INTRODUCTION:

Oral drug delivery is the most preferable route of drug administration due to ease of administration, flexibility in formulation, patient compliance, etc. However, in the case of the oral route, there are several challenges such as limited drug absorption resulting in poor bioavailability. Drug absorption from the gastrointestinal (GI) tract can be limited by a range of factors with the most significant contributors being poor aqueous solubility of the drug molecule.

When taking orally, it must first dissolve in GI fluids before permeating through GI membranes to reach systemic circulation. Thus, a drug with poor solubility will exhibit dissolution rate limited absorption¹ Nifedipine is an oral calcium-channel blocking agent and belongs to class II as per BCS classification system², widely used in the treatment of angina pectoris and hypertension. Nifedipine is a poorly water-soluble drug and its oral bioavailability is very low. Improvement of the aqueous solubility of poorly water-soluble drugs is one of the important factors for the enhancement of absorption and obtaining adequate oral bioavailability^3,4. The various methods reported till the date for solubility and dissolution rate enhancement poorly soluble drugs include liquisolid compact technique^5,6, use of dendrimer⁷, compaction with hydroxypropylmethylcellulose⁸, co-grinding with HPMC⁹, the formation of solid dispersions^10,11, inclusion complexes with beta-cyclodextrin¹², use of novel solubilizer like sepitrap 4000¹³ etc.

The rate of drug dissolution of poorly water-soluble drugs depends upon the effective surface area, crystal habit, and the energy state within the drug crystals. A relatively newer group of carriers include porous carriers, which are low-density solids with open or closed pore structure and that provide a large exposed surface area for drug loading. Their hydrophobicity varies from completely hydrophilic carriers, which immediately disperse or dissolve in water, to completely hydrophobic ones, which float on water for hours. Owing to a wide range of useful properties, porous carriers have been used in pharmaceuticals for many purposes including the development of novel drug delivery systems such as floating drug delivery systems and sustained drug delivery systems; improvement of solubility of poorly soluble drugs; and enzyme immobilization.^14-16 Examples of pharmaceutically exploited porous carriers include porous silicon dioxide (Sylysia), polypropylene foam powder (Accurel), porous calcium silicate (Florite), magnesium aluminometa silicate (Neusilin), and porous ceramic. Florite RE (FLR) is a porous calcium silicate that possesses many interparticle and intraparticle pores, particularly of sizes 12 and 0.15 μm, respectively, on its surface. FLR is easily dispersible in all aqueous fluids and has been used to adsorb oily and other drugs, as a compressive agent in pharmaceuticals, and to improve solubility^17,18. In the present investigation, attempt was made to improve solubility and dissolution rate of poorly soluble antihypertensive drug Nifedipine by its adsorption on porous calcium silicate by volatile solvent chloroform¹⁹.

MATERIAL and METHODS:

Material:

Nifedipine was obtained as a gift sample from Zydus Cadila Ltd, Ahmadabad, India. Florite RE was used as adsorbent due to its porous nature. All other chemicals and solvents used were of the pharmaceutical and analytical grade. Double distilled water was used throughout the study for all the experimental procedures.

Adsorption of Nifedipine over FLR:

Accurately weighed quantity of Nifedipine (200 mg) dissolved completely in the minimum quantity of chloroform, into a 500 ml round bottom flask. Calcium silicate (300/600/900 mg in ratio 1: 1.5, 1:3 and 1: 4.5) dispersed into a drug solution, with shaking. Chloroform allowed evaporating completely and dried samples were kept in the desiccator over anhydrous calcium chloride. After complete removal of solvent, solid mass was pulverized and passed through 120 mesh sieve and kept in airtight container^{19, 20}.

Characterization of Nifedipine adsorbed over FLR:

Drug content and yield of adsorption Process:

Dispersed system (10 mg) was weighed accurately and extracted using 100 mL of phosphate buffer pH 6.8 by shaking for 12 hours on the rotary shaker. After shaking sample filter through Whatman filter paper and after sufficient dilutions, samples were analyzed spectrophotometrically at 238nm (Shimadzu UV spectrophotometer 1800). Drug content was calculated from the standard curve of Nifedipine in phosphate buffer pH 6.8²¹ Yield of adsorption process was determined by the co-relating weight of added solute to that of recovered one.

