Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

Hot "Dissolving" Extrusion of Lurasidone with Natural Liquid Small Molecule for Amorphous Solid Dispersion Based Self-Assembled Submicron Emulsion.

Nowadays, ≈90% of new drug candidates under development are poorly bioavailable due to their low solubility and/or permeability. Herein, a natural liquid small molecule trans-anethole (TA) is introduced into the drug-polymer system lurasidone (LUS)-poly (1-vinylpyrrolidone-co-vinyl acetate) (VA64), notably improving the compatibility of components for the successful preparation of amorphous solid dispersion (ASD) and facilitating the formation of self-emulsifying drug delivery system (SEDDS) during dissolution. LUS-TA-VA64 ASD shows enhanced supersaturation with a long maintenance time of at least 24 h over pure LUS. The strong non-covalent force between VA64 (as emulsifier) and TA (as oil phase)/ water promotes the self-assembly of submicron emulsion and ensures its stability for at least 10 h. Compared to the commercial salt form of LUS, the ASD shows twofold increase in peak plasma concentration (Cmax ) and area under plasma concentration-time profiles (AUC), 1.5-fold increase in peak time (Tmax ), and twofold decrease in AUC-based coefficient of variation (CV) (59%→26%) after a single oral dose to a rabbit.

A prediction system: Regulating effect of small-molecule additives on properties of amorphous solid dispersions prepared by hot-melt extrusion technology.

Amorphous solid dispersions (ASDs) with solubility advantage are suffering from the recrystallization risk and subsequent reduced dissolution triggered by high hygroscopicity of hydrophilic polymers and the supersaturation of ASD solutions. To address these issues, in this study, small-molecule additives (SMAs) in the Generally Recognized as Safe (GRAS) list were introduced into drug-polymer ASD. For the first time, we systematically revealed the intrinsic correlation between SMAs and properties of ASDs at the molecular level and constructed a prediction system for the regulation of properties of ASDs. The types and dosages of SMAs were screened by Hansen solubility and Flory-Huggins interaction parameters, as well as differential scanning calorimetry. X-ray photoelectron spectroscopy and adsorption energy (Eabs) calculation showed that the surface group distribution of ASDs and Eabs between ASD system and solvent were vital factors affecting the hygroscopicity and then stability. The radial distribution function revealed that interactions between components were proposed to be the critical factor for the dissolution performance. Based on this, a prediction system for regulating the properties of ASDs was successfully constructed mainly via molecular dynamics simulations and simple solid-state characterizations, and then validated by cases, which efficiently reduces the time and economic cost of pre-screening ASDs.

Switch between Cocrystal and Coamorphous Forms Depending on Thermal Modulation of Hot-Melt Extrusion.

Cocrystal (CC) and coamorphous (CM) techniques have become green technologies to improve the solubility and bioavailability of water-soluble drugs. In this study, hot-melt extrusion (HME) was employed to produce CC and CM formulations of indomethacin (IMC) and nicotinamide (NIC) due to its advantages like solvent-free and large-scale manufacturing. Interestingly, for the first time, IMC-NIC CC and CM were selectively prepared depending on the barrel temperatures of HME at a constant screw speed of 20 rpm and a feed rate of 1.0 g/min. IMC-NIC CC was obtained at 105-120 °C, IMC-NIC CM was produced at 125-150 °C, and the mixture of CC and CM was obtained between 120 and 125 °C (like a door switch of CC and CM). SS NMR combined with RDF and Ebind calculations revealed the formation mechanisms of CC and CM, where strong interactions between heteromeric molecules formed at lower temperatures favored periodic molecular organization of CC, whereas discrete and weak interactions formed at higher temperatures promoted disordered molecular arrangement of CM. Additionally, IMC-NIC CC and CM showed enhanced dissolution and stability over crystalline/amorphous IMC. This study provides an easy-to-operate and environmentally friendly strategy for the flexible regulation of CC and CM formulations with different properties through modulation of the barrel temperature of HME.

Gelation switch of polyamorphic indomethacin depending on the thermal procedure.

Amorphous indomethacin (IMC) prepared under different thermal procedures via melt quenching method showed significantly different dissolution behaviors. This study aims to investigate the influence of thermal procedures on the formation of IMC polyamorphism and to explore the mechanism for their different dissolution behaviors. Amorphous IMC samples were prepared by melting crystalline IMC under a series of temperatures (160-195 °C), respectively, followed by quenching in liquid nitrogen. Samples obtained under 170 °C exhibited bi-halo shapes at ∼15° and ∼26° (2θ), while the ones above 175 °C showed a single halo at ∼21° (2θ), suggesting amorphous IMC prepared under different thermal procedures probably have different local molecular arrangements. In comparison to crystalline IMC, amorphous IMC obtained under 170 °C showed significantly higher dissolution profiles with good dispersibility in aqueous medium, however, all amorphous IMC samples prepared above 175 °C demonstrated much lower dissolution with significant gelation, which seemed like a gelation switch existed for polyamorphic IMC when the preparation temperature was between 170 and 175 °C. Based on physicochemical characterizations, amorphous IMC prepared under 170 °C had higher surface free energy, more surficial hydrophilic groups and better wettability than the ones made above 175 °C. Molecular dynamics simulations revealed that the amorphous samples prepared below 170 °C had similar binding energy values in the range of 310.045-325.479 kcal/mol, while those prepared above 175 °C were significantly lower within 212.193-235.073 kcal/mol. Such binding energy difference might be responsible for their different local molecular arrangements after different thermal procedures. The current study deeply reminds us that the thermal procedure of preparation methods may significantly affect the physicochemical properties of amorphous materials, which should be paid special attention to the polymorphic selection during pharmaceutical development.

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride.

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3+ group of CYS after coamorphization. A fluorescence quenching test with a Stern-Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.