INTRODUCTION:

The release of active pharmaceutical ingredient from drug product, the dissolution of the drug under physiological conditions, and the permeability across gastro-intestinal tract determine drug absorption. Based on this, In vitro dissolution may be vital in assessing in vivo Dissolution testing serves as tool to distinguish between acceptable and unacceptable products.

It is also used to assess the lot-to-lot quality of drug product and can guide the development of new formulations. The development of dissolution procedure involves selecting the dissolution medium, apparatus, and agitation rate appropriate to the product.

It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus Pioglitazone Hydrochloride 15mg tablets helps control the level of sugar in type 2 diabetes by make better use of the insulin it produces. Metformin is an oral diabetes medicine that helps control blood sugar levels. Metformin is used to improve blood sugar control in people with type 2 diabetes. It is sometimes used in combination with insulin or other medications.

EXPERIMENTAL:

1. Materials:

The marketed brands PIOGLIT® MF-15, PIOZ MF-15 and PIOMED-MF-15 containing the combination of Pioglitazon and metformin Hydrochloride (15,500mg strengths) were procured from the commercial market, PIOZMF15 (mfg.date:01/2016,exp.date: 12/2017) PIOGLIT®MF15 (mfg.date:07/2015, exp. Date:06/2017) and PIOMED-MF15 (mfg.date:12/2015, exp.date:11/2015). Hydrochloroic acid, sodium hydroxide and potassium dihydrogen phosphate used,distilled water was used throughout the study. USP dissolution apparatus (Labindia) and UV-Visible spectrophotometer (shimadzu) were used.

2. Method:

a. QC test on Pioglitazon and metformin Hydrochloride tablet the common available three different brands containing the combination of Pioglitazone and metformin Hydrochloride were subjected to different QC tests like hardness, friability weight variation, disintegration, dissolution studies. The detailed procedure is presented below:

1. Hardness:

(Crushing strength) Tablets require a certain amount of strength, or hardness to withstand the mechanical shocks of handling and transportation yet soft enough to be able to disintegrate properly after swallowing. Since there is also a relationship between hardness and disintegration rate of the tablets, it is essential that the hardness of the tablets are within the acceptable range. Tablets with increased hardness values tend to have increasing disintegration time. Make hardness test on 5 tablets and then take the average hardness.

2. Friability:

It is the tendency of the tablets to power chip or fragment and this effect the elegance appearance or consumer acceptance of the tablet. It is a property that is related to the hardness of the tablet. An instrument called fribilator (roche) is used to evaluate the ability of the tablet to with stand abrasion in packaging, handling and shipping. 10 tablets were weighed all together (w1) and put these tablets in the friabilator and adjust the instrument at 100rpm (i.e25rpm for 4minuts) .10 tablets were weighed (only the intact once w2) then calculated it must be less than to 1%.

3. Weight variation test:

This test was conducted for three brands of Pioglitazone metformin Hydrochloride. A total of 20 tablets were weighed and then average weight was calculated. Then individual tablets was weighed and finally tablet percentage deviation was calculated by using the below mentioned formula.

Average weight – Individual Weight

%Deviation =______________________________x 100

Average weight

4. In vitro drug release studies:

Three different brands of pioglitazone and metformin hydrochloride tablets were subjected to dissolution studies. In vitro dissolution test was performed on dissolution tester using USP apparatus-2 with 900ml of medium at 37±0.5°C. The stirrer speed was 75rpm and the dissolution media is 0.1N HCl (4) and phosphate buffer I.P (pH6.8) (5). At regular intervals of 5 minutes, 5ml of sample was collected up to 45minutes for pioglitazone.hcl and then up to10hours for Metformin.hcl. Then same volume was replenished with fresh dissolution medium. The withdrawn samples were filtered through whatmann filter paper no.41, and analysed with UV-visible spectrophotometer at a maximum wavelength of 269,233nm respectively for pioglitazone and metformin .

Drug release kinetics:

The data obtained from Invitro release study was fitted into kinetics equation. The kinetic model used in first order (log cumulative percent drug release versus time). Regression coefficient and k value was calculated from linear curves obtained by regression analysis. Dissolution efficiency (DE) was computed as follows for comparison of three commercially available brands of pioglitazone and metformin hydrochloride:

½(C1+C2)(t2 – t1) + ½½(C1+C2)(t2 – t1)

DE = ___________________________________

T x 100

Where T= Time taken for the drug to dissolve in the medium.

