United States Patent
`Sarkar
`
`[,9]
`
`[11]
`
`[45]
`
`4,001,211
`
`Jan. 4, 1977
`
`[54] PHARMACEUTICAL CAPSULES FROM
`IMPROVED THERMOGELLING METHYL
`CELLULOSE ETIIERS
`
`[75]
`
`Inventor: Nitis Sarkar, Midland, Mich.
`
`[73] Assignee: The Dow Chemical Company,
`Midland, Mich.
`
`[22]
`
`Oct. 1, 1975
`Filed:
`Appl. No.2 618,549
`
`3.0l4.808
`3,453.26]
`3,493,407
`3,617,588
`3,7 l2.886
`3,852,421
`3.870.702
`
`12/I96l
`7/I969
`2/i970
`ll/l97l
`l/I973
`I2/[974
`3/I975
`
`Nyberg ........................ .. I06/l97 R
`Scherff
`260/231 A
`.
`Greminger et al.
`.... .. 264/30!
`Langman . . . . . . . . . .. . .
`. . . . .. 264/301
`Koyanagi et al.
`260/231 R
`Koyanagi ct al.
`260/23l R
`Koyanagi et al.
`............ .. 260/231 R
`
`Primary Exa'htirier——Ronald W. Griffin
`Attorney, Agent, or Firm——David B. Kellom
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 528,830, Dec. 2,
`I974, abandoned.
`
`U.S. Cl. ............................... .. 536/84; I06/170;
`106/197 R; 264/25; 264/30l; 264/DIG. 37;
`424/35
`Int. Cl.’ ........ .; ...... ..B29C 13/00; cossn/os;_
`1
`C083 ll/I93
`[58] Field of Search ................... 260/231 A, 231 R;
`264/25, 301, DIG. 37; 424/35; I06/170, I97
`.
`R
`
`[56]
`
`References Cited
`UNITED STATES PATENTS
`
`’ ABSTRACT
`[57]
`Improved thermogelling methyl cellulose ether compo-
`sitions for use in preparing pharmaceutical capsules by
`the pin dip coating process are prepared by blending
`the properties of water soluble methyl and C2-C3 hy-
`droxyalkyl cellulose ethers to achieve an essentially
`Newtonian dip coating solution and a rapid high ther-
`mal gel yield strength. These properties require a cellu-
`lose ether with a relatively narrow molecular weight
`distribution. Blends of low viscosity methyl cellulose
`and hydioxypropylmethyl cellulose provide particu-
`larly suitable dip solution properties, gel yield strength,
`and capsule dissolution rates.
`
`_
`
`2,526,683
`
`l0/1950 Murphy ........................... .. 264/304
`
`10 Claims, 2 Drawing Figures
`
`
`
`Mo/e cu/or we/’ hr‘
`
`Mylan v. Qualicaps, IPR2017-00203
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`
`

`

`U.S. Patent
`
`Jan. 4, 1977
`
`Sheet 1 gm
`
`4,001,211
`
`PM — 5
`H
`c /
`
`/00
`
`/0
`
`VJ
`-"3
`°
`3
`$3‘
`
`3U
`
`-2\
`
`0.15
`
`/.0
`
`/o
`
`/00
`
`5/wear rafe, .sec‘ "
`
`/£’z_‘9/.1
`
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`
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`QUALICAPS EX. 2020 - 2/8
`
`

`

`U.S. Patent
`
`Jan.4,1977
`
`Sheet2of2
`
`4,001,211
`
`GEL PERME/77'/ON CHROMHTOGRHPHY
`
`30
`
`‘E1’
`
`Percen/'
`
`'0
`
`MW: 34/oo
`44,7: 7800
`
`Mo/e cu/ar we/:96 2‘
`
`F43/.2
`
`V
`”'
`
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`QUALICAPS EX. 2020 — 3/8
`
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`QUALICAPS EX. 2020 - 3/8
`
`

`

`1
`
`4,001,211
`
`2
`
`PHARMACEUTICAL CAPSULES FROM
`IMPROVED THERMOGELLING METHYL
`CELLULOSE ETHERS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`‘
`
`5
`
`This application is a continuation-in-part of U.S.
`application Ser. No. 528,830 filed Dec. 2, 1974, now
`abandoned.
