`
`Continousp Motion Machines?
`
`149
`
`
`
`Fig. 10.56. The Zanasi BZ-72 automatic rotary capsule-filling machine.
`
`of weight variation. The body and cap are then
`aligned and closed (6).
`Pellets can be filled in a similar way. This
`vacuum—assisted method gives good weight consis-
`tency.
`
`THE ZANASI BZ-150
`
`This machine, illustrated in Fig. 10.58, has an out-
`put of up to 150 000 capsules per hour. It is a conti-
`nuous motion machine, and is claimed to be
`suitable for powders, granules, and tablets.
`A plan of the layout of the machine is shown
`« in Fig. 10.59. The operating sequence is similar
`in some respects to the method of compressing
`tablets on a rotary tablet machine. Themecha-
`nisms of opening, filling, and closing the capsules
`aresimilar to those of the BZ-72. There is a central
`turret (1), an empty-capsule feed hopper (2), and
`a powder supply hopper (3), all supported on a
`rectangular base (4). The turret houses the annular
`powder trough into which powder is fed from the
`
`powder hopper, 72 bushes into which empty cap-
`sules are fed from the empty-capsule hopper, and
`72 dosators to fill the capsules.
`Powder flows from the powder hopper, aided
`by a single flat-bladed stirrer similar to that used
`in the AZ-60,
`into the central powder trough
`through a tube fitted with a screw feeder. The
`powder flow can be controlled (a) by a valve fitted
`in the tube, and (b) by the screw feeder being
`activated by high- and low-level probes fitted with
`a mixing device which ensures the uniformity of
`composition and density of the powder in the
`trough, despite the disturbance due to withdrawal
`of the powder plug. It is necessary to raise the
`turret to allow the trough to be emptied for clean-
`ing, and also for fitting different bushes, pistons
`and dosators 'when a different size of capsule is
`to be filled.
`
`The turret rotates at a maximum speed of
`35 rpm, whilst the empty-capsule hopper rotates
`at 70 rpm as it has only 36 empty-capsule filling
`
`H
`
`.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 164/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 164/326
`
`

`

`150
`
`Capsule-filling Machinery
`
`Illllllll
`
`Fig. 10.57. Schematic diagram of the operation of the Zanasi BZ-72 capsule-filling machine. 1, capsule separation; 2, filling,
`of the dosator; 3, removal of powder plug; 4, removal of excess fill; 5, ejection of powder into capsule body; 6, closing
`of the capsule.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 165/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 165/326
`
`
`
`

`

`Continuous Motion Machines
`
`151
`
`
`
`Tables 10.6 and 10.7 show typical results obtained
`from filling a placebo formulation and an in—line
`product.
`Figure 10.60 shows the layout of three BZ-150
`machines at the Merck Sharp and Dohme plant
`at Cramlington, England.
`
`6.13
`
`5.08
`
`7.39
`
`11.32 8.80
`
`7.52
`
`Table 10.6. Statistical analysis of weight variation of two
`batches of capsules filled on the Zanasi BZ-150 encapsulation
`machine at 152000 capsules per hour, taking three samples
`of each batch. The target weight was 300 mg.
`2
`2
`2
`Batch number
`1
`.
`1
`1.
`Mean weight (mg)
`309.7 311.4 312.1 297.9 299.5 299.3
`Degrees of freedom 62
`57
`59
`58
`55
`55
`Variance
`37.64 25.82 54.65 128.2177.47 56.51
`Standard deviation
`(mg)
`Coefficient of
`variation(%)
`
`1.98
`
`1.63
`
`2.36
`
`3.80 2.93
`
`2.51
`
`tubes. The hopper has a very low effective capacity
`considering its size, because the capsules tend to
`be thrown outwards by centrifugal force, which
`poses a problem of supply when the machine is
`running at full speed. The level of capsules in this
`hopper must be kept fairly low so that the operator
`can remove damaged capsules quickly when block-
`ages occur in the feed tubes.
`The following problems may occur in operating
`the machine.
`
`1. The capacity of the empty-capsule hopper is
`low so that it requires replenishing too frequently.
`2. The effect of damaged empty capsules is much
`more apparent on this machine than on, for exam-
`ple, the AZ-60. Since 2500 capsules are filled every
`minute, a defect level of only 0.04% will cause
`a feed tube blockage every minute.
`3. The dust extraction and the number of cleaning
`points on the machine are not fully capable of deal-
`ing with the excess powder and the dust that are
`created during filling.
`4. It is basically a single capsule-size machine. The
`estimated time for change-over to another size of
`capsule is of the order of one to two days. The
`change parts required are 72 dosators, pistons,
`bushes and push rods for ejecting the filled cap-
`sules, and 36 empty-capsule feed tubes.
`
`Table 10.7. Statistical analysis of one batch of capsules filled
`on the Zanasi BZ-150 encapsulation machine at a speed of
`152 000 capsules per hour. The target weight was 290 mg.
`Batch number
`3
`3
`Mean weight (mg)
`284.5
`286.7
`Degrees of freedom
`60
`60
`Variance
`»
`65.91
`44.65
`Standard deviation (mg)
`8.12
`6.68
`' Coefficient of variation (%)
`2.85
`2.33
`
`3
`287.8
`60
`70.45
`8.40
`2.91
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 166/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 166/326
`
`

