Polymer Erosion and Drug Release Characterization of Hydroxypropyl

Methylcellulose Matrices
THOMAS D. REYNOLDS,
,
STEVIN H. GEHRKE,

AJAZ S. HUSSAIN,
|
AND LATIF S. SHENOUDA*
,
Contribution from the College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0004.
Received January 6, 1998. Accepted for publication July 7, 1998.
Abstract 0 Polymer erosion of matrices of similarly substituted
hydroxypropyl methylcellulose (HPMC) polymers was examined, and
drug release in terms of diffusion and erosion contributions was
characterized, focusing on matrices containing either polymer alone
or a drug content of 25% level with no added excipients. A novel
approach was utilized to separate diffusional and erosional contributions
to drug release. Diffusional drug release was determined by fitting
release data versus (time)
0.45
, and the drug release due to erosion
was quantified by subtracting the percent predicted for diffusional drug
release from the total drug release at each specific time point. Drug
release resulting from polymer erosion was linear versus time and
was found to be a function of the number average molecular weight
of the polymer. In contrast, diffusional release rates were comparable
for all HPMC grades studied and, thus, were independent of number
average molecular weight of the polymers studied. Under stirring
conditions of 10100 rpm as well as static condition, the detachment
of individual polymer chains at the matrix surface occurred at a faster
rate relative to diffusion away from the matrix surface. The erosion
study indicated that polymer diffusion of the HPMC polymer chains
through the aqueous diffusion layer was the rate-limiting step for
polymer erosion. In general, polymer erosion was found to be inversely
related to the polymer number average molecular weight. A scaling
law was used to relate polymer erosion rate with the respective polymer
number average molecular weight. Similar relationships were obtained
for matrices with and without drug at a stirring rate of 100 rpm.
Introduction
Among the vari ous types of cel l ul ose ether deri vati ves,
hydroxypropyl methyl cel l ul ose (HPMC) pol ymers are most
popul ar i n control l ed rel ease matri ces due to thei r compat-
i bi l i ty wi th numerous drugs.
1
Because HPMC i s water
sol ubl e, water penetrates the matri x hydrati ng the pol ymer
chai ns whi ch eventual l y di sentangl e from the matri x.
Pol ymer chai n di ssol uti on from the matri x surface i nvol ves
two di sti ngui shabl e processes. The fi rst step i nvol ves the
di sentangl ement of i ndi vi dual mol ecul es at the matri x
surface, whi ch depends on the rate of hydrati on. Thi s
occurs at a cri ti cal pol ymer concentrati on, defi ned as the
pol ymer di sentangl ement concentrati on, C
p,di s
.
2-6
Thi s
pol ymer concentrati on depends on the properti es of the
pol ymer and sol vent.
7
The second step i nvol ves the trans-
port of these mol ecul es from the surface across an aqueous
di ffusi on l ayer, adjacent to the matri x, to the bul k sol uti on.
Most publ i shed rel ease data from HPMC matri ces
i ndi cate that the overal l drug rel ease depends on the
vi scosi ty grade of the materi al .
8-10
Rel ease rates, cal cu-
l ated mai nl y as di ffusi on, decrease as vi scosi ty i ncrease.
I t i s of i nterest to a formul ator to exami ne and gai n a better
understandi ng of the rel ease between two vi scosi ty grades.
To our knowl edge, no data have been presented on i nter-
medi ate vi scosi ty grades between 100 and 4000 cps (these
two pol ymers are represented by the commerci al grades
of METHOCEL K100LV Premi um (USP Type 2208, nomi -
nal vi scosi ty of a 2% w/v sol uti on of 100 cps, and number
average mol ecul ar wei ght of approxi matel y 48 kDa) and
K4M Premi um (USP Type 2208, nomi nal vi scosi ty of a 2%
w/v sol uti on of 4000 cps, and number average mol ecul ar
wei ght of approxi matel y 148 kDa). For thi s purpose, an
experi mental grade of HPMC havi ng si mi l ar substi tuti on
as the USP Type 2208 (nomi nal vi scosi ty of a 2% w/v
sol uti on of 700 cps, number average mol ecul ar wei ght of
84 kDa, henceforth desi gnated EXP7) was used.
Several authors
3,6,11
have attempted to model the erosi on
mechani sm of swel l abl e pol ymeri c matri ces. They pre-
sented mathemati cal model s descri bi ng the overal l pol ymer
di ssol uti on process ei ther i n the absence or i n the presence
of drug. Model i ng of both drug di ffusi on and rel ease due
to pol ymer di ssol uti on are i ncl uded i n the model s descri bed
by Lee
6
and Harl and et al .
3
Due to the i mportance of
pol ymer di ssol uti on on drug rel ease from HPMC matri ces,
several researchers have attempted to quanti tati vel y de-
termi ne the degree of surface erosi on of cel l ul ose ether
deri vati ve matri ces. Bonferoni et al .
4
determi ned the
amount of pol ymer erosi on by usi ng the gravi metri c method
for matri ces contai ni ng a bl end of sodi um carboxymethyl -
cel l ul ose and HPMC. I n another erosi on study usi ng the
gravi metri c method, Tahara et al .
12
exami ned the erosi on
of HPMC matri ces contai ni ng l actose. Skoug et al .