`‘
`
`10
`
`BACKGROUND OF THE INVENTION
`
`15
`
`20
`
`In 1950 Murphy U.S. Pat. No. 2,526,683 first de-
`scribed a process for preparing methyl cellulose medic-
`inal capsules by a dip coating process using the appara-
`tus described in US. Pat. No. 1,787,777 or similar dip
`coating apparatus. The process consists of dipping a
`capsule forming pin pre-heated to 40°—85° C into a
`cellulose ether solution kept at a temperature below
`the incipient gelation temperature (l0°—30° C), with-
`drawing the pinsat a predetermined withdrawal speed
`and then placing the pins in ovens kept at temperatures
`above the gelation temperature (45°—85° C), exposing .
`the pins to a lower temperature first and then gradually
`25
`to higher temperature until the film is dry. The dry
`capsule is then stripped, cut to size and the body and
`caps are fitted together.
`'
`The resulting methyl cellulose capsules had several
`advantages over conventional gelatin capsules includ-
`ing resistance to microorganisms and greater stability
`under extreme humidity conditions. However, these
`capsules failed to dissolve in the gastrointestinal fluid at
`body temperature in an acceptable time. Furthermore,
`the different rheological properties of the thermally
`gelling methyl cellulose made handling on the Colton
`machines designed for gelatin extremely difficult.
`To overcome some of these problems, Greminger
`and Davis, U.S. Pat. No. 3,493,407, proposed the use
`of non-thermal gelling dip coating solutions of certain
`hydroxyalkylmethyl cellulose ethers in aqueous sol-
`vents. Langman, U.S. Pat. No. 3,617,588, describes the
`use of an induction heater to thermally gel cellulose
`ether dip coated pins after removal from the coating
`bath. However, these advances have not yet met the
`rigid requirements of commercial production.
`STATEMENT OF THE INVENTION
`
`30
`
`35
`
`40
`
`45
`
`The invention relates to medicinal capsules, particu-
`larly to capsules of thermal gelling cellulose ethers such
`as methyl cellulose and hydroxypropylmethyl cellulose.
`These cellulose ethers are soluble in cold water and
`insoluble in hot water. The viscosity of aqueous solu-
`tions decreases with the rise in temperature and then
`rapidly increases through a relatively narrow range of
`temperature with gel formation a few degrees above
`the temperature at which minimum viscosity is ob-
`served.
`
`This thermogelling characteristic is critical to the dip
`coating process. However, some rigid restrictions that
`the solution must follow from a rheological standpoint
`have now been identified by further research. These
`discoveries have led to improved methyl cellulose ether
`compositions for producing medicinal capsules. By
`controlling the non-Newtonian properties of cellulose
`ether solution, the gel strength at elevated temperature,
`and the solution rate of the capsules by proper adjust-
`ment of the cellulose ether molecular weight, MW
`
`50
`
`55
`
`60
`
`65
`
`distribution, degree and type of substitution, improved
`medicinal capsules are obtained.
`More specifically,
`these improved cellulose ether
`compositions for use in preparing pharmaceutical cap-
`sules by the pin dip coating process are characterized
`by having:
`A. A methoxyl degree of substitution (DS) of about
`l.5—2.0 and a C2-C3 hydroxyalkoxyl molar substitution
`(MS) of about 0.1-0.4;
`B. As a 2 wt % aqueous solution, a viscosity of about
`2-10 cps at 20° C and a thermal gel point of about
`50°-80° C;
`C. As a 15-30 wt % aqueous solution at 20° C, a
`viscosity of about 1,000—l0,000 cps with essentially
`Newtonian fluid properties as defined by a power law
`coeficient, n, of 0.9-1.0 at shear rates of between
`0.l—l0 sec“; and
`‘
`D. As a 15-30 wt % aqueous solution, a 50 sec‘ gel
`yield strength at 65° C of at least 150 dynes/cm’-
`In practice the capsules are prepared by dipping pins
`preheated to about 40°—85° C in an aqueous dip coating
`bath containing about 15-30 weight percent of the
`improved cellulose ether composition at a bath temper-
`ature below about 40° C. The clip coated pins are then
`withdrawn and dried at a temperature above the gel
`point of the cellulose ether to obtain the dry capsule
`shells.
`
`General Description — Rheological Requirements
`
`In spite of continued developments in the design of
`capsule dip baths, as shown for example by Whitecar,
`U.S. Pat. No. 3,592,445, the rheologicalrequirements
`of the dip solution used with the Colton capsule ma-
`chines have not been previously examined in detail.
`When the hot pin is dipped into the solution in the
`dipping dish, the solution gels in the surface of the pin
`and as the pin is withdrawn, a film of gelled liquid of
`certain thickness is formed on the pin. The pin is then
`turned 180° to an upright position and placed in the
`oven to dry. To obtain the desired 4i-0.5 mils dry film
`thickness, a wet gel thickness of about 20-60 mils is
`required. Furthermore it is essential that the wet gel
`film thickness as the pin is withdrawn be quite uniform
`and that the wet film have sufiicient strength to prevent
`rundown or other distortion from gravitational pull on
`the film or rotational forces as the pin moves_ to the
`drying oven.
