Classifications

• • 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
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
  • C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch

Definitions

• This invention relates to pharmaceutical products containing starches and flours.
• Heat/moisture treatment and annealing of starches and/or flours are taught in the literature and distinguished by the amount of water present. "Annealing” involves slurrying a granular starch with excess water at temperatures below the starch's gelatinization temperature, whereas “heat/moisture-treatment” involves a semi-dry treatment at temperatures below the starch's gelatinization temperature, with no added moisture and with the only moisture present being that normally present in a starch granule (which is typically 10% or more) .
• GB 263.897 discloses an improvement in the heat treatment process of GB 228.829.
• the process of the '829 patent involves dry heating flour or wheat to a point at which substantially all of the gluten is rendered non-retainable in a washing test and then blending the treated flour or wheat with untreated flour or wheat to provide a blend having superior strength.
• the improvement of the '897 patent is continuing the dry heating, without, however, gelatinizing the starch, for a considerable time beyond that necessary to render all of the gluten non-retainable.
• “Dry-heating” excludes heating in a steam atmosphere or an atmosphere containing considerable quantities of water vapor which would tend to gelatinize the starch.
• the wheat or flour may contain the usual amount of moisture, preferably not greater than 15%.
• the heat treatment may exceed 7 hours at 77-93°C (170- 200 ⁇ F) , e.g., 8 to 14 hours at 82 ⁇ C (180 ⁇ F) or 6 hours at 100 ⁇ C (212°F).
• GB 530.226 discloses a method for drying a starch cake containing about 40-50% water with hot air or another gas at 149°C (300°F) or above without gelatinizing the starch.
• the starch cake is disintegrated by milling it to a finely divided state prior to drying.
• GB-595.552 discloses treatment of starch, more particularly a corn starch, which involves drying the starch to a relatively low moisture content of 1-2%, not exceeding 3%, and subsequently dry heating the substantially moisture-free starch at 115-126'C for 1 to 3 hours.
• the treatment is intended to render the starch free from thermophilic bacteria.
• the starch should not be heated longer than necessary to effect the desired sterilization.
• U.S. 3.490.917 discloses a process for preparing a non- chlorinated cake flour suitable for use in cakes and sponges having a high sugar to flour ratio.
• the starch or a flour in which the gluten is substantially or completely detached from the starch granules is heated to a temperature of from 100-140°C and then cooled.
• the conditions are selected so that dextrinization does not occur, e.g., about 15 minutes at 100-115°C and no hold and rapid cooling at the higher temperatures.
• the heat treatment should be carried out under conditions which allow the water vapor to escape. The reduction in moisture content due to the heat treatment depends upon the temperature employed.
• the moisture content is reduced from 10-12% to 8-9%, by weight, while at medium and high temperatures the moisture content is typically reduced to 7% or less.
• the moisture is allowed to reach moisture equilibrium with the atmosphere.
• the gelatinization temperature of the heat treated starch or flour is approximately 0.5-l°C higher than that of a comparable chlorinated flour or starch.
• the heating can be carried out in many ways, including heating in a hot air fluidized bed.
• U.S. 3.578.497 discloses a process for non-chemically improving the paste and gel properties of potato starch and imparting a swelling temperature as much as -7 to -1°C (20 to 30°F) higher.
• a concentrated suspension (20-40% dry solids) at a neutral pH (5.5-8.0, preferably 6-7.5) is heated either for a long time at a relatively low temperature or for a short time at successively higher temperatures.
• the suspension is first heated at a temperature below the incipient swelling temperature of the particular batch of starch being treated (preferably 49°C - 120°F) . Then the temperature is gradually raised until a temperature well above the original swelling temperature is attained.
• Amylose-free starches such as waxy corn starch
• the Brabender viscosity of cooked pastes derived from the treated starch was used to determine the inhibition level. Inhibition was indicated by a delayed peak time in the case of the treated corn starch, by the lack of a peak and a higher final viscosity in the case of the treated achira starch, and by the loss of cohesiveness in the case of the treated tapioca starch.
• the granular starch is suspended in water in the presence of salts which raise the starch's gelatinization temperature so that the suspension may be heated to high temperatures without causing the starch granules to swell and rupture yielding a gelatinized product.
• the preferred salts are sodium, ammonium, magnesium or potassium sulfate; sodium, potassium or ammonium chloride; and sodium, potassium or ammonium phosphate.
• About 10-60 parts of salt are used per 100 parts by weight of starch.
• Preferably, about 110 to 220 parts of water are used per 100 parts by weight of starch.
• the suspension is heated at 50-100°C, preferably 60-90°C, for about 0.5 to 30 hours.
• the pH of the suspension is maintained at about 3-9, preferably 4-7. Highly alkaline systems, i.e., pH levels above 9 retard inhibition.
• U.S. 4.013.799 discloses heating a tapioca starch above its gelatinization temperature with insufficient moisture (15 to 35% by total weight) to produce gelatinization.
• the starch is heated to 70-130 ⁇ C for 1 to 72 hours.
• the starch is used as a thickener in wet, pre-cooked baby foods having a pH below about 4.5.
• U.S. 4.303.451 (issued December 1, 1981 to Seidel et al.) discloses a method for preparing a pregelatinized waxy maize starch having improved flavor characteristics reminiscent of a tapioca starch.
• the starch is heat treated at 120-200°C for 15 to 20 minutes.
• the pregelatinized starch has gel strength and viscosity characteristics suitable for use in pudding mixes.
• U.S. 4.303.452 (issued Dec. 1, 1981 to Ohira et al.) discloses smoking a waxy maize starch to improve gel strength and impart a smoky taste.
• the pH of the starch is raised to pH 9-11 before smoking.
• the preferred water content of the starch during smoking is 10-20%.
• Chiu discloses instant gelling tapioca and potato starches which are non-granular and which have a reduced viscosity. Unmodified potato and tapioca starches do not normally gel.
• the starches of the patent are rendered non-granular and cold-water-dispersible by forming an aqueous slurry of the native starch at a pH of about 5-12 and then drum-drying the slurry.
• the starches are rendered gelling by heat treating the drum-dried starch for about 1.5 to 24 hours at 125-180°C to reduce the viscosity to within defined Brabender viscosity limitations.
• U.S. 4.491.483 discloses subjecting a semi-moist blend of a granular starch with at least 0.25 wt. % of a fatty acid surfactant and sufficient water (about 10-40 wt. %) to a heat-moisture treatment at from about 50-120°C, followed by drying to about 5-15 wt. %, preferably 10 wt. %, moisture.
• the heat-moisture treated starch-surfactant product is characterized by a hot water dispersibility of from about 60-100% and a higher pasting temperature than the granular starch from which it is derived.
• the treatment takes place in a closed container so that the moisture can be maintained at a constant level.
• the preferred conditions are 3 to 16 hours at 60-90°C. Degradation and dextrinization reactions are undesirable as they destroy the thickening ability of the starch.
• the use of conditions, such as, e.g., 35% moisture at 90°C for 16 hours results in reduced paste viscosity. It is believed the presence of the surfactant during the treatment permits formation of a complex within the partially swollen starch matrix with straight chain portions of the starch molecules. The limited moisture environment allows complex formation without gelatinization.
• Japanese Patent Publication No. 61-254602. discloses a wet and dry method for heating waxy corn starch and derivatives thereof to impart emulsification properties.
• the wet or dry starch is heated at l00-200 ⁇ C, preferably 130-150°C, for 0.5 to 6 hours.
• the water content is 10%, preferably 5%, or less.
• the water content is 5 to 50%, preferably 20-30%.
• the pH is 3.5-8, preferably 4-5.
• a combined treatment involving annealing a heat/moisture- treated potato starch leads to a further increase in gelatinization temperature without detectable changes in gelatinization enthalapy and with retention of the viscosity changes caused by the heat treatment.
• a combined treatment involving annealing a heat/moisture-treat potato starch does not lower the gelatinization temperature, when compared to the base starch, and increases the gelatinization temperature at higher heat/moisture treatment levels.
• Starches and flours are chemically modified with difunctional reagents such as phosphorus oxychloride, sodium trimetaphosphate, adipic anhydride, acetic anhydride and epichlorohydrin to produce chemically crosslinked starches having excellent tolerance to processing variables such as heat, shear, and pH extremes.
• difunctional reagents such as phosphorus oxychloride, sodium trimetaphosphate, adipic anhydride, acetic anhydride and epichlorohydrin to produce chemically crosslinked starches having excellent tolerance to processing variables such as heat, shear, and pH extremes.
• Such chemically crosslinked starches also referred to as “inhibited starches” provide a desirable smooth texture and possess viscosity stability throughout processing operations and normal shelf life.
• Pharmaceutical Products Starches are used in pharmaceutical products as a filler, diluent, or carrier; as a wet granulation or direct compression binder; as a disintegrant or erosion- promoting agent; as an energy source for absorbed bacteria; in controlled release compositions; in extended-release suspensions; as a dusting powder; as a coating; and for forming capsule shells.