Saturation solubility studies:

A saturation solubility study was carried out to determine increase in the solubility Nifedipine adsorbed on calcium silicate compared with pure Nifedipine. An excess amount of the pure drug and Nifedipine adsorbed product in different proportion was added in 250 mL conical flasks containing 25 mL of double distilled water. Then flasks were covered with cellophane membrane to avoid any loss of solvent and then kept in the rotary shaker for 48 h at 37± 0.5⁰C. The extra care was taken by covering the flask with black paper to protect the drug from photodegradation studies as Nifedipine is highly photosensitive. Aliquots were then withdrawn and filtered through Whatman filter paper. The concentration of Nifedipine was determined by using UV visible spectrophotometer at 238nm (Shimadzu UV spectrophotometer 1800) after appropriate dilution²². Three determinations were carried out for each sample to calculate the solubility of Nifedipine. Increase in solubility of an adsorbed product as compared to the pure drug is given in figure no.1

Fourier Transform Infrared spectrophotometer studies:

FT-IR has been employed as a useful tool to identify drug excipient interaction. Samples were analyzed by the potassium bromide pellet method in an IR spectrophotometer (Alpha T Bruker) in the region from 4000 to 400 cm^-1. Pure Nifedipine and adsorbed product was evaluated by comparing its FT-IR spectra ^23.The FT-IR spectra of Pure Nifedipine and adsorbed product are shown in figure No.2

Differential scanning calorimeter (DSC) Analysis:

Differential scanning calorimetry (DSC) has been one of the most widely used calorimetric techniques to study the solid state interaction of the drug with Physical mixtures²⁴. Samples of the pure drug and adsorbed product were taken in flat-bottomed aluminum pans and heated over a temperature range of 30 to 300 °C at a constant rate of 10°/min with purging of nitrogen (50 ml/min) using alumina as a reference standard in a differential scanning calorimeter (Mettler Toledo, Staresw 920).²⁵ The DSC thermogram of Pure Nifedipine and adsorbed product are shown in figure No.3

Powder X-ray diffractometry (PXRD) Analysis:

The Powder X-ray diffraction technique has been extensively utilized to study the interaction and to obtain the changes in the crystallanity of the adsorbed product. PXRD study was carried out by using X-ray diffractometer (Miniflex 600 X-ray diffractometer, Rigaku corporation Japan ) For this the samples of pure drug and adsorbed product were irradiated with monochromatized CuKα radiation and analyzed between from 5^° to 60^° (2θ)²⁶. The PXRD Diffractograms of Pure Nifedipine and adsorbed product are shown in figure no.4

Scanning Electron Microscopy (SEM) studies:

The surface morphology of pure Nifedipine and adsorbed product was observed by using a scanning electron microscope (VEG A3 TESCAN), under accelerating voltage of 15 keV. Samples were fixed on SEM stub with double-sided adhesive tape and then coated in a vacuum with thin gold layer before investigation²⁷. The SEM images of Nifedipine and adsorbed product are shown in figure 5

Dissolution studies in phosphate buffer:

An accurately weighed amount of Nifedipine and adsorbed product in the different proportion equivalent to 20mg of added to the dissolution medium. The dissolution study was performed in Phosphate buffer pH 6.8. The dissolution study was carried out using USP apparatus II (Shimadzu UV spectrophotometer 1800) at 37+0.5 ^OC and 100 rpm paddle speed. The samples were withdrawn from dissolution media at specified time interval up to 60 min and the absorbance of the sample was recorded using UV spectrophotometer at 238 nm²⁸. Dissolution profiles are shown in figure no .6

Stability Study:

Stability Study for Nifedipine adsorbed on porous calcium silicate in 1:3 proportions was carried out with the help of stability chamber (Remi SC-19 Plus) by storing 1gm of above sample in an ambered colored screw-capped glass bottles at accelerated and controlled temperatures 40⁰C and relative humidity (75%) for a period of 3 months.^29-31The physical mixture was evaluated for physical appearance and in-vitro dissolution at the end of three months.

RESULT AND DISCUSSION:

Drug Content and yield of adsorption Process:

Nifedipine is slightly soluble in methanol and ethanol but freely soluble in acetone and chloroform.³² Therefore, chloroform was selected as a solvent in which Nifedipine showed maximum solubility as compared to other organic solvents. Because of the porous nature of calcium silicate, it possesses a low density and hence to limit bulk volume, the ratio of drug: FLR was restricted to a maximum of 1:4.5. Practical drug content of adsorbed product 1 (AP1), AP2 and AP3 was found to be 38.02 ± 1.23, 23.12 ± 0.93 and 17.15± 0.70 respectively which was co-relating to the ratio of the drug with FLR. The yield of the adsorption process was found in the range of 90 -95% which indicates negligible loss during chloroform treatment. Drug content and yield of the adsorption process is summarized in table No.1

Saturation solubility studies:

Enhancement in the solubility of Nifedipine adsorption on FLR was observed in the saturation solubility studies. Pure Nifedipine exhibited saturation solubility of 8.45 ± 0.03 μg/mL in distilled water. Saturation solubility of Nifedipine adsorbed on porous calcium silicate in different proportion in the various adsorbed product that is AP1, AP2 and AP3 was found to be 15.92 ± 0.08, 22.13±0.06 and 23.03±0.08 μg/mL respectively. The maximum increase in solubility was found up to 273% indicating adsorption of poorly soluble drug on porous calcium silicate was prominent in solubility enhancement. There was no remarkable difference between 1:3 ratio and 1:4.5 ratio indicates for one portion of Nifedipine three portions of FLR is optimum for solubility enhancement by forming the drug adsorbed product. Increase in solubility due to pore structure of FLR and that provide a large exposed surface area for drug loading and which confirms FLR is prominent for use. The solubility of Nifedipine and percent increase in solubility due to use of porous adsorbent FLR are shown in figure no.1

Figure No.1 Saturation solubility of Nifedipine in distilled water with different proportions of porous calcium silicate.

Fourier Transform Infrared spectrophotometer studies:

The FT-IT analysis has been carried out in order to study the interaction between Nifedipine and porous calcium silicate. Pure Nifedipine showed characteristics peaks as per reported FTIR spectra. Absorption bands at 1689 cm^-1 for ester carbonyl stretching band, 1122 cm^-1 and 1125 cm^-1for ether absorption bands of C₃and C₅respectively. C=C in stretching vibration in the aromatic ring observed at 1625, 1574 cm^-1.IR absorption peak at 1310 cm^-1and 1529.6 cm^-1 denotes nitro group. The peak at 3333.10 cm^-1denotes N-H stretching. Pure IR spectra of calcium silicate showed characteristics peaks at 1.11.92 cm^-1, 898.42 cm^-1and 641.37 cm^-1which match with standard peaks. Chloroform treated adsorbed product of Nifedipine-calcium silicate does not show any new peaks and also retained principle IR peaks of Nifedipine which indicates there was no any unwanted interaction between Nifedipine and calcium silicate. FT-IR indicates that porous calcium silicate can be used for enhancement of solubility and dissolution rate as it was found compatible with NDP. FI-IR spectra of Pure Nifedipine, pure calcium silicate and Nifedipine adsorbed product is shown in figure no.2

Figure No.2 FT-IT Spectra of A] Pure Nifedipine, B] Pure Calcium Silicate and C] Nifedipine adsorbed product 1: 3 ratio

Differential scanning calorimeter (DSC) Analysis:

Thermal analysis was employed to demonstrate any unexpected interaction between Nifedipine and calcium silicate. A Sharp endothermic peak with an onset 172⁰C and peak at 173.54⁰C correspond to the melting point of Nifedipine. Nifedipine adsorbed product showed onset 170⁰C and peak at 174.14⁰C. Slight broadening in peak as well reduction in intensity and early onset as compared to the pure Nifedipine indicates adsorption of Nifedipine on porous calcium silicate useful for reduction in drug crystallanity and conversion in amorphous form. Reduction in crystalline nature of drug definitely affects in the enhancement of solubility and addition to it porous nature of calcium silicate provides larger surface area. Slight Broadening and reduction in intensity with shifting of drug endotherm slightly to higher temperature demonstrate the positive effect. Drug adsorbed product showed a slight shifting of endotherm but there is no new peaks were found, this result revealed that there is no unexpected interaction between drug and calcium silicate. The DSC Thermograms of Pure Nifedipine, and drug adsorbed product are shown in fig no. 3

Figure No.3 DSC Thermograms of A] Pure Nifedipine, B] Nifedipine Adsorbed product 1:3 ratio

Powder X-ray diffractometry (PXRD) Analysis:

Powder X-ray diffraction spectroscopy was used to asses the degree of crystallanity of the given sample due to adsorption technique. When drug adsorbed on porous calcium silicate in presence of common volatile solvent chloroform, overall crystallanity of drug decreases and with an increase in amorphous nature. Pure Nifedipine showed numerous distinctive peaks at 11.68, 11.70, 11.72, 11.74, 16.12 etc with high peak intensity that indicated a high crystallanity thus; the final adsorbed product with 1:3 ratio sample shows fewer, less intense peaks. This shows that overall crystallanity of the poorly soluble drug was decreased and due to a more amorphous nature, it may help in increasing its solubility in specific pH conditions of the GI tract. Significant reduction in peak intensities in PXRD pattern was observed in case drug adsorbed product as compared to the pure drug was attributed to the dilution effect of porous calcium silicate. No new peak was detected and hence there was no unexpected interaction of the drug with calcium silicate indicated in IR and in DSC studies. PXRD Diffractograms of Pure Nifedipine and Nifedipine Adsorbed product (1:3 ratio) are shown in figure no.4

