The potential of supramolecular synthon to develop coamorphous systems with tailored physical stability: Mechanistic insights integrating kinetics and thermodynamics.

Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state 13C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.

Thylakoid-based green preparation of porous microneedles for antibiotic residues detection in food samples.

BACKGROUND: Antibiotic residues in food chain have raised concerns regarding their toxicity and involvement in antimicrobial resistance. However, most existing antibiotic biosensors are primarily applicable to liquid food samples. Given the complex matrix characteristics of foods, there is an urgent need for the development of effective antibiotic detection platforms that exhibit high universality and flexibility. Porous microneedles (PMN) are microdevice structures with needle-like shapes and microscale pores throughout their composition, which facilitate rapid sampling. Consequently, the integration of PMN with biosensors holds significant promise for the detection of antibiotic residues in complex food samples. RESULTS: In this study, hydrogel-forming PMN are fabricated by leveraging the oxygen-production capacity of thylakoid to generate bubbles and form porous structures. These PMN are then integrated with a fluorescence aptasensor for the quantification of the antibiotic netilmicin. The aptasensor consists of a netilmicin (NET) aptamer with stem loop and hairpin structure, which facilitated the binding of SYBR Green I to produce a fluorescent signal. In the presence of NET, the complete binding between NET and the aptamer results in a reduction of fluorescence intensity, thereby generating a detectable signal change for the detection of NET. Utilizing capillary action accelerate fluid extraction (2.9 times faster than nonporous microneedles) and a large specific surface area (5.1072 m2/g) conducive to aptasensor adsorb, the PMN achieve efficient capture and quantification of antibiotic with limits of detection and quantitation of 5.99 nM and 19.8 nM, respectively. SIGNIFICANCE: Porous microneedles with tunable porosity and desirable mechanical properties are successfully fabricated. The integration of PMN with aptasensor enable the efficient detection of netilmicin in fish, milk and river water samples, demonstrating high recovery rates. The PMN represent potential tools for the convenient and rapid detection of antibiotic residues within complex food matrices, thereby enhancing food safety monitoring.

Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture.

The dissolution behavior of tablets, particularly those containing poorly water-soluble drugs, is a critical factor in determining their absorption and therapeutic efficacy. Traditionally, the particle size of excipients has been considered a key property affecting tablet dissolution. However, lurasidone hydrochloride (LH) tablets prepared by similar particle size mannitol, namely M200 (D90 = 209.68 ± 1.42 µm) and 160C (D90 = 195.38 ± 6.87 µm), exhibiting significant differences in their dissolution behavior. In order to find the fundamental influential factors of mannitol influencing the dissolution of LH tablets, the properties (particle size, water content, true density, bulk density, tapped density, specific surface area, circularity, surface free energy, mechanical properties and flowability) of five grades mannitol including M200 and 160C were investigated. Principal component analysis (PCA) was used to establish a relationship between mannitol properties and the dissolution behavior of LH. The results demonstrated that specific surface area (SSA) emerged as the key property influencing the dissolution of LH tablets. Moreover, our investigation based on the percolation theory provided further insights that the SSA of mannitol influences the probability of LH-LH bonding and LH infinite cluster formation, resulting in the different percolation threshold states, then led to different dissolution behaviors. Importantly, it is worth noting that these findings do not invalidate previous conclusions, as reducing particle size generally increases SSA, thereby affecting the percolation threshold and dissolution behavior of LH. Instead, this study provides a deeper understanding of the underlying role played by excipient SSA in the dissolution of drug tablets. This study provides valuable guidance for the development of novel excipients aimed at improving drug dissolution functionality.

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.

Crystal defects creation in Mannitol@CaCl2 metal-organic framework by induced dehydration strategy for enhanced excipient mechanical properties.

