Compatibility studies of montelukast with pharmaceutical excipients used in tablet formulations using thermal and chromatographic techniques

Radhe Shyam Sahu¹ and Deepti Jain^1,2*
*Correspondence: Deepti Jain, School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, P.O.BOX 462036, Gandhi Nagar, Bhopal, Madhya Pradesh, India, Tel: +91 9425004366, Fax: 0755-2742006, Email:

Keywords

Montelukast • Excipients • Incompatibility • Differential scanning calorimetry • Isothermal stress testing

Introduction

Excipients may be inorganic or organic in composition, synthetic or semi synthetic, or derived from biological or natural sources. It may be possible on occasion to exploit such attributes to stabilize unstable materials, but more usually interactions lead to loss of quality [1]. Excipients may have functional groups that interact directly with active pharmaceutical ingredients. Alternatively, they may contain impurities or residues, or form degradation products that in turn cause decomposition of the drug substance. They can also cause unwanted effects such as irritation of the skin or mucosal surfaces, sensitization reactions or adversely affect appearance or organoleptic properties [1,2].

The present study was undertaken to establish the compatibility of montelukast, or 2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2yl)vinyl]phenyl]-3[2- (1-hydroxy1methylethyl) phenyl] propylsulfanylmethyl]cyclopropyl] acetic acid sodium, a Leukotriene Receptor Antagonist (LTRA), with a number of commonly used tablet excipients, used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies [3]. Thermo Gravimetry (TG) and Differential Scanning Calorimetry (DSC) were used extensively to evaluate the physical properties of drugs, including melting and vaporization temperatures and with the corresponding enthalpies, glass transitions, vapor pressures, as well as to study the compatibility and stability of the components of pharmaceutical preparations [4-6]. DSC allows a rapid evaluation of possible incompatibilities by revealing changes in the appearance, shift or disappearance of melting or other exothermic processes and variations in the corresponding enthalpies of reaction [7-9]. The DSC curves of the pure drug and of each of the investigated excipients were compared with those obtained from their 1:1 w/w mixtures. The 1:1 w/w ratio was selected to maximize the likelihood of observing any interaction [10,11]. Isothermal Stress Testing (IST), Fourier Transformation-Infrared Spectroscopy (FTIR) and Thermo Gravimetry Analysis (TGA) were used as complementary techniques to assist in the interpretation of DSC results.

Result and Discussion

Drug-excipient compatibility testing by DSC

In the first phase of the study, compatibility of MNLT with different excipients were tested using DSC. Selected DSC scans of MNLT and MNLT-excipient mixtures are shown in Figure 1. Thermo analytical data of Montelukast and Selected Excipients were discussed in Table 1. DSC of MNLT with individual excipients are shown in (Figures 2a-2k).Ratio of MNLT with excipients were taken in equal quantity (3 mg to 4 mg each). The DSC thermogram of amorphous form of MNLT exhibited melting within the range from about 60°C to 100°C (Figure 3).

The DSC scan of Microcrystalline Cellulose (MCC) showed a broad endotherm at 63.29°C (starting from 28.98°C and ending at 104.76°C), which may be attributed to the loss of adsorbed water (Figure 1). The thermogram of MNLT-MCC mixture (Figure 2a) showed same appearance of endothermic peak of drug as in MNLT alone, indicating that there was no interaction. Characteristic bands of montelukast were well retained in the IR spectrum of MNLT-MCC mixture without any new bands, indicating that there was no change in the structure of drug. Based on above results, it was concluded that montelukast is compatible with MCC.

The DSC scan of lactose showed endothermic peaks at 145.50°C (corresponding to dehydration of bound water) [13], 172.10°C (crystalline transition), 217.53°C (melting point) represents the fusion followed by immediate thermal decomposition (Figure 1) [10]. Crystalline transition peak of lactose was present in MNLT–lactose mixture (Figure 2b), but lack of melting point peak of lactose suggesting further interpretation with other technique such as FTIR, TGA, and HPLC. A sharp melting endotherm was observed at 166.45°C in the DSC trace of mannitol D (Figure 1). In case of MNLT- mannitol D mixture, there was broadening of melting endotherm of mannitol D (at 168.78°C) (Figure 2c) [10]. The drug endotherm peak appeared at same range. It was concluded that there is no chemical incompatibility between MNLT and mannitol D.

In DSC trace of magnesium stearate, an endothermic peak was observed at 83°C (Figure 4). A small peak was also present at 120°C, which might be due to palmitate impurity [14].The DSC scans of MNLTmagnesium stearate showed several endothermic peaks that could not be correlated directly either with magnesium stearate or MNLT. The DSC trace of MNLT-magnesium stearate mixture suggests that there is no incompatibility (Figure 2d).

