Monolithic tablet for controlled drug release

A swellable hydrophillic matrix tablet that delivers drugs in a controlled manner over a long period of time and is easy to manufacture. More specifically, the drug is disposed in a matrix composed of HPMC or polyethylene oxide, in the presence of a salt, which may be a combination of salts. Suitable salts include sodium bicarbonate, sodium chloride, potassium bicarbonate, calcium chloride, sodium bisulfate, sodium sulfite, and magnesium sulfate. Outward diffusion of the drug is controlled by an inwardly progressing hardening reaction between the salt and the dissolution medium, possibly also involving the drug itself.

BACKGROUND OF THE INVENTION 
The present invention pertains to a controlled release dosage form, based 
on a modified hydrophillic matrix composition. 
Controlled release pharmaceutical dosage forms have received much attention 
in recent years and are highly desirable for providing a constant level of 
pharmaceutical agent to a patient over some extended period of time. The 
use of single or multiple unit dosage forms as controlled drug delivery 
devices encompasses a wide range of technologies and includes polymeric as 
well as nonpolymeric excipients. These dosage forms optimize the drug 
input rate into the systemic circulation, improve patient compliance, 
minimize side effects, and maximize drug product efficacy. 
The use of controlled release products is frequently necessary for chronic 
drug administration, such as in the delivery of the calcium-channel 
blockers nifedipine and diltiazem and the beta-adrenergic blocker 
Propranolol in the management of angina and hypertension For delivery 
system design, physiochemical properties and intrinsic characteristics of 
the drug, such as high or low solubility, limited adsorption, or 
presystemic metabolism, may impose specific constraints during product 
development. 
Advancements of extended release drug products have come about by the 
simultaneous convergence of many factors, including the discovery of novel 
polymers, formulation optimization, better understanding of physiological 
and pathological constraints, prohibitive cost of developing new drug 
entities, and the introduction of biopharmaceutics in drug product design. 
One aspect of research about controlled-release delivery systems involves 
designing a system which produces steady-state plasma drug levels, which 
is also referred to as zero-order drug release kinetics. To meet this 
objective, numerous design variations have been attempted, and their major 
controlling mechanisms include diffusion/dissolution, chemical reactions, 
the use of osmotic pump devices, and multiple layer tablet designs, all of 
which incorporate numerous manufacturing steps and many associated drug 
release mechanisms. The complicated processes involved in the manufacture 
of such ultimately contributes to increased costs to the consumer. 
One attractive design for potential zero-order drug release is the use of 
hydrophilic swellable matrices. Drug diffusion from the matrix is 
accomplished by swelling, dissolution and/or erosion. The major component 
of these systems is a hydrophilic polymer. In general, diffusivity is high 
in polymers containing flexible chains and low in crystalline polymers. 
With changes in morphological characteristics, the mobility of the polymer 
segments will change and diffusivity can be controlled. Addition of other 
components, such as a drug, another polymer, soluble or insoluble fillers, 
or solvent, can alter the intermolecular forces, free volume, glass 
transition temperature, and consequently, can alter the transport 
mechanisms. Cost is also a factor in these modified compositions. Still 
better controlled, time dependent drug release from these compositions is 
a continuing objective of research in this area, as is controlled 
diffusivity compositions which are more easily manufactured. Such 
compositions, which are more easily manufacturable, have the potential to 
lower cost of the dosage form. 
SUMMARY OF THE INVENTION 
The present invention is a new monolithic dosage form that delivers 
pharmaceutically active agents in a controlled release manner, and that is 
easy to manufacture. This dosage form, in a form such as a monolithic 
tablet, may approach zero order delivery of drugs which are either of high 
or low solubility. This dosage form or tablet is comprised of a 
hydrophilic swellable matrix, in which is disposed a pharmaceutically 
active agent and a salt The salt, either in combination with the drug or 
another salt upon reaction in an aqueous medium, causes a hardening 
reaction of the matrix. The rate of outward diffusion is controlled by 
exposing the product to an aqueous medium. This in turn causes a hardening 
reaction to occur in a time dependent manner from the outer boundaries 
towards the inner boundaries of the product; the hardened reaction 
product, in turn limits outward diffusion of the drug as the inward 
ingress of aqueous medium causes a progressive hardening from the outer 
boundaries of the dosage form or tablet in a direction towards the inner 
core there.

