United States Patent 1191
`Gallian et al.
`
`Patent Number:
`[11]
`[45] Date of Patent:
`
`5,047,246
`Sep. 10, 1991
`
`[54] DIRECT COMPRESSION
`CYCLOPHQSPHAMIDE TABLET
`'
`[75] Inventors: Claude E. Gallian, Newburgh;
`Charles Williams, Evansville, both of
`
`3,873,694 3/1975 Kanig ................................ .. 424/127
`4,072,535 1/1978 Short et a1. ....................... 1. 106/210
`4,198,507 4/1980 Barry et a1v ................... .. 514/869 X
`4,218,471 8/1980 Brock et a1.
`514/578
`4,439,453 3/1984 Vogel ........ ..
`.1 106/210
`
`Ind,
`
`4,457,907 7/1984 Porter . . l . . . . . .
`
`. . . . .. 424/71
`
`[731 Assigneer Bristol-Myers Company, New York,
`NY.
`
`4,753,789 6/1988 Tyers et a1. ................... .. 514/917 X
`4,910,218 3/1990 Bair ................................... .. 514/443
`
`[21] Appl' No’: 242’84'9
`[22] Filed:
`Sep. 9, 1988
`
`Primary Examiner-Thurman K. Page
`Attorney, Agent, or Firm—Robert H. Uloth
`[57]
`ABSTRACT
`
`[51] Int. Cl.5 .............................................. .. A61K 9/30
`[52] Us Cl
`424/464_ 424/465
`'
`'
`' """
`424/479’, 424/499’
`[58] Field of Search ....... .f .... .. 424/489 464,465, 470,
`424/475’ 479, 499
`
`[56]
`
`_
`References C'ted
`U.S. PATENT DOCUMENTS
`
`.
`.
`.
`.
`.
`A directly compressible pharmaceutical composition
`comprising cyclophosphamide and a partially or fully
`Pmgelatinized Starch is disclosed The Pharmaceutical
`composition, when directly compressed into a tablet,
`exhibits unexpected stability when compared to cyclo
`phospharnide in combination with other direct com
`pression vehicles.
`
`3,584,114 6/1971 Cavalli et a1. ....................... .. 424/38
`3,725,556 4/1973 Hanssen et a1. ................... .. 424/357
`
`‘
`14 Claims, 1 Drawing Sheet
`
`SODIUM STARCH
`
`GLYCOLATE
`
`CYCLOPHOSPHAMIDE
`
`LACTOSE
`1
`‘
`WET BLENDING
`DEC YELLOW
`#10 A.L. _" (LODIGE)
`COLLOIDAL
`SILICON DIOXIDE
`
`POVIDONE
`FD
`
`ABEUE
`
`'
`
`'
`
`y
`
`DRY SCREENING
`(ROTARY GRANULATOR)
`
`DRY BLENDING
`tcou'ow MIXER)
`
`EXTRUSION
`‘COW-l
`
`DRYING
`(FORCED AIR OVEN)
`
`“9 STEARATE
`CORE GRANULATION
`
`DRY MILLING
`(ROTARY GRANULATOR)
`
`PREGELATINIZED
`STARCH
`
`SODIUM STARCH
`GLYCOLATE
`
`PARTICLE SIZING
`(sweco SIFTER)
`BLUE GRAiVULATION
`COLLOlDAL
`SILICON 010x105
`
`DRY mums
`(ROTARY GRANULATOR)
`
`MICROCRYSTALUNE
`CELLULOSE
`
`DRY BLENDING
`PREGELATINIZED
`STARCH _" (LODIGE)
`l
`COAT GRANULATION
`'
`
`TABLETING
`(MANESTY 90o DRY c0741)
`
`M9
`STEARATE
`
`DC CYCLOPHOSPHAMIDE
`TABLETS
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 001
`
`

`

`U.S. Patent
`
`Sep. 10, 1991‘
`
`5,047,246
`
`SODIUM STARCH
`
`GLYCOLATE
`
`LACTOSE
`
`POVIDONE
`FD gcl: Flue
`I
`
`'
`
`'
`
`CYCLOPHOSPHAMIDE
`
`Dac YELLOW
`#Io A.L. —->
`COLLOIDAL
`SILICON DIOXIDE
`
`WET BLENDING
`(LODIGE)
`
`DRY SCREENING
`(ROTARY GRANULATOR)
`
`DRY BLENDING
`(COLTON MIXER)
`
`Mg STEARATE
`CORE GRANULATION
`
`PREGELATINIZED
`STARCH
`
`SODIUM STARCH
`GLYCOLATE
`
`EXTRUSION
`(COMM
`I
`
`DRYING
`(FORCED AIR OVEN)
`I
`
`DRY MILLING
`(ROTARY GRANULATOR)
`
`I
`
`PARTICLE SIZING
`(SWECO SIFTER)
`BLUE GRARULATION
`
`- COLLOIDAL
`SILICON DIOXIDE
`
`DRY MILLING
`(ROTARY GRANULATOR)
`
`MICROCRYSTALLINE
`
`CELLULOSE
`
`.
