FORMULATION AND EVALUATION OF PROPAFENONE HYDROCHLORIDE EXTENDED RELEASE TABLETS

Abstract

Propafenone hydrochloride is used for the therapy of supraventricular tachyarrhythmiasis. Conventional tablet (150mg) of Propafenone is available in market is used three times a day for effective treatment of supraventricular tachyarrhythmiasis. Decrease in frequency of high dose drug via extended drug release would reduce incidence of acute toxicity. With this aim by using polymers hydroxy propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC) Propafenone hydrochloride extended release tablets containing 225mg were prepared by wet granulation method. It is to be used twice a day to provide patient compliance and constant blood level, consequently to decrease side effects.The tablets were subjected to different evaluations like thickness, diameter, weight variation test, hardness, friability, drug content and in-vitro release studies. In-vitro dissolution study conducted in pH 1.2 HCl buffer followed by pH 6.8 phosphate buffer solutions according to the method II in USP2. Drug release was faster in formulations containing 10%w/w polymer HPMC, HPC and slower in formulations containing Ethyl cellulose (3% w/w polymer) containing batch. Combination of hydrophilic polymer (HPMC 6CPS) and hydrophobic polymer (EC 22cps) in the concentration of 10% w/w and 3%w/w respectively is suitable to get desired drug release profile as per innovator. Formulations were optimized on the basis of in-vitro drug release and F2 factor. The results of dissolution study and F2 factor indicated that formulation F9 (HPMC 10%w/w, EC 3%w/w) was most successful and exhibited drug release pattern very close to innovator drug release profile. [PUBLICATION ABSTRACT]

Headnote

ABSTRACT

Propafenone hydrochloride is used for the therapy of supraventricular tachyarrhythmiasis. Conventional tablet (150mg) of Propafenone is available in market is used three times a day for effective treatment of supraventricular tachyarrhythmiasis. Decrease in frequency of high dose drug via extended drug release would reduce incidence of acute toxicity. With this aim by using polymers hydroxy propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC) Propafenone hydrochloride extended release tablets containing 225mg were prepared by wet granulation method. It is to be used twice a day to provide patient compliance and constant blood level, consequently to decrease side effects.The tablets were subjected to different evaluations like thickness, diameter, weight variation test, hardness, friability, drug content and in-vitro release studies. In-vitro dissolution study conducted in pH 1.2 HCl buffer followed by pH 6.8 phosphate buffer solutions according to the method II in USP2. Drug release was faster in formulations containing 10%w/w polymer HPMC, HPC and slower in formulations containing Ethyl cellulose (3% w/w polymer) containing batch. Combination of hydrophilic polymer (HPMC 6CPS) and hydrophobic polymer (EC 22cps) in the concentration of 10% w/w and 3%w/w respectively is suitable to get desired drug release profile as per innovator. Formulations were optimized on the basis of in-vitro drug release and F2 factor. The results of dissolution study and F2 factor indicated that formulation F9 (HPMC 10%w/w, EC 3%w/w) was most successful and exhibited drug release pattern very close to innovator drug release profile.

Keywords: Propafenone hydrochloride; supraventricular tachyarrhythmiasis; extended release; matrix tablet; Hydroxy propyl methyl cellulose.

INTRODUCTION

Extended release formulations are defined as formulations from which the drug release is controlled over certain period of time.1 They are intended for administration via the oral route. Expressions such as controlled-release, prolonged-action, repeat action and sustained-release have also been used to describe such dosage forms. A typical controlled release system is designed to keep concentration of drug in the blood or other target tissues at an optimum level over an extended period of time. In practical terms, an oral controlled release system shall allow a reduction in dosing frequency as compared to when the same drug is presented as a traditional dosage form.

Water-soluble or hydrophilic matrices are a well known type of ER oral dosage forms. Polymers used for the formulation of matrix tablets were hydroxy propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC).

The chemical name of HPMC and HPC are cellulose, 2-hydroxy methyl ether and carboxypolymethylene.lt is a synthetic high molecular weight, cross linked polymer of

acrylic acid copolymerized with approximately 0.75-2% w/w of polyalkyl sucrose. There are numerous report highlighting the low toxicity and biocompatibility of HPMC and HPC respectively. On exposure of hydrophilic matrix to the aqueous fluid, the matrix take up water, and the polymer starts hydrating to form a gel layer. Drug release is controlled by a gel diffusional barrier and/or by surface erosion.2 5 An initial burst of soluble drug may occur due to the surface leaching. When a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state, which is associated with the swelling process. This is due to decrease of transition temperature of polymer that depend on temperature & thermodynamic of interactions of polymer and aqueous medium.610

Propafenone Hydrochloride is an antiarrythmic drug, The electrophysiological effect of Propafenone Hydrochloride manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions.1119 Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone Hydrochloride reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in-vitro, it can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Hence there is a potential need for extended release tablet for prolonged action and to improve patient's compliance.20 39

The aim of current research work is to study the release characteristics of a polymer such as HPMC and HPC containing Propafenone by wet granulation followed by compression using lactose, Magnesium streate as lubricants.

