Solid-liquid equilibrium of nicotinamide in water-ethanol and water-propylene glycol mixtures

Highlights

• Behaviour of nicotinamide solubility in ethanol–water and propylene glycol–water solutions at different temperatures.

• Investigation of solid phase behavior at different conditions of solid–liquid equilibrium.

• Adjustment of four different thermodynamic models - Apelblat, Wilson, UNIQUAC and NRTL – to experimental data of solubility.

• Determination of Gibbs energy, enthalpy and entropy of solution of nicotinamide in water, ethanol and propylene glycol.

Abstract

Nicotinamide is an active pharmaceutical ingredient (API) with high structural complexity and one form of vitamin B3 still poorly understood. For the pharmaceutical industry, the solubility knowledge of APIs is truly relevant for their production, bioavailability, and to be careful with polymorphs formation. In this context, it was determined nicotinamide solid–liquid equilibrium in temperatures from 20 to 50 °C for two solvent systems: water–ethanol and water-propylene glycol (PG), by a refractometric method. The experimental results were compared with a correlative thermodynamic model (Apelblat), three activity coefficient models (Wilson, UNIQUAC, NRTL) with (Δ_cp = 0, Δ_cp = ΔS, Δ_cp = f(t)) and with literature data. The Apelblat model showed a good correlation in both solvent systems, the best predictive fit model. For the water–ethanol system was NRTL (Δ_cp = 0), and for the water-PG was UNIQUAC (Δ_cp = 0). Maximum solubility values were observed in a 25 % m/m water-PG composition at 50 °C. The results of this work were compared with the literature and indicated to be in good agreement for the water-nicotinamide and ethanol-nicotinamide data. X-ray diffraction measurements of the solids in equilibrium with the liquid indicated that the behavior of solubility curves is not associated with a change in the crystalline structure of solids, probably due to the formation of oligomers in solution.

Introduction

Nicotinamide is an active pharmaceutical ingredient (API), a form of vitamin B3, water-soluble, with intracellular action acting on cellular respiration, synthesis of steroids and cholesterol, and maintaining the integrity of the genome [1], [2]. In normal conditions, it is a white crystalline powder, odorless and stable in solution pH between 3.5 and 7 at a temperature of 20 °C [3], [4].

The production of the APIs has as a crucial stage of the crystallization process, either in an intermediary stage in the separation of products or the final purification stage of these APIs. Thus, the solubility study is among the most relevant properties that must be known for the production and purification of these APIs [5], [6].

Published solubility data for nicotinamide are still very scarce. At the NIST database (2020) [7] there is only one recommended literature for nicotinamide solubility in pure water and ethanol by Wu et al. (2014) [8], one for the water–ethanol solvent system by Hamedi et al. (2007) [9] and no recommended literature for propylene glycol and water-propylene glycol systems.

The high structural diversity of these API, including their polymorphs (the same chemical species with more than one possible crystalline type) and several solvates (formation of crystals with the presence of solvents physically similar), is still very poorly understood [10], [11]. Hamedi et al. (2007) [9] reported a solubility curve for the water–ethanol system with nicotinamide and entrusted the non-ideality of the curve to crystalline structure change of nicotinamide, however, wasn’t report the characterization data of the crystals.

The polymorphic structures of nicotinamide began to be discussed in 2001 from the evidence of the DSC analysis by Hino et al. (2001) [12], who determined four polymorphic forms for nicotinamide; by 2010 had already been determined 27 structures of cocrystals with nicotinamide [13]. According to Kundu and Kishore (2003) [14] the amide group of nicotinamide associates in aqueous solution, forming oligomers. Both the polymorphism and the aggregation of the amide group can change the solubility of the solution [14], [15].

For the solubility study of actives pharmaceutical ingredients, many thermodynamic models can be tested and used to avoid the use of large amounts of APIs and time to obtain experimental solubility, Hojjati and Rohani (2006) [16].

The UNIQUAC model shows good correlations in binary and ternary systems [17], [18], [19]. Systems with high structural complexity molecules and, consequently drugs, have good results within this model [16], [18], [19]. Furthermore, Ouyang et al. (2018) [20] presented Apelblat, Wilson, and NRTL models to represent nicotinamide solubility in pure solvents with a good correlation between the reported data, however, haven’t be studied systems with more than one solvent. Wilson, NRTL, and UNIQUAC are activity coefficient models, while Apelblat is a semi-empirical correlation model.

The solubility equation in terms of temperature and enthalpy at the melting point is described in Eq. (1) [21].

$$\ln \frac{1}{x_1{\gamma }_1}=\frac{\mathrm{\Delta }{H}_m^{\mathit{fus}}}{R}\left(\frac{1}{T}-\frac{1}{T_m}\right)+\frac{1}{\mathit{RT}}{\int }_{T_m}^T\mathrm{\Delta }{c}_{p}dT-\frac{1}{R}{\int }_{T_m}^T\frac{\mathrm{\Delta }{c}_p}{T}dT$$

A common approach to Eq. (1) is the van't Hoff approximation (Δc_p = 0); for many systems, a more suitable solution is given by (Δc_p = ΔS_m). Both simplifications are presented in Eqs. (2), (3), respectively [15].

$$x^{\mathit{sat}}=\frac{1}{{\gamma }^{\mathit{sat}}}\exp \left[\frac{\mathrm{\Delta }{H}_m^{\mathit{fus}}}{R}\left(\frac{1}{T_m}-\frac{1}{T}\right)\right]$$

$$x^{\mathit{sat}}=\frac{1}{{\gamma }^{\mathit{sat}}}\exp \left[-\frac{\mathrm{\Delta }{H}_m^{\mathit{fus}}}{R{T}_m}\ln \frac{T_m}{T}\right]$$

In which x^sat is the molar fraction, ɣ^sat is the activity coefficient, ΔH_m is the enthalpy at melting point temperature, R is the universal gas constant and T_m is the melting temperature.

Another possible consideration for Eq. (1) is to find an equation that represents the behavior of Δc_p with temperature [21]. For a second-degree equation, Eq. (1) can be rewritten as:

$$\mathrm{\Delta }{c}_p=a{T}^2+bT+c$$

$$x^{\mathit{sat}}=\frac{1}{{\gamma }^{\mathit{sat}}}\exp \left[\frac{\mathrm{\Delta }{H}_m^{\mathit{fus}}}{R{T}_m}\left(1-T_r\right)+\frac{a{T}_m^2}{6R}\left(\frac{1}{T_r^2}+2T_r-3\right)+\frac{b{T}_m}{2R}\left(\frac{1}{T_r}+T_r-2\right)+\frac{c}{R}\left(T_r-1-\ln T_r\right)\right]$$

In which a, b, and c are constants equation of Δc_p and T_r is the relative temperature (T_r = T_m/T).

Thus, the high structural complexity and few references of nicotinamide, mainly for multicomponent systems, lead to the evaluation in this work of the experimental solubility data of nicotinamide in systems of water–ethanol and water-propylene glycol. Comparison with one correlative thermodynamic model (Apelblat) and three thermodynamic activity coefficient models (Wilson, UNIQUAC, NRTL) was performed by applying Eqs. (2), (3), and (5). An evaluation of the solids in equilibrium with the solution is made by the X-ray diffraction (XRD) technique.