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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • 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

Definitions

• This invention relates to high content granules of ibuprofen medicaments made from ibuprofen sodium salt dihydrate, to process technology for producing such granules, and to uses of such granules in preparing non-effervescent solid dosage forms for oral administration.
• Sodium ibuprofen is an effective pain killer, and one of the advantages associated with it is the fact that it is easily absorbed through the lining of the stomach and can thus easily be taken in oral doses.
• solid dosage forms made from sodium ibuprofen are superior in pharmaceutical kinetics (i.e., they enter and peak in the blood stream more rapidly than other solid dosage forms of ibuprofen).
• sodium ibuprofen may be more effective in smaller amounts than its hydrogen substituted analog, ibuprofen, due to this ease of absorption.
• Sodium ibuprofen is easily prepared as a powder. However, despite intensive research in the field, it remains difficult to prepare solid dosage forms from sodium ibuprofen using conventional approaches.
• One of the difficulties is that sodium ibuprofen dihydrate has poor flowability characteristics and thus tends to cake readily even when blended with conventional anti-caking agents such as colloidal silica or talc.
• the poor flow characteristics of sodium ibuprofen dihydrate even though formulated with flow improvers, can result in erratic weight variations in the solid dosage forms such as tablets and caplets being produced.
• sodium ibuprofen is unpalatable, having a taste that is difficult to mask; and when it is compressed into tablets, such tablets resist disintegration into the component powder, once swallowed, until reaching the stomach. Therefore, such tablets must be small enough such that they can easily transit as a whole down the esophagus.
• a primary challenge in formulating sodium ibuprofen for easy dosing is the strong tendency for it to stick to the punch used to compress it into tablets, forming a film on the punch surface. It has been found that despite the use of lubricants, formulations high in sodium ibuprofen, including many of those of the present invention, are prone to sticking to punch surfaces. This film coating that is formed on the punch surface is undesirable from several standpoints. From an aesthetic standpoint, the coating on the punch reduces the "shine" of the tablets formed on that punch. From a practical perspective, the coating on the punch surface results in what is known as sticking, picking, and capping.
• a further disadvantage is that the punches must be cleaned of the accumulated sodium ibuprofen formulation or the aesthetic and dosage discrepancy can increase with time.
• cleaning the punch generally requires that the tableting operation temporarily be shut down, resulting in equipment downtime which inevitably increases the cost per unit.
• Ibuprofen is a racemic compound - methods of preparation generally give two enantiomers, and a single unit cell crystal of crystalline ibuprofen will contain one molecule of each enantiomer.
• sodium ibuprofen is a racemic conglomerate, i.e., it is generally characterized by an equal molar physical mixture of the individual enantiomeric crystals, such that only one enantiomer is present in each crystal and in each unit cell of the crystal lattice.
• compositions of the present invention can be used in conjunction with tablet punches and presses having chrome-plated surfaces to produce aesthetic, reliably-dosed, easily-swallowed tablets. It has been found that by using a chrome-plated punch, it is possible for sodium ibuprofen formulations, comprising a sufficiently high concentration of sodium ibuprofen to be formed into tablets of a size that can be easily swallowed, to be punched into tablets with little or no tendency to stick to the surfaces of the punch.
• the method of the present invention can be used with formulations containing little or no wax to prepare aesthetically acceptable sodium ibuprofen dihydrate tablets having extremely high active content, as high as 90 wt %, 95 wt% or even higher.
• punch product such as a tablet or caplet
• punch product is essentially free of any visible capping, picking or sticking of press or punch origin.
• this invention provides:
• a process for forming tables of sodium ibuprofen dihydrate comprising forming tablets in a press comprising chrome contact surfaces, from granules of sodium ibuprofen dihydrate, the granules having been formed by a process comprising the steps of:
• a high shear granulator components comprised of (i) at least 80 parts by weight on a dry basis of sodium ibuprofen dihydrate, (ii) 1 to 4 parts by weight on a dry basis of sodium carbonate, (iii) 1 to 15 parts by weight on a dry basis of non-crosslinked polyvinylpyrrolidone, and (iv) 8 to 12 parts by weight of water based on the total weight of (i), (ii), (iii), and (iv) to form a wet mixture;
• drying wet granules to form dried granules having a moisture content in the range of about 11 to 15 wt%, and preferably in the range of about 12 to about 15 wt%, as determinable by measurement of weight loss at 110°C;
• the main compression force is in the range of 10 to 20 kilonewtons; wherein the main compression is in the range of about 12 to about 16 kilonewtons; wherein the precompression force in the range of about 0.8 to about 1.0 kilonewtons; wherein the contact surfaces of the punch are chrome-plated; wherein the contact surfaces of the punch are chrome; wherein the punch speed is in the range of about 5 to about 20 RPM; wherein the press comprises a 10-station rotary press comprising chrome contact surfaces; wherein the main compression is in the range of about 12 to about 16 kilonewtons, and the press comprises a 10-station rotary press comprising chrome or chrome-plated contact surfaces; and wherein said granulating takes place in a high shear granulator. Also provided are tablets formed by such processes, including standard 400 mg as active round tablets.
