Solid Dispersion Research Articles

Synchrotron computed tomography combined with AI-based image analysis for the advanced characterization of spray dried amorphous solid dispersion particles.

Particle engineering aims to design particles with specific properties. A deeper understanding of how particle formation relates to material attributes and process conditions are critical to strengthen knowledge on powder properties and enhance modeling capabilities. New, alternative powder characterization techniques can offer novel and more accurate measures for particle properties, giving more advanced characterization information. In this context, a case study is presented in which spray dried amorphous solid dispersion powders produced by modifying process conditions were characterized by both well-established compendial methods (i.e., laser light diffraction, SEM image analysis, bulk and tapped density, and gas adsorption), as well as a new method combining synchrotron computed tomography (SyncCT) with AI-based image analysis. SyncCT was used to classify and quantify the spray dried particles as hollow spheres and solid particles, giving a more detailed quality measure of the particle shape, as they impact downstream processing differently. Moreover, hollow particle wall thicknesses, as well as internal and external particle surface areas were measured by SyncCT. Altogether, powder characterization data from SyncCT show similar trends to that obtained from compendial techniques and giving additional quality measure regarding particle shape, showing promise of this new and advanced characterization method.

DDDR-11. INHIBITING OXIDATIVE PHOSPHORYLATION AND HYPOXIA WITH ATOVAQUONE – A STRATEGY TO RADIOSENSITIZE DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment is a main feature of solid tumours including gliomas and a major contributor to radioresistance. Therefore, alleviating tumour hypoxia to enhance the effectiveness of radiotherapy is a potential therapeutic strategy to improve the survival outcomes of DMG patients. We found evidence suggesting increased mitochondrial oxidative phosphorylation (OXPHOS) in DMG. Hence, we aimed to target OXPHOS by decreasing the oxygen consumption rate (OCR) of DMG cells, which in turn will alleviate hypoxia by sparing more oxygen and subsequently improve the radiosensitivity of DMG cells. We performed a high-throughput screening to identify potent OCR inhibitors from a library of 1963 FDA-approved drugs. The most promising OCR inhibitor identified was atovaquone, a drug used for treatment of pneumocystis pneumonia and malaria. We found that atovaquone inhibited mitochondrial metabolism of DMG cells by specifically targeting the mitochondrial complex III. Increased mitochondrial reactive oxygen species after exposure to atovaquone suggested that it increases oxidative stress. The treatment alleviated hypoxia and decreased the expression of hypoxia-inducible factor-1a in 3-dimensional DMG neurospheres and improved the radiosensitivity in several DMG cultures. To overcome the poor bioavailability of commercially available atovaquone that results in low therapeutically effective brain concentrations, we tested its efficacy against the amorphous solid dispersion (ASD) atovaquone formulation which appears to enhance atovaquone levels in the brain. We found that both the formulations inhibited OCR and hypoxia at similar doses and enhanced DMG radiosensitivity. The combination of ASD atovaquone and radiation significantly improved survival in orthotopic DMG mouse model. Collectively, this data provides evidence of atovaquone as a potential radiosensitizer for DMG.

Study of nifedipine solubility in physical mixtures and solid dispersions

Introduction. Poor aqueous solubility significantly hinders the bioavailability of numerous orally administered drugs. Nifedipine, a widely-used cardiovascular agent, is categorized as practically insoluble according to pharmacopoeias, thus presenting a significant challenge in formulation development. This study investigates the potential of solid dispersion (SD) technology and physical mixtures to improve the dissolution profile of nifedipine.Aim. Development of a technological method for increasing the solubility of nifedipine by developing physical mixtures and SD with the aim of creating a dosage form with improved properties.Materials and methods. Nifedipine, methanol, nifedipine standard samples, potassium dihydrogen phosphate, sodium heptanesulfonate, phosphoric acid (85 %), purified water, and pvp K-30. Solubility studies were performed by HPLC using three objects: nifedipine, a physical mixture (PM), and SD of nifedipine with PVP K-30. The study assessed the effect of different ratios (nifedipine : PVP K-30) in the physical mixture and SD on nifedipine solubility. Fourier transform infrared spectroscopy (IR spectroscopy) and powder X-ray diffractometry were used to characterize the samples.Results and discussion. A notable increase in nifedipine solubility was observed in both PM3 (1 : 3 nifedipine : PVP K-30) and SD3 (1 : 3 nifedipine : PVP K-30). PM3 exhibited a solubility of 9.70 %, while SD3 demonstrated a remarkable enhancement to 32.07 % compared to the pure nifedipine (0.24 %). FTIR analysis did not reveal significant interactions between nifedipine and PVP K-30. PXRD results confirmed the transition of nifedipine from a crystalline to amorphous form within the hydrophilic PVP K-30 matrix, contributing to the observed solubility enhancement.Conclusion. The study highlights the effectiveness of SD technology in significantly improving nifedipine solubility and potential bioavailability. The 134-fold increase in solubility achieved with SD3 at a 1 : 3 ratio demonstrates the significant potential of this approach for enhancing the pharmacokinetic properties of poorly soluble drugs. This research opens up new avenues for developing innovative formulations with improved dissolution characteristics and potentially enhanced therapeutic efficacy.