`

`152
`
`Capsule-filling Machinery
`
`
`
`Fig. 10.58. The Zanasi BZ-150 automatic rotary capsule-filling machine.
`
`THE ZANASI Z 5000 RANGE
`The Zanasi BZ range of fillers has been replaced
`by the Z 5000-R series. One of these machines
`is illustrated in Fig. 10.61. There are three models,
`the Z 5000-R1, Z 50,00-R2, and Z 5000-R3, with
`maximum outputs in’ capsules per hour of 70000,
`110000, and 150000, respectively.
`The dimensions of the machines in this series
`have been reduced, and the control console has
`been attached to the main frame of the machine.
`A reduction in noise level to 79-85 dB (A) has been
`achieved. The d.c. motor of the BZ series has been
`replaced by an a.c. motor which requires less
`maintenance and is more reliable. A schematic
`diagram of the operation of the Z 5000 is shown
`in Fig. 10.62.
`The control console incorporates a small built-in
`computer control system for a more detailed ana-
`lysis of capsule weight. Any part of the machine
`
`which has a fault can be quickly identified by this
`system. The Siemens fan has been replaced by
`compressed air for the capsule transfer system,
`which has led to a reduction in noise level and
`in heat generation during capsule filling. A better
`guarding system is fitted, which is lighter, and
`which allows adjustment of weight and compres-
`sion without removing the guard and stopping the
`machine. The two vacuum pumps have been rep-
`laced by one, with savings in noise, size, dimen-
`sions, and maintenance. Improvements have been
`made to the method of fitting the lower pins which
`assist in the opening, closing, and ejection of unse-
`parated capsules. These pins cannot now free
`themselves during the operation of the machine
`and yet a quick change from one size to another
`can be accomplished without tools. A modification
`has also been made to the location of the upper
`and lower pins at the point where the cap and
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 167/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 167/326
`
`

`

`ll
`
`EjectionChut
`.
`~ L
`Re,ect Fillede
`capsules
`Empty Capsule
`Hopper
`Filled Capsule
`
`
`
`Continuous Motion Machines
`
`153
`
`’
`To Control Consol ’
`
`Dosator Path
`
`‘Powder Trough
`
`Weight 3. Pressure
`Control
`
`Powder Fee
`Tube
`
`Powder Hopper.___
`
`Reject Empty
`Capsules
`
`Flat Bladed
`Stirrer
`
`l720mrn
`
`'
`950mm
`
`)2 Path of Bodies
`) Path of Caps
`
`Fig. 10.59. Plan of the Zanasi BZ—150 capsule-filling machine. 1, central turret; 2, empty—capsule feed hopper; 3, powder
`supply hopper; 4, rectangular base.
`
`filled body are reunited. The two bushes are now
`better aligned, which reduces the likelihood of
`splitting in the body or cap.
`The annular hopper from which the dosators
`pick up powder has been separated from the main
`drive of the machine and its speed relative to the
`turret has been altered. This ensures that the dosa-
`tor does not enter the powder at the same point
`on each revolution, resulting in better dosage
`weight uniformity.
`The sequence of operations is illustrated in Fig.
`10.63. Powder dosing is. effected by means of a
`cylindrical tube in which a piston is used to regu-
`late volume. The dosator enters the powder bed
`then rises holding the volume volume of powder.
`The capsule body is brought under the dosator
`
`and the powder charge is ejected by means of the
`piston.
`For the filling of pellets, the volumetric principle
`is again employed with the assistance of vacuum
`for transfer of the product. By this means, even
`micro-capsules containing liquid or pellets with
`soft coatings such as wax can be handled without
`damage. High-accuracy filling is achieved by
`means of a dosator levelling system which operates
`after the dosator enters the product bed. Employ-
`ment of this principle, rather than gravity filling,
`enables pellets with poor electrostatic qualities to
`be handled without affecting accuracy.
`An attachment which is available for the Z 5000-
`R1 allows feeding of a tablet into the capsule body
`followed by a powder dose (Fig. 10.64). Every
`
`:—
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 168/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 168/326
`
`

