INTRODUCTION:

The aim of drug delivery system is to deliver a therapeutic amount of drug to a suitable site of the body, to promptly accomplish and continue the desired therapeutic drug concentration that elicits the desired pharmacological action and to diminish the incidence and severity of undesirable adverse effects.¹ The oral route of administration for sustained release systems has received greater attention because of more flexibility in dosage form design.² Oral administration of drugs has been the most common and preferred route for delivery of most therapeutic agents. The popularity of the oral route is attributed patient acceptance, ease of administration, accurate dosing, cost effective manufacturing method and generally improved shelf-life of the product.³ Majority of the drugs absorption is more in upper part of small intestine (duodenum), for a drug to reach the small intestine it had to pass through stomach.⁴

So, drug absorption depends on gastric emptying time. If the gastric emptying is simply too fast drug may not absorb to required level or if it too slows it should get mix-up with gastric contents and will adsorb to food which gives unintended effects. Mini tablets having a reproducible plasma drug concentrations. Plasma drug concentration is unswervingly proportional for the absorption.⁵ These effects are more in case of single unit dosage forms because of their size but in case of mini tablets will not depend upon gastric emptying and easily get skilled pylorus. In case of a large size of tablets there is diminish intra and inter subject variability.⁶ Mini tablets are easily separated and administered without loss of activity. Elderly and paediatric patients who sometimes chew the tablets which releases drug all right away and should cause toxicity in case just in case of normal tablet but in circumstance of Mini tablets they can be chewed as now each mini tablet depot in a formulation act independently dose dumping may not occur.⁴

Drotaverine hydrochloride is 1-[(3, 4-diethoxy phenyl) methylene group]-6,7-diethoxy-1,2,3,4- tetra hydroisoquinolene is an equivalent to papaverine.⁷ It is phosphodiesterase IV enzyme inhibitor acts as an spasmolytic agent, It mainly used for smooth muscle spasm and aching, used to reduce unnecessary work pain.^8,9 Drotaverine HCl is a practically soluble drug which is having a same bitter taste and the patients are reluctant to its taste when normal tablet is set aside on tongue during swallowing.¹⁰Hence mini tablets of Drotaverine HCl were prepared for upgrading in its solubility and dissolution rate for patient compliance and improved bioavailability.

MATERIALS AND METHODS:

Drotaverine hcl pure drug was received as a gift from Shree swami Samarth Ayurvedic Pharmacy (Allopathic division) Jalgaon. other excipients like Gallen Gum, Carbopol 940, PVP k30, Talc, Mg Stearate and Lactose were purchased from S.D. Fine Chem. Ltd. Mumbai

Preparation of Drotaverine HCl Mini Tablet:

Drotaverine HCl mini tables were prepared by direct compression method. All the powders conceded over a ‘’60’’ mesh sieve. The vital quantity of drug, The countless polymer mixtures and diluent were varied thoroughly in a polybags. The blend was lubricated with the magnesium stearate for 4‐5mins and talc was added as a glidant were the blended was compressed into a mini-tablet weighing 75 mg by using 5 mm circular convex punches in a rotating tablet press of (Rimek Tiny press, classic RSB/4 M.S: “Karnavati industries” Ahmedabad). All the tablets were stored in the airtight containers for further study. (Table 1)

Figure. 1 Prepared Mini Tablet of Drotaverine hydrochloride

Evaluation of pre-compression parameters:

Dry powder blends of all formulations (F1- F9) were subjected for evaluation of pre-compression parameters such as Bulk density, Tapped density, Carr’s index, Hausner’s ratio, Angle of repose as per the standard procedure given in IP. All studies were passed out in triplicate (n=3) and usual values were reported. Drug excipients compatibility studies were done by FTIR and DSC.¹¹

Bulk Density:

Accurately weighed 5g powder of blends from each formulation which was previously passed through 20 # sieve, and then transferred in to 10 ml measuring cylinder. The powder in the cylinder was levelled without compacting, and unsettled apparent volume (V0) was noted. The deceptive bulk density (gm/ml) was calculated by the following formula:

wt. of powder

BD= -----------------------------------

Volume of the packing

Tapped bulk density

Accurately weighed 5g of powder blends from each formulation, previously lightly shaken to break any agglomerates formed; were introduced into a 10 ml measuring cylinder. Then the cylinder comprising the sample was reflexively tapped by raising the cylinder and allowing it to drop under its own weight by using instinctively tapped density tester that provides a fixed drop of 15± 2 mm at a nominal rate of 300 drops per minute. The cylinder was tapped 500 times initially and the tapped volume (V1) was leisurely to the nearest graduated units, the tapping was recurrent an extra 750 times and the tapped volume (V2) was leisurely to the near graduated units. If the difference between two volumes is less than 2% then the final volume (V2). The tapped bulk density in gm/ml was calculated by the following formula:

Wt. of the powder

Tapped Density = -----------------------

Tapped volume

Table 1: List of the ingredient for different batches of mini tablet of Drotaverine HCl

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Drotaverine	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Gallen Gum	15	30	45	15	30	45	15	30	45
Carbopol 940	4	4	4	8	8	8	12	12	12
PVP k30	8	8	8	8	8	8	8	8	8
Talc	1	1	1	1	1	1	1	1	1
Magnesium stearate	1	1	1	1	1	1	1	1	1
Lactose	38.5	23.5	8.5	34.5	19.5	4.5	30.5	15.5	0.5
Total	75	75	75	75	75	75	75	75	75

Note: All ingredients taken in mg.

Compressibility Index:

The Compressibility Index of powder blend was resolute by Carr’s compressibility index. It’s a modest test to evaluate the BD and TD of a powder and the rate at which it is filled down. The formula for Carr’s Index is less.

Tapped Density – Bulk Density

Carr’s Index = ------------------------------× 100

Tapped Density

Hausner’s Ratio:

It shows the flow properties of the granules and is restrained by the ratio of tapped

density to the bulk density.

Tapped density

Hausner’s Ratio = ---------------

Bulk density

Angle of repose:

The angle of repose of Drotaverine HCL powder was determined by the funnel method. The accurately weight of powder blend were taken in the funnel. The stature of the funnel was attuned in such a way the tip of funnel just touched the apex of powder blend. The powder blend was permitted to flow through the funnel spontaneously on to the surface. The diameter of powder cone was restrained and the angle of repose was calculated using the following equation.

tan θ = h/r

Where, h and r are the stature and radius of the powder cone singly.

Evaluation of pre-compression parameters:

Tablets were evaluated for their thickness, weight uniformity, hardness, friability, disintegration tine and dissolution profiles by using standard procedure^.11,12

Appearance:

The thickness of the tablet as dimensional impulsive was evaluated. The tablet thickness was controlled inside average cost. The colour, odour then other flaws like fries, cracks, shallow texture etc. and other important of morphological characteristics were observed.

Thickness and Diameter:

The Thickness of the tablet is an imperative for the uniformity of tablet size. The thickness and diameter of mini tablets stood measured with the help of vernier calliper. It was determined by checking of the thickness of ten tablets of each formulation. The regular diameter and thickness of tablet was calculated. The test was passed if none of the individual diameter and thickness value deviated by ± 5% of the standard average.

Weight variation test:

For the Tablet are weighing 40mg or more, Thane weight of the tablet being made was frequently determined to ensure that a tablet contains the proper amount of drug. The USP weight variation test is thru by considering of 20 tablets exclusively and shrewd the average weight and comparison the individual weights to the average. The tablets saw the USP specification that non more than 2 tablets are exterior the fraction limits and no tablet varies by extra than 2 times the percentage limit. The tablets were weighed exclusively and the weight variation was determined.

Hardness test:

Tablet hardness is defined as force essential to shipping or breakage under circumstances of storage, carriage and handling before usage depends on its hardness and crushing the tablet in diametric compression test. The hardness was restrained with the Monsanto hardness tester. The hardness was leisurely in terms of kg-cm². 4 tablets were selected randomly and tested for hardness. The tablets stayed sited utterly between two plungers and lower plunger is kept in contact of tablet to recite as zero. The upper plunger is obligatory against a spring by revolving the screw until tablet fractures.

Friability test:

Friability is mostly raises to lose weight of tablets in the containers owing to removal of fines from the tablet exterior. Twenty ‘’20’’ tablets were weighed and imperilled to friability test in Roche friabilator. The pre-weighed sample was sited in friabilator which revolves at 25rpm for 4minutes dipping the tablets through a distance of 8inch with each revolution. This method was recurring for all formulations and the percentage friability was calculated.

Initial wt. of tablets - Final wt. of tablets

% Loss = --------------------------------------- x 100

Initial wt. of tablets

Drug Content uniformity:

The tablets stayed tested for the drug content uniformity. Casually certain 4 tablets were evaluated and powdered. The powder equivalent to 30mg of Drotaverine HCl was weighed accurately and softened in 100ml of 0.1 N HCl in water. The solution was dazed thoroughly. The undissolved material was detached by filtration over Whatman No.41 filter paper. Then the sequential dilutions were carried out. The absorbance of the diluted solutions stood measured at 234 nm. The concentration of Drotaverine HCl was determined by using UV.