The mechanical properties of solid pharmaceutical excipients are important for assisting drug tables production, and they determine the quality of the drug tablets. The purpose of this study was to explore the potential and mechanism of crystal defect engineering to improve the mechanical properties of Mannitol@CaCl2 MOF, a pharmaceutical excipient with metal-organic framework (MOF) structure designed and prepared in our previous study. In this study, a simple and efficient "induced dehydration strategy" was proposed to prepare Mannitol@CaCl2 MOF with crystal defects (DEMOF). SEM, TEM, HRTEM, PXRD, FTIR, DSC-TGA, and N2 adsorption-desorption isotherm revealed the successful introduction of lattice vacancy and macrostructural defects while preserving MOF's skeleton structure. Tabletability profiles indicated that DEMOF presented much better mechanical properties than the original MOF at the powder level. On single crystal and atomic scales, nanoindentation and DFT calculations revealed that the defect structure increased plasticity, decreased brittleness, and improved compressibility, resulting in DEMOF tablets with much higher tensile strength that met the criteria for direct compression excipients. The achieved performance modification illustrated the capability of defect engineering to tune mechanical properties of MOFs, and the Mannitol@CaCl2 DEMOF exhibited great potential to serve as a new direct compression pharmaceutical excipient.

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.

Metal-organic gels: recent advances in their classification, characterization, and application in the pharmaceutical field.

Metal-organic gels (MOGs) are a type of functional soft substance with a three-dimensional (3D) network structure and solid-like rheological behavior, which are constructed by metal ions and bridging ligands formed under the driving force of coordination interactions or other non-covalent interactions. As the homologous substances of metal-organic frameworks (MOFs) and gels, they exhibit the potential advantages of high porosity, flexible structure, and adjustable mechanical properties, causing them to attract extensive research interest in the pharmaceutical field. For instance, MOGs are often used as excellent vehicles for intelligent drug delivery and programmable drug release to improve the clinical curative effect with reduced side effects. Also, MOGs are often applied as advanced biomedical materials for the repair and treatment of pathological tissue and sensitive detection of drugs or other molecules. However, despite the vigorous research on MOGs in recent years, there is no systematic summary of their applications in the pharmaceutical field to date. The present review systematically summarize the recent research progress on MOGs in the pharmaceutical field, including drug delivery systems, drug detection, pharmaceutical materials, and disease therapies. In addition, the formation principles and classification of MOGs are complemented and refined, and the techniques for the characterization of the structures/properties of MOGs are overviewed in this review.

An efficient cocrystallization strategy for separation of dihydromyricetin from vine tea and enhanced its antibacterial activity for food preserving application.

The objective of this study was to optimize the separation and purification of dihydromyricetin (DMY) from vine tea to obtain high purity, antibacterial and antioxidant crystal forms. We developed a cocrystallization approach for separation of DMY from vine tea with easy operation and high efficiency. The type and concentration of co-formers as well as solvent for separation have been investigated in detail. Under the optimal conditions, DMY with a purity of 92.41% and its two co-crystal forms (purity >97%) can be obtained. Three DMY crystal forms had consistent and good antioxidant activities according to DPPH radical scavenging results. DMY had effective antibacterial activity against the two kinds of drug-resistant bacteria including CRAB and MRSA, and DMY co-crystals had a greater advantage than DMY itself on CRAB. This work implies that cocrystallization can be used for the DMY separation and enhanced its anti-drug-resistant bacteria activity in food preservation.

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.

Functional in situ formed deep eutectic solvents improving mechanical properties of powders by enhancing interfacial interactions.