`

`154
`
`Capsule-filling Machinery
`
`
`
`3>
`is-:~ NR.»
`
`.
`
`V‘
`
`%V
`
`i
`
`c
`
`"'
`
`Fig. 10.60. A general view of three Zanasi BZ-150 machines at the Cramlington plant of MSD.
`
`capsule is checked for the presence of a tablet.
`Capsules without
`tablets
`are
`automatically
`ejected. Regulation of the dosing volume and the
`compression of the plug are effected by single con-
`trols operating on all dosators simultaneously.
`Control can be effected while the machine is in
`motion without nullifying the safety interlocks. In
`
`the event of excessive compression, a safety inter‘-
`lock protects the working parts against mechanical
`damage.
`The overall design of the equipment and parts
`is to the highest standard of good manufacturing
`practice, and allows simple, effective, and speedy
`cleaning. Most components are smooth shapes
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 169/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 169/326
`
`

`

`Continuous Motion Machines
`
`155
`
`
`
`Fig. 10.61. The Zanasi Z 5000-R automatic rotary capsule-filling machine.
`
`without corners or joins where the product might
`lodge. The manufacturers claim that a change in
`the size of capsules to be filled can be accomplished
`in less than one hour.
`
`FARMATIC MACHINES
`
`This series consists of 3 machines, the 2000/ 15,
`2000/30, and 2000/60, with maximum outputs of
`40 000, 80 000, and 160 000 capsules per hour, res-
`pectively.
`These machines have a single operating tower
`(Fig. 10.65), with a separate turret to hold the
`powder. A central hopper holds the empty cap-
`sules which are fed into special scoops for inter-
`cepting and rejecting damaged and distorted
`capsules. In a lower part of this central turret, the
`capsules are rectified, separated, filled, and re-
`
`If a capsule is missing from a dosing
`united.
`the powder plug is ejected from the
`station,
`machine. Selection of samples for check-weighing
`is accomplished by an electronic pneumatic device
`which monitors the dosator.
`
`THE ELANCO ROTOFIL
`
`The Elanco Rotofil (Eli Lilly & Co.), shown in
`Fig. 10.66, is a continuous motion pellet filler cap-
`able of a maximum rate of 60000 capsules per
`hour. A weight variation of i2% is claimed. It
`is essentially a volume filler, and the product has
`to be formulated specifically for the volume of the
`.capsule to be filled. Capsule sizes 0 to 4 can be
`filled and it is claimed that the size change-over
`and cleaning take 2 hours. Excess pellets can be
`recycled to the filling hopper.
`
`Mylan v. Qualicaps, |PR2017—00203
`QUALICAPS EX. 2001 — 170/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 170/326
`
`

`

`156
`
`Capsule-filling Machinery
`
`Fig.- 10.62. Schematic diagram of the operation of the Zanasi Z 5000-R series of machines. 1, capsule feed; 2, capsule opening;
`3, powder or pellet feeding; 4, unopened-capsule rejection; 5, dosing; 6, product ejection in case of empty bushings; 6a,
`tablet feeding; 7, commencement of capsule closure; 7a, end of capsule closure; 8, finished-capsule ejection; 9, cleaning of
`bushings.
`
`«
`
`
`
`Fig. 10.63. Schematic diagram of powder closing in the Zanasi Z5000-R series.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 171/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 171/326
`
`

`

`Fig. 10.64. Schematic diagram of the dosing of a tablet and powder on the Zanasi Z5000-R1.
`
`The Filling of Liquids and Pastes into Hard
`Capsules
`
`There have been a number of significant develop-
`ments in the use of hard shell two-piece _capsules
`for liquids, pastes, and thixotropic_ formulations.
`Both Nuova Zanasi, and Hofliger and Karg have
`produced machines based on their existing model
`range which are capable of this technique. Walker
`et al. (1980) and Francois and Jones (1979) des-
`cribe the process and its requirements in detail.
`The important physical properties of the formu-
`lated mass are its viscosity, surface tension, and
`melting point, which govern how the product can
`withstand handling and storage. If the thixotropic
`effect is low then the problems of leakage will be
`greater.
`A
`'
`A variety of medicines which are normally filled
`into soft gelatin capsules can now be presented
`in hard capsules. The limitations to this technique
`are the interactions of the materials with hard gela-
`tin; materials with low moisture content, and oils,
`are preferable. One advantage of this process is
`that a simple machine can be placed at the formu-
`1ator’s bench and relatively small amounts of
`material are sufficient for filling trials. Greater
`accuracy can also be claimed for this method com-
`pared to normal powder filling and, since the
`
`amount of gelatin used for a hard shell capsule ,
`is less than for a soft shell one, it is cheaper as
`well.
`.
`
`Machines which are available for filling liquids
`into’ hard capsules include the Zanasi RM/L-75,
`Zanasi RM/P-75, a series of machines from Hof-
`liger and Karg, and the Harro Hofliger unit.
`
`THE ZAi~IAs1 RM/L-75
`The basic machine, illustrated in Fig. 10.67, can
`carry out six sequential operations: feeding of
`empty capsules, and rectification; opening of cap-
`sules by vacuum; sorting and ejection of faulty
`capsules; filling of capsules with liquid products
`by means of dosing pistons and liquid-injecting
`needles; closing of capsules, and the ejectionof
`filled capsules. The machine must be fitted with
`the size-parts relating to both the capsules and the
`product.
`The two-piece hard shell capsules must meet
`the standard dimensional requirements, but can
`be either the standard or the self—locking type. The
`range of sizesthat can be handled is listed below,
`and the contained volumes are also given here for
`ease of reference: size 000 (1.37 ml), size 00
`(0.95 ml), size 0 (0.68 ml), size 1 (0.50 ml), size
`2 (0.37 ml), size 3 (0.30 ml), size 4 (0.21 ml), and
`size 5 (0.13 ml).
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 172/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 172/326
`
`

