Dynamic Inhibition of Calcite Dissolution in Flowing Acidic Pb2+ Solutions.

Reactions of mineral surfaces with dissolved metal ions at far-from-equilibrium conditions can deviate significantly from those in near-equilibrium systems due to steep concentration gradients, ion-surface interactions, and reactant transport effects that can lead to emergent behavior. We explored the effect of dissolved Pb2+ on the dissolution rate and topographic evolution of calcite (104) surfaces under far-from-equilibrium acidic conditions (pH 3.7) in a confined single-pass laminar-flow geometry. Operando measurements by digital holographic microscopy were conducted over a range of Pb2+ concentrations ([Pb2+] = 0 to 5 × 10-2 M) and flow velocities (v = 1.67-53.3 mm s-1). Calcite (104) surface dissolution rates decreased with increasing [Pb2+]. The inhibition of dissolution and the emergence of unique topographic features, including micropyramids, variable etch pit shapes, and larger scale topographic patterns, became increasingly apparent at [Pb2+] ≥ 5 × 10-3 M. A better understanding of such dynamic reactivity could be crucial for constructing accurate models of geochemical transport in aqueous carbonate systems.

Enhanced dissolution rates of glibenclamide through solid dispersions on microcrystalline cellulose and mannitol, combined with phosphatidylcholine.

OBJECTIVE: This study aimed to investigate the impact of physical solid dispersions of spray-dried glibenclamide (SG) on the surface of microcrystalline cellulose (MC) and mannitol (M) surfaces, as well as their combination with phosphatidylcholine (P), on enhancing the dissolution rate of glibenclamide (G). METHODS: Solid dispersions were prepared using varying proportions of 1:1, 1:4, and 1:10 for SG on the surface of MC (SGA) and M (SGM), and then combined with P, in a proportion of 1:4:0.02 using spray drying. The particle size, specific surface area, scanning electron microscopy (SEM), X-ray diffraction (XRD), and dissolution rate of SGA and SGM were characterized. RESULTS: SEM analysis revealed successful adhesion of SG onto the surface of the carrier surfaces. XRD showed reduced crystalline characteristic peaks for SGA, while SGM exhibited a sharp peaks pattern. Both SGA and SGM demonstrated higher dissolution rates compared to SG and G alone. Furthermore, the dissolution rates of the solid dispersions of SG, MC and P (SGAP), and SG, M, and P (SGMP) were sequentially higher than that of SGA and SGM. CONCLUSIONS: The study suggests that physical solid dispersions of SG on MC and M, along with their combination with P, can effectively enhance the dissolution rate of G. These findings may be valuable in developing of oral solid drug dosage forms utilizing SGA, SGM, SGAP, and SGMP.

Improving cellular uptake and synergetic anti-tumor effects of magnolol and Brucea javanica oil through self-microemulsion.

OBJECTIVE: Magnolol (MG) and Brucea javanica (L.) Merr. oil (BJO) possess synergetic anti-tumor effects, but have poor water solubility and stability, which results in low oral bioavailability. SIGNIFICANCE: The MG loaded self-microemulsion drug delivery system (MG-SMDDS) with BJO as oil phase component was utilized to improve the cellular uptake and synergetic anti-tumor effects. METHODS: Compatibility study and pseudoternary phase diagram (PTPD) were respectively employed to screen for the composition and proportion of oil phase in the formulation. Central composite design-effect surface method was applied to optimize proportion of each formulation condition. The droplet size, ζ-potential, colloid stability, encapsulation rate (ER) and in vitro dissolution rate of MG-SMDDS were evaluated. Furthermore, cellular uptake and cytotoxicity of the microemulsion on HepG2 cells were assessed. RESULTS: The optimal composition of MG-SMDDS was: MG (9.09%), castor oil (7.40%), BJO (2.47%), Cremophor EL 35 (54.04%) and 1, 2-propanediol (27.01%). The MG-SMDDS exhibited satisfactory droplet size, ζ-potential, colloid stability and ER, as well as faster dissolution rate than free MG. More importantly, SMEDDS containing BJO could enhance the cellular uptake and cytotoxicity of free BJO and free MG on tumor cells. CONCLUSIONS: The BJO self-microemulsion delivery technique can provide an idea for design of oral delivery vehicles based on BJO.

