DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 15(6&7), 975-999 (1989)
`
`HY DROXY PROPYLMETHYLCELLULOSE
`
`SUSTAINED RELEASE TECHNOLOGY
`
`2.E. Hogan
`
`Colorgon Limited, Murray Road,
`
`St. Pauls Cray, Orpington, Kent BR5 3QY
`
`ABSTRACT
`
`The use of polymers in controlling the release of
`
`drugs has become important in the formulation of pharma-
`
`ceuticals. Watersoluble polyncrs such as polyethylene
`
`glycol and polyvinylpyrrolidone may be used to increase
`1
`the dissolution rates of poorly soluble drugs (Ford)
`
`and slowly soluble, biodegradable polymers such as poly-
`
`lactic acid may be used for controlled release implants
`
`(Rak et a1.2), Hydrogels provide the basis €or implanta-
`
`tion, transdermal and oral-controlled release systems.
`
`Hydroxypropylmethylcellulose (HPMC) are cellulose ethers
`
`which may be used as the basic €or hydrophilic matrices
`
`€or controlled release oral delivery.
`
`In tablet matrix systems the tablet is in the form
`
`of compressed compact containing an active ingredient,
`
`97 5
`
`Copyright @ 1989 by Marcel Dekker, Inc
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`lubricant, excipient, filler or binder. The matrix may
`
`be tabletted from wet-massed granules or by direct
`
`compression.
`
`This review article examines a previously published
`
`series of work and concentrates on the following aspects
`
`of the subject; the relationship between release rate
`
`and quantity of polymers, such consideration allow a
`
`certain predicability in release rates to be made. Also
`
`the effect of drug particle size, tablet shape and the
`
`presence of additional diluents in the formula are
`
`examined.
`
`INTRODUCTION
`
`The use of polymers in controlling the release of
`
`drugs has become important in the formulation of pharma-
`
`ceuticals. Water-soluble polymers such as polyethylene
`
`glycol and polyvinylprrolidone may be used to increase
`1
`the dissolution rates of poorly soluble drugs (Ford
`
`and slowly soluble, biodegradable polymers such as poly-
`
`lactic acid may be used for controlled release implants
`L
`(Rak et al. ) . Hydrogels provide the basis for implanta-
`tion, transdermal and oral-controlled release systems.
`
`Hydroxypropylmethylcellulose (HPMC) are cellulose ethers
`
`which may be used as the basis for hydrophilic matrices
`
`for controlled release oral delivery.
`
`In tablet matrix systems the tablet is in the form
`
`Of a compressed compact containing an active ingredient,
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`HYDROXYPROPYLMETHYLCELLLJLOSE
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`l u b r i c a n t , e x c i p i e n t , f i l l e r o r b i n d e r . The m a t r i x may
`
`be t a b l e t t e d from wet-massed g r a n u l e s o r by d i r e c t
`
`c o m p r e s s i o n .
`
`The o p e r a t i v e p r i n c i p l e c o n t r o l l i n g d r u g release i n
`
`m a t r i x t a b l e t s i s t h a t on e x p o s u r e t o a q u e o u s f l u i d s t h e
`
`t a b l e t s u r f a c e becomes w e t a n d t h e p o l y m e r s t a r t s t o p a r -
`
`t i a l l y h y d r a t e t o form a g e l l a y e r . An
`
`i n i t i a l b u r s t O f
`
`s o l u b l e d r u g f r o m t h e e x t e r n a l l a y e r may be r e l a s e d .
`
`T h e r e f o l l o w s a n e x p a n s i o n o f t h e g e l l a y e r when water
`
`p e r m e a t e s i n t o t h e t a b l e t i n c r e a s i n g t h e t h i c k n e s s o f
`
`t h e g e l l a y e r a n d s o l u b l e d r u g d i f f u s e s t h r o u g h t h e g e l
`
`b a r r i e r . C o n c o m i t a n t l y t h e o u t e r l a y e r s become f u l l y hy-
`
`d r a t e d a n d d i s s o l v e , a p r o c e s s g e n e r a l l y r e f e r r e d t o a s
`
`e r o s i o n . Water c o n t i n u e s t o p e n e t r a t e t o w a r d s t h e t a b l e t
`
`core u n t i l it h a s d i s s o l v e d .
`
`T h i s review a r t i c l e e x a m i n e s a p r e v i o u s l y p u b l i s h e d
`
`series o f work and c o n c e n t r a t e s on t h e f o l l o w i n g a s p e c t s
`
`of t h e s u b j e c t ; t h e r e l a t i o n s h i p b e t w e e n r e l e a s e r a t e
`
`and q u a n t i t y of p o l y m e r , s u c h c o n s i d e r a t i o n s a l l o w a c e r -
`
