Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials.
Amorphous
solid dispersions (ASD) are increasingly used to improve
the oral bioavailability of poorly water-soluble compounds. However,
hydrophilic polymers in ASD have high water-binding properties and,
upon water contact, they often form a gel on the surface of the tablet,
impacting the rate and extent of drug release. Most inorganic salts
decrease water solubility of organic solutes, changing the gel properties
of hydrophilic polymers. In this study, the effect of inorganic salts
on drug release from a tablet formulation containing an itraconazole
(ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated.
The cloud point of a 1% HPMC solution with and without inorganic salts
(KCl, KH2PO4, KHCO3, and potassium
iodate (KI)) was determined to classify the salts according to their
salting-out or salting-in effect. A kosmotropic effect on HPMC was
observed for KCl, KH2PO4, and KHCO3, whereas KI exhibited a chaotropic effect. To prove the effect of
these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate
(20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose,
and different types and amounts of KHCO3, KH2PO4, KCl, and KI were compressed (same solid fraction
of 0.83–0.85). Tablets without salts showed a slow release
and low peak concentrations during dissolution in simulated gastric
fluids. By adding the kosmotropic salts to the tablets, the rate and
extent of drug release were increased, whereas the chaotropic anion
iodide had no effect. The effect was pronounced even with the addition
of as little as 2% of inorganic salts and tended to increase with
the increasing amount of salt in the formulation. Tablets without
salt stored under either dry or humid conditions exhibited a large
difference in dissolution profiles, whereas little variation was observed
for tablets with kosmotropic salts. In conclusion, the effect of inorganic
salts was mechanistically clarified on ASD containing commonly used
HPMC. This approach can be beneficial to successfully develop robust
formulations containing ASD.
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