Abstract:
Methods of manufacturing effervescent dosage forms. Methods of manufacturing an effervescent tablet using a dry, direct compression process are disclosed. The methods do not result in the sticking of the mixture to be tableted to the punches during production.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit under 35 U.S.C. §119(e) of the earlier filing date of U.S. provisional patent application No. 61/790,213 filed on Mar. 15, 2013. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Various formulations for effervescent tablets have been disclosed in U.S. Pat. No. 5,178,878; U.S. Pat. No. 6,200,604; U.S. Pat. No. 8,119,158; U.S. Pat. No. 6,974,590; U.S. Pat. No. 5,223,264; U.S. Pat. No. 5,458,879; EP 1,814,831; US 2011/0281008; U.S. Pat. No. 5,171,571; U.S. Pat. No. 5,817,337; EP 2,515,857; U.S. Pat. No. 6,066,355; U.S. Pat. No. 5,707,654; and U.S. Pat. No. 5,888,544, which are hereby incorporated by reference in their entireties. However, these teach directly mixing the acid and base parts of the effervescent couple, along with other excipients, before tableting. EP 1,945,190 teaches the wet granulation of the acid and the active with silicon dioxide. We found that using a variety of these methods resulted in sticking of the mixture to the tablet punches, which results in a loss of active potency over the course of the run. Alternatively, U.S. Pat. No. 3,577,490 (which is hereby incorporated by reference in its entirety) states that in order to get a tablet which can be manufactured with commercially feasible tableting rates, that the use of Mg stearate and other non-water soluble lubricants must be avoided. 
       SUMMARY OF THE INVENTION 
       [0003]    The present invention encompasses a method of manufacturing an effervescent tablet using a dry, direct compression process which does not result in the sticking of the mixture to be tableted to the punches. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0004]    Initially, a blend           compress process was evaluated and determined to be unacceptable due to poor compression characteristics of the final blend, in particular sticking. In an effort to improve the processing characteristics, experiments were conducted utilizing a series of blending and milling steps prior to compression. The process of individually blending the effervescent agents (sodium bicarbonate/sodium carbonate and citric acid) with the glidant (silicon dioxide) followed by the milling process, and incorporating the filler (mannitol) and disintegrant (sodium starch glycolate) through blending and milling steps, produced a blend with acceptable flow, density, and tableting characteristics. The processes and formulations of the present invention result in good tablets across all normal operating conditions, including in the higher humidity range of 20-60% relative humidity. As such, the present invention provides a robust method of formulating solid dosage forms that is resilient to traditionally disruptive variables, such as humidity. 
         [0005]    The process of coating the acid and/or base components with the glidant protects these agents from ambient moisture as well as from reaction with each other. When either event occurs, the mixture that is in the process of being tableted becomes sticky and gummy. The formulations exemplified here use colloidal silicon dioxide as a coating agent. However, any neutral, non-hygroscopic material with a small enough particle size would function in the same way to evenly coat and protect the acid and/or base component from adventitious reaction with water and/or the complementary half of the effervescent couple. Obvious examples of this include silicon dioxide, talc, and starch. Other examples might include diluents such as cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, starch derivatives such as moderately cross-linked starch; acrylic polymers such as carbomer and its derivatives (Polycarbophyl, Carbopol™, etc.), or microcrystalline cellulose such as Avicel. 
         [0006]    Note also that in cases where the acid or base component is not very hygroscopic, then coating of that component is not necessary. See, for examples, some of the following examples where tartaric acid can be used without coating. 
         [0007]    The tablet composition itself is fairly straightforward. Appropriate formulation methods are well known to the person skilled in the art: see, for instance, Pharmaceutical Dosage Form: Tablets. Volume 1, 2nd Edition, Lieberman H A et al.; Eds.; Marcel Dekker. New York and Basel 1989, p. 354-356, and literature cited therein, which are hereby incorporated by reference. Suitable additives cited therein comprise additional carrier agents, preservatives, lubricants, gliding agents, disintegrants, flavorings, and dyestuffs. 
         [0008]    In addition to the active agent and the glidant, other excipients such as binders, lubricants, humectants, disintegrants, basic agents, acidic agents, sweeteners and the like can be used. 
         [0009]    Binder can be selected from, but not limited to, a group comprising ethyl cellulose, gelatine, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, and povidone. 
         [0010]    Lubricant can be selected from, but not limited to, a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG6000, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium stearyl fumarate, and leucine. 
         [0011]    Humectant can be selected from, but not limited to, a group comprising anhydrous sodium sulphate, silica gel, and potassium carbonate. 
         [0012]    Disintegrant can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate, starch, and combinations thereof. 
         [0013]    Diluent can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium sulfate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrine, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol, and combinations thereof. 
         [0014]    The alkaline component of the effervescent couple can be any suitable alkaline effervescent compound, and typically it is an inorganic base (e.g., an alkali metal carbonate) that is safe for human consumption and provides an effective and rapid effervescent disintegration upon contact with water and the acid compound. The alkaline effervescing compound may be selected from the group consisting of carbonate salts, bicarbonate salts, and mixtures thereof. In some embodiments, the alkaline compound is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, and potassium bicarbonate, sodium glycine carbonate, calcium carbonate, L-lysine carbonate, arginine carbonate, and combinations thereof. In some embodiments, the alkaline effervescing compound is sodium bicarbonate, potassium bicarbonate, sodium carbonate, or mixtures thereof. 
         [0015]    The acid component of the effervescent couple can be any suitable acid for effervescent compositions. Typically, the acid is an organic or mineral acid that is safe for consumption and which provides effective and rapid effervescent disintegration upon contact with water and the alkaline effervescent compound. The acid may be selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides, related organic acids, and their mixtures. In some embodiments, the acid is citric acid, and especially useful is anhydrous citric acid or tartaric acid. 
         [0016]    The acid salt of the composition can be any suitable acid salt or any mixture of suitable salts. Examples of such a suitable acid salt include disodium dihydrogen pyrophosphate, acid citrate salts including mono sodium citrate, and other salts of related organic acids. Combinations thereof are possible. In some embodiments, the acid salt is a salt of citric acid or tartaric acid, and especially useful is monosodium citrate or monosodium tartarate. 
       EXAMPLE 1 
       [0017]    Initial development studies were conducted using placebo blends. Based on information found in the literature, an effervescent dosage form was manufactured to evaluate tablet physical properties such as hardness, thickness, friability and disintegration time. These blend/compress experiments exhibited marginal compressibility with a maximum hardness of 3.5 kp, resulting in a tablet friability of greater than 1% for these formulations. Additionally, sticking was observed during the compression process. The spray dried mannitol exhibited slightly better compressibility and less sticking than the granular grade of mannitol. These experiments are summarized in the Table 1. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Placebo Effervescent Dosage Form Experiments 
               