`
`PREGELATINIZED
`STARCH
`
`-
`
`I
`TABLETlNG
`(MANESTY 900 DRY COTA) _ _“
`‘
`
`I
`I
`DRY BLENDING
`(LODIGE)
`I
`COAT GRANULATION
`S'T'EARATE
`
`M9
`
`DC CYCLOPHOSPHAMIDE
`TABLETS
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 002
`
`

`

`1
`
`5,047,246
`
`DIRECT COMPRESSION CYCLOPHOSPHAMIDE
`
`TABLET
`
`'
`
`FIELD OF THE INVENTION
`This invention relates to a novel pharmaceutical com
`. position. More particularly, this invention relates to an
`unexpectedly stable pharmaceutical composition com
`prising cyclophosphamide and a partially or fully pre
`gelatinized starch, which composition can be directly
`compressed to form a pharmaceutical tablet.
`
`5
`
`30
`
`35
`
`2
`3,584,114 to Cavalli, et al., U.S. Pat. No. 3,725,556 to
`I-lanssen, et al., U.S. Pat. No. 3,873,694 to Kanig, U.S.
`Pat. No. 4,072,535 to Short, and U.S. Pat. No. 4,439,453
`to Vogel.
`There are currently several available binders or ex
`cipients which can be used as direct compression vehi
`cles. They include spray-dried lactose; anhydrous lac
`tose: microcrystalline cellulose; dicalcium phosphate
`dihydrate, unmilled; spray-congealed mannitol; unge
`latinized starch (e.g., corn starch), and partially or fully
`pregelatinized starch.
`Starch, as de?ned by the National Formulary XVI,
`“consists of the granules separated from the mature
`grain of corn {Zea mays Ll'nne (Fam.Gramineae)} or of
`wheat {T riticum asen'vum Lz'nne (Fam.Gramineae)}, or
`from tubers of the potato {Solanum tuberosum Linne
`(Fam.Solanaceae)}.” Pregelatinized starch is de?ned by
`the National Formulary XVI as “starch that has been
`chemically and/or mechanically processed to rupture
`all or part of the granules in the presence of water and
`subsequently dried. Some types of pregelatinized starch
`may be modi?ed to render them compressible and flow
`able in character.” Many types of partially or fully
`pregelatinized starches are commercially available for
`use in direct compression tablet formulations.
`With the advent of the above described direct com
`pression vehicles, drug manufacturers are seeking to
`formulate or reformulate pharmaceutically active com
`pounds into compositions which are directly compress
`ible into tablets. One such compound is cyclophospha:
`. mide, an anti-neoplastic agent manufactured by Bristol
`Myers Company under the trademark CYTOXAN ®,
`which is currently tableted with specially prepared
`directly compressible diluent. This DC diluent is pro
`duced by a wet granulation process. However, process
`ing cyclophosphamide using wet granulation method
`has certain drawbacks. A major problem is that it is
`dif?cult to control the moisture of the resulting tablet.
`A second problem is that the dissolution rate, i.e., the
`rate at which the tablet dissolves in water, decreases '
`over time. The third problem is that the dissolution rate
`of the tablet varies from batch to batch, with some
`batches having unacceptably low rates.
`Obviously, a direct compression cyclophosphamide
`tablet would be desirable. Unfortunately, cyclophos
`phamide is not one of the few known compounds which
`possesses the cohesive strength and flowability to allow
`direct compression. Thus, there is a need for a directly
`compressible composition comprising cyclophospha
`mide and a direct compression vehicle, which composi
`tion obviates the problems resultant from wet process
`ing.
`Accordingly, it is an object of this invention to pro
`vide a directly compressible pharmaceutical composi
`tion comprising cyclophosphamide and a direction
`compression vehicle.
`
`BACKGROUND OF THE INVENTION
`The compressed tablet is one of the oldest and most
`popular unit dosage forms for medicinal substances.
`The tablet as a dosage form can be traced to well over
`1,000 years ago when a procedure for molding solid
`forms containing medicinal ingredients was recorded.