`t a i n p r e d i c t a b i l i t y i n r e l e a s e r a t e s t o m e m a d e . A l s o t h e
`
`e f f e c t o f d r u g p a r t i c l e s i z e , t a b l e t s h a p e a n d t h e p r e s -
`
`e n c e o f a d d i t i o n a l d i l u e n t s i n t h e f o r m u l a a r e e x a m i n e d .
`
`MATERIALS AND METHODS
`
`A l
`
`l
`
` drugs were B . P . grade. Hydroxypropylmethyl-
`
`c e l l u l o s e , Methocel ( [ l o w C h e m i c a l , U . S . A . )
`was used without further preparation. Magnesium
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`stearate (B.D.H., U.K.) was used as lubricant. Calcium
`
`phosphate (B.D.H.) or spray-dried lactose were used as
`
`required as diluents. Compaction was accomplished
`
`using direct compression of the blends that had been
`
`thoroughly mixed f o r 15 min using a tumbler mixer. The
`
`following variables were examined.
`
`Influence of Drua:HPMC Ratios
`
`Blends were compressed to the following formulae.
`
`( i ) Promethazine hydrochloride (250-500 ym):
`
`25mg, HPMC K15M: 20, 25, 40, 50, 80, 120 or
`
`160mg, magnesium stearate: 0.75%.
`
`Compaction pressure was 1395 MN.mWL
`3
`Ford 1 .
`
`(as
`
`(ii) Aminophylline (125-180 pm): 225mg, HPMC
`
`K15M: 45, 60, 90, 180 or 270mg, magnesium
`
`stearate: 0.85%. Compaction pressure was 455
`
`MN.mP2 ( a s Ford et a1 .4).
`(iii) Propranolol hydrochloride (125-180 pm): 160
`
`mg, HPMC K15M: 57, 71, 95, 140 or 285mg,
`
`magnesium stearate: 0.75%. Compaction
`
`pressure was 348.5 MN.m-2 (as Ford et a1.4).
`
`( i v ) Indomethacin (90-125 rm): 25mg, HPMC K15M:
`
`25.8, 36, 61.5 or 200mg, magnesium stearate:
`0.75%. Compaction pressure was 1395 MN.m -2
`(as Ford et al. 1 .
`r 3
`( v ) Tetracycline hydrochloride (125-180 p m ) :
`250mg, HPMC K15M: 45, 60, 90, 180 or 270m9,
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`HYDROXYPROPYLMETHYLCELLULOSE
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`magnesium stearate: 0.75%. Compaction
`
`pressure was 455 MN.m-L.
`
`(vi) Theophylline hydrochloride (125-180 pm):
`
`225mg, HPMC K 1 5 M : 60, 90, 180 or 270mg,
`magnesium stearate: 0.75%. Compaction
`-2
`pressure was 455 MN.m .
`(vii) Diazepam (125-180 um): lOmg, HPMC K15M: 50,
`
`61.5, 80, 114.3 or 200m9, magnesium
`
`stearate: 0.75%. Compaction pressure was
`
`1395 MN.m-2.
`
`Compaction was accomplished using flat-faced
`
`punches on a Manesty F3 single-punch tableting machine.
`
`Propranolol tablets were 0.5 inch diameter,
`
`promethazine, indomethacin and diazepam tablets were
`
`0.25 inch diameter, the remainder were 0.4375 inch
`
`diameter.
`
`Dissolution Studies
`
`The dissolution rates of the tablets were
`
`monitored using a Copley-Series 8000 dissolution tester
`
`(Copley Instruments, Nottingham, U.K.).
`
`l O O O m l of
`
`distilled water was used as dissolution media and main-
`tained at 37OC. The USP 1 dissolution method was used
`
`at a rotation speed of 100 rpm. Dissolution was contin-
`
`uously recorded using a spectrophotometer (Kontrol, mod-
`
`el Uvikon 810) at 250 nm connected to a Commodore Model
`
`8032 microprocessor. Dissolution studies were performed
`
`in triplicate €or each batch of tablets.
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`TABLE 1
`1 % Promethazine
`Statistical Data Giving the Slope M (
`HCL I lmin 1 -‘I2 I mg HPMC I ) and Intercept C ( I %Promethaz ine
`I min 1
`HCL 1
`- 1 / 2
`) and Pression Coefficients of theplots of
`Promethazine HCL Release Rate (%min-l’*) Against Recip-
`-1
`rocal Hydroxypropylmethylcellulose concentration (mg )
`
`HPMC grade
`
`Slope M
`Intercept C
`(%rnin -1 12 .mg) (%min-l)
`
`209.7
`146.8
`132.0
`168.3
`
`K100
`K4M
`K15M
`K1 OOM
`*A1 1 significant P < 0.001.
`
`4.19
`3.54
`3.33
`2.98
`
`Regression coefficient *
`(r)
`0.993
`0.992
`0.995
`0.997
`
`RESULTS AND DISCUSSION
`
`Relationship Between Release Rate and Polymer Quantity
`
`Examination of dissolution curves of the drug pro-
`
`methazine hydrochloride with differing polymer quantity
`
`shows that as the polymer fraction increases, the dis-
`solution of the drug decreases.This is shown inTable 1.
`
`The generaliscd relationship for each of these
`
`lines can b e expressed by the relationship:
`
`Equation 1
`
`1 -
`Where R = Higuchian release rate ( % min - * )
`M = Slope of the derived line
`W = Weight of HPMC ( m g )
