Field of the Invention The invention relates to compressible compositions and dosage forms based thereo, such as tablets and lozenges, which, when ingested, quickly dissolve in the mouth, but which effectively mask the taste of unpleasant active agent (s) therein. Also, the invention relates ; o readily processable compositions having enhanced friability and hardness properties which permit shaping, e. g. , tableting, without the need for complex packaging equipment.

Background The post-genomics phase in the life sciences arena has brought an increased yield of, lew small molecules that are pursued to target particular diseases based on the new understanding of the molecular basis of disease. The tremendous progress achieved in molecular structural biology has allowed the identification and de novo design of efficient molecules or so called "smart drugs. "The new technologies based on the unraveling of the human genome, the intensive progress in elucidating the structures of the enzymes encoded therein combined with the efficiencies of combinatorial chemistry will continue to generate small molecules that neeq to be administered to patients in efficient and organoliptically acceptable forms. One aspect associated with ameliorating the effects of ingesting molecules that are generally unpalatable ie, to provide the drug in dosage forms, such as tablets and lozenges, which, when ingested, quick y dissolve in the mouth.

Tablets may be defined as solid dosage pharmaceutical forms containing drug substances with c r without suitable fillers. They are produced by compression or compaction of a formulation containing the drug and certain excipients selected to aid in the processing and to improve the properties of the product. Tablets may be coated or uncoated and are made from powdered, crystalline materials. They may include various diluents, binders, disintegrants, lubricants, glidants and in many cases, colorants. Excipients used are classified according to the function they perform. For example, a glidant may be used to improve the flow of powder blend in the hopper and into the tablet die.

There has been widespread use of tablets since the latter part of the 19. sup. th century and the majority of pharmaceutical dosage forms are marketed as tablets. Major reasons of tablet popularity as a dosage form among pharmaceutical manufacturers are simplicity, low cost, and the speed of production. Other reasons include stability of drug product, convenience in packaging, shipping, and dispensing. To the patient or consumer, tablets offer convenience of administration, ease of accurate dosage, compactness, portability, blandness of taste, ease of administration, and elegant distinctive appearance.

Tablets may be plain, film or sugar coated, bisected, embossed, layered, or sustained release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed, or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantation beneath the skin.

In addition to the active or therapeutic ingredients, tablets may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition includes a filler, binder, lubricant, and glidant. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets. Without excipients most drugs and pharmaceutical ingredients cannot be directly compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps such as wet granulation, slugging, spray drying spheronization, or crystallization.

Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight.

In addition, tablets often contain diluents which are added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary where the lose of the drug is relatively small.

Another commonly used class of excipients in tablets is binders. Binders are agen s, which impart cohesive qualities to the powdered material. Commonly used binders includ starch, and sugars such as sucrose, glucose, dextrose, and lactose.

Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.

Other desirable characteristics of excipients include the following: . High compressibility to allow strong tablets to be made at low compression for es.

Good flow properties that can improve the flow of other excipients in the formu ; a.

Cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).

The three processes for making compressed tablets are wet granulation, direct compression, and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, disintegrating abili y, and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and t le properties of the final tablets. Preformulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients.

The properties of the drug, its dosage forms, and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet.

The dry granulation method may be used where one of the constituents, either the drug (r the diluent, has sufficient cohesive properties to be tableted. The method consists of blending, slugging the ingredients, dry screening, lubrication, and compression.

The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried ? y tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill.

The overall process includes : weighing, dry powder blending, wet granulating, drying, mi ling, blending lubrication and compression.

In general, powders do not have sufficient adhesive or cohesive properties to form'lard, strong granules. A binder is usually required to bond the powder particles together due to ti te poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be <BR> <BR> <BR> manufactured using wet granulation. The large number of processing steps and processing lime<BR> are problems due to high level manufacturing costs. Wet granulation has also been known<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> reduce the compressibility of some pharmaceutical excipients such as microcrystalline cellulose.<BR> <P> Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of he drug. The active ingredient (s), direct compression excipients and other auxiliary substances such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing was believed to be essential in order to prepare"pharmaceutically acceptable"dosage forms. For example, Remington's Pharmaceutical Sciences (RPS), pp 1203 to 1932 17. sup. th edition (1985), cautions pharmaceutical scientists,'hat the manner in which a lubricant is added to a formulation must be carefully controlled.

Accordingly, lubricants are usually added to a granulation by gentle mixing. RPS want s that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Furthermore, Ansel et al (1995) Pharmaceutical Dosage Forms and Drug Delivery Systems, 6. sup. th Ed. p. 199, indicates that excessive blendil lg of lubricants with the granulate ingredients cause water proofing of the granule and reduces tablet hardness or strength of the compressed tablet. For these reasons, high shear mixing conditions have not been used to prepare direct compression dosage forms.

The advantages of direct compression include uniformity of blend, few manufacturing steps involved, (i. e. the overall process involves weighing of powders, blending and compression, hence less cost), elimination of heat and moisture, prime particle dissociation, and physical stability.

In addition to the assignee of the subject application, Biovail Laboratories, current manufacturers of rapidly disintegrating or dissolving solid dose oral formulations include Cima Labs, Prographarm/Ethypharm, R. P. Scherer, and Yamanouchi-Shaklee. All of these manufacturers market different types of rapidly dissolving solid oral dosage forms.

Cima Labs markets OraSolv, which is an effervescent direct compression tablet purportedly having an oral dissolution time of five to thirty seconds, and DuraSolv, which is a direct compression tablet having a taste-masked active agent and a purported oral dissolution time of 15 to 45 seconds. Cima's U. S. Pat. No. 5,607, 697, for"Taste Masking Microparticles for Oral Dosage Forms, "describes a solid dosage form consisting of coated microparticles that disintegrate in the mouth. The microparticle core has a pharmaceutical agent and one or more sweet-tasting compounds having a negative heat of solution selected from mannitol, sorbitol, a mixture of an artificial sweetener and menthol, a mixture of sugar and menthol, and methyl salicylate. The microparticle core is coated, at least partially, with a material that retards dissolution in the mouth and masks the taste of the pharmaceutical agent. The microparticles are then compressed to form a tablet. Other excipients can also be added to the tablet formulation.

WO 98/46215 for"Rapidly Dissolving Robust Dosage Form,"assigned to Cima Labs, is directed to a hard, compressed, fast melt formulation having an active ingredient and a matrix of at least a non-direct compression filler and lubricant. A non-direct compression filler is typically not free-flowing, in contrast to a direct compression (DC grade) filler, and usually requires additionally processing to form free-flowing granules.

Cima also has U. S. patents and international patent applications directed to effervescent dosage forms (U. S. Pat. Nos. 5,503, 846,5, 223,264, and 5,178, 878) and tableting aids for rapidly dissolving dosage forms (U. S. Pat. Nos. 5,401, 513 and 5,219, 574), and rapidly dissolving dosage forms for water soluble drugs (WO 98/14179 for"Taste-Masked Microcapsule Composition and Methods of Manufacture").

Prographarm/Ethypharm markets Flashtab-Tm, which is a fast melt tablet having a disintegrating agent such as carboxymethyl cellulose, a swelling agent such as a modified starch, and a taste-masked active agent. The tablets have a purported oral disintegration time of under one minute (U. S. Pat. No. 5,464, 632).

R. P. Scherer markets ZydisTM, which is a freeze-dried tablet having an oral dissolution time of 2 to 5 seconds. Lyophilized tablets are costly to manufacture and difficult to package because of the tablets sensitivity to moisture and temperature. U. S. Pat. No. 4,642, 903 (R. P.

Scherer Corp. ) refers to a fast melt dosage formulation prepared by dispersing a gas throi ghout a solution or suspension to be freeze-dried. U. S. Pat. No. 5,188, 825 (R. P. Scherer Corp.) re fers to freeze-dried dosage forms prepared by bonding or complexing a water-soluble active age ? t to or with an ion exchange resin to form a substantially water insoluble complex, which is then'mixed with an appropriate carrier and freeze dried. U. S. Pat. No. 5,631, 023 (R. P. Scherer Corp.) refers to freeze-dried drug dosage forms made by adding xanthan gum to a suspension of gelatin ; and active agent. U. S. Pat. No. 5,827, 541 (R. P. Scherer Corp. ) discloses a process for preparing solid pharmaceutical dosage forms of hydrophobic substances. The process involves freeze- drying a dispersion containing a hydrophobic active ingredient and a surfactant, in a non-aq IFleous phase; and a carrier material, in an aqueous phase.

Yamanouchi-Shaklee markets Wowtab, which is a tablet having a combination of a low moldability and a high moldability saccharide. U. S. Patents covering this technology include U. S. Pat. No. 5,576, 014 for"Intrabuccally Dissolving Compressed Moldings and Production Process Thereof, "and U. S. Pat. No. 5,446, 464 for"Intrabuccally Disintegrating Preparation tnd Production Thereof." Other companies owning rapidly dissolving technology include Janssen Pharmaceutic.

U. S. patents assigned to Janssen describe rapidly dissolving tablets having two polypeptide (cr gelatin) components and a bulking agent, wherein the two components have a net charge of tb e same sign, and the first component is more soluble in aqueous solution than the second component. See U. S. Pat. No. 5,807, 576 for"Rapidly Dissolving Tablet ;" U. S. Pat. No.

5,635, 210 for"Method of Making a Rapidly Dissolving Tablet ;" U. S. Pat. No. 5,595, 761 for "Particulate Support Matrix for Making a Rapidly Dissolving Tablet ;" U. S. Pat. No. 5,587, 180 for"Process for Making a Particulate Support Matrix for Making a Rapidly Dissolving Tablet ;' and U. S. Pat. No. 5,776, 491 for"Rapidly Dissolving Dosage Form." Eurand America, Inc. has U. S. patents directed to a rapidly dissolving effervescent composition having a mixture of sodium bicarbonate, citric acid, and ethylcellulose (U. S. Pat.

Nos. 5,639, 475 and 5,709, 886).

L. A. B. Pharmaceutical Research owns U. S. patents directed to effervescent-based rapidly dissolving formulations having an effervescent couple of an effervescent acid and an effervescent base (U. S. Pat. Nos. 5,807, 578 and 5,807, 577).

Schering Corporation has technology relating to buccal tablets having an active agent, an excipient (which can be a surfactant) or at least one of sucrose, lactose, or sorbitol, and either magnesium stearate or sodium dodecyl sulfate (U. S. Pat. Nos. 5,112, 616 and 5,073, 374).

Laboratoire L. LaFon owns technology directed to conventional dosage forms made by lyophilization of an oil-in-water emulsion in which at least one of the two phases contains a surfactant (U. S. Pat. No. 4, 616, 047). For this type of formulation, the active ingredient is maintained in a frozen suspension state and is tableted without micronization or compression, as such processes could damage the active agent.

Takeda Chemicals Inc. , Ltd. owns technology directed to a method of making a fast dissolving tablet in which an active agent and a moistened, soluble carbohydrate are compression molded into a tablet, followed by drying of the tablets.

Biovail Corporation (the parent of the assignee of the subject application) markets Flash Dose, which is a direct compression tablet containing a processed excipient called Shearfortn. Shearform is a floss type substance of mixed polysaccharides converted to amorphous fibers. U. S. patents describing this technology include U. S. Pat. No. 5,871, 781 for "Apparatus for Making Rapidly Dissolving Dosage Units ;" U. S. Pat. No. 5,869, 098 for"Fast- Dissolving Comestible Units Formed Under High-Speed/High-Pressure Conditions ;" U. S. Pat.

Nos. 5,866, 163,5, 851, 553, and 5,622, 719, all for"Process and Apparatus for Making Rapidly Dissolving Dosage Units and Product Therefrom ;" U. S. Pat. No. 5,567, 439 for"Delivery of Controlled-Release Systems ;" and U. S. Pat. No. 5,587, 172 for"Process for Forming Quickly Dispersing Comestible Unit and Product Therefrom." One way to provide self-binding flowable formulations is to formulate using Shearform matrices or flosses. These matrices result when using certain processing techniques, such as the following: U. S. Pat. No. 5,587, 172, incorporated herein by reference, discusses the use of flash heat techniques to produce sucrose-containing shearform flosses, which are then processed to yield quick-dissolving tablets.

