Abstract:
New dosage forms of vitamin D and calcium carbonate having improved content uniformity are described. The improvements are realized through modifications to the formulation, the raw material specifications, and the process of manufacture.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 60/926,133, filed on Apr. 25, 2007. 
    
    
     TECHNICAL FIELD 
     The present invention is directed to new dosage forms of Vitamin D having improved content uniformity. The improvements are realized through modifications to the formulation, the raw material specifications, and the process of manufacture. 
     BACKGROUND OF THE INVENTION 
     Content uniformity is a regulatory concern for all finished pharmaceutical products. This is particularly true for solid oral dosage forms such as tablets and capsules. While typical regulatory requirements may not be as rigorous for nutritional supplements such as vitamins, where vitamins are packaged with another pharmaceutical product, content uniformity requirements become rigorous for all components. 
     Anytime that a vitamin is added to any pharmaceutical formulation it will be present in very low quantities by weight (typically from 0.001 to 0.05 percent). Therefore meeting the pharmaceutical requirements for content uniformity of &lt;6% relative standard deviation (RSD) is a major challenge. Most of the combination vitamin products on the market today only have to meet nutritional standards that have no content uniformity requirement. Typical calcium plus vitamin D nutritional products currently on the market have content uniformity for vitamin D of 7-15% RSD. The FDA has been clear that any pharmaceutical product or nutritional product packaged with another pharmaceutical product must meet all pharmaceutical specifications. Formulations of calcium carbonate and vitamin D have been problematic in terms of acceptable content uniformity. 
     Dosage forms comprising vitamin D have been discussed in the prior art. Much of the prior art has been concerned with the stability of vitamin D dosage forms. Makino et al, in U.S. Pat. No. 4,729,895 teaches solid pharmaceutical preparations of vitamins D 3  prepared by forming an outer layer comprising vitamin D 3  and an excipient, which is readily soluble in an organic solvent, around an inner layer comprising an excipient which is slightly soluble in an organic solvent. Makino teaches markedly improved stability for such solid pharmaceutical preparations of vitamins D 3 . 
     In U.S. Pat. No. 5,328,903, Ishii, et al. teaches a composition for solid pharmaceutical dosage forms of vitamin D in which the vitamin D is uniformly distributed in the composition. The composition comprises an excipient comprising mannitol and/or sugar; a degradative agent comprising hydroxypropyl cellulose; and/or a binder comprising polyvinyl pyrrolidone and/or hydroxypropylmethyl cellulose. 
     In PCT publication WO 92/09271, Wozny, et al. teaches solid pharmaceutical preparations containing vitamin D 3  which are significantly stabilized. The compositions include hydroxypropylmethyl cellulose to which is attached active vitamin D 3  and a polymer which is readily soluble in an organic solvent. 
     The inventors have found that by modifying the formulation, raw material specifications, and the process, we can improve the content uniformity and meet pharmaceutical specifications. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention is directed to improved formulations of vitamin D that meet pharmaceutical specifications with respect to content uniformity as measured by standard compendial (i.e., United States Pharmacopeia (USP)) content uniformity tests. A secondary benefit is that more stringent content uniformity will reduce variation in stability tests which can result in increased shelf life and/or reduced overages. 
     In one aspect of the present invention, there is a method of manufacturing vitamin D containing tablets comprising forming a premix comprising a mixture of vitamin D granulation and silicon dioxide; adding a second nutritional or pharmaceutical active component (“second component”) that has a size ratio to the vitamin D component of at least about 1.4, preferably at least about 1.5, to said premix to form a first vitamin D/second component granulation mixture; mixing and sieving the first vitamin D/second component granulation mixture; blending the first vitamin D/second component granulation mixture in a V blender; dividing the first vitamin D/second component granulation mixture into four equal portions and adding the second component to each portion to form a second vitamin D/second component granulation mixture; blending the second vitamin D/second component granulation mixture in a V blender; and, forming tablets from a composition comprising the second vitamin D/second component granulation mixture. In some embodiments, the premix of vitamin D and silicon dioxide is in a mass ratio of about 25:9 vitamin D:silicon dioxide. In some embodiments, the first mixture is in a mass ratio of about 1000:25:9 second component:vitamin D:silicon dioxide. In some embodiments, the step of mixing and sieving comprises sieving through a US 20 Mesh sieve. In some embodiments, the step of blending the first mixture in a 16 quart V blender comprises blending for about 2 minutes. The step of dividing the first mixture into four equal portions and adding the second component may comprise adding 2.0 kg of the second component. In some embodiments, the method further comprises the step of milling and sieving the second component granulation to produce second component and vitamin D granulations having median particle sizes within ±40% of one another. The median particle sizes are more preferably within ±25% of one another. The median particle sizes are most preferably within ±15% of one another. In preferred embodiments, the method further comprises the step of milling and sieving the second component granulation to have a D 20  value of less than 110 microns. In preferred embodiments, the method further comprises the step of milling and sieving the second component granulation to have a D 16  value of less than 95 microns. 
