INTRODUCTION:

The bioavailability with oral administration of a drug depends on its solubility and/or dissolution rate. If these drugs are not completely released in the gastrointestinal tract, they will have a low bioavailability^1-4. Drug release is a major and limiting step for oral drug bio availability, particularly for drugs with low gastrointestinal solubility and high permeability.

Thus, efforts to increase dissolution of drugs with limited aqueous solubility are often required⁵. Improvement of aqueous solubility of such drugs is one of the major concerning factors of the pharmaceutical industries. Poorly Water soluble molecules must be either chemically altered or pharmaceutically prepared into their final dosage form so as to enhance their solubility before administration as a medicine.

Various techniques have been developed to address the solubility issue, dissolution enhancement including micronization, surfactant-aid dispersion, the use of organic solvents, emulsions and micro emulsions, solid dispersion technology and carriers based on polymers and liposomesetc. Solid dispersions are molecular mixtures of poorly aqueous soluble solid drug in an inert hydrophilic carrier. Drug release profile from such mixtures is driven by the polymer properties^6-8.

Teneligliptin Hydrobromide is anenduring, pyrolidone-based inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. Teneligliptin Hydrobromide can also scale back plasma triglyceride levels through a sustained increase in GLP-1 levels. Teneligliptin Hydrobromide is eliminated via excretion with a half-life of 24.2 hours in human plasma from the kidney and metabolism involving certain enzymes. The bioavailability of Teneligliptin Hydrobromide is concerning 60-80%. The solubility of teneligliptin hydrobromide is approx 1.7mg/ml in water⁹.

MATERIALS AND METHODS:

Teneligliptin Hydrobromide was procured from Yarrowchem, Pvt Ltd., Mumbai, PVP was procured from Loba Chemicals, Mumbai. HPMC was obtained as a gift sample from Colorcon India, Goa. All other chemicals and reagents used were of analytical grade and used as obtained without any further purification.

Drug-Excipients Interaction:

The FT-IR study of the drug and excipient was carried out by Infrared spectrophotometer (Shimadzu Affinity-l) by conventional KBr plate method in order to study the interaction of the drug and polymer so as to determine the physical as well as chemical changes that can occur during the formulation. For this the mixture of powder of polymer and teneligliptin hydrobromide was mixed in a ratio of 1:1 with potassium bromide and the small pellet was formed by pressing the mixture in a hydraulic press and the FT-IR was carried out in the frequency range 400-4000 cm ^-1. The significant peaks were recorded and were matched with standard FTIR^10-11.

Standard Calibration Curve:

The standard calibration curve of teneligliptin hydrobromide was carried out on UV spectrophotometer by using phosphate buffer as the solvent. From solution having concentration 100µg/ml samples of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5ml were pipette out into 10ml volumetric flasks. The volume was made up to the mark with Phosphate buffer 6.8 to get the final concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50µg/ml respectively. The absorbance of concentration was measured at 250.00nm¹².

Preparation of PVP- teneligliptin hydrobromide and HPMC- teneligliptin hydrobromide Solid Dispersion

a) Preparation of physical mixture:

The physical mixture of teneligliptin hydrobromide - PVP and teneligliptin hydrobromide- HPMC each were prepared in 1:1, 1:2, 2:1 ratios by mixing accurately weighed amounts of drugs and various carriers with the help of a spatula in a glass mortar¹³.

b) Preparation by kneading method:

The required amount of teneligliptin hydrobromide and carrier in 1:1, 1:2 and 2:1 ratio were wetted with sufficient volume of methanol and kneaded thoroughly for 30 minutes in a glass mortar. The paste formed was dried under vacuum for 24 hours. Dried powder was passed through sieve no. 60 and stored in desiccators until further evaluation¹⁴.