Enhanced Solubility of Ibuprofen by Complexation with ß-Cyclodextrin and Citric Acid.

The ability of ß-CD to form inclusion complexes with ibuprofen (IBU) and at the same time to make a two-phase system with citric acid was explored in the present study for achieving improved solubility and dissolution rate of IBU. Mechanical milling as well as mechanical milling combined with thermal annealing of the powder mixtures were applied as synthetic methods. Solubility and dissolution kinetics of the complexes were studied in compliance with European Pharmacopoeia (ICH Q4B). ß-CD and citric acid (CA) molecules were shown to interact by both ball milling (BM), thermal annealing, as well as BM with subsequent annealing. Complexes were also formed by milling the three compounds (ß-CD, CA and IBU) simultaneously, as well as by a consecutive first including IBU into ß-CD and then binding the formed ß-CD/IBU inclusion complex with CA. As a result, ternary ß-CD/IBU/CA complex formed by initial incorporation of ibuprofen into ß-CD, followed by successive formation of a two-phase mixture with CA, exhibited notably improved dissolution kinetics compared to the pure ibuprofen and slightly better compared to the binary ß-CD/IBU system. Although the addition of CA to ß-CD/IBU does not significantly increase the solubility rate of IBU, it must be considered that the amount of ß-CD is significantly less in the ternary complex compared to the binary ß-CD/IBU.

DSC, TGA-FTIR and FTIR Assisted by Chemometric Factor Analysis and PXRD in Assessing the Incompatibility of the Antiviral Drug Arbidol Hydrochloride with Pharmaceutical Excipients.

Arbidol hydrochloride is an antiviral product widely used in Russia and China for the treatment of, among other diseases, influenza. In recent years, it has turned out to be highly effective against COVID-19. However, there is little knowledge about its physicochemical properties and its behavior in the presence of various pharmaceutical excipients, which could be useful in the development of new preparations by increasing its solubility and bioavailability. For this reason, binary mixtures composed of arbidol hydrochloride and selected pharmaceutical excipients such as chitosan, polyvinylpyrrolione K-30 and magnesium stearate were prepared and subjected to differential scanning calorimetry (DSC), thermogravimetry combined with Fourier transform infrared spectrometry (TGA-FTIR) and Fourier transform infrared spectrometry (FTIR) analyses. In order to obtain clarity in the interpretation of the outcomes, chemometric calculations with factor analysis (FA) were used. Additionally, a powder X-ray diffraction (PXRD) and an intrinsic dissolution rate study were performed for arbidol hydrochloride itself and in the presence of excipients. As a result of the study, it was revealed that arbidol hydrochloride may undergo polymorphic transformations and be incompatible with chitosan and magnesium stearate. However, mixing arbidol hydrochloride with polyvinylpyrrolidone K-30 guarantees the obtaining of durable and safe pharmaceutical preparations.

Formulation development, characterization, and evaluation of bedaquiline fumarate - Soluplus® - solid dispersion.

Bedaquiline fumarate (BQF) is classified as a BCS class II drug and has poor water solubility and dissolution rate, which ultimately compromises bioavailability. The objective of this study is to improve the biopharmaceutical properties of BQF through a solid dispersion system by using Soluplus®. Two solid dispersion systems were prepared i.e. binary solid dispersion (BSD) and ternary solid dispersion (TSD) where 14.31-fold and 20.43-fold increase in solubility of BQF was observed with BSD and TSD in comparison to BQF. In our previous research work, we explored the BSD and TSD of BQF with a crystalline polymer, poloxamer 188, which showed an increment in the solubility of BQF. In the current research, amorphous Soluplus® polymer was selected to formulate BSD and TSD with BQF and showed higher solubility than poloxamer 188. The various solid and liquid state characterization results confirmed the presence of an amorphous form of BQF inside solid dispersion. The Fourier transform infrared spectroscopy showed no chemical interactions between BQF and polymer. The cellular uptake results demonstrated higher uptake in Caco-2 cell lines. Pharmacokinetic studies showed enhanced solubility and bioavailability of TSDs. Hence, the present research shows a promising formulation strategy for enhancing the biopharmaceutical performance of BQF by increasing its solubility.

