FORMULATION, EVALUATION AND ESTIMATION OF PROPRANOLOL HYDROCHLORIDE AND FLUNARIZINE DIHYDROCHLORIDE CONVENTIONAL TABLETS IN COMBINED DOSAGE FORM AND ITS COMPARISON WITH MARKETED FORMULATIONS

FORMULATION, EVALUATION AND ESTIMATION OF PROPRANOLOL HYDROCHLORIDE AND FLUNARIZINE DIHYDROCHLORIDE CONVENTIONAL   TABLETS   IN COMBINED DOSAGE FORM AND ITS COMPARISON WITH MARKETED FORMULATIONS

Dipali Malhotra* and Ravi Sharma

Department of Pharmaceutical Analysis, ASBASJSM College of Pharmacy, BELA (Ropar) 140111, Punjab, India

ABSTRACT: Oral route of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance. This study was aimed at development of Propranolol hydrochloride and flunarizine dihydrochloride conventional dissolving tablets in combined dosage form. Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta (1)- adrenergic receptors in the heart, inhibiting sympathetic stimulation and Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking  activity both are effective in the treatment of coexistence of hypertension & migraine

Flunarizine    Dihydrochloride,

INTRODUCTION: Migraine is a neurologic disease, associated with throbbing intense headache in one half of the head. It is characterized by recurrent attacks of intense headache and nausea that occur at irregular intervals and last for several hours. Flunarizine is a selective calcium channel blocker and coupled with its antihistaminic property it is claimed to be effective in prophylaxis of migraine. It is effective in migraine by reducing intra-cellular Ca²⁺ overload due to brain hypoxia and thus prevents the deleterious effects of cellular calcium overload. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimized by taking the daily dose in the evening ¹.

Propranolol hydrochloride is a non-specific beta-adrenergic blocking agent used in the treatment of hypertension. The absolute bioavailability is only approximately 26% due to extensive hepatic metabolism. So, conventional tablet of both drugs can be effective in the treatment of coexistence of migraine and hypertension ². Chemical structures of Propranolol hydrochloride and Flunarizine dihydrochloride are given in (Fig.1).

FIG.1. (a) FLUNARIZINE

FIG.1. (b) PROPRANOLOL                                                                            

MATERIALS AND METHODS:

Propranolol Hydrochloride and Flunarizine Dihydrochloride were obtained as a gift sample from Tanpal Pharmaceuticals Nabha. Lactose, Talcum and Magnesium stearate were obtained from ASBASJSM College of Pharmacy Bela (Ropar). All chemicals and reagents used were of Analytical grade.

Formulation of Conventional Tablets:

Propranolol Hydrochloride, Flunarizine Dihydrochloride and excipients like lactose, Talcum, Magnesium stearate, blank dummy granules were co-grounded in pestle mortar (except talc and magnesium stearate) and were passed through mesh. No.60. Finally talc and magnesium stearate were added and mixed for 5 min.  The mixed blends of excipients were compressed using a single punch tablet machine to produce convex faced tablets weighing 225 mg each with thickness between 3.0-3.4 mm and 8 mm in diameter by direct compression method. Composition of conventional tablets is shown in (Table 1).

Composition of Blank Dummy:

It is composed of starch forming paste, gelatin, methyl paraben sodium, propyl paraben sodium, starch, dibasic calcium phosphate, microcrystalline cellulose phosphate.

TABLE 1: COMPOSITION OF CONVENTIONAL TABLETS TABLE   

Evaluation of MDT_S:

Pre-compression characterization:

Bulk Density: ^{3, 4}

Apparent bulk density was determined by pouring the 5gm of powder into a 100 ml                 granulated cylinder. The bulk volume (V) poured drug was determined. The bulk density was calculated using the formula.  Result is shown in (Table 2).

ρ_b = M / V

Where: ρ_b - bulk density, M- is the weight of powder, V- is the volume of powder.

Tapped Density: ^{3, 4}

Weight 5gm of powder and placed in a measuring cylinder. Measuring cylinder containing known mass (5gm) of powder was tapped for 100 times or fixed time. The minimum volume (V_t) occupied was measured. The tapped density was calculated using following formula. Result is shown in (Table 2).

