvent may be considered when calculating the total solvent in the slurry. The ratio of dry components in the slurry reflects the proportions already discussed. In some embodiments, the dry components of the slurry may impact the acidity of the slurry. In some embodiments, the pH of the slurry is at least 4 or at least 5 or at least 6 or at least 7. In some embodiments, the pH of the slurry is at most 10 or at most 8 or at most 7.5 or at most 7. In some embodiments, pH may be controlled by buffers. Suitable buffers are known and commercially-available. Examples may include citrates and citrate salts and phosphate salts. The slurry is spray-dried according to known techniques. Spray-drying equipment is commercially available with instructions for its use, and spray-drying is described in many publications such as: Santos et al., “Spray Drying – A Overview”, available at: http://dx.doi.org/10.5772/intechopen.72247; “Spray Dry Manual” published by Bete Performance Spray Engineering at www.BETE.com; and More Swati et al, “Review on Spray Drying Technology” 4(2) IJPCBS 219-225 (2014). In summary, the spray-drying step has the following sub-steps: 1. The slurry is atomized (sprayed) to form atomized droplets in a drying chamber; 2. The atomized droplets are contacted in the drying chamber with a heated gas under conditions that dry the droplets into dry granules; and 3. The dried granules are separated from the gas and recovered. In some embodiments, the drying chamber may have a cylindrical section and a narrowing conic section at the bottom where dried granules are collected and removed from the drying chamber. Several different types of atomizers are known, including spray nozzles and rotary atomizers. In some embodiments the heated gas is air, and in some embodiments the heated gas is an inert gas such as nitrogen or carbon dioxide. Spray drying processes are sometimes classified as: 1. Co-current: Both the slurry and the drying gas are fed into the drying chamber at the top of the chamber and flow together in the same direction out of the bottom of the chamber. 2. Counter-current: The slurry is fed into the drying chamber at the top of the chamber and flows to the bottom and out from the bottom. The drying gas is fed into the drying chamber near or below the bottom of the cylindrical section of the chamber and flows up and out of the top of the drying chamber, in the opposite direction from the slurry/granules. 3. Mixed-Mode: The slurry is fed into the chamber and atomized near the bottom of the cylindrical section of the chamber. The drying gas is fed into the drying chamber at the top of the chamber. Dried granules fall to the bottom of the chamber and are recovered there, while the drying gas may flow out at the bottom of the chamber or at an intermediate point. The spray-drying step in the present invention may use any one of these configurations. In some embodiments it is mixed-mode spray drying. In some embodiments, other excipients and/or active ingredients may be sprayed into the drying chamber separately from the slurry. For example, in a mixed-mode spray-dryer, the slurry containing MCC and polyalkylene oxide may be fed and atomized at the usual point near the bottom of the cylindrical section of the chamber. One or more other excipients or active ingredients may be sprayed separately into the drying chamber near or above the top of the cylindrical section. The spray-drying process of this invention is carried out at a temperature and a rate of gas flow at which the atomized droplets dry rapidly without substantially degrading the ingredients of the granular composition. Typically, the temperature at the inlet is higher than at the outflow. In some embodiments, the inlet temperature is at least 100℃ or at least 120℃ or at least 130℃ or at least 140℃. In some embodiments the inlet temperature is no more than 200℃ or no more than 180℃ or no more than 160℃ or no more than 150℃. Gas flow rates will vary depending on the equipment; in general, the rate should be fast enough to rapidly dry the atomized particles without agglomerating them but slow enough that the granules are not carried out with the gas. In some embodiments, the atomized droplets become sufficiently dry to prevent substantial further agglomeration in no more than 60 seconds or 30 seconds or 15 seconds. There is no minimum drying time, but in some embodiments drying times of less than 1 second or 5 seconds are unnecessary. In some embodiments, the resulting granules contain no more than 15 weight percent water or no more than 10 weight percent or no more