it has been found that ec , a water - insoluble , hydrophobic cellulose ether , which is commonly used as a drug release retarding agent in barrier film coatings or hydrophobic non - disintegrating matrix tablets , can act as a synergistic tablet binder for rapidly disintegrating tablet formulations . ec , a non - hygroscopic , non - reactive tablet binder can readily be dry blended or co - processed ( for example by co - milling or through use of agglomeration techniques including but not limited to roller compaction and wet granulation ) with other formulation components to provide the combined attributes of fast disintegration ( less than 60 seconds and frequently less than 20 seconds ), relative inertness , near ph neutrality , ease of manufacturing by conventional direct compression tablet technology , and high tablet robustness as defined by low tablet friability ( less than 1 % and frequently less than 0 . 5 % friable by weight ). the invention also provides for tablet formulations with low hygroscopicity prior to compression into tablets and tablets also have very low hygroscopicity , not withstanding the fast dispersion in water . typical moisture uptake is less than 2 % ( on a dry weight basis ) at 50 % relative humidity and 25 ° c . ethylcellulose ( ec ) is a cellulose ether that is versatile with many uses . a preferred ec is described in u . s . pat . no . 6 , 592 , 901 , which is incorporated herein by reference in its entirety . the following grade types of ec are commercially available from hercules incorporated : types k , n , and t of ec are used in food and food contact applications . more specifically , k and t are used for food and contact such as paper or paperboard in contact with food . n types were used as a binder or coating in pharmaceutical applications . type x is used in inks and other industrial applications . while any grade of ec is of utility in this invention , the use of optimized direct compression grades such as high ethoxyl , low viscosity ec ( t10 ec pharm grade , available from aqualon division , a business unit of hercules incorporated ), is especially preferred . this ec type combines high compressibility with good powder flow characteristics . other commercially available grades of ec with lower ethoxyl and lower or higher viscosity ( such as n7 , n10 , n14 , n22 , n50 and n100 pharm grade ec , all available from aqualon division , a business unit of hercules incorporated ), while possibly less effective than t10 ec pharm grade , are also useful in the tablet formulations of the current invention . it is well known in the art how to make ec . normally , either chemical grade cotton linters or wood pulp is used to prepare ec . the sequence of chemical reactions is similar to that for methylation of cellulose . in commercial practice , sodium hydroxide concentrations of 50 % or higher are used to prepare the alkali cellulose . staged additions of solid sodium hydroxide during the reactions can be used to reduce side reactions . ethyl chloride is added to the alkali cellulose in nickel - clad reactors at 90 - 150 ° c . and 828 to 965 kpa ( 120 to 140 psi ) for 6 - 12 hours . diluents such as benzene or toluene can be used . at the end of the reaction , the volatiles such as ethyl chloride , diethyl ether , ethanol , and diluent are recovered and recycled . the ethylcellulose in solution is precipitated in the form of granules with further recovery of the carrier solvents . washing with water completes the processing . control of metallic impurities is important to achieve stability during storage . anitoxidants can also be incorporated to inhibit loss of viscosity . while any grade of ec is of utility in this invention , a preferred ec of use in the present invention has a higher ethoxyl content ( greater than 49 . 6 %) and simultaneously a low viscosity ( less than 53 cps ) and the average particle size is greater than 50 micrometers . the preferred ec of use in the present invention has an ethoxyl content lower limit of 49 . 6 %, preferably 49 . 8 %, and more preferably 50 . 0 %. the upper limit of the ethoxyl content of the ec is 54 . 88 %, preferably 53 . 0 % and more preferably and more preferably 52 . 0 %. the viscosity of the ec is less than 53 . 0 cps , preferably less than 25 cps and more preferably less than about 17 cps , with a lower limit of about 3 cps . the ec binder is co - formulated with typical disintegrants and other common tablet aids such as fillers and tablet lubricants and flow aids . typical disintegrants include and may be selected from the group consisting of cross - linked povidone , sodium cross carmellose ( cross - linked sodium carboxymethyl cellulose ), sodium starch glycollate , low substituted hydroxypropyl cellulose , and guar . low - substituted hydroxypropyl cellulose may be defined as having a hydroxypropoxyl content in the range of 5 . 