`

`158
`
`Capsule-filling Machinery
`
`Fig; 10.65. The Farmatic model 2000 automatic rotary capsule-filling machine.
`
`£
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 173/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 173/326
`
`

`

`The Filling of Liquids and Pastes into Hard Capsules
`
`159
`
`
`
`Fig. 10.66. The Elanco Rotofll automatic pellet filler.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 174/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 174/326
`
`

`

`160
`
`Capsule-filling Machinery
`
`J
`
`Fig. 10.67. The Zanasi RM/L-75 automatic machine for filling liquids into hard capsules.
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 175/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 175/326
`
`

`

`The Filling of liquids and Pastes into Hard Capsules
`
`161
`
`Fig. 10.68. The Zanasi RM/P-75 automatic machine for filling pastes into hard capsules.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 176/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 176/326
`
`

`

`
`
`162
`
`Capsule-filling Machinery
`
`The machine has a general rotary motion but
`is intermittent. Empty capsules are fed into a high-
`capacity container inside which is a plate, with two
`vertical channels each having a slightly larger dia-
`meter than the capsules. The capsules fall through
`these channels and are rectified, body downwards.
`The turntable then transfers the capsules to the
`opening station for the separation of the cap from
`the body. This operation is performed by pins and
`vacuum. In their passage from the opening station
`to the sorting station, all the bodies are positioned
`at the same height, and at the sorting station all
`those capsules which have not opened are
`rejected.
`The bodies then move to the filling station which
`has a container for the liquid, two dosing pistons
`with micrometric adjustments, two filling needles,
`and two valves for suction and delivery of the pro-
`duct. When the bodies are under the filling station,
`they are checked by a ‘no capsule body—no filling’
`device which allows the needle to be lowered’ only
`when a capsule body is present. The whole filling
`unit is made of stainless steel. After completion
`of the filling operation, the capsules are trans-
`ferred to the closing station where the cap and 7.
`body are reunited. The filled and closed capsules
`are transferred to the last station, where ejection
`
`is brought about by two hollow pins, which push
`the capsules out and down a chute into a container.
`The output is up to 12 000 capsules per hour.
`
`THE_ ZANASI RM/P-75
`The Zanasi model RM/P-75, illustrated in Fig.
`10.68,; will fill pastes into hard shell capsules by
`means of special dosators fitted with a micrometric '
`adjustment. The basic machine is the same as the
`RM/L—75”, but the filling station consists of a hop-
`per, paste-extruding unit, and four dosators with
`micrometric adjustment. When the bodies are
`under the filling station,
`they are filled by two
`dosators, whilst the other two dosators pick up
`the paste as formed by the extruder to repeat the
`filling cycle. The paste is extruded in the desired
`shape and size by a piston and screw feeder, work-
`ing inside a cylinder which has a cavity and cooling-
`water jacket. Waste material is retained on a plate,
`and can be recycled. After filling, the capsules are
`transferred to the closing’ station where the cap
`and body are reunited.
`‘
`All moving parts on both these Zanasi machines
`are located within a single base and are surrounded
`on all sides by safety guards with‘ safety devices
`on the doors. The working table can be protected
`by means of a transparent anti-dust and anti-noise
`
`
`
`Fig. 10.69. The mechanism of filling liquids into hard capsules on the Hofliger and Karg machines. 1. control valve, outlet
`valve, and filling needle; 2, dosing piston; 3, j acketted product container; 4, stirrer.
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 177/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 177/326
`
`