             
          
           
               
                 Experiment number 
                   
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 X08-036 
                 1A1 
                 1A2 
                 AB1 
                 2B2 
               
             
          
           
               
                 Part I 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
               
               
                   
               
             
          
           
               
                 Mannitol (spray-dried) 
                 102 
                 51 
                 255 
                 51 
                 255 
                 51.0 
                   
                   
               
               
                 Mannitol (granular) 
                   
                   
                   
                   
                   
                   
                 255 
                 510 
               
               
                 Sodium bicarbonate 
                 42 
                 21 
                 105 
                 21 
                 105 
                 21 
                 105 
                 210 
               
               
                 Sodium carbonate 
                 16 
                 8 
                 40 
                 8 
                 40 
                 8 
                 40 
                 8.0 
               
               
                 Sodium starch 
                 8 
                 4 
                 20 
                 4 
                 20 
                 4 
                 20 
                 4.0 
               
               
                 glycolate (explotab/ 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Citric Acid, 
                 30 
                 15 
                 75 
                 15 
                 75 
                 15 
                 75 
                 15.0 
               
               
                 Anhydrous 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Magnesium Stearate 
                 2 
                 1 
                 5 
                 1 
                 5 
                 1 
                 5 
                 1.0 
               
               
                 (Veg) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total Core Weight 
                 200 
                 100 
                 500 
                 100 
                 500 
                 100 
                 500 
                 100 
               
             
          
           
               
                 Process 
                 Screen/Blend 
                 Screen/Bag Blend 
                 Screen/Blend  
                 Screen/Blend  
               
               
                   
                 (8 quart) 
                   
                 (4 quart) 
                 (4 quart) 
               
             
          
           
               
                 Compression/Tablet 
                   
                   
                   
                   
                   
                   
                   
               
               
                 properties 
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 Notes 
                 All of Part II 
                 Material was 
                 Repeat of 1A2 
                 Repeat of 1B1 
               
               
                   
                 including Mag 
                 blended, a sample 
                 using a 4 quart 
                 using Granular 
               
               
                   
                 was blended in 
                 was pulled for 
                 blender. Material 
                 Mannitol. 
               