Preparation and Evaluation of Berberine-Excipient Complexes in Enhancing the Dissolution Rate of Berberine Incorporated into Pellet Formulations.

Berberine is used in the treatment of metabolic syndrome and its low solubility and very poor oral bioavailability of berberine was one of the primary hurdles for its market approval. This study aimed to improve the solubility and bioavailability of berberine by preparing pellet formulations containing drug-excipient complex (obtained by solid dispersion). Berberine-excipient solid dispersion complexes were obtained with different ratios by the solvent evaporation method. The maximum saturation solubility test was performed as a key factor for choosing the optimal complex for the drug-excipient. The properties of these complexes were investigated by FTIR, DSC, XRD and dissolution tests. The obtained pellets were evaluated and compared in terms of pelletization efficiency, particle size, mechanical strength, sphericity and drug release profile in simulated media of gastric and intestine. Solid-state analysis showed complex formation between the drug and excipients used in solid dispersion. The optimal berberine-phospholipid complex showed a 2-fold increase and the optimal berberine-gelucire and berberine-citric acid complexes showed more than a 3-fold increase in the solubility of berberine compared to pure berberine powder. The evaluation of pellets from each of the optimal complexes showed that the rate and amount of drug released from all pellet formulations in the simulated gastric medium were significantly lower than in the intestine medium. The results of this study showed that the use of berberine-citric acid or berberine-gelucire complex could be considered a promising technique to increase the saturation solubility and improve the release characteristics of berberine from the pellet formulation.

Mesoporous Matrices as a Promising New Generation of Carriers for Multipolymorphic Active Pharmaceutical Ingredient Aripiprazole.

The enhancement of the properties (i.e., poor solubility and low bioavailability) of currently available active pharmaceutical ingredients (APIs) is one of the major goals of modern pharmaceutical sciences. Among different strategies, a novel and innovative route to reach this milestone seems to be the application of nanotechnology, especially the incorporation of APIs into porous membranes composed of pores of nanometric size and made of nontoxic materials. Therefore, in this work, taking the antipsychotic API aripiprazole (APZ) infiltrated into various types of mesoporous matrices (anodic aluminum oxide, native, and silanized silica) characterized by similar pore diameters (d = 8-10 nm) as an example, we showed the advantage of incorporated systems in comparison to the bulk substance considering the crystallization kinetics, molecular dynamics, and physical stability. Calorimetric investigations supported by the temperature-dependent X-ray diffraction measurements revealed that in the bulk system the recrystallization of polymorph III, which next is converted to the mixture of forms IV and I, is visible, while in the case of confined samples polymorphic forms I and III of APZ are produced upon heating of the molten API with different rates. Importantly, the two-step crystallization observed in thermograms obtained for the API infiltrated into native silica templates may suggest crystal formation by the interfacial and core molecules. Furthermore, dielectric studies enabled us to conclude that there is no trace of crystallization of spatially restricted API during one month of storage at T = 298 K. Finally, we found that in contrast to the crystalline and amorphous bulk samples, all examined confined systems show a logarithmic increase in API dissolution over time (very close to a prolonged release effect) without any sign of precipitation. Our data demonstrated that mesoporous matrices appear to be interesting candidates as carriers for unstable amorphous APIs, like APZ. In addition to protecting them against crystallization, they can provide the desired prolonged release effect, which may increase the drug concentration in the blood (resulting in higher bioavailability). We believe that the "nanostructirization" in terms of the application of porous membranes as a novel generation of drug carriers might open unique perspectives in the further development of drugs characterized by prolonged release.

Impact of Crystal Nuclei on Dissolution of Amorphous Drugs.