than 8 weight percent or no more than 7 weight percent. In some embodiments, the resulting granules contain at least 1 weight percent water or at least 2 weight percent or at least 3 weight percent or at least 5 weight percent. The spray-dried granules are separated from the drying gas and recovered by known means, such as by cyclone separators, or bag filters or electrostatic precipitators. Spray-drying causes the granular composition to have a different morphology than it would have if the components were physically blended. Physical blending would produce a mixture containing discrete particles of MCC and polyalkylene oxide and other excipients and/or active ingredients. On the other hand, spray drying the slurry causes the alkylene oxide to dry as a coating that partially or wholly encapsulates the outside of the MCC particles. In some embodiments, the encapsulated granules have a core that contains MCC and a shell that contains polyalkylene glycol. In some embodiments, the MCC is primarily found in the core of the particles, and the polyalkylene oxide is primarily found in the shell of the particles. In some embodiments, other excipients in the slurry are also located in the shell. If the other excipients are water-soluble, they may be blended with the polyalkylene oxide in the shell. If the other excipients are water-insoluble, discrete particles may be embedded in the polyalkylene oxide shell on the MCC particles, or they may also be coated with a shell of polyalkylene oxide. The ratio of dry components in the granules reflects the proportions already discussed. In some embodiments, particles of the granular composition have a mean particle size of at least 50 micron or at least 75 micron or at least 100 micron. In some embodiments, particles of the granular composition have a mean particle size of at most 300 micron or at most 250 micron or at most 200 micron or at most 150 micron. In some embodiments, the angle of repose for the granular compositions of this invention is no more than 35˚ or no more than 33˚ or no more than 32˚ or no more than 31˚ or no more than 30˚. In some embodiments, the angle of repose for the granular compositions of this invention is at least 20˚ or at least 25˚ or at least 26˚ or at least 27˚ or at least 28˚. In some embodiments, the angle of repose for the granular compositions of this invention is at least 1˚ lower than the angle of repose for a physical blend of the starting ingredients (in the form they had before being added to the slurry) or at least 2˚ lower or at least 3˚ lower or at least 5˚ lower or at least 7˚ lower. In some embodiments, the angle of repose for the granular compositions of this invention is no more than 15˚ lower than the angle of repose for a physical blend of the starting ingredients or no more than 10˚ lower. In some embodiments, low angle of repose may indicate that the granular composition flows well and is easy to process. In some embodiments, such as when a surface modifying excipient was added to the slurry, granular compositions of this invention may have an improved ability to form homogeneous mixtures with other dry granules or powders (mixability). Mixability is difficult to quantify but can be demonstrated visually by blending the granular composition with a powdered pigment such as iron oxide. The granular compositions of this invention may be compressed into tablets by known means. Before compression, the granular composition may optionally be blended with active ingredients or other excipients, as previously described. The blending may be carried out using known equipment, such as impellers or rotating drums. In some embodiments, the composition to be compressed contains at least 50 weight percent granular composition of this invention (as recovered from the spray-drying), or at least 60 weight percent, or at least 70 weight percent or at least 80 weight percent or at least 90 weight percent or at least 95 weight percent or at least 98 weight percent. In some embodiments, the composition to be compressed contains up to 100 weight percent granular composition of this invention (as recovered from the spray-drying), or no more than 99.99 weight percent or no more than 99.9 weight percent or no more than 99.5 weight percent or no more than 99 weight percent. Equipment to compress tablets is commercially available, with instructions for its use. Optimum compression pressure to make tablets varies widely depending on components selected for the granular composition. In some embodiments, the compression takes place at a pressure of at least 10 MPa or