Table No.1: Formulation Chart of Physical Mixture (F1-F6) and Kneading Method (F7-F12)

Batch	Drug: HPMC	Drug: HPMC	Drug: HPMC	Drug: PVP	Drug: PVP	Drug: PVP
F1	1:1
F2		1:2
F3			2:1
F4				1:1
F5					1:2
F6						2:1
F7	1:1
F8		1:2
F9			2:1
F10				1:1
F11					1:2
F12						2:1

Evaluation parameters:

MicromeriticsStudy^15-19:

Tap Density: Physical mixture (10 g) was accurately weighed and transferred to a suitable graduated cylinder. The cylinder was then gently tapped to the base on a slightly resilient surface, such as a rubber pad or book, until the height of the sample in the cylinder reached at a minimum that is the sample height does not reduce with further tapping. Volume of sample in cc (ml) was read off.

D_t= M/V_t

Where,

D_t = Tapped density (g/ml), M = Mass of powder (g)

V_t = Tapped volume of powder (ml)

Bulk density: Sample (10g) was passed through a sieve with aperture of 1.0 mm. In a measuring cylinder, sample up to 250 ml was introduced gently without compacting. The unsettled apparent volume was read and bulk density was calculated using following formula.

D_b= M/V_o

Where,

M= Mass of powder (gm/cc)

V_o = Bulk volume of powder (ml)

Compressibility index (CI):

It is a manifestation of the compressibility of a powder. And it was calculated by using following equation,

I = (1-V/V_o) × 100

Where,

V= the volume occupied by the sample of powder after being subjected to standardized tapping procedure and

V_o= the volume before tapping

Hausner’s ratio:

Hauser ratio is defined as a ratio of a tapped density to bulk density. It’s a measure of relative importance of inter particulate interactions. Tapped density and bulk density were measured and therefore the Hauser’s ratio was calculated using the subsequent equation.

Hauser ratio = Bulk density/Tapped density

Angle of repose: Angle of repose is defined as the maximum angle possible between the surfaces of pile of powder and horizontal plan. The angle of repose for the powder of every formulation was determined by the funnel method. The powder was made to permit effuse of the funnel opening fixed at a height of 2 cm from the surface on a plane paper kept on the horizontal platform. After this, gradual addition of the powder from the funnel mouth was done which forms a pile of powder at the surface, this was continued until the pile touch the tip of the funnel. A circle was drawn round the pile base to calculate the radius of the powder cone was measured. Angle of repose was calculated with the utilization of the subsequent equation.

Ө = tan^-1[h/r]

Where,

h = height of pile formed

r = radius of pile formed

Drug content ²⁰: Drug content is that the ratio of experimentally measured drug content to the theoretical value, expressed as percentage (%).In this method pre-weighed solid dispersions were collected to determine practical yield (PY) from the following equation.

Percent Practical Yield = (Weight of Practical solid dispersions× 100)

Theoretical weight (Drug + Polymer)

In-vitro Drug Release: In-vitro drug release profiles for each batch was performed using USP type II dissolution apparatus. The pure drug was prepared solid dispersions of teneligliptin hydrobromide were entrapped in dialysis membrane and tied from upper and lower part which was previously soaked in phosphate buffer (pH-7.4) overnight. Solid dispersions of teneligliptin hydrobromide prepared by both the techniques was kept in the basket of dissolution apparatus and immersed in 900 ml distilled water at 37 ± 0.5° C and stirred at 100 RPM. Aliquot of 5 ml was withdrawn at time intervals of 5, 10, 15, 20, 30, 45 and 60 min. The same amount of withdrawn volume was replaced with the dissolution medium in order to maintain the sink condition^21-22. The sample withdrawn was analyzed at 250.00 nm.

Stability Study: The need of stability testing is to test the product and also to provide evidence on how the quality of a drug substance or drug product varies with time underneath the influence of assorted environmental factors like temperature, light, humidity, and allows suggested storage conditions, re-test periods and shelf lives to be established ^[23].In the present study, stability studies were carried out at Room Temperature: 25°C ± 2°C / 60 % RH ± 5% RH and Accelerated testing: 40°C ± 2°C / 75 % RH ± 5% RH for 3 months for the optimized formulation.