`

`References
`
`163
`
`protection hood, which is also fitted with safety
`devices on the doors.
`
`HoFL1G1=.R AND KARG MACHINES
`
`Hofliger and Karg offer three versions of their
`standard range of capsule fillers equipped to fill
`liquids into hard shell capsules. Table 10.8 shows
`the variations that are possible. The dosing
`mechanism is shown in Fig. 10.69. In the left-hand
`illustration, the control valve is in the upper posi-
`tion and product is d-rawn into the dosing cylinder.
`
`The stroke of the piston is adjustable. The closing
`stroke is shown in the right-hand illustration. The
`downward movement of the control valve causes
`
`the outlet valve to shut off the product flow. Simul-
`taneously, the dosing piston forces the measured
`dose through the dosing needle into the capsule.
`
`References
`
`Francois, D. and Jones, B. E., Mfg Chem., 1979, 50(3), 37,
`38, 41.
`Walker, S. E. et al., J. Pharm. Pharmac., 1980,32, 389-393.
`
`Table 10.8. Applications for liquid pumps on Hiifliger and Karg machines
`
`No. of holes
`in carrier
`segment
`
`3
`
`3
`
`6
`
`Model
`
`330L*
`
`330
`
`603
`
`Dosing possibilities
`(in order ofsequence
`with the stations on
`the machine)
`
`liquids only
`
`pellets-powder-pellets
`tablets-powder-pellets
`pellets-liquids-pellets
`tablets—liquids-pellets
`liquids-powder-pellets
`pellets-powder-pellets
`tablets-powder-pellets
`
`603L*
`1200L*
`
`6
`12
`
`liquids only
`liquids only
`
`Description of
`liquid pump
`3-Head pump with drive
`motor in place of powder
`filling station (brake-
`clutch combination).
`Dosing impulse comes from
`cam-operated switches.
`Dosing disk can be stopped
`manually, whilst the dosing
`piston continues to operate.
`As for 330L
`
`Output tcapsg min)
`tablets
`pellets
`powder
`
`liquids
`50-60
`
`——
`
`110
`
`50-60
`
`6-Head pump, drive synchro-
`nised with main drive shaft.
`Dosing disk can be manually
`stopped, whilst the dosing
`piston continues to operate.
`As for 603
`Two 6-head pumps in place
`of pellet stations.
`Otherwise same as for 603.
`
`105
`
`—
`—
`
`"
`
`70
`
`70
`70
`
`'
`
`* These models cannot be equipped with additional dosing systems
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 178/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 178/326
`
`

`

`
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 179/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 179/326
`
`

`

`Chapter 11
`
`Capsule Types, Filling Tests, and
`Formulation
`
`G. C. Cole
`
`0
`
`Capsule Sizes and Types
`
`There are eight sizes of hard gelatin capsules com-
`mercially available:
`
`Capsule size
`Volume in ml
`
`5
`4
`3
`2
`1
`0
`00
`000
`1.37 0.95 0.68 0.50 0.37 0.30 0.21 0.13
`
`For pharmaceutical products it is unusual to use
`a size larger than 0 because of the difficulty in
`swallowing larger sizes, whilst size 5 is rarely used
`due to ‘difficulties in the automatic filling process.
`Other sizes are available to order but are used
`
`mainly in veterinary practice.
`The main suppliers of capsules are the Elanco
`Qualicaps division of Eli Lilly & Co., the Capsugel
`Division of Parke, Davis & Co. Ltd, and R. P.
`Scherer Ltd. The sizes and specifications adopted
`by the three manufacturers are very similar, which
`allows any of their sizes to be used on standard
`automatic filling machines. Each manufacturer
`produces a range of standard capsules which are
`designed so that the body and the cap do not separ-
`ate before the filling operation takes place. They
`each also make a range of capsules which are
`locked after filling to ensure that the contents do
`not leak during packaging and distribution. Each
`company uses its own brand name to market its
`regular and locking capsules.
`
`SELF-LOCKING CAPSULES
`
`The self-locking capsule was developed as an alter-
`native to the dot-sealing or banding of capsules
`which was used by Parke, Davis & Co. for a
`number of their products and was a costly, diffi-
`cult, and lengthy process. To eliminate this pro-
`cess, Eli Lilly produce the Lok-Cap and Posilok
`capsules, Parke, Davis the Snap-Fit and Coni-
`Snap capsules, and R. P. Scherer the Star-Lock
`and Lox-It capsules. These are described and illus-
`trated below.
`
`165
`
`Fig. 11.1 The Snap-Fit capsule. The protuberances (1) prevent
`premature opening;
`the grooves (2)
`lock the two halves
`together once the capsule has been filled.
`
`The Snap-Fit principle is shown in Fig. 11.1. A
`development of this design is
`the Coni-Snap
`(Fig. 11.2) which is claimed to reduce defects dur-
`ing the filling operation. In 1983, Parke, Davis
`introduced the Coni-Snap Supro capsule, claiming
`it to be virtually tamper proof. To achieve this,
`the dimensions of the capsule have been changed
`and given new designated sizes from A to E. The
`capacity is related to the standard Coni-Snap cap-
`sules as shown in Table 11.1(b) The cap is so
`designed that after filling and closing only the
`rounded end of the body is visible. Due to this
`change in dimensions, additional machine change
`parts are required for the filling and packaging
`operations. The dimensions of capsules made by
`Parke, Davis are given in Table 11.1(a) and (b).
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 180/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 180/326
`
`

