Formulating Amorphous Solid Dispersions: Impact of Inorganic Salts on Drug Release from Tablets Containing Itraconazole-HPMC Extrudate

Abstract

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.

Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools

“…Identifying the critical process parameters (CPPs) and critical quality attributes of materials (CMAs) impacting the CQAs of the product is the next step. CPPs are "process parameter whose variability has an impact on a critical quality attribute of the product and therefore should be monitored or controlled to ensure the process produces the desired quality" [24]. The CPPs for each unit operation (filling, pre-compression, main compression, de-compression and ejection) during the direct compression process must be considered (Figure 2).…”

“…Previous studies have also explored the use of inorganic salts with hydroxypropyl methyl cellulose (HPMC) and Soluplus ® with various drugs and have found enhanced dissolution rate of the ASDs [20][21][22][23]. Takano et al [24] also reported that tablets of ITZ ASD and potassium salts (KCl, KH 2 PO 4 , KHCO 3 ) had a faster drug release compared to tablets without salts during dissolution. These are known to be kosmotropic salts, which are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution [25].…”

Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions

“…Thus, the difference in the performance of suspensions and solid dosage forms has been increasingly observed recently. The most typical approach to fill this gap is to improve the dissolution behavior of ASDs using additives such as inorganic salts [21,22].…”

Statistically 2 Level Factorial by Design Expert: In-vitro Design and Formulation of Levitiracetam Extended Release Tablets

“…The recent research found by HPMC polymers are reported. [8][9][10][11][12][13][14] The HPMC K100LV or K4M slows the release of the medication by 4 or 8 hr, respectively. The HPMC K100M was preferred for a sustained-released period of more than 12 hr, and the percentage of HPMC K100M in formulations grew to 41%.…”