ρ_t = M / V_t

Where: ρ_t - tapped density, M- is the weight of powder, V_t- is the volume of powder

Compressibility Index: ^{4, 5}

The simplest way for measurement of free flow of powder is compressibility, an indication of the ease with which a material can be induced to flow is given by Compressibility Index. The value below 15% indicates a powder with give rice to good flow properties, whereas above 25% indicate poor flowability. This is calculated as follow. Result is shown (Table 2).

% C.I. = ρ_t –ρ_b /ρ_t ˟ 100

Hausner ratio: ⁴

Hausner ratio is an indirect index of ease of powder flow. Hausner ratio is the ratio of tapped density (ρ_t) to bulk density (ρ_b). Lower the value of Hausner ratio better is the flow property. Powder with Lower Hausner ratio (<1.25) indicates better flow properties than higher ones (> 1.25). It is calculated by following formula. Result is shown in (Table 2).

Hausner ratio = ρ_t / ρ_b

Angle of repose: ^{4, 6}

The angle of repose was determined using funnel method. Funnel can be fit vertically with stand at 6.3cm height. The opening end of funnel is closed with thumb until drugs are poured. The 5 gm of powder was poured into funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and the angle of repose (ϴ) was calculated using the formula. Result is shown in (Table 2).

ϴ = tan^-1 (h / r)

 TABLE 2:  PRE-COMPRESSION PARAMETERS (CHARACTERIZATION OF BLENDS)

Infrared spectral assignment (Drug polymer interaction studies):

The IR analysis of sample was carried out for qualitative compound identification. The infrared spectra of Propranolol hydrochloride and Flunarizine Dihydrochloride was performed on Fourier transformed infrared spectrophotometer. The infrared absorption spectra of drug and mixture of polymer and drug were run between 4000 – 400 cm^-1. Results are shown in (Fig. 2, 3) and (Table 3)

FIGURE 2:  IR SPECTRA OF PURE PROPRANOLOL HYDROCHLORIDE

FIG. 3:  IR SPECTRA OF PURE FLUNARIZINE DIHYDROCHLORIDE

TABLE 3:  IR Study Data

Post- Compression Characterization: ⁷

Hardness:

The test is done as per the standard methods. The hardness of three randomly selected   tablets    from each formulation is determined by placing each tablet diagonally between the two plungers of tablet hardness tester (with the nozzle) and applying pressure until the tablet broke down into two parts completely and the reading on the scale is noted down in kg/cm². Result is shown in (Table 4).

 Thickness:

The thickness of three randomly selected tablets from each formulation is determined in mm   using a vernier caliper. The average values are calculated. Result is shown in (Table 4).

Uniformity of Weight: ^{8, 9}

Weight variation test is done as per standard procedure. Twenty tablets from each formulation are weighed using an electronic balance and the average weigh are calculated.

Result is shown in (Table 4).

 Friability:

The friability of tablets using 10 tablets as a sample is measured using a Roche Friabilator. Tablets are rotated at 25 rpm for 4 minutes or up to 100 revolutions. The tablets are then taken out, dedusted and reweighted. The percentage friability is calculated from the loss in weight as given in equation below. The weight loss should not more than 1%.

%Friability = (initial weight- final weight)/ (initial weight) x 100

Result is shown in (Table 4).

 TABLE 4: POST-COMPRESSION PARAMETERS (CHARACTERIZATION OF CONVENTIONAL TABLETS)

 Drug Content determination by Absorbance ratio method:

Absorption maximum, isopiestic point determination and Preparation of calibration curves in Methanol and distilled water.

Standard stock solutions of FLU and PRO were prepared separately by dissolving 10 mg of each drug in 10ml of methanol to get standard stock solution of 1000μg/ml respectively and 1 ml was pipette out and further volume was made up to 10 ml with distilled water to obtain concentration of 100μg/ml.

Further dilutions were made in distilled water from stock solution to get concentrations 8-48μg/ml for propranolol hydrochloride and 6-36 μg/ml for flunarizine dihydrochloride. Results are shown in (Fig. 4, 5, 6, 7, 8, 9, 10).

