Formulation of Eutectic mixture of Curcumin with Salicylic Acid for improving its Dissolution Profile

 

Brahamdutt¹, Sonia Narwal², Aditay Kumar¹, Manjusha Chaudhary³, Vikas Budhwar¹*

¹Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana), India - 124001.

²Faculty of Pharmaceutical Sciences, PDM University, Bahadurgarh.

³University Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, India -136119.

 

ABSTRACT:

Background: Eutectics are basically multi-component crystalline solids closely related to solid solutions. However, the structural organization of eutectics has not been studied in as much detail as solid solutions, which are defined based on the arrangement of a major (solvent) and a minor (solute) component in the crystal lattice. Purpose: The goal of this study is basically improvement in aqueous solubility of poorly water soluble drug i.e curcumin via its eutectic formation by using salicylic acid as coformer. Material and Method: Here the eutectic mixture of curcumin and salicylic acid was prepared by solvent evaporation technique for improving the dissolution behaviour of curcumin. DSC and FT-IR spectroscopy were used as analytical techniques for characterization of eutectic mixture. Result: The DSC and FT-IR spectroscopy conformed the formation of eutectic mixture and In-Vitro dissolution studies revealed an improved dissolution behaviour for eutectic mixture (69.38 %) as compared to the pure curcumin (40.53%). Conclusion: The study conclude that binary systems improved the dissolution behaviour of poorly water soluble drugs without changing the physiochemical and pharmacological properties of concerned API.

 

 

 

 

INTRODUCTION:

A eutectic mixture is a mixture of two components that are completely miscible in the liquid state but immiscible in the solid state. Eutectics are considered to be as closely mixed mixture of drug and conformer. Thermodynamically studies reveals that these mixtures have lower melting point in comparison to the either component of the system. But this is only assumption, not a sure shot criteria for defining a binary mixture to be a eutectic mixture. The improvement in dissolution rate of poorly soluble drugs is directly related to enhance surface area of the components. In design of dosage forms crystalline materials are often employed. Some may exist in different crystalline forms.

 

There are varieties of reasons for such changes in space lattice of crystal. It largely depends on how the crystallization of drug is conducted, the nature of solvent (s) used, the processing conditions such as temperature, pressure, cooling rate, agitation, use of the co-solvents, presence of other solutes and ions¹. The crystallization of both components i.e drug and coformer via nonbonding interactions leads to formation of this binary system². The synthesis of crystalline supramolecular structures mediated by hydrogen bonds is of considerable importance³, the main difference between co-crystals and salts, for example, is that in salts, a proton is transferred from the acidic to the basic functionality of the constituent free base molecule, or vice versa if applicable, whereas in co-crystals, no such transfer occurs⁴. The major difference between various binary systems viz. cocrystals, eutectics or solvates etc. is their physical state. When either of component is liquid at room temperature, formation of hydrates or solvates are maximum while both components are solid at room temperature, chances of cocrystals formation is higher⁵. Hydrogen bonding is one of the most important fundamental interactions that cause association of organic molecules, forming the building block units known as supramolecular synthons⁶.

 

Curcumin, the main component of the spice turmeric, has been successfully used as a therapy to treat human multiple myeloma and also has shown to possess anti- inflammatory and anti-cancer activities. However, curcumin has extremely poor water solubility and bioavailability. A series of pharmaceutically acceptable co-crystal formers are under investigation to screen for co-crystal formation of curcumin⁷.

 

The study that had been done by Sanphui et al. reveals the major problem in use of curcumin⁸, the bioactive herbal ingredient is its low solubility and bioavailability. The cocrystals of curcumin could provide higher solubility and faster dissolving solid dosage forms of curcumin which are relatively stable for drug development⁹. The most appropriate co-crystals can be selected using various Analytical techniques and rational physicochemical studies that include investigations of solubility and stability¹⁰. The goal of present work is to enhance the dissolution properties of curcumin by formulating its eutectic mixture with salicylic acid which can leads to enhance the bioavailability and reducing dosing frequency. Salicylic acid is used as conformer here.

 

MATERIALS AND METHODS:

Chemicals used:

Curcumin was purchased from Organic India Company, New Delhi, Salicylic acid was obtained from Central Drug House (P) Ltd. New Delhi, sodium hydroxide from Loba Chemie Pvt. Ltd., Mumbai and All other reagents and chemicals used were of analytical grade.

