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Journal of Formulation Science & Bioavailability
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Research on Formulation and Evaluation of Lipid Based Solid Dispersions of Lafutidine

Sireesha M*

SVS Pharmaceutical Sciences, Warangal, Telangana, India

*Corresponding Author:
Sireesha M
Assistant Professor
SVS Pharmaceutical Sciences
Warangal, Telangana, India
Tel: 0870 2453900
E-mail: [email protected]

Received Date: January 30, 2017; Accepted Date: February 21, 2017; Published Date: February 25, 2017

Citation: Sireesha M (2017) Research on Formulation and Evaluation of Lipid Based Solid Dispersions of Lafutidine. J Formul Sci Bioavailab 1: 104.

Copyright: © 2017 Sireesha M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Drug delivery through the oral mucous film is considered to be a promising contrasting option to the oral course. Sublingual course is a quick onset of activity and preferred patient consistence over orally ingested tablets. Sublingual (contracted SL), from the Latin for "under the tongue", alludes to the pharmacological course of organization by which drugs diffuse into the blood through tissues under the tongue. Sublingual course is a valuable when fast onset of activity is wanted with preferable patient consistence over orally ingested tablets. Regarding penetrability, the sublingual al range of the oral pit (i.e. the floor of the mouth) is more porous than the buccal (cheek) range, which thusly is more penetrable than the palatal (top of the mouth) territory.

Keywords

X-ray diffraction; Calorimetry; Griseofulvin; Pharmacologically; Solid dispersion

Introduction

Orally administered dosage forms has a major share in the market among all the other dosage forms as this is most convenient method of drug delivery. The drug molecules delivered through this route permeates across the gastro intestinal membranes and finally reaches the systemic circulation. The pre-requisite condition for permeation to occur is, the drug must be presented in solution form. The fluids in the body and mainly in the gastrointestinal tract are aqueous in nature and hence the water solubility of a drug molecule is a critical parameter in the process of drug development as well as formulation development. The intestinal absorption of drug can be predicted by applying biopharmaceutical classification system (BCS) approved by U.S Food and Drug Administration (FDA). In BCS classification drugs are classified according to their intestinal permeability, aqueous solubility and aqueous dissolution [1-5].

Absorption of the drug is defined as the method of movement of unchanged drug from the site of administration to systemic circulation. The absorption of a drug from a drug product in systemic circulation consists of a rate process solid oral, immediate release drug products. Its includes dissolution of the drug in the solution, absorption through cell membranes into systemic circulation For drugs that have very poor aqueous solubility, the rate at which the drug get dissolves is the slowest or rate limiting step effect bioavailability in other case if the drug has high solubility their it rapid the rate process. Examples such as griseofulvin, digoxin, phenytoin, sulphathiazole and chloramphenicol come immediately to mind. With the recent advent of high through put screening of potential therapeutic agents, the number of poorly soluble drug candidates has risen sharply and the formulation of poorly soluble. Most of the compounds for the oral delivery are the challenging formulation scientists in the pharmaceutical industry.

Drug Dispersion in Carriers

Co-precipitates and melts are solid dispersions that provide a means of reducing particle size to the molecular level. Sekiguchi and obi first introduced the concept of using solid dispersions to improve bioavailability of poorly water soluble drugs in 1961. They demonstrated that the eutectic of sulfthiazole and the physiologically inert watersoluble- carrier urea exhibited higher absorption and excretion after oral administration than sulfathiazole alone [6-10].

Mechanism of increasing dissolution rate by solid dispersions

The enhancement of dissolution rate as a result of solid dispersion formation relative to pure drug varies from as high as 400 fold to less than two fold. Corrigan reviewed the current understanding of the mechanism of release from solid dispersions. The increase in dissolution rate for solid dispersions can be attributed to a number of factors. The main factors for solid dispersions are:

A) Reduction in particle size: The improvement in dissolution characteristics was first attributed 100% to the reduction in particle size. The ultimate particle size reduction is molecular dispersion, and after the carrier has dissolved, the drug is molecularly dispersed in the dissolution medium.