     In another aspect of the present invention, there is a method of manufacturing calcium carbonate/vitamin D tablets comprising forming a premix comprising a mixture of vitamin D granulation and silicon dioxide; adding a calcium carbonate granulation to said premix to form a first vitamin D/calcium carbonate granulation mixture; mixing and sieving the first vitamin D/calcium carbonate granulation mixture; blending the first vitamin D/calcium carbonate granulation mixture in a V blender; dividing the first vitamin D/calcium carbonate granulation mixture into four equal portions and adding calcium carbonate to each portion to form a second vitamin D/calcium carbonate granulation mixture; blending the second vitamin D/calcium carbonate granulation mixture in a V blender; and, forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture. In some embodiments, the premix of vitamin D and silicon dioxide is in a mass ratio of about 25:9 vitamin D:silicon dioxide. In some embodiments, the first mixture is in a mass ratio of about 1000:25:9 calcium carbonate:vitamin D:silicon dioxide. In some embodiments, the step of mixing and sieving comprises sieving through a US 20 Mesh sieve. In some embodiments, the step of blending the first mixture in a 16 quart V blender comprises blending for about 2 minutes. The step of dividing the first mixture into four equal portions and adding calcium carbonate may comprise adding 2.0 kg of calcium carbonate. In some embodiments, the method further comprises the step of milling and sieving the calcium carbonate granulation to produce calcium carbonate and vitamin D granulations having median particle sizes within ±40% of one another. The median particle sizes are more preferably within ±25% of one another. The median particle sizes are most preferably within ±15% of one another. In preferred embodiments, the method further comprises the step of milling and sieving the calcium carbonate granulation to have a D 20  value of less than 110 microns. In preferred embodiments, the method further comprises the step of milling and sieving the calcium carbonate granulation to have a D 16  value of less than 95 microns. 
     In another aspect of the present invention, there is a method of manufacturing calcium carbonate/vitamin D tablets comprising forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide and another layer of calcium carbonate; sieving and blending the premix to form a first vitamin D/calcium carbonate granulation mixture; adding calcium carbonate to the first vitamin D/calcium carbonate granulation mixture such that there is a layer of calcium carbonate granulation, a layer of the first granulation mixture, and another layer of calcium carbonate to form a second vitamin D/calcium carbonate granulation mixture; sieving and blending the second vitamin D/calcium carbonate granulation mixture; and forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture. In preferred embodiments, one or both of the steps of sieving and blending the premix and sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a Comil. In some embodiments, one or both of the steps of sieving and blending the premix and sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender. In some embodiments, the step of sieving and blending the premix comprises blending with a V blender comprises blending for about 8 minutes. In some embodiments, the step of sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender comprises blending for about 50 minutes. In some embodiments, the step of forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide, and another layer of calcium carbonate comprises adding two layers of about 500 kg each of calcium carbonate. In some embodiments, the first mixture is in a mass ratio of about 1600:20:7 calcium carbonate:vitamin D:silicon dioxide. 
     In another aspect of the present invention, there is a pharmaceutical tablet of calcium carbonate and vitamin D produced by the process comprising forming a premix comprising a mixture of vitamin D granulation and silicon dioxide; adding a calcium carbonate granulation to said premix to form a first vitamin D/calcium carbonate granulation mixture; mixing and sieving the first vitamin D/calcium carbonate granulation mixture; blending the first vitamin D/calcium carbonate granulation mixture in a V blender; dividing the first vitamin D/calcium carbonate granulation mixture into four equal portions and adding calcium carbonate each portion to form a second vitamin D/calcium carbonate granulation mixture; blending the second vitamin D/calcium carbonate granulation mixture in a V blender; and, pressing a composition comprising the second vitamin D/calcium carbonate granulation mixture into a tablet. In some embodiments, the premix of vitamin D and silicon dioxide is in a mass ratio of about 25:9 vitamin D:silicon dioxide. In some embodiments, the first mixture is in a mass ratio of about 1000:25:9 calcium carbonate:vitamin D:silicon dioxide. In some embodiments, the step of mixing and sieving comprises sieving through a US 20 Mesh sieve. In some embodiments, the step of blending the first mixture in a V blender comprises blending for about 2 minutes. In some embodiments, the step of dividing the first mixture into four equal portions and adding calcium carbonate comprises adding 2.0 kg of calcium carbonate. In some embodiments, the method further comprises the step of milling and sieving the calcium carbonate granulation to produce calcium carbonate and vitamin D granulations having median particle sizes within ±40% of one another. More preferably, the median particle sizes are within ±25% of one another. Most preferably, the median particle sizes are within ±15% of one another. In preferred embodiments, the process further comprises the step of milling and sieving the calcium carbonate granulation to have a D 20  value of less than 110 microns. In preferred embodiments, the process further comprises the step of milling and sieving said calcium carbonate granulation to have a D 16  value of less than 95 microns. 