• a filler, diluent, or carrier as a wet granulation or direct compression binder
• a disintegrant or erosion- promoting agent as an energy source for absorbed bacteria
• in controlled release compositions in extended-release suspensions
• as a dusting powder as a coating
• a coating for forming capsule shells.
• McKee et al. which discloses the use of a cold water swelling and cold water insoluble starch in intact granular form (e.g., corn phosphate or potato sulfate) as a disintegrant;
• U.S. 3.453.368 (issued July 1, 1969 to L. Magid) which discloses the use of pregelatinized starches, optionally modified and stabilized, as binders for compressed ascorbic acid tablets;
• U.S. 3.490.742 (issued January 20, 1970 to G.K. Nichols et al.) which discloses a non-granular amylose (at least 50%) obtained from the fractionation of corn starch for use as a binder- disintegrant in direct compression and dry granulation tablets;
• U.S. 3.453.368 issued July 1, 1969 to L. Magid
• U.S. 3.490.742 (issued January 20, 1970 to G.K. Nichols et al.) which discloses a non-granular amylose (at least 50%)
• Duane et al. which discloses the use of water-soluble starch ethers (e.g., hydroxyalklyl ethers) containing at least 50% amylose for use in forming capsule shells;
• U.S. 4.308.251 (issued December 29, 1981 to J.M. Dunn et al.) which discloses the use of corn, rice, potato, and modified starches as an erosion-promoting agent in controlled release formulations prepared by wet granulation;
• U.S. 4.369.308 (issued January 18, 1983 to P.C. Trubiano) which discloses the use of crosslinked pregelatinized starches as tablet disintergants; U.S. 4.383.111 (issued May 10, 1983 to K.
• Mehta et al. which discloses the use of sodium starch glycolate (i.e.. the sodium salt of a carboxymethyl starch ether) as a disintegrant in an undercoating for the 3rd of three groups of spheroids having different controlled release characteristics contained in a gelatin capsule and which also discloses the use of starch as an excipient in the group of double coated spheroids;
• U.S. 4.818.542 which discloses starch as a biodegradable or bioerodable polymer for porous micropheres possibly coated with a crosslinking agent to inhibit or control drug release;
• U.S. 4.888.178 issued December 19, 1989 to L.G.
• Rotini et al. which discloses the use of starch, preferably maize starch, and sodium starch glycolate as disintegrants in the immediate release of a programmed release Naproxen formulation containing immediate release and controlled release granulates in the form of tablets, capsules, or suspensions in a suitable liquid media
• U.S. 5.004.614 issued April 2, 1991 to J.N. Staniforth
• U.S. 5.292.519 which discloses the use of a white corn starch (obtained from a starch bearing plant which is homozygous with the white gene) as a binder.
• the present invention provides improved pharmaceutical products such as tablets, liquid medicaments, dusting powders, suppositories, and the like which contain an active ingredient and a thermally- inhibited starch or flour as a filler, diluent, carrier, viscosifier, wet granulation or direct compression binder, disintegrant, coating, moisture sink, and like uses where starches are conventionally used.
• active ingredient means an ingredient which provides the desired pharmaceutical effect, i.e., therapeutic, preventative, nutrative, and the like.
• the starches and flours are thermally inhibited, without the addition of chemical reagents, in a heat treatment process that results in the starch or flour becoming and remaining inhibited.
• the starches and flours are referred to as “inhibited” or “thermally-inhibited (abbreviated « ⁇ -I”) .
• thermally-inhibited starches and flours When these thermally-inhibited starches and flours are dispersed and/or cooked in water, they exhibit the textural and viscosity properties characteristic of a chemically-crosslinked starch.
• the starch granules are more resistant to viscosity breakdown.
• the starches and flours that are substantially completely thermally inhibited will resist gelatinization.
• the starches and flours that are highly inhibited will gelatinize to a limited extent and show a continuing rise in viscosity but will not attain a peak viscosity.
• the starches and flours that are moderately inhibited will exhibit a lower peak viscosity and a lower percentage breakdown in viscosity compared to the same starch that is not inhibited.
• the starches and flours that are lightly inhibited will show a slight increase in peak viscosity and a lower percentage breakdown in viscosity compared to the same starch that is not inhibited.
• the starches and flours are inhibited by a process which comprises the steps of dehydrating the starch or flour until it is anhydrous or substantially anhydrous and then heat treating the anhydrous or substantially anhydrous starch or flour at a temperature and for a period of time sufficient to inhibit the starch or flour.
• substantially anhydrous means containing less than 1% moisture by weight.
• the dehydration may be a thermal dehydration or a non-thermal dehydration such alcohol extraction or freeze drying.
• An optional, but preferred, step is adjusting the pH of the starch or flour to neutral or greater prior to the dehydration step.
• the amount of thermal inhibition required will depend on the reason the starch or flour is included in the pharmaceutical product, e.g., for thickening or gelling or as a moisture sink, as well as the particular processing conditions used to prepare the pharmaceutical product.
• Pharmaceuticals prepared with the thermally-inhibited starches and flours will possess viscosity stability, process tolerance such as resistance to heat, acid and shear, and improved texture.
• any physical form (non-pregelatinized granular form or pregelatinized granular or non-granular form) of the thermally-inhibited starches or flours can be used.
• the preferred forms are non- pregelatinized granular starches or pregelatinized granular starches.
• fillers, diluents, carriers, dusting powders, coatings, and moisture sinks all physical forms of the thermally-inhibited starches and flours are suitable.
• the pregelatinized starches and flours are prepared using conventional methods which disrupt or retain the granular structure.
• the thermally-inhibited starch or flour is bleached using known bleaching agents.
• the bleaching agents useful herein include chlorite salts/ such as sodium chlorite; hypochlorite salts/ such as calcium or sodium hypochlorite; peroxides/ such as hydrogen peroxide or peracetic acid; persulfate salts/ such as sodium, potassium or ammonium persulfate; permanganate salts/ such as potassium permanganate; chlorine dioxide; and ozone.
• chlorite salts/ such as sodium chlorite
• hypochlorite salts/ such as calcium or sodium hypochlorite
• peroxides/ such as hydrogen peroxide or peracetic acid
• persulfate salts/ such as sodium, potassium or ammonium persulfate
• permanganate salts/ such as potassium permanganate
• chlorine dioxide and ozone.
• Thermally-inhibited starches and flours are used where a low moisture content and/or improved flowability are required, e.g., dry powder uses. Their substantially reduced microbial content makes them advantageous for all pharmaceutical applications.
• the thermally-inhibited starches and flours are subsequently handled, whether for pH adjustment, additional physical modification or chemical modification (e.g., bleaching), or stored, the low moisture content, improved flowability and substantially reduced microbial content may be compromised.
• additional physical modification or chemical modification e.g., bleaching
• the thermally-inhibited starches and flours have to be carefully handled to maintain, or if necessary, re-establish these beneficial properties.
• thermally-inhibited starches and flours are not desirable as there may be an interaction with the active ingredient in the pharmaceutical.
• the thermally-inhibited starches and flours are advantageous as a replacement for chemically crosslinked starches and flours in these applications.
• the active ingredients are moisture sensitive.
• the thermally-inhibited starches and flours act as a moisture sink and protect the active ingredient by absorbing moisture.
• thermally-inhibited starches and flours are inert natural materials. More significantly, the thermally-inhibited starches and flours are substantially sterilized and, if stored and maintained properly, have a significantly reduced microbial content.
• the thermally-inhibited starches and flours can be derived from any native source.
• a "native" starch or flour is one as it is found in nature in unmodified form.
• Typical sources for the starches and flours are cereals, tubers, roots, legumes and fruits.
• the native source can be corn, white corn, pea, potato, sweet potato, banana, barley, wheat, rice, sago, amaranth, tapioca, sorghum, waxy maize, waxy tapioca, waxy rice, waxy barley, waxy potato, waxy sorghum, high amylose starches containing greater than 40% amylose, and the like.
• Preferred starches are potato, corn, rice, oat, tapioca, starches having an amylose content of 40% or greater, and waxy starches such as waxy maize, waxy tapioca, waxy rice, or waxy barley.
• the preferred flour is tapioca flour.
• the thermal inhibition process may be carried out prior to or after other starch or flour reactions used to modify the starch or flour.
• the starches may be modified by conversion (i.e., acid-, enzyme-, and/or heat- conversion) , oxidation, phosphorylation, etherification (e.g., by reaction with propylene oxide), esterification (e.g., by reaction with acetic anhydride or octenylsuccinic anhydride), and/or chemical crosslinking (e.g., by reaction with phosphorus oxychloride or sodium tri etaphosphate) .