DETAILED DESCRIPTION OF THE INVENTION 
The invention encompasses formulations for the controlled release, 
preferably zero order release, of bioactive material from a new monolithic 
system. 
These formulations are based on simple swellable hydrodynamically balanced 
monolithic matrix tablet in which may be incorporated a range of 
water-soluble (low to high) bioactive drugs and salts. Extended or zero 
order release is accomplished through the novel application of polymeric 
matrix modification, as detailed below, by incorporating a salt in a 
swellable matrix: 
As a tablet passes through the human digestive tract, it is subjected to pH 
values ranging from 1.5 to 7.4. The saliva of the mouth has a neutral pH, 
the stomach has a pH varying from 2.0-4.0, and the pH of the intestines 
carries a pH between 5.0-7.5. Therefore, it is important to consider the 
effects of this pH range on dissolution of a drug tablet. For a drug to 
approach zero-order release, it's dissolution must be independent of the 
pH in the surrounding environment. 
Through processes of ionic interaction/complexation/molecular and/or self 
association between a drug and a salt or salt/drug combinations, 
homogeneously dispersed in a swellable polymer such as 
hydroxypropylmethylcellulose (HPMC), modify the dynamics of the matrix 
swelling rate and erosion of the swellable polymer, in accordance with 
variations in an external pH environment ranging from 1.5-7.0. 
These interactions result in controlled matrix hardening. Such hardening is 
responsible for the control of polymer erosion/dissolution and drug 
release rates. By design, solvent penetrates the periphery of the tablet 
and a rapid initial interaction between drug and salt embedded in the 
polymeric matrix causes immediate hardening of the outer tablet boundary, 
the rate of hardening consistently decreases toward the center of the 
matrix core in a time-dependent manner over a long period of time (e.g. 24 
hours). 
The effervescent nature of sodium bicarbonate causes a generation of gas 
within the tablet and production of air bubbles. These air bubbles may 
result in floatation of the tablet, which may increase the gastric 
residence time of the tablet and result in a prolonged release of the drug 
in the acidic environment. In addition, this enhances the total mean 
gastrointestinal residence time and allows for increased biavailability. 
This is shown schematically in FIG. 18, where the tablet progresses over 
time from an intact and unswollen state to a floatable matrix which is 
loose and clear. 
The differential rate of matrix hardening is the driving principle in the 
novel system of the present invention, which is dependent on and 
controlled by the rate of liquid ingress to the tablet core. With the 
simultaneous time-dependent decrease in gel layer integrity, the rate of 
drug diffusion decreases. This phenomenon compensates for the increase in 
diffusion path length and decrease in the surface area of the receding 
core which arises from the swelling property of the polymer. Hence, better 
controlled, preferably zero order, drug release is achieved. The drug 
release process can be tailored for up to 24 hours. Control of the changes 
in core hardness and synchronization of the rubbery/swelling front and 
described receding phase boundaries as well as erosion of the dissolution 
front boundary (i.e. erosion of the tablet periphery) results in 
controlled drug release, preferably including zero order kinetics. 
Optionally, polymer matrix hardenings is also easily achievable through 
double salt interaction. This binary salt combination is also uniformly 
dispersed in the polymeric matrix, which through ionic 
interaction/complexation/molecular and/or self association, increases the 
relative strength and rigidity of the matrix, resulting in controlled drug 
release with a similar mechanism to that described above. 
Drugs such as the calcium-channel blockers Diltiazem and Verapamil and the 
beta-adrenergic blocker Propranolol (as the hydrochloride salts), with 
water solubilities of 50, 8 and 5% respectively, have been used in the 
present invention. 