Amorphous drugs are used to improve bioavailability of poorly water-soluble drugs. Crystallization must be managed to take full advantage of this formulation strategy. Crystallization of amorphous drugs proceeds in a sequence of crystal nucleation and growth, with different kinetics. At low temperatures, crystal nucleation is fast, but crystal growth is slow. Therefore, amorphous drugs may generate dense but nanoscale crystal nuclei. Such tiny nuclei cannot be detected using routine powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). However, they may negate the dissolution advantage of amorphous drugs. In this work, for the first time, the impact of crystal nuclei on dissolution of amorphous drugs was studied by monitoring the real-time dissolution from amorphous drug films, with and without crystal nuclei, and the evolving crystallinity in the films. Three model drugs (ritonavir/RTV, posaconazole/POS, and nifedipine/NIF) were chosen to represent different crystallization tendencies in the supercooled liquid state, namely, slow-nucleation-and-slow-growth (SN-SG), fast-nucleation-and-slow-growth (FN-SG), and fast-nucleation-and-fast-growth (FN-FG), respectively. We find that although the amorphous films containing nuclei do not show obvious differences from the nuclei-free films under PLM and PXRD before dissolution, they have inferior dissolution performance relative to the nuclei-free amorphous films. For SN-SG drug RTV, crystal nuclei have negligible impact on the crystallization of amorphous films, dissolution rate, and supersaturation achieved. However, they cause earlier de-supersaturation by inducing crystallization in solution as heterogeneous seeds. For FN-SG drug POS and FN-FG drug NIF, crystal nuclei accelerate crystallization in the amorphous films leading to lower supersaturation achieved with POS, and elimination of any supersaturation with NIF. Dissolution profiles of amorphous films can be further analyzed using a derivative function of the apparent dissolution rate, which yields amorphous solubility, initial intrinsic dissolution rate, and onset of crystallization in the amorphous films. This study highlights that although crystal nuclei are undetectable with routine analytical methods, they can significantly negate, or even eliminate, the dissolution advantage of amorphous drugs. Hence, understanding crystal nucleation process and developing approaches to prevent it are necessary to fully realize the benefits of amorphous solids.

Pharmaceutical and Immunological Evaluation of Cholera Toxin A1 Subunit as an Adjuvant of Hepatitis B Vaccine Microneedles.

PURPOSE: For successful delivery of a solid vaccine formulation into the skin using microneedles, the solubility of an adjuvant should be considered because the decrease in the dissolution rate by the addition of adjuvant decreases the delivery efficiency of the vaccine. METHODS: In this study, cholera toxin A subunit 1 (CTA1) was examined as an adjuvant to Hepatitis B vaccine (HBV) microneedles because of its good water solubility, improved safety, and positive effect as shown in intramuscular administration of a liquid vaccine. RESULTS: All solid formulations with CTA 1 dissolved in in vivo mouse skin within 30 min, and they were successfully delivered into the skin. In experiments with mice, the addition of CTA1 led to improved IgG immune response compared to the use of an aluminum hydroxide-based formulation and intramuscular administration of HBV. In addition, CTA1 induced CD8 + T cell response as much as in which the aluminum hydroxide-based formulation induced. CONCLUSIONS: CTA1 is an adjuvant that satisfies both the delivery efficiency and the immunological characteristics required for vaccine microneedles. CTA1 will be used as a potential adjuvant through vaccine microneedles.

Self-emulsifying micelles as a drug nanocarrier system for itraconazole oral bioavailability enhancement; in vitro and in vivo assessment.

Itraconazole (ITZ) is a renowned antifungal medication, however its therapeutic efficacy is limited by low solubility and oral bioavailability. The current research work attempted to augment the oral bioavailability of ITZ by incorporating into self-emulsifying micelles (SEMCs). To fabricate the SEMCs, various preparation techniques including physical mixture, melt-emulsification, solvent evaporation and kneading, were opted by using different weight ratio of drug and solubilizers i.e. Gelucire-50/13 or Gelucire-44/14 and characterized both in vitro and in vivo. The prepared SEMCs were found to be in the size range from 63.4 ± 5.2 to 284.2 ± 19.5 nm with surface charges ranging from -16 ± 1.2 to -27 ± 2.0 mV. The drug solubility was improved to a reasonable extent with all investigated formulations, however, SEMCs in group 6 prepared by kneading method (KMG6) using Gelucire-44/14: drug (10:1 presented 87.6 folds' increase (964.93 ± 2 µg/mL) compared to solubility of crystalline ITZ (11 ± 2 µg/mL) through kneading method. In addition, KMG6 SEMCs shows the fast drug release compared to other SEMCs. Further, KMG6 SEMCs also exhibited 5.12-fold higher relative intestinal serosal fluid absorption compared to crystalline ITZ. The pharmacokinetic parameters such Cmax, AUC and Tmax of KMG6 SEMCs significantly improved compared to crystalline ITZ. In conclusion, the manipulation of ITZ solubility, dissolution rate and absorption using SEMCs is a promising strategy for bioavailability enhancement.

[Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines(â ¢): classification of granule dissolving behaviors].

Solubility is an important sensory quality attribute of traditional Chinese medicine(TCM) granules. In this paper, 90 batches of granules(30 batches of TCM formula granules, 30 batches of Chinese patent medicine granules and 30 batches of Japanese Kampo granules) were used as the research objects. The turbidity sensor was used to characterize the turbidity curve of the granule dissolution process. The classification system of granule dissolution behaviors was constructed from three dimensions: dissolution degree, equilibrium time, and dissolution mechanism. According to the equilibrium time, the granule dissolution rates were divided into three categories : faster(<100 s), general(101-300 s) and slow(>301 s). According to the turbidity curve profile, the granule dissolution mechanisms were classified into dissolution-controlled type(α-type), dispersion-controlled type(ß-type), and dispersion-controlled type followed by dissolution-controlled type(γ-type). The proportion of TCM formula granules, Chinese patent medicine granules and Japanese Kampo granules with complete dissolution or slight turbidity at the end of dissolution was 46.7%, 96.7%, and 10.0%. The proportion of TCM formula granules, Chinese patent medicine granules, and Japanese Kampo granules with faster dissolution rates(<100 s) was 23.3%, 26.7%, and 40.0%. The average dissolution rate of Japanese Kampo granules was faster than that of TCM formula granules, and it was slightly faster than the average dissolution rate of Chinese patent medicine granules. The dissolution mechanism of Chinese patent medicine granules was mainly α-type, while that of Japanese Kampo granules was mainly ß-type, and the three types of dissolution mechanisms of TCM formula granules accounted for a relatively average. The purpose of improving the solubility and dispersion of granules can be achieved by combining the comprehensive application of various functional excipients with the small dosage of Japanese Kampo granules and the wide addition scope of excipients. In the process of transforming TCM compound prescriptions into formulas, there is still much room for innovation in formula excipients and process optimization.

Studies on the Vitrified and Cryomilled Bosentan.

In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

The Relationship between the Drug Delivery Properties of a Formulation of Teriparatide Microneedles and the Pharmacokinetic Evaluation of Teriparatide Administration in Rats.

PURPOSE: Teriparatide is an effective drug for the treatment of osteoporosis. This study examines the relationship between the drug delivery properties of the solid formulation with teriparatide and the pharmacokinetic properties of teriparatide in vivo. METHODS: Teriparatide microneedles with different dissolution rates were prepared using sucrose and carboxymethylcellulose (CMC). There were three aspects of this study: (1) The dissolution rate of teriparatide from both formulations (sucrose and CMC) was measured in vitro. (2) After administration into porcine skin ex vivo, the diffusion rate of FITC-dextran was observed using a confocal microscope. (3) Pharmacokinetic studies were performed in rats and pharmacokinetic data compared with the release rate and the diffusion pattern. RESULTS: In the in vitro dissolution experiment, 80% of teriparatide was released within 30 min from the CMC MNs, whereas 80% of teriparatide was released within 10 min from the sucrose MNs. After 30 min, the fluorescence intensity on the surface of the MNs was 40% of the initial intensity for sucrose MNs and 90% for CMC MNs. In the pharmacokinetic study, the Cmax values of the CMC and sucrose MNs were 868 pg/mL and 6809 pg/mL, respectively, and the AUClast values were 6771 pg*hr/mL for the CMC MNs and 17,171 pg*hr/mL for the sucrose MNs. CONCLUSIONS: When teriparatide is delivered into the skin using microneedles, the release rate from the solid formulation determines the drug's pharmacokinetic properties. The diffusion pattern of fluorescence into the skin can be used to anticipate the pharmacokinetic properties of the drug.

Development of eplerenone nano sono-crystals using factorial design: enhanced solubility and dissolution rate via anti solvent crystallization technique.

