INTRODUCTION:

The USPNF 23 describes glyceryl monostearate as consisting of not less than 90% of monoglycerides, chiefly glyceryl monostearate (C₂₁H₄₂O₄) and glyceryl monopalmitate (C₁₉H₃₈O₄). Glyceryl monostearate is a white to cream-colored, waxlike solid in the form of beads, flakes, or powder. It is waxy to the touch and has a slight fatty odor and taste. Glyceryl monostearate is a lubricant for tablet manufacturing and may be used to form sustained-release matrices for solid dosage forms. It has also been used in a novel fluidized hot-melt granulation technique for the production of granules and tablets.

The USPNF 23 describes stearic acid as a mixture of stearic acid (C₁₈H₃₆O₂) and palmitic acid (C₁₆H₃₂O₂). Stearic acid is widely used in oral and topical pharmaceutical formulations. It is mainly used in oral formulations as a tablet and capsule lubricant; it has also been suggested that stearic acid may be used as a sustained-release drug carrier.¹

Waxes have been extensively investigated for sustaining the release of drugs. In forming a wax matrix system, different processing methods such as dry blending (direct compression), wet granulation, melt granulation and extrusion spheronization are used.^{2, 3, 4} The sustaining effect by simply incorporating wax into granulation is not sufficient, especially for highly water soluble drugs. It has been reported that formulation and process variables including manufacturing process influences physical properties of the blends and granules and affects the resulted dissolution profiles of tablets.⁵

Melt granulation is the process in which granulation is obtained through the addition of meltable binder which melts/soften at relatively low temperature, after melting binder acts as binding liquid. There is no need of drying steps because dried granules are obtained by cooling it to room temperature. Moreover amount of liquid binder can be controlled precisely and the production and equipment costs are reduced. This method can be used for granulating water sensitive material and producing SR granulation. Melt granulation technique fulfill today’s Pharmaceutical industry need because it is simple, continuous and efficient and also has many advantages over conventional methods of granulation such as wet and dry granulation. ^{6, 7}

Table: 1 Formulation and evaluation of tablet

Formu

lation

Drug: wax

ratio

% drug

content

Hard

Ness

(Kg/

cm²)

Thick

ness

(mm)

Friab

ility

(%)

VPH:GMS

(1:1)

99.88± 0.16

5.6 ±

0.54

5.242±

0.01

0.35±

0.03

VPH:GMS

(1:2)

98.77± 0.76

6.8±

0.44

5.238±

0.01

0.25±

0.01

VPH:GMS

(1:3)

100.0± 0.77

7.6±

0.57

5.243±

0.04

0.34±

0.03

VPH:SA

(1:1)

97.55± 0.27

5.6±

0.50

5.241±

0.02

0.26±

0.03

VPH:SA

(1:2)

95.78±

0.42

6.4±

0.26

5.242±

0.03

0.22±

0.02

VPH:SA

(1:3)

98.25±

2.05

7.8±

0.57

5.237±

0.04

0.24±

0.04

VPH:GMS

:SA(1:1:1)

96.98±

0.78

8.2±

0.68

5.241±

0.04

0.19±

0.03

VPH:GMS

:SA(1:2:1)

98.10 ±

0.32

8.4±

0.32

5.245±

0.03

0.144±

0.01

VPH:GMS

:SA(1:1:2)

99.88±

0.16

9.1±

0.87

5.250±

0.04

0.36±

0.02

Verapamil hydrochloride (VPH) is a calcium channel-blocking agent used in the treatment of angina pectoris, hypertension and cardiac arrhythmia. It is completely absorbed from the gastrointestinal tract. Its biological half-life is 4 to 6 hours with a usual dose of 40 to 240 mg three times a day. Because of the high frequency of administration and short biological half-life, Verapamil hydrochloride was considered as an ideal drug for designing SR formulation. ^8,
9

Hence present study was aimed towards formulation and in-vitro evaluation of sustained release matrix tablet of Verapamil hydrochloride by melt granulation technique by using Glyceryl monostearate (GMS) and Stearic acid (SA) as meltable binders to reduce dosage regimen, better therapeutic efficacy and improved patient compliance with less toxicity.

MATERIALS AND METHODS:

Materials:

Verapamil hydrochloride was obtained as gift sample from Ranbaxy Research Laboratories, Gurgaon, Glyceryl monostearate and Stearic acid were obtained as gift samples from Colorcon Asia Pvt. Ltd., Goa. Excipients and other chemicals used in preparing matrix tablets were of analytical grade.

