Jayanthi et al / IJRAP 2011, 2 (2) 577-580

Research Article Available online through

www.ijrap.net ISSN 2229-3566

pH-INDEPENDENT CONTROLLED RELEASE SWELLABLE MATRIX TABLETS

Jayanthi*, Mathews Rashmi, Bhaskaran Shyamala, Sateesha S.B., Abraham Sindhu
Nargund College of Pharmacy, Bangalore-85, Karnataka, India

Received on: 12/01/2011 Revised on: 12/03/2011 Accepted on: 25/03/2011

ABSTRACT
The aim of this study was to overcome pH-dependent release of weakly basic drug and to achieve pH-independent
drug release. An anti-hypertensive drug, Propranolol hydrochloride was chosen due to its pH- dependent solubility.
One of the approaches to solve the problem of pH-dependent release of weakly basic drug has been done in this work.
The water soluble and highly swellable HPMC was used as a matrix former and organic acids Citric acid and
Succinic acid were added to the drug polymer system in different formulations in varying proportions (at 10, 20, 40
and 80mg) as release modifiers. The addition of organic acids was found to maintain an acidic micro environmental
pH inside the polymer matrices during drug release in phosphate buffer pH 7.4. On the other hand, the amount of
each organic acid added to the system had no effect on the drug release in acidic solution 0.1N HCL. So the micro
environmental conditions for the dissolution and diffusion of drug were almost kept constant. Thus, the release of
Propranolol hydrochloride from tablets containing HPMC and organic acids was found to be pH-Independent.
Between the two organic acids, Succinic acid showed slightly better release when compared to Citric acid.
KEYWORDS: pH-independent, weakly basic drug, HPMC, solubility and swell-ability of HPMC.

*Corresponding Author
Jayanthi, Dept of Pharmaceutics, Nargund College of Pharmacy, Bangalore-85, Karnataka
E mail: jayanthia6@gmail.com

INTRODUCTION demonstrated in this work, i.e., using organic acids

Many drugs are weak bases or salts thereof and thus (Citric acid, Succinic acid) to create an acidic micro-
demonstrate pH dependent solubility in the pH range of environmental pH inside the polymer matrices5.
the GI tract1. With controlled release dosage forms, a Propranolol HCl is an adrenergic blocking agent,
possible pH-dependent release could result in in-vivo effective in treatment of hypertension and angina.
variability and bioavailability problems. Hence pH- Propranolol HCl has short plasma half-life of 3-5hrs
independent drug release is desirable to better assure a owing to which, multiple doses are needed to maintain
reliable drug therapy and to build a greater control into a therapeutic concentration of the drug in plasma for better
dosage form. therapeutic response and improved patient compliance.
Several attempts to overcome the problem of pH Therefore, it is necessary to develop sustained release
dependent solubility of weakly basic drugs have been preparations with extended clinical effects6, 7.
published2. They are mostly based on the presence of MATERIALS AND METHODS
acidic Excipients such as water-soluble or insoluble The materials used were procured from the following
polymers or organic acids3 that either increases the sources: Propranolol hydrochloride (Zydus Cadila
permeability of the drug delivery system by leaching out pharmaceuticals ltd. -Bangalore), Hydroxy propyl methyl
at higher pH-values or which keep the pH within the cellulose (HPMC, Methocelâ, K-15M, BPRL Pvt. Ltd.
system in the intestinal pH-range low and thus the Bangalore), Magnesium stearate (Loba chemie -
solubility of the drug high. Mumbai), lactose (Fast flow, Pharmatose, Nice
The objective of this study is to achieve a pH- chemicals) citric acid, Succinic acid (Nice chemicals-
independent release of a weakly basic drug from matrix Cochin) and all the other reagents used were laboratory
tablets consisting of HPMC, a swellable and water- grade. Magnesium stearate was used as lubricant. After
soluble polymer4. One of the approaches to overcome the evaluating the pre-compression parameters the lubricated
problem of pH-dependent drug release has been granules were compressed using 10-station Rimek mini-