13
qual i tati vel y determi ned the rel ati ve contri buti ons of ero-
si on and di ffusi on to overal l drug rel ease from commerci al
sustai ned rel ease (SR) tabl ets measuri ng pol ymer rel ease
i nto di ssol uti on medi a usi ng si ze excl usi on chromatography
and vi scometri c detecti on. Later, Ju et al .
5
used thi s same
techni que to moni tor the pol ymer concentrati on i n aqueous
sol uti on for a seri es of HPMC vi scosi ty grades i n sustai ned
rel ease dosage forms contai ni ng an acti ve i ngredi ent and
l actose. Si nce i t i s general l y recogni zed that drug rel ease
from HPMC matri ces fol l ows two mechani sms, drug di f-
fusi on through the swel l i ng gel l ayer and rel ease by matri x
erosi on of the swol l en l ayer,
1,12-15
therefore, quanti fyi ng
the percent contri buti on of di ffusi on and erosi on to the
overal l drug rel ease i s i mportant. I n addi ti on, bl ends of
HPMC pol ymers have been previ ousl y studi ed by several
authors.
13,16
Franz et al .
16
found a nonl i near rel ati onshi p
between the Hi xson-Crowel l cube root di ssol uti on rate
constant and the ei ghth root of vi scosi ty; however, these
formul ati ons contai ned hi gh l evel s of l actose. Sol ubl e
exci pi ents such as l actose are expected to affect pol ymer
erosi on, si nce there i s competi ti on for water between the
addi ti ves and pol ymer. I t may be desi rabl e to desi gn a
pol ymeri c matri x whi ch al l ows one to control the overal l
* To whom correspondence shoul d be di rected.

Di vi si on of Pharmaceuti cal Sci ences.

Current address: The Dow Chemi cal Company, Mi dl and, MI .

Current address: Department of Chemi cal Engi neeri ng, Kansas

State Uni versi ty, Manhattan, KN.
|
Current address: Di vi si on of Product Qual i ty Research, CDER,
FDA, Rockvi l l e, MD.
1998, American Chemical Society and S0022-3549(98)00004-5 CCC: $15.00 Journal of Pharmaceutical Sciences / 1115
American Pharmaceutical Association Vol. 87, No. 9, September 1998 Published on Web 08/14/1998
rel ease of a drug vi a the appropri ate choi ce of pol ymer
bl end, uti l i zi ng the di fferent erosi on contri buti ons of the
i ndi vi dual pol ymers to produce the desi red overal l drug
rel ease.
The objecti ve of thi s study was to exami ne the pol ymer
erosi on of si mi l arl y substi tuted HPMC pol ymers of di ffer-
ent mol ecul ar wei ghts and to characteri ze the rel ease i n
terms of di ffusi on and erosi on contri buti ons. Two model
drugs were used, namel y, theophyl l i ne and propranol ol
hydrochl ori de, representi ng two drugs of di fferent sol ubi l -
i ty. I n contrast to other studi es that uti l i zed drug, pol ymer,
and exci pi ents,
5,10
thi s study focused on the performance
of HPMC matri ces contai ni ng ei ther pol ymer al one or drug-
pol ymer wi th no addi ti onal i ngredi ents.
Experimental Section
MaterialssCommerci al l y avai l abl e HPMC, donated by Dow
Chemi cal (Mi dl and, MI ), was used as suppl i ed, HPMC USP Type
2208 of two vi scosi ty grades, METHOCEL cel l ul ose ether K100LV
Premi um CR and K4M Premi um CR, and an experi mental ,
vi scosi ty grade of HPMC USP Type 2208, EXP7. The apparent
vi scosi ti es of 2% (w/v) aqueous sol uti ons for these pol ymers were
reported as 109, 4250, and 640 mPas (cps), respecti vel y, based
on the manufacturers certi fi cate of anal ysi s. Propranol ol hydro-
chl ori de from Si gma Chemi cal Co. (St. Loui s, MO) was used as
recei ved, and 100% passed through 120 mesh (l ess than 125 m).
Anhydrous theophyl l i ne from Si gma Chemi cal Co. was mi l l ed and
si eved to a product si ze of 125-177 m.
Preparation of TabletssThe wei ghts of pure pol ymer di sks
were ei ther 400 or 480 mg. The drug/pol ymer rati o was mai n-
tai ned as 1:3 (or 25% acti ve). Propranol ol hydrochl ori de tabl ets
contai ned 120 mg acti ve and theophyl l i ne tabl ets contai ned 100
mg acti ve; thus, the tabl et wei ghts were 480 and 400 mg for
propranol ol hydrochl ori de and theophyl l i ne tabl ets, respecti vel y.
These drug l evel s were sel ected to be dosages comparabl e to
commerci al products. A 0.1% sol uti on of steari c aci d i n acetone
was used as a l ubri cant, whi ch was l i ghtl y appl i ed to the punches
and di e. An amount of mi xture correspondi ng to the respecti ve
tabl et wei ghts were i ndi vi dual l y wei ghed and di rectl y compressed
wi th l i ghtl y l ubri cated 12.7 mm fl at-faced punches and di e usi ng
a Carver Laboratory Press (Fred S. Carver, I nc., Menomonee Fal l s,
WI ) at a compressi on pressure of 35.1 MPa wi th a 10 s dwel l ti me.