B) Wettability and dispensability: The carrier material may also have an enhancing effect on the wettability and dispensability of the drug in the dissolution media. This should retard any agglomeration or aggregation of the particles, which can slow the dissolution process.

• A further reason for the improvement in the dissolution rate is that the drug has no crystal structure in the solid solution therefore; the energy normally required to breaking is not a limitation to the release of the drug from a solid solution.

• After the solid solution has dissolved, the drug is presents as a supersaturated solution. In some cases, the carriers may serve to inhibits precipitation of the drug from the supersaturated solution.

• It has also been speculated that, if the drug does precipitate it will precipitate out as a metastable polymorph with a high solubility compared to that of thermo stable form.

Selection of a carrier: The properties of the bearer affect the disintegration attributes of the scattered medication. A transporter ought to meet the accompanying criteria to be appropriate for expanding the disintegration rate of a medication. Be unreservedly water solvent with inborn quick disintegration properties. Be non lethal and pharmacologically idle. Be warm stable with a low softening point for the liquefy strategy. • Be dissolvable in an assortment of solvents and go through a vitreous state upon dissolvable dissipation for the dissolvable technique. •Be ready to best, increment the fluid solvency of the medication and Be artificially good with the medication and not emphatically reinforced complex with the medication.

Materials used as carrier for solid dispersions

Sugars: Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Mannitol, Lactose.

Acids: Citric acid, Succinic acid.

Polymeric materials: Povidone, Polyethylene glycol, Hydroxypropyl methyl cellulose, Cyclodextrins, Hydroxypropyl cellulose, pectin.

Insoluble or enteric polymers: Hydroxy propyl methyl cellulose phthalate, Eudragit L-100, Eudragit-S 100, Eudragit RL and Eudragit RS, Polyooxyethylenestearate.

Surfactants: Polyooxyethylene stearate.

Miscellaneous: Urea and Urethane

Methods of preparation of solid dispersions

The solid dispersions can be prepared by the following methods:

a. Melting method or fusion method: This strategy was initially proposed by Sekiguchi and Obi in 1961. In this strategy the transporter and the medications were intertwined to get ready quick discharge strong scattering dose shapes. The physical blend of a medication and a water-solvent bearer was warmed until it liquefied. The liquefied blend was then cooled and cemented quickly in an ice shower under lively mixing. The last strong mass was smashed, pounded and sieved. Such a method was in this manner utilized with some change by Gold berg et al., and Chiou and Riegelmann. To encourage speedier hardening, the homogeneous soften was poured in a type of a thin layer onto a stainless steel plate and cooled by streaming air or water on the opposite side of the plate. The principle favorable circumstances of this immediate softening strategy are its straightforwardness and economy. It is less tedious. There is no utilization of poisonous solvents. Likewise, a super immersion of solute or medication in a framework can regularly be gotten by extinguishing liquefy quickly from a high temperature. The hindrance is that numerous substances either, medication or bearer, may disintegrate or vanish amid combination handle. For instance succinic corrosive utilized as a bearer for griseofulvin is very unpredictable and may in part break down by drying out close to its liquefying point. Goldberg et al. highlighted other potential issues, for example, warm debasement, sublimation and polymorphic changes. The set mass is regularly shabby and unhandable.

b. Common solvent method: Tachibana and Nakamura reported this method. In this method the solid dispersions are prepared by dissolving a physical mixture of solid components in a common solvent, followed by evaporation of the solvent, resulting in the coprecipitation of dissolved substances from the solution. When such coprecipitate was exposed to water, it leads to the formation of a colloidal dispersion.

c. Melting solvent method: In this method, the solid dispersions were prepared by dissolving the drug in a suitable solvent and incorporation of the resultant solution directly, into the melt of the carrier such as Mannitol, PEG 6000, PEG 4000 etc. This method possesses the advantages of both the melting and solvent methods. Chiou and Smith reported that 5-10% w/v of liquid can be incorporated into the PEG 6000 without significant loss of the solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of PEG. The solvent used may affect the polymorphic form of the drug precipitated in the solid dispersion.

d. Supercritical fluid process: Supercritical CO2 is a good solvent for water insoluble as well as water soluble compounds under suitable conditions of temperature and pressure. Therefore supercritical CO2 has potential as an alternative for conventional organic solvents used in solvent based processes for forming solid dispersions due to the favourable properties of being non-toxic and inexpensive.