`

`166
`
`Capsule Types, Filling Tests, and Formulation
`
`Table 11.2. The manufacturers recommend stor-
`
`age at 24°C and about 50% relative humidity.
`
`
`\.a.__, o
`
`-ex-;
`
`pre-closed
`
`open
`
`Standard
`
`Lox-It
`
`Fig. 11.2 The Coni-Snap capsule. The tapered rim (1) avoids
`telescoping; the protuberances (2) prevent premature opening;
`3;: ggzgvffislég lock the two halves together once the capsule
`
`
`
`_:_j
`
`Fig. 11.3 Standard (or Star-Lock) and Lox-It capsules.
`
`Table ll.1(a). Dimensions of Coni-Snap capsules made by
`Parke, Davis, measured atamoisture content of 12-16%
`Capsule
`Cap
`Body
`Cap
`Body
`slze
`length
`length
`diam.
`diam.
`mm
`mm
`mm
`mm
`11.74*
`20.22*
`8.53
`3.13
`10.72*
`18.44*
`7.64
`7.33
`:3
`£3;
`gig;
`23?]
`8.08
`13.59
`5.83
`5.57
`721
`12,19
`5,32
`505
`*:0.51
`*3c0.51
`+0 46
`+0 46
`_
`_
`
`00
`0
`%
`3
`4
`Tolerance
`
`A Posilok capsule is illustrated in Fig. 11.4. The
`pre'10ek feature is designed to Prevent the eap and
`bod
`from se aratin
`durin
`transit from the
`Y
`P
`8
`8
`_
`.
`manufacturer to the purchaser. Air 1S released
`through vents during closure with a resultant
`increase in the final holdingforce between the cap
`and the body. The dimensions of capsules made
`by Elanco Qualicaps are shown in Table 11.3. Tar-
`get4weights for empty shells are shown in Table
`'
`'
`‘
`,
`Capsules can be manufactured with elongated
`bodies to meet specific requirements, and specifi-
`cations for these capsules are supplied to indi
`vidual customers. Capsule diameters are not a
`Table 1l.1(b). Dimensions.~of Coni-Snap Supro capsules com-
`directly controlled parameter and various factors
`pared with standard Coni-Snap capsules.
`’
`Com-_Sm,p Sup“, Capsules
`,
`e. g. _moisture content, wall thickness, length, etc.,
`External diam.
`»
`Standard capsule
`can influence them.
`body/WP
`Volume
`Size with same
`Hard gelatin capsules with a larger volume than
`mm
`‘"1
`VOW”?
`‘1“""e‘e’
`size 000 (1.37 ml) are available (e. g. from Kruger,
`8.18/8.53
`0.68
`0
`00
`Willi K. G.). In the United Kingdom they are sup-
`1
`3-18/3-53
`0-50
`00
`plied by Davcaps. The sizes range from 3.5 ml to
`g:gg%:g‘11
`3%
`(1)
`§
`51.5 ml; dimensions of these capsules are shown
`4
`6.07/6.35
`0.21
`2
`in Fig- 11-5-
`Standard and Lox-It capsules are illustratedvin EXPerime“ta'iFi“i“g Tests
`Fig. 11.3. R. P. Scherer also manufacture capsules The results of a number of filling trials, comparing
`with the registered name ‘Star-Lock’. The dimen- Coni-Snap and conventional capsules, are given
`sions of capsules made by Scherer are shown in
`in Table 11.5 (Latchem, 1979; Mallory, 1980).
`
`Size
`
`mUow>
`
`1
`
`3
`
`‘
`‘
`
`.9
`
`1
`
`3
`
`3
`
`;
`
`'
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 181/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 181/326
`
`

