Supersaturating Drug Delivery Systems Research Articles

Ternary solid dispersions of lacidipine: Enhancing dissolution and supersaturation maintenance through strategic formulation optimization

The study aimed to address the challenges related to insufficient dissolution and maintenance of supersaturation in binary solid dispersions. Lacidipine, categorized as a BCS class II drug, was employed as the model drug. A systematic screening of excipients was conducted to determine the most effective carriers for the formulations of the ternary solid dispersions, utilizing the solvent transfer method and equilibrium solubility measurements. Both binary and ternary solid dispersions were prepared via spray drying, and comprehensive physicochemical characterization confirmed the successful preparation of amorphous solid dispersions. In vitro dissolution tests, the ternary solid dispersion exhibited marked superiority over the binary solid dispersion in dissolution and maintenance of supersaturation. Furthermore, an exploration into the factors influencing the stability of ternary solid dispersions revealed their robust resistance under light-protected, room-temperature, and desiccated conditions. The formation of intermolecular hydrogen bonding within the molecules of the ternary solid dispersions significantly enhanced drug solubility and system stability. Strategic formulation optimization, coupled with judicious selection of suitable carrier types and ratios, may serve as a promising approach for designing supersaturated drug delivery systems.

Simple preparation and greatly improved oral bioavailability: The supersaturated drug delivery system of quercetin based on PVP K30.

Quercetin, as a representative flavonoid, is widely present in daily diet and has been developed as a dietary supplement due to its beneficial physiological activities. However, the application of quercetin is limited due to its poor water solubility and extensive metabolism. So far, the nano-drug delivery systems designed to improve its bioavailability generally have the shortcomings of low drug loading content and difficulty in industrial production. In order to tackle these problems, quercetin supersaturated drug delivery system (QSDDS) was successfully prepared using solvent method, for which PVP K30 was employed as a crystallization and precipitation inhibitor to maintain the supersaturated state of quercetin in aqueous system. The obtained QSDDS, with a relative high drug loading content of 13%, could quickly disperse in water and form colloidal system with the mean particle size of about 200nm, meanwhile induce the generation of supersaturated quercetin solution more than 12h. In vivo pharmacokinetic study proved that QSDDS achieved a high absolute bioavailability of 36.05%, 10 times as that of physical quercetin suspension, which was dose-dependent with higher bioavailability at higher dose. Considering the simple preparation method, QSDDS provided a feasible strategy and a simple way to improve oral absorption of insoluble flavonoids.

Formulation, Optimization and Evaluation of Dabigartan Etexilate Encapsulated Solid Supersaturated Self-Nanoemulsifying Drug Delivery System

Objective:: The present study proposed Dabigatran Etexilate loaded solid supersaturat-ed self-nanoemulsifying drug delivery system (solid S-SNEDDS) for enhancement of payload, drug solubility, dissolution rate as well as minimization of drug precipitation. Methods:: The study involved formulation optimization using the Box-Behnken design. The op-timal SNEDDS consisting of Caprylic acid (32.9% w/w), Cremophor EL (50.2% w/w) and Transcutol HP (18.8% w/w) as Oil, Surfactant and Co-surfactant, respectively were formulated and evaluated for particle size, PDI, Zeta potential and saturation solubility. The SNEDDS was further incorporated with PPIs for the preparation of supersaturated SNEDDS (S-SNEDDS) to in-crease the drug payload in the formulation. S-SNEDDS was converted to solid S-SNEDDS by ad-sorption onto the porous carrier i.e., Aerosil®200. The in-vitro drug release study was also con-ducted for solid S-SNEDDS. Results:: SNEDDS had size, PDI, and Zeta potential of 82nm, 0.347, -10.50mV, respectively. SNEDDS enhanced the saturation solubility of the drug by 93.65-fold. Among PPIs, HPMC K4M showed the most effective response for the formulation of S-SNEDDS. The S-SNEDDS had a more substantial drug payload, which further increased the solubility by 150 times of pure drugs and 16 times of SNEDDS. Solid S-SNEDDS exhibited free-flowing properties. Reconstituted sol-id S-SNEDDS had acceptable size, PDI, and Zeta potential of 131.3nm, 0.457, and -11.3 mV, re-spectively. In-vitro drug release study revealed higher drug dissolution and minimized drug pre-cipitation by SNEDDS compared to marketed products and pure drugs. Conclusion:: Proposed nano-formulation was found to efficiently improve the aqueous solubility of the drug and avoid the drug precipitation, thereby avoiding drug loss and improving drug bioa-vailability.

Design and Evaluation of Ginkgolides Gastric Floating Controlled Release Tablets Based on Solid Supersaturated Self-nanoemulsifying.