`C = Constant
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`HYDROXYPROPYLMETHYLCELLULOSE
`
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`
`TABLE 2
`Statistical 3ata Giving the Slopes m ( I % Drug 1 imin
`-1 / 2
`I I TI
`HPMC 1 ) and Intercepts C (
`1
`) and Regression
`Coefficients of the Plots o f Drug Release Rate ( % min-’”)
`Againts
`the Reciprocal Hydroxypropylgethylcel lulose Concentration (mg-’ )
`for Propranolol Hydrochloride and Aminophyll ine
`
` % Drug 1 lmin -”‘ I
`
`Drug
`
`Aminophylline
`
`Propranolol
`hydrochloride
`
`HPMC
`grade
`KlOO
`K4M
`K15M
`KlOOM
`
`KlOO
`K4M
`K15M
`KlOOM
`
`Slope M
`(% rnin-’.mg)
`764.5
`288.6
`258.9
`247.1
`
`Intercept C
`(% min-’)
`2.68
`3.24
`3.29
`3.47
`
`Regression
`coefficient (V)
`0.996
`0.994
`0.987
`0.986
`
`724.4
`321 .5
`207.9
`251.0
`
`2.37
`3.06
`2.97
`3.21
`
`0.998
`0.992
`0.996
`0.936
`
`Degree of
`significance
`P < 0.001
`P < 0.01
`P < 0.01
`P < 0.01
`
`P < 0.001
`P <0.001
`P < 0.001
`P < 0.02
`
`A similar treatment with the drugs aminophylline
`and propranolol hydrochloride provides the data in
`
`Table 2
`
`The compositions of the blends of drug and HPMC being
`
`given i n the materials and methods section.
`
`The relationships indicated by Tables 1 and 2
`
`allow predictions of release rates to be made for
`
`drug:HPMC ratios not experimentally determined. It
`
`would be equally beneficial to estimate the release
`
`rates of other drugs, not experimentally determined.
`
`However, problems such as variation in the dose of drug
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`TABLE 3
`
`Estimated Release Rates (%min-lI2or mg. min - ‘ I 2 ) of Aminophylline,
`Propranolol Hydrochloride and Promethazine Hydrochloride from
`their HPMC Matrix Tablets Containing 1:l or 1:2 Drug: HPMC for
`4 Viscosity Grades of HPMC
`
`Drug
`(dose)
`
`HPMC viscnsity
`grade
`
`Drug IIPMC Release rates
`ratio
`
`KlOO
`
`K4M
`
`K15M
`
`KlOOM
`
`KlOO
`
`K4M
`
`KI5M
`
`KlOOM
`
`KlOO
`
`K4M
`
`KISM
`
`KlOOM
`
`Propranolol
`hydrochloride
`(160 mg)
`
`Promet hazinc
`hydrochloride
`(25 mg)
`
`’ Data from Ford ec at.’
`* * W//’ = (wt of HPMC)’/’
`
`1 : l
`1 . 2
`1 : l
`1 . 2
`1 : l
`1 . 2
`1 . 1
`: 2
`
`: I
`: 2
`: I
`4 . -
`: I
`: 2
`: I
`: 2
`
`: 1
`: 2
`: I
`: z
`: 1
`1 : 2
`1 : l
`1 : 2
`
`6.08
`4.38
`4.52
`3.88
`4.44
`3.87
`4.57
`4.02
`
`6.89
`4.63
`5.07
`4.07
`4.26
`3.62
`4.78
`3.99
`
`12.37
`8.13
`9.45
`6.48
`8.61
`5.97
`9.1 1
`6.35
`
`1368
`9.85
`10.18
`8.73
`9.99
`8.70
`10.28
`9.04
`
`11.03
`7.41
`8 I 1
`6.51
`6 83
`5 79
`7 64
`6 39
`
`3 09
`2.03
`2.36
`1.62
`2.15
`1.49
`2.43
`1.59
`
`Mod I lied
`
`w;/i ..
`
`36 98
`16.78
`21.52
`14.87
`27.01
`14.82
`27.79
`16.78
`
`37.43
`15.84
`27.52
`13.92
`23 18
`12.38
`25.92
`13.66
`
`36.14
`14.96
`27.60
`1 1.94
`25.17
`11 .XI
`28.42
`11.72
`
`o r p o s s i b l e drug-HPMC
`
`i n t e r a c t i o n s may c o m p l i c a t e s u c h
`
`c a l c u l a t i o n s . N o n e t h e l e s s , a s a f i r s t s t e p t o i n t e r -
`
`r e l a t e t h e d i s s o l u t i o n r a t e s of
`
`t h e t h r e e d r u g s i n t h i s
`
`s t u d y E q n . 1 w a s u s e d t o p r e d i c t t h e d i s s o l u t i o n
`
`r a t e s f r o m 1:l t o 1 : 2 drug:HPMC matrices. T h e s e
`
`c a l c u l a t e d r a t e s a r e e x p r e s s e d i n T a b l e 3 .
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`1 -
`Direct comparison of the % min-2 data is somewhat
`
`confusing since it indicates, €or example, that
`
`promethazine is liberated approximately twice as fast
`
`as aminophylline from similar drug:HPMC ratio matrices.
`1 -
`However, a similar comparison of the rng.min-2 data
`
`indicates that as the dose of the drug and consequently
`
`as the amount of HPMC within the tablet increases, the
`
`dissolution rates increases. In fact, a straight-line
`
`relationship existed between the logarithm of the
`
`tablet HPMC content and the logarithm of the release
`
`1 -
`rates (mg.minP2) at similar drug:HPMC ratios. The
`eight sets of data in Table 3 ( 4 HPMC grades x 2
`
`druq:HPMC ratios) can therefore be reduced to the
`
`following relationship:
`
`log R = m log HPMC + contant A
`where log R = log of Higuchi-type release rate
`- _
`1
` and log HPMC = log of tablet content of
`(mg. min 2 )
`,
`HPMC (mg).
`
`Equation 2
`