• this invention provides:
• a highly dispersible, free-flowing granule composition having a high content of sodium ibuprofen dihydrate which composition is formed from components in powder form, said components comprising (i) 80 to 98 parts by weight of sodium ibuprofen dihydrate on a dry basis, (ii) 1 to 4 parts by weight of anhydrous sodium carbonate on a dry basis, and (iii) 1 to 15 parts by weight of non-crosslinked polyvinylpyrrolidone on a dry basis.
• microcrystalline cellulose • 0 to about 25 wt% of microcrystalline cellulose, calcium hydrogen phosphate, or both;
• composition embodiments of this invention is the following:
• the size of the DSC peak, which peak corresponds to solids-to-solids phase transition, is at least about 150 joules per gram.
• Fig. 1 is a differential scanning calorimetry curve of the granules of this invention produced in Example 11.
• Fig. 2 is a differential scanning calorimetry curve of the granules of this invention produced in Example 12.
• Fig. 3 is a differential scanning calorimetry curve of the granules of this invention produced in Example 13.
• Fig. 4 is a differential scanning calorimetry curve of the granules of this invention produced in Example 14.
• Fig. 5 is a differential scanning calorimetry curve of granules of this invention produced in Example 15 sampled with a drier inlet temperature set at 70°C, and when the drying temperature of the granules reached 35°C.
• Fig. 6 is a differential scanning calorimetry curve of granules of this invention produced in Example 15 sampled with a drier inlet temperature set at 70°C, and when the drying temperature of the granules reached 40°C.
• Fig. 7 is a differential scanning calorimetry curve of granules of this invention produced in Example 15 sampled with a drier inlet temperature set at 70°C, and when the drying temperature of the granules reached 45 °C.
• Fig. 8 is a differential scanning calorimetry curve of granules of this invention produced in Example 15 sampled with a drier inlet temperature set at 70°C, and when the drying temperature of the granules reached 48°C.
• Fig. 9 is a differential scanning calorimetry curve of granules of this invention produced in Example 16 sampled with a drier inlet temperature set at 70°C, and when the drying temperature of the granules reached 40°C.
• Fig. 10 is a differential scanning calorimetry curve of granules of this invention produced in Example 16 with a drier inlet temperature set at 70°C, and sampled 10 minutes after the sample of Fig. 10 were taken.
• Fig. 11 is a differential scanning calorimetry curve of granules of this invention produced in Example 16 with a dryer inlet temperature set at 70°C, and sampled 30 minutes after the sample of Fig. 10 was taken.
• Fig. 12 is a differential scanning calorimetry curve of granules of this invention produced in Example 17 with a dryer inlet temperature set at 70°C, and sampled when the granules reached a temperature of 60 °C.
• Fig. 13 is a differential scanning calorimetry curve of granules of this invention produced in Example 17 by reducing the dryer inlet air temperature from 70 to 60 °C, and sampled when the granules were at a temperature of 60°C for 20 minutes.
• Fig. 14 is a differential scanning calorimetry curve of granules of this invention produced in Example 17 by reducing the dryer inlet air temperature from 70 to 60 °C, and sampled when the granules were at a temperature of 60°C for 60 minutes.
• Fig. 15 is a differential scanning calorimetry curve of the granules of this invention produced in Example 18.
• Fig. 16 is a differential scanning calorimetry curve of the granules of this invention produced in Example 19.
• Fig. 17 is a differential scanning calorimetry curve of the granules of this invention produced in Example 20.
• oven temperatures for drying of the granules is in the range of about 60 to about 70 °C.
• the inlet temperature is also preferably in the range of about 60 to about 70°C.
• the temperature of the outlet air is monitored so that the drying is terminated when the outlet air temperature reaches about 40°C.
• the total moisture content of the granules is in the preferred range of about 12 to about 15, and more preferably is around 13.5 wt%, which is about the amount of hydrate water in sodium ibuprofen dihydrate.
• the dried product is then sieved to remove oversized material (e.g. , greater than 16 mesh). Such oversized material is typically milled and recycled to the granulation operation.
• the sodium ibuprofen dihydrate into the high shear granulator followed by a preformed solution of polyvinylpyrrolidone in water. After thorough blending of these components the requisite amount of sodium carbonate is then added and the mixture is subjected to additional high shear granulation. The granulation is conducted at a temperature in the range of about 15 to about 35°C, using cooling if necessary to remove excess heat generated during granulation.
• the rate of shear of the chopper in the high shear granulator prior to addition of the sodium carbonate is typically in the range of about 1000 to about 2000 rpm for a period in the range of about 3 to about 6 minutes.
• the chopper rate is then reduced to a low shear rate of about 200 to about 500 rpm for an additional period of about 3 to about 6 minutes.
• this same two stage operation of the chopper is repeated (i.e. , ca. 1000 to ca. 2000 rpm for ca. 3 to ca. 6 minutes and then ca. 200 to ca. 500 rpm for ca. 3 to ca. 6 minutes).
• the apparatus may contain another mechanism for effecting motion of the mixture in the granulator, which mechanism is known as a paddle.
• the rate at which the paddle is operated is of lesser importance and thus can be varied.
