Solubility of oxcarbazepine in eight solvents within the temperature range T = (288.15–308.15) K

Highlights

• Solubility of oxcarbazepine in eight pure solvents was determined.

• The solubility of oxcarbazepine was observed highest in tetrahydrofuran.

• The measured solubility data were correlated well with the modified Apelblat equation in all solvents investigated.

Abstract

In this study, the solubility of oxcarbazepine in pure methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, and tetrahydrofuran was analysed across the temperature range of 288.15–308.15 K under atmospheric pressure by using a solid-liquid equilibrium method. The experimental values obtained data were correlated using the modified Apelblat model at each temperature. The mole fraction solubility of oxcarbazepine in all eight pure solvents increased gradually in a temperature-dependent manner. The highest mole fraction solubility of 3.08 × 10⁻³ at 308.15 K was observed for tetrahydrofuran, followed by acetone (1.82 × 10⁻³ at 308.15 K), acetonitrile (1.22 × 10⁻³ at 308.15 K), methanol (1.11 × 10⁻³ at 308.15 K), ethanol (6.17 × 10⁻⁴ at 308.15 K), 1-butanol (6.17 × 10⁻⁴ at 308.15 K), 1-propanol (6.16 × 10⁻⁴ at 308.15 K), and 2-propanol (4.13 × 10⁻⁴ at 308.15 K). The experimental solubility in all solvents correlated well with that calculated using the modified Apelblat equation across the temperature range of (288.15–308.15) K. Therefore, the experimental solubility and correlation equations established in this study could be useful during the crystallization/purification, pre-formulation, and formulation stages of oxcarbazepine production in laboratories and related industries.

Introduction

Oxcarbazepine, 10,11-dihydro-10-oxo-5H-dibenz(b,f)azepine-5-carboxamide, is an off-white to faintly orange crystalline powder with a molecular formula and molar mass of C₁₅H₁₂N₂O₂ and 252.27 g·mol⁻¹, respectively (Fig. 1). Chemically, it can be considered a tricyclic antidepressant similar to carbamazepine, but with a different metabolism profile. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (active metabolite) [1]. Oxcarbazepine and its active metabolite are both anticonvulsants, and are therefore used to lessen the occurrence of epileptic episodes; they act as mood stabilizers as well [2], [3]. Oxcarbazepine was developed by Novartis under the trade name Trileptal, approved by the Food and Drug Administration (FDA), and is commercially available as film-coated tablets or as an oral suspension at a recommended dose of 300 mg twice a day. It is also available as an extended-release formulation marketed as Oxtellar XR by Supernus Pharmaceuticals. Oxcarbazepine is poorly water soluble with an aqueous solubility of approximately 0.07 mg·mL⁻¹ at room temperature and shows similar solubility throughout the physiological pH range of the gastrointestinal tract. In addition, oxcarbazepine is reported to exhibit high permeability across the Caco-2 cell monolayer [4]. Therefore, according to the Biopharmaceutical Classification System (BCS), oxcarbazepine is categorized as a class II agent and its dissolution is the rate-limiting step for its absorption.

The use of BCS Class II drugs in pharmaceutical formulation has been limited owing to their low aqueous solubility and bioavailability, which impede their efficient therapeutic use [5]. Various formulation strategies such as the synthesis of co-crystals, complexation with cyclodextrin, amorphous solid dispersions, lipid-based formulations, and particle size reduction (nanonization) can be used to overcome this problem [6], [7]. In particular, for the preparation of drug nano-suspensions, the solubility behaviour of drugs is critical in solvent displacement method using anti-solvent nanoprecipitation (involving the addition of an organic phase containing a polymer and drug into an aqueous phase containing a stabilizer) [8]. This is because the solubility in solvents determines the degree of super-saturation during precipitation and the yield and productivity of the process [9]. In addition, it is very useful to know the solubility of oxcarbazepine as a function of temperature and solvent composition in selected solvents required for the preparation and purification of the products. Unfortunately, the solubility of oxcarbazepine in various solvents at different temperatures has not yet been reported. In this study, the solubility of oxcarbazepine in pure methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, and tetrahydrofuran was analysed across the temperature range of (288.15–308.15) K under atmospheric pressure by using a solid-liquid equilibrium method. The obtained experimental solubility data were correlated with the modified Apelblat model at each temperature.