Methods:

1. Preparation of Matrices by Melt granulation:

The Glyceryl monostearate and Stearic acid individually melted in porcelain dish on a water bath maintained at constant temperature of 75⁰C. The Verapamil HCl was gradually added to the molten wax with continuous stirring. The molten mixture was allowed to cool and solidified at room temperature. The drug was present in its solid form within the molten mixture. The solidified mass was pulverized in mortar and sieved through a 16 # screen¹⁰ Sustained release matrices of Verapamil HCl with Glyceryl monostearate and Stearic acid (1:1, 1:2 and 1:3 for each batch) and with combination of both waxes (1:1:1, 1:1:2 and 1:2:1) were prepared. (Table 1)

Figure 1: Kawakita plot

Fig.2: IR spectrum of Verapamil, meltable binders and matrices of Verapamil and meltable binder

Fig. 3: Dissolution profile of formulation F1, F2, F3 containing GMS and marketed product (M)

Table 2: Values of slope ‘m’, ‘a’, ‘b’ and coefficient ‘r’ from Kawakita plots

Formulation	m (slope)	a	b	r
F2	4.633	0.2158	0.3414	0.9972
F5	3.845	0.2600	0.3547	0.9978
F8	7.797	0.1282	0.4435	0.9971

2. Evaluation of sustained release matrices:

Granules were evaluated for various parameters such as particle size distribution, angle of repose, bulk density, compressibility index, Hausner’s ratio^{11, 12} and Kawakita plot.

Kawakita plot: ¹³

The flowability and compaction behavior of the granules was also studied by using Kawakita plot on formulation F2, F5 and F8. The reduction in volume after tapping (using measuring cylinder) was noted. And the plot of number of tapping Vs the degree of volume reduction was plotted and the values of ‘a’ and ‘b’ were calculated by using equation,

n/c = n/a+1/ab

Where, 'n' is the number of tapping, 'c' is the degree of volume reduction equal to

C= (V₀-V_∞)/V₀

Where, V₀ is initial volume before tapping and V∞ is volume after tapping.

Drug: wax interaction study:

Pure drug, wax and prepared matrices were subjected to IR spectroscopic study using FTIR spectrophotometer (Shimadzu, 8400S, Japan).

3. Preparation of Tablets:

The granules passed through 16 # sieve were mixed with lactose and compressed into a tablet with 10 mm deep concave punch using single punch tablet machine (Cadmach mach. Comp, CMS, H/338/88)

4. Evaluation of Tablets:

Prepared tablets were evaluated for thickness, weight variation, drug content, hardness, friability and in-vitro release studies.¹⁴

In-vitro dissolution study:

In-vitro drug release study for the prepared matrix tablets was conducted for period of 8 hours using a six-station USP XXVII type I (basket) apparatus at 37⁰C ± 0.5⁰C and 100-rpm speed. The dissolution studies were carried out in acid buffer of pH 1.2 for one hour and in Phosphate buffer pH 6.8 for further seven hours under sink condition. At one hour and then 2, 3.5, 5 and 8 hours interval samples of 5 ml were withdrawn from dissolution medium and replaced with fresh medium to maintain the volume constant. After filtration the sample solution was analyzed at 278 nm for Verapamil HCl by a UV-spectrophotometer. The amounts of drug present in the samples were calculated with the help of appropriate calibration curve constructed from reference standard. Also the in-vitro drug release study for the marketed tablets (Calaptin SR 120 mg) was conducted.¹⁵

Figure 4: Dissolution profile of formulation F4, F5, F6 containing SA and marketed product (M)

RESULTS AND DISCUSSION:

1. Preparation of Matrices by Melt granulation:

It was easy to prepare sustained release matrices of Verapamil HCl by melt granulation technique.

2. Evaluation of Granules:

Result of particle size distribution showed that the amount of fine powder (size < 250µm) and the amount of big lumps (size > 1000 µm) were low. The main fraction was 250-1000 µm and maximum percentage of granules was present in this range. The angle of repose of matrices of all the formulations was found to be in the range of 13⁰.19^’ to 16⁰.55’ indicating excellent flow property. The loose bulk density and tapped bulk density for all the formulations varied in the range of 0.387±0.02 gm/ml to 0.699±0.03 gm/ml and 0.461±0.04 gm/ml to 0.873±0.06 gm/ml respectively. The values obtained lies within the acceptable range. These results may further influence properties such as compressibility and tablet dissolution. The percent compressibility for all formulations lies within the range of 14.79± 0.04 to 21.05±0.02 and Hausner’s ratio was found to be in the range of 1.17±0.01 to 1.26± 0.04 showed that all formulations showed good compressibility and good flow properties.