Gravimetric Erosion StudiessErosi on studi es were con-
ducted i n 900 mL of dei oni zed, deaerated water equi l i brated at
37 ( 0.5 C i n di ssol uti on vessel s (VK7000, VanKel , Edi son, NJ).
Di sks from al l vi scosi ty grades of HPMC fl oat, thus tabl ets were
i ndi vi dual l y pl aced under a no. 10 mesh screen (7 cm i n di ameter)
to keep the di sks submerged. Data were col l ected at the same
desi gnated ti mes used i n the rel ease studi es. Three new di sks
were used for every desi gnated ti me poi nt. The i ndi vi dual
hydrated di sks were wi thdrawn usi ng a prewei ghed no. 10 mesh
screen (2.5 cm i n di ameter), bl otted once to remove any excess
water on the bottom surface of the screen, pl aced i n a prewei ghed
al umi num pan, and wei ghed on a Mettl er AE240 anal yti cal
bal ance (Mettl er I nstrument Corp., Hi ghtstown, NJ). After wei gh-
i ng, the wetted di sks were dri ed at 105 C i n an oven under
vacuum for a 24 h peri od. The tabl ets were then cool ed i n a
desi ccator over Dri eri te before wei ghi ng. Thi s dryi ng-cool i ng-
wei ghi ng process was repeated unti l an equi l i bri um wei ght was
attai ned. Thi s equi l i bri um wei ght was usual l y reached after the
fi rst dryi ng, but to ensure compl ete dryi ng, the process was
repeated two addi ti onal ti mes. I n the case where agi tati on was
i ncl uded, the modi fi ed USP paddl e eval uated by Shenouda et al .
17
was uti l i zed. A sti rri ng rate of 100 rpm was uti l i zed i n studi es
requi ri ng agi tati on. I t was bel i eved thi s woul d produce a measur-
abl e di fference i n erosi on wi th respect to stati c condi ti on.
Release StudiessModified Paddle MethodsA 7.0 cm i n
di ameter no. 10 mesh stai nl ess steel screen was pl aced i n the
round-bottom di ssol uti on vessel of a USP di ssol uti on apparatus
to prevent the tabl et from fl oati ng to the top and remai n
submerged i n the di ssol uti on medi a. The di ssol uti on studi es were
done by pl aci ng i ndi vi dual tabl ets i n each of 900 mL of dei oni zed
water. The fl asks are kept i n a thermostati cal l y control l ed
ci rcul ati on water bath at 37 ( 0.5 C. Rel ease studi es were
conducted at rotati onal speeds of 0, 10, 25, 50, and 100 rpm usi ng
ei ther the VanderKamp 600 di ssol uti on apparatus or the VK7000
wi th VK8000 automati c sampl er.
SamplingProceduresSampl es of 10 mL were wi thdrawn at 0.5,
1, 2, 3, 4, 6, 8, 10, and 12 h, fol l owed by repl eni shment after each
wi thdrawal wi th the same vol ume of fresh dei oni zed water
equi l i brated at 37 ( 0.5 C. I n the study i nvol vi ng di fferent
agi tati ons, prel i mi nary experi ments di ctated sampl e wi thdrawal
every 10 mi n up to 1.5 h. Sampl es were appropri atel y fi l tered,
di l uted when necessary, and anal yzed by UV spectrophotometry
(Vari an DMS 100) at max ) 288 nm and max ) 269 nm for
propranol ol hydrochl ori de and theophyl l i ne, respecti vel y.
Results and Discussion
Polymer ErosionwithPolymer MatricesOnlysThe
basi c mass transfer rel ati onshi p rel ates fl ux to concentra-
ti on di fference,
18
as shown i n eq 1,
where J i s the fl ux of the transferri ng mass at the i nterface,
C
s
and C
b
are the concentrati ons at the i nterface and i n
the bul k sol uti on, respecti vel y, and k i s a mass transfer
coeffi ci ent. Under si nk condi ti on duri ng di ssol uti on test-
i ng, the bul k sol uti on concentrati on i s consi dered negl i gi bl e
rel ati ve to the i nterface concentrati on, whi ch i n the case
of a di ssol vi ng pol ymeri c matri x, i s consi dered to be equal
to the di sentangl ement concentrati on, C
p,di s
. Therefore,
substi tuti ng C
p,di s
i n eq 1 for C
s
, eq 2 resul ts whi ch descri bes
the erosi on from a pol ymeri c matri x.
The functi onal form of the mass transfer coeffi ci ent, k,
depends on whether the system i s under free or forced
convecti on condi ti ons. The dri vi ng force for mass transfer
i s the val ue of the di sentangl ement concentrati on. I n
general , hi gher mol ecul ar wei ght pol ymers have l ower
di sentangl ement concentrati on val ues, whi l e l ower mol ec-
ul ar wei ght pol ymer have hi gher di sentangl ement concen-
trati ons. I n any reacti on that i nvol ves consecuti ve stages,
the overal l rate of mass transport wi l l be determi ned by
the sl owest step. I n the case where pol ymer di sentangl e-
ment occurs at a faster rate rel ati ve to transport of pol ymer
chai ns away from the matri x surface, the rate-l i mi ti ng step
i s the mass transfer process to the bul k sol uti on. I n
unsti rred condi ti ons, mass transfer can produce densi ty
gradi ents that resul t i n fl ui d fl ow, often referred to as free
convecti on.