• the flours may be modified by bleaching or enzyme conversion. Procedures for modifying starches are described in the Chapter "Starch and Its Modification" by M.W. Rutenberg, pages 22-26 to 22-47, Handbook of Water Saluble Gums and Resins, R.L. Davidson, Editor (McGraw- Hill, Inc., New York, NY 1980).
• Native granular starches have a natural pH of about 5.0-6.5.
• acid hydrolysis i.e., degradation
• This degradation impedes or prevents inhibition. Therefore, the dehydration conditions need to be chosen so that degradation is minimized or avoided. Suitable conditions are thermally dehydrating at low temperatures and the starch's natural pH or thermally dehydrating at higher temperatures after increasing the pH of the starch to neutral or above.
• neutral covers the range of pH values around pH 7 and is meant to include from about pH 6.5-7.5. A pH of at least 7 is preferred. More preferably, the pH is 7.5-10.5. The most preferred pH range is above 8 to below 10.
• the non-pregelatinized granular starch or flour is typically slurried in water or another aqueous medium, in a ratio of 1.5 to 2.0 parts of water to 1.0 part of starch or flour, and the pH is raised by the addition of any suitable base.
• Buffers such as sodium phosphate, may be used to maintain the pH if needed.
• a solution of a base may be sprayed onto the powdered starch or flour until the starch or flour attains the desired pH, or an alkaline gas such as ammonia can be infused into the starch or flour.
• the slurry is then either dewatered and dried, or dried directly, typically to a 2-15% moisture content.
• the starches or flours can be pregelatinized prior to or after the thermal inhibition process using methods known in the art.
• the amount of pregelatinization, and consequently, whether the starch will display a high or a low initial viscosity when dispersed in water, can be regulated by the pregelatinization procedure used, as is known in the art.
• the resulting pregelatinized starches are useful in applications where cold-water-soluble or cold-water-dispersible starches are used.
• Pregelatinized granular starches and flours have retained their granular structure but lost their polarization crosses.
• Pregelatinized non-granular have also lost their polarization crossese and have become so swollen that the starches have lost their granular structure and broken into fragments. They can be according to any of the known physical, chemical or thermal pregelatinization processes that destroy the granule such as drum drying, extrusion, or jet-cooking. See U.S. 1.516.512 (issued Nov. 25, 1924 to R.W. G. Stutzke) ; U.S. 1.901.109. (issued March 14, 1933 to W. Maier) ; US. 2.314.459 (issued March 23, 1943 to A.A. Salzburg; US. 2.582.198 (issued January 8, 1957 to O.R. Ethridge) ; US.
• the pH is adjusted by slurrying the pregelatinized granular starch or flour in water in a ratio of 1.5-2.0 parts to 1.0 part starch, and optionally, the pH is adjusted to neutral or greater.
• the slurry is simultaneously pregelatinized and dried and the dried, starch or flour is thermally inhibited. If the thermal inhibition process is performed first, the starch or flour is slurried in water, the pH of the starch or flour is adjusted to neutral or greater, and the starch or flour is dried to about 2-15% moisture. The dried starch or flour is then dehydrated and heat treated. The inhibited starch or flour is reslurried in water, optionally pH adjusted, and simultaneously pregelatinized and dried. For non-granular pregelatinized starches or flours prepared by drum drying, the pH is raised by slurrying the starch or flour in water at 30-40% solids and adding a sufficient amount of a solution of a base until the desired pH is reached.
• starch or flours prepared by the continuous coupled jet- cooking/spray-drying process of U.S. 5.131.953 or the dual atomization/spray-drying process of U.S. 4.280.851 the starch or flour is slurred at 6-10% solids in water and the pH is adjusted to the desired pH by adding a sufficient amount of a solution of a base until the desired pH is reached.
• Suitable bases for use in the pH adjustment step include, but are not limited to, sodium hydroxide, sodium carbonate, tetrasodium pyrophosphate, ammonium orthophosphate, disodium orthophosphate, trisodium phosphate, calcium carbonate, calcium hydroxide, potassium carbonate, and potassium hydroxide, and any other bases approved for use under the applicable regulatory laws.
• the preferred base is sodium carbonate. It may be possible to use bases not approved provided they can be washed from the starch or flour so that the final product conforms to good manufacturing practices for the desired end use.
• a thermal dehydration is carried out by heating the starch or flour in a heating device for a time and at a temperature sufficient to reduce the moisture content to less than 1%, preferably 0%.
• the temperatures used are 125°C or less, more preferably 100-120°C.
• the dehydrating temperature can be lower than 100°C, but a temperature of at least 100°C will be more efficient for removing moisture.
• Representative processes for carrying out a non- thermal dehydration include freeze drying or extracting the water from the starch or flour using a solvent, preferably a hydrophilic solvent, more preferably a hydrophilic solvent which forms an azeotropic mixture with water (e.g., ethanol) .
• a solvent preferably a hydrophilic solvent, more preferably a hydrophilic solvent which forms an azeotropic mixture with water (e.g., ethanol) .
• the starch or flour (about 4-5% moisture) is placed in a Soxhlet thimble which is then placed in a Soxhlet apparatus.
• a suitable solvent is placed in the apparatus, heated to its reflux temperature, and refluxed for a time sufficient to dehydrate the starch or flour. Since during the refluxing the solvent is condensed onto the starch or flour, the starch or flour is exposed to a lower temperature than the solvent's boiling point. For example, during ethanol extraction the temperature of the starch is only about 40-50°C even though ethanol's boiling point is about 78°C. When ethanol is used as the solvent, the refluxing is continued for about 17 hours.
• the extracted starch or flour is removed from the thimble, spread out on a tray, and the excess solvent is allowed to flash off.
• the time required for ethanol to flash off is about 20-30 minutes.
• the dehydrated starch or flour is immediately placed in a suitable heating apparatus for the heat treatment.
• a suitable heating apparatus for the heat treatment for a commercial scale dehydration any continuous extraction apparatus is suitable.
• the starch or flour (4-5% moisture) is placed on a tray and put into a freeze dryer.
• a suitable bulk tray freeze dryer is available from FTS Systems of Stone Ridge, New York under the trademark Dura-Tap.
• the freeze dryer is run through a programmed cycle to remove the moisture.
• the temperature is held constant at about 20°C and a vacuum is drawn to about 50 milliTorr (mT) .
• the starch or flour is removed from the freeze dryer and immediately placed into a suitable heating apparatus for the heat treatment.
• the starch or flour is heat treated for a time and at a temperature sufficient to inhibit the starch or flour.
• the temperature required will depend upon the starch base, with waxy starches requiring a higher temperature.
• the preferred heating temperatures are greater than about 100°C.
• the upper limit of the heat treating temperature is about 200 ⁇ C.
• Typical temperatures are 120-180°C, preferably 140- 160°C, most preferably 160°C.
• the temperature selected will depend upon the amount of inhibition desired and the rate at which it is to be achieved.
• the time at the final heating temperature will depend upon the level of inhibition desired. When a conventional oven is used, the time ranges from 1 to 20 hours, typically 2 to 5 hours, usually 3.5 to 4.5 hours. When a fluidized bed is used, the times range from 0 minutes to 20 hours, typically 0.5 to 3.0 hours. Longer times are required at lower temperatures to obtain more inhibited starches. For most applications, the thermal dehydrating and heat treating steps will be continuous and accomplished by the application of heat to the starch or flour beginning from ambient temperature. The moisture will be driven off during the heating and the starch or flour will become anhydrous or substantially anhydrous.
• the peak viscosities are higher than the peak viscosities of starches or flours heated for longer times, although there will be greater breakdown in viscosity from the peak viscosity. With continued heat treating, the peak viscosities are lower, but the viscosity breakdowns are less.
• the process may be carried out as part of a continuous process involving the extraction of the starch from a plant material.
• the source of the starch or flour, initial pH, dehydrating conditions, heating time and temperature, and equipment used are all interrelated variables that affect the amount of inhibition.
• the heating steps may be performed at normal pressures, under vacuum or under pressure, and may be accomplished by conventional means known in the art.
• the preferred method is by the application of dry heat in dry air or in an inert gaseous environment.
• the heat treating step can be carried out in the same apparatus in which the thermal dehydration occurs. Most conveniently, the process is continuous with the thermal dehydration and heat treating occurring in the same apparatus, as when a fluidized bed reactor is used.
• the dehydrating and heat treating apparatus can be any industrial ovens, conventional ovens, microwave ovens, dextrinizers, dryers, mixers and blenders equipped with heating devices and other types of heaters, provided that the apparatus is fitted with a vent to the atmosphere so that moisture does not accumulate and precipitate onto the starch or flour.
• the preferred apparatus is a fluidized bed.
• the apparatus is equipped with a means for removing water vapor, such as, a vacuum or a blower to sweep air or the fluidizing gas from the head ⁇ space of the fluidized bed.
• Suitable fluidizing gases are air and nitrogen. For safety reasons, it is preferable to use a gas containing less than 12% oxygen.