MATERIAL AND METHODS

Propafenone Hydrochloride obtained from Mylan laboratories Hyderabad, Hydroxyl Propyl Methylcellulose, Hydroxy Propyl cellulose HXF obtained from Dow Chemicals Ltd Hyderabad. All materials used were of

analytical grade procured from commercial sources.

Preparation of Extended release matrix tablets:

Matrix tablets containing Propafenone HCl were prepared by wet granulation. The compositions of different formulations were weighed as performulation, all the ingredients were sifted through #40. All the ingredients except lubricants were mixed in double cone blender for 30 min. Granulating fluid (water) was added to powder blend, mixed thoroughly in order to get coherent mass and passed through #10. The wet mass was dried in tray drier until moisture content in granules reached to 5%. Air-dried granules were screened through sieve #24. Then granules were further mixed with magnesium stearate. The lubricated granules were compressed using 11.6x5.7 capsule shape punches.

EVALUATION OF TABLETS

Pre-Compression Parameters

Bulk Density: An accurately weighed quantity of powder, which was previously passed through sieve #40 [USP] and carefully poured into graduated cylinder. Then after pouring the powder into the graduated cylinder the powder bed was made uniform without disturbing. Then the volume was measured directly from the graduation marks on the cylinder as ml. The volume measure was called as the bulk volume and the bulk density is calculated by following formula:

...

Where, m = Weight of powder

V0 = Bulk volume

Tapped Density: After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 300 taps drop per minute and operated for 500 taps. Volume was noted as (Va) and again tapped for 750 times and volume was noted as (Vb). If the difference between Va and Vb not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following formula:

...

Where, m = Weight of powder

V = Tapped volume

Carr's Index [Compressibility Index]: It is one of the most important parameter to characteristic the nature of powders and granules. It can be calculated from the following equation:

...

Where, Dt = Tapped density

Db = Bulk density

Haussner's Ratio: Haussner's ratio is an important character to determine the flow property of powder and granules. This can be calculation by the following formula:

...

Where, Db = Bulk density

Dt = Tapped density

Value < 1.25 indicate good flow (=20% Carr)

While > 1.50 indicate poor flow (=35% carr)

Between 1.25 and 1.5, adding Glidant will improve flow. The index of Carr is a one point determination and does not reflect the ease or speed with which consolidation occur. Indeed some materials have high index suggesting poor flow but may consolidate rapidly, which is essential for uniform filling on tablet machines when the power flows at nearly equal to bulk density in to the die and consolidates to approaching tapped density prior to compression.

Angle of Repose: The powder was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of granules formed.

...

Where, θ = Angle of repose.

h = Height of powder heap.

r = Radius of the powder cone

RESULTS AND DISCUSSION

All the formulations from Fl to FIO have shown good results for the above evaluation parameters. Compressibility index of all the formulations was found in between 16 to 20, indicates Fair compressibility index. Angle of repose of all formulations is found to be <35 declares that all the formulations are possessing good flow properties. And Hausner's ratio of all formulations was found to be 1.19 to 1.25, which satisfies the limits of compressibility for uniform flow of granules. All formulations were tested for Physical parameters like Hardness, thickness, Weight Variation, Friability and found to be within the Pharmacopoeial limits (Figure 1, 2, 3, 4). The results of the tests were tabulated. The drug content of all the formulations was determined and was found to be within the permissible limit. This study indicated that all the prepared formulations were good.

In the above data burst release was observed in all preliminary trials (F1-F4) because these formulations contain hydrophilic polymer (different grades of HPMC) so to control the burst release hydrophobic polymer (EC) used in F5 but drug release is more retarded. So to get the desired dissolution profile combination of hydrophilic (HPMC 6CPS) and hydrophobic polymer (EC) used in batch no F6-F10.

From above dissolution data it was stated that trial no F9 is more effective compared to all other trials. It given desired dissolution profile as per innovator Formulation F6, F7, F8 given fast drug release, the concentration of EC is not sufficient to release the required concentration of drug at specified time and formulation F10 given more retard in release because of increase in concentration of EC. So formulation F9 taken as an optimized trial and it is compared to innovator product.

Dissolution profile of batch F9 found to be similar compared to innovator's product.

There is no significant change in hardness, friability and assay after stability study.

There is no significant change in in-vitro dissolution profile after stability study.