18
I n sti rred condi ti ons, eq 2 sti l l appl i es;
however, the functi onal form of the mass transfer coef-
fi ci ent wi l l be di fferent. Ju et al .
5
model ed HPMC rel ease
as a resul t of pol ymer rel ease and i ts subsequent di ffusi on
through the boundary l ayer to the bul k sol uti on. Levi ch
19
expressed the mass transfer rate or fl ux as a functi on of
the di ffusi on coeffi ci ent, the sol uti on ki nemati c vi scosi ty,
the bul k sol uti on vel oci ty, and concentrati on di fference.
Accordi ngl y, Ju et al .
5
arri ved at an equati on si mi l ar to
that of Levi ch by usi ng an average di ffusi on coeffi ci ent and
di sentangl ement concentrati on, C
p,di s
, as shown i n eq 3.
where (f
p
D
p
2/3

-1/6

1/2
) represents the mass transfer coef-
fi ci ent under forced convecti on, f
p
i s a constant that vari es
wi th experi mental setti ngs, D
p
i s the average di ffusi on
coeffi ci ent, i s the sol vent ki nemati c vi scosi ty, and i s
the rotati onal vel oci ty repl aci ng the bul k fl ui d vel oci ty, u
b
,
when a rotati ng mechani sm i s used to create fl ow. I t
J ) k(C
s
- C
b
) (1)
J
p
) kC
p,di s
(2)
J
p
) (f
p
D
p
2/3

-1/6

1/2
)C
p,di s
(3)
1116 / Journal of Pharmaceutical Sciences
Vol. 87, No. 9, September 1998
shoul d be emphasi zed that the mass transfer coeffi ci ent i s
di fferent under sti rred and unsti rred condi ti ons.
The erosi on profi l es for LV, EXP7, and 4M matri ces
under stati c condi ti on and 100 rpm agi tati on are depi cted
i n Fi gures 1 and 2, respecti vel y. Under stati c condi ti on,
the pol ymer erosi on rates are constant up to 30%pol ymer
erosi on and are equal to 2.69, 1.06, and 0.49% h
-1
for LV,
EXP7, and 4M, respecti vel y. At 100 rpm agi tati on, the
pol ymer erosi on rates are constant up to 80% pol ymer
erosi on and are equal to 6.75, 3.55, and 2.11% h
-1
for LV,
EXP7, and 4M, respecti vel y. These resul ts show that the
rate of pol ymer erosi on i ncreases wi th a decrease i n
mol ecul ar wei ght.
I n an attempt to rel ate pol ymer erosi on to a pol ymer
i ntri nsi c property uti l i zi ng eq 3, Ju et al .
5
surmi sed that
the average di ffusi on coeffi ci ent and di sentangl ement
concentrati on were the onl y vari abl es that rel ated to the
matri x composi ti on. They devel oped a scal i ng l aw that
rel ated pol ymer erosi on to mol ecul ar wei ght based on the
depi cted mass transfer equati on for forced convecti on (eq
3). The two i ntri nsi c factors i n thi s equati on are D
p
and
C
p,di s
. They further reported that the average di ffusi on
coeffi ci ent and di sentangl ement concentrati on are both
i nversel y proporti onal to HPMC mol ecul ar wei ght, and
establ i shed a scal i ng l aw based on onl y these two vari abl es.
Si nce the pl ots of pol ymer erosi on are l i near versus ti me
(Fi gures 1 and 2), and rather than usi ng fracti onal rel ease
as previ ousl y used by Ju et al .,
5
the fol l owi ng power-l aw
rel ati onshi p was uti l i zed i n thi s study to rel ate pol ymer
erosi on rate, i nstead of fl ux, to number average mol ecul ar
wei ght.
where ER i s the erosi on rate. Usi ng a l og-l og pl ot wi th
the rati o of two pol ymers for pol ymer erosi on rates versus
the rati o of the correspondi ng pol ymer number average
mol ecul ar wei ght, the val ue of a i s determi ned from the
sl ope. Fi gure 3 i s an exampl e of such a pl ot under stati c
condi ti on. A val ue of a of -1.46 i s used as the exponent
for pl otti ng these data i n Fi gure 4. I n one study usi ng a
mi xture of 4M and LV at a 3:1 rati o, respecti vel y, the
pol ymer erosi on rate for that mi xture i s al so shown i n
Fi gure 4. The number-average mol ecul ar wei ght for thi s
bl end of pol ymers was cal cul ated usi ng the fol l owi ng
general expressi on.
where Mh
n
i s the number-average mol ecul ar wei ght, w
i
i s
the wei ght fracti on of the ith monodi sperse fracti on, and
M
i
i s the homogeneous mol ecul ar wei ght. The experi men-
tal val ue of the erosi on rate i s wi thi n 10% of the predi cted
val ue obtai ned from the strai ght l i ne. Thi s approach shows
a l i mi ted demonstrati on of the versati l i ty of the scal i ng-
l aw and suggests i ts potenti al useful ness i n predi cti ng
pol ymer erosi on from vari ous mi xtures of HPMC rangi ng
from LV to 4M.