SUBLIMATION-BASED CUTTING-EDGE TECHNOLOGY (SUSTAINABLE DEVELOPMENT GOALS 9 and 15) TO DEVELOP CURCUMIN NANOPARTICLES BY SOLVENT-FREE GREEN CHEMISTRY METHOD FOR THEIR ANTIOXIDANT AND ANTICANCER ACTIVITY

Objective: This research aimed to develop a new, cost-effective, solvent/surfactant/supercritical carbon dioxide-free, sublimation-based method to prepare curcumin nanoparticles. The research objective was to meet Sustainable Development Goals (SDG-3,9 and 15). The problem of poor absorption of curcumin is sorted out by micro or nanonization, solid dispersion, solid solution, β-cyclodextrin complexation, micelle formation, and solution-enhanced dispersion by supercritical carbon dioxide. Methods: The curcumin, mixed with menthol, was allowed to melt at 29 °C and placed under vacuum for 6 H (h). The menthol sublimates and leaves the curcumin particles as residue. The residual curcumin particles were characterised, and stability studies were also performed. Results: The curcumin nanoparticles were stable, in the nano-size range (10-300 nm); Fourier Transform Infrared Spectroscopy (FTIR) showed the presence of CH3 and CH2 bending, aromatic C=C and C=O stretching, aromatic CC and OH stretching, aliphatic C-H bending, aromatic-OH bending with both pure curcumin and curcumin nanoparticles, that no change in bonds and groups, and differential scanning calorimetry (DSC) showed the temperature (T) =162.03, 185.64 and peak maximum is 177.986 for pure curcumin while T=164.43, 185.68 and peak maximum is 177.784 for curcumin nanoparticles that indicated compatibility between curcumin and menthol. The curcumin nanoparticles showed improved solubility, dissolution, and antioxidant activity by calculating Inhibitory Concentration50 (IC50) value 114.51 and in vitro cytotoxicity (IC50=165.6±0.084 µg/ml) of curcumin nanoparticles against MCF-7, a human breast cancer cell line with estrogen, progesterone, and glucocorticoid receptors. Conclusion: It concluded that the sublimation technique can used to prepare the nanoparticles of drugs or might be for thermo-labile drugs.

Formulation and optimization of xanthohumol loaded solid dispersion for effective treatment of Parkinson's disease in rats: In vitro and in vivo assessment

Xanthohumol (XH) is a prenylated flavonoid that possesses neuroprotective effects by increasing the levels of dopamine (DA), reducing oxidative stress, and neuroinflammation against Parkinson's disease (PD). However, the neuroprotective efficacy of XH in managing PD is limited by its low solubility, poor bioavailability, and less blood-brain barrier (BBB) permeability leading to decreased therapeutic activity. To overcome these limitations, XH-loaded solid dispersion (SD) has been formulated using the Central Composite Design (CCD) approach. The optimized formulation was evaluated by determining the angle of repose, drug loading, percentage drug release, PXRD, DSC, FTIR, and SEM. The results of PXRD, DSC, and SEM demonstrated the formation of SD. The XH-SD showed a 6.45-fold enhancement in dissolution rate, a 12.7-fold increase in Cmax, and 26.11-fold increase in XH's area under curve (AUC) as compared to the naïve XH. In the pharmacokinetic studies, XH-SD showed a 42.20 folds increase in relative bioavailability(0-∞) compared to naïve XH. To assess pharmacodynamic effects, PD was induced using rotenone. The motor and non-motor functions were evaluated by assessing various behavioral parameters such as catalepsy, spontaneous locomotor activity and muscle coordination test. The formulation exhibited dose-dependent effects, with both low and high doses of XH-SD resulting in significant enhancements (P < 0.001) in motor functions in rats induced with PD. Furthermore, biochemical estimations showed that XH-SD at both doses increased the levels of dopamine (DA), and reduced oxidative stress and neuroinflammation.