`The data for Eqn. 2 are determined at a constant
`
`drug:HPMC ratio. Such treatment theoretically allows
`
`a potential formulator to predict the dissolution
`
`rate of a drug from its HPMC matrix provided the
`
`rates of other drugs at similar drug:HPMC ratios
`
`have previously been determined.
`
`However, for the extension of these findings to
`
`other drugs, certain restrictions or assumptions have
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`to be made. The doses of drugs so far studied have
`
`been between 25 and 225mg, since this was the range
`over which Eqn. 2 was developed. Similarly it is va1.id
`
`for lubricant (or other insoluble excipient) levels of
`
`up to only 0.85%. Ford et al.3 previously showed that
`
`the absence or presence of 0.75% lubricant did not
`
`modify dissolution rates.
`
`Eqn. 2 was also constructed from data derived for
`
`water-soluble drugs. Promethazine hydrochloride,
`
`aminophylline and propranolol hydrochloride have
`
`aqueous solubilities of 1 in 0.6, 1 in 5 and 1 in 20
`
`parts of water, respectively, and the application of
`
`Eqn. 2 to drugs of lower solubility is unclear. It has
`
`been assumed that the drugs used i n this study alter
`similarly the tortuosity of HPMC matrices. Both the
`
`promethazine and propranolol salts possess chloride
`
`ions as the counterbalancing moiety to the base and
`
`arninophylline is the free base. However, Lapidus and
`
`Lordi6 have shown that certain ions, e.g.
`
`the sodium
`
`ion, may decrease the tortuosity of the HPMC gel by
`
`dehydrating the polymer. The applicatiblity of Eqn. 2
`
`to other drug-HPMC systems probably depends on the
`
`other drugs dehydrating the polymer to a similar
`ex tent .
`The explanation of the relationship described by
`
`Eqn. 2 is probably through a surface area relationship.
`
`The tablets, on exposure to water, swelled due to
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`HYDROXYPROPYLMETHYLCELLLJLOSE
`
`98 5
`
`h y d r a t i o n of
`
`t h e HPMC b u t d i d n o t m a i n t a i n t h e i r
`
`t y p i c a l form a n d became b i c o n v e x , s o m e w h a t a n a l o g o u s
`
`t o a s p h e r e .
`
`F o r a l l r e g u l a r - s h a p e d o b j e c t s , a l i n e a r
`
`r e l a t i o n s h i p c a n be o b t a i n e d b e t w e e n t h e l o g w e i g h t a n d
`
`l o g s u r f a c e a r e a . A s s u m i n g t h a t t h e d r u g d i s s o l v e s t o
`
`l e a v e t h e HPMC w h i c h s w e l l s t o a n a p p r o x i m a t e s p h e r i c a l
`
`s h a p e , i . e . t h e d r u g d o e s n o t c o n t r i b u t e t o t h e o v e r a l l
`
`s i z e o f t h e h y d r a t e d m a t r i x , t h e n t h e s u r f a c e a r e a A
`
`c a n be r e l a t e d t o HPMC w e i g h t b y t h e r e l a t i o n s h i p s :
`
`v d w d r 3
`
`E q u a t i o n 3
`
`w h e r e V = v o l u m e o f s p h e r e , W = w e i g h t o f s p h e r e , r =
`
`t h e s p h e r e , a n d t h e r e f o r e :
`r a d i u s of
`s d r 2~ w*/
`E q u a t i o n 4
`C o n s e q u e n t l y t h e s u r f a c e a r e a S v a r i e s t o W 2 / 3 .
`
`A s s u m i n g t h a t a l l t h e HPMC v i s c o s i t y g r a d e s s w e l l t o t h e
`
`same e x t e n t w h e n h y d r a t e d , a n d t h a t t h e h y d r a t e d m a t r i c e s
`
`h a v e t h e same d e n s i t y , t h e n t h e e f f e c t i v e s u r f a c e a r e a
`p r e s e n t e d b y t h e t a b l e t s s h o u l d be p r o p o r t i o n a l t o W 2 / 3 .
`2 / 3
`1
`'
`i s t h e w e i g h t of HPMC, g i v e s t h e m o d i f i e d
`
`D i v i d i n g t h e r e l e a s e r a t e s g i v e n i n T a b l e 3 b y W
`
`
`
`w h e r e W
`
`1
`r e l e a s e r a t e s .
`
`I t i s a p p a r e n t i n T a b l e 3
`
`t h a t t h e s e
`
`m o d i f i e d r a t e s a r e s i m i l a r w h e n d e r i v e d from HPMC K4M,
`
`HPMC K15M a n d HPMC K l O O M m a t r i c e s t h e r e b y e x p l a i n i n g t h e
`
`r e l a t i o n s h i p s o u t l i n e d b y E q n . 2 .
`
`T h e h i g h e r v a l u e s o f
`
`HPMC K l O O m a t r i c e s ( T a b l e 3 ) i n d i c a t e t h a t e i t h e r t h i s
`
`m a t r i x i s l e s s t o r t u o u s t h a n m a t r i c e s of
`
`t h e o t h e r HPMCs,
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`QUALICAPS EX. 2051 - 11/25
`
`

