Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the most commonly employed means to deliver drug substances is the tablet, typically obtained through the compression of appropriately formulated excipient powders. Tablets should be free of defects, have the strength to withstand mechanical shocks, and have the chemical and physical stability to maintain physical attributes over time and during storage. Undesirable changes in either chemical or physical stability can result in unacceptable changes in the bioavailability of the drug substance. In addition, tablets must be able to release the drug substance in a predictable and reproducible manner.
• the present invention relates to a novel excipient for use in the manufacture of pharmaceutical solid dosage forms such as tablets.
• the novel excipient is advantageously combined with at least one drug substance, hereinafter active pharmaceutical ingredient (API), and formed into tablets using a direct compression manufacturing method.
• API active pharmaceutical ingredient
• the tableting mixture In order to successfully form tablets, the tableting mixture must flow freely from a feeder hopper into a tablet die, and be suitably compressible. Since most APIs have poor flowability and compressibility, APIs are typically mixed with varying proportions of various excipients to impart desired flow and compressibility properties, ⁇ n typical practice, a compressible mixture is obtained by blending an API with excipients such as diluents/fillers, binders/adhesives, disintegrants, glidants/flow promoters, colors, and flavors. These materials may be simply blended, or may be wet or dry granulated by conventional methods. Once mixing is complete, a lubricating excipient is typically added and the resulting material compressed into tablets.
• excipients such as diluents/fillers, binders/adhesives, disintegrants, glidants/flow promoters, colors, and flavors.
• Two conventional methods of making tablets are dry blending followed by direct compression, and granulation followed by direct compression.
• the API is blended with the desired excipients such as diluent/filler, binder, disintegrant, glidant, and colors. Once blending is complete a lubricating excipient is added and the resulting material is compressed into tablets.
• the direct compression method is limited by and dependent on the specific API properties, and further upon the combination of the various excipients. Therefore granulation of the excipients with the API is typically employed in order to achieve satisfactory tablets and/or improve tablet production speed.
• Traditional methods of granulation include dry granulation, wet granulation, and spray granulation. Each of these methods has limitations regarding the particles produced from the process.
• the dry granulation method consists of mixing the components to form a blend which is roll compacted. This process is limited as the particles are not held together strongly and easily fall apart. Roll compaction processing also results in reduction of compactibility of many excipients.
• Wet granulation is a process in which excipients are bound together in the presence of a liquid binder in a blender system, to produce a wet granular blend which is dried.
• Spray granulation is a process in which excipients are bound together in a fluidized bed. These processes are batch processes, which limits production speed, and can produce a variable product.
• U.S. Patent No. 4,675,188 to Chu et al discloses a granular directly compressible anhydrous dicalcium phosphate excipient which purports to have a particle size sufficient for efficient direct compression tableting.
• dicalcium phosphate is dehydrated, and then granulated with a binder.
• the resulting product is purportedly a granular anhydrous dicalcium phosphate, characterized in that at least 90 percent of the particles are larger than 44 microns.
• This granular product purports to improve over commonly used precipitated anhydrous dicalcium phosphate, which is a fine, dense powder that must be agglomerated with a binder such as starch before it can be used in direct compression tableting.
• the process disclosed in this patent consists of coating anhydrous calcium phosphate with starch or another binder, purportedly resulting in binding of calcium phosphate particles to each other forming large particles.
• this granulated product is not a universal excipient, in that it lacks other necessary excipients, such as disintegrants, that are necessary to produce a pharmaceutically acceptable tablet after compression.
• 6,746,693 discloses an agglomerated microcrystalline cellulose blend containing silicon dioxide, purported to have improved compressibility.
• the disclosure states that silicon dioxide is a critical component to improve compressibility.
• the two step process described includes spray granulation followed by wet granulation, and does not provide a complete universal excipient.
• Ludipress® A commercially available excipient, Ludipress®, is disclosed in EP 0192173B1.
• Ludipress® is composed of lactose, crospovidone, and povidone. Lactose is known to have better flowability than microcrystalline cellulose due to inherently different particle shape and morphology. Lactose and povidone are water soluble components that mix well with a third non-water soluble component for granulation by spray drying. There is no disclosure of a complete universal excipient including two or more insoluble components, or a specific particle morphology to enable increased flowability, compactibility with various APIs and varying degrees of loading.
• An illustrative aspect of the present invention is a composition comprising about 75% to about 98% microcrystalline cellulose, about 1% to about 10% at least one binder, and about 1 % to about 20% at least one disintegrant, wherein the microcrystalline cellulose, binder and disintegrant are indistinguishable when viewed with a SEM, thereby forming substantially homogeneous, substantially spherical particles.