Ginkgolides are receptor antagonist of platelet activating factor with great clinical prospect, but its application is limited by its low solubility, short half-life and poor alkaline environment stability. It is difficult to solve these problems with a single drug delivery system. In this study, supersaturated self-nanoemulsifying gastric floating tablets of ginkgolides were developed through the combination of solid supersaturated self-nanoemulsifying drug delivery system (solid S-SNEDDS) and gastric retentive floating drug delivery system (GFDDS) to solve these problems of ginkgolides. Solid S-SNEDDS was prepared by D-optimal mixture design, normalization method and single factor experiment. The properties of solid-S-SNEDDS were studied by TEM, PXRD, FT-IR, SEM and in vitro drug release profile. Then, the optimal formulation of stomach floating tablet was obtained through single factor experiment and center composite design, followed by the study of in vitro release, model and mechanism of release, in vitro buoyancy and kinetics of erosion and swelling. PXRD and FT-IR showed that the drug in solid S-SNEDDS existed in an amorphous manner and formed hydrogen bond with excipients. The results showed that the cumulative release of GA and GB in the optimal tablets was 96.12% and 92.57% higher than the simple tablets within 12 h. The release mechanism of the tablet was skeleton erosion and drug diffusion. In 12 h, the optimal tablets can float stably in vitro and release the drug at a constant rate, with a cumulative release of more than 80%. In summary, the combination of SNEDDS and GFDDS is a promising means to solve the problems of ginkgolides.

Assessing the permeability of supersaturating drug delivery system of amorphous drug-polyelectrolyte/protein nanoplexes in Caco-2 cell monolayer

Solubility enhancements of amorphous drug-polyelectrolyte and drug-protein nanoparticle complexes (nanoplexes) by virtue of their supersaturation generation were established previously. Their permeability across intestinal membrane, however, had not been assessed. The present work evaluated the membrane permeability of amorphous drug-polyelectrolyte/drug-protein nanoplexes across Caco-2 cell monolayer in comparison to the native drugs. Ciprofloxacin (CIP)-dextran sulfate (DXT) and curcumin (CUR)-bovine serum albumin (BSA) were used as the model drug-polyelectrolyte and drug-protein nanoplexes, respectively. The permeability was evaluated for aqueous suspension and granules of the nanoplex. The results showed the CIP-DXT nanoplex exhibited higher apical-to-basal permeability and lower efflux ratio than native CIP, hence higher net CIP absorption. The effect of CIP concentration on permeability was insignificant indicating passive diffusion. The CUR-BSA nanoplex exhibited higher permeability than native CUR in both apical-to-basal and basal-to-apical directions caused by weakened Caco-2 cells' tight junctions in the presence of nanoplex. Efflux ratios of the CUR-BSA nanoplex and native CUR were nonetheless similar. Aqueous suspension and granules of the nanoplex exhibited similar permeability profiles attributed to granules’ good aqueous reconstitution. Importantly, both nanoplexes exhibited similar cytotoxicity towards Caco-2 cells as the native drugs, rendering nanoplex a promising formulation approach for solubility and permeability enhancements.

Functionalized calcium carbonate (FCC) as a novel carrier to solidify supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)

Functionalized calcium carbonate (FCC), a novel pharmaceutical excipient, has shown promising properties in the field of oral drug delivery. The current study aimed at evaluating the feasibility of FCC as a carrier for the solidification of self-nanoemulsifying drug delivery systems (SNEDDS) containing the poorly water-soluble model drug carvedilol (CRV). Conventional, subsaturated SNEDDS (80 %-SNEDDSliquid) and supersaturated SNEDDS (200 %-SNEDDSliquid) were loaded onto FCC via physical adsorption at three ratios; 2.5:1, 3.0:1 and 3.5:1 (w/w) of FCC:SNEDDSliquid, respectively, generating free-flowing powders (SNEDDSFCC) with drug loading ranging from 0.8 % to 2.6 % (w/w) CRV. The emulsification of SNEDDSFCC in a USP II dissolution setup (in purified water) was characterized using dynamic light scattering, resulting in similar droplet sizes and PDIs as observed for their liquid counterparts. The morphology and physical state of the obtained SNEDDSFCC were characterized using scanning electron microscopy and differential scanning calorimetry. The physical stability and drug release upon dispersion were assessed as a function of storage time. The 200 %-SNEDDSliquid were physically stable for 6 days, however, solidification using FCC stabilized the supersaturated concentrations of CRV for a test period of up to 10 weeks (solidification ratios 3.0:1 and 3.5:1 (FCC:SNEDDSliquid)). SNEDDSFCC achieved an improved rate and extent of drug release upon dispersion compared to the crystalline CRV in tap water (pH 7.5), however, to a lesser extent than their liquid counterparts. After 8 weeks of storage (25 °C at dry conditions), FCC was still able to rapidly release the SNEDDSliquid and demonstrated the same rate and extent of drug release as freshly prepared samples. The solidification of 200 %-SNEDDSliquid in presence of FCC greatly improved the drug loading and showed an enhanced drug release profile compared to the conventional systems. In conclusion, FCC showed potential as a carrier for solidification of SNEDDS and for the development of novel supersaturated solid SNEDDS for the oral delivery of poorly water-soluble drugs.