The use of shearform matrices for forming comestible units is described in W095/34290 (published Dec. 21,1995) from co-assigned PCT application No. PCT/US95/07144, filed Jun. 6, 1995. This case discloses a quick dissolving tablet which is formed by: (1) using flash-flow technology to provide a shearform matrix ; (2) combining the partially recrystallized shcarform matrix with an additive to form flowable, compactible particulate blends ; and (3) compacting the blends at relatively low pressures to produce dosage forms, such as tablets.

Additionally, PCT publication WO 95/34293 (published Dec. 21,1995) from co-assigned PCT Application No. PCT/US95/07194, filed Jun. 6,1995, discloses a process and apparatus for making rapidly dissolving dosage forms by flash-flow processing. In this PCT application, a shearform matrix is formed by the flash-flow process, the shearform matrix is combined with an additive, and the matrix is molded to make a unit dosage form.

Co-owned U. S. patent applications Ser. No. 08/915,068, filed Aug. 20,1997, now U. S.

Pat. No. 5,840, 331 ; and Ser. No. 09/132,986, filed Aug. 12,1998, now U. S. Pat. No. 6,048, 541, describe tablet formulations derived from saccharide-based carriers in which the use of a unique combination of feedstock ingredients yields self-binding, flowable matrices and tablet compositions. This combination--which uses a blend of sugar alcohols, i. e. , sorbitol and xylitol-- is superior to glycerine in providing cohesive properties and flowability.

Shapeable, preferably tabletable, compositions derived from partially hygroscopic matrices containing these sugar alcohols are useful--in the presence of tableting aids and crystallization promoters--in both high--and low-pressure tableting processes. Tablets and other dosage forms, e. g. , lozenges, made therefrom rapidly dissolve when placed in the mouth, generally in less than 30 seconds.

The production of microspheres containing active agent (s) is described in co-owned U. S.

Pat. No. 5,683, 720, incorporated herein by reference. The patent deals with the use of Liquiflash processing to spheronize compositions containing one or more active agents.

Co-owned US Patent No. 6,165, 512 provides compositions and shaped oral dosage forms made therefrom having improved properties. Among those properties are improved processability before shaping and enhanced dissolution and taste-masking properties when the dosage forms are used. The compositions of the'512 patent are based on matrices, or flosses, which comprise at least one sugar alcohol, which matrices are generally considered"single floss" or"unifloss"systems. These systems are exemplified by xylitol-containing shearform matrixes, or flosses, containing a carrier and two or more sugar alcohols.

Various ingredients, such as coated microspheres containing active agent (s), are added, in suitable amounts, to the compositions of the present invention after the matrices are collected and chopped, but before they are shaped, e. g. , by tabletting.

Highly useful dosage forms result when microspheres made from compositions containing active agents, solubilizers and spheronization aids are coated with taste-mask] ig agents, then combined with flosses and conventional pharmaceutical ingredients. The res dotant tablets enjoy the processing ease associated with the use of glycerine-free flosses and the : aste and release properties associated with coated microspheres.

The above mentioned existing quick dissolve technologies present numerous limit. Miens.

The above mentioned Prographarm (Ethypharm) dosage forms require relatively high leve ls of super disintegrant which complicates their use and limits their friability and hardness there by requiring specialized packaging. Similarly, the Cima dosage forms require effervescent excipients which also reduces their friability and hardness qualities. The RP Scherer, Yamanouchi and Takada technoligies employ complicated processing techniques (i. e. lyophilization, solvents with heat treatment or drying). Those techniques increase the cost associated with the formation of the dosage forms on a large scale.

While Shearform matrices are an advance in the art, they also involve an increases cost associated with the processing of the floss matrix which limits their use at a large scale. As'vell, these amorphous matrices require specialized robotic tableting equipment and generally do rot provide friability and hardness properties required for bulk packaging such as in bottles.

As indicated above, disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. Thus, there still exists a need for non-sticking tabletable compositio is which, can be used to make fast-dissolving, pleasant tasting dosage forms at a low cost and without the need for excessive amounts of super disintegrant or complicated processing equipment.

Summary of the Invention The present invention is based on the unexpected discovery that quick dissolve Flashdose tablets can be provided without the need for floss matrices. The inventors have unexpectedly discovered that under certain processing conditions, direct compression of LiquiflashTM microspheres, in particular microspheres prepared according to co-owned US Patent Application Serial No. 09/179,926 provides quick dissolve dosage without the need for a floss matrix or super disintegrant as defined below or with quantities of super disintegrant that are well below the levels employed with the dosage forms discussed in the background section.

In addition to the fast dissolve properties provided by the compositions of the invention, other advantages of the invention include the use of appropriate excipient mass (e. g. , directly compressible inorganic salt ; cellulose derivatives, etc. ), which in turn facilitates the processing of the composition and eliminates the need for complex processing equipment. The components of the composition of the invention and the processing methods associated therewith allow for substantially lowering the cost associated with the production of the quick dissolve dosage forms of the invention which in turn facilitates their use at a large scale. Also, the simplicity of the excipients and the techniques employed in forming the dosage forms of the invention reduces the number of steps in manufacturing the dosage forms, thereby drastically reducing the opportunities for contamination and other quality impacting deleterious effects. The dosage forms of the invention are also advantageous in that higher loads of active agent can be obtained.

As well, the compositions and dosage forms of the invention are greatly advantageous in that packaging is simplified. In fact, the present invention provides a unique combination of materials and processing techniques that allows the packaging of quick dissolve dosage forms in recipients as commonly used and easy to access as prescription or over the counter bottles and blister packaging. The simpler packaging advantages of the composition of the invention are due at least in part to the improved friability and hardness obtained with the quick dissolve dosage forms of the invention.

In one embodiment, the invention provides a composition useful for making oral dosage forms capable of dissolving in the mouth in less than 40 seconds without the need for a conventional super disintegrant and having a friability of less than 1% ; wherein the composition comprises drug-containing liquiflash particles and an excipient mass. Preferred excipient mass comprises a directly compressible inorganic salt, a cellulose derivative or a mixture of a directly compressible salt and a cellulose derivative. Preferably, the liquiflash particles and the mass of excipient are combined in proportions such that the active ingredient remains substantially within the microspheres when the composition is compressed to obtain a dosage form having a hardness of about 20 N to 50 N. The improved hardness and friability are obtained due to the discovery that the combination of the microspheres and the excipient mass allows for higher compression force.

The liquiflash particles are preferably coated with at least one taste-masking coa ing. The coating preferably contains at least one cellulosic polymer. To improve the dissolution properties of the dosage form of the invention the composition may further comprises microcrystalline cellulose which facilitates disintegration in the mouth without having stl rer disintegrant properties. A preferred linear polyol comprises manitol, alone or in combine tion with sorbitol.

A preferred embodiment of the invention provides a composition useful for makin a oral dosage forms capable of dissolving in the mouth in less than 30 seconds and having a friability of less than 1%; wherein the composition comprises liquiflash particles containing at least one bioaffecting agent and a combination of at least one solubilizer and at least one spheroniza ; ion aid, said liquiflash particles being coated after spheronization; a mass comprising an excipe sont mass and less than 2.5% by weight of a super disintegrant.

As indicated below, the compositions of the invention can be successfully employee to prepare oral dosage forms of a variety of active agents. Particularly preferred active agents include fluoxetine ; paroxetine and zolpidem.

Detailed Description of the Invention The invention is concerned with bio-affecting microparticles produced from compositions containing a unique combination of ingredients. The composition, the microparticles, their production and comestible units containing them are disclosed.

Unless stated otherwise, all percentages recited herein are weight percentages, based ; en total composition weight.

I. Disintegrants and super disintegrants: A disintegrant is an excipient which is added to a tablet or capsule blend to aid in the break up of the compacted mass when it is put into a fluid environment. This is especially important for immediate release products where rapid release of drug substance is required. A disintegrant can be added to a powder blend for direct compression or encapsulation. It can also be used with products that are wet granulated. In wet granulation formulations, the disintegrant s normally effective when incorporated into the granule (intragranularly). However, it may be more effective if added 50% intragranularly, and 50% extra-granularly (e., in the final dry mixture). While there are some tablet fillers (e. g. , starch and microcrystalline cellulose) which aid in disintegration, there are more effective agents referred to as superdisintegrants. Sc ne superdisintegrants and their properties are listed below. Crosscarmelose sodium High swelling capacity, effective at low concentrations (0. 5 2. 0% i but can be used up to 5.0%). Crospovidone Completely insoluble in water. Rapidly disperses and swells ir water, but does not gel even after prolonged exposure. Greates rate of swelling compared to other disintegrants. Greater surface arf la to volume ratio than other disintegrants. Recommended concentration : ! 1 to 3% Available in micronized grades if needed to improve uniform dispersion in the powder blend. Sodium Starch Glycolate Absorbs water rapidly, resulting in swelling which leads to rapid ! disintegration of tablets and granules. Recommended concentratii) n : 1. 0-4. 0% but may need to use up to 6.0%. Gels on prolonged exposure to water. High concentrations may cause gelling and los ; of disintegration.

A super disintegrant according to the invention is a disintegrant that has a Eq. Moisture content at 25C/90% RH of over 50%. A list of exemplary disintegrants, super disintegrants and other formulations with some disintegrant qualities are provided below: Superdisintegrants and Disintegrants Brand Common Classificatio Function Properties Eq. Typical uses name name n al Moisture Category content at 25C/90% R H CL-Crospovido Polyvinylpo Tablet Hygroscopi Disintegrant in Kollidon ne lypyrrolidon super c 62% dry e disintegra Swelling-and wet nt 18% in 10s, granulation 45% in 20s Ac-Croscarmell Cellulose, Tablet Hygroscopi 88% Disintegrant for Disol ose sodium carboxymet and c capsules, tablets Primello hyl ether, capsule Wicking and granules se sodium salt, super and crosslinked disintegra swelling- nt 12% in 10s, 23% in 20s Explota Sodium Sodium Tablet Swelling Disintegrant in b starch carboxymet and capacity: in dry and wet Primojel glycolate hyl starch capsule water swells granulation super up to 300 disintegra times its nt volume Explota Sodium (Cross Super Swells to Disintegration b V 17 starch linked low disintegra greater and dissolution glycolate substituted nt extent than aid. Not for use carboxymet explotab in wet hyl granulation ether) Sodiu m carboxymet hyl starch Explota Sodium (Cross Super Designed for b CLV starch linked low disintegra wet granulation glycolate substituted nt that utilize high carboxymet shear equipment hyl ether) Sodiu m carboxymet hyl starch, highly cross linked L-HPC Hydroxypro Cellulose, Tablet Hygroscopi 37% Tablet pyl 2-and c disinteg ant, cellulose, hydroxypro capsule Swelling-binder ii, wet low-pyl ether disintegra 13% in 10s, granulat on substituted (low nt, tablet 50% in 20s substituted) binder Amberli Polacrilin Cation Tablet Swelling Tablet te IRP Potassium exchange disintegra ability disintegrant 88 resin nt Starch Starch, Pregelatiniz Tablet Hygroscopi 22% Capsule a nd 1500 pregelatiniz ed starch and c tablet binder, ed capsule diluent, diluent, disintegra, it disintegra nt, tablet binder Avicel Microcrysta Cellulose Tablet Hygroscopi 18% Binder/dili ent, lline and c Swelling-has also so ne cellulose capsule 12% in 10s, lubricant aid diluent, 18% in 20s disintegrani tablet properties disintegra nt II. Compositions The compositions of the invention employ optional excipients with (a) a bioaffectin ; agent and (b) one or more processing aids.

A. Bio-affecting Agents The active ingredients useful herein can be selected from a large group of therapeutic agents. Respective classes include those in the following therapeutic categories : ace-inhibitor ; alkaloids; antacids; analgesics; anabolic agents; anti-anginal drugs; anti-allergy agents; anti- arrhythmia agents; antiasthmatics; antibiotics; anticholesterolemics ; anticonvulsants; anticoagulants; antidepressants; antidiarrheal preparations; anti-emetics; antihistamines; antihypertensives ; anti-infectives; anti-inflammatories ; antilipid agents; antimanics; anti-migraine agents; antinauseants; antipsychotics; antistroke agents; antithyroid preparations; anabolic drugs; antiobesity agents; antiparasitics; antipsychotics ; antipyretics; antispasmodics; antithrombotics; antitumor agents; antitussives; antiulcer agents; anti-uricemic agents; anxiolyti : agents ; appetite stimulants; appetite suppressants; beta-blocking agents; bronchodilators ; cardiovascular agents; cerebral dilators; chelating agents; cholecystekinin antagonists; chemotherapeutic agents; cognition activators; contraceptives; coronary dilators; cough suppressants; decongestants; deodorants; dermatological agents; diabetes agents; diuretics; emollients; enzymes; erythropoietic drugs; expectorants; fertility agents; fungicides; gastrointestinal agents; growth regulators; hormone replacement agents; hyperglycemic agents; hypoglycemic agents; ion-exchange resins; laxatives; migraine treatments; mineral supplements; mucolytics, narcotics; neuroleptics; neuromuscular drugs; non-steroidal anti-inflammatories (NSAIDs); nutritional additives; peripheral vasodilators; polypeptides; prostaglandins; psychotropics; renin inhibitors; respiratory stimulants; sedatives; steroids; stimulants; sympatholytics; thyroid preparations; tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors; vasodilators; vertigo agents; vitamins; wound healing agents; and others.