• Superior inhibited starches and flours having high viscosities with low percentage breakdown in viscosity are obtained in shorter times in the fluidized bed reactor than can be achieved using other conventional heating ovens or dryers.
• the starches may be inhibited individually or more than one may be inhibited at the same time.
• the starches may be inhibited in the presence of other materials or ingredients that would not interfere with the thermal inhibition process or alter the properties of the starch product.
• the resulting starches may be screened to the desired particle size. If the starch is a non-pregelatinized granular starch, the starch can be slurried in water, washed, filtered, dried, and bleached. If the starch is a granular pregelatinized starch, the starch can be washed by any known methods that will maintain granular integrity. If desired, the pH may be adjusted.
• thermally-inhibited starches and flours can be used wherever starches and flours are conventionally used in pharmaceutical products. They may be used in amounts ranging from ⁇ 1% to up to 100%. Such uses are set out below.
• Fillers and Carriers act as diluents or bulking agents. Thermally-inhibited starches are particularly useful fillers for dry dosage capsules because of their improved flow characteristics.
• Thermally-inhibited granular starches are useful as a carrier or diluent in tablets.
• corn, potato, and tapioca starches are used because they are inexpensive and/or widely available.
• Thermally-inhibited starches, particularly granular starches are also useful as carriers in dry, powdered medications such as the germicide and healing composition described in U.S. 4.668.692 (issued May 26, 1987 to D.O. Noorlander et al.). Since the carrier is the major part of the medicament, the improved flow properties of the thermally-inhibited starches are advantageous.
• Suitable lightly inhibited starches and flours include corn starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-90 minutes; potato starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes; tapioca starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes; waxy corn starch which is adjusted to pH 8-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes; and waxy rice flour which is adjusted to pH 9.5 and thermally dehydrated and heat treated at 140-160°C for 0-15 minutes.
• Wet Granulation Binders wet Granulation Binders
• thermally-inhibited starches and flours are useful as wet granulation binders or wet spheronization binders.
• Processing equipment such as extruders or high speed-high shear mixer/granulators is used to mix pharmaceutical formulas with solutions of the binders.
• the binders function to glue the tablet ingredients together.
• the resulting granulates should be more uniform in size, shape, and density, thus making them more suitable for pharmaceutical preparations such as solid dosage forms or for dry powder applications.
• the binders are stable, non- reactive materials that are wetted (cooked granular starches or dispersed pregelatinized starches) and used by those skilled in the art according to the processing equipment and final product requirements.
• the binders may dually serve as carrier coatings to additionally form barriers to protect, for example, moisture-sensitive and oxidation-sensitive ingredients, or used as coatings for controlled release formulas, or used as enteric coatings.
• a preferred modification for the thermally- inhibited starches and flours used as wet granulation binders is conversion. This allows for higher paste concentrations for ease of use and maximizes performance.
• the conversion can be carried out prior to or after the thermal inhibitions. For wet spheronisation non-converted starches are preferred.
• Suitable lightly inhibited starches include waxy maize starches which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes; waxy rice flour which is adjusted to pH 9.5 and thermally dehydrated and heat treated at 140-160 ⁇ C for 0-15 minutes; corn starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-90 minutes; tapioca starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-45 minutes, and potato starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes.
• Suitable moderately inhibited starches include waxy maize starch which is adjusted to pH 9.5 and thermally dehydrated and heat treated at 160°C for 60-120 minutes; waxy rice flour which is adjusted to pH 9.5 and thermally dehydrated and heat treated at 160°C for 15-30 minutes; tapioca starch which is adjusted to pH 9.5 and thermally dehydrated and heat treated at 160°C for 45-90 minutes; and potato starch which is adjusted to pH 9.5 and thermally dehydrated and heat treated to 160°C for 60-90 minutes. Also suitable is a lightly inhibited, low viscosity converted starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160°C for 0-60 minutes.
• Direct Compression Binders When natine starches are used in direct compression, the tablets formed may vary in weight and hardness due to poor filling of the tablet press during manufacture. This is especially true when the pharmaceutical powder contains a high level of natine starch. Thermally-inhibited starches improved filling due to their improved flow properties and result in tablets having more uniform weight hardness.
• non- pregelatinized or pregelatinized granular starches which have a low level of thermal inhibition and which are bleached are preferred. Low moisture, good flow properties, and absence of microbiological organisms are advantageous.
• Suitable starches include corn starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160 ⁇ C for 0-90 minutes; potato starch which is adjusted to pH 8.0-9.5 and heat-treated at 150-160°C for 0-60 minutes; and tapioca starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150- 160°C for 0-45 minutes.
• a waxy maize starch which is adjusted to pH 8.0-9.5 and thermally dehydrated and heat treated at 150-160 ⁇ C for 0-60 minutes. Bleaching before or after the thermal inhibition is optional.
• thermally-inhibited granular starch preferably bleached
• a thermally-inhibited starch having the properties required for a direct compression binder is preferred. Low levels of thermal inhibition are preferred.
• the low moisture content of the thermally- inhibited starches and flours makes them useful as moisture sinks. Excess free water in pharmaceutical formulations is preferentially absorbed by the starch to protect the moisture-sensitive ingredients and to increase the storage stability of the pharmaceutical composition.
• Suitable thermally-inhibited starches and flours include all granular and non-granular forms and all degrees of thermal inhibition. Low levels of thermal inhibition are preferred. Because of their improved flow properties and low microbiological content, the thermally-inhibited starches and flours are particularly useful as moisture sinks.
• thermally-inhibited starches and flours are useful as coating agents, particularly where high speed- high shear mixing and/or processing is used, where extrusion processing is used, or where spray applications using fluid bed processing are used.
• the coating agent is used to form barriers or coats to protect moisture- sensitive ingredients or to protect against oxidation.
• the coating agent is also used for controlled release formulations or where enteric coatings are desired. Suitable starches have been discussed under wet-granulation and spheronization.
• Thermally-inhibited flours provide additional hydrophobic properties making their use for controlled release or enteric formulations particularly useful. For example, a waxy rice flour adjusted to pH 9.5 and dehydrated and heat treated at 160°C for 1 to 4 hours is suitable. When used as a coating for particulates (e.g..).
• Vitamin A in bead form or for time release beads, the thermally-inhibited starches act as a moisture barrier and protect moisture-sensitive ingredients, provide stability during processing, protect against oxidation, and are microbiologically sterile. Amylose-containing thermally- inhibited starches are preferred. For such uses, the level of thermal inhibition is dictated by the coating requirements, and it is reasonable to use any level of inhibition provided the desired functional properties are achieved.
• Disintegrants are used in tablets to help the tablet break apart and release the active ingredient when the tablet is placed in a fluid environment.
• the thermally-inhibited starches are microbiologically sterile and possess controlled swelling which makes them advantageous in disintegrants, providing the materials do not become tacky and impede water penetration into the solid dosage forms. If non-pregelatinized thermally-inhibited starches are used as disintegrants, they should be lightly or moderately inhibited. Suitable thermally-inhibited starches are discussed under Wet Granulation Binders. If pregelatinized granular or pregelatinized non-granular starches are used as disintegrants, they should be moderately to highly inhibited.
• starches should contain hydrophilic groups such as carboxymethyl groups, starch phosphates, or starch sulfates. Suitable starches are adjusted to pH 8-9.5 and dehydrated and heat treated at 150-160°C for 0-180 minutes.
• the more thermally-inhibited starches are useful as dusting powders, e.g., surgical dusting powders, because of their microbiological sterility and greater resistance to gelatinization.
• Surgical rubber gloves are sterilized before use by steam autoclaving and accordingly any dusting powder used on the gloves must withstand steam sterilization.
• a highly inhibited starch is needed.
• a high amylose starch, preferably crosslinked prior to thermal inhibition, is particularly useful.
• Suitable starches include a crosslinked starch which is adjusted to pH 9.5 and dehydrated and heat treated at 160°C for 1.5-3 hours, a non-crosslinked starch which is adjusted to pH 9.5 and dehydrated and heat treated at 160-180°C for 3-6 hours; and a flour which is adjusted to pH 9.5 and dehydrated and heat treated at 160°C for 1-4 hours.
• pregelatinized thermally-inhibited starches are also suitable. ViscQsifjers
• Thermally-inhibited starches are useful as shear and pH stable viscosifiers for liquid medications such as cough syrups and parenteral injectables (e.g., for tube feeding) and as components of inhalant sprays.
• Chemically stabilized amylopectin-containing starches are preferred in granular or pregelatinized form. Suitable chemical modifications include derivatization with octenylsuccinic anhydride (for surface active properties) or treatment with propylene oxide or acetic anhydride (for stabilization) ; or treatment with multifunctional crosslinking reagents (for additional inhibition effects) .
• the chemical derivatization is preferably carried out before the thermal inhibition.