One hydrophilic matrix material useful in the present invention is HPMC 
K4M. This is a nonionic swellable hydrophillic polymer manufactured by 
"The Dow Chemical Company" under the tradename "Methocel". HPMC K4M is 
also abbreviated as HPMC K4MP, in which the "P" refers to premium 
cellulose ether designed for controlled release formulations. The "4" in 
the abbreviation suggests that the polymer has a nominal viscosity (2% in 
water) of 4000. The percent of methoxyl and hydroxypropryl groups are 
19-24 and 7-12, respectively. In its physical form, HPMC K4M is a 
free-flowing, off-white powder with a particle size limitation of 90%&lt;100 
mesh screen. There are other types of HPMC such as K100LVP, K15MP, K100MP, 
E4MP and E10MP CR with nominal viscosities of 100, 1500, 100000, 4000, and 
10000 respectively. 
Formulations of the present invention may also include salts such as sodium 
bisulfate, potassium bicarbonate, magnesium sulfate, calcium chloride, 
sodium chloride, sodium sulfite and sodium carbonate in their 
formulations. FIG. 16 illustrates the use of some of these salts with 
diltiazem hydrochloride. 
It is believed that an interaction between drug and salt forms a complex in 
the surrounding swellable matrix in a layered fashion because it occurs in 
a time-dependent manner as the solvent media for drug release penetrates 
the tablet inwardly. Likewise, because the catalyst for the initiation of 
drug release is liquid ingress, so too is the rate of drug release 
controlled by the inwardly progressive hardening of the salt complex. 
A binary salt system (e.g. calcium chloride and sodium carbonate) may also 
be used, may also be used, in which case the hardening reaction may be a 
function of interaction between the salts. Calcium chloride may be 
incorporated to form a complex with sodium carbonate. With this 
combination, the reaction products are insoluble calcium carbonate and 
soluble channel former, sodium chloride. Hence the calcium carbonate 
embeds itself in the polymer matrix, initiates hardening and slowly 
dissolves with liquid ingress and the subsequent creation of diffusion 
channels as drug diffuses out. In a similar way, other binary salt 
combinations display time-dependent "hardening/de-hardening" behavior. 
The amount of salt to be used may easily be determined, by those skilled in 
the art, taking into consideration the solubility of the drug, the nature 
of the polymer and the required degree of matrix hardening desired. In 
case of diltiazem hydrochloride in a HPMC matrix, 100 mg of sodium 
bicarbonate provides suitable matrix hardening for zero order controlled 
release, while in the case of the same amount of drug in a different 
polymer such as polyethylene oxide, 50 mg of sodium bicarbonate appears to 
be ideal for the attainment of controlled zero order release. 
On the basis of the drug release profiles presented in FIG. 14, the change 
in pH of the dissolution media, from acidic to basic, does not markedly 
change the pattern except for a burst effect at pH.gtoreq.5.4, which is 
not a limiting factor considering the fact that the tablet will not be 
immediately exposed to pH 5.4 in the gastrointestinal tract, and instead 
must first pass through the acidic gastric environment. This has been 
confirmed by subjecting the formulation (A5) to a carefully synchronized 
test of continuous changing pH environment simulating the gastrointestinal 
tract. This has been achieved with the aid of the Bio Dis Release Rate 
Tester (Vankel Instruments). The resulting drug release profile is 
provided in FIG. 17. The addition of salt in the formulation is not used 
as a pH modifying agent. Therefore, the relative salt proportion is 
essentially irrelevant with respect to changes in pH. 
EXAMPLES 
The formulations of the inventions are illustrated by the following 
examples. The use of particular polymers, buffers, and inert additive and 
fillers in the particular amounts shown are not intended to limit the 
scope of this invention but are exemplary only. All ingredients are 
initially individually massed and simultaneously incorporated. The premix 
is blended in a V-blender. The resultant homogeneous powder is compressed 
into tablets using conventional technologies. 