OBJECTIVE: The purpose of this work was to improve EP solubility by using a sono-crystalization approach to reduce particle size and hence, increase the dissolution rate. Significance Eplerenone (EP) is an antagonist of the aldosterone receptor and is used for the treatment of hypertension and chronic heart failure. EP was classed as biopharmaceutical classification (BCS) class II because of its poor solubility and high permeability, which retards dissolution rate and drug absorption, and decreases bioavailability. METHODS: Three-factors and two-level (23) multifactorial design have been employed to study the effect of independent variables which are drug concentration; (X1), stabilizer type (X2), and stabilizer concentration (X3) on responses; saturated solubility of EP in distilled water (Y1), saturated solubility in acidic media pH 1.2 (Y2), particle size (Y3), and polydispersity index, PDI (Y4). Also, they were characterized by Fourier transformed infrared spectroscopy (FTIR), Powder X-ray diffraction (PXRD), Differential scanning calorimetry (DSC), and yield percentage. The optimum formula was further subjected to an in-vitro release study. RESULTS: The optimized formulation showed a saturated solubility of EP as 1.29, and 1.86 (mg/ml) in distilled water and acidic media (pH 1.2) respectively. Also, the particle size of 133 nm, and PDI of 0.824 with a small percentage of the difference between the observed and predicted values. Ninety-one percent of EP was released within 10 min., and it was completely released within 45 min. with a significantly higher release rate compared to raw drug. CONCLUSION: This work resulted in a satisfactory enhancement of solubility and dissolution rate which, is suitable for further in-vivo analysis.

Insight into the Inclusion Complexation of Fluconazole with Sulfonatocalix[4]naphthalene in Aqueous Solution, Solid-State, and Its Antimycotic Activity.

The study aims to assess the interaction between fluconazole and sulfonatocalix[4]naphthalene towards enhancing its dissolution performance and antimycotic activity. A solubility study was carried out at different pH conditions, and the results revealed the formation of a 1:1 molar ratio fluconazole-sulfonatocalix[4]naphthalene inclusion complex with an AL type phase solubility diagrams. The solid powder systems of fluconazole-sulfonatocalix[4]naphthalene were prepared using kneaded and co-evaporation techniques and physical mixtures. DCS, PXRD, TGA-DTG, FT-IR, and in vitro dissolution performance characterize the prepared systems. According to physicochemical characterization, the co-evaporation approach produces an amorphous inclusion complex of the drug inside the cavity of sulfonatocalix[4]naphthalene. The co-evaporate product significantly increased the drug dissolution rate up to 93 ± 1.77% within 10 min, unlike other prepared solid powders. The antimycotic activity showed an increase substantially (p ≤ 0.05, t-test) antimycotic activity of fluconazole co-evaporate mixture with sulfonatocalix[4]naphthalene compared with fluconazole alone against clinical strains of Candida albicans and Candida glabrata. In conclusion, sulfonatocalix[4]naphthalene could be considered an efficient complexing agent for fluconazole to enhance its aqueous solubility, dissolution performance, and antimycotic activity.

Enhancement of Dissolving Capacity and Reducing Gastric Mucosa Irritation by Complex Formation of Resibufogenin with ß-Cyclodextrin or 2-Hydroxypropyl-ß-cyclodextrin.

Resibufogenin (RBG) is a natural medicinal ingredient with promising cardiac protection and antitumor activity. However, poor solubility and severe gastric mucosa irritation restrict its application in the pharmaceutical field. In this study, the inclusion complex of RBG with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was prepared using the co-evaporation method, and the molar ratio of RBG to CD was determined to be approximately 1:2 by continuous variation plot for both CDs. The formation of inclusion complexes between RBG and each CD (RBG/ß-CD and RBG/HP-ß-CD) was evaluated by phase solubility study, Fourier transform infrared spectroscopy, and thin-layer chromatography. Powder X-ray diffraction and differential scanning calorimetry confirmed drug amorphization and encapsulation in the molecular cage for both CDs. Moreover, the inclusion complexes' morphologies were observed using scanning electron microscopy. The dissolution rate of the inclusion complexes was markedly improved compared to that of RBG, and the complexes retained their antitumor activity, as shown in the in vitro cytotoxicity assay on a human lung adenocarcinoma cancer (A549) cell line. Moreover, less gastric mucosal irritation was observed for the inclusion complex. Thus, the inclusion complex should be considered a promising strategy for the delivery of poorly water-soluble anticancer agents, such as RBG.

Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption.