As novel green solvents, deep eutectic solvent (DES) with distinct liquid properties has gained increasing interest in pharmaceutical fields. In this study, DES was firstly utilized for improving powder mechanical properties and tabletability of drugs, and the interfacial interaction mechanism was explored. Honokiol (HON), a natural bioactive compound, was used as model drug, and two novel HON-based DESs were synthesized with choline chloride (ChCl) and l-menthol (Men), respectively. The extensive non-covalent interactions were account for DES formation according to FTIR, 1H NMR and DFT calculation. PLM, DSC and solid-liquid phase diagram revealed that DES successfully in situ formed in HON powders, and the introduction of trace amount DES (99:1 w/w for HON-ChCl, 98:2 w/w for HON-Men) significantly improve mechanical properties of HON. Surface energy analysis and molecular simulation revealed that the introduced DES promoted the formation of solid-liquid interfaces and generation of polar interactions, which increase interparticulate interactions, thus better tabletability. Compared to nonionic HON-Men DES, ionic HON-ChCl DES exhibited better improvement effect, since their more hydrogen-bonding interactions and higher viscosity promote stronger interfacial interactions and adhesion effect. The current study provides a brand-new green strategy for improving powder mechanical properties and fills in the blank of DES application in pharmaceutical industry.

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.

Are all poorly soluble drugs dissolved in deep eutectic solvents true solutions?

HYPOTHESIS: The ability of deep eutectic solvents (DES) to enhance solubility of poorly soluble drugs has attracted increasing attention. Researchers have shown that drugs could be dissolved well in DES. In this study, we propose a new existence state of drugs in DES: a quasi-two-phase colloidal system. EXPERIMENTS: Six poorly soluble drugs were used as the models. The formation of colloidal systems was observed visually by the Tyndall effect and DLS. TEM and SAXS were performed to obtain their structure information. The intermolecular interactions between components were probed via DSC and 1H1H-ROESY. In addition, the properties of colloidal systems were further studied. FINDINGS: Our key finding is that several drugs like lurasidone hydrochloride (LH) could form stable colloids in [Th (thymol)] - [Da (decanoic acid)] DES, resulting from weak interactions between drugs and DES, which is different from the true solution of drugs like ibuprofen where strong interactions were formed. In this LH-DES colloidal system, DES solvation layer was directly observed on the surface of drug particles. In addition, the colloidal system with polydispersity shows superior physical and chemical stability. Different to the prevailing view that substances are fully dissolved in DES, this study discovers another existence state as stable colloidal particles in DES.

Mechanistic insights into the crystallization of coamorphous drug systems.

In our previous study, the coamorphous formulation of lurasidone hydrochloride (LH) with saccharin (SAC) showed significantly enhanced dissolution and physical stability compared to crystalline/amorphous LH. However, the coamorphous system is still in amorphous state, and has the tendency to recrystallization, which will in turn result in the loss of above advantages. In this study, the crystallization kinetics under isothermal and non-isothermal conditions was investigated. Compared to amorphous LH, coamorphous LH-SAC showed 68.3-361.2 and 2.6-6.1 times lower crystallization rates in glassy state and supercooled liquid state, respectively. After co-amorphization, the addition of SAC changed the crystallization mechanism of amorphous LH from nucleation-controlled to diffusion-controlled manner. Amorphous LH followed the site-saturated nucleation, whereas the coamorphous system exhibited a fixed number of nuclei. The non-isothermal crystallization indicated amorphous LH and coamorphous LH-SAC showed two-dimensional (JMAEK 2) and three-dimensional (JMAEK 3) growth of nuclei, respectively. Furthermore, coamorphous LH-SAC exhibited higher molecular mobility and dynamic fragility (mD) than amorphous LH, which is kinetically unfavorable for its physical stability. However, from thermodynamic perspective, coamorphous LH-SAC had a higher configurational entropy, i.e., a higher entropy barrier for crystallization, which is beneficial to hinder its crystallization. Therefore, it was concluded that the higher configurational entropy rather than the molecular mobility was proposed to be responsible for its improved stability. In addition, molecular dynamics simulations with miscibility, radial distribution function and binding energy calculations suggested coamorphous components exhibited good miscibility and strong intermolecular interactions, which was also conductive to the enhancement in its stability. This study offers an in-depth understanding about the effect of the coformer on the crystallization kinetics of coamorphous systems, and points out the important contribution of the configurational entropy in stabilizing the coamorphous systems.