 

Characterization of drug and conformer:

FT-IR Study:

The drug and conformer characterization were performed by using FT-IR Spectrophotometric method (FT-IR Bruker 1206 0280, Germany). The powdered Drug and Coformer separately were analysed over a range of 4000-400 cm^-1 respectively. The spectrum (Figure 1 and 2) obtained was compared for the presence of any peak in the eutectic mixture (Figure 5).

 

DSC Study

DSC analysis was performed by using (DSC Q10 V9.9 Build 303, US instrument). 2mg of each curcumin (Figure 3), and salicylic acid (Figure 4) were taken in closed aluminium pain respectively. Each pain containing curcumin and salicylic acid were heated separately from 20^o to 250⁰C in an atmosphere of Nitrogen gas passing at a flow of 60ml/min. An empty aluminium pan was taken as reference pan.

Preparation of Eutectic mixture:

Solvent evaporation method was used for the preparation of Eutectic mixture¹¹. Ethanol was employed as a solvent for this method. Curcumin and Salicylic acid were taken in the molar ratio (1:1) and dissolved in Ethanol. The prepared solution was kept at room temperature for 5 days till completely evaporated.

 

Characterization of Eutectic Mixture:

The characterization of prepared eutectic mixture was done by using Differential scanning calorimetry (DSC) and Infra-red spectroscopy.

 

FT-IR Analysis:

The FT-IR of the eutectic mixture was performed on (FT-IR Bruker 1206 0280, Germany) instrument by KBr disc technique. The spectrum was recorded (Figure 5) over the range of 4000- 400 nm¹². The obtained spectrum was than interpreted.

 

DSC Analysis:

DSC analysis (Figure 6) was performed by using (DSC Q10 V9.9 Build 303, US) instrument. 2mg of the eutectic mixture taken in closed aluminium pain was heated from 30^o to 250^o C in an atmosphere of Nitrogen gas passing at a flow of 60ml/min. An empty aluminium pan was taken as reference pan¹³.

 

In-Vitro dissolution studies:

Preparation of calibration curve:

100mg of Curcumin was taken and dissolved in 1000ml of 2% SLS solution as dissolution media. Now 1ml of this solution was diluted with 100ml of dissolution media. Further dilution were performed to obtain the different concentrations viz. 2, 4, 6, 8, 10µg/ml solutions. λ_max value was determined and calibration curve was prepared by UV Spectrophotometer (UV- 1800, Shimadzu Corp., Japan)¹⁴.

 

Dissolution study:

The dissolution studies were conducted in 900mL of 2% SLS solution at 50rpm maintained at 37±0.5°C in a dissolution apparatus (Model Disso 2000 tablet dissolution test apparatus, Lab India, India) using the paddle method. 100mg of drug and its equivalent amount of eutectic mixture was added to dissolution medium and the samples were withdrawn at appropriate time intervals. The volume of dissolution medium was adjusted to 900ml by replacing it with fresh medium¹⁵. The samples were immediately filtered through 0.45μm membrane filter, suitably diluted and analysed spectrophotometrically (UV- 1800, Shimadzu Corp., Japan) at 426.24nm.

 

RESULT AND DISCUSSION:

Drug and Coformer characterization:

FT-IR study:

The FTIR analysis of drug (Figure 1) and coformer (Figure 2) were performed separately. The characteristic peaks of curcumin were found in the spectra viz. 3554-3824 for free O-H, 1498 for C=C, 1153-1272 for C-N stretch, 1025-1200 for C-O and 857-958 for =C-H bending. While we obtained characteristic peaks of Salicylic acid in the spectra viz. 3088-3447 for O-H, 1615-1911 for C=O, 848-1065 for C-O functional group respectively.

 

DSC Study:

The DSC thermogram of Curcumin (Figure 3) and Salicylic acid (Figure 4) showed a sharp endothermic peak at 173.85^o C and 151.91^o C respectively, which indicated their melting point. It confirmed the purity of drug sample used for DSC study.

 

 

 

Figure 1: FT-IR Spectra of Curcumin

 

 

Figure 2: FT-IR Spectra of Salicylic Acid

 

 

Figure 3: DSC Thermogram of Curcumin

 

Figure 4: DSC Thermogram of Salicylic Acid

Characterization of Eutectic Mixture:

FT-IR Analysis:

The FT-IR spectrum of the eutectic mixture (Figure 5) revealed the characteristic peaks at 3304-3447 for O-H (H Bonded), 2812-3088 for C-H Stretch, 1615-1911 for C=O stretch and 848-1065 for =C-H stretch respectively. The shifting of some peaks in the spectrum of eutectic mixture might be due to the interaction between drug and Coformer¹⁶. Some of characteristic peaks are also absent in the eutectic mixture spectrum in comparison to the drug and conformer spectrum. This confirmed the formation of eutectic mixture.