• Another illustrative aspect of the present invention is an excipient comprising about 75% to about 98% microcrystalline cellulose, about 1% to about 10% at least one binder, and about 1% to about 20% at least one disintegrant, wherein the excipient is formed by spraying an aqueous slurry comprised of the microcrystalline cellulose, binder and disintegrant.
• Yet another illustrative aspect of the present invention is a method of making an excipient.
• the method comprises mixing a microcrystalline cellulose slurry with a disintegrant slurry to form a microcrystalline cellulose/disintegrant slurry; mixing a binder in water to form a viscous binder slurry; homogenizing the binder slurry with the microcrystalline cellulose/disintegrant slurry to form a homogenized slurry; and spray dry granulating the homogenized slurry to form substantially homogeneous, substantially spherical particles of excipient.
• a further illustrative aspect of the present invention is a pharmaceutical tablet comprising at least one active pharmaceutical ingredient and an excipient.
• the excipient comprises substantially homogeneous, substantially spherical particles including microcrystalline cellulose, at least one binder, and at least one disintegrant.
• Yet a further illustrative aspect of the present invention is a method of making a pharmaceutical tablet.
• the method comprises mixing at least one active pharmaceutical ingredient and an excipient and compressing the resulting mixture to form a tablet.
• the excipient comprises substantially homogeneous, substantially spherical particles including microcrystalline cellulose, at least one binder, and at least one disintegrant.
• An alternate illustrative aspect of the present invention is a composition comprising substantially homogeneous particles including about 90% to about 99% microcrystalline cellulose and about 1% to about 10% at least one binder.
• Another alternate illustrative aspect of the present invention is an excipient comprising about 95% to about 99% microcrystalline cellulose and about 1% to about 5% at least one binder, wherein the excipient is formed by spray dry granulating an aqueous slurry comprised of the microcrystalline cellulose and binder.
• Yet another alternate illustrative aspect of the present invention is a method of making an excipient.
• the method comprises mixing a binder in water to form a viscous solution, homogenizing microcrystalline cellulose into the viscous solution to form a slurry; and spraying the slurry to form substantially homogeneous particles of excipient.
• Still another alternate illustrative aspect of the present invention is another method of making an excipient.
• the method comprises dissolving hydroxypropyl methylcellulose in water to form a viscous solution; mixing and homogenizing microcrystalline cellulose into the viscous solution to form a slurry; and spraying the slurry to form substantially homogeneous particles.
• a further alternate illustrative aspect of the present invention is a pharmaceutical tablet comprising at least one active pharmaceutical ingredient, a disintegrant and an excipient.
• the excipient comprises substantially homogeneous particles including microcrystalline cellulose and at least one binder.
• a further alternate illustrative aspect of the present invention is a method of making a pharmaceutical tablet.
• the method comprises mixing at least one active pharmaceutical ingredient, a disintegrant and an excipient and compressing the resulting mixture to form a tablet.
• the excipient comprises substantially homogeneous particles including microcrystalline cellulose and at least one binder.
• Figure 1 is an illustration of SEM micrographs of the improved excipient of the present invention produced according to Example 1.
• Figure 2 is an illustration of SEM micrographs of the improved excipient of the present invention produced according to Example 2.
• Figure 3 is an illustration of SEM micrographs of microcrystalline cellulose.
• Figure 4 is an illustration of SEM micrographs of a commercially available excipient, Prosolv®90.
• FIG. 5 is an illustration of SEM micrographs of a commercially available excipient, Ludipress®
• Figure 6 is an illustration of SEM micrographs of an excipient manufactured by conventional high shear wet granulation method according to Example 4.
• Figure 7 is an illustration of a flowability index comparison of an excipient made by conventional high shear wet granulation according to example 4 and the improved excipient of the present invention produced according to Examples 1 , 2 and 3.
• Figure 8 is an illustration of SEM micrographs of multiple samplings of the improved excipient of the present invention produced according to Example 3.
• Figure 9 is an illustration of the dissolution profile for 62.5% Ibuprofen/Example 1 excipient/silica/magnesium stearate tablets.
• Figure 10 is an illustration of the effect of compression force on tablet hardness and tablet disintegration time for tablets pressed according to Example 21.
• Figure 1 1 is an illustration of the effect of variable tonnage on tablet hardness for tablets pressed according to Example 21.
• Figure 12 is an illustration of SEM micrographs of multiple samplings of the alternate improved excipient of the present invention produced according to Example 22,
• Figure 13 is an illustration of SEM micrographs of multiple samplings of the alternate improved excipient of the present invention produced according to Example 23.
• Figure 14 is an illustration of SEM micrographs of MCC (98%) - HPMC (2%) prepared by high shear wet granulation (HSWG) according to Example 24.
• an excipient comprising substantially homogeneous, substantially spherical particles of a highly compressible granular microcrystalline cellulose based excipient, herein denoted the “improved excipient.”
