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Damage to intervertebral discs (IVD) can lead to chronic pain and disability, and no current treatments can fully restore their function. Some non-surgical treatments have shown promise; however, these approaches are generally limited by burst release and poor localization of diverse molecules. In this proof-of-concept study, we developed a nanoparticle (NP) delivery system to efficiently deliver high- and low-solubility drug molecules. Nanoparticles of cellulose acetate and polycaprolactone-polyethylene glycol conjugated with 1-oxo-1H-pyrido [2,1-b][1,3]benzoxazole-3-carboxylic acid (PBC), a novel fluorescent dye, were prepared by the oil-in-water emulsion. Two drugs, a water insoluble indomethacin (IND) and a water soluble 4-aminopyridine (4-AP), were used to study their release patterns. Electron microscopy confirmed the spherical nature and rough surface of nanoparticles. The particle size analysis revealed a hydrodynamic radius ranging ~150–162 nm based on dynamic light scattering. Zeta potential increased with PBC conjugation implying their enhanced stability. IND encapsulation efficiency was almost 3-fold higher than 4-AP, with release lasting up to 4 days, signifying enhanced solubility, while the release of 4-AP continued for up to 7 days. Nanoparticles and their drug formulations did not show any apparent cytotoxicity and were taken up by human IVD nucleus pulposus cells. When injected into coccygeal mouse IVDs in vivo, the nanoparticles remained within the nucleus pulposus cells and the injection site of the nucleus pulposus and annulus fibrosus of the IVD. These fluorescent nano-formulations may serve as a platform technology to deliver therapeutic agents to IVDs and other tissues that require localized drug injections. [ABSTRACT FROM AUTHOR]

Indomethacin (IND) is one of the supporting drug candidates for colonic targeting but it belongs to BCS class II category presenting a challenge in optimal targeting at the colonic site. To overcome this challenge, we sought to prepare a pH-dependent soluble ternary solid dispersion (SD) of IND of improved solubility and dissolution rate at the colon without the need for a coating. The current study focuses on the preparation of binary SDs of API (IND) with shellac (SSB 55) and Eudragit FS 100 (EFS) and ternary mixtures of IND, SSB 55 together with a new grade of HPMC (A15). Respective SDs were prepared via HME to achieve gastric protection and improved dissolution performance including maintenance of supersaturation. The SDs were characterized and tested for in-vitro dissolution performance using a pH shift dissolution method from 1.1, 5.5, 6.8, and 7.4. A ternary extrudate of IND, SSB 55, and A15 showed improved protection below pH 5.5 with a complete release of 99.5% at pH 7.4 compared to IND neat and binary extrudates from IND-A15, IND-SSB 55, and IND-EFS. It was attributed to an increased level of intermolecular interaction confirmed by ATR-IR and was studied for stability. It was found that in a ternary mixture containing IND, A15 and SSB 55 an increased hydrogen bonding interaction is present, which resulted in improved dissolution performance compared to binary mixtures. Therefore, ternary SDs proved to be a promising concept for future development of colon targeting of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The antidiabetic drug gliclazide (GLZ) has a slow absorption rate and a low bioavailability due to its poor solubility. GLZ is often prescribed along with an antihypertensive, as many diabetic patients have coexistent hypertension. Cocrystallization and coamorphization are attractive strategies to enhance dissolution rates and to reduce the number of medications a patient has to take. In this work the formation of cocrystals and coamorphous systems of GLZ with various antihypertensive drugs was studied, namely chlorothiazide (CTZ), hydrochlorothiazide (HTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF) as well as benzamidine (BZA) as a model for the amidine pharmacophore. TRI, IND and HTZ were found to form coamorphous systems with GLZ that are stable for at least six months at 22 ± 2 °C and 56% relative humidity. Coamorphous GLZ-TRI is also stable in dissolution medium. Coamorphization of GLZ-TRI with 15% sodium taurocholate gave a viable coamorphous formulation with an enhanced dissolution rate. Comilling of GLZ with BZA and cocrystallization from solution gave the amorphous and crystalline salt, respectively and the X-ray structure is reported. During attempts to obtain X-ray suitable cocrystals crystals of Na+GLZ− and IND 0.5H 2 O were obtained. Redetermination of the published structure of IND 0.5H 2 O revealed a unit cell with the length of the a axis doubled, a different space group and no disorder. Liquid-assisted grinding of a 1:1 mixture of GLZ and IND indicated the transformation of IND to a new solid-state form, while GLZ remained unaltered. Milling- and heating-induced solid-state transformations of IND are discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Amorphous solid dispersions (ASDs) based on water-insoluble hydrophilic polymers can sustain supersaturation in their kinetic solubility profiles (KSPs) compared to soluble carriers. However, in the limit of very high swelling capacity, the achievable extent of drug supersaturation has not been fully examined. This study explores the limiting supersaturation behavior of ASDs of poorly soluble indomethacin (IND) and posaconazole (PCZ) based on a high-swelling excipient, low-substituted hydroxypropyl cellulose (L-HPC). Using IND as a reference, we showed that the rapid initial supersaturation buildup in the KSP of IND ASD can be simulated through sequential IND infusion steps, however at large times the KSP of IND release from ASD appears more sustained than direct IND infusion. This has been attributed to potential trapping of seed crystals generated in the L-HPC gel matrix thus limiting their growth and rate of desupersaturation. Similar result is also expected in PCZ ASD. Furthermore, the current drug loading process for ASD preparation resulted in the agglomeration of L-HPC based ASD particles, producing granules of up to 300–500 µm (cf. 20 µm individual particle), with distinct kinetic solubility profiles. This feature makes L-HPC particularly suitable as ASD carriers for fine tuning of supersaturation to achieve enhanced bioavailability for poorly soluble drugs. [ABSTRACT FROM AUTHOR]

