Patent Publication Number: US-2011061345-A1

Title: Solid and semi-solid dosage forms and systems and methods for forming and packaging thereof

Description:
This application claims the priority of U.S. Provisional Patent Application No. 61/221,386, filed Jun. 29, 2009, which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a solid/semi solid dosage form packaging, and methods and system for making the solid/semi solid dosage form packaging. 
     BACKGROUND OF THE INVENTION 
     Pharmaceutical compositions may be produced in a variety of dosage forms, depending upon the desired route of administration of the active ingredient. Oral dosage forms, for example, include such solid/semi-solid compositions as tablets, granules, powders, beads, minitablets, and pellets. The particular dosage form utilized will depend on such factors as the solubility and chemical reactivity of the active ingredient. Further, the dosage form may be selected so as to optimize delivery of the active ingredient and/or consumer acceptability of the composition. 
     Also, the accuracy of the doses is of importance. Pharmaceutical compositions often contain active drug components that are harmful if the given dose is too high. On the other hand, the desired effect of the medicament is not achieved if the dose is too low. 
     When two or more ingredients are contained in a dosage form, uniform mixing of the ingredients prior to packaging is important in maintaining consistency and accuracy of the doses. It is, however, difficult to uniformly mix two or more solid ingredients having different physical characteristics, such as particle size, density, and flowability, as the ingredients tend to separate. 
     Therefore, a need remains for providing consistent and accurate pharmaceutical dosages, especially for rapid melt dosages. Such compositions are ideal for uses in the fields of pediatric and geriatric care, that is, for use with people or mammals who has severe health issues, who can not swallow the tablet or capsule, and people who do not have any teeth. Such compositions are also used in the cancer patients. Such compositions can be administered without water. 
     SUMMARY OF THE INVENTION 
     By individually metering and dispensing specific volumes of each component of the dosage, the amount of the components for each dose is secured with very high accuracy. Thus, one of the advantages with the present invention is that the accuracy and precision of the amount of the components can be monitored and metered, and the result used to secure the quality of the pharmaceutical product. 
     The present invention relates to a new method for dosing a pharmaceutical product in a sealed container, such as a packet, sachet and blister pack, comprising a first component and a second component. In an embodiment, the first component are rapid melt granules or bead, and the second component is an active ingredient. The rapid melt granules serve as carriers that allow the active ingredient to dissolve in the mouth and be swallowed without the administration of water. When in use, the user merely opens the container and empties its content into the mouth. The same principle can be used to make pharmaceutical products containing more than two components. 
     The two component dosage form can be packaged in a sealed container, such as a packet, sachet, blister pack, or other unit dose form. The method comprises providing the first component by weighing the volume of the first component. Thus, a defined dose of the first component is provided, for example beads. Further, the method comprises introducing the first component into a package, weighing the volume of the second component, introducing the second component into the package, and sealing the package. Subsequent components are also individually metered before being added to the package. When all the components are added to the container, it is sealed and ready for use. 
     The present invention also provides a machine, system, apparatuses, or devices for making the two or one component dosage form. The machine includes at least two hoppers, each for holding and dispensing a component of the final dosage form. Each hopper dispenses its content into a dosing wheel which includes holes on its peripheries. Thus, if there are two components in the final dosage form, each component is contained in a hopper which is associated with a dosage wheel. The wheel spins on its center axis and allows the component contained in the hopper to fill the holes. A scraper removes the excess component to ensure that the volume of the material is accurate. As the hole aligns with a funnel, its component empties into the funnel which funnels the ingredient into a package for forming the dosage form. The multiple wheels are timed so that the components are added to the funnel and packaged together. This way, the ingredients are individually metered and added to the packaged dosage form to ensure accuracy and consistency. Preferably, the amount of each component within the package varies no more than 5%, preferably no more than 2.5%, most preferably no more than 1.5% between batches and packages. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a picture showing an embodiment of the present invention. 
         FIG. 2  is a picture showing a dosing wheel. 
         FIG. 3  is a picture showing the bottom side of a dosing wheel with a closed cover. 
         FIG. 4  is a picture showing the bottom side of a dosing wheel with an opened cover. 
         FIG. 5  is a picture showing a dosing wheel with a scraper. 
         FIG. 6A  is a drawing showing the top view of a dosing wheel. 
         FIG. 6B  is a drawing showing a cross-section of a dosing cup. 
         FIG. 7  is a drawing showing the top view of a dosing wheel for handling two components. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below. 
     The singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a drug” includes reference to one or more of such drugs, and reference to “an excipient” includes reference to one or more of such excipients. 
     As used herein, the terms “formulation” and “composition” and “component” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients. 
     As used herein, “active agent,” “bioactive agent,” “pharmaceutically active agent,” “pharmaceutical,” “active ingredient” or “functional agents” variations thereof may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. It is to be understood that the term “drug” is expressly encompassed by the present definition as many drugs and prodrugs are known to have specific physiologic activities. These terms of art are well-known in the pharmaceutical and medicinal arts. 
     As used herein, “subject” refers to a mammal that may benefit from the administration of a drug composition or method of this invention. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. 
     As used herein, “blood level” may be used interchangeably with terms such as blood plasma concentration, plasma level, plasma concentration, serum level, serum concentration, serum blood level and serum blood concentration. 
     As used herein, “oral dosage form” and the like refers to a formulation that is ready for administration to a subject through the oral route of administration. Examples of known oral dosage forms, include without limitation, tablets, caplets, powders, pellets, granules, beads and mini tablets and combinations there of etc. Such formulations also include multilayered tablets wherein a given layer may represent a different drug. In some aspects, granules, powders, pellets, minitablet (under 7 mm in diameter, preferably under 5 mm, most preferably under 4 mm), or nanoparticles may be coated with a suitable polymer/fats/waxes/emulsifiers/carbohydrates or a conventional coating material to achieve, for example, greater stability in the oral cavity, gastrointestinal tract, to achieve the desired rate of release, or to improve taste. Tablets and caplets may be scored to facilitate division of dosing. Alternatively, the dosage forms of the present invention may be unit dosage forms wherein the dosage form is intended to deliver one therapeutic dose per administration. Particular embodiments or groups of embodiments may be expressly limited to subsets of these dosage forms. 
     As used herein, “packet” or “stick pack” refers to a small, sealed packet containing a quantity of material, which is a single-use or unit dose quantity. 
     As used herein, an “effective amount” or a “therapeutically effective amount” of a drug or active ingredient refers to a sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount” or a “therapeutically effective amount” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographs in Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein by reference. 
     As used herein, “pharmaceutically acceptable carrier” and “carrier” may be used interchangeably, and refer to any inert and pharmaceutically acceptable material that has substantially no biological activity, and makes up a substantial part of the formulation. 
     The term “admixed” means that the drug and/or other ingredients can be dissolved, dispersed, or suspended in the carrier. In some cases, the drug may be uniformly admixed in the carrier. 
     As used herein, the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result. For example, a composition that is “substantially free of” particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles. In other words, a composition that is “substantially free of” an ingredient or element may still actually contain such item as long as there is no measurable effect thereof. 
     As used herein, the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. 
     As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. 
     Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. 
     This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. 
     “Rapid melt granules,” as used herein, are granules, powders, beads, minitablets, pellets, nanoparticles, or combinations there off that, when placed in the mouth, dissolves within 60 second, preferably 30 seconds, more preferably 20 seconds, yet more preferably 10 seconds, and most preferably 5 seconds. The granules, powders, beads, minitablets, pellets, nanoparticles, or combinations thereof can contain an active ingredient, but that is not necessary. Rapid melt granules can be made using the process disclosed in U.S. Patent Application Publication No. 2010/0010101, which is incorporated herein by reference. 
     The dosage form of the present invention comprises at least a first and a second component that are provided in a sealed container. In an embodiment, the first component is a rapid melt granule and the second component is an active ingredient, preferably in powder, granule, beads, minitablets, pellets, nanoparticles, or combinations there off. The rapid melt granules acts as a carrier for the active ingredient so that, when the dosage form is placed in the mouth, the active ingredient can be rapidly dissolves and ingested without additional administration of water. Although water is not required to dissolve the active ingredient, in certain embodiment, water may be used to assist in ingestion of the dosage form. 
     The dosage from can be made by providing the first component by metering a desired volume of the first component. Thus, a defined dose of the first component is provided, for example beads. Further, the method comprises introducing the first component into a package, metering a desired volume of the second component, introducing the second component into the same package, sealing the package into which the components have been introduced. Subsequent components can similarly be added to the same package. 
     In another embodiment, the method comprises sealing the package after introducing the components. 
     In one embodiment, the present invention provides a solid or semi solid product comprising at least a first and a second component in the same dosage form. The product can be contained, e.g. in a package. Preferably, at least one of the components contains an active ingredient. It is also desirable to have least one of the components containing placebo rapid melt granules. The placebo rapid melt granules are preferably flavored. Preferably, the weight ratio of the active ingredient to the rapid melt granules is 0.1:100 to 100:0.1, preferably 1:2 to 1:7. 
     In another embodiment, the present invention provides a dosage form in a sealed container containing at least two components. The dosage form can be contained, e.g. in a package. Preferably, at least one of the components contains an active ingredient, while at least one of the other components contains placebo rapid melt granules, preferably flavor rapid melt granules. 
     The active ingredient delivery forms are preferably beads, mini tablets, granules, crystals, powder and combinations there off. The active ingredients can also be modified for taste masking, or controlled or sustained release. The active ingredient, as a component of the dosage form, can be uncoated or coated beads, mini tablets, granules, crystals or powder and combinations there off in the form of a unit dose packet. The taste masking of the active ingredients can be achieved with polymers (methacrylate polymers, cellulose polymers, or combinations there off), resins, fats, waxes, or carbohydrates. Processes for taste masking of the active ingredients include granulation, complexation, spray congealing, spray drying and fluid bed coating, which are known in the art. 
     In another embodiment, a machine is used for making the dosage form with least two components. The machine is preferably a volumetric feeder system that can be used to dose various pharmaceutical dosage forms. The machine contains at least two hoppers with corresponding dosing wheels for metering each component into a package. Preferably, the machine also includes mechanisms for forming and sealing the package, e.g. stick pack, as it is being filled. These mechanisms include, vertical forming jaws, horizontal sealing jaws, stick forming tube, and heaters. 
     The equipment can be used to accurately feed one, two or three different ingredients into a single unit dose. The dosing disc is made up of fixed or variable thickness to accommodate different fill weights. Volume of the dosing cup determines the fill weight of each ingredient into a packet (or stick). The accuracy of fill is achieved by measuring the density of the product being dosed and the required dosage. Volume of the cup is then determined to achieve the required fill weight. Based on the size of the granules/beads/powders/minitablets/pellets/nanoparticles and the thickness of the dosing disc, the diameter of the dosing hole is determined. 
     Referring to  FIGS. 1-6  which show an embodiment of the machine for filling the dosage form, which includes hoppers  2  and  4 . Although the Figures shows two hoppers for filling dosage forms containing two components, additional hoppers and associated components can be added to accommodate dosage forms having more than two components. The hoppers  2  and  4  contain different components of the final dosage form. For example, the first hopper  2  can contain a powdered active pharmaceutical ingredient, while the second hopper  4  can contain taste enhanced, e.g. flavor, rapid melt granules. 
     Each hopper  2  or  4  drains its component into a dosing wheel  8 , preferably locating directly below the hopper. The dosing wheel  8  contains a plurality of dosing cups  12  in its periphery ( FIG. 6A ). The dosing cup ( FIG. 6B ) is essentially a cylindrical disc having a through hole  10  in its center for metering the component dispensed from the hopper  2  or  4 . The hole  10  can be of different sizes depending on the desired amount of the component being dispensed into the final package. The dosing cups  12  fit into open recesses  18  in the dosing wheel  8 , so that its can be removed/replaced to accommodate different amounts of the desired component. The volume of the component can be changed by changing the hole  10  diameter and/or the thickness of the dosing wheel  8 . Because it is generally impractical to change the thickness of the dosing wheel  8 , the volume of the component is determined by varying the diameter of the hole  10 . Thus, to increase the amount of active ingredient, the operator removes the dosing cup  12  and replaces it with another dosing cup  12  having a hole  10  with a larger diameter. The desired volume of a component is calculated from its bulk density. Because each component is homogenous, its bulk volume is generally consistent and does not vary from batch to batch, as compared to heterogeneous mixtures of the components. 
     In operation, the dosing wheel  8  spins around its center axis  20  at a fixed speed while the desired component from the hopper  2  or  4  is being drained into the dosing wheel  8  to fill the holes  10 . During each revolution, when a dosing cup  12  comes into alignment with a funnel  6 , it empties its content into the funnel  6 . Although “funnel  6 ” is used herein, it should be understood that the “funnel  6 ” needs not have the shape of a common funnel as long as it is capable of directing the components into their package. Prior to coming into alignment with the funnel  6 , a scraper  16  ( FIGS. 5 and 6A ) scrapes excess material of the top of the dosing cup  12  such that the component is only contained within the volume of the hole  10 , with no overfill. That way, a consistent and accurate amount of the component is ensured. Normally, the bottom of the hole  10  is closed by a cover  14  ( FIG. 3 ). When the dosing cup  12  is in alignment with the funnel  6 , the cover  14  opens ( FIG. 4 ) revealing the hole  10  and, as a result, emptying the content of the dosing cup  12  into the funnel  6 . The closing and opening of the cover  14  can be accomplished mechanically or by electronic control. Mechanical opening and closing can be accomplished, for example, by a pair of stationary posts. Just before the dosing cup  12  comes into alignment with the funnel  6 , the door may be tripped into an open position with a first stationary post; and as it leaves the funnel  6 , the cover  14  hits a second stationary post which pushes it into a closed position. Alternatively, electronic controls may be used to open and close the cover  14  when it is in alignment with the funnel  6 . Mechanical opening and closing of the cover is generally preferred because it is a simpler system. 
     The power to spin the dosing wheel  8  is preferably provided via a drive shaft  22 . Each dosing wheel  8  must be timed to synchronize with the other dosing wheel(s) so that the components are dispensed into the funnel  6  at substantially the same time. Preferably, this is accomplished by driving all dosing wheels  8  by a single motor. This way it is possible to spin the dosing wheels  8  at the same speed and to achieve proper delivery of the components to the funnel  6 . In this preferred embodiment, it is desirable to include a clutch for each dosing wheel  8 , so that it can be disengaged from the motor during operation for quality checks or repair. 
     Once the components are delivered to the funnel  6 , they are directed to a container for packaging. The container can be, but not limited to, a package, a sachet, or a packet. Preferably, the container is a flexible package made from plastic, foil, glass, heat sealable laminated film (paper and polyethylene (PE), polyethylene terephthalate (PET) and PE, foil and PE, foil and paper and PE, PET and foil and PE), or combinations thereof. In certain embodiments, the machine also contains equipment for printing on the package, sealing (vertical and horizontal sealing jaws), heating, forming a tube from the packaging material, and cutting the package. Those equipments, when present, are synchronized with the dosing cups to properly package the final dosage form. In an example, the sealing jaws and cutter can be driven using the same motor driving the dosing wheel  8  to achieve synchronization. Alternatively, electronic controls can also be used to synchronize the equipment. Preferably, the final package has dimensions of 0.7 in. to 3.5 in. wide and 1 in. to 6 in. long. 
     In an embodiment, it is desirable to add an inert gas, such as nitrogen, to the package before sealing. This could be accomplished by blowing gas through the funnel  6  along with the components. This way, the gas is delivered through the funnel into the package before sealing. In an embodiment, the inert gas can be delivered to the funnel through a tube that connects a gas container to the funnel  6  inlet. Preferably, a valve is placed between the gas container and the funnel  6  to regulate the pressure of the gas entering the package. The regulated pressure is preferably between about 2 PSI to about 7.5 PSI, with minimum of about 50 PSI pressure in tank at all times 
     In an embodiment, to prevent clogging of the equipment by the components, vibrators can be placed, e.g., to provide vibration in the funnel  6 , the dosing wheel  8 , and/or the hoppers  2  and  4  to prevent clogging of the machine. Preferably, the vibration is 4,000 vibrations per minute (vpm) to 18,200 vpm. Other than vibration, the surfaces that come into contact with the components can also be coated to prevent clogging. For example, the surface can be coated with polytetrafluoroethylene (PTFE) to reduce friction and improve flow of the components. Other friction reducing techniques are also known in the art. Alternatively, the component is itself formulated to impart flowability, by adjusting the amount of excipients to accommodate formulation-related flowability. For example, a lubricant, e.g. alkaline stearates (preferably magnesium stearate), silicon dioxide, talc, or stearic acid, can be added to improve flow of a component. 
     In a preferred operation, the components are filled on to the dosing wheels  8  through hoppers  2  and  4 . The dosing wheels  8  rotate at a set speed filling the components into the dosing cups  12  of their respective dosing wheels  8 . Scrapers  16  removes overfill components on top of the cups and ensures accurate fill of the ingredient. The dosing wheels move further and empty their contents into a funnel  6  located below the wheel. The components are then dosed into a dosage form, preferably a flexible package. After filling of required ingredients the horizontal sealing jaws pull the stick downwards and seal and cut the stick from the top, while forming a second package and the process continues. 
     For example, a composition containing taste masked guaifenesin (beads, granules, powder, minitablets, pellets, nanoparticles, or combinations thereof) and flavored placebo rapid melt granules combination, two discs with two hoppers can be used. Speed of each disc is controlled using a single drive unit so that the contents of the cup are emptied into a single feed tube at the same time. Thus, all material is dosed into the stick to form a unit dose. 
     Although the drawings depict a two component dosage form, additional set-up can be made to dose three or more components into a final dosage form. Three hoppers, with three dosing discs will be used for a three component dose operation; four hoppers, with four dosing discs will be used for a three component dose operation; etc. Those dosage forms and machines for forming thereof are within the scope of the present invention. 
     In a preferred embodiment, the machine for used with the present invention has following specification: 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Pack style 
                 Pillow type 
               