Active agents which may be used in the invention include: acetaminophen ; acetic acid; acetylsalicylic acid, including its buffered forms ; acrivastine; albuterol and its sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum acetate, carbonate, chlorohydrate and hydroxide; alprozolam ; amino acids; aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame; astemizole; atenolol; azatidine and its maleate; bacitracin; balsam peru; BCNU (carmustine); beclomethasone diproprionate ; benzocaine; benzoic acid; benzophenones ; benzoyl peroxide; benzquinamide and its hydrochloride; bethanechol; biotin; bisacodyl; bismuth subsalicylate ; bornyl acetate; bromopheniramine and its maleate; buspirone; caffeine; calamine ; calcium carbonate, casinate and hydroxide; camphor; captopril; cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin; centrizine and its hydrochloride; cetyl alcohol; cetylpyridinium chloride; chelated minerals; chloramphenicol; chlorcyclizine hydrochloride; chlorhexidine gluconate; chloroxylenol; chloropentostatin; chlorpheniramine and its maleates and tannates; chlorpromazine; cholestyramine resin; choline tartrate ; chondrogenic stimulating protein; cimetidine and its hydrochloride; cinnamedrine hydrochloride; citalopram; citric acid; clarithromycin; clemastine and its fumarate; clonidine and its hydrochloride salt; clorfibrate; cocoa butter; cod liver oil; codeine and its fumarate and phosphate; cortisone acetate; ciprofloxacin HCI; cyanocobalamin; cyclizine hydrochloride; cyproheptadine and its hyddrochloride; danthron; dexbromopheniramine maleate; dextromethorphan and its hydrohalides ; diazepam; dibucaine; dichloralphenazone; diclofen and its alkali metal sales; diclofenac sodium; digoxin; dihydroergotamine and its hydrogenates/mesylates ; diltiazem; dimethicone ; dioxybenzone; diphenhydramine and its citrate; diphenhydramine and its hydrochloride; divalproex and its alkali metal salts; docusate calcium, potassium, and sodium; doxycycline hydrate; doxylamine succinate; dronabinol; efaroxan; enalapril; enoxacin; ergotamine and its tartrate; erythromycin ; estropipate; ethinyl estradiol; ephedrine; epinephrine bitartrate; erythropoietin; eucalyptol; famotidine ; fenoprofen and its metal salts; ferrous fumarate, gluconate and sulfate; fluoxetine ; folic acid; fosphenytoin; 5-fluorouracil (5-FU) ; fluoxetine and its hydrochloride; flurbiprofen; furosemide; gabapentan; gentamicin; gemfibrozil; glipizide; glycerine; glyceryl stearate; granisetron and its hydrochloride; griseofulvin ; growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide; hydrocodone and its tartrates; hydrocortisone and its acetate; 8-hydroxyquinoline sulfate ; hydroxyzine and its pamoate and hydrochloride salts; ibuprofen ; indomethacin; inositol; insulin; iodine; ipecac; iron; isosorbide and its monoand dinitrates; isoxicam; ketamine; kaolin; ketoprofen; lactic acid; lanolin; lecithin; leuprolide acetate; lidocaine and its hydrochloride salt; lifinopril; liotrix; loratadine; lovastatin; luteinizing hormore ; LHRH (lutenizing hormone replacement hormone); magnesium carbonate, hydroxide, salicylate, and trisilicate ; meclizine and its hyddrochloride ; mefenamic acid; meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate; methenamine mandelate; menthol; meperidine hydrochloride; metaproterenol sulfate; methscopolamine and its nitrates ; methsergide and its maleate; methyl nicotinate; methyl salicylate; methyl cellulose; methsuximide ; metoclopramide and its halides/hydrates; metronidazole and its hydrochloride; metoprotol tartrate; miconazole nitrate; mineral oil; minoxidil; morphine; naproxen and its alkali metal sodium salts; nifedipine; neomycin sulfate; niacin; niacinamide; nicotine; nicotinamide; nimesulide; nitroglycerine; nonoxynol-9; norethindrone and its acetate; nystatin; octoxynol; octoxynol-9; octyl dimethyl PABA; octyl methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole; ondansetron and its hydrochloride; oxolinic acid; oxybenzone; oxtriphylline; para-aminobenzoic acid (PABA); padimate-O ; paramethadione; pentastatin; peppermint oil; pentaerythritol tetranitrate; pentobarbital sodium; perphenazine; phenelzine sulfate; phenindamine and its tartrate; pheniramine maleate; phenobarbital; phenol; phenolphthalein; phenylephrine and its tannates and hydrochlorides; phenylpropanolamine and its hydrochloride salt; phenytoin; pirmenol ; piroxicam and its salts; polymicin B sulfate; potassium chloride and nitrate; prazepam ; procainamide hydrochloride; procaterol; promethazine and its hydrochloride; propoxyphene and its hydrochloride and napsylate; pramiracetin; pramoxine and its hydrochloride salt; prochlorperazine and its maleate; propanolol and its hydrochloride; promethazine and its hydrochloride; propanolol; pseudoephedrine and its sulfates and hydrochorides; pyridoxine ; pyrolamine and its hydrochlorides and tannates; quinapril; q linidine gluconate and sulfate ; quinestrol; ralitoline; ranitadine; resorcinol; riboflavin; salicylic a,-id ; scopolamine; sesame oil; shark liver oil; simethicone; sodium bicarbonate, citrate, and fl ioride ; sodium monofluorophosphate; sucralfate; sulfanethoxazole; sulfasalazine; sulfur; sumatr ptan and its succinate; tacrine and its hydrochloride ; theophylline; terfenadine; thiethylperazir> and its maleate; timolol and its maleate; thioperidone; tramadol; trimetrexate; triazolam ; tretii oin; tetracycline hydrochloride; tolmetin; tolnaftate; triclosan; trimethobenzamide and its hydrochloride ; tripelennamine and its hydrochloride; tripolidine hydrochloride; undecylei. ic acid ; vancomycin; verapamil HCI; vidaribine phosphate; vitamins A, B, C, D, BI, B2, B6, B, 2, and K; witch hazel; xylometazoline hydrochloride; zinc; zinc sulfate ; zinc undecylenate. Mixte res and pharmaceutically acceptable salts of these and other actives can be used.

Particularly useful active agents are sparingly soluble solid agents whose dissolution and release properties are enhanced by the solubilizing agents used herein. These agents include HZ antagonists, analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), anticholesterolemics, anti-allergy agents, and anti-migraine agents.

Analgesics include aspirin, acetaminophen, acetaminophen plus caffeine, and non-steroidal anti-inflammatory drugs (NSAIDS), e. g. , ibuprofen and nimesulide.

Useful NSAIDs include ibuprofen; diclofenac and its alkali metal salts; fenoprofen ai d its metal salts; fluriprofen; ketoprofen; naproxen and its alkali metal salts; nimesulide; and piroxicam and its salts.

H2-antagonists which are contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidin' ;, pisatidine and aceroxatidine.

Useful anti-allergy agents include hydricodone and its tartrates; clemastine and its fumarate ; azatadine and its maleate; acetaminophen; hydroxyzine and its pamoate and hydrochloride salts; chlorpheniramine and its maleates and tannates ; pseudoephedrine and its sulfates and hydrochlorides; broinopheniramine and its maleate; dextromethorphan and its hydrohalides ; loratadine; phenylephrine and its tannates and hydrochlorides; methscopolamine and its nitrates; phenylpropanolamine and its hydrochlorides; codeine and its hydrochloride; codeine and its phosphate; terfenadine; acrivastine ; astemizole ; cetrizine and its hydrochloride; phenindamine and its tartrate; tripelennamine and its hydrochloride; cyproheptadine and its hydrochloride; promethazine and its hydrochloride; and pyrilamine and its hydrochlorides and tannates.

Useful antimigraine agents include divalproex and its alkali metal salts; timolol and its maleate; propanolol and its hydrohalides ; ergotamine and its tartrate; caffeine; sumatriptan and its succinate; dihydroergotamine, its hydrogenates/mesylates ; methsergide and its maleate; isometheptene mucate; and dichloralphenazone.

Another class of drugs which can be used are antiemetics. Useful antiemetics include: meclizine and its hydrochloride; hydroxyzine and its hydrochloride and pamoate; diphenhydramine and its hydrochloride; prochlorperazine and its maleate; benzquinamide and its hydrochloride; granisetron and its hydrochloride; dronabinol; bismuth subsalicylate; promethazine and its hydrochloride; metoclopramide and its halides/hydrates; chlorpromazine ; trimethobenzamide and its hydrochloride; thiethylperazine and its maleate; scopolamine ; perphenazine; and ondansetron and its hydrochloride.

Other active ingredients for use in the present invention include antidiarrheals such as immodium AD, antihistamines, antitussives, decongestants, vitamins, and breath freshers. Also contemplated for use herein are anxiolytics such as Xanax; antipsychotics such as Clozaril and Haldon ; antihistamines such as Seldane, Hismanal, Relafen, and Tavist; antiemetics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil ; antimigranes such as Imigran, ACE-inhibitors such as Vasotec, Capoten and Zestril ; Anti-Alzheimers agents such as Nicergoline; and Call-Antagonists such as Procardia, Adalat, and Calan.

Among the anticholesterolemics, the statins, e. g. , lovastatin, provastatin and the like are notable.

Fluoxetine, paroxetine and zolpidem are preferred active agents.

Combinations of various types of drugs, as well as combinations of individual drugs, are contemplated.

B. Processing Aids The processing aids of the invention include high molecular weight polyethylene glycols (PEG's) and/or polyethylene glycol glyceryl esters. When microspheres are made, these materials can be called"spheronization aids." By"high molecular weight polyethylene glycols (PEG), "applicants mean PEG'. having molecular weights of about 3,000 to about 8,000."PEG 4600, "having an average molec ilar weight of about 4400 to 4800, is a preferred material. Mixtures can be used.

In chemical terms, useful PEGs are those molecules having the structural formul i HOCH2 (CH2OCH2) m CH20H, wherein m is the average number of oxyethylene groups. PEG's used for this invention are those in which m is from about 0 to about 13.

Useful PEGS are solids. They are discussed on pages 355-361 of the Handbook a f Pharmaceutical Excipients, 2nd ed. (1994).

The polyethylene glycol glyceryl esters useful herein are selected from those cont. lining about 30 to about 35 oxyethylene groups. Polyethylene glycol 32 glyceryl ester sold as "GELUCIRE 50/13"by Gattefosse S. A. of France is a preferred ester. Mixtures are operaM te.

The amounts of ingredients used in the compositions are generally within those sh wn in the following table. Broad range Narrow range Preferred range Bio-affecting agent (s) 1-50% 5-40% 20-30% PEG 0-90% 60-90% 60-80% Glyceryl ester 0-60% 1-10% 2.5-7. 5% Excipient (s) 0-98% 10-50% 10-30% III. Processes Useful processes for making the microparticles of the invention include liquiflash conditions as well as other thermoforming processes known in the art, eg., extrusion."Liquifla sh conditions"are generally those under which the material, called a feedstock, is rapidly heated just to the point at which it undergoes intraparticulate flow and partially deforms or liquifies so that it can pass through openings in a suitable spinning device. The passage of the liquiflash particles through openings is in response to centrifugal forces within the spinning head, which forces"expel"the particles, as discrete solids out of the device and into the atmosphere. The expelled materials instantly reform into particles, without the application of external shaping forces, which particles have different morphologies from those of the feedstocks.

