1. INTRODUCTION:

Oral bioavailability of a drug depends on its solubility and/or dissolution rate, and dissolution may be rate determining step for appearance of medicinal effect, therefore efforts to increase dissolution of drug with limited water solubility is often needed. Many methods are available to improve these characteristics, including salt formation, micronization and addition of solvent or surface active agents¹. Telmisartan is 4’-[1,4’-dimethyl-2-propyl [2,6’-bi-benzimidazole]-1’-yl] methyl 1,1’- biphenyl 2-carboxylic acid. It is practically insoluble in water; sparingly soluble in strong acid; soluble in strong bases². Telmisartan is an anti-hypertensive drug. It is an

angiotensin II receptor antagonist. It acts by binding to the angiotensin II type one receptors, resulting in the inhibition of angiotensin II on vascular smooth muscles. As angiotensin II is a vasoconstrictor, inhibition of its effect on vascular smooth muscles results in decreases in systemic vascular resistance. Telmisartan comes under the class II of biopharmaceutical classification system (BCS). Being a BCS class II drug, it is very poorly soluble in water, which results in the slow dissolution and hence low bioavailability when administered orally (~42%). The absolute bioavailability of Telmisartan is dose-dependent³. Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility and dissolution rate of drug molecules. Solubility and dissolution rate are the important parameters to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown⁴. The microspheres used for improvement of solubility of poorly water soluble drugs. A number of drugs have been shown to exhibit better aqueous solubility and dissolution characteristics in the form of microspheres. To overcome the low bioavailability, spray drying technique can be used to increase bioavailability of Telmisartan by using hydrophilic carriers. In the present study spray drying method had been used to prepare the microsphere. Methanol was used as the solvent. PVP K30 was used as the hydrophilic carriers. The samples were prepared at different drug: carrier weight ratios. PVP K30 have been successfully used to improve the water solubility and dissolution (hence bioavailability) of several drugs.

2. MATERIALS AND METHODS:

Telmisartan was obtained as a gift from IPCA Pharmaceuticals, Mumbai, India. PVP K30 was purchased from Research-Lab Fine Chem Industries, Mumbai. All other chemicals were of analytical grade and were used as procured.

2) Methodology:

2.1) Characterization of drug:

a. Organoleptic properties: The sample of Telmisartan was evaluated for its color, odor and physical appearance.

b. Determination of Melting Point: Melting point of Telmisartan was determined by open capillary method using Thiele’s tube. Average of triplicate reading was taken, and compared with literature.

2.2) Spectroscopic analysis⁵:

a. Determination of λ max: Stock solution of 100μg/ml was prepared by adding 10 mg of pure Telmisartan in 10ml of solvent methanol. Then, 1ml of stock solution was taken and suitably diluted with solution of methanol to make 10μg/ml of Telmisartan solution. The solution was then filtered and its UV spectrum was recorded in the wavelength range 200 - 400 nm using spectrophotometer of Jasco V630, Japan.

b. Preparation of calibration curve for Telmisartan: Stock solution of 100μg/ml of Telmisartan was prepared in solvent methanol and further subsequently diluted with methanol to get solutions with concentration range 1-5μg/ml. The solutions were then filtered and analyzed spectrophotometrically at 296 nm using UV-Spectrophotometer (Jasco V630, Japan) and standard curve was plotted and values of slope, intercept and coefficient of correlation were calculated.

c. Solubility studies of Telmisartan: Solubility of Telmisartan was determined in distilled water. Initially, known excess amount of Telmisartan was added to 10ml each of the above solutions in 10 ml of volumetric flask. Then these volumetric flasks were shaken using mechanical shaker for 24 hours. The samples were then filtered, diluted suitably and analyzed spectrophotometrically at 296 nm.

d. Compatibility studies between drug and excipient:

Incompatibility is the result of mixing of two or more substances and is detected by physical, chemical and therapeutic qualities. It may affect the safety, efficacy and appearance of the dosage form.

FT-IR Studies⁶: Structural changes and lack of a crystal structure can lead to changes in bonding between functional groups which can be detected by infrared spectroscopy. The infrared absorption spectrum of pure Telmisartan, Polyvinylpyrolidone-K30, and its physical mixture with drug was recorded on FT-IR spectrophotometer for evaluating the chemical compatibility of Telmisartan with the hydrophilic polymer. The sample was placed in the IR light path and the IR spectra were recorded.

2.3) X-ray diffraction analysis (XRD)

X-Ray powder diffraction patterns were obtained at room temperature using a Philips X’ Pert MPD diffractometer, with Cu as anode material and graphite monochromator, operated at a voltage of 40 mA, 45 kV. The process parameters used were set as scan step size of 0.0170.