The optimized tablets from batch F9 were charged for stability studies at 40°C and 75% RH. There was no change in physical appearance, color. Formulations were analyzed at the end of 3 months for general tablet properties like hardness, friability, drug content and dissolution studies. Tablets have shown no much deviation in hardness, friability values. Average drug content of the tablets were found to be 98.5±0.6% of the labeled claim. In-vitro dissolution profile showed that there was no significant change in the release rate of the drug from optimized tablets at the end of 3 months. So the shelf life of tablet was determined as 4 years.

CONCLUSION

Extended release tablets were prepared by using various hydrophobic and hydrophilic polymers like EC, H PC, H PMC etc. and other Excipients. Before the development of extended release tablets, various pre-formulation tests were carried out like bulk density, tapped density, compressibility index, hausner's ratio, solubility, particle size, drug-Excipients compatibility (by physical observation and DSC).

Pre-formulation study of drug shows that the Propafenone hydrochloride is white in color, bitter to very bitter in taste, odorless and has slightly soluble in water. The Propafenone hydrochloride has bulk density 0.663g/ml, tapped density 0.768g/ml, Compressibility index and Hausner's ratio were also good and angle of repose was poor and drug has moisture content of 0.3% w/w. which is within limit. As per drug-excipient compatibility study, results reveal that all selected excipients were compatible with Propafenone hydrochloride.

References

REFERENCES

1. Alfonso R Gennaro; Extended Release and Targeted Drug Delivery Systems, In The Science And Practice Of Pharmacy. 21st Edn. Lippincott Williamsons & Willkins CLwwj. 2005; Vol -1:939-946.

2. Lee Τ W, Robinson J R; In Remington: The science and practice of pharmacy. Gennaro Ed; Lippincott Williams and Wilkins, Baltimore, 2nd Edition. 2000; 903-929.

3. Vyas S Ρ, Khar R K; Polymer. In Control Drug Delivery System. CBS publishers and distributiors. 1st Ed, Vallabh Prakashan, Delhi, India. 2002; 105-155.

4. Lachman Leon, Liberman Η A and Kanig J L; The Theory and Practice of Industrial Pharmacy, Varghese publishing House Bombay. 3rd Ed, 1987; 430-456.

5. Chien Y W; Novel drug delivery systems. Developmental concepts, biomedical assessments, Marcel Dekker Inc. New York, 2nd Edition. 1992; 139-40.

6. Gudsoorkar V R, Rambhau D; Sustained release of drugs, control release drug delivery system. The Eastern Pharmacist, 2nd Ed. 1993; 17-22.

7. Hoffman A; Pharmacodynamic aspects of sustained release preparations. Advance Drug Delivery systems. 3rd Ed. 1998; 185-99.

8. Li V H; Influence of drug properties and routes of drug administration on the design of sustained and controlled release systems. Chapter 1 in Controlled drug delivery: fundamentals and applications, edited by Robinson J R, Vincent Lee. Marcel Dekker Inc, New York. 2nd Ed. 1978; 5-36.

9. M Flu Lu; Control release drug delivery System. Drug Development and Industrial Pharmacy. 17th Ed. 1991.

10. Edith M; Encyclopedia of controlled drug delivery system. New York: wiley-interscience publication- John wiles sonsvol. 1999; 2:938.

11.Nigayale A G; Drug Development and Industrial Pharmacy. A journal of pharmaceutical science. 1990; 16:2-8.

12.Yie W, Chien; Rate controlled drug delivery systems, Marcel Dekker, New York, Revised and expanded, 2nd Ed. 2005; 120-30.

13.Brahmannkar D M, Jaiswal S ?; Biopharmaceutics and Pharmacokinetic, A Treatise vallabh prakashan Delhi, 10th Ed. 2009; 335-346.

14.Jantzen G M, Robinson J R; Sustained- and Controlled-Release Drug Delivery Systems in Modern Pharmaceutics; (Banker G., Rhodes, C. Edts], Marcel Dekker Inc, 3rd Ed. 1996; 196-211.

15.Venkatraman S, Davar N, Chester A, Kleiner L; An Overview of Controlled-Release Systems in Handbook of Pharmaceutical Controlled Release Technology (Wise, D. L. Edt), Marcel Dekker Inc. 4th Ed. 2000; 233-40.

16.Chiao C S L, Robinson J R; factors influencing oral sustain release dosage form. Sustained Release Drug Delivery System; 2nd Ed. 1995; 244-258.

17.Lordi Ν G; Sustained release dosage form, Theory and practice of Industrial Pharmacy. Edited by Lachman, Varghese Publishing House, Delhi. 3rd Ed. 1991; 430-43.