The data of pure pol ymer erosi on at 100 rpm were
treated i n the same manner as those obtai ned under stati c
condi ti on. A si mi l ar pl ot to Fi gure 3 was obtai ned and a
val ue of a was cal cul ated from the sl ope. Thi s val ue i s
equal to -0.993 and taken as -1.0. A pl ot of erosi on rate
Figure 1s% Polymer eroded versus time for (a) LV, (b) EXP7, and (c) 4M
matrices under static condition in deionized water.
Figure 2s% Polymer eroded versus time for (a) LV, (b) EXP7, and (c) 4M
matrices at 100 rpm agitation in deionized water.
Figure 3sln(Erosion rate ratio) versus ln(number average molecular weight
ratio) for LV, EXP7, and 4M matrices under static conditions. ER1 and ER2,
MWn,1, and MWn,2 represent the erosion rates (ER) of various polymers with
their corresponding number average molecular weights (MWn). Subscripts 1
and 2 correspond to any two polymers of known molecular weights.
ER M
n
-a
(4)
Mh
n
)
1

w
i
/M
i
(5)
Journal of Pharmaceutical Sciences / 1117
Vol. 87, No. 9, September 1998
versus the reci procal of the average number mol ecul ar
wei ght i s l i near as shown i n Fi gure 5 for the three pol ymers
at 100 rpm.
Under si nk condi ti ons, the erosi on rate i s constant
accordi ng to eq 2 si nce C
p,di s
i s constant for the respecti ve
pol ymer grades. I t i s bel i eved that pol ymer di ssol uti on i s
mass transfer l i mi ted. The presence of agi tati on decreases
the aqueous di ffusi on l ayer thi ckness and, thus, resul ts i n
an i ncrease i n the mass transport from the matri x surface,
whi ch i s consi stent wi th the rel ati onshi p between J
p
and
depi cted i n eq 3. Si nce pol ymer erosi on i s mass transfer
l i mi ted i n the presence of sti rri ng, the same l i mi ti ng
condi ti on wi l l exi st i n the absence of sti rri ng. I n fact,
pol ymer erosi on remai ned l i near over ti me under stati c
condi ti on, suggesti ng that pol ymer chai n di sentangl ement
does not pl ay a l i mi ti ng rol e i n ei ther free or forced
convecti on pol ymer di ssol uti on. However, chai n di sen-
tangl ement concentrati on i s cri ti cal i n establ i shi ng the
dri vi ng force for mass transfer. I t has been reported
5
that
the di sentangl ement concentrati on of a pol ymer fol l ows a
nonl i near, i nverse rel ati onshi p wi th mol ecul ar wei ght.
Therefore, reduci ng the mol ecul ar wei ght of the pol ymer
makes the matri x erode faster because thi s i ncreases the
di sentangl ement concentrati on.
Polymer ErosionwithDrugintheMatrixsPol ymer
erosi on studi es were conducted to exami ne the effect of
drugs i n the matri x. The pol ymer erosi on profi l es versus
ti me for theophyl l i ne and propranol ol hydrochl ori de ma-
tri ces of LV, EXP7, and 4M at 100 rpm agi tati on are
summari zed i n Tabl e 1. As was the case i n matri ces
wi thout drug, the pol ymer erosi on resul ts are l i near versus
ti me for theophyl l i ne and propranol ol hydrochl ori de ma-
tri ces of EXP7 and 4M. The erosi on profi l es for LV
matri ces contai ni ng theophyl l i ne and propranol ol hydro-
chl ori de are i ni ti al l y l i near. The sl ope of the l i near porti on
i s used to quanti fy the erosi on rate of LV matri ces, as
shown i n Tabl e 1, and the ti me peri od for fi tti ng i s shorter
for THLV and PRLV due to negati ve devi ati on from
l i neari ty at l ater ti mes. The erosi on rate data i ndi cates
that the presence of drug i n the matri ces si gni fi cantl y
affects pol ymer erosi on. Thi s i s possi bl y due to l ower
pol ymer concentrati ons i n the matri x resul ti ng i n fewer
pol ymer-pol ymer entangl ements.
The respecti ve val ues of a from eq 4 for the theophyl l i ne
and propranol ol hydrochl ori de matri xes were obtai ned i n
a si mi l ar fashi on as done wi th matri xes contai ni ng no drug.
The data gave val ues of -0.97 and -1.04 for theophyl l i ne
and propranol ol hydrochl ori de matri ces, respecti vel y, and
were taken as equal to -1.0. Accordi ngl y, the pol ymer
erosi on rate was pl otted versus the reci procal of the
mol ecul ar wei ght al so shown i n Fi gure 5. Agai n pol ymer
erosi on rate fol l ows an i nverse rel ati onshi p to pol ymer
mol ecul ar wei ght, as previ ousl y observed wi th the same
pol ymers contai ni ng no drug at 100 rpm.
The sl opes of these pl ots are si mi l ar, 4.6 10
5
for
theophyl l i ne matri ces versus 4.23 10
5
for propranol ol
Table 1sStatistical Parameters for Polymer Erosion and Drug Release from LV, EXP7, and 4M Matrices
a
parameters from linear fits versus time
polymer type active in matrix
b
time period (h) % drug dissolved after 12 h erosion rate (% h
-1
) correlation coefficient
LV 0.512.0 6.75 0.9990
EXP7 0.512.0 3.55 0.9984
4M 0.512.0 2.11 0.9983
LV theophylline 0.56.0 97.3 (1.9) 10.28 0.9995
EXP7 theophylline 0.512.0 89.7 (4.1) 5.26 0.9993
4M theophylline 0.512.0 79.6 (2.3) 3.36 0.9980
LV propranolol hydrochloride 0.58.0 95.4 (4.6) 9.13 0.9959
EXP7 propranolol hydrochloride 0.512.0 89.5 (2.6) 4.72 0.9959
4M propranolol hydrochloride 0.512.0 83.6 ( 2.8) 2.71 0.9991
a
Numbers in parentheses represent one standard deviation.
b
Level of active in matrix was 25%.