• a 160 liter, Fluid Air Pharmx High Shear Granulator, Model PX150 it was found convenient to operate the paddle in a two stage manner in which during the first stage the paddle was operated at 100 rpm and in the second stage at 30 rpm. These stages coincided with the two stage operation of the chopper.
• the sodium carbonate used in forming the granules should be of NF or USP grade and initially may be hydrated, but preferably is in the form of an anhydrous powder.
• Polyvinylpyrrolidone of pharmaceutically acceptable grade is available in various forms which may be used in the practice of this invention. However, it is preferred to utilize polyvinylpyrrolidone with a K value in the range of 30 to 120, with a K value of 90 being more preferred.
• the sodium ibuprofen dihydrate is a racemic mixture of pharmaceutically acceptable grade and preferably is used in powder form.
• the amount of sodium carbonate used in forming the granules is typically in the range of about 1 to 4% by weight of the total mixture. Preferably the amount is in the range of about 2 to about 3% by weight of the total mixture.
• the amount of polyvinylpyrrolidone is typically in the range of about 1 to about 10 % by weight of the total mixture.
• the amount of polyvinylpyrrolidone is in the range of about 2 to about 4 % by weight of the total mixture.
• the balance to 100% by weight of the total mixture is composed of sodium ibuprofen dihydrate.
• excipients can be used, provided they do not adversely interact with any of the three principal components or otherwise interfere with the preparation of the granules or solid dosage forms produced therefrom.
• inclusion of such excipients in the granules is not advisable since such usage would reduce the concentration of the sodium ibuprofen dihydrate in the granules and result in increased production costs and record keeping.
• the water used is also of sufficient purity to meet regulatory requirements.
• the amount of water used in forming the granules is typically in the range of about 5 to about 15 wt% of the total weight of the wet mixture of components.
• the amount of water used for granule formation is in the range of about 8 to 12 wt% of the total weight of the wet mixture of components. If too little water is used, insufficient granulation will occur. On the other hand, if too much water is used, the mixture will have the consistency of a bakery dough. In either case, after drying, the product will not have a desirable average (mean) particle size.
• the average particle size of the dry granules is typically in the range of about 150 to about 600 microns, and preferably is in the range of about 200 to about 300 microns.
• Especially preferred granules of this invention in wet form are prepared from the following components in the amounts specified: sodium ibuprofen dihydrate, 85.95 wt%; non-crosslinked polyvinylpyrrolidone (especially K-90), 2.25 wt%; anhydrous sodium carbonate powder, 1.80 wt%; purified water, 10 wt%.
• Especially preferred granules of this invention in dry form have the following composition: 95.50 wt% as sodium ibuprofen dihydrate; 2.50 wt% of polyvinylpyrrolidone (especially K-90); and 2.00 wt% as anhydrous sodium carbonate.
• this invention provides in preferred embodiments granules and granules formulations which are characterized by exhibiting during differential scanning calorimetry a phase transition peaking in the range of about 100°C to about 102°C, and wherein the size of the DSC peak, which peak corresponds to solids-to-solids phase transition, is at least about 150 joules per gram.
• the existence of this peaking ensures that the granules, when suitably formulated - as in the formulation designated E) above - will produce solid dosage forms having excellent processing characteristics in a rotary press and that will thereby produce solid dosage forms of high quality and that comply with present day regulatory requirements.
• DSC differential scanning calorimetry
• the granules can be heated at a temperature and for a period of time sufficient to achieve the foregoing DSC thermal characteristics. Suggested heating conditions include heating at about 30 to about 70°C for a period of about 5 to about 50 minutes;
• the time period during which wet granulation is conducted can be increased. In bench scale operations, this total period of wet granulation was found to be at least about 12 to 16 minutes. When the operation is conducted on a larger scale, the total period of wet granulation may differ at least somewhat from 12 to 16 minutes in order to achieve the desired DSC thermal characteristics, and thus a few pilot experiments should be conducted if necessary, in order to determine the appropriate time period for wet granulation when operating on a larger scale;
• microcrystalline cellulose can be utilized as a component in formulations for use in producing solid dosage forms. Indeed, microcrystalline cellulose is a preferred component for use in such formulations.
• the formulations of the present invention can be used to easily form tablets having high doses of ibuprofen as well as being small enough to easily swallow, as well as aesthetically acceptable and reliably dosed.
• Such tablets are made possible by the use of chrome surfaces to contact the ibuprofen during tablet formation, for example, a punch having chrome or chrome-plated punch surfaces which are in contact with the active during at least the main compression stage of the tablet compression process.
• punches that are known and used in the art, for example, rotary press punches (such as 10-station rotary press punches available from Globepharma, Inc., ), and the like, may be suitable for use in processes of this invention.
• the punch surfaces can be altered from their purchased state by chrome-plating the surfaces after purchase.
• the former is a chrome surface, which has not been laid by electroplating. Examples of the former include surfaces which are part of a solid chrome bulk, regardless of whether the bulk is a tablet formation cavity that is itself of chrome, or a "veneer” or a pressure applied layer of chrome.
• the press comprises a GLOBEPHARMA 10-station rotary press comprising chrome contact surfaces.
• the settings can include a main compression force of between about 8 and about 22 kilonewtons, with between about 10 and about 20 kilonewtons more preferable in order to minimize capping and occasional tablet breakage.