               
                 Packing dimension 
                 W2″ - minimum 15 mm to maximum 152 mm 
               
               
                   
                 L2″ - minimum 60 mm to maximum 279 mm 
               
               
                 Packing speed 
                 20-60 Bags/min 
               
               
                 Max. film dimension 
                 Ø12″ W 11″ 
               
               
                   
                 Thickness 3 mil. 
               
               
                 Power supply 
                 220 V, 60 Hz, 8 Kw 
               
               
                   
                 single phase 
               
               
                 Machine weight 
                 800 Lb 
               
               
                 Machine dim. 
                 W 20″ × L 30″ × H 92″ 
               
               
                   
               
            
           
         
       
     
     In another preferred embodiment, packaging machine has following features can also be used: 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Filling System 
                 Adjustable telescopic Disc Volumetric Cup Filler 
               
               
                 Filling Accuracy 
                 ±1 to 1.5% 
               
               
                   
                 Depend upon Nature of Product 
               
               
                 Type of Seal 
                 3 SideCentre or Back Seal 
               
               
                 Filling Range 
                 500 mg to 50 gm 
               
               
                 Packed Material 
                 Granules and free flowing beads 
               
               
                 Size of Bag/Pouch 
                 W - 100 to 160 mm 
               
               
                   
                 L - 80 to 130 mm 
               
               
                 Speed capacity 
                 40 to 70 bag/min. 
               
            
           
           
               
               
               
            
               
                 Machine size 
                 H 
                 2150 mm 
               
               
                   
                 W 
                  680 mm 
               
               
                   
                 L 
                  900 mm 
               
               
                 Wooden case 
                 H 
                 1700 mm 
               
               
                   
                 W 
                 1000 mm 
               
               
                   
                 L 
                 1100 mm 
               
            
           
           
               
               
            
               
                 Film roll size 
                 O.D 250 to 300 mm max 
               
               
                   
                 1. D Film Reel Pipe 
               
               
                   
                 75 mm min. 
               
               
                 Power consumption 
                 Moto ½ H.P 
               
               
                   
                 220 V AC Single Phase 
               
               
                   
                 50 to 60 Hz 
               
               
                   
                 Heater 150 × 2 + 
               
               
                   
                 300 × 2 
               
               
                 Film Quality 
                 Laminated Roll + Aluminum Foil 
               
               
                   
               
            
           
         
       
     