• the term 'substantially homogenous particles' is defined as a composition in which the individual components of the composition are not individually distinguishable when viewed under SEM.
• the improved excipient provides enhanced flowability/good flow properties, excellent/high compactibility, and increased API loading and blendability as compared to the individual components, and as compared to conventional excipients formed from the same materials.
• the improved excipient has strong intraparticle bonding bridges between the components, resulting in a unique structural morphology including significant open structures or hollow pores. The presence of these pores provides a surface roughness that is the ideal environment for improved blending with an API. Excellent blendability is an essential characteristic of an excipient as it allows tablets to be produced that contain a uniform amount of the API. Additionally, this improved excipient includes the necessary excipients, except for the optional lubricant, that are required to produce a pharmaceutically acceptable tablet.
• the improved excipient is engineered to have particle size that results in the excipient being directly compressible, complete, and universal excipient for making pharmaceutical tablets.
• the excipient is considered complete since it includes a diluent, a binder and a disintegrant, and universal since it is surprisingly compatible with a variety of APIs.
• the components and physical characteristics of the improved excipient were carefully chosen and optimized to ensure its use in formulating a wide range of APIs.
• the universality of this excipient overcomes the need for the traditional time consuming approach to formulation development, wherein the scientist develops a custom blend of various excipients to optimize flowability and compressibility for the particular API. It was unexpectedly discovered that the disclosed composition and process of making the improved excipient provides a substantially homogeneous, strong spherical particle having high increased porosity that provides good flowability and high compactibilily.
• the improved excipient typically has an aerated bulk density of about 0.1-0.4 g/cc.
• Unprocessed microcrystalline cellulose has a needle-like shape when viewed under SEM (as illustrated in Figure 3).
• the particle morphology of the improved excipient disclosed herein is unexpectedly unique as a substantially homogeneous spherical structure with holes or pores and hollow portions in the particles that can improve API loading capacity.
• the term substantially homogeneous is meant herein to denote a structure in which the individual components cannot be distinguished under SEM scan. This contrasts with traditional excipients such as Prosolv® (as illustrated in Figure 4) and Ludipress® (as illustrated in Figure 5).
• MCC is processed in combination with a polymeric binder and a cross-linked hygroscopic polymer to produce spherical particles having high porosity and strong intraparticle binding.
• the polymeric binder is selected from the class of cellulosic polymers or organic synthetic polymers having thermal stability at about 80 0 C to about 120 °C, dynamic viscosity in the range of about 2 mPa to about 50 mPa for a water solution of about 0.5% to about 5% wt/vol, water solubility in the range of about 0.5% to about 5% wt/vol and providing a surface tension in the range of about 40 dynes/cm to about 65 dynes/cm for about 0.5% to about 5% wt/vol water solution.
• Preferred binders from this class include hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and polyvinyl alcohol-polyethylene glycol graft copolymer and vinylpyrrolidone-vinyl acetate copolymer.
• HPMC hydroxypropyl methylcellulose
• HPMC hydroxypropyl methylcellulose
• the cross-linked hygroscopic polymer disintegrant is preferably crospovidone (CPVD).
• the processed particles are a substantially homogeneous composition of spheres with porous portions leading to at least partially hollow portions of the spheres.
• the granules are produced by the actual physical binding of the slurry mixture that becomes distinct particles when ejected out of the nozzle.
• the porosity and hollow portions result in improved API loading and blendability.
• the improved excipient has excellent flowability.
• additional glidants such as silicon dioxide are added to improve flow. If the powder flow is not sufficient, poor tablet productivity will result.
• Characterization of the improved excipient particles by the Carr method showed a flowability index that exceeds 80, where a flowability index over 70 indicates good flowability.
• a Hosokawa powder tester a test instrument that measures powder characteristics using a set of automated tests using the Carr method was used to determine that the improved excipient of Example 1 has a flowability index of 82.
• Fig. 7 illustrates a comparison of flowability index for a conventionally prepared excipient according to Example 4 with the improved excipient of the present invention.
• the granules of the material produced according to the invention are stronger than those of a similar material produced by a traditional high shear wet granulation process.
• the improved excipient of the present invention produced acceptable tablets by direct compression when directly mixed with as low as about 1% API or as high as about 50% API. This indicates universal application and use of the material produced according to this invention.
• the use of greater than about 50% API may be accomplished by the use of a glidant component in the composition.
• the process disclosed herein is a novel form of the spray drying granulation process.
• the new process consists of the homogenization of all three components of the excipient in the presence of water to create a slurry of the components.