Production sustained release dosage forms from deliquescent substances by solid dispersion systems

Introduction. The production of solid dosage forms from hygroscopic substances is a complex technological task. The addition of hygroscopic substances into a polymer matrix allows to reduce their moisture absorption capacity.Aim. Reducing the hygroscopicity of deliquescent substances and obtaining sustained release solid dosage forms by using solid dispersion systems.Materials and methods. Substance: DEAE; excipients: Kollidon® VA 64, Soluplus®, PEG 1500, PEG 6000, PEG 8000, Poloxamer Kolliphor® P 188 and Kolliphor® P 407; reagents: hydrochloric acid, sodium dihydrogen phosphate, potassium hydrogen phosphate. The melt of the components was obtained on a twin-screw laboratory extruder and cast into silicone molds. The resulting solid dosage forms were studied for disintegration in three environments corresponding to the sections of the human gastrointestinal tract.Results and discussion. The active pharmaceutical substance DEAE is characterized as deliquescent substance. The introduction of DEAE into PEG-polymer matrices made it possible to reduce the hygroscopicity of solid dosage forms in the form of bars. The introduction of solubilizers into the melt made it possible to obtain bars with the appropriate organoleptic properties. The release of DEAE from bear- or toroid-shaped bars occurs on average 29–47 % faster than from heart-shaped bars.Conclusion. Compositions based on Soluplus® and Kolliphor® P 407 have proven promising for further development of tiles containing DEAE. In order to create tiles with a slow release, it is recommended to use heart-shaped forms, as they have a smaller surface area.

Nanotechnology in Drug Delivery: Overcoming Poor Solubility Challenges through Nanoformulations

Abstract: The pharmaceutical sector continues to face difficulties with poorly soluble drug solubility. Insufficiently soluble drugs have low bioavailability, and their effectiveness is frequently affected. Numerous approaches have been developed in response to this challenge, including using various dosage forms, solid dispersions, nano-suspensions, self-emulsifying drug delivery systems, and cyclodextrin complexes. By improving drug dissolving, decreasing drug particle size, and increasing drug dispersion, these dosage forms seek to increase drug solubility. Nanotechnology is one of the latest advances that has the potential to revolutionize the delivery of drugs and significantly improve the solubility of drugs that are now poorly soluble. Since they have a larger surface area and can pass through biological barriers, nanoparticles are particularly well suited for the delivery of drugs. These technologies can potentially enable the development of more effective and efficient drug formulations for the treatment of various diseases. In addition, the review highlights recent advances in the field, including emerging technologies such as nanotechnology, which can revolutionize drug delivery and significantly improve the solubility of poorly soluble drugs with their potential applications.

Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization. We posit that polymers bearing tertiary amides are particularly well suited to stabilizing drugs containing H-bond donors, as they offer strong H-bonding potential between the polymer and drug. The aim of this study was to compare new and established polymers with tertiary amides as excipients for ASDs. Experimental amphiphilic ABA triblock copolymers comprising poly(2-methyl-2-oxazoline) (pMeOx), poly(2-butyl-2-oxazoline) (pBuOx) and poly(2-butyl-2-oxazine) (pBuOzi) blocks, were compared with the established excipients, PVP and P(VP-co-VA). ASDs with indomethacin as the model drug were prepared at high drug loadings via hot melt extrusion. The extrudates were studied with DSC and PXRD, revealing the ASDs to be fully amorphous up to 75wt% indomethacin, independent of the polymer used. 13C CPMAS NMR provided insights into intermolecular associations as a function of drug loading, and suggested the presence of drug dimers at 75wt% drug loading in pMeOx-pBuOzi-pMeOx and pMeOx-pBuOx-pMeOx, which could affect physical stability. Independent of the polymers, the solid-state form of the drug in the ASD was found to affect the dissolution profile of the samples, insofar as the samples containing crystalline indomethacin showed slower dissolution than the fully amorphous ones. This study shows that the polymers comprising poly(2-oxazoline) and poly(2-oxazine) are effective polymers for ASD preparation, similar to PVP and P(VP-co-VA) which merits further investigations into these novel polymers for formulating ASDs.

