Original Research Paper
Functionality improvement of Nimesulide by eutectic formation with nicotinamide: Exploration using temperature-composition phase diagram

https://doi.org/10.1016/j.apt.2019.02.010Get rights and content

Highlights

  • Nimesulide was fused with nicotinamide in different molar ratio.

  • Resulted eutectic mass showed improved physico-mechanical properties.

  • Eutectic powder was converted into directly compressible tablet formulation.

  • Final formulation was found stable in nature after accelerated stability study.

Abstract

The aim of present work was to explore the temperature-composition phase diagram for detection of formation of a multi-component system. Fusion of model drug Nimesulide (NIM) and Nicotinamide (NIC) was prepared and evaluated for possible interaction using thermal analysis. Phase diagram and the appearance of single endotherm confirmed Eutectic formation with the molar ratio of 1:2 (NIM: NIC). Spray dried powder in same molar ratio showed improved functionality in terms of solubility (14 folds), dissolution (2 folds) in distilled water and drug content (92.27%). SEM study revealed that the particles of eutectic mixture were of nearly same size in all directions in shape with bigger particle size compared to the pure drug, which was responsible for its improved flow. The compressibility of prepared eutectic was greatly enhanced which was followed by formation of directly compressible tablets. FT-IR study explained the possibility of formation of hydrogen bond between both the components. Stability data proved the stable nature of the eutectic mixture as well as its prepared formulation. The study explained the way to prepare thermal phase diagram by taking solidus and liquidus points in DSC diagram, which was finally used as a confirmatory parameter for the formation of the eutectic. Simultaneous improvement in physicochemical and mechanical properties was highlighted.

Introduction

As far as the research and development in pharmaceutical industries is concerned, poor solubility and dissolution of APIs are one of the biggest problems. Majority of already existing molecules and new molecules under the drug discovery process are poorly water-soluble [1]. Pharmaceutical industries are facing a big challenge to convert such molecules into a robust formulation within the preview of regulatory constraints.

Various methods like solid dispersion [2], SEDDS [3], milling [4], complexation [5], co-solvency [6], polymorphic modifications [7], nanotechnology [8] and many more have been tried to improve the physicochemical properties of APIs like solubility and dissolution.

There are many more APIs which are poor not only in physicochemical properties but also in flow properties and compressibility. Such API requires a large quantity of glidants and binders in their manufacturing. It again cost a lot to the industries and industry has no choice except to go for multi-step, more laborious, costly wet granulation process instead of much cheaper and time-labour saving direct compression process [9], [10].

It is very important to understand that for any robust formulation, not only the physicochemical properties but also the mechanical properties should be satisfactory. Very few research works are going on such processes which can improve the functionality of API in all dimensions. Means, a common technique which can improve physic-mechanical properties of APIs have great importance in industrial research.

Various techniques have been followed to manipulate the functionality of APIs and to address the problems raised in the formulation. Salt and hydrates formation is widely utilized to improve the solubility and dissolution of APIs. As far as neutral or weakly acidic drugs are concerned, it is very difficult to prepare salt due to poor proton transfer capacity [11]. In such cases, cocrystallization can play a crucial role in the overall improvement of the functionality of APIs. In this process, API and coformer material are interacting with each other in a particular molar ratio by a certain kind of supramolecular complex formation [12]. In majority cases, eutectic, solid solution or cocrystal formation is resulted mainly due to the interaction happens between supramolecular synthones. There are various examples available which suggest that if the homomolecular (cohesive) interactions predominate with the isomorphous materials, solid solutions are formed whereas, with the non- isomorphous materials, eutectics are produced. Conversely, if the heteromolecular (adhesive) interactions between targeted molecules, it results in cocrystal formation [13], [14], [15].

After X-ray diffraction technique, thermal technique specifically Differential scanning calorimetry (DSC) is most approachable and accurate to determine the formation of cocrystal or eutectic. Various research works have been published where the thermal method has been used to determine the formation of any of these forms, but still, it is difficult to understand for beginners to interpret thermal events. As per literature, thermal behaviours by DSC diagrams (at the low heating rate) give a single endothermic peak in case of eutectic formation whereas in case of cocrystal. As explained in Fig. 1, the individual component A and B melt together followed by formation of a cocrystal at the metastable eutectic point. This event can be described by an endotherm immediately followed by an exothermic peak. On further heating, the cocrystal of A and B (AB) melts which is illustrated by a second endothermic peak (Fig. 1A and A-1). At the same time, if the solid A and B do not have the capability to form cocrystal, a single sharp endothermic peak in DSC shows eutectic melting of A and B (Fig. 1B and B-1) [16].