Applicants have found that one particular spinning device is highly useful in making the microspheres of the, invention. In U. S. Patent 5,458, 823, a spinning device is described vhich uses a spinning head including a base and a cover. A plurality of closely spaced heating elements are positioned between the base and cover, forming a barrier through which the material to be processed passes. In use, the head rotates and the heating elements are heated to tempera ures that bring about liquiflash conditions in the materials being processed. As the spinning h, ! ad rotates, the centrifugal force created by its rotation expels the material through spaces between the heating elements. The material forms discrete, generally spherical particles as it exits.

The production of microspheres for use in the subject invention maybe optimize. ! by the use of a V-groove insert inside the spinner head. The insert is described in pending U.S. Patent Application Serial No. 08/874,515 field June 13, 1997 The insert has grooves therein, which grooves have a uniform depth and width through their length, so that highly uniform discrete microspheres or other particles are produced. Using this or a similor insert, the spinning device is operated at 50 to 75 Hz, at about 10 to 25% power, and at temperatures which yield liquiflash conditions.

It should be noted that"liquiflash conditions"vary with the properties of the mater al, or feedstock, being processed. Since the feedstocks contain many substances in varying amok nts, the parameters need to yield"liquiflash conditions"for a particular mixture must be ascerta ined by processing small quantities or samples before processing large ones. Typically, the feedstocks contain active agent (s) and processing aids.

Among the co-assigned patents and patent applications which describe the preparati ns of microspheres containing bio-affecting agents re: U. S. 5, 458, 823; U. S. 5, 0q, 720; and U. S.

SN: 08/874, 215, filed June 13,1997.

III. Microparticles While particulates made using various thermoprocessing technologies are useful, microspheres described below are preferred.

The microspheres or other particulates are generally solid spherical bodies of about 1 zu to about 250 microns mean particle diameter.

It is preferred that they be produced via a direct spheronization process, such as liquiflash or other suitable techniques. However, they may be made by physically altering the size and/or shape of non-spherical particles by extrusion/spheronization or melt granulation processes.

When microspheres are made by direct spheronization of compositions containing active agent (s), the fatty esters and optional emulsifiers/surfactants, the fatty esters function as spheronization aids.

The microspheres may be used as is, i. e. , in powder or sachet products for delivering active agents. Alternatively, they may be used in the production of solid, liquid (suspensions), or semi-solid (e. g. , gel-like) comestible units, etc. Tablets and capsules are preferred.

It is preferred that the microspheres of the invention be used in combination with. excipients which have been formed into floss or matrix particles. Useful flosses are generally made from saccharide based carriers. See U. S. patents 5,622, 719 and 5, 587, 172.

Once the floss and microsphere ingredients are combined, they can be shaped into comestible units.

IV. Coatings One or both of the microspheres and the dosage units can be coated or encapsulated with at least one coating. Useful coating formulations contain polymeric ingredients as well as excipients conventionally employed in such coatings. The coatings are generally used for such purposes as taste-masking, controlling release and the like.

Useful taste-masking coatings can include (meth) acrylate/cellulosic polymers.

Ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polymethacrylate polymers, such as Eudragit RS, Eudragit RL or mixtures thereof are useful. Preferred combinations include EC/HPC and Eudragit RS/Eudragit RL.

Controlled release coatings generally contain at least one of : ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and the like. The "Eudragits"designated as NE 300, RS, L 30 D, are useful. Mixtures are operable.

Coating levels of about 0 to about 150% are effective, with levels of about 5% to about 30% being preferred.

Coating devices include those conventionally used in pharmaceutical processing, with fluidized bed coating devices being preferred.

Formulations according to the invention are illustrated by the examples provide l below, which should in no way limit the scope of the appended claims. The friability results si own below correspond to Drop tests conducted with a Roche drum equiped with two seperat tdrums, the motor rotate the drum at 100 revolution/min. the actual drums is made from plexigla ; s and is seperated into parts, the drum body and removable cover, which opens to fill, discharge and clean the drum. For the Abrasion tests one of the two drums is replaced with an abrasior drum.

EXAMPLES The examples and counterexamples provided below illustrate formulations and processing conditions for forming dosage forms according to the invention.

Formulatin No 1 CEFORM or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty) Mannitol*: 29.1-77. 1% Microcrystalline Cellulose** : 12-18% I-HPC, LH-11 : 2-4% Citric Acid: 1. 5% Acesulfame K: 0.2% Magnasweet 100: 0.2% Flavor: 0. 5% Syloid: 0.5% Pruv: 1.0% Formulation NO 2 CEFORMTM or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet bt t gritty) Mannitol*: 29.1-77. 1% Microcrystalline Cellulose**: 12-18%, preferably 15%-18% Kollidon CL: 2-4% Citric Acid: 1.5% Acesulfame K: 0.2% Magnasweet 100: 0.2% Flavor: 0. 5% Syloid: 0.5% Pruv: 1.0% Formulation No 3 (more referred platform) : CEFORMTM or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty) Mannitol*: 27.1-83. 6% Microcrystalline Cellulose**: 5-20%, preferably 15-18% Kollidon CL: 2% 1-HPC, LH-11 : 2% Citric Acid: 1.5% Acesulfame K: 0.2% Magnasweet 100: 0.2% Flavor: 0. 5% Syloid: 0.5% Pruv: 1.0% *Mannitols evaluated and found acceptable: Pearlitol 400DC, 300DC, Parteck M200, Parteck M300, Roquette Lab 3038. No differences were observed in disintegration time.

**Microcrystalline cellulose evaluated and found acceptable: Avicel PH 101, 102,113, Prosolv 50, Prosolv 90. No differences were observed in disintegration time.