Kawakita plot:

Kawakita plot is used to analyze the behavior of powder from the bulk density state to the tap density state. The constants ‘a’ and ‘b’ of Kawakita plot were determined from the slope and intercept of graph of n/c versus number of tapping. The value of ‘a’ indicated compressibility or densification due to tapping and ‘b’ as rate of achieving final packing. The small value of ‘a’ and high value of ‘b’ indicated good flowability and small cohesiveness.

The studies on Kawakita plot for formulation F2, F5 and F8 showed that the value of ‘a’ was least, and ‘b’ was maximum in granules of all three formulations indicating good flowability as seen in table 2 and figure 1.

Drug: wax interaction study:

Spectrum of prepared granules were compared with that of pure drug IR spectra and were found to show no significant change in the appearance of characteristic peaks of pure drug spectra. This indicates that the drug is compatible with the meltable binders such as Glyceryl monostearate and Stearic acid. (Figure 3)

3. Preparation of Tablets:

Verapamil HCl tablets were prepared successfully by melt granulation technique.

4. Evaluation of Tablets:

In weight variation test, the Pharmacopoeial limit for percent of deviation for tablets of more than 250 mg is ± 5%. The average percent deviation of all tablets was found to be within the limit and hence all formulations passed the weight variation test. The drug content was found to be uniform among all formulations and ranged from 97.55 ± 0.27to 100.0 ± 0.77%. The hardness of tablets of all formulations were in the range of 5.6 ± 0.50 to 7.6± 0.57Kg/cm². As the concentration of lipophilic binder increases, cold welding of waxes increases in melt granules and therefore tablet hardness increases.¹⁶ The friability of tablets of all formulations was in the range of 0.25±0.01to 0.35±0.03% i.e. less than 1%. The thickness

of tablets ranged from 5.238±0.01 to 5.243±0.04. All formulations showed uniform thickness.

In-vitro dissolution study:

Effect of different drug: wax ratio on drug release:

Effect of different drug: wax ratio (F1 to F9) on release profile of Verapamil HCl was studied and it was found that as concentration of wax increases, release of Verapamil HCl from tablet decreases (Figure 3, 4, 5). It may be due to the slower penetration of dissolution medium in matrices due to increased lipophilicity of waxy substances.¹⁷

Results also showed that release of F2 formulation containing VPH: GMS (1:2) was equivalent to that of marketed formulation.

Effect of combination of waxes on drug release:

The release of Verapamil HCl from matrices of combination of waxes get more retarded than that of GMS and SA used alone, it may be due to higher lipophilicity offered by combination of waxes.

Effect of release enhancers such as MCC and Lactose:

From results it was found that as concentration of MCC and Lactose increases release of Verapamil HCL increases. Results also showed that use of lactose produces a higher release of drug compared to MCC. It was due to rapid solubility of lactose and a tendency to form pores in matrix which allow the dissolution medium to penetrate the matrix and dissolve the drug.¹⁸

Figure 5: Dissolution profile of formulation F7, F8, F9 containing GMS and marketed product (M)

CONCLUSION:

Among all the formulations, F₂ containing 20% of Glyceryl monostearate showed in-vitro drug release 87.17±1.44 % and which is equivalent to marketed preparation hence considered as most promising formulation. Results also showed that among meltable binder GMS and SA, GMS sustain more drugs than SA. Combination of GMS and SA retain drug more than that of individual meltable binder. From the results of effect of release enhancer such as MCC and Lactose it can conclude that the control of these factors can be successfully used to modulate the release rate from matrices. Hence the study was concluded that Glyceryl monostearate and stearic acid are appropriate waxy material that can utilized as matrix forming agent in melt granulation technique to sustain the release of water soluble drug such as verapamil hydrochloride.

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Formulation

m (slope)

a

b

r

F2

4.633

0.2158

0.3414

0.9972

F5

3.845

0.2600

0.3547

0.9978

F8

7.797

0.1282

0.4435

0.9971