Vasisht et al. generated highly soluble eutectics with improved biological efficacy of hesperetin which was decided by the thermal phase diagram [17]. Dalvi and Sathisaran constructed a binary phase diagram for the curcumin-salicylic acid system which resulted in the formation of eutectic at curcumin mole fraction of 0.33 [18]. Bansal et al. investigated that microstructure of aspirin-paracetamol eutectic system offered greater compressibility, tabletability, and compactibility as compared with the physical mixture of that system [19]. Sangamwar et al. studied the eutectic mixture of α-eprosartan with p-hydroxybenzoic acid in 1:3 stoichiometry ratio showed better physicochemical and pharmacokinetic behaviour compared to parent drug [20]. Various other APIs and their eutectics like etodolac with paracetamol and propranolol hydrochloride [21], simvastatin-aspirin [22], hydrochlorothiazide-atenolol [23] and felodipine-nicotinamide [24] have been reported for their improved properties.

Here, authors have tried to explore the thermal technique for determination of formation of new solid material and its molar ratio by using Nimesulide (NIM) as a model drug and Nicotinamide (NIC) as coformer.

Nimesulide chemically 4′-Nitro-2′-phenoxy methane sulfonanilide, is a weakly acidic nonsteroidal anti-inflammatory drug (Fig. 2). Nimesulide is considered a BCS class II drug and is very sparingly soluble in water (≈0.01 mg/ml). Moreover, Nimesulide have poor flowability character. Due to poor aqueous solubility and wettability, Nimesulide leads to difficulties in pharmaceutical formulations for oral or parenteral delivery.

The selection of coformer can be determined by understanding supramolecular synthon, pKa difference, molecular weight, Hansen solubility parameter and melting point [25]. Here, Nicotinamide (NIC), 3-Pyridinecarboxamide, was used as hydrophilic conformer (aqueous solubility is 500 g/L) in the context of non-covalent derivative forms [26]. NIC contains nitrogen atom at the pyridine group and amide group can easily form homosynthon or heterosynthon with NIM [27]. Authors have used DSC as a thermal technique to prepare fusion of drug and coformer to determine the formation of crystal form followed by spray drying to generate a cocrystallized material having improved solubility, dissolution and other mechanical properties. Finally, the material was converted into a directly compressible formulation as a tablet dosage form.

Section snippets

Materials

Nimesulide (NIM) and Nicotinamide (NIC) were procured from Nectar Drug Pvt. Ltd. (Mumbai, India) and Sisco Research Laboratories Pvt. Ltd., (Mumbai, India), respectively. All other chemicals and solvents used were of analytical grade. Distilled water was generated from a Millipore Direct—Q ultra-pure water system (Merck Millipore, India).

Thermal-composition phase diagram for the screening study

NIM (308.3 g/mol) and NIC (122.1 g/mol) in various molar ratios (NIM:NIC) like 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9 and 0:10 mixed together in

Construction of thermal-composition phase diagram

Out of several methods, thermal analysis can be one of the best methods to determine whether any interaction happens between drug and coformer or not [41]. Based on the thermal phase diagrams, one can predict a type of interaction between two components [15]. Preliminarily fusion experiment was carried out for the screening purpose using a DSC instrument. Fig. 3 shows the DSC overlay of the NIM-NIC binary mixtures at various compositions. The study was conducted at a lower heating rate (here

Conclusion

In the present work, NIM was selected as a model drug and was fused with NIC in various molar ratios. The drug and conformer formed eutectic with the molar ratio of 1:2. Finally, a large scale batch was prepared by spray drying by taking the above ratio. The resulted product was much improved in its physicochemical and mechanical properties compared to pure drug. Based on the FT-IR data, there might be a possibility of formation of hydrogen bond for this multi-component interaction. The

Declaration of interest

Authors are not having any declaration of interest.

Acknowledgement

The author is very much grateful to Prof. (Dr.) Arvind Bansal, Head, Department of Pharmaceutics, NIPER-Mohali and Prof. (Dr.) Changquan Calvin Sun, Professor, Department of Pharmaceutics, University of Minnesota, the USA for their continuous guidance and support throughout the study. The author also acknowledges Internal Quality Assurance Cell, Saurashtra University, Rajkot, Gujarat (I) for their financial assistance in carrying out the study.

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