• A micellar solubilization model describes the effect of different surfactants on API solubility. • A pH-dependent solubility model quantifies the effect of buffer components on API solubility. • The proposed modeling strategy models the biorelevant solubility of APIs accurately. • The solubilization ability of CTAB for NAP and IND is greater than that of SDS. • Both surfactants and buffer components highly influenced API solubility. The solubility of active pharmaceutical ingredients (APIs) in biorelevant media is important fundamental data for API formulation design and contributes to better evaluation of in vivo dissolution kinetics. However, these data are mainly determined by experimental measurements, which is rather time and cost consuming. Therefore, it is essential to develop a novel theoretical strategy to describe and predict API solubility in biorelevant media. In this work, the solubilization effect of micelle and the effect of pH as well as ion components on the solubility of naproxen and indomethacin were determined experimentally. A micellar solubilization model and pH-dependent solubility model were proposed to model the effect of various micelles and pH (including buffer components) on API aqueous solubility, respectively. The combination of the two model successfully described the biorelevant solubility of APIs as function of temperature. The proposed strategy could provide insights into the mechanisms of micelle and different pH regulated by different buffer components on API solubility and could accurately describe the solubility of APIs in biorelevant media. This work is expected to provide theoretical guidance for API formulation development. [ABSTRACT FROM AUTHOR]

[Display omitted] The formulation of amorphous solid dispersions (ASDs) represents a promising strategy for improving the poor bioavailability of many active pharmaceutical ingredients (APIs). The objective of this study was to investigate and compare the long-term physical stability (LTPS) of polyvinyl alcohol (PVA)-based solid dispersions formulated via hot-melt extrusion (HME) with their respective API–PVA temperature–composition (T–C) phase diagram. Furthermore, the impact of API glass-forming ability (GFA) on the LTPS was evaluated through the selection of two APIs with contrasting GFA (i.e. , indomethacin (IND; good GFA) and naproxen (NAP; poor GFA)). Even though the predicted solubility of both APIs in PVA was less than 1 wt% at T = 25 °C, IND remained fully amorphous in HME-formulated IND–PVA extrudates with initial API loadings of 50, 40, and 30 wt% after a 24-month storage period. Meanwhile, NAP recrystallized to a considerable degree in each analogous sample with an amorphous NAP content of 22.5–23.5 wt% remaining after a 12-month storage period. While the constructed T–C phase diagrams were still in agreement with their respective LTPS study, they did not account for the impact of water uptake as well as potential HME-induced effects on the extrudate glass-transition temperature. This work may serve as a useful reference point for researchers who are interested in determining the solubility of an API in a semi-crystalline polymer and the challenges therein. [ABSTRACT FROM AUTHOR]

[Display omitted] In this study, new co-amorphous drug systems were designed using a pharmacologically relevant combination to improve the solubility and dissolution of indomethacin. Combinations of indomethacin-paracetamol (IND-PAR) as an anti-inflammatory/pain killer, and indomethacin-nicotinamide (IND-NCT) for prevention of gastric ulcers caused by IND, were developed for co-amorphization. The effect of PAR and NCT on the solubility, supersaturation, and dissolution of the poorly soluble counterpart, IND, was investigated. PAR and NCT were found to enhance the solubility and supersaturation of IND in biorelevant medium (FaSSIF) and in FaSSIF blank. Differential scanning calorimetry (DSC) showed capability of IND-PAR and IND-NCT binary mixtures to form eutectic mixture. Powder X-ray diffraction and DSC indicated the formation of a homogenous co-amorphous system with single T g value. Hydrogen bonding between IND and each of PAR and NCT were found to stabilize the co-amorphous systems as supported by FTIR studies. The intrinsic dissolution rate under sink conditions was improved over that of plain amorphous IND both in FaSSIF and FaSSIF blank. IND-PAR 2:1 and IND-NCT 1:1 were extremely stable and remained amorphous for 7 months at 25 °C, while all co-amorphous formulations were stable at least up to one month at 40 °C under dry condition. The present work demonstrates an improved approach to combine IND-PAR and IND-NCT as promising co-amorphous systems for potential therapeutical applications. [ABSTRACT FROM AUTHOR]

• Cocrystal formations of IND-NIC and IND-SAC are characterized using THz spectroscopy. • DFT calculations at PBE-D3 level well predict the features of experimental spectra. • Vibrational energy has comparable impact on cocrystallization with electronic energy. Co-crystallization is an effective strategy to improve the drug properties such as solubility and stability. However, its thermodynamic backgrounds, especially lattice vibration, haven't been fully understood. In this work, indomethacin (IND) cocrystals formed with nicotinamide (NIC) and saccharin (SAC) are successfully characterized by using terahertz spectroscopy. DFT calculations at PBE-D3 level with and without constrained unit cell are performed to predict the absorption peaks at spectral range. The results suggest that the DFT calculations with constrained unit cell achieve a better agreement with experimental observations. Based on the optimized geometries and calculated phonons, the thermodynamic contributions from lattice vibrations to cocrystal formations are further evaluated. The findings reveal that the vibrational energy plays a comparable role with electronic energy, but has an opposite impact on these two cocrystal formations. [ABSTRACT FROM AUTHOR]