0 to 16 . 0 % by weight and an apparent average degree of polymerization in the range of 350 to 700 . low - substituted hydroxypropyl cellulose is disclosed in u . s . pat . no . 6 , 380 , 381 , incorporated herein by reference . suitable fillers include sucrose , lactose , dextrose , mannitol , xylitol , sorbitol , lactiol , maltodexrin , isomalt , polydextrose , starch and microcrystalline cellulose . lubricants and flow aids include metal stearates , such as magnesium and calcium stearate , stearic acid , hydrogenated vegetable oils , poletheylene glycols , amino acids , stearyl fumarate , talc and colloidal silicone dioxide . other additives which are typically used in small amounts but are important for organoleptic enhancements include sweetners , flavors , tastemasking agents and colorants . examples of sweeteners include sucralose , sodium saccharin , acesulfame k and aspartame . examples of flavoring and tastemasking agents include peppermint , citrus and vanilla extracts , amino acid derivatives such as glutamic acid based derivatives . the above is not meant to be an exhaustive list of possible organoleptic enhancing aids . suitable use levels of ec are 1 - 20 %, more preferably 3 - 18 % and most preferably 5 - 15 %. suitable use levels for disintegrant are 2 - 15 %, more preferably 3 - 12 % and most preferably 5 - 10 %. suitable lubricant levels range from 0 . 1 % to 2 . 5 %. more preferably 0 . 25 to 2 . 0 % and most preferably 0 . 5 % to 1 . 5 %. while any grade of ec is of utility in this invention , the use of optimized direct compression grades such as high ethoxyl , low viscosity ec ( t10 ec pharm grade , available from aqualon division , a business unit of hercules incorporated ), is especially preferred . this ec type combines high compressibility with good powder flow characteristics . other commercially available grades of ec with lower ethoxyl and lower or higher viscosity ( such as n7 , n10 , n14 , n22 , n50 and n100 pharm grade ec , all available from aqualon division , a business unit of hercules incorporated ), while possibly less effective than t10 ec pharm grade , are also useful in the tablet formulations of the current invention . the rapidly disintegrating , low friable tablet formulation of the present invention also can be combined with an active pharmaceutical ingredient or medicaments to prepare a formulation suitable for tableting or pelletizing . one or more active pharmaceutical ingredients may be combined in a single dosage form , depending on the chemical compatibility of the combined active ingredients and the ability to obtain the desired release rate from the dosage form for each active ingredient . the determination of the effective amount of the medicament per dosage unit is easily determined by skilled clinicians . representative types of active pharmaceutical ingredients include antacids , anti - inflammatory substances , anti - infectives , psychotropics , antimanics , anti - parkinson &# 39 ; s agents , anti - alzheimer &# 39 ; s agents , anti - parkinson &# 39 ; s agents , anti - alzheimer &# 39 ; s agents , stimulants , antihistamines , laxatives , decongestants , nutritional supplements , gastrointestinal sedatives , antidiarrheal preparations , antianginal drugs , antiarrhythmics , antihypertensive drugs , vasoconstrictors and migraine treatments , anticoagulants and anti - thrombotic drugs , analgesics , anti - pyretics , hypnotics , sedatives , antiemetics , anti - nauseants , anticonvulsants , neuromuscular drugs , hyper - and hypoglycemic agents , thyroid and antithyroid preparations , diuretics , antispasmodics , uterine relaxants , mineral and nutritional additives , anti - obesity drugs , anabolic drugs , erythropoietic drugs , antiasthmatics , expectorants , cough suppressants , mucolytics , antiuricemic drugs , topical analgesics , local anesthetics , polypeptide drugs , anti - hiv drugs , anti - diabetic agents , chemotherapeutic and anti - neoplastic drugs . examples of specific active pharmaceutical ingredients include aluminum hydroxide , prednisolone , dexamethasone , aspirin , acetaminophen , ibuprofen , isosorbide dinitrate , nicotinic acid , tetracycline , ampicillin , dexbrompheniramine , chlorpheniramine , albuterol pseudoephedrine , loratadine , theophylline , ascorbic acid , tocopherol , pyridoxine , methoclopramide , magnesium hydroxide , verapamil , procainamide hydrochloride , propranolol , captopril , ergotamine , furazepam , diazepam , lithium carbonate , insulin , furosemide , hydrochlorothiazide , guaiphenesin , dextromethorphan , benzocaine , ondansetron , cetrizine , dimenhydrinate , diphenhydramine , vitamin b12 , famotidine , ranitidine , omerpazole , rabeprazole , esomeprazole , sildenafil , tadalafil , atorvastatin , simvastatin , valsartan , lorsartan , donepezil , galantamine , rivastigmine , carbidopa , levodopa , sertaline , pramipexole and ropinirole . it should be understood that any active pharmaceutical ingredients that is physically and chemically compatible with the ec of the present invention and other dosage form ingredients can be used in the present invention . in the below mentioned examples , a cross linked cmc level of 5 % by weight of the total formulation was found to be highly effective , yielding fast disintegration and low friability . it is however expected that depending on a formulation requirements e . g ., drug solubility , load and desired disintegration time , the disintegrant level may vary between 2 and 15 % by weight of the formulation . however , a distinguishing advantage of the current invention is that even though a formulation contains 25 % of a hydrophobic drug , dimenhydrinate , the tablet none the less disintegrates in about 15 seconds while only requiring 5 % by weight disintegrant — low levels of disintegrant in combination with a non - hygroscopic ec therefore decrease the hygroscopicity of the overall formulation . similarly , a t10 ec level of 5 - 10 % by weight was found to be highly effective in reducing tablet friability and maintaining low disintegration time . however it is understood that depending on formulation characteristics , especially compactibility characteristics and mechanical properties and dose of drug , the level of ec binder may vary from 1 to 20 % by weight of the total formulation . the following examples will serve to illustrate the invention , parts and percentages being by weight unless otherwise indicated . in accordance with astm d4794 , ethoxyl content was determined by a zeisel ( sealed ) tube method by reacting ec with hydriodic acid , liberating one mole of ethyl iodide for each mole of ethoxyl substitution on the cellulose chain . the ethyl iodide was then extracted with o - xylene and quantitated by gas chromatography using toluene as an internal standard . a typical set of apparatus , reagents and procedures for this test are listed below : 1 . gas chromatograph , perkin - elmer 900 , or equivalent equipped with thermal conductivity detector , chart recorder , and integrator . 2 . column 6 ′. times . ⅛ ″ stainless steel packed with 10 % sp - 2100 on 100 / 120 supelcoport , supelco , inc ., bellefonte , pa . upon receipt , columns were conditioned overnight at 200 ° c . 3 . reacti - vials , 5 ml , equipped with mininert valves . ( pierce chemical co ., # 13223 and # 10135 ). 4 . silli - therm heating module , 110 v , 19791 , pierce chemical co ., rockford , ill . 6 cover , stainless steel , fabricated to cover six ( 6 ) reacti - bar 21 units on the silli - therm heating module 7 dispenser 0 - 5 ml , labindustries repipet , or equivalent . syringe , 100 . mu . l , hamilton 710 n or equivalent . 9 micro - set pipet adjusted to deliver 2 . 0 ml ( lancer product # 8885 - 890007 ). 1 dried about 0 . 5 grams of sample in 105 ° c . oven for 1 hour . 3 into a tared 5 ml reacti - vial , weighed 0 . 05 - 0 . 08 gram of cooled sample . recorded weight to the nearest 0 . 0001 gram , samples were run in duplicate or triplicate . 4 added 2 ml of hydriodic acid using a transfer pipet . capped sample . 5 added 2 ml of internal standard solution using the repipet dispenser or equivalent . 6 immediately recapped vials with mininert valve tops and shook vials . monitored block temperature at 180 +/− 5 ° c . with a thermometer . 7 placed vials into block and replaced metal cover . kept samples behind safety shield while heating . 10 shook each sample vigorously and allowed to stand for about 20 minutes . 11 chromatographed 1 . 0 mu . l of the upper solvent layer of each sample on the gas chromatograph . viscosity was determined by preparing a 5 % solution of ec in a toluene : ethanol ( 80 : 20 ) solvent mixture . viscosity of the solution was measured using a hercules horizontal capillary viscometer ( following astm d914 - 00 , 33 . 