SCF techniques can be applied to the preparation of solvent-free solid dispersion dosage forms to enhance the solubility of poorly soluble compounds. Traditional methods suffer from the use of mechanical forces and excess organic solvents. A solid disperssion of carbamazepine in polyethylene glycol 4000 (PEG4000) increased the rate and extent of dissolution of carbamazepine. In this method, a precipitation vessel was loaded with solution of carbamazepine and PEG4000 in acetone, which was expanded with supercritical CO2 from the bottom of the vessel to obtain solvent-free particles.

e. Kneading technique: In this method both drug and polymer was taken in a glass mortar and triturated by using a small volume of organic solvent to give a thick paste which was kneaded up to 30 minutes and then kept for air dry. Then the dried mass was scratched and pulverized and sifted through mesh # 80.

f. Co-grinding technique: Weighed quantities of carrier and drug were taken in a mortar and grinded for20 min and finally sifted through sieve 100 and were stored in airtight container until evaporation.

Evaluation of Solid Dispersions

Various methods are available which can give information regarding the physical nature of solid dispersion system. The commonly used methods are the following:

Thermal methods

This method is most commonly used to observe the Physicochemical interactions of two or more compounds. It utilizes the principle of change of thermal energy as a function of temperature and can be performed by the following techniques.

Cooling curve method

Physical mixtures of components in various properties are heated to a homogenous melt. During the cooling process temperature of each mixture is plotted as a function of time. Critical temperatures are noted and plotted against composition to provide the phase diagram.

The method is time consuming, requires relatively larger amounts of samples and is not applicable to samples that decompose after melting. Moreover changes in slope can be mixed, especially if cooling takes place rapidly.

Thaw melt method

A solidified sample in a capillary tube is heated gradually and the thaw and melting points are noted by visual observation. Since the method depends on visual observation the results are not reproducible.

Thermo microscopic method

Physical mixtures of drug and carrier placed in a slide covered with a cover slip and scaled with silicone grease to prevent sublimation. The mixture is heated until it completely liquefies. After cooling, the mixture is reheated. The melting points are noted and a phase diagram is constructed.

Differential thermal analysis (DTA)

It is effective for studying phase equilibrium of pure compounds as well as their mixtures. This method is limited to compounds with high thermal stability and low volatility. In addition to thaw and melting points, polymorphic transitions, evaporation, sublimation, dissolvation and other types of decomposition can also be detected by thermal analysis. The greatest advantage lies in constructing phase diagrams of high reproducibility.

X-ray diffraction method

It is very important and efficient tool in studying physical nature of solid dispersions. In simple eutectic systems, diffraction peaks of each crystalline compound can be found in the diffraction spectra. In substitutions solid solutions, the lattice parameter of the solvent crystal is either increased, remains unchanged or decreased depending on the relative size of the solute atom or molecule. In continuous solid solutions, there is a shift from the positions of the peaks in one pure component to those in other. In interstitial solid solutions the diffraction pattern of solvent component may or may not change while that of the solute component disappears.

The X-ray diffraction method can be applicable in detecting compound or complex formation. Since the spectra of lattice parameters of a complex are different from those of pure compound.

Dissolution rate determination

This method can be used to study degree or crystallinity in solid-solid equilibria. This method involves comparison of in-vitro dissolution rates of solute component from a constant surface tablet with the physical mixture of same composition. The technique is simple to perform except that in some binary systems, the tablet may not be constant due to the leaching of particulars into dissolution media. It has been shown to be applicable to simulated systems of indomethacin- PEG-6000 and sulphathiazole-urea.