`To achieve the essential uniform coating of the pins
`with a wet thermal gel of sufficient strength, requires
`that the cellulose‘ ether dip coating solution and the
`themial gel meet some rigid rheological requirements.
`First the cellulose ether concentration of the solution
`in the dipping dish must be sufficiently high (15-30
`percent) to ensure proper film formation and ease of
`drying. Then the complex flow patterns in the dipping
`dish and around the pins result in a shear rate on the
`moving pin that varies from point to point. To obtain
`uniform wet gel film thickness under these conditions
`requires that the clipping solution be essentially Newto-
`nian.
`
`Assuming a 12.5 percent variation of film thickness is
`acceptable (4.0i0.5 mils), the viscosity variation be-
`tween the highest and lowest shear rates on the pin
`should not be more than 25 percent. Using the standard
`viscosity power-law equation (cf. Van Wazer ea “Vis-
`cosity and Flow Measurement”, Interscience Publish-
`ers, New York, I963, p. 15):
`
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`

`7’ = Ka.n—l
`
`3
`
`4,001,211
`
`where 1) is the viscosity, 0' the shear rate, K the consis-
`tency index constant, and n the power law coefficient,
`it has been found essential that the dip coating solution
`have a power law coefficient of 0.9-1.0 over a shear
`rate range of 0.1-10 sec“ to achieve the requisite gel
`film uniformity.
`Such an essentially Newtonian solution (n=0.9-1.0),
`’ can be obtained by appropriate control of the cellulose
`ether molecular weight and dip bath conditions. Thus
`as shown further in the examples it is important to
`keep:
`i.e., a 2 wt %
`1. The molecular weight fairly low,
`aqueous solution viscosity of about 2-10 cps at 20° C‘,
`2. The molecular weight distribution fairly low with
`minimum amount of very high MW fractions, i.e., less
`than about 0.1 wt % MW above 200,000;
`3. The salt concentration-in the bath less than 1 wt %
`and
`
`4. The dip bath concentration and temperature as
`low as possible consistent with the necessary wet gel
`thickness.
`.
`
`The importance of the molecular weight distribution
`is shown in FIG. 1. The two hydroxypropylmethyl cel-
`lulose ether samples have essentially the same chemical
`composition and 2 percent aqueous solution viscosities.
`However Sample B, with a wide molecular weight dis-
`tribution and more than 0.15 weight percent of a very
`high MW fraction, has a wholly unacceptable power
`law coefficient of 0.86. In general a Mu,/Mn ratio less
`than about 3.5 is desired.
`
`Secondly, in order to prevent rundown or other dis-
`placement of the wet thermal gel film prior to oven
`drying,
`the gel must have enough yield strength to
`counteract gravitational and rotational stresses while in
`wet form on the pin. For normal Size 000 to Size 5
`pharmaceutical capsule body and cap pins (average
`diameters of 0.452-0.983 cm), yield values (S) calcu-
`lated as a function of wet gel thickness required to
`eliminate rundown of wet gel range from about 60 to
`160 dynes/cm’ for wet film thicknesses of 20-50 mils.
`In practice a wet gel yield strength of at least 150 dy-
`nes/cm” measured after 30-50 sec at 65° C is desirable
`to cover the normal range of capsule sizes.
`Factors found to influence the wet gel strength of
`aqueous cellulose ether solutions include:
`1. The degree and type of alkyl substitution;
`2. A high cellulose ether molecular weight;
`3. High cellulose ether concentrations; and
`4. High pin and oven temperatures.
`Clearly a proper balance must be achieved of proper-
`ties affecting the Newtonian character of the dip bath
`and the strength of the wet gel.
`
`Methyl Cellulose Ethers
`
`Critical to this invention are certain properties of the
`thermogelling methyl cellulose ether composition. That
`it has a 2 percent aqueous solution viscosity of about
`3-10 cps and gel point of about 50°-80° C was recog-
`nized in the prior art. Also the degree and type of ether
`substituents is known to affect the rate of capsule disso-
`lution in gastrointestinal fluid. However, the criticality
`of the molecular weight distribution, the wet gel yield
`strength, and the effect of the substituents on the gel
`strength have not been previously identified.