`

`986
`
`HOGAN
`
`o r t h a t t h e a s s u m p t i o n t h a t t h e m a t r i c e s of t h e p o l y m e r s ,
`
`when h y d r a t e d , s w e l l t o a s i m i l a r e x t e n t i s i n c o r r e c t .
`
`S h o u l d t h e l a t t e r be t h e c o r r e c t a s s u m p t i o n t h e n a n o v e r -
`
`a l l o w a n c e was made f o r t h e s w e l l i n g c a p a c i t y of
`
`t h i s
`
`p o l y m e r when h y d r a t e d a n d HPMC K l O O d o e s n o t s w e l l t o t h e
`
`same e x t e n t a s t h e o t h e r g r a d e s . C e r t a i n l y , h o w e v e r ,
`
`t h e r e i s e v i d e n c e w i t h i n t h e l i t e r a t u r e t h a t t h e h i g h e r
`
`m o l e c u l a r w e i g h t HPMCs f o r m g e l s p o s s e s s i n g t h e s a m e g e l
`
`s t r e n g t h s w h e r e a s t h e l o w e r m o l e c u l a r w e i g h t p o l y m e r s
`7
`p o s s e s s lower g e l s t r e n g t h s ( S a r k a r 1 .
`
`I t i s p r o b a b l e
`
`t h a t o t h e r p h y s i c o c h e m i c a l p r o p e r t i e s s h o w t h e same
`
`d i s c o n t i n u i t y w i t h m o l e c u l a r w e i g h t a n d a r e r e s p o n s i b l e
`
`f o r t h e a p p a r e n t e f f e c t s o f m o l e c u l a r w e i q h t o n r e l e a s e
`
`r a t e o b s e r v e d h e r e .
`E f f e c t of Drua Particle Size
`
`T h e p a r t i c l e s i z e r a n g e of a d r u g o v e r w h i c h E q n . 2
`
`a p p l i e s a l s o n e e d s e l u c i d a t i n g .
`
`F o r d e t a 1 . 3 p r e v i o u s l y
`
`i n d i c a t e d t h a t a s t h e p a r t i c l e s i z e o f p r o m e t h a z i n e
`h y d r o c h l o r i d e was i n c r e a s e d from 4 5 - 6 3 pm
`
`t o 5 0 0 - 7 5 0 p m ,
`
`o n l y a c o r r e s p o n d i n g 1 2 % i n c r e a s e i n d i s s o l u t i o n r a t e
`
`was a c h i e v e d from 4 . 6 2 t o 5 . 1 8 % m i n - l .
`T h e d a t a u s e d f o r
`T a b l e 3 were t a k e n from t h e 2 5 0 - 5 0 0 p m r a n g e of
`p r o m e t h a z i n e b u t from t h e 1 2 5 - 1 8 0 pm
`r a n g e of b o t h
`
`a m i n o p h y l l i n e a n d p r o p r a n o l o l . H o w e v e r , t h e d i f f e r e n c e
`i n r e s u l t s b e t w e e n t h e 1 2 5 - 1 8 0 a n d 2 5 0 - 5 0 0 pm
`
`r a n g e s f o r
`
`p r o m e t h a z i n e w a s o n l y 3 . 5 % a n d t h e r e f o r e t h e s e
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 12/25
`
`