Other preferred formulations based on model drug fluoxetine : Formulation Lot# Hardness Disintegration Friability Comments (N) time % FluoxetineTMMS : 28.69 29.7 Mouth: 10s 0.8 Can be used with Pearlitol 400DC : any drug 48.41 Avicel PH 101: 16. 0 USP basket L-HPC 11: 4.0 rack assembly: Citric acid: 1.0 20s AsesulK: 0.2 Tangerine: 0.2 Syloid: 0.5 Pruv: 1.0 Avicel PH101/L- HPC11 ratio (80/20) Lot#/mfg date : 1242- 124 250g batch/l lmm Flat Face Radial Edge/450mg FluoxetineTMMS: 28.69 34.0 Mouth: 10s 0.8 Can be used with Pearlitol 400DC : any drug 48.41 Avicel PH 101 : 18.0 USP basket L-HPC 11: 2.0 rack assembly: Citric acid: 1.0 20s AsesulK: 0.2 Tangerine: 0.2 Syloid : 0.5 Pruv : 1.0 Avicel PH101/L- HPC11 (90/10) ratio Lot#/mfg date : 1242- 125 250g batch/I lmm Flat Face Radial Edge/450mg FluoxetineTMMS : 28.69 29.5 Mouth: 10s, 0.3 Can be used with Pearlitol 400DC : 24.4 15s, 20s, 10s, 0. 3 any drug 51.41 28.4 los 0.2 Avicel PH 101 : 15.0 26.0 0.2 L-HPC 11: 2.0 28.3 0.4 Citric acid : 1.0 USP basket AsesulK: 0.2 rack assembly: Tangerine: 0.2 15s, 20s,-, Syloid: 0.5 19s,- Pruv: 1.0 *can be # Avicel 113, 1242- 140 . Avicel 102,1242- 139 . Prosolv 50, 1242- 138 Prosolv 90, 1242- 137 Lot#/mfg date : 1242- 135,140, 139,138, 137 250g batch/l 1mm Flat Face Radial Edge/450mg FluoxetineTMMS : 28.69 28.4 Mouth: 15s. 0.5 Can be used wi : h Advantose 100 : Good tablets any drug excep the 12.85 No significant drugs that have Pearlitol 400DC : difference amine group. 38.56 between 1242- Avicel PH 101 : 15.0 147 L-HPC 11 : 2.0 Citric acid: 1.0 AsesulK: 0.2 USP basket Tangerine: 0.2 rack assembly: Syloid: 0.5 19s Pruv: 1.0 Advantose 100/Pearlitol 400DC (25/75) ratio Lot#/mfg date : 1242- 148/ 2-4-02 250g batch/1 lmm Flat Face Radial Edge/450mg FluoxetineTMMS : 28.69 33.9 Mouth: 7-lOs 0.6 Can be used with Pearlitol 400DC : very fast tablet any drug 51.41 Avicel PH 101 : 15.0 Kollidon CL: 2.0 USP basket Citric acid: 1.0 rack assembly: AsesulK : 0.2 31 s Syloid: 0.5 Tangerine: 0.2 Pruv: 1.0 Lot#/mfg date : 1242- 152/ 2-5-02 250g batch/1 1mm Flat Face Radial Edge/450mg FluoxetineTMMS : 28.69 30.8 Mouth: 10s 0.2 Can be used with Pearlitol 400DC : very fast tablet any drug except the 38.56 drugs that have Advantose 100: 12.85 amine group. Avicel PH 101: 15.0 USP basket Kollidon CL: 2.0 rack assembly: Citric acid: 1.0 19s AsesulK: 0.2 Syloid: 0.5 Tangerine: 0.2 Pruv: 1.0 Lot#/mfg date : 1242- 153/ 2-5-02 250g batch/I lmm Flat Face Radial Edge/450mg FluoxetineTMMS: 28.69 29.4 Mouth: 10s 0.6 Can be used with Pearlitol 400DC : very fast tablet, any drug 49.41 no difference Avicel PH 101: 15.0 between 1242- Kollidon CL : 2.0 154 & 140 L-HPC 11 : 4. 0 batches Citric acid : 1.0 AsesulK: 0.2 Syloid: 0.5 USP basket Tangerine: 0.2 rack assembly: Pruv : 1.0 23s Lot#/mfg date: 1242- 157/ 2-6-02 250g batch/1 lmm Flat Face Radial Edge/450mg FluoxetineTMMS : 28.69 33.1 Mouth: 12-15s 0.6 Can be used with' Pearlitol 400DC : good tablet any drug except he 37.06 drugs that have Advantose 100: 12.35 amine group. Avicel PH 101: 15.0 USP basket Kollidon CL: 2.0 rack assembly: L-HPC 11 : 2.0 12s Citric acid : 1.0 AsesulK: 0.2 Syloid: 0.5 Tangerine: 0.2 Pruv: 1.0 Lot#/mfg date : 1242- 158/ 2-6-02 250g batch/1 1mm Flat Face Radial Edge/450mg Fast Disintegrating Non Floss Tablet Additional Preferred Formulation FluoxetineTMMS: 28.69 28.4 Mouth: 8-10s 0.5 Can be used with Pearlitol 400DC : very good any drug 48. 41 tablet Avicel PH 101 : 16. 0 Kollidon CL: 2.0 L-HPC 11 : 2.0 USP basket Citric acid: 1.0 rack assembly : AsesulK : 0.2 12s Magnasweet 100: 0.2 Tangerine : 0.2 Syloid : 0.5 Pruv : 1. 0 Lot#/mfg date : 1242- 167/ 2-13-02 250g batch/l lmm Flat Face Radial Edge/450mg Additional formulations : Formulation Lot# Objective Mixing procedure & Hardn Disintegrati 1'riabilit Equipment used ess on y % (N) Time Fluoxetine TMMS: Investigate ½ Pearlitol 400DC, Abrasio 28.69 high level all MS n Pearlitol 400DC : of Kollidon ½ Pearlitol 400DC, 32.4 Mouth: 10S 0.3 58.41 XL for fast mix for 3 min. Add Kolidon XL : 10 disintegrati all Citric acid, all Drop : Citric acid: 1.0 on using AcesuK, all syloid, 2. AsesulK: 0.2 high all Kollidon, all Tangerine: 0.2 compressio tangerine, mix for Syloid: 0.5 n. 5min. Then pour all Pruv: 1.0 pruv and mix for 2 min using Turbula Lot#/mfg date: mixer. 1242-117/1-14-02 250g batch Piccola tablets press 11 mm punch FFRE 450mg table Fluoxetine TMMS : Evaluate % z Parteck M200, all Abrtsio 28.69 different MS, n: Pearlitol 400DC : from I/2 Parteck M200 mix 22.2 Mouth: 10S 1.4 58.41 different for 3 min. Add all Kolidon XL : 10 suppliers. Citric acid, all Dro : Citric acid: 1.0 AcesuK, all syloid, 4.1 AsesulK: 0.2 all Kollidon, all Tangerine: 0.2 tangerine, mix for 5 Syloid: 0.5 min. Then pour all Pruv: 1.0 pruv and mix for 2 min. using Turbula Lot#/mfg date: mixer. 1242-118/1-14-02 250g batch Piccola tablets press 11 mm punch FFRE 450mg tablet Fluoxetine TMMS : Evaluate % z Parteck M300, all Abrasio 28.69 different MS n: Pearlitol 400DC : mannitol I/z Parteck M300, mix 29.9 Mouth: 10S 0.8 58.41 from for 3 min. Add all Kolidon XL : 10 different Citric acid, all Drop: Citric acid: 1.0 suppliers. AcesuK, all syloid, 3.0 AsesulK: 0.2 all Kollidon, all Tangerine: 0.2 tangerine, mix for 5 Syloid: 0.5 min. Then pour all Pruv: 1.0 pruv and mix for 2 min. using Turbula Lot#/mfg date: mixer. 1242-119/1-14-02 250g batch Piccola tablets press 11 mm punch FFRE 450mg tablet Fluoxetine TMMS : Increase ½ Pearlitol 400DC, Abrasio 28.69 the all MS n: Pearlitol 400DC : Kollidon pearlitol400DC, 29.6 Mouth: 10S 0.4 48.41 XL from mix for 3 min. Add Kolidon XL : 20 10% to all Citric acid, all Drop: Citric acid: 1.0 20% to AcesuK, all syloid, 2.3 AsesulK: 0.2 determine all Kollidon, all Tangerine: 0.2 the effect tangerine, mix for Syloid: 0.5 of 5min. Then pour all Pruv: 1.0 disintegrant pruv and mix for 2 concentrati min using Turbula Lot#/mfg date: on on mixer. 1242-120/1-15-02 disintegrati 250g batch on time Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Invesdtigate ½ Pearlitol 400DC, Abrasio 28.69 alternative all MS n: Pearlitol 400DC : distintegran % Z Pearlitol 400DC, 16.2 Mouth: 20S, 14.8 48.41 t like L-mix for 3 min. Add at 20 and 30 L-HPC 11 : 2.0 HPC11 all Citric acid, all N tablets Drop: Citric acid: 1.0 AcesuK, all syloid, very slow to Powder AsesulK: 0.2 all L-HPC, all disintegrate collectio Tangerine: 0.2 tangerine, mix for 5 n Syloid : 0. 5 min. Then pour all Pruv: 1.0 pruv and mix for 2 min using Turbula Lot#/mfg date: mixer. 1242-123/1-16-02 250g batch Piccola tablets press 11 mm punch FFRE 450mg tablet Fluoxetine TMMS : Increase I/2 Pearlitol 400DC, Abrasio 28.69 the all MS n: Pearlitol 400DC : Kollidon I/2 pearlitol 400DC, 29.7 Mouth: 10S 0. 2 48.41 XL from mix for 3 min. Add Avicel PH 101: 16.0 10% to all Citric acid, all'Drop : L-HPC 11 : 4.0 20% to AcesuK, all syloid,). 8 Citric acid: 1.0 determine all avicel, all L-HPC, AsesulK: 0.2 the effect all tangerine, mix for Tangerine: 0.2 of 5min. Then pour all Syloid: 0. 5 disintegrant pruv and mix for 2 Pruv : 1.0 concentrati min using Turbula on on mixer. Lot#/mfg date: disintegrati 1242-124/1-16-02 on time 250g batch Piccola tablets press Avicel PH101/L-11 mm punch FFRE HPC11 ratio 450mg tablet (80/20) Fluoxetine TMMS : Evaluate ½ Pearl 400DC, all Atrasio 28.69 different MS zu Pearlitol 400DC : ratio of 1/2Pearlitol 40ODC, 34. 0 Mouth: ! OS 0. 3 48.41 avicel PH mix for 3 min. Add Avicel PH 101: 18.0 101/L-HPC all Citric acid, all Dr) p : L-HPC 11 : 2.0 11 to AcesuK, all syloid, 0.8 Citric acid: 1.0 determine all avicel, all LOHPC, AsesulK: 0.2 which all tangerine, mix for Tangerine: 0.2 excipient 5min. Then pour all Syloid: 0.5 affect more pruv and mix for 2 Pruv: 1.0 the min using Turbula disintegrati mixer. Lot#/mfg date: on in the 1242-125/1-16-02 mouth. Piccola tablets press 250g batch 11 mm punch FFRE Avicel PH 101/L-450mg table HPC11 ratio (90/10) Fluoxetine TMMS : Evaluate ½ Pearlitol 400DC, abra@io 28.69 different all MS, n: Pearlitol 400DC : ratio of Pearlitot 400DC, 31. 0 Mouth: 10S 0.2 48.41 avicel PH mix for 3 min. Add Avicel PH 101: 18.0 101/L-HPC all Citric acid, all Drop: L-HPC 11: 2.0 11 to AcesuK, all syloid, 1.0 Citric acid: 1. 0 determine all Kollidon, all AsesulK: 0.2 which tangerine, mix for 5 Tangerine: 0.2 excipient min. Then pour all Syloid: 0. 5 affect more pruv and mix for 2 Pruv: 1.0 the min. using Turbula disintegrati mixer. on in the Lot#/mfg date: mouth. Piccola tablets press 1242-129/1-19-02 11 mm punch FFRE 250g batch 450mg tablet Avicel PH 101/L- HPC11 ratio (90/10) fluxetine TMMS : Comparativ I/z Pearlitol 400DC, M tbrasio 28.69 e study of all MS, n: Pearlitol 400DC : disintegrati ½ Pearitol 400DC, 33.8 Mouth 10: oil 48.41 on time of mix for 3 min. Add 10S Avicel PH 101: 16.0 avicel PH all Citric acid, all Drop : Kollidon XL : 4.0 101/L- Acesu K, all syloid, 1.5 Citric acid: 1.0 HPC11 all avicel, all AsesulK: 0.2 formulation Kollidon, all Tangerine: 0.2 versus tangerine, mix for 5 Syloid: 0.5 avicel PH min. Then pour all Pruv: 1.0 101/Kollid pruv and mix for 2 on XL min using Turbula Lot#/mfg date: mixer. 1242-126/1-17-02 250g batch Piccola tablets press Avicel PH 11 mm punch FFRE 101/Kollidon ratio 450mg tablet (80/20 Fluoxetine TMMS : Comparativ ½ Pearlitol 400DC, Abrasio 28.69 e study of all MS, n : Pearlitol 400DC : disintegrati ½ Pearlitol 400DC, 31-37 Mouth 10: 0.04 48.41 on time of mix for 3 min. Add 10S Avicel PH 101: 4.0 avicel PH all Citric acid, all Drop : Kollidon XL : 16. 0 101/L-Acesu K, all syloid, 1. 6 Citric acid: 1.0 HPC11 all avicel, all AsesulK: 0.2 formulation Kollidon, all Tangerine: 0.2 versus tangerine, mix for 5 Syloid: 0.5 avicel PH min. Then pour all Pruv: 1.0 101/Kollid pruv and mix for 2 on XL min using Turbula Lot#/mfg date: mixer. 1242-127/1-17-02 250g batch Piccola tablets press Avicel PH 11 mmpunch FFRE 101/Kollidon. ratio 450mg tablet (20/80) Fluoxetine TMMS : Comparativ'/a Pearlitol 400DC, Abrasio 28.69 e study of all MS, n: Pearlitol 400DC : disintegrati /z Pearlitol 400DC, 36.4 Mouth 10 : 1.0 52.41 on time of mix for 3 min. Add 10S Kollidon XL : 16.0 16% all Citric acid, all Drop: Citric acid: 1.0 Kollidon to Acesu K, all syloid, 2.5 AsesulK: 0.2 10 and all avicel, all Tangerine: 0.2 20% Kollidon, all Syloid : 0.5 tangerine, mix for 5 Pruv: 1.0 min. Then pour all Lot#/mfg date: pruv and mix for 2 1242-130/1-19-02 min using Turbula 250g batch mixer. Piccola tablets press 11 mm punch FFRE 450mg tablet Fluoxetine TMMS : Increase ½ Pearlitol 400DC, Abrasio 28.69 the level of all MS, n: Pearlitol 400DC : avicel to I/2 Pearlitol 400DC, 29.4 Mouth: 10S 1. 7 26.25 improve mix for 3 min. Add Avicel PH 101 : the all Citric acid, all Drop: 26.25 disintegrati Acesu K, all syloid, 1.8 L-HPC: 16 on time. all avicel, all L-HPC, Citric acid: 1.0 Avicel is all tangerine, mix for AsesulK: 0.2 porous and 5 min. Then pour all Tangerine: 0.2 therefore, it pruv and mix for 2 Syloid: 0.5 absorbs lot min using Turbula Pruv: 1. 0 of water mixer. which Lot#/mfg date: helps the 1242-131/1-21-02 swelling of F tablets press 250g batch L-HPC 11 mm punch FFRE. 450mg tablet Fluoxetine TMMS : Same % z Pearlitol 400DC, Abrasio 28.69 objective all MS n: Pearlitol 400DC : as 1242- ½ Pearlitol 400DC, 29.7 Mouth: 10S 0.3 26.25 131, except mix for 3 min. Add Avicel PH 101 : Kollidon all Citric acid, all Drop: 26.25 was used. AcesuK, all syloid, 1.8 Kolidon XL : 16 all Kollidon, all Citric acid: 1.0 tangerine, mix for 5 AsesulK: 0.2 min. Then pour all Tangerine: 0.2 pruv and mix for 2 Syloid : 0. 5 min using Turbula Pruv: 1.0 mixer. Lot#/mfg date: F tablets press 1242-132/1-21-02 11 mm punch FFRE 250g batch 450mg table Ireland Formulation Enalapril 26 Mouth: 10S Abrasio FD tablets x : 36mg zu 5 Drop: 0.3 Fluoxetin TMMS : Investigate ½ Pearlitol 400DC, Abrasio 28.69 the effect all MS L: Pearlitol 400DC : of MCC on ½ Pearlitol 400DC, 28.3 Mouth: 15-0 3 54.41 the mix for 3 min. Add 20S Avicel PH 101 : 12.0 disintegrati all Citric acid, all Slower than Drop : L-HPC 11 : 2.0 on of the AcesuK, all syloid, 1242-125 0 : 3 Citric acid: 1.0 tablets. all avicel, all L- AsesulK : 0.2 Decrease HPCn, all tangerine, Tangerine: 0.2 MCC from mix for 5 min. Then Syloid: 0.5 18 to 12% pour all pruv and mix Pruv: 1.0 for 2 min using Turbula mixer. Lot#/mfg date: 1242-133/1-23-02 250g batch F tablets press 11 mm punch FFRE 450mg table Fluxetine TMMS : Investigate I/2 Pearlitol 400DC, Abl asio 28.69 the effect all MS n: Pearlitol 400DC : of MCC on ½ Pearlitol 400DC, 28.1 Mouth: 20S 0.4 60.41 the mix for 3 min. Add Slower than Avicel PH 101 : 6.0 disintegrati all Citric acid, all 1242-133 Dro : L-HPC 11 : 2.0 on of the AcesuK, all syloid, 0. 