• a suitable viscosifier-texturizer includes tapioca starch or waxy maize starch which is adjusted to pH 9.5 and dehydrated and heat treated at 160° for 30-90 minutes.
• Thermally-inhibited starches are used in a liquid medicament base to suspend controlled release active ingredients (e.g., hydrocodone which is a semi-synthetic narcotic antitussive and analgesic) or uncoated active ingredients (e.g., chlorpheniramine, which is an antihistamine drug) .
• active ingredients e.g., hydrocodone which is a semi-synthetic narcotic antitussive and analgesic
• uncoated active ingredients e.g., chlorpheniramine, which is an antihistamine drug
• the thermally-inhibited starches preferably pregelatinized unless a cooking step is included in the preparation of the suspensions, are typically used in amounts sufficient to act as a thickener and viscosity stabilizer, e.g., about 12 wt. % of the aqueous base.
• the starch in combination with the other conventional ingredients used in the aqueous base should provide the rheology necessary to suspend the active ingredients throughout the liquid medicament.
• the other conventional ingredients used in the aqueous base e.g., dyes, flavor, propylene glycol, methyl and propyl parabene, xanthan gum, sugar, ascorbic acid, polysorbate 80, and/or high fructose corn syrup, should provide the rheology necessary to suspend the active ingredients throughout the liquid medicament.
• Suppositiories Thermally-inhibited amylose-containing starches which form a solid gel when dispersed in aqueous solutions are suitable.
• the preferred starches are converted, pregelatinized starches from root or tuber sources which are adjusted to pH 8.0-9.5 and dehydrated and heat treated at 150-160°C for 0-60 minutes. These starches may also be lightly chemically crosslinked. Sample Preparation Unless indicated otherwise, all the starches and flours used were provided by National Starch and Chemical Company of Bridgewater, New Jersey. The controls for the test samples were from the same native source as the test samples, were unmodified or modified in the same manner as the test samples, and were at the same pH unless otherwise indicated.
• the pH of the samples was raised by slurrying the starch or flour in water at 30-40% solids and adding a sufficient amount of a 5% sodium carbonate solution until the desired pH was reached. Measurements of pH, either on samples before or after the thermal inhibition steps, were made on samples consisting of one part starch or flour to four parts water. After the pH adjustments, if any, all non- pregelatinized granular samples were spray-dried or flash- dried as conventional in the art (without gelatinization) to about 2-15% moisture.
• the spray nozzle had the following configurations: fluid cap 251376, air cap
• the starch or flour was slurred at 6-10% solids in water and the pH was adjusted to the desired pH by adding a sufficient amount of 5% sodium carbonate solution until the desired pH was reached. Except where a conventional oven or dextrinizer is specified, the test samples were dehydrated and heat treated in a fluidized bed reactor, model number FDR-100, manufactured by Procedyne Corporation of New Brunswick, New Jersey. The cross-sectional area of the fluidized bed reactor was 0.05 sq meter.
• the starting bed height was 0.3-0.8 meter, but usually 0.77 meter.
• the fluidizing gas was air except where otherwise indicated.
• the gas was used at a velocity of 5-15 meter/min.
• pregelatinized granular starches were being heat treated, the gas was used at a velocity of 15-21 meter/min.
• the side walls of the reactor were heated with hot oil, and the fluidizing gas was heated with an electric heater.
• the samples were loaded into the reactor and then the fluidizing gas was introduced, or the samples were loaded while the fluidizing gas was being introduced. No difference was noted in the samples in the order of loading. Unless otherwise specified, the samples were brought from ambient temperature up to no more than 125°C until the samples became anhydrous and were further heated to the specified heat treating temperatures. When the heating temperature was 160°C, the time to reach that temperature was less than three hours.
• the moisture level of the samples at the final heating temperature was 0%, except where otherwise stated. Portions of the samples were removed and tested for inhibition at the temperatures and times indicated in the tables. Unless specified otherwise, the samples were tested for inhibition using the following Brabender Procedures.
• the VISCO ⁇ Amylo ⁇ GRAPH records the torque required to balance the viscosity that develops when a starch slurry is subjected to a programmed heating cycle.
• the record consists of a curve tracing the viscosity through the heating cycle in arbitrary units of measurement termed Brabender Units (BU) .
• BU Brabender Unit
• the starch slurry is heated rapidly to 92°C and held for 10 minutes.
• the peak viscosity and viscosity ten minutes after peak viscosity were recorded in Brabender Units (BU) .
• the percentage breakdown in viscosity ( ⁇ 2%) was calculated according to the formula:
• peak is the peak viscosity in Brabender units
• peak + 10' is the viscosity in Brabender Units at ten minutes after peak viscosity. If no peak viscosity was reached, i.e., the data indicate a rising (ris.) curve or a flat curve, the viscosity at 92°C and the viscosity at 30 minutes after attaining 92°C were recorded.
• the cooking cycle passes through the initiation of viscosity, usually at about 60-70 ⁇ C, the development of a peak viscosity in the range of 67-95°C, and any breakdown in viscosity when the starch is held at an elevated temperature, usually 92-95°C.
• Inhibited starches will show a Brabender curve different from the curve of the same starch that has not been inhibited (hereinafter the control starch) .
• the control starch At low levels of inhibition, an inhibited starch will attain a peak viscosity somewhat higher than the peak viscosity of the control, and there may be no decrease in percentage breakdown in viscosity compared to the control. As the amount of inhibition increases, the peak viscosity and the breakdown in viscosity decrease.
• the rate of gelatinization and swelling of the granules decreases, the peak viscosity disappears, and with prolonged cooking the Brabender trace becomes a rising curve indicating a slow continuing increase in viscosity.
• VISCO/A ylo/GRAPH fitted with a 350 cm/gram cartridge and the viscosity measured as the slurry was heated to 30°C and held for 10 minutes. The viscosity at 30°C and 10 minutes after hold at 30°C were recorded. The viscosity data at these temperatures are a measurement of the extent of pregelatinization. The higher the viscosity at 30°C, the grater the extent of granular swelling and hydration during the pregelatinization process.
• Heating was continued to 95°C and held at that temperature for 10 minutes.
• thermally-inhibited starch is made more conclusively by reference to a measurement of its viscosity after it is dispersed in water and gelatinized using the instrument described above.
• the level of viscosity when dispersed in cold water will be dependent on the extent to which the starch was initially cooked out during the pregelatinization process. If the granules were not fully swollen and hydrated during pregelatinization, gelatinization will continue when the starch is dispersed in water and heated. Inhibition was determined by a measurement of the starch viscosity when the starch was dispersed at 4.6% solids in water at pH 3 and heated to 95 ⁇ C.
• the resulting Brabender traces will be as follows: for a highly inhibited that the starch, the trace will be a flat curve, indicating that the starch is already very swollen and is so inhibited starch it is resisting any further gelatinization or the trace will be a rising curve, indicating that further gelatinization is occurring at a slow rate and to a limited extent; for a less inhibited starch, the trace will he a dropping curve, indicating that some of the granules are fragmenting, but the overall breakdown in viscosity will be lower than that for a non-inhibited control or the trace will show a second peak but the breakdown in viscosity will be lower than that for a non-inhibited control.
• the resulting Brabender traces will be as follows: for a highly inhibited starch, the trace will be a rising curve, indicating that further gelatinization is occurring at a slow rate and to a limited extent; for a less inhibited starch, the trace will show a peak viscosity as gelatinization occurs and then a drop in viscosity, but with a lower percentage breakdown in viscosity than for a non-inhibited control.
• the resulting Brabender traces will be as follows: for a highly inhibited starch the trace will be flat, indicating that the starch is so inhibited that it is resisting any further gelatinization or the trace will be a rising curve, indicating that further gelatinization is occurring at a slow rate and to a limited extent; for a less inhibited starch, the trace will show a dropping curve, but the overall breakdown in viscosity from the peak viscosity will be lower than that for a non-inhibited control.
• a dry blend of 7 g of starch or flour (anhydrous basis) and 14 g of sugar were added to 91 ml of water in a
• Waring blender cup at low speed then transferred to a cook-up beaker, allowed to stand for 10 minutes, and then evaluated for viscosity, color, clarity and texture.
• Rapid Visco Analyzer RVA ⁇
• This test is used to determine the onset of gelatinization, i.e., the pasting temperature.
• the onset of gelatinization is indicated by an increase in the viscosity of the starch slurry as the starch granules begin to swell.
• a 5 g starch sample (anhydrous basis) is placed in the analysis cup of a Model RVA-4 Analyzer and slurried in water at 20% solids. The total charge is 25 g.
• the cup is placed into the analyzer, rotated at 160 rpm, and heated from an initial temperature of 50 ⁇ C up to a final temperature of 80°C at a rate of 3°C/minute.
• a plot is generated showing time, temperature, and viscosity in centipoises (cP) .