     In another aspect of the present invention, there is a pharmaceutical tablet of calcium carbonate and vitamin D produced by the process comprising forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide and another layer of calcium carbonate; sieving and blending the premix to form a first vitamin D/calcium carbonate granulation mixture; adding calcium carbonate to the first vitamin D/calcium carbonate granulation mixture such that there is a layer of calcium carbonate granulation, a layer of the first granulation mixture, and another layer of calcium carbonate, to form a second vitamin D/calcium carbonate granulation mixture; sieving and blending the second vitamin D/calcium carbonate granulation mixture; and forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture. In preferred embodiments, one or both of the steps of sieving and blending the premix and sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a Comil. In some embodiments, one or both of said steps of sieving and blending the premix and sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender. In some embodiments, the step of sieving and blending the premix comprises blending with a V blender comprises blending for about 8 minutes. In some embodiments, the step of sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender comprises blending for about 50 minutes. In some embodiments, the step of forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide and another layer of calcium carbonate comprises adding two layers of about 500 kg each of calcium carbonate. In some embodiments, the first mixture is in a mass ratio of about 1600:20:7 calcium carbonate:vitamin D:silicon dioxide. 
     The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawing, in which: 
         FIG. 1  is a block flow diagram of the standard process (trial  1 ) for calcium carbonate/vitamin D tablets. 
         FIG. 2  illustrates the particle size profile for calcium carbonate and vitamin D for the standard process. 
         FIG. 3  is a block flow diagram of the modified process. 
         FIG. 4  illustrates the particle size profile for calcium carbonate and vitamin D for the modified process. 
         FIG. 5 . illustrates recovery (composite assay) for the standard and modified processes as a function of blend time. 
         FIG. 6  illustrates content uniformity for the standard and modified processes as a function of blend time. 
         FIG. 7  is the block flow diagram for a large scale process of the modified process. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As used herein, “a” or “an” means one or more. Unless otherwise indicated, the singular contains the plural and the plural contains the singular. 
     The theoretical best content uniformity can be calculated based on the number of particles per scale of scrutiny (in this case a tablet). In general a robust pharmaceutical tablet has &gt;10,000 particles per unit of scrutiny and results in an actual content uniformity RSD of 1-2%. The standard vitamin tablet formulation has 150-200 vitamin granules per unit of scrutiny and results in a theoretical best RSD of 5-7%. In reality content uniformity of vitamin tablets have an RSD of 7-15%. Any thing that increases the number of particles of vitamin per gram will improve content uniformity RSD (e.g. screening out the larger vitamin particles from the vitamin premix, reducing the vitamin premix potency, increasing the vitamin assay per tablet (e.g. 400 IU to 800 IU)). 
     If one wet or dry granulates the vitamin with a carrier like lactose, maltodextrin, etc and then mills the granulation, one can increase the number of vitamin particle which then improves the theoretical content uniformity RSD. It has also been found that if the vitamin premix is milled so that there are more particles per gram of premix, the content uniformity RSD can be reduced. Additionally, a lower strength (IU/gram) vitamin premix results in an increase in the number of particle per gram and a lower content uniformity RSD. 
     The theoretical calculation assumes that the mixing process is perfect and that there is no segregation after the powders are mixed. We have found that vitamin premixes have a static charge that inhibits mixing. By adding silicon dioxide, we reduce the static charge and promote thorough mixing. Additionally by matching the particle size distribution (PSD) of the second component and the vitamin premix powder, we can minimize the segregation potential of a powder blend. 
     The vitamin D3 may be any vitamin D3 source but as used in the examples herein is supplied by BASF as beadlets with a potency of 100 IU/mg or 50 IU/mg. The standard process (trial  1 ) for the small scale manufacture of calcium carbonate/vitamin D tablets is illustrated in the flow diagram of  FIG. 1 . 21.1 g of vitamin D and 1.0 kg of calcium carbonate are mixed and sieved through US 20 Mesh. The resulting mixture is introduced into a 16 qt. V blender and blended for 2 minutes. The blended mixture is then divided into four equal portions and each portion is mixed with 2.0 kg of calcium carbonate. The portions are combined and introduced into a V blender. The blending times are varied and the result reported herein. Five blend times a reevaluated for tablet uniformity: 15, 20, 25, and 30 minutes. Tablets are manufactured by compaction and coating of the resulting blend. 
     The second component of the pharmaceutical dosage forms herein may be a nutritional component and/or a pharmaceutical active component with a particle size ratio of at least 1.4, preferably at least 1.5, the particle size of the vitamin D3. Such components include but are not limited to calcium carbonate, calcium phosphate, or calcium citrate maleate. 
     Particle size analyses are performed for the second component granulation, including but not limited to calcium carbonate, calcium phosphate and calcium citrate maleate, and for vitamin D. One hundred gram samples are tested in a ro-tap apparatus. Material is sieved through 40, 70, 80, 100, 120, 140, and 200 US Mesh Sieves. The data is provided below in tabular form and graphically in  FIG. 2 . A measurement of particle size distribution is the mean particle size of a powder sample. Another preferred measurement of particle size distribution is the median particle size, denoted D 50 . Another preferred measurement of particle size distribution is the size for the smallest 16% (D 16 ) and 20% (D 20 ) of the particle size distribution. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Calcium Carbonate Particle Size Analysis Trial 1. 
               