18.Welling Ρ G, Dobrinska M R; Dosing considerations and bioavailability assessment of controlled drug delivery systems, Chapter 6 in Controlled drug delivery fundamentals and applications, edited by Robinson J R, Vincent Lee. Marcel Dekker Inc. 2nd Ed. 1978; 29:254-289.

19.Vyas S Ρ, Khar R K; Controlled drug delivery: concepts and advances. Vallabh prakashan, Delhi. 1st Ed. 2002; 1-150,167.

20.Robinson J R, Lee L Η Editors; Controlled drug delivery fundamentals and application. New York: Informa Healthcare, 2ndEd. 2005; 2:4-35,255.

21.Hui Ho-Wah; Design and fabrication of oral controlled release drug delivery systems, "Controlled drug delivery; fundamentals and applications, edited by Robinson J R, Vincent Lee, Marcel Dekker Inc., 2nd ed. 1978; 391-420.

22.George M, Grass I V, Robinson J; Sustained and controlled release drug delivery system, Modern Pharmaceutics, edited by Banker G S, Rhodes C T; Marcel Dekker, 2nd ed. 1990; 639-658.

23.Xiaoling Li, Bhaskara J R Editor. Design of controlled release drug delivery system. New York: McGraw-Hill Professional Publishing. 2005; 120-12.

24.Nakagami H, Keshikawa T, Matsumura M, Tsukamoto H; Application of Aqueous Suspensions and Latex Dispersions of Water-Insoluble Polymers for Tablet and Granule Coating; Chemistry and Pharmaceutical. Bulletin. 1991; 39(7):1837-1842.

25.Donbrow M, Friedman M; Enhancement of Permeability of Ethyl Cellulose Films for Drug Penetration. Journal of Pharmacy and Pharmacology. 1975; 633-646.

26.Serota D G, Meyer M C, Autian J; The Effects of Structure on the Permeability of Substituted Anilines from Aqueous Solutions Through Polythene; Journal of Pharmaceutical Science. Drug Cosmet Ind. 1970; 107 (3):416-419.

27. Kala H, Dittgen M, Moldenhauer H, Zessin G; On The Pharmaceutical Technology of Film Coating. Pharmazie. 1979; 34(1Γ):134-138.

28.Arshady R; Microspheres and Microcapsules, A Survey of Manufacturing Techniques 1: Suspension and Crosslinking. Polymer Eng Science. 1990; 30(15]:905-914.

29.Arshady R; Microspheres and Microcapsules: A Survey of Manufacturing Techniques. 2: Coacervation. Polymer Eng Science. 1990; 30(15):905-914.

30.Stannett V T, Koros W J, Paul D R, Lonsdlale H K, Baker RW; Recent Advances in Membrane Science and Technology. Advances in Polymer Science. 1979; 32:69-12.

31.Zentner G M, Rork G S, Himmelstein Κ J; Osmotic Flow Through Controlled Porosity Films: An Approach to Delivery of Water Soluble Compounds. Journal of Controlled Release. 1985; 2:217-229.

32.Li L C, Peck G ?; Water Based Silicone Elastomer Controlled Release Tablet Film Coating III - Drug Release Mechanisms; Drug Development and Industrial Pharmacy. 1989; 15(12):1943-1968.

33.Benita S, Donbrow M; Dissolution Rate Control of the Release Kinetics of Water-Soluble Compounds from Ethyl Cellulose Film-Type Microcapsule. International Journal of Pharmaceutics.vo\ume. 1982; 12:251-264.

34.Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y; Hollow Mocrospheres for use as a Floating Controlled Drug delviery System in the Stomach. Journal of Pharmaceutical Science. 1992; 82(2):135-140.

35.Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y; Control of Prolonged Drug Release and Compression Properties of Ibuprofen Microsponges with Acrylic Polymer. Eudragit R S, by changing their Intraparticle Density. Chem Pharm Bull. 1992; 40(1):196-201.

36.Higuchi T; Mechanism of Sustained Action Medication: Theoretical Analysis of Rate of Release of Solid Drugs Dispersed in Solid Matrices. Journal of Pharmaceutical Science. 1963; 52:1145-1149.

37.Theeuwes F; Elementary Osmotic Pump. Journal of Pharmaceutical Science. 1975; 64(12): 1987-1991.

38.Scholsky Κ M, Fitch R M; Controlled Release of Pendant Bioactive Materials from Acrylic Polymer Colloids. Journal of Controlled Release. 1986; 3:87-108.

39.Chafi N, Montheard J P, Vergnaud J M; Dosage Form with Drug Attached to Polymer (Polyanhidride] Dispersed in a Eudragit Matrix: Preparation and Release of Drug in Gastric Liquid. International Journal of Pharmaceutics. 1988; 45(3):229-236.