`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`987
`
`TABLE 4
`The Influence of Aminophylline Particle Size on the Release
`Rates of Aminophylline from Tablets Containing 225 mg
`Aminophylline and 45 or 180 mg HPMC K15M
`Aminophylline
`Wt. of HPMC K15M
`
`Particle Size ( p m )
`
`63-90
`125-180
`180-250
`
`45mg
`ReleaselRates
`( % min-2)
`
`8.88
`9.12
`9.75
`
`180 rng
`
`5.26
`4.93
`5.05
`
`TABLE 5
`The Influence of Propranolol Hydrochloride Particle Size on
`the Release Rates of Propranolol from Tablets Containing
`160mg Propranolol Hydrochloride and 57 or 285mg HPMC K15M
`
`Propranolol Hydrochloride
`r-'
`Particle Size ( m )
`
`63-90
`90-125
`125-180
`180-250
`250-500
`
`Wt. of HPMC K15M
`
`5 7 rng
`Release,Rates
`( % rnin-*)
`7.83
`7.52
`6.49
`7.98
`28.30
`
`285 m g
`
`3 - 6 3
`3.77
`3.64
`3.80
`3.98
`
`differences have been considered as rnarglnal and would
`
`not affect Table 3 or Eqn. 2.
`
`The influence of particle size on the drug release
`
`rate is indicated by Tables 4 and 5. It is evident that
`
`for both aminophylline and propranolol, an increase in
`
`particle size alters little the release rate of drug. In
`
`fact i t is only at the low drug:HPMC ratio, and at the
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 13/25
`
`

`

`988
`
`HOGAN
`
`largest particle size that any noticeable effect is seen.
`
`This is only because the matrix was presumably very loose
`
`rm
`
`and tended to disintegrate (especially for the 250-500
`
`range of propranolol) during release studies. These data
`
`therefore tend to indicate that Eqn. 2 would be valid
`
`over a wide drug particle size range, i.e. 63-250 p m and
`
`only become invalid in matrices containing low levels
`
`of HPMC with a large particle size of drug. In this
`
`case, rapid solution of the water-soluble drug would
`
`leave a matrix with a low tortuosity and high porosity.
`
`Further Investigations into the Kicetics of Crug Kelease
`The kinetics of drug release from matrices were
`8
`examined for both freely soluble (Higuchi and
`9
`poorly water-soluble drugs (Higuchi and
`
`mathematical models have been developed to allow for the
`
`temperatures on release (Peppas''
`
`influences of hydration, swelling and glass transition
`.
`; Lee''
`Korsmeyer et a1 .12 derived a simple relationship
`
`(Eqn. 5 ) which may be used to describe drug release from
`
`polymeric systems in which release deviates from Fickian
`
`diffusion and follows a non-Fickian (anomalous)
`
`behaviour.
`
`n
`= k.t
`
`M
`t
`-
`M G O
`
`Equation 5
`
`where Mt/Mdis the fractional release of the drug, t is
`
`Mylan v. Qualicaps, IPR2017-00203
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`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`989
`
`the release time, k is a constant incorporating
`
`structural and geometric characteristic of the release
`
`device and n is the release exponent indicative of the
`
`mechanism of release.
`
`For instance n = 0.5 for Jtime
`kinetics and n = 1.0 for zero-order release.
`Alternatively:
`
`M t
`= log k + n.log t
`log -
`M,
`
`Equation 6
`
`Table 6 gives the values of n obtained by regression
`13
`analysis for each of the tablet formulations. Peppas
`
`used values of M /Ma of c O . 6 for data analysis whilst
`t
`Korsmeyer et al.
`
`showed that data of Mt/M& of 40.15 were
`
`non-linear.
`
`Data with range Mt/Moo = 9 . 0 5 - 0 . 7 0 were found
`to be generally linear (with the exception of
`
`tetracycline) and therefore acceptable for determination
`
`of the exponent n of Eqns. 3 and 4 by linear regression.
`
`Two values for each indomethacin:HPMC ratio are included
`
`corresponding to the range of linearity previously used
`-
`Because the
`and ‘1.
`i n h i m e determinations (Ford et a l .
`&me
`data for tetracycline were not Ilnear, values of n
`
`were determined throughout the data range.
`The derived values of n (Table 6 ) were relatively
`
`invariant for each particular drug system, although for
`
`promethazine and diazepam matrices they appeared
`
`slightly higher at low HPMC content. The values of n
`
`were similar (0.65-0.71) for the highly soluble drugs
`
`Mylan v. Qualicaps, IPR2017-00203
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`
`