Crystallization inhibitory effects of konjac glucomannan, sodium alginate and xanthan gum on curcumin in supersaturated solution

Supersaturating drug delivery system (SDDS) is a promising approach to enhance the solubility of hydrophobic functional components. However, SDDS is thermodynamically unstable and crystallization tends to occur. In this work, curcumin was used as a model compound, and the crystallization inhibitory effect of konjac glucomannan (KGM), sodium alginate (SA) and xanthan gum (XTG) on curcumin in supersaturated solution was investigated. Amorphous solubility of curcumin was determined using ultraviolet extinction, fluorescence spectroscopy and dynamic light scattering methods. Nucleation induction time (NIT) and crystal growth rate of curcumin were evaluated using ultraviolet probe in the absence and presence of various natural polysaccharides (NPs). Results showed that amorphous solubility of curcumin was approximately 30 μg/mL in pH 6.8 phosphate buffer. NPs used in this work restrained nucleation or crystal growth of curcumin effectively. The NITs of curcumin in the absence of NPs and in the presence of XTG, KGM and SA (1 μg/mL) were 3.7, 60.7, 20.0 and 8.0 min, respectively. The crystal growth rate of curcumin in the absence of NPs and in the presence of XTG, SA and KGM (1 μg/mL) were 0.0103, 0.00752, 0.00286 and 0.000306 min−1, respectively. The nucleation inhibitory effect of NPs on curcumin was ranked as XTG > KGM > SA. The order of crystal growth inhibition capacity of NPs was KGM > SA > XTG. In conclusion, NPs could be incorporated into SDDS to maintain supersaturation of hydrophobic components for enhanced bioavailability.

The effects of degree and duration of supersaturation on in vivo absorption profiles for highly permeable drugs, dipyridamole and ketoconazole

The prediction of oral absorption from a supersaturating drug delivery system (SDDS) remains a significant challenge. Here we evaluated the effects of the degree and duration of supersaturation on in vivoabsorption for dipyridamole and ketoconazole. Various dose concentrations of supersaturated suspensions were prepared by a pH shift method, and in vitro dissolution and in vivo absorption profiles were determined. For dipyridamole, the duration of supersaturation decreased with the increase of the dose concentration owing to rapid precipitation. For ketoconazole, the initially constant dissolved concentrations due probably to the liquid–liquid phase separation (LLPS) as a reservoir were observed at high dose concentrations. However, the LLPS did not delay the peak plasma concentration of ketoconazole in rats, indicating that drug molecules were immediately released from the oil phase to the bulk aqueous phase. For both model drugs, the degree of supersaturation, but not the duration of supersaturation, correlated with systemic exposure, indicating quick drug absorption before precipitation. Therefore, the degree of supersaturation is an important parameter compared with the duration of supersaturation for enhancing the in vivo absorption of highly permeable drugs. These findings would help develop a promising SDDS.

Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs.

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition. Solutions of PVP K15, K30, K60 or K120 at concentrations of 0.1, 0.5 and 1% (w/v), as well as isoviscous solutions of PVP of increasing molecular weight, were prepared. Supersaturation of the three model drugs was induced by the use of a solvent-shift method. Precipitation of the three model drugs from supersaturated solutions in the absence and presence of polymer was investigated by the use of a solvent-shift method. Time-concentration profiles of the respective drugs in the absence and presence of polymer pre-dissolved in the dissolution medium were obtained by the use of a μDISS Profiler™ to determine the onset of nucleation and the precipitation rate. Multiple linear regression was used to evaluate the hypothesis that precipitation inhibition is influenced by the PVP concentration (i.e., the number of repeat units of the polymer) and the medium viscosity of the polymer for the three model drugs. This study showed that an increased concentration of PVP (i.e., an increased concentration of the PVP repeat units, independent of the molecular weight of the polymer) in solution increased the onset of nucleation and decreased the precipitation rate of the respective drugs during supersaturation, which can be explained by an increase in molecular interactions between the drug and polymer with increasing concentrations of polymer. In contrast, the medium viscosity had no significant influence on the onset of the nucleation and precipitation rate of the drugs, which can be explained by solution viscosity having a negligible effect on the rate of drug diffusion from bulk solution to the crystal nuclei. In conclusion, the precipitation inhibition of the respective drugs is influenced by the concentration of PVP, i.e., by molecular interactions between the drug and polymer. In contrast, the molecular mobility of the drug in solution, i.e., the medium viscosity, has no influence on the precipitation inhibition of the drugs.