• a slurry of MCC is mixed with a slurry of cross-linked polyvinylpyrrolidone slurry to form a MCC/ cross-linked polyvinylpyrrolidone slurry, Hydroxypropyl methylcellulose is then mixed with water to form a viscous hydroxypropyl methylcellulose slurry.
• the hydroxypropyl methylcellulose slurry is then mixed/homogenized with the MCC/ cross-linked polyvinylpyrrolidone slurry to form a homogenized slurry.
• the homogenized slurry is then spray dry granulated to form substantially homogeneous, substantially spherical particles of excipient.
• the homogenization process is carried out to bring the two insoluble components, MCC and a disintegrant, in contact with each other and bound in close association with a viscous binder solution, for example hydroxypropyl methylcellulose.
• a viscous binder solution for example hydroxypropyl methylcellulose.
• a traditional spray drying method uses compositions of one or two soluble components.
• Example 4, Figure 6 illustrates the composition components of the present invention processed by the traditional wet granulation method.
• the material produced from the conventional high shear wet granulation process consisted of needle like friable particles that did not perform as well as the product formed by the present method, as illustrated in Examples 1 and 3.
• Example 7 Compressiblity decreased, resulting in a 1.8 times decrease in the hardness of the placebo tablets pressed from the conventionally produced material as compared to the improved according to Example 1, see Example 7.
• the particle morphology is composed of irregular particles bonded together by simple intergranular bridges, as seen in Figure 6.
• the components of the improved excipient are processed by an improved wet homogenization/spray dry granulation method.
• a slurry is formed of two water insoluble components (typically with a large difference in composition between the two water insoluble components) and a third water soluble component.
• the resulting slurry is granulated to a desired particle size, typically greater than about 50 ⁇ m, preferably about 50 ⁇ m to about 250 ⁇ m, and more preferably about 90 ⁇ m to about 150 ⁇ m.
• the excipient is formed by processing, or homogenizing, MCC with the polymeric binder and a cross-linked hygroscopic polymer disintegrant.
• the excipient is formed from about 75% to about 98% MCC, in combination with about 1 % to about 10% binder and about 1% to about 20% disintegrant.
• the excipient is formed from about 80% to about 90% MCC, about 2% to about 8% binder and about 3% to about 12% disintegrant.
• the excipient is formed from about 85% to about 93%, about 2% to about 5% binder and about 10% disintegrant.
• the use of the improved excipient will reduce formulation development to a series of blending steps: blending of an API with the improved excipient (which contains the essential components of tablet formulation, diluent, binder and disintegrant) and optionally a lubricant.
• the blending process will typically be followed by pressing high quality tablets by direct compression, for example by a rotary tabletting machine.
• the "active ingredient” or “active agent”, referred herein as the API refers to one or more compounds that have pharmaceutical activity, including therapeutic, diagnostic or prophylactic utility.
• the pharmaceutical agent may be present in an amorphous state, a crystalline state or a mixture thereof.
• the active ingredient may be present as is, taste masked, coated for enteric or controlled release.
• active pharmaceutical ingredient API
• API active pharmaceutical ingredient
• Illustrative suitable active ingredients include, but are not limited to: Antiviral agents, including but not limited to acyclovir, famciclovir; anthelmintic agents, including but not limited to albendazole; lipid regulating agents, including but not limited to atorvastatin calcium, simvastatin; angiotensin converting enzyme inhibitor including but not limited to benazepril hydrochloride, fosinopril sodium; angiotensin II receptor antagonist including but not limited to irbesartan, losartan potassium, valsartan; antibiotic including but not limited to doxycyclinc hydrochloride; antibacterial including but not limited to linezolid, metronidazole, norfloxacin; antifungal including but not limited to terbinafine; antimicrobial agent including but not limited to ciprofloxacin, cefdinir, cefixime; antidepressant, including but not limited to bupropione hydrochloride,
• tablet formulations including an API can be found in the Examples, specifically acetaminophen, Examples 10-14; ibuprofen, example 16; naproxen sodium, Example 15; and atorvastatin calcium, Example 21.
• the tablets produced utilizing the improved excipient of the present invention may include further additives and/or fillers as is known in the art.
• These addition components include but are not limited to excipients such as diluents/fillers, binders/adhesives, disintegrants, glidants/flow promoters, colors, and flavors.
• excipients such as diluents/fillers, binders/adhesives, disintegrants, glidants/flow promoters, colors, and flavors.
• Illustrative Examples of tablet formulations of various weights, punches and embossing are shown in Example 18; coated tablets in Example 19; and tablets including fillers in Example 20.
• composition and processing steps disclosed herein produce an improved excipient exhibiting novel final particle morphology and unexpectedly improved compressibility.
• the improved excipient is formulated from MCC and a binder, without a disintegrant (hereinafter the 'alternate improved excipient')
• the alternate improved excipient comprised of MCC and at least one binder and formed according to the present invention, provides better flowability and higher compactibility than various grades of MCC.