The release data obtained were fitted to zero order (6), first order (7), Higuchi (8) and korsmeyer peppas(9-11) equations to determine the corresponding release rate and mechanism of drug release from bilayer tablet.

RESULT AND DISCUSSION:

Hardness Test:

Different brands of marketed tablets were measured using Monsanto hardness tester. The hardness was found to be 4.7kg/cm².

Friability Test:

The friability value was found to be less than 1%. Hence the tablet compiles friability test as per I.P.

Weight Variation Test:

The weight variation test was done for four different marketed brands. The tablets satisfied the pharmacopeial requirements.

Invitro Dissolution Studies:

The Invitro dissolution studies was done for three commercially available brands of pioglitazone and metformin hcl in dissolution media and the results are showed in graph 1 and graph 2.

Graph 1: Invitro dissolution profile of pioglitazone hydrochloride

Graph 2 : Invitro dissolution profile of Metformin hydrochloride

The pioglitazone release from all brands followed first order kinetics as the graphs drawn between time and log% drug undissolved was found to be linear. The Metformin release from all brands followed zero order kinetics as the graphs drawn between time and amount of drug dissolved was found to be linear. Various Invitro dissolution parameters with respect to pioglitazone was computed and presented in table 1 the observed parameters were subjected to one way anova followed by Dunnetts T test to detect the statistical Significances. Significant differences were noticed among these formulations. Based on DE values the formulations can be ranked as f2>f1>f3, and based on K values, they can be ranked as f3>f2>f1. As per USP requirements, the amount of Metformin to be released from extended release formulations at 1,3and10hrs is 20-40%, 45-65%and not less than 85%. All the marketed formulations satisfied this requirements and the observed %drug release data is presented in table2.

Table 1: Invitro dissolution kinetics of pioglitazone HCl

Brands	Correlation coefficient(r)		K value		T₅₀(Min)	T₉₀(Min)	DE10
Brands	Zero order	First order	Zero order mg/min	First order mg/min^-1	T₅₀(Min)	T₉₀(Min)	DE10
F1	0.5550	0.955	2.595	0.0587	11.8	39.2	40.20
F2	0.4988	0.9529	2.8396	0.0946	7.3	24.4	66.530
F3	0.7411	0.9908	2.8911	0.1085	6.4	21.2	31.78

Table 2: Invitro release kinetics of metformin HCl

Brands	Correlation coefficient(r)				K value		T₅₀ (min)	T₉₀ (min)	n	%Drug release at time(T) in hr
Brands	Zero order	First order	Higuchi	Pepass	Zero order mg/hr	First order hr^-1	T₅₀ (min)	T₉₀ (min)	n	1	3	10
F1	0.9927	0.8516	0.9354	0.9295	73.42	0.368	3.4	6.1	1.37	17.6	50.4	98.7
F2	0.9685	0.9047	0.9626	0.8781	74.15	1.335	3.4	6.1	1.21	31.8	44.1	99.1
F3	0.9513	0.9028	0.9702	0.8957	78.46	0.387	3.2	5.7	1.20	24.6	57.4	98.4

To ascertain the mechanism and kinetics of drug release, the drug release data of metformin was analyzed with various equations and concerned results are depicted in table2The mechanism of drug release was found to be diffusion control as the correlation coefficients observed from Higuchi model was higher compared to Peppas plot. The drug release rate observed from these brands was also calculated and presented in table2. The observed parameters were subjected to one way an oval followed by Dunnetts T test to detect the statistical Significances. Significant differences were noticed among these formulations. Based on K values, the formulations can be ranked as f2>f3>f1.

CONCLUSION:

All commercial brands satisfied the pharmacopeial standards. However significant differences in Invitro dissolution parameters were noticed among the brands for both the drugs. The variations in these parameters may be due to either formulations or process variables observed during the production process.

Abbreviations:

HCl= Hydrochloric acid. UV= Ultra violet. I.P=Indian Pharmacopoeia. QC= Quality control. RPM= Rotation per Minute. USP = United states Pharmacopoeia.

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Received on 02.11.2016 Modified on 20.12.2016

Res. J. Pharm. Dosage Form. & Tech. 9(1): Jan.-Mar. 2017; Page 15-18.

DOI: 10.5958/0975-4377.2017.00003.9