Impact of Surfactants on Solution Behavior and Membrane Transport of Amorphous Solid Dispersions

The purpose of the study was to develop an amorphous solid dispersion (ASD) of a poorly soluble compound (AK100) and investigate the impact of different surfactants on its dissolution, supersaturation and membrane transport. The solubility of the AK100 was determined in crystalline and amorphous form in the absence and presence of three surfactants at different concentrations: sodium dodecyl sulphate (SDS), polysorbate 80 (PS80) and D-α-tocopherol polyethylene glycol succinate (TPGS). The relation between solubility and surfactant solubilization was evaluated using a computational model. The ASD powder was prepared by solvent evaporation for non-sink dissolution experiments with and without the pre-dissolved surfactants. A transport study with Caco-2 cells was conducted to evaluate the impact of surfactants-based formulation on membrane transport. Both the corresponding crystalline and amorphous solubility of AK100 increased linearly as a function of the surfactant concentrations. The supersaturation was maintained for at least three hours in absence of surfactant and in presence of TPGS, whereas supersaturation declined with SDS and PS80. As expected, the membrane flux of the AK100 was higher for the ASD than for the crystalline powder, and further increased with increased concentration of TPGS. The supersaturation ratio based on the activity-based calculation from Caco-2 cells study was always higher than that of the concentration-based one for the amorphous and crystalline forms of AK100. This study shows how additional solubilizing excipients during formulation development can improve the resulting dissolution and phase behavior of supersaturated drug solution.

Understanding the effect of plasticizers in film coat materials on the physical stability of amorphous solid dispersions

Amorphous solid dispersions (ASDs) have been extensively utilized to improve the bioavailability of drugs that have low aqueous solubility. The influence of different excipients on the conversion of amorphous drugs into their crystalline forms in ASDs has been extensively researched. However, there is limited knowledge examining the impact of film coating materials on the physical stability of oral tablet formulations containing ASDs. In this study, we demonstrate that plasticizers present in film coats can have a detrimental impact on the physical stability of ASDs. We systematically compared two frequently used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). To gain mechanistic insights into the detrimental effects of plasticizers on the physical stability of ASDs, plasticizer leaching studies and physical stability studies of solvent-evaporated and spray-dried intermediates (SDI) using two BCS class II drugs were conducted. Triacetin was found to leach into the tablet core within one week when stressed at 40°C/75% RH, whereas no leaching was observed for PEG 3350, as discerned from spectroscopic studies. We also found that triacetin-containing ASDs exhibited greater amorphous to crystalline form conversion of the drug compared to PEG 3350-containing ASDs after stability testing. Moreover, the incorporation of triacetin into polymers was found to cause a significant depression of glass transition temperature and upon equilibration with moisture, a drop below room temperature. Overall, these observations underscore the importance of carefully selecting plasticizers to be present in film coatings when developing ASD pharmaceutical products.

Counteracting the Loss of Release for Indomethacin-Copovidone ASDs

This work revisits the changing release behavior of indomethacin(IND)-copovidone amorphous solid dispersions (ASDs) when increasing their drug load (DL). While showing congruent release behavior at DL 0.1, ASDs with DLs of 0.3 and higher show incongruent release finally resulting in a complete loss of release. To study and explain this phenomenon, we modeled the release kinetics of these ASDs and looked into their phase behavior both experimentally and theoretically. We applied a diffusion model to accurately describe experimental release profiles for congruent release, incongruent release as well as for loss of release. Predicted concentration profiles for IND, copovidone, and water within the ASD revealed the formation of an ASD layer that almost exclusively contains amorphous IND. Our phase-diagram predictions and experimental data explain this phenomenon by water-induced phase separation in those parts of the ASD which did absorb water from the dissolution medium. Whereas the evolving copovidone-rich phase dissolved, the IND-rich phase remained undissolved and formed a super-hydrophobic cover of the remaining inner core of the ASD, thus finally completely preventing its dissolution. Higher DLs promote phase separation. This leads to the counterintuitive effect that the higher the DL, the lower the absolute amount of IND released. While the ASD containing 6 mg IND (DL 0.1) released 6 mg IND, the one containing 42 mg IND (DL 0.7) released only 1 mg IND. The theoretical approach applied in this work is for the first time able to quantitatively predict that reducing DL or tablet size could be used to overcome this problem.