Electromicroscopy

Often used to get primary information of the systems and to detect amorphous and crystalline structure.

Thermodynamic methods

The phase diagrams of eutectic and solid solution systems can be evaluated by phase thermodynamic parameters. The knowledge of heats of fusion, entropies and partial pressure at various compositions enables the determination of the solubility gap below the solid-liquid equilibrium temperature.

Chemical modification

Poorly water-soluble drug is to be converted into the soluble drug by chemically modifying with the help of suitable functional groups. Most extensively research work has been done successfully by using carriers like polyethylene glycol. PEG forms covalent bonding with the drugs which will have suitable functional groups. The type of conjugation comes under the class covalent polymer drug conjugates.

Rationale of the Work

• Lafutidine is a second generation H2 receptor antagonist having multimodal mechanism of action. The major drawback in the therapeutic application and efficacy of lafutidine as oral dosage form is its very low aqueous solubility. Poor aqueous solubility and slow dissolution rate of the drug lead to low oral bioavailability consequently irreproducible clinical response or therapeutic failure.

• Therefore, it is important to develop effective methods to enhance the solubility and dissolution rate of the drug aiming to improve its bioavailability, increase the predictability of the response and/or reduce the dose.

• Lipid based solid dispersions have been widely used to enhance the oral bioavailability of poorly soluble drugs by increasing the drug solubility, dissolution rate.

Thus lafutidine was selected as an insoluble drug to formulate solid dispersion using Gelucire 50/13 and Vitamin E TPGS as lipid carriers along with porous calcium silicate as inert carrier [11-15].

Experimental Methodology

Analytical method to estimate lafutidine in water

Accurately weighed amount of 10 mg of drug was taken in volumetric flask (10 ml) and dissolved in small amount of methanol. Finally the volume was made up to the mark with methanol (Primary stock-1 mg/ml). The secondary stock was prepared by taking 1 ml solution of primary stock in 10 ml of volumetric flask and the volume was made up to mark (Secondary Stock II, 100 μg/ml) with water. From the secondary stock different concentrations (4-20 μg/ml) were taken and absorbance values were noted at λmax 215 nm. A calibration curve was plotted by taking concentrations on x-axis and absorbance values on y-axis. Slope and R2 values were noted [16-21].

Analytical method to estimate lafutidine in methanol

Accurately weighed amount of 10 mg of drug was taken in volumetric flask (10 ml) and dissolved in small amount of methanol. Finally the volume was made up to the mark with methanol (Primary stock-1 mg/ml). The secondary stock was prepared by taking 1 ml solution of primary stock in 10 ml of volumetric flask and the volume was made up to mark (Secondary stock-100 μg/ml) with methanol. From the secondary stock different concentrations (4-20 μg/ml) were taken and absorbance values were noted at λmax 215 nm. A calibration curve was plotted by taking concentrations on x-axis and absorbance values on y-axis. Slope and R2 values were noted.

Phase solubility studies

Phase solubility studies were done by taking different concentrations of Gelucire 50/13 and Vitamin E TPGS (1%, 3%, 5%, and 7%) in distilled water. To each of these concentrations excess amount of drug was added. Then these solutions were kept for shaking on shaker for 48 hours. After 48 hours samples were filtered through the Whatman filter paper then the solution diluted and estimated for lafutidine concentration using UV-spectroscopy at 215 nm. Three determinations were carried out for each sample to calculate the solubility of lafutidine.