• the pasting temperature is the temperature at which the viscosity reaches 500 cP. Both pasting temperature and pasting time are recorded.
• This test provides a quantitative measurement of the enthalapy ( ⁇ H) of the energy transformation that occurs during the gelatinization of the starch granule. The peak temperature and time required for gelatinization are recorded.
• a Perkin-Elmer DSC-4 differential scanning calorimeter with data station and large volume high pressure sample cells is used. The cells are prepared by weighing accurately 10 mg of starch (dry basis) and the appropriate amount of distilled water to approximately equal 40 mg of total water weight (moisture of starch and distilled water) . The cells are then sealed and allowed to equilibrate overnight at 4 * C before being scanned at from 25-150 * C at the rate of lO'C/minute. An empty cell is used as the blank.
• a chemical funnel having a 100 mm top interior diameter (ID) (Kimax 58) is modified by removing the existing stem and annealing a 8 mm I.D. glass tubing 85 mm in length as the stem.
• the modified funnel is placed in the large ring and the height is adjusted so that the orifice of the funnel is 1 + 0.1 cm above the paper.
• a powder funnel having a 60 mm top I.D. and 13 mm stem I.D. (Kimax 29020-04) is placed in the small ring and the ring is lowered as far as possible, i.e., until the clamps meet.
• the small funnel should be centered above the large funnel with the orifice of the large funnel stem parallel to the paper.
• the average radius of the sample pile is calculated and the angle of repose is determined using the following formula: Tangent (angle of repose) ⁇ height of funnel orifice average radius of pile
• Horiba Wet Particle Size Determination For determination of the Horiba wet particle size determination, the thermally-inhibited starches were analyzed, according to the instruction manual-version 1.81C, of the Horiba, Model #LA-900, Laser Scattering Particle Size Distribution Analyzer (Horiba Instrument Inc., Irvine, CA 92174). This determination requires that the sample be added under agitation to a cup which contains distilled or de-ionized water until a desired concentration is achieved. The software package then automatically initiates the analysis.
• thermally inhibited starches and controls in the following examples were prepared as described above and are defined by textural characteristics or in relation to data taken from Brabender curves using the above described procedures.
• the thermally-inhibited starches and flours are referred to as "T-I" starches and flours.
• thermally-inhibited starches and flours referred to a "granular" starches are non-pregelatinized granular starches and flours.
• the moisture indicated is the moisture of the starch before the dehydration and heat treating steps. As indicated above, as the starches were brought from ambient temperature up to the heating temperature, the starches became anhydrous or substantially anhydrous.
• EXAMPLE 1 This example illustrates the preparation of the starches of this invention from a commercial granular waxy maize base starch by the heat treatment process of this invention.
• EXAMPLE 2 This example illustrates that a variety of granular starches may be processed by the method of this invention to provide a non-cohesive thickener with properties similar to chemically crosslinked starches. Processing conditions and their effects on the viscosity and texture of waxy barley, tapioca, V.O. hybrid and waxy rice starches are set forth in the tables below.
• Waxy barley starch samples were commercial granular starch obtained from AIKo, Finland.
• Waxy rice starch samples were commercial granular starch obtained from Mitsubishi Corporation, Japan.
• Samples were cooked by slurring 7.5 g of starch at 12% moisture in 100 mis of water and heating the starch slurry for 20 minutes in a boiling water bath.
• V.O. 5.9 11.4 heavy cohesive Hybrid Control a. V.O. hybrid starch samples were granular starches obtained from National Starch and Chemical Company, Bridgewater, New Jersey. b. Samples were cooked by slurrying 7.5 g of starch at 12% moisture in 100 is of water and heating the starch slurry for 20 minutes in a boiling water bath.
• non-cohesive, heat-stable starch thickener may be prepared from waxy barley, V.O. hybrid, tapioca and waxy rice starches by the process of this invention.
• the amount of inhibition (non-cohesive, thickening character in cooked aqueous dispersion) increased with increasing time of heat treatment.
• EXAMPLE 3 This example illustrates the effects of temperature, the pH, and starch moisture content on the viscosity and texture of the treated starch.
• a waxy maize starch sample (100 g) containing
• Samples (900 g) of a commercial granular waxy maize starch obtained from National Starch and Chemical Company, Bridgewater, New Jersey) were placed in a 10" x 15" x 0.75" aluminum tray and heated in an oven at 180 * c for 15, 30, 45 and 60 minutes. The pH of the starch was not adjusted and remained at about 5.2 during the heating process. Sample viscosity and texture were evaluated by the method of Example 1.
• a combination of selected factors including the pH, moisture content and the type of native starch, determine whether a desirable, non-cohesive, heat-stable starch thickener is produced by the process of this invention.
• EXAMPLE 4 This example shows carrying out the thermal inhibition in the fluidized bed previously described. The effects of temperature and time at the indicated temperature on the level of inhibition granular waxy maize starch at pH 9.5 are shown below.
• the data show that inhibited anhydrous or substantially anhydrous samples can be obtained at heat treating temperatures between 110 and 200°C, with more inhibition occurring at higher temperatures or when the heat treatment was carried out for longer times at lower temperatures.
• the starch samples heated at 200°C were highly inhibited, as shown by the rising curve, or completely inhibited, as shown by the fact the starch did not gelatinize.
• EXAMPLE 5 This example shows the preparation of pregelatinized granular thermally-inhibited waxy maize starches. The pregelatinization step was carried out prior to the thermal inhibition. The fluidized bed previously described was used.
• the spray nozzle had the following configuration: fluid cap, 251376, and air cap, 4691312.
• the resulting high and low viscosity and pregelatinized granular starches were dehydrated and heat treated at the temperature and time indicated.
• the thermally-inhibited starches were evaluated for inhibition using the Brabender procedure previously described.
• Control 250 250 820 340 130 84 160°C for 0 min. 50 100 690 460 270 61
• pH 10 Low Initial Viscosity Control 200 190 615 350 190 69
• Samples of a granular high amylose starch (Hylon V-50% amylose) at its natural pH and pH 9.5 were evaluated for the effect of the high amylose content on inhibition.
• the starches were thermally inhibited at 160°C in the fluidized bed for the indicated time. Due to the high levels of amylose, it was necessary to use a pressurized Visco/amylo/Graph (C.W. Brabender, Ralphensack, NJ) to obtai Brabender curves. Samples were slurried at 10% starch solids, heated to 120°C, and held for 30 minutes.
• This example describes the preparation of thermally-inhibited pregelatinized granular starches from additional starch bases as well as a waxy maize starch.
• the granular starches were adjusted to the indicated pH, pregelatinized using the procedure previously described, and heat treated in an oven at 140°C for the indicated time.
• the cook evaluation and Brabender results are shown below.
• EXAMPLE 8 This example shows the preparation of pregelatinized, non-granular starches which were pregelatinized by drum drying and then thermally inhibited.
• T-I Tapioca - PH 6 2 very heavy cohesive, pulpy 4 heavy to very heavy slightly cohesive, pulpy 6 moderately heavy slightly cohesive, pulpy 8 heavy slightly cohesive, pulp Heating Time Cook Viscosity Cook Texture
• This example shows the preparation of another pregelantinized non-granular which was jet-cooked, spray- dried, and then thermally inhibited.
• a granular high amylose starch (50% amylose) was jet-cooked and spray-dried using the continuous coupled jet-cooking/spray-drying process described in U.S. 5.131.953 and then thermally inhibited for 8 hours at 140°C.
• the jet-cooking/spray-drying conditions used were as follows: slurry - pH 8.5-9.0; cook solids - 10%; moyno setting - about 1.5; cooking temperature - about 145°C; excess steam - 20%; boiler pressure - about 85 psi; back pressure - 65 psi; spray-dryer - Niro dryer; inlet temperature - 245°C; outlet temperature - 115°C; atomizer - centrifugal wheel.
• the pregelatinized non-granular starch was adjusted to pH 8.7 and dehydrated and heat treated for 8 hours in an oven at 140°C. The characteristics of the resulting thermally inhibited starches are set out below.
• T-I 350 240 420 410 335 20 The results show that even a high amylose starch can be inhibited. There was less breakdown for the thermally-inhibited starch and the overall viscosity was higher.
• EXAMPLE 10 This example shows that thermally-inhibited starches can be prepared by drum-drying the starches prior to thermal inhibition.
• the resulting pregelatinized non-granular thermally-inhibited waxy maize starches are compared with thermally-inhibited pregelatinized non-granular waxy maize starches prepared by the continuous coupled jet-cooking and spray-drying process used in Example 4 and the thermally-inhibited pregelatinized granular starches prepared by the dual atomization/spray drying process described in U.S. 4.280.251 (which was used in Example 5) .
• Control 100 1010 1080 340 170 84
• the dried pH 5.3, pH 7.0, and pH 9.5 starches were each separated into two samples.
