Introduction

Poor water solubility and slow dissolution into the gastrointestinal tract (GIT) are the two major obstacles impeding the pharmaceutical industry in releasing new dosage forms into the market. These issues have been responsible for the rejection of 70% of the potentially active drugs. Eutectic mixtures have played a key role in improving the absorption of many compounds by increasing their solubility and dissolution properties [1].

A eutectic is a mixture of two or more compounds having a melting point lower that of each constituent, in this case a poorly water soluble drug and a highly water soluble carrier molecule [2]. This combination in general is immiscible in the solid state and miscible in the liquid state. Upon crystallization of a liquid mixture, a reduction in particle size is obtained resulting in a final product where the drug is incorporated into the interstitial spaces of the carrier molecule. Formation of this mixture causes faster release of the drug present in the carrier [3].

The general method of preparing the samples, running through the Differential Scanning Calorimetry (DSC), and interpreting the results to obtain the eutectic point is labor-intensive and time consuming. A short and sweet preformulation predictive method has been proposed by Van’t Hoff, which involves the use of a modified Van’t Hoff equation. The equation is as follows [4]:

$$ T_{\text{mix}} = T_{\text{d}}^{\text{f}} - {{w_{\text{p}} \left[ {R\left( {T_{\text{d}}^{\text{f}} } \right)^{2} } \right]} \mathord{\left/ {\vphantom {{w_{\text{p}} \left[ {R\left( {T_{\text{d}}^{\text{f}} } \right)^{2} } \right]} {\Updelta H_{\text{d}}^{\text{f}} }}} \right. \kern-\nulldelimiterspace} {\Updelta H_{\text{d}}^{\text{f}} }} $$
(1)

where \( T_{\text{d}}^{\text{f}} \) melting point of the major component, w p weight fraction of the minor component, R universal gas constant, \( \Updelta H_{\text{d}}^{\text{f}} \) molar heat of fusion of the major component and T mix is the temperature along the liquidus line as a function of w p.

On the basis of the above equation, Law et al. [5] proposed an index, (I c ), which is useful in the calculation of the eutectic point by using the melting points of the drug and PEG carrier [5]. The equation is as follows:

$$ I_{c} = \left( {T_{\text{d}}^{\text{f}} - T_{\text{p}}^{\text{f}} } \right){{\Updelta H_{\text{d}}^{\text{f}} } \mathord{\left/ {\vphantom {{\Updelta H_{\text{d}}^{\text{f}} } {R\left( {T_{\text{d}}^{\text{f}} } \right)^{2} }}} \right. \kern-\nulldelimiterspace} {R\left( {T_{\text{d}}^{\text{f}} } \right)^{2} }} $$
(2)

where I c is the dimensionless index, \( T_{\text{d}}^{\text{f}} \) is the melting point of the drug, \( T_{\text{p}}^{\text{f}} \) is the melting point of PEG 8000, R is the universal gas constant, \( \Updelta H_{\text{d}}^{\text{f}} \) is the molar heat of fusion of the drug molecule.

The I c value obtained from the calculations can be used to determine the eutectic point (as shown in Table 1).

Table 1 The I c and PEG Drug composition (proposed by Law et al. [5])
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In previous studies, five PEG–drug systems, whose composition consisted of hydrochlorothiazide, menadione, propylthiouracil, quinine sulfate, and sulfamerazine, were evaluated by this equation [4]. The formula was found to be in agreement in all of the cases, except for quinine sulfate, which is a salt form of the drug, whereas the remaining drugs were either weak acids, weak bases or neutral compounds. In order to test the success of the formula, further work has been performed on samples of PEG with acetylsalicylic acid, acetaminophen, diflunisal, dimenhydrinate, ketoconazole, and mefenamic acid.

Experimental

Chemicals

Acetyl salicylic acid, acetaminophen, diflunisal, dimenhydrinate, ketoconazole, and mefenamic acid were obtained from Spectrum chemicals. Solvents such as acetonitrile, methylene chloride were used for the eutectic formation by the solvent method and were obtained from Fischer Scientific. Ethanol, which is also used as a solvent, was obtained from Pharmaco products Inc.