In case of HPMC, no peak was observed in the range of 25°C to 300°C (Figure 1). The superposition of DSC curves of pure MNLT and HPMC evidencing the absence of incompatibility with MNLT. In the DSC trace of MNLT-HPMC mixture, the melting endotherm of the drug was well retained at 55°C to 70°C (Figure 2e), indicating that the drug is compatible with HPMC.

In case of HEC, no peak was observed in the range of 25°C to 320°C (Figure 2). The superposition of DSC curves of pure MNLT and HEC evidencing the absence of incompatibility with MNLT. In the DSC trace of MNLT-HEC mixture, melting endotherm of the drug was well retained at 55°C to 70°C (Figure 2f), indicating that the drug is compatible with HEC. DSC thermogram of carnauba wax reveals appearance of broad endotherm peak in the region of 75°C to 85°C (Figure 1). The superposition of DSC curves of pure montelukast and carnauba wax evidencing the absence of incompatibility with MNLT. In the DSC trace of montelukastcarnauba wax mixture, the melting endotherm of the drug was well retained at 55°C to 70°C, indicating that the drug is compatible with carnauba wax (Figure 2g).

In case of Talc, no peak was observed in the range of 25°C to 320°C (Figure 1). The superposition of DSC curves of pure montelukast and talc evidencing the absence of incompatibility with MNLT. In the DSC trace of MNLT-talc mixture, the melting endotherm of the drug was well retained at 55°C to 70°C (Figure 2h) [10] indicating that the drug is compatible with talc.

In DSC trace of sodium starch glycolate, a very narrow endothermic peak was observed at 170°C (Figure 1). A broad endothermic peak appeared, which might be due to dehydration of bound water. The DSC scans of MNLT-SSG showed exothermic peaks that could not be correlated directly either with SSG or MNLT (Figure 2i). The DSC trace of MNLT-SSG mixture suggests that there is no incompatibility.

The DSC scan of Croscarmellose Sodium (CMC) shown an endotherm at 140°C (Figure 1), which may be attributed to the loss of adsorbed water. The thermogram of CMC mixture showed same appearance of endothermic peak of drug as in MNLT alone, indicating that there was no interaction (Figure 2j). Based on that, it was concluded that MNLT is compatible with CMC.

Thermogram of Citric acid and MNLT exhibits significant peak shifting in the thermogram. Citric acid exhibits three peaks in its thermogram (Figures 1-6) where first is due to loss of absorbed water in the region of 50°C to 80°C which just in the melting range of MNLT (60°C to 100°C) provides ideal condition for interaction (Figure 2k). It led to change in melting peak as well as decomposition peak of citric acid. These peak shifting encouraged to go for other techniques such as FTIR, TGA and HPLC which may further support for its interpretation.

Drug-excipient compatibility testing by HPLC

Chromatograms of IST samples of MNLT and its binary mixtures with excipients were taken on HPLC and data were collected for qualitative and quantitative measurements (Table 2). Chromatographic data for control and IST samples were depicted in Tables 3 and 4 respectively. Stressed sample of citric acid exhibited an extra peak in chromatographic run eluted at about 3.5 min when compared to chromatogram of control sample of citric acid with MNLT (Figures 7 and 8) suggesting interaction between them. Chromatographic area for MNLT-Citric acid in IST sample had lower response of MNLT when compared to data from Control suggested an interaction of MNLT with citric acid.

Drug-excipient compatibility testing by FTIR and TGA

FTIR and TGA spectra were also then scanned for further interpretation of data obtained from DSC and HPLC. FTIR spectra of binary mixture of MNLT-citric acid exhibited appearance of an extra sharp peak at 2400 cm^-1 to 2300 cm^-1 wave number (Figures 9 and 10) indicates formation of new chemical bond due to interaction while TGA study of montelukast and citric acid exhibited weight gain due to formation of new chemical bond (Figures 11 and 12).

Conclusion

Twelve excipients were tested for their compatibilities with MNLT. Present study has demonstrated the successful utilization of techniques of DSC and IST (By HPLC) to assess the compatibility of MNLT with the excipients used in the development of tablet formulations. Based on the results of DSC alone, majority of the excipients were found to be compatible with MNLT. However, results showed that there is sign of interaction between MNLT and citric acid. Results of IST and FTIR confirmed that there is chemical interaction between MNLT and citric acid. In conclusion, DSC and IST were successfully used with further interpretation by TGA and FTIR for compatibility studies of MNLT with excipients for tablet formulations.

Acknowledgement

The authors are also very thankful to Ranbaxy Laboratories, Dewas, for providing gift samples of MNLT.

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