`As a result of the introduction of new carriers and com
`pression vehicles, tablets are replacing many forms of 20
`pills, powders and capsules. Accordingly, tablets pres
`ently represent the largest production volume of all
`pharmaceuticals.
`The reasons for the widespread use of tablets are
`apparent, since tablets facilitate: (l) administration of 25
`medication in an accurate dose; (2) fast and accurate
`dispensing with less chance of error and contamination:
`(3) case of administration: (4) administration in a form in
`which the time and areaof contact between the active
`ingredient and the taste buds are reduced, thus obviat
`ing the physiological problems associated with the oral
`administration of drugs that possess a bitter taste and, in
`the case of coated tablets, with drugs that possess a
`disagreeable odor; (5) release of drugs at speci?c loca
`tions in the gastro-intestinal tract to prevent degrada
`tion of drugs sensitive to the low pH environment in the
`stomach, prevent release of drugs that irritate the gas
`tric mucosa in the stomach, and facilitate local action or
`preferential absorption at speci?c sites in the tract: (6)
`enhanced stability by effecting a marked reduction in
`the surface of the drug exposed to the environment; (7)
`rapid production; and (8) economy and ease in storage,
`packaging and shipping.
`There are currently three basic methods for tableting.
`They are the wet granulation method, the dry granula
`tion method and the direct compression (DC) method.
`The direct compression method is by far the desired
`method from the standpoint of processing time and
`requirements of equipment and materials. However,
`only a very limited number of pharmaceutical sub
`stances possess enough cohesive strength and flowabil
`ity to allow direct compression without previous granu
`lation. Certain crystalline materials, such as potassium
`bromide and potassium chloride can be compressed
`without preliminary treatment. Also, drugs such as
`aspirin and phenolphthaline can be directly compressed
`after blending with suitable tableting excipients.
`It has been estimated that about 20 percent of the
`materials used for tableting in the pharmaceutical ?eld
`may be compressed directly. In order to use this method
`to a greater extent, many more materials are modi?ed
`either by treating the material in some special way dur
`ing early stages of preparation, or by adding a direct
`compression vehicle, i.e., a dry binder or excipient ma
`terial which will mix with the active ingredient to pro
`vide a flowable powder and form an easily compressible
`carrier. Exemplary United States patents relating to
`directly compressible tablets include U.S. Pat. No.
`
`45
`
`55
`
`SUMMARY OF THE INVENTION
`_ Surprisingly, a directly compressible pharmaceutical
`composition has been discovered comprising cyclo
`phosphamide and a partially or fully pregelatinized
`starch. It has been found that this composition, when
`directly compressed into a tablet, exhibits unexpected
`and remarkable stability when compared to CYTOX
`AN® tablets or cyclophosphamide in combination
`with other directly compressible vehicles.
`
`65
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 003
`
`

`

`3
`BRIEF DESCRIPTION OF THE DRAWING
`FIG. 1 is a schematic diagram ofa process for making
`a direct compression cyclophosphamide tablet in accor‘
`dance with this invention.
`
`5,047,246
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`cyclophosphamide is listed as a cytotoxic agent by
`the Environmental Protection Agency. Accordingly, a
`“core tablet blend" containing the cyclophosphamide is
`?rst prepared and compressed to form a compressed
`core tablet. The compressed core tablet is then covered
`or encapsulated by a second compressed coating called
`a “press coat blend", which contains no active ingredi
`ents. Thus, persons handling the tablets do not directly
`contact the carcinogenic cyclophosphamide.
`
`I. THE CORE TABLET BLEND
`The core tablet blend in accordance with this inven
`tion comprises a mixture of cyclophosphamide, a par
`tially or fully pregelatinized starch, and optionally,
`additional diluents or other ingredients such as disinte
`grants, lubricants, glidants, et .
`'
`
`5
`
`4
`It has been found that STARCH 1500 provides the
`best results, but that the other pregelatinized starches
`mentioned above will also provide good results.
`STARCH 1500 is a modi?ed, partially pregelatinized
`corn starch containing approximately 5 percent amy
`lose, 15 percent amylopectin, and 80 percent unmodi
`?ed corn starch. STARCH 1500 has a cold water solu
`ble fraction of l0-2O percent.
`All starches contain two types of carbohydrate
`chains, i.e., amylose and amylopectin, which both have
`the same basic chemical structure. However, they are
`slightly different, which accounts for their very differ
`ent individual properties. Amylose has a straight chain
`molecular make-up, while the amylopectin has a multi
`branched make-up. In unmodi?ed corn starch, amylose
`and amylopectin are randomly mixed throughout the
`starch grains and are held together by hydrogen bond
`ing that prevents them from functioning independently.
`The gelatinized process breaks that hydrogen bonding
`and allows the two chains to function separately.
`STARCH 1500, when used as a capsule excipient for
`aspirin, is known to provide better stability than either
`anhydrous lactose or microcrystalline cellulose excipi
`ents. It is also known that aspirin is an ester that easily
`undergoes hydrolysis in the solid state when exposed to
`ambient moisture. STARCH 1500 has a high moisture
`content; however, this moisture is apparently not avail~
`‘able to hydrolyze the aspirin molecule. In contrast,’
`degradation of cyclophosphamide (CY) monohydrate
`‘in solid dose forms is initiated by dehydration resulting
`in the loss of CY monohydrate crystalline structure. CY
`monohydrate degrades rapidly when the moisture con
`tent is less than the monohydrate equivalent. Without
`being bound by theory, the improved stability is be
`lieved to be due to the moisture of STARCH 1500
`maintaining the CY in its monohydrate state. This is
`surprising and unexpected since the moisture is tightly
`bound and essentially unavailable as indicated by the
`stability of aspirin in the presence of STARCH 1500.
`The pregelatinized starch can be dried prior to mix
`ing with cyclophosphamide. However. no signi?cant
`differences have been observed using dried pregelati
`nized starches versus using undried pregelatinized
`starches.
`.
`Using STARCH 1500, it has been found that a cyclo
`phosphamide/pregelatinized starch ratio of approxi
`mately 2:1 provides an adequate blend compatibility to
`produce core tablets that can be transferred intact for
`compression coating on a tablet press. Such a blend is
`advantageous because it is predominantly cyclophos
`phamide, resulting in a smaller, more easily swallowable
`tablet.
`
`55
`
`65
`
`B. Additional Diluents
`Optionally, other direct compression vehicles can be
`added to the core tablet blend. However, such diluents
`are not necessary because a core tablet blend of cyclo
`phosphamide and pregelatinized starch is usually suffi
`ciently compressible to provide an acceptable com
`pressed core tablet. Moreover, the presence of other
`diluents might have a detrimental effect on stability.
`Other diluents include lactose monohydrate. microcrys
`talline cellulose, calcium phosphate (dibasic, milled).
`ungelatinized corn starch, and dextrates.
`C. Disintegrants
`Disintegrants are substances that are added to the
`ingredients of a pharmaceutical tablet to facilitate its
`
`25
`
`40
`
`45
`
`50
`
`A. The Cyclophosphamide and Pregelatinized Starch
`The cyclophosphamide used in this invention is the
`crystalline monohydrate form. For purposes ofthe pro
`cedures described below it is preferred that the particle
`size be approximately 40 mesh or smaller. Due to its low
`melting point (46° C.), cyclophosphamide is not condu
`cive to milling. When orally administered, cyclophos
`phamide is usually prescribed in dosages of 25 mg, 50
`mg, or 100 mg.
`Several different types of partially or fully pregelati
`nized starch (hereinafter simply “pregelatinized
`starch”) can be used in accordance with this invention.
`The pregelatinized starch should meet all National For
`mulary XVI standards and be capable of mixing with
`cyclophosphamide to form a directly compressible tab
`let. These skilled in the art can by simple routine experi
`mentation determine those starches capable of forming
`direct compression tablets with cyclophosphamide, and
`the optimum mixtures for doing so.
`Commercially available pregelatinized starches
`which can be used include STARCH l500 (formerly
`STA-RX 1500), which is a modi?ed, partially gelati
`nized corn starch produced by Colorcon, Inc., West
`Point, Penna; several pregelatinized starches produced
`by the Hubinger Company, Keokuk, Iowa, including
`CERI-GEL 300, a ?ve percent modi?ed, fully pregelat
`inized corn starch, CERI-GEL 433, which is a modi
`?ed, fully pregelatinized corn starch, PREGEL, which
`is an unmodi?ed, fully pregelatinized corn starch, IN
`STANT KEOGEL, which is a 100 percent modi?ed,
`fully pregelatinized corn starch, and TENDER JEL,
`which is a 100 percent modi?ed, fully pregelatinized
`corn starch; WHEATGEL 100, which is a fully prege
`latinized wheat starch produced by International Grain
`Products, Montreal, Canada: and several pregelatinized
`starches produced by the A. E. Staley Manufacturing
`Company, Hulton, Ma., including BINASOL 15, which
`is a modi?ed, fully pregelatinized tapioca starch, BINA
`SOL 81, which is a modi?ed, fully pregelatinized tapi
`oca starch, INSTANT TENDER JEL, which is a 99
`percent modi?ed, fully pregelatinized waxy corn
`starch, and STA-RX, which is a modi?ed, fully prege
`latinized corn starch.