at least 20 MPa or at least 40 MPa or at least 50 MPa. In some embodiments, the compression takes place at a pressure of no more than 500 MPa or no more than 400 MPa or no more than 300 MPa or no more than 250 MPa. In some embodiments, the compression takes place at a temperature of at least 0℃ or at least 20℃. In some embodiments, the compression takes place at a temperature of no more than 70℃ or no more than 40℃. The resulting tablet may be any size that is appropriate for oral administration. In some embodiments, the sum of length plus width plus depth for the tablet is at least 9 mm or at least 11 mm or at least 13 mm. In some embodiments, the sum of length plus width plus depth for the tablet is at most 35 mm or at most 30 mm or at most 25 mm. Optionally, the tablet may be coated after it is compressed, such as with gelatin or a delayed-release coating. In some embodiments, tablets of this invention may have a crush resistance (hardness) of at least 6000 gf/mm or at least 7000 gf/mm or at least 7500 gf/mm or at least 8000 gf/mm or at least 8500 gf/mm or at least 9000 gf/mm. There is no maximum desired crush resistance, but in some embodiments crush resistance above 15,000 gf/mm or 10,000 gf/mm is unnecessary. In some embodiments, tablets of this invention may have a crush resistance (hardness) that is at least 100 gf/mm higher than tablets made from a physically blended mixture of the same ingredients or at least 200 gf/mm higher or at least 300 gf/mm higher or at least 500 gf/mm higher or at least 1000 gf/mm higher. There is no maximum desired crush resistance improvement, but in some embodiments improvement above 2000 gf/mm or 1500 gf/mm is unnecessary. In some embodiments, tablets of this invention may dissolve faster than tablets made from a physically blended mixture of the same ingredients, such as with no more than 50% of the dissolution time or no more than 30% of the dissolution time or no more than 10% of the dissolution time. TEST METHODS Properties described in this paper are measured using the following test methods, unless it is clear from the context that a different method is intended. Melting Temperature Vendor provides le at 00 to he to a ng C m th is ed he to he er ly

Mixability: A 0.5 g sample of powder to be tested is weighed into 2 dram vials and sealed using a cap with a flat insert. The sealed vial is inverted to allow the powder to flow to the top of the vial and flipped right side up again. is used as a coloring agent. A 0.02 g quantity of iron oxide (0.5 micron) is added to the vial. The vial is resealed and is again inverted once to allow all of the material to flow to the top of the vial. The glass vials are spun using a Yuhappy VH-2 powder mixer in which the V-shaped mixing vessel was removed and replaced with a block that can hold 2 dram glass vials (17 x 60 mm; Qorpak Item# GLC-00986). The mixer is set to 20 rpm and mixed for 2, 15, 30, and 90 minutes. At each time point, the mixer is stopped, and the vials are photographed in an imaging chamber illuminated with side lighting before being placed back on the mixer. Because the images are all taken under the same lighting conditions, image analysis can be used to quantify how effectively the iron oxide was mixed into the co-excipient. Using ImageJ, a region of the image is selected for analysis and the average L*a*b* values are reported. The overall color difference ΔE* between a sample and a pure white material is calculated by ΔE* = [(L*sample - L*white)² + (a*sample - a*white)² + (b*sample - b*white)²], where L*white = 100, a*white = 0, and b*white = 0. Higher ΔE* values after mixing indicate better mixability. EXAMPLES The following Examples illustrate some embodiments of the invention. The Examples use the materials in Table 1. Table 1 Ingredient Product Name Further Description Type e

For Inventive Examples 1 to 3 (IE1, IE2 and IE3), the materials from Table 1 are blended with water in the proportions shown in Table 2 to form a homogeneous slurry containing about 20 weight percent solids. The slurries are spray dried according to the following procedure, to make a granular composition. The spray drier is a Mobile Minor spray dryer (GEA Process Engineering Inc.) fitted with a two-fluid nozzle atomizer. The spray drying is performed under an inert atmosphere of nitrogen. Nitrogen is supplied to the atomizer at ambient temperature at 1 bar and 50% flow, which is equivalent to 6.0 kg/hour of flow rate. The slurry is fed into the atomizer at about 30 mL/min using a peristaltic pump (Masterflex L/S). Heated nitrogen is fed as drying gas