Polymer-embedded deep eutectic solvents (PEDES) as a novel bio-enabling formulation approach

There is a growing interest in using deep eutectic solvents (DES) as a pharmaceutical delivery system for poorly water-soluble compounds. To reduce the risk of drug precipitation following oral administration, this study addresses the hypothesis that directly including a polymeric precipitation inhibitor (PI) in a DES mixture could obtain a polymer-embedded deep eutectic system (PEDES) as a novel bio-enabling formulation principle. Following broad formulation screening, a PEDES embedding 15% w/w of polyvinyl pyrrolidone K30 (PVP) in L-carnitine:ethylene glycol (1:4, molar ratio) DES was successfully formulated as a supersaturating formulation using indomethacin as model compound. The drug solubility of 175.6 mg/mL obtained in DES was remarkably high, and upon release (phosphate buffer, pH 6.5) a maximum supersaturation factor of 9.8 was recorded, whereby the release kinetics displayed a suitable “parachute effect”. The formulation was further characterized to include a molecular dynamics simulation. It can be concluded that PEDES appears to be a viable novel formulation approach, setting solid grounds for further research to assess the full potential of this novel type of supersaturating drug delivery system.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.

The Influence of Blonanserin Supersaturation in Liquid and Silica Stabilised Self-Nanoemulsifying Drug Delivery Systems on In Vitro Solubilisation.

Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90-300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application.

Biorelevant Dissolution Method Considerations for the Appropriate Evaluation of Amorphous Solid Dispersions: are Two Stages Necessary?

Biorelevant dissolution testing has been widely used to better understand a drug or formulation's behavior in the human gastrointestinal (GI) tract. The successful evaluation of biorelevant dissolution behavior requires recognizing the importance of utilizing suitable biorelevant media in conjunction with an appropriate dissolution method, especially for supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs). However, most conventional biorelevant dissolution testing methods are not able to accurately reflect the dissolution, supersaturation, and precipitation tendencies of a drug or formulation, which could misinform ASD formulation screening and optimization. In this study, we developed a single compartment 2-stage pH-shift dissolution testing method to simulate the changes in pH, media composition, and transit time in the GI tract, and results were compared against the conventional single compartment 1-stage dissolution method. Nine model drugs were selected based on their ionization properties (i.e. acid, base or neutral) and precipitation tendency (i.e. moderate or slow crystallizer). The dissolution results confirmed that 2-stage pH-shift dissolution is the preferred biorelevant dissolution method to assess non-ionized weak base (nifedipine) and neutral (griseofulvin) compounds exhibiting a moderate precipitation rate from solution when formulated as ASDs. Finally, we designed a flowchart guidance for the appropriate biorelevant dissolution performance characterization of different categories of ASD formulations.

Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer.

The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended "spring-parachute" process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.

Hot-melt extrusion promotes dissolution, extends “spring-parachute” process and inhibits crystallization in supersaturating microparticle systems

Despite the potential advantages of amorphism-induced supersaturation, the merit of new amorphization formation methods on the properties of the amorphous drug including the stability of the amorphous state, dissolution/solubility, supersaturation, and “spring-parachute” process is still poorly understood, particularly for certain amorphous supersaturating drug delivery systems (aSDDS). The present work aimed to explore the detailed merit of current attractive amorphization manufacturing methods (i. g., hot-melt extrusion (HME) technique) on the property improvement of aSDDS in form of amorphous solid dispersion microparticles by employing a model BCS II drug nitrendipine and a polyvinylpyrrolidone-based model polymer copovidone. Many aSDDS systems were developed by various methods, and their physicochemical properties were characterized by SEM, PXRD and DSC. HME-triggered amorphization induced superior supersaturation by the observation of the highest dissolution and solubility. HME induced the optimal supersaturation duration by the observed greatest extension of “spring-parachute” process (e. g., maximum AUCspring-parachute). HME technique is comparable with other techniques for the stabilization of amorphous state during storage. All aSDDS systems by HME and other methods showed improved long-term stability of the amorphous state in comparison to the pure amorphous drug. Fourier transformation infrared spectroscopy, Noyes-Whitney equation, nucleation theory and Gibbs free energy of transfer (ΔGto) were used to analyze the underlying mechanisms. Molecular mechanism studies indicated that HME caused a stronger crystallization inhibition effect in the aSDDS systems than other methods, but molecular interaction is not a dominant mechanism for property enhancement caused by HME. For the mechanism associated with the polymer itself (PVPVA64), it could inhibit the drug recrystallization, solubilize the drug spontaneously and cause the improved molecular interactions in all aSDDS systems. This study provided a deep insight into detailed advantage of HME-triggered supersaturation/amorphization and facilitated the applications of the technique both in the field of particuology and in pharmaceutical industry.