Prediction of Successful Amorphous Solid Dispersion Pairs through Liquid State Nuclear Magnetic Resonance.

Amorphous solid dispersions (ASDs) function in part via a "parachute effect", i.e., polymer-enabled prolonged drug supersaturation, presumably through drug-polymer interactions in the liquid state. We aim to expand the utility of liquid state nuclear magnetic resonance (1HNMR) to streamline polymer selection for ASDs. Our hypothesis is that strong molecular interactions between polymer and drug in 1HNMR anticipate reduced precipitation kinetics in supersaturation studies. For three drug-polymer pairs (i.e., etravirine with each HPMC, HPMCAS-M, and PVP-VA), 1HNMR findings were compared to more common supersaturation studies. Drug-polymer interactions were assessed by saturation transfer difference NMR (STD-NMR) and T1 relaxation time. 2D-1H NOESY experiments were also performed. Supersaturation studies involved precipitation inhibition using the solvent-shift methodology. The results from STD-NMR and T1 relaxation time indicate etravirine bound preferably to HPMCAS-M > HPMC ≫ PVP-VA. STD-NMR and T1 relaxation time yielded insight into which fragments of etravirine structure bind with HPMCAS-M and HPMC. The strong interactions from STD-NMR and T1 relaxation time changes indicated that HPMCAS-M and HPMC, but not PVP-VA, are suitable polymers to maintain etravirine supersaturation and inhibit drug precipitation. 2D-1H NOESY results corroborate the findings of STD-NMR and T1 relaxation time, showing that etravirine interacts preferably to HPMCAS-M than to PVP-VA. Supersaturation studies using solvent-shift technique corroborated our hypothesis as predissolved HPMCAS-M and HPMC, but to a less extent PVP-VA, markedly promoted etravirine supersaturation and inhibited drug precipitation. Supersaturation studies agreed with STD-NMR and T1 relaxation time predictions, as HPMC and HPMCAS-M maintained etravirine in solution for longer time than PVP-VA. The results show promise of 1HNMR to streamline polymer selection in a nondestructive and resource sparing fashion for subsequent ASD development.

The Excellent Chemical Interaction Properties of Poloxamer and Pullulan with Alpha Mangostin on Amorphous Solid Dispersion System: Molecular Dynamics Simulation.

Alpha mangostin (AM) has demonstrated significant potential as an anticancer agent, owing to its potent bioactivity. However, its clinical application is limited by poor solubility, which hampers its bioavailability and effectiveness. Amorphous solid dispersion (ASD) presents a promising technique to enhance the solubility and stability of AM. Molecular dynamics simulation offers a rapid, efficient, and precise method to evaluate and optimize ASD formulations before production. In this study, we conducted molecular dynamics simulations to explore the ASD development of AM with poloxamer and pullulan. Our results revealed that AM-poloxamer complexes exhibit superior interaction characteristics compared to AM-pullulan, with a 1:5 ratio of AM to poloxamer and a cooling rate of 1 °C/ns demonstrating the most favorable outcomes. This combination showed enhanced hydrogen bonding, a more compact molecular structure, and higher stability, making it the optimal choice for ASD formulation. The integration of molecular dynamics simulation into ASD development significantly accelerates the formulation process and provides critical insights into achieving a stable and effective AM dispersion. The AM-poloxamer complex, particularly at a 1:5 ratio with a 1 °C/ns cooling rate, offers the best potential for improving AM solubility and therapeutic efficacy.