• the alternate improved excipient typically has an aerated bulk density of about 0.2 to 0.3 g/cc, and spherically shaped particles that have a roughness associated with them that allows better API blendability than various grades of MCC. This alternate improved excipient is suitable for both dry and wet granulation.
• the alternate improved excipient When wet granulated the alternate improved excipient does not lose compressibility as compared with various grades of MCC which typically lose compressibility upon wet granulation.
• the alternate improved excipient is produced as described above, without the addition of a disintegrant.
• the alternate improved excipient comprises about 90% to about 99% MCC and about 1% to about 10% binder; in a more preferred embodiment the alternate improved excipient comprises about 95% to about 99% MCC and about 1% to about 5% binder; and in a most preferred embodiment the alternate improved excipient comprises about 97% to about 99% MCC and about 1% to about 3% binder.
• Examples 22 and 23 illustrate methods of making the alternate improved excipient, utilizing 98% MCC/2% HPMC and 95% MCC/5HPMC, respectively, utilizing a homogenization/spray dry granulation method.
• Examples 24, 25 and 26 illustrate methods of making the alternate improved excipient, utilizing 98% MCC/2% HPMC, 95% MCC/5HPMC, and 90% MCC/10% HPMC, respectively, utilizing a conventional wet granulation method, high shear wet granulation.
• Example 27 discloses the production of a prior art formulation, a powdered blend of MCC and HPMC.
• Examples 28 through 39 illustrate comparative testing of the alternate improved excipient and commercially available MCC.
• the alternate improved excipient provides homogeneous spherical granules with an average particle size of 100-150 microns.
• the alternate improved excipient has better flowability than various grades of MCC and due to the roughness associated to its particles has a better blendability with APIs,
• the alternate embodiment excipient granules are hard and do not break when tested for friability as compared to granules of similar composition prepared by HSWG.
• the alternate embodiment excipient does not lose compressibility when wet granulated as compared to MCC.
• Example 1 Preparation of microcrystalline cellulose- 2% hydroxypropyl methylcellulose - crospovidone excipient according to the present invention:
• the improved excipient consists of microcrystalline cellulose at 85%, hydroxypropyl methyl cellulose at 2%, and crospovidone at 13%.
• the excipient was produced by a wet homogenization/spray dry granulation process.
• the apparatus used for the production of the excipient was a Co-current atomizer disc type with the disc RPM between 12000 and 25000 and the inlet temperatures of 180-250 °C. Powdered MCC was converted into a slurry in a mixing chamber with deionized water to give a concentration of 23.3%.
• the other components, HPMC and crospovidone were also converted to a slurry with deionized water in a separate mixing chamber at 60 0 C to a concentration of 5,9%.
• the MCC slurry was then transferred to the chamber containing the HPMC/crospovidone slurry and homogenized into a uniform mixture at 40-60 0 C for 1 hour using circulating shear pump and an agitator to keep solids suspended in the solution thereby forming a uniform slurry.
• the slurry mixture was then spray dried through a rotary nozzle at a motor frequency of 33 Hz in the presence of hot air at an outlet temperature of 106-109 0 C. This constitutes the granule formation step.
• the fines were removed in a cyclone and the final product was collected to give the new improved excipient. SEM micrographs of the excipient of Example 1 are seen in Figure 1.
• the compressibility, aerated bulk density and tapped bulk density of the granular material were measured using a Powder Tester (Hosokawa Micron Corporation) Model PT-S.
• a computer which uses the Hosokawa Powder Tester software was used to control the Hosokawa Powder Tester during the measurement operation, enabling simple use and data processing.
• For measuring the aerated bulk density and tapped bulk density a 50 cc cup was employed.
• the standard tapping counts for measuring the tapped bulk density were 180 and the tapping stroke was 18 mm. D50 value was calculated based on the data collected in a "particle size distribution" measurement.
• An Air Jet Sieving instrument (Hosokawa Micron System) was used to determine the particle size distribution of the granular material.
• a set of four sieves (270 mesh, 200 mesh, 100 mesh and 60 mesh) was used.
• the sieving time for each sieve was 60 sec, while the vacuum pressure was maintained at 12-14 in. H 2 O.
• the sample size was 5 g.
• the "loss on drying” (LOD) value was determined using a Mcttler Toledo Infrared Dryer LP 16. The set temperature was 120 0 C and the analysis was stopped when constant weight was reached.
• Example 2 Preparation of microcrystalline cellulose- 5.5% hydroxypropyl methylcellulose - crospovidone excipient according to the present invention:
• the excipient consists of microcrystalline cellulose at 85.5%, hydroxypropyl methyl cellulose at 5.5%, and crospovidone at 9%.