 Curve in Methanol and Distilled water:

 Preparation of calibration curves in 0.1 M HCl

Standard stock solutions of FLU and PRO were prepared separately by dissolving 10 mg of each drug in 10ml of 0.1N to get standard stock solution of 1000 μg/ml respectively and 1 ml was pipette out and further volume was made up to 10 ml with 0.1HCl to obtain concentration of 100μg/ml. Further dilutions were made in distilled water from stock solution to get concentrations 8-48ug/ml for propranolol hydrochloride and 6-36 ug/ml for flunarizine dihydrochloride. Results are shown in (Fig. 11, 12, 13, 14).

For the content uniformity test, 20 tablets were weighed and pulverized to a fine powder, a quantity of powder equivalent to 10 mg of Propranolol Hydrochloride and Flunarizine Dihydrochloride was accurately weighed, transferred into a 100 ml flask, dissolved in methanol to get concentration of 100ug/ml and this solution was sonicated for about 30 minutes then volume was made up to 10 ml and filtered to separate any insoluble matter .The clear solution obtained was diluted to get appropriate concentration with distilled water. The concentrations of two drugs in the mixture were calculated by using Absorbance ratio method at 290nm (λ_max of Propranolol Hydrochloride) and 264.5nm (isobestic point of Propranolol Hydrochloride and Flunarizine dihydrochloride)

Q_M - Q_Y           A₁

Cx =       -------------- ×    -----

Q_X - QY          ax₁

Q_M– Q_X            A₂

C_Y =        -------------- ×    -----

Q_Y– Q_X            ay₂

Where, Q_M= A₂/A₁; Q_X = ax₂/ax₁; Q_Y = ay₂/ay₁

A₁ and A₂ are the absorbance of diluted samples at λ₁ and λ₂, ax₁ and ax₂ are the absorptivity of X, ay₁ and ay₂ are the absorptivity of Y. Result is shown in (Table 5).

Wetting Time: ⁷

The tablets wetting time is measured by a procedure modified from that reported by Bi et al. The tablet is placed at the center of two layers of absorbent paper fitted into a dish. After paper is thoroughly wetted with distilled water, excess water is completely drained out of the dish. The time required for the water to diffuse from the wetted absorbent paper throughout the entire tablet is then recorded using a stopwatch. Result is shown in (Table 5).

In- vitro Disintegration Time:

Six tablets were placed individually in each tube of disintegration test apparatus and discs were placed. The water was maintained at a temperature of 37°±2°C and time taken for the entire tablet to disintegrate completely was noted. Result is shown in (Table 5).

TABLE 5: POST-COMPRESSION PARAMETERS (CHARACTERIZATION OF MOUTH DISSOLVING AND CONVENTIONAL TABLETS)

In- vitro drug release study:

The release rate of Propranolol Hydrochloride and Flunarizine Dihydrochloride from conventional tablets was determined using USP XXIV dissolution testing apparatus II (paddle method) using 900 ml of in 0.1M HCl as a dissolution medium at 37 ± 0.5˚C and 75 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus at different time interval (min). The samples were filtered through a Whatman filter paper. Absorbance of these solutions was measured at 290 nm ((λ_max of Propranolol Hydrochloride) 264.5nm (isobestic point of Propranolol Hydrochloride and Flunarizine Dihydrochloride). Results are shown in (Table 6) (Fig.15).

TABLE 6:  DISSOLUTION PROFILE OF CONVENTIONAL TABLETS

FIG.15:  PERCENT RELEASE OF CONVENTIONAL TABLETS

Comparison with marketed formulations:

In vitro drug release and drug content of conventional tablets was determined and compared with marketed conventional tablets of Provanol Plus 10(Propranolol 20mg, Flunarizine 10mg). Results are shown in (Table 7) and (Figure 16)

Stability Studies:

Temperature dependent stability studies:

The Combined conventional tablets of Propanolol Hydrochloride and Flunarizine Dihydrochloride were packed in wide mouth air tight glass container and stored at (40 ± 2 ˚C and 75 ± 5 % RH) for a period of 3 months.

