Systematic evaluation of the impact of solid-state polymorphism on the bioavailability of thalidomide

• Published in: European journal of pharmaceutical sciences Vol. 136; p. 104937
• Main Authors: de Oliveira, Guilherme Henrique Onório, do Nascimento, Sara Batista, de Oliveira, Flávio Martins, Belo, Vinícius Silva, de Alencar Danda, Lucas José, Soares-Sobrinho, José Lamartine, Fialho, Silvia Ligório, Bedor, Danilo César Galindo, de Castro, Whocely Victor
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2019
• Subjects: Animals; Area Under Curve; Biological Availability; Capsules - chemistry; Capsules - pharmacokinetics; Dissolution; Drug Liberation - drug effects; Excipients - chemistry; HIV Infections - drug therapy; HIV Infections - metabolism; Male; Pharmacokinetic; Polymorphism; Rats; Rats, Wistar; Solubility - drug effects; Thalidomide; Thalidomide - chemistry; Thalidomide - pharmacokinetics; Thalidomide; Dissolution; Pharmacokinetic; Polymorphism
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2019.05.015

Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and β-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or β-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and β-TLD were not significantly different (α = 56.2 ± 0.5 μg·mL−1; β = 55.2 ± 0.2 μg·mL−1). However, the dissolution profile of α-TLD presented the fastest rate and the largest extension of drug dissolution than that from β-TLD (80% in 4 h versus 55% in 4 h). The α-TLD provided a more favorable pharmacokinetic than the β-TLD (maximum plasma concentration — Cmax: 5.4 ± 0.90 μg·mL−1versus 2.6 ± 0.2 μg·mL−1; area under the curve of the concentration-time profile from time zero to infinity — AUC0-∞: 44.3 ± 8.8 μg·h·mL−1versus 33.9 ± 4.7 μg·h·mL−1; absolute bioavailability — F: 92.2 ± 18.5% versus 70.5 ± 9.9%, respectively). Drug suppliers and pharmaceutical companies should strictly control the technological processes involved in the TLD API synthesis as well as in the production of the pharmaceutical dosage form in order to guarantee the inter-batch homogeneity and therefore, product compliance. [Display omitted]