`

`J
`
`0.67
`0.64
`0.65
`0.61
`
`n
`
`Theophylline 225 mg
`
`5-16
`5-16
`5-16
`5-16
`
`JI
`
`270
`180
`90
`60
`HPMC
`mg
`
`0.70
`0.77
`0.83
`0.90
`0.91
`
`n *
`
`6-28
`5-28
`6-28
`8-27
`9-27
`
`fi *
`
`0.64
`0.76
`0.81
`0.86
`0.85
`
`n
`
`19-28
`20-28
`20-28
`19-27
`19-27
`
`200
`114.3
`80
`61.5
`50
`HPMC
`mg
`
`Jt
`Diazepam 10 mg
`
`0.82
`1.03
`0.83
`0.92
`
`6-30
`6-24
`5-22
`5-20
`
`h* n*
`
`0.90
`1.07
`0.82
`0.93
`
`n
`
`17-26
`15-25
`13-23
`14-21
`
`200
`61.5
`36
`25.8
`
`0.63
`0.66
`0.67
`0.68
`0.69
`
`4-25
`4-19
`4-16
`4-14
`4-13
`
`JT
`25 mg
`I ndomethacin
`
`HPMC
`mg
`
`hydrochloride 160 mg
`Propranolol
`
`n
`
`h
`
`285
`140
`95
`71
`57
`
`HPMC
`
`mg
`
`0.66
`0.63
`0.64
`0.63
`0.69
`
`n
`
`0.42
`0.46
`0.45
`0.46
`0.46
`
`n*
`
`5-20
`5-16
`5-13
`5-12
`5-11
`
`5-13
`5-13
`5-13
`5-13
`5-13
`
`0.51
`0.52
`0.47
`0.51
`0.53
`
`5-28
`5-28
`5-28
`5-28
`5-28
`
`JI*
`Tetracycline hydrochloride 250 mg
`
`n
`
`h
`
`770
`1 so
`90
`60
`45
`HPMC
`mi?
`
`JI
`225 mg
`~ Aminophylline
`
`270
`180
`90
`60
`45
`HPMC
`mg
`
`0.67
`0.68
`0.68
`0.72
`0.76
`0.75
`
`n
`
`5-18
`5-18
`5-16
`5-14
`4-11
`4-11
`
`160
`120
`50
`40
`25
`20
`HPMC
`mg
`Jr
`-
`hydrochloride 25 mg
`~~ Promethazine
`
`~
`
`from Dissolution Data for 7 Drugs
`The Effect of Drug: Fydroxypropylmethylcellulose Ratio on the Exponent n Derived
`
`0
`9
`9
`
`TABLE 6
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 16/25
`
`

`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`991
`
`promethazine hydrochloride, aminophylline and propranolol
`
`hydrochloride and additionally theophylline ( 0 . 6 4 ) .
`1 3
`Peppas
`stated that diffusional controlled (Fickian)
`
`release from planar surfaces gave a value of n=0.5,
`
`giving the time dependent release of Eqns. 5 and 6.
`
`Higuchi’ derived equation 7 which describes the release
`
`of poorly water soluble drug from the single face of a
`tablet.
`
`where W = amount of drug dissolved in time t , W =dose of
`r
`0
`the drug, ,!?=effective diffusional area, V=effective
`
`volume of the hydrated matrix, C s is the solubility of
`the drug in the release medium,c=porosity of the
`
`hydrated matrix and D =apparent diffusion coefficient of
`
`the drug in the hydrated matrix. However, if the drug
`
`has high aqueous solubility and has dissolved when the
`8
`matrix is hydrated then Eqn. 8 applies (Higuchi 1 -
`
`Equation 8
`
`Eqn. 5 was derived for release from a planar
`
`surface and not from an erodible matrix. Nonetheless the
`
`values in Table 7 for these drugs are close to the
`
`values predicted €or diffusional release.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 17/25
`
`

`

`992
`
`HOGAN
`
`TABLE 7
`Mean Exponent n Values (Eqn.7) an2 Predicted Release
`Rates from Tablets Containing HPllC
`
`Drug
`
`Exponent ) I value
`(number of H P M C : drug
`ranges)
`Prometharine-HCI
`25.2
`0.71 f0.04 (7)
`0.65 ? 0.03 (5)
`Aminophylline
`27.0
`0.45 k0.02 ( 5 )
`Tetracycline-HCI
`10.4
`0.67 rt 0.02 (5)
`23.2
`Propranolol-HCI
`Theophylline
`0.64 f 0.03 (4)
`11.8
`0.82 f0.09 ( 5 )
`Diazepam
`15.4
`0.90f0.10 (4)
`lndomethacin
`6.6
`’ ( r n g [ d r ~ g ] ) m i n - ” ~ (mg[HPMC])-”3 x 100 at
`drug: HPMC ratio.
`
`f-’redicted
`release ‘
`
`1 : 1
`
`The values for the two poorly soluble drugs were
`
`0.82 and 0.9 for diazepam and indomethacin, respectively.
`
`A value of n=l would indicate zero-order release from a
`
`planar surface (Peppas13) but €or spheres and
`
`cylinders a value of-1
`
`may not correspond to zero-
`
`order release due to geometric factors involved in the
`
`mathematical analysis. Thus the values of n obtained for
`
`indomethacin and diazepam merely emphasise that release
`
`€or these drugs is not Fickian-controlled and may
`
`indicate large contributions by tablet erosion to drug
`
`release.
`
`The anomalous behaviour €or tetracycline matrices
`
`with a value of n = 0 . 4 5 emphasises the complexity of
`1 3
`release of this drug. Peppas
`
`did not interpret n
`
`values of < 0 . 5 but stated that such occurrences were an
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 18/25
`
`