• the main compression is between about 12 and about 16 kilonewtons.
• the initial compression step is generally for the purpose of minimizing the air in the precompressed formulation prior to main compression. The variations in initial compression force are not expected to greatly affect the beneficial effects of the inventive method.
• initial compression forces which can be in the range of from 0.4 to .01 of the than the main compression force, are used, with wide variations not expected to greatly affect the aesthetic and consistent dosage advantages.
• the main compression is in the range of about 12 and about 16 kilonewtons, and the initial compression is in the range of about 0.8 to about 1.0 kilonewtons. It has been found that the ejection force does not greatly affect the lack of sticking to chrome punch surfaces, but in one embodiment, the ejection force is in the range of 0.1 to about 0.5 kilonewtons.
• the inventive method can be used in a wide variety of punch sizes, such as for ibuprofen round or caplets that contain 200, 400, 600, and 800 of active.
• the tablet size is a standard 400 mg active round size.
• Punch speed has little effect on the ability of the present method to exhibit little or no sticking to the surfaces of chrome presses.
• a punch RPM in the range of from about 5 to about 20 RPM can be conveniently used. It should be noted that optimum compression force, pre-compression force, ejection force and RPM punch setting ranges can vary from one tablet press to another. It may be necessary to establish set points for each tablet press individually. One of skill in the art will have the knowledge necessary to establish the set points in order to obtain the benefits of the invention, given the teachings of our specification.
• one or more lubricants can be included in the formulation. If a lubricant is used, it is preferred to use a wax -based lubricant, examples of which include stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, and the like, with stearic acid being preferred. However, non-wax -based lubricants such as fumed silica, talc, or other mineral lubricants can be used. While such lubricants are not essential, if a wax based lubricant is used, it is preferred to be used in amounts in the range of about 1 to about 1.5 wt% percent based upon the weight of the dry formulation.
• the lubricant be used in amounts in the range of 1 to 1.5 based upon the weight of the dry formulation.
• non-stick preparation of tablets can be carried out with granules which have been granulated in a variety of ways.
• Methods of granulation which can be used include, but are not limited to, low shear granulation, high shear granulation and fluidized-bed granulation, with high shear granulation preferred.
• the present invention comprises a process for forming tablets of sodium ibuprofen dihydrate, said process comprising forming tablets in a press comprising chrome contact surfaces, from granules of sodium ibuprofen dihydrate, the granules having been formed by a process comprising the steps of
• a high shear granulator components comprised of (i) at least 80 parts by weight on a dry basis of sodium ibuprofen dihydrate, (ii) 1 to 4 parts by weight on a dry basis of sodium carbonate, (iii) 1 to 15 parts by weight on a dry basis of non-crosslinked polyvinylpyrrolidone, and (iv) 8 to 12 parts by weight of water based on the total weight of (i), (ii), (iii), and (iv) to form a wet mixture;
• the invention further comprises the use of granules which are lubricant free in the inventive process.
• the invention comprises a process in which the tablets produced by the inventive process above are lubricant-free.
• the invention comprises tablets formed by the inventive process.
• the tablets formed by the inventive process are lubricant-free.
• Granules composed of 95.5 wt% of sodium ibuprofen hydrate, 2 wt% of sodium carbonate and 2.5 wt% of polyvinylpyrrolidone (Plasdone K-90, International Specialty Products Inc., Wayne, NJ) were prepared by a wet granulation process of this invention.
• the process used involved dissolving the Plasdone K-90 in water, adding the solution to sodium ibuprofen dihydrate in a V-blender equipped with a high shear intensifier drive (MAXI-BLEND LAB V-BLENDER manufactured by GlobePharma, Inc., New Brunswick, NJ), and forming the granule by operating the blender using high shear, adding sieved sodium carbonate powder to the wet mixture in the blender, mixing for another 5 minutes utilizing the intensifier drive. After discharging the blender content into a pan, the granules were dried in an oven maintained at 50°C until all added water was removed. The product was then sieved through a stainless steel 16-mesh U.S.A. standard sieve.
• Example 1 The granules formed as in Example 1 were used to prepare a fully formulated blend for tablet preparation using rotary press. In this operation, the granules were mixed with microcrystalline cellulose (MCC) and colloidal silica by means of dry blending. The formulation processed well in a 10-station rotary press and the resulting tablets showed good friability, dissolution, and disintegration. The final blend was composed of 75 wt% of sodium ibuprofen hydrate, 2.37 wt% of polyvinylpyrrolidone, 1.58 wt% of sodium carbonate, 20.95 wt% of microcrystalline cellulose, and 0.1 wt% of colloidal silica.
• MCC microcrystalline cellulose
• colloidal silica colloidal silica
• Example 1 The characteristics of the high active-content granules formed as in Example 1 and the tablet formulation formed as in Example 2 A are given in Table 1.
• the flowability index showed that both the granules and the fully formulated blends have good flow characteristics.
• the tablets met all desired performance criteria.
• Example 2B Granules formed as in Example 1 were used to prepare a fully formulated blend for tablet preparation using rotary press, as described in Example 2A, except that the granules were mixed with crospovidone by means of dry blending.
• the formulation processed well in a 10-station rotary press and the resulting tablets showed acceptable friability and good dissolution properties.