     This packaging machine is specially designed to control weight variation of the components to +0.5% to +0.1%. 
     Although the above disclose two dosing wheels handling two components, it is possible to design one dosing wheel handling two components. Such a dosing wheel  700  is shown in  FIG. 7 , which contains two concentric circular portions. The outer portion  702  handles the first component, while the inner portion  704  handles the second component. The inner  702  and outer portions  704  are separated, e.g. by a wall, so that components in each portion do not intermix. The outer portion  702  contains recesses  708  for containing dosing cups, similar to the recesses  18  as previously described. The inner portion  704  also contains recesses  710  for containing dosing cups. Preferably, the recesses  708  and  710  are paired, such that each pair lays on a radius line of the dosing wheel  700 . At the bottom of each recess  708 ,  710  is a cover, as previously disclosed for recesses  18 , that can be opened to allow the content of the dosing cup to be emptied into a funnel. A stationary scrapers are preferably included to ensure accuracy and consistency as previously discussed. In this embodiment, a scraper is included in the inner portion  704  (inner scraper); and one is included in the outer portion  702  (outer scraper). 
     During operation, the dosing wheel  700  rotates on its axis by, e.g. a center shaft  706 . A first hopper, containing the first component, drains its content into the outer portion  702 ; and a second hopper, containing the second component, drains its content into the inner portion  704 . As the wheel rotates, just before the paired recesses  708  and  710  (and thus the corresponding dosing cups) reach a predetermined position where the recesses  708  and  710  are in alignment with the funnel, e.g. position x on  FIG. 7 , the scrapers remove overfill components on top of the dosing cups and ensure accurate fill of the component. When the recesses  708  and  710  reaches, e.g. position x. The covers below the recess pair open to allow the components contained in the dosing cups to empty into the funnel located below the dosing wheel. One the contents are emptied the covers are closed and the cycle continues. The mechanical or electronic control of the covers can be accomplished as previously disclosed. Once emptied into the funnel, the components can be processed a previously disclosed. 
     Although dosing wheel  700  has been disclosed above to handle two components, that wheel can be adapted to handle three or more components. In this embodiment, the wheel can be designed to include three or more concentric portions, where each component from a hopper is added to the a portion of the wheel. 
     The amount of active ingredient in the preparation is in the range of 0.1 mg to 10 g. Preferred prophylactic or therapeutic active ingredients contemplated for use in the present inventive subject matter are, without limitation, guaifenesin, mesalamine, diltiazem, metoprolol, balsalazide, aspirin, benzocaine, diphenhydramine, acetaminophen, ibuprophen and mixtures thereof. 
     Preferred prophylactic or therapeutic active ingredients contemplated for use in the present inventive subject matter are antibiotic, which is selected from the group consisting of amoxicillin and clavulanate potassium, ciprofloxacin HCl, azithromycin, clarithromycin, sterile ceftriaxone sodium, cefuroxime axetil, imipenem cilastatin, levofloxacin, ceftazidime, ampicillin sodium and sulbactum sodium, cefaclor, amoxicillin, cefdinir, roxithromycin, sterile cefotaxime sodium, vancomycin, piperacillin sodium and tazobactam sodium, morniflumate, flomoxef sodium, cefotiam dihydrochloride, ofloxacin, mupirocin calcium, vancomycin HCl, teicoplanin, cefadroxil monohydrate, sulbactum cefoperazone, meropenem, ofloxacin, cephalexin, cefepime HCl, cefuroxime sodium, minocycline HCl, cefaclor, cefazolin, trimethoprim and sulfamethoxazole, norfloxacin, trovafloxacin, cefpodoxime proxetil, cefdinir, cefixime, panipenem, ceftibuten, levofloxacin, cefoxopran HCl, amikacin sulfate, aztreonam, minocycline HCl, ticarcillin disodium or mixtures thereof. 
     Another preferred active ingredient can be selected from the class antibiotics including beta-lactamse inhibitor, quinolone, macrolide, cephalosporin, glycopeptide, cephem, immunoglobin tetracycline, fluoroquinolone aminoglycoside, and monobactam antibiotics. 
     Many of the active ingredients listed above have unpalatable tastes. Taste-masking of compositions with those unpalatable active materials is well-known in the art. The active ingredient may coated with a suitable polymer/fats/waxes/emulsifiers/carbohydrates. The use of flavors and sweeteners to mask the unpalatability of the active materials is also well-known. Thus, other materials which can be incorporated into composition include flavors, colors and sweeteners. Importantly, it is possible to incorporate high levels of flavors, sweeteners and other taste-masking agents, making the compositions more palatable when undesirable tastes accompany the active materials. 
     Taste masking may be chosen from natural and synthetic flavor liquids. Flavors useful include, without limitation, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting list of examples include citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors. 
     Taste masking of the active ingredients can be done using the well-known processes in the art such as fluidization, spray drying, spray congealing, complex co-acervation, resin complexation, matrix granulation using carbohydrates, resins, polymers, waxes &amp; fats. 
     Taste enhancers may be chosen from natural and synthetic flavor liquids. Flavors useful include, without limitation, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting list of examples include citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors. fat 
     Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., alphacitral (lemon, lime), neral, i.e., betal-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), and mixtures thereof. 
     The compositions are “storage stable”, meaning that the compositions are stable in the absence of special handling procedures. The inventive compositions are stable both prior to packaging and after packaging. Importantly, the inventive compositions maintain their stability and integrity without refrigeration and without humidity controls being implemented during handling, packaging and storing of the products. Additionally, since the compositions exhibit increased integrity and stability, the compositions can be used in most of the current economical packages suitable for a global environment. Further, high temperatures are not needed when processing the packaging and sealing. 
     Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and use the present invention. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in the examples. 
     Example 1 
     General Procedure 
     The following procedure describes filling of two or more separate ingredients being filled into a single stick pack using the innovation claimed in this innovation. 
     The equipment consisted of a two-hopper system with two dosing wheels, vertical forming jaws, horizontal sealing jaws, stick forming tube, and heaters. 
     The dosing wheels were made of fixed thickness to accommodate different fill weights. Volume of the dosing cup determined the fill weight of each ingredient into the stick (final package). The accuracy of fill was achieved by measuring the density of the product being dosed and the required dosage. Volume of the cup was determined to achieve the required fill weight. Based on the size of the granules/beads and the thickness of the dosing disc, the diameter of the dosing hole was determined. The dosing wheels were placed on a central vertical shaft and had holes made on the periphery. The size of the hole determined the maximum fill weight that can be achieved with the fixed depth (X) wheel. The components were filled on to the respective dosing wheels through the hopper. The wheels rotated at a set speed filling the components into their cups. The scrapers took off extra components on top of the cup and ensure complete accurate fill of the ingredient. The dosing wheels moved further and emptied their contents into the funnel located below the dosing wheels. The components were thus dosed into the stick (final package). The film rolled to form the stick sealed on the bottom and sides. After filling of the required components, the horizontal sealing jaws pulled the stick downward and sealed and cut the stick from the top, while forming the second stick to repeat the process. 
     Two hoppers, with two dosing wheels, were used for two dose operation to form a dosage form containing guaifenesin encapsulated beads and rapid melt granules. The components were dosed into the packet to form a unit dose. 
     Example 2 
     Placebo Rapid Melt Granules 
     Placebo (not containing an active ingredient) rapid melt granules (can also be powders, beads, minitablets, pellets, nanoparticles, or combinations thereof) can be made using the following formulations: 
     
       
         
           
               
            
               
                   
               
               
                 Placebo Rapid Melt Granules Formulation 1 
               
            
           
           
               
               
               
            
               
                   
                 Ingredients 
                 Quantity by weight (%) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Sugar 6x 
                 40.26 
               
               
                   
                 Bakers Special Sugar 
                 35.00 
               
               
                   
                 Sucralose Micronized 
                 0.50 
               
               
                   
                 Natural Seal Orange flavor 
                 2.54 
               
               
                   
                 Polyplasdone XL-10 
                 3.00 
               
               
                   
                 Cocoa Butter 
                 12.00 
               
               
                   
                 S-Maz 60K (Monoemul-60) 
                 3.00 
               
               
                   
                 Carbowax Sentry PEG 3350, 
                 3.00 
               
               
                   
                 Granular 
               
               
                   
                 Stepanol WA 100 
                 0.05 
               
               
                   
                 Tween 80K 
                 0.15 
               
               
                   
                 Syloid 244FP 
                 0.50 
               
               
                   
                 Total 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Placebo Rapid Melt Granules Formulation 2 
               
            
           
           
               
               
               
            
               
                   
                 Ingredients 
                 Quantity by weight (%) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Diluents 
                   
               
               
                   
                 Mannitol Powder Pearlitol 160C 
                 39.90 
               
               
                   
                 Sorbitol Powder Neosorb P60W 
                 35.00 
               
               
                   
                 Emcocel 90M 
                 15.00 
               
               
                   
                 Sweetening Agent 
               
               
                   
                 Sucralose Powder 
                 0.50 
               
               
                   
                 Flavor 
               
               
                   
                 Bubble Gum FL S/D Powder # 
                 2.50 
               
               
                   
                 209V47 
               
               
                   
                 Disintegrants 
               
               
                   
                 Polyplasdone XL-10 
                 4.00 
               
               
                   
                 Sodium Starch Glycolate 
                 2.00 
               
               
                   
                 Emulsifiers 
               
               
                   
                 Tween 80K 
                 0.25 
               
               
                   
                 Sodium Lauryl Sulfate 
                 0.10 
               
               
                   
                 Binder 
               
               
                   
                 Plasdone K 29/32 
                 0.75 
               
               
                   
                 Purified USP water 
                   
               
               
                   
                 Total 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Placebo Rapid Melt Granules Formula 3 
               
            
           
           
               
               
               
            
               
                   
                 Ingredients 
                 Quantity by weight (%) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Diluents 
                   
               
               
                   
                 Mannitol Powder Pearlitol 160C 
                 81.15 
               
               
                   
                 Emcocel 90M 
                 10.00 
               
               
                   
                 Sweetening Agent 
               
               
                   
                 Sucralose Powder 
                 0.50 
               
               
                   
                 Flavor 
               
               
                   
                 Bubble Gum FL S/D Powder # 
                 2.50 
               
               
                   
                 209V47 
               
               
                   
                 Disintegrants 
               
               
                   
                 Polyplasdone XL-10 
                 5.00 
               
               
                   
                 Emulsifiers 
               
               
                   
                 Tween 80K 
                 0.15 
               
               
                   
                 Sodium Lauryl Sulfate 
                 0.10 
               
               
                   
                 Binder 
               
               
                   
                 Plasdone K 29/32 
                 0.60 
               
               
                   
                 Purified USP water 
                   
               
               
                   
                 Total 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     The above formulations can be made as granules, powders, beads, minitablets, pellets, nanoparticles, or combinations thereof for use in the packs of the present invention. Although the flavors are specified in the formulations, it can be changed as desired without adversely compromising the fast melting property of the formulation. The formulations of this example can be used in the subsequent examples. 
     Example 3 
     Guaifenesin/Rapid Melt Granules in a Delivery Form 
     The general procedure of example 1 is carried out for weighing 180 mg of encapsulated guaifenesin beads and 780 mg of placebo rapid melt granules—grape flavor. 
     Further, the general procedure of Example 1 was carried out for packaging and sealing to give a fill weight 960 mg per dosage form for guaifenesin rapid melt granules—grape flavor. The flavored rapid melt granules dissolved in the mouth within less than 5 seconds and the saliva took away the encapsulated guaifenesin beads. Thus, the rapid melt granules helped to swallow the encapsulated beads. 
     Component 1: Beads of encapsulated Guaifenesin having bulk density 0.70 g/mL, Particle size: retained above #16 is 0.1%, above #20 is 30.2%, above #25 is 65.4%, above #35 is 4.2%. 
     Component 2: flavored Placebo rapid melt granules with bulk density 0.6 g/mL and particle size between #8 mesh and #60 mesh. 
     Assay is performed on the packaged products to verify the dose accuracy, assay is 99%. Also, the compositions are stable both prior to packaging and after packaging. 
     The Weight Variation is checked on the packaged product: 
     
       
         
           
               
            
               
                   
               
               
                 Weight variation for Placebo Guaifenesin 50 mg Rapid melt 
               
               
                 granules - Grape flavor (960 mg) Packaged 
               
            
           
           
               
               
               
               
            
               
                 Sachets S. 
                   