In vitro dissolution profile of formulation batches:

Mini-tablets were imperiled to in-vitro drug release studies in virtual gastric and intestinal fluids to evaluate their cleverness in providing the desired controlled drug delivery. Drug release studies were official out using USP dissolution test apparatus II at 100rpm, 37±0.5°C and 0.1 N HCl (900 ml) for 2 hours. then there average gastric emptying time is around 2 hours. The dissolution medium was replaced with 0.1 N HCl (900ml) and experiment continued for another 10 hours. At different time interludes, 1ml of the samples were withdrawn and changed with 1ml of dissolution medium. The samples withdrawn stood analyzed by UV spectrophotometer by using multi component mode of analysis at 234, 276 nm wave length^.

Kinetics of drug release:

The drug release which studied by PCP Disso Version 3 software to study the kinetics of drug release mechanism.

Stability Studies:

On the source of in vitro evaluation for all formulation batches in a various parameters, formulations were bursting in a thick aluminium foil and stowed in stability chambers (Thermolab) for the accelerated stability studies. The tablets were kept in the stability chamber at the controlled circumstances of temperature and virtual humidity. The stability of tablets was considered for the dimension of 90 days at a temperature 40⁰C ± 2⁰C and 75% ± 5% of relative humidity. The tablets were then evaluated for the several parameters viz. hardness, thickness, and weight variation and the release studies.

RESULT AND DISCUSSION:

Mini tablets of Drotaverine HCL (F1 to F 9) were prepared with direct compression method by using various polymers such as Gellan Gum and Carbopol 940. All batches were evaluated by various pre compression and post compression evaluation parameters.

Pre-compression Evaluation of powder:

Blend of all tablet formulation were subjected for various evaluation such as Angle of repose, Bulk and Tapped density, Compressibility, Hausner’s ratio, Car’s index. Result of all pre compression parameters shows good flow characteristics, and compressibility index. The pure drug and the solid admixture of drug and various polymers used in the preparation of muccoadhesive tablet formulation were characterized by FT-IR spectroscopy and DSC to know the compatibility. There was no significant difference and characteristic peaks of pure drug were unchanged in spectrum of tablet formulation.

Table 2: Pre-compression Parameters of Powder.

Formulation	Bulk density(g/ml)	Tapped density(g/ml)	Car’s index (%)	Hausner, ratio	Angle of repose
F1	0.44±0.013	0.52±0.027	11.72±0.75	1.13±0.058	26°.12±0.22
F2	0.50±0.009	0.58±0.25	13.78±0.60	1.16±0.036	27°.18±0.49
F3	0.46±0.010	0.53±0.022	13.20±0.38	1.15±0.044	28°.32±0.76
F4	0.47±0.010	0.56±0.029	13.58±0.49	1.16±0.012	27°.21±0.30
F5	0.48±0.015	0.55±0.034	12.72±0.45	1.14±0.039	26°.19±0.88
F6	0.49±0.013	0.56±0.027	12.50±0.30	1.14±0.078	25°.22±0.17
F7	0.46±0.019	0.52±0.056	11.43±0.66	1.13±0.080	28°.58±0.20
F8	0.51±0.022	0.59±0.017	13.55±0.42	1.15±0.036	29°.21±0.2
F9	0.50±0.010	0.53±0.026	13.73±0.18	1.12±0.028	25°.42±0.38

Figure 2: FT-IR spectra of Drotaverine HCl

Figure 3: FTIR spectrum of Drotaverine with Gellan Gum

Figure 4: FTIR spectrum of Formulation blend

Figure 5: DSC of Pure Drug Drotaverine Hydrochloride

Figure 6: DSC of drug Excipients Compatibility Analysis

Table 3: Post-compression Parameters of Mini Tablet

Formulation batches	Thickness (mm) (±SD),	Hardness (kg/cm²) (±SD)	Friability (%) (±SD)	Weight variation (mg) (±SD)	Disintegration time (sec)	Drug content (mg ± SD)
F1	1.86±0.12	3.65 ± 0.319	0.32	76.51 ± 1.78	127	87.43 ± 3.07
F2	2.51±0.059	3.30 ± 0.264	0.50	74.06 ± 0.89	144	94.23±0.65
F3	2.47±0.038	3.30 ± 0.211	0.45	74.61 ± 1.40	162	93.89±0.57
F4	1.96±0.13	3.25 ± 0.078	0.56	73.36 ± 1.14	186	91.53±0.58
F5	2.62±0.021	3.70 ± 0.337	0.62	75.02 ± 0.83	206	97.35±0.89
F6	1.95±0.20	3.10 ± 0.257	0.68	74.16 ± 1.49	220	90.43 ± 3.86
F7	2.37±0.027	4.10 ± 0.564	0.47	73.06 ± 2.07	234	95.35±0.69
F8	2.46±0.054	4.40 ± 0.580	0.59	73.08 ± 1.64	248	88.55 ± 2.94
F9	2.49±0.076	4.20 ± 0.273	0.49	74.08 ± 0.85	278	92.76 ± 3.78