4 Citric acid: 1.0 tablets. all avicel, all L-HPC, AsesulK: 0.2 Decrease all tangerine, mix for Tangerine: 0.2 MCC from 5 min. Then pour all Syloid: 0.5 18 to 6% pruv and mix for 2 Pruv : 1.0 min using Turbula mixer. Lot#/mfg date: 1242-134/1-23-02 F tablets press 250g batch 11 mm punch FFRE 450mg table Fluoxetine TMMS : Decreasing % z Pearlitol 400DC, Abrasio 28.69 the level of all MS n : Pearlitol 400DC : MCC from I/2 Pearlitol 400DC, 29.5 Mouth: 10S 0.3 51.41 18 to 12% mix for 3 min. Add As good as Avicel PH 101: 15.0 in the all Citric acid, all 1242-125 Drop: L-HPC 11 : 2.0 formulation AcesuK, all syloid, 0.3 Citric acid: 1.0 slowed all avicel, all L-HPC, AsesulK: 0.2 down all tangerine, mix for Tangerine: 0.2 slightly the 5 min. Then pour all Syloid: 0.5 disintegrati pruv and mix for 2 Pruv: 1.0 on of the min using Turbula tablets, but mixer. Lot#/mfg date: it appeared 1242-135/1-24-02 to be an 250g batch optimum F tablets press level in 11 mm punch FFRE between. 450mg table The level of MCC was decreased to 15% instead. Fluoxetine TMMS : To Pearlitol400DC, Ahrasio 28.69 investigate all MS n: Pearlitol 400DC : if the use'4PearlitoI400DC, 27.5 Mouth: 20S 0.@ 53.41 of L-HPC mix for 3 min. Add Disintegrate Avicel PH 101: 15.0 is all Citric acid, all with a core Dr op : Citric acid: 1.0 necessary AcesuK, all syloid, 0. AsesulK: 0.2 in the all avicel, all Tangerine: 0.2 formulation tangerine, mix for 5 Syloid: 0.5 to enhance min. Then pour all Pruv: 1.0 the pruv and mix for 2 disintegrati min using Turbula Lot#/mfg date: on of the mixer. 1242-136/1-24-02 tablet. 250g batch F tablets press 11 mm punch FFRE 450mg table Fluoxetine TMMS : Investigate I/2 Pearlltol 400DC, Abrasio 28.69 other all MS n : Pearlitol 400DC : grades of ½ Pearlitol 400DC, 28.3 Mouth: 20S 0.2 51. 41 MCC mix for 3 min. Add As good as Prosolv 90 : 15.0 all Citric acid, all 1242-125 Drop: L-HPC 11: 2.0 AcesuK, all syloid, 0.4 Citric acid: 1.0 all prosolv, all AsesulK : 0.2 tangerine, mix for 5 Tangerine: 0.2 min. Then pour all Syloid: 0.5 pruv and mix for 2 Pruv: 1.0 min using Turbula mixer. Lot#/mfg date: 1242-137/1-24-02 F tablets press 250g batch 11 mm punch FFRE 450mg table Fluxetine TMMS: Investigate ½ Pearlitol 400DC, Abrasio 28.69 other all MS n: Pearlitol 400DC : grades of ½ Perlitol 400DC, 26.0 Mouth: 10S 0.3 51.41 MCC mix for 3 min. Add Better than Prosolv 90: 15.0 all Citric acid, all 1242-124 Drop: L-HPC 11: 2.0 AcesuK, all syloid, 0.2 Citric acid: 1.0 all prosolv, all L- AsesulK: 0.2 HPC, all tangerine, Tangerine: 0.2 mix for 5 min. Then Syloid: 0.5 pour all pruv and mix Pruv: 1.0 for 2 min using Turbula mixer. Lot#/mfg date: 1242-138/1-24-02 F tablets press 250g batch 11 mm punch FFRE 450mg table Fluoxetine TMMS : Investigate ½ Pearlitol 400DC, Abrasio 28.69 other all MS n: Pearlitol 400DC : greades of ½ Pearlitol 400DC, 28.4 Mouth: lSS-0. 2 51.41 MCC mix for 3 min. Add 20S Avicel PH 102"all Citric acid, all Drop: 15.0 AcesuK, all syloid, 0.2 L-HPC 11: 2.0 all avicel, all L-HPC, Citric acid: 1.0 all tangerine, mix for AsesulK : 0.2 5 min. Then pour all Tangerine : 0.2 pruv and mix for 2 Syloid : 0.5 min using Turbula Pruv: 1. 0 mixer. Lot#/mfg date: F tablets press- 1242-139/1-24-02 11 mm punch FFRE 250g batch 450mg table Fluoxetine TMMS: Investigate ½ Pearlitol 400DC, Abrasio 28.69 other all MS t : Pearlitol 400DC : greades of % a Pearlitol 400DC, 24.4 Mouth: 15S v1. 3 53.41 MCC mix for 3 min. Add Avicel PH 113: 15.0 all Citric acid, all 1. rop : L-HPC 11: 2.0 AcesuK, all syloid, G'. 3 Citric acid: 1.0 all avicel, all L-HPC, AsesulK : 0.2 all tangerine, mix for Tangerine: 0.2 5 min. Then pour all Syloid: 0. 5 pruv and mix for 2 Pruv: 1.0 min using Turbula mixer. Lot#/mfg date: 1242-140/1-25-02 F tablets press 250g batch 11 mm punch FFRE 450mg table Fluoxetine TMMS : To s/2 advantose, all MS Ab rasio 28.69 investigate 1/2 advantose, mix for D : ; Advantose 100: alternative 3 min. Add all Citric 26.9 Mouth: 20S 0. 8 68.41 polyols. In acid, all AcesuK, all with a core. Citric acid: 1.0 this syloid, all tangerine, Tablet sweet Drc p : AsesulK: 0.2 experiment, mix for 5 min. Then and have 2.0 Tangerine: 0.2 determine pour all pruv and mix good Syloid: 0. 5 the for 2 min using mouthieel. Pruv: 1.0 compressibi Turbula mixer. lity of Lot#/mfg date: maltose F tablets press 1242-141/1-25-02 (advantose 11 mm punch FFRE 250g batch 100) 450mg table FluoxetineTMMS : To'4 advantose, all MS Abrasio 28.69 investigate I/2 advantose, mix for n: Advantose 100 : alternative 3 min. Add all Citric 27.9 Mouth: 10S 1.0 53.41 polyols. In acid, all AcesuK, all Not as good Prosolv 50: 15 this syloid, all Prosolv, all as 1242-143 Drop : Citric acid: 1.0 experiment, tangerine, mix for 5 4.2 AsesulK: 0.2 determine min. Then pour all Tangerine: 0.2 the pruv and mix for 2 Syloid: 0.5 compressibi min using Turbula Pruv: 1.0 lity of mixer. maltose Lot#/mfg date: (advantose F tablets press 1242-142/1-27-02 100) and 11 mm punch FFRE 250g batch MCC 450mg table' Fluoxetine TMMS : To advantose, all MS Abrasio 28.69 investigate ½ advantose, mix for In'-, Advantose 100 : alternative 3 min. Add all Citric 27.9 Mouth: 10S 10 51.41 poyols. In acid, all AcesuK, all Good tablets Prosolv 50: 15 this syloid, all Prosolv, all Drop : L-HPC 11 : 2.0 experiment, tangerine, mix for 5 3.7 Citric acid: 1.0 determine min. Then pour all AsesulK: 0.2 the pruv and mix for 2 Tangerine: 0.2 compressibi min using Turbula Syloid: 0. 5 lity of mixer. Pruv: 1.0 maltose (advantose Lot#/mfg date : 100) /F tablets press 1242-143/1-27-02 MCC/L-11 mm punch FFRE 250g batch HPC 450mg table Fluoxetine TMMS : To /a advantose, all MS Ab asio 28.69 investigate 1/2advantose, mix for n : Advantose 100 : the effect of 3 min. Add all Citric 26.3 Mouth: 15S 0.6 61.41 MCC on the acid, all AcesuK, all Not as good Prosolv 50: 5 disintegratio syloid, all Prosolv, all as 1242-Dro @: L-HPC 11 : 2.0 n of the L-HPC, all tangerine, 143.1. 8 Citric acid: 1.0 tablets mix for 5 min. Then AsesulK: 0.2 pour all pruv and mix Tangerine: 0.2 for 2 min using Syloid : 0.5 Turbula mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-144/1-27-02 450mg table 250g batch Fluoxetine TMMS: To /z advantose, all MS Abrasio 28.69 investigate ½ advantose, mix for n: Advantose 100: the effect of 3 min. Add all Citric Mouth: 20-0.0 56.41 MCC on the acid, all AcesuK, all 25S Prosolv 50: 10.0 disintegratio syloid, all Prosolv, all Not as good Drop: L-HPC 11 : 2.0 n of the L-HPC, all tangerine, as 1242-1. 0 Citric acid: 1.0 tablets mix for 5 min. Then 143. AsesulK: 0.2 pour all pruv and mix Tangerine: 0.2 for 2 min using Syloid: 0.5 Turbula mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-145/1-27-02 450mg table 250g batch Fluoxetine TMMS: To compare I/2 advantose, all MS Abrasio 28.69 the use of ½ advantose, mix for n: Advantose 100: avicel to 3 min. Add all Citric 29.0 Mouth: 10-1.0 51.41 prosolv and acid, all AcesuK, all 15S Avicel PH 101: their effect syloid, all syloid, all Good tablets Drop: 15.0 on friability avicel, all tangerine, 2.0 L-HPC 11: 2.0 mix for 5 min. Then Citric acid: 1.0 pour all pruv and mix AsesulK: 0.2 for 2 min using Tangerine: 0.2 Turbula mixer. Syloid: 0.5 Pruv: 1.0 F tablets press 11 mm punch FFRE Lot#/mfg date: 450mg table 1242-146/2-4-02 250g batch Fluoxetine TMMS: To 1/2 advantose, l/2 Abrasio 28.69 investigate Pearlitol, all Mus, 1/2 n: Advantose 100: the Peqrlitol, l/2 27. 8 Mouth: 10S 0.5 25.70 combination advantose, mix for 3 Good tablets Pearlitol 400DC : of 2 polyols min. Add all Citric Drop: 25. 71 at different acid, all Acesu K, all 1.9 Avicel PH 101 : ratio and syloid, all avicel, all 15.0 their effect L-HPC, all tangerine, L-HPC 11: 2.0 on mix for 5 min. Then Citric acid: 1.0 disintegratio pour all pruv and mix AsesulK: 0.2 n and for 2 min using Tangerine: 0.2 friability. Turbula mixer. Syloid: 0. 5 Pruv : 1.0 F tablets press 11 mm punch FFRE Lot#/mfg date: 450mg table 1242-147/2-4-02 250g batch Advantose 100/Perlitol 400DC (50/50) ratio Fluoxetine TMMS : To I/2 advantose, l/2 Abrasio 28.69 investigate Pearlitol, all MS, ½ n: Advantose 100: the Pearlitol,'/2 28.4 Mouth: 15S 13 12.85 combination advantose, mix for 3 Good tablets Pearlitol 400DC : of 2 polyols min. Add all Citric No) rop: 38.56 at different acid, all Acesu K, all significant 1. 5 Avicel PH 101 : ratio and syloid, all avicel, all difference 15.0 their effect L-HPC, all tangerine, between L-HPC 11 : 2.0 on mix for 5 min. Then 1242-147 Citric acid: 1.0 disintegratio pour all pruv and mix AsesulK: 0.2 n and for 2 min using Tangerine: 0.2 friability. Turbula mixer. Syloid: 0.5 Pruv: 1.0 F tablets press 11 mm punch FFRE Lot#/mfg date: 450mg table 1242-148/2-4-02 250g batch Advantose 100/Perlitol 400DC (25/75) ratio FluoxetineTMMS : To ½ advantose, ½ Ab@asio 28.69 investigate Pearlitol, all MS, I/2 n : Advantose 100 : the Pearlitol, /2 28. 4 Mouth: 10S 0.5 38.56 combination advantose, mix for 3 Good tablets Pearlitol 400DC : of 2 polyols min. Add all Citric Faster than Drop : 12.85 at different acid, all Acesu K, all 1242-147 & 1. 6 Avicel PH 101 : ratio and syloid, all avicel, all 148 15.0 their effect L-HPC, all tangerine, L-HPC 11: 2.0 on mix for 5 min. Then Citric acid: 1.0 disintegratio pour all pruv and mix AsesulK: 0.2 n and for 2 min using Tangerine: 0.2 friability. Turbula mixer. Syloid: 0.5 Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-149/2-4-02 450mg table 250g batch Advantose 100/Perlitol 400DC (75/25) ratio Fluoxetine TMMS : To compare ½ Pearlitol, all MS Abrasio 28.69 the physical ½ Pearlitol, mix for 3 n: Pearlitol 400DC : properties of min. Add all Citric 27.1 Mouth: 35S 0.2 68.41 pearlitol to acid, all AcesuK, all Very slow Citric acid: 1.0 advantols syloid, all syloid, all Drop: AsesulK : 0.2 tangerine, mix for 5 0.3 Tangerine: 0.2 min. Then pour all Syloid: 0.5 pruv and mix for 2 Pruv: 1.0 min using Turbula mixer. Lot#/mfg date: F tablets press 1242-151/2-4-02 11 mm punch FFRE 250g batch 450mg table Fluoxetine TMMS : To evaluate I/2 Pearlitol, all MS Abrasio 28.69 the Kollidon % z Pearlitol, mix for 3 n: Pearlitol 400DC : CL and its min. Add all Citric 33.9 Mouth: 7-0.2 51.41 effect on acid, all AcesuK, all-10S Avicel PH 101: disintegratio syloid, all syloid, all Very fast Drop: 15.0 n and avicel, all kollidon, tablet 0.6 Kollidon CL: 2.0 friability in all tangerine, mix for Citric acid: 1.0 the pearlitol 5 min. Then pour all AsesulK: 0.2 formulation. pruv and mix for 2 Tangerine: 0.2 min using Turbula Syloid: 0.5 mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-152/2-5-02 450mg table 250g batch Fluoxetine TMMS : To evaluate'/zadvantose, ' Abrasio 28.69 the Kollidon Pearlitol, all MS, l/2 n: Pearlitol 400Dc : CL and its Pearlitol, I/2 30. 8 Mouth: 10S 0.2 38.56 effect on advantose, mix for 3 Very fast Advantose 100 : disintegratio min. Add all Citric tablet no Drop: 51.41 n and acid, all AcesuK, all difference to 0.2 Avicel PH 101: friability in syloid, all syloid, all 1242-152. 15.0 the pearlitol avicel, all kollidon, At 40N, Kollidon CL: 2.0 formulation. all tangerine, mix for tablets Citric acid: 1.0 5 min. Then pour all disintegrate AsesulK: 0. 2pruv and mix for 2 within 15s. Tangerine: 0.2 min using Turbula Syloid: 0.5 mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-153/2-4-02 450mg table 250g batch Fluoxetine TMMS : Optimize l2 Pearlitol, all MS Abrasio 28.69 the avicel I/2 Pearlitol, mix for 3 n : Pearlitol 400DC : level min. Add all Citric 35.7 Mouth: 15S 0.2 56.41 acid, all AcesuK, all Not as fast Avicel PH 101: syloid, all syloid, all as 15% Drop: 10.0 avicel, all kollidon, avicel 0.3 Kollidon CL: 2.0 all tangerine, mix for Citric acid: 1.0 5 min. Then pour all AsesulK: 0.2 pruv and mix for 2 Tangerine: 0.2 min using Turbula Syloid: 0.5 mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-154/2-5-02 450mg table 250g batch Fluoxetine TMMS: Optimize ½ advantose, ½ Abrasio 28.69 the avicel Pearlitol, all MS % z n: Pearlitol 400DC : level Pearlitol, 1/2 26.7 Mouth: 10-0.3 42.31 advantose, mix for 3 15S Advantose 100 : min. Add all Citric Not as fast Drop: 51.41 acid, all AcesuK, all 15% avicel 0.8 Avicel PH 101: syloid, all syloid, all 15.0 avicel, all kollidon, Kollidon CL: 2.0 tangerine, mix for 5 Citric acid: 1.0 min. Then pour all AsesulK: 0.2 pruv and mix for 2 Tangerine: 0.2 min using Turbula Syloid: 0.5 mixer. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-155/2-5-02 450mg table 250g batch Fluoxetine TMMS: Optimize ½ advantose, ½ Abrasio 28.69 the level of Pearlitol, all MS, l/2 n: Pearlitol 400DC : avicel Pearlitol, l/2 21.6 Mouth: 35 0. 