The tablets were withdrawn after a repeated period of 15 days and analyzed for physical characterization and drug content spectrophotometrically at 290nm and 264.5nm. Among several methods investigated for dissolution profile comparison, f2 is the simplest.

f₂= 50•log {[1+1/n ²]^-0.5• 100

Where R_t and T_t are the cumulative percentage dissolved at each of the selected n time points of the reference and test product respectively.

When the two profiles are identical, f2=100. An average difference of 10% at all measured time point’s results in an f2 value of 50. FDA has set a public standard of f2 value between 50-100 indicate similarity between two dissolution profiles. Results are shown in (Table 8, 9, 10) (Fig. 17)

TABLE 7: COMPARISON OF IN VITRO DRUG RELEASE WITH MARKETED FORMULATION

TABLE 8:  EFFECT OF STORAGE CONDITIONS ON CONVENTIONAL TABLETS

 Comparison of drug release data before and after storage of Conventional tablets:

TABLE 9: BEFORE STORAGE

TABLE 10: AFTER STORAGE

 FIG. 16: PERCENT RELEASE OF PROPRANOLOL HYDROCHLORIDE AND FLUNARIZINE DIHYDROCHLORIDE IN COMBINED CONVENTIONAL TABLET AND COMBINED CONVENTIONAL MARKETED FORMULATED TABLET

FIG. 17:  COMPARISON OF DRUG RELEASE BEFORE AND AFTER STABILITY STUDIES OF MOUTH DISSOLVING TABLETS

 RESULT AND DISCUSSION: Combined Conventional tablets of Propranolol Hydrochloride and Flunarizine Dihydrochloride were prepared by

direct compression method. Table 1 shows the composition of Conventional tablets and Table 2 shows the Pre-compression evaluation of tablets. Conventional tablets were evaluated for various pre and post compression parameters.

Pre – Compression parameters like bulk density, tapped density, Hausner’s ratio, compressibility index, angle of repose, IR studies of pure drugs for identification are shown in Fig. 2, 3 and Table 3. Post- compression parameters such as hardness, friability, wetting time, disintegration time, dissolution studies, and drug content were evaluated shown in Table 4, 5. Drug content was determined by Absorption ratio method by selecting two wavelengths 290 (λ_max of Propranolol Hydrochloride) and 264.5 (isobestic point of Propranolol Hydrochloride and Flunarizine Dihydrochloride) and the standard plots in methanol and in 0.1M HCl are shown in Fig. 7,8,9,10,11,12,13,14. The in- vitro disintegration time is within the prescribe limit and comply with the criteria for Conventional tablets, the value as 720±1.25 seconds). In- vitro dissolution study is shown in Table 6 and in Fig.15. It shows highest drug release of Propranolol Hydrochloride 83.67%, Flunarizine Dihydrochloride 84.74% at 45minutes.

Comparison of the in- vitro drug release of combined Conventional tablet of Propranolol Hydrochloride and Flunarizine Dihydrochloride with marketed combined tablet: - Provanol plus 10 (Propranolol 20mg, Flunarizine 10mg) is shown in Table 7 and in Fig.16. Stability studies of Conventional tablets are shown in Table 8,9,10 and Fig. 17.

 CONCLUSION: Formulated conventional tablet was having high percentage of drug release as compare to marketed formulation. Simultaneously and quantitatively estimated by U.V. spetrophotometric Q- Absorbance Ratio Method.

AKNOWLEDGEMENT: We acknowledge ASBASJSM College of Pharmacy, Bela (Ropar) for providing all the facilities and Tanpal Pharmaceuticals Nabha for providing gift samples of Propranolol Hydrochloride and Flunarizine Dihydrochloride.

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How to cite this article:

Malhotra D and Sharma R: Formulation, Evaluation and Estimation of Propranolol Hydrochloride and Flunarizine Dihydrochloride Conventional   Tablets   in Combined Dosage Form and Its Comparison with Marketed Formulations. Int J Pharm Sci Res 2015; 6(3): 1200-09.doi: 10.13040/IJPSR.0975-8232.6(3).1200-09.

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