3. PREPARATION OF MICROSPHERES⁷:

Telmisartan microsphere were prepared by spray drying method using carrier (PVP-K30) in proportions viz 1:1, 1:2,1:3 and 1:4 (drug : carrier). The drug (1gm) and carrier (1, 2, 3 and 4 gm) were dissolved in 100 ml methanol. The solvent was evaporated by spray drying process, which was carried out using laboratory scale spray dryer conditions mentioned in Table 2.

Table no 1: Composition of microspheres

Sr. no	Batch	Drug polymer ratio(g)
1	A	1:1
2	B	1:2
3	C	1:3
4	D	1:4

Table no 2: Conditions mentioned in spray dryer

Sr. No	Parameters	Values
1	Inlet Temperature	40
2	Outlet Temperature	35
3	Cool temperature	55
4	Inlet high	60
5	Outlet high	55
6	Aspiratory Speed	55
7	Feed pump flow	2 ml per min
8	D-Block on	1 sec
9	D-Block off	60 sec
10	Data log interval	225 min max

3.1) Characterization of Microspheres:

a. Percentage practical yield:

Percentage practical yields were calculated to know about percent yield or efficiency of the method, thus it helps in selection of appropriate method of production. Microspheres were collected and weighed to determine practical yield.

b. Determination of % Drug Content⁸:

Microspheres equivalent to 10 mg of Telmisartan were weighed accurately and dissolved in suitable quantity of solvent mixture methanol. The drug content was determined at 296 nm by UV spectrophotometer. Each sample analyzed in triplicate.

c. Determination of saturation solubility of prepared microspheres:

The saturation solubility studies were carried out to determine the solubility of microspheres. Excess amount of different microspheres formulations of Telmisartan were added to 10ml of Water, 0.1N HCL and phosphate buffer7.5 in 10ml volumetric flasks. Samples were shaken using mechanical shaker for 48 hours .Samples were then filtered, diluted suitably and analyzed spectrophotometrically at 296 nm.

d. Scanning Electron Microscopy (SEM):

SEM of microspheres was carried out using JSM 6360, JEOL India Pvt. Ltd. to study themorphological characteristics of the optimized batch of microspheres.

e. In-vitro dissolution studies of Telmisartan microspheres systems⁹:

Prepared microspheres of Telmisartan (equivalent to 40 mg of pure drug) was placed in 900 mL of dissolution medium. Study was carried out at 75 rpm for 30 min. Amount of drug release was determined using UV spectrophotometer (UV1800, Shimadzu) at λ max 296.Same procedure was applied for API. All the experiments were repeated in triplicate. A graph of cumulative % drug releases vs. time in minute was plotted.

4) RESULT AND DISCUSSION:

4.1) Authentication of Drug

a. Visual inspection:

Physical appearance of drug was examined for following organoleptic properties:

· Color: White

· Odor: Odorless

· State: crystalline powder.

b. Melting point:

Temperature was noted at which solid drug changes into liquid. It was found to be 263°C. (Std. 261-263°C).

4.2) Spectroscopic analysis:

a. Determination of λ max:

The standard solution of Telmisartan of concentration 10 μg/ml showed maximum absorbance at the wavelength of 296 nm Hence the λ max of Telmisartan was found to be 296nm.(Standard Range 295 – 297).

b. Calibration curve of Telmisartan:

As per calibration curve, the correlation coefficient was found to be 0.999. Calibration curve obeyed Beer’s law in the range 1-5 µg/ ml.

c. Solubility studies of Telmisartan:

The saturation solubility of pure drug was found to be 0.0036 mg/mL in distilled water. Results obtained from saturation solubility study of Telmisartan are presented in the Table 3.

Table no.3 Saturation Solubility Study of Telmisartan

Solvent	Solubility(mg/ml)
Distilled water	0.0036
Phosphate buffer 7.5	0.0157
0.1N HCL	1.0988

d. Fourier Transform Infrared (FT-IR) Studies:

From the FTIR data, it was found that there were no new bands observed in the spectrum, which confirms that no new chemical bonds were formed between the drug and the excipient. The FTIR spectra were shown in figures 1, 2 and 3.

The solubility of Telmisartan was markely enhanced by PVP-K30. Among all the batches of Telmisartan, batch D exhibited greater enhancement of aqueous solubility (2.611).The enhancement of drug solubility could be explained by solubilization effect of carriers, their improving influence on drug wettability.

c. % Drug content of Telmisartan in prepared microspheres:

The spray dried compositions had drug content of 89.33 to 95.42% of Telmisartan suggesting that the spray drying process was successful in achieving good encapsulation of the drug. Percent drug content of Telmisartan in spray dried microspheres was found to be increased with increase in the concentration hydrophilic polymers. The percent drug content values of Telmisartan in different microspheres batches are shown in Table No 6.