2 49.81 advantose mix for 3 Very slow' Advantose 100 : min. Add all Citric Drop: 16.60 acid, all AcesuK, all 0.3 Kollidon CL: 2.0 syloid, all syloid, all Citric acid: 1.0 kollidon, tangerine, AsesulK: 0.2 mix for 5 min. Then Tangerine: 0.2 pour all pruv and mix Syloid: 0.5 for 2 min using Pruv: 1.0 Turbula mixer. Lot#/mfg date: F tablets press 1242-156/2-5-02 11 mm punch FFRE 250g batch 450m table Fluoxetine TMMS: To evalute % a Pearlitol, all MS Abrasio 28.69 the'/2 Pearlitol, mix for 3 n: Pearlitol 400DC : combination min. Add all Citric 29.4 Mouth: 10S ; 0.4 49.41 of Kollidon acid, all AcesuK, all Very fast Avicel PH 101: CL/LOHPC syloid, all syloid, all tablet, no Drop: 15.0 and their kollidon, all-HPC, difference 0.6 Kollidon CL: 2.0 synergetic all tangerine, mix for between L-HPC 11 : 2.0 effect on 5 min. Then pour all 1242-154 & Citric acid: 1.0 disintegratio pruv and mix for 2 140 batches AsesulK : 0.2 n and min using Turbula Tangerine: 0.2 friability mixer. Syloid: 0.5 formulation. Pruv: 1.0 F tablets press Lot#/mfg date: 11 mm punch FFRE 1242-157/2-6-02 450mg table 250 batch Fluoxetine TMMS : To evalute ½ advantose, ½ Abrasio 28.69 the Pearlitol, all MS, ½ n Pearlitol 400DC : combination Pearlitol, 33.1 Mouth: 12-0 3 37.06 of Kollidon advantose, mix for 3 15S Advantose 100 : CL/LOHPC min. Add all Citric Good tablets Drop: 12.35 and their acid, all AcesuK, all 0.6 Avicel PH 101 : synergetic syloid, all syloid, all 15.0 effect on kollidon, all Kollidon CL: 2.0 disintegratio tangerine, mix for 5 L-HPC 11 : 2.0 n and min. Then pour all Citric acid: 1.0 friability pruv and mix for 2 AsesulK: 0.2 formulation. min using Turbula Tangerine: 0.2 mixer. Syloid: 0.5 Pruv: 1.0 F tablets press 11 mm punch FFRE Lot#/mfg date: 450mg table 1242-158/2-6-02 250g batch Fluoxetine TMMS: To evaluate 1/2 lab, all MS l/2 lab, Abrasio 28.69 alternative mix for 3 min. Add n: Lab 3038: 51.41 polyols with all Citric acid, all 25.3 Mouth: 10S 0.6 Avicel PH 101 : Kollidon AcesuK, all syloid, Good tablets 15.0 and their all syloid, all Drop: Kollidon CL: 2.0 effect on kollidon, all 2.0 Citric acid: 1.0 disintegratio tangerine, mix for 5 AsesulK: 0.2 n min. Then pour all Tangerine: 0.2 pruv and mix for 2 Syloid: 0.5 min using Turbula Pruv: 1.0 mixer. Lot#/mfg date: F tablets press 1242-159/2-6-02 11 mm punch FFRE 250g batch 450mg table Fluoxetine TMMS: To evaluate l/2 lab, all MS l/2 lab, Abrasio 28.69 alternative mix for 3 min. Add n: Lab 3038: 68.41 polyols with all Citric acid, all 32.4 Mouth: 20S 0.2 Avicel PH 101: L-HPC and AcesuK, all syloid, 15.0 their effect all syloid, all HPC, Drop: L-HPC 11: 2.0 on all tangerine, mix for 0.8 Citric acid: 1. 0 disintegratio 5 min. Then pour all AsesulK: 0.2 n. pruv and mix for 2 Tangerine: 0.2 min using Turbula Syloid: 0.5 mixer. Pruv: 1.0 Lot#/mfg date : F tablets press 1242-160/2-6-02 11 mmpunch FFRE 250g batch 450mg table Additional Non-Floss Formulations Formulation Lot# Objectiv Mixing Hardn Disintegrati Fri tbilit Dissolut e procedure & ess on y on % Equipment (N) time % Used Fluoxetine TMMS : Investigat ½ Pearl Abrasio 28.69 e high 400DC, all 32 Mouth: ! OS n: 0@3 Pearlitol 400DC : level of MS½ pearlitol 58.41 Kollidon 400DC, mix Drop : Kolidon XL : 10 XL for for 3 min. Add 2. 1 Citric a cid: 1.0 fast all Citric acid, AsesulK: 0.2 disintegra all AcesuK, all Syloid: 0.5 tion syloid, all Tangerine : 0.2 using Kollidon, all Pruv : 1.0 high tangerine, mix compress for 5min. Then Lot# 1242-117 ion. pour all pruv and mix for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Evaluate ½ Parteck Abrasi@ 28.69 different M200, all MS, 22.2 n: 1.4 Parteck M200 : mannitol I/2 Parteck Mouth: ! OS 58.41 from M200 mix for Drop: Kolidon XL: 10 different 3 min. Add all 4.1 Citric acid: 1.0 suppliers. Citric acid, all AsesulK: 0.2 AcesuK, all Syloid: 0.5 syloid, all Tangerine : 0.2 Kollidon, all Pruv: 1. 0tangerine, mix for 5 min. Lot# 1242-118 Then pour all pruv and mix for 2 min. using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Evaluate 1/2Parteck Abrasio 28.69 different M300, all MS, 30.0 n: 0.8 Parteck M300 : mannitol % a Parteck Mouth: 10S 58.41 from M300, mix for Drop: Kolidon XL : 10 different 3 min. Add all 3.0 Citric acid: 1.0 suppliers. Citric acid, all AsesulK: 0.2 Acesu K, all Syloid: 0.5 syloid, all Tangerine: 0.2 Kollidon, all Pruv: 1.0 tangerine, mix for 5 min. Lot# 1242-119 Then pour all pruv and mix for 2 min. using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Increase I/2 Pearlitol Abrasio 28.69 the 400DC, all 27.0 n: 0.4 Pearlitol 400DC : Kollidon MS, Mouth: 10S 48.41 XL from Pearlitol Drop: Kolidon XL : 20 10% to 400DC, mix 2.3 Citric acid: 1.0 20% to for 3 min. Add AsesulK: 0.2 determin all Citric acid, Syloid: 0.5 e the all Acesu K, all Tangerine: 0.2 effect of syloid, all Pruv : 1.0 disintegra Kollidon, all nt tangerine, mix Lot# 1242-120 concentra for 5 min. tion on Then pour all disintegra pruv and mix tion. time for 2 min. using Turbula mixer. Piccola tablets press 11 mm punch FFRE FluoxetineTMMS Investigat I/2 Pearlitol Al rasio 28.69 e 400DC, all 16.2 n: t4. 8 Pearlitol 400DC : alternativ MS, Mouth: 48.41 e ½ Pearlitol 20S, at 20 Dl p : L-HPC11 : 20 disintegra 400DC, mix and 30 N po, % der Citric acid: 1.0 nt like L-for 3 min. Add tablets very coli ectio AsesulK: 0.2 HPC11 all Citric acid, slow to n Syloid: 0.5 all Acesu K, all disintegrate Tangerine: 0.2 syloid, all L- Pruv: 1.0 HPC, all tangerine, mix Lot# 1242-123 for 5 min. Then pour all pruv and mix for 2 min. using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS Introduce I/2 Pearlitol Abras lo 28.69 microcry 400DC, all 30.0 n: 0.2 Pearlitol 400DC : stalline MS, Mouth: 10S 48.41 cellulose ½ Pearlitol Drop: Avicel PH 101: 16.0 as a 400DC, mix 0.8 L-HPC 11: 4.0 wicking for 3 min. Add Citri c acid: 1.0 and all Citric acid, AsesulK: 0.2 dispersin all Acesu K, all Syloid: 0.5 g agent to syloid, all Tangerine: 0.2 improve avicel, all L- Pruv : 1.0 the HPC, all disintegra tangerine, mix Lot# 1242-124 tion of for 5 min.. Avicel PH101/L-the Then pour all HPC11 ratio (80/20) tablets. pruv and mix for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Evaluate /a Pearlitol Abrasio 28.69 different 400DC, all 34.0 n: 0.2 Pearlitol 400DC : ratio of MS, Mouth: lOS 48.41 avicel PH l/2 Pearlitol Drop: Avicel PH 101: 18.0 101/L-400DC, mix 0.8 L-HPC 11: 2.0 HPC 11 for 3 min. Add Citri cacid: 1. 0 to all Citric acid, AsesulK : 0.2 determin all Acesu K, all Syloid: 0.5 e which syloid, all Tangerine: 0.2 excipient avicel, all L- Pruv: 1.0 affect HPC, all more the tangerine, mix Lot# 1242-125 disintegra for 5 min. Avicel PH 101/L-tion in Then pour all HPC11 ratio (90/10) the pruv and mix mouth for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Evaluate ½ Pearlitol Abrasio 28.69 different 400DC, all 34.0 n: 0.2 Pear-litol 400DC : ratio of MS, Mouth: lOS 48.41 avicel PH'/2 Pearlitol Drop: Avicel PH 101: 14.0 101/L-400DC, mix 1. 0 L-HPC 11: 6.0 HPC 11 for 3 min. Add Citri cacid: 1.0 to all Citric acid, AsesulK: 0.2 determin all Acesu K, all Syloid: 0.5 e which syloid, all Tangerine : 0.2 excipient avicel, all L- Pruv: 1. 0 affect HPC, all more the tangerine, mix Lot# 1242-129 disintegra for 5 min. Avicel PH 101/L-tion in Then pour all HPC11 ratio (70/30) the pruv and mix mouth for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Comparat % z Pearlitol A1 rasio 28.69 ive study 400DC, all 34.0 n:0.1 Pearlitol 400DC : MS, Mouth: 10S 48.41 of I/2 Pearlitol Drop : Avicel PH 101 : 16. 0 400DC, mix 1. 5 Kollidon XL : 4.0 disintegra for 3 min. Add Citri cacid : 1.0 tion time all Citric acid, Asesulk: 0.2 all Acesu K, all of avicel Syloid: 0.5 syloid, all Tangerine: 0.2 PH avicel, all Pruv: 1.0 101/L- Killidon, all tangerine, mix Lot# 1242-126 HPC11 for 5 min. Avicel PH formulate Then pour all 101/Kollidon ratio pruv and mix (80/20) on versus for 2 min using Turbula mixer. avicel PH 101/Kolli Piccola tablets press don XL 11 mm punch FFRE Fluoxetine TMMS : Comparat ½ Pearlitol Abrasio 28.69 ive study 400DC, all 31-37 n: 0. 0@ Pearlitol 400DC : of MS, Mouth: 1 OS 48.41 disintegra ½ Pearlitol Drop: Avicel PH 101: 4.0 tion time 400DC, mix 1.6 Kollidon XL: 16.0 of avicel for 3 min. Add Citri cacid : 1.0 PH all Citric acid, AsesulK: 0.2 101/L- all Acesu K, all Syloid: 0.5 HPC11 syloid, all Tangerine: 0.2 formulai avicel, all Pruv: 1.0 on versus Kollidon, all avicel PH tangerine, mix Lot# 1242-127 101/Kolli for 5 min. Avicel PH don Thenpourall 101/Kollidon ratio pruv and mix (20/80) for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE Fluoxetine TMMS : Comparat t/2 Pearlitol Abrasio 28.69 ive study 400DC, all n: 1.0 Pearlitol400DC : of MS, 33.3 Mouth: ! OS 52.41 disintegra % 2 Pearlitol Drop: Kollidon XL : 16.0 tion time 400DC, mix 2.5 Citri cacid: 1.0 of 16% for 3 min. Add AsesulK: 0.2 Kollidon all Citric acid, Syloid: 0.5 to 10 and all Acesu K, all Tangerine: 0.2 20% syloid, all Pruv: 1.0 Kollidon, all tangerine, mix Lot# 1242-130 for 5 min. Then pour all pruv and mix for 2 min using Turbula mixer. Piccola tablets press 11 mm punch FFRE. FluoxetineTMMS: Increase ½ Pearlitol Abrasio 28.69 the level 400DC, all 29. 4, Mouth: 10S n: 1.7 Pearlitol 400DC : of avicel MS, 26.25 to % 2 Pearlitol Drop: Avicel PH 101 : 26.25 improve 400DC, mix 1.8 L-HPC : 16 the for 3 min. Add Citri ca cid: 1.0 disintegra all Citric acid, AsesulK: 0.2 tion time. all Acesu K, all Syloid: 0.5 Avicel is syloid, all Tangerine: 0.2 porous avicel, all L- Pruv: 1.0 and HPC, all therefore, tangerine, mix Lot# 1242-131 it absorbs for 5 min. lot of Then pour all water pruv and mix which for 2 min- helps the using Turbula swelling mixer. of L-HPC F tablets press 11 mm punch FFRE. Fluoxetine TMMS : Same ½ Pearlitol Abrasio 28.69 objective 400DC, all 29.7 Mouth: l OS Il 0.3 Pearlitol 400DC : as 1242-MS, 26.25 131, I/2 Pearlitol D rop : Avicel PH 101: 26.25 except 400DC, mix 0. 3 Kolidon XL : 16 Kollidon for 3 min. Add Citri ca cid: 1.0 was used. all Citric acid, AsesulK: 0.2 all Acesu K, all Syloid: 0.5 syloid, all Tangerine: 0.2 avicel, all Pruv: 1.0 Kollidon, all tangerine, mix Lot# 1242-132 for 5 min. Then pour all pruv and mix for 2 min. using Turbula mixer. F tablets press 11 mm punch FFRE. Ireland Formulation Enapril Abra sio FD 26 Mouth: 10S n : 2.5 EXP 988 tablets 36mg Drop : 13. 5 FluoxetineTMMS: Study the I/z Pearlitol Abrasio 28.69 effect of 400DC, all 28.3 Mouth: 15 n: 0.3 Pearlitol 400DC : avicel on MS, to 20S 54.41 the I/2 Pearlitol Drop: Avicel PH 101 : 12 tablets 400DC, mix 0.3 L-HPC: 2 formulai for 3 min. Add Citri ca cid: 1.0 on at all Citric acid, AsesulK: 0.2 differents all Acesu K, all Syloid: 0.5 level syloid, all Tangerine: 0.2 12% and avicel, all L- Pruv: 1.0 6% as HPC, all results of tangerine, mix Lot# 1242-133 lot 1242-for 5 min. 125 Then pour all pruv and mix for 2 min using Turbula mixer. F tablets press 11 mm punch FFRE. FluoxetineTMMS: To I/2 Pearlitol Abrasio 28.69 improve 400DC, all 28.1 Mouth: 20S n: 0.4 Pearlitol 400DC : the MS, slow 60.41 mouth I/2 Pearlitol compared to Drop: Avicel PH 101 : 6 feel and 400DC, mix 1242-133 0.4 L-HPC: 2 gritty for 3 min. Add Citri ca cid: 1.0 taste of all Citric acid, AsesulK: 0.2 the all Acesu K, all Syloid: 0.5 tablets. syloid, all Tangerine: 0.2 Avicel avicel, all L- Pruv: 1.0 was HPC, all reduced tangerine, mix Lot# 1242-134 from for 5 min. 18% to Then pour all 12% by pruv and mix keeping for 2 min L-HPC using Turbula 11 to 2% mixer. level in tablets F tablets press formulai 11 mm punch on FFRE. FluoxetineTMMS : As results 1/2 Pearlitol Abrasio 28.69 of 400DC, all MS, 29.5 Mouth: 10S n: 0.3 Pearlitol 400DC : 1242-1/2 Pearlitol 51. 41 125and 400DC, mix for Drop: Avicel PH 101: 15 1242-133 3 min. Add all 0. 3 L-HPC : 2 on the Citric acid, all Citri ca cid: 1.0 tablets Acesu K, all disintegrat syloid, all AsesulK: 0.2 ion, is avicel, all L- Syloid: 0.5 been HPC, all Tangerine : 0.2 found that tangerine, mix Pruv: 1.0 the lot for 5 min. Then 1242-125 pour all pruv Lot# 1242-135 gave and mix for 2 better min using disintegrat Turbula mixer. ion which the level F tablets press of Avicel 11 mm punch was FFRE. increased to 15% Fluoxetine TMMS : Evaluate W/2 Pearlitol A rasio 28.69 the used 400DC, all MS, 27.5 Mouth: 20S n. 0.2 Pearlitol 400DC : of avicel % z Pearlitol 53. 41 alone in 400DC, mix for Di op: the tablets 3 min. Add all 0.@ Avicel PH 101:15 formulatio Citric acid, all Citric acid: 1.0 n. To Acesu K, all AsesulK: 0.2 determine syloid, Syloid : 0.5 the effect all avicel, all Tangerine: 0.2 of the tangerine, mix Pruv: 1.0 disintegrat for 5 min. Then ion while pour all pruv Lot# 1242-136 L-HPC11 and mix for 2 was min using removed. Turbula mixer. F tablets press 11 mm punch FFRE. FluoxetineTMMS: Investigat ½ Pearlitol Abrasio 28. 69 e another 400DC, all MS, 28.3 Mouth: lOS n: 0.@ Pearlitol 400DC: disintegra ½ Pearlitol better disint 51 41 nt 400DC, mix for than 1242-Drop, Prosolv90 : 15 Prosolv90 3 min. Add all 125 0. 4 L_HPC11: 2 to study Citric acid, all the Acesu K, all disintegrat syloid, AsesulK: 0.2 ion all Prosolv90, Syloid: 0.5 properties all L_HPC11, Tangerine: 0.2 and all tangerine, Pruv : 1.0 compare mix for 5 min. its Then pour all Lot# 1242-137 effectiven pruv and mix for ess with 2 min using avicel in a Turbula mixer. direct compactio F tablets press n. 11 mm punch FFRE.