               
                 CALCIUM CARBONATE GRANULATION 
               
               
                 Sample Size: 100 g 
               
             
          
           
               
                   
                   
                 Gross 
                 Tare 
                 Net 
                   
               
               
                 US 
                   
                 Wt. 
                 Wt. 
                 Wt 
                 Percent 
               
               
                 Mesh 
                 Microns 
                 (g) 
                 (g) 
                 (g) 
                 Retained 
               
               
                   
               
             
          
           
               
                 40 
                 425 
                 394.88 
                 355.96 
                 38.92 
                 38.904 
               
               
                 70 
                 212 
                 374.06 
                 350.47 
                 23.59 
                 23.581 
               
               
                 80 
                 177 
                 409.36 
                 399.77 
                 9.59 
                 9.586 
               
               
                 100 
                 150 
                 362.44 
                 354.92 
                 7.52 
                 7.517 
               
               
                 120 
                 125 
                 363.14 
                 346.63 
                 16.51 
                 16.503 
               
               
                 140 
                 106 
                 310.17 
                 306.45 
                 3.72 
                 3.719 
               
               
                 200 
                 75 
                 337.57 
                 337.39 
                 0.18 
                 0.180 
               
               
                 Fines 
                   
                 378.77 
                 378.76 
                 0.01 
                 0.010 
               
             
          
           
               
                   
                 Total 
                 100.04 
                 100 
               
               
                   
               
               
                 D 50  306 micron 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Vitamin D Particle Size Analysis Trial 1. 
               
               
                 PARTICLE SIZE ANALYSIS - VITAMIN D 
               
               
                 Sample Size: 100 g 
               
             
          
           
               
                   
                   
                 Gross 
                 Tare 
                 Net 
                   
               
               
                 US 
                   
                 Wt. 
                 Wt. 
                 Wt. 
                 Percent 
               
               
                 Mesh 
                 Microns 
                 (g) 
                 (g) 
                 (g) 
                 Retained 
               
               
                   
               
             
          
           
               
                 40 
                 425 
                 356.28 
                 355.79 
                 0.49 
                 0.489 
               
               
                 70 
                 212 
                 387.09 
                 350.28 
                 36.81 
                 36.733 
               
               
                 80 
                 177 
                 434.15 
                 398.89 
                 35.26 
                 35.186 
               
               
                 100 
                 150 
                 370.72 
                 353.75 
                 16.97 
                 16.934 
               
               
                 120 
                 125 
                 354.19 
                 345.53 
                 8.66 
                 8.642 
               
               
                 140 
                 106 
                 307.27 
                 305.45 
                 1.82 
                 1.816 
               
               
                 200 
                 75 
                 337.15 
                 336.96 
                 0.19 
                 0.190 
               
               
                 Fines 
                   
                 378.74 
                 378.73 
                 0.01 
                 0.010 
               
             
          
           
               
                   
                 Total 
                 100.21 
                 100 
               
               
                   
               
               
                 D 50  199 micron 
               
             
          
         
       
     
     The ratio of the calcium carbonate D 50  (306 microns) and the vitamin D D 50  (199 microns) is 1.54. Blend uniformity studies are conducted with tablets manufactured at a 20% overage of vitamin D and blend times of 15, 20, 25 and 30 minutes. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Blend Uniformity for 20% Overage; 15 Minute 
               
               
                 Blend Time; Target Weight of 1.423 g. 
               
             
          
           
               
                   
                 % Label 
                 Wt. 
                 % 
                 Wt. Adjusted 
               
               
                   
                 Claim 
                 (g) 
                 Wt. 
                 Assay 
               
               
                   
                   
               
             
          
           
               
                   
                   
                 106 
                 1.4422 
                 101.3 
                 104.6 
               
               
                   
                   
                 112 
                 1.445 
                 101.5 
                 110.3 
               
               
                   
                   
                 111 
                 1.4373 
                 101.0 
                 109.9 
               
               
                   
                   
                 105 
                 1.4338 
                 100.8 
                 104.2 
               
               
                   
                   
                 112 
                 1.4316 
                 100.6 
                 111.3 
               
               
                   
                   
                 113 
                 1.4342 
                 100.8 
                 112.1 
               
               
                   
                   
                 105 
                 1.4345 
                 100.8 
                 104.2 
               
               
                   