`Required is a methyl cellulose ether composition
`having a methoxyl DS of about 1.5-2.0 and a C2-C3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`hydroxylalkoxyl MS of about 0.1-0.4. The substituents
`can be combined in a single hydroxyalkylmethyl cellu-
`lose ether such as a hydroxypropylmethyl cellulose
`ether having a methoxyl DS of about 1.50-2.00 and a
`hydroxypropoxyl MS of about 0.1-0.3 and a 2 percent
`aqueous solution viscosity of about 2-10 cps at 20° C.
`Alternately compositions with suitable substitution
`can be obtained by blending methyl cellulose with non-
`ionic hydroxyalkyl cellulose ethers. Particularly useful
`are .blends of a methyl cellulose having a methoxyl DS
`of about 1.64-1.90 and a 2 percent aqueous solution
`viscosity at 20° C of about 5-4000 cps with hydroxy-
`propylmethyl cellulose hydroxyethylmethyl cellulose,
`hydroxypropyl cellulose, hydroxyethyl cellulose, hy-
`droxyethylhydroxypropylmethyl cellulose, etc. Most
`useful are non-ionic hydroxyalkyl cellulose ethers hav-
`ing a 2 percent aqueous solution viscosity of about
`2-10 cps at 20° C. and a thermal gel point below 100°
`C. Thus as shown in Example 2B blends of 20-50
`weight percent methyl cellulose (methoxyl DS of
`1.64-1.90) and 80-50 weight percent hydroxypropyl-
`methyl cellulose (methoxyl DS of 1.68-1.80, hydroxy-
`propoxyl MS of 0.17-0.30) provide a ready means for
`controlling rheological and other properties critical to
`this invention.
`
`For example, a capsule prepared from 9 cps methyl
`cellulose (1.64-1.90 DS) required 20 minutes to dis-
`solve under normal gastrointestinal conditions in con-
`trast to the usual 3 minutes for gelatin capsules. But a
`1:2.67 blend of this methyl cellulose with 2-10 cps
`hydroxypropylmethyl cellulose provides a capsule that
`dissolves in 4 minutes.
`
`Suitable cellulose ethers are commercially available.
`However, their normal characterization by viscosity
`and type and degree of substitution is not alone ade-
`quate to define the improved cellulose ether composi-
`tions. As shown in Example 1, the rheological charac-
`teristics of the aqueous dip bath are extremely sensitive
`to other properties of the cellulose ether. To obtain an
`essentially Newtonian solution as defined by a power
`law coefficient (n) of 0.9-1.0 at shear rates of between
`0.1-10 sec“ requires a fairly narrow molecular weight
`range and elimination of any very high MW fractions.
`The presence of as little as 0.1 weight percent of a
`cellulose ether fraction having a molecular weight
`above about 200,000 will cause the solution to be non-
`Newtonian (n<0.9).
`In practice, the power law coefficient determined at
`dip bath concentration (15-30 weight percent) and
`temperature (below about 40° C) at shear rates be-
`tween 0.1-10 sec“ is an accurate and functional mea-
`sure of a suitable cellulose ether composition.
`The gel strength of the cellulose ether solution is also
`greatly influenced by the ether substituents. Firrnest
`gels are obtained with methyl substitution while hy-
`droxyalkyl substituents provide softer gels with usually
`higher gel point temperatures. As noted above, a 50 sec
`yield value of at least 150 dynes/cm” and preferably
`about 150-300 dynes/cm’ is required for effective op-
`eration with nonnal size capsule pins.
`Again a direct measurement of the wet gel strength
`provides suitable process control. Also blends provide
`a ready means for adjustment to achieve the desired
`final properties.
`Finally, note that the solution rate and gel strength
`both depend on hydroxypropyl substitution but in an
`opposite way. That is, solution rate of cellulose ether
`films increases and gel strength decreases with increas-
`
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`

`

`5
`ing hydroxy"pro‘pyl substitution. So, a compromise has
`to be made ‘to“’obtain a suitable solution "rate and yield
`"stress. Thismciari be achieved by optimizing MS of hy-
`droxyalkyl ‘substitution and blending methyl cellulose
`with hydroxypropylmethyl cellulose.
`
`Dip Coating Process '
`
`In practice, the improved pharmaceutical capsules
`are obtained by dipping capsule pins preheated to
`about “40°-85° C in an aqueous dip coating bath con-
`taining about 15-30 weight percent of the methyl cellu-
`lose compositions defined above. The dip coating bath
`is held ‘at anoperational temperature below about 40°
`C,‘ and usually between about 10°-30°’ C. An opera-
`tional viscosity of about lO00—10,000 cps, and prefer-
`ably about 2000-5000 cps is desirable.
`‘
`'
`As the preheated pins dip into the coating bath, the
`cellulose ether thermally gels on the surface of the pin.