Formulation of Solid Dispersions

Lipid based solid dispersions of lafutidine were prepared by using different hydrophilic lipid based carriers such as gelucire 50/13 in different ratios such as 1:1,1:3 and 1:5 and vitamin E TPGS in different ratios such as 1:1, 1:3, and 1:5. These ratios were decided based on the results obtained in phase solubility studies. Porous calcium silicate was used as inert carrier in all the formulations. Compositions of various formulations are given in the Table 1. LBSD of lafutidine were prepared by solvent evaporation method. Lafutidine 10 mg was taken and dissolved in 10 ml solvent mixture of ethanol and dichloromethane. To the drug required quantity of lipid based carrier and porous calcium silicate were added. This solution was taken into round bottom flask, attached to the rotary flash evaporator and evaporated at 37°C, rpm was 60 for 15 min. Solid dispersions were obtained, collected and dried in the dessicator till it was completely dried. The method followed in the preparation of solid dispersions.

Formulation Lafutidine Gelucire 50/13 Vitamin E TPGS Porous calcium silicate Ratio
SD1 10 10 - 10 01:01:01
SD2 10 30 - 30 01:03:03
SD3 10 50 - 50 01:05:05
SD4 10 - 10 10 01:01:01
SD5 10 - 30 30 01:03:03
SD6 10 - 50 50 01:05:05

Table 1: Formulation of solid dispersions with Gelucire 50/13 and Vitamin E TPGS.

Content uniformity of lipid based solid dispersions

Lipid based solid dispersions of lafutidine solid dispersions were taken in 50 ml of methanol in a conical flask and kept on a rotary shaker for 1 hour. After this time period, the solutions were filtered through a 0.45 μm membrane filter and diluted suitably. These samples were the analyzed with UV Spectroscopy. Each content determination was performed in triplicate and the average and standard deviations were calculated.

In vitro dissolution studies

Dissolution studies of pure lafutidine, dispersions and physical mixtures were performed by using USP (XXIV) type II apparatus (Electrolab, Mumbai, India) at the paddle rotation speed of 50 rpm in 900 mL distilled water as dissolution media at 37 ± 0.5°C. A sample equivalent to 10 mg of lafutidine of the prepared systems was placed in the dissolution medium. Aliquots of 5 mL were collected at predetermined time intervals over a period of 1 h and were replaced with the same volume of fresh dissolution medium. The samples were subsequently filtered using 0.45 mm membrane filter and the filtrate obtained was suitably diluted and analyzed by UV-spectroscopy. Samples were performed in triplicate.

Saturation solubility studies

Saturation solubility study of pure drug lafutidine, and all formulation was done by adding excess amounts in distilled water at 37 ± 0.5°C, respectively. The solutions were equilibrated under continuous agitation for 48 hr and centrifuged. The samples were analysed by UV-spectroscopy at 215 nm and the concentrations in μg/ ml were determined. Each sample was determined in triplicate.

Drug and Excipient Compatibility Studies

Fourier transform infrared spectroscopy

Fourier transform infrared (FT-IR) spectra were obtained using a IR prestige 21 Shimadzu model FTIR spectrometer which was employed to characterize the possible interactions between the drug and the carrier in the solid state. The samples are prepared by the KBr pellet method and the spectrum was recorded in the range of 4000–400 cm−1.

X-ray diffraction

Lafutidine and carriers (Gelucire 50/13, vitamin E TPGS), and the solid dispersion in carriers were analyzed by X-Ray Diffraction (X’Pert PRO MPD diffractometer). The diffraction pattern was measured with at a dwell time of 45 s at each step between 3 and 50 2θ at ambient temperature.

Differential scanning calorimetry

The principle involved in DSC is difference in amount of heat required to raise the temperature of sample and reference is measured as a function of temperature. Polymorphic studies of drug were performed by DSC. This technique is used to know crystallinity, glass transition temperature enthalpy changes. DSC thermograms were obtained using differential scanning calorimetry (Mettler DSC 823e, Mettler-Toledo, Germany) calibrated with indium (calibration standard, purity >99.9%). Accurately weighed sample (4 mg) was placed in a flat bottomed standard aluminium pan and scanned at a scanning speed of 10°C/min from 20°C to 300°C under a nitrogen gas flow of 80 mL/min.