Figure 4sPolymer erosion rate versus (number average molecular weight)
-1.46
for LV, EXP7, and 4M matrices and a mixture of LV and 4M (1:3) under
static conditions in deionized water.
Figure 5sPolymer erosion rate versus (number average molecular weight)
-1.0
for matrices containing LV, EXP7, and 4M alone and matrixes containing either
theophylline or propranolol hydrochloride at 100 rpm agitation in deionized
water.
1118 / Journal of Pharmaceutical Sciences
Vol. 87, No. 9, September 1998
hydrochl ori de matri ces. Al though the sol ubi l i ty of propra-
nol ol hydrochl ori de i s approxi matel y fi ve ti mes that of
theophyl l i ne, the sl ope obtai ned from the l atter di d not
show a si gni fi cant effect of sol ubi l i ty on the rel ati onshi p
between pol ymer erosi on rate and the reci procal of the
number average mol ecul ar wei ght. Pl ots of pol ymer ero-
si on rate versus the reci procal of mol ecul ar wei ght are
potenti al l y val uabl e i n predi cti ng the erosi on characteri s-
ti cs of matri ces contai ni ng a drug i n a pol ymer wi th a
number-average mol ecul ar wei ght val ue between those of
LV and 4M or a mi xture of these two pol ymers as was
observed under stati c condi ti on.
Drug Release Studies in Deionized Water from
HPMC MatricessDrug rel ease from HPMC matri ces
fol l ows two mechani sms, di ffusi on through the swel l i ng gel
l ayer and rel ease by matri x erosi on of the swol l en gel l ayer.
Most pharmaceuti cal l i terature rel ease data from HPMC
matri ces are pl otted as cumul ati ve percent drug rel ease
versus the square root of ti me yi el di ng a strai ght l i ne wi th
a negati ve i ntercept.
8,9,14
HPMC matri ces swel l and even-
tual l y erode, provi di ng an addi ti onal erosi onal component
to the overal l drug rel ease.
I ni ti al l y drug rel ease from HPMC matri ces occur vi a a
di ffusi on process unti l the outer gel l ayer reaches i ts cri ti cal
di sentangl ement concentrati on, and the addi ti onal rel ease
component due to erosi on i s mani fested. To exami ne the
di fferences i n the rel ease performance of the pol ymers
uti l i zed i n thi s study, a mathemati cal di ffusi onal model was
sel ected to cal cul ate the di ffusi onal rel ease. Descri bi ng
rel ease from cyl i ndri cal di sks as a functi on of square root
ti me i s not appropri ate. The tabl ets, uti l i zed i n thi s study,
have an average aspect rati o of 3.2, thus fal l i ng i n the
nonmonotoni c porti on representi ng three-di mensi onal di f-
fusi on descri bed i n the l i terature.
20
I n thi s study, i t i s
hypothesi zed that the i ni ti al drug rel ease fol l ows (ti me)
0.45
;
i f a strai ght l i ne exi sts for a peri od of ti me, i t i s assumed
that di ffusi on i s the predomi nant mechani sm for that
speci fi c ti me i nterval . Thi s procedure al l owed the cal cul a-
ti on of di ffusi onal drug rel ease for conducti ng comparati ve
anal ysi s between di fferent pol ymers and drugs. Quanti -
tati on of erosi onal drug rel ease was determi ned by taki ng
the di fference between the overal l drug rel ease and that
cal cul ated on the basi s of di ffusi on equati on.
Diffusional DrugReleasesThe data obtai ned from the
rel ease studi es were fi tted usi ng a BASI C l east squares
program. The correl ati on coeffi ci ent (r g 0.999) and mean
resi dual sum of squares were the cri teri a used to deci de
the ti me peri od that fol l owed the fol l owi ng equati on.
Further, the mean wei ghted resi dual s were pl otted
versus ti me to check for randomness. The ti me peri od
sel ected for the best fi t was chosen as to have maxi mum
scatter i n the wei ghted resi dual pl ot. The rate of rel ease,
or sl ope, and y-i ntercept were cal cul ated from the model
fi tti ng for i ndi vi dual tabl ets, and the average and the
standard devi ati on val ues were computed. The overal l
correl ati on coeffi ci ent was computed by fi tti ng the mean
rel ease val ues to (ti me)
0.45
.
A compari son of the theophyl l i ne rel ease data i n Tabl e
2 i ndi cates that the rel ease rates wi thi n a parti cul ar
Table 2sDiffusion Rates for Theophylline Release Fit to (time)
0.45
for
LV, EXP7, and 4M Matrices
a
rpm
THLV slope
(% h
-0.45
)
THEXP7 slope
(% h
-0.45
)
TH4M slope
(% h
-0.45
)
0 24.19 (1.97) 21.91 (0.59) 22.69 (0.89)
10 24.06 (0.69) 23.14 (0.46) 21.77 (0.77)
25 24.74 (0.83) 24.62 (0.95) 23.69 (0.44)
50 23.16 (1.37) 24.53 (0.95) 24.77 (0.73)
100 25.02 (3.02) 25.07 (1.09) 23.20 ( 0.69)
a
Numbers in parentheses represent one standard deviation.