`When the pins are withdrawn, a film‘ of gelled cellulose
`ether remains on the pin. A wet thermal gel film thick-
`ness of about 20-60 mils, preferably about 30-50 mils,
`is necessary to obtain a final dry film thickness of 4i0.5
`mils. The coated pins then travel through an oven held
`at temperatures above the cellulose ether‘ gelation tem-
`perature. The dry capsule pieces are then stripped, cut
`to size, and fitted together.
`'
`Normally, the cellulose ether capsules are relatively
`clear and transparent. However, if opaque capsules are
`desired, a>3_l:nlnOl' amount of inert non-toxic pigment
`such as powdered charcoal or finely’divided titanium
`dioxide can be incorporated in the coating composi-
`tion. Conventional non-toxic dyes and fillers can also
`be used. For increased flexibility, an appropriate plasti-
`cizer suchjas glycerine, propylene glycol, or hydroxy-
`propyl glycerine can be included in a moderate
`amount, e.g. 5 to 20 percent.
`This process is particularly suited for preparing phar-
`maceutical capsule shells which dissolve at a rate com-
`parable to gelatin capsules. Delay release characteris-
`tics can be obtained by incorporation of a less water-
`soluble cellulose ether such as ethyl cellulose as de-
`scribed by Greminger and Windover U.S. Pat. No.
`2,887,440.
`To illustrate further the present invention, the follow-
`ing "examples are given. Unless otherwise specified, all
`parts and percentages are by weight. Solution viscosi-
`ties are_ determined by the method of ASTM D-1347-
`64.
`-
`'
`
`EXAMPLE 1
`
`Dip Coating Bath Rheology I
`
`10
`
`15
`
`20
`
`25
`
`by Van Wazer ea “Viscosity and Flow Measurement”
`op. cit., p. 79-80. Because of gel breakdown from the
`moving rotor, these measured yield “values are lower
`than static‘ values measured by the penetrometer
`method of A. J. Haighton, J. Am. Oil Chem. Soc., 36,
`345( 1959).
`I
`.
`Further study of the Van Wazer method led to a
`more refined and accurate measure of the essentially
`instantaneous gel strength required for commercial dip
`coating operations. For this measurement," the rotor
`and bob of a'I-Iaake MV II rotoviscometer are pre-
`heated to 65° C, a 15-30 wt % aqueous solution of the
`cellulose ether is added, allowed to warm up and equili-
`brate for 30 seconds, and then the gel strength mea-
`sured within a total time of 50 seconds. The resulting
`“50 sec” yield strength correlates well with the require-
`ments of commercial capsule dip coating machines.
`B. A second sample of hydroxypropylmethyl cellu-
`lose having similar methyl and hydroxypropyl substitu-
`tion and a 2 wt % aqueous solution viscosity of 3.74 cps
`at 20° C was dissolved in water to give a 27.0 wt %
`solution. Its viscosity was also measured at 30° C over
`a similar range of shear rates with the results given in
`FIG. 1, Curve B. The calculated power law coefficient
`was 0.86 suggesting a different molecular weight distri-
`bution of the two cellulose ethers.
`C. The different molecular weight distributions for
`‘ the two cellulose ethers, HPMC 1A and 1B, was con-
`firmed by gel permeation chromatography as shown in
`30
`FIG. 2.
`D. When examined in a laboratory dip test with Size
`01 pins, Solution 1A gave essential uniformly coated
`pins while Solution 1B gave stringy tails and visible
`non-uniforrnity when withdrawn from the dip bath.
`However, neither solution had sufficient gel strength to
`prevent subsequent run down and formation of tires,
`striations and other defects during drying.
`EXAMPLE 2
`
`35
`
`40
`
`45
`
`50
`
`4,001 ,211
`
`6
`
`Wet Thermal Gel Strength
`
`When a preheated pin is dipped into the aqueous
`cellulose ether dip coating bath, a portion of the solu-
`tion gels on the pin to form a wet gel coating which
`clings to the‘ pin as it is withdrawn. To prevent run
`down and loss of the essentially uniform coating re-
`quired for mating capsule shells, the gel must have
`sufficient yield strength to maintain its form as it moves
`from the dip bath to the drying oven.
`A. The wet thermal gel strength of the methyl cellu-
`lose ether compositions can be determined as de-
`scribed in Example 1A. Using standard equations,
`known dimensions for capsule body and cap pins, and
`desired final capsule film thickness of 4i0.5 mils, a
`table of yield values has been calculated for each pin
`size and wet gel thickness of 20-60 mils. Typical calcu-
`lated values for 35 and 50 mil wet films are given in
`Table 2.