• the excipient was produced by a wet homogenization/spray drying granulation process.
• the apparatus used for the production of the excipient is a Co-current atomizer disc type with the disc RPM between 12000 - 25000 and the inlet temperatures of 180 - 250 0 C. After granulation a cyclone separation device was used to remove the fines.
• Powdered MCC was converted into a slurry using deionized water in a mixing chamber to reach a concentration of 25.1%.
• the other components HPMC and crospovidone were first dry mixed and then also converted into a slurry with deionized water in a separate mixing chamber to a concentration of 11.4%,
• the MCC slurry was then transferred to the chamber containing the HPMC/crospovidone slurry and homogenized into a uniform mixture at 40-60 0 C for 1 hour using circulating shear pump and an agitator to keep solid suspended in the solution to form uniform slurry
• the slurry mixture was then spray dried through a rotary nozzle at the motor frequency of 40.1 Hz in the presence of hot air at an outlet temperature of 106-109 0 C. This constitutes the granule formation step.
• the fines were removed in a cyclone and the final product was collected, see Figure 2.
• the excipient consists of microcrystalline cellulose at 89%, hydroxypropyl methyl cellulose at 2%, and crospovidone at 9%.
• the excipient was produced by a wet homogenization/spray drying granulation process.
• the apparatus used for the production of the excipient was a Co-current atomizer disc type with the disc RPM between 12000 - 25000 and the inlet temperatures of 180 - 250 0 C. After granulation a cyclone separation device was used to remove the fines.
• the production of the granular excipient begins with converting powdered MCC (which consists of rod like particles) into a slurry using deionized water in a mixing chamber to a concentration of 23.3%.
• the resulting slurry mixture was then spray dried through a rotary nozzle at the motor frequency of 32.5 Hz in the presence of hot air at an outlet temperature of 106-109 0 C. This constitutes the granule formation step.
• the fines were removed in a cyclone and the final product was collected. The uniformity of product taken from several samplings is illustrated in Figure 8.
• the wet massing time was 60 seconds maintaining the same impeller and chopper speed as during the liquid addition.
• the wet granular material was dried in a tray at 60 0 C.
• the resulting granular material (moisture content 2.4%) was screened through a 30 mesh sieve.
• the yield of the granular material that passed through 30 mesh screen was 116,7 g (79.3% referenced to dry starting materials and dry product). See Figure 6.
• Example 5 Granule friability test for the Example 1 excipient and the material obtained by high shear wet granulation as per Example 4: 75 - 10O g of granular material were loaded in a 4 L V-Blender and tumbled for 2 h. The granular material was collected and analyzed. An Air Jet Sieving instrument (Hosokawa Micron System) was used to determine the particle size distribution of the granular material before and after tumbling. A set of four sieves (270 mesh, 200 mesh, 100 mesh and 60 mesh) was used. The sieving time for each sieve was 60 sec, while the vacuum pressure was maintained at 12-14 in, H 2 O, The sample size was 5 g.
• Hosokawa Micron System Hosokawa Micron System
• Example 6 Comparison of Powder Characteristics for Example 1 and Example 3 excipient and the material obtained by high shear wet granulation as per example 4:
• the powder characteristics of the granular materials were measured using a Powder Tester (Hosokawa Micron Corporation) Model PT-S.
• the Hosokawa Powder tester determines flowability of dry solids in accordance with the proven method of R. L. Carr.
• a computer which uses the Hosokawa Powder Tester software was used to control the Hosokawa Powder Tester during the measurement operation, enabling simple use and data processing.
• For measuring the aerated bulk density and tapped bulk density a 50 cc cup was employed.
• the standard tapping counts for measuring the tapped bulk density were 180 and the tapping stroke was 18 mm. Table 5
• Example 7 Comparison of hardness vs. compression force profiles for placebo tablets prepared using Example 1 excipient and the material obtained by high shear wet granulation as per example 4:
• Example 8 Comparison of Hausner Ratio and Carr's Compressibility Index (%) of microcrystalline cellulose from different commercial sources, commercial co-processed excipients containing microcrystalline cellulose, and Example 1, 2 and 3 excipients:
• Carr's compressibility index and Hausner ratio can be calculated.
• a value of 20-21% or less for the Carr's compressibility index and a value below 1.25 for the Hausner ratio indicate a material with good flowability.
• Emcocel 90 1.32 24.5
• Example 9 Disintegration Time vs. Hardness for Placebo Tablets of MCC Based Granular Excipients:
• Example 10 Powder properties of a mixture of 5% Acetaminophen with Example 1 excipient:
• Example 7 7.9 g acetaminophen was blended with 150 g of Example 1 excipient in a 4 L V-blender for 1 h 30 min.
• the powder characteristics were measured using the same method mentioned in Example 6.
• the D50 value was calculated based on the data collected in a "particle size distribution" measurement similar to the one described in Example 5,
• Example 1 1 Powder properties of a mixture of 30% Acetaminophen with Example 1 excipient:
• Example 64.9 g acetaminophen was blended with 150 g of Example 1 excipient in a 4 L V- blender for 1 h 30 min.
• the powder characteristics were measured using the same method mentioned in Example 6.
• the D50 value was calculated based on the data collected in a "particle size distribution" measurement similar to the one described in Example 5.
• Example 12 Powder properties of a mixture of 30% Ibuprofen with Example 1 excipient.
• Example 64.3 g ibuprofen was blended with 15O g of Example 1 excipient in a 4 L V-blender for 1 h 30 min.
• the powder characteristics were measured using the same method mentioned in Example 6.
• the D50 value was calculated based on the data collected in a "particle size distribution" measurement similar to the one described in Example 5.
• Example 13 Preparation of 5% Acetaminophen tablets using the powder blend prepared according to Example 10:
• Example 14 Preparation of 30% Acetaminophen tablets using the powder blend prepared according to Example 11 :
• 80 g naproxen sodium was blended with 80 g example 3 excipient and 800 mg (0.5%) amorphous silica (glidant) in a 4 L V-blender for 1 h 30 min.
• Approximately 0.5 g tablets were pressed from the corresponding granular material at various compression forces using a Carver manual press and a 13 mm die. The dwell time was 5 seconds. No lubricant was added.
• the hardness of the tablets was measured using a Vaxian, BenchsaverTM Series, VK 200 Tablet Hardness Tester. The values recorded in the table below are an average of three measurements.
• the disintegration experiments were performed with a Distek Disintegration System 3100, using 900 mL deionoized water at 37 degrees Celsius.
• Ibuprofen, granular excipient as per Example 1 and Silica were blended in a V-blender for 15 min at 20 rpm. The mixture was passed through a 30 mesh sieve and blended in a V-blender with Mg Stearate for 2 min at 20 rpm. The resulted blend was transferred to a 10 station rotary tableting machine (Mini Press II, Globe Pharma). Tablets were pressed using 10 mm dies and a force feeder operated at 10% power. Table 17 lists the tableting parameters used in the study.
• the ibuprofen tablets prepared as per Example 16 were characterized for tablet weight (Table 18), tablet thickness (Table 19), tablet hardness (Table 20), tablet friability (Table 21), tablet disintegration (Table 22) and Ibuprofen dissolution (Figure 9).
• Example 15 The hardness and disintegration of the tablets were measured as described in Example 15.
• the tablet friability test was performed according to the USP recommendations for friability determination of compressed, uncoated tablets (see USP chapter ⁇ 1216>) using a Varian Friabilator.
• the dissolution experiment was conducted according to the USP
• the Excipient as per Example 1 was passed through a 40 mesh sieve and Mg Stearate was passed through a 60 mesh sieve before mixing them with each other in a drum blender at a speed of 20 rpm for 2 min. Two batches were prepared according to Table 23.
• the lubricated blend of batch I was subdivided in 4 parts and the lubricated batch II was subdivided in two parts and taken for compression on a 16 station compression machine.
• the compression parameters are listed in Table 24.
• the effect of punch and embossing variation is given in Table 25.
• the resulted coated tablets were defect free and uniformly coated.
• Example 1 excipient Blends of Example 1 excipient and a filler in 4:1, 2:1 and 1:1 ratio (by weight) were
• the fillers used in this study were: macrocrystalline cellulose, spray dried lactose and dibasic calcium phosphate.
• a 3000 tablet batch size of a formulation (Table 29) of atorvastatin calcium (a crystalline form) was prepared using a 16 station compression machine. The compression
• Atorvastatin Calcium 80.0 Example 1 excipient 478.0
• the alternate improved excipient consists of 98% microcrystalline cellulose and 2% hydroxypropyl methylcellulose.
• the excipient was produced by a wet homogenization/spray dry granulation process.
• the apparatus used for the production of the excipient was a Co- current atomizer disc type with the disc RPM between 12000 and 25000 and the inlet temperature of 180-250 0 C.
• Powdered MCC was converted into a slurry with deionized water to give a concentration of 23.58% w/w
• the HPMC was mixed with deionized water, stirred and circulated for 60 - 70 mill to give a concentration of 16.1 1% w/w.
• the prepared HPMC slurry was added to the MCC slurry.
• the HPMC slurry tank was washed
• the compressibility, aerated bulk density and tapped bulk density of the granular material were measured using a Powder Tester (Hosokawa Micron Corporation) Model PT-S (Table 31).
