Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac dimethyl urea cocrystals

• Published in: AAPS PharmSciTech 2021-02, Vol.22 (2), p.68, Article 68
• Main Authors: Afzal, Hafsa, Abbas, Nasir, Hussain, Amjad, Latif, Sumera, Fatima, Kanwal, Arshad, Muhammad Sohail, Bukhari, Nadeem Irfan
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Crystallization; Diclofenac - analogs & derivatives; Diclofenac - chemistry; Diclofenac - pharmacokinetics; Drug Liberation; Drug Stability; Female; Male; Pharmacology/Toxicology; Pharmacy; Rabbits; Research Article; Tablets - chemistry; Urea - chemistry
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-021-01938-7

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC 0-∞ (37.87±1.3 μgh/ml) and C max (6.94±2.94 μg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced ( p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.