• One sample was dried on trays in a forced draft oven at 80°C overnight to thermally dehydrate the starch to ⁇ 1% (0%) moisture.
• the other sample was placed in a Soxhlet extractor and allowed to reflux overnight (about 17 hours) with anhydrous ethanol (boiling point 78.32°C).
• the ethanol-extracted sample was placed on paper so that the excess alcohol could flash off which took about 30 minutes.
• the ethanol-extracted starch was a free flowing powder which was dry to the touch.
• the oven-dehydrated starches and ethanol-extracted starches were placed on trays in a forced draft oven and heated for 3, 5, and 7 hours at 160°C.
• EXAMPLE 1 Granular tapioca, corn and waxy rice starches and waxy rice flour were adjusted to pH 9.5, dehydrated in an oven and by extraction with ethanol, and heat treated at 160°C for the indicated time. They were evaluated for Brabender viscosity using the procedure previously described.
• EXAMPLE 13 This example compares ethanol-extracted granular waxy maize starches and oven-dehydrated waxy maize starches which were heat treated in an oven for 5 and 7 hours at 160°C. The starches were adjusted to pH 8.03 prior to the dehydration.
• the thermally-inhibited starches were slurried at 6.6% solids (anhydrous basis), pH adjusted to 6.0-6.5, and then cooked out in a boiling water bath for 20 minutes. The resulting cooks were allowed to cool and then evaluated for viscosity, texture, and color.
• a granular waxy maize starch was pH adjusted to pH 9.5 as previously described. The starch was then placed in a freeze dryer and dried for 3 days until it was anhydrous (0% moisture) . The freeze-dried (FD) starch was heat treated for 6 and 8 hours at 160°C in a forced draft oven. Brabender evaluations were run. The results are shown below: Viscosity Breakdown
• This example shows that thermal inhibition reduced the gelatinization temperature of the granular waxy maize starches.
• the gelatinization temperature of an untreated waxy maize, a thermally-inhibited (T-I) waxy maize (pH adjusted to 9.5 "as is” at pH 6.0), and chemically- crosslinked (X-linked) waxy maize starches (0.02%, 0.04%, and 0.06% phosphorus oxychloride) were determined by Differential Scanning Calorimetry.
• the starches were thermally dehydrated and heat treated at 160°C in an oven for the indicated time and temperature.
• the chemically crosslinked (X- linked) starches are essentially identical to the unmodified waxy starch in peak gelatinization temperature (72-74'C vs. 74 * C) and enthlapy (4.2-4.4 vs 4.3 cal/g).
• the reduced gelatinization temperature and decreased enthalapy of the thermally-inhibited starches suggest that the overall granular structure has been altered by the thermal inhibition process (i.e., dehydration and heat treatment) .
• the heat treatment also reduced the enthlapy ( ⁇ H) from 4.3 cal/g for the unmodified starch to 2.8 - 2.9 cal/g for the thermally-inhibited (T-I) starch.
• EXAMPLE 16 This example shows that the thermal inhibition may begin as early as 110° (230 ⁇ F) , that it is substantially noticeable at 160°C (320°F) , and that the gelatinization is unchanged or reduced.
• Granular wavy maize starches were pH adjusted to 7.0 and 9.5 and dehydrated and heat treated using air having a Dew point below 9.4°C (15 ⁇ F) in the fluidized bed previously described at the indicated temperature and time.
• Peak Peak +10' Breakdown t% ⁇ Control (pH 9.5) 1240 300 75.8 93 ⁇ C for 0 min. 1200 300 75.0 104 ⁇ C for 0 min. 1205 320 73.4 110 ⁇ C for 0 min. 1260 400 68.3 121°C for 0 min. 1230 430 65.0 127 ⁇ C for 0 min. 1255 420 66.5 138 ⁇ c for 0 min. 1245 465 62.7 149 ⁇ C for 0 min. 1300 490 62.3 160 ⁇ C for 0 min. 1120 910 18.8 160°C for 60 min. 750 730 2.7 160°C for 90 min. 690 680 1.4
• the DSC results show that at the onset of inhibition there was a slight reduction in the peak gelatinization temperature and that as the inhibition temperature and time increased there is a reduction in the peak gelatinization temperature.
• the DSC results show that the enthlapy is unchanged or slightly higher unlike the enthlapy of the starches of the prior example which were thermally inhibited in the oven.
• EXAMPLE 17 This example shows the correlation between the RVA pasting temperature and time and DSC peak gelatinization temperature and time and the reduction in Brabender viscosity breakdown for various starch bases and for waxy maize starches dehydrated by various methods including heating, ethanol (ETOH) extraction, and freeze.
• the base starches were unmodified.
• the comparative starches dehydrated by drying starches were all adjusted to pH 9.5 before dehydration.
• the ethanol-extraction and freeze-drying were pH adjusted but not heat treated.
• the starches were heat treated in an oven at 160°C for the indicated time except for the starches chemically crosslinked with 0.12% sodium trimetaphosphate (STMP) which were heat treated at 160°C for the indicated time in the fluidized bed.
• STMP sodium trimetaphosphate
• EXAMPLE 19 This example describes a visual evaluation of the dry powder flow properties of granular waxy maize starches adjusted to pH 9.5 and thermally dehydrated and heat treated in the fluidized bed previously described. The starches evaluated are shown below:
• Powder No. 1 distributed fairly evenly and the flow pattern was uniform. It was somewhat fluid and had some dynamic quality. Only a slight amount of air was entrapped in the body of the powder.
• Powder No. 2 distributed evenly and the flow pattern was uniform. The powder was fluid and had a dynamic quality. There was no air entrapment in the body of the powder.
• Powder No. 3 distributed evenly and the flow pattern was uniform. The powder was fluid, water-like, and had a dynamic quality. No air was entrapped in the body of the powder. The control starch powder clumped and had an irregular flow. It had a cake-like static quality. Air was entrapped in the body of the powder.
• EXAMPLE 19 This example measures the flow properties of thermally-inhibited waxy maize starches by determining the angle of repose which is an indication of performance with regard to mobility/flow.
• the starches were adjusted to pH 9.5 and thermally inhibited by dehydration and heat treatment in the fluidized bed previously described.
• the thermally-inhibited starches had good flow properties.
• the control did not flow.
• a chemically crosslinked and derivatized waxy corn starch also did not flow.
• the funnels were completely blocked upon addition of the sample. This starch would not even flow through powder funnels with larger internal diameter orifices without constant tapping. Similar results, i.e., no flow, were observed with native corn starch.
• EXAMPLE 20 The following example shows the wet particle size of waxy maize starches adjusted to pH 9.5 and dehydrated and heat treated in the fluidized bed previously described.
• This example shows that the thermally-inhibited starches and flours are substantially sterilized by the dehydration heat treatment in the fuidized bed. This property is useful in all pharmaceutical applications.
• the starch was adjusted to pH 9.5, and thermally-inhibited under the conditions shown below, and stored for about 2 months in non-sterilized, covered glass containers.
• the thermally-inhibited starches and the control starch were microbiologically tested for their total plate count and the presence of organisms using the above procedure. The results are shown below.
• EXAMPLE 22 This example shows that alcohol dehydration provides better tasting thermally-inhibited starches.
• the test performed was a "Triangle Taste Test" which employs three coded samples, two identical and one different, presented simultaneously. None of the samples is identified as the standard. Control and experimental treatments were systematically varied so that each was presented in odd and identical sample positions an equal number of times. The judge determined which of the three samples differed from the other two. A forced choice was required, statistical analysis was used to determine whether a significant difference between treatments existed. The probability of choosing the different or odd sample by chance alone was one-third. Once the odd sample was chosen the judges were asked why the samples were different and which they preferred.
• the starches tested were waxy maize starches adjusted to pH 9.5 and heat treated for 7 hours at 140 ⁇ C. One sample was dehydrated by ethanol extraction and the other sample was thermally dehydrated prior to the thermal inhibition step.
• the thermally-inhibited granular starches were washed by slurring the granular starch with 1.5 parts water, mixing for 10 minutes on a stir plate, vacuum filtering the slurry, and washing the starch cake twice with 50 ml. of distilled water. Then sufficient water was added to bring the slurry solids to 3%, the pH was adjusted to 6.0-6.5 , and the slurry was cooked 20 minutes in a boiling water bath, cooled to slightly above room temperature, and evaluated. The judges were given 20 ml samples for tasting. They observed a significant difference between the oven-dehydrated and ethanol-dehydrated starches. Nine out of the twelve judges chose the one different sample. All nine of the judges who could determine the different sample preferred the sample that was ethanol- extracted. Attributes that were used to describe the ethanol-extracted sample included clean, not bitter, and smooth compared to the oven-dehydrated sample.
• EXAMPLE 23 This example shows that an alcohol extraction of a granular thermally-inhibited starch provides a better tasting starch.