                 Avg. 
                 Relative standard 
               
               
                 No 
                 Weight (mg) 
                 Weight (mg) 
                 deviation (RSD) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 958.9 
                 953.9 
                 0.8 
               
               
                 2 
                 953.2 
               
               
                 3 
                 955.1 
                 Min 
                 Max 
               
               
                 4 
                 952 
                 942.1 
                 971.5 
               
               
                 5 
                 957.5 
               
            
           
           
               
               
               
            
               
                 6 
                 950.9 
                 Target 
               
            
           
           
               
               
               
               
            
               
                 7 
                 953.1 
                 960 
                 mg 
               
            
           
           
               
               
               
            
               
                 8 
                 958.1 
                 Batch# 
               
               
                 9 
                 953.2 
                 CPI-198PL-001 and CPI-181C-005 
               
               
                 10 
                 959.9 
                 Acceptance criteria 
               
               
                 11 
                 944.9 
               
               
                 12 
                 946.5 
               
               
                 13 
                 960.9 
               
            
           
           
               
               
               
               
            
               
                 14 
                 956.4 
                 Low limit 
                 High limit 
               
               
                 15 
                 955.2 
                 888 
                 1032 
               
               
                 16 
                 949 
                 Below 722 mg 
                 Above 839 mg 
               
               
                 17 
                 943.1 
                 0 
                 0 
               
               
                 18 
                 950.8 
                 Allowable limit 
                 ±7.5% 
               
               
                 19 
                 971.5 
               
               
                 20 
                 945.4 
                 Actual variation 
                 &lt;±2.0% 
               
               
                 21 
                 949.2 
               
               
                 22 
                 970.4 
               
               
                 23 
                 966.8 
               
               
                 24 
                 942.1 
               
               
                 25 
                 942.9 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Weight variation for Guaifenesin 50 mg Rapid melt 
               
               
                 granules (180 mg) Packaged 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sachets 
                   
                   
                   
               
               
                   
                 S. No 
                 Wt (mg) 
                 Avg Wt (mg) 
                 RSD 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 180.5 
                 181.3 
                 1.3 
               
               
                   
                 2 
                 178.1 
               
               
                   
                 3 
                 182.4 
                 Min 
                 Max 
               
               
                   
                 4 
                 179.1 
                 177.8 
                 187.2 
               
               
                   
                 5 
                 180.1 
               
            
           
           
               
               
               
               
               
            
               
                   
                 6 
                 181.2 
                 Target 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7 
                 180.8 
                 180 
                 mg 
               
            
           
           
               
               
               
               
               
            
               
                   
                 8 
                 184 
                 Batch# 
                   
               
               
                   
                 9 
                 183.9 
                 CPI-181C-005 
               
               
                   
                 10 
                 183.5 
                 Acceptance criteria 
               
               
                   
                 11 
                 180.7 
               
               
                   
                 12 
                 182.9 
               
               
                   
                 13 
                 179 
               
            
           
           
               
               
               
               
               
            
               
                   
                 14 
                 181.6 
                 Low limit 
                 High limit 
               
               
                   
                 15 
                 180.9 
                 171 
                 189 
               
               
                   
                 16 
                 182.7 
                 Below 171 mg 
                 Above 189 mg 
               
               
                   
                 17 
                 187.2 
                 0 
                 0 
               
               
                   
                 18 
                 179.4 
                 Allowable 
                 ±5% 
               
               
                   
                 19 
                 179 
                 limit 
               
               
                   
                 20 
                 178.8 
               
               
                   
                 21 
                 185.2 
               
               
                   
                 22 
                 177.8 
               
               
                   
                 23 
                 181.8 
               
               
                   
                 24 
                 179.4 
               
               
                   
                 25 
                 183.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Weight variation for Placebo Guaifenesin 50 mg 
               
               
                 Rapid melt granules - Grape flavor (780 mg) 
               
               
                 Packaged 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sachets 
                   
                   
                   
               
               
                   
                 S. No 
                 Wt (mg) 
                 Avg Wt (mg) 
                 RSD 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 793.1 
                 783.7 
                 1.0 
               
               
                   
                 2 
                 780.6 
               
               
                   
                 3 
                 788.9 
                 Min 
                 Max 
               
               
                   
                 4 
                 789.6 
                 765.9 
                 796.5 
               
               
                   
                 5 
                 781.1 
               
            
           
           
               
               
               
               
               
            
               
                   
                 6 
                 780.2 
                 Target 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7 
                 788.6 
                 780 
                 mg 
               
            
           
           
               
               
               
               
               
            
               
                   
                 8 
                 771.8 
                 Batch# 
                   
               
               
                   
                 9 
                 767 
                 CPI-198PL-001 
               
               
                   
                 10 
                 765.9 
                 Acceptance criteria 
               
               
                   
                 11 
                 783.6 
               
               
                   
                 12 
                 794.5 
               
               
                   
                 13 
                 779.4 
               
            
           
           
               
               
               
               
               
            
               
                   
                 14 
                 779.7 
                 Low limit 
                 High limit 
               
               
                   
                 15 
                 783.1 
                 722 
                 839 
               
               
                   
                 16 
                 785.3 
                 Below 722 mg 
                 Above 839 mg 
               
               
                   
                 17 
                 785.8 
                 0 
                 0 
               
               
                   
                 18 
                 793.7 
                 Allowable 
                 ±7.5% 
               
               
                   
                 19 
                 783.9 
                 limit 
               
               
                   
                 20 
                 796.5 
                 Actual 
                 &lt;±2.2 
               
               
                   
                 21 
                 777.2 
                 Variation 
               
               
                   
                 22 
                 782.8 
               
               
                   
                 23 
                 793 
               
               
                   
                 24 
                 784.8 
               
               
                   
                 25 
                 782.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Weight variation for Guaifenesin 50 mg Rapid melt 
               
               
                 granules (180 mg) Packaged 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sachets 
                   
                   
                   
               
               
                   
                 S. No 
                 Wt (mg) 
                 Avg Wt (mg) 
                 RSD 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 185.4 
                 179.8 
                 1.8 
               
               
                   
                 2 
                 182.8 
               
               
                   
                 3 
                 177.4 
                 Min 
                 Max 
               
               
                   
                 4 
                 185.5 
                 172.5 
                 185.5 
               
               
                   
                 5 
                 180.6 
               
            
           
           
               
               
               
               
               
            
               
                   
                 6 
                 180 
                 Target 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7 
                 182.3 
                 180 
                 mg 
               
            
           
           
               
               
               
               
               
            
               
                   
                 8 
                 182.1 
                 Batch# 
                   
               
               
                   
                 9 
                 179.3 
                 CPI-181C-004 
               
               
                   
                 10 
                 177.5 
                 Acceptance criteria 
               
               
                   
                 11 
                 178.7 
               
               
                   
                 12 
                 177.7 
               
               
                   
                 13 
                 175.5 
               
            
           
           
               
               
               
               
               
            
               
                   
                 14 
                 181 
                 Low limit 
                 High limit 
               
               
                   
                 15 
                 176 
                 171 
                 189 
               
               
                   
                 16 
                 180.9 
                 Below 171 mg 
                 Above 189 mg 
               
               
                   
                 17 
                 172.5 
                 0 
                 0 
               
               
                   
                 18 
                 178.9 
                 Allowable 
                 ±5% 
               
               
                   
                 19 
                 177.3 
                 limit 
               
               
                   
                 20 
                 182.1 
               
               
                   
                 21 
                 179.6 
               
               
                   
                 22 
                 177.1 
               
               
                   
                 23 
                 178.6 
               
               
                   
                 24 
                 180.7 
               
               
                   
                 25 
                 185.4 
               
               
                   
                   
               
            
           
         
       
     
     The amount of guaifenesin per dosage form can be 50 mg or 100 mg and fill weight of encapsulated guaifenesin beads 30% was changed accordingly. The fill weight for flavored rapid melt granules can be 300 mg to 1500 mg. 
     The compositions in packet are stable over the months. 
     Example 4 
     Diphenhydramine HCl 25 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 250 mg of diphenhydramine HCl beads 10% and 550 mg placebo rapid melt granules—black cherry flavor. Further, the general procedure of Example 1 was carried out for packaging and sealing to give fill weight 800 mg per dosage form for diphenhydramine HCl 25 mg rapid melt granules—black cherry flavor. 
     Component 1: Diphenhydramine HCl beads 10%
 
Bulk density: 0.75 g/ml
 
Particle size: % retained on #40 is 3.9%, #60 is 13.0%, #80 is 21.8% and #100 is 9.6%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 5 
     Acetaminophen 80 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 88 mg of Encapsulated Acetaminophen beads 91% and 812 mg of placebo rapid melt granules—grape flavor. Further, the general procedure of Example 1 was carried out for packaging and sealing to give fill weight 900 mg per dosage form of acetaminophen 80 mg rapid melt granules—grape flavor. 
     Component 1: Encapsulated Acetaminophen 91% 
     Bulk density: 0.49 g/ml
 
Particle size: % retained on #40 is 28% and on #80 is 70%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 6 
     Acetaminophen 80 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing, packaging and sealing for 1100 mg of acetaminophen granules or beads (rapid melt granules) to give fill weight 1100 mg per dosage form for acetaminophen 80 mg rapid melt granules. 
     Example 7 
     Acetaminophen 160 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 176 mg of Encapsulated Acetaminophen beads 91% and 812 mg of placebo rapid melt granules—grape flavor. Further, the general procedure of Example 1 was carried out for packaging and sealing to give fill weight of 988 mg per dosage form of acetaminophen 160 mg rapid melt granules—grape flavor. 
     Component 1: Encapsulated Acetaminophen 91% 
     Bulk density: 0.49 g/ml
 
Particle size: % retained on #40 is 28% and on #80 is 70%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 8 
     Acetaminophen 160 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing, packaging and sealing for 1212 mg of acetaminophen granules or beads (rapid melt granules)—grape flavor to give fill weight of 1212 mg per dosage form of acetaminophen 160 mg rapid melt granules—grape flavor. 
     Example 9 
     Acetaminophen 325 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 357 mg of Encapsulated Acetaminophen beads 91% and 812 mg of placebo rapid melt granules—grape flavor. Further, the general procedure of example 1 is carried out for packaging and sealing to give fill weight 1169 mg per dosage form for acetaminophen 325 mg rapid melt granules—grape flavor. 
     Component 1: Encapsulated Acetaminophen 91% 
     Bulk density: 0.49 g/ml
 
Particle size: % retained on #40 is 28% and on #80 is 70%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 10 
     Acetaminophen 325 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing, packaging and sealing for 1457.5 mg of acetaminophen granules or beads (rapid melt granules)—grape flavor to give fill weight 1457.5 mg per dosage form for acetaminophen 325 mg rapid melt granules. 
     Example 11 
     Acetaminophen 500 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 549 mg of Encapsulated Acetaminophen beads 91% and 1001 mg of placebo rapid melt granules—grape flavor. Further, the general procedure of Example 1 was carried out for packaging and sealing to give fill weight 1550 mg per dosage form for acetaminophen 500 mg rapid melt granules—grape flavor. 
     Component 1: Encapsulated Acetaminophen 91% 
     Bulk density: 0.49 g/ml
 