RESULTS AND DISCUSSION:

Drug-Excipient Interaction Study: From the FT-IR study it was found that there were no physical or chemical interactions between the drug and the polymer because there was no disappearance or mismatch of any peak when matched with the standard reference.

Figure 1: FTIR of Pure Drug Teneligliptin Hydrobromide

Figure 2: FTIR of Optimized Formulation of Powder Method

Figure 3: FTIR of Optimized Formulation of Kneading Method

Standard Calibration Curve:

From the calibration curve study it was found that the absorbance was linear and follows the beer lambert’s law. The equation obtained from the calibration curve was y=0.017x + 0.072 and R² value was found to be 0.990.

Micromeritics Study and % Drug Content:

The micromeritics study of the prepared solid dispersion showed the good results of tap density in the range of 0.713±0.36– 0.929±0.07 gm/cm³, bulk density in the range of 0.741±0.04-0.902±0.03 gm/cm³, carr’s index in the range of 3.8-7.7, hauser’s ratio in the range of 1.03-1.08, the angle of repose in the range of 14.86⁰±0.47-20.25⁰±0.71 which shows the good flow property and lastly, the % drug content was found to be in the range of 94.58±2.01% -99.60±1.25%resp. From the results it was seen that the formulation F5 from the physical method and F8 from the kneading method were having the better results than compared with other formulations. The F5 was having the tap density of 0.872±0.12, bulk density 0.825±0.07, carr’s index of 5.3, hauser’s ratio 1.05, angle of repose of 16.85⁰±0.08 and lastly, % drug content of 98.90±1.09% while the formulation of F8 shows the tap density 0.792±0.02, bulk density 0.786±0.36, carr’s index 4.8, hauser’s ratio 1.03, angle of repose of 21.28⁰±0.45 and the % drug content of 99.60±2.01%. From the results it was seen that the formulations F5 of physical method and F8 of kneading method were having maximum drug content therefore it can be regarded as the optimum formulations for further studies.

Figure 4: Standard Calibration Curve of Teneligliptin Hydrobromide

Table 2: Micromeritics Study of Physical Mixture (F1-F6) and Kneading Method (F7-F8)

Batch	Tap Density (gm/cm³)	Bulk Density (gm/cm³)	Carr’s Index	Hauser’s Ratio	Angle of Repose.	% Drug Content
F1	0.803±0.36	0.741±0.04	7.7	1.08	19.50⁰±0.25	96.68±1.99
F2	0.827±0.02	0.795±0.36	3.8	1.04	20.25⁰±0.71	95.40±2.42
F3	0.923±0.06	0.865±0.17	6.2	1.06	15.67⁰±0.06	96.82±2.60
F4	0.843±0.58	0.798±0.29	5.3	1.05	18.78⁰±0.02	97.90±1.06
F5	0.872±0.12	0.825±0.07	5.3	1.05	16.85⁰±0.08	98.90±1.09
F6	0.909±0.07	0.862±0.03	5.1	1.05	14.86⁰±0.47	95.75±2.91
F7	0.713±0.36	0.752±0.04	6.7	1.07	20.30⁰±0.35	97.32±0.61
F8	0.797±0.02	0.786±0.36	4.8	1.03	21.28⁰±0.45	99.60±2.01
F9	0.833±0.06	0.878±0.17	7.2	1.04	17.53⁰±0.26	96.60±1.25
F10	0.883±0.58	0.784±0.29	6.3	1.08	16.63⁰±0.12	94.58±2.01
F11	0.922±0.12	0.862±0.07	4.3	1.03	17.78⁰±0.38	95.18±1.68
F12	0.929±0.07	0.902±0.03	6.1	1.05	16.63⁰±0.24	96.21±2.56

In-vitro Drug Release:

The drug release study of pure drug shows that less amount of drug is released but the results of the dispersions shows that the % cumulative drug release of anti-diabetic drug increases in the formulations prepared by kneading method has better release characteristics as compared to the formulations prepared by physical mix method. Dissolution rate for solid dispersions were greater in teneligliptin hydrobromide and HPMC as compared to all other formulations of teneligliptin hydrobromide and PVP in different ratios. The ratio of 1:2 of teneligliptin hydrobromide and HPMC prepared by kneading method showed the greatest release profile than all other formulations. From all the formulations prepared by physical mixture the % drug release was found to be in the range of 34.18% - 97.16%and the formulation prepared by kneading method was found to be in the range of 28.21% - 98.91%. From the results it was seen that the formulation F5 shows the drug release of 97.16% while F8 shows 98.91%. There fore it was considered that the formulation F5 and F8 were to be optimum as they show better drug release property than compared with other formulations.

Figure 5 (A): % Cumulative Drug Release of Formulations byPhysical Mixture

Figure 5 (B): % Cumulative Drug Release of Formulations by Kneading Method

Stability Study: The results of the stability of both the formulations F5 and F8 showed that there was no degradation in both the formulation as there was no significant difference was seen in the % drug content and % cumulative drug release. As there was no significant change was seen in the stability study it was concluded that both the formulations were found to be stable under both the tested conditions.

Table 3: Stability Study at Room Temperature: 25°C ± 2°C / 60 % RH ± 5% RH

Day	F5		F8
Day	% Drug Content	% CDR	% Drug Content	% CDR
0	98.90±1.09	97.16	99.60±2.01	98.91
15	98.90±1.09	97.16	99.60±2.01	98.91
30	98.90±1.14	97.16	99.60±2.01	98.91
60	98.80±2.57	96.42	99.54±1.07	98.89
90	98.79±1.42	96.37	99.43±1.74	98.75

Table 4: Stability Study at Accelerated testing: 40°C ± 2°C / 75 % RH ± 5% RH

Day	F5		F8
Day	% Drug Content	% CDR	% Drug Content	% CDR
0	98.90±1.09	97.16	99.60±2.01	98.91
15	98.90±1.09	97.16	99.60±2.01	98.91
30	98.90±2.71	97.10	99.60±1.05	98.91
60	98.75±1.94	96.84	99.41±1.41	98.86
90	98.70±2.48	96.79	99.38±1.01	98.86

CONCLUSION:

The current study was to prepare solid dispersion of teneligliptin hydrobromide which is having low water solubility. So, therefore to enhance its dissolution property the solid dispersions were prepared by two different methods i.e. physical mixture and kneading method. The drug-excipient interaction study revealed that there was no interaction between the drug and the water soluble carriers as there was no difference in the peaks when compared with the standard value it was found to be compatible. The standard calibration curve showed that the drug follows beers lamberts law as it shows linearity with the equation y=0.017x + 0.072 and R² value of 0.990. The physical testing of the prepared formulations showed that the micromeritics study was having satisfactory results with better flow property. From the evaluation parameters it was seen that the formulations F5 and F8 were having the maximum drug content of 98.90±1.09 and 99.60±2.01. The dissolution studies of the prepared dispersions showed that the drug release from physical mixture was found to be in the range of 34.18% - 97.16% while from the kneading method was found to be in the range of 28.21% - 98.91%. From the results it was seen that the better drug release was seen in the formulation F5 and F8 which was of 97.16% in F5 and F8 shows 98.91%. From the study it can be concluded that the kneading method was more optimized method can be used to enhance the drug release characteristics of poorly soluble drug in pharmaceutical formulations.

ACKNOWLEDGMENTS:

The author wishes to thank Dr. Rajendra Gode Institute of Pharmacy, Amravati, Maharashtra for providing the laboratory, chemicals and instruments for research work.

CONFLICT OF INTEREST:

None declared.

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Received on 14.09.2021 Modified on 16.11.2021

Asian J. Pharm. Res. 2022; 12(2):137-142.

DOI: 10.52711/2231-5691.2022.00021