Formulation of Dapagliflozin and Saxagliptin Tablets and In vitro Evaluation by RP-HPLC Method

 

Vinutha Kommineni¹, K.P.R. Chowdary², S.V.U.M. Prasad³

¹Sri Venkateshwara College of Pharmacy, Hyderabad and Ph. D Research Scholar, JNTUK, Kakinada.

²Research Director, Vikas Institute of Pharmaceutical Sciences, Near Air Port, Rajahmundry

³School of Pharmacy, JNTUK, Kakinada

 

ABSTRACT:

Dapagliflozin and Saxagliptin is an efficient combination for the treatment of Type 2 diabetis introduced in 2017. No reports are available on the formulation of Dapagliflozin and Saxagliptin combined drug tablets. The objective of the present study is to formulate Dapagliflozin and Saxagliptin combined drug tablets and to perform their In vitro evaluation by an RP-HPLC method. Tablets each containing 10mg of Dapagliflozin and 5mg of Saxagliptin were formulated employing commonly used tablet excipients (lactose, dicalciumphosphate, Starch 1500 and β-cyclodextrin) and the tablets were prepared by direct compression method. All the prepared tablets and one commercial brand (Qtern) were evaluated for hardness, friability, disintegration time, content of active ingredients and dissolution rate of Dapagliflozin and Saxagliptin. An RP-HPLC method was used for simultaneous determination of Dapagliflozin and Saxagliptin content in the tablets and in the in vitro dissolution samples. Tablets of Dapagliflozin (10mg) and Saxagliptin (5mg) could be prepared employing commonly used tablet excipients (lactose, dicalcium phosphate, Starch 1500, b-cyclodextrin) by direct compression method. The physical parameters of the tablets prepared (hardness, friability, content of active ingredient and disintegration time) are comparable with those of commercial tablets, Qtern. Formulation F1 prepared using lactose as excipient gave dissolution similar to Qtern with regard to both Dapaliflozin and Saxagliptine. Formulations F3 and F4 which contain Starch 1500 and bCD respectively as excipients gave higher dissolution than Qtern tablets. Formulation F1 is considered equivalent to Qtern and formulations F3 and F4 are considered superior to Qtern. An RP-HPLC method could be used to estimate the content of Dapaliflozin and Saxagliptine in the tablets and also in dissolution samples.

 

 

 

 

INTRODUCTION:

Type 2 diabetes mellitus (T2DM) is a chronic progressive metabolic disorder characterized by insulin deficiency [1]. Several new drug molecules were introduced in recent years for effective control of diabetes by using them either alone or in combination. Dapagliflozin (Dapa) and Saxagliptin (Saxa) is one such combination introduced in 2017.

Dapagliflozinworks by inhibiting the sodium-glucose co-transporter 2 (SGLT2) in the kidney, thus leading to increased glucose excretion [2,5]. Saxagliptinis a DPP-4 inhibitorthat improve glycemic control by preventing the inactivation of the incretin hormones GLP-1.This increases GLP-1 levels, stimulates insulin secretion, and reduces postprandial glucagon and glucose levels [3,4]. Combining these mechanisms of action should therefore enhance their glucose-lowering effects; a DPP-4 inhibitor could counteract the effects of an SGLT2 inhibitor on endogenous glucose production and glucagon secretion [6].

 

Much of the literature on Dapa and Saxa concerns with HPLC [7-12] and other analytical methods [13-15] for their estimation in bulk and dosage forms and also in biological fluids [16-17]. Formulation studies are rather scanty. Rafaela et al. [18] reported dissolution method development for Dapa using UV-Spectrophotometric method. Balasaheb et al. [19] reported development of sustained release pellets of Saxa and their evaluation. Iswariya formulated and evaluated Orodispersible tablets of Saxa by direct compression method [20]. No reports are available on the formulation of Dapa and Saxa combined drug tablets. Only one commercial brand, Qtern containing Dapa 10 mg and Saxa 5mg are available. The objective of the present study is to formulate Dapa and Saxa combined drug tablets and to performtheir in vitroevaluationby an RP-HPLC method.We have earlier reported the development and validation of an RP-HPLC method for the simultaneous estimation of Dapa and Saxa [21-22]. The RP-HPLC method developed was used for the assay and dissolution rate testing in the present work. The earlier authors used only uv-spectrophotometric method in formulation development work. As the drugs are highly potent a more selective and sensitive method is needed for dissolution rate testing. Hence an RP-HPLC method was used for the assay and dissolution rate testing of Dapa and Saxa tablets.