Particle size: % retained on #40 is 28% and on #80 is 70%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 12 
     Acetaminophen 500 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing, packaging and sealing for 1900 mg of acetaminophen granules or rapid melt granules—grape flavor to give 1900 mg fill weight per dosage form for acetaminophen 500 mg rapid melt granules. 
     Example 13 
     Acetaminophen 650 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 714 mg of Encapsulated Acetaminophen beads 91% and 1001 mg of placebo rapid melt granules—grape flavor. Further, the general procedure of Example 1 was carried out for packaging and sealing to give 1714 mg fill weight per dosage form for acetaminophen 650 mg rapid melt granules—grape flavor. 
     Component 1: Encapsulated Acetaminophen 91% 
     Bulk density: 0.49 g/ml
 
Particle size: % retained on #40 is 28% and on #80 is 70%
 
Component 2: Flavored Placebo Rapid melt granules:
 
Bulk density: 0.6 g/mL
 
Particle size: NLT 75% retained on #35 mesh
 
     Example 14 
     Acetaminophen 650 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing, packaging and sealing for 2000 mg of acetaminophen granules or beads (rapid melt granules)—grape flavor in dosage form to give fill weight 2000 mg per dosage form for acetaminophen 650 mg rapid melt granules. 
     Example 15 
     Benzocaine 6 mg/Rapid Melt Granules—Grape Flavor in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 500 mg of benzocaine 6 mg rapid melt granules—grape flavor, for packaging and sealing to give benzoaine 6 mg grape flavor in a dosage form. 
     Bulk density of benzocaine rapid melt granules: 0.7 g/mL
 
Particle size: % retained on #16 is 6.1%, % retained on #25 is 90.6%, % retained on #35 is 3.0%, % retained on #40 is 0.1% and passed through #40 is 0.3%
 
After packaging the analytical testing is conducted to verify the dose accuracy.
 
Assay is 100.8% which shows the dose accuracy.
 
     Example 16 
     Extended Release Mesalamine in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 1773 mg of mesalamine extended release beads, for packaging and sealing to give extended release mesalamine 500 mg beads in a dosage form. 
     Particle size: passed through #16 mesh and retained on #25 mesh
 
Bulk density: 0.8 g/mL
 
     The amount of mesalamine per dosage form can be, from about 200 mg to about 2000 mg, including specific intermediate amounts such as 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 750 mg, 1000 mg, 1200 mg, 1500 mg, and 1800 mg. The fill weight of mesalamine extended release beads per dosage form can be 500 mg to 5000 mg. The flavored placebo rapid melt granules can optionally be used with mesalamine extended release beads. 
     Example 17 
     Extended Release Metoprolol Succinate in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 700 mg metoprolol succinate extended release beads, for packaging and sealing to give extended release metoprolol succinate 200 mg beads in a delivery form. 
     Particle size: passed through #25 mesh and retained on #40 mesh
 
Bulk density: 0.55-0.65 g/mL
 
     The amount of metoprolol succinate per dosage form can be 25 mg, 50 mg, 100 mg or 200 mg. The fill weight of metoprolol succinate extended release beads per dosage form will change accordingly. The flavored placebo rapid melt granules can optionally be used with metoprolol succinate extended release beads. 
     Example 18 
     Extended Release Diltiazem in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 1285 mg of diltiazem extended release beads, for packaging and for sealing to give extended release diltiazem 420 mg beads in a delivery form. 
     Particle size: Passed through #14 mesh and retained on #20 mesh
 
Bulk Density: 0.65 g/mL-0.75 g/mL
 
     The amount of diltiazem per dosage form can be 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg. The fill weight of diltiazem extended release beads per dosage form can be 200 mg to 1500 mg. The flavored placebo rapid melt granules can optionally be used with diltiazem extended release beads. 
     Example 19 
     Extended Release Balsalazide 2.2 g in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing 2.8 g of balsalazide extended release beads, for packaging and for sealing to give extended release balsalazid 2.2 g dosage form in a delivery form. 
     The balsalazide 2.2 g can optionally be filled in delivery form with flavored placebo rapid melt granules 2.8 g in a dosage form such as packet or a sealed container. 
     Example 20 
     Amoxicillin and Clavulanate Potassium in a Delivery Form 
     The general procedure of Example 1 was carried out for weighing taste masked amoxicillin (152 g) and clavulanate potassium (32 g). Further, the general procedure of Example 1 was carried out for packaging and for sealing to give amoxicillin 125 mg and clavulanate potassium 32 mg beads in a dosage form in a sealed container. 
     The amount of Amoxicillin and Clavulanate Potassium per dosage form can be 125/32 mg, 200/29 mg, 250/63 mg, and 400/57 mg. The fill weight of Amoxicillin and Clavulanate Potassium beads per dosage form in a sealed container can be 400 mg to 1500 mg. The flavored placebo rapid melt granules can optionally be used with amoxicillin and clavulanate potassium. 
     Example 21 
     Validation for Guaifenesin 50 mg and Grape Flavor Rapid Melt Granules 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 922 mg, which included a blend of encapsulate guaifenesin coated beads and rapid melt granules (grape flavor). Each packet contained 178 mg of encapsulated guaifenesin coated beads (equivalent to 50 mg of guaifenesin). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated guaifenesin beads. 
     Component 1: Encapsulated Guaifenesin Beads (CPI-181C) were spherical to near spherical shaped, white to off-white colored free flowing beads of sizes varying between 0.80-1.30 mm. 
     Component 2: Rapid melt granules—Grape Flavor was white to off white colored free flowing granules. 
     Three batches were performed and the results were as follows (weight variations and content uniformity were tested in accordance with USP32-NF 27 &lt;905&gt;): 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Tests 
                 Specifications 
                 Batch 1 
                 Batch 2 
                 Batch 3 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Content Uniformity (CU) Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Weight Variation 
                 922 mg ± 7.5% (853 mg to 991 mg) 
                 Min: 937 mg 
                 Min: 942 mg 
                 Min: 942 mg 
               
               
                   
                   
                 Max: 968 mg 
                 Max: 962 mg 
                 Max: 961 mg 
               
               
                 Content 
                 Acceptance Value NMT 15.0 
                 CU1: 13.4 
                 CU1: 4.2 
                 CU1: 3.0 
               
               
                 Uniformity 
                   
                 CU2: 9.1 
                 CU2: 4.0 
                 CU2: 5.1 
               
               
                   
                   
                 CU3: 5.4 
                 CU3: 13.6 
                 CU3: 4.4 
               
               
                   
                   
                 CU4: 4.7 
                 CU4: 10.1 
                 CU4: 8.4 
               
            
           
           
               
            
               
                 Composite Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Description 
                 Each Packet contains white to off-white 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 colored, spherical to near-spherical free 
               
               
                   
                 flowing beads. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Identification 
                 A. 
                 Evaporated filtrate of Guaifenesin 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                   
                 and chloroform upon treatment 
               
               
                   
                   
                 with few drops of Formaldehyde 
               
               
                   
                   
                 and Sulfuric Acid gives a deep 
               
               
                   
                   
                 Cherry-Red to Purple color. 
               
               
                   
                 B. 
                 Retention time of the 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                   
                 Guaifenesin peak in the 
               
               
                   
                   
                 Chromatogram of the Assay 
               
               
                   
                   
                 preparation corresponds to that 
               
               
                   
                   
                 of the Guaifenesin Peak in the 
               
               
                   
                   
                 chromatogram of the standard 
               
               
                   
                   
                 preparation. 
               
            
           
           
               
               
               
               
               
            
               
                 Assay 
                 Each Packet contains Guaifenesin NLT 
                  54 mg 
                  51 mg 
                  50 mg 
               
               
                   
                 45 mg to NMT 55 mg 
               
               
                 Average Weight 
                 Each Packet contains 922 mg ± 5% 
                 978 mg 
                 962 mg 
                 962 mg 
               
               
                   
                 (876 mg to 986 mg) 
               
               
                 Weight Variation 
                 922 mg ± 7.5% (853 mg to 991 mg) 
                 Ave: 958 mg 
                 Ave: 956 mg 
                 Ave: 957 mg 
               
               
                   
                   
                 Min: 949 mg 
                 Min: 943 mg 
                 Min: 952 mg 
               
               
                   
                   
                 Max: 963 mg 
                 Max: 962 mg 
                 Max: 962 mg 
               
               
                 Content 
                 Acceptance Value NMT 15.0 
                 8.4 
                 5.9 
                 4.5 
               
               
                 Uniformity 
               
               
                 Related 
                 β isomer: NMT 1.5% 
                  0.4% 
                  0.4% 
                  0.4% 
               
               
                 Substances 
                 Guaiacol: NMT 0.03% 
                 0.00% 
                 0.00% 
                 0.00% 
               
               
                   
                 Other Impurities: NMT 0.5% 
                  0.1% 
                  0.1% 
                  0.1% 
               
               
                   
                 Total Impurities: NMT 1.0% 
                  0.1% 
                  0.1% 
                  0.1% 
               
               
                 Microbiological 
                 Total Bacteria Count: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
               
               
                 Testing 
                 Yeast and Mold: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
               
               
                   
                   E. coli : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   Salmonella : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   Staph. Aureus : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   P. aeruginosa : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
               
            
           
         
       
     
     The following table showed the yield for the three batches: 
     
       
         
           
               
               
               
            
               
                   
                   
               
               
                   
                 Process Waste 
                 % Process Yield 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Rapid melt 
                   
                 Rapid melt 
               
               
                 Batch # 
                 Theoretical Yield 
                 Guaifenesin 
                 granules 
                 Guaifenesin 
                 granules 
               
               
                   
               
               
                 1 
                 39,325 Sticks 
                 4507 sticks 
                 1650 sticks 
                  85%* 
                 93% 
               
               
                 2 
                 39,325 Sticks 
                  565 Sticks 
                  565 Sticks 
                 95% 
                 93% 
               
               
                 3 
                 39,325 Sticks 
                 1055 Sticks 
                 1055 Sticks 
                 96% 
                 93% 
               
               
                   
               
               
                 *yield of encapsulated guaifenesin beads in validation batch #1 was low due to accidental spillage. 
               