• the final blend was composed of 93.6 wt% of sodium ibuprofen hydrate, 2.45 wt% of polyvinylpyrrolidone, 1.96 wt% of sodium carbonate, and 2 wt% of crospovidone.
• Example 1 Granules formed as in Example 1 were used to prepare a fully formulated blend for tablet preparation using rotary press, as described in Example 2A, except that the granules were mixed with Na croscarmellose by means of dry blending.
• the formulation flowed well into a 10-station rotary press and the resulting tablets showed acceptable friability and good dissolution properties
• the final blend was composed of 93.6 wt% of sodium ibuprofen hydrate, 2.45 wt% of polyvinylpyrrolidone, 1.96 wt% of sodium carbonate, and 2 wt% of Na croscarmellose.
• Anhydrous sodium carbonate powder (previously sieved through a 20-mesh screen) is then added to the bowl and the mixing continued for another high shear-low shear mixing cycle.
• the wet granules produced in run 1 were discharged into a beaker before adding to a fluid bed dryer. Dried materials collected in plastic bags show the presence of significant amount of granules of greater than 16 mesh.
• K-90 solution polyvinylpyrrolidone
• Units used for chopper & impeller are RPM and for time are seconds, unless otherwise specified.
• Example 4 de-lumping efficiency of the high shear chopper was measured by checking the presence of lumps in the granulator at various blending intervals. It was concluded that de-lumping of sodium ibuprofen dihydrate in its original particulate form is not efficient and de-lumping becomes significantly more efficient after the povidone solution is added. We found no detectable lumps after about 120 seconds at the high shear mixing cycle. After the granulator operation, the contents of the granulator bowl were transferred to a fluidized bed dryer pneumatically using a vacuum tube applied to the hole in the cover and with suction generated by the fluid bed dryer. The dried materials collected showed very little content of granules greater than 16-mesh in size. Because of these findings in Examples 5-10 the de-lumping steps were omitted and vacuum transfer to the fluidized bed dryer was employed.
• Example 5 went smoothly and the granules produced looked good. It was decided then that we should check the robustness of the process. There are two aspects of process robustness. The first is the ability of the process to produce granules with the same quality on a consistent basis. The second aspect of process robustness is whether the process can be carried out, independently, with a skilled technician. Accordingly, a skilled technician carried out the operations of Examples 6-10.
• Example 6 in addition to the conditions summarized in Tables 1 and 2, the dryer parameters were documented. The data relating to the dryer operation are summarized in Table 4. In all cases, vacuum transfer to the fluidized bed dryer was used.
• composition of the formulation used in producing the tablets (sometimes hereinafter designated Formulation DTH) is 75% of sodium ibuprofen dihydrate, 21.37% of microcrystalline cellulose (MCC PH102; FMC Corporation), 1.96% PVP K-90 (Plasdone K-90, International Specialty Products Inc., Wayne, NJ), 1.57% anhydrous sodium carbonate, and 0.10% colloidal silica (Aerosil 200; Evonik Industries, formerly Degussa Corporation).
• the tablet formulation is prepared by blending the granules with the microcrystalline cellulose and colloidal silica. For every 100 parts by weight of granules used for the DTH preparation, 21.21 parts by weight of microcrystalline cellulose and 0.127 parts by weight of colloidal silica are incorporated.
• Formulation DTH To prepare Formulation DTH, the following procedure is recommended: de-lump the granules and microcrystalline cellulose by sieving them separately through a 16-mesh screen. Weigh all three ingredients separately, prepare a preblend of colloidal silica and microcrystalline cellulose by mixing the colloidal silica and a portion of microcrystalline cellulose, pass this mixture through a 20-mesh sieve. Discharge the granules, the remaining microcrystalline cellulose, and the preblend into a low shear blender and blend for 10 minutes. [0075] It is to be understood that Formulation DTH, while constituting a preferred formulation of this invention, should not be construed as limiting this invention to this particular formulation. For example, good results can be achieved by eliminating the sodium croscarmellose component from Formulation DTH. Other formulations utilizing the granules of this invention based on this disclosure may now occur to those of ordinary skill in the art.
• DSC Differential scanning calorimetry
• Examples 11-20 involve experimental work conducted in order to determine what causes the stress and how to eliminate the stress, which appeared to be related to drying conditions. In addition to studying drying conditions, blending time in the wet granulation process was generally increased from 10 to 16 minutes. The experiments were conducted at batch sizes of 0.5 kg.
• Example 11-20 The procedures used in Examples 11-20 involved wet granulation of the components, drying of the granules, and analysis of the granules. In the granulation, operations of all Examples except Example 20, samples from the same specific lot of sodium ibuprofen dihydrate were used.
• the sodium ibuprofen dihydrate was a composite mixture of products from small bench scale crystallizations of sodium ibuprofen dihydrate recovered from an ibuprofen product sodium stream. This latter bench scale sodium ibuprofen dihydrate had a particle size several times greater than that of the lot of sodium ibuprofen dihydrate used in Examples 11-19.