1 ). the list of apparatus , reagents and procedures are described below . 6 . viscometer , hercules horizontal capillary viscometer — calibrated to give viscosity readings in centipoise . 1 . determined the temperature of the 80 : 20 solvent to be used . the temperature of the solvent must be between 20 and 30 ° c . if 111 . 8 ml . burette is to be used in this determination . 3 . measured 111 . 8 ml . of 80 : 20 solvent from burette ( the equivalent of 95 . 0 grams of solvent ) into an 8 - oz . bottle . added the sample to the solvent , making an effort to disperse the sample and avoid lumping . covered the neck of the bottle with a sheet of cellophane and applied the screw cap . 4 . placed the sample on a shaker and allowed it to shake until dissolution is complete . 5 . placed the bottle into a 25 ° c . bath for 30 minutes and the solution was free of air bubbles . 6 . with the viscometer in the raised position ( reservoir vertical ), filled the reservoir to the etched mark . made sure that no air remained trapped in the sample . placed a finger over the end of the capillary . released brace and carefully lowered the viscometer to horizontal . ( it was essential that the liquid was allowed to come to an equilibrium level before placing the finger over the end of the capillary and lowering it to the horizontal .) 7 . released the finger and measured the time for the liquid to flow from the first to the second mark in the capillary tube . reported as time t . 8 . calculated the viscosity as follows : n = td / d where : n = viscosity , cps . t = time of flow for the sample d = density of sample solution at 25 ° c . ( 0 . 86 ) d = density of the oil used for calibration of the viscometer . friability is measured by placing an accurately weighed sample of 20 tablets in the drum of a standard roche - type friabilator and rotating the drum for 250 rotations . % friability is then calculated as the % weight loss of the de - dusted tablets after rotation relative to the same sample of tablets prior to rotation in the friabilator . disintegration time is measured by placing 6 tablets into a standard usp disintegration apparatus without disc inserts . the tablets are then dipped and reciprocated in a ph 6 . 8 phosphate buffer solution ( as defined in the usp ) and carefully observed and timed . disintegration time is recorded as the time where no discernible tablet core remains and all the pieces of the disintegrated tablet have fallen through the mesh screen of the disintegration cell . the temperature of the test solution is 37 ° c .+/− 1 ° c . for all examples , the various formulation components , with exception of magnesium stearate and stearic acid , were first dry blended in a patterson - kelly v - type blender for 15 minutes . magnesium stearate and stearic acid were then added to the mixture through a 20 mesh screen , and the entire mass was then blended for another 3 minutes . tablets were then directly compressed at 37 rpm on an instrumented manesty beta press , equipped with ¼ ″ standard concave tooling , except where larger tooling is indicated . a target weight of 100 mg was set , except where a different weight is indicated . tablets were compressed at 5 kn and approximately 8 kn of compressive force for examples using ¼ ″ standard concave tooling . for larger tooling , 15 , 20 and 25 kn compressive force was used . for larger tooling 15 , 20 and 25 kn compressive force was used . tablet crushing strength was determined by diametrically compressing tablets using a key pharmatest ht500s hardness tester . a 500 gram batch of dry blended powder without ec was prepared and then tableted into 100 mg . tablets as a control formulation : table 1 . resultant crushing strength , friability and disintegration times for the control formulation in example 1 . tablets were made at 5 kn and 8 kn compression force using a rotary tablet press . the combination of mannitol and croscarmellose were able to provide relatively fast disintegration of a tablet comprising 25 % of a low soluble drug , dimenhydrinate . however , tablet friability was unacceptably high at 9 % weight loss . a 500 gram batch of dry blended powder was prepared as above , however a low viscosity water soluble binder klucel ® exf pharm hydroxypropyl cellulose , available from aqualon division , a business unit of hercules incorporated was added and tableted into 100 mg . tablets : table 2 . resultant crushing strength , friability and disintegration times for the control formulation in example 2 . tablets were made at 5 kn and 8 kn compression force using a rotary tablet press . a 