            
           
         
       
     
     Example 22 
     Validation for Guaifenesin 100 mg and Bubble Gum Flavor Rapid Melt Granules 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1100 mg, which included a blend of encapsulate guaifenesin coated beads and rapid melt granules (bubble gum flavor). Each packet contained 356 mg of encapsulated guaifenesin coated beads (equivalent to 100 mg of guaifenesin). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated guaifenesin beads. 
     Component 1: Encapsulated Guaifenesin Beads (CPI-181C) were spherical to near spherical shaped, white to off-white colored free flowing beads of sizes varying between 0.80-1.30 mm. 
     Component 2: Rapid melt granules (bubble gum flavor) was white to off white colored free flowing granules. 
     Six batches were performed and the results were as follows (weight variations and content uniformity were tested in accordance with USP32-NF 27 &lt;905&gt;): 
     
       
         
           
               
            
               
                   
               
               
                 Batches 1-3 
               
            
           
           
               
               
               
               
               
            
               
                 Tests 
                 Specifications 
                 Batch #1 
                 Batch #2 
                 Batch #3 
               
               
                   
               
            
           
           
               
            
               
                 Content Uniformity (CU) Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Weight Variation 
                 1100 mg ± 7.5% (1018 mg to 1183 mg) 
                 CU1: 
                 CU1: 
                 CU1: 
               
               
                   
                   
                 Min: 1099 mg 
                 Min: 1066 mg 
                 Min: 1104 mg 
               
               
                   
                   
                 Max: 1127 mg 
                 Max: 1166 mg 
                 Max: 1109 mg 
               
               
                   
                   
                 CU2: 
                 CU2: 
                 CU2: 
               
               
                   
                   
                 Min: 1051 mg 
                 Min: 1078 mg 
                 Min: 1103 mg 
               
               
                   
                   
                 Max: 1099 mg 
                 Max: 1113 mg 
                 Max: 1110 mg 
               
               
                   
                   
                 CU3: 
                 CU3: 
                 CU3: 
               
               
                   
                   
                 Min: 1066 mg 
                 Min: 1072 mg 
                 Min: 1106 mg 
               
               
                   
                   
                 Max: 1084 mg 
                 Max: 1107 mg 
                 Max: 1115 mg 
               
               
                   
                   
                 CU4: 
                 CU4: 
                 CU4: 
               
               
                   
                   
                 Min: 1064 mg 
                 Min: 1068 mg 
                 Min: 1104 mg 
               
               
                   
                   
                 Max: 1107 mg 
                 Max: 1102 mg 
                 Max: 1112 mg 
               
               
                 Content 
                 Acceptance Value NMT 15.0 
                 CU1: 7.9 
                 CU1: 4.5 
                 CU1: 5.6 
               
               
                 Uniformity 
                   
                 CU2: 9.0 
                 CU2: 9.6 
                 CU2: 3.3 
               
               
                   
                   
                 CU3: 7.9 
                 CU3: 6.1 
                 CU3: 5.6 
               
               
                   
                   
                 CU4: 11.6 
                 CU4: 9.3 
                 CU4: 7.8 
               
            
           
           
               
            
               
                 Composite Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Description 
                 Each Packet contains white to off-white 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 colored, spherical to near-spherical free 
               
               
                   
                 flowing beads. 
               
               
                 Identification 
                 A. Evaporated filtrate of Guaifenesin 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 and chloroform upon treatment 
               
               
                   
                 with few drops of Formaldehyde 
               
               
                   
                 and Sulfuric Acid gives a deep 
               
               
                   
                 Cherry-Red to Purple color. 
               
               
                   
                 C. Retention time of the 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 Guaifenesin peak in the 
               
               
                   
                 Chromatogram of the Assay 
               
               
                   
                 preparation corresponds to that 
               
               
                   
                 of the Guaifenesin Peak in the 
               
               
                   
                 chromatogram of the standard 
               
               
                   
                 preparation. 
               
               
                 Assay 
                 Each Packet contains Guaifenesin NLT 
                  103 mg 
                  100 mg 
                  101 mg 
               
               
                   
                 90 mg to NMT 110 mg 
               
               
                 Average Weight 
                 Each Packet contains 1100 mg ± 5% 
                 1070 mg 
                 1081 mg 
                 1133 mg 
               
               
                   
                 (1045 mg to 1155 mg) 
               
               
                 Weight Variation 
                 1100 mg ± 7.5% (1018 mg to 1183 mg) 
                 Min: 1059 mg 
                 Min: 1062 mg 
                 Min: 1100 mg 
               
               
                   
                   
                 Max: 1079 mg 
                 Max: 1098 mg 
                 Max: 1123 mg 
               
               
                 Content 
                 Acceptance Value NMT 15.0 
                 9.2 
                 11.2 
                 4.0 
               
               
                 Uniformity 
               
               
                 Related 
                 β isomer: NMT 1.5% 
                  0.4% 
                  0.4% 
                  0.4% 
               
               
                 Substances 
                 Guaiacol: NMT 0.03% 
                 0.00% 
                 0.00% 
                 0.00% 
               
               
                   
                 Other Impurities: NMT 0.5% 
                  0.2% 
                  0.2% 
                  0.2% 
               
               
                   
                 Total Impurities: NMT 1.0% 
                  0.4% 
                  0.4% 
                  0.3% 
               
               
                 Water Activity 
                 NMT 0.75 Aw 
                 0.39 Aw 
                 0.56 Aw 
                 0.58 Aw 
               
               
                 Microbiological 
                 Total Bacteria Count: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
               
               
                 Testing 
                 Yeast and Mold: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
                 Less than 10 cfu/g 
               
               
                   
                   E. coli : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   Salmonella : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   Staph. Aureus : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   P. aeruginosa : Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
                 Negative in 10 g 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Batches 4-6 
               
            
           
           
               
               
               
               
               
            
               
                 Tests 
                 Specifications 
                 Batch #4 
                 Batch #5 
                 Batch #6 
               
               
                   
               
            
           
           
               
            
               
                 Content Uniformity Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Weight Variation 
                 1100 mg ± 7.5% (1018 mg to 1183 mg) 
                 CU1: 
                 CU1: 
                 CU1: 
               
               
                   
                   
                 Min: 1102 mg 
                 Min: 1117 mg 
                 Min: 1125 mg 
               
               
                   
                   
                 Max: 1129 mg 
                 Max: 1142 mg 
                 Max: 1141 mg 
               
               
                   
                   
                 CU2: 
                 CU2: 
                 CU2: 
               
               
                   
                   
                 Min: 1115 mg 
                 Min: 1122 mg 
                 Min: 1107 mg 
               
               
                   
                   
                 Max: 1131 mg 
                 Max: 1134 mg 
                 Max: 1138 mg 
               
               
                   
                   
                 CU3: 
                 CU3: 
                 CU3: 
               
               
                   
                   
                 Min: 1107 mg 
                 Min: 1111 mg 
                 Min: 1130 mg 
               
               
                   
                   
                 Max: 1134 mg 
                 Max: 1134 mg 
                 Max: 1153 mg 
               
               
                   
                   
                 CU4: 
                 CU4: 
                 CU4: 
               
               
                   
                   
                 Min: 1103 mg 
                 Min: 1097 mg 
                 Min: 1122 mg 
               
               
                   
                   
                 Max: 1123 mg 
                 Max: 1116 mg 
                 Max: 1143 mg 
               
               
                 Visual Inspection 
                 Vertical and Horizontal Seals shall be 
                 CU1: Good 
                 CU1: Good 
                 CU1: Good 
               
               
                 (3 sticks) 
                 aligned uniformly and offer resistance 
                 CU2: Good 
                 CU2: Good 
                 CU2: Good 
               
               
                   
                 while trying to open it. 
                 CU3: Good 
                 CU3: Good 
                 CU3: Good 
               
               
                   
                   
                 CU4: Good 
                 CU4: Good 
                 CU4: Good 
               
               
                 Leak Test 
                 All stick shall pass leak test 
                 CU1: Passed 
                 CU1: Passed 
                 CU1: Passed 
               
               
                   
                   
                 CU2: Passed 
                 CU2: Passed 
                 CU2: Passed 
               
               
                   
                   
                 CU3: Passed 
                 CU3: Passed 
                 CU3: Passed 
               
               
                   
                   
                 CU4: Passed 
                 CU4: Passed 
                 CU4: Passed 
               
            
           
           
               
            
               
                 Composite Sample Testing 
               
            
           
           
               
               
               
               
               
            
               
                 Description 
                 Each Packet contains white to off-white 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 colored, spherical to near-spherical free 
               
               
                   
                 flowing beads. 
               
               
                 Identification 
                 A. Evaporated filtrate of Guaifenesin 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 and chloroform upon treatment 
               
               
                   
                 with few drops of Formaldehyde 
               
               
                   
                 and Sulfuric Acid gives a deep 
               
               
                   
                 Cherry-Red to Purple color. 
               
               
                   
                 D. Retention time of the 
                 Conforms 
                 Conforms 
                 Conforms 
               
               
                   
                 Guaifenesin peak in the 
               
               
                   
                 Chromatogram of the Assay 
               
               
                   
                 preparation corresponds to that 
               
               
                   
                 of the Guaifenesin Peak in the 
               
               
                   
                 chromatogram of the standard 
               
               
                   
                 preparation. 
               
               
                 Assay 
                 Each Packet contains Guaifenesin NLT 
                  103 mg 
                  101 mg 
                  101 mg 
               
               
                   
                 90 mg to NMT 110 mg 
               
               
                 Average Weight 
                 Each Packet contains 1100 mg ± 5% 
                 1117 mg 
                 1113 mg 
                 1133 mg 
               
               
                   
                 (1045 mg to 1155 mg) 
               
               
                 Weight Variation 
                 1100 mg ± 7.5% (1018 mg to 1183 mg) 
                 Min: 1105 mg 
                 Min: 1112 mg 
                 Min: 1116 mg 
               
               
                   
                   
                 Max: 1117 mg 
                 Max: 1123 mg 
                 Max: 1123 mg 
               
               
                 Content 
                 Acceptance Value NMT 15.0 
                 4.4 
                 6.0 
                 5.2 
               
               
                 Uniformity 
               
               
                 Related 
                 β isomer: NMT 1.5% 
                  0.4% 
                  0.4% 
                  0.4% 
               
               
                 Substances 
                 Guaiacol: NMT 0.03% 
                 0.00% 
                 0.00% 
                 0.00% 
               
               
                   
                 Other Impurities: NMT 0.5% 
                  0.2% 
                  0.2% 
                  0.2% 
               
               
                   
                 Total Impurities: NMT 1.0% 
                  0.3% 
                  0.4% 
                  0.3% 
               
               
                 Water Activity 
                 NMT 0.75 Aw 
                 0.34 Aw 
                 0.25 Aw 
                 0.32 Aw 
               
               
                 Microbiological 
                 Total Bacteria Count: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
                 NA 
                 NA 
               
               
                 Testing (To be 
                 Yeast and Mold: Less than 1000 cfu/g 
                 Less than 10 cfu/g 
               
               
                 done only if water 
                   E. coli : Negative in 10 g 
                 Negative in 10 g 
               
               
                 activity fails) 
                   Salmonella : Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   Staph. Aureus : Negative in 10 g 
                 Negative in 10 g 
               
               
                   
                   P. aeruginosa : Negative in 10 g 
                 Negative in 10 g 
               
               
                   
               
            
           
         
       
     
     The following table showed the yield for the six batches: 
     
       
         
           
               
               
               
            
               
                   
                   
               
               
                   
                 Process Waste 
                 % Process Yield 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Rapid melt 
                   
                 Rapid melt 
               
               
                 Batch # 
                 Theoretical Yield 
                 Guaifenesin 
                 granules 
                 Guaifenesin 
                 granules 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 19,662 Sticks 
                 209 sticks 
                 496 sticks 
                 99% 
                 100% 
               