`

`Experimental Filling Tests
`
`167
`
`Table 11.2. Dimensions of capsules made by Scherer, measured at a moisture content of 12-16%
`
`Capsule
`size
`
`0
`1
`2
`3
`4
`Tolerance
`
`Body
`length (A)
`mm
`
`Cap
`length (B)
`mm
`
`Body
`diameter
`mm
`
`Cap
`diameter
`mm
`
`Filled
`length ~(C)
`mm
`
`Volume of
`standard
`length
`ml
`
`Volume of
`elongated
`length
`ml
`
`18.69
`16.55
`15.29
`13.66
`12.39
`:03
`
`11.05
`9.82
`9.04
`8.12
`7.36
`i0.3
`
`7.35
`6.65
`6.10
`5.60
`5.09
`i0.05
`
`7.65
`6.90
`6.36
`5.85
`5.34
`i0.05
`
`22.0
`19.6
`18.0
`16.2
`14.7
`—
`
`0.7
`0.5
`0.4
`0.3
`0.21
`—
`
`0.76
`0.54
`0.45
`0.34
`0.22
`——
`
`CAP SECTION
`AT LOCK LEVEL
`
`QLDCK FEATURE
`
`AFTER CLOSING
`
`\
`
`I
`
`V
`
`|
`'
`
`
`
`PRELOCK FEATURE D
`
`BEFORE CLOSING
`
`Fig. 11.4 The Posilok capsule.
`
`These results show a reduction in the number of
`
`filling defects when the Coni-Snap design is used.
`The results from a series of fillings of Elanco
`Qualicaps capsules followed by controlled inspec-
`tions are shown in Tables 11.6, 11.7, and 11.8.
`An examination of the results shown in these
`tables will illustrate that the fault levels are rea-
`
`sonably constant for each machine. One reason
`
`Table 11.3. Dimensions of capsules made by Elanco Quali-
`caps, measured at a moisture content of 13 to 16% w/w
`Closed
`
`Capsule
`size
`
`00
`0
`1
`
`2
`3
`4
`Tolerance
`
`Cap
`length
`mm
`11.4
`10.9
`9.7
`
`8.9
`7.9
`7.2
`$0.3
`
`Body
`length
`mm
`20.2
`18.5
`16.5
`
`15.1
`13.5
`12.3
`i0.3
`
`Body
`Cap
`diameter diameter
`mm
`mm
`8.51
`8.16
`7.63
`7.33
`6.90
`6.62
`
`6.35
`5.82
`5.32
`i0.05
`
`6.07
`5.56
`5.06
`i0.05
`
`joined
`length
`mm
`22.9
`21.8
`19.5
`
`17.-8
`15.9
`14.5
`i0.3
`
`Table 11.4. Average weights of 100 capsules manufactured by
`Elanco Qualicaps
`-
`
`Capsule
`size
`
`00
`0
`1
`2
`3
`4
`
`Average
`weight
`mg
`126
`98
`76
`63
`50
`40
`
`Limit
`mg
`i 12
`i9
`i7
`i6
`i5
`:4
`
`for this may be the age -of the capsule bushings.
`If they are very worn, the number of telescoped
`capsules ‘increases, whilst if the bushings are new
`the itightness of fit results in more cracked ends.
`Generally, the level of defects in the empty cap-
`sules from all manufacturers is very low and the
`quality high. There can be consider-able batch-to-
`batch variation in capsules from the same supplier,
`and the conditions of storage can affect the quality
`significantly. For instance, in a trial ‘to -examine
`the performance of capsules from two different
`suppliers,
`'-“one manufacturer supplied capsules
`containing only 8% moisture, ‘which were very
`brittle.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 182/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 182/326
`
`