`
`
`Table 2
`Calculated Yield Values (3) to Eliminate Rundown
`P_in
`AV- Dia
`
`5'"
`cm
`35 "ms
`50 ""18
`000
`0-940
`95-4
`141.3
`0
`0.716
`98.0
`146.5
`2
`0.592
`.000
`1512
`
`5
`0.452
`io4.3
`159.4
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2020 — 6/8
`
`55
`
`A. An aqueous dip coating solution containing 28.7
`wt % of 3.96 cps (2 wt %, 20° C) hydroxypropylmethyl
`cellulose, was prepared from a commercial methyl cel-
`lulose having a methoxyl DS of 1.68-1.80, a hydroxy-
`propoxyl‘ MS of 0.17-0.30 and a thermal gel point of
`about 60° C (Methocel 6OHG from the Dow Chemical
`Company). Its viscosity at 30° C at shear rates of from
`about 0.1—l0sec'-‘ was determined using a I-Iaake Roto- 60
`V3590 ViS90m¢t€1'- The results, are SW81? in FIG- 1: CUFVC
`A. The power law coefficient (n) was 0.98 indicating
`an essentially Newtonian fluid under conditions suit-
`able for capsule dip coating operation.
`.
`.
`.
`-
`A portion of the dip coating solution was thermally 65
`gelled by heating in a water bath to about 50°-60° C.
`The yield value of the soft gel was determined using the
`Haake instrument and the on-off technique described
`
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`

`

`4,001,211
`
`15
`
`Y‘1dV1
`Cone. wt;
`“ax:
`HPMC _ Mc
`HpMc/MC
`2
`0
`—
`2
`20
`2
`.0
`:3
`2
`2-:7
`,7
`5
`3:4
`16
`6
`2.67
`
`Table 3
`fB1 ddHPMC dMC
`3“ 250% visa. 3“
`50 Sec “em
`cps, 20°C
`dynes/cmz
`2285
`102
`3415
`.42
`‘Sig?
`6429
`7864
`
`245
`286
`
`7
`8
`B. Once the significance of the wet gel yield strength
`in sufficient water to give a solution containing 22.0
`weight percent cellulose ether. The solution had a vis-
`to the capsule dip coating process has been recognized,
`it provides a simple and effective test for evaluating
`cosity of about 5000 cps at 30° C and was essentially
`Newtonian at shear rates from 0.l_——lO sec“' with a
`methyl cellulose compositions for use in this process.
`5 power law coefficient (n) of 0.95. Its gel point was
`Table 3 provides a simple illustration of the effect of
`about 35° C. A fimi rigid gel was obtained at 50° C with
`blending methyl cellulose (MC) with a hydroxypropyl-
`a yield value of about 101 dynes/cm” as measured by
`methyl cellulose (HPMC) to improve its yield value or
`the Van Wazer method.
`wet gel strength. The methyl cellulose (MC-2B) had a
`B. Capsule shells were prepared from this HPMC-
`methoxyl D8 of 1.64-1.90 and a 2 wt % aqueous solu-
`tion viscosity of 11 cps at 20° C. The hydroxypropyl- 10 MC dip solution using No. 0 capsule pins machined
`methyl cellulose (HPMC-2B) had a methoxyl DS of
`from Type 313 stainless steel and lightly coated with a
`1.68-1.80, a hydroxypropyl MS of 0.17-0.30, and a
`lubricant using a standard Colton dip coating machine.
`viscosity of 3.75 cps (2 wt %, 20° C.) The test solutions
`Pins preheated to about 65° C were dipped into the
`contained a total of 22 wt % cellulose ether and were
`HPMC—MC solution held at 30° C and after 10-15 sec
`gelled by heating at 55°—60° C.
`smoothly withdrawn, inverted, and passed through the
`oven drier held at 50°—70° C. The resulting capsule
`_
`_
`_
`shells were stripped from the pins and examined for
`-
`-
`-
`~
`-
`-
`uniformity and dissolution time.
`In clarity, freedom
`from surface defects, uniformity, ease of assembling
`.
`.
`20 cap and body shells, these HPMC—MC shells met the
`standard set for pharmaceutical capsules. The average
`dissolution time was 4 minutes.
`C. Table 4 presents data from blends of methyl cellu-
`lose and otherhydroxypropyl cellulose ethers.