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 004
`
`

`

`5,047,246
`5
`disintegration in the presence of water or biological
`fluids, and thus hasten the release of the active ingredi
`ents. In experiments with the core tablet blend of this
`invention, sodium starch glycolate was used to facilitate
`disintegration. Experiments in which the level of dis
`integrant was 0.0 percent, 4.0 percent and 8.0 percent
`. were carried out to evaluate the effects on tablet disso
`lution, disintegration, hardness, durability and weight
`variation. The test results indicated that increasing or
`decreasing the disintegrant level had no adverse effect
`on the physical attributes of the tablet. Even though the
`test results indicated that a disintegrant is unnecessary,
`it is preferred to include sodium starch glycolate at a 4.0
`percent level to assure disintegration and performance
`of aged tablets or tablets made with different batches of
`excipients.
`
`15
`
`6
`bility testing was generally greater than 1.0 percent and
`tablet picking and sticking often occurred. Therefore,
`mixtures of pregelatinized starch and microcrystalline
`cellulose at concentrations of 3:1, 1:1 and 1:3 have been
`evaluated. When microcrystalline cellulose comprises
`at least 50 percent of the diluent, the resulting tablets
`have acceptable tableting characteristics. The stability
`of the cyclophosphamide is not influenced signi?cantly
`by these ratios of pregelatinized starch to microcrystal~
`line cellulose. Thus, it is preferred to use a press coat
`blend comprising one part pregelatinized starch and
`three parts microcrystalline cellulose.
`The press coat blend can, of course, be comprised of
`other additives such as disintegrants, lubricants and
`glidants useful in preparing any direct compression
`tablets. The press coat can also include coloring addi
`tives to enable visual recognition of the tablet. In the
`case of CYTOXAN ®, the press coat blend contains
`blue flecks which give the finished tablet a distinctive
`appearance. A discussion of how to color the tablets
`with blue ?ecks is given below.
`
`D. Lubricants
`Lubricants are ingredients that can be added to a
`tablet blend to facilitate ejection of the tablets from the
`dies after compression and to prevent tablets from stick
`ing to the punch faces. Acceptable tablets can be manu
`factured using magnesium stearate in concentrations of
`0.25 percent, 0.5 percent and 1.0 percent of the tablet
`weight, with no tablet picking or sticking to the punch
`faces. However, a 1.0 percent concentration has a detri
`mental effect on tablet durability and maximum achiev
`able hardness. Prolonged mixing of the powder blend
`containing 0.5 percent does not signi?cantly effect the
`dissolution characteristics, durability or tablet com
`pressibility, and therefore, approximately 0.5 percent
`magnesium stearate is a preferred level of lubricant.
`
`25
`
`30
`
`III. PROCESSING THE TABLETS
`A. Preparing the Core Tablet and Press Coat Blends
`A schematic diagram of an overall process for pre
`paring direct compression tablets in accordance with
`this'invention is shown in FIG. 1.
`The ?rst step in preparing the core tablet blend is to
`deagglomerate the cyclophosphamide and additives
`such as sodium starch glycolate (disintegrant) and col-.
`loidal silicon dioxide (glidant) by dry screening in a
`rotary granulator. The deagglomeration step is used to
`break up aggregates of the cyclophosphamide and addi
`tives.
`Experiments were carried out to determine whether a
`Model D, Fitzmill or a Colton Rotary Granulator could
`suf?ciently deagglomerate cyclophosphamide, sodium
`starch glycolate and colloidal silicon dioxide. That was
`accomplished by passing the ingredients concurrently
`through the Fitzmill or Granulator. Laboratory experi
`ments demonstrated that the Fitzmill equipped with a
`number 2A plate, knives forward and medium speed
`could suf?ciently break apart aggregates ofthose excip
`ients. That is, there were no visual lumps in the excipi
`ents after passing through the Fitzmill. Also, the Fitz
`mill and a rotary granulator equipped with a 12 mesh
`screen were both shown to be operable when large
`scale laboratory or production batches were prepared.