                   
                 104 
                 1.4303 
                 100.5 
                 103.5 
               
               
                   
                   
                 107 
                 1.4371 
                 101.0 
                 106.0 
               
               
                   
                   
                 107 
                 1.4401 
                 101.2 
                 105.7 
               
               
                   
                 AVERAGE 
                 108.2 
                 1.43661 
                   
                 107.2 
               
               
                   
                 STDEV 
                 3.43 
                 0.00 
                   
                 3.35 
               
               
                   
                 RSD 
                 3.17 
                 0.33 
                   
                 3.12 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Blend Uniformity for 20% Overage; 20 Minute 
               
               
                 Blend Time; Target Weight of 1.423 g. 
               
             
          
           
               
                   
                 % 
                   
                   
                 Wt. 
                   
               
               
                   
                 Label 
                 Wt. 
                 % 
                 Adjusted 
               
               
                   
                 Claim 
                 (g) 
                 Wt. 
                 Assay 
                 *DUPLICATE* 
               
               
                   
                   
               
             
          
           
               
                   
                 121 
                 1.4372 
                 101.0 
                 119.8 
                 108 
               
               
                   
                 113 
                 1.4142 
                 99.4 
                 113.7 
                 133 
               
               
                   
                 110 
                 1.4174 
                 99.6 
                 110.4 
                 111 
               
               
                   
                 116 
                 1.4353 
                 100.9 
                 115.0 
                 124 
               
               
                   
                 123 
                 1.437 
                 101.0 
                 121.8 
                 138 
               
               
                   
                 136 
                 1.4235 
                 100.0 
                 136.0 
                 102 
               
               
                   
                 112 
                 1.4163 
                 99.5 
                 112.5 
                 121 
               
               
                   
                 127 
                 1.4221 
                 99.9 
                 127.1 
                 107 
               
               
                   
                 134 
                 1.4318 
                 100.6 
                 133.2 
                 105 
               
               
                   
                 129 
                 1.4262 
                 100.2 
                 128.7 
                 116 
               
               
                 AVERAGE 
                 122.1 
                 1.4261 
                   
                 121.8 
                 116.5 
               
               
                 STDEV 
                 9.29 
                 0.01 
                   
                 9.04 
                 12.23 
               
               
                 RSD 
                 7.61 
                 0.62 
                   
                 7.42 
                 10.50 
               
               
                   
               
               
                 *Duplicate analysis performed to verify results 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Blend Uniformity for 20% Overage; 25 Minute 
               
               
                 Blend Time; Target Weight of 1.423 g. 
               
             
          
           
               
                   
                 % Label 
                 Wt. 
                 % 
                 Wt. Adjusted 
               
               
                   
                 Claim 
                 (g) 
                 Wt. 
                 Assay 
               
               
                   
                   
               
             
          
           
               
                   
                   
                 108 
                 1.4377 
                 101.0 
                 106.9 
               
               
                   
                   
                 132 
                 1.4308 
                 100.5 
                 131.3 
               
               
                   
                   
                 116 
                 1.4375 
                 101.0 
                 114.8 
               
               
                   
                   
                 103 
                 1.4368 
                 101.0 
                 102.0 
               
               
                   
                   
                 98 
                 1.4308 
                 100.5 
                 97.5 
               
               
                   
                   
                 106 
                 1.4339 
                 100.8 
                 105.2 
               
               
                   
                   
                 99 
                 1.4311 
                 100.6 
                 98.4 
               
               
                   
                   
                 109 
                 1.4338 
                 100.8 
                 108.2 
               
               
                   
                   
                 94 
                 1.4318 
                 100.6 
                 93.4 
               
               
                   
                   
                 105 
                 1.4367 
                 101.0 
                 104.0 
               
               
                   
                 AVERAGE 
                 107.0 
                 1.43409 
                   
                 106.2 
               
               
                   
                 STDEV 
                 10.78 
                 0.00 
                   
                 10.70 
               
               
                   
                 RSD 
                 10.08 
                 0.20 
                   
                 10.08 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Blend Uniformity for 20% Overage; 30 Minute 
               
               
                 Blend Time; Target Weight of 1.423 g. 
               