               
                   
                 an 8 quart 
                 carver testing. 
                 blended for 10 
                 Maximum hardness 
               
               
                   
                 blender for 15 
                 The mag was 
                 minutes, mag 
                 1.2 kp. Filming 
               
               
                   
                 minutes. 
                 added and 
                 added blended 
                 occurred on 
               
               
                   
                 Tablets 
                 continue to blend. 
                 additional 5 
                 punches during the 
               
               
                   
                 capping off the 
                 Samples were 
                 minutes. 
                 short compression 
               
               
                   
                 press. 
                 pulled at several 
                 Maximum 
                 time (1700 tablet 
               
               
                   
                 Maximumhard 
                 bland time 
                 hardness 3.5 kp. 
                 batch size) 
               
             
          
           
               
                   
                 ness 2.5 kp. 
                 intervals. Carver 
                 No sticking 
                   
                   
               
               
                   
                 Sticking on 
                 Test demonstrated 
                 occurred during 
                   
                   
               
               
                   
                 punches (8000 
                 a lubricant blend  
                 the short 
                   
                   
               
               
                   
                 tablet batch 
                 time 
                 compression time 
                   
                   
               
               
                   
                 size). 
                 compressibility 
                 (1700 tablet batch 
                   
                   
               
             
          
           
               
                   
                   
                   
                 correlation. 
                 size) 
                   
                   
               
               
                   
               
             
          
         
       
     
       EXAMPLE 2 
       [0018]    In an effort to minimize the observed sticking, a series of experiments were conducted to improve processing characteristics for the effervescent dosage form utilizing a series of blending and milling steps prior to compression. The experiments are summarized in Table 2. It was observed that the citric acid in the presence of the sodium carbonate/sodium bicarbonate resulted in the filming/sticking of the material to the punch faces during compression. By pre-blending the sodium carbonate/sodium bicarbonate with silicon dioxide (Syloid) and passing it through a mill as well as pre-blending the citric acid with silicon dioxide prior to milling, the sticking was eliminated during the compression process. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Effervescent Dosage Form Blending/Milling Experiments containing Citric Acid 
               
             
          
           
               
                   
                 Experiment Number X08-36 
               
             
          
           
               
                   
                 97A2 
                 97B1 
                 97C1 
                 97D1 
               
             
          
           
               
                   
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
               
               
                   
                   
               
             
          
           
               
                 Part I 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Mannitol (mannogem EZ spray 
                 98.00 
                 49.0 
                 98.00 
                 49.0 
                 98.00 
                 49.0 
                 98.00 
                 49.0 
               
               
                 dried) 
               
               
                 Syloid 244FP 
                 2.00 
                 1.0 
                 2.00 
                 1.0 
                 1.00 
                 0.5 
                 1.40 
                 0.7 
               
               
                 Sodium Starch Glycolate 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
               
               
                 Sodium Bicarbonate 
                 42.0 
                 21.0 
                 42.0 
                 21.0 
                 42.0 
                 21.0 
                 42.0 
                 21.0 
               
               
                 Sodium Carbonate 
                 18.0 
                 9.0 
                 18.0 
                 9.0 
                 18.0 
                 9.0 
                 18.0 
                 9.0 
               
               
                 Part II 
               
               
                 Citric Acid granular 
                 30.0 
                 15.0 
                 30.0 
                 15.0 
                 30.0 
                 15.0 
                 30.0 
                 15.0 
               
               
                 Syloid 244FP 
                   
                   
                   
                   
                 1.00 
                 0.5 
                 0.60 
                 0.3 
               
               
                 Part III 
               
               
                 Magnesium Stearate 
                 2.0 
                 1.0 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
               