`

`
`
`V
`
`:
`
`'
`.1.
`I
`i
`i
`‘»
`
`1‘
`’
`1,
`’
`
`K
`J,
`
`,
`
`.
`(
`
`j,
`‘
`
`L (mm)
`120
`115
`"0
`105
`100
`95
`90
`85
`80
`75
`
`70
`55
`so
`55
`so
`as
`40
`as
`so
`25
`2o
`15
`10
`
`168
`
`Capsule Types, Filling Tests, and Formulation
`
`L (mm)
`120
`1 15
`1 10
`105
`mu
`55
`go
`55
`no
`75
`
`‘
`
`7a
`65
`so
`55
`so
`45
`an
`as
`no
`25
`20
`15
`to
`
`
`
`|1o||12||1a,s||14||
`
`15
`
`||
`
`17
`
`|
`
`13.5
`Q) (mm)
`
` I
`
`20
`
`22
`
`23
`
`Fig. 11.5 The dimensions of capsule bodies larger than size 000, showing diameter (to), length (L), and the volume (ml) contained
`at various filling levels.
`
`Table 11.5. Summary of trials comparing filling defects between Coni-Snap and conventional capsules on different capsule-filling
`machines
`
`Defects per 100 000 capsules
`Split capsules
`Punched ends
`Conventional
`Coni-Snap
`Conventional
`Coni-Snap
`37
`0
`6
`0
`167
`3
`49
`2
`19
`0
`0
`0
`9
`0
`4.5
`0
`11
`2
`1
`1
`30
`5
`105
`55
`20
`2
`1
`1
`11
`2
`36
`16
`1
`0.1
`14
`0.3
`18
`0.2
`2
`0
`
`6
`
`0
`
`17
`
`0
`
`Filling
`rate
`c.p.h.
`32 000
`
`32 000
`58 000
`60 000
`36 000
`38 000
`
`73 000
`70 000
`to
`80 000
`70 000
`to
`
`80 000
`
`Machine
`AZ-25“
`AZ-30“
`AZ-30’
`AZ-60“
`AZ-60*‘
`GFK-600"
`GFK-700“
`GFK-1000"
`GFK-1200”
`GFK-1200"
`
`G37“
`
`‘Zanasi
`"I-léfliger and Karg
`‘mG2
`
`The type of capsule-filling machine may also
`have a significant effect on the level of defects.
`In a trial which compared Coni-Snap capsules with
`Posilok capsules, the former fared better when
`filled on a Zanasi BZ-72 machine, whereas the
`Posilok capsules showed a lower level of defects
`when filled on an mG2 G37/N machine.
`
`When pellets are being filled into Coni-Snap
`capsules, material can lodge on the lip of the body
`and hinder closure. This is also true if the powder
`plugs are loosely packed. The body-edge chamfer
`also reduces the area of contact between the body
`and the cap when the capsules are empty, which
`causes a higher than normal level of separated
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 183/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 183/326
`
`

`

`Table 11.6. Faults in a batch of filled capsules (Opaque Yellow,
`size 3), from three Zanasi BZ-150 fillers; sample size, 1200
`capsules
`
`Table 11.8. Summary of defects found after inspections of 50
`different batches of capsules from three different Zanasi BZ-
`150 fillérs
`
`The Formulation of Capsule Products
`
`169
`
`Sample] Sample2 Sample3 Total (%)
`I
`
`Defect
`
`Highest Lowest Mean
`%
`%
`%
`
`Machine No. I ~
`Telescopes
`Crush cracks
`Other faults
`Total
`
`Machine No. 2
`Telescopes
`Crush cracks
`Other faults
`Total
`
`Machine No. 3
`Telescopes
`' Crush cracks
`Other faults
`Total
`
`9
`1
`2
`12
`
`1 '
`22
`0
`23
`
`2
`5
`5
`12
`
`4
`2
`1
`7
`
`4
`18
`2
`24
`
`2
`10
`1
`13
`
`8
`2
`3
`13
`
`2
`16
`2
`20
`
`12
`8
`1
`21
`
`0.58
`0.14
`0.17
`0.89
`
`0.19
`1.56
`0.11
`1.86
`
`0.44
`0.64
`0.19
`1.27
`
`Machine 1
`(36 inspections)
`
`Machine 2
`(33 inspections)
`
`Telescopes
`Crush cracks
`Others
`Total
`
`Telescopes
`Crush cracks
`Others
`Total
`
`0.70
`0.44
`0.21
`
`0.64
`0.35
`0.18
`
`0.09
`0
`0
`
`0
`0
`0
`
`Machine 3
`(33 inspections)
`
`Telescopes
`Crush cracks
`Others
`Total
`Overall mean defects from 102 inspections = 0.38%
`
`0.70
`0.26
`0.32
`
`0
`0
`0
`
`0.25
`0.13
`0.09
`0.47
`
`0.16
`0.10
`0.07
`0.33
`
`0.13
`0.10
`0.11
`0.34
`
`Table 11.7. Faults in two samples, each of 10000 capsules
`(Opaque Yellow, size 3), from one Zanasi BZ-1'50 filler
`Sample 1
`%
`Sample 2
`63
`0.63
`22
`6
`0.06
`4
`16
`0.16
`6
`4
`0.04
`3
`1
`0.01
`0
`O
`0
`0
`0
`0
`1
`12
`0.12
`0
`1
`0.01
`O
`10
`0.10
`0
`113
`1.13
`36
`8
`0
`0
`
`Telescopes
`Dented
`Crush cracks
`Split
`Holed body
`Overclosure
`Thin spot
`Halves
`Empty
`Dirty
`Total
`Print defects
`
`%
`0.22
`0.04
`0.06
`0.03
`0
`0
`0.1
`0
`0
`0
`0.36
`0
`
`empty capsules. Howev