Enhancing the In vivo Bioavailability and Absorption of Niclosamide with Amorphous Solid Dispersion via Solvent Method

Abstract Objective This research aims to prepare a superior amorphous solid dispersion (ASD) formulation via solvent method for the oral delivery of Niclosamide to enhance oral bioavailability and absorption. Methods Phase solubility tests were conducted to select an optimal carrier combination for Niclosamide solid dispersion (SD). The Niclosamide amorphous solid dispersion was synthesized using a solvent rotary evaporation method and characterized through in vitro dissolution tests, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction, and scanning electron microscopy. In vivo oral pharmacokinetic studies were conducted in in Sprague Dawley rats at a dose of 50 mg/kg. Key findings PEG6000 and poloxamer 188 combination was selected as optimal carrier. ASD named ASD-5 was successfully prepared, encompassing a 25% drug loading, Niclosamide within ASD-5 remains amorphous and stable. 75% of Niclosamide in ASD-5 rapidly dissolved in 5 min, while below 5% of pure Niclosamide and physical mixture dissolved in longer time. Amorphization of Niclosamide in ASD-5 notably contributes to its dissolution rate and extent. Furthermore, among reported Niclosamide solid dispersion formulations with drug loading above 25%, ASD-5 demonstrated the highest bioavailability, showing a 2.33-fold increase in plasma exposure and bioavailability compared to pure Niclosamide. Conclusion Amorphous ASD-5 prepared by solvent method has higher drug loading and be scalable in pre-clinical stage preparation. Due to using PEG6000 and poloxamer 188 combination, ASD-5 had the highest bioavailability among reported Niclosamide solid dispersions with a drug load exceeding 25%. Also, ASD-5 presented simplified preparation procedure compared to other reported Niclosamide solid dispersion.

Complexation of telmisartan with cyclodextrins as a tool of solubility enhancement: A comparative analysis of influence of the cyclodextrin type and method of solid dispersion preparation

Cardiovascular telmisartan (TMS) was complexed with modified cyclodextrins (CD) aiming at improvement of its poor solubility which results into low bioavailability. Inclusion complexes with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) in liquid and solid state was evaluated for first time. Phase solubility isotherm diagrams of TMS versus the CD concentration were plotted in a buffer pH 7.4. It was found that TMS/CD complexes are formed in solution in an equimolar stoichiometric ratio of 1:1. The aqueous solubility of TMS with the addition of 0.05 mol·L−1 HP-β-CD increased by 23 times and was 38.9·10−5 mol·L−1, and the presence of the same amount of SBE-β-CD in solution increased the solubility of the drug by 7 times, reaching a value of 12.6·10−5 mol·L−1.The binding constants were found to 468 and 114 L·mol−1 for HP-β-CD and SBE-β-CD, respectively. Novel solid forms of TMS with both CDs were prepared using the grinding and evaporation approaches. Successful formation of supramolecular TMS/HP-β-CD and TMS/SBE-β-CD solid complexes was confirmed by FTIR, PXRD, DSC, TGA and SEM. The residual crystallinity of all obtained solid dispersions of TMS/CD did not exceed 10 %. Supersaturation was observed during the dissolution of all the solid complexes. The grinding technique was found to be more advantageous as it ensured the biggest improvement of the drug maximum concentration in the aqueous solution: the TMS solubility in the TMS/HP-β-CD(gr) and TMS/SBE-β-CD(gr) solid complexes increased by 27 and 33 times, respectively. Besides, polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG) were tested as crystallization inhibitors. Addition of 1 wt% PVP as a stabilizer is a promising approach for the preparation of TMS pharmaceutical formulations with improved bioavailability.

Optimized freeze-dried solid-dispersions boost naringin solubility, antibacterial and in-vitro anticancer activity

