Thursday, June 4, 2009

An Optimized Viscosity Approach


Editors Note: This is the first of a two-part article on the formulation and optimization of propranolol hydrochloride, controlled release matrix tablets. The second part, including references, if space permits, will be published in the August issue.

Formulation and Optimization of Propranolol Hydrochloride Controlled Release Matrix Tablets


The purpose of this study is to investigate the effect of polymer viscosity on in vitro drug release of the delivery system. Hydroxypropylmethylcellulose K15M (HPMC) and Carbopol 934P (Carbopol) were used in formulating the propranolol hydrochloride (PrHCl) controlled release, matrix tablet. Here, an optimized viscosity approach was applied to carry out a systematic study because the polymer viscosity demonstrated significant effect on in vitro drug release profile.

The theoretical calculation of viscosity of a polymer and polymer blends was carried out using equation given by Dow Chemical Co. The tablets subjected to in vitro drug release and were tested according to USP 24 modified release products. Linear regression analysis was carried out between theoretical calculated viscosity with t50 and t80. Results of linear regression analysis revealed good correlation (0.9803/0.9883 for t50 and t80 respectively). The generated equation was used for calculation of optimum viscosity. Optimized batches were deemed to have in vitro drug release profile similar to theoretical release profile (f2= 73.85/79.23). Similarity factor (f2) and Mean dissolution time (MDT) values were calculated, which indicate no significant difference between in vitro drug release profile values of optimize batches and theoretical profile. Kinetic modeling and release mechanism of all batches was calculated. The in vitro release data of all batches shows higher correlation with Higuchi and Kormeyer-Peppas model. Keywords: Propranolol hydrochloride, hydroxypropylmethylcellulose K15M, Carbopol 934P, Controlled release, matrix tablet.


PrHCl is an � adrenergic blocker and it has been widely used for the treatment of hypertension and angina. The initial oral dose of PrHCl is generally 40 to 80 mg/day. PrHCl is highly lipophilic and is almost completely absorbed after oral administration. Its oral bioavailability is about 26 �10 percent and t1/2is about 3.4 �1.3 hour.1

The objective was to optimize the formulation of PrHCl controlled release matrix tablet containing HPMC and Carbopol.

Use of a hydrophilic polymer matrix system is a popular approach in formulating a controlled release dosage form.2-4 This is due to the fact that these formulations are relatively flexible and a well designed system usually gives a reproducible release profile. There have been many studies demonstrating that the in vitro drug release profile from a hydrophilic matrix tablet is influenced by the viscosity of the gel layer formed due to its polymer hydration.2,5,6 Also, it has been shown that it depends on various other factors, like water-solubility and particle size of the drug, particle size and type of the polymer, type of diluents used, drug-to-polymer ratio and temperature of the release media.7-12

Combined usage of HPMC and Carbopol in a mucoadhesive delivery has been reported to improve mucoadhesiveness of the combined system.13, 14 However, there are a few reports on the application of Carbopol with HPMC for controlled release matrix tablets.15-19

The present work was intended to study the effect of polymer combination on the in vitro drug release rate from matrix tablets. Another objective was to prepare the mixture of HPMC and Carbopol in such a proportion as to give drug release profile as similar as theoretical release profile. Similarity factor (f2) and mean dissolution time (MDT) values were calculated from the data. The in vitro release data obtained were fitted into various kinetic models (zero order, first order and Higuchi Equation). And to fdetermine the release mechanism, the in vitro release data were applied in the Korsmeyer-Peppas equation.

Materials and Methods

PrHCl was received from IPCA Laboratories ltd. Mumbai. HPMC was provided by Alembic Pharmaceutical Co. Carbopol 934P and Carbopol 940 were received as samples, while Novean, Dibasic calcium phosphate (DCP) and Microcrystalline cellulose (MCC) were purchased from S. D. Fine Chem. Ltd. (Ahmedabad, India). All other ingredients were of laboratory grade.

The pharmacokinetic parameters of PrHCl were utilized for the calculation of theoretical drug release profile for 12-hour dosage form. The immediate release part of sustained release PrHCl was calculated using this equation:

Where Css is steady-state plasma concentration (Avg. Cmax), Vd is volume of distribution and F is fractional bioavailability. The total dose of PrHCl required for 12-hour release profile was calculated using this equation:

Where t is time up to which controlled release is required, t1/2 is half life of drug. PrHCl controlled release matrix tablets were prepared by direct compression technique, according to the formulation shown in Table1. For each formulation, the drug and polymer(s) were weighed and premixed for five minutes in mixing bag. Filler and glidant were added and mixed for 10 minutes. Magnesium stearate was added at the end and mixed for additional two minutes. The formulations were compressed on an automated rotary press using 9.6 mm round-concave punch to 300mg target tablet weight and 4-6kg/cm2 tablet hardness. The tablets were evaluated for physical properties: weight (n=20), thickness (n=10), hardness (n=20) and friability.

A quantity of the powder equivalent to 20 mg of PrHCl and agitated with 20 ml of water for 10 minutes. Add 50 ml of methanol, shake for a further 10 minutes, add sufficient methanol to produce 100.0 ml and filter. Dilute 10.0 ml of the filtrate to 50.0 ml with methanol and measure the absorbance of the resulting solution at the maximum of about 288 nm.20

The viscosity of polymer mixture was computed by using the empirical equation provided by Dow.21

Where � is the desired combined viscosity, F1 and F2 are the fraction of HPMC and Carbopol respectively. Consequently, n1 is the viscosity of HPMC (0.5 percent) - 400 mPas; and n2 is the viscosity of Carbopol (0.5 percent) - 33000 mPas.