• the granulation processing steps used involved (i) discharging sodium ibuprofen dihydrate (Na IBU) into the granulator bowl of the high shear granulator, (ii) de-lumping Na IBU, (iii) adding povidone solution to promote granulation under high shear, (iv) adding anhydrous sodium carbonate powder into the blend and resume blending, and (v) transferring granules to a fluidized bed dryer for drying. Only in Example 12 was a de-lumping step used. In Example 12, before addition of PVP solution, sodium ibuprofen dihydrate was de-lumped for 90 seconds by operating the chopper at 2500 RPM and at an impeller speed of 300 RPM.
• Table 9 summarizes the operating conditions used in the wet granulation process after adding the powdery anhydrous sodium carbonate to the contents in the granulator. In this way, the wet granulation procedure was completed.
• CPR again designates “chopper” and “IMP” designates “impeller”.
• n/a designates “not applicable”.
• Example 14 At the end of the granulator operations, all of the wet granules were pneumatically transferred immediately to a fluidized bed dryer except for Example 14. In Example 14, the wet granules were kept in the granulator for 30 minutes before they were pneumatically transferred to the fluidized bed dryer for drying. The use of such holding time was for the purpose of determining whether stress in the wet granules may be released by allowing them to stand for a period of time prior to drying.
• Table 10 outlines drying parameters used in this study.
• the base case for drying was use of an inlet air temperature of 70°C with a product temperature of 40°C as a control for moisture content as determined by weight loss at 110°C.
• Examples 11, 12, 13, 14, and 20 were conducted with inlet temperature set at 70°C, and the drying operations were terminated once product temperature reached 40°C.
• Example 15 was performed with inlet temperature set at 70°C, however samplings were carried out when product temperature reached 35, 40, 45 and 48°C. Instead of using product temperature as a control, Examples 16 and 17 used drying time as the control.
• Example 16 at an inlet temperature of 70 °C, the first sample for analysis was collected when product temperature reached 40°C, and the drying was continued at the same inlet temperature with additional samples being collected after additional 10 and 30 minutes of drying, respectively.
• Example 17 at an inlet temperature of 70°C, the first sample was collected when product temperature reached 40°C. At this point, the inlet temperature was reduced to 60°C and additional samples were collected after additional drying periods of 20 and 60 minutes, respectively.
• Example 18 employed an inlet temperature of 80°C and Example 19 used an inlet temperature of 60°C. Table 10 provides a summary of these operations.
• Table 11 provides differential scanning calorimeter data and moisture content, as determined by moisture balance of granules collected under varying fluid bed drying conditions. The data show that about all granules with a moisture content of 13.0% or greater have a heat of transition >170 joule/gram. It is also clear that over drying may lead to lower heat of phase transition. Nevertheless, overdried samples that provide DSC thermal treatment curves which peak in the range of about 100°C to about 102°C, and which the size of the DSC peak, which peak corresponds to solids -to- solids phase transition, is at least about 150 joules per gram, will give satisfactory results when utilized in forming solid dosage forms.
• This sample is deemed overdried and thus is not a preferred sample; however, it exhibited desirable DSC thermal characteristics and thus may be used in preparing solid dosage forms.
• Example 20 which as prepared from a composite sodium ibuprofen dihydrate crystallized from ibuprofen product sodium stream (PSS).
• PSD ibuprofen product sodium stream
• the average mean particle size for granules generated from the sodium ibuprofen dihydrate lot used in Examples 11-19 was 172 microns with a standard deviation of 12 microns.
• the mean particle size of the composite sodium ibuprofen dihydrate used in Example 20 was 324 microns and the granule prepared had a mean particle size of 232 microns.
• Example 12 Twenty grams of granules from Example 12 and 18 were placed on a stack of 12- inch diameter sieves consisting 20, 30, 40, 60, 80, 100, and 200 mesh stainless steel sieves. After shaking for 20 minutes, granules retained on each sieve were weighed and the retained granules of selected size fractions were submitted for HPLC assay determination.
• the assay contents expressed as wt% of theoretical are given in Table 12 below. The data show that about 90 wt% of the particles are in the 40-200 mesh range and generally lager particle size corresponds to higher assay content. It also shows that the difference in assay content for majority of the particles (40-200 mesh range) is negligible.
• granules produced in Example 11 , 12, 13, 18, 19, and 20 were blended individually with other excipients to produce a formulation, in this case Formulation DTH, for use in forming tablets.
• the individual Formulation DTH blends were then sequentially fed into a 10-station rotary press (Minipress II; GlobePharma, Inc., New Brunswick, NJ) to prepare tablets containing about 600 mg of ibuprofen equivalent of the sodium salt.
• the main compression was kept at about 10 kilonewton (KN), pre-compression was kept at about 1.5 KN and the production rate was kept in the range of 100-120 tablets per minute. Tablet samples were collected throughout the runs. At least one set of tablet sample of about 30 tablets was collected for each blend. A total of 12 tablet sample sets were collected from the seven Formulation DTH blends processed through the tablet preparation process.
• Dissolution of the tablets shows an average theoretical dissolution of 59 % at 10 minutes, 98% dissolution at 20 minutes and 13.9 minutes at 80% dissolution.
• the dissolution rates of Formulation DTH tablets tested were significantly better than regulatory dissolution rates.