Table 4: In-vitro of dissolution studies of formulation batch F1-F9

Time/Batch Code	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	8.30	6.25	9.52	8.77	10.9	6.20	6.30	9.30	12.6
2	16.3	21.3	19.5	16.5	15.4	12.1	9.50	11.3	16.5
3	21.6	24.9	22.5	19.5	18.5	14.4	21.7	18.7	31.4
4	25	29.1	27	23.4	23.3	18.5	28.1	29.7	38
5	32.2	34	32.5	28	29	23.8	36	41	44.3
6	40.3	40.2	37.8	34.2	35.7	30	47.1	53	48.3
7	48.8	46.2	44.7	41.7	43.6	37.2	55.3	56.4	52.9
8	56.6	54.3	52.3	50	52.6	45.8	61.7	60	58.6
9	66.4	63.6	60	60.4	62.7	55.4	70	65.4	65.9
10	71.5	72.7	71.2	71.7	74	66	77.2	71.1	73.8
11	79.5	84.2	80	81.7	86.2	77.2	86.2	77.2	83.2
12	87.6	95.2	92.7	94.7	97.7	90	95.2	93	91.6

Figure 7: 11In vitro % release of Drotaverine Hydrochloride

Post-compression evaluation of formulation batches:

The Mini tablets were evaluated for weight variation, hardness, thickness, friability, drug content, and in-vitro dissolution studies. Results are given in table 3.

In vitro dissolution profile of formulation batches:

The dissolution study of Optimized batches was performed in USP dissolution test apparatus, the release of drug is ranges from 87.6 to 97.7%. The formulation batch FB5 shows best drug release. The details of values of drug release data are given in table 5.

The in-vitro drug dissolution of all test and factorial designed formulations was considered in 0.1 N HCl. Each of the tablet in all the formulations contain7.5mg of Drotaverine Hydrochloride, Gellan Gum and Spray dried lactose as straight compressible vehicle. The percentage of drug release was initiate to be in the range of 87.62 to 99.72% and 90.68 to 91.44% respectively. The results show that is improved rate of release of drug gradually decreases. They rank in the fallowing order F1 to F9. Also, the in-vitro release data was subjected to blimey of fit test by linear regression analysis according to zero order, first order kinetic equations, higuchi equation, korsmeyer peppas and Hixson-crowell, models to determine the scheme of drug release. The result of linear regression analysis of data counting regression coefficient and the study was displays that mini tablet of Drotaverine hydrochloride follows the korsmeyer peppas release order kinetic.

The formulation F5 was the best formulation by using Gellan Gum and Carbopol and it was following zero order kinetics.

Kinetics of drug release:

The results showed that the factorial design batches followed Zero Order models shown table 4. The rate of drug release from the mini tablet is swift initially followed by progressively slow drug release through the tablet. The slow release of the drug from they may be due to the formation of Gellan Gum and Carbopol 940.

Table 5: Drug release kinetics of the optimized batch

Batch code	R²
Batch code	Zero order	1st order	Peppas	Hixson Crowell
F 5	0.9848	0.9690	0.9166	0.9814

Stability Studies:

The stability of the tablets was studied for the extent of 3 Months at temperature 40⁰C ± 2⁰C and 75% ± 5% relative humidity. The tablets was then evaluated for various parameters viz. thickness, hardness, and drug content and release studies.

Table 6: Stability studies

Sr. no	Parameters	0 Months	After 3 Months
1	Drug release	97.72 %	96.26 %

Figure 8: Stability Study

CONCLUTION:

In conclusion, we reported here the formulation of Drotaverine Hydrochloride mini tablet were prepared by using design of experiment and optimized with the help of response surface methodology. The prepared Mini tablets exhibited satisfactory physic-chemical characteristics. All prepared batches shown good in-vitro dissolution studies. The formulation F 5 was found to be optimized with desirable properties, which gives drug release 97.72% in 12hrs. Therefore, Drotaverine Hydrochloride mini tablet can be conveniently administered orally as sustained release formulation.

CONFLICT OF INTEREST:

The authors have no conflict of interest regarding this investigation.

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Received on 13.10.2021 Modified on 28.12.2021

Asian J. Pharm. Tech. 2022; 12(1):6-12.

DOI: 10.52711/2231-5713.2022.00002