`After deagglomeration, the mixture is dry blended
`_ together with the pregelatinized starch and other addi
`tives such as magnesium stearate (lubricant). A 2.5
`cubic foot Peerless Radial Arm mixer can be used for
`the dry blending. Aliquots of core tablet blends have
`been taken from six different areas of the Peerless mixer
`and assayed for cyclophosphamide content. The results
`indicate that cyclophosphamide is adequately distrib
`uted throughout the core tablet blends after 2, 5 and 30
`minutes of blending. Therefore, a blending time of ?ve
`minutes is preferred. It is noted that blending for 30
`minutes does not cause a slowing of the disintegration/
`dissolution rates- of the resulting tablets.
`To determine whether there is any signi?cant vari
`ability among different mixers, both the core tablet and
`press coat blends were prepared in four different mix
`ers, i.e., at2.5 cubic foot Peerless Radial Arm mixer. a
`5.0 cubic foot Patterson~Kelley Twin Shell blender, and
`a 3.3 cubic foot and a 22.2 cubic foot Lodige mixer.
`
`E. Glidants
`Glidants are compounds which are used to improve
`the flow of the powder blend and to minimize tablet
`weight variation. Core blends and the resulting tablets
`containing 0.0 percent, 0.2 percent and 0.5 percent col
`loidal silicon dioxide have been evaluated for flowabil
`ity and weight variation. These results show that the
`addition of 0.2 percent and 0.5 percent improves core
`blend ?owability and decreases tablet weight variation.
`The results also indicate that increasing the level of
`colloidal silicon dioxide beyond 0.2 percent does not
`further improve the ?owability or weight variation.
`Therefore, 0.2 percent colloidal silicon dioxide is a pre
`ferred level of glidant in the core tablet blend.
`It will be readily apparent to those skilled in the art
`that pregelatinized starches, diluents, disintegrants, lu
`bricants and glidants other than those speci?cally re
`cited can be used. Determining the optimum levels of
`such ingredients is well within the ordinary skill of such
`persons using routine experimentation similar to that
`described above.
`
`35
`
`40
`
`45
`
`II. THE PRESS COAT BLEND
`As discussed above, cyclophosphamide is cytotoxic,
`and therefore direct contact with cyclophoshhamide is
`a potential health risk. Accordingly, after compressing
`the core tablet blend containing cyclophosphamide, a
`press coat blend of inert, edible materials is used to
`encapsulate the compressed core tablet blend.
`It is preferable that the composition of the press coat
`blend contain pregelatinized starch, most preferably
`STARCH 1500. While pregelatinized starch is the only
`diluent required in the core tablet blend, tableting char
`acteristics are poor when used as the only diluent in the
`press coat. For instance, tablet weight loss during dura
`
`55
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 005
`
`

`

`5,047,246
`7
`Fifty-six batches of core tablet blends ranging in size
`from 2000 tablets to 138,000 tablets were blended. Con
`tent uniformity and dissolution test results revealed no
`signi?cant variability among the four mixers. Core tab
`let blend and tablet assay results indicated that the po
`tencies were near target and well within batch accep
`tance limits.
`Compressibility test results of two scale-up batches
`indicate that prolonged blending has a slight effect on
`the coat blend compressibility. That is, the maximum
`mean hardness for the 100 mg tablets compressed from
`blends that were blended 2, 5 and 30 minutes were 34,
`34 and 26 Strong-Cobb units (SCU), respectively. How
`ever, all of those maximum mean hardnesses were well
`above the intended upper limit of 18 SCU.
`
`8
`EXAMPLE 1
`Composition of 25 mg DC Cyclophosphamide Tablets
`
`10
`
`Ingredient
`m
`Crystalline Cyclophosphamide
`Monohydrate
`Pregelatinized Starch, NF.
`Sodium Starch Glycolate
`Magnesium Stearate
`Colloidal Silicon Dioxide
`
`. Total
`
`Press Coat Blend:
`Lactose Powder
`Color, FD&C Blue #1, Alum. Lake
`Color. D&C Yellow #10, Alum. Lake
`Povidone
`Microcrystalline Cellulose, NF.
`Pregelatinized Starch. NF.
`Sodium Starch Glycolate
`Magnesium Stearate
`Colloidal Silicon Dioxide
`
`Total
`Total (Whole Tablet)
`Note (1): Blue granulation.
