Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System–Biowaiver

Abstract

Since the publication of Lindenberg et al., which classified orally administered active pharmaceutical ingredients (APIs) on the 2004 Essential Medicines List (EML) of the World Health Organization according to the Biopharmaceutics Classification System (BCS), various APIs have been added to the EML. In this work, BCS classifications for 16 of the orally administered APIs which were added to the EML after 2004 were determined. To establish a reliable solubility classification for all these compounds, a miniaturized shake-flask method was introduced. This method enables a fast, economical determination of the BCS solubility class while reliably discriminating between "highly soluble" and "not highly soluble" compounds. Nine of the 16 APIs investigated were classified as "highly soluble" compounds, making them potential candidates for an approval of multisource drug products via the BCS-based biowaiver procedure. The choice of dose definition (which currently varies among the guidances pertaining to BCS-based bioequivalence published by various regulatory authorities) had no effect on the solubility classification of any of the 16 substances evaluated. BCS classification of the compounds was then completed using permeability data obtained from the literature. As several APIs decomposed at one or more pH values, a decision tree for determining their solubility was established.

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics

“…The experimental mole fraction solubilities of ECT (x e ) in different "PEG-400 + water" combinations and mono solvents at "T = 298.2 to 318.2 K" and "p = 0.1 MPa" were calculated using Equations (1) and (2) and results are summarized in Table 1. Table 1.…”

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate

“…3 hours) was applied to the additional solubility studies. 67 Because of degradation issues during dissolution tests and HPLC analysis of the samples, the protocol for the dissolution tests was also adapted at pH 4.5 and 6.8 to minimize the time between sampling and analysis (see section on in vitro dissolution studies).…”

“…The chromatograms showed additional peaks that were assigned to degradation products of cephalexin monohydrate. Based on the suggestions of Pl€ oger and Hofs€ ass et al 67 and as a consequence of those observations, degradation studies and subsequently 3-h solubility studies were performed. The D/S ratios calculated from the resulting solubility values at pH 4.5 and 6.8 were <250 mL.…”

“…65 Although cephalexin undergoes degradation in certain buffers as a function of pH (see section Stability and Degradation), degradation is expected to be <10% over usual passage times in the upper gastrointestinal tract. 67 Furthermore, degradation does not seem to pose a limitation to uptake, as underscored by the high bioavailability of cephalexin after oral dosing.…”

Perbaikan Kelarutan Albendazol Melalui Pembentukan Kristal Multikomponen dengan Asam Malat

“…Uji kelarutan di dalam air dilakukan pada suhu ruang bertujuan untuk mendapatkan informasi awal yang umumnya diperlukan saat praformulasi sediaan farmasi. Sedangkan uji kelarutan di larutan dapar dengan tiga pH berbeda dilakukan pada suhu tubuh (37°C) bertujuan untuk memperoleh informasi kelarutan obat tersebut pada bagian-bagian saluran pencernaan, yaitu pH 1,2 (lambung dalam keadaan kosong), pH 4,5 (usus duabelas jari), dan pH 6,8 (ileum dan jejenum) yang berhubungan dengan proses absorpsi obat ketika diberikan secara oral (Plöger et al, 2018). Tabel 1 menunjukkan kelarutan kristal multikomponen ABZ-MAL lebih baik daripada ABZ murni.…”