 

MATERIALS AND METHODS:

Materials:

The Dapagliflozin Propanediol and Saxagliptine Hydrochloridewere gift samples from HiQ Pharma Labs PvtLtd., Hyderabad, India. Qtern tablet containing Saxagliptine 5mg and Dapagliflozin 10mg (Astrazeneca Pharmaceutical Ltd.) was procured from UK market. Acetonitrile (HPLC grade) and water (HPLC grade) were obtained from LichrosolR, Merck Lifesciences Pvt. Ltd., Mumbai, India.b-cyclodextrin, Crosspovidone and Starch 1500 were gift samples from M/s Micro Labs, Pondicherry. Lactose, I. PDicalcium phosphate (Qualigens), Talc (Qualigens), Magnesium Sterate (Qualigens). Potassium Dihydrogen phosphate (Thermo Fischer Scientific Pvt Ltd., Mumbai, India), and Ortho phosphoric acid (S D Fine –Chem. Ltd., Mumbai, India) were used.

 

Methods:

Estimation of Dapagliflozin and Saxagliptine:

A reported HPLC method [21] was used for the simultaneous estimation of Dapa and Saxa in tablet formulations and in dissolution rate studies. The method is revalidated before using in the study as follows.

 

Instrumentation:

Chromatography was performed on a WATERS 2695 HPLC (waters corporation, Mildord, USA) with an autosampler and equipped with a 2996 series of PDA detector with a spectral bandpass of 1.2nm. Components were detected using UV and that processing was achieved by Empower 2 software.

 

Chromatography conditions:

The chromatographic separation was performed on XTerra C₁₈ (4.6 x 150mm, 5mm particle size) at an ambient column temperature. The samples were eluted using Phosphate buffer (pH adjusted to 4 with OPA): Acetonitrile (50:50v/v) as the mobile phase at a flow rate of 1ml/min the mobile phase and samples were degassed by ultrasonication for 20 min and filtered through 0.45µm Nylon (N66) 47mm membrane filter. The measurements were carried out with an injection volume of 10μL, flow rate was set to 1 mL/min, and UV detection was carried out at 225 nm. All determinations were done at ambient column temperature (30°C). Canagliflozin at a concentration of 5000ng/ml was used as Internal standard.

 

Preparation of Standard Solutions:

Standard stock solution of Dapagliflozin was prepared by dissolving 10 mg of Dapagliflozin in 10 ml of mobile phase in a 10 ml volumetric flask and the solutions was filtered through 0.45μm nylon membrane filter and degassed by sonicator to get the concentration of 1000µg/ml of Dapagliflozin.

 

Standard stock solution of Saxagliptine was prepared by dissolving 10 mg of Saxagliptine in 10 ml of mobile phase in a 10 ml volumetric flask and the solution was filtered through 0.45μm nylon membrane filter and degassed by sonicator to get the concentration of 1000µg/ml of Saxagliptine.

 

Standard stock solution of Canagliflozin was prepared by dissolving 10 mg of Canagliflozin in 10ml of mobile phasein a 10ml volumetric flask and the solution was filtered through 0.45μm nylon membrane filter and degassed by sonicator.

 

Calibration curve:

Standard solutions of Dapa and Saxa were suitably diluted with mobile phase to yield a series of solutions each containing Dapa and Saxa in various concentrations along with Internal standard 5000 ng/mL in each. Six replicates of each concentration were independently prepared and injected in to HPLC system to asses the precision (Repeatability) of the method.