`
`25
`
`Quantity Per
`Tablet, mg
`
`'
`
`26.750
`
`11.500
`1.500
`0.200
`0.050
`
`40.000
`
`7.152 (1)
`0.040 (I)
`0008 (l)
`0.800 (1)
`79.800
`27.000
`4,500
`0.500
`0.200
`120.000
`160.000
`
`B. The Blue Fleck Granulation
`Currently marketed CYTOXAN ® tablets contain
`blue ?ecks in the coat to give the tablets a unique ap
`pearance. Using a wet granulation process, a blue ?eck
`formulation was prepared containing lactose as the
`diluent, povidone as the granulating agent, and two
`aluminum lake'colors, FD&C Blue #1 and FD&C Yel
`low #10. The ratio of ?ve parts blue and one part yel
`low resulted in the desired color.
`
`20
`
`Processing Instructions for 100,000 Tablets (25 mg)
`Blue Granulation
`1. Mix the following to dissolve:
`
`a. Povidone
`in
`b. Puri?ed Water
`
`400 g
`
`1200 g
`
`2. Blend the following to achieve a rough blend:
`
`a. Lactose Powder
`b. Color. FDStC Blue #1 - Alum. Lake
`c. Color. D&C Yellow #10 - Alum. Lake
`
`200.0 g
`40 g
`0.8 g
`
`30
`
`40
`
`50
`
`C. Tableting
`Processes for tableting are ‘well known to those
`skilled in the art. A Manestry D3A Dry Cota rotary
`tablet press has been used and provides good results. It
`will be appreciated by those skilled in the art that other
`tableting machines capable of compressing a tablet
`within a tablet can also be used.
`Cracking along the tablet sidewall may be prevented
`by selecting tablet sizes with an adequate distance be
`tween the perimeter of the core tablet and the perimeter
`of the press coat. A distance of at least 0.0859 inch for
`the 100 mg product and 0.0625 inch (1/16") for the 25
`mg and 50 mg products should be used.
`Using various compression forces (0.1 to 6.0 tons),
`4 LII
`tablet hardness limits of 7.0 SCU to 11.0 SCU, 10.0 SCU
`to 14.0 SCU and 14.0 SCU to 18.0 SCU for the 25 mg,
`50 mg and 100 mg tablets, respectively, will provide
`acceptable results. Those hardnesses result in accept
`able adherence of the press coat to the core tablet for all
`three products, with no picking, capping or lamination.
`When the direct compression compositions are com
`pressed within those hardness limits, no broken or
`chipped tablets have been found, and weight loss has
`been less than one percent. Tablet thicknesses‘ are
`within ?ve percent of the average thicknesses and tablet
`dissolution results are well within the speci?cation of
`Q=75% in 45 minutes according to the U.S. Pharmaco
`peia National Formulary.
`The invention is illustrated in the following examples.
`The examples do not limit the scope of the invention in
`any manner. All percentages and ratios are by weight
`unless otherwise stated.
`Examples 1-3 illustrate the compositions and pro
`cesses for producing batches of 100,000 direct compres
`sion tablets in accordance with this invention.
`
`3. Mill or screen the rough blend to remove agglom
`erates and to facilitate dispersal of the colorants.
`4. Blend the following until uniform in color:
`
`a. Milled or screened materials
`from Step 3.
`b. Povidone
`c. Lactose Powder
`
`40.0 g
`515.2 g
`
`5. While blending, add the povidone solution to gran
`ulate the powders.
`Note: Additional water may be added if necessary to
`achieve the proper consistency.
`6. Continue blending to achieve the desired consis
`tency.
`7. Dry the material until the moisture content is
`within speci?cation limits.
`8. Mill or screen the dried material to achieve a suit
`able particle side distribution.
`9. Classify the sized material through a series of sieves
`to collect the fraction suitable for blue ?ecks (12 to 30
`mesh).
`
`Press Coat Blend
`1. Blend the following to achieve a rough blend:
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 006
`
`

`

`9
`
`5,047,246
`
`10
`-continued
`
`a.
`b.
`
`Sodium Starch Glycolate
`Colloidal Silicon Dioxide
`
`450.0 g
`20.0 g
`
`Ingredient
`
`2. Mill or screen the rough blend to remove agglom-
`. erates.
`
`5
`
`Total (Whole Tablet)
`NO" <ll= 51" granulaIiO?
`
`Quantity Per
`Tablet, mg
`
`240.00
`
`3. Blend the following materials until homogenous:
`
`Processing Instructicns for 100,000 Tablets (50 mg)
`
`a. Milled or Screened Materials
`from Step 2‘
`b. Pregelatinized Starch, NF.
`c. Microcrystalline Cellulose, NF.