`’
`Table 4
`Other MC Blends
`Ag. Soln, 20° C
`Wt% CE
`Visc. cps
`22
`5334
`22
`7552
`22
`8811
`22
`9871
`18
`2718
`18
`4189
`17
`3259
`15
`7368
`16
`4204
`16
`4690
`15
`5140
`
`Cellulose Ethers'
`4-1 HPMC-3/MC-2
`
`4-2 HPMC-3/MC-3
`4-3 HPMC-3/MC-4
`4-4 HPMC-4/MC-2
`
`4-5 HPC-1/MC-2
`
`4-6 HPC-1/MC-1
`
`Ratio
`20/2
`19/3
`18/4
`17.5/4.5
`16/2
`15/3
`14/3
`10/5
`8/8
`7/9 .
`5/10
`
`50 Sec Yield. 65° C
`dynes/cm’
`245
`296
`259
`297
`146
`185
`50‘
`120'
`185
`220
`265
`
`3,4 cps hydroxypropyl cellulose (2.5—4 MS)
`'HPC-l
`3,6 cps hydroxypropylmethyl cellulose (1.88 DS; 0.21 MS)
`HPMC-3
`3.7 cps hydroxypropylmethyl cellulose (1.38 DS; 0.20 MS)
`HPMC~4
`25 cps methyl cellulose (1.83 DS)
`MC-2
`16 cps methyl cellulose (1.83 DS)
`MC-3
`14 cps methyl cellulose (1.83 DS)
`MC-4
`1 I cps methyl cellulose (1.80 DS)
`MC-1
`‘Unsatisfactory for capsule process
`
`‘Modified Van Wazer method. 65° C
`
`EXAMPLE 3
`
`Capsules from HPMC—MC Blends
`A. An aqueous dip coating solution was prepared by
`dissolving a blend of
`72.7 parts of 3.75 cps hydroxypropylmethyl cellulose
`(Methocel 60 HG, 1.8 methoxyl DS, 0.30 hydroxy-
`propoxyl MS, 2 percent gel point of 60? C.)
`27.3 parts of 1 1.0 cps methyl cellulose (Methocel
`MC, 1.80 methoxyl DS, 2 percent gel point of 50°
`C.)
`
`50
`
`55
`
`D. In a similar manner capsules can be made from
`other therrnogelling, blends of methyl cellulose and
`other non-ionic hydroxyethyl and hydroxypropyl cellu-
`lose ethers which provide an essentially Newtonian dip
`bath solution and a thermal gel of requisite yield
`strength to provide a dimensionally uniform and stable
`wet gel coating.
`
`_
`
`EXAMPLE 4
`
`Capsules from Other Cellulose Ethers
`
`Table 5 gives typical 50 second yield values for a
`number of other low viscosity cellulose ethers.
`
`Table 5
`
`
`50 Second Yield Values, 65° C
`_
`Composition, Wt %
`Ag. Soln 20° C
`50 Sec Yield
`
`Cellulose Ether‘
`MeO(DS)
`HAO(MS)
`Wt % CE
`Visc
`- dynes/cm’
`5-1
`3.66 cps EHEC
`-35 wt %
`ethoxyl-
`20
`10280
`255
`5-2
`3.33 cps HEMC
`1.37
`0.38
`18
`1277
`162
`5—3
`3.37 cps HEMC
`1.55
`0.21
`18
`1262
`168
`54
`3.43 cps HBMC
`1.41
`0.08 '
`18
`1598
`168
`5-5
`3.77 cps HBMC
`1.27
`0.13
`18
`3079
`198
`5-6
`4.03 cps HBMC
`1.46
`0.19
`20
`6318
`272
`5-7
`2.76 cps HPMC
`1.79
`0.03’
`18
`811
`193
`
`V
`V
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2020 — 7/8
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2020 - 7/8
`
`

`

`9
`
`4,001,211
`
`10
`
`Table 5-continued
`50 Second Yield Values. 65° C
`Composition, W; %
`A . Soln 20°
`MeO(DS)
`HAO(MS)
`Wt % CE
`Vise
`
`50 Sec Yield
`dynes/cm’
`
`Cellulose Ether‘
`
`270
`3278
`25
`0.10
`1.77
`2.77 cps HPMC
`5-8
`190
`3239
`25
`0.12
`1.72
`2.88 cps HPMC
`5-9
`1.692.90 cps HPMC5-10 160 0.17 25 2494
`
`
`
`
`
`
`‘EHEC - Ethylhydroxycthyl cellulose
`HEMC - Hydroxyethylmethyl cellulose
`HBMC - Hydroxybutylmethyl cellulose
`HPMC - Hydroxypropylmethyl cellulose
`
`Such data, coupled with the Newtonian properties of 15
`the aqueous cellulose ether at dip bath operating condi-
`tions, provide requisite rheological
`information for
`capsule dip coating operations.