Table 3sDiffusion Rates for Propranolol Hydrochloride Release fit to
(time)
0.45
for LV, EXP7, and 4M Matrices
a
rpm
PRLV slope
(% h
-0.45
)
PREXP7 slope
(% h
-0.45
)
PR4M slope
(% h
-0.45
)
0 30.99 (2.30) 30.79 (1.77) 28.73 (1.84)
10 29.92 (0.92) 26.75 (2.40) 27.14 (0.49)
25 29.01 (0.88) 28.73 (1.49) 30.62 (1.38)
50 27.67 (0.70) 30.33 (0.88) 29.56 (1.18)
100 29.89 (0.94) 29.41 (1.10) 29.07 (0.73)
a
Numbers in parentheses represent one standard deviation.
Figure 6s% Release versus time
0.45
under static conditions for (a) THLV, (b)
THEXP7, and (c) TH4M matrices in deionized water.
%rel ease )
(
M
t
M

)
100 ) kt
0.45
- b (6)
Journal of Pharmaceutical Sciences / 1119
Vol. 87, No. 9, September 1998
pol ymer grade are si mi l ar for the di fferent sti rri ng rates
and al so are comparabl e between the di fferent pol ymer
grades. The overal l si mi l ari ty of the rel ease rates suggests
that the di ffusi onal rel ease rates are i ndependent of
external sti rri ng condi ti ons and pol ymer mol ecul ar wei ght
for the grades used i n thi s study. I t appears that di ffusi on
of the drug through the swol l en pol ymer matri x i s the
control l i ng factor. The rel ease rates from propranol ol
hydrochl ori de matri ces are shown i n Tabl e 3. The data
i l l ustrate si mi l ar patterns as those observed wi th theo-
phyl l i ne matri ces.
The rel ease profi l es for theophyl l i ne and propranol ol
hydrochl ori de matri ces versus (ti me)
0.45
are depi cted i n
Fi gures 6 and 7 for stati c condi ti on, and Fi gures 8 and 9
at 100 rpm agi tati on, respecti vel y. The i ni ti al nonl i near
rel ease i s i ndi cati ve of a surface effect. Thi s occurs as a
resul t of bl ocki ng of surface pores due to hydrati on and
swel l i ng. The l atter l eads to resi stance to sol vent i nfl ux.
For theophyl l i ne and propranol ol hydrochl ori de matri ces,
an i ncrease i n the sti rri ng rate l ed to an earl i er occurrence
of l i neari ty accordi ng to eq 6. Thi s was fol l owed by posi ti ve
devi ati on from l i neari ty due to si gni fi cant drug rel ease
resul ti ng from pol ymer erosi on. Thi s devi ati on from
l i neari ty has been previ ousl y observed.
14,21,22
I n the present
study, drug rel ease due to erosi on i s quanti tati vel y ana-
l yzed.
Erosional Drug ReleasesSi nce erosi onal drug rel ease
occurs as a resul t of pol ymer erosi on, i t i s not surpri si ng
that the pl ots of erosi onal drug rel ease are al so l i near
versus ti me for the vari ous sti rri ng rates for al l pol ymers.
The erosi onal drug rel ease for THLV and PRLV are
depi cted i n Fi gures 10 and 11, respecti vel y. Li near ero-
si onal drug rel ease suggests that there i s a constant
amount of drug present i n the erodi ng pol ymer duri ng
speci fi ed ti me i nterval s. These resul ts al so i ndi cate that
the erosi onal component of overal l rel ease i ncreases wi th
an i ncrease i n sti rri ng rate. Thi s rel ati onshi p i s further
Figure 7s% Release versus time
0.45
under static conditions for (a) PRLV,
(b) PREXP7, and (c) PR4M matrices in deionized water.
Figure 8s% Release versus time
0.45
at 100 rpm agitation for (a) THLV, (b)
THEXP7, and (c) TH4M matrices in deionized water.
1120 / Journal of Pharmaceutical Sciences
Vol. 87, No. 9, September 1998
substanti ated by uti l i zi ng eq 3 to rel ate erosi onal drug
rel ease rates wi th the square root of sti rri ng rate. Fi gure
12 depi cts the erosi onal drug rel ease rate for theophyl l i ne
and propranol ol hydrochl ori de i n LV matri ces. I t i s
evi dent, from Fi gure 12, that under these forced convecti on
condi ti ons, the l i near rel ati onshi p exi sts between these two
vari abl es. However, under stati c condi ti on, pol ymer ero-
si on rate occurs by natural convecti on from l ocal densi ty
di fferences that exi st at the matri x surface, and erosi onal
drug rel ease does not fol l ow the same rel ati onshi p under
stati c condi ti on rel ati ve to sti rred condi ti ons due to di ffer-
ences i n the magni tude of the mass transfer coeffi ci ent (eq
1). Fi nal l y, i t was observed that the rate of erosi onal drug
rel ease i s i ndependent of sti rri ng for 4M at the studi ed
sti rri ng condi ti ons, suggesti ng that a di fferent rate-l i mi ti ng
step, such as pol ymer hydrati on and/or pol ymer chai n
di sentangl ement, exi sts for erosi onal drug rel ease of hi gher
mol ecul ar wei ght pol ymers.