Results and Discussion

Analytical method to estimate the lafutidine

Calibration curves of lafutidine were plotted in different solvents of methanol, water which are shown in Figure 1. R2 and slope values were calculated and are given in Table 2.

Solvent R2 Slope
Water 0.996 0.044
Methanol 0.995 0.045

Table 2: R2 values and slope values of lafutidine in different solvents.

formulation-science-bioavailability-curve

Figure 1: Calibration curve of lafutidine in water.

Phase solubility studies of lafutidine in vitamin E TPGS

Phase solubility studies were performed in different concentrations of vitamin E TPGS and the values obtained were represented in bar chart which is shown in Figures 2 and 3. It was observed that the phase solubility of lafutidine increased with the increased concentration of vitamin E TPGS.

formulation-science-bioavailability-lafutidine

Figure 2: Calibration curve of lafutidine in methanol.

formulation-science-bioavailability-concentrations

Figure 3: Phase solubility of lafutidine in different concentrations of vitamin E TPGS.

Phase solubility studies were performed in different concentrations of Gelucire 50/13 and the values obtained were represented in bar chart which is shown in Figure 4 . It was observed that the phase solubility of lafutidine increased with the increased concentration of Gelucire 50/13.

formulation-science-bioavailability-solubility

Figure 4: Phase solubility of lafutidine in different concentrations of Gelucire 50/13.

Reprecipitation study

As shown in Figure 5A and 5B the test media without any carrier became turbid immediately after addition of drug solution and remained turbid for more than 24 h; where as the test media with carriers less turbid than test media without carrier and remained clear (Figure 5C-5F) upto 24 h. Figure 6 shows the highest solubility of drug in both the carrier solutions and maintained up to 24 h. However, test media without carrier showed declining of the drug solubility throughout the period of study. These results suggest the solubility enhancing property of these carriers by inhibiting reprecipitation of drug. As these carriers are surfactant in nature the hydrogen bonding and hydrophobic interactions between drug and carrier may inhibit the reprecipitation of drug by improving the solubility.

formulation-science-bioavailability-gelucire

Figure 5: Reprecipitation studies in (A) Water, (B) Water+Drug, (C) Gelucire 50/13, (D) Gelucire 50/13+Drug, (E) Vitamin E TPGS, (F) Vitamin E TPGS+Drug.

formulation-science-bioavailability-profiles

Figure 6: Reprecipitation profiles of lafutidine in different test solutions.

Drug content

The drug content of the prepared dispersions was found to be in the range of 95.6-102% indicating the application of the present method for the preparation of simple dispersion with high content uniformity.

In vitro dissolution study of pure drug

Dissolution study of pure drug was done in water as dissolution media. Percentage drug dissolved at various time intervals were calculated and shown in Table 3. A graph was plotted by taking time on X-axis and corresponding% drug dissolved on Y-axis and is shown in Figure 7.

formulation-science-bioavailability-drug

Figure 7: In vitro dissolution profile of pure drug in water.

Carrier Drug and carrier ratio % Drug content
Gelucire 50/13 01:01 100.5 ± 0.12
01:03 95.6 ± 0.8
01:05 102.3 ± 0.68
Vitamin E TPGS 01:01 98.6 ± 2.5
01:03 102.2 ± 0.81
01:05 99.8 ± 0.52

Table 3: Drug content determination in water.

In vitro drug release studies of lipid based solid dispersions

In vitro drug release studies of lipid based solid dispersions were carried out in water and% drug release at various time intervals was calculated. The values obtained are shown in Table 4-6 and were plotted by taking time on X-axis and corresponding% drug dissolved on Y-axis and are shown in Figures 8 and 9.

Time (min) % Drug dissolved
0 0
10 26.3 ± 0.8
20 32.4 ± 1.7
30 40.7 ± 0.4
45 46.3 ± 0.02
60 49.9 ± 0.41

Table 4: In vitro of pure drug dissolution in water.