500 gram batch of dry blended powder was prepared as above in comparative example 2 , however in place hydroxypropyl cellulose , water insoluble t10 pharm ec , available from aqualon division , a business unit of hercules incorporated , was substituted in the composition and tableted into 100 mg . tablets : table 3 . resultant crushing strength , friability and disintegration times for the control formulation in example 1 . tablets were made at 5 kn and 8 kn compression force using a rotary tablet press . substitution of hydroxypropyl cellulose with t10 pharm ec was effective in maintaining the low friability and improved tablet strength relative to control , and was also effective in maintaining a rapid disintegration time of less than 30 seconds . a 500 gram batch of dry blended powder was prepared as above in example 1 , however in place of 15 % water insoluble t10 pharm ec only 10 % of t10 pharm ec was included and tableted into 100 mg . tablets : table 4 . resultant crushing strength , friability and disintegration times for the control formulation in example 2 . tablets were made at 5 and 8 kn compression force using a rotary tablet press . reducing the ec component from 15 % to 10 % did not compromise low tablet friability while providing rapid disintegration times similar to those of the control . a 500 gram batch of dry blended powder was prepared as above in example 2 , however in place of 10 % water insoluble t10 pharm ec only 5 % of t10 pharm ec was included and tableted into 100 mg . tablets : table 5 . resultant crushing strength , friability and disintegration times for the control formulation in example 3 . tablets were made at 5 kn and 8 kn compression force using a rotary tablet press . reducing the ec component from 10 % to 5 % again allowed significant improvements in tablet friability relative to the control in comparative example 1 , while maintaining rapid disintegration times below 30 seconds . a 500 gram batch of dry blended powder was prepared as above in example 2 , however in place of dimenhydrinate , 25 % directly compressible ( pre - granulated ) acetaminophen granulation was included . the tablet weight was increased from 100 mg used in comparative examples 1 - 2 and examples 1 - 3 to 120 mg . : table 6 . resultant crushing strength , friability and disintegration times for the control formulation in example 2 . tablets were made at 5 kn , 8 kn and 15 kn compression force using a rotary tablet press . acetaminophen is commonly known as a poorly compressible drug . the data show that the formulation system is able to accommodate a series of different physico - chemical drug characteristics while maintaining low friability and rapid disintegration . a 500 gram batch of dry blended powder was prepared as above in example 4 , however in addition to granular mannitol , 10 % liquid sorbitol was added after initial dry blending of drug , ethylcellulose , mannitol , croscarmellose . the liquid sorbitol ( 70 % sorbitol in 30 % water ) was added gradually while mixing to form a homogenous , “ dry to the touch ”, free flowing powder . the amount of ethylcellulose and croscarmelose were also increased . after lubricant addition the 120 mg tablets were then compressed as in example 4 . a 500 gram batch of dry blended powder was prepared as above in example 5 , however in place of liquid sorbitol , 10 % spray dried sorbitol was used . the tablets were compressed using ⅝ ″ round troche tooling with circular elevation in the center of the punch face , such that the center of the tablet was thinner than the perimeter of the tablet . tablet target weight was 900 mg and tablets were compressed at 15 , 20 and 25 kn . examples 5 and 6 show the versatility of the system with regard to different tablet sizes and geometries , as well as inclusion of a diverse range of and physical forms of sugar alcohols and ingredients . it is not intended that the examples presented here should be construed to limit the invention , but rather they are submitted to illustrate some of the specific embodiments of the invention .
a rapidly disintegrating , orally administered tablet or compressed dosage form , comprising ethylcellulose as a directly compressible binder which enhances tablet robustness as manifested by improved strength , lower friability , lower hygroscopicity and yet , hydrophobic nature notwithstanding , does not retard disintegration , but shortens disintegration time or is disintegration time neutral when co - formulated with disintegrants and other water - soluble excipients such as sugar alcohols .