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 577-580

 Jayanthi et al / IJRAP 2011, 2 (2) 577-580
press RSB-4 tablet punching machine using 8mm RESULTS AND DISCUSSION
diameter concave punches. The total weight of the tablet Propranolol HCl is a useful model drug to test the
was maintained at 250mg. The hardness of all the tablets formulation concept because of its distinct pH-dependent
was maintained to 4kg\cm2. solubility (mg).
Formulation of tablets The solubility of Propranolol HCl at pH 2.0 is
Weighed quantity of drug, polymer, organic acids (citric 120.5224mg/ml; at pH 3.6 it is 71.2462mg/ml, at pH 6.0
acid and Succinic acid) and diluents (lactose) were it decreases to about 63.5386 mg/ml and at basic pH 8.0
passed through sieve # 80 and mixed in geometric it reduces to 63.0042 mg/ml. Due to this pH-dependent
proportion using a mortar and pestle followed by solubility a remarkable difference in the resulting drug
lubrication using Magnesium stearate (0.5 %9)(table 1). release from HPMC tablet was observed in 0.1N HCl
250 mg of the lubricated physical mixture were and in Phosphate buffer pH 7.4 solutions.
compressed using a 10- station ‘Remek’ mini-press tablet Hydroxy Propyl Methyl cellulose polymer was used as a
punching machine using flat punches (8mm matrix former in which the drug Propranolol HCl was
diameter)3,8,9,10. Characteristics of the blend such as bulk embedded. The drug: polymer ratio were
density, compressibility index, and angle of repose were 1:1,1:1.5,1:2,1:2.5,1:3 for Hydroxy propyl methyl
determined for each formulation11, 12. cellulose polymer. The drug: polymer ratio of 1:3 was
Weight variation test was conducted as per specifications selected as an optimised formula. To this optimised
of IP. Hardness of the tablet was kept constant formula, organic acids such as citric acid and Succinic
(approximately 4 kg/cm2) for all the formulations. acid were added.
Evaluation of tablets: The tablets were subjected to In the case of highly swellable HPMC matrix tablets
various evaluation tests such as (Table-I formulation No. 5), approximately 7.7% and
1. Weight variation test: The tablets complied with the 4.6% of the drug was released after 1 hour in 0.1N HCl
I.P. requirements in the test for weight variation. and Phosphate buffer respectively. After 8 hours, 48% of
2. Friability test: less than 0.1% the drug was released in 0.1N HCl versus only 20% was
3. Drug content determination: released in Phosphate buffer solution, pH 7.4. (Shown in
The tablets were powdered, the tablet triturate equivalent graph 1).
to 40mg of propranolol HCL was taken in 100 ml The reason for this behaviour is that HPMC swells to a
volumetric flask, dissolved and volume was made up to significant extent upon contact with the release medium.
the mark with simulated gastric fluid. From this solution, The drug is not predominantly released by diffusion
0.5 ml was pipetted into a 50 ml volumetric flask and through water-filled pores but by diffusion through the
volume was made up to 50 ml with simulated gastric swollen polymer network. In addition the swelling of
fluid. The absorbance was measured at 216 nm against HPMC polymer matrix also plays an important role.
reagent blank (0.1 N HCl) using UV (Elico-SL159) Hence the approach to adjust the release profile of
spectrophotometer. . The procedure was repeated for four weakly basic drugs in Phosphate buffer to that in 0.1N
more tablets of the same formulation and the average HCl was based on the addition of organic acids to create
value of all five tablets was calculated. The drug content a constant acidic microenvironment inside the tablets.
was calculated using the following equation. Ideally, these acids should dissolve rather slowly to
Amount of drug present = Absorbance ± Intercept / slope remain within the tablet during the entire period of drug
´ Dilution Factor release independent of the pH value of the dissolution
In-vitro dissolution profile medium, the pH inside the tablet matrix was expected to
Dissolution studies were carried out by USP-Type II be acidic and thus the solubility of the weakly basic drug
method at 370 ± 0.50 C. The paddle was set to rotate at to be high. In this case, drug release should be pH-
50 rpm. One tablet, previously weighed, was kept in the independent. For this purpose, substances with high
dissolution media. The dissolution media, acidic buffer acidic strength (low pKa value) and relatively low
pH 1.2 for 12 hours and Phosphate buffer, pH 7.4 for 12 solubility in 0.1N HCl are suitable. Citric acid and
hours were used. 5ml of samples were withdrawn at Succinic acids were selected. In addition, the organic
each hour with replacement and diluted to 50ml and acids can act as pore-formers at high pH values.
absorbance was measured at 216nm in a UV (Elico- The addition of organic acids to HPMC-based matrix
SL159) spectrophotometer.13, 14,15 systems significantly increased the drug release in
Phosphate buffer (pH 7.4) with increasing amount of
organic acids (10 to 80 mg). The resulting release
profiles almost overlapped with the ones in 0.1N HCl.
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 577-580
 Jayanthi et al / IJRAP 2011, 2 (2) 577-580
This is in good agreement with above described REFERENCES
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Table 1: Tablet formulations

FORMULATION INGREDIENTS*
Formulation Propranolol HPMC Lactose Magnesium Citric Succinic
Code Hydrochloride 4000 CPS stearate acid acid

F1 40 40 168.5 1.5 - -
F2 40 60 148.5 1.5 - -
F3 40 80 128.5 1.5 - -
F4 40 100 108.5 1.5 - -
F5 40 120 88.5 1.5 - -
FC10 40 120 78.5 1.5 10 -
FC20 40 120 68.5 1.5 20 -
FC40 40 120 48.5 1.5 40 -
FC80 40 120 8.5 1.5 80 -
FS10 40 120 78.5 1.5 - 10
FS20 40 120 68.5 1.5 - 20
FS40 40 120 48.5 1.5 - 40
FS80 40 120 8.5 1.5 - 80
*All quantities are in milligrams/tablet

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 577-580

 Jayanthi et al / IJRAP 2011, 2 (2) 577-580

Graph 1
IN VITRO RELEASE PROFILE OF FORMULATION F5 - pH 1.2 & 7.4

Time (hrs) à

Graph 2
IN VITRO DISSOLUTION PROFILE OF FORMULATIONS FS10, FS20, FS40, FS80

Source of support: Nil, Conflict of interest: None Declared

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 577-580