Time (min) %Drug released
SD1 G(1:1) SD2 G(1:3) SD3 G(1:5) PM G DRUG
0 0 0 0 0 0
10 92.2 ± 1.4 74.4 ± 8.1 91.4 ± 4.3 49 ± 2.8 26.3 ± 0.8
20 98.2 ± 5.7 77.5 ± 10.1 94.3 ± 4.9 53.4 ± 2.9 32.4 ± 1.7
30 100.1 ± 4.8 83.7 ± 8.6 93.7 ± 0.6 57.8 ± 2.9 40.7 ± 0.4
45 97.6 ± 2.3 87 ± 8.8 98 ± 1.3 64.2 ± 2.9 46.3 ± 0.02
60 96 ± 1.3 92.4 ± 2.6 95.4 ± 1.2 67.7 ± 1.5 49.9 ± 0.41

Table 5: In vitrodrug release of formulations SD1-SD3, PM G and drug.

Time (min) % Drug released
SD4 V(1:1) SD5 V(1:3) SD6 V(1:5) PM V DRUG
0 0 0 0 0 0
10 74.8 ± 13.3 96.1 ± 2.3 87.7 ± 0.8 47 ± 2.8 26.3 ± 0.8
20 80.1 ± 12.2 95.9 ± 1.2 89.9 ± 0.4 54.4 ± 7.2 32.4 ± 1.7
30 84.5 ± 10.8 93.2 ± 2.4 94.3 ± 1.2 58.8 ± 7.2 40.7 ± 0.4
45 92.7 ± 8.5 96.7 ± 1.9 98.3 ± 7.9 66.3 ± 2.9 46.3 ± 0.02
60 100 ± 5.4 100 ± 0.6 100.8 ± 6.6 69.7 ± 1.5 49.9 ± 0.41

Table 6: In vitro drug release of formulations SD4 to SD6, PM V and drug.

formulation-science-bioavailability-vitro

Figure 8: In vitro drug release of formulations SD1 to SD3, PMG and drug.

formulation-science-bioavailability-release

Figure 9: In vitro drug release of formulations SD4 to SD6, PM V and drug.

The results shows improved dissolution rate of the drug with increasing Gelucire 50/13 ratios. It was found that formulation prepared with Gelucire 50/13 have shown faster drug release than the formulation prepared with vitamin E TPGS.

It was also found that SD1 formulation (1:1 with Gelucire 50/13) is the best formulation among all the other formulations, as 100.1 ± 4.8 of drug was released at 30 min which is shown in Figures 8-12.

formulation-science-bioavailability-release

Figure 10: In vitro drug release of all the formulations.

formulation-science-bioavailability-studies

Figure 11: Saturation solubility studies.

formulation-science-bioavailability-solubility

Figure 12: Saturation solubility studies.

Saturation Solubility Studies of Solid Dispersion of Gelucire 50/13 and Pure Drug

Solid state characterisation

A) Fourier transform infrared spectroscopy: The FTIR spectra of pure drug, Gelucire 50/13, vitamin E TPGS optimized ratio of solid dispersion and respective physical mixture were shown in Figures 13 and 14. The prominent peaks of drug were observed at 3324.3-3016.48 cm-1 (-C-H and -CH2) vibration, 2853.73 cm-1 (alkane –CH3,CH2) stretching, 1738.2 cm-1 (C?O), 1635.90 cm-1 (C?O,-NH), 1561.57 cm-1 and 1525.80 cm-1 (1° and 2° amine). Vitamin E TPGS peaks observed at 1028.37 cm-1. Solid dispersion peaks were observed at 3324.64 cm-1, 2854.23 cm-1, 1635.52 cm-1 and 1041.78 cm-1 and gelucire 50/13 peaks observed at 3318.54 cm-1, 2850.30 cm-1, 1738.90, 1636 and 1032.92 cm-1. These peaks are slightly changed when compared to drug. Retention of characteristic drug peaks with additive carrier peaks without any significant change to the position of drug peaks in the solid dispersion clearly suggest no possible interaction between drug and carriers and conforms the stability of drug in the solid dispersion.

formulation-science-bioavailability-mixture

Figure 13: FTIR spectra of A) Drug B) Vitamin E TPGS C) Physical mixture D) Solid dispersion.

formulation-science-bioavailability-spectra

Figure 14: FTIR spectra of A) Drug B) Gelucire 50/13 C) Physical mixture D) Solid dispersion.