Naringin (NRG) is a water insoluble glycoside having wide range of therapeutic efficacy. Its efficacy is limited due to its poor water solubility and bioavailability. In the current research, solid dispersions (SDs) were prepared by freeze drying method using different carriers KollidonVA64, KollidonVA30, Soluplus and Poloxamer188. The prepared binary SDs were characterized for solubility and dissolution study to select the optimized composition and further ternary SDs was prepared with carrier blend (KollidonVA64 and Soluplus). Finally, the ternary SDs (F6) was evaluated for solid state characterization (DSC, XRD, SEM), drug polymer interaction (IR), in vitro antioxidant, antimicrobial as well as cell viability study against neuroblastoma cell. The binary SDs developed with KollidonVA64 and Soluplus showed greater solubility than KollidonVA30 and Poloxamer188. The ternary SDs (F6), showed a significant enhancement in the saturation solubility and dissolution than binary SDs (F1-F4). The binary SDs (F1-F4) displayed the maximum release in 120 min (73.5±2.8 to 94.6±3.1%), whereas the ternary SDs (F6) showed the maximum release in 60 min (99.2±1.6%). The spectroscopy results confirm the formation of a stable dispersion and no drug polymer interaction was observed. The thermogram, diffractogram and microscopic image confirms the conversion of crystalline NRG to amorphous form. These findings support the results of saturation solubility and dissolution data. The in vitro antioxidant, antimicrobial and cytotoxicity assessment displayed a greater activity of developed NRG SDs than the free NRG. The enhancement in the results may be due to the enhanced solubility of NRG after formation of SDs using the KollidonVA64 and Soluplus carrier blend.

Development and Characterization of Fast-Dissolving Tablets to Enhance Bioavailability of BCS Class II Drugs by Solid Dispersion Method

Background: Rapid tablet or capsule dissolution requires the tablet to disintegrate and dissolve at a higher rate, enhancing drug dissolution and bioavailability. Suitable disintegrants have shown an appreciable rate of disintegration or dissolution. Using factorial design for formulation to improve bioavailability is a key focus in pharmaceutical research to enhance dissolution Methods: Azelnidipine (Azp) tablets were formulated with Hydroxypropyl β-cyclodextrin (HβCD), β-cyclodextrin (βCD), and Kolliphor HS15 (HS15) to enhance solubility. A 23 factorial design optimized the formulation, focusing on disintegration time (DT) and time for 90% dissolution (T90). Eight formulations (F1-F8) were prepared using the kneading method. Tablets were evaluated for physical properties, drug content, friability, dissolution, and drugexcipient interactions (FTIR and DSC). The optimal formulation (F9) was determined via desirability analysis. Results: Tablets showed acceptable Carr's index (CI), Hausner ratio (HR), and Angle of Repose (AR). Increasing βCD concentration decreased DT, enhancing water absorption and faster dissolution. βCD tablets had the lowest DT among the formulations, with F4 showing the best disintegration. Higher HS15 concentration also reduced DT, with F8 achieving the highest drug release (T90%) within 60 minutes. R² values ranged from 0.922 to 0.994, indicating high predictability. The optimal formulation had a desirability of 1.0, consisting of 3.523 mg HS15, 28.4 mg βCD, and 1.49 mg βCD, with a DT of 102 ± 1.13 seconds and 98% dissolution. FTIR and DSC confirmed no drug–excipient interactions. Conclusion: Optimized super disintegrant concentrations and wet granulation techniques resulted in tablets with strong mechanical properties, rapid disintegration, and consistent drug content. Future research and in vivo studies should explore additional excipient combinations.

Screening of Polymers for Oral Ritonavir Amorphous Solid Dispersions by Film Casting

Background/Objectives: Drug–polymer interactions and miscibility promote the formation and performance of amorphous solid dispersions (ASDs) of poorly soluble drugs for improved oral bioavailability. The objective of this study was to employ drug–polymer interaction calculations and small-scale experimental characterization to screen polymers for potential ASDs of ritonavir. Methods: Seven polymers across four polymer types were screened as follows: an enteric one (EudragitS100), amphiphilic ones (HPMCAS-L, HPMCAS-H, and their 1:1 combination), hydrophilic ones (PEG-6000, PVP-VA), and a surfactant (Soluplus), including PVP-VA as a positive control, as the commercial ASD employs PVP-VA. Drug–polymer interaction calculations were performed for Hansen solubility parameter, Flory–Huggins parameter, and glass transition temperature. ASDs were prepared via film casting. Experimental characterizations included drug solubility in polymer solutions, polymer inhibition of drug precipitation, polarized light microscopy, differential scanning calorimetry, solubilization capacity, and dissolution studies. Results: HPMCAS-L, HPMCAS L:H, and Soluplus, along with the positive control PVP-VA, were identified as polymers for potential ASDs of ritonavir, with HPMCAS-L and PVP-VA being preferable. HPMCAS-L and the positive control PVP-VA were always viable for both 20% and 40% drug loads across all tests. Films with each of these four polymers showed improved dissolution compared to amorphous ritonavir without polymer. Drug–polymer interaction calculations anticipated the unfavorable small-scale experimental results for PEG-6000 and EudragitS100. Conclusion: Overall, the results contribute towards a resource-sparing approach to identify polymers for ASDs.