 

Preparation of Dapagliflozin and Saxagliptin Tablets:

Tablets each containing Dapagliflozin (10mg) and saxagliptine(5mg) were prepared as per the formulae given in Table 3 by direct compression method. Four tablet formulations using different types of excipients were prepared and evaluated for various physical parameters and in vitro dissolution rate by RP-HPLC method.

 

In each case the required quantities of ingredients as per formulae are weighed and taken in closed polythene bag and were mixed thoroughly. The blend of ingredients were subjected to pre compressional evaluation by measuring angle of repose and compressibility index to asses their flow properties before compression. The blend of ingredients were then compressed in to 250mg tablets on a 8- station RIMEK tablet punching machine employing 9mm round and flat punches.

 

Evaluation of Tablets:

All the tablets prepared were evaluated for content of active ingredients, hardness, friability, disintegration time and dissolution rate as follows.

 

Hardness:

The hardness of prepared tablets was determined by using Monsanto hardness tester and measured in terms of kg/cm2.

 

Friability:

The friability of the tablets was measured in a Roche friabilator using the formula

 

Friability(%)=[(Initial weight- Final weight)/(Initial weight)] x 100

 

Content of Active Ingredients:

The content of Dapa and Saxa in tablets was determined by an RP-HPLC method as follows.

 

Weighed tablets (20) were powdered and mixed thoroughlyin a glass mortar and pestle. An accurately weighed quantity of powder equivalent to 100mg of Dapa and 50mg of Saxa was taken into 50 mlvolumetric flask, methanol(40ml) was added, mixed and sonicated for 10min. The volume was made up with methanol. The solution was filtered and then suitably diluted with mobile phase to get a concentration of 40 µg/ml of Saxagliptine and 80 µg/ml of Dapagliflozin.10µl of solution was then injected in to HPLC column.

 

 

Disintegration time:

Disintegration time of the tablets was determined using single unit disintegration test apparatus (Make: Paramount) employing water as test fluid.

 

Dissolution Rate Study:

Dissolution Rate of Dapa and Saxa from the tablets prepared and from the commercial product (Qtern) was studied in simulated gastric fluid with outenzhymes of P^H 1.2 (900 ml) employing eight station dissolution rate test apparatus (LABINDIA, DS 8000) using paddle stirrer at 50 rpm and at a temperature of 37°C ± 1°C. One tablet was used in each test. Samples of dissolution fluid (5 ml) were withdrawn through a filter at different time intervals and assayed forDapa and Saxa by an RP-HPLC method as described below.

 

The sample of dissolution fluid withdrawn at each time was replaced with fresh drug free dissolution fluid and a suitable correction was made for the amount of drug present in the samples withdrawn in calculating percent dissolved at various times. Each dissolution experiment was run in triplicate (n=3).

 

Determination of Dapa and Saxa in the Dissolution samples:

For HPLC analysis 0.5ml of dissolution sample were taken in to dry centrifuge tubes, 0.5ml of internal standard solution was added and mixed. Acetonitrile (5ml) were then added and mixed thoroughly for 5 min. The mixtures were then centrifuged at 5000 RPM for 10min.The supernatant organic phase (4ml) was collected in to dry test tubes and dried in a hot water bath at 60^0C.To each tube 1.0ml of mobile phase was added and mixed thoroughly to dissolve the residue. The resulting solution (10µl) was then injected into column for chromatography.

 

RESULTS AND DISCUSSION:

The objective of the study is to formulate Dapa and Saxa combined drug tablets and to evaluate them by in-vitro methods using RP-HPLC method. In a few earlier studies [18-20] content of active ingredients and dissolution rate of the tablets were evaluated using UV-Spectrophotometric method. As Dapa and Saxa are highly potent drugs a more selective and sensitive method is needed even for in-vitro evaluation.In the present study an RP-HPLC method developed and reported [19-20] by the authors was used for the in-vitro evaluation of Dapa and Saxa combined drug tablets formulated and commercial brand.The developed RP-HPLC method involves separation on XTerra C 18 column (150mm x 4.6mm x5µm particle size). The optimized mobile phase consists of phosphate buffer (pH 4) and Acetonitrile (50:50v/v) with a flow rate of 1ml/min and UV detection at 225nm. Retention time was 5.3 min for Dapa, 3.2 min forSaxaand 9.56min for Canagliflozin (IS). The method was revalidated for system suitability, Linearity (Calibration curve) and precision. The optimized chromatogram is shown in Fig.1.The system suitability parameters of the method are given inTable 1.The different concentrations prepared for calibration curve along with peak areas are given in Table 2.Good linearity was observed in theconcentration range of 20-300ng/ml in the case of Saxagliptine and 100-1500ng/ml in the case of dapagliflozin.The linearity curves are shown in Fig.2,3. The precision parameter (% RSD) was less than 2% at all concentration levels. Thus the method was found to be reproducible. The RP-HPLC method was applied for the simultaneous estimation of Dapa and Saxa in the dissolution fluid (simulated gastric fluid). A typical chromatogram of Dapa and Saxa in the dissolution sample collected at 20min is shown in Fig.4.

 

Figure 1. Optimized Chromatogram of Saxa and Dapa

 

Table 1. System suitabilityparameters of Saxa and Dapa

Parameter	Saxagliptine	Dapagliflozin	Canagliflozin
Peak area	5114	9852	447556
Theoretical plates	3527.32	5776.38	4677.98
Retention time	3.26	5.37	9.56
Tailing factor	1.72	1.56	1.18

 

Table 2. Linearity Data of Saxagliptine and Dapagliflozin

Level	Conc. of Saxa (ng/ml)	Peak area (A)	A/ A0 Ratio	Conc of Dapa (ng/ml)	Peak area (A)	A/ A0  Ratio
1	20	1278	0.002	100	2463	0.004
2	40	2557	0.004	200	4926	0.007
3	80	3835	0.007	400	7389	0.013
4	120	5114	0.010	600	9852	0.018
5	180	6392	0.013	800	12315	0.025
6	200	7671	0.016	1000	14777	0.031
7	240	8949	0.020	1300	17240	0.037
8	300	10228	0.023	1500	19703	0.044

 

Figure 2. Linearity graph of Saxagliptine

 

Figure 3. Linearity graph of Dapagliflozin

 

Figure 4. Chromatogram of Dapa and Saxa in the dissolution sample collected at 20min

 

Tablets each containing 10mg of Dapa and 5mg of Saxa were prepared as per the formulae given in Table 3. Four tablet formulations were made using different excipients. The blend of ingredients in each case exhibited good flow characteristics evidenced by angle of repose in the range 20⁰-22⁰ and compressibility index values in the range 10-12 percent. Hence the tablets were made by direct compression method. All the tablets prepared were evaluated for hardness, friability, disintegration time, content of active ingredients and dissolution rate of Dapa and Saxa. The physical parameters of the tablets prepared are given in Table 4. Hardness of the tablets was in the range 4.5-5.5 kg/sq.cm. Percent weight loss in the friability test was less than 1.12 % in all the cases. All prepared tablets disintegrated with in 3min. Formulations F1 and F3 disintegrated very rapidly with in 1min. Content of Dapa and Saxa in the tablets prepared was determined by using the RP-HPLC method developed. Dapa content was in the range 98.0-101.5% and Saxa content was in the range 97.8-101.0% of the labeled claim. For comparison the commercial product (Qtern tablets) was also evaluated and results are given in Table 4.

 

Table 3. Formulae of Dapa and Saxa tablets prepared

Ingredients (mg/Tablet)	F1	F2	F3	F4
Dapagliflozin Propanediol (equivalent to 10 mg of Dapa)	12.3	12.3	12.3	12.3
Saxagliptine Hydrochloride (equivalent to 5 mg of Saxa)	5.95	5.95	5.95	5.95
Lactose	209.25	-	-	-
Dicalcium phosphate	-	209.25	-	-
Starch 1500	-	-	209.25	-
bCD	-	-	-	209.25
Crosspovidone	12.5	12.5	12.5	12.5
Talc	5	5	5	5
Magnesium Sterate	5	5	5	5
Total weight (mg/Tablet)	250	250	250	250