into the top of the drying chamber at a flow rate of about 20 SCFM. The inlet temperature is set at 140°C, and the outlet temperature is equilibrated at 40-50°C by fine tuning the slurry feed rate. Flow aid is added at the top of the drying chamber through a Coperion K-TRON screw feeder at a feed rate of 0.1 g/min. The resulting spray-dried granular composition is recovered in a cyclone and subsequently vacuum dried at room temperature to removed residual moisture. For Comparative Examples 1 to 3 (CE1, CE2 and CE3), the materials from Table 1 are physically blended in the proportions shown in Table 2 using by combining them in plastic cups tumbling end-over- end for 24 h until a homogeneously mixed granular composition is obtained. For Comparative Examples 4 to 6 (CE4-CE6), commercial powdered excipient formulations from Table 1 are used as sold. Formulation D_mean Particle D50 particle size (micron) size (micron)

The particle sizes, flowability and mixability of each granular composition are measured as described in the Test Methods. Particle Size Distributions are shown in Table 2 and Figure 1. Flowability and mixability results are shown in Table 3. Each granular composition is compressed to make tablets using a Carver compression molder. A 2 gram sample of each granular composition is weighed into the template and a weight of 5000 pounds is applied to make a round-disk shape tablet with a diameter of 13/16 inch. The hardness and dissolution of the tablets are tested as set out in the Test Methods. Results are set out in Table 3. For Dissolution Rate: • very fast = less than 10 seconds, • fast = 10 to 60 seconds, • slow = 60 to 600 seconds, and • very slow = more than 600 seconds Table 3: Test Results Sample Mixability ( Mixability Tablet Tablet # ^{Angle of} ΔE* repose(°) at 2 min) (ΔE* at 15 Dissolution Hardness i R t f/

Claims

CLAIMS: 1. A granular composition comprising: a) From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and b) From 75 to 97 weight percent of microcrystalline cellulose, wherein the granules comprise particles of microcrystalline cellulose encapsulated wholly or in part by polyalkylene glycol. 2. The granular composition of Claim 1 wherein the granules comprise a core that contains . microcrystalline cellulose and a shell that contains polyalkylene glycol. 3. The granular composition of Claim 2 wherein the polyalkylene glycol is a polyethylene glycol or a polyethylene glycol-polypropylene glycol copolymer. 4. The granular composition of Claim 3 wherein the polyalkylene glycol has a number average molecular weight of at least 2000 Da and no more than 25,000 Da. 5. The granular composition of Claim 4 wherein the polyalkylene glycol has a molecular weight of at least 4000 Da and at most 12,000 Da. 6. The granular composition of Claim 2 which contains at least 5 weight percent polyalkylene glycol and at least 80 weight percent microcrystalline cellulose. 7. The granular composition of Claim 2 which contains from 5 to 15 weight percent polyalkylene glycol, from 80 to 95 weight percent microcrystalline cellulose and from 2 to 10 weight percent of one or more other excipients. 8. The granular composition of Claim 7 wherein the other excipients contain colloidal silica. 9. The granular composition of Claim 7 wherein the other excipients contain a dibasic phosphate salt. 10. The granular composition of any of Claims 1 to 9 wherein the mean particle size of the granules is from 50 microns to 200 microns. 11. The granular composition of Claim 10 which has an angle of repose of no more than 32˚. 12. A solid tablet comprising: (1) a pharmaceutically effective amount of an oral pharmaceutical dispersed in (2) a compressed granular composition of Claim 1. 13. The tablet of Claim 12 which has a crush resistance of at least 8000 gf/mm. 14. A process to make a granular excipient composition comprising the steps of: a) making a slurry that contains the following dry components: i) From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and ii) From 75 to 97 weight percent of microcrystalline cellulose; and in a solvent that dissolves the polyalkylene glycol but not the microcrystalline cellulose, wherein the weight percentages are based on the total weight dry ingredients, excluding the solvent; and b) Spray-drying the slurry to form a dry granular composition. 15. A granular composition made by the process of Claim 14 and that contains: a) From 3 to 25 weight percent of a water-soluble polyalkylene glycol that is solid up to at least 35℃; and b) From 75 to 97 weight percent of microcrystalline cellulose.