               
                 Total Core Weight 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
               
             
          
           
               
                 Processing Comments: 
                 Premix 
                 Premix 
                 Premix 
                 Premix 
               
               
                   
                 carbonates with 
                 carbonates 
                 carbonates 
                 carbonates 
               
               
                   
                 syloid. Clean 
                 with syloid 
                 with syloid 
                 with syloid 
               
               
                   
                 mill with Part II. 
                 increase 
                 pass through 
                 pass through 
               
               
                   
                 Compressed on 
                 mixing time. 
                 mill. Premix 
                 mill. Premix 
               
               
                   
                 Hata. Upper 
                 Clean mill 
                 citric acid with 
                 citric acid with 
               
               
                   
                 punch faces light 
                 with Part II. 
                 syloid then 
                 syloid then 
               
               
                   
                 film lead to 
                 Compressed 
                 clean mill with 
                 clean mill with 
               
               
                   
                 picking. 
                 on Hata. After 
                 part II. Some 
                 part II. After 
               
               
                   
                   
                 60 min run 
                 haze on upper 
                 60 min run 
               
               
                   
                   
                 punch faces 
                 punch only. 
                 time punch 
               
               
                   
                   
                 had film 
                   
                 faces clean. 
               
               
                   
                   
                 present but 
                   
                 Soft sample 
               
               
                   
                   
                 improved from 
                   
                 punch faces 
               
               
                   
                   
                 97A2. 
                   
                 clean. 
               
               
                   
               
             
          
         
       
     
       EXAMPLE 3 
       [0019]    Additionally an alternative acid was evaluated, summarized in Table 3. It was determined that tartaric acid which is slightly less water soluble than citric acid exhibited less filming/sticking characteristics. It was possible to eliminate the sticking by screening only the sodium carbonate/sodium bicarbonate/silicon dioxide (SYLOID) premix. It was not required to blend the tartaric acid with silicon dioxide. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Effervescent Dosage Form Blending/Milling Experiments containing Tartaric Acid 
               
             
          
           
               
                   
                 Experiment Number 
               
             
          
           
               
                   
                 93A1 
                 93B1 
                 93C1 
               
             
          
           
               
                   
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
               
               
                   
                   
               
             
          
           
               
                 Part I 
                   
                   
                   
                   
                   
                   
               
               
                 Mannitol (mannogem EZ spray 
                 98.00 
                 49.0 
                 98.00 
                 49.0 
                 98.00 
                 49.0 
               
               
                 dried) 
               
               
                 Syloid 244FP 
                 2.00 
                 1.0 
                 2.00 
                 1.0 
                 2.00 
                 1.0 
               
               
                 Sodium Starch Glycolate 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
               
               
                 Tartaric Acid 
                 30.0 
                 15.0 
               
               
                 Sodium Bicarbonate 
                   
                   
                 42.0 
                 21.0 
                 42.0 
                 21.0 
               
               
                 Sodium Carbonate 
                   
                   
                 18.0 
                 9.0 
                 18.0 
                 9.0 
               
               
                 Part II 
               
               
                 Tartaric Acid 
                   
                   
                 30.0 
                 15.0 
                 30.0 
                 15.0 
               
               
                 Sodium Bicarbonate 
                 42.0 
                 21.0 
               
               
                 Sodium Carbonate 
                 18.0 
                 9.0 
               
               
                 Part III 
               
               
                 Magnesium Stearate 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
               
               
                 Total Core Weight 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
               
             
          
           
               
                   
                 Premix mannitol 
                 Premix mannitol 
                 Premix carbonates 
               
               
                   
                 with syloid. 
                 and carbonates 
                 with syloid then 
               
               
                   
                 Clean mill with 
                 with syloid then 
                 screen. Clean mill 
               
               
                   
                 Part II. Lower 
                 screen. Clean 
                 with part II. 
               
               
                   
                 punch faces 
                 mill with Part II. 
                 Punch faces clean 
               
               
                   
                 shiny. Upper 
                 Upper punch 
                 the entire run. 
               
               
                   
                 punch faces film 
                 face filming 
               
               
                   
                 present. Need to 
                 significantly 
               
               
                   
                 blend carbonates 
                 improved. 
               