 

 

 

Figure 5: FT-IR Spectrum of Eutectic Mixture

 

 

DSC Study:

The thermogram of eutectic mixture (Figure 6) indicate melting point at 167.34^oC, which lies between the melting point of drug (Figure 3) and Coformer (Figure 4). It conform the formation of curcumin: Salicylic acid (1:1) eutectic mixture.

 

 

Figure 6: DSC Thermogram of Eutectic Mixture

 

In-Vitro dissolution study:

The dissolution studies were conducted in 900mL of 2% SLS solution at 50rpm maintained at 37±0.5°C in a dissolution apparatus (Model Disso 2000 tablet dissolution test apparatus, Lab India, India) using the paddle method. 5ml of sample were withdrawn for one hour at interval of 10 minutes viz. 10, 20, 30, 40, 50 and 60minute respectively. Samples were analysed spectrophotometrically (UV- 1800, Shimadzu Corp., Japan) at 426.24nm. The amount of drug release with time was reported in (Table 1) and shown in (Figure 7).

 

Figure 7: Amount of Drug release with time

 

Table 1: Amount of drug release with time

Time (Minutes)	Amount of Drug Release
	Pure Curcumin	Eutectic Mixture
10 20 30 40 50 60	4.28 11.51 17.83 27.23 35.58 40.53	8.57 19.82 29.98 42.36 64.11 69.38

 

Summary:

Curcumin belongs to BCS class II category, having low solubility profile in aqueous medium, but by formulating its eutectic mixture with Salicylic acid, we can improve its dissolution behavior. Here solubility of pure curcumin was found 40.53% over a period of one hour while its eutectic preparation improved it up to 69.38% in the same time. The formation of eutectic mixture was confirmed by DSC studies and FT-IR based analysis of drug, conformer and their eutectic formulation¹⁷. The DSC studies revealed the melting points of drug (Figure 3), coformer (Figure 4) and eutectic mixture (Figure 5) at 173.85, 151.91 and 167.34^o C respectively. The FT-IR studies exhibited the characteristic peaks of drug (Figure 1) at 3554-3824 for free O-H, 1498 for C=C, 1153-1272 for C-N stretch, 1025-1200 for C-O and 857-958 for =C-H bending, coformer (Figure 2) at 3088-3447 for O-H, 1615-1911 for C=O, 848-1065 for C-O functional group and eutectic mixture (Figure 6) at 3304-3447 for O-H (H Bonded), 2812-3088 for C-H Stretch, 1615-1911 for C=O stretch and 848-1065 for =C-H stretch respectively. Both analytical techniques conformed the formation of eutectic mixture. Overall summary concluded that eutectics could be a new formulation technique for improving the dissolution as well as other pharmaceutical parameters viz. solubility, permeability, bioavailability etc. The molecular interactions between two molecules leads to the formation of new chemically bonded molecules having the better physicochemical properties than the parent molecules without altering their pharmacological or therapeutical properties.

 

CONCLUSION:

Eutectics are basically multi-component crystalline solids closely related to solid solutions yet the formation of eutectics is not much studied compared to solid solutions, as these are defined on the basis of their composition or arrangements of solute and solvents in the crystalline lattice. The detailing of internal structural composition via XRD studies of eutectics are rarely available as compared to solid solution. A deep analysis of structural detailing is required for eutectics in pharmaceutical scenario like famous tin-lead eutectic was studied by inorganic chemists. The present study conclude that the aqueous solubility profile of curcumin could be enhanced by formulating its eutectic mixture with salicylic acid. Like Salicylic acid, there are numerous GRAS listed coformers are available, whom have the potential to manipulate pharmaceutical characteristics of drugs having solubility, permeability problems. Further In- vivo bioavailability studies are required to co-relate the results in body and confirm the findings.

 

CONFLICT OF INTEREST:

The authors report no declarations of interest.

 

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Received on 12.05.2020            Modified on 06.06.2020

Accepted on 26.06.2020         © RJPT All right reserved