Example 1 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS A1 (ctrl) 
A2 A3 A4 A5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
HPMC K4M 200 200 200 200 200 
Sodium 0 10 50 75 100 
bicarbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
As shown in FIG. 1 the results of this Example reflect a progressive 
decrease in the release of diltiazem hydrochloride with an increase in the 
sodium bicarbonate content within the HPMC matrix. This increase in salt 
content is accompanied by an increase in the linearity of the drug release 
profiles. In particular, formulation A5, which contains 100 mg of sodium 
bicarbonate provides drug release which most closely approaches zero order 
over a 24-hour period. 
Example 2 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS B1 (ctrl) 
B2 B3 B4 B5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
PEO 4M 200 200 200 200 200 
Sodium 0 10 50 75 100 
bicarbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
This Example demonstrates, as depicted in FIG. 2, that salt induced 
controlled drug release is also observed with polyethylene oxide as the 
polymeric matrix. This suggests that the present invention is not 
polymer-limited. The linearity in profiles seen at even the lowest salt 
concentration, 10 mg. At higher concentrations (above 50 mg), the profiles 
tend to become concave, which suggests that the level of salt required for 
linear drug release is lower for polyethylene oxide than for HPMC. 
Example 3 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS C1 (ctrl) 
C2 C3 C4 C5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
HPMC K4M 200 200 200 200 200 
Sodium 0 10 50 75 100 
carbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
Example 3 demonstrates and FIG. 3 illustrates that the suppression of 
diltiazem release from HPMC matrices can also be attained by the 
application of other salts such as sodium carbonate, and linearity of 
release rate is still observed. 
Example 4 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS D1 (ctrl) 
D2 D3 D4 D5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
PEO 4M 200 200 200 200 200 
Sodium 0 10 50 75 100 
carbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
Example 4 demonstrates and FIG. 4 demonstrates that in using polyethylene 
oxide as the polymeric matrix, and sodium bicarbonate as the incorporated 
salt, an initial slow release followed by a more rapid linear release can 
be obtained. The initial slow release phase causes dilution of the drug in 
the gastric environment and subsequent reduction in gastrointestinal 
irritation. 
Example 5 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS E1 (ctrl) 
E2 E3 E4 E5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
HPMC K4M 200 200 200 200 200 
Potassium 0 10 50 75 100 
bicarbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
As depicted in FIG. 5, Example 5 demonstrates the use of potassium 
bicarbonate as the incorporated salt. Linear retardation of drug release 
is observed after an initial burst phase corresponding to approximately 
10% of the drug. This phenomenon has importance in the provision of a 
mini-loading dose prior to gradual metering of the drug which may be 
useful in some combinations. 
Example 6 
______________________________________ 
FORMULATIONS 
FORMULATIONS (mg/tablet) 
INGREDIENTS F1 (ctrl) 
F2 F3 F4 F5 
______________________________________ 
Diltiazem HCl 
100 100 100 100 100 
PEO 4M 200 200 200 200 200 
Potassium 0 10 50 75 100 
bicarbonate 
TOTAL 300 310 350 375 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
In this example, potassium bicarbonate is incorporated in a polyethylene 
matrix system. The result are seen graphically in FIG. 6. Suppression of 
drug release achieved while still maintaining a linear drug release. In 
addition, the suppression of drug release is virtually unchanged at salt 
concentrations beyond 50 mg/tablet. 
Example 7 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS G1 (ctrl) G2 
______________________________________ 
Propanolol HCl 100 100 
HPMC K4M 200 200 
Sodium 0 100 
bicarbonate 
TOTAL 300 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
This example, as depicted in FIG. 7, demonstrates that HPMC and sodium 
bicarbonate are a suitable combination for the release of drugs such as 
propranolol. The presence of sodium bicarbonate results in a substantial 
suppression of drug release, as compared to the use of HPMC alone. 