               
                 2 
                 19,662 Sticks 
                 916 sticks 
                 920 sticks 
                 95% 
                 95% 
               
               
                 3 
                 19,662 Sticks 
                 212 sticks 
                 588 sticks 
                 99% 
                 100% 
               
               
                 4 
                 19,662 Sticks 
                 228 sticks 
                 739 sticks 
                 99% 
                 96% 
               
               
                 5 
                 19,662 Sticks 
                  62 sticks 
                 958 sticks 
                 100% 
                 95% 
               
               
                 6 
                 19,662 Sticks 
                 695 sticks 
                 1767 sticks  
                 96% 
                 91% 
               
               
                   
               
            
           
         
       
     
     Example 23 
     Guaifenesin 100 mg and Dextromethorphan HBr 5 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulate coated beads containing guaifenesin and dextromethorphan Hbr and placebo rapid melt granules (orange flavor). Each packet contained 356 mg of encapsulated guaifenesin and dextromethorphan HBr coated beads (equivalent to 100 mg of guaifenesin &amp; 5 mg of dextromethorphan HBr). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated guaifenesin and dextromethorphan HBr beads. 
     Component 1: Encapsulated guaifenesin and dextromethorphan HBr beads were semi-spherical to near oblong shaped, white to off-white colored free flowing beads of sizes varying between 0.595-1.19 mm. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh 
     The guaifenesin and dextromethorphan HBr coated beads were made by first making guaifenesin and dextromethorphan HBr uncoated beads using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Guaifenesin and dextromethorphan 
               
               
                 HBr uncoated beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Guaifenesin USP 
                 30.00 
               
               
                   
                 Dextromethorphan HBr USP 
                 1.50 
               
               
                   
                 Emcocel 90M (Microcrystalline cellulose) 
                 18.80 
               
               
                   
                 Emcocel 90M (Microcrystalline cellulose) 
                 18.80 
               
               
                   
                 Lactose Anhydrous, NF DT 
                 20.00 
               
               
                   
                 (Lactose) 
               
               
                   
                 Starch 1500 
                 8.00 
               
               
                   
                 (Pregelatinised starch) 
               
               
                   
                 Plasdone K-29/32 
                 2.00 
               
               
                   
                 (Povidone) 
               
               
                   
                 Stepanol WA-100 
                 0.40 
               
               
                   
                 (Sodium Lauryl Sulfate) 
               
               
                   
                 Tween 80K (Polysorbate 80) 
                 0.30 
               
               
                   
                 Syloid 244 FP 
                 0.20 
               
               
                   
                 (Silicondioxide) 
               
               
                   
                 Purified water 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
               
                   
                 + indicates the component evaporated in the final product 
               
            
           
         
       
     
     The uncoated guaifenesin and dextromethorphan HBr is then coated using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Guaifenesin and dextromethorphan 
               
               
                 HBr coated beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Guaifenesin 30% Dextromethorphen 1.5% 
                 93.88 
               
               
                   
                 Uncoated beads 
               
               
                   
                 Eudragit L100 55 
                 3.70 
               
               
                   
                 Triethyl Citrate NF 
                 0.37 
               
               
                   
                 Talc 
                 1.85 
               
               
                   
                 Sylloid 244FP 
                 0.20 
               
               
                   
                 Isopropyl Alcohol, USP* 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     Example 24 
     Diphenhydramine HCL 12.5 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 900 mg, which included a blend of encapsulated diphenhydramine HCl granules 16% and rapid melt granules (cherry flavor). Each packet contained 78.27 mg of encapsulated diphenhydramine HCl granules (equivalent to 12.5 mg of Diphenhydramine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated diphenhydramine HCl granules. 
     Component 1: Encapsulated diphenhydramine HCl Granules were spherical to near spherical, white to off-white colored free flowing granules of sizes varying between 0.125-0.595 mm. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The diphenhydramine HCl coated granules were made by first making the uncoated granules using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Uncoated diphenhydramine HCl 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                   
                 (weight 
               
               
                   
                 Ingredients 
                 %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Diphenhydramine HCl 
                 20.00 
               
               
                   
                 USP 
               
               
                   
                 Emcocel 90M 
                 62.00 
               
               
                   
                 (Microcrystalline cellulose 
               
               
                   
                 USP) 
               
               
                   
                 Emcompress (Dibasic, 
                 12.00 
               
               
                   
                 Calcium Phosphate) 
               
               
                   
                 Surelease E-7-19040 
                 4.00 
               
               
                   
                 (Ethylcellulose Aqueous 
               
               
                   
                 Dispersion) 
               
               
                   
                 Splenda Sucralose 
                 1.00 
               
               
                   
                 Syloid 244 FP (Silicon 
                 1.00 
               
               
                   
                 dioxide) 
               
               
                   
                 Purified Water USP 
                 + 
               
               
                   
                 TOTAL 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     The uncoated diphenhydramine HCl granules are then double coated using the following formulation to produce the encapsulated diphenhydramine HCl: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated diphenhydramine HCl 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                   
                 (weight 
               
               
                   
                 Ingredients 
                 %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Diphenhydramine HCl uncoated 
                 79.85 
               
               
                   
                 Granules 20% 
               
            
           
           
               
            
               
                 Coating I 
               
            
           
           
               
               
               
            
               
                   
                 Surelease E-7-19040 †   
                 10.00 
               
               
                   
                 Triacetin USP 
                 2.00 
               
               
                   
                 Talc, USP 
                 2.00 
               
               
                   
                 Purified water* 
                 * 
               
               
                   
                 Purified water* 
                 * 
               
            
           
           
               
            
               
                 Coating II 
               
            
           
           
               
               
               
            
               
                   
                 Eudragit L30D-55 ‡   
                 3.50 
               
               
                   
                 Triacetin USP 
                 0.70 
               
               
                   
                 Talc, USP 
                 1.75 
               
               
                   
                 Purified water* 
                 * 
               
               
                   
                 Purified water* 
                 * 
               
               
                   
                 Syloid 244FP 
                 0.20 
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Example 25 
     Diphenhydramine HCL 25 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1100 mg, which included a blend of encapsulated diphenhydramine HCl granules 16% and rapid melt granules (cherry flavor). Each packet contained 156.54 mg of encapsulated diphenhydramine HCl granules (equivalent to 25 mg of diphenhydramine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated diphenhydramine HCl granules. 
     Component 1: Encapsulated Diphenhydramine HCl Granules were spherical to near spherical, white to off-white colored free flowing granules of sizes varying between 0.125-0.595 mm. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (Cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 26 
     Diphenhydramine HCL 50 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulated diphenhydramine HCl granules 16% and rapid melt granules (cherry flavor). Each packet contained 313.08 of encapsulated diphenhydramine HCl granules (equivalent to 50 mg of Diphenhydramine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated diphenhydramine HCl granules. 
     Component 1: Encapsulated Diphenhydramine HCl Granules were spherical to near spherical, white to off-white colored free flowing granules of sizes varying between 0.125-0.595 mm. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (Cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 27 
     Ibuprophen 100 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1100 mg, which included a blend of encapsulated ibuprofen crystals 87% and rapid melt granules (orange flavor). Each packet contained 115 mg of encapsulated ibuprofen crystals (equivalent to 100 mg of ibuprofen). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated ibuprofen crystals. 
     Component 1: Encapsulated ibuprofen crystals were semi-spherical to near oblong shaped, white to off-white colored free flowing granules. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (Orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The ibuprofen crystals were encapsulated using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated ibuprofen crystals 
               
            
           
           
               
               
               
            
               
                   
                   
                 Ind. 
               
               
                   
                   
                 Qty. 
               
               
                   
                   
                 (% 
               
               
                   
                 Material Name 
                 w/w) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Ibuprofen Crystals 
                 88.90 
               
               
                   
                 Primary coating Coating 
               
               
                   
                 Polymers 
               
               
                   
                 Eudragit L 100 55 
                 8.00 
               
               
                   
                 Plasticizer 
               
               
                   
                 Triethyl Citrate 
                 1.50 
               
               
                   
                 Tachy agent 
               
               
                   
                 Purified Talc 
                 1.00 
               
               
                   
                 Coating Solvent 
               
               
                   
                 Isopropyl Alcohol 
                 + 
               
               
                   
                 (Commertial) ml (6% solution 
               
               
                   
                 wb of Eudragit/v) 
               
               
                   
                 Sylloid 244 FP 
                 0.60 
               
               
                   
                 Total 
                 100.00 
               
               
                   
                 Second Coating 
               
               
                   
                 Coating Polymers 
               
               
                   
                 Part 1Coated Ibuprofen 
                 96.00 
               
               
                   
                 (88.9%) 
               
               
                   
                 Eudragit S100 
                 3.00 
               
               
                   
                 Plastisizer 
               
               
                   
                 Triethyl citrate 
                 0.20 
               
               
                   
                 Tachy agent 
               
               
                   
                 Purified Talc 
                 1.00 
               
               
                   
                 Coating Solvent 
               
               
                   
                 Isopropyl Alcohol 
                 + 
               
               
                   
                 (commertial) 
                   
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Example 28 
     Ibuprophen 100 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulated ibuprofen crystals 87% and rapid melt granules (orange flavor). Each packet contained 230 mg of encapsulated ibuprofen crystals (equivalent to 100 mg of Ibuprofen). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated ibuprofen crystals. 
     Component 1: Encapsulated Ibuprofen Crystals were semi-spherical to near oblong shaped, white to off-white colored free flowing granules. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (Orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 29 
     Ibuprophen 100 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulated ibuprofen beads 28.5% and rapid melt granules (grape flavor). Each packet contained 356 mg of encapsulated ibuprofen beads (equivalent to 100 mg of ibuprofen). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated ibuprofen beads. 
     Component 1: Encapsulated ibuprofen beads were spherical to oblong shaped, white to off-white colored free flowing beads. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (Orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The encapsulated ibuprofen beads were made by first making the uncoated beads using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Ibuprofen uncoated beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Ibuprofen 
                 31.50 
               
               
                   
                 Emcocel 90M (Microcrystalline 
                 18.80 
               
               
                   
                 cellulose) 
               
               
                   
                 Emcocel 90M (Microcrystalline 
                 18.80 
               
               
                   
                 cellulose) 
               
               
                   
                 Lactose Anhydrous, NF DT 
                 20.00 
               
               
                   
                 (Lactose) 
               
               
                   
                 Starch 1500 
                 8.00 
               
               
                   
                 (Pregelatinised starch) 
               
               
                   
                 Plasdone K-29/32 
                 2.00 
               
               
                   
                 (Povidone) 
               
               
                   
                 Stepanol WA-100 
                 0.40 
               
               
                   
                 (Sodium Lauryl Sulfate) 
               
               
                   
                 Tween 80K (Polysorbate 80) 
                 0.30 
               
               
                   
                 Syloid 244 FP 
                 0.20 
               
               
                   
                 (Silicondioxide) 
               
               
                   
                 Purified water 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     The uncoated ibuprofen beads are then coated using the following formulation to produce the encapsulated ibuprofen beads: 
     
       
         
           
               
            
               
                   
               
               
                 Ibuprofen coated beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Ibuprofen Uncoated beads 
                 93.88 
               
               
                   
                 Eudragit L100 55 
                 3.70 
               
               
                   
                 Triethyl Citrate NF 
                 0.37 
               
               
                   
                 Talc 
                 1.85 
               
               
                   
                 Sylloid 244FP 
                 0.20 
               
               
                   
                 Isopropyl Alcohol, USP* 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     Example 30 
     Dextromethorphan Hbr 7.5 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 800 mg, which included a blend of encapsulated dextromethorphan HBr powder 31.83% and rapid melt granules (cherry flavor). Each packet contained 23.56 mg of encapsulated dextromethorphan HBr powder (equivalent to 7.5 mg of dextromethorphan HBr). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated dextromethorphan HBr powder. 
     Component 1: Encapsulated dextromethorphan HBr powder was light brown to brown color powder. 
     Component 2: Rapid melt granules (Cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The encapsulated dextromethorphan HBr powder was made using the following formulation: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated Dextromethorphan HBr 
               
               
                 Powder 
               
            
           
           
               
               
               
            
               
                   
                   
                 Qty. 
               