• a thermally-inhibited, granular waxy maize (adjusted to pH 9.5 and dehydrated and heat treated at 160°C for 180 minutes in the fluidized bed previously described was placed in a Soxhlet extraction apparatus and allowed to reflux overnight (about 17 hrs) using ethanol as the solvent.
• the extracted starch was then laid on paper to allow excess ethanol to flash off.
• the resulting dry starch was washed by slurring the starch with 1.5 parts water, mixing for 10 minutes on a stir plate, vacuum filtering the slurry, and washing the starch cake twice with 1.5 parts distilled water.
• EXAMPLE 24 This example shows the effect of protein removal on the flavor (i.e., taste and smell) of a thermally-inhibited waxy maize starch.
• the protein Prior to the thermal inhibition process, the protein was extracted as follows. The starch was slurried at W-1.5 (50 lbs starch to 75 lbs of water) and the pH was adjusted to 3-3.5 with sulfuric acid. Sodium chlorite was added to give 2% on the weight of the starch. The starch was steeped overnight at room temperature. The pH was raised to about 9.5 using a 3% sodium hydroxide solution. The pH adjusted starch was washed well prior to drying. The protein level of the starch was reduced to about 0.1%.
• the protein-extracted starch and untreated starch were thermally dehydrated and heat treated at 160°C in the fluidized bed previously described.
• the protein level of the thermally-inhibited waxy maize control (pH 9.5) was about 0.3%.
• the protein-reduced, thermally-inhibited waxy maize was compared to the thermally-inhibited waxy maize which had not been protein-reduced prior to heat treatment.
• the number indicates those respondents who selected the protein-reduced product as being cleaner in flavor.
• the ⁇ values were determined from a statistical table. An ⁇ risk of 5% indicates (with 95% confidence) that the samples are statistically different, i.e., that the protein-reduced product is cleaner than the control.
• This example shows the preparation of potato starches modified with an amino-multicarboxylic acid (CEPA) reagent, i.e., 2-chloroethylaminodipropionic acid and their subsequent thermal-inhibition. Overhead stirring was used throughout this reaction.
• Deionized water 150 ml was added to a liter beaker and heated to 45 * C with an external constant temperature bath.
• a total of 30 g sodium sulfate (30% on starch) was dissolved in the water followed by the addition of 100 g of the potato starch.
• a solution of 3% aqueous sodium hydroxide (25 ml) was added slowly with good agitation to minimize starch swelling.
• a 25% aqueous solution of the CEPA reagent 32 ml to give an 8% starch treatment (dry basis) was added simultaneously with a 3% aqueous sodium hydroxide solution (170 ml) .
• the addition rates used kept the level of caustic high so that pH was about 11.0 to 11.5 during the reaction.
• the reaction was run at 42-45"C for 16 hours and then neutralized by adding 3 N hydrochloric acid to adjust pH to about 6.5, followed by stirring for 30 minutes.
• the starch was then filtered and washed twice with 150 ml of water and allowed to air dry. Analysis of the starch for bound nitrogen showed 0.25% N (dry basis).
• the starches were adjusted to pH 9.5 and heat treated at 100 * C, 110 * C, 120 * C, 130 * C and 140 * C for 0 minutes using the fluidized bed previously described.
• EXAMPLE 29 This example shows the thermal inhibition of converted starches.
• Samples of waxy maize and tapioca starch were slurried in 1.5 parts water. The slurries were placed in a 52'C water bath, with agitation, and allowed to equilibrate for one hour. Concentrated hydrochloric acid was added at 0.8% on the weight of the samples. The samples were allowed to convert at 52'C for one hour. The pH was then adjusted to 5.5 with sodium carbonate and then to pH 8.5 with sodium hydroxide. The samples were recovered by filtering and air drying (approximately 11% moisture) . The starches in 50 g amounts were placed in an aluminum tray, covered and placed into a forced draft oven at 140"C for 5.5 hours.
• Viscosity Viscosity (BV) Viscosity (BU)
• the thermally-inhibited starch samples were cooked in tap water at 88-93"C (190-200 * F) bath temperature for 30-60 minutes to yield solutions having a Brookfield viscosity of approximately 3000 cps. The viscosity stability at room temperature was evaluated.
• a granular waxy maize starch (pH 8.7) which had been lightly crosslinked with 0.04% phosphorous oxychloride was thermally-inhibited.
• the granular starch was jet-cooked and spray-dried using the coupled continuous jet-cooking/spray-drying process and conditions described in Example 8.
• the spray-dried starch was oven dehydrated and heat treated for 8 hours at 140 ⁇ C.
• EXAMPLE 31 This example illustrates the use of a thermally-inhibited unmodified starch as a carrier in a medicament.
• a dry composition useful for treating dairy animals for mastitis is prepared by mixing 10-15% ascorbic acid, 7-10% allantoin, and 75-83% of a lightly inhibited granular corn starch, with the total being 100%.
• the corn starch is adjusted to pH 9.5, heated to 160°C for 0 minutes to dehydrate and thermally-inhibited the starch, substantially reduce the microbial content, and improve the dry flow properties of the starch.
• EXAMPLE 32 This example shows the use of lightly inhibited pregelatinized starch as a wet granulation binder in a compressed ascorbic acid tablet.
• a total of 7 parts of a pregelatinized non- granular waxy maize starch or a pregelatinized granular corn starch is adjusted to pH 9.5 and dehydrated and heat treated at 160°C for about 15 minutes. It is charged to a stainless steel mixer. Then 93 parts of ascorbic acid, in the form of unground crystals (29 wt.% retained on a 200 mesh screen and 71 wt.% passed by a 200 mesh screen), are then added. The mixture is granulated using about 25 parts of distilled water. The wet granulate is passed through a Fitzpatrick mill, equipped with a No. 5 screen operating at low speed, with knives forward.
• the milled granulate is dried overnight at about (105 ⁇ F) and then passed through a Fitzpatrick mill, equipped with a No. 12 screen operating at medium speed, with knives forward. Then 98 parts of the granulate are added to a mixture of 2 parts of calcium stearate. A granulate with low mechanical friability is obtained. It is compressed at a tablet weight of 570 mg using a 15/32" flat-faced beveled edge, scored punch. The tablets should be comparable to compressed tablets prepared with conventional pregelatinized corn starches such as National 1551 and Colorcon starch 1500. The tablets should release the active ingredient more rapidly due to the inhibition of its starch. EXAMPLE 33 This example describes the use of a thermally- inhibited corn starch (adjusted to pH 9.0 and dehydrated and heat treated at 160°C for 30 minutes) in a controlled release formulation containing aspirin.
• Aspirin (4.375 kg, 40 mesh/inch crystal USP) and the thermally-inhibited corn starch (0.2255 kg) are deaggregated through a 40 mesh/inch screen into the bowl of a Hobart mixer.
• the dry powders are mixed for 5 minutes at speed 1.
• a cellulose acetate phthalate solution is added to the mixing powders over a 30 second period while mixing at speed 1 and then for 4 minutes at speed 2.
• the wet granulate is discharged onto stainless steel trays and air dried until it can be forced through a 20 mesh/inch screen.
• the screened granulate is further air dried to remove residual solvent.
• the granulates are weighed, blended by tumbling, and compressed on a conventional rotary tablet press (half-inch flat bevelled edge tooling) using sufficient pressure to produce tablets containing 650 mg aspirin and having a hardness of 8-10 K_ (Schleuniger) .
• thermally-inhibited starch will act as a disintegrant and a moisture sink thus improving the storage stability and reducing hydrolysis of the aspirin over time.
• EXAMPLE 34 This example describes the use of thermally- inhibited corn starch or potato starch (pH 8-9.5/0-15 min. at 140-160°C) as a carrier in a capsule containing an active ingredient which is used in the treatment of liver complaints, fibrinolysis, ulcers and immunological diseases such as articular rheumatism asthma and nephritis.
• the suppositories are gelatin capsules which contain (a) Doderlein bacteria adsorbed on a thermally- inhibited, sterilized potato starch or corn starch (pH 8- 9.5/140-l60°C for 0-15 min.) and (b) oestriol.
• the formulations contain 100-150 mg starch/bacteria adsorbate (105-107 live cells/gl., 0.4- 0.6 g oestriol, and 350-400 mg bacteria-free starch.
• the starch serves as an absolute and an energy source which ensures the relatively prolonged survival of the bacteria.
• EXAMPLE 36 This example describes the use of a pregelatinized, converted or unconverted thermally- inhibited starch (pH 8-9.5/0-15 min at 140-160°C) as a starch matrix for controlled release compositions.
• Suitable starch bases include potato, corn, rice, tapioca, rye, oat, wheat or waxy maize.
• the drug, flavor, sweetener, and other conventional ingredients are dispersed in a solidified starch melt and then formulated as tablets, capsules, granules, syrups, suspensions, gels, implants, aerosols, transdermal patches, or injectable dosage forms.

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