• Figs. 1-17 are differential scanning calorimetry curves of granules of this invention produced in Examples 11 through 20 and as discussed in relation to Table 11 and summarized under the Brief Description of the Drawings. As noted in connection with that Table, the samples of Figures 8, 11 , and 14 were deemed usable but are not preferred because of having been overdried during the drying step.
• composition of one type of preferred granules of this invention and the composition of one type of preferred formulation for producing tablets of this invention are described in Table 13. Batch sizes and compositions of such preferred granules and of a preferred tablet formulation of this invention are described in Table 14. TABLE 13
• a typical procedure for the preparation of one type of preferred granules of this invention at 40 kg dry batch size scale is as follows:
• PVP K-90 polyvinylpyrrolidone
• One type of preferred formulation of this invention is formed from the preferred granules made as just described above, and has the composition shown in Table 15 below.
• the above formulation also produced high quality tablets using a 10-station rotary press (Minipress II; GlobePharma, Inc., New Brunswick, NJ) to prepare tablets containing about 400 mg of ibuprofen equivalent of the sodium salt. Dissolution of the tablets made from this formulation showed an average theoretical dissolution of over 80 % at 20 minutes. This is far better than the regulatory requirement of 80% at 60 minutes. For these tablets, the average friability for 100 drops was 0.23 wt%.
• Formulation AA is a formulation which comprises:
• a formulation formed from components which comprise a granule composition formed from components in powder form which components comprise (i) 80 to 98 parts by weight of sodium ibuprofen dihydrate on a dry basis, (ii) 1 to 4 parts by weight of anhydrous sodium carbonate on a dry basis, and (iii) 1 to 15 parts by weight of non-crosslinked polyvinylpyrrolidone on a dry basis;
• microcrystalline cellulose • 0 to about 25 wt% of microcrystalline cellulose, calcium hydrogen phosphate, or both;
• Formulation BB is a formulation in which the amount of the granule composition is in the range of about 70 to about 100 wt%, the amount of microcrystalline cellulose is 0 to about 20 wt%, and the amount of crospovidone or sodium croscarmellose is 0 to about 8 wt%, and the amount of colloidal silica is about 0.05 to about 0.2 wt%.
• Formulation CC is a formulation in which the amount of the granule composition is in the range of about 75 to about 100 wt%, the amount of microcrystalline cellulose is 0 to about 20 wt%, and the amount of crospovidone or sodium croscarmellose is 0 to about 6 wt%, and the amount of colloidal silica is 0 to about 0.2 wt%.
• Formulation DD) is a formulation in which the amount of the granule composition is in the range of about 60 to about 90 wt%, the amount of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, or both, is about 10 to about 30 wt%, the amount of starch is 0 to about 6 wt%, the amount of crospovidone or sodium croscarmellose is 0 to about 6 wt%, the amount of colloidal silica is 0 to about 0.25 wt%, and the amount of stearic acid, magnesium stearate, or both, is 0 to about 2 wt%.
• Formulation EE is a formulation in which the amount of the granule composition is in the range of about 85 to about 100 wt%, the amount of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, or both, is 0 to about 10 wt%, the amount of starch is 0 to about 6 wt%, the amount of crospovidone or sodium croscarmellose is 0 to about 5 wt%, the amount of colloidal silica is 0 to about 0.25 wt%, and the amount of stearic acid, magnesium stearate, or both, is 0 to about 2 wt%.
• This invention also provides solid dosage form formed from a formulation of any of AA), BB), CC), DD), or EE). Also provided by this invention are dosage forms which comprise a hard-shell capsule containing a granule composition formed from components in powder form, which components comprise (i) 80 to 98 parts by weight of sodium ibuprofen dihydrate on a dry basis, (ii) 1 to 4 parts by weight of anhydrous sodium carbonate on a dry basis, and (iii) 1 to 15 parts by weight of non-crosslinked polyvinylpyrrolidone on a dry basis.
• this invention provides a method of preparing solid dosage forms of sodium ibuprofen dihydrate, which method comprises compressing in a rotary press a granule composition as described in the immediately preceding sentence.
• the polyvinylpyrrolidone (Povidone K-90) was dissolved in water to form a solution prior to combining with other components (including sodium carbonate) in an effort to provide a uniform size distribution of the granules.
• the solution was then added to sodium ibuprofen in a V-blender equipped with a high shear intensifier bar (Maxi-Blend Lab V-B lender manufactured by GlobePharma, Inc.), and the granules were formed by operating the V-blender using high shear setting.
• the sodium carbonate powder is sieved and then added to the V-Blender, and allowed to mix. The wet granules are discharged from the V-Blender into a pan.
• the granules are placed in an oven and dried at 50°C.
• the water content of the granules was measured to be between 12.5 to 15 wt% as determinable by measurement of weight loss at 110°C.
• the material is then sieved to remove large granules.
• the granules are then used to prepare a fully formulated blend for tablet preparation.
• the granules are dry blended using the V-blender.
• the sieved microcrystalline cellulose, sodium croscarmellose, and disintegrant of choice are allowed to mix for 10 minutes.
• the sieved fumed silica is then added to V-blender and allowed to blend for 5 minutes.
• the sieved lubricant of choice is added to the V-blender and allowed to mix for 5 minutes.