               
                   
                 Material Name 
                 (w/w %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Adsorbant/Resin 
                   
               
               
                   
                 Amberlite IRP88** 
                 70.00 
               
               
                   
                 Active 
               
               
                   
                 Dextromethorphan HBr 
                 30.00 
               
               
                   
                 Solvent 
               
               
                   
                 Purified water* 
                   
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Example 31 
     Dextromethorphan Hbr 15 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1000 mg, which included a blend of encapsulated dextromethorphan HBr powder 31.83% and rapid melt granules (cherry flavor). Each packet contained 47.13 mg of encapsulated dextromethorphan HBr powder (equivalent to 15 mg of dextromethorphan Hbr). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated dextromethorphan HBr powder. 
     Component 1: Encapsulated Dextromethorphan Hbr powder was light brown to brown color powder. 
     Component 2: Rapid melt granules (cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 32 
     Dextromethorphan Hbr 30 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulated dextromethorphan HBr powder 31.83% and rapid melt granules (cherry flavor). Each packet contained 94.25 mg of encapsulated dextromethorphan HBr powder (equivalent to 30 mg of dextromethorphan HBr). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated dextromethorphan HBr powder. 
     Component 1: Encapsulated Dextromethorphan HBr powder was light brown to brown color powder. 
     Component 2: Rapid melt granules (Cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 33 
     Dextromethorphan HBr 30 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1300 mg, which included a blend of encapsulated dextromethorphan HBr beads and rapid melt granules (cherry flavor). Each packet contained 356 mg of encapsulated dextromethorphan HBr beads (equivalent to 30 mg of dextromethorphan HBr). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated dextromethorphan HBr beads. 
     Component 1: Encapsulated dextromethorphan HBr beads were white to off white spherical to near spherical shaped beads. Bulk density is 0.5-0.7 g/mL. 
     Component 2: Rapid melt granules (cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Encapsulated dextromethorphan HBr beads were made by first making uncoated beads using the formulation below: 
     
       
         
           
               
            
               
                   
               
               
                 Dextromethorphan HBr Uncoated Beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Dextromethorphan HBr USP 
                 30.00 
               
               
                   
                 Emcocel 90M (Microcrystalline cellulose) 
                 19.55 
               
               
                   
                 Emcocel 90M (Microcrystalline cellulose) 
                 19.55 
               
               
                   
                 Lactose Anhydrous, NF DT 
                 20.00 
               
               
                   
                 (Lactose) 
               
               
                   
                 Starch 1500 
                 8.00 
               
               
                   
                 (Pregelatinised starch) 
               
               
                   
                 Plasdone K-29/32 
                 2.00 
               
               
                   
                 (Povidone) 
               
               
                   
                 Stepanol WA-100 
                 0.40 
               
               
                   
                 (Sodium Lauryl Sulfate) 
               
               
                   
                 Tween 80K (Polysorbate 80) 
                 0.30 
               
               
                   
                 Syloid 244 FP 
                 0.20 
               
               
                   
                 (Silicondioxide) 
               
               
                   
                 Purified water 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     The dextromethorphan HBr uncoated beads were then coated using the formulation below to produce encapsulated dextromethorphan HBr beads: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated Dextromethorphan HBr Beads 
               
            
           
           
               
               
               
            
               
                   
                   
                 Quantity 
               
               
                   
                 Ingredients 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Dextromethorphan Hbr Uncoated beads 
                 93.88 
               
               
                   
                 Eudragit L100 55 
                 3.70 
               
               
                   
                 Triethyl Citrate NF 
                 0.37 
               
               
                   
                 Talc 
                 1.85 
               
               
                   
                 Sylloid 244FP 
                 0.20 
               
               
                   
                 Isopropyl Alcohol, USP* 
                 + 
               
               
                   
                 TOTAL 
                 100.00% 
               
               
                   
                   
               
            
           
         
       
     
     Example 34 
     Caffeine 50 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1100 mg, which included a blend of encapsulated caffeine 40% and rapid melt granules (cherry flavor). Each packet contained 125 mg of encapsulated encapsulate caffeine (equivalent to 50 mg of caffeine). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated caffeine powder. 
     Component 1: Encapsulated caffeine was light yellow to yellow colored free flowing powder. 
     Component 2: Rapid melt granules (cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The encapsulated caffeine was made using the formulation below: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated Caffeine 
               
            
           
           
               
               
               
            
               
                   
                   
                 Qty. 
               
               
                   
                 Material Name 
                 (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Part-I 
                   
               
               
                   
                 Wax 
               
               
                   
                 Carnuba Wax 
                 55.00 
               
               
                   
                 Active Ingredient 
               
               
                   
                 Caffeine Anhydrous 
                 40.00 
               
               
                   
                 USP 
               
               
                   
                 Plasticizer 
               
               
                   
                 Dist. Acetylated 
                 5.00 
               
               
                   
                 Monoglyceride 5-07 
               
               
                   
                 (Myvacet 5-07) 
                   
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Example 35 
     Caffeine 100 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1500 mg, which included a blend of encapsulated caffeine 40% and rapid melt granules (cherry flavor). Each packet contained 250 mg of encapsulated caffeine powder (equivalent to 100 mg of caffeine). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated caffeine. 
     Component 1: Encapsulated Caffeine was light yellow to yellow colored free flowing powder. 
     Component 2: Rapid melt granules (Cherry flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 36 
     Phenylephrine HCL 5 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 750 mg, which included a blend of encapsulated phenylephrine HCl granules 10% and rapid melt granules (orange flavor). Each packet contained 50 mg of encapsulated phenylephrine HCl granules (equivalent to 5 mg of phenylephrine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated phenylephrine HCl granules. 
     Component 1: Encapsulated phenylephrine HCl granules were spherical to near spherical, white to off-white colored free flowing granules. 
     Component 2: Rapid melt granules (Orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     The encapsulated phenylephrine HCl granules were made in two steps. First, the phenylephrine HCl is granulated using the formulation in Part A below. Second, the granulated phenylephrine HCl granules were then encapsulated using the formulation shown in Part B. 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated Phenylephrine HCl Granules 
               
            
           
           
               
               
               
            
               
                   
                 Ingredient Name 
                 Qty. (weight %) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Part A - Drug resin granulation 
                   
               
               
                   
                 Phenylephrine HCl 
                 31.66 
               
               
                   
                 Amberlite IRP88 (Polacrilin 
                 63.33 
               
               
                   
                 Potassium, Methacrylic acid &amp; 
               
               
                   
                 Divinylbenzene polymer) 
               
               
                   
                 Purified Water (*) 
                 + 
               
               
                   
                 Part B - Ethyl Cellulose 
               
               
                   
                 granulation 
               
               
                   
                 Drug Resin Granules from Part A 
                 (95.00) 
               
               
                   
                 Ethocel Standard 4 Premium 
                 5.00 
               
               
                   
                 (Ethyl Cellulose 4 cps) 
               
               
                   
                 Isopropyl Alcohol USP 
                 + 
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Example 37 
     Phenylephrine HCL 10 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 900 mg, which included a blend of encapsulated phenylephrine HCl granules 10% and rapid melt granules (orange flavor). Each packet contained 100 mg of encapsulated phenylephrine HCl granules (equivalent to 10 mg of phenylephrine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated phenylephrine HCl granules. 
     Component 1: Encapsulated Phenylephrine HCl Granules were spherical to near spherical, white to off-white colored free flowing granules. 
     Component 2: Rapid melt granules (orange flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Example 38 
     Acetaminophen 500 mg and Diphenhydramine HCl 25 mg/Rapid Melt Granules in a Delivery Form 
     The general procedure of Example 1 was carried out for packaging and sealing to give a fill weight of 1500 mg, which included a blend of encapsulate coated granules containing acetaminophen and diphenhydramine HCl granules and rapid melt granules (Grape flavor). Each packet contained 625 mg of encapsulated acetaminophen and diphenhydramine HCl granules (equivalent to 500 mg of acetaminophen and 25 mg of diphenhydramine HCl). The flavored rapid melt granules dissolved in the mouth within less than 5 seconds; and the saliva took away the encapsulated acetaminophen and diphenhydramine HCl granules. 
     Component 1: Encapsulated acetaminophen and diphenhydramine HCl granules were white to off-white colored free flowing granules. 
     Component 2: Rapid melt granules (grape flavor) was white to off white colored free flowing granules. Bulk density: 0.6 g/mL. Particle size: NLT 75% retained on #35 mesh. 
     Acetaminophen and diphenhydramine HCl granules were encapsulated using the formulation below: 
     
       
         
           
               
            
               
                   
               
               
                 Encapsulated Acetaminophen and 
               
               
                 Diphenhydramine HCl Granules 
               
            
           
           
               
               
               
            
               
                   
                 Material Name 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Active drug 
                   
               
               
                   
                 Acetaminophen &amp; 
                 92.60 
               
               
                   
                 dDiphenhydramine HCl 
               
               
                   
                 granules 
               
               
                   
                 Polymer 
               
               
                   
                 Methacrylic acid Co-polymer 
                 4.50 
               
               
                   
                 (Eudragit L100-55) 
               
               
                   
                 Plasticizer 
               
               
                   
                 Triethylcitrate 
                 0.45 
               
               
                   
                 Glident 
               
               
                   
                 Purified Talc 
                 2.25 
               
               
                   
                 Sylloid 244FP (Silicondioxide) 
                 0.20 
               
               
                   
                 Solvent 
               
               
                   
                 IPA USP (6% solid content) 
                 + 
               
               
                   
                 IPA for homogenization 
                 + 
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     Although certain presently preferred embodiments of the invention have been specifically described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the various embodiments shown and described herein may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.