Example 8 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS H1 (ctrl) H2 
______________________________________ 
Propanolol HCl 100 100 
PEO K4M 200 200 
Sodium 0 100 
bicarbonate 
TOTAL 300 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
As depicted in FIG. 8, Example 8 demonstrates the use of potassium 
bicarbonate as the incorporated salt with polyethylene oxide as the 
polymeric matrix. Linear retardation of drug release is observed upon the 
addition of 100 mg of salt. 
Example 9 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS I1 (ctrl) I2 
______________________________________ 
Verapamil HCl 100 100 
HPMC 200 200 
Sodium 0 100 
bicarbonate 
TOTAL 300 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
The use of Verapamil HCl in the present invention is demonstrated in 
Example 9 and depicted in FIG. 9. As shown, the use of 100 mg of sodium 
bicarbonate results in a decreased rate of release of Verapamil HCl from a 
matrix. The formulations I1-I2 of Table 9 are particularly relevant in 
this regard. 
Example 10 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS J1 (ctrl) J2 
______________________________________ 
Verapamil HCl 100 100 
PEO 4M: 200 200 
Sodium 0 100 
bicarbonate 
TOTAL 300 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
Example 10 demonstrates and FIG. 10 illustrates that by selection of a 
suitable polymer for the matrix, a more controlled retardation of 
Verapamil hydrochloride may be effected. Although the release curve 
deviates from linearity toward concavity, such a profile is desirable when 
a slow onset of drug action is preferred. The concavity in release is 
evident only with polyethylene oxide. This is due to the sensitivity, in 
this combination, of the drug release profile to low salt content. 
Example 11 (Comparative) 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS K1 (ctrl) K2 
______________________________________ 
Diltiazem HCl 100 100 
HPMC K4M 200 200 
Lactose 0 150 
TOTAL 300 450 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
FIG. 11 is a graph of data from (Comparative) Example 11, showing the 
fractional release of diltiazem hydrochloride from hydrophillic matrix 
tablets in the absence of salt and with lactose as a salt substitute. The 
addition of 150 mg of lactose, as compared to the salt addition of other 
examples, resulted in no significant change in the release pattern. In 
this case the high solubility of diltiazem is the dominant factor in 
determining release rate. 
Example 12 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS L1 (ctrl) L2 
______________________________________ 
Diltiazem HCl 100 100 
HPMC K4M 200 200 
Sodium 100 100 
bicarbonate 
Lactose 0 150 
TOTAL 400 550 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
In Example 12, as depicted in FIG. 12, compositions like those of 
Comparative Example 11 are modified by the addition of sodium bicarbonate. 
In each case, the formulations L1-L2 of Table 12 exhibit a more linear 
drug release rate, as compared to the control sample of Comparative 
Example 11. This illustrates that the presence of relatively large amounts 
of excipients such as lactose do not alter the principle of a drug release 
which is based on differential hardening rate within the matrix and in 
turn, results in a greater potential in formulation flexibility. 
Example 13 
______________________________________ 
FORMULATIONS (mg/tablet) 
FORMULATIONS Dilacor XR .RTM. 
INGREDIENTS 
M1 (ctrl) 
M2 M3 M4* 
______________________________________ 
Diltiazem HCl 
240 240 240 240 
HPMC K4M 200 200 250 n/a 
Sodium 0 100 100 n/a 
bicarbonate 
TOTAL 300 310 350 936 
WEIGHT OF 
TABLET 
*Commercial multitablet, multilayer preparation 
DISSOLUTION CONDITIONS: 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
FIG. 13 is a graph showing the fractional release of diltiazem 
hydrochloride from the hydrophillic matrix tablets in accordance with 
Example 13 of the present invention and formulations M1-M4 of Table 13. 
The swellable, floatable monolithic tablet system, when formulated with a 
salt such as sodium bicarbonate (100 mg) exhibits a drug release profile 
which is similar to the commercial multilayer multitablet system of 
Dilacor.RTM. XR. Each commercial capsule of Dilacor.RTM. XR contains 4 
three-layered tablets equivalent to 240 mg of Diltiazem hydrochloride. 