`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`993
`
`indication of statistical analysis problems or were due
`
`to diffusion through a polymeric network where diffusion
`
`occurred partially through a swollen matrix and partly
`
`through water-filled pores. It is possible that
`
`tetracycline hydrochloride undergoes a complexation
`
`reaction with HPMC in the gel state in the hydrating
`
`matrix, retarding its release.
`
`E f f e c t o f T a b l e t Shape
`Table 8 summarises the influences of tablet shape
`
`and size on the time release rates of promethazine
`
`hydrochloride tablets compressed to the same weight and
`
`formula. Ford et al. demonstrated that compaction
`
`pressure variations little affected the dissolution rate
`
`from promethazine-HPMC matrix tablets and also that
`
`surface area of the tablet is related to HPMC content
`
`and may influence release rates. Table 8 confirms that
`
`the time release rate is proportional to the surface
`
`J
`
`area of the tablet prior to compression since release
`
`rates decreased as the tablet surface area decreased.
`
`In fact a linear relationship existed between release
`
`rate and surface area. Consequently the results
`
`indicate that for maximum maintenance of controlled
`
`release, tablet matrices should be as near spherical as
`
`possible to produce minimum release rates.
`E f f e c t of HPMC Replacement by D i l u e n t s
`
`Formulation of matrix tablets may require the
`
`addition of excipients to alter the size of the tablet
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 19/25
`
`

`

`4.23
`4.1 3
`4.61
`5.99
`
`(% min-”2)
`Release rates
`
`179.1 & 0.6
`162.4 k 0.8
`197.9 & 0.1
`295.8 + 4.3
`(m2)
`Surface area
`
`890
`1580
`890
`392
`
`(MN.~-~)
`Compaction pressure
`
`0.375
`0.25
`0.375
`0.5
`
`(inches)
`Diameter
`
`Concave
`Flat-face
`Flat-face
`Flat-face
`
`Shape
`
`120mg. and 0.75% Magnesium Stearate
`from Tablets Containing Promethazine Hydrochloride 25mg. HPMC K15M
`The Effect of Tablet Shape on the Dissolution Rates of Promethazine
`
`TABLE 8
`
`9 P
`UY
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 20/25
`
`

`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`995
`
`or to replace a portion of the HPMC to modify drug
`
`release rate. Therefore the effects of partial
`
`replacement of the HPMC by either lactose or calcium
`
`phosphate were examined on release rates. The
`
`dissolution profiles, plotted on a time basis were
`
`.I-
`
`acceptably linear for up to 80% drug release for either
`excipient at each diluent:HPMC level. The calculated
`
`time release rates (Table 9) for the comparative 90-125
`
`/-
`
`p m excipient fractions indicate that virtually no
`
`differences in release rates were observed despite the
`
`solubility differences of the diluents. Only in tablets
`
`containing 10 mg HPMC and 30 mg of lactose or calcium
`
`phosphate were differences between the excipients
`
`apparent when the matrices containing lactose displayed
`
`higher release rates, although no positive deviations in
`
`the release profiles occurred despite the high level of
`
`soluble solids in the matrix ( * 8 5 % ) .
`
`Interestingly the
`
`value of the exponent n (Eqn. 5 ) appeared not to vary
`
`from the range 0 . 6 - 0 . 7 4 indicating probably diffusion-
`
`controlled drug release. These results confirm the
`
`findings of Lapidus and Lordi that replacement of HPMC
`
`by either a soluble or insoluble diluent increased
`
`dissolution rate. Additionally they confirm that only
`at high diluent levels ( ' 5 0 % ) are differences apparent
`
`between soluble and insoluble excipi.ents (Lapidus and
`6
`Lordi ) .
`only large differences were apparent when total soluble
`
`Indeed for chlorpheniramine rnaleate tablets
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 21/25
`
`

`

`E~cipient particle size was 90-125 prn excrp~ 3' 45-63. b. 180-250 and c: 125-180 prn
`
`-
`0 64
`0.74
`0 64
`0.64
`0.67
`0.64
`n
`
`-
`6.10
`5.63
`7.60
`5.97
`4.70
`4.00
`
`160 rng
`
`-
`
`0.70
`0 68
`0.69
`0.74
`0.65
`0.63
`n
`
`-
`7.13
`8.66
`10.60
`7.70
`6.29
`4.99
`
`40 rng
`Lactose
`
`0.64
`-
`0.60
`0.64
`0.63
`0.62
`0.64
`n
`
`5.76
`- -
`5.66
`7.36
`6.07
`4.54
`4.00
`
`160 rng
`
`0.64
`
`0.68
`0.60
`0.73
`0.70
`0.63
`n
`
`40 rng
`Calcium phosphate
`Dissolution rates
`
`h 91
`-
`7 22
`9.57
`7 73
`6 31
`4 99
`
`I (c)
`1
`1 : 1 (b)
`1 : 1 (a)
`1.3
`1:1
`3:1
`1 :o
`HPMC : diluent weight
`Diluent
`HPMC - diluent ratio
`
`Stearate and either 40 or 160mg HPMC: Diluent
`Containing 25mg Promethazine Hydrochloride, 0.75% Magnesium
`on the Dissolution Rate of Promethazine from Matrix Tablets
`The Effect of Diluent Particle Size and Diluent: HPMC Ratio
`
`TABLE 9
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2051 - 22/25
`
`

`

`HYDROXYPROPYLMETHYLCELLULOSE
`
`99 7
`
`solid content was 83% (Lapidus and Lordi').
`
`Additionally
`
`the results contradict the statement of Alderman14 that
`
`as little as 10% insoluble solid such