• a computer which uses the Hosokawa Powder Tester software was used to control the Hosokawa Powder Tester during the measurement operation, enabling simple use and data processing.
• For measuring the aerated bulk density and tapped bulk density a 50 cc cup was employed.
• the standard tapping counts for measuring the tapped bulk density were 180 and the tapping stroke was 18 mm. D50 value was calculated based on the data collected in a "particle size distribution" measurement.
• An Air Jet Sieving instrument (Hosokawa Micron System) was used to determine the particle size distribution of the granular material.
• a set of four sieves (270 mesh, 200 mesh, 100 mesh and 60 mesh) was used.
• the sieving time for each sieve was 60 sec, while the vacuum pressure was maintained at 10-12 in. H 2 O.
• the sample size was 5 g
• the "loss on drying” (LOD) value was determined using a Mettler Toledo Infrared Dryer LP 16. The set temperature was 120 0 C and the analysis was stopped when constant weight was reached.
• This embodiment of the alternate improved excipient consists of 95% microcrystalline cellulose and 5% hydroxypropyl methylcellulose.
• the excipient was produced by a wet homogenization/spray dry granulation process.
• the apparatus used for the production of the excipient was a Co-current atomizer disc type with the disc RPM between 12000 and 25000 and the inlet temperature of 180-250 °C.
• Powdered MCC was converted into a slurry with deionized water to give a concentration of 23,0% w/w.
• the HPMC was mixed with deionized water, stirred and circulated for 60 - 70 min to give a concentration of 17.20% w/w.
• the prepared HPMC slurry was added to the MCC slurry.
• the HPMC slurry tank was washed with 5 L of water and the washings were added to the MCC slurry.
• the resulted mixture together with additional deionized water was stirred, circulated and homogenized into a uniform slurry of 22.44% concentration for 60 min using a circulating
• the slurry mixture was then spray dried through a rotary nozzle at a motor frequency of 35 Hz in the presence of hot air at an outlet
• the wet granular material was dried in a tray at 60 0 C. The resulted granular material (moisture content 2.00%) was screened through
• microcrystailine cellulose 135.0 g microcrystailine cellulose and 15.0 g Hydroxypropyl methylcellulose were
• Example 24 The high shear wet granulation process was conducted as in Example 24 with the exception that the amount of water (“liquid binder”) added was 66 g. The resulted granular materia] (moisture content 4.5%) was screened through
• methylcellulose were blended in a V-blender for an hour.
• the powder properties (Tables 34 and 35) of the materials prepared in Example 22, 23, 27a, 27b, Avicel 102 and MCCl 02-RanQ were measured using a Powder Tester (Hosokawa Micron Corporation) Model PT-S.
• the Hosokawa Powder tester determines flowability of dry solids in accordance with the proven method of R. L. Carr.
• a computer which uses the Hosokawa Powder Tester software was used to control the Hosokawa Powder Tester during the measurement operation, enabling simple use and data processing.
• For measuring the aerated bulk density and tapped bulk density a 50 cc cup was employed.
• the standard tapping counts for measuring the tapped bulk density were 180 and the tapping stroke was 18 mm.
• Carr's compressibility index and Hausner ratio can be calculated (Table 36). A value of 20-21% or less for the Carr's compressibility index indicate a material with good flowability.
• Emcocel 90 1.32 24.5 Avicel PH 102 1.32 24.2 MCC 102 RanQ 1.35 26.1
• Example 22 1.26 20.8
• Example 23 1.26 20.8
• Example 30 Granule Friability test for Example 23 and Example 25 excipients 75 - 10O g of granular material was analyzed for particle size distribution and then was loaded in a 4 L V-Blender and tumbled for 2 h. The granular material was collected and analyzed again for particle size distribution (Table 37).
• An Air Jet Sieving instrument Hosokawa Micron System
• a set of four sieves (270 mesh, 200 mesh, 100 mesh and 60 mesh) was used. The sieving time for each sieve was 60 sec, while the vacuum pressure was maintained at 12-14 in. H 2 O, The sample size was 5 g. Table 37
• Example 23 150 g excipient prepared as per Example 23 were placed in a 1 L stainless steel bowl. The bowl was attached to a GMX.01 vector micro high shear mixer/granulator (Vector Corporation). The high shear wet granulation process was conducted as in Example 24. The resulted granular material (moisture content 3%) was screened through a 30 mesh sieve.
• microcrystalline cellulose MCC102RanQ 150 g microcrystalline cellulose MCC102RanQ were placed in a 1 L stainless steel bowl. The bowl was attached to a GMX.01 vector micro high shear mixer/granulator (Vector Corporation). The high shear wet granulation process was conducted as in Example 24. The resulted granular material (moisture content 3%) was screened through a 30 mesh sieve.

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