             
          
           
               
                   
                 % Label 
                 Wt. 
                 % 
                 Wt. Adjusted 
               
               
                   
                 Claim 
                 (g) 
                 Wt. 
                 Assay 
               
               
                   
                   
               
             
          
           
               
                   
                   
                 116 
                 1.4331 
                 100.7 
                 115.2 
               
               
                   
                   
                 107 
                 1.4294 
                 100.4 
                 106.5 
               
               
                   
                   
                 118 
                 1.4328 
                 100.7 
                 117.2 
               
               
                   
                   
                 112 
                 1.4378 
                 101.0 
                 110.8 
               
               
                   
                   
                 109 
                 1.4387 
                 101.1 
                 107.8 
               
               
                   
                   
                 121 
                 1.4376 
                 101.0 
                 119.8 
               
               
                   
                   
                 116 
                 1.4303 
                 100.5 
                 115.4 
               
               
                   
                   
                 123 
                 1.4344 
                 100.8 
                 122.0 
               
               
                   
                   
                 107 
                 1.4311 
                 100.6 
                 106.4 
               
               
                   
                   
                 122 
                 1.4364 
                 100.9 
                 120.9 
               
               
                   
                 AVERAGE 
                 115.1 
                 1.43416 
                   
                 114.2 
               
               
                   
                 STDEV 
                 6.08 
                 0.00 
                   
                 5.96 
               
               
                   
                 RSD 
                 5.28 
                 0.23 
                   
                 5.22 
               
               
                   
                   
               
             
          
         
       
     
     Following this standard procedure, low recovery of vitamin D may occur and the variability may be high as vitamin D has an affinity for plastic materials such as plastic bags that may be used in the manufacturing. [0033] A modified manufacturing process (trial  2 ) is used to improve recovery and content uniformity of vitamin D/calcium carbonate tablets. The modified process for the small scale manufacture of calcium carbonate/vitamin D tablets is illustrated in the flow diagram of  FIG. 3 . In the modified process, a premix of vitamin D (25.1 g) and silicon dioxide (8.8 g) is made and this is added to 1.0 kg of calcium carbonate granulation. The silicon dioxide is added in an attempt to minimize or eliminate the electrostatic interaction of vitamin D with the surfaces in which it comes into contact in the manufacturing process of vitamin D tablets. The mixture is then mixed and sieved through US 20 Mesh. The resulting mixture is introduced into a 16 qt. V blender and blended for 2 minutes. The blended mixture is then divided into four equal portions and each portion is mixed with 2.0 kg of calcium carbonate. The portions are combined and introduced into a V blender. The blending times are varied and the results reported herein. Vitamin D at a 20% overage and the same blend times are evaluated for tablet uniformity: 15, 20, 25, and 30 minutes. Tablets are manufactured by compaction and coating of the resulting blend. 
     The match between D 50  values is preferably about ±40%, more preferably about ±25%, and most preferably about ±15% to achieve good content uniformity. If one of the components, for example, the calcium carbonate had a D 50  of 200 microns then the vitamin D component should have a D 50  of 120-280 microns, more preferably 150-250 microns, and most preferably 170-230 microns. 
     The particle size profile of the calcium carbonate is modified to more closely match the vitamin D particle size profile by appropriate milling and sieving. The particle size data is provided below, and is provided in graphical form in  FIG. 4  for calcium carbonate and vitamin D. 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Calcium Carbonate Particle Size Analysis Trial 2. 
               
               
                 PARTICLE SIZE ANALYSIS - CALCIUM CARBONATE 
               
               
                 Sample Size: 100 g 
               
             
          
           
               
                   
                 US 
                   
                   
                   
                   
                 Percent 
               
               
                   
                 Mesh 
                 Microns 
                 Gross 
                 Tare 
                 Net 
                 Retained 
               
               
                   
                   
               
             
          
           
               
                   
                 40 
                 425 
                 419.3 
                 385.5 
                 33.8 
                 33.868 
               
               
                   
                 70 
                 212 
                 372 
                 350.3 
                 21.7 
                 21.743 
               
               
                   
                 80 
                 177 
                 404.7 
                 398.9 
                 5.8 
                 5.812 
               
               
                   
                 100 
                 150 
                 358.9 
                 353.6 
                 5.3 
                 5.311 
               
               
                   
                 120 
                 125 
                 356 
                 345.4 
                 10.6 
                 10.621 
               
               
                   
                 140 
                 106 
                 307.9 
                 305.3 
                 2.6 
                 2.605 
               
               
                   
                 200 
                 75 
                 345.7 
                 336.9 
                 8.8 
                 8.818 
               
               
                   
                 Fines 
                   
                 389.9 
                 378.7 
                 11.2 
                 11.222 
               
             
          
           
               
                   
                 Total 
                 99.8 
                 100 
               
               
                   
               
               
                 D 50  254 micron 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Vitamin D Particle Size Analysis Trial 2. 
               