In Vitro Drug Release Study

In vitro drug release was tested according to USP 24 NF 19 modified release products in apparatus I at 50 rpm, using 750 ml of 0.1N HCl for the first two hours followed by 1000 ml of pH 6.8 buffer (adjusted by addition of 250 ml of 0.2 M trisodium phosphate). A 10 ml sample was withdrawn at appropriate time interval and it was replaced fresh dissolution medium. The samples were analyzed at 288 nm using reference blank dissolution medium on Shimadzu 1601 UV-VIS spectrophotometer. The drug release study was conducted in triplicate and mean values were plot. The in vitro drug release profile of all batches with theoretical drug release profile was compared using similarity factor (f2).22

Where, Rt, Tt are the percentage release of the reference and test profile, respectively, at the t time point. n is total number of sample times. Mean dissolution time (MDT) of all batches were calculated using this equation:22

Where, t is mid point between two sampling point, dM(t) is additional mass in t time.

A water uptake study was also carried out by putting tablets into a Petri dish containing 0.1NHCl for two hours followed by a 6.8 pH buffer solutionf for up to 12 hours at 37�1oC by putting on heating plate. At predetermined time intervals (2, 4, 6, 9 and 12 hour), tablets were removed from the medium and lightly patted using tissue paper and weighed. The following equations were used to determine percent weight gain (water uptake):23

Data obtained form in vitro drug release studies were fitted to various kinetic equations. The kinetic models used are zero order, first order and Higuchi equation.22 The following plots were made for appropriate model.

  • Q Vs t (zero order kinetic model)

  • Log (Qo - Qt) Vs t (first order kinetic model)

  • Qt Vs vt (Higuchi model)

Where Qt is the amount of PrHCl released at time t and Qo is the initial amount of PrHCl in tablets. To investigate the mechanism of in vitro drug release and to compare the release profile differences among these matrix formulations, the percent drug released versus time profiles were used. Data corresponding to 60 percent �5 release were fitted using the equation proposed KorsmeyerPeppas.22

Where, Mt/M8 is the fraction of drug released at time t, k the kinetic constant, and n the release exponent that characterizes the mechanism of drug release. For matrix tablets, n = 0.5 indicated pure diffusion controlled drug release and n = 1 indicated swelling-controlled drug release or Case II transport. Other values for n indicated anomalous transport kinetics,24 i.e. a combined mechanism of pure diffusion and Case II transport. The special case with n = 0.5 in the above equation represents the Higuchi model.25

Total Dose Calculation and Theoretical Drug Release Profile

An ideal controlled release tablet should release the required quantity of drug with predetermined kinetics in order to maintain effective drug plasma concentration. To achieve constant drug plasma concentration a tablet should be formulated in such a way that it can release the drug in a predetermined and reproducible manner. By considering the bio-pharmaceutics and pharmacokinetic profile of the drug, required release from the tablet can be predetermined. To achieve the predetermined release profile, various formulation factors like polymer/drug ratio, polymer viscosity, hardness and additives should be modified.

The pharmacokinetics parameters of PrHCl were used to calculate a theoretical drug release profile for a 12-hour dosage form. The immediate release part for controlled release PrHCl was calculated and found to be 14.88 mg. Hence, the formulation should release 14.88 mg (31.82 percent) of drug in one hour like conventional tablets and 2.88 mg (6.19 percent) per hour up to 12 hour thereafter (Figure 1). The t50 and t80 of the theoretical dissolution profile is 236 and 526 minutes respectively.

Figure 1. Theoretical Drug Release Profile.

To evaluate an effect of polymer viscosity on in vitro drug release profile of different batches (A1 to A9) were formulated using various ratios of HPMC and Carbopol. The viscosity of the prepared tablet polymer composition was determined by equation given by Dow Chemical Company. The formulations of the batches to study the effect of polymer viscosity on in vitro drug release are shown in Table1. All the batches were formulated by direct compression as per procedure described above.

The in vitro release profile of formulations for 12 hours was tested according to procedure described above. Figure 2 shows the effect of polymer viscosity on the in vitro drug release profile of Propranolol hydrochloride.

Figure 2: Effect of Polymer Viscosity on in vitro Drug Release Profile of PrHcl (A1 to A9 batches)

The in vitro drug release profile of A1 to A9 batch were compared with the theoretical release profile and results of similarity factor and mean dissolution time (MDT) are shown in Table 2. The similarity factor was highest for batch A7 (f2 = 66.27), having polymer viscosity of 14952 mPaS. Further increase in viscosity to 22431mPaS caused decrease in the similarity factor (f2 = 51.89). The results also indicated that the value MDT increases with increase in polymer viscosity.

Hence, it was assumed that by controlling the apparent viscosity of polymer, we may achieve drug release profile, which is identical to theoretical release profile. -PFQ

Ritesh Patel, Jayvadan Patel, Girish Patel, Geeta Patel, Praful Bharadia and Madhabhai Patel, of the Department of Pharmaceutics and Pharmaceutical Technology, S.K.Patel College of Pharmaceutical Education and Research, (Gujarat, India) can be reached through Ritesh Patel at

No comments: