international journal of pharmaceutical science and ...

Int J Pharm Sci Bio 2010;1(3):155-160

RESEARCH ARTICLE

INTERNATIONAL JOURNAL OF PHARMACEUTICAL

ISSN 2229-3604

SCIENCE AND BIOTECHNOLOGY Available Online at http://www.ijpsb.com

FORMULATION AND EVALUATION OF GLYCERYL TRINITRATE CONTROLLED DRUG DELIVERY SYSTEM *

Kalimuthu Panneer1, Janakiraman Ashokkumar2, Thotlaganahalli Krishnappa Pavithra1, Nanjundan Suresh1, Sundarapandian Ramkanth3

Department of pharmaceutics, sri K.V.college pharmacy,Chickballapur-562101, 2 Department of pharmaceutics, PRIST University,Thanjavur-614904, 3 Annamacharya College of pharmacy, Rajampet,Andhra Pradesh. 1

ABSTRACT Over the past few decades, advances in hydrogel technologies have spurred development in many biomedical applications including controlled drug delivery. Many novel hydrogel-based delivery matrices have been designed and fabricated to fulfill the ever-increasing needs of the pharmaceutical and medical fields. Tablets prepared by dry compression process tablets. The matrix swelling behavior was investigated. The dissolution profiles of formulations were found that increase in the concentration of HPMC, In conclusion results of the present study suggest that drug release kinetics from these formulations corresponding best to zero-order kinetics. The amount of HPMC plays a dominant role for the drug release. The release mechanism of glyceryl trinitrate from matrix tablet formulations follows nonFickian diffusion indicating significant contribution of erosion. Increasing in drug loading resulted in acceleration of the drug release and in anomalous controlled-release mechanism due to delayed hydration of the tablets. Key words: Glyceryl trinitrate, hydrogel technology, HPMC, controlled-release drug delivery.

INTRODUCTION The development of oral controlledrelease dosage forms has attracted much attention in recent years. Hydrogels are being increasingly investigated for controlled-release. In addition the hydrogels have the ability to release the entrapped drug in aqueous medium and to regulate the release by controlling the swelling. Hydrogels can be applied for the release of both hydrophilic and hydrophobic drugs and charged solutes. Hydrogel provide the basis for implantation, transdermal and oral controlled-release systems. Hydrophilic polymers, in particular cellulose derivatives, have been widely used in the formulation of hydrogel matrices which satisfy the key criteria for the development of controlled-release oral solid dosage forms. The hydration rate of these polymers depends on the nature of substitutes and the degree of substitution. Once the polymer hydrates quickly enough to form a gelatinous layer, a change in polymer viscosity will directly change the dissolution rate. Corresponding Author: K Panneer, Department of Pharmaceutics, sri K.V. College of Pharmacy, Chickballapur, Karnataka - 562101. Email:[email protected]

Usually two main mechanisms are involved, diffusion and erosion. In the case of cellulose polymer-based matrix, drug release can be described as being controlled by the rate of swelling. However, drug release in general is not purely swelling controlled, since it occurs mostly as the result of a combination of polymer relaxation and Fickian diffusion. In practice for the controlling and programming of drug release from matrix devices, different types of modified cellulose polymers are usually employed, either alone or in mixtures with other swellable polymers or with hydrophobic polymers which may alter the release mechanism and rate [1,2,3]. Glyceryl trinitrate is an Anti-anginal vasodilators. This is prepared by the nitration of anhydrous glycerol with nitric and fuming nitric acids. Available in the form of oily liquid and it is slightly volatile. The Clinical diagnosis of active substituent may be difficult to obtain, as the early flushing of the skin disappears when hypotension develops. Nitro glycerin is available in different dosage forms such as Tablets for sublingual ( 0.15 to 0.6 mg), Sustained release tablet (1 to 13mg), Solution for intravenous use (0.8 mg/ml

Panneer K, et al.: Formulation and evaluation of Glyceryl Trinitrate Controlled Drug Delivery System


and 5 mg/ml solutions), Ointment (2%), Transdermal system (12.5 to 104 mg), Aerosol spray (0.3 to 0.4 metered dose). Glyceryl trinitrate tablets are instable unless they are stored under air tight conditions and protected from light, It is suggested that glyceryl trinitrate tablets should be dispersed only in glass contains sealed with a foil lined cap without cotton wool wadding [4,5,6].

MATERIALS AND METHOD Diluted nitro glycerin 10% (Diluted with HPMC-EO5), HPMC K- 100 M 1HS, HPMC K-4M 1HS, Lactose DCL-11 BP, Micro crystalline cellulose pH102, Povidone K-30 BP, Glyceryl behanate (compritol) HIS, Purified talc BP, Calcium stearate BP, Erythrosine lake HIS [7]. Direct compression method Micro crystalline cellulose and lactose DCL 11 were milled together and collected in a drum.

HPMC K-100,HPMC K-4,Glyceryl behanate,talc were milled together and collected in another drum. Diluted nitro glycerin USP and the milled MCC/lactose DCL 11 mix were loaded in to a blender equipped with an intensifier bar on. Then, the milled HPMC K-100,HPMC K-4,Glyceryl behanate,talc mix and the Povidone k30 were added to the blender and blended for 15 minutes with the intensifier bar on. Calcium stearate was added to the blender and the materials were blended for 5 minutes.Erythrosine Lake added and blended for 10 minutes. In these formulations lactose,MCC was used as the diluents and binder. Povidone k30 as the disintegrant, HPMC as the stabilizer, Talc as the flow-aid agent and calcium stearate as the lubricant. The powder blends were compressed in to tablets using suitable tablet press machine [8].

Table 1:Working formula:F1-F6 By dry compression method

S No

Ingredients

Trial F1

F2

F3

F4

F5

F6

1

Diluted Nitro glycerin 10 % USP

64 mg

64 mg

64 mg

64 mg

64 mg

64 mg

(Diluted with HPMC- E05 ) 2

HPMC k-100 M IHS

50 mg

60 mg

70 mg

85 mg

92.4 mg

92.4 mg

3

HPMC K-4M IHS

5 mg

10 mg

15 mg

16 mg

16.8 mg

16.8 mg

4

Lectose DCL-11BP

172.7 mg

156.7 mg

140.3 mg

126.2 mg

123 mg

123 mg

5

MCC pH 102 BP

125 mg

120 mg

115 mg

110 mg

105 mg

105 mg

6

Povidone k-30 BP

4 mg

8 mg

10.5 mg

10.5 mg

10.5 mg

10.5 mg

7

Glyceryl behanate (Compritol)

-

-

1.9 mg

1.9 mg

1.9 mg

1.9 mg

8

Purified Talc BP

3 mg

4 mg

5 mg

6.3 mg

6.3 mg

6.3 mg

9

Calcium stearate BP

-

1 mg

2 mg

3.8 mg

3.8 mg

3.8 mg

10

Erythrosine lake IHS

1.272 mg

1.272 mg

1.272 mg

1.272 mg

1.272 mg

1.3 mg

The above guantities are expressed in terms of mg per tablet. IHS- In house specification. * Diluted nitro glycerin shall be dispensed based on assay and LOD ** Lactose DCL 11 shall be adjusted based on the calculated dilute nitro glycerin. Calculation- {Actual qty of Nitro glycerin} =

Standard quantity X 100 X 100 -------------------------------------------Assay on dried basis X (100-LOD)

EVALUATION PARAMETERS Evaluated for both precompression and post compression parameters, they includes Bulk density, Tapped density, Compressed Index, Angle of Repose, Hardness, Friability, Weight variation test, Thickness [9]. Drug Content Five tablets were powdered in a mortar. Weighed accurately the quantity equivalent to 50mg of Diluted Nitroglycerin transferred to a 100ml volumetric flask containing few ml of dis

tilled water and mixed well, made up the volume up to 100ml with distilled water. Pipette out 10 ml from the stock solution into another 100 ml volumetric flask and made up the volume with distilled water. From the above solution withdrew the aliquots of 2ml, 2.4ml and 3.2ml (as per Beer’s range 2-20 μg/ml) and the volume was made up to 10 ml with distilled water. The absorbance was measured at 205 nm using distilled water as blank.(Table 4)



In-vitro release studies [10] Chromatographic conditions Column : C18 Mobile phase : Methanol: water (50:50) Wave length : 220 nm Injection volume : 20µl Flow rate : 1.0ml/mt

Standard preparation: Weigh accurately 75mg of diluted Nitroglycerin USP 10% working standard in a 100ml volumetric flask add 40ml mobile phase sonicate to dissolve and make up to the volume with mobile phase. Sample preparation: Weigh and powder 20 tablets. Weigh accurately powder equivalent to 7.5mg of Nitroglycerin in a 100ml volumetric flask add 40ml mobile phase, Sonicate well and make up to the volume with mobile phase. Filtered through 0.45µ filter paper. Procedure: inject separately 20µl of standard preparation and sample preparation in to the chromatograph and record the response for major peaks and calculate the amount of Nitroglycerin present in tablet. Results is mentioned in table 2. Calculation: Sam. area Std.wt 100 Std.purity (as is) ----------- x ---------- x -------- x -------------------- x Avg.wt Std.area 100 Sam.wt 100 Table 2: Dissolution for (GTN Tablet) Drug Release S No

Time (T) Hours

√T

Log T

1. 2. 3.

1 4 8

1 2 2.83

0 0.602 0.903

Amount Release (mg) 1.12 2.85 5.49

% Drug Release 17.58 44.64 85.74

Curve fitting analysis Dissolution profiles of the formulations were fitted to various mathematical models for describing the release mechanism; KorsmeyerPeppas, Zero-order and Higuchi release models [11,12,13] . Stability studies The optimized formulations were packed in amber colored bottles, which were tightly plugged with cotton and capped. They were then stored at 450C/75% RH and 300 C/65% RH for 3

months. The samples were withdrawn at 15 days intervals and checked for physical changes, drug content and in vitro drug release studies [14].

RESULTS & DISCUSSION

Compatibility studies In order to investigate the possible interactions between glyceryl trinitrate and distinct polymers and/or diluents, FT-IR and DSC studies were carried out. FT-IR results proved that the drug was found to be compatible with excipients as wave numbers are almost similar for pure drug and also drug excipients mixture. FT-IR results proved that the drug was found to be compatible with excipients as wave numbers are almost similar for pure drug and also drug excipients mixture. DSC studies indicate that chosen excipients for the formulation were found to be compatible with the active ingredient as the melting endothermic peaks are in the range of 170240oC which is same as the melting point of glyceryl trinitrate. Evaluation of Matrix Tablets

Evaluation of pre-compression parameters Based on the results of pre-compression tests, all the formulations showed Hauser ratio ranging from 1.0826 to 1.1061 indicating a excellent flow property (Table 3) and Compressibility index ranging from 7.6378 to 9.5967%, indicating compressibility of the powders are excellent (Table 3).

Evaluation of post-compression parameters The tablets of different formulations were subjected to various evaluation tests, such as thickness, uniformity of weight, hardness, friability, and drug content and the result are shown in Table 4. All the formulations showed uniform thickness. The thickness and hardness of the tablets were in the range of 3.89 ± 0.01 to 4.10 ± 0.01 mm and 4.7 ± 0.40 to 5.7 ± 0.40 kg/cm2 respectively. The percentage friability was found to be less than 1% indicating that the friability is within the prescribed limits. In weight variation test, the average percentage deviation of all tablet formulations was found to be within the limit, and hence they met the test as per official requirements and were found to contain 423 ± 0.92 to 443± 1.80 mg of the labeled amount of glyceryl trinitrate indicating uniformity of drug content.


Int J Pharm Sci Bio 2010;1(3):155-160 Table 3: Pre-compression parameters of matrix tablets Formula F1 F2 F3 F4 F5 F6

Formula F1 F2 F3 F4 F5 F6

Bulk density (g/cc) 1.3967 1.3858 1.3963 1.4070 1.3898 1.3923

Weight Variation (mg) 423±1.048 427±1.36 423±0.92 443±1.80 440±1.07 431±1.73

Parameters Tapped density (g/cc) Compressibility Index (%) 1.5122 7.6378 1.5213

8.9068

1.5140 1.5230 1.5321 1.5401

7.7741 7.6165 9.2879 9.5967

Table 4: Post-compression parameters of matrix tablets

Drug Content (mg) 97.76 98.01 97.81 98.20 97.79 97.89

Parameters Hardness (kg/cm2) 5.6±0.40 4.7±0.40 4.9±0.00 5.3±0.40 5.2±0.40 5.7±0.40

In-vitro release Tablets subjected for dissolution studies shown drug release at 1 hr was ranging between 17.58 ± 2.97 to 32.52 ± 0.30%. As the dissolution studies continued, the release from each dosage form showed an incremental release in sustained manner for a long time suggesting a sustained release pattern (Figure 1). The release of the drug at 8 hr varied from 83.01 ± 0.58 to 85.74 ± 3.56 % indicating that the overall drug release from the dosage form depends upon the composition of tablet matrix which varies from one formula to another. From this study it may be concluded, that the independent variables included in the study were found to show significant variation for the response variables. Figure 1: Dissolution profile for matrix tablets Formulations F1 – F6

Thickness (mm) 3.94±0.02 3.90±0.01 4.10±0.01 3.89±0.01 3.91±0.00 3.97±0.01

Hauser ratio 1.0826 1.0977 1.0842 1.1023 1.1023 1.1061

% Friability 0.08±0.00 0.09±0.00 0.03±0.00 0.06±0.00 0.08±0.00 0.05±0.00

not well known or when more than one type of release phenomenon is involved.[15,16]The results for optimized formulation with n value of 0.8776 confirmed that the formulation followed zero order kinetics indicating glyceryl trinitrate release from controlled drug delivery system were by both diffusion and erosion mechanism.

Optimization The optimized formulation (Table 5) was prepared and evaluated for various precompression, post-compression parameters and various responses.Pre-compression parameters of optimized formulation having the Hausner ratio in the range of 1.0958 indicating a excellent flow property and Compressibility Index in the range of 8.4699 % indicating compressibility of the powders are excellent (Table 6). Table 5: Optimized formula for matrix tablets

S No 1 2

(Diluted with HPMC-E05)

Quantity per tablet 64

HPMC K-100 M IHS

92.4

4

Lactose DCL-11 BP

123

6

Povidone K-30 BP

10.5

Purified Talc BP

6.3

3

Curve fitting analysis To study the release kinetics from hydrogel-based matrix tablets, the release data were fitted to the well-known exponential equation (Korsmeyer– Peppas equation) and which is often used to describe the drug release behavior from polymeric systems when the mechanism is

Ingredients Diluted nitroglycerin 10% USP

5

HPMC K-4 M IHS MCC pH 102 BP

7

Glyceryl behanate(compritol)

9

Calcium Stearate BP

8 10

Erythrosine lake IHS

16.8 105 1.9 3.8 1.3

The above quantities are expressed in terms of mg per tablet


Int J Pharm Sci Bio 2010;1(3):155-160 Table 6: Pre-compression parameters of Optimized matrix tablets Parameters Bulk density(g/cc) Tapped density(g/cc) Compressibility Index (%) Hauser ratio

Values 1.3946 1.5237 8.4699 1.0958

ness and drug content after 2 months when it is stored under accelerated stability conditions as per ICH guidelines. Figure2 : Dissolution profile for Optimized formula

Post-compression parameters of optimized formulation having the weight variation in the range of 431±1.32 mg, thickness in the range of 3.95±0.01 mm, hardness in the range of 5.23±0.33kg/cm2 and friability 0.06%, which shows all the post-compression parameters, met the test as per official requirements (Table 7). Table 7: Post-compression parameters of Optimized matrix tablets Parameters Weight variation(mg) Drug content(mg) Hardness(kg/cm2) Thickness(mm) % Friability

Values 431±1.32 97.91 5.23±0.33 3.95±0.01 0.06±0.00

In case of in-vitro dissolution profile the optimized formulation showing drug release at 1 hr was 17.58±2.97, at 4hrs was 44.64±1.05 and release of the drug at 8 hr was 85.74±3.56 indicating that the overall drug release from the dosage form follows zero order drug release profile (Figure 2). Stability studies The optimized formulation was found to be stable in terms of physical appearance, hard-

CONCLUSION The application of experimental design assisted in successfully developing an oral controlled release dosage form for Glyceryl trinitrate. Simplex Lattice design was used to study the effect of different formulation variables on the release profile to select optimized formulation by using numerical optimization technique.Finally it can be concluded that preparation of controlled release drug delivery system is simplified by the use of simple, cost-effective, naturally occurring excipients. This method may be promising in the field of preparation of delayed release dosage form as the drug release profile is complying with USP tolerance.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

Cerri B, Grasso F, Cefis M, Pollavini G. Comparative evaluation of the effect of two doses of nitroderm TTS on exercise related parameters in patients with angina pectoris. Eur heart Jour 1984; 5:710-15. Al-Saidan SM, Krishnaiah YS, Patro SS, Satyanaryana V. In-vitro and in-vivo evaluation of guar matrix tablets for oral controlled release of water soluble Diltiazem HCl, AAPS Pharm Sci Tech 2005;6(1):14 -21. Demots Glasser and the transderm vitro study group. Intermitted nitroglycerin therapy in treatment of table angina. J Am Cou Cardiol 1989;13;786-93. Reichek N, Priest C, Zimrin D, Chander T, John Sutton M. Anti anginal effects of nitroglycerin patches. AMJ cardiol 1984; 54:1-7. Parker JO, Vankoughnett KA,Fung H-L. Transdrmal isosorbide dinitrate in angina pectoris: Effect of acute and sustained therapy. AMJ cardiol 1984; 54; 8-13. Naafs MAB, De Boer AC, Koster R.W. Klazen C W, DunningAj Exercise capacity with transdermal nitroglycerin in patients stable angina pectoris. Eur heart Jour 1984; 5:705-9. Khullar P, Khar RK, Agarwal SP. Evaluation of hydrogel based controlled release Niacin tablets. Drug Dev

8. 9. 10. 11. 12. 13.

Ind Pharm 1998;24(5):479-83. Capella; Roberto L (Landing.NJ), Warner- Lambert company (Morris plains, NJ) compressed nitro glycerin tablet and its method of manufacture. United States Patent April 15, 1999. Lachman L, Lieberman HA, Kanig JL editors. The theory and practice of industrial pharmacy, Varghee publishing house, Bombay, 1991;293-430. Gupta NV, Satish CS, Shivakumar HG. Preparation and characterization of gelatin-poly (methacrylic acid) interpenetrating polymer network hydrogels as a pHsensitive delivery system for Glipizide. Ind J Pharm Sci 2007;69:91-95. Higuchi T. Mechanism of sustained action medication: Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963;52: 1145-49. Lee PI. Novel zero order drug delivery via immobilized nonuniformed drug distribution in glassy hydrogels, J Pharm Sci 1984;73:1344-47. Rinaki E, Valsami G, Macheras P. The power law can describe the ‘entire’ drug release curve from HPMC-


Int J Pharm Sci Bio 2010;1(3):155-160 based matrix tablets: a hypothesis. Int J Pharm 2004;255(1-2):199-07. 14. International conference on harmonization (ICH) guidelines. Stability testing of new drug substances and products. ICH Q1A (R2) 2003 London; CPMP/ICH/2736/99.

15. Huchi WI. Analysis of data the medicament release from ointments. J Pharm Sci 1962;51(8)802-04. 16. Peppas NA. Analysis of Fickian and non-Fickion drug release from polymers. Fitting controlled release and dissolution data. Pharma Acta Helv 1985(60)110-11.