`d. Magnesium Stearate
`e. Blue Granulation
`
`2.7000 g
`7,980.0 g
`_ 50.0 g
`800.0 g
`
`Core Tablet Blend
`1. Blend the following to achieve a rough blend:
`
`_
`8' ¢yclot>hosphamlde Monohydrare
`b. Colloidal Silicon Dioxide
`
`2,6750 3
`5.0 g
`
`10
`
`Blue Granulation
`.
`.
`.
`1. Mix the following to dissolve.
`
`15
`
`20
`
`_
`a- Povldone
`m I
`b. Purified Water
`
`500%
`
`1500 g
`
`2. Blend the following to achieve a rough blend:
`
`a. Lactose Powder
`bv Color, FD&C Blue #1 - Alum. Lake
`c. Color, DSLC Yellow #10 - Alum. Lake
`
`200.0 g
`5.0 g
`1.0 g
`
`2. Mill or screen the rough blend to remove agglom- 25
`erates.
`3. Blend the following until homogenous:
`
`3. Mill or screen the rough blend to remove agglom
`crates and to facilitate dispersal of the colorants.
`4. Blend the following until uniform in color:
`
`a. Milled or Screened Materials
`from Step 2.
`b. Pregelatinized Starch, N.F.
`c. Sodium Starch Glycolate
`d. Magnesium Stearate
`
`1,150.0 g
`150.0 g
`20.0 g
`
`>
`
`30
`
`a. Milled or screened materials
`from Step 3.
`b. Povidone
`c. Lactose Powder
`
`50.0 g
`694.0 g
`
`5. While blending, add the povidone solution to gran
`35 ulate the powders.
`Note: Additional water may be added if necessary to
`achieve the proper consistency.
`6. Continue blending to achieve the desired consis
`tency.
`7. Dry the material until the moisture content is
`within speci?cation limits.
`8. Mill or screen the dried material to achieve a suite
`able particle side distribution.
`9. Classify the sized material through a series of sieves
`45 to collect the fraction suitable for blue ?ecks (12 to 30
`mesh)
`
`Tablets
`l. Compress the core tablet blend to provide core
`tablets ranging from 1.17 to 1.23 grams per 30 tablets
`with the minimum hardness that will allow transfer of
`4O
`the core tablets without breakage.
`2. Compress the press coat blend around the trans
`ferred core tablet to provide whole tablet weights rang
`ing from 1.57 to 1.63 grams per 10 tablets having hard
`“C55 values rangmg from 7 to H SCU'
`EXAMPLE 2
`Composition of 50 mg DC Cyclophosphamide Tablets
`
`Press Coat Blend
`
`1. Blend the following to achieve a rough blend:
`
`a. Sodium Starch Glycolate
`b. Colloidal Silicon Dioxide
`
`,
`
`600.0 g
`30.0 g
`
`Quantity Per
`T bl t,
`a 8 mg
`
`50
`
`d~ t
`l
`ngre ‘en
`Swim
`Crystalline Cyclophosphamide
`Monohydrate
`Pregelatinized Starch, N.F.
`Sodium Starch Glycolate
`MagneslutriStcarale _
`Colloidal Silicon Dioxide
`
`Total
`
`ML '
`Lactose Powder
`-
`Color, FD&C Blue #1, Alum. Lake
`Color. D&C Yellow #10, Alum. Lake
`Povidone
`Microcrystalline Cellulose, NF.
`Pregelatinized Starch, N.F.
`Sodium Starch Glycolate
`Magnesium Stearate
`Colloidal Silicon Dioxide
`
`Total
`
`53.50
`
`23.00
`3.00
`Q40
`0.10
`80.00
`
`8.94 (1)
`005 (1)
`0.01 (1)
`1.00 (1)
`107.00
`36.00
`6.00
`0.70
`0.30
`160.00
`
`55
`
`_
`2. Mill or screen the rough blend to remove agglom
`crates.
`3. Blend the following materials until homogenous:
`
`60
`
`_
`
`65
`
`a.
`
`b.
`c.
`d.
`e
`
`’
`
`Milled or Screened Materials
`from Step 2.
`Pregelatinized Starch, NF.
`Microcrystalline Cellulose. N.F.
`Magnesium Stearate
`Blue Granulation
`
`.
`
`3,600.0 g
`10.7000 g
`70.0 g
`1.0000 g
`
`Core Tablet Blend
`1. Blend the following to achieve a rough blend:
`
`Par Pharm., Inc.
`Exhibit 1049
`Page 007
`
`

`

`11
`
`5,047,246
`
`a.
`b.
`
`Cyclophosphamide Monohydrate
`Colloidal Silicon Dioxide