 

Table 4. Physical parameters of tablets prepared

Formulation	Hardness Kg/sq.cm	Friability (%weight loss)	D.T (Sec.)	Content of active ingredient
				Dapa	Saxa
F1	5.0	0.85	55	9.90	4.98
F2	4.5	1.12	180	9.80	4.90
F3	5.5	0.65	40	10.01	5.05
F4	4.5	0.80	125	10.15	4.89
QTERN	8.5	0.45	250	9.85	4.95

 

The dissolution rate of Dapa and Saxa from the formulated and commercial tablets (Qtern) was studied in 900ml of simulated gastric fluid (PH 1.2) as suggested by Rafaelaet.al [18]. The dissolution profiles are shown in Figs.5-6. The dissolution parameters estimated are given in Table 5. Dissolution of both the drugs obeyed first order kinetics with a regression coefficient(R²) values greater than 0.965. The first order dissolution rate constants (K₁) values estimated from the slopes of the first order linear dissolution plots are given in Table 5. Rapid dissolution of Dapa and Saxa was observed from all the formulated and commercial tablets. Formulations F3 and F4 which containStarch 1500 and bCD as excipients gave higher dissolution than Qtern tablets. The increasing order of dissolution rate (K₁) observed with various tablet formulations was F4_>F3 >F1>F2 in the case of Dapa and F3 >F4 >F1 >F2 in the case of Saxa. Formulation F1 prepared using lactose as excipient gave dissolution similar to Qtern with both Dapa and Saxa. Hence formulation F1 is considered equivalent to Qtern and formulations F3 and F4 are considered superior to Qtern.

 

Table 5. Dissolution Parameters of the Tablets prepared

Formulation	Dissolution Parameter
	PD10(%)		K1(min-1)		DE30(%)
	Dapa	Saxa	Dapa	Saxa	Dapa	Saxa
F1	46.4	55.4	0.052	0.065	79.6	85.1
F2	39.6	41.8	0.037	0.054	69.2	78.2
F3	65.4	69.5	0.082	0.100	92.4	98.2
F4	66.8	65.4	0.084	0.087	95.6	97.6
QTERN	50.4	56.0	0.057	0.069	84.2	88.4

 

Figure 5. Dissolution graph of Dapagiflozin

 

Figure 6. Dissolution graph of Saxagliptine

 

CONCLUSION:

Tablets of Dapagliflozin (10mg) and Saxagliptin (5mg) could be prepared employing commonly used tablet excipients (lactose, dicalcium phosphate, Starch 1500, b-cyclodextrin) by direct compression method. The physical parameters of the tablets prepared (hardness, friability, content of active ingredient and disintegration time) are comparable with those of commercial tablets, Qtern. Content of active ingredients and dissolution rate of Dapa and saxa from the tablets were evaluated by an RP-HPLC method and compared with those of a commercial brand, Qtern .Formulation F1 prepared using lactose as excipient gave dissolution similar to Qtern with both Dapa and Saxa.Formulations F3 and F4 which containStarch 1500 and bCD respectively asexcipients gave higher dissolution than Qtern tablets.Hence formulation F1 is considered equivalent to Qtern and formulations F3 and F4 are considered superior to Qtern.An RP-HPLC method could be used to estimate the content of Dapaliflozin and Saxagliptine in the tablets and also in dissolution samples.

 

ACKNOWLEDGEMENT:

The author would like to thankHiQ Pharma Labs Pvt Ltd, Hyderabad for providing the gift samples of Dapagliflozin and Saxagliptin. We gratefully acknowledge Venkateswara College of Pharmacy, Hyderabad for providing research facilities. This work forms a part of Ph.D thesis of K.Vinutha under JNTU Kakinada.

 

CONFLICT OF INTEREST:

There are no conflicts of interest.

 

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Received on 27.04.2019                 Accepted on 07.05.2019

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Asian J. Pharm. Ana. 2019; 9(2):93-98.