Understanding the pH Dependence of Supersaturation State—A Case Study of Telmisartan

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3–8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson–Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pKa values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry.

Polymer selection to increase in vitro supersaturation generated by lamotrigine nicotinamide monohydrate cocrystal: An evaluation with predissolved and solid polymers

Cocrystals can improve drug dissolution by generating supersaturated drug delivery systems. However, supersaturation is a high-energetic state with a tendency to precipitate. Polymers are used as precipitation inhibitors to inhibit nucleation or crystal growth. Our aim was to evaluate the influence of different polymers, predissolved or in powder form, on the supersaturation dissolution of lamotrigine-nicotinamide monohydrate (LAM.NIC.H2O) cocrystals. First, the polymers were dissolved in water. Hydroxypropyl methylcellulose polymers (HPMC E6 and HPMC K100LV) presented the greatest dissolution advantage, while polyvinylpyrrolidone presented the most stable dissolution profile. Then, the cocrystal and polymer powder mixture, in different proportions, were simultaneously added to water for dissolution and evaluated to identify the ideal cocrystal/polymer ratio for the development of a solid pharmaceutical dosage form. The cocrystal and polymer powder mixture of HPMC E6 and HPMC K100 LV (1:0.1 and 1:0.25, w/w) presented the best supersaturation enhancement with high area under the curve values. The study of FaSSIF for cocrystal and HPMC E6 powder mixture (1:0.1 and 1:0.25, w/w) presented promising results, as the supersaturated state was maintained for a relevant period. Thus, this study suggests a polymer selection design for supersaturation studies and supports the future development of LAM.NIC.H2O cocrystal solid formulations.

Supersaturation-Based Drug Delivery Systems: Strategy for Bioavailability Enhancement of Poorly Water-Soluble Drugs.

At present, the majority of APIs synthesized today remain challenging tasks for formulation development. Many technologies are being utilized or explored for enhancing solubility, such as chemical modification, novel drug delivery systems (microemulsions, nanoparticles, liposomes, etc.), salt formation, and many more. One promising avenue attaining attention presently is supersaturated drug delivery systems. When exposed to gastrointestinal fluids, drug concentration exceeds equilibrium solubility and a supersaturation state is maintained long enough to be absorbed, enhancing bioavailability. In this review, the latest developments in supersaturated drug delivery systems are addressed in depth.

Eutectic mixture and amorphous solid dispersion: Two different supersaturating drug delivery system strategies to improve griseofulvin release using saccharin

This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC —with the carrier that forms a eutectic mixture with GSF —provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment’s hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.

Design and molecular insights of drug-active metabolite based co-amorphous formulation: A case study of toltrazuril-ponazuril co-amorphous

Co-amorphous supersaturated drug delivery systems are emerging as an alternative strategy to improve the water solubility of BCS II drugs. Typically, the supersaturation and stability of co-amorphous systems largely depend on the type of employed co-former. This study aims to assess the potential for active metabolites of drugs as co-former in drug-drug co-amorphous formulations. Toltrazuril (Tol) was chosen as the model drug, to which ponazuril (Pon) was added as co-former. Considering the importance of intermolecular interactions in co-amorphous systems, we performed highlighted investigations including molecular dynamics simulation and quantum mechanics calculations. The results indicated that Tol and Pon molecules were connected by N-H···O = C hydrogen bonds in the form of a complementary pairing of amide groups. Further, the solubility/dissolution and solid-state stability of the co-amorphous system were investigated. We found that co-amorphous Tol-Pon was stable for at least one month at 40 °C/75% RH, while amorphous materials underwent recrystallization within 10 days. Moreover, both drugs in the co-amorphous system exhibited enhanced “spring parachute effect” during the dissolution process. This could be attributed to the noticeably increased solid-state stabilization as well as inhibition of Pon on the crystallization of Tol from a supersaturated state. In general, our study provides some useful information and molecular insights to guide the development of drug-active metabolite-based co-amorphous formulations.