               
                 PARTICLE SIZE ANALYSIS - VITAMIN D 
               
               
                 Sample Size: 25.6 g 
               
             
          
           
               
                   
                 US 
                   
                   
                   
                   
                 Percent 
               
               
                   
                 Mesh 
                 Microns 
                 Gross 
                 Tare 
                 Net 
                 Retained 
               
               
                   
                   
               
             
          
           
               
                   
                 40 
                 425 
                 385.5 
                 385.4 
                 0.1 
                 0.392 
               
               
                   
                 70 
                 212 
                 358.7 
                 350.3 
                 8.4 
                 32.941 
               
               
                   
                 80 
                 177 
                 406.9 
                 399 
                 7.9 
                 30.980 
               
               
                   
                 100 
                 150 
                 359.1 
                 353.8 
                 5.3 
                 20.784 
               
               
                   
                 120 
                 125 
                 348.5 
                 345.6 
                 2.9 
                 11.373 
               
               
                   
                 140 
                 106 
                 306 
                 305.3 
                 0.7 
                 2.745 
               
               
                   
                 170 
                 90 
                 0 
                 0 
                 0 
                 0.000 
               
               
                   
                 200 
                 75 
                 337.1 
                 337 
                 0.1 
                 0.392 
               
               
                   
                 230 
                 63 
                 0 
                 0 
                 0 
                 0.000 
               
               
                   
                 270 
                 53 
                 0 
                 0 
                 0 
                 0.000 
               
               
                   
                 400 
                 38 
                 0 
                 0 
                 0 
                 0.000 
               
               
                   
                 Fines 
                   
                 378.7 
                 378.6 
                 0.1 
                 0.392 
               
             
          
           
               
                   
                 Total 
                 25.5 
                 100 
               
               
                   
               
               
                 D 50  193 micron 
               
             
          
         
       
     
     In the modified processes, the calcium carbonate granulation is milled and sieved in such a way as to give a particle size distribution that more closely matches the vitamin D particle size distribution. This can be seen when comparing  FIG. 2  (trial  1 ) and  FIG. 4  (trial  2 ). The particle size profiles of calcium carbonate and vitamin D more closely match one another in the modified process. The ratio of the calcium carbonate D 50  (254 micron) and the vitamin D D 50  (193 micron) is now 1.32. 
     The improvement in recovery for the modified process can be seen in  FIG. 5 , which graphically presents recovery in % of label claims versus blend time for blend times of 15, 20, 25, and 30 minutes for both trial  1  and trial  2 . While results continue to be lower than target, they are more consistent and closer to target than that seen in the standard process. 
     A similar improvement is observed for content uniformity.  FIG. 6  illustrates the improvement in content uniformity obtained with the modified process (trial  2 ) as a function of blend time for blend times of 15, 20, 25, and 30 minutes as compared with the standard process (trial  1 ). The corresponding data is given in Table 10 below: 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Content Uniformity of Modified Process (Trial 2). 
               
             
          
           
               
                   
                 Time 
                 Assay 
                 % RSD 
                 L.C. 
               
               
                   
                   
               
               
                   
                 15 
                 115.4 
                 3.34 
                 120 
               
               
                   
                 20 
                 109.0 
                 3.90 
                 120 
               
               
                   
                 25 
                 114.2 
                 3.70 
                 120 
               
               
                   
                 30 
                 115.1 
                 4.64 
                 120 
               
               
                   
                   
               
             
          
         
       
     
     A large scale method of manufacturing calcium carbonate/vitamin D tablets is developed by forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide, and another layer of calcium carbonate; sieving and blending the first vitamin D/calcium carbonate granulation mixture in a 60 cubic foot V blender to form a first vitamin D/calcium carbonate granulation mixture; adding calcium carbonate granulation to said premix such that there is a layer of calcium carbonate granulation, a layer of the first vitamin D/calcium carbonate granulation mixture, and another layer of calcium carbonate granulation to form a second vitamin D/calcium carbonate granulation mixture; sieving and blending the second vitamin D/calcium carbonate granulation mixture in a V blender; and, forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture. The first mixture is in a mass ratio of about 1600:20:7 calcium carbonate:vitamin D:silicon dioxide. The step of sieving comprises sieving through a Comil. The step of blending the first mixture in a 60 cubic foot V blender comprises blending for about 8 minutes. The step of adding calcium carbonate granulation to the first mixture may comprise adding two layers of about 500 kg each of calcium carbonate granulation. This process flowchart is given in  FIG. 7 . 
     The large scale method further uses the step of milling and sieving the calcium carbonate granulation to produce calcium carbonate and vitamin D granulations having desired particle size characteristics. The milling and sieving of the calcium carbonate leaves a small particle size tail to the distribution. In other words, it generates some fines that spread the distribution towards smaller particle sizes. This is best described in terms of the actual distribution of the particles sizes of the calcium carbonate at the lower end of particle sizes. 
     The data in Table 10 reports the particle size distribution by segments. The comparative trial example against the four inventive trial examples is highlighted. It can be seen at the lower end (e.g., D 16  and D 20 ) where the grinding lowers the particle size of that segment. So for example, in the comparative trial 20% of the particles have a particle size below 149 microns while for the inventive trials the D 20  is 92-106 microns. A preferred calcium carbonate granulation is one having a characteristic production of fines, or increase in small particles. Preferably, the calcium carbonate would have a value of D 20  of below 110 microns and/or a D 16  value of below 95 microns. 
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Particle Size Distribution by Segments. 
               