Figure 10s% Erosional drug release versus time for THLV matrices at (a)
100, (b) 50, (c) 25, (d) 10, and (e) 0 rpm agitation in deionized water.
Figure 11s% Erosional drug release versus time for PRLV matrices at (a)
100, (b) 50, (c) 25, and (d) 10 rpm agitation in deionized water.
Figure 12sRate of erosional drug release versus (rpm)
1/2
agitation for THLV
and PRLV matrices in deionized water.
Figure 9s% Release versus time
0.45
at 100 rpm agitation for (a) PRLV, (b)
PREXP7, and (c) PR4M matrices in deionized water.
Journal of Pharmaceutical Sciences / 1121
Vol. 87, No. 9, September 1998
Si nce pol ymer erosi on rate di rectl y affects erosi onal drug
rel ease from HPMC matri ces, the scal i ng l aw previ ousl y
uti l i zed was used to rel ate erosi onal drug rel ease rates and
the pol ymer number average mol ecul ar wei ght. As seen
i n Fi gures 13 and 14, the rates of erosi onal drug rel ease
are l i near versus the reci procal of pol ymer mol ecul ar
wei ght for theophyl l i ne at 25, 50, and 100 rpm sti rri ng,
and propranol ol hydrochl ori de at 100 rpm agi tati on, re-
specti vel y. The potenti al uti l i ty of thi s rel ati on i s i n
esti mati ng the erosi onal drug rel ease for vari ous pol ymers
i n the regi on between LV and 4M. However, the l i mi tati on
of thi s method i s that a mi ni mum sti rri ng rate may exi st
for a speci fi c drug bel ow whi ch a l i mi ti ng erosi onal drug
rel ease rate persi sts. Thi s was the case for propranol ol
hydrochl ori de i n EXP7 and 4M matri ces bel ow 100 rpm
sti rri ng.
Drug rel ease as a resul t of pol ymer erosi on i s a l i near
functi on of ti me and the dependency of drug rel ease rates
(resul ti ng from erosi on) i s l i near versus (rpm)
0.5
l end strong
evi dence i n support of the presented hypothesi s and the
appropri ateness of anal ysi s of data presented i n the previ -
ous secti ons. Al though pol ymer erosi on i s si gni fi cant for
l ow mol ecul ar wei ght pol ymers, i ts contri buti on to drug
rel ease can be descri bed as modest at best. The data
anal ysi s presented here casts some doubt on the fi tti ng of
rel ease data to a di ffusi on model onl y. Drug rel ease due
to pol ymer erosi on shoul d be quanti fi ed. The anal yti cal
approach presented here may serve as a means for sepa-
rati ng di ffusi on and erosi on whi ch substi tutes for the
nomencl ature of anomal ous behavi or. I n concl usi on, the
mathemati cal anal ysi s of data presented together wi th the
uti l i zati on of the scal i ng l aws di scussed provi de a formul a-
tor an opportuni ty to predi ct the degree of pol ymer erosi on
for other i ntermedi ate pol ymer grades and/or mi xtures of
the pol ymers uti l i zed i n thi s study.
References and Notes
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Pharm. Technol. Prod. Mfr. 1984, 5, 1-9.
2. Brochard, F.; de Gennes, P. G. Ki neti cs of pol ymer di ssol u-
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Peppas, N. A. Drug/pol ymer matri x swel l i ng and di ssol uti on.
Pharm. Res. 1988, 5, 488-494.
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hydrophi l i c matri ces. 1. New scal i ng l aws for predi cti ng
pol ymer and drug rel ease based on the pol ymer di sentangl e-
ment concentrati on and the di ffusi on l ayer. J . Pharm. Sci.
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Figure 13s% Erosional drug release versus (MWn)
-1.0
for THLV (series of
points on extreme right), THEXP7 (series of points in middle), and TH4M
(series of points on extreme left) matrices at (a) 100 rpm, (b) 50 rpm, and (c)
25 rpm agitation in deionized water.
Figure 14s% Erosional drug release versus (MWn)
-1.0
for PRLV (series of
points on extreme right), PREXP7 (series of points in middle), and PR4M
(series of points on extreme left) matrices at (a) 100 rpm, (b) 50 rpm, and (c)
25 rpm agitation in deionized water.
1122 / Journal of Pharmaceutical Sciences
Vol. 87, No. 9, September 1998
16. Franz, R. M.; Sytsma, J. A.; Smi th, B. P.; Luci sano, L. J. I n
vi tro eval uati on of a mi xed pol ymeri c sustai ned rel ease
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21. Lapi dus, H.; Lordi , N. G. Some factors affecti ng the rel ease
of a water-sol ubl e drug from a compressed hydrophi l i c
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Acknowledgments
Thi s research was supported, i n part, by the Dow Chemi cal
Company and a two-year Predoctoral Fel l owshi p (T.D.R.) from the
Ameri can Foundati on for Pharmaceuti cal Educati on.
JS980004Q
Journal of Pharmaceutical Sciences / 1123
Vol. 87, No. 9, September 1998