Enhancing Ketoprofen Solubility: A Strategic Approach Using Solid Dispersion and Response Surface Methodology.

In the pharmaceutical sciences, the solubility profile of therapeutic molecules is crucial for identifying and formulating drugs and evaluating their quality across the drug discovery pipeline based on factors like oral bioavailability, metabolic transformation, biodistribution kinetics, and potential toxicological implications. The investigation aims to enhance the solubility parameters of ketoprofen (BCS-II class), which exhibits low solubility and high permeability. In this method, hydrotrope blends of aromatic sodium benzoate and electrolyte sodium acetate were employed to enhance the solubility parameter of ketoprofen. Several batches of solid dispersion of ketoprofen were made using a solvent evaporation method, and the response surface method 3² factorial design was used to find the best one. The optimised formulation, KSD9, underwent in-vitro drug dissolution, DSC, pXRD, and SEM studies. The optimized batch demonstrated substantial improvement in ketoprofen solubility, attributed to mixed hydrotropy. The results indicated that both solubility and %CDR improved when hydrotropes were employed, suggesting a direct proportionality between the rise in solubility and %CDR. Formulations KSD1-KSD9 exhibited solubility enhancements ranging from 2.23 to 5.77-fold, along with an elevation in %CDR from 72.28% to 94.76%. This implies that the %CDR was modulated by the hydrotropes, specifically influenced by the concentration levels of the independent variables. An increase in hydrotrope levels corresponded to an increase in %CDR. The positive coefficients in the quadratic equation for %CDR underscored the significant role of these independent variables in augmenting the in-vitro release of Ketoprofen. Similarly, during a comparative dissolution investigation, the optimized KSD9 formulation exhibited remarkable solubility and drug content compared to conventional Ketoprofen dispersible tablets. The synergistic effect of combining two hydrotropic agents significantly increased the solubility of ketoprofen by up to 58 times. The results indicated that the independent variables exerted a positive influence on solubility and %CDR. Furthermore, the responses were contingent on the specific hydrotropes selected, which functioned as the independent variables. Analyzing the r² and ANOVA results suggested that the dependent variables aligned well with the chosen model. Visual representations, such as the 3D response surface plot and contour plot, demonstrated the impact of each hydrotrope individually and when combined. Overall, employing hydrotropes led to improved solubility and %CDR, highlighting a direct proportionality between the rise in solubility and %CDR. Mixed hydrotropic lessens the toxicity associated with individual hydrotrope concentrations while also offering a sustainable and eco-friendly alternative. This study paves the way for future research aiming to improve the solubility of low- solubility drugs, broadening their clinical applications.

Meloxicam-amino acids salts/ion pair complexes with advanced solubility, dissolution, and gastric safety

Amino acids have attracted attention as a potential functional excipient for optimizing biopharmaceutics characteristics of poorly soluble drugs. The amino acids are a diverse class with many functional groups, natural compounds, biocompatible and low molecular weight substances. Two amino acids serine and arginine were investigated with meloxicam. Meloxicam has extremely low solubility; being NSAIDs, gastric upset and ulcer are common side effects. Solid dispersions were produced by precipitation and physical mixing techniques. The produced combinations underwent in vitro dissolution, docking, DSC, FTIR, XRD, solubility and gastric ulcer formation studies. Docking indicated formation of ion pair/salt between the basic amino acid arginine and meloxicam. Both solubility and dissolution rates were increased by up to 3000- and 12-fold, respectively. DSC, FTIR an XRD supported these findings. Rats treated with meloxicam showed loss of surface gastric epithelium integrity and ulceration. The animal group received meloxicam: arginine showed intact gastric mucosa with the surface epithelium and gastric glands well organized and nearly similar to the untreated control. Arginine with the guanidine group that was capable of preserving gastric mucosa after repeated administration for 10 days. This study highlighted the role of arginine as a functional excipient that did not only improve solubility and dissolution rates but ameliorated the long-standing gastric side effects attributed to meloxicam.