`1 claim:
`
`20
`
`1. A thermal gelling methyl cellulose ether composi-
`tion suitable for use in preparing pharmaceutical cap-
`sules by an aqueous dip coating process using pre-
`heated pins and having a methoxyl D8 of about
`1.5-2.0, a C2-C3 hydroxyalkyl MS of about 0.1-0.4, a 2
`wt. % aqueous solution viscosity of about 2-10 cps at
`20° C and a thermal gel point of about 50°—80° C, and
`a 15-30 wt. % aqueous solution viscosity of ' about
`1,000-10,000 cps at 20° C, said composition being
`further characterized by having as a 15-30 wt. % aque-
`ous solution:
`
`A. Essentially Newtonian fluid properties as defined
`by a power law coefficient, n, of 0.9-1.0 at shear
`rates of between 0.1-10 sec“, and
`B. A 50 sec gel yield strength of at least 150 dy-
`nes/cm’ at 65° C.
`2. The cellulose ether composition of claim 1 where
`the cellulose ether is a blend of a methyl cellulose hav-
`ing a methoxyl DS of about 1.64-1.90 and a non-ionic
`Cz—C3 hydroxyalkyl cellulose ether.
`3. The cellulose ether composition of claim 2 where
`the non-ionic hydroxyalkyl cellulose ether has a ther-
`mal gel point of about 50°-90° C as a 2 percent aqueous
`solution.
`4. The cellulose ether composition of claim 2 where
`the non-ionic cellulose ether is a hydroxypropylmethyl
`cellulose ether with a 2 percent aqueous solution vis-
`cosity of about 2-10 cps at 20° C.
`5. The cellulose ether composition of claim 2 where
`the cellulose ether is a blend of (1) about 20-50 weight
`percent of methyl cellulose having a methoxyl DS of
`about 1.64-1.90 and (2) about 80-50 weight percent
`of a hydroxypropylmethyl cellulose having a methoxyl
`DS of about 1.68-1.80 and a hydroxypropoxyl MS of
`about 0.17-0.30.
`
`6. The cellulose ether composition of claim 1 where
`the cellulose ether is a hydroxypropylmethyl cellulose
`ether with a methoxyl DS of about 1.50-2.00, a hydrox-
`ypropoxyl MS of about 0.1-0.3, and a 2 percent aque-
`ous solution viscosity of about 2-10 cps at 20° C.
`7. The cellulose ether composition of claim 1 where
`the cellulose ether has a narrow molecular weight dis-
`tribution with a M.,,/M. ratio less than about 3.5 and
`contains less than 0.1 wt % of material having a molec-
`ular weight above about 200,000.
`8. In a process for preparing pharmaceutical capsules
`by an aqueous dip coating process using preheated pins
`and an aqueous bath containing about 15-30 wt. % of
`a thermal gelling methyl cellulose ether composition
`having a'methoxyl DS of about 1.5-2.0, a C2-C3 hy-
`droxyalkoxyl MS of about 0.1-0.4, a 2 wt. % aqueous
`' solution viscosity of about 2-10 cps at 20° C and ther-
`30
`mal gel point of about 50°—80° C, and a 15-30 wt. %
`aqueous solution viscosity of about 1,000-10,000 cps
`at 20° C, the improvement comprising using a methyl
`cellulose ether composition further characterized by
`having as a 15-30 wt. % aqueous solution:
`A. Essentially Newtonian fluid properties as defined
`by a power law coefficient, n, of 0.9-1.0 at shear
`rates of between 0.l—l0 sec", and
`B. A 50 sec gel yield strength of at least 150 dy-
`nes/cm“ at 65° C,
`as the shell fonning component of the aqueous dip
`coating bath.
`9. The process of claim 8 where the cellulose ether
`has a 50 sec gel yield strength of 150-300 dynes/cm’ at
`65° C.
`
`'
`25
`
`35
`
`40
`
`10. The process of claim 8 where size No. 1 capsule
`pins preheated to about 50°—60° C are dipped into a
`20-30 wt % aqueous solution of a blend of (1) about 73
`wt % of a hydroxypropylmethyl cellulose having a me-
`thoxyl DS of about 1.68-1.80 and a hydroxypropoxyl
`MS of about 0.17-0.30 and (2) about 27 wt % of
`methyl cellulose having a methoxyl DS of about
`1.64-1.90 and the resulting dip coated pins are oven
`dried at about 45°-80° C to give capsule shells having a
`wall thickness of about 4:05 mils.
`*
`*
`*
`*
`*
`
`45
`
`.50
`
`55
`
`60
`
`65
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALIACAPS EX. 2020 — 8/8
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2020 - 8/8
`
`