Gelation Elimination and Crystallization Inhibition by Co-Amorphous Strategy for Amorphous Curcumin.

In the previous study, the development of amorphous curcumin (CUR) aimed to enhance the solubility/dissolution of CUR by disrupting its crystal lattice, but it unexpectedly showed a decreased dissolution than its crystalline counterpart on account of gel formation in its dissolution process. Whether such gelation could be eliminated by co-amorphous strategy was answered in this study. Herein, CUR by co-amorphization with chlorogenic acid (CHA) was successfully prepared using quench cooling. The formed co-amorphous material (namely CUR-CHA CM) eliminated the gelation and hence performed superior dissolution performance than crystalline/amorphous CUR. Meanwhile, it exhibited higher physical stability than amorphous CUR during dissolution as well as under long-term/accelerated conditions. To further study the such enhancement mechanism, the internal molecular interactions were investigated for CUR-CHA CM in the solid state as well as in aqueous solution. FTIR and solid-state 13C NMR spectra confirmed that intermolecular hydrogen bonds formed between CUR and CHA after co-amorphization. Furthermore, the nucleation of CUR was significantly inhibited by CHA in an aqueous solution, thus maintaining the supersaturated dissolution for a long time. The present study offers a feasible strategy to eliminate gelation and enhance stability of amorphous solids by co-amorphization and crystallization inhibition.

Recent advances on small molecular gels: formation mechanism and their application in pharmaceutical fields.

INTRODUCTION: As an essential complement to chemically cross-linked macromolecular gels, drug delivery systems based on small molecular gels formed under the driving forces of non-covalent interactions are attracting considerable research interest due to their potential advantages of high structural functionality, lower biological toxicity, reversible stimulus-response, and so on. AREA COVERED: The present review summarizes recent advances in small molecular gels and provides their updates as a comprehensive overview in terms of gelation mechanism, gel properties, and physicochemical characterizations. In particular, this manuscript reviews the effects of drug-based small molecular gels on the drug development and their potential applications in the pharmaceutical fields. EXPERT OPINION: Small molecular-based gel systems, constructed by inactive compounds or active pharmaceutical ingredients, have been extensively studied as carriers for drug delivery in pharmaceutical field, such as oral formulations, injectable formulations, and transdermal formulations. However, the construction of such gel systems yet faces several challenges such as rational and efficient design of functional gelators and the great occasionality of drug-based gel formation. Thus, a deeper understanding of the gelation mechanism and its relationship with gel properties will be conducive to the construction of small molecular gels systems and their future application.

Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule.

Honokiol (HK), a BCS class II drug with a wide range of pharmacological activities, has poor solubility and low oral bioavailability, severely limiting its clinical application. In the current study, incorporating a water-soluble meglumine (MEG) into the crystal lattice of HK molecule was performed to improve its physicochemical properties. The binary mixture of HK and MEG was obtained by anti-solvent method and characterized by TGA, DSC, FTIR, and PXRD. The SCXRD analysis showed that two HK- molecules and two MEG+ molecules were coupled in each unit cell via the ionic interaction along with intermolecular hydrogen bonds, suggesting the formation of a salt, which was further confirmed by the XPS measurements. However, the ∆pKa value between HK and MEG was found to be less than 1, which did not follow the oft-quoted ∆pKa rule for salt formation. After salification with MEG, the solubility and dissolution rate of HK exhibited 3.50 and 25.33 times improvement than crystalline HK, respectively. Simultaneously, the powder flowability, tabletability and stability of HK-MEG salt was also significantly enhanced, and the salt was not more hygroscopic, and that salt formation did not compromise processability in that regard. Further, in vivo pharmacokinetic study showed that Cmax and AUC0-t of HK-MEG salt were enhanced by 2.92-fold and 2.01-fold compared to those of HK, respectively, indicating a considerable improvement in HK oral bioavailability.

A novel soluble lornoxicam-sodium chelate monohydrate with improved plasticity and tabletability.