Figure No.4 PXRD diffractograms for A] Pure Nifedipine, B] Nifedipine Adsorbed product 1:3 ratio

Scanning Electron Microscopy (SEM) studies:

The SEM study was done to check surface morphology of the drug particles and its relevant changes when adsorbed on porous calcium silicate in presence of chloroform as an organic volatile solvent. Nifedipine particles were variable shaped with the rough surface and exhibiting loose aggregates of irregular shape. SEM images were taken at different magnification power to study the change in surface morphology and to confirm the adsorption of the drug on porous calcium silicate. SEM showed microsized drug crystals as well as agglomerates of pure Nifedipine and calcium silicate particles with pores on the surface (Figure 5). Drug adsorption over FLR particles seen in surface topography of adsorbed product. The significant change in surface morphology of Nifedipine was observed due to complete solubilization of Nifedipine and porous calcium silicate in common organic solvent and further recovery after complete evaporation of chloroform. The successful adsorption of the drug on Porous calcium silicate will provide effective surface area result in enhancement of solubility as well as dissolution rate. SEM images of pure Nifedipine and adsorbed product at different magnification are shown in figure 5

Figure No.5 SEM images of A] Pure Nifedipine a) Lower magnification b) Higher magnification and B] Adsorbed Product in 1: 3 ratio a) Lower magnification b) Higher magnification

In-Vitro Dissolution studies in phosphate buffer 6.8:

The dissolution study was carried out in phosphate buffer pH 6.8 for comparison of its percent drug release. Pure Nifedipine showed drug dissolution of 18.21 % in 30 min while adsorbed in different proportion like 1:1.5 (AP1), 1:3 (AP2) and 1:4.5 (AP3) showed the dissolution of 50.21, 62.56 and 63.85 % respectively in 30 minutes. The maximum drug release was found to be 75.25 % at the end of 60 minutes from the adsorbed product containing 1:4.5 proportion of calcium silicate while AP2 contain 1:3 proportion also showed 74.56% drug release which is near to adsorbed product contains the maximum proportion of calcium silicate. The dissolution of Nifedipine was significantly enhanced due to its adsorption on porous calcium silicate which provides maximum effective surface area. The dissolution rate of the drug from adsorbed products was significantly rapid compared with pure drug, and the dissolution rate increases with increase in the proportion of porous calcium silicate from 1:1.5 to 1:3, but as we further increase the proportion of calcium silicate there was no significant increase in its dissolution indicating saturation. Enhancement in Nifedipine dissolution was explained to be mainly due to the increase in effective surface area attributed by adsorption on the porous nature of calcium silicate. The drug adsorbed product was found also beneficial for an increase in dissolution rate in acidic pH also (dissolution profile not shown). The dissolution profiles of Pure Nifedipine and Adsorbed product (AP) in various proportions in phosphate buffer 6.8 are shown in figure No.6

Fig No.6 Dissolution studies of Pure Nifedipine and Adsorbed product (AP) in various proportions.

Stability studies:

There was no significant change in the physical appearance and percent drug dissolution in the adsorbed product of Nifedipine in 1:3 ratio. A stability results clearly indicate that adsorbed product was sufficiently stable under accelerated and controlled conditions. No change in physical appearance and other parameters indicates that adsorbed product was found stable under accelerated temperature condition as it gives more protection to the drug as compared to drug alone.

CONCLUSION:

The present study determined the utility of the porous calcium silicate to enhance the solubility and dissolution rate of the insoluble drug Nifedipine. Dissolution study indicates that adsorbed product in 1:3 proportion is most useful for enhancement of solubility of Nifedipine as compare to the drug alone. Nifedipine adsorbed product can be used for further development of floating or floating pulsatile drug delivery system as the porous nature of calcium silicate lowers the density of product.

ACKNOWLEDGEMENT:

Authors are thankful to the Zydus Cadila Ltd Ahmadabad for providing gift sample of Nifedipine. Shivaji University, Kolhapur and D Y Patil University Kolhapur is acknowledged for assistance with analytical work.

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Received on 17.10.2018 Modified on 27.11.2018

Research J. Pharm. and Tech. 2019; 12(3): 1273-1279.

DOI: 10.5958/0974-360X.2019.00213.0

Product Code	Ratio (Drug: FLR)	Theoretical drug content (%)	* Practical drug content (%)	* Yield of Adsorption Process (%)
AP1	1:1.5	40.00	38. 02 ± 1.23	95. 05 ± 0.62
AP2	1:3	25.00	23. 12 ± 0.93	92. 36 ± 0.34
AP3	1:4.5	18.18	17. 15 ± 0.70	94. 32 ± 0.80