Example 14 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS N1 
______________________________________ 
Diltiazem HCl 100 
HPMC K4M 200 
Sodium 100 
bicarbonate 
TOTAL 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Potassium chloride buffer pH 1.5, Potassium 
phosphate buffers pH 5.4, 6, 6.4, and 6.8. 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
FIG. 14 demonstrates the influence of dissolution medium pH on the release 
of Diltiazem HCl. On exposure of the tablets to an increasingly basic 
environment, a more pronounced burst effect is observed, while still 
approaching a zero order drug release. Comparatively, a change in 
dissolution medium pH does not produce marked variation in drug release 
when compared to the release at pH 1.5. 
Example 15 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS O1 (ctrl) O2 O3 
______________________________________ 
Metoprolol 100 100 100 
Tartrate 
HPMC K4M 200 200 200 
Sodium -- 100 200 
bicarbonate 
Calcium -- 100 200 
chloride 
TOTAL 300 500 700 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Deionized water pH 5.5. 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
FIG. 15 illustrates the influence of double salt interaction on the control 
of the 100% water soluble drug, matoprolol tartrate. As the salt content 
is increased from 100 to 200 mg in both cases, there is a progressive 
decrease in drug release. This is indicative of an increase in matrix 
hardening when higher salt contents are used in the formulation, which in 
turn causes a slower drug release effect. 
Example 16 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS P1 P2 P3 P4 
______________________________________ 
Diltiazem HCl 
100 100 100 100 
HPMC K4M 200 200 200 200 
Sodium 100 0 0 0 
bisulfate 
Potassium 0 100 0 0 
bicarbonate 
Magnesium 0 0 100 0 
chloride 
Calcium 0 0 0 100 
chloride 
TOTAL 400 400 400 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS: 
Medium: Potassium chloride buffer pH 1.5 
Volume: 900 ml 
Apparatus: Rotating paddle 
RPM: 50 
______________________________________ 
Example 16, as depicted in FIG. 16, demonstrates that controlled drug 
release may also be attained by the use of other salts. As a result, the 
formulation is not be restricted to sodium bicarbonate. The quantity of 
salt used dictates the degree of drug release suppression which approaches 
zero-order. 
Example 17 
______________________________________ 
FORMULATIONS FORMULATIONS (mg/tablet) 
INGREDIENTS Q1 (ctrl) Q2 
______________________________________ 
Diltiazem HCl 100 100 
HPMC K4M 200 200 
Sodium -- 100 
bicarbonate 
TOTAL 300 400 
WEIGHT OF 
TABLET 
DISSOLUTION CONDITIONS 
Medium: Row 1 - Potassium chloride buffer pH 1.5 (6 vessels) 
Row 2 - Potassium chloride buffer pH 3 (6 vessels) 
Row 3 - Potassium phosphate buffer pH 5.4 (6 vessels) 
Row 4 - Potassium phosphate buffer pH 6 (6 vessels) 
Row 5 - Potassium phosphate buffer pH 6.4 (6 vessels) 
Row 6 - Potassium phosphate buffer pH 6.8 (6 vessels) 
Duration spent by tablet in each row: 
Row 1 - 4 hours 
Row 2 - 0.5 hours 
Row 3 - 0.5 hours 
Row 4 - 6 hours 
Row 5 - 6 hours 
Row 6 - 7 hours 
Total duration of test: 24 hours 
Volume of medium in each vessel: 220 ml 
Apparatus: Bio Dis Release Rate Tester (Vankel Instruments) 
Dips per minute (dpm): 10 
______________________________________ 
Example 17, as depicted in FIG. 17, illustrates that by conducting one 
continuous test using media which simulates the gastrointestinal milieu as 
well as simulating the gastrointestinal transit time, the drug release 
from formulation Q2 maintains essentially a controlled zero-order release. 
This indicates that the formulation is relatively insensitive to changes 
in gastrointestinal pH.