Abstract
Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires® (Gelucire® 50/13 and Gelucire® 48/16 in different ratio) of three BCS class II model compounds (carbamazepine, CBZ, tolbutamide, TBM, and cinnarizine, CIN) having different physicochemical properties (logP, pKa, Tm) were produced by spray congealing process. The obtained MPs were investigated in terms of morphology, particles size, drug content, solid state properties, drug-carrier interactions, solubility, and dissolution performances. The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN. The in vitro tests suggested that the drug solubility was mainly influenced by carrier composition, while the drug dissolution behavior was affected by the API solid state in the MPs after the spray congealing process. Among the tested APIs, TBM-Gelucire dispersions showed the highest enhancement in drug dissolution as a result of the reduced drug crystallinity.
Highlights
Solid dispersion (SD) of active pharmaceutical ingredients (APIs) in hydrophilic carriers is a well-established strategy to increase the solubility and/or the dissolution rate of poorly water-soluble compounds
The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN
Solid dispersion of three different Biopharmaceutic Classification System (BCS) class II drugs based on hydrophilic semicrystalline carriers (Gelucire® 50/13 and Gelucire® 48/16 in different ratio) were successfully produced by spray congealing in form of MPs
Summary
Solid dispersion (SD) of active pharmaceutical ingredients (APIs) in hydrophilic carriers is a well-established strategy to increase the solubility and/or the dissolution rate of poorly water-soluble compounds. Gelucires® with high HLB (44/14, 58/18, 50/13 and the most recently marketed 48/16) are composed of PEG-esters of long chain fatty acids, a small glyceride fraction and, sometimes, free PEG Due to their structure, these carriers improved the bioavailability of poorly water soluble drugs such as piroxicam [13], meloxicam [14], and atorvastatin [15]. Changes in the API solid state might occur, but they are strictly related to the drug-to-carrier ratio and to the SD production method, i.e., by melting or solvent evaporation [14] These and other aspects about the dissolution based-mechanisms of high HLB Gelucires® (50/13 and 55/18) dispersions containing theophylline have been elucidated by Craig and coworkers [17]. Tablets based on Gelucire® 50/13 solid dispersions containing caffeine and paracetamol as model drugs were investigated upon storage. [19]
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