             
          
           
               
                   
                 Comparative 
                 Inventive 
                   
                   
                 Inventive 
                 Inventive 
                 Inventive 
               
               
                   
                 Example 
                 Example 
                   
                   
                 Example 
                 Example 
                 Example 
               
               
                   
                 Trial 1 
                 Trial 2 
                 Vit D 1 
                 Vit D 2 
                 Gran 1 
                 Gran 2 
                 Gran 3 
               
               
                   
                   
               
             
          
           
               
                 D 10 
                 134 
                 n/a 
                 148 
                 139 
                 n/a 
                 n/a 
                 n/a 
               
               
                 D 16 
                 143 
                 90.5 
                 158 
                 151 
                 80.4 
                 86 
                 77.3 
               
               
                 D 20 
                 149 
                 106 
                 164 
                 156 
                 94.7 
                 105 
                 92.1 
               
               
                 D 30 
                 184 
                 142 
                 179 
                 169 
                 143 
                 170 
                 143 
               
               
                 D 40 
                 228 
                 185 
                 189 
                 182 
                 237 
                 259 
                 208 
               
               
                 D 45 
                 264 
                 216 
                 194 
                 187 
                 290 
                 312 
                 246 
               
               
                 D 50 
                 306 
                 254 
                 199 
                 192 
                 349 
                 376 
                 297 
               
               
                 D 60 
                 412 
                 349 
                 209 
                 204 
                 464 
                 476 
                 362 
               
               
                 D 70 
                 n/a 
                 n/a 
                 243 
                 228 
                 565 
                 568 
                 515 
               
               
                 D 80 
                 n/a 
                 n/a 
                 294 
                 281 
                 689 
                 679 
                 631 
               
               
                 D 84 
                 n/a 
                 n/a 
                 317 
                 306 
                 746 
                 729 
                 685 
               
               
                 D 90 
                 n/a 
                 n/a 
                 355 
                 347 
                 840 
                 811 
                 774 
               
               
                   
               
             
          
         
       
     
     The resulting blends are evaluated for content uniformity and the results are given in Table 11. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Content Uniformity for Large Scale Modified Process. 
               
             
          
           
               
                 Vitamin D 
                 Tablet Label 
                 Vitamin D 
                 Batch 
                 % 
               
               
                 Potency 
                 Claim 
                 Overage 
                 Number 
                 RSD 
               
               
                   
               
               
                 100,000 IU/g  
                 400 IU 
                 10% 
                 423720 
                 5.8 
               
               
                 100,000 IU/g  
                 400 IU 
                 10% 
                 424134 
                 5.3 
               
               
                 100,000 IU/g  
                 400 IU 
                 10% 
                 424135 
                 5.3 
               
               
                 100,000 IU/g  
                 400 IU 
                 10% 
                 424136 
                 7.6 
               
               
                 100,000 IU/g  
                 400 IU 
                 20% 
                 424137 
                 5.5 
               
               
                 100,000 IU/g  
                 400 IU 
                 20% 
                 424138 
                 3.5 
               
               
                 100,000 IU/g  
                 400 IU 
                 20% 
                 424139 
                 5.1 
               
               
                 50,000 IU/g 
                 400 IU 
                  0% 
                 428154 
                 3.9 
               
               
                 50,000 IU/g 
                 400 IU 
                  0% 
                 428155 
                 1.9 
               
               
                 50,000 IU/g 
                 400 IU 
                  0% 
                 428156 
                 3.7 
               
               
                 50,000 IU/g 
                 400 IU 
                 10% 
                 428157 
                 2.7 
               
               
                 50,000 IU/g 
                 400 IU 
                 10% 
                 428158 
                 4.1 
               
               
                 50,000 IU/g 
                 400 IU 
                 10% 
                 428159 
                 3.9 
               
               
                 50,000 IU/g 
                 800 IU 
                  0% 
                 428142 
                 2.5 
               
               
                 50,000 IU/g 
                 800 IU 
                  0% 
                 428143 
                 2.8 
               
               
                 50,000 IU/g 
                 800 IU 
                  0% 
                 428144 
                 4.1 
               
               
                 50,000 IU/g 
                 800 IU 
                 10% 
                 428145 
                 2.8 
               
               
                 50,000 IU/g 
                 800 IU 
                 10% 
                 428146 
                 3.8 
               
               
                 50,000 IU/g 
                 800 IU 
                 10% 
                 428147 
                 3.2 
               
               
                   
               
             
          
         
       
     
     It is suspected that the combination of 1) the addition of silicon dioxide in the formulation and 2) the matching of particle size profiles of vitamin D granulation and calcium carbonate granulation results in improved recovery and content uniformity of vitamin D in tablets. This is important from both a quality and regulatory perspective, as nutritional products, such as vitamins, when packaged with pharmaceutical products, must meet all pharmaceutical specifications, including but not limited to those for composite assay and dose uniformity. 
     Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.