B) X-ray diffraction: The Diffractogram pattern of pure lafutidine, porous calcium silicate, porous calcium silicate + gelucire 50/13, physical mixture and solid dispersion of gelucire 50/13 are shown in the Figure 15. The XRD scan of pure drug showed intensed peaks of crystallinity at 20.56, 21.60, 23.60 position (º2θ) whereas the XRD pattern of prepared physical mixture and solid dispersion exhibited a reduction in intensity of drug peaks at 20.56, 21.60 positions compared to the pure drug indicating decrease in crystallinity in the prepared formulation (solid dispersion and physical mixture). The relative degree of crystallinity at 20.56, 21.60 positions of drug with those of solid dispersion and physical mixture are found to be 0.33, 0.428 and 0.445, 0.3694 respectively. The absence of few peaks in the formulation suggest the lack of interaction between drug and carrier

formulation-science-bioavailability-silicate

Figure 15: X-ray diffraction of A) Drug B) Porous calcium silicate C) Porous calcium silicate+Gelucire 50/13 D) Physical mixture E) Solid dispersion.

The Diffractogram pattern of pure lafutidine, porous calcium silicate, porous calcium silicate + vitamin E TPGS, physical mixture and solid dispersion of vitamin E TPGS are shown in the Figure 16. The XRD scan of pure drug showed intensed peaks of crystallinity at 20.56, 21.60, 23.60 position (º2θ) whereas the XRD pattern of prepared physical mixture and solid dispersion exhibited a reduction in intensity of drug peaks at 20.56, 21.60 positions compared to the pure drug indicating decrease in crystallinity in the prepared formulation (solid dispersion and physical mixture). The relative degree of crystallinity at 20.56, 21.60 positions of drug with those of solid dispersion and physical mixture are found to be 0.029, 0.291 and 0.232, 0.36 respectively. The absence of few peaks in the formulations suggest the lack of interaction between drug and carrier (Figure 17).

formulation-science-bioavailability-dispersion

Figure 16: X-ray diffraction of A) Drug B) Porous calcium silicate C) Porous calcium silicate+Vitamin E TPGS D) Physical mixture E) Solid dispersion.

formulation-science-bioavailability-drug

Figure 17: DSC of A) Drug B) Gelucire 50/13 C) Physical mixture D) Solid dispersion.

c) Differential scanning calorimetry: DSC was employed to evaluate the phase of transformation of lafutidine during the formation of solid dispersion. As illustrated in Figure 17 the free drug was characterized by a single sharp melting endotherm peak 99.15°C. Corresponding to melting point of drug confirming its crystallinity. Gelucire 50/13 and Vitamin E TPGS physical mixtures showed endothermic peaks at 98.51°C and 97.74°C respectively but gelucire 50/13 and vitamin E TPGS solid dispersion did not show the melting endothermic peak of drug suggesting there is reduction in crystallinity.

Conclusion

The solubility of lafutidine was enhanced by the use of Gelucire 50/13 and vitamin E TPGS studied at increasing concentrations indicating AL type phase solubility diagram. The dissolution parameters indicated increased dissolution of lafutidine in solid dispersions. DSC studies reveals that the solid dispersion did not show the melting endothermic peak of drug suggesting there is decrease in crystallinity. The solid state characterization using XRD studies revealed decrease in crystalline nature of drug. The FTIR studies indicated there is no evidence of interaction between the drug and carriers studied. In conclusion, lipid based solid dispersions developed using Gelucire 50/13, vitamin E TPGS were shown to be prominent systems to improve the dissolution of poorly water soluble drugs.

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