Lopinavir is an antiretroviral, antiparasitic agent and recently utilized in treatment of COVID-19. Unfortunately, lopinavir exhibited poor oral bioavailability due to poor dissolution, extensive pre-systemic metabolism, and significant P-glycoprotein intestinal efflux. Accordingly, the aim was to enhance dissolution rate and intestinal absorption of lopinavir. This employed co-processing with menthol which is believed to modify crystalline structures and inhibit intestinal efflux. Lopinavir was mixed with menthol at different molar ratios before ethanol assisted kneading. Formulations were evaluated using FTIR spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and dissolution studies. Optimum ratio was utilized to assess lopinavir intestinal permeability. This employed in situ rabbit intestinal perfusion technique. FTIR, DSC and XRD indicated formation of lopinavir-menthol co-crystals at optimum molar ratio of 1:2. Additional menthol underwent phase separation due to possible self-association. Co-crystallization significantly enhanced lopinavir dissolution rate compared with pure drug to increase the dissolution efficiency from 24.96% in case of unprocessed lopinavir to 91.43% in optimum formulation. Lopinavir showed incomplete absorption from duodenum and jejuno-iliac segments with lower absorptive clearance from jejuno-ileum reflecting P-gp efflux. Co-perfusion with menthol increased lopinavir intestinal permeability. The study introduced menthol as co-crystal co-former for enhanced dissolution and augmented intestinal absorption of lopinavir.

Supercritical CO2 versus water as an antisolvent in the crystallization process to enhance dissolution rate of curcumin.

Antisolvent crystallization approach using either water (in conventional crystallization process (WAS)), or supercritical CO2 (in supercritical anti-solvent crystallization (SCAS)), was employed in presence of hydroxypropyl methylcellulose (HPMC) to enhance the dissolution of curcumin. The impact of pressure, temperature and depressurization time on the SCAS process was studied using the Box-Behnken design to achieve the highest saturation solubility. A physical mixture of curcumin-HPMC was prepared for comparison purposes. Saturation solubility, scanning electron microscopy, differential scanning calorimetry, X-ray diffraction analysis and Fourier transform infrared spectroscopy were conducted to characterize the solid-state characteristics of the crystallized samples. Dissolution studies helped in ascertaining the effects of the crystallization techniques on the performance of the formulation. Curcumin crystalized by different antisolvent displayed varied shapes, sizes, saturation solubility's and dissolution properties. In SCAS process, the maximum saturation solubility (2.83 µg/mL) was obtained when the pressure, temperature and depressurization time were 275 bars, 55 °C, and 22 min respectively. The SCAS samples showed the highest dissolution (70%) in 30 min compared to WAS (27%), physical mixture (18%) and unprocessed curcumin (16%). The improved dissolution rate of SCAS sample originates from the development of sponge-like particles with augmented porosity, decreased crystallinity as well as increased solubility of curcumin.

Surface Characterization as a Tool for Identifying the Factors Affecting the Dissolution Rate of Amorphous Solid Dispersion Tablets.

An amorphous solid dispersion (ASD) is a commonly used approach to enhancing the dissolution of poorly aqueous soluble drugs. Selecting the desired polymer and drug loading can be time-consuming. Surface properties, such as surface composition and wetting behavior, are essential factors controlling the dissolution of ASD tablets. Thus, our study aims to use surface characterization to understand the factors that affect the dissolution rate of ASD tablets. In this work, we prepared ASDs with itraconazole and hypromellose acetate succinate (HPMCAS) using spray drying. ASDs were prepared using three grades of HPMCAS and different drug loading levels (10%, 30%, and 50%). We prepared ASD tablets with two porosities. For each tablet, contact angles were measured using the Drop Shape Analyzer; surface free energies, disperse, and polar fractions were calculated based on the contact angles. We conducted near-infrared (NIR) and dissolution measurements of ASD tablets. Principal component analysis (PCA) was carried out to investigate the NIR spectra further. The relative PCA scores were reported with other sample properties. A partial least square (PLS) model using NIR scores, tablets' wetting properties, and dissolution rates revealed that water and buffer contact angles, surface free energy, and polar fraction are the most significant factors attributing to the dissolution rate of ASD tablets. This work understood the interplay between the surface properties and the dissolution rate of ASD tablets. Moreover, surface characterization can be the tool to screen the formulation and compaction process of ASD tablets in early development.