• the final drum -to-hopper composition had the composition as set forth in the tables.
• the granule formulation in Table 16 was prepared by adding a lubricant (1 wt% Stearic acid) to the 75 wt% blend intended for drum to hopper applications (DTH).
• DTH drum to hopper applications
• a function of a lubricant in a tablet formulation is to prevent sticking of the tablet to the punch faces, and to reduce friction between the die wall and the tablet during compression and ejection of the tablet.
• GLOBEPHARMA 10-station rotary press equipped with transducers that measures pre-compression, main compression, ejection and RPM heavy sticking was observed.
• the final blend was composed of 74.2 wt% of sodium ibuprofen dihydrate, 1.57 wt% sodium carbonate, 1.94 wt% polyvinylpyrrolidone, 4.95 wt% sodium croscarmellose, and 16.21% microcrystalline cellulose.
• the main compression force was 13.9 KN
• the recompression force was 0.2 KN
• the ejection force was 0.1 kilonewtons
• the press speed was 9 RPM.
• Drum-to-Hopper Composition (75 wt%) and Lubricant Stearic Acid
• the granule formulation in Table 17 was made by adding a lubricant (1 wt% Calcium Stearate) to the DTH 75 wt% blend.
• the formulation is comprised of 74.40 wt% sodium ibuprofen, 1.49 wt% sodium carbonate, 1.86 wt% povidone K-90, 4.75 wt% sodium croscarmellose, 0.10 wt% fumed silica, 15.55 wt% microcrystalline cellulose, and 1 wt% calcium stearate. These granules were formed into 400 mg tablets using conventional steel tablet punches.
• the punch used was a GLOBEPHARMA 10-station rotary press equipped with transducers that measure pre-compression, main compression, ejection and RPM.
• the main compression force was 15.1 KN
• the precompression force was 0.1 KN
• the ejection force was 0.2 kilonewtons
• the press speed was 9 RPM.
• Drum-to-Hopper Composition 75 wt%) and Lubricant (Calcium Stearate)
• the granule formulation in Table 18 was comprised of 74.20 wt% sodium ibuprofen, 1.57 wt% sodium carbonate, 1.94 wt% povidone K-90, 4.75 wt% sodium croscarmellose, 0.16 wt% fumed silica, 16.21 wt% microcrystalline cellulose, and 1 wt% magnesium stearate.
• the granules were formed into 400 mg as active tablets using conventional steel tablet punches.
• the punch used was a GLOBEPHARMA 10-station rotary press equipped with transducers that measure pre-compression, main compression, ejection and RPM.
• the main compression force was 14.7 KN
• the precompression force was 0.1 KN
• the ejection force was 0.1 kilonewtons
• the press speed was 13 RPM.
• Drum-to-Hopper Composition 75 wt%) and Lubricant (Magnesium Stearate)
• Sodium lauryl sulfate and conventional steel punches gave heavy sticking to punch surfaces.
• the formulation in Table 20 was made by adding a surfactant (1 wt% Sodium Lauryl Sulfate) to the DTH 75 wt% blend. This formulation was composed of 74.20 wt% sodium ibuprofen, 1.57 wt% sodium carbonate, 1.94 wt% povidone K-90, 4.95 wt% sodium croscarmellose, 0.16 wt% fumed silica, 16.21 wt% microcrystalline cellulose, and 1 wt% sodium lauryl sulfate. These granules were made into 400 mg as active tablets using conventional steel tablet punches.
• the punch used was a GLOBEPHARMA 10- station rotary press equipped with transducers that measure pre-compression, main compression, ejection and RPM.
• the main compression force was 16 KN
• the precompression force was 0.4 KN
• the ejection force was 0.1 kilonewtons
• the press speed was 8 RPM.
• Drum-to-Hopper Composition (75 wt%), Lubricant (Sodium Lauryl Sulfate)
• Chrome plated punches were used to make 400 mg as active tablets using high active content (95.5 wt%) sodium ibuprofen granules See Table 21.
• the three components in this formulation include sodium ibuprofen dihydrate, sodium carbonate, and polyvinylpyrrolidone.
• the punch used was a GLOBEPHARMA 10-station rotary press equipped with transducers that measure pre-compression, main compression, ejection and RPM.
• the main compression force was 15.8 KN
• the precompression force was 0.2 KN
• the ejection force was 0.1 kilonewtons
• the press speed was 10 RPM. Even though a lubricant was not used, the appearances of the tablets were marketably acceptable.
• Chrome plate punches were used to make 400 mg as active tablets.
• the formulation in Table 22 was composed of 75 wt% sodium ibuprofen, 1.57 wt% sodium carbonate, 1.96 wt% povidone K-90, 16.37 wt% microcrystalline cellulose, 2 wt% crospovidone, 2 wt% starch 1500, 0.10 wt% fumed silica, and 1 wt% stearic acid.
• the punch used was a GLOBEPHARMA 10-station rotary press equipped with transducers that measure pre-compression, main compression, ejection and RPM.
• the main compression force was 13.8 KN
• the precompression force was 0.2 KN
• the ejection force was 0.1 kilonewtons
• the press speed was 13 RPM.
• the tablet appearance was excellent, with no visible imperfections.

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