Preferred oormulations based on directly compressible inorganic Salts, alone or in combination with a cellulose derivative: The present preferred illustartive embodiments of the invention relate to the introduction of directly compressible inorganic salt with a cellulose derivative.

Formulation I : This formulation is based on an excipient mass containing a misture of dibasic calcium phosphate dihydrate (Emcompress) and microcrystalline cellulose (Avicel).

% FluoxetineTMMS* : 28. 69 Pearlitol 400DC 36.31 Emcompress: 12.10 Avicel PH 101: 15.00 L-HPC LH-11 : 2.00 XL Kollidon : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation I1 : This formulation is based on an excipient mass wherein mannitol is substituted with the dicalcium phosphate dihydrate.

% Fluoxetine TMMS*: 28. 69 Emcompress: 48. 41 Avicel PH 101 : 15.00 XL Kollidon : 2.00 L-HPCLH-11 : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1. 00 Formulation III: This formulation is based on an excipient mnass wherein microcrystalline 4 cellulose (Avicel) is substituted with the dicalcium phosphate dihydrate (Emcompress) % Fluoxetine TMMS* : 28.69 Pearlitol 400DC : 48.41 Emcompress: 15.00 L-HPC LH-11 : 2.00 XL Kollidon : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous : 1. 50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation IV: This formulation is based on an excipient mass containing a combination of P Narlitol 400DC/dicalcium phosphate dihydrate at ratio 75/25 % Fluoxetine TMMS* : 28.69 Pearlitol 400DC : 36. 69 Emcompress: 12.10 Avicel PH 101 : 15.00 XL Kollidon: 2.00 L-HPC LH-11 : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation V: % Fluoxetine TMMS*: 28.69 Pearlitol 400DC : 36.31 Emcompress: 17.10 Avicel PH 101: 10.00 XL Kollidon : 2.00 L-HPC LH-11 : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation VI: This formulation is based on an excipient mass contaning a combination of low level of Avicel with Emcompress.

% Fluoxetine TMMS* : 28.69 Pearlitol 400DC : 43.81 Emcompress: 12.10 Avicel PH 101 : 7.50 XL Kollidon: 2.00 L-HPC LH-11 : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation VII: % Fluoxetine TMMS* : 28.69 Pearlitol 400DC : 48.41 Emcompress: 7.50 Avice PH 101 : 7.50 XL Kollidon: 2.00 L-HPC LH-11 : 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation VIII: This formulation illustrates how the introduction of Clay (magnabrite) in tablet formulation according to the invention allows for covering the unpleasant and gritty taste of the microspheres and therevy improve the patient's ability to to swallow a tablet based on this formulation.

% Fluoxetine TMMS* : 28.69 Pearlitol 400DC : 43.81 Emcompress: 12.10 Avicel PH 101 : 6.50 XL Kollidon : 2.00 L-HPC LH-11 : 2.00 Magnabrite F : 1.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1. 00 Formulation IX: % Fluoxetine TMMS*: 28.69 Pearlitol 400DC : 43.81 Emcompress: 12.10 Avicel PH 101 : 7.50 XL Kollidon: 2.00 Magnabrite F: 2.00 Acesulfame K: 0.20 Magnasweet 100: 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 Formulation X: % Fluoxetine TMMS*: 28.69 Pearlitol 400DC : 43.81 Emcompress: 12.10 Avicel PH 101 : 7.50 Magnabrite F: 4.00 AcesulfameK: 0.20 Magnasweetl 00 : 0.20 Tangerine Flavor: 0.50 Citric Acid anhydrous: 1.50 Syloid 244FP: 0.50 Pruv: 1.00 *Note: TMMS = Taste Masked Microspheres. Fluoxetine was used as a model drug, but these formulas cover the use of any coated or uncoated CEFORM Microsphere.

Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.