Table No 6: Drug content of Telmisartan in prepared microspheres

Sr. No	Batch code	% drug content
1	A	89.33%
2	B	91.45%
3	C	94.36%
4	D	96.42%

d. Scanning Electron Microscopy (SEM):

Scanning electron microscope (SEM) photomicrograph of the prepared Telmisartan microspheres is shown in Fig.5. A and B. SEM showed smooth surface of Telmisartan microspheres particles indicated the complete coating of Telmisartan with polymer particles. Pure Telmisartan performed irregular rod like angular shape. Microspheres particles looked like an irregular shaped matrices which suggest that particle shape and surface topography is changed during formation of microspheres. These findings demonstrate that reduction in particle size, increased surface area and close contact between drug and carrier may be responsible for the enhanced solubility of drug.

(A)

(B)

Fig: 5 A) Pure Telmisartan B) Microspheres

e. In-vitro dissolution studies of Telmisartan microspheres:

The cumulative % drug release of API against formulation TEL: PVP complex in ratios 1:1 to1:4 in pH 7.5 phosphate and in-vitro release profiles are as shown in Fig.6

5. CONCLUSION:

Telmisartan microspheres were successfully prepared by spray drying method with PVP K 30. In formulation of telmisartan with PVP K30 in ratio 1:4 prepared by spray drying method showed significant improvement in solubility and dissolution rate than API alone, which may contribute to improved bioavailability of Telmisartan.

6. REFERENCES:

1) Sucheta Bhise, Dyandevi Mathure, Mithun V.K. Patil, Rajendra D. Patankar. Solubility enhancement of antihypertensive agent by solid dispersion technique. International Journal of Pharmacy & Life Sciences. 2011; 2(8): 970-975.

2) Phulzalke S.B, Kate B.A, Bagade M. Y. Solubility Enhancement of Telmisartan Using Mixed Hydrotropy Approach. Asian Journal of Biomedical and Pharmaceutical Sciences, 5(50), 2015, 37-39.

3) Dubey, A. A. Kharia, D. P. Chatterjee. Enhancement of Aqueous Solubility and Dissolution of Telmisartan Using Solid Dispersion Technique. International Journal of Pharmaceutical Sciences and Research.2014; 5(10): 4478-4485.

4) K. P. R. Chowdary, A. Pavan Kumarrecent Research On Formulation Development of BCS Class II Drugs – A Review Int. Res J Pharm. App Sci., 2013; 3(1): 173-181.

5) Anton A. Smith, Manavalan R and Kannan K. Simple and sensitive spectrophotometric method for the determination of Bicalutamide in bulk and formulations. Rasayan J Chem.2009. 2(1): 204-210.

6) Jaiprakash B Gaja, Dr. F. J. Sayyad. Enhancement of solubility and dissolution rate of telmisartan by spray drying technique. Indo American Journal of Pharm Research.2013; 3(2):1732-1745.

7) Amol M. Patil, Manoj M. Nitalikar, Shrinivas K. Mohite. Improvement of Dissolution Profile of Lornoxicam by Solid Dispersion Using Spray Drying Technique. International Journal of Universal Pharmacy and Bio Sciences. 2014; 3(5):66-72.

8) Mukesh Sharma, Kirti Parmar, Atul Baria, Tushar M. Patel, Rohan Lalani, Rajesh K Parikh. Gastro Retentive Tablet of Febuxostat: Formulation, Drug Release Dynamics and Factorial Design. World Journal of Pharmaceutical Research.2015; 4(1): 1063-1082.

9) Shwetha Krishnamurthy, Srinivasan Bharath, Varadharajan Madhavan. Solubility Enhancement Of BCS Class II Antihypertensive Drug Using Solid Self Emulsification Technique. World Journal of Pharmaceutical Research. 2014; 3(2):2179-2192.

Received on 16.05.2018 Accepted on 11.07.2018

Asian J. Pharm. Tech. 2018; 8 (4):264-269.

DOI: 10.5958/2231-5713.2018.00040.5

Sr. No	Batch code	Percentage Yield (%)
1	A	32%
2	B	45%
3	C	57%
4	D	61%

Sr. No.	Batch	Polymer	Drug: Polymer Ratio	Solubility in dist. Water (mg /ml)	Increase in solubility in distilled water (no. of folds)	Solubility in Phosphate buffer 7.5 (mg/ml)	Increase in solubility in Phosphate buffer 7.5
1	A	PVP	1:1	0.0048	1.333	0.0179	1.140
2	B	PVP	1:2	0.0058	1.611	0.0287	1.828
3	C	PVP	1:3	0.0069	1.916	0.0312	1.987
4	D	PVP	1:4	0.0094	2.611	0.0456	2.904

Time (min)	Pure Drug Release (%)	% Cumulative drug release microspheres
Time (min)	Pure Drug Release (%)	A	B	C	D
5	4	10.33	17.81	19.56	24.37
10	7.20	18.9	29.47	30	39.24
15	12.61	25	38.64	41.52	58
20	15	36.55	49.91	55.28	72.76
25	18.43	42.92	57	67.19	87
30	21.81	47	65.36	79.8	96.36