Equipment

Mettler Toledo DSC 822e fitted with a TSO801RO sample robot and a TSO800GCI Gas controller using Star (e) software V8.10 was used to obtain the scans. Samples in the range of 9–10 mg were weighed in 40 or 100 μL aluminum pans using the Mettler MT 5 microbalance. The measured pans are hermetically sealed and placed in the DSC. A heating rate of 5 °C min−1 was applied to all the mixtures. A purge gas of nitrogen gas flowed at the rate of 50 mL min−1. Any presence of crystallization in the drug–PEG mixture may be identified by using the X-Ray Diffractometer—PANalytical X-Pert Pro v. 1.6 with X-Pert Data Collector v. 2.1 with an angular range of 5–35° for aspirin and 5–55° for the remaining compounds. Scanning was done at a rate of 1 °C min−1 on passing the sample through a 100 mesh size. Visual observation of the melting point may be done with a hot-stage microscopy. A Bausch & Lomb microscope was equipped with a hot stage (Powerstat® variable autotransformer 3PN116B, The Superior Electric Co.) was used. A heating rate of 10 °C min−1 was maintained [5].

Procedure

Drug and PEG 8000 are placed in a beaker and mixed with a suitable solvent. Ethanol is used as a solvent for all the mixtures except ketoconazole, where methylene chloride was used. The mixture is then heated on low flame on a plate and is vacuum dried for 2 h. It is then placed overnight in a desiccator for the complete removal of the solvent. It is then stored at −20 °C for 4 days to ensure crystallization. The presence of crystallization may be verified by X-ray diffractometer. Samples are then ground in a mortar with a pestle and are passed through a US standard sieve. Size-reduced samples are then accurately weighed on the microbalance and placed into aluminum pans, hermetically sealed, and are scanned from 25 °C to temperatures above the melting point of the drug. Samples were purged at 50 °C min−1 in a stream of nitrogen gas at a heating rate of 10 °C min−1.

Results and discussion

DSC scans

The mixtures of drugs and PEG 8000 were analyzed on the DSC and the following scans (Figs. 1, 2, 3, 4, 5, 6) were obtained and interpreted for the point at which the mixture exists in its homogeneous form.

Fig. 1
figure 1

Overlay for the DSC scan of the mixture acetaminophen and PEG 8000

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Fig. 2
figure 2

Overlay for the DSC scan of the mixture diflunisal and PEG 8000

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Fig. 3
figure 3

Overlay for the DSC scan of the mixture dimenhydrinate and PEG 8000

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Fig. 4
figure 4

Overlay for the DSC scan of the mixture ketoconazole and PEG 8000

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Fig. 5
figure 5

Overlay for the DSC scan of the mixture mefenamic acid and PEG 8000

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Fig. 6
figure 6

Overlay for the DSC scan of the mixture acetyl salicylic acid (ASA) and PEG 8000

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Calculations

All the mixtures of drug and PEG, thus formed, were found to show eutectic type behavior, and their eutectic point was determined from the DSC scans. These points were compared with the ones calculated by the use of the Van’t Hoff equation. Table 2 shows the comparison.

Table 2 The correlation of the results obtained from DSC scans and the index I c
Full size table

The table shows a good correlation of the measured points with that of the calculated ones by using the “Higher heating rate index” (I c ). Three of the six results were in excellent agreement, while the other three differed by 5%.

However, finally, upon characterization of these mixtures by various other analytical techniques like Wide Angle X-Ray Diffraction and Scanning Electron Microscopy, it was found that only acetyl salicylic acid showed eutectic type behavior, while the rest of the drugs only showed this behavior in their preliminary stages. Thus, the equation once again proved its validity as a preformulation tool in predicting the eutectic compositions of various drugs and excipients at their preliminary stages of formulation.

Conclusions

From the results, provided in the tables, it is clear that a good correlation exists between the values calculated by the higher heating rate index (I c ) and those obtained from the phase diagrams of the DSC. Three of the six calculations were in excellent agreement, while the other three differed by a deviation of 5%. Hence, the equation was found to show satisfactory results in calculating the expected eutectic points (% drug w/w) of these samples without actually constructing the phase diagrams. In summary, it can be concluded that the index has been successful in predicting the eutectic point compositions of most of the mixtures and hence can be used as a preformulation tool to give an approximate idea of the composition at which a eutectic might be formed.

Recently, several quality articles on eutectics have elucidated the structure property relationship (see S. O. Firstov et al.) [6]. Their observations can be applied to other eutectics composed of drugs and excipients. Sathyapal Hegde, K. Narayan Prabhu [7] and S. M. Lakiza [8] investigated and studied the structure and physical mechanical properties of various eutectic metal alloys. Sathyapal and Narayan reported that “The mechanical properties of Al–Si alloys are strongly related to the size, shape and distribution of eutectic silicon present in the microstructure.” Lakiza studied directionally solidified eutectics in Al2O3–ZrO2–Ln(Y)2O3 systems and emphasized their use as structural materials at high temperatures [8].