Lornoxicam (LOR), a BCS II nonsteroidal anti-inflammatory drug, has been clinically utilized for moderate to severe acute pain management. However, it has poor water solubility and insufficient tabletability, leading to erratic absorption and challenge in tablet processability. This study reported a novel solid state of LOR (i.e., LOR sodium chelate monohydrate, LOR-Na·H2O) with significantly improved solubility, dissolution rate and tabletability. The prepared chelate (CCDC No.: 2125157) contains LOR-, Na+, and H2O in a molar ratio of 1:1:1, where Na+ ions bridged with O(5) of amide group, and N(2) of pyridine group on LOR-, as well as O(4) on H2O through coordination bonds. LOR-Na·H2O displayed a superior dissolution rate (5 âˆ¼ 465 folds) than commercial LOR due to its increased wettability (contact angle: 74.5° vs 85.6°) and lower solvation free energy (∼2-fold). In addition, the significant improvement in tabletability was caused by high plasticity and deformability, which was attributed to its special interlayer gliding with weak bonding interactions across layers but strong coordination bonding interactions within layers. The novel LOR-Na·H2O with significantly enhanced pharmaceutical performance offers a promising strategy for further product development.

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.

Deaggregation and Crystallization Inhibition by Small Amount of Polymer Addition for a Co-Amorphous Curcumin-Magnolol System.

Different from previously reported co-amorphous systems, a co-amorphous curcumin-magnolol (CUR-MAG CM) system, as compared with its crystalline counterparts, exhibited decreased dissolution due to its aggregation during dissolution. The main purpose of the present study is to deaggregate CUR-MAG CM to optimize drug dissolution and explore the deaggregation mechanism involved. Herein, a small amount of polymer (HPMC, HPC, and PVP K30) was co-formulated at 5% (w/w) with CUR-MAG CM as ternary co-amorphous systems. The polymer addition changed the surface properties of CUR-MAG CM including improved water wettability enhanced surface free energy, and hence exerted a deaggregating effect. As a result, the ternary co-amorphous systems showed faster and higher dissolution as compared with crystalline CUR/MAG and CUR-MAG CM. In addition, the nucleation and crystal growth of dissolved CUR and MAG molecules were significantly inhibited by the added polymer, maintaining a supersaturated concentration for a long time. Furthermore, polymer addition increased the Tg of CUR-MAG CM, potentially involving molecular interactions and inhibiting molecular mobility, resulting in enhanced physical stability under 25 °C/60% RH and 40 °C/75% RH conditions. Therefore, this study provides a promising strategy to optimize the dissolution and physical stability of co-amorphous systems by deaggregation and crystallization inhibition via adding small amounts of polymers.

Coamorphization combined with complexation enhances dissolution of lurasidone hydrochloride and puerarin with synchronized release.

Coamorphous systems have gained increasing interests due to their ability to enhance solubility and dissolution of poorly soluble drugs. In the current study, coamorphous system of lurasidone hydrochloride (LH), a BCS class II drug, with puerarin (PUE) was prepared by the solvent-evaporation method. The observation of a single Tg at 65.8 °C in differential scanning calorimetry thermogram and the absence of crystalline diffraction peaks in powder X-ray diffraction pattern indicated the formation of coamorphous LH-PUE. Compared to physical mixture of amorphous LH and amorphous PUE, peak shifts in FTIR with principal component analysis indicated potential intermolecular hydrogen bonding formed between the carbonyl group of LH and the hydroxyl group of PUE in the coamorphous system. In comparison to crystalline/amorphous LH and PUE, the coamorphous system exhibited significantly enhanced dissolution with synchronized release behavior of LH and PUE, which was mainly due to the complexation formation between LH and PUE in solution proved by fluorescence quenching test and phase-solubility diagram. In addition, coamorphous LH-PUE showed superior physical stability over pure amorphous LH and PUE under both long-term and accelerated storage conditions.