               
                   
                 with syloid then 
                 Remove 
               
               
                   
                 screen. 
                 mannitol out of 
               
               
                   
                   
                 premix. 
               
               
                   
               
             
          
         
       
     
       EXAMPLE 4 
       [0020]    Studies were conducted to evaluate sorbitol in place of mannitol. It was determined that the sorbitol formulations exhibited increase tablet hardness. Table 4 is a summary of the experiments. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Effervescent Dosage Form Experiments containing Sorbitol or Mannitol 
               
             
          
           
               
                   
                 Experiment Number X08-36 
               
             
          
           
               
                   
                 95A1 
                 96A1 
                 103A1 
                 100A1 
               
             
          
           
               
                   
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
                 mg/unit 
                 % 
               
               
                   
                   
               
             
          
           
               
                 Part I 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Fentanyl Citrate 
                 0.628 
                 0.3 
                 0.628 
                 0.3 
                 0.628 
                 0.3 
                 0.628 
                 0.3 
               
               
                 Mannitol (mannogem EZ 
                 94.372 
                 46.3 
                   
                   
                 97.372 
                 48.7 
               
               
                 spray dried) 
               
               
                 Sorbitol 
                   
                   
                 94.372 
                 47.2 
                   
                   
                 97.372 
                 48.7 
               
               
                 Syloid 244FP 
                 2.00 
                 1.0 
                 2.00 
                 1.0 
                 1.40 
                 0.7 
                 1.40 
                 0.7 
               
               
                 Sodium Starch Glycolate 
                 8.0 
                 3.9 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
                 8.0 
                 4.0 
               
               
                 Sodium Bicarbondate 
                 42.0 
                 20.6 
                 42.0 
                 21.0 
                 42.0 
                 21.0 
                 42.0 
                 21.0 
               
               
                 Sodium Carbonate 
                 21.0 
                 10.3 
                 21.0 
                 10.5 
                 18.0 
                 9.0 
                 18.0 
                 9.0 
               
               
                 Part II 
               
               
                 Tartaric Acid 
                 34.0 
                 16.7 
                 30.0 
                 15.0 
               
               
                 Citric Acid granular 
                   
                   
                   
                   
                 30.0 
                 15.0 
                 30.0 
                 15.0 
               
               
                 Syloid 244FP 
                   
                   
                   
                   
                 0.60 
                 0.3 
                 0.60 
                 0.3 
               
               
                 Part III 
               
               
                 Magnesium Stearate 
                 2.0 
                 0.98 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
                 2.0 
                 1.00 
               
               
                 Total Core Weight 
                 204.0 
                 100.0 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
                 200.0 
                 100.0 
               
             
          
           
               
                 Tablet Properties 
                 Max hardness 
                 Max hardness 
                 Max hardness 
                 Max hardness 
               
               
                   
                 1.4 kp. 
                 4.2 kp. 
                 1.5 kp. 
                 4.5 kp. 
               
               
                   
               
             
          
         
       
     
         [0021]    Formulations 103A1 and 100A1 exhibited acceptable potency, content uniformity, and dissolution assays, and were chosen for further development. 
         [0022]    Table 5 discloses a % range of excipients that could be used in Formulations 103A1 and 100A1 m (Table 4): 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
             
             
               
                   
                   
               
               
                   
                 Target 
                   
                 % range 
                   
               
             
          
           
               
                   
                 mg/unit 
                 % 
                 Low 
                 High 
               
               
                   
                   
               
             
          
           
               
                 Mannitol or Sorbitol 
                 93.372 
                 46.686 
                 25 
                 75 
               
               
                 Syloid 244FP 
                 4 
                 2 
                 1 
                 5 
               
               
                 Sodium Starch Glycolate 
                 8 
                 4 
                 1 
                 10 
               
               
                 Sodium Bicarbonate 
                 42 
                 21 
                 5 
                 30 
               
               
                 Sodium Carbonate 
                 20 
                 10 
                 3 
                 15 
               
               
                 Citric Acid granular 
                 30 
                 15 
                 5 
                 25 
               
               
                 Magnesium Stearate 
